Virtual Library

Background
Despite the established causal relationship between tobacco smoking and cancer many cancer patients continue to smoke after diagnosis. This partly reflects the ignorance of the beneficial effects of smoking cessation even after diagnosis. The aim of the study is to demonstrate the effect of continuing or quitting smoking in patients with diagnosed cancer.

Methods
This study is based on a review of medical databases (Pub Med CENTRAL, MEDLINE, Cochrane Library) of the last thirty years. All articles included in the present analysis were in English.

Results
In patients with early stage lung cancer, continued smoking after diagnosis is associated with an increased risk of all cause mortality and decreased survival. Research has demonstrated significant difference in actuarial overall survival favoring the non-smoking group among patients with lung cancer. In patients with oral cancer smoking cessation or reduction leads to a significant reduction in mortality. There is also evidence that tobacco smoking exacerbates and prolongs radiotherapy induced complications.Of particular importance is the evidence that continued smoking is associated with adverse effects during anticancer treatment. Smoking increases tumor progression and resistance to chemotherapy due to nicotine-induced resistance to apoptosis by modulating mitochondrial signaling. Continuing smoking is also related with inferior outcomes during treatment with novel targeted therapies such as erlotinib. Continuing smoking in gastric and lung cancer patients is also associated with an increased risk of developing second primary tumors. Quitting smoking after lung cancer diagnosis is associated with better performance status while persistent smokers have worse overall quality of life. Patients who continued to smoke despite being diagnosed with cancer report more severe pain than never smokers and a greater interference from pain.

Conclusion
Continuing smoking after cancer diagnosis is related with reduced treatment efficacy and reduced survival, risk for more secondary malignancies and deterioration in quality of life.

Background
According to the World Health Organization, tobacco use is a major cause of illness and death worldwide, especially lung cancer. Currently in Portugal, tobacco use among young people has increased. It has been observed that adolescents’ smokers have a high probability of becoming adult smokers. Objective: To assess tobacco use in high school students and the associated social and family factors.

Methods
Based on all students aged between 15 and 19 years old, 100 adolescents were recruited from each of three high schools. The smoking habits of adolescents were evaluated according to a protocol adapted from the Global Youth Survey (GYTS), Center of Disease Control and Prevention (2001). The questionnaire consisted of 34 questions related to tobacco use, knowledge and attitudes towards smoking, smoking cessation, school regulation and the family role in preventing smoking. Participants were classified as: 1 - never having tried smoking; 2 - have just tried smoking (not smoked in the previous month); 3 - occasional smokers (smoked at least 1 day during the previous month); 4 - current smokers (smoked at least 20 days in the previous month). The protocol was approved by the School Direction and statistical analysis was performed with SPSS ® for the entire sample and by gender.

Results
Of the total sample (n=285), 46% were males and 54% females whose average age was 16.6 ± 1.2 years (min:15; max:19). About 59.6% of adolescents have experienced smoking at least once, 54% of who were female. Although the average age of tobacco onset was between 12-15 years (64%), we found that 21% of subjects experienced smoking before 11 years of age. Over 90% admitted smoking with friends and public spaces were the place preferred (38%) followed by social events (21%). Regarding the harmful effects of tobacco on health, school revealed a reducer role as a trainer, since 51.6% of adolescents admitted that the issue of smoking was never raised during the present school year. There is a statistically significant association regarding the initiation of smoking and parents educational level (mother: p=0.001; father: p=0.05). The same occurred when the mother is a smoker (p = 0.002).

Conclusion
There is an early initiation of smoking in this population and a high percentage of adolescents do it regularly. We emphasize the enormous importance of an effective intervention strategy in relation to the harmful effects of tobacco, with strong involvement of the school and family, in order to reduce tobacco consumption and prevent its health consequences with regard to morbidity and mortality.

Background
Many patients in a multidiscipinary thoracic oncology surgery clinic smoke, and are treated for diseases related to smoking. While some patients may be former smokers, many are actively smoking and unable to quit. In the short term, perioperative complications such as impaired wound healing, and increased respiratory complications are linked to continued tobacco use whereas long term survival may be impacted by smoking causing increased cardiovascular risk, worsening emphysema and future development of metachronous primary tumors. Although quitting smoking has proven health benefits, nicotine addiction is one of the most challenging to overcome leading to a nihilistic view of tobacco cessation in this setting by some patients and clinicians. Unaided cessation has a poor success rate (<5%), while a combination of physician recommendation, face to face counseling by certified tobacco treatment specialists (TTS), individualized pharmacotherapy and ongoing follow up can improve quit rates and tobacco abstinence.

Methods
A multidisciplinary team from thoracic surgery, the college of nursing and the college of health professions was assembled with the goal of providing multifaceted, evidence-based tobacco treatment as an integrated part of our thoracic oncology surgery clinic. Three team members obtained TTS training. After institutional board review approval, all clinic patients were queried for tobacco use, and any patient actively smoking underwent brief intervention by the thoracic surgeon (who is a TTS) and was referred for more in depth counseling to another member of the team who is also a TTS. For patient convenience, and increased compliance with referral to cessation services, the counseling took place in clinic, in a private conference room adjacent to the exam rooms. Demographic data, tobacco use data, other drug/alcohol use and medication use data were recorded prospectively in a database. Follow up visits were conducted in the inpatient setting, upon return to clinic and/or contact via phone. Exhaled breath carbon monoxide monitoring was used during the visits to confirm initial active use and also used to confirm successful cessation.

Results
Over the initial seven months, 60 patients were identified as active smokers. All received brief intervention by the surgeon and referral to the quitline and in-clinic TTS counselor. Despite physician recommendation, the free of charge service, and the convenience of the service in clinic, 23/60 patients refused to meet the TTS counselor. Of the patients (24/60) who agreed to meet with the TTS, consented to enroll in the program, and agreed to follow up contact, 17/24 (70.8%) quit and remained abstinent at last contact (between 1-6 month follow up). Some patients did not meet inclusion criteria yet still met with the TTS counselor for referral to the quitline, or to talk about continued abstinence after quitting.

Conclusion
Integrating TTS in the multidisciplinary thoracic oncology surgery clinic can be accomplished. For those that enroll and consent to follow up, this pilot data demonstrates excellent short-term quit rates in this setting. Ongoing enrollment, further follow up, and planned expansion to involve other clinics (pulmonary and medical oncology) will allow better understanding of the efficacy of tobacco cessation services integrated into clinical settings.

Background
Background: Tobacco use increases toxicity, recurrence, second primary cancers, and mortality in cancer patients. However, oncologists do not routinely provide assistance with tobacco cessation and little is known about potential barriers that could be addressed to improve cessation practices among oncologists.

Methods
Methods: An online survey was sent to IASLC members querying demographics, tobacco assessment and cessation practices, perceptions of tobacco use by cancer patients, and barriers to tobacco cessation intervention. Results are reported and multivariate analyses were performed to identify likely barriers to tobacco assessment and cessation.

Results
Results: A total of 1,507 IASLC members responded to the survey representing a 40.5% response rate. Most respondents reported that tobacco use affected cancer outcome (92%) and that tobacco cessation should be a standard part of cancer care (90%). However, whereas 90% indicated that they regularly asked about tobacco use, only about 40% regularly discussed medications or provided cessation assistance. A lower likelihood of assessing tobacco use was associated with the following demographic variables: a) location outside of the United States (USA), b) practice non-academic centers, c) fewer years of service as a medical provider, d) less time spent on clinical activities, or e) current smoking. Variables associated with a decreased likelihood of giving advice to stop smoking were a) location outside of the USA and b) less time spent in clinic. A lower likelihood of providing cessation assistance was associated with providers outside of the USA. After adjustment for demographic variables, variables associated with increased likelihood of assessing tobacco use were a) providers who felt cessation affected outcome and b) providers who reported more training on cessation is needed. An increased likelihood to advise patients to stop smoking was observed in respondents who reported that additional cessation training is needed whereas a lack of time was reported as a variable that decreased likelihood to provide patient advice. Variables associated with a decreased likelihood to provide tobacco cessation assistance included: a) lack of time, b) lack of training, c) lack of available resources, and d) perception that tobacco cessation was a waste of time. However, variables associated with an increased likelihood to discuss medications or provide cessation assistance included respondents who a) reported having had adequate training in tobacco cessation or b) who reported that additional training is needed for clinicians.

Conclusion
Conclusions: Most IASLC member oncologists who responded to the survey asked about tobacco use, but few routinely provided tobacco cessation assistance to their patients. Cancer patients need increased access to tobacco cessation support. Differences in the measurements of perceived barriers suggest that efforts are needed to increase cessation resources and clinician education in order to improve tobacco cessation support for cancer patients.

Background
Smoking-related stigma may increase psychological distress and result in isolation and lack of communication, complicating attempts to mitigate stigma’s harmful effects felt by individuals dealing with lung cancer. However, monitored on-line communities ensure anonymity, foster positive coping through mutual support and negate feelings of being alone, allowing stigmatized individuals to reach out to ‘trusted others’ without fear of reprisal. This study explored the content and tenor of ‘naturally’ occurring communication in a monitored on-line lung cancer support community in the United States, as well as who uses the on-line support community and their issues and concerns.

Methods
This qualitative study comprised a convenience sample of archived on-line threaded messages posted in a monitored on-line lung cancer support community. A three phased content analysis approach was employed to analyze a sample of 688 pages (from a total of 4,916 pages) that contained threaded messages across two time periods: August to September 2008 and January to February 2009. Sixty-eight main posts and 586 replies in 344 pages for period one (262 users) and 55 main posts and 697 replies in 344 pages for period two (307 users) were analyzed. Themes capturing the issues, concerns, and emotions raised by community users were identified.

Results
Most of the 569 users were female, half were individuals diagnosed with lung cancer. Information requests and replies were often embedded within narratives of personal experiences with lung cancer and emotional support. Message tenor tended to be respectful, carefully crafted and even caveat-laden concerning personal experiences. An overarching sense of solidarity was evident in reflections of feelings, goals, responsibilities and interests in living with lung cancer. Nine major themes were captured from main posts and replies: Disease-related information, Diagnostic-related information, Treatment-related information, Symptoms and their meaning, Deterioration of health status, Advocacy, Experiences with health care providers/health care system, Survivorship issues, and Psychosocial concerns and feelings.

Conclusion
Individuals living with lung cancer freely shared their unmet needs consistent with those dealing with other types of cancer who receive on-line empathic support and guidance. A number of users expressed dissatisfaction and mistrust of health care providers due to their disengagement in providing timely support and practical information about diagnosis, prognosis, treatment effects and their lack of positive attitudes. Health care providers cannot address all information and emotional needs of diagnosed individuals and families due to the demands put on their time. But they can be encouraged by this study’s findings that suggest monitored on-line support communities serve as a complement to, not a replacement for, formal health care. Monitored on-line support communities can help individuals overcome frustrations and fears by serving as an added resource that helps them to communicate and ask questions of others who are in similar situations that, in turn, foster their control as partners with physicians in making decisions about their care.

Background
Malignant pleural effusion s occur in up to 15% of patients with advance malignancies. However, the incidence of lung entrapment in patients with malignant pleural effusions has never been reported. This may have an impact in the management of patients with malignant pleural effusions, as pleurodesis is unlikely to suceed. A two year review of patients with malignant pleural effusions who underwent medical pleuroscopy was perform, looking at the incidence of lung entrapment. Medical pleuroscopy has been performed in our hospital since January 2011.

Methods
A review of the records of patient who underwent medical pleuroscopy from 1 January 2011 to 31 December 2012 was performed. Patients with histology proven malignant effusions were included in our analysis. The incidence of lung entrapment was recorded based on the procedure report entered by the performing physician.

Results
Over a two year period, seventy-three medical pleuroscopies were performed. All patients underwent pleuroscopy guided parietal pleura biopsies. Out of 73 cases, thirty six (49.3%) were confirmed malignant on histology. Of the cases with histology proven malignant effusion, there were twenty five cases of primary lung cancer (69.4%), 10 cases of primary breast cancer (27.8%) and one case of primary cervical cancer (2.8%). Adenocarcinoma was the histology in 96% of patients with metastatic lung cancer (twenty four out of 25 patients) . The remaining patient patient with metastatic lung cancer was found to have squamous cell carcinoma. The incidence of lung entrapment among patients with histology proven malignant pleural effusion who had undergone pleuroscopy in our study was 94.4% (thirtyy four of 36 patients). Entrapment was not seen in two cases of metastatic lung adenocarcinoma.

Conclusion
Our study shows a 94.4% incidence of lung entrapment in patients with malignant pleural effusion who had undergone medical pleuroscopy. However, more studies are needed to look at the incidence of lung entrapment, as not all patients are fit to undergo medical pleuroscopy. Furthermore, pleuroscopy is not readily available in most hospitals world wide. If the overall incidence is indeed high, the long term management of malignant plerual effusions will require a review, in particular, the use of talc in pleurodesis.

Background
New Zealand’s National Lung Cancer Working Group (NLCWG) has established a number of standards for the management of patients with lung cancer as part of the Standards of Service Provision for Lung Cancer Patients in New Zealand. Standard One, relating to timely access to services, is that patients requiring active treatment should start treatment within 62 days of secondary care receiving a referral. The Ministry of Health has subsequently introduced Faster Cancer Treatment (FCT) Indicators for all cancer streams. • Indicator one (62 day target): time between referral with a high-suspicion of cancer and start of first cancer treatment • Indicator two (14 day target): time between referral and first specialist assessment (FSA) •Indicator three (31 day target): time between decision to treat and start of first cancer treatment Compliance targets around these indicators have not yet been set. A retrospective comparative audit performed by the Southern Cancer Network showed that only 28.3% of patients from the Upper South Island (incorporating the Nelson-Marlborough, West Coast, Canterbury and South Canterbury District health Boards) referred for curative intent treatment in 2010 met NLCWG Standard One. We performed a 3 month prospective audit to Determine if performance in the region around NLCWG Standard One had improved Identify barriers to compliance with the above targets

Methods
Data was collected prospectively for all patients presented at the regional lung cancer multidisciplinary meeting (MDM) from 1 August to 31 October 2012. Patients were included in the final audit if the recommendation of the decision MDM was that they should be offered curative intent treatment.

Results
A total of 73 patients were discussed at MDM during the audit period. 27 (37%) were recommended to undergo curative intent treatment. For these patients the median time between referral and FSA (Indicator 2) and between treatment FSA and start of definitive treatment (Indicator 3) were within target, with compliance of 88% and 78% respectively. However the median time between referral and start of first cancer treatment at 67.5 days did not meet Standard 1/ Indicator 1, with only 39.1% compliance with the 62 day target

FCT Indicator Median Interval (days) Ref - FSA 7 (0-33) Tx FSA to Tx 18 (3-55) Ref - Tx 67.5 (14-118)

Factors identified as barriers to achieving targets included diagnostic modality (bronchoscopy versus CT), number of staging investigations required and referral processes between services.

Conclusion
Performance against the 62 day target for patients in our region had improved but remained below the national recommended standard. A dedicated lung Cancer Clinic is to be established and referral processes between services streamlined to achieve acceptable performance against standards.

Background
The echinoderm microtubule-associated protein-like 4 (EML4)-anaplastic lymphoma kinase (ALK) is a recently identified fusion-type oncoprotein that occurs in about 4-5% of non small cell lung cancer (NSCLC). Important features associated with ALK-positive lung cancers include younger age, adenocarcinoma histology, and never or light smoking habit.

Methods
Review of medical record and of pathology slides.

Results
A 20 year old no-smoker girl presented in August 2012 with weight loss (8 kg over 6 months), intermittent fever, cough and thrombosis of the popliteal and subclavian veins. A total body Computed Tomography (tbCT) scan showed lymphadenopathy in the mediastinum, in the supraclavear and laterocervical areas, a lung mass in the right inferior lobe with omolateral pleural effusion, a nodule in the controlateral lung and an ovarian teratoma. A supraclavear node biopsy demonstrated a lung adenocarcinoma (cytokeratin (CK) 7 and thyroid transcription factor-1 (TTF-1) positive). Molecular analysis showed translocation of ALK and absence of mutations of the epidermal growth factor receptor (EGFR). Because of worsening of symptoms, a first line chemotherapy with cisplatin and docetaxel was started, while waiting for the molecular analysis. After three cycles, in Dicember 2012, the tbCT scan showed a substantial stable disease. By cause of the worsening of symptoms and of the chemotherapy toxicity (G4 neutropenia, G2 anemia), an oral treatment with Crizotinib was started. It was well tolerated. After 13 weeks of treatment the CT scan showed a partial response (40% according to Recist criteria); the ovarian teratoma and the thrombosis were stable.

Conclusion
Patients with EML4-ALK mutant NSCLC are reportedly significantly younger than patients with wild-type, however, to our knowledge, only a younger case of our patient was until today reported (14-year old[1]). This case confirms that Crizotinib is effective and well tollerated in very young patients. [1] Kim SJ, J Clin Oncol. 2012 Jun 1;30(16):e147-50. Realized with the support of: "Associazione Genitori "Per un sorriso in piu'".

Background
Lobectomy is the standard of Surgical care for medically fit patients with primary Non-Small Cell Lung Cancer. It is a well known fact that those with small peripheral lesions and those unfit for surgery (impaired Performance Status or Poor Pulmonary Functional capacity) could be considered for Lesser Resections (Wedge Resection or Segmentectomy) albeit with increased risk of recurrence. We have attempted in this study to identify factors other than poor PFTs (FEV1/DLCO <45%) as an indication for performing Lesser Resections rather than stereotactic Radiotherapy or best supportive care.

Methods
70 patients underwent a Lesser Resection for primary Lung Cancer from 2002 to 2012. This was a retrospective study. Sixteen patients were excluded because the final histopathology was not consistent with primary lung cancer. Alternative diagnoses such as metastatic disease, benign disease and carcinoid tumours were made. Thus 54 patients were available for the final analysis of which only nine patients had poor PFTs. Therefore 45 patients with primary Lung cancer underwent a Wedge Resection or Segmentectomy although they were fit for Lobectomy as per their Pulmonary Function Test.

Results
Of the 54 patients who underwent a Lesser Resection, 31 were chronic smokers with greater than 20 pack years smoking history. All the tumours were Stage I (88% stage Ia and 12% stage Ib). The majority of the patients had Adenocarcinoma (61%) and 19% were Squamous Cell carcinomas with the remainder being Large Cell or Not Otherwise Specified Non-Small Cell Carcinomas. There were no Small Cell carcinomas in our study popultaion. The most important unfavourable factors other than decreased PFTs included Chronic Obstructive Airway Disease (53.7%), Coronary Artery Disease (20.3%) and other factors such as Hypertension, Diabetes and Obesity ranging from 7% to 11%. At least half the study population had three or more unfavourable medical comorbidities. Three patients had other advanced cancers in the past. Twenty one patients (39%) had metachronous primary Lung Cancers compared to only 7% having synchronous lung primary tumours. Three patients (5%) had local recurrence and three (5%) had regional recurrence. Five patients (9%) had distant metastasis. The median survival for the entire population was 21 months as compared to historical controls where best supportive care has an overall survival of only 13 months in stage 1 Lung Cancer.

Conclusion
From this study we conclude that chronic heavy smokers and patients with other unfavourable factors outlined above may still benefit from Lesser Resections. The theoretical advantages of a Lesser Resections include preservation of pulmonary function,and the ability of the patient to undergo further resections in the future if a second primary lung cancer should develop. Although the numbers are small and longer follow up periods are needed it may be one of the other indications for lesser resections besides poor PFTs. We have shown that the presence of a positive synchronous and/or metachronous Cancer history has significantly influenced our surgical strategy for stage 1 patients that my have otherwise been suitable for Lobectomy.

Background
Endobronchial ultrasonography (EBUS) have reached an important position in diagnosis of tumors and enlarged lymph nodes involving mostly mediastinum. The puncture of pathological mediastinal masses under EBUS control is perfomed with thin needle and the obtained samples are mainly evaluated by means of cytology, which in case of malignant tumors does not give definite diagnosis including subtyping of tumor. Thus we aimed to evaluate the EBUS puncture samples also by means of histopathology including immunohistochemistry.

Methods
During one year we investigated 94 patients (53 males, 41 females, mean age 52 years) with enalrged lymph nodes or tumor spread involving mediastinum by EBUS puncture with sampling for cytology, histopathology and immunohistochemistry. 42 patients had suspicion of sarcoidosis, 32 lung cancer with diastinal involvement, 7 metastates of extrapulmonary tumor to mediastinal lymph nodes, 3 lymphoma and 10 pulmonary infiltrates with mediastinal lymphadenopathy probably of inflammatory origin. The investigation was performed under general anesthesy and the other samples from the invoved sites of lungs (aspirates, brushes, excisions, transbronchial biopsies (TBB), bronchoalveolar lavage (BAL)) were taken ad the same time.

Results
In the sarcoidosis group we obtained histopathologically evaluable samples from EBUS puncture of lymph nodes in 19 patients (45%) and in 8 of them (19%) the sarcoid granulomas were described. In lung cancer group we had valid samples in 23 patients (72%) and in 17 of them (53%) we diagnosed the carcinoma histopathologically including immunohistochemical analysis, and in 6 patients (19%) we confirmed normal lymph nodes. In the group of patients with extrapulmonary malignancy we defined histopathologically the metastases in mediastinal lymph nodes in 2 of 7 patients and in 1 sarcoidosis. In the patients with suspect lymhopma histopathological evaluation of lymph nodes did not support the diagnosis. In the group of pulmonary infiltrates with mediastinal lymhadenopathy we proved by histopathology normal or inflammatory lymph nodes in 5 of 10 patients.

Conclusion
Histopathological evaluation including immunohistochemical analysis of samples from EBUS puncture of tumors involving mediastinum and mediastinal lymh nodes is of important value mainly in lung cancer and metastatic cancer involvement. This approach enables the patients to avoid surgical bioptic procedures in non-resectable cases and thus helps to start the targetted tratment of lung cancer as early as possible. In case of sarcoidosis the histopathological evaluation of lymph node puncture samples rises the propability of stating definite diagnosis in combination with other prcedures (BAL, TBB).Figure 1 Fig.1 Small cell cancer, sample from EBUS puncture, EMA staining

Background
Many clinical practice guidelines recommend that all lung cancer patients should be discussed at a multidisciplinary team meeting (MDM) to determine a management plan. Previous studies have shown that lung cancer MDM recommendations are largely concordant with guidelines. There are limited data on whether these recommendations are translated into actual treatment received. The aim of this study was to evaluate whether patients discussed at a lung cancer MDM actually received guideline-recommended treatment (GRT) and determine reasons for not receiving GRT.

Methods
The Liverpool/Macarthur lung cancer MDM prospectively collects data on new lung cancer patients including patient and tumour characteristics, staging investigations, referrals and treatment recommendations. All new lung cancer patients discussed at the MDM between 1/12/05 – 31/12/2010 were identified. Details of patient demographics, tumour characteristics and treatment were obtained from the MDM database and the Area Clinical Cancer Registry. GRT was assigned to each patient according to pathology, stage and ECOG performance status as per the 2004 Australian Lung Cancer Guidelines. This was compared to actual treatment received to determine adherence to GRT. For those who did not receive GRT, the medical record was reviewed to determine the reason why. Survival was compared between patients who did and did not receive GRT.

Results
808 patients were discussed at the MDM. 64% were male and the median age was 68 years. Pathology was NSCLC in 657 (81%), SCLC in 119 (15%) and not confirmed in 32 (4%). 128 (16%) had Stage I or II NSCLC, 306 (38%) Stage III NSCLC or limited stage SCLC and 372 (46%) metastatic disease. GRT could be assigned in 98% of patients who had both stage and ECOG performance status documented. Overall 411 (51%) of patients received GRT, and 380 (47%) did not receive GRT. The main reasons for not receiving GRT were decline in performance status (24%), large tumour volume precluding radical RT (17%), co-morbidities (14%) and patient preference (13%). On multivariate analysis, ECOG performance status, stage and age were significantly associated with receipt of GRT. GRT, ECOG performance status and stage were significant predictors of survival.

Conclusion
Despite discussion at an MDM, a significant proportion of patients were unable to receive GRT due to legitimate reasons. This may reflect the characteristics of the underlying lung cancer population who are older and have coexisting comorbidities. Alternative treatment strategies are needed for patients who are not suitable for GRT.

Background
Primary epithelial-myoepithelial carcinoma of the lung is a rare entity with fewer than 30 cases reported in the literature. These tumours are thought to arise from bronchial submucosal glands and have histological features similar to their salivary gland counterparts. In view of the infrequent nature of the disease, biological behaviour and clinical course have yet to be fully defined. Although considered a low-grade malignancy, there is a potential for invasion and metastasis; for this reason the majority of case reports have advocated complete surgical resection as the treatment of choice. Here we present a case of tracheal epithelial-myoepithelial carcinoma treated with recurrent bronchoscopy and cryotherapy as surgical resection was not possible.

Methods
A 46 year old lady presented with acute shortness of breath and wheeze. Given her past history of asthma she was initially treated for an exacerbation with steroids, antibiotics and nebulisers. The patient had no other history of note and had been a life-long non-smoker. Following a further deterioration leading to type I respiratory failure and episodes of haemoptysis she required intubation. CTPA demonstrated a tracheal mass. At bronchoscopy this well-circumscribed, vascular lesion was clearly identified 2cm above the carina (Figure 1). Multiple biopsies were taken confirming a primary epithelial-myoepithelial carcinoma of the lung. Figure 1 Figure 1: Tracheal tumour at bronchoscopy

Results
Following multidisciplinary discussion the patient was admitted for surgical excision. However, at the time of surgery it was not possible to achieve adequate single lung ventilation and the procedure was therefore abandoned. As an alternative management option the patient has undergone regular bronchoscopy and cryotherapy. There has been no evidence of local recurrence or metastasis in the 14 months since diagnosis.

Conclusion
Histologically these tumours are characterised by variable proportions of two cell types, with epithelial and myoepithelial cells forming duct-like structures. In the majority of cases a polypoid endobronchial mass is present and patients therefore present with symptoms associated with airways obstruction. Although considered a low-grade malignancy there has been one case report of extensive local and lymph node involvement. In addition, follow-up time has been too short to conclusively elucidate clinical behaviour. Here we have demonstrated the use of cryotherapy in the management of inoperable epithelial-myoepithelial carcinoma of the lung. The patient remains disease free at 14 months but will require on-going surveillance. We would agree that surgical excision remains the gold-standard in this patient group, but have provided a possible alternative strategy for inoperable cases.

Background
This is a clinical case of an EGFR-mutant Non-Small Cell Lung Cancer (NSCLC) with adenocarcinoma (ADC) histology: a subsequent diagnosis of high grade neuroendocrine small-cell lung cancer (SCLC) carrying an EGFR mutation was done at the first re-biopsy and further, a sarcomatous cancer was finally diagnosed. Recent publications were focused on drug-resistance mechanisms in patients with a specific biomolecular alteration re-biopsed after receiving the targeted therapy: in some cases morphologic and immunophenotypic changes were described. This finding suggests the possibility of "clonal resistance" with a selective pressure of some groups of cells, even if the histopathological features of these mechanisms have not yet been completely elucidated.

Methods
A 62-year-old caucasian man, with past smoking habit, presented with a 2-week history of cough and dyspnea. After a diagnosis of stage IV lung ADC, he received, on March 2010, 1st line treatment with cisplatin 75 mg/m2 plus pemetrexed 500 mg/m2 on Day 1 every 21 days, for 6 cycles. He achieved a partial response on computed tomography (CT) and a marked regression of his symptoms. On August 2011, a CT scan revealed a progressive disease (PD); he started treatment with Erlotinib plus ARQ-197/placebo within a clinical trial. As deemed by protocol, molecular analyses were performed on biopsy specimen at time of diagnosis, evidencing exon 21 – point mutation, p.Leu858Arg at EGFR mutational assessment. After 4 cycles, a local progressive disease was described by CT scan and a fibrobronchoscopic re-biopsy was performed in order to define the novel biomolecular profile at that time of the history of the disease. The histological evaluation highlighted a SCLC and molecular analyses confirmed the p.Leu858Arg mutation. Based on new histological diagnosis, he underwent chemotherapy with AUC6 carboplatin on Day 1 every 21 days plus etoposide 100 mg/m2 on Day 1,2,3 every 21 days, for a total of 6 cycles, until May 2012, achieving partial response at CT scan. On August 2012, because of radiological evidence of disease progression, he underwent chemotherapy with Cyclophosphamide 800 mg/m2, Doxorubicine 40mg/m2 and Vincristine 1mg/m2 on Day 1 every 21 days. After 3 cycles, he reported intense swelling in the supraclavicular right fossa and a fine needle aspiration of supraclavicular right lymphadenopathy was performed. The final pathological diagnosis was undifferentiated sarcoma cells (CK-,TTF1-, VIM+) . Patient died, on January 2013, because of worsening of clinical conditions.

Results
Not applicable

Conclusion
Many studies hypothesize that SCLC either evolved from the previously diagnosed NSCLC or that both arose from a common precursor. Further comparative molecular analysis of these histologically distinct tumors would be of value to better understand the potential role of EGFR in the evolution of lung cancer and the role of selection for an EGFR-mutant SCLC cell subclone as an unusual mechanism of acquired resistance to EGFR inhibitors in NSCLC.

Background
Cancer has a great impact on psychological functioning of patients and relatives and can be associated with various psychological disorders and symptoms. Mindfulness Based Intervention (MBI) is a relatively brief and cost-effective program that has been studied in patients with several diseases. Recent analyses have shown the efficacy of MBI in improving psychological symptoms related with physical illnesses like cancer, chronic fatigue syndrome, fibromyalgia, chronic pain, arthritis, diabetes, heart disease, stroke, and traumatic brain injury. MBI is based on the assumption that a non-judgmental awareness and acceptance of one’s moment-to-moment experience have an effect on the distressing tendencies to escape from or to over-engage with one’s disturbing feelings, emotions and thoughts. MBI can positively impact on coping strategies and on the adaptation to the disease, by encouraging patients to relate differently to their physical and psychological symptoms, resulting in a reduction of the psychological burden and improving patients’ Quality of Life (QoL). MB-BAI integrates MBI basic practices with increased attention to somatic resources and application of mindfulness in relationships.

Methods
We aim to evaluate whether a group-based Mindfulness Based Body and Affective Intervention can reduce psychological symptoms like anxiety, depression, perceived stress and improve the QoL of patients with cancer. Furthermore, our study involve patients’ caregivers/relatives in order to decrease the load of stress and difficulties related to the management of a disabling diseases like cancer. This project is designed as an observational study. The subjects currently involved in all are 36, including patients with advanced malignant disease (mostly lung cancer), their caregivers/relatives and the control group. Participants were enrolled at the Oncology Unit of San Luigi University Hospital of Orbassano, Italy, in collaboration with WALCE (Women Against Lung Cancer in Europe). The experimental group underwent a 8 weekly sessions of 3 hours each (plus an all day session) with a group based MB-BAI. The control group hasn’t receive any psychological intervention. The psychological assessment was performed at pre-intervention and after treatment for both groups. The evaluation encompasses the administration of the self-reportquestionnaires: Hospital Anxiety and Depression Scale (HADS), Perceived Stress Scale (PSS), Five Facet Mindfulness Questionnaire (FFMQ), Posttraumatic Growth Inventory (PTGI) and WHOQoL-Brief, patients qualitative reports.

Results
not applicable

Conclusion
The study is currently ongoing. As far as we know this is the first MBI applicationinadvanced lung cancer. Specific attention to somatic resources and relationships may increase its effectiveness. Preliminary results from patients’ reports suggest that the MB-BAI both reduces symptoms of anxiety and depression and improves resources. Results will be presented after the complete achievement of the after-treatment assessment; we hope they will confirm that MBI favor positively impact on the adaptation to the disease, resulting in a reduction of the psychological burden and improving patients’ Quality of Life (QoL).

Background
Since Billroth s report, in 1889, of a patient with multiple synchronous tumors, multiple primary malignances (MPM) have been recognized as a growing problem. The increase in incidence of MPM has been ascribe to several factors, such as increase in the incidence of many forms of cancer, the increase in longevity and cancer survival and better cancer follow-up.

Methods
Case report

Results
Here we present 65-year old ex-smoker with history of recent surgery for vocal cord squamous cell cancer who was seen in pulmonary out-patient clinic due to nodular lesion in the left lung seen on chest x-ray. Subsequent chest CT scan revealed focal lesion 18 mm in diameter with spicular margins located in the right upper lobe, another lesion with septa and cavitation, 62 x 58 mm in the right lower lobe and calcified nodule in the left lung, no enlarged lymph nodes or pleural effusion was seen. He underwent upper right lobe resection and sleeve resection of the lower right lobe. Histopathological examination revealed adenocarcinoma in the right upper lobe with lymph node metastasis. Tumor emboli in tumor lymphatic and pleural vessels were reported along with infiltration of visceral pleura. Examination of the right lower lobe showed squamous cell carcinoma with tumor emboli in tumor blood vessels. Subsequently, the patient was treated with adjuvant chemotherapy.He subsequently was treated with adiuvant chemotherapy (cisplatin+vinerolabine). During seven months of follow up he remained in good health with no signs of disease progression. MPM are defined as malignant tumors based on histology criteria with distinct location, which do not represent skip lesions, metastatic disease or recurrence of a primary pulmonary malignancy. According to time category they can divided as synchronous or metachornous. Retrospective date show an increased risk of developing a second lung cancer following the diagnosis of a first lung neoplasm, in patients who survive more than three years as many as 10 to 25% will develop a second primary lung cancer. The male to female ratio of individuals developing pulmonary MPMs is approximately 3:1 with the median age at presentation in the sixth decade. Patients who present with pulmonary MPM have a greater cigarette smoke exposure than those who developed a single lung cancer. 50 to 70% of patients have similar tumor histology in both primaries and identical genetic changes are find in 77% of tumors, supporting monoclonal origin in majority of MPMs. Diagnosis of multiple synchronous primary cancers must be distinguished from a primary tumor with one or more pulmonary metastases and from an extrapulmonary primary tumor with multiple lung metastases. Moreover, a second synchronous primary cancer must be distinguished from a coexisting benign pulmonary nodule detected on preoperative imagining.

Conclusion
Patients with synchronous multiple primary lung malignances have significantly worse prognosis than those with single primary lung malignancy, although it can be considerably improved with an aggressive surgical approach.

Background
Study in tertiary hospital in the thoracic surgery service by a group of surgeons, during which corroborate the usefulness of thoracoscopy in the diagnosis and management of different chest tumors that were presented in the thoracic surgery service for a period of one year: 2011 – 2012. During the procedure was used in all patients selective lung intubation, was performed intraoperative intercostal block for pain control, postoperative management was all endopleural tube, pain control with morphine and radiographic control to assess each 24hr endopleural catheter in 2 patients (15.3%) underwent incision of 2 and 4 cm to remove the tumor.

Methods
In one year 23 patients was admited to the Pachuca General Hospital with the diagnosis of lung tumors, all patients complete preoperative protocol wich include chest CT, lung or tumor biopsy, assesment by anesthesiology, internal medicine, pulmonomogist an medical oncology, the procedures include no anatomic segmentectomy with tumor free margin, exceresis tumor, lung and pleural biopsy, VATS lobectomy, lymph node dissection was performed mainly from stations 4, 5 and 7. Pathology reports were branchial cyst, mesothelioma sarcomatoid, bonchogenic cyst with ulcerated necrotic pneumonia, chondroid hamartoma with congestion and sclerosis, moderately differentiated adenocarcinoma and small cell carcinoma. In patients who had pleural effusions was performed on the basis of lung expansion chemical pleurodesis with 20ml yodopovidona more 10ml xylocaine 1% dilute to 100cc with saline.

Results
Radiological and histopathological diagnosis was corroborated in 95% of cases, the procedures include no anatomic segmentectomy, exceresis tumor, lung and pleural biopsy, VATS lobectomy, lymph node dissection. Pathology reports were branchial cyst, mesothelioma sarcomatoid, bonchogenic cyst with ulcerated necrotic pneumonia, chondroid hamartoma with congestion and sclerosis, moderately differentiated adenocarcinoma and small cell carcinoma. All patients continue managemnent with a multidiciplinary team getting support with other institutions in cancer management. In patients who had pleural effusions was performed on the basis of lung expansion chemical pleurodesis with 20ml yodopovidona more 10ml xylocaine 1% dilute to 100cc with saline was done and chest drain mainteined for 3 to 4 days. In cases of recurrence of pleural effusion a tunelized thoracic catheter was put on and in cases of persistent pneumothorax a Heimlich valve was colocated.

Conclusion
Pleuropulmonary tumors in patients with, sensitivity and specificity for the diagnosis and treatment by thoracoscopy is over 90% to reliably be able to obtain sufficient tissue for histopathological examination or final intraoperative complete resections and procedures, achieving an aesthetic addition.

Background
Some lung cancer patients experience unnecessary delays in their care in the US; these delays are not currently well-documented outside the Veterans Administration Hospital system. We evaluated the accuracy of patient interviews as a method of documenting timeliness of care. Our results will be used to implement a larger study that will inform the development of targeted interventions to reduce time to treatment for lung cancer patients.

Methods
Oncologists referred 36 patients with lung cancer. The initial 20 patients were interviewed to collect 11 dates pertinent to their cancer care (Figure 1). The next 16 patients completed the interview and their charts were reviewed in order to analyze the correspondence of patient-reported data with chart-reported data. We conducted quantitative and qualitative analysis of the interview data to document time intervals and examine delays. Figure 1

Results
Results: For the 16 patients whose charts were reviewed: patient-reported and chart-reported median time from the first visit to the first treatment was the same (41.5 days) median time difference between patient-reported and chart-reported dates varied from 0 to 8 days Lin’s correlation coefficient indicated almost perfect agreement (ρ >0.99) for five dates; and poor agreement (ρ <0.90) for six dates 2.25% of total dates were lacking from charts For the entire cohort (36 patients), based on the interview data: time to treatment varied (Table 1) 22 of 36 (61%) patients experienced one or more delays that could possibly be avoided 5.28% of total dates were not recalled by patients Figure 1

Conclusion
Interviewing patients has limitations but is an appropriate method of collecting dates regarding lung cancer care. There are multiple opportunities to reduce time to treatment for patients with lung cancer. More research is needed to understand delays in lung cancer care.

Background
Bone is the most frequent site of metastasis for lung cancer, and metastatic bone disease causes pain. Furthermore, bone metastasis may produce skeletal-related events (SREs) that greatly reduce quality of life and may even lead to death. Several guidelines have recommended use of bone-modifying agents (BMA) such as zoledronic acid (ZA) at the first diagnosis of bone metastases in patients with solid tumors, continued every 3-4 weeks as long as the patient is able to tolerate therapy or until evidence of a substantial decline in performance status. However, due to the risk of osteonecrosis of the jaw (ONJ) and a perceived lack of evidence for reduced SRE in lung cancer, some physicians have hesitated to administer ZA in lung cancer patients with bone metastasis. Therefore, the main objective of the present study was both to describe real world data of ZA and to compare SREs among previous reports.

Methods
All patients with non-small cell lung cancer (NSCLC) accompanied by metastatic bone disease (MBD) who were administered ZA at least twice from 12 hospitals in the TORG in Japan between January 2008 and December 2009 were eligible for inclusion in the study.

Results
A total of 198 consecutive patients (126 men, 72 women; median age, 64 years; range, 44-89 years) were identified. Histological type was as follows: adenocarcinoma (n=131, 66%); squamous cell carcinoma (n=30, 15%); and others (n=37, 19%). About two-thirds of patients experienced SRE before starting anti-cancer therapy. Median duration of ZA administration was 106 days (range, 28-1126 days), and median number of ZA administrations was four (range, 2-41). Median time to first SRE in patients who experienced SRE after treatment was 202 days (range, 156-264 days). No ONJ was reported from the 198 patients.

Conclusion
We found that ZA was not used sufficiently in clinical practice in Japan. Our data suggest that ONJ during the treatment of lung cancer patients is very rare, and ZA is potentially useful in lung patients with bone metastasis.

Background
Hermansky-Pudlak Syndrome (HPS) is a rarely seen autosomal recessive disease characterized by oculocutaneous albinism, bleeding tendency from platelet storage pool deficiency, and lysosomal occumulation of ceroid in the reticuloendothelial system. Ceroid occumulation in alveolary macrophages causes pulmonary inflammation and interstitial pneumonia. Pulmonary fibrosis is the most serious complication and main reason of mortality. Pulmonary fibrosis is also a well known etiology for the onset of lung carcinoma.

Methods
N/A

Results
A 64-year-old albino patient admitted with dyspnea, back pain, and weakness. He had a smoking history of 40 pack-years. In his past medical history, he has recurrent nasal bleeding, and he was given inhaler bronchodilators for dyspnea on exertion last year. Rutin laboratory analysis was normal. There was a mild hypoxemia (PaO2: 63 mmHg). There was a restirictive pulmonary functional deficit with a reduced diffusion capacity (%56). A thorax CT demonstrated pulmonary fibrosis, left pleural effusion, and irregularly marginated collapse and consolidation areas adjacent to pleural effusion. On PET/CT a mass lesion 6 cm in largest diameter (SUVmax: 15.6) is distiguised in left lower lobe superior segment. There was also a nodular pleural thickening (SUVmax: 13.5) on the left hemitorax and multiple mediastinal lymph nodes with high SUVmax levels. The presence of albinism, the history of bleeding diathesis, and the presence of pulmonary fibrosis suggested the diagnosis of HPS. The patient referred to ophthalmology consultation. There were hypopigmentation on coroid layer and iris. Hematology clinic comfirmed the presence of platelet dysfunction. After all the patient was diagnosed as HPS. After transfusion of platelets, a transtoracic needle biopsy was performed and the pathology was compatible with adenocarcinoma (Stage 4, pleural involvement). The patient refused any therapy and discharged from hospital with home oxygen therapy.

Conclusion
Herein we present a rare case with pulmonary fibrosis diagnosed simultaneously as HPS and pulmonary adenocarcinoma.

Background
Myoepithelial tumors commonly occur in the salivary glands, the sweat glands or the mammary glands, but extremely rare in the lung. We present a case of primary myoepithelial carcinoma of the lung with reports of previous cases.

Methods
A 67-year-old man presented with a nodular lesion in the lower lobe of the left lung. The patient had a surgical history of stenosis of the small intestine, and his serum carcinoembryonic antigen (CEA) level was slightly elevated. Histopathological examination revealed that the cause of intestinal stenosis was the ischemic enteritis. Computed tomography (CT) was carried out as screening for elevated CEA, and a small nodule was detected at the posterior basal segment (S[10]) of the left lung. The pulmonary nodule developed a tendency to increase during progress observation of half a year. Because of the clinical suspicion of malignancy, he underwent a wedge resection of the left lower lobe by video-assisted thoracic surgery (VATS).

Results
Macroscopically, the tumor was a whitish, well-circumscribed, irregular shaped, and solid mass measuring 10×8×6 mm in size. Microscopically, the tumor was mainly located outside the bronchial mucosa with focal invasion into the lamina propria of the mucosa, and composed of atypical cells arranged in trabecular or alveolar pattern and basement membrane-like eosinophilic hyaline stroma. The tumor cells had ovoid pleomorphic nuclei varying in size and clear cytoplasm. Small necrotic foci were scattered in the tumor. Mitotic figures were frequently seen (> 14/10 HPF) and abnormal mitoses were occasionally encountered. No ductal structures were found throughout the tumor. Immunohistochemical staining showed the tumor cells were positive for 34βE12, P-63, S-100, α-SMA, but negative for CK7, TTF-1, chromogranin A, synaptophysin, CD56. On the basis of the above features, the tumor was diagnosed as primary myoepithelial carcinoma of the lung (pT1aN0M0, Stage IA). The patient is doing well without recurrence for 22 months after the operation.

Conclusion
We present a rare case of primary myoepithelial carcinoma of the lung. To our knowledge, only nine cases of pulmonary myoepithelial carcinoma have been reported in the literature so far. Because the clinical course of those cases was poor, further studies will be necessary in order to clarify their histological features, biological behavior, effects of chemotherapy or radiotherapy, and clinical outcome.

Background
The prognosis of patients with non-small cell lung cancer and distant metastasis is poor. The aim of this study was to evaluate the value of local treatment to the primary site for patients with stage IV non-small cell lung cancer and oligometastatic disease at diagnosis, particularly the influence of local treatment to the primary site on prognosis.

Methods
From January 2004 to December 2011, 69 consecutive patients with stage IV non-small cell lung cancer treated with local palliative radiotherapy to the primary site were enrolled in this retrospective study. The prognosis factors including the patients’ general condition, disease characteristics and treatment factors were analysed. Patients were divided into two groups based on the number of distant metastases (Oligometastasis, OMT, 1-4 metastases; Polymetastasis, PMT, > 5 metastases). The relationship between the prognosis and treatment factors was explored. Overall survival was estimated using the Kaplan-Meier method, and prognostic factors were identified by univariate and multivariate analyses.

Results
The median overall survival was 14.1 (95%CI:7.3-20.8) months and the 1, 3-year overall survival rates were 53.0% and 9.0% , respectively. Gender, smoking index and performance status of Zubrod-ECOG-WHO were significantly associated with prognosis under univariate analysis. There was marginally significant associated with prognosis for those patients who received chemotherapy(P = 0.054) and received a sufficient dose of local palliative radiation to the primary site (at least 60Gy) (P = 0.063). On multiplicity analysis, chemotherapy and performance status retained significance. In the hierarchical analysis, patients who received at least 60 Gy of local radiotherapy to the primary site(P=0.048)(Fig 1.) and received chemotherapy (P= 0.041) achieved better overall survival in the OMT group.Figure 1

Conclusion
For non-small cell lung cancer with OMT, local aggressive treatment to the primary site may improve overall survival. Our results suggest that the selected non-small cell lung cancer patients with distant metastasis may benefit from aggressive local therapy.

Background
Desmiod tumor (aggressive fibromatosis) is an aggressive fibroblastic proliferation of well-circumscribed, locally invasive, differentiated fibrous tissue. Chest wall desmoids account for approximately 20% of all desmoids tumors. The etiology of this tumors is unknown. Local inflammatory changes involved in the healing response after trauma have often been postulated as stimulating the development of desmiod tumors. Although distant spread has not been documented in long-term follow-up studies, these tumors have a strong propensity to recur locally after resection. Several authors have emphasized the use of external radiotherapy as an adjunct to surgery to improve local control.

Methods
A 62-year-old male underwent left upper lobectomy using an anterolateral approach. The postoperative diagnosis was pulmonary adenocarcinoma (pT1N0M0 stage1A). Two years after operation, a computed tomography showed the 65x45x25mm diameter mass on the left chest wall around the previous operative scar. Three months later, the mass rapidly enlarged 110x100x55mm in size. A desmoid tumor was suspected from the specimen of an incisional biopsy.Figure 1

Results
A Resection of the tumor with the chest wall (from the 2nd rib to the 4th rib) was performed. And thoracoplasty using a myocutaneous flap made of latissimus dorsi muscle with the 10th rib and a titanium plates and Composix Mesh was performed for a defect in the chest wall. Histopathological examination revealed a desmoid tumor. The specimen showed proliferation of spindle shape cells with collagen fibers. No mitoses were present. Tumor cells invaded to ribs and intercostals muscles but surgical margin was negative. Adjuvant radiation therapy with a total dose of 50.4Gy was administered to prevent local recurrence.

Conclusion
He is doing well without recurrence at 37months after surgery and radiation. Wide local excision with negative pathological margins is the treatment of choice for most desmoid tumors. Postoperative radiation may be a treatment of choice to prevent local recurrence because the development of local recurrence would result in mutilating reopreration with disfigurement or even amputation.

Background
The treatment for non small cell lung cancer (NSCLC) with operable primary lesion and solitary brain metastasis has not formed but the combined local therapy with surgical pulmonary resection of primary lesion and curative neurosurgical intervention of solitary brain metastatic site is becoming a standard option for such patients. The purpose of this study is to assess the efficacy and safety of the combined local therapy for NSCLC with operable primary lesion and solitary brain metastasis.

Methods
Within 1781 NSCLC patients underwent surgical resection from December 1993 to December 2010 at Osaka City General Hospital, 11 cases with synchronous (within 1 month of the primary NSCLC diagnosis) solitary brain metastasis and treated with curative neurosurgical intervention were identified. We retrospectively reviewed these cases and analyzed the treatment, pathology, prognosis and prognostic characteristics. Overall survival was recorded from the date of lung surgery until the last follow-up observation.

Results
The study group consisted of 7 male and 4 female. The median age at the time of pulmonary resection was 57 years (range, 39-76 years). The histological subgroup was adenocarcinoma in 10 cases and large cell carcinoma in 1 case. Neurological symptoms as the initial symptom were recognized in 3 cases. Type of pulmonary resection for primary lesion were lobectomy in 10 patients and sleeve lobectomy in 1 patient, and lymphatic extension was pN0 in 7 patients and N1-2 in 4 patients. All patients received gamma knife stereotactic radiosurgery (GKSRS) for management of the solitary brain metastasis and curative neurosurgical resection was performed in 1 patient before GKSRS. Both pulmonary resection and neurological intervention caused no serious adverse events. Of 11 patients, 7 patients had died of disease and 4 patients (3 with pN0 and 1 with pN1) were alive and with disease. The median overall survival time was 14 months and the 3-year overall survival rate was 36.4%.

Conclusion
The aggressive combined local therapy with pulmonary resection and neurological intervention for NSCLC patients with operable primary lesion and synchronous solitary brain metastasis should be considered effective and safe for selected patients. The multicentre prospective randomized studies are required to clarify the effectiveness and optimal method of this local treatment for such patients.

Background
The World Health Organization (WHO) currently classifies Large Cell Neuroendocrine Lung Carcinoma (LCNEC) as a distinct subtype of pulmonary large cell carcinoma, however, the survival after surgical-resection of LCNEC appears to be substantially worse than for other Non-small cell carcinoma (NSCLC), resembling more the survival of small cell carcinoma. The question remains whether LCNEC is best treated the same as other NSCLC. The purpose of this study is to analyze the feasibility of the multidisciplinary treatment for LCNEC.

Methods
The records of 6 LCNEC (2.9%) out of 210 patients, who underwent an intended curative resection for lung cancer in our institute during a 10-year period beginning in 2002, were reviewed. The patients consisted of 6 male current smokers, with a median age of 68 years (63 – 82). The clinical stages were 2 in stage IB, 2 in stage IIA, 1 stage IIB and 1 stage IIIA. 5 patients underwent an anatomical resection. The rest of them underwent tumorectomy. 3 patients underwent not only pulmonary resection but also adjuvant chemotherapy for primary cancer. Median follow-up time was 37.5 months (15-81).

Results
The two patients with clinical stage IIA were upgraded to pathological stage IIIA after operation. Two of them, who were pathological stage IB and IIIA, died of pneumonia and secondary cancer without LCNEC recurrence 11 and 15 months after the operation. Recurrence of disease was observed in three patients with pathological stage IIB and IIIA. One of the patients died in 55 postoperative months after receiving adrenalectomy, chemotherapy and radiation therapy for 25 months for recurrent cancer. Two of the patients are still alive after receiving either surgery pus chemotherapy or radiation therapy for 32 months and 43months since undergoing initial treatment.

Conclusion
Multidisciplinary treatment should be considered as complementary technique to surgery for LCNEC and examined in larger trial.

Background
Since the validation of CT screening for lung cancer in 2010 in the United States by the National Cancer Institute’s National Lung Screening Trial, several well-respected professional societies have endorsed lung cancer screening and developed guidelines using low dose CT (LDCT). Despite this progress, adoption of lung cancer screening has been slow to advance. In 2011, in recognition of the importance of screening for lung cancer in a responsible way, Lung Cancer Alliance (LCA) convened a panel to review current evidence and develop a framework document to educate the public about their risk and guide healthcare professionals developing screening programs. This began a multi-year strategy to ensure responsible screening through a process of outreach, education and data collection with the goals of raising public awareness about the risks and benefits of screening and contributing to the refinement of screening guidelines and risk definitions. The focus of this abstract is the process of outreach and education as development of a data collection system is still in progress.

Methods
The National Framework for Excellence in Lung Cancer Screening and Continuum of Care was developed to educate consumers about rights, guide responsible screening center development and lay the groundwork for a data collection strategy. A list of screening Centers of Excellence was developed based on commitment to the National Framework guiding principles. Outreach to additional centers continues. A multi-pronged approach was adopted. A national media campaign focused on understanding lung cancer risks and the value of early detection. Educational materials were developed to educate those at risk about various aspects of screening. Center coordinators received regular communication about educational opportunities related to screening, journal articles and other information of interest. A needs assessment of existing centers was carried out to understand implementation challenges and identify what role LCA can play in addressing them. A network of center coordinators willing to talk with other coordinators about specific programmatic challenges was developed.

Results
At the time of submission, there were 90 centers on the LCA Screening Centers of Excellence list with an additional 50 centers identified for outreach. Regular communication occurs between LCA and the coordinators. Based on needs assessment results, tools have been developed to help coordinators learn from each other. Future goals include developing webinars and other ways to address challenging issues faced by centers and evaluation of these approaches.

Conclusion
Charities can play an important role in supporting the development of responsible lung cancer screening, as is evidenced by the actions of LCA in the United States. Because charities are well-connected to those at risk for lung cancer and to lung cancer treatment programs, they are ideal parties to be involved in furthering adoption of programs and behaviors. By identifying the barriers to adoption of responsible lung cancer screening and helping develop strategies to address them, lung cancer advocacy charities are a valuable partner in the effort to raise awareness of the risk for lung cancer and ensure that screening is done responsibly.

Background
Background: Expenditures in the United States on health care have reached and estimated $2.5 trillion and cost control measures have become major features of the current health care reform debate in this country. An approach to reducing ballooning health care costs has been to focus on quality and uniformity of standards of care using health informatic technologies. We have designed and implemented a web- based clinician-to-clinician communication and collaboration platform that is mobile device enabled. The system permits asynchronous communication among clinicians in conjunction with robust sharing of the content of the Electronic Medical Record (EMR) including X-rays, digital histopathologic images and molecular diagnostics. Principle aims of the project incluided (1) documenting accurate diagnoses (2) appropriate consultation and input from specialty services (3) treatment plan optimization spanning disciplines and (4) archiving the results of multidisciplinary decision making in a virtual environment.

Methods
Methods: Using Extensible Markup Language (XML) based system; a federal patient privacy regulation (HIPAA) compliant secure platform for communication was built according to specifications designated by clinicians in the Thoracic Oncology Section of UCSF Medical Center. The web based platform was approved by a committed on human research. The system was designed with integration of a Picture Archives Viewing System (PACS) and digitized pathology images to permit specific file upload, and annotation in a scalable manner allowing collaborations between two clinicians or among a group as large as 35. User group questionnaires and focus groups were performed to refine the computer-human interface and customize user experience. Members of the Thoracic Oncology Program (N=35) at the University of California at San Francisco were invited to participate in pilot study of the efficiency and ease of use of a novel web-based collaborative system for the purposes of an asynchronous “Virtual Tumor Board”.

Results
Results: A Trial of 50 patients had care plans coordinated via the virtual tumor board with input of the multi-disciplinary focus groups used in the development of the computer - human interface. 20% of clinicians related concerns over ease of use. 10% related concerns regarding excessive electronic messaging as a disruption of work flow. 15% voiced a main concern regarding clinician reimbursement for web based consultation. Of the cases presented on the virtual tumor board platform 100% achieved clinician consensus opinion with 5 days (mean 2.5 days). Patient Satisfaction assays suggested patient comfort with protected health information transfer on a secure platform. No adverse events were directly referable to system use.

Conclusion
Conclusion: A novel web based system for collaboration among clinicians holds the promise for reducing delays in optimized treatment planning and is regarded by clinicians as worthy approach to error reduction and reduction in delay to definitive treatment plan determination. Consensus opinions were rapidly obtained and archived records of discussion facilitates outcome reviews. Clinician concern included reimbursement patterns and efficiency but patient opinion was favorable toward this approach to collaborative decision making in oncology.

Background
Pneumonectomies are usually considered contraindicated for advanced NSCLC.

Methods
A 49 year old female patient was admitted for acute severe respiratory distress requiring intubation and mechanical ventilation shortly after admittance. The patient was cachectic (BMI 16) with a hetero-anamnesis of Graves disease, 30 pack-years smoking and progressive dyspnea over weeks for which the patient did not seek medical advice prior to admission. Chest X-ray on admission showed a "white" left hemi-thorax and mediastinal shift to the right. Bronchoscopy showed tumor occlusion of the left main bronchus where biopsies revealed non-small cell lung cancer. CT-scan showed a huge tumor mass almost completely filling the left hemi-thorax and displacing the mediastinum to the right, a >3 cm subcarinal adenopathy, a small left pleural effusion and a likely invasion of the left axillary chest wall. Cerebral CT-scan was normal. In this hopeless seeming situation, the next of kin expressed their wish for an attempt at palliative surgery, given the chance that relieve from compression and circulatory shunt might bring the patient to a possible extubation and ability to communicate with their children, even if only for a short time.Figure 1

Results
Via median sternotomy and left hemi-clamshell incision an intra-pericardic, extrapleural pneumonectomy extended to ribs 3-5, pericardium and thymus was performed. Pathologic examination, showed G3 "non-small cell" lung cancer, TTF-1 positive, Ki67 index 90%, involvement of pericardium and positive pericardial fluid. Subcarinal and all other 20 lymph nodes were negative. pT3N0M1a (pleural cytology), R1. Postoperatively, the patient's state improved quickly to extubation but she later required a temporary tracheostomy (day 7) because of exhaustion and overall muscle weakness. She could be revalidated and discharged at post-operative day 74. At 9 months follow-up she is fully ambulatory and CT-scan shows no sign of recurrence. Figure 1

Conclusion
In exceptional circumstances, palliative resections up to extended extrapleural pneumonectomy may be justifiable.

Background
Lymphangioma usually occurs in the head and neck area. We present a very rare case of cystic lymphangioma that originated from the diaphragm. Few cases were reported in the literature.

Methods
A 69-year-old woman was referred to our hospital for macrocytic anemia and weight loss. Pernicious anemia was diagnosed by the presence of the atrophic gastritis, the decreased serum vitamin B12 level, and the anti-parietal cell antibodies and anti-intrinsic factor antibodies in blood serum. In addition, on chest computed tomography (CT) she was found to have a multicystic mass, measuring 50 mm in diameter, which seemed located in the anterior mediastinum and abdominal cavity, across the diaphragm. The cranial part of the mass consisted of solid structure including fat components but no calcification, and the caudal part consisted of multicystic structure, of which septal wall was slightly enhanced. The mass did not appear to invade the liver but to compress. Fluorine-18-fluorodeoxyglucose positron emission tomography (PET) scan showed no abnormal uptake. The mass was suspected a cystic teratoma, a bronchial cyst, a lipoma, a thymoma, or Morgagni hernia. It was resected through right diagonal thoraco-laparotomy with short upper midline incision.

Results
Seen from intrathoracic side the mass did not invade the pericardium and seemed to have firm adhesion to the diaphragm, and from intraabdominal side did not perforate the peritoneum or invade the liver, and no hernia canal was seen. The mass was not able to apart from the diaphragm, and combined resection of the diaphragm was performed. Pathologically it was diagnosed as a lymphangioma.

Conclusion
Lymphangioma arising from diaphragm is a very rare tumor. It should be considered in the differential diagnosis of diaphragm tumor.

Background
NHS Scotland is committed to improving the quality of healthcare services and patient-centered care is at the heart of Better Cancer Care (2008). The importance of experiences of patients in the planning and delivery of cancer services is a priority in improving cancer services across Scotland and increasingly emphasis is being put on how services are being delivered at a local level.

Methods
A questionnaire developed by Gloucestershire Health Authority to elicit the views of patients with lung cancer was identified. This had been adapted by South-east Scotland Cancer Network (SCAN) in 2010 to survey their patient population. Permission was sought and granted from NHS Gloucester and NHS Lothian to further adapt the questionnaire and use it in the wider Scottish population. All three networks were involved adjusting the questionnaire to explore areas of care at the time of diagnosis, during treatment and in the follow-up period. The survey has a mixture of qualitative and quantitative components with room for free text for clarification after many of the questions. All patients with lung cancer and Mesothelioma attending Oncology follow-up were asked to completed the survey. New patients, patients on surgical follow-up and those currently receiving chemotherapy or radiotherapy were excluded. The questionnaire was handed out to all patients with lung cancer and mesothelioma attending oncology clinics during June 2013 in Scotland. The questionnaires were distributed by the receptionists or clinic staff to be completed prior to seeing their oncologist. All questionnaires were anonymous and once completed were collected and returned to the researchers. Assistance with the quantitative analysis will be obtained from the Clinical Effectiveness Team in NHS Lanarkshire. The questionnaires will be analysed using SPSS and Excel. Bar graphs will be provided for each question. Data will be cross tabulated against each region where the diagnosis of lung cancer was made. Free text will be collated into themes and assistance with this analysis obtained from the University of Dundee.

Results
'Not applicable as yet, awaiting results'

Conclusion
Not applicable as yet, awaiting results

Background
Solitary fibrous tumor of the pleura (SFT) is an infrequent diagnosis and presents with a spectrum of radiographic and clinical findings. SFT can follow indolent or agressive clinical courses. This report describes clinical, radiologic and pathologic findings from four patients with this diagnosis. Surgical management options and the role of surveillance are reviewed.

Methods
The medical records and pathology reports of these patients were abstracted. The pathology slides were reviewed and interpreted by a single pathologist.

Results
Each patient had unique presentation and clinical course. Two patients did not have cardiopulmonary symptoms; two had progressive dyspnea, cardiac arrythmia, or pleuritic pain. Surgical approaches included robotic-assisted surgery (2), limited thoracotomy (1), and posterolateral thoracotomy with median sternotomy (1). All patients did well in the short term and there were no mortalities. All tumors showed typical spindle cell morphology with hemagiopericytoma like vasculature. Two patients showed significant necrosis. One patient developed bilateral pulmonary and subcutaneous metastasis one year after R0 resection; this tumor showed increased mitotic activity and necrosis on original pathology. FIGURE 1: CT chest of a large fibrous tumor of the pleura Figure 1 FIGURE 2: CT Chest of pulmonary metastasis Figure 2

Conclusion
Our experience with management of solitary fibrous tumor of the pleura emphasizes the variety of radiographic and clinical presentations for this entity. In our series, one patient had disease progression despite original pathology interpretation indicating typical morphology. Interestingly, this patient had the greatest number of mitotic figures in the tumor. Surgical resection remains the standard of care. Because these tumors have malignant potential, ongoing radiographic surveillance is appropriate management in patients with this diagnosis.

Background
Lung cancer patients have been shown to have some of the highest level of unmet psychological, physical and daily living needs. Despite this, patients have limited access to the interdisciplinary team in the outpatient setting. Current best practice indicates that an interdisciplinary team can better meet the needs of patients through a collaborative approach to treatment, planning, supportive care and preserving current function Specifically at Sir Charles Gairdner Hospital, patients have limited access to interdisciplinary team members in an outpatient setting. This has resulted in the concept of the Lung INterdisciplinary Clinic (LINC) where patients will be routinely assessed and provided with appropriate interventions aimed at reducing their distress and increasing or maintaining their function. Health professionals included in the LINC clinic include a nurse, social worker, occupational therapist, physiotherapist & dietician.

Methods
This is a prospective cross sectional study of lung cancer and mesothelioma patients carried out between April 2013 and September 2013. Participants will be recruited to the study via the Lung multi-disciplinary team meeting (MDT), those referred directly from any outpatient clinic or self-referred. Participants under 18, have a cognitive impairment or NESB will be exluded. Initial Screen: Participants will complete the Distress Thermometer (DT), rating their overall distress on a scale of 0 to 10 and identifying items on a list that cause them distress. Referral pathway and intervention delivery: Based on the problem items selected by the patient, a referral will be made to the appropriate health professional to receive intervention to address the problem. The timeframe for when the intervention will be provided is dictated by the distress the problem causes the patient –see belowFigure 1 Evaluation of service: Following intervention by the required health professional(s), the patient will be contacted by phone and the DT will again be administered. A qualitative questionnaire will also be administered at this time.

Results
not available at this point

Conclusion
This project has significant benefits to the patient, the health service and the wider community. The study plans to provide a new and improved method of interdisciplinary service delivery to an underserviced population. At present there is no literature related to the significance of interventions completed in an outpatient setting aimed at reducing distress and concerns in lung cancer/mesothelioma patients. Therefore this research will aim to expand the current body of literature related to this population.

Background
Incidence of Lung cancer is on the rise, especially among women in India. NSCLC constitutes the vast majority and there is tendency of rise in adenocarcinomas especially in smokers. Recent advances suggest that NSCLC is not a single entity but a cohort of different types based on molecular markers. IHC is a simple method to detect these changes. Recent trend is the use of IHC markers for molecular sub typing. A retrospective analysis of 35 patients who were diagnosed to have NSCLC and received at least 3 cycles of chemotherapy was included in this study. The objectives of the study: (1) To explore IHC pattern (Ki67, EGFR, Her2neu & ALK) (2) To correlate the IHC pattern to clinical presentation and response to chemotherapy.

Methods
Paraffin blocks of 35 cases of NSCLC were retrieved and analyzed. Histopathology sub-typing was done based on WHO classification. IHC markers (Biogenics) EGFR, Her2 neu, ALK & Ki67 were done & interpreted by using intensity of staining and percentage of positive cells. H-score was calculated for EGFR and allocated into low EGFR (< 200) & high (≥200-Positive). Her2neu analysis was graded from 0 to 3+, ALKs scoring was done using 0 to 3+scale and Ki67 was scored low (≤10% cells) and high (> 10% of nuclear positivity).

Results
Out of 35 cases studied, 7 cases were <50 years. Male 26, Female 9. 21 cases were smokers. 7 patients had significant weight loss. Morphological classification revealed adenocarcinoma 26 (76%) & squamous 8 (24%). EGFR was positive in 28 cases out of which 21 (80%) were adenocarcinoma and 7 (87%) squamous cell carcinoma. The positivity of Her2 and ALK was seen in one case each. High Ki67 was seen in 21 cases out of which 50% adenocarcinoma & 100% squamous cell carcinoma. EGFR Positivity was observed in 6 (85%) <50 years of age. There was no difference in sex distribution. Loss of weight did not correlate with high Ki67. Among EGFR positive cases high Ki67 was found in 17 cases (58%). The EGFR positivity did not differ between smokers and non smokers. Response (Partial Response & Stable Disease) to either Taxane / Gemcitabine based combination therapy was observed in 90% of low Ki67 group. In EGFR positive, 75% of chemotherapy group had good response (PR+SD) compared to upfront targeted therapy (Erlotinib). All the patients who received upfront targeted therapy were in low performance status.

Conclusion
This study has shown some interesting data. The EGFR status did not differ between smokers and non smokers. The observation of percentage positivity of ALK and Her2 was very low in this study. Low Ki67 patients responded well to chemotherapy. The response to treatment in EGFR positive NSCLC with Gemcitabine / Taxane with Platinum based combination chemotherapy was much better than those patients who received upfront EGFR targeted therapy, but needs more patients for statistical significance.

Background
Sorafenib is an orally available multikinase inhibitor with antiproliferative and anti-angiogenic activity. Reported oral adverse events of any grade are stomatitis/mucositis (11-38%, mostly ≤ CTC-AE grade 2), oral mucosal pain and dysphagia in the absence of clinical lesions. Sorafenib is under investigation in NSCLC. We report a patient who developed symptomatic progression of an esophageal stenosis during sorafenib treatment.

Methods
not appicable

Results
Case: A 67-year old male presented at the outpatient clinic with dysphagia CTC-AE grade 3. He was diagnosed with a cT3N3M1a (oligometastatic adenocarcinoma, KRAS mutated) NSCLC in January 2011 for which he was treated with concurrent chemoradiotherapy. Treatment was complicated with grade 3 radiation esophagitis (confirmed with duodenogastroscopy) for which he was treated with a feeding tube and proton pump inhibition. Because of remaining grade 1 dysphagia, duodenogastroscopies were performed in August 2011 and February 2012. A stable relative stenosis of the upper esophagus was found, easy to pass with the duodenogastroscope. Because of progressive disease he was subsequently treated with erlotinib/ pemetrexed (September 2011, study) and docetaxel monotherapy (August 2012). February 2013 he progressed again with subsequent participation in a phase II study with sorafenib 400 mg BID and metformin 1000 mg BID. Within three weeks he developed dysphagia for solid foods. A chest computed tomography showed no external compression of the esophagus and no tumor progression. Duodenogastroscopy revealed a stenosis with ulceration in the upper part of the esophagus, passing the stenosis was only possible with a baby-duodenogastroscope. Because of swallowing problems, sorafenib was temporarily stopped and placement of a percutaneous feeding tube was planned. However, two days after stopping sorafenib, his dysphagia completely resolved and food passage was normal. So, ten days later sorafenib was restarted with dose reduction (200 mg BID). After restarting sorafenib his dysphagia returned with grade 3 within six weeks. Again, sorafenib was temporarily stopped and in a couple of days his dysphagia resolved. After another restart of sorafenib at the latter dose he again developed dysphagia, but this time manageable.

Conclusion
We present a patient who developed a grade 3 stenosis of the esophagus during treatment with sorafenib which clinically resolved shortly after stopping sorafenib but reoccurred after rechallenge with sorafenib at a lower dose. Dysphagia resolved again after stopping the sorafenib with again complaints after restarting. No other explanation was found (e.g. progression of malignancy, external compression). 1.5 year before, after concurrent chemoradiotherapy, he was diagnosed with a relative stenosis of the upper esophagus, but this remained stable until sorafenib treatment was started. He scored 8/13 points on the Naranjo score, making sorafenib a probable cause of the stenosis. The underlying mechanism is unknown. A possible explanation is sorafenib inhibition of the VEGF and MAP-kinase pathway. These pathways are both involved in the process of mucosal defense and repair, and it could be that blocking this pathway combined with sensitization by previous irradiation caused progression of the stenosis. This case stresses the importance of being aware of unusual side effects of medication and taking into account possible interactions with previous treatments.

Background
Despite the rising incidence of NSCLC in the elderly population in Thailand, a well defined chemotherapy regimen for these patients has not been reported. This study examines the toxicity and activity of doublet carboplatin and gemcitabine in Thai patients with advanced NSCLC.

Methods
Chemotherapy-naive patients with histological/cytological proven advanced NSCLC, aged > 65 years, ECOG 0-1 and adequate organs function were treated with carboplatin (AUC5) and gemcitabine (1000 mg/m[2] in a 30-min infusion D1, 8) every 21 day for maximum 6 cycles. The primary endpoint was objective tumor response rate and tolerability to this regimen.

Results
From November 2011 to February 2013, 30 patients were evaluated. Median age was 73 years (range 65-83), 70% were male, 70% were smoker and all patients had PS 0 (30%) or PS 1 (70%). Stage IIIb disease in 13% patients and stage IV in 87% patients. Non-squamous cell carcinoma in 73% patients (adenocarcinoma 66%, large cell carcinoma 3.5%, other 3.5%) and squamous cell carcinoma in 27% patients. The median number of cycle was 4 (range 2-6). Among the 29 patients with measurable disease, there were 7 PR, 15 SD and 7 PD (response rate 24%). The most common hematologic toxicity was grade 3 anemia in 20% and grade 3 leukopenia in 10%. Febrile neutropenia occurred in 3%. No treatment related death was observed. Non-hematologic toxicity was generally mild and grade 1 fatigue occurred in 30%. The median progression free survival was 4.9 months (range 2-16).

Conclusion
The doublets carboplatin and gemcitabine could be a valuable treatment option in elderly Thai patients. The activity and safety observed in this report is within the range of data reported for doublet chemotherapy regimen in the elderly patient with NSCLC.

Methods
HT-ANAM-301 (NCT01387269) and HT-ANAM-302 (NCT01387282), also known as ROMANA 1 and ROMANA 2, are double-blind, placebo-controlled, randomized (2:1 anamorelin HCl vs. placebo) Phase III trials in patients with NSCLC cachexia, with a target enrollment of 477 patients per study. Eligible patients must have unresectable Stage III or IV NSCLC and cachexia (weight loss of ≥5% body weight within prior 6 months or BMI <20 kg/m[2]). Patients receive once daily oral doses of anamorelin HCl (100 mg) or placebo for 12 weeks. Co-primary endpoints are the change from baseline in LBM as measured by DXA scan and in muscle strength as measured by handgrip strength (HGS). Secondary endpoints include change in body weight, overall survival, and quality of life. For HT-ANAM-301 only, blood samples are collected at Week 6 for population pharmacokinetics. After 12 weeks of treatment, patients may continue in a separate 12-week safety extension study (HT-ANAM-303 [ROMANA 3] NCT01395914).

Results
As of June 2013, 448 patients (93.9%) have been enrolled in ROMANA 2, and key baseline characteristics based on preliminary data available to-date are presented in the Table.Figure 1

Background
Lung cancer patients increasingly seek a second opinion in order to make sure they are receiving an exact diagnosis and an optimal treatment. A second opinion is more likely to be comprehensive when performed in centers with high level of expertise and within a multidisciplinary team.

Methods
A dedicated second opinion outpatient clinic was started within the Thoracic Oncology Unit of Ghent University Hospital, in March 2012, aiming at a quick access and evaluating its impact on diagnosis and treatment decisions. Second opinion was defined as a review of the cancer diagnosis and/or the treatment recommendations by another independent oncologist and/or multidisciplinary team. Patients had to be referred by either their general practitioner or the treating specialist. Prior to the consultation relevant investigations (medical history, pathology and imaging) had to be provided.

Results
Between March 2012 and June 2013, 79 pts were referred: 31 women and 48 men with a median age of 64 years [17-81 yrs]. Of these, 17 (22%) were never smokers, 18 (23%) smokers and 40 (51%) ex-smokers. Median interval was 3 working days [0-15 days] after first referral. Eighteen percent of patients were referred by their GP’s versus 80% by their treating specialist. Medical information including imaging was available in all pts at the moment of the consultation. Diagnosis included: adenocarcinoma (n=43 - 54%), squamous cell carcinoma (n=8 - 10%), NSCLC, NOS (n=1 large cell neuroendocrine carcinoma (n=3 - 4%), small cell lung cancer (n=4 - 5%), mesothelioma (n=6 - 8%), thymoma (n=2 - 3%), carcinoid tumor (n= 4 - 5%). In 4 patients no diagnosis had been established. Eleven patients were referred for confirmation of diagnosis and treatment, 11 for staging and 57 for treatment advice. Median consultation duration was 35 minutes [15-60 min], median time of multidisciplinary counseling 15 minutes [5-60 min]. In 43% of the referrals, diagnosis and treatment was confirmed, in 21% other diagnostic examinations were advised and in 29% a substantial change in treatment was proposed. Six percent of patients entered into a clinical trial. Almost 50% of patients continued their treatment at our center (26% on request of the referring physician, 23% on patient's request). Patient's satisfaction on waiting time and quality of the advice was high.

Conclusion
This dedicated second opinion outpatient clinic confirms the need for an academic second medical advice and provided a quick access. In 50% of cases a substantial change in diagnostic procedure or treatment was proposed.

Background
Echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase (EML4-ALK) fusion genes occur in approximately 4-7% of patients with adenocarcinoma of the lung (ACL). These tend to occur in individuals with limited or no tobacco exposure and largely occur in exclusion of KRAS mutations. The presence of a KRAS mutation is associated with a worse prognosis and predicts lack of response to targeted therapeutics such as crizotinib. We believe this to be the first case reported of a concurrent KRAS mutation and EML4-ALK translocation with a subsequent response to crizotinib.

Methods
Not applicable

Results
A 56 yo White female smoker had a recent diagnosis of cirrhosis due to hepatitis B and C. Imaging for her liver revealed an incidental finding of bilateral lung opacities, both of which were suspicious for malignancy. A biopsy of the LLL lesion confirmed ACL. Resection of the superior segment of the LLL was performed and confirmed a well-differentiated ACL with BAC features (T1b, N0, M0). Analysis revealed a KRAS mutation (p.G13C (c.37G>T); EGFR and EML4-ALK analysis were not performed. The right-sided lesion was observed. One year later, disease progression was identified in the right hilum and mediastinum. EBUS confirmed the presence of ACL in levels 10R and 4R lymph nodes. Molecular analysis again confirmed the presence of a KRAS mutation, albeit a different mutation (p.G12A (c.35G>C) than was observed in the left lung. There was no ALK gene rearrangement. She was treated with concurrent chemoradiation with cisplatin as the radiosensitizer in light of her pre-existing grade 2-3 thrombocytopenia from her underlying liver disease. She received 38 out of a planned 60 Gy due to thrombocytopenia and subsequent interruptions in therapy. Nonetheless, she did respond to therapy, but she had a local recurrence less than 8 months after therapy was terminated. At the time of progression, the patient sought further surgical intervention and a pneumonectomy was offered; however, mediastinoscopy confirmed the presence of adenocarcinoma in a level 7 node and plans for further resection were aborted. Mutational analysis confirmed the presence of the activating KRAS mutation, (p.G12A (c.35G>C) and negativity for an EGFR mutation; however, an EML4-ALk translocation was identified in 20% of cells analyzed. The patient was treated with crizotinib. After 8 weeks of therapy, PET/CT demonstrated objective evidence of response to therapy with the maximum SUV decreasing from a baseline of 11.3 to 6.8, with the lesion remaining stable in size. Therapy was well-tolerated, although the patient had an unexpected finding of normalization of her platelet count while on therapy with crizotinib.

Conclusion
This unusual case of a female smoker with a co-existing EML4-ALK translocation and activating KRAS mutation highlights several important points: 1. EML4-ALK translocations are not mutually exclusive of KRAS mutations in all patients with ACL. 2. Discordance in EML4-ALK translocation status can occur in metastatic deposits. 3. Individuals harboring both an EML4-ALK translocation and a KRAS mutation can respond to crizotinib. 4. Commonly used algorithms for molecular testing in ACL do not identify all patients who may benefit from molecularly targeted therapies.

Background
Primary pulmonary lymphoma (PPL) is a rare disease. Half of the patients are asymptomatic and other patients can present nonspecific symptoms such as cough, mild dyspnea, chest pain, or hemoptysis. The diagnosis of disease is based on histological examination and we can obtain a tissue by surgical biopsy, transbronchial or transthoracic biopsy. We report a case that PPL mimicking lung abscess was confirmed by surgical biopsy.

Methods
68-year-old female presenting with continuous mild fever and cough for 2 weeks, and suspected as pneumonia or lung abscess at the initial evaluation. There was no clinical improvement after antibiotic therapy for 5 weeks. Chest computed tomography showed as organizing pneumonia with abscess formation right middle lobe RML). So, we performed right middle lobe lobectomy. In operative findings, there was large amount milkfish drainage with hard mass in RML. There was no culture positive in milkfish drainage. Post op 7th day, she discharge without any complication.

Results
Pathologic findings reveals the mass was malignant primary pulmonary lymphoma in (diffuse large cell type B-cell lymphoma).

Conclusion
PPL is a vary rare entity and the diagnosis based on radiological findings is limited so, we reports it.

Background
Major goals in advanced NSCLC include accurate evaluation of survival and quality of life. Few trials evaluate both of these major endpoints well. In many studies, only a minority of patients have quality of life and other patient reported outcomes (PROs) such as symptoms systematically followed over time, which decreases the value of the assessment of the treatment. Prior studies have identified barriers to measuring quality of life in clinical trials and in practice. To overcome these barriers, we used a computer-assisted version of the validated LCSS measure and tested this prospectively in a large study in patients with Stage IV and IIIB NSCLC. The eLCSS-QL requires only two minutes for completion of the patient version and proved to be highly acceptable in earlier studies (Hollen, Supp Care Cancer 2012).

Methods
This trial was conducted at 65 sites in 9 Asian countries. 622 patients received first-line treatment with docetaxel -based chemotherapy. Patient demographics included: 70% male; 65% adenocarcinoma; median: KPS = 90; ECOG = 1 (27% ECOG 0). Stages: IV (72%), IIIB (28%). 84% had two or more major symptoms. 80% received combination chemotherapy with cisplatin (52%) or carboplatin (28%). The eLCSS-QL was completed every 3 weeks at the clinic. We also surveyed 98 physicians and nurses treating these patients regarding their experiences concerning communication, usefulness and acceptability of the eLCSS-QL.

Results
Ninety-seven percent of patients completed the eLCSS-QL at baseline; 90% completed follow-up evaluations. Over 90% found the eLCSS-QL easy to use and acceptable to complete at each visit. More than 80% of patients reported increased awareness of symptoms and that the quality of life evaluation made it easier to speak with doctors and nurses. 1% refused eLCSS-QL completion. Of physicians and nurses, more than 90% found the eLCSS-QL easy to use and increased symptom awareness; 80% reported improved communication, enhanced satisfaction with the patient visit, and would recommend its use to others. Nearly 90% of physicians reported they could identify benefit from chemotherapy earlier; 76% would order fewer imaging tests and 80% said the eLCSS-QL could save time. Cross-cultural testing was performed in this 9 nation trial. Cronbach’s alpha scores were high for each country, and exceeded 0.85 overall, demonstrating good cross-cultural reliability. Treatment outcomes: major response rate 37%; median survivals: 13.9 months (docetaxel + cisplatin), 12.7 months (docetaxel + carboplatin).

Conclusion
Placing the well validated LCSS onto an electronic platform (eLCSS-QL) helped overcome barriers to evaluating QL in this large clinical trial, with 90% of patients completing baseline and repeated QL measures. Patients, physicians, and nurses all found the eLCSS-QL to be highly acceptable and easy to use. The good cross-cultural aspects of the eLCSS-QL indicate that the electronic platform is particularly suitable for multinational trials. This large prospective trial demonstrates that improved compliance with quality of life and PRO evaluation is feasible and can easily be accomplished in large clinical trials. Additionally, the electronic format enhances the potential for the use of PROs in decision making in clinical practice.

Background
The tradition of Lung Cancer Awareness Month (LCAM) started in Slovakia in November 2008 with the help of several organizations, including Slovak Oncological Society, Ministry of Health, Ministry of Education, Ministry of Agriculture, Roche Slovakia, leading lung cancer centers, and many others, including volunteers, with the main purpose to raise awareness about all aspects of lung cancer. Several interesting projects were realized as a part of LCAMs in 2008 – 2012. Among them were the press conferences with participation of patients, leading experts, well known persons from cultural and political life; lung function testing in the Parliament of the Slovak Republic; lung function testing and educational leaflets distribution in the largest shopping centers in the country; the moving exhibition of lung models colored by the VIPs from the Slovakian cultural and sport life, i.e. by well known writers, actors and actresses, and sport stars; teaching activities at the secondary schools; publishing of free educational materials for patients and their relatives. In addition, during the LCAM in 2011 the Second Breath (Druhy Dych) Citizens Organization was established to help patients with lung cancer, and successfully continues with their activities (www.druhydych.eu). We decided to assess the influence of LCAMs on public awareness of lung cancer.

Methods
1. Search for the Slovak web pages containing the term “rakovina pluc” (“lung cancer“) was done in Google.sk for the time periods: 01.NOV.2007 – 31.DEC.2007, 01.NOV.2008 – 31.DEC.2008, and 01.NOV.2012 – 31.DEC.2012. 2. Another search was done in a Newton Media Database, aimed at the major Slovak media, for the years 2007 and 2012 to find the entries with the term “rakovina pluc” (“lung cancer”).

Results
1. The number of the Slovak web pages with the term “rakovina pluc” (“lung cancer”) in the time periods 01.NOV. – 31.DEC.2007, 01.NOV. – 31.DEC.2008, and O1.NOV. – 31.DEC.2012 was 14, 58, and 130, respectively. 2. The number of entries with the term “rakovina pluc” (“lung cancer”) in the Newton Media Database was 16 in 2007, and 36 in 2012.

Conclusion
Our results confirm, that LCAMs in Slovakia attracted media and public attention and thus increased the awareness of lung cancer. We believe that this has a positive impact on lung cancer patients’ care, and encourages us to continue with the LCAMs tradition.

Background
The management of non-small cell lung cancer (NSCLC) has changed markedly over last decade with the discovery of distinct molecular and genetic changes within the lung cancer genome and the availability of new therapeutic agents to target these genetic aberrations. However, the clinical benefits observed are not without significant financial costs. These include diagnostic testing to identify molecular targets and an increasing cost of cancer treatment. Chromosomal rearrangements of the anaplastic lymphoma kinase gene (ALK) are predictive for clinical response to crizotinib, a first-in-class oral ALK inhibitor. In a recent phase 3 trial, crizotinib was associated with a higher response rate, improved progression-free survival and improved quality of life when compared with docetaxel or pemetrexed as second-line chemotherapy for advanced NSCLC following platinum-based chemotherapy. We performed an analysis to estimate the cost-effectiveness of ALK testing and crizotinib treatment in the second-line setting for patients with stage IV ALK-rearranged NSCLC in the province of Ontario, Canada.

Methods
We developed a Markov state-transition model to compare the costs and effectiveness of ALK testing and treatment with crizotinib in positive cases with the current standard of care (docetaxel or pemetrexed chemotherapy). Patients had stage IV NSCLC with non-squamous histology and were previously treated with a platinum-based regimen. The analysis was conducted from the Canadian public health perspective (Ontario) and a “lifetime” time horizon was used. Transition probabilities, mortality rates and costs were calculated from the Ontario Registry, Cancer Care Ontario New Drug Funding Program, Ontario Case Costing Initiative, University Health Network and published literature, including a recent second-line randomized trial of crizotinib versus chemotherapy (Shaw et al. New Engl J Med 2013). Population-based ALK testing included initial immunohistochemical (IHC) staining followed by fluorescent in-situ hybridization (FISH) for positive cases. The outcome of the analysis was incremental cost per quality-adjusted life-years (QALY). The survival impact of crizotinib in ALK-positive NSCLC was derived from a retrospective study (Shaw et al. J Clin Oncol 2012), as the second-line randomized trial of crizotinib versus chemotherapy permitted >80% crossover from the standard chemotherapy arm to crizotinib.

Results
The use of crizotinib compared to pemetrexed and docetaxel in ALK-rearranged NSCLC, based on our preliminary model, could yield as much as +0.309 QALY and +0.433 QALY respectively, assuming no crossover from chemotherapy to crizotinib. Incremental costs based on the preliminary model are estimated at CAD $88,446 for pemetrexed and $102,764 for docetaxel, with incremental cost-effectiveness ratios of $286,198/QALY ($162,814/life-year) and $237,575/QALY ($136,707/life-year) gained respectively. Major drivers of cost-effectiveness included the cost of drug therapy and incremental survival. Data on the impact of ALK testing on the overall cost-effectiveness ratio will be presented at the 2013 WCLC meeting, as will refined cost estimates after further model calibration.

Conclusion
While crizotinib therapy 2[nd] line for advanced ALK-rearranged NSCLC is clearly superior to chemotherapy, the cost-effectiveness ratio is higher than traditionally accepted thresholds, driven largely by drug cost. Payors and manufacturers should collaborate to ensure that highly effective NSCLC treatments are available and affordable to patients with NSCLC.

Background
After decades of very slow progresses, lung cancer management rapidly evolved in the past few years. One could anticipate a possible leap in perception of the disease between patients and physicians.

Methods
We conducted a prospective nationwide observational survey of 2200 healthy subjects selected within a representative permanent polling database according to the relevant national and European laws. We collected data in relation to aetiology, epidemiology, diagnostic, therapy and prognostic by using a specific questionnaire as well as perception of lung cancer by using a lexical approach. Among them, 1629 returned the questionnaire and 1469 were eligible for a full analysis.

Results
We observed that the population has an average high level of information regarding epidemiological changes of lung cancer (“same incidence” for 40%, “higher incidence” for 47%, “increase in women” for 75%), and main risk factors (tobacco 93%, occupational 81% and environmental exposure 56%). Two thirds (67%) are aware of the danger of passive smoking. Only 22% of the whole population believed to be at risk of lung cancer. Differences were seen according to smoking habits as 62% of current smokers, 21% of former smokers and 6% of never-smokers believed to be at risk (p < 0.05) and according to the age, as 15% of responders above 65 years old thought to be at risk in comparison of 26% of responders below 34 (p < 0.05). The population overestimated the overall survival of lung cancer (32%) and underestimated the potential cure of early stage disease (52%). The participants clearly identified lung cancer as a severe disease (82%) with a worse prognostic than other cancers (colorectal, breast, prostate, p < 0.05). Most of the population was aware of the main treatments of lung cancer (surgery, chemotherapy and radiotherapy) but only 45% cited targeted therapy. By using lexical tests we observed that corpus can be split in two main lexical repertoires: a) the major repertoire in which the significant units have encoded lung cancer identified as a tobacco-induced, life-threatening disease, imposing heavy treatment and b) the minor repertoire in which significant units belonged to the representation of lung cancer as an environmental-induced disease. In comparison with breast cancer, lung cancer is characterized by a greater feeling of guilt and a more frequent association with the way of life.

Conclusion
We deciphered some aspects of lung cancer perception in the general population and anticipated that it may improve psychological adjustment in patient-doctor communication, fill in the knowledge gap of the perception of the disease and eventually help in lung cancer management.

Background
Malignant pleural effusion (MPE) is a disabling condition in patients with metastatic disease. Pleurodesis is a well established treatment for recurrent MPE; however, the best sclerosing agent is still a matter of debate. Iodopovidone is described in the literature as a sclerosing agent easily obtained, easy to use, and inexpensive; nevertheless, its safety has not been systematically evaluated. The objective of this study was to analyze the occurrence of frequent (>5%) adverse events after pleurodesis using two different dosages of Iodopovidone in patients with MPE.

Methods
Randomized double blind clinical trial including patients with recurrent MPE eligible for pleurodesis. All patients were randomized into two groups; group 1 received 1% Iodopovidone and group 2 received 2% Iodopovidone. We sought adverse events systematically after pleurodesis through pain analog scale, dyspnea scale, oxygen saturation, heart frequency, arterial blood pressure, body temperature, visual acuity, EKG, chest x-ray and laboratory tests (CRP, hemogram, renal function, liver function and thyroid function). All adverse events were registered and classified according to the CTCAEV v3.0. We considered pleurodesis as failed when the patient underwent new pleural procedures. We compared groups as for adverse events, quality-of-life, and success using, chi-square or t-test, p<0.05 was considered significant.

Results
Fifty patients underwent pleurodesis over the study period, 45 females and 5 males with a mean age of 56,7 years. The etiology of MPE was breast cancer in 34 patients (68%), lung cancer in 6 patients (12%), and other neoplasms in 10 patients (20%). We found no difference in patient’s demographical data between groups. The most frequent adverse event was elevation of alkaline phosphatase, which occurred in 21 patients (42%), 6 in group 1 and 15 in group 2 (p = 0.03). Hyponatremia was the second most common adverse event, it occurred in 19 patients (38%), 5 in group 1 and 14 in group 2 (p= 0,02). In no patient did these laboratorial alterations require further care. The most frequent clinical adverse event was severe pain, it was observed in 5 patients (10%), 1 patients from group 1 and in 4 patients from group 2 (p=0.69). Hypotension occurred in one patient from each group (p=1). Two patients had postoperative empyema in group 2, and none in group 1 (p=0,35). Other adverse effects or complications commonly reported in the literature such as fever, renal or visual disorder were not found. Pleurodesis success rate was 92% in the Group 1 and 84% in Group 2 (p = 0.5).

Conclusion
Clinically relevant adverse events are not frequent after iodopovidone pleurodesis, being pain the most common. Apparently, the occurrence of laboratorial alterations is dose-dependent

Background
Malignant pleural mesothelioma (MPM) is the main primary malignant tumor of the pleura. It is extremely aggressive and associated with poor survival, despite multimodal treatment appropriate. Most series report the experience accumulated with the treatment of MPM in a few North American or European specialized centers. In literature, we found very little information on epidemiology and treatment of mesothelioma in Latin America. The aim of this study was to describe the experience with MPM in a tertiary university hospital in Brazil.

Methods
Retrospective study with patients diagnosed with MPM between December 1999 and December 2011. Diagnosis was established by histopathological analysis of the pleura. Tumor staging included CT scans of the head, thorax and abdomen. Pet Scan/PET-CT has been included since 2002. Mediastinoscopy is routinely performed since 2002. All patients were initially considered for multimodal therapy (extrapleural pleuropneumonectomy with chemotherapy and radiotherapy). The chemotherapy regimens used were cisplatin, doxorubicin, cyclophosphamide, and recently, Pemetrexed. Categorical variables were presented as percentage and continuous variables as mean and standard deviation. Kaplan-Meier estimate was used for survival analysis.

Results
Fifty-nine patients were included (45 M/ 14 F); mean age 49 years (13-79). Forty-five patients had epithelioid tumors (76%); 4 (7%) had sarcomathoid tumors; 8 had biphasic tumors (14%), and 2 (3%) had desmoplastic tumors. 36% of the patients had confirmed asbestos exposure. Clincal stage was Stage I, 18 patients; Stage II, 8 patients; Stage III, 21 patients: and, Stage IV, 12 patients. Therapeutic approaches were multimodal (pleuropneumonectomy extrapleural plus chemotherapy-radiotherapy) in 21 patients (36%), chemotherapy and radiotherapy in 8 (14%), radiotherapy alone in 4 (7%), chemotherapy alone in 25 (43%). Survival among patients operated was 16 + 2 months, and 15.9 + 5.7 months in the non-operated group. There was no statistical difference in survival between the groups operated and non-operated. Surgical mortality was 15%, with 40% morbidity.

Conclusion
The pattern of our demographic data is similar to other international series. Despite aggressive treatment, poor survival was observed in the present study.

Background
Crizotinib(Xalkori®) was developed as a medicine for anaplastic lymphoma kinase (ALK)-rearranged non-small cell lung cancer (NSCLC). Multi institutes studies established its efficacy and safety for advanced lung carcinoma. After crizotinib release in Japan, there has been no report about usage of crizotinib for postoperative recurrence of lung cancer. We have four patients with postoperative recurrence of ALK-rearranged NSCLC who were treated with crizotinib. We herein report the efficacy and safety of the treatment.

Methods
not applicable

Results
Case report ALK-rearrangements were confirmed by FISH examination from surgical specimen in　all four patients. Histological diagnoses were pulmonary adenocarcinoma in all cases. Case 1. A 62-year-old man underwent the right middle and lower lobectomy (pT3N2M0) followed by adjuvant chemotherapy with platinum doublet. He had a mediastinum lymph node relapse six months after the operation. Crizotinib was administered as the 2[nd] line. A long stable disease (SD, six months) was obtained in this patient. Case 2. A 62-year-old woman underwent the right upper and middle lobectomy (pT2aN2M1a) followed by adjuvant chemotherapy with platinum doublet. She had multiple lung metastases thirty-one months after the operation. Progressive disease (PD) was detected after four courses of platinum doublet. Crizotinib was administered as the 5[th] line and partial response (PR) was obtained over 5 months. Case 3. A 63-year-old man underwent preoperative chemotherapy followed by the right upper lobectomy (ypT3N2M0). He received an adjuvant chemotherapy with platinum doublet. He developed brain metastases five months after the operation. Crizotinib was administered one month as the 4[th] line, and PR was obtained. Case 4. An 83-year-old woman underwent the left lower lobe wedge resection. (pT2aNXM1a) followed by four regimens of chemotherapy, resulting in PD. Crizotinib was administered as the 5[th] line. The side effects with increase in body weight (+4kg, Grade1), leg edema (Grade 2) and liver dysfunction (Grade 1) deveroped on the 7[th] day. Her symptoms quickly disappeared after discontinue of crizotinib. Another regimen chemotherapy was administered because she rejected restart of the crizotinib treatment.

Conclusion
In the efficacies of the crizotinib treatment, two cases were PR, one case was SD and one case was drop out. The crizotinib was effective in two cases which were PD with other regimen treatments. Crizotinib has possibilities of giving dramatic clinical response in ALK-rearranged NSCLC patients. In safeties of the crizotinib treatment, no adverse event was occurred in three cases and Grade 2 adverse in one case. There have been no serious complications.　Crizotinib treatments in ALK-rearranged NSCLC patients have great possibilities of having a clinical benefit. Crizotinib can also be effective and safe in postoperative recurrence of ALK-rearranged NSCLC patients. We reacknowledge an importance of molecular targeted therapy that creates dramatic clinical effects within a short time period. Further observation and accumulation of cases will be necessary to evaluate the clinical effectiveness of this treatment in postoperative recurrence of ALK-rearranged NSCLC patients.

Background
Malignancy after organ transplantation is generally the result of de-novo occurrence or recurrence of prior malignancy. Donor-related malignancy, defined as direct transmission of tumor from the donor organ or tumor arising from cells of donor origin in a recipient of a solid organ or hematopoietic stem cell transplant, is less common (0.02-0.2% of solid organ transplants). When organs from donors with known malignancy are used, the rate of transmission is up to 45%, with a mortality of 33-42%. We present the first case of donor-transmitted lung cancer in 550 liver transplants at Mayo Clinic Arizona.

Methods
Case report and literature review.

Results
A 69 year-old Caucasian male, former smoker, underwent deceased-donor liver transplantation for alcoholic cirrhosis and hepatocellular carcinoma. He was seen for a routine 4 month follow-up visit, had no complaints and was compliant with immunosuppression. Physical exam and laboratory tests were unremarkable. Abdominal CT revealed 3 small, solid, indeterminate liver masses. Follow-up MRI 6 weeks later demonstrated an increase in number and size of liver lesions. US-guided biopsy revealed poorly differentiated carcinoma most consistent with non-small cell carcinoma of the lung, with a minor component of small cell carcinoma. On PET-CT, the abnormal uptake was limited solely to the liver. Suspicion of donor-transmitted malignancy arose. The donor was a 50 year-old man, with history of alcohol and nicotine dependence (>20 pack/year), without history of malignancy. Chest x-ray, bronchoscopy and surgical lung examination, performed as part of procurement protocol, were normal. No other organ from this donor was transplanted. A PCR-panel of markers that recognize highly variable regions of DNA was used to compare donor liver tissue to the tumor and recipient liver tissue. Results confirmed cancer cells were of donor origin. Cancer was confined to the donor organ, but the patient could not undergo graft removal and re-transplantation. Immunosuppression was reduced, and chemotherapy (etoposide & carboplatin) was begun with initial response. Progression of metastatic liver disease led to second-line therapy with erlotinib. Unfortunately, patient succumbed shortly thereafter.

Conclusion
Donor-derived bronchogenic carcinoma after solid organ transplantation is extremely rare. One series reported lung cancer in 9 of 3374 patients (0.3%) transplanted over a 15 year period. Of these 9 patients, 3 patients had a kidney transplant, 3 had liver transplant, 2 had heart transplant and 1 had lung transplant. Treatment includes reduction/discontinuation of immunosuppression, chemotherapy and/or radiation therapy as appropriate, as well as removal of the transplanted organ and re-transplantation when feasible. In the present case we hypothesize that the donor had an undiagnosed lung cancer with subclinical hepatic metastases transmitted to our patient at the time of liver transplantation. Donor-derived lung cancer is extremely rare and can lead to significant morbidity and mortality. Proper diagnosis of donor origin is critical since it has a significant impact on management of these patients.

Background
Emerging research suggests that LC may be associated with greater levels of stigma, shame and hopelessness compared to other cancers. This study measured explicit, conscious attitudes (EAs) and used the Implicit Association Test (IAT) to assess implicit, unconscious attitudes (IAs) and stereotypes (ISs) of LC relative to BC.

Methods
To assess EAs, participants (Ps), [people with cancer (n=243), caregivers (n=677), healthcare providers (HCPs, n=142), and the general public (n=864)] were asked to rate their agreement, on a six-point scale, with statements about how people with LC and BC “do feel” (descriptive attitudes) or “ought to feel” (normative attitudes) about their disease. Implicit attitudes were measured with three IATs that used LC or BC images with words representing good/bad; hope/despair; or suitable/shameful. Implicit stereotypes used images representing smoking cigarettes, drinking alcohol and eating unhealthy foods. An IAT D score indicated the strength of bias against LC relative to BC: >0.65 = strong bias; 0.35-0.65 = moderate bias; 0.15-0.35 = slight bias; -0.15 -+0.15 = no bias, and < -0.15 indicated bias against BC.

Results
EAs and IAs were substantially more negative towards LC. Most Ps provided more negative ratings for LC than BC for both descriptive (70%vs.8%) and normative statements (56% vs. 3%). Ps had strong negative IAs towards LC compared to BC (bad: 74% vs. 10%; despair: 75% vs. 9%; shame: 67% vs. 17%). In the stereotype IATs, Ps were far more likely to associate LC with smoking than with eating unhealthy foods or drinking alcohol. Conversely, Ps were far less likely to associate BC with smoking than with eating or drinking (smoking: 86% LC vs. 7% BC; eating: 86% LC vs. 7% BC; drinking: 67% LC vs. 18%BC). These trends were consistent across caregivers, patients, HCPs, and the public. EAs, IAs and ISs were uncorrelated.

	Caregivers	Patients	HCPs	General Public
EXPLICIT
Negative Descriptive	75%, 7%, 18%	81%, 7%, 12%	88%, 5%, 7%	74%, 8%, 18%
Negative Normative	59%, 3%, 38%	64%, 2%, 34%	65%, 3%, 32%	56%, 3%, 41%
IMPLICIT ATTITUDES
Bad	D=0.43 73%, 12%, 15%	D=0.33 72%, 13%, 15%	D=0.33 63%, 17%, 20.0%	D=0.44 74%, 9%, 17%
Despair	D=0.43 73%, 10%, 17%	D=0.54 76%, 5%, 19%	D=0.44 77%, 13%, 10%	D=0.47 77%, 8%, 15%
Shame	D=0.32 65%, 18%, 17%	D=0.52 82%, 9%, 9%	D=0.41 72%, 11%, 17%	D=0.35 66%, 17%, 17%
IMPLICIT STEREOTYPES
Smoking vs. Eating	D=0.69 89%, 5%, 6%	D=0.71 90%, 5%, 5%	D=0.79 94%, 3%, 3%	D=0.57 84%, 8%, 8%
Smoking vs. Drinking	D=0.34 65%, 18%, 17%	D=0.17 54%, 31%, 15%	D=0.54 81%, 5%, 14%	D=0.34 69%, 17%, 14%
Drinking vs. Eating	D=0.10 40%,33%,27%	D=0.22 54%, 23%, 23%	D=0.21 59%, 29%, 12%	D=0.16 50%, 27%, 23%

Percentage order: LC bias%, BC bias%, No bias%. D=mean IAT score. All D scores significantly > 0 with ps<0.001

Conclusion
Ps had greater explicit and implicit negative bias against LC compared to BC.

Background
Bronchial sleeve lobectomy concomitant with pulmonary artery reconstruction (double sleeve) is a reasonable alternative procedure for pneumonectomy in appropriately selected patients with non-small cell lung cancer. However, video-assisted thoracic surgery double sleeve lobectomy is technically more challenging than routine lobectomy, and has never been reported. We aimed to report the first attempt on video-assisted thoracic surgery double sleeve lobectomy for non-small cell lung cancer.

Methods
From May 2012 to February 2013, three patients with non-small cell lung cancer of the left hilum directly involving the pulmonary artery were selected for curative resection via the VATS approach. Surgical procedures were performed with four ports for the first patient and three ports for the next two patients. The bronchus and pulmonary artery were reconstructed by end-to-end anastomosis using running Prolene stitches. Low-molecular heparin was subcutaneously administered during the first week after surgery.

Results
Surgical duration ranged from 350 to 490 min with blood loss between 30 to 200 ml. The first two patients developed pneumonia after surgery with no mortalities. All the patients were discharged home within 9-14 days after surgery. A total of 17, 12 and 14 lymph nodes were removed, and pathological stage of these three patients were T~2b~N~1~M~0~, T~2a~N~0~M~0~ and T~2b~N~0~M~0~ respectively. The reconstructed bronchus and artery worked well during 3-12 months follow-up.

Conclusion
video-assisted thoracic surgery double sleeve lobectomy is technically difficult but feasible. The operation can be successfully finished by skilled thoracoscopic surgeons, but the surgical incisions, procedures, and specific instruments still require further improvement.

Background
Chemotherapy is the standard treatment for most (stage II and beyond) lung cancer patients and treatment duration can be long ranging from months to years. Rural lung cancer patients often have to travel long distances for such specialist treatment. Geographical isolation and remoteness is implicated as one of the factors leading to inferior outcomes in these patients. Since 2007 Townsville cancer centre has been providing chemotherapy services to Mount Isa at a distance of 1000 km via Teleoncology ( using video conferencing). This model has previously been shown to be effective, safe, cost saving and sustainable. This study evaluates the feasibility and safety of chemotherapy for lung cancer patients treated via Teleoncology.

Methods
All patients with a diagnosis of lung cancer from Townsville Teleoncology data resource (comprising all patients treated with chemotherapy at Mount Isa Base hospital using videoconferencing from Townsville cancer centre) between April 2007 and March 2012 were eligible. Patient and tumour characteristics were studied and feasibility was evaluated using number and type of cycles, dose intensity and completion rates for chemotherapy administration. Toxicity was graded as per common terminology criteria for adverse events (CTCAE) v 4.0.

Results
Out of total 170 patients treated using Teleoncology, 33 (22%) had lung cancer. Of these 3 (9%) were small cell (SCLC) and remaining non small cell lung carcinomas. A total of 287 chemotherapy cycles (148 in first line, 97 in second line and 42 in third line) were administered under distant supervision. Of these, 8 cycles were neoadjuvant, 15 cycles in adjuvant and 254 cycles in palliative setting. One patient of SCLC had emergency chemotherapy initiated via Teleoncology. Carboplatin(C) and Gemcitabine(G) was the commonest regimen (72 cycles 25%) followed by Pemetrexate (66 cycles 23%) and C and Paclitaxel (56 cycles 19%). Other types of regimen administered were Cisplatin (Cis) and G, C and Etoposide (Eto), Cis and Vinorelbine (Vnb), and single agent Docetaxel, Gem, Vnb, Eto, C and Erlotinib. Commonest toxicities were fatigue, neuropathy, thrombocytopenia and anaemia. Grade 3-4 toxicity requiring dose reduction was 4% in first line, 32% in second line and 58% in third line setting. Accounting for dose reductions based on toxicity, anticipated chemotherapy dose intensity could be maintained in 261 cycles (91%). There were 7 episodes of inpatient admission at Mount Isa (3 febrile neutropenia and 2 each pulmonary embolism and recurrent pleural effusion), all supervised via Teleoncology from Townsville. 29 of these 33 patients had all of their chemotherapy treatment at Mount Isa without travelling to Townsville. Only 3 patients needed to travel to Townsville during palliative treatment, two for brain radiotherapy and one for VATS pleurodesis.

Conclusion
Teleoncology is a novel model of care for rural lung cancer patients. Using this model, standard chemotherapy for lung cancer can be safely administered with expected dose intensity. The feasibility and safety results from this study are comparable to published literature in lung cancer. Use of teleoncology has the potential to overcome the barrier of travel time associated with long distances and possibly improve outcome for rural lung cancer patients.

Background
Pulmonary papillary adenoma is an extremely rare tumor and considered to be benign although its malignancy potentiality is not completely understood. It is usually asymptomatic and detected incidentally as peripheral lesions in chest radiography. It originates from type II pneumocytes. The largest mass of 20 cases which has been reported in English literature was 3 cm in diameter. The diameter of the tumor of our case was 4 cm. We present our postoperatively diagnosed papillary adenoma case due to its rarity and central location.

Methods
Twenty-one year old male patient was admitted with a round mass lesion with regular margins was observed on the right side of his chest radiography. This 4 cm diameter mass in the right upper lobe closed to bronchus has been observed in thorax computed tomography. Any endobronchial lesion could be detected with bronchoscopy.

Results
Right thoracotomy was performed. The solid mass was enucleated and capitonnage was performed. The patient being discharged on the 7th postoperative day is being followed for 8 months.

Conclusion
Our case is a centrally localized pulmonary papillary adenoma although most of the cases presented in the literature are peripheral. This case should be considered in the differential diagnosis of solid pulmonary masses. The recommended treatment for this mass is surgically removal of the mass because of its malignancy potentiality.

Background
Patients with advanced lung cancer have been reported to be at high risk for venous thromboembolism (VTE). In patients with cancer, a rate of unexpected pulmonary embolism (UPE) of about 1.5% has been reported.The aim of the study was to determine the prevalence of UPE in patients with stage IIIB or IV NSCLC or extensive SCLC who underwent CT scans for cancer staging.

Methods
We reviewed the contrast-enhanced CT scans of the chest performed for routine cancer staging in consecutive patients with advanced lung cancer (stage IIIB or IV NSCLC or extensive SCLC) referred to the Division of Medical Oncology at the hospital of Perugia between 2008 and 2012. All CT scans were reviewed by an ad hoc panel composed by 3 radiologists. PE was defined as unexpected when a filling defect in central, lobar, segmental or sub-segmental pulmonary arteries was observed in absence of clinical suspicion of PE.

Results
Overall, 223 patients were included in the analysis: 180 patients with stage IV-NSCLC, 24 patients with stage IIIB-NSCLC, and 19 patients with extensive SCLC. A total of 899 CT scans were reviewed. The prevalence of UPE was 19.7% (44/223): 34 (77.3%) in patients with stage IV-NSCLC, 7 (15.9%) in patients with stage IIIB-NSCLC, and 3 (6.8%) in patients with advanced SCLC. Patients with UPE were 26 males and 18 females and had a mean age of 58 years (range 24-78). UPE was monolateral in 30 patients and bilateral in 14 patients. UPE involved central pulmonary arteries in 6 patients, lobar arteries in 16 patients and segmental arteries in 19 patients. 3 patients had an isolated sub-segmental UPE. The mean time between cancer diagnosis and UPE was 11.8 months. 27% of cancer patients with UPE had the positive CT scan at diagnosis and 50% within 3 months. A recurrence of UPE was observed in one patient.

Conclusion
Patients with stage IIIB or IV NSCLC or extensive SCLC have a high rate of UPE at CT scan performed for cancer staging. UPE was bilateral in about one third of patients. A minority of UPE involved isolated sub-segmental arteries.

Background
The American Society of Clinical Oncology issued a Provisional Clinical Opinion on the integration of palliative care (PC) with anti-cancer care which states, “Based upon strong evidence from a phase III RCT, patients with metastatic non-small-cell lung cancer should be offered concurrent palliative care and standard oncologic care at time of initial diagnosis.” There is both a national shortage of PC providers, as well as a lack of guidelines on the best operational ways to integrate PC into oncologic care. Here we describe different models of palliative care integration into anti-cancer care models performed at the Stanford Cancer Institute.

Methods
Three methods of PC integration into oncology care at Stanford Hospital and Clinics, a tertiary medical center, are being tested. These include a low resource model using a social work (SW) only intervention for advance care planning and goals of care, as well as two high resource models using an MD, advance nurse practitioner, and social worker. The first high resource model is concurrent care with joint PC and oncology visits, and the second is a traditional model of separate PC and oncology visits. Observations around successes and barriers within these various models, as well as resources needed, will be described. Data evaluated include volume, referral patterns, advance care planning, symptom assessment, and resource utilization.

Results
The SW only intervention was run as a pilot in thoracic oncology. Resources required for appropriate implementation included information technology (IT) for appropriate cohort identification, operations support, data management support, and team cooperation from the physician and nursing team. Process outcomes measured included % of patients seen by SW within 3 visits, documentation of advance care planning within the medical record, and co-signature of advance care planning documentation by the physician. The joint visit model utilized a high resource team (physician, nurse practitioner, and social worker) which was present concurrently with the oncology visit for advance care planning and symptom management. In addition to the resources required for the SW only intervention, this model also included a care coordinator for visit coordination. Process outcomes measured included lead time to arrange for the joint visit and documentation of advance care planning. End outcomes included discharge to hospice, hospital utilization patterns, and effective symptom management. Other outcomes included volume and number of referring providers. Our third model was a traditional clinic visit with the PC team only, not coordinated with the oncology team. Resources and outcomes were the same as for the joint visit model. A total of 529 consults were seen in the first year. 61% were seen in a traditional clinic model and 39% were seen in the concurrent model. Volume of consults have increased over time. There were 10 consults per month in January of 2012. Currently over 100 consults are seen per month.

Conclusion
Appropriate integration of PC into oncology care for thoracic oncology patients is still under investigation. Here we describe the strengths and weaknesses of three separate models of integration of PC with oncology care at an academic medical center.

Background
Distant metastases of MPM to the skeletal muscle, endocardium and skin have not been reported previously.

Methods
A 75 year-old male admitted to our pulmonary diseases clinic with chest and lower limb pain. He was a heavy smoker and exposed to asbestos in his childhood. Respiratory system was normal in physical examination. The thigh muscles were observed to be thick and hard and palpation was painful. There were few nodular lesions on the scalp which he reported to appear 2 months ago as well as the accompanying femoral thickening.

Results
Chest X-ray showed upper mediastinal enlargement and a mass in left superior lobe. Thorax CT revealed a pleural mass in the left apical region, left hilar lymphadenopathy and pleural thickening. Pathological FDG uptakes were observed over the right paraspinal muscle (C6), posterior scalp, paratracheal and left hilar lymp nodes, left apical mass, left pleura in lower and middle zone, left diaphragma, anterior pericardium, interventricular septum, left axilla, right 4. costochondral region, liver segment 8, right paraspinal muscle in L3 level, right abdominal oblic muscles, bilateral gluteal muscles and bilateral muscles in femoral region. Tru-cut biopsy was performed from the left apical mass and the diagnose was epitheloid type malignant pleural mesothelioma. A second biopsy was performed from anterior thigh muscles. The morphologic pattern was the same with the biopsy taken from lungs

Conclusion
Metastases of a MPM are very rare. We are presenting this case for the skeletal muscle metastasis defined for the first time.

Background
Angiosarcomas (AS) are rare aggressive tumors that represent about 1-2% of all soft-tissue sarcomas; 9.5% of them arise in the thorax. We describe five patients diagnosed with thoracic AS who were treated at ICESP.

Methods
It is a case series descriptive study with review of the medical files from five consecutively registered patients with AS confirmed by immunohistochemistry at our institution between June 2010 and March 2013.

Results
Case 1: A 49-year-old woman was admitted with pulmonary AS presenting progressive dyspnea and a recent hemoptysis. Pneumonectomy was performed in April 2011 and she was treated with adjuvant doxorubicin (every 3 weeks, 4 cycles) and paclitaxel (12 weeks). After 7 months, she developed progressive disease (PD) in liver, bones and lymph nodes. Weekly paclitaxel was restarted, but she had hepatic PD. Since May 2013 she has been treated with liposomal doxorubicin. She is alive after 26 months of diagnosis. Case 2: A 62-year-old woman was diagnosed with metastatic paracardiac AS after cardiac tamponade. She was treated with weekly paclitaxel and developed PD in liver and lungs. She died 3 months after diagnosis. Case 3: A 32-year-old man, was diagnosed with a primary AS in the right ventricle, metastatic to lungs, was admitted with recurrent pericardial effusion for 6 months. The tumor was considered unresectable and he was treated with doxorubicin and ifosfamide (only one cycle), temporarily interrupted due to febrile neutropenia grade 4, but with a partial response. He is alive after 3 months of diagnosis. Case 4: A 31-year-old man was diagnosed with unresectable AS in the right atrium after developing a superior vena cava syndrome. Weekly paclitaxel was started, with initial clinical improvement, but PD was detected after 6 cycles (24 weeks). As a second-line treatment, doxorubicin and ifosfamide were administered, with PD in lungs after 5 cycles. He died 13 months after the beginning of chemotherapy. Case 5: A 58-year-old woman was diagnosed with a right infraclavicular unresectable AS with local pain and edema in the upper right arm for one year. No response was seen after two cycles of doxorubicin and ifosfamide. Palliative radiotherapy followed by weekly paclitaxel was attempted as a second-line therapy with no response. Best supportive care was started and she is alive 6 months after diagnosis.

Conclusion
We concluded that thoracic AS presents a very dismal prognosis, due to the primary location and the high incidence of metastatic disease. For those patients with resectable disease and curative intent, surgery must always be considered. Weekly paclitaxel and the combination of doxorubicin and ifosfamide are both active in thoracic AS, but responses usually were not long-lasting. Oral tyrosine kinase inhibitors with antiangiogenic properties may be an option to be better explored.

Background
not applicable

Methods
Figure 1 This patient is a 50-year-old Hispanic woman who had been diagnosed with idiopathic edema of the right upper extremity and chest wall which progressed gradually over the last 8 years. Over the last year and-a-half, she has developed dyspnea on exertion with occasional cough. She has occasional right chest wall discomfort, but no abdominal pain. She has arm and back pain from the massive swelling. She has no GI complaints with the exception of nausea after meals. She has no lower extremity edema, no fever, chills or sweats. During our evaluation she was found to have massive right-sided pleural effusion.

Results
Figure 1 Biopsies of the pleura , soft tissues, and skin showed a myxoid mesenchymal neoplasm. Brain MRI showed no intracranial or meningeal masses. Her pleural fluid was most consistent with exudate. Cultures and cytology was negative. Glucose in the pleural fluid was not decreased. Triglycerides in the pleural fluid were 21 mg/dL.

Conclusion
This is an unsual case of a soft tissue sarcoma with significant swelling of the entire arm and ipsilateral chest with metastasis to the pleura. She had previously been diagnosed with idiopathic lymphededma and treated for that for years. The swelling was likely not due to lymphatic obstruction but rather due to slow progressive growth of the myxoid mesenchymal neoplasm. Earlier definitive diagnosis could have led to potential surgical resection, but with the massive involvement of her entire right arm, and ispilateral hemithorax, supportive care and systemic chemotherapy are the only treatment options.

Background
Lung cancer is the main cause of cancer death in men and women in Australia. Cure can be achieved by identifying patients with early (i.e. stage I and II) disease, treating them with surgery or radical radiotherapy. Despite this, the 5 year survival for stage I and II patients is reported at 60%. We looked at the cause of death in patients treated with curative intent over a 2 year period.

Methods
Local clinical practice information was collected in a prospective database. Cases presented at a multidisciplinary lung cancer meeting over a 24 month period (April 2006 -March 2008) were analysed. Patients with early stage NSCLC (stage I and stage II) based on the 6[th] edition IASLC TNM classification were identified (n=62). Treatment data was obtained for all identified cases (n=62/62) via hospital records. Cause of Death was determined via the death certificate as submitted to the Registry of Births, Deaths and Marriages.

Results
Five year survival was 25% (16/62) for early stage NSCLC. Cause of death of obtained for all but 3 patients (43/46). 74% (46/62) of patients received treatment with curative intent, 37% (23/62) surgery and 20% (13/62) radical radiotherapy. Of all patients who underwent radical treatment, lung cancer was the primary cause of death in 16% (10/46). Respiratory conditions were the second most common cause of death with 13% (6/46) attributed. The main cause was reported as pneumonia in 7 patients, COPD, IPF and Respiratory failure being others. The loss of lung from surgery or radiotherapy could be hypothesised to be a factor in these deaths due to reduce lung volume. Cardiac disease was the cause of death in 5 patients and 3 patients died due to bladder cancer, both diseases strongly associated with smoking. 1 patient died due to colonic cancer and 1 due to vascular dementia. Patients who underwent surgical resection had lower mortality rates than those who underwent radiotherapy with a 5 year survival in the surgical cohort of 60% (14/23) vs 7% (1/13) in the radical radiotherapy cohort as well as lower rates of lung cancer related death 17% (4/23) vs 46% (6/13).

Conclusion
Mortality in early stage lung cancer remains high in our cohort with recurrence of the lung cancer being the main cause of death. All patients were staged with PETCT prior to treatment. Diseases strongly associated with smoking were a common cause of disease as may be expected. Patients with radical therapy presenting with pneumonia are at high risk of death.

Background
Lung cancer is the leading cause of cancer death despite the improvement of therapeutics.Most patients (pts) present with advanced disease when first diagnosed. Erlotinib is an inhibitor of the epidermal growth factor receptor (EGFR) that is standardtreatment for non-small cell lung cancer (NSCLC) after failure of previous chemotherapy and 1[st] line in EGFR mutated pts. There are few data on toxicity observed in clinical practice described in the literature.

Methods
Retrospective study of all consecutive patients with advanced NSCLC treated with erlotinib in our department from October 2005 to November 2012.Primaryendpoint was to evaluate thetoxicity, secondary endpoint was to evaluate time to progression and survival. Data were obtained from clinical files and namely:demographics, histology, performance status (ECOG), stage and toxicity according to common terminology criteria for adverse events (CTCAE) version 4.

Results
From the 194pts treated with erlotinib, 111 pts (57%) were male and 83(43%) female, with a median age of 62 years (range 28-92); 37(19%) pts were former smokers, 87(45%) smokers and 70(36%) non-smokers. Histology was adenocarcinoma in 146 (75%) pts, squamous-cell in 25 (13%) and NSCLC-NOS in 23 (12%). Mutation: 21(11%) pts were EGFR mutated. Staging at the diagnosis: III in 71(37%) pts and IV 123(63%) pts. Before erlotinib 93(48%) pts had one line-chemotherapy, 79(41%) two-lines and 3 more than two-lines. Most commons used regimens were platin-based. Skin toxicity was observed in 85 pts (20 pts G2/3 toxicity) and gastro-intestinal toxicity in 21pts, 9 pts with G2/3 toxicity; 4 stop treatment due to toxicity (2 pts due to gastro-intestinal, 2 due to cutaneous). There were no treatment-related deaths or hospitalization. Complete/partial response was observed in 19(9.8%) pts, stable disease in 51 pts. The median TTP and survival after erlotinib treatment were 2.6 months, range (0.2-61) and 5 months range (0.7-160), respectively (CI 95%) with a median follow-up 6 months, (1- 61). Mutated pts had a longer TTP 9,4 month (6.6-12.2) than non-mutated 2,5 months(2,1-2,9),p< 0,001. Pts with cutaneous toxicity had a better TTP 2 months vs 4.2 months (p< 0.001) and survival 3,9months vs 9.4 months (p<0.001).

Conclusion
Although in our data there were no death related-treatments, the toxicity observed was highercomparing tothe literature. The efficacy results were similar. Cutaneous toxicity was positively correlated with better outcomes namely TTP and survival.

Background
Increasingly, neoadjuvant therapy is being used for the treatment of NSCLC. While several randomized controlled trials have been performed to evaluate this approach in patients with N2 disease, limited data exists in patients less than N2 disease. We examined our experience with neoadjuvant therapy in our institution and compared it to patients receiving adjuvant therapy.

Methods
This retrospective analysis included patients with less than clinical N2 disease that underwent curative surgical resection and received either neoadjuvant or adjuvant chemotherapy with or without radiation therapy from 2005 to 2010. Patient characteristics, peri-operative outcomes and survival data were analyzed for patients receiving neoadjuvant vs. adjuvant therapy. Comparison of categorical, continuous and survival variables across groups were performed using chi-square, t-test and Kaplan-Meier methods respectively. Multivariate analyses were performed using Cox Regression analyses.

Results
130 patients fulfilled the inclusion criteria – 54 patients had neoadjuvant therapy and 76 patients had adjuvant therapy. Patient characteristics in both comparison groups are summarized in Table 1. No peri-operative deaths were seen in either group. There was no statistically significant difference between the comparison groups with respect to age, gender, race, histology and grade. Patients with neoadjuvant therapy had a higher clinical stage than those that had adjuvant therapy. At a median follow-up of 41.5 months, there was no difference in the overall survival and recurrence free survival of patients in both groups in univariate analyses and in multivariate analyses after adjusting for potentially confounding variables including stage. Patients treated with neoadjuvant therapy had a higher rate of empyema (11.1% vs. 0%; p=0.004) and a trend toward increased arrhythmia and pneumonia than those treated with adjuvant therapy.

Conclusion
For NSCLC less than N2 disease, neoadjuvant therapy increases peri-operative morbidity without an improvement in overall and recurrence free survival. For this patient population, the role of neo-adjuvant therapy is questionable. Figure 1Figure 2

Background
The National Lung Cancer Forum for Nurses (NLCFN) is a UK professional organization which has a membership of around 280 Lung Cancer Nurse Specialists (LCNS) who primarily with lung cancer patients. LCNSs are the multi-disciplinary team members who spend the most time with patients. Therefore they add a unique and valued contribution to the debate regarding research priorities in lung cancer. The NLCFN is committed to developing the evidence base to inform the effectiveness and quality of their clinical care. The NLCFN recognized a need to develop research skills and capacity amongst its membership and facilitate research collaborations between academics and practitioners. To this aim the NLCFN established a Research Interest Group (RIG) in 2009. This paper summarizes a research development project undertaken by the NLCFN to increase research utilisation and capacity in lung cancer nursing.

Methods
A structured approach was taken building on research into evidence utilisation in health. (Birdell et al, 2005, Tod et al 2004, Palfreyman et al 2003a/b). Research development activity focused on four key areas, roles and responsibilities, relevance, relationships and partnerships, and organisational culture.

Results
Over a four year period the NLCFN has successfully developed its research activity and the infrastructure to support subsequent growth. Roles: The RIG is chaired jointly by a Professor of Health Services Research and NLCFN Chair. All NLCFN members are encouraged to have a role by contributing to the critical discussion regarding evidence. However, a core group of research active members take responsibility to lead on research. The RIG has provided a mechanism for the NLCFN to liaise with key national lung cancer groups and committees regarding evidence for practice and new project development, for example a current national project exploring the contribution of lung nurse specialists to clinical trial recruitment. Research relevance is guided by an on-going research prioritisation exercise. Research partnerships have been developed through shared membership of the RIG between clinical and academic staff. The partnership has fostered five applications for research funding from a range of funding organisations, two of which have been successful, one is currently in review. Funded projects include an evaluation of the LCNS role in treatment access. Another is evaluating the use of support roles in lung multi-disciplinary teams. Current applications include an analysis of treatment and health outcomes using linked national data sources. In addition a new PhD studentship has been developed through a collaboration between the NLCFN and Sheffield Hallam University. Regular meetings, good communication, sharing of good practice and support provide a culture to allow research ideas to flourish.

Conclusion
In four years the NLCFN has made remarkable progress regarding research development and capacity building. By taking a structured and systematic approach the outcomes have been impressive. It has supported LCNSs to be a valued partner in research prioritisation and in generating evidence to support lung cancer practice at a local and National level. The foundations for research growth have been built and an infrastructure developed to enhance future nursing engagement in research at all levels from application to leadership.

Background
The development of molecular targeted therapies has provided many cancer patients with promising treatment options. Tyrosine kinase inhibitors (TKIs) are a group of biological molecules designed to block specific molecular targets within the cell. They are easily taken in tablet form but can have significant systemic side effects causing physical and psychological discomfort. The importance of preparing the patient before treatment starts, evaluating the toxicities carefully using various validated tools and implementing appropriate care is well recognised. This study aimed to examine the physical side effects and psychosocial experiences of patients with advanced lung cancer taking TKIs. By using the Medical Research Council (MRC) framework for developing and evaluating complex interventions, this study forms the first stage of data gathering to inform the design of subsequent research projects. The overall aim is to develop a more specific toxicity measurement tool. A grant was awarded from the National Lung Cancer Forum for Nurses Research Interest Group.

Methods
Clinical teams at 4 hospitals within the West Anglia Cancer Research Network approached patients with advanced lung cancer taking TKI therapy for 3 to 24 months. Written informed consent was taken prior to focus group meetings which were held in the comfort of a cancer support centre. Separate provision was made for carers. Conversation was captured using two digital recorders and transcribed verbatim. A topic guide shaped the conversation. Field notes were taken to describe the dynamics of the group. The transcripts were analysed using grounded theory techniques of constant comparison of the narrative, incorporating memos of the researchers thoughts during the recordings, and deviant case analysis. Data was analysed and coded independently by two researchers and the findings compared and discussed. The theories generated were validated by checking the findings against the original data demonstrating a systematic research process of rigour and transparency. Analysis was aided by the use of NVivo 10 software.

Results
Two focus groups including 3 and 4 patients respectively were conducted. Of the 7 participants 6 were female, average age 68 years (range 58 - 81 years). All were currently taking Gefitinib, average 13 months (range 5 - 23 months). Early analysis shows common themes emerging such as pragmatic acceptance about their situation, feelings of isolation, experiencing the inconsistency and variety of chronic physical toxicities, the necessity of self-management, the need for support and uncertainty about their future. Body image changes were a significant problem for females including hair and skin changes. It is clear from the data that there is an on-going and changing psychosocial and physical experience for the patient. The nature of this experience will be expanded upon with individual anonymous quotes.

Conclusion
The experience of taking TKI’s, over an indefinite period of time, for advanced lung cancer is complex. Using the MRC framework we aim to evaluate the themes identified, so assessing not only the quantitative physical toxicities of the treatment but also the qualitative issues, the provision of support and the patients’ understanding of the side effects and management of their treatment.

Background
Recently, early movement on bed was encouraged to promote gastrointestinal function recovery. However, due to old ages and weak physical strength, the effects remain limited.

Methods
We selected 40 old patients with lung tumors receiving surgeries between January 2009 and December 2010.The patient evenly randomly assigned them into regular nursing care group(RNC) and acupoint electric stimulation group(AES) group each with 20 cases. Patients in the RNC group received regular nursing care and patients in the AES group received regular nursing care plus electric stimulation on acupoints. We evaluated the serum concentration of gastrin(GAS), motilin(MOT), cholecystokinin(CCK) and electrogastrogram(EGG) on the first, third and fifth day after surgery. We also recorded the anal exhaust time and the number of cases with such gastrointestinal function disorders as abdominal pain, abdominal distention and diarrhea.

Results
Comparison between two groups in GAS, MOT, EGG, the anal exhaust time, abdominal pain, abdominal distention and diarrhea showed significant statistical difference(P<0.05).

Conclusion
Electric stimulation on acupoints could increase postoperative GAS, MOT levels, promote recovery of gastrointestinal functions and decrease complications among senile patients with lung tumors.

Abstract not provided

Background
Pemetrexed combined with cisplatin is an approved first-line treatment regimen for patients with advanced/metastatic nonsquamous non-small cell lung cancer (NSCLC). New targets are needed to further improve first-line therapy outcomes. Cixutumumab, a fully human IgG1 monoclonal antibody, specifically blocks the insulin-like growth factor-type 1 receptor, inhibiting its activation and signal transduction. Early studies have reported clinical efficacy and safety with cixutumumab. However, the clinical benefit of adding cixutumumab to conventional chemotherapy is yet to be established. This study assessed whether pemetrexed and cisplatin combined with cixutumumab was superior to pemetrexed and cisplatin as first-line therapy.

Methods
This open-label, multicenter, randomized, phase II study (N=172) enrolled patients ≥18 years of age with stage IV nonsquamous NSCLC and ECOG performance status 0–1. Patients were randomized (1:1) to receive cixutumumab 20 mg/kg combined with pemetrexed 500 mg/m[2] and cisplatin 75 mg/m[2] (cixutumumab arm; n=87) or pemetrexed and cisplatin (control arm; n=85) every 21 days up to 6 cycles of induction therapy. Patients eligible for maintenance therapy received pemetrexed and cixutumumab (cixutumumab arm) or pemetrexed (control arm). The primary endpoint was progression-free survival (PFS) based on radiographic assessments. To test for superiority (1-sided significance level 20%; study power 80%), a median PFS of 7.16 months in the cixutumumab arm (HR cixutumumab/control=0.74) was expected. Secondary endpoints included objective response rate (ORR), duration of response, and overall survival (OS). Adverse events (AEs) were assessed using CTCAE version 4.0. Between-arm comparisons of unstratified data are presented.

Results
Baseline patient and disease characteristics were similar between arms in the intent-to-treat population. The mean age of the population was 59 years (range, 32 to 83). Dose intensity for all treatments was ≥90% during both study phases. Median PFS was 5.45 months (95% CI, 3.88–6.05) vs. 5.22 months (95% CI, 4.24–6.74) in the cixutumumab and control arms, respectively (HR 1.15, 95% CI, 0.81–1.61; P=0.440). ORR did not significantly differ between treatments (37.9% cixutumumab vs. 30.6% control; P=0.338); however, the median duration of response was numerically greater in the cixutumumab arm (4.9 months; 95% CI, 4.17–6.28) than in the control arm (3.91 months; 95% CI, 2.92–6.41), although differences were not significant (HR 0.74, 95% CI, 0.40–1.38; P=0.340). Median OS was 10.68 months (95% CI, 8.74–not evaluable) in cixutumumab vs. 10.38 months (95% CI, 7.43–14.39) in control patients (HR 0.85, 95% CI, 0.56–1.30; P=0.450). Common AEs reported in ≥10% of patients were nausea, hyperglycemia, fatigue, vomiting, and anemia. A greater proportion of patients in the cixutumumab arm (74.1%) had grade 3/4 AEs than patients in the control arm (61.7%). Grade 3/4 hyperglycemia occurred at a higher rate in the cixutumumab arm than the control arm (11.8% vs. 1.2%). One possibly cixutumumab-related death occurred during the study.

Conclusion
Superior PFS was not achieved in nonsquamous NSCLC patients when cixutumumab was added to the pemetrexed and cisplatin treatment regimen, and no significant improvement for any other endpoint was observed. Pemetrexed combined with cisplatin and cixutumumab was tolerable, with no new safety concerns reported.

Background
Smoothened (SMO) is a 7-membrane spanning receptor involved in the hedgehog signaling pathway. In the absence of Patched inhibition, SMO accumulates and inhibits proteolytic cleavage of transcription factors. We previously identified a lung cancer patient with SMO mutation (Patient A, Table 1) and successfully treated him with erivedge, a hedgehog inhibitor. We therefore sought to determine the incidence of SMO mutations in The Cancer Genome Atlas (TCGA) lung cohorts, identify additional NSCLC patients with SMO mutations, and initiate therapy with hedgehog inhibition as proof-of-concept.

Methods
TCGA databases for lung adenocarcinoma (n=230) and squamous cell carcinoma (n=178) were interrogated for SMO mutations and hedgehog pathway dyregulation. Mutations were determined by whole exome sequencing. Copy number was assessed by GISTIC 2.0 (scores of 2 considered high level amplification). The lung SMO mutation patients were undergoing treatment at M.D. Anderson Cancer Center Thoracic Clinic for metastatic/refractory disease. Mutations in hotspot regions of 46 cancer-related genes including SMO was performed as part of their clinical diagnostic evaluation (Ion AmpliSeq Cancer Panel; Life Technologies, CA).

Results
In TCGA lung adenocarcinomas, alterations in SMO (mutation, amplification, mRNA overexpression) were observed in 12.2% of tumors. The incidence of SMO mutations was 2.6% and SMO gene amplifications 5%. SMO mutations and amplifications strongly correlated with sonic hedgehog gene dysregulation (p<0.0001). In TCGA squamous cell, SMO was altered in 10.1% of tumors, primarily via mRNA upregulation. Only 1 SMO missense mutation was identified in the Lung SCC cohort (D209Y). We identified 3 NSCLC patients with SMO mutations (Table 1) by the 46-gene panel. Patient A was treated with erivedge as he had a concomitant localized basal cell carcinoma (BCC) with a significant reduction in tumor burden. He continues to respond to therapy after 14 weeks. It is possible that Patient A’s NSCLC-SCC was misidentified and that this was metastatic BCC or that this is a germline variant. Germ-line mutation analysis is underway. However, the precise SMO mutation in Patient A was also identified in a lung adenocarcinoma Patient C (Table 1). Two additional SMO-mutated patients have just initiated erivedge and updates on their status will be provided at WLCC.

Table 1

Patient	Biopsy site	SMO mutation	Reported Histology	Duration of Erivedge Therapy	Response to Erivedge
A	Lung	Codon 641, exon 11 (CCT to GCT) p. Pro641Ala	NSCLC SCC	14 weeks	PR
A	Skin lesion	Codon 641, exon 11 (CCT to GCT) p. Pro641Ala	BCC	14 weeks	CR
B	AP window lymph node	Codon 525, exon 9 (ATG to TTG) p.Met525Leu	NSCLC Adenoca	pending	pending
C	Axillary lymph node	Codon 641, exon 11 (CCT to GCT) p.Pro241Ala	NSCLC Adenoca	pending	pending

Conclusion
SMO mutations and pathway alterations occur in NSCLC and may be an actionable target with hedgehog inhibitors; a clinical trial is under development. Screening lung SCC tumors for SMO mutations is recommended to prevent misdiagnosis of metastatic BCC. Additional analysis of hedgehog signaling pathway alterations is underway and will subsequently be reported.

Background
MARQUEE, a Phase 3 study which investigated the role of tivantinib, a c-MET inhibitor, in previously treated non-squamous NSCLC, collected EGFR and KRAS genotype on >90% of randomized patients, and MET expression was determined for 42%. In the ITT population, addition of tivantinib to erlotinib significantly improved PFS and ORR but did not show benefit in OS. Additional efficacy analyses in the pre-defined molecular subgroups are presented.

Methods
Patients with locally advanced or metastatic non-squamous, EGFR inhibitor naive NSCLC previously treated with 1 or 2 lines of systemic therapy, including a platinum-doublet, were stratified by number of prior therapies, sex, smoking history, and EGFR and KRAS mutation status, then randomized to oral tivantinib (360 mg twice daily) + erlotinib (150 mg once daily) or placebo + erlotinib until disease progression. Primary endpoint was OS with one interim analysis for futility/superiority. MET was assessed centrally by IHC using CONFIRM (SP44) antibody. Based upon a stability study, tumor tissue must have been sectioned within 90 days prior to MET immunostaining to be considered reliable. MET High was pre-specified as ≥50% of tumor cells staining with 2+ or 3+ intensity.

Results
From 1/2011 to 7/2012, 1048 patients were randomized to tivantinib + erlotinib (TE, n=526) or placebo + erlotinib (PE, n=522). Baseline characteristics were median age = 62 years (range, 24-89), prior therapies = 1 (66%) or 2 (34%), ECOG performance status = 0 (32%) or 1 (68%), EGFR mutant (10.4%), and KRAS mutant (27.1%). In 9/2012, the data monitoring committee recommended trial discontinuation because the pre-planned interim analysis of OS crossed the futility boundary. At the 12/2012 data cutoff, median OS was 8.5 months and 7.8 months for TE and PE, respectively (hazard ratio [HR] = 0.98; 95% CI, 0.84-1.15; p = 0.81). Median PFS was 3.6 months and 1.9 months, respectively (HR = 0.74; 95% CI, 0.62-0.89; p < 0.0001). Overall response rate (ORR) improved to 10.3% for TE compared with 6.5% for PE (p < 0.05). MET expression was obtained for 445 patients. In the pre-specified, MET High subgroup (n = 211), median OS improved to 9.3 months for TE vs 5.9 months for PE (HR = 0.70; 95% CI, 0.49-1.01; p = 0.03). In the MET Low subgroup (n = 234), median OS was 8.5 months for TE and 7.7 months for PE (HR=.90, 95% CI, 0.64-1.26, p=.53). OS did not differ between treatments in KRAS wildtype (n=702), KRAS mutant (n=284), and EGFR wildtype (n=937) subgroups; OS was immature for the EGFR mutant (n=109) subgroup at the cut-off time. Consistent with ITT, PFS was increased with TE vs PE across all molecular subgroups. Common adverse events (TE vs PE, respectively) included rash (33.1% vs 37.3%), diarrhea (34.6% vs 41.0%), and asthenia/fatigue (43.5% vs 38.1%), which occurred at similar rates between treatments; neutropenia (Grade 3/4: 10.0% vs 1.0%) was more common with TE.

Conclusion
Tivantinib significantly improved PFS and OS in the prospectively defined MET High subgroup. Further investigation of tivantinib in MET High selected, non-squamous NSCLC is warranted.

Background
Immunotherapy is now accepted as the fourth most important modality for malignant tumours, and is currently being applied in the treatment of non-small cell lung cancer (NSCLC). CD1d, a MHC class-like molecule, presents glycolipids to natural killer T (NKT) cells. In doing so, CD1D contributes to their anti-tumour activity. CD1d is expressed in certain tumour types, and there is increasing evidence that CD1d acts as a target for NKT-mediated cell killing, however most human and mouse solid tumours are CD1d-negative. Recently evidence has indicated that CD1d expression is epigenetically regulated through HDAC1/2 and Spl.

Methods
CD1d levels were examined at the mRNA level by RT-PCR. To determine whether CD1d expression is subject to epigenetic regulation, non-small cell lung cancer (NSCLC) cell lines were treated with various epigenetic modifying agents. The A549 (adenocarcinoma) and SK-MES-1 (Squamous cell carcinoma) cell lines were treated with HDACi, (a) SAHA at a dose of 5 µM for 24 h. Treatments with other epigenetic modifyng agents such as trichostatin A (TSA) and DNA methyltransferase inhibitors are currenly ongoing. iNKT cells were co-cultured wiht NSCLC cells to examine their antitumourigenic activity using a CD107a externalised assay.

Results
Using RT-PCR it was possible to confirm that SAHA significantly induced CD1d expression in both A549 and SKMES cell lines (p ≤ <0.005). RT-PCR was also performed on A549 and SKMES cell lines that had been allowed to recover, following treatment with SAHA. A549 cells showed a statistically significant induction in recovered SAHA-treated cells (p < 0.05). Using flow cytometry the cytotoxic T-lymphocytes (CTL) activity of iNKTs was measured. While there was a slight induction of CD107a-bearing iNKT cells, it is believed that treatment with HDACi will increase the anti-tumour activity of these cells. This work is ongoing at present.

Conclusion
CD1d expression is significantly induced using the HDACi, SAHA. This induction is present in A549 cells treated with SAHA and allowed to recover; indicating that SAHA may possibly be used to increase the anti-tumourigenic activity of iNKT cells. These results may have important consequences for treating patients with combined epigenetic targeting agents and immunotherapy.

Background
The elderly have less-robust immune responses to infections, immunizations, and tumors, compared with younger people. Furthermore, preclinical studies have indicated that immunotherapeutic interventions are less effective in older animals. Considering the effects of age-associated changes in immune function, most clinical trials of cancer-related immunotherapy have been conducted in relatively young patients. With the increasing focus on immunotherapy for non-small cell lung cancer (NSCLC), we investigated the relationship between patient age and tumor immune parameters in stage I NSCLC.

Methods
Tissue microarrays from patients with stage I NSCLC (n=1371; 1995-2009; median follow-up, 3.5 years) were constructed, and immunohistochemical analyses for immune cell infiltration (CD3, CD4, CD8, CD20, FoxP3) were performed. Patients were categorized into 3 groups: (1) ≤65 years old, (2) 66-79 years old, and (3) ≥80 years old. Stains were analyzed for immune cell infiltration (low vs high) in the tumor nest. The Chi-Square test was used to analyze the association between immune parameters and age group. The Kaplan-Meier method was used to estimate recurrence-free survival (RFS).

Results
In total, 1116 patients with stage I lung adenocarcinoma and 255 patients with stage I squamous cell carcinoma were enrolled. Patients aged ≥80 years did not have a significantly poorer prognosis (n=155; 5-year RFS, 76.0%) than the patients in the two younger groups (p=0.65; Figure 1A). There were no statistically significant differences in numbers of tumor-infiltrating lymphocytes in the tumor nest between the three groups (Figure 1B), nor was there a statistically significant difference between the elderly group and the younger patients when effector regulatory immune response ratios were compared (FoxP3/CD3 ratio; high vs low, p=0.85). Figure 1

Conclusion
In this large cohort of stage I NSCLC patients selected for surgical resection, the tumor microenvironment among elderly patients resembles other age groups. Our study provides important information while considering immunotherapy in elderly patients with lung cancer.

Background
EGFR tyrosine kinase inhibitors (TKIs) have an important role in the treatment of NSCLC, particularly in the context of activating mutations, but resistance invariably develops. Recently, the immune checkpoint blockers anti-PD1 and anti-PDL1 were the first immunotherapies to demonstrate activity in advanced lung cancer. As immunotherapies such as anti-CTLA4, anti-PD1 and anti-PD-L1 antibodies enter clinical practice, there is potential to combine immunotherapies with TKIs to improve patient outcomes. The immune effects of EGFR-TKIs have not been elucidated, and the aim of this study is to examine the effect of TKIs on the immune response in patients with NSCLC, to provide a rationale and pilot data to underpin future clinical development of combinations of TKIs and immunotherapy.

Methods
Patients with advanced NSCLC who were commencing an EGFR-TKI were included in this prospective study. Eligible patients had a confirmed diagnosis of NSCLC, were treated with a single-agent EGFR-TKI , had no concurrent autoimmune disease and received no chemotherapy within 21 days, or corticosteroid therapy within 3 days of study entry. Peripheral blood samples were collected before commencing a TKI and 7 days, 21 days and 8 weeks after start of treatment. Peripheral blood mononuclear cells (PBMCs) were isolated and immediately frozen for subsequent analysis by 8-colour flow cytometry for relevant surface and intracellular marker expression. 4 panels were developed to examine the activation and proliferation status of effector CD8[+] T and CD4[+] T-regulatory cells (Tregs), enumeration of dendritic cells and B-cells, as well as the inhibitory pathway programmed death-1 (PD-1) receptor and its ligands PD-L1 and PD-L2 on T cells and antigen-presenting cells. Changes in immune parameters will be correlated with overall survival (OS) and radiological response (RECIST 1.1 criteria) at 8 weeks post-treatment.

Results
33 eligible patients were prospectively enrolled. Histopathology was adenocarcinoma (n=23), squamous cell carcinoma (n=7) and NSCLC not otherwise specified (NOS, n=3)). 12 patients had an activating EGFR mutation, 11 were EGFR wild type, and mutation-status was unknown in 10. 6 patients received the TKI gefitinib and 4 received erlotinib as first-line treatment for EGFR-mutation positive disease. 22 patients received erlotinib and 1 patient received afatinib as second or subsequent line therapy. At time of this report, 22/33 patients were deceased. Median OS from study entry was: all patients (7.7 months); mutation-positive (11.1 months); and mutation negative (4.4 months). Samples for 13 patients (2 were mutation-positive) have been analysed for effector T cell and Treg panels and no significant changes were seen between baseline and subsequent time points. Data will be presented for all samples.

Conclusion
This is the first study to explore to the immune effects of EGFR-TKIs. Initial results have not revealed a significant effect on peripheral T-cells, and analysis of remaining patient samples and other panels is in progress. An understanding of the immune effects of targeted therapies will be crucial in the rational development of strategies for incorporating immunotherapy into the anti-EGFR treatment paradigm, in an era of promising immunotherapy and checkpoint blockade approaches.

Abstract not provided

Background
EGFR-tyrosine kinase inhibitor Gefitinib interrupts signaling through the EGFR in non-small-cell lung cancer (NSCLC) cells with EGFR driver mutation and has shown impressive activity in terms of clinical benefit for patients with NSCLC, however, almost all patients develop resistance to this drug. Although much research is focusing on the mechanisms of drug resistance in tumor cell, the role of EGFR signaling in tumor escape from the host immune system is poorly understood. NK cell activity is promoted via NK group 2, member D (NKG2D) on NK cells. The engagement between NKG2D and its ligands enhances cell-mediated cytotoxicity and cytokine production against transformed cells. Both MHC class I-related chain A and B (MICA/B) and UL16 binding protein (ULBP)s are expressed by intestinal epithelial and at low levels also by other non-malignant cell types. Primary tumor cells and tumor cell lines frequently express NKG2D ligands, but the mechanisms responsible for the induction of NKG2D ligands during oncogenesis are also poorly understood. Here we demonstrate Gefitinib downregulates NK group 2 member D (NKG2D) ligand MICA/B and ULBPs, resulting in attenuation of NK cell-mediated cytotoxicity in NSCLC cells.

Methods
Possible influences of Gefitinib on expressions of MHC class I, MICA/B and ULBP1-3 in 5 NSCLC cell lines (A549, PC-9, RERF-LC-KJ, RERF-LC-AI, and LC2/ad) were investigated by flow cytometry. We also assessed whether genetic silencing of EGFR using siRNA of EGFR affected on the expression of NKG2D ligands. To ask the main downstream pathway of EGFR regulating the expression of NKG2D ligands, the cells were treated with PI3K-AKT inhibitor LY294002 or MEK inhibitor PD98059 then the expression of NKG2D ligands was analyzed. NK cell-mediated cytotoxicity against cancer cells was assessed by [51]Cr release assay or flow cytometry based CD107a degranulation assay.

Results
Gefitinib downregulated NKG2D ligands in NSCLC cell lines. In line with these results, siRNA-mediated silencing of EGFR downregulated the expression of NKG2D ligand. Among the major downstream pathways activated by EGFR signaling, the expression of NKG2D ligands was mainly regulated by the PI3K-AKT pathway. Treatment with EGF promoted MICA/B expression in 2 of 5 cell lines, while EGF decreased MICA/B in 1 of 5 cell lines. These observations further emphasize that EGFR signaling is one of the major pathways regulating the expression of NKG2D ligands in NSCLC cells. As expected, inhibition of EGFR signaling-downregulated NKG2D ligands attenuated NK cell-mediated cytotoxicity.

Conclusion
We conclude that EGFR signaling directly regulates the expression of NKG2D ligands and that this may influence the recognition of tumor cells by the innate immune system.

Background
Identifying key molecules in the pathobiology of malignant mesothelioma is needed to develop new therapies and biomarkers. Fibroblast growth factor-9 (FGF-9) is an exciting and novel target uncovered from our global gene profiling of human MPM samples. Recently FGF-9 has been implicated in cancer development and neoplastic transformation of embryonic fibroblasts. We have verified over-expression of FGF-9 in MPM over other cancers and benign pleuritis in five separate cohorts of human pleural tissues and effusions. Our preliminary in vitro work demonstrated that FGF-9 induces mesothelioma cell proliferation and matrix invasion. We therefore hypothesised that antagonising FGF-9 may reduce tumour aggressiveness, growth and induce tumour regression in vivo.

Methods
To study the ‘necessity’ of FGF-9 in MPM development in vivo we transfected the mouse MM cell line, AB1, with shRNA directed against murine FGF-9 (or control vector expressing a scrambled sequence). For the heterotopic model murine AB1-FGF-9 knock-down cells (or controls) were injected (5x10[5 ]cells) subcutaneously into the flank of Balb/c mice. Tumour dimensions were measured thrice weekly and animals sacrificed when tumours reached 100mm[2] and tumour tissues harvested. FGF-9 expression in tumour tissue was determined by immunohistochemistry. For orthotopic experiments, Balb/c mice received a single intraperitoneal injection of 5x10[5 ]AB1-FGF-9 knock-down cells (or controls). At day 13, animals were sacrificed and the number of peritoneal tumour nodules enumerated by blinded investigators. To determine whether the immune system plays a role in the regulation of AB1 MM tumour growth, 5x10[5 ]AB1-FGF-9 knock-down cells (or controls) were injected subcutaneously into nude mice. To elucidate the immune cells involved in AB1 MM tumour growth regulation, T cells were depleted in Balb/c tumour bearing mice using specific antibodies to CD4 and CD8 and tumour growth monitored. T cell depletion was confirmed using flow cytometry.

Results
Heterotopic tumour growth was significantly retarded in mice inoculated with AB1-FGF-9 knockdown cells compared to the scrambled vector and parent MM cells (p<0.001). A significant reduction in the number, and hence tumour burden, of tumour nodules was also observed for AB1-FGF-9 knockdown tumours in the orthotopic peritoneal model compared to controls (p<0.001). When grown in nude mice, which lack a functional T cell repertoire, AB1-FGF-9 knockdown tumours grew at a similar rate to that of the parent and vector controls which was suggestive of a role of the immune response in the regulation of MM tumours lacking FGF-9. AB1-FGF-9 knockdown tumours demonstrated significantly greater tumour burden in mice depleted of CD4+ and CD8+ T cells, either alone or in combination, when compared to saline controls which is highly suggestive of a T cell-mediated immune response to these tumours. These results also suggest that FGF-9 inhibits the tumour-specific immune response in MM.

Conclusion
In combination with our previous in vitro data which clearly demonstrated the proliferative and invasive properties of FGF-9, we suggest that FGF-9 has an important role in the pathobiological characteristics of MM in vivo and represents a novel therapeutic target.

Background
Increasing evidence supports the concept of a unique population of cells within a tumor with stem cell-like characteristics. These cancer-initiating cells (CICs) are thought to be responsible for tumor organization, maintenance, progression and recurrence, as well as contributing to radiation and chemotherapy resistance. In this study we outline a new characteristic of CICs, one in which the CIC can subvert the host immune response. We pose that this characteristic is essential for the establishment of a tumor in an immunocompetent host and may represent a mechanism in which lung tumors may gain resistance to immune based therapies.

Methods
We examined whether lung CICs could be enriched from murine and human cell lines through the use of tumorsphere culture assays. We vaccinated mice against the HPV E7 antigen and challenged mice with HPV E6/7 expressing murine lung cancer cells (TC-1) enriched for CICs. We also examined ex-vivo the capacity of CD8 and NK cells derived from vaccinated mice to lyse CICs. We examined by flow cytometry the expression of MHC-I and NK activating ligands. We examined the effect of interferon gamma (IFN-γ) on MHC-I expression by CICs and determined whether increased MHC-I by CICs would inhibit tumor formation in an immunocompetent animal.

Results
We showed that both murine and human lung cancer cells can be grown and maintained in tumorsphere culture conditions. The resulting cells were enriched for CICs as evidenced by increased OCT4, NANOG, and/or SOX2 expression. Additionally, tumorsphere cultures of murine tumor lines had increased tumor take in immunocompetent animals, however this was significantly less than that seen in immunodeficient mice; indicating that true CICs must be able to thwart the immune response to establish tumors. In order to further examine this, we vaccinated mice with HPV E7 peptides and challenged with TC-1 non-CICs or CICs. We showed that mice challenged with CICs had no survival advantage compared to non-vaccinated animals; whereas those animals challenged with non-CICs exhibited a vaccine induced survival advantage. Further we showed ex-vivo that CICs were resistant to lysis from CD8+ T-cells compared to the non-CICs. Next, we showed that both murine and human lung CICs have down-regulated expression of MHC-I as well as a number of ligands for NK cell activating receptors, essentially making them “opaque” to the immune system and therefore less susceptible to CTL or NK cell lysis. Further, we demonstrate that IFN-γ increases MHC-I expression on CICs and restores sensitivity to CTL killing. Finally, we demonstrate that decreased MHC-I expression is a critical component of the ability of CICs to establish tumor in immunocompetent hosts.

Conclusion
Increasing evidence indicates that CICs are critical players in the development and establishment of cancers. In this study we demonstrated that these cells also subvert tumor immune surveillance and play a key role in the resistance of tumors to cancer vaccines through their ability to escape host immune responses. Our results demonstrated that modulation of MHC-I on CICs can alter their susceptibility to T-cell mediated lysis thus opening a new target for cancer vaccine strategies.

Abstract not provided

Background
In NSCLC, antitumor immune response may be inhibited by PD-L1 expression. MPDL3280A, a human monoclonal antibody containing an engineered Fc-domain designed to optimize efficacy and safety, aims to restore tumor-specific T-cell immunity by blocking PD-L1 binding to its receptors, PD-1 and B7.1.

Methods
Patients with squamous or nonsquamous NSCLC received MPDL3280A IV q3w up to 1 year as part of a phase I dose escalation/expansion study. Objective response rate (ORR) was assessed by RECIST v1.1 and included unconfirmed/confirmed responses. EGFR and KRAS status was initially assessed locally by investigators. Archival tumor tissues were evaluated centrally by IHC for PD-L1 and CD8. A qPCR-based gene expression panel measuring ≈90 immune-related genes was used to characterize the tumor immune microenvironment at baseline and during MPDL3280A treatment.

Results
41 NSCLC patients first dosed at 1-20 mg/kg prior to Aug 1, 2012, were evaluable for efficacy with an ORR of 22%. Baseline tumor samples were available for IHC (n=33) and for gene expression analysis (n=29). Of patients with available tissue, 5 were PD-L1 tumor status positive and 28 were PD-L1 tumor status negative. Relationship between PD-L1 status and EGFR/KRAS status is described below (table). Elevated baseline PD-L1 expression was associated with response to MPDL3280A (80% ORR vs 14% ORR for PD-L1negative patients), and PD-L1 expression coordinated with CD8+ T cells. A Th1-type T-cell gene signature (including CD8, Granzyme-B and EOMES) was associated with treatment response. Non-responders exhibited at least a 2-fold higher ratio over CD8 of genes associated with immunosuppression, including RORC, FOXP3, TGFb1 and IL10 compared with responders. On treatment, responding tumors across indications showed increasing PD-L1 expression and a Th1-dominant immune infiltrate, providing evidence for adaptive PD-L1 up-regulation.

Conclusion
PD-L1 expression and a Th1 driven T-cell gene signature correlated with response to MPDL3280A in NSCLC, and MPDL3280A therapy led to T-cell reactivation and restored antitumor immunity. Additionally, expression of immune suppressive factors in NSCLC tumors is associated with a lack of benefit from MPDL3280A. These data provide mechanistic insights into immunotherapy and patient selection for MPDL3280A monotherapy. Preliminary observations suggest clinical activity and molecular characteristics may be associated with PD-L1 tumor expression. Updated data will be presented. Table: Relationship between PD-L1 status and EGFR/KRAS mutational status

	PD-L1-Positive (n = 5)	PD-L1-Negative (n = 28)	PD-L1 Unknown (n = 7)	Overall (n = 40)*
EGFRm, n	1	2	1	4
EGFR WT, n	2	20	4	26
EGFR Unknown, n	2	6	2	10
KRASm, n	1	4	1	6
KRAS WT, n	2	8	3	13
KRAS Unknown, n	2	16	3	21
* 1 patient had missing data.

Background
Programmed Death Ligand 1 (PD-L1, CD274, B7-H1) is an immune checkpoint molecule that binds to the receptors PD-1 and B7.1 on activated T cells. Binding negatively regulates T-cell function in both physiological and pathological conditions. Recent clinical studies have suggested that numerous cancers, including NSCLC, may utilize PD-L1 expression to escape T-cell mediated cytotoxic activity. Inhibition of PD-L1 can restore anti-tumor immunity, leading to clinical responses. A better understanding of PD-L1 expression patterns, co-expression with other immune markers and actionable disease associated biomarkers may provide insight into the future design of cancer immunotherapy trials in NSCLC.

Methods
Expression of PD-L1 was measured by immunohistochemistry (IHC) in archival tumors and, in some cases, in paired metastases in 2 FFPE NSCLC tumor tissue collections. Set 1 (N=561) was collected from patients who were eligible for surgery with curative intent from 2003 to 2005 at MD Anderson Cancer Center. The samples from Set 2 (N=300) contained surgically resected NSCLC tissue collected between 2006 and 2011 (UCCC and Norwegian Radium Hospital). PD-L1 expression was analyzed in both malignant and non-malignant cells (e.g., infiltrating immune cells). In addition, a multiplex qPCR assay that measures ≈90 immune-related genes was used to characterize the tumor immune microenvironment in the NSCLC tumor samples. Disease associated biomarkers, including the mutation status of EGFR and KRAS, as well as expression of MET (by IHC) were also evaluated.

Results
Prevalence of PD-L1 was comparable between adenocarcinoma and squamous cell carcinoma (≈30% in tumor cells; ≈45% and ≈50%, respectively, in immune cells). PD-L1 prevalence varied depending on the pathological stage, and was higher in Stages I-IIIA than in Stages IIIB-IV. Similarly, the prognostic value of PD-L1 varied by both stage and histology. In adenocarcinoma, tumors with PD-L1–positive tumor cells had a higher frequency of KRAS mutation and high Met expression, and a lower frequency of EGFR mutation compared with PD-L1–negative tumors. In contrast, tumors with PD-L1–positive and PD-L1–negative immune cells had a comparable frequency of high Met expression. Expression of PD-L1 was frequently co-localized with CD8+ T-cell infiltrates. Gene expression profiling revealed differences in the tumor immune environment, including genes associated with cytotoxic T-cells, between adenocarcinomas and squamous cell carcinomas. PD-L1 protein and immune gene expression associations with patient characteristics will be described in further detail.

Conclusion
These data provide a comprehensive description of PD-L1 expression in the context of disease biology utilizing large independent cohorts of well-characterized lung cancer tissues. The results highlight the complexity of the tumor immune environment in NSCLC with particular emphasis on the association with factors such as pathological stage, histology and oncogenic mutational status. These analyses may help guide future development of immunotherapy trials in NSCLC.

Background
Programmed Death Ligand-1 is a ligand for Programmed cell death protein 1 which is a key receptor regarding one of the immune checkpoints. PD-L1 expression in tumor is known to correlate with post-operative survival in different set of cancer patients. In the present study, we investigated PD-L1 expression of tumor cells in specimens acquired from non-small cell lung cancer patients and analyzed the correlation between the PD-L1 expression and clinicopathological characteristics and postoperative prognosis of 208 Non-Small Cell Lung Cancer patients.

Methods
PD-L1 expression in 208 specimens of NSCLC was assessed through an immunohistochemical process and inspected double-blinded.

Results
PD-L1 expression is associated with clinicopathological features (histology, P=0.047 and differentiation, P=0.023). No significant association observed between PD-L1 expression and post-operative prognosis. However, subgroup analysis of squamous carcinoma patients with positive PD-L1 protein expression showed a tendency of poor overall survival and disease-free survival compared with those with negative PD-L1 protein expression.

Conclusion
we have shown for the first time that PD-L1 expression is associated with clinicopathological features (histology and differentiation). In the subgroup analysis of squamous carcinoma patients, patients with positive PD-L1 expression showed a tendency to be associated with poorer survival compared with those with negative PD-L1 expression, which suggested that patients with squamous carcinoma might be the most benefit population in the anti-PD-1 immunotherapy.

Background
The prognostic significance of the tumor immune microenvironment in lung adenocarcinoma has been established by us (CCR 2011, JCO 2013, Oncoimmunology 2013) and others. Here, we investigate whether tumor-infiltrating immune cells correlate with prognosis, independent from TNM staging, in lung squamous cell carcinoma (SCC).

Methods
All available tumor slides from therapy-naive, surgically resected solitary lung SCCs (n=485; 1999-2009) were reviewed. Tissue microarrays were constructed using 451 cases (stage I, 255; II, 131; III, 65) from 3 representative tumor areas. Immunostaining for CD3 (pan T cell marker), CD45RO (memory T cell), CD8 (cytotoxic T cell), CD4 (helper T cell), FoxP3 (regulatory T cell), CD20 (B cell), CD68 (macrophage), and CD10 (neutrophil) was performed. For each case, the average number of cells positive for T cell markers was recorded as the ratio to CD3+ lymphocytes, and classified as low or high by use of the median. CD20, CD68, and CD10 were classified as low or high by the number of positive cells (≥20, ≥50, and ≥10, respectively) as our recent publication (JCO 2013). Overall survival (OS) was estimated using the Kaplan-Meier method; multivariate analyses were performed using the Cox proportional hazards model.

Results
Five-year OS was 59% for the entire cohort and 68% for stage I patients. Analysis of single immune cell infiltration revealed that high CD10+ neutrophil count was correlated with lower OS (5-year OS, 53%; n=160) than low CD10+ count (5-year OS, 61%; n=286; p=0.006). Analysis of biologically relevant immune cell combinations identified 2 significant factors of prognosis: (1) patients with high CD4+ and high FoxP3+ T cell ratios had worse prognosis (5-year OS, 52%; n=140) than the other groups (5-year OS, 62%; n=304; p=0.008), and (2) patients with high CD10+ neutrophil and low CD20+ B lymphocyte counts had worse prognosis (5-year OS, 43%; n=102) than the other groups (5-year OS, 63%; n=340; p<0.001). These results were confirmed in a subgroup analysis limited to stage I patients (p=0.020 for high CD4/high FoxP3+ ratios; p=0.007 for high CD10+/low CD20+ counts). In multivariate analysis, high CD4+/high FoxP3+ ratios (HR=1.58; p=0.001) and high CD10+/low CD20+ counts (HR=1.71; p<0.001) remained significantly associated with poorer survival (Table).

Table. Multivariate analysis for overall survival

Variable	HR	95% CI	p
High CD4+/high FoxP3+ ratios	1.58	1.21–2.06	0.001
High CD10+/low CD20+ counts	1.71	1.28–2.27	<0.001
Age (>65 years old)	1.51	1.09–2.09	0.014
Sex (male vs. female)	1.31	1.01–1.69	0.043
Smoking pack years (>90)	1.01	1.00–1.01	0.003
Stage (II and III vs. I)	1.53	1.16–2.02	0.002
Lymphovascular invasion	1.38	1.02–1.88	0.040

Conclusion
High CD4+/high FoxP3+ ratios and high CD10+/low CD20+ counts are significant factors of prognosis for lung SCC, independent of TNM staging. Targeting regulatory T cells or enhancing tumor-specific B-cell responses may thus have applicability for the treatment of lung SCC.

Abstract not provided

Background
We discovered that PKCι is an oncogene in non-small cell lung cancer (NSCLC), elucidated a major oncogenic PKCι signaling mechanism, and identified therapeutic agents that target oncogenic PKCι signaling. We have shown that PKCι signaling is genetically activated in approximately 70% of lung squamous cell carcinomas (LSCCs) through tumor-specific amplification of the PKCι gene, PRKCI. More recently, we have investigated the role of PKCι in bronchio-alveolar stem cells (BASCs), which are putative lung tumor-initiating cells (TICs). We demonstrated that PKCι is required for Kras-mediated transformation of BASCs in a mouse model of Kras-mediated lung adenocarcinoma. We hypothesize that PKCι plays a critical role in the development and maintenance of the TIC phenotype in LSCC by activating cell autonomous proliferative signaling mechanisms.

Methods
We isolated “oncospheres” from four human LSCC cell lines (H1703, H1299, Calu-1, and ChagoK1) grown in non-adherent culture in defined stem cell medium using established protocols. Lentiviral shRNA techniques were used to genetically knock down expression of PKCι to assess the effect of PKCι depletion on the TIC phenotype. Non-target (NT) and PKCι RNAi TICs were assessed for the ability to grow as non-adherent oncospheres, to clonally expand, express stem marker genes, form colonies in soft agar, and initiate tumors in immune deficient mice. The effect of the selective and potent PKCι signaling inhibitor auranofin on TIC behavior and PKCι signaling activity was assessed as was the mTOR inhibitor, rapamycin.

Results
LSCC oncospheres exhibited characteristics of cancer stem or tumor-initiating cells including the ability to redifferentiate into bulk tumor cells when returned to adherent culture. Oncosphere cells express elevated levels of stem genes, clonally expand, exhibit enhanced transformed growth, and efficiently initiate and maintain lung orthotopic tumors and metastases. Biochemical studies indicate that the oncogenic PKCι-Rac1-Ect2-MMP10 signaling axis is activated in LSCC TICs. To assess the role of PKCι in TIC growth, we knocked down PKCι in TIC cultures derived from the four LSCC cell lines described above. Whereas TICs expressing NT RNAi grew efficiently as anchorage-independent colonies in soft agar and clonally expanded, PKCι RNAi TICs were severely impaired in soft agar growth, clonal expansion, and tumorigenicity in vivo. Treatment of TICs with the potent and selective PKCι inhibitor auranofin (ANF) likewise led to inhibition of PKCι signaling, TIC growth, clonal expansion, and tumorigenicity. Combined inhibition of PKCι and mTOR with ANF plus rapamycin was synergistic against TIC proliferation in vitro.

Conclusion
Our data demonstrate that PKCι signaling is activated in LSCC TICs and that PKCι signaling is important for maintaining the TIC phenotype. We showed that the selective PKCι inhibitor ANF potently inhibits LSCC TIC behavior. Taken together, our data support the targeting of LSCC TICs through selective inhibition of PKCι for treatment of patients with LSCC. Based on these and earlier results showing synergistic tumor inhibition with combined PKCι and mTOR inhibition, a phase I clinical trial of auranofin with the mTOR inhibitor sirolimus has been instituted as maintenance therapy for LSCC patients who have completed initial chemotherapy.

Background
Inhibition of MEK is a promising treatment strategy for non-small cell lung cancer (NSCLC). MEK inhibitors are being investigated for KRAS mutant disease, but KRAS alone is not predictive of efficacy, and other predictors of response and resistance are not known. The downstream effects of MEK inhibition have not been fully described. Here, we report broad proteomic analysis of NSCLC cell lines before and after treatment with MEK inhibitor BAY86-9766.

Methods
We treated 109 NSCLC cell lines with BAY86-9766. Drug sensitivity was determined by CellTiter-Glo assay and cell lines were classified as sensitive or resistant based on whether their IC50 values were in the highest or lowest 1/3[rd] of those tested. Proteomic analysis for regular and phospho-proteins was performed by reverse phase protein array. Using paired t-tests, we compared pre- versus post-treatment protein levels in the overall group and between the sensitive vs. resistant cell lines.

Results
Increased activation of the PI3 kinase pathway at baseline correlated with resistance to MEK inhibition, with resistant cell lines showing higher baseline levels of pAkt (S437), pAkt (T308), pPDK1, and p4E-BP1 (S65), and lower baseline levels of PTEN (all p<0.05). Cell lines with increased MEK phosphorylation at baseline were more sensitive to MEK inhibition (p=0.048). BAY86-9766 was very effective at reducing pERK (p=1.65x10[-35]) but this modulation was not significantly different between sensitive and resistant cell lines (p=0.64). Increased phosphorylation of MEK was seen with treatment (1.66x10[-16]). mTOR signaling was suppressed by MEK inhibition, with decreased phospho-p70S6K, pS6 (S235/236), and pS6 (S240/S244) and increased eIF4E following treatment (all p<0.02). These effects were significantly more pronounced in sensitive vs resistant cell lines (all p<0.01). Higher levels of LKB1 total protein, pAMPK, and pTSC2 were also seen following treatment (all p<0.02).

Conclusion
We have performed broad proteomic analysis of NSCLC cell lines treated with MEK inhibitor BAY86-9766. Baseline activation of the PI3K/Akt pathway predicts for resistance to MEK inhibition. Sensitive cell lines, but not resistant cell lines, show suppression of mTOR activity with treatment with BAY86-9766. The effects of MEK inhibition of mTOR may be modulated by p90RSK through an LKB1 dependent pathway. This suggests a basis for combining targeted agents to overcome resistance, such as combinations of MEK inhibitors with PI3K inhibitors or mTOR inhibitors.

Background
The PI3K-Akt- mTOR pathway regulates cell growth and proliferation and is often dysregulated in cancer due to mutation, amplification, deletion, methylation and post-translational modifications. PI3K pathway activation in NSCLC has been shown by us and others to lead to a more aggressive disease correlating to poor prognosis for patients. Multiple novel agents, targeting different regulators within the pathway are currently under development. GDC-0980 is a selective dual inhibitor of PI3K and mTOR, which demonstrated excellent downstream inhibition of the PI3K pathway in vitro, with the strongest effects being observed in lung, breast and prostate cancer cell lines. There are 12 clinical trials ongoing for this drug, with Phase I studies in solid tumours and Phase II studies in endometrial carcinoma, renal cell carcinoma, prostate cancer and breast cancer. As with all targeted therapies, acquired resistance to GDC-0980 is anticipated to be a major hurdle in the success of this drug. Multiple mechanisms of resistance to GDC-0980 may develop while a patient is being treated with this drug. The aim of this project is to develop four cell line models of resistance to GDC-0980, each representing a different molecular subtype of NSCLC, in order to predict which mechanisms of resistance may occur in patients. This will allow us to identify biomarkers of response/resistance to the drug that may dictate beneficial treatment strategies.

Methods
H460, A549, H1975 and SKMES-1 cells were treated with a dose response curve of GDC-0980 and BrdU proliferation assays determined IC50 values for each cell line. Each cell line was then cultured in GDC-0980 at IC50 concentrations over a period of several months, along with matched ‘parent’ cell lines. Each month, BrdU proliferation assay were carried out in order to track the development of resistance to the drug. When a log fold difference between the parent and resistant IC50s was observed, the cells were deemed to be resistant. Matched parent and resistant cells were then screened for a panel of mutations. Cells lines were also screened for gene alterations using a human cancer drug resistance PCR array. Identified genes of interest were validated at the RNA and protein level by PCR and Western blot, respectively.

Results
All four cell lines exhibited a dose-dependent decrease in proliferation when treated with GDC-0980. H1975 cells (adenocarcinoma; PIK3CA mutant) were most sensitive to GDC-0980, however they developed resistance to the drug more rapidly than the other 3 cell lines. Results from mutational analysis and investigation of the gene and protein expression of each of the 4 pairs of parent and resistant cell lines will be presented.

Conclusion
While the panel of four NSCLC cell lines all responded well to GDC-0980 treatment initially, resistance to the drug developed rapidly. As such, understanding the mechanisms involved in the development of resistance to this drug will be crucial so that we may design optimal treatment strategies. Specific conclusions regarding the mechanisms of resistance in this panel of cell lines will be drawn based on identified genes and proteins of interest.

Background
The combination of AFAT and CET has demonstrated remarkable clinical activity in patients with acquired resistance to erlotinib. Preclinical modeling in genetically engineered mice and cell lines predicted activity in cases where erlotinib resistance was mediated by the EGFR T790M gatekeeper mutation. However, in the clinic, patients lacking T790M-positive tumors showed equivalent benefit from this combination, suggesting alternative mechanisms of synergy. We explored the individual and combined molecular and growth inhibitory activity of these agents in PDX models derived from NSCLC patient tumors with distinct mechanisms of acquired resistance to erlotinib. These models were developed by the UC Davis - Jackson Laboratories Consortium, which has xenotransplanted over 170 NSCLC models using the nod/scid/IL2Rgamma chain-null (NSG) mouse.

Methods
EGFR-mutant PDX models LG0703 (T790M-negative) and LG1049 (T790M-positive) were established from tumor biopsies from patients who progressed following durable responses to erlotinib. Both patients were subsequently treated with AFAT+CET, with the LG0703 donor patient exhibiting a prolonged response and the LG1049 donor patient exhibiting a transient response followed by rapid progression. Excised tumors from passage 1 PDXs were fragmented and implanted into treatment cohorts. When tumors reached 300mm[3], mice were randomized to erlotinib (50 mg/kg qd po), AFAT (20 mg/kg qd po), CET (10 mg/kg twice weekly iv), AFAT-CET, or vehicle control (n per arm = 12) for 3 weeks followed by a 75-day monitoring period. In a parallel cohort, tumor pharmacodynamic changes in signal transduction mediators and RTKs were assessed after 6 and 24h treatment exposures using kinase arrays (R&D systems) and immunoblotting.

Results
In LG0703, AFAT, CET and AFAT-CET resulted in complete tumor response (CR) during the 21-day treatment period. After cessation of treatment, mice treated with CET or AFAT-CET remained in complete remission; whereas AFAT-treated mice progressed within 2 weeks. Clinical activity in this model was associated with complete blockade of EGFR and Her2 phosphorylation. Substantial down-regulation of AKT1, AKT2, ERK1, p38a, RSK1 and p70S6K phosphorylation was evident within 6h of treatment. In contrast, the T790M-postive LG1049 model demonstrated only modest clinical benefit from AFAT, with no single-agent CET activity, and no CET-mediated synergy with AFAT. No treatments were able to ablate EGFR phosphorylation or downstream signal transduction, and compensatory induction of EGFR, HER2, ERK1 and p38 were noted after 24h of drug exposure.

Conclusion
In these PDX models derived from patients with EGFR-activating mutant cancer with acquired resistance to erlotinib, treatment with AFAT+CET recapitulated the clinical experience of the donor patients receiving this combination. In the LG0703 model, both the AFAT-CET combination as well as single-agent CET resulted in complete tumor regression associated with total ablation of EGFR phosphorylation and subsequent blockade of multiple signal transduction pathways. In the LG1049 model, AFAT prompted limited but statistically significant tumor delay, with no additional benefit from CET. These experiments demonstrate the considerable potential of this PDX resource to assess therapeutic strategies in models representing individual patients. Supported by BJALCF.

Abstract not provided

Background
Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related death worldwide. Pemetrexed (PEM), a multi-target folate antagonist, has demonstrated targeted efficacy in NSCLC histological subtypes characterized by low thymidylate synthase (TS, one of PEM’s molecular targets) expression. Recently, TS expression has been found to be regulated by histone acetylation status, thus raising the interesting hypothesis that histone deacetylase inhibitors (HDACi) may sensitize NSCLC cells to PEM cytotoxicity.

Methods
Molecular and functional effects of single and combined HDAC inhibition and PEM exposure were assessed in NSCLC cell lines (A549, H1299, H1650, Calu-1) and patient-derived lung cancer stem cells (L-CSC). Pharmacologic interactions were assessed by conservative isobologram analysis using the Chou-Talalay method and the Calcusyn software. TS expression was studied by WB analysis and real-time PCR. Apoposis induction was assessed by flow cytometry and WB. Autophagy was assessed by analysis of autophagosome formation in EGFP-LC3B expressing cells, detection of acidic vesicle organelles (AVO) formation and WB. In vivo experiments were conducted in xenograft models established by i.m. injection of NSCLC cells into 6-8 week-old male athymic mice (nu/nu).

Results
In NSCLC cell lines and L-CSC, the HDACi ITF2357 dose-dependently inhibited cell growth (IC~50~: <1-20 mM), induced histone H3 acetylation, and downregulated TS expression at the mRNA and protein levels. Combined HDAC inhibition and PEM exposure was then tested using three different administration schedules: simultaneous exposure to both drugs, ITF2357 followed by PEM, and the reverse sequence. Simultaneous PEM/ITF2357 treatment resulted in antagonistic growth inhibitory interactions (combination index – CI >1) in all cell lines tested, while ITF2357 followed by PEM had additive effects in A549 cells and slightly synergistic effects in H1299 and Calu-1 cells; conversely, PEM followed by ITF2357 had strikingly synergistic effects (CI <<1) in all NSCLC cell lines, as well as in the L-CSC143. Most notably, only the ITF2357 followed by PEM sequence synergistically induced apoptosis, resulting in approximately 50% Annexin V-positive cells; apoptosis was only partially rescued by caspase inhibition by z-VAD-fmk, which led us to investigate autophagy as an alternative mechanism of combination-induced cell death. Indeed, ITF2357, and to a significantly greater extent PEM followed by ITF2357, induced autophagy as evidenced by AVO formation, LC3BII processing, p62 downregulation, and Beclin1 induction. Most importantly, autophagy induction was instrumental to the cytotoxic interaction between PEM and ITF2357, as Beclin1 silencing by shRNA completely reversed their growth inhibitory synergism and prevented both autophagy and apoptosis induction. The synergistic cytotoxic interaction between PEM and ITF2357 was at least partly due to ITF2357 ability to prevent PEM-induced TS upregulation, as TS silencing by siRNA further enhanced apoptosis induction by single and combined PEM/ITF2357 exposure. Finally, both H1650 and H1299 xenografts had a robust response to sequential PEM/ITF2357 administration in vivo, resulting in an approximately doubled mice survival in the H1650 model.

Conclusion
Overall, our data indicate that HDAC inhibition by ITF2357 downregulates TS expression and synergistically potentiates apoptosis and autophagy induction following PEM exposure, supporting the clinical investigation of sequential PEM/ITF2357 schedules for the treatment of advanced NSCLC.

Background
Given limited progress in developing novel chemotherapies for mesothelioma and multi-negative NSCLC, new technology is needed to identify promising drug strategies. A drug-induced apoptosis assay has been developed that has been applied in acute myelocytic leukemia, ovarian cancer, and a variety of solid tumors including breast cancer (Cancer Research 2012; 72:3901). We explored the use of the MiCK assay in mesothelioma and NSCLC tumor specimens.

Methods
Fresh tumor specimens from resected tissue or malignant effusions were processed in a central laboratory. Cell separation techniques were used to prepare >95% tumor cell suspensions for the MiCK assay (as described in Cancer 2012; 118: 4877). Over 48 hours in short term culture, optical techniques based on Mie light scattering measured apoptosis in control wells and test wells containing different chemotherapy drugs or combinations. Significant apoptosis gave results over 1.0 kinetic units (KU). Drugs or combinations producing the highest KU +/- 1 SD compared to other drugs were defined as best regimens. Differences of over 0.57 KU correlated with clinically significant better responses.

Results
15 specimens have been submitted with 9 successfully assayed to date. Mean numbers of drugs or combinations assayed successfully were 32 in mesothelioma and 20 in NSCLC. New treatment strategies in individual patients with mesothelioma were: epirubicin 5.0 and 9 KU, idarubicin 4.0 KU, pemetrexed+doxorubicin 4.9 and 4.6 KU, ifosfamide 3.4 and 2.2 KU, bendamustine 4.0 KU, dactinomycin 4.7 and 3.4 KU, vinorelbine 4.7 KU, asacytidine 3.8 KU, bortezomib 3.0 KU, doxorubicin 3.9 KU, cyclophosphamide+doxorubicin+vincristine 3.0 KU and cisplatin+irinotecan 3.1 KU. New treatment strategies in individual patients with NSCLC were: doxorubicin 2.0, 1.7 and 1.7 KU, epirubicin 1.6 KU, 5-fluorouracil+leucovorin 1.3 KU, and cyclophosphamide+doxorubicin+vincristine 2.3 KU. In class differences in drug activity were apparent in individual patients: cisplatin>carboplatin, epirubicin>doxorubicin, and docetaxel>paclitaxel. In one mesothelioma patient with paired specimens from malignant effusion and solid tumor the most active (pemetrexed+doxorubicin) and least active regimens (cisplatin+paclitaxel) were concordant. In mesothelioma, the most active chemotherapy regimens in individual patients were epirubicin, idarubicin, pemetrexed+doxorubicin, vinorelbine, cisplatin+etoposide, cisplatin+irinotecan, cyclophosphamide+doxorubicin+vincristine, and dactinomycin. In NSCLC, the most active regimens were doxorubicin, cisplatin, docetaxel, irinotecan, and cyclophosphamide+doxorubicin+vincristine.

Conclusion
Use of the MiCK assay in mesothelioma and NSCLC can identify unexpected new leads for innovative therapeutic strategies for individual patients, and for candidate enrollment in phase II and III studies. The MiCK assay may play a role in designing precision therapeutics for patients with mesothelioma and NSCLC. Marked differences between patients in individual drug activities, and discordant in-class drug effectiveness indicate the need for individualized patient tumor testing of drug-induced apoptosis. Since use of the MiCK assay has correlated with improved clinical outcomes in prior studies, clinical trials of drugs with unexpected activity may be warranted in mesothelioma and NSCLC patients.

Background
Considerable evidence has shown that cancer cell repopulation during the intervals of chemotherapy is a neglected factor of treatment failure. The efficacy of cancer treatment may be improved if this process could be effectively controlled. It has been demonstrated that the number of invariant natural killer T cells (iNKT) increased during the development of murine mesothelioma models. NKT cells specifically recognize the glycolipid α-galactosylceramide (KRN7000, KRN) through CD1d molecule resulting in their activation and expansion. Our goal is to study the impact of NKT cell activation by KRN on cancer cell repopulation between cycles of chemotherapy in murine mesothelioma model.

Methods
Tumor-bearing mice were treated with chemotherapy once weekly, and KRN was followed after each cycle of chemotherapy. Both WT and CD1dKO mice were used to evaluate the effect on tumor growth. Cancer cell proliferation and apoptosis was evaluated by Ki67 and TUNEL immunohistochemistry, respectively. The proportion of CD4[+] and CD8[+] T cells and their activation in the tumor, spleen, draining lymph node and peripheral blood from tumor-bearing mice were determined by using flow cytometry, and gene expression of activated T cell-related cytokines and cytolytic enzymes were quantified by RT-PCR. NKT were recognized specifically by CD1d-tetramer staining.

Results
In WT mice, tumor growth delay was achieved by chemotherapy alone, and this effect was improved when combined with KRN. Cancer cell repopulation between cycles of chemotherapy was significantly inhibited by KRN, whereas apoptosis changed inversely. KRN following chemotherapy resulted in an increase of IFN-γ production in the draining lymph node, blood and spleen. Strikingly, the percentage of ICOS+CD4 T cells, Th17 and Tc17 cells increased in splenocytes. NKT expansion was observed in both peripheral blood and lymphoid organs. Gene expression of immune-associated cytokines was somewhat upregulated after NKT cell activation during the intervals of chemotherapy. In KO mice, however, Cis alone or Cis+KRN was less effective than in WT mice. KRN alone had little effect in both animals.

Conclusion
NKT activation between cycles of chemotherapy can improve the efficacy of treatment through modulating anti-tumor immunity against cancer cell repopulation. KRN may be a promising agent for mesothelioma immunotherapy.

Background
Radiotherapy can induce direct cancer cell death and systemic anti-tumor immunity known as abscopal effect. For malignant pleural mesothelioma (MPM), postoperative hemithoracic radiation is important to control recurrence and metastasis for the resectable patients. We hypothesized that the abscopal effect also exists in malignant mesothelioma, and removal of the immunosuppressive checkpoints was able to enhance this effect induced by local radiotherapy.

Methods
Murine malignant mesothelioma AB12 cells were injected subcutaneously into the right leg and flank of Balb/c mice either sequentially (primary/secondary tumors) or concurrently (local/distant tumors). Treatment was initiated on day 5 when primary (local) tumors were developed, and the immune-deficient NOD/SCID mice were used as controls. Local radiotherapy (LRT) with Gammacell-40 Irradiator was delivered to the tumor-bearing leg, whereas the rest of the body was protected with a lead chamber. CTLA-4 blockade with mAb was given 1 day after LRT. Tumor size was measured twice weekly to evaluate the anti-tumor effect. The immune responses, especially T cell activation in tumor, spleen and lymph node was determined by flow Cytometry. The expression of immune-related genes was quantified by RT-PCR, and tumor-infiltrating T cells were determined by immunofluorescent staining.

Results
The growth of primary tumors was significantly inhibited by LRT alone, and addition of anti-CTLA-4 mAb enhanced the antitumor effect. Interestingly, the secondary or distant tumors grew more slowly in mice whose primary tumor was treated with LRT than those untreated mice. Some secondary tumors were completely rejected when combined with anti-CTLA4 mAb. There was no such effect on the distant tumors in the immune deficient mice. Results demonstrated that LRT resulted in more T cell infiltration into both primary and secondary tumors. Tumor-infiltrating T cells had higher levels of ICOS and IFN-γ, and proliferated more rapidly after injection of irradiated AB12 cells. More activated CD4 and CD8 T cells were observed in the the draining lymph node (dLn) and spleen, and more dendritic cells trafficked to the dLn. The gene expression of cytolytic enzymes and cytokines was upregulated as well.

Conclusion
LRT on primary tumors has abscopal effect on the secondary or distant tumor, and this effect can be enhanced by systemic blockade of CTLA-4 in murine mesothelioma. This approach might be translated into clinical trials for MPM patients.

Abstract not provided

Background
2nd-line therapy for advanced NSCLC patients (pts) after progression on platinum-based regimens typically employs CT or E. A test for optimizing choice of treatment in these pts is of clinical value. VeriStrat (VS) is a serum protein test that assigns "good" (VSG) or "poor" (VSP) classification and has demonstrated prognostic and predictive utility. PROSE is a multicenter prospective randomized biomarker validation trial, designed to evaluate the ability of VS to predict survival in 2nd- line NSCLC pts treated with E or CT. As reported at 2013 ASCO1, PROSE met its primary endpoint of demonstrating significant treatment*VS interaction with a p value of 0.031, with VSG pts deriving similar overall survival (OS) benefit from both treatments (hazard ratio (HR) for E=1.06; p=0.71) and VSP pts benefitting more from CT than E (HR for E=1.72; p=0.02). Previous studies in EGFR-TKI-treated pts have shown that at progression around 30% of pre-treatment VSG pts have changed classification to VSP2. The present report discusses the exploratory analysis of longitudinal VS classifications generated during the PROSE study.

Methods
Of the 263 pts in the PROSE primary analysis population, 89 provided serum samples during treatment and 108 at progression, with 47 pts providing both. VS testing was performed on these longitudinal samples blinded to all clinical and treatment outcomes and pts and physicians remained blinded to VS results.

Results
VSG or VSP classifications were obtained for 89 pts from treatment samples (67 VSG / 22 VSP) and 107 pts (one sample was classified as indeterminate) from progression samples (59 VSG / 48 VSP). In pts with matched baseline and progression samples, the percentage of VSG classifications was lower at progression (55%) than at baseline (77%) (p < 0.001 ). Twenty eight pts (34%) classified at baseline as VSG changed to VSP at progression, in line with previous studies2, and this did not show any significant dependence on treatment. When treated with E, pts whose classification changed from VSG at baseline to VSP during treatment (n=6) had inferior PFS to the 25 pts who remained VSG (p=0.001, median PFS: 3.6 and 7.7 months (mos), respectively). Patients whose classification changed from VSG at baseline to VSP at progression on E (n=18) had numerically inferior OS (median 10.0 mos) compared with the 31 pts who remained VSG at progression (median 14.6 mos) and significantly superior OS (median 5.0 mos) compared with the 10 pts who were VSP at both time points (p<0.001).

Conclusion
The observed changes in VS classification at progression demonstrate the importance of obtaining a VS result prior to each line of therapy for which erlotinib is considered as a therapeutic option. The proportion of patients who are good candidates for erlotinib therapy (VSG) decreases from 2[nd] to 3[rd] line and the possible impact of this on treatment sequencing and monitoring for 2[nd] and higher line advanced NSCLC pts merits further studies.

Background
Preclinical data have shown that the EGFR-T790M mutation confers resistance to reversible EGFR-TKIs (gefitinib, erlotinib) but not to irreversible EGFR-TKIs (afatinib). This study evaluated advanced NSCLC patients (pts) harboring an activated EGFR mutation (exon 18-21) to investigate the incidence of the T790M mutation in pretreatment tumor samples and the correlation between the T790M mutation and the clinical outcome, comparing patients positive for the T790M mutation treated with reversible TKIs, an irreversible TKI or chemotherapy to patients negative for the T790M mutation treated with the same agents.

Methods
We screened 317 advanced NSCLC pts for EGFR mutations using the PCR/Sanger sequencing (PSS) method. Tumor tissues from EGFR-mutated pts were analyzed for the EGFR-T790M mutation using a highly sensitive locked nucleic acid-PSS method (LNA-PSS) capable of detecting EGFR-T790M-mutated alleles at extremely low frequencies. The response rate (RR), progression-free survival (PFS) and overall survival (OS) were evaluated retrospectively in these pts.

Results
Using PSS, 17.3% (55/317) of pts had an activating mutation in the EGFR-TK domain; 56.3% (31/55) of pts had an in-frame deletion in exon 19, 32.7% (18/55) of pts had point mutation L858R in exon 21, 3.6% (2/55) of pts had an insertion in exon 20, and 7.2% (4/55) of pts had both the T790M mutation and either an exon 19 or 21 mutation. Forty-two pts with EGFR-activating mutations (82.3%) without the T790M mutation (by PSS) were successfully analyzed for the T790M mutation using LNA-PSS. The T790M mutation was detected in 17 (40.5%) pts, with a higher incidence in never smokers (47.7%), adenocarcinoma (76.2%) and females (71.4%). A treatment response evaluation was available in 39 pts, 18 of whom (46.1%) harbored the T790M mutation. Pts with T790M had a lower RR (22.2%) to TKIs than wild-type pts (35.3%); however, mutated pts had better PFS and OS (median PFS 9.2 vs 7 months, respectively; median OS 15.2 vs 11.1 months, respectively). Pts treated with afatinib and positive for T790M obtained longer PFS compared to pts negative for T790M (median PFS 4.7 vs 3.2 months, respectively), but their OS was shorter (median OS, 16.3 vs 18.2 months, respectively). Notably, pts with the T790M mutation had a greater response to chemotherapy (44.4%) compared to pts without the mutation (18.2%) and had a longer PFS (median PFS 8.2 vs 6.1 months, respectively) and OS (median OS 21.8 vs 12.4 months, respectively).

Conclusion
In this study, the high proportion of pretreatment tumor samples positive for the EGFR-T790M mutation indicates that its identification at diagnosis is more common than expected using a highly sensitive method. Consequently, in NSCLC pts with EGFR-activating mutations, detection of the T790M mutation at diagnosis can help customize therapy and identify a subset of patients with a relatively more favorable prognosis.

Background
Erlotinib is a standard treatment for NSCLC patients harboring EGFR mutations. Many tumors acquire resistance mutations during erlotinib treatment; consequently, confirmation of EGFR mutation status is important to select appropriate subsequent therapy after progression. Obtaining tumor samples is not easy, therefore, serum samples are more applicable for this purpose. This analysis measured serum EGFR mutations before and after administration of erlotinib in a phase II study in Japanese chemotherapy-naïve patients with advanced NSCLC harboring EGFR mutations (JO22903).

Methods
We analysed serum samples from patients in the JO22903 study by Scorpion-ARMS to confirm the presence of EGFR mutations before and after erlotinib administration (190 days post treatment initiation and at disease progression). The mutation results were evaluated in relation to clinical characteristics and effects of erlotinib.

Results
Of the 103 patients registered in JO22903, 95 consented to the examination of EGFR mutations in serum samples prior to and following administration of erlotinib. Of these 95 patients, 26 were positive for EGFR mutations (16 were exon 19 deletions, nine were exon 21 L858R mutations, one was an exon 20 S768I mutation). In the 26 patients classed as EGFR mutation-positive in serum samples, the concordance rate between tumor samples and serum samples was 96.2% (matching 25 cases except the S768I mutation case). The EGFR mutation detection rate in serum samples prior to erlotinib administration was 35.6% for exon 19 deletions (16/45) and 18.0% for L858R mutations (9/50). In six cases where exon 20 T790M or minor mutations were detected alongside major mutations in tumor samples, the major mutations were detected in corresponding serum samples of four patients but the T790M mutations or minor mutations were not detected in any serum samples. In the 65 cases in which serum samples were taken 190 days after erlotinib administration, five were positive for EGFR mutations (exon 19 deletions in four, and L858R in one). Four of these cases were consistent with the mutation type of the tumor samples taken before erlotinib administration; one case changed from L858R to exon 19 deletion. Serum samples at disease progression were taken for 72 patients. Of these, 16 were positive for EGFR mutations (three were exon 19 deletions, five were exon 19 deletions + T790M, six were L858R and two were L858R + T790M). EGFR mutation type had changed after administration of erlotinib in three cases; these cases also had multiple metastases. Characteristics of EGFR mutation-positive cases in the pre-treatment serum samples were large tumor size, and metastases to other organs (bone, brain, liver). Patients with baseline serum EGFR mutations had median PFS of 9.7 months and those without baseline serum EGFR mutations had median PFS of 15.2 months. Further efficacy results will be presented.

Conclusion
The sensitivity of these analyses was not enough to draw firm conclusions; however, results show the possibility that serum EGFR mutations correlate with disease activity and emergence of resistance mutations. Further study is recommended to measure serum EGFR mutations throughout the treatment course, to ascertain whether this can predict the risk of disease progression.

Background
A significantly greater proportion of females and adenocarcinoma patients is found in never-smoking NSCLC groups than in smoking NSCLC groups. Recent studies have demonstrated that estrogens may contribute to the carcinogenesis and development of lung carcinoma. In the present study, we investigate the correlation between the expression of aromatase (CYP19-1) and clinicopathologic factors and assess the prognostic significance of the aromatase expression in patients with primary lung adenocarcinoma.

Methods
The aromatase mRNA expression levels in the primary tumors and corresponding nonneoplastic lung specimens of 110 Japanese patients who underwent complete resection for primary lung adenocarcinoma were evaluated using quantitative RT-PCR. The relationships between the aromatase expression and clinicopathologic factors or survival were analyzed. To test the growth inhibitory effects of the aromatase inhibitor exemestane alone and in combination with the EGFR-TKI erlotinib in vitro, the cell proliferation of the lung adenocarcinoma cell lines HCC4006 and 11-18 was measured according to the WST-8 method.

Results
The mRNA expression level of aromatase in the carcinoma tissues was significantly higher than that in the corresponding normal lung tissues (P = 0.013). The aromatase expression in the lung adenocarcinoma tissues was not correlated with the clinicopathologic factors, including patient gender, age, smoking status, EGFR mutation status or pathologic stage. A high aromatase expression was associated with a poor prognosis in terms of both the recurrence-free survival (RFS) (P = 0.004) and overall survival (OS) (P = 0.003). A multivariate analysis showed that the aromatase expression was a significant prognostic factor, with a relative risk of 2.35 (P = 0.043) for RFS and 5.19 (P = 0.004) for OS. We further stratified the population according to gender, smoking status and EGFR mutation status. A high aromatase expression was related to a poor prognosis in femles (RFS; P = 0.008, OS; P < 0.001), never-smokers (RFS; P = 0.009, OS; P < 0.001) and patients with EGFR mutations (RFS; P = 0.005, OS; P = 0.003). A multivariate analysis showed that the aromatase expression was a significant prognostic factor, with a relative risk of 5.22 (P = 0.013) for RFS in the patients with EGFR mutations. HCC4006, harboring an EGFR mutation with a low aromatase mRNA expression, was not sensitive to exemestane alone or combination with erlotinib. In contrast, 11-18, harboring an EGFR mutation with a high aromatase mRNA expression, was sensitive to exemestane alone. In addition, cell growth was significantly inhibited by the combination of exemestane and erlotinib.

Conclusion
A high expression of aromatase is correlated with a poor outcome in patients with lung adenocarcinoma, especially those harboring EGFR mutations. Aromatase may be a therapeutic target in lung adenocarcinoma with a high aromatase expression and with an EGFR mutation.

Background
NSCLC patients with EGFR mutations initially respond to EGFR tyrosine kinase inhibitors (TKIs) but ultimately relapse. Sub-genomic molecular studies indicate that the EGFR T790M mutation and the activation of MET, PI3K, AXL, HER2 and MAPK can lead to acquired resistance to EGFR TKIs. To date, no integrated comprehensive genomic investigation of EGFR TKI resistance has been reported.

Methods
FFPE biopsies of erlotinib-sensitive and erlotinib-resistant tumors were obtained from 13 EGFR mutant NSCLC patients. The samples were analyzed by whole exome sequencing and whole transcriptome sequencing utilizing the Illumina HiSeq2500 platform. In addition, targeted gene sequencing was performed with the Illumina TruSeq Amplicon-Cancer Panel and run on the MiSeq system.

Results
Erlotinib resistant NSCLC specimens harbored known resistance drivers, including EGFR T790M mutations (9/13; 69%), MET amplification (3/13; 23%), HER2 amplification (3/13; 23%), and AXL upregulation (3/13; 23%). Differential expression analysis between resistant and pre-treatment states revealed enrichment in the pre-treatment tumors of immune signaling pathways, and in the resistant tumors upregulation of ERBB2, mTOR, PI3 kinase and ribosomal signaling pathways. PI3K/AKT pathway upregulation also occurred through somatic mutations in AKT and LKB1 in the resistant tumors. Copy number analysis demonstrated both large scale and focal amplifications and deletions in the resistant tumors, including the focal loss of EGFR and gain of c-Myc and NKX2-1. There was strong correlation between the copy number changes observed and the expression mRNA levels of the involved cancer-associated genes. Of note, each resistant tumor exhibited greater copy number similarity to the corresponding matched pre-treatment sample compared to other tumors within the resistance cohort.

Conclusion
We conducted the first ever comprehensive integrated genomic analysis of EGFR TKI resistant NSCLC patients, and identified both known and potentially novel drivers of EGFR TKI resistance. This study demonstrated the feasibility and utility of comprehensive genomic analysis in the clinical management of NSCLC receiving targeted therapy. Together, our data provide unprecedented insight into the molecular pathogenesis of escape from EGFR oncogene inhibition in NSCLC. We are now conducting a prospective observational study in additional NSCLC patients on targeted therapy.

Abstract not provided

Background
EGFR TKI sensitizing mutations in plasma DNA isolated prior to treatment were shown to be a potent predictor for survival outcome of advanced NSCLC (T. Mok, ASCO 2013). Levels of EGFR mutations (pEGFRmut) in plasma during treatment, including sensitizing and resistance mutations, may offer an opportunity to monitor patient’s response to therapy and disease progression. In this study, we measured the levels of pEGFRmut at every 4 weeks during erlotinib treatment and investigated the emergence of the T790M mutation in relationship to disease progression.

Methods
Retrospective EGFR mutation testing of plasma samples from an unselected cohort of 227 patients with adenocarcinoma with an allele-specific PCR assay, cobas® EGFR_blood test (in development at Roche Molecular Systems, Inc.). The test is designed to detect 42 mutations in exon 18-21 of the EGFR gene including TKI sensitizing mutations (Exon 19 deletions, L858R, G719X and L861Q), resistance mutation (T790M) and atypical mutations (S768I and Exon 20 Insertions). 2 ml plasma of each patient was used for EGFR_blood PCR test. The genomic equivalent copy number of plasma DNA was determined by comparing to a standard curve of genomic DNA.

Results
25 (11%) of 227 unselected patients with adenocarcinoma had a sensitizing EGFR mutation in their plasma prior to the erlotinib treatment. Sequential plasma samples were retrieved for 23 of the 25 pEGFRmut+ patients. 22 (96%) of the 23 pEGFRmut+ patients had lower TKI sensitizing mutations after the first cycle (4 weeks) of erlotinib treatment. The mutated DNA was reduced below the limit of detection for 13 (57%) of the 23 pEGFRmut+ patients during the course of erlotinib treatment. At the time of progression, 6/23 had the same EGFR sensitizing mutations, 9/23 developed T790M mutation with the original mutation and 6/23 patients had no detectable mutation. T790M mutation was not detected in 227 plasma samples taken prior to erlotinib treatment. The figure shows the time course of two representative patients where a T790M resistance mutation emerges. In the 9 patients with T790M mutation, it can be detected in the blood between 15 and 344 days (mean of 98 days) before progression is clinically evident.Figure 1

Conclusion
The amounts of EGFR TKI sensitizing mutant DNA in plasma change during the erlotinib treatment. T790M mutation was not detected prior to erlotinib treatment and is detected between 15 and 344 days before disease progression is evident.

Background
EGFR TKI sensitizing mutations from plasma prior to treatment were shown to be a potent predictor for survival outcome of advanced NSCLC (T. Mok, ASCO 2013). In this study, we tested EGFR mutations in the archived plasma from 199 advanced adenocarcinoma. The plasma samples were taken when they progressed on their chemotherapy and before their 2nd erlotinib treatment a mean of 10.5 months after the diagnostic biopsy was obtained. EGFR mutations detected in plasma after chemotherapy and in the tumor DNA from their original diagnostic biopsies were also compared.

Methods
Plasma DNA and tumor DNA were tested with two allele-specific PCR assays, cobas® EGFR_ FFPET tissue test and cobas® EGFR_blood test (in development at Roche Molecular Systems, Inc.). Both allele-specific PCR assays detect 41 mutations in exon 18-21 of the EGFR gene including TKI sensitizing mutations (Exon 19 deletions, L858R and G719X), resistance mutation (T790M) and atypical mutations (S768I and Exon 20 Insertions). cobas® EGFR_blood test also detects L861Q. Plasma samples of all 199 adenocarcinoma were collected immediately (less than 2 days) prior to the patient’s erlotinib treatment and stored at -80°C. From 197 (99%) of 199 of the patients tumor DNA was extracted from the diagnostic biopsy.

Results
Among 199 advanced adenocarcinoma patients, 24/199 (12%) were EGFR mutation positive in plasma. 28/196 (14%) were EGFR mutation positive in tumor DNA. The comparison of EGFR mutation in plasma and tumor DNA is shown in the table 1. The overall concordance of EGFR mutation status in plasma and tumor biopsy was 91% (179/196). 17/196 (9%) patients had the same EGFR mutations in plasma as in their original diagnosis biopsy and 162/196 (82%) patients were mutation negative in both samples. In this study, different EGFR mutation status in plasma and original biopsy was observed in 17 of 196 (9%) patients. 6 of 17 were EGFR mutation positive in plasma only and 11 of 17 were EGFR positive in tumor DNA only. These differences could reflect alterations in the tumor cells between sampling of biopsy and blood (average of 10.5 months) where the patients are treated with chemotherapy. Another possibility is limitations of assay technology with circulating cell-free DNA in plasma or heterogeneity of tumor.

Conclusion
Tumor mutations in the patient’s original diagnostic biopsy can be detected in their plasma when they progress on chemotherapy which may provide another opportunity for mutation testing. Table 1. Comparison of EGFR mutations detected in plasma and diagnostic biopsy. MND=Mutation-Not-Detected.Figure 1

Background
Resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) in advanced non-small cell lung cancer patients (NSCLC) is attributed to the T790M mutation of EGFR. Here, we evaluated T790M mutation using dynamic, quantitative and non-invasive method and explored its role predicting outcomes of EGFR-TKI treatment.

Methods
We enrolled 135 EGFR-TKI-resistant NSCLC patients in the study. Pre- and post-EGFR-TKI treatment (pre-TKI and post-TKI, respectively) plasma samples were obtained for analysis. T790M mutation was measured qualitatively and quantitatively by the amplification refractory mutation system (ARMS) and digital polymerase chain reaction (D-PCR).

Results
D-PCR was more sensitive than ARMS in detecting the T790M mutation (pre-TKI: 29.4% (32/109) vs 5.5% (6/109), P<0.001; post-TKI: 43.0% (58/135) vs 25.2% (34/135), P=0.001). Patients with a pre-TKI T790M mutation (N=32) showed shorter progression free survival (PFS) and overall survival (OS) than patients without a T790M mutation (N=77) (9.2 vs 12.7 months, P=0.004; and 19.3 vs 31.9 months, P=0.001, respectively). No differences were observed in post-TKIPFS or OS (12.5 vs 12.2 months, P=0.744; and 27.0 vs 29.7 months, P=0.636, respectively). Post-treatment patients were divided into high-frequency (>4.375%) and low-frequency (≤4.375%) groups, according to the mutant T790M-to-wild-type gene ratio calculated from D-PCR results. Patients in the high-frequency group showed a significantly shorter OS than the low-frequency group (20.67 vs 29.13 months, P=0.009).

Conclusion
D-PCR is more sensitive than ARMS in detecting the T790M mutation. The presence of a pre-TKI T790M mutation and a high frequency of post-TKI T790M mutation predicted poor outcomes of EGFR-TKI treatment.

Background
Background: We explored the minimally-invasive detection of EGFR mutations in circulating free DNA from plasma and studied the concordance of EGFR mutation status between matched plasma and tumor tissue in a cohort of newly diagnosed or relapsed patients with advanced NSCLC. CO-1686 is an oral, potent, small-molecule irreversible tyrosine kinase inhibitor that selectively targets mutant forms of EGFR, including T790M and the common initial activating mutations, while sparing wild-type EGFR. Promising clinical activity has recently been reported from an on-going Phase I/II trial.

Methods
Methods: Matched tumor tissue and blood from 80 Stage IIIB/IV NSCLC patients, 41 treated with CO-1686, were tested using two allele-specific PCR assays, the cobas® EGFR FFPET and cobas® EGFR blood tests. Each test detects 41 mutations in EGFR, including the T790M resistance mutation, exon 19 deletions and L858R. We also used BEAMing, a highly quantitative and sensitive technology based on digital PCR, to assess a subset of 18 patients treated with CO-1686. BEAMing was compared to cobas analysis at baseline, and also used to serially monitor plasma EGFR mutation levels in response to CO-1686.

Results
Results: Using tissue as reference, the positive percent agreement between tissue and plasma was 76% (44/58) for activating mutations and 63% (17/27) for T790M. The cobas® EGFR blood test identified two patients with T790M mutations in plasma that were not detected in the corresponding tumor biopsy—likely because of tumor heterogeneity. The M1a/M1b status was known for 63 EGFR mutation-positive patients. Of the 44 with extrathoracic metastatic disease (M1b), 38 were found to have an activating mutation in plasma (86%). Conversely, only 53% (10/19) of EGFR mutation-positive patients with intrathoracic metastatic disease (M1a) had detectable activating mutations in plasma (p = 0.0081). For the 18 patients profiled by BEAMing, the overall percent agreement between BEAMing and the cobas® EGFR blood test was 94% (17/18) for T790M and 83% (15/18) for activating mutations. Nine of the 18 patients had detectable baseline plasma T790M levels, and several patients treated with CO-1686 had an initial decrease in plasma T790M by BEAMing.

Conclusion
Conclusions: Using the cobas® EGFR blood test, a high proportion of EGFR mutations identified in tissue were also detected in plasma. Mutations were more readily detectable in the plasma of patients with M1b rather than M1a disease. These findings suggest that the cobas® EGFR blood test and BEAMing can be useful tools for the non-invasive assessment and monitoring of EGFR mutations in NSCLC patients.

EGFR mutation	Evaluable patients	Patients with tissue mutations*	Patients with plasma mutations**	Patients with same mutation detected in tissue and plasma	Positive Percent Agreement***
L858R, del19, S768I, G719X, or ex20ins	80	58	44	44	76%
T790M	80	27	19	17	63%
* identified by the cobas® EGFR tissue test
** identified by the cobas® EGFR blood test
***agreement of blood and tissue mutation-positive results with tissue as reference; although tissue is reference, some mutations may be missed due to tumor heterogeneity

Abstract not provided

Background
The first generation EGFR TKIs gefitinib and erlotinib provide significant clinical benefit in patients with advanced EGFR mutant NSCLC but many patients ultimately develop disease progression due to acquired resistance. The EGFR T790M mutation is the most common mechanism of acquired drug resistance, detected in more than 50% of gefitinib/erlotinib resistant patients. Current therapeutic strategies are limited for NSCLC patients with EGFR T790M.

Methods
AZD9291 is an oral, irreversible, third generation inhibitor of both EGFR activating (EGFRm+) and resistance mutations (T790M). The mechanistic and functional activity of AZD9291 was characterised in vitro across a number of cell lines harbouring various EGFR-mutations or wild type EGFR. Efficacy of AZD9291 was further evaluated across a number of different EGFR-mutant xenograft and transgenic models in vivo. One open label, dose escalation phase I study of AZD9291 (NCT01802632) is ongoing to determine the safety and tolerability [primary measure], pharmacokinetics and preliminary efficacy profiles of AZD9291, in patients with advanced NSCLC who have progressed following EGFR TKI. Sequential cohorts of 3-6 patients with advanced NSCLC who have had at least one prior regimen containing an EGFR TKI agent (with confirmed EGFRm+ status or Jackman criteria), were treated with AZD9291 once daily. Other key inclusion criteria were PS 0-1, measurable disease, and no prior history of ILD. RECIST assessments were scheduled 6 weekly. Dose escalation can occur after ≥ 3 patients complete both single dose and the first 21-day cycle of AZD9291 multiple dosing with no DLT.

Results
AZD9291 potently inhibits EGFR phosphorylation in EGFRm+ (PC9; 14nM) and EGFRm+/T790M (H1975; 13nM) cell lines in vitro, whilst demonstrating much less activity against wild-type EGFR lines (LoVo; 400nM). Consistently, AZD9291 showed significantly more potent inhibition of proliferation in mutant EGFR cell lines compared to wild-type in vitro. In addition, AZD9291 treatment caused profound growth regression across multiple EGFRm+ (PC9; 250% growth inhibition) and EGFRm+/T790M (H1975; 132% growth inhibition) tumour models in vivo, at doses as low as 5mg/kg after 14 days. Tumour growth inhibition was associated with profound inhibition of EGFR activity and key downstream signaling pathways. Chronic long-term treatment of in vivo PC9 and H1975 xenograft tumours with AZD9291 led to a complete and sustained macroscopic response. In the phase I study, clinical activity with RECIST responses have already been observed at the starting dose level of 20mg once daily, with good tolerability, no reported events of EGFR wild-type rash, and only grade 1 diarrhoea (based on preliminary data, unvalidated and subject to change).

Conclusion
Preclinical data demonstrates that AZD9291 is a potent and effective inhibitor of both EGFR activating (EGFRm+) and resistance mutations (T790M) whilst sparing wild-type EGFR and, early clinical data have been promising. Taken together, these data support the further clinical investigation of AZD9291 in advanced EGFR mutant NSCLC.

Background
Surgical resection is the first line treatment offered to patients with early stage non-small cell lung cancer (NSCLC) who are considered medically fit. Many studies have shown that patients undergoing surgery for lung cancer benefit from receiving treatment in hospitals where high numbers of lung cancer resections are carried out. This study explores the association between hospital volume and survival among all NSCLC patients diagnosed in England who underwent surgical resection and takes into account the differences in case selection and propensity to resect.

Methods
We analysed data on 134,293 patients with NSCLC diagnosed in England between 2004 and 2008 of whom 12,862 (9·6%) underwent surgical resection. Hospital volume was defined according to the number of patients with resected lung cancer in each hospital in each year of diagnosis. Cox proportional hazard regression analyses were used to assess the association between hospital volume and survival among resected patients. We calculated multivariable hazard ratios according to hospital volume, with adjustment for potential confounders (sex, age, socioeconomic deprivation, comorbidity and resection quintile). In addition, to account for the risk of death potentially varying between groups of patients treated within a given hospital, a shared frailty Cox model was used, with hospital as a random effect. The follow-up period was divided into three pre-defined periods: 0-30 days, 31-365 days and >365 days post-surgery.

Results
There was increased survival in hospitals performing more than 150 surgical resections compared with those carrying out less than 70 [HR 0·78 (95% CI 0·67-0·90), p~trend~ <0·01]. The association between hospital volume and survival was present in all three periods of follow-up, but the magnitude of the association was greatest in the period 0-30 days (HR for the 150+ hospital volume group compared with less than 70: 0·58, 95% CI 0·38-0·89) and smallest in the period after 365 days (HR 0·84, 95% CI 0·71-0·99).

Conclusion
High volume hospitals have higher resection rates, operate on patients who are older, have lower socioeconomic status, more comorbidities and despite that they achieve better survival, most notably in the early post-operative period.

Background
Surgery is the most effective way to treat lung cancer. There are significant differences between countries in the effectiveness of surgical treatment. The resection rate differe from 10 to over 20% in Europe

Methods
The National Registry of lung cancer in Poland comprises over 95% of patients with NSCLC treated with surgery. Resection rate (RR) is monitored for 20 years in Poland. Each year RR is calculated by the following formula: R R = (number of resected patients with NSCLC/ number of new cases) x 100 This ratio is calculated for each and even the smallest administrative area (16 provinces and 380 districts). To achieve such a result- the patient's place of residence is taken into account rather than a place where he had his surgery. This allows to determine how many of the patients in particular area have been diagnosed in certain stage of acceptance (mainly I and II) In year 2012, 3591 patients had surgery in Poland. The incidence of NSCLC this year was 22 348 new cases.

Results
The RR in Poland in 2012 was 16.1%. The difference in many provinces ranged from 10.2% - 22%. In few districts the RR was reported from 0% - 46%. 79% of patients were in stage I and II, 11.2% in IIIa, 2.7% in IIIb and and 1.9% in stage IV. Comparing to 2011, resection rate increased by 5%, and within five years - 16.8%. Since 2010 in the areas with the lowest RR a screening program with low-dose computed tomography was implemented. The RR increased from 1,2 to 22% in majority of districts (14/16)

Conclusion
1 Implementation of the resection rate allows to monitor the effectiveness of early diagnosis of lung cancer in different areas 2 Monitoring of the resection rate allows to improve the efficiency of diagnosis of lung cancer in areas where detection was low. 3. Regular evaluation of the RR supports the efforts to improve the results of surgical tratment of NSCLC

Background
The importance of postoperative follow-up and rehabilitation after lung cancer surgery remains a controversial topic. Previous studies have showed that follow-up programs did not influence survival but at that time there was little focus on the effects of rehabilitation. Introduction of new diagnostic procedures, improvements in treatment modalities and increasing awareness on quality of life after treatment has changed guidelines and recommendations for follow-up programs. There is little evidence for these recommendations which prompted us to conduct a randomized study to evaluate the effect of an intense follow-up program on survival and quality of life for patients undergoing surgery for lung cancer (NSCLC).

Methods
Between January 2003 and April 2008 a total 197 NSCLC patients were included in the study after undergoing surgical resection (wedge, lobectomy or pneumonectomy) through a posterolateral thoracotomy. Adjuvant chemotherapy was offered to stage Ib - IIIa. Postoperatively patients were randomized to either active rehabilitation and follow-up (POREFU, N=103) or passive follow-up (Standard, N=94). Patients in the POREFU group had intensive follow-up in the form of annual clinical evaluation, chest X-ray, chest CT, bronchoscopy and EBUS (Endobronchial Ultrasound) for 5 years. In the POREFU group patients were also evaluated by a nurse and a physiotherapist after 6 weeks, 6 months and at annual controls. When indicated, interventions were established to correct patient symptoms. Patients in the standard treatment group were offered a chest X-ray one year after surgery and a clinical examination by their family doctors upon request. Quality of life in both groups was assessed after 6 weeks, 6 months, 12 months and 2, 3, 4 and 5 years evaluating EORTC QLQ-C30/LC13. All survivors were followed for 5 years.

Results
Figure 1There was no significant difference in survival between the two groups (Kaplan Meier plot). There was a significant difference between the two groups in favour of active follow-up regarding Global health status as well as “Physical”, “Role” and “Emotional” functioning and POREFU patients had significant less pain and fatigue. There was no statistical significant improvement of other symptoms or functional issues.

Conclusion
This randomized trial shows that a follow-up program with an additional focus on rehabilitation and intervention towards reported symptoms in patients operated for NSCLC significantly improves quality of life but has no effect on overall survival.

Background
There is marked variation in the management of Thoracic surgical patients post-operatively, both between individual surgeons and surgical centres. This lack of standardisation can lead to staff and patient dissatisfaction, and differing outcomes for patients. In 2012 we introduced a more standardised approach to the management of patients undergoing Thoracic surgery under the care of one consultant (Consultant A). This was based on the ‘fast-track’ protocol published in 2001 by Cerfolio et al. We aimed to determine whether this approach to patient management has affected patient outcome.

Methods
Data for all patients undergoing lung resection at a single centre from April 2012 to March 2013 were collected. The patients were split into two groups, those under the care of Consultant A (group A), and those under the care of the remaining 4 consultants (group B). Group A were managed according to the new standardised pathway which included; stopping the routine use of suction unless clinically required, chest drain removal with cessation of an air leak and drainage below 400mls in 24 hours, and epidural catheter removal on post-operative day 2. Those in group B were managed according to the instructions of the operating Consultant, or the surgical registrars covering the ward. Pre-operative, operative and post-operative data were collected and analysed. Patients were then propensity matched using operation and age.

Results
Two hundred and thirty one patients were identified. Overall mean length of stay for all patients in group A was 5.65 days (SD±4.68), and in group B; 9.97 days (SD±12.06), p<0.001. Of these patients 94 were suitable for propensity matching. There were no significant differences found in the proportion of patients with benign versus malignant pathology, the number with primary lung cancer, or in the stage of the resected primary lung cancer. In-hospital mortality for both groups was one patient (2.13%). There was a lower number of drains inserted peri-operatively in group A patients (p<0.001). Mean time to drain removal (all drains) was 3.42 days (SD±6.35) for group A and 4.24 days (SD±3.08) for group B, p=0.026. Mean length of stay for group A was 6.00 days (SD± 4.86) and for group B 10.33 days (SD±19.29), p=0.042.

Conclusion
Standardising care following surgery has been shown to improve patient safety, and both patient and staff satisfaction. We have found that reducing variation, and following a validated management pathway, significantly reduces the time to chest drain removal and in-hospital length of stay for patients undergoing lung resection for any pathology. We are currently analysing the various elements of the pathway to determine which specific factors impact patient outcome. Further work is required to determine the effect these differences have on patient reported outcome measures, including overall satisfaction.

Background
Surgical resection is the standard of care for patients with early stage non-small cell lung cancer (NSCLC). However outcomes in older patients, especially octogenarians, following resection have not been studied in detail. This analysis was undertaken to evaluate the variations in patterns of care over time and outcomes following resection in octogenarians with early stage NSCLC.

Methods
Patients 80 years of age and older diagnosed with clinical stages I and II NSCLC, between 1988 and 2007, were identified from the SEER database. Data abstracted included age at diagnosis, stage, gender, race, histology, year of diagnosis and cause of death. The type of surgical resection was not available for a majority of patients and hence was not considered. Overall survival was estimated as the time from the date of diagnosis to death, or date of last contact (if censored). Factors associated with survival were assessed using regression analysis based on the Cox proportional hazards model. Temporal trends in survival were compared using log-rank test. Lung cancer specific survival (LCSS) was also estimated in these patients and temporal trends were compared using log-rank tests.

Results
Six hundred and forty-nine patients ≥80 years of age, who underwent surgical resection for stages I and II NSCLC, were identified. The majority of these patients had stage I disease (n=549), were white (n=586) and had an adenocarcinoma (n=325). Females comprised 50.6% of stage I, but only 37% of stage II patients. Factors associated with worse overall survival on multivariate analysis in this cohort were: increasing age [Hazard ratio (HR) - 1.08; 95% CI - 1.03, 1.12], male gender (HR - 1.33; 95% CI - 1.07, 1.65), stage II (HR - 2.21; 95% CI - 1.71, 2.87) and squamous histology (HR - 1.36; 95% CI - 1.07, 1.74). The percentage of patients undergoing surgery increased over time. Of the patients who underwent surgery 8.6% were diagnosed between 1988-1992, 16% between 1993-1997, 24.2% between 1998-2002 and 51.2% between 2002-2007. Despite this the median survival was not significantly different over these time periods. Median survivals for the four different time periods were as follows: 1988-1992 – 3.9 years; 1993-1997 – 3.2 years; 1998-2002 – 3.8 years; 2002-2007 – 3.3 years (p = 0.09). These are comparable to those reported previously in younger patients (ages 65-75 years) (5.92 years - stage I, 2.6 years - stage II). Similarly lung cancer specific survival was not significantly different between the different time points. Median LCSS for the four time periods were 9.2 years, 6.8 years, 7.9 years, and not reached, respectively (p = 0.51).

Conclusion
Among octogenarians who had surgical resection for lung cancer, increasing age, male gender, higher stage and squamous histology were associated with worse survival. Despite an increased incidence of surgical resection for octogenarians, outcomes remained unchanged between 1988 and 2007. Octogenarians, when carefully selected, are capable of experiencing a similar advantage provided by surgical resection of early stage non small cell lung cancer as younger patients.

Abstract not provided

Background
We previously reported a retrospective study indicating the prognostic impact of local treatment of postoperative oligometastases in patients with non-small cell lung cancer (NSCLC) (Yano T et al. J Surg Oncol 2010;102:852-855). However, previous studies have not been sufficient to determine the therapeutic significance of local treatment for postoperative oligometastases since the conclusions were based on retrospectively collected data and the assessment of overall survival. In the present study, we prospectively observed postoperative oligometastatic patients and investigated the effects of local treatment on progression-free survival (PFS).

Methods
Using a prospectively maintained database of patients with completely resected NSCLC treated between October 2007 and December 2011, we identified 52 consecutive patients with postoperative recurrence. Of these patients, 31 suffering from distant metastases alone without primary site recurrence were included in this study. In order to exclude cases of second primary carcinoma of the lungs, the criteria of Martini and Melamed, modified by Antakli et al., were used to differentiate between second primary lung cancer and pulmonary metastasis. According to the definition of ‘oligometastases’ as limited recurrence potentially controlled with local treatment, 17 patients had oligometastatic disease. The number of metastases was less than four.

Results
The oligometastatic sites included the lungs in five patients, the brain in four patients, bone in four patients, the lungs and brain in two patients, the adrenal glands in one patient and soft tissue in one patient. Fifteen of the 17 patients first received local treatment. Three patients (lung, adrenal gland, soft tissue) underwent surgical resection, and the remaining 12 patients received radiotherapy. The median PFS was 33 months in the oligometastatic patients who received local treatment. There were seven patients with a PFS of longer than two years. The metastatic sites in these patients varied, and the number of lesions in three patients was two or three. On the other hand, the two remaining patients first received a systemic chemotherapy of their own selection. The PFS of these two patients was five and 15 months, respectively.

Conclusion
Both our previous retrospective study and the present study favor a choice of local treatment in patients with postoperative oligometastatic NSCLC.

Background
Stage IIIA-N2 non-small cell lung cancer (NSCLC) is currently mainly managed with chemotherapy and radiation therapy with limited outcome. Whether surgical resection should be offered to patients with resectable IIIA-N2 NSCLC as part of a multi-modality approach with adjuvant or neoadjuvant treatment remains unclear. We sought to determine the long-term result of resected IIIA-N2 NSCLC in a single institution.

Methods
We reviewed the charts from a consecutive series of 263 patients with a mean age of 62 years (range, 37-68) undergoing lung resection and complete en bloc lymph node dissection for IIIA-N2 NSCLC from 01/2000 to 12/2011. Clinical N2 (cN2) patients were diagnosed preoperatively on chest CT scan and/or PET scan and were histologically proven by mediastinoscopy or EBUS. Patients with cN2 with a single site of mediastinal disease were occasionally treated with surgery upfront followed by adjuvant chemotherapy with or without radiation (cN2 adj, n=70). The remaining patients with cN2 disease were treated with neoadjuvant therapy followed by surgery (cN2 neoadj, n=55). Minimal N2 patients were diagnosed postoperatively on final pathology report and received adjuvant therapy (mN2, n=138).

Results
Lung resection was a pneumonectomy in 75 patients and a lobectomy in 188 patients with a post-operative mortality of 1.3% and 3.1%, respectively. Adjuvant chemo- or chemoradiation therapy was administered in 181 patients. The overall 5-year survival was 43.6%, with no significant difference between the type of lung resection (pneumonectomy: 38.9% vs. lobectomy: 45.5%, p=0.18) or the number of mediastinal lymph node site involvement (1 site 44.8% vs. 37,7% for multiple sites, p=0.9). Long-term survival tended to be better for mN2 compared to cN2 (5-year survival of 50.4% vs. 35.9%, respectively; p=0.08). However, survival for cN2 was similar between neoadjuvant and adjuvant therapy (5-year survival of 30.3% vs. 40.2%, respectively; p=0.53). The number of mediastinal lymph node site involvement did not impact survival in patients with cN2 disease (1 site 37.6% vs 27.6% for multiple sites, p=0.59).

Conclusion
Surgery for Stage IIIA-N2 NSCLC achieved good long-term survival when combined with chemotherapy or chemo-radiation therapy in well selected patients. Long-term survival was similar in patients with clinical N2 disease whether they received adjuvant or neoadjuvant therapy. Surgery should be considered as part of a multimodality treatment for patients with stage III-N2 NSCLC.

Background
The objectives of this study were to report the surgical techniques and clinical outcome of thoracoscopic half carina resection and thoracoscopic bronchial sleeve resection for central lung cancer.

Methods
Between January 2011 and November 2012, 675 patients with lung cancer underwent radical surgery by thoracoscopy, 49 (7.3%) underwent bronchial sleeve resection. Among 49 patients, 20 (41%) received thoracoscopic bronchial sleeve lobectomy. Perioperative variables and postoperative outcomes of these cases were analyzed to evaluate the technical feasibility and safety of this operation.

Results
In one patient, right upper lung sleeve resection was combined with half-carinal resection and reconstruction. In another, right medial lung sleeve resection was combined with lower right dorsal segment resection. The average time of surgery was 239 min (range, 142-330 min, 239±51 min), and the average time of airway reconstruction was 44 min (range, 22-75 min, 44±17 min). The intraoperative blood loss averaged 207 ml (range, 80-550 ml, 207±96 min). The median postoperative hospital stay was 10 days (interquartile range, 8-12 days). Postoperatively, extubation was achieved in the recovery room without further need for mechanical ventilation. None of the patients developed anastomotic leak. Perioperative mortality was not observed.

Conclusion
Thoracoscopic bronchial sleeve resection can be considered a feasible and safe operation for selected patients with central lung cancer. The complicated anastomosis technique of half carina resection was feasible.

Background
Concurrent chemo-radiation is the standard of care for patients with inoperable stage III NSCLC and good performance status. Following concurrent chemo-radiation some patients may have operable disease, and surgery may be considered to improve the prospects of cure for patients with negative mediastinal nodes and evidence of residual activity in the primary tumour. Surgery is usually not considered for patients who have received radiation doses higher than 45 Gy in 2 Gy daily fractions because of the perceived risk of post operative complications.

Methods
Our standard concurrent chemo-radiotherapy regimen comprises 55 Gy in 20 fractions of 2.75 Gy per day, given over four weeks with cisplatinum 20 mg/m[2] given with radiotherapy fractions 1-4 and 16-19, and vinorelbine 15 mg/m[2 ]IV (40 mg/m[2] orally for patients without dysphagia) with fractions 1, 6, 15 and 20. Twenty-two patients at the Liverpool Heart and Chest Hospital have undergone thoracotomy with a view to resection of residual tumour after completion of this concurrent chemo-radiotherapy schedule.

Results
Resection of residual disease was achieved in 21 out of 22 cases. In one patient, resection was not possible due to dense fibrosis and adhesions at the tumour site. Five patients underwent pneumonectomy, 15 lobectomy and one underwent wedge resection. There was one death in the 30 days following surgery and one patient developed a fistula at 4 months. Histological examination of resection specimens confirmed complete histological response in 14 out of 21 cases (66%). Median survival for was 93.8 months, with 5 year survival of 58.8% and 27.6% of patients surviving 10 years from start of treatment.

Conclusion
Surgical resection is feasible after concurrent chemo-radiation to a dose of 55 Gy in 20 fractions over 4 weeks. The remarkably high complete histological response rate in this series confirms the effectiveness of a strategy to minimise accelerated repopulation by using hypofractionated radiotherapy with cisplatinum and vinorelbine over four weeks.

Background
Non-small cell lung cancer (NSCLC) with pleural spread carries a dismal prognosis of 6-9 months median survival. Standard treatment is palliative chemotherapy. Surgery typically has no role, with studies showing no overall survival (OS) benefit and high rates of local recurrence of up to 90% due to microscopic residual disease following resection. This study investigated the use of surgery with the intent of achieving a gross total resection and intraoperative photodynamic therapy (PDT) to target microscopic residual disease for patients with NSCLC with pleural metastasis to improve local control and OS.

Methods
All patients with NSCLC with pleural metastasis treated with definitive surgery and PDT (porfimer sodium, 24hr drug-light interval, 630nm, 30-60J/cm[2]) from 1997-2012 on either of two IRB-approved prospective clinical trials were assessed. Progression-free survival (PFS) and OS were defined as the time from surgery to recurrence and death, respectively, or to last contact. Pleural control was defined as absence of ipsilateral pleural disease after surgery, whereas locoregional control was defined as absence of lung parenchymal or intrathoracic nodal disease.

Results
34 consecutive patients were assessed, all with ECOG performance status 0-1. The cohort was 50% male, predominantly Caucasian (85%), and a median of 55yrs at the time of surgery (range, 35-73yrs). Most had adenocarcinoma (79%), clinical N2 nodal metastasis (64%), and received neoadjuvant chemotherapy (94%) and/or radiotherapy (12%). Over half (56%) underwent pneumonectomy, whereas 38% received a lesser anatomic resection. Two patients were found intraoperatively to have unresectable disease due to pericardial effusion (n=1) or trans-diaphragmatic extension (n=1). Pathologic staging was pT4N0 (24%) or pT4N2 (76%). Four patients (3/19 pneumonectomy, 1/13 lung-sparing) suffered peri-operative mortality (day 11-98), with one death attributable to PDT (ARDS, day 11). Following surgery/PDT, 59% of patients received mediastinal radiotherapy (median 50.4Gy/1.8Gy) and 50% received chemotherapy. Pleural recurrence rates and OS were similar for patients undergoing pneumonectomy or other procedures (p>0.05 for both). Cohort median OS was 21.4 months (0.4-161.1 months), and survival rates were 59% at 1yr and 41% at 2yrs. Median overall PFS was 7.5 months, with numerous patients achieving durable disease-free intervals (mean PFS 18.4 months). Median pleural PFS was 13.6 months, with pleural recurrences occurring in only 32%. Overall, 79% experienced recurrence or unresectable disease progression, and distant failure was most commonly observed (53%).

Conclusion
This study demonstrates that surgery and intraoperative PDT can achieve durable local control and prolonged survival for NSCLC patients with pleural dissemination. Compared with current standard treatment, which offers a median survival of 6-9 months from pleural metastasis diagnosis, our cohort lived a median of 24.7 months from pleural diagnosis and 21.4 months from surgery/PDT. This study also demonstrates that surgery/PDT can be performed with acceptable morbidity. Distant recurrence was the most common failure, indicating need for improved adjuvant systemic therapy. These results are sufficiently encouraging to warrant further study and suggest that stage IVA NSCLC patients with pleural dissemination, good performance statuses, disease limited to one hemithorax, and of the mind to be aggressive about their disease could be considered for this investigational treatment approach.

Abstract not provided

Background
[68]Ga-macroaggregated-albumin ([68]Ga-MAA) perfusion PET/CT is a novel molecular imaging technique for the assessment of functional lung volumes. This prospective study aims to investigate the utility of four-dimensional (4D) [68]Ga-perfusion PET/CT for functional adaptation of radiation therapy (RT) planning in patients with non-small cell lung cancer (NSCLC).

Methods
An interim analysis was performed of a prospective clinical study of patients with NSCLC who underwent 4D-perfusion PET/CT scanning prior to curative intent RT. All patients were planned to 60Gy in 30fx with or without concurrent chemotherapy based on conventional anatomical lung volumes. Subsequently, a single nuclear medicine physician in conjunction with a single radiation oncologist contoured the functional ‘perfused’ lung using a visually adapted threshold. Functional lung was defined as lung parenchyma with Ga-MAA uptake. A second volume labeled as ‘high-perfused’ lung was created based on a visually adapted 30% max SUV threshold (figure 1). A single RT planner optimised the 3D conformal radiotherapy plan to spare the functionally ‘perfused’ and ‘high-perfused’ lung volumes respectively. Dose volumetrics were compared using mean lung dose (MLD), V5, V10, V20, V30, V40, V50 and V60 parameters. Figure 1 figure 1 - RT Plans optimised to each of the conventional, 'perfused' and 'high perfused' lung volumes.

Results
14 consecutive patients had RT plans adapted to functional lung volumes based on perfusion PET/CT. This patient cohort consisted of ex-smokers with pre-existing airways disease, with a mean FEV1 of 1.87L (0.83L-2.82L) and DLCO of 54% (27%-87%). The average MLD of the original treatment plans was 11.44Gy using conventional anatomical lung measurements. When considering the functional ‘perfused’ lung and ‘high perfused’ lung, the original plan produced an average MLD of 11.12Gy and 12.41Gy respectively. Plans optimized for ‘perfused’ lung only showed significant improvement of the V60 dose parameter (median 1.00Gy, p=0.04). However, plans optimized for ‘high perfused’ lung improved MLD, V30, V40, V50 and V60 (all p-values <0.05). The MLD was improved by a median of 0.86Gy, p<0.01. The largest improvement was found in the V30 parameter, with a median difference of 1.76Gy.

Conclusion
This is the first study of [68]Ga perfusion PET/CT for planning the treatment of lung cancer patients. RT plans adapted to ‘high perfused’ but not ‘perfused’ functional lung volumes allows for significant technical improvement of conventional RT for NSCLC patients. The clinical impact of this improvement in planning technique should be validated in the context of a prospective study measuring patient toxicity outcomes.

Background
Radiation-induced lung damage (RILD) is an important problem. Although physical parameters such as the mean lung dose are used in clinical practice, they are not suited for individualised radiotherapy. As radiosensitivity varies between patients, genetic correlations have been investigated, which appear to be difficult to repeat in validation studies. This may be due, in part, to differences in methods for measuring RILD across studies. Objective, quantitative measurements of RILD on a continuous instead of on an ordinal, semi-quantitative, semi-subjective scale, are needed.

Methods
Hounsfield Unit (HU) changes before vs. 3 months post-radiotherapy were correlated per voxel with the radiotherapy dose. Deformable registration was used to register pre and post CT scans and the density increase was quantified for various dose bins. The dose-response curve for increased HU was quantified using the slope of a linear regression (HU/Gy). The end-point for the toxicity analysis was dyspnoea ≥ grade 2.

Results
95 lung cancer patients were studied. Radiation dose was linearly correlated with the change in HU (mean R[2]=0.74 ± 0.28). No differences in HU/Gy between groups treated with stereotactic radiotherapy, conventional radiotherapy alone, sequential or concurrent chemo-radiotherapy were observed. In the whole patient group, 33/95 (34.7 %) had dyspnoea ≥ G2. Of the 48 patients with a HU/Gy below the median, 16 (33.3 %) developed dyspnoea ≥ G2, while in the 47 patients with a HU/Gy above the median, 17 (36.1 %) had dyspnoea ≥ G2 (not significant). Individual patients showed a nearly 21-fold difference in radiosensitivity, with HU/Gy ranging from 0 to 10 HU/Gy. Figure 1

Conclusion
HU changes identify objectively the whole range of individual radiosensitivity on a continuous, quantitative scale. CT density changes may allow more robust and accurate radiogenomics studies.

Background
The Dutch Society for Radiotherapy and Oncology (NVRO) aims to ensure transparency regarding clinical outcome, quality and safety of lung cancer treatments in radiotherapy departments throughout The Netherlands. Auditing is considered the best instrument to achieve this. The quality of the radiotherapy will become transparent by using objective and reliable data from accurate registration of clinical outcome linked to patient and treatment characteristics The results of the audit are communicated to the health professionals that supplied the data. This outcome registration will provide the local health professionals with a robust instrument to compare and improve their lung cancer treatments. The decision was made to seek collaboration with the thoracic surgeons as their group were already committed to the DICA (Dutch Institute for Clinical Auditing) .

Methods
The Quality Assurance Committee of the NVRO, in collaboration with a platform of Dutch radiation oncologists dedicated to lung cancer treatment, received a grant to set-up a quality assurance program for lung cancer treatment. Quality indicators to be collected were defined within the platform of Dutch radiation oncologists and a database was setup in October 2012. All patients receiving primary thoracic radiation treatment with curative intent for (primary or recurrent) stage I-IIIB lung cancer will be included in the registry. Information will be collected on patient, tumor and treatment characteristics, the incidence and severity of acute toxicity, mortality within three months of radical radiotherapy and the time interval between diagnostic work-up and start of radiotherapy The adherence to the NVRO and Dutch guidelines will be registered and analyzed, as well as the use of new treatment techniques like stereotactic radiotherapy and image-guided radiotherapy. A pilot phase was initiated to test the feasibility of enrolling patients from six participating centers.

Results
The pilot-database was tested in 6 Dutch centers: NKI-AVL (Amsterdam), MAASTRO clinic (Maastricht), RIF (Leeuwarden), RISO (Deventer), UMC Radboud (Nijmegen) and ARTI (Arnhem). A total of 196 patients were entered from January to June 2013. Analysis of the patients entered is ongoing. We expect to have a national roll-out in October 2013. The patient records were very complete with a few exceptions: lung function tests, the Mean Lung Dose / Lung V20, gross tumor volume (23% missing) and the non-mandatory follow-up items. The mean age was 68 years (range 41-90) with 57% males. Charlson comorbidity index ≥ 2 was scored in 39% of patients. Most patients (66%) were cN+ with 14% T4 tumours. Most patients received IMRT or VMAT irradiation. Ninety-five percent of patients completed treatment. All registered patients had position verification during irradiation, mostly 3D (70%). Acute 3-month toxicity (grade≥ III) was registered in 18% of patients and 3-month mortality was 4.4%.

Conclusion
This national audit on outcome after radiotherapy is directed towards an improvement of care for lung cancer patients and will help to direct evidence into clinical practice. It is expected to have an important impact on quality assurance ,safety and possibly patient mortality.

Background
CONVERT is an international randomised phase III trial comparing 45Gy in 30 fractions twice-daily and 66Gy in 33 fractions once-daily (given concurrently with cisplatin/etoposide) for good performance status patients with limited stage small cell lung cancer. A QA programme was set-up to standardise radiotherapy (RT) delivery across all centres.

Methods
The pre-trial QA exercise (PQE) involved completion of a questionnaire and treatment planning exercise. Each participating clinician was asked to select a previously treated patient, who fitted the entry criteria for the trial, and provide disease and organs at risk (OAR) outlines and a treatment plan for both arms of the trial. QA guidelines, including an atlas for OAR outlining, were distributed to participating centres. Additionally, at least one RT plan per centre was randomly collected during the trial (ongoing QA exercise-OQE). A comparison was made between the PQE and OQE for each centre, including a review of eligibility criteria, OAR and gross tumour volume (GTV) outlining, expansion to clinical target volume (CTV) and planning target volume (PTV).

Results
Twenty nine clinicians from 28 centres who had completed both the pre-trial QA and the ongoing QA were included in the analysis. From the pre-trial questionnaire it was reported that 3 centres were using beam energies of 10MV or more which was not permitted as per protocol. Subsequently the PQE showed that these all used acceptable beam energies. Four clinicians submitted ineligible patients for the PQE and none for the OQE. Twenty five clinicians (86.2%) used the correct GTV to CTV and CTV to PTV expansions for the PQE and OQE. Table 1 shows a comparison of adherence to protocol regarding OAR outlining between the PQE and OQE. Table 1

	Oesophagus outline	Spinal canal outline	Heart outline	Lung-PTV outline
PQE-OAR outline as per protocol (n=29)	19 (65.5%)	14 (48.3%)	4 (13.8%)	20 (68.9%)
OQE-OAR outline as per protocol (n=29)	21 (72.4%)	18 (62.1%)	8 (27.6%)	20 (68.9%)

Organ at risk doses were found to be within the tolerances specified in the trial protocol for both PQE and OQE.

Conclusion
A PQE improves clinicians’ compliance to trial protocol, and has been found in the OQE to reduce deviations across the participating centres that may confound the results of the study. Despite the fact that consistency of OAR outlining remained an issue in both the PQE and the OQE an overall improvement was seen following the PQE.

Background
CONVERT is an international randomised phase III trial, comparing 45Gy in 30 fractions twice-daily or 66Gy in 33 fractions once-daily (given concurrently with cisplatin/etoposide) for good performance status patients with limited stage small cell lung cancer. A survey was sent out to 69 clinicians who had randomised patients into the trial with the aim of establishing how radiotherapy techniques for lung cancer have changed over the 5 years since the trial opened.

Methods
As part of the pre-trial quality assurance process each centre was asked to complete a facility questionnaire giving details of treatment planning, delivery and verification techniques. Recruitment to the trial began in April 2008 and in January 2013, a further facility questionnaire was sent to centres. The survey was completed using an on-line survey tool.

Results
This analysis includes answers from the 34 clinicians who responded to the questionnaire. Changes in treatment planning techniques and verification since the beginning of the trial are summarised in table 1. Table 1 Figure 1 *Note that some centres reported using more than one beam arrangement, beam energy, planning algorithm or treatment verification technique. Out of the 34 clinicians who answered the questionnaire, 14 (41.1%) are currently using 4DCT, 3 (8.8%) are using breathold techniques and 16 (47.1%) are not using any technique to account for respiratory motion for simulation and treatment planning of lung patients. Data on management of respiratory motion were not available in 2008.

Conclusion
During the 5 years the CONVERT Trial has been open there have been significant advances in radiotherapy treatment technology. Major changes include the use of Type B treatment planning algorithms and PET CT for planning, IMRT for treatment and CBCT for treatment verification of patients with small cell lung cancer.

Abstract not provided

Background
Manual target volume delineation using CT/FDG-PET is the standard method used for radiotherapy treatment planning of non-small cell lung cancer (NSCLC) patients. Since manual delineation is prone to inter-observer variability and is time consuming, many FDG-PET auto-contouring methods were proposed in literature. The purpose of this study was to investigate to what extent a gradient-based FDG-PET auto-contouring method reduces observer variation, reduces delineation time and influences delineation behavior in radiotherapy treatment planning for NSCLC patients.

Methods
Seven radiation oncologists (observers) dedicated to lung cancer treatment delineated the primary tumor (PT) and involved lymph nodes (LN) for 10 patients with stage IIA-IIIB NSCLC on a co-registered CT/FDG-PET scan. The study was separated in two phases. In the first phase, the observers manually delineated the PT and LN for all patients. For the second phase (four months later), auto-contours were generated for both the PT and LN using a gradient-based FDG-PET segmentation method. Bone and air tissue were removed from these auto-contours using CT thresholding. These auto-contours were provided as initial delineation and were adapted by the observers. Delineation times, delineated contours and agreement with the auto-contour were analyzed. Delineated contours were analyzed based on volume, the ratio between the common volume and the encompassing volume (C/E), Dice Index (DI), local standard deviation (SD) and the local distance between median surface and delineated surface. Regions were identified where the observers did or did not change the provided auto-contours.

Results
The observers agreed with the provided auto-contour for 37.3% of the PT and for 42.6% of the LN. Notable regions of agreement were the tumor/bone and tumor/air interfaces. The mean delineation time was reduced by 23.9% from 25.5 minutes in phase 1 to 19.4 minutes for phase 2 (p=0.000). The mean delineated volume was smaller in phase 2 compared to phase 1: 8.9% for the PT (155.8 to 142.0 cm[3], p=0.000) and by 9.1% for the LN (13.2 to 12.0 cm[3], p=0.001), respectively. The C/E ratio and DI both did not change significantly and were 0.79 and 0.88 for the PT and 0.54 and 0.67 for the LN in both phases. The mean local SD for the PT was 1.7 mm and 1.5 mm and for the LN was 1.5 mm and 1.4 mm and both did not change significantly, for both phases respectively. The mean distance between the median surface and PT delineations was slightly reduced from 2.1 to 1.8 mm for phase 2, and was 2.0 mm for the LN in both phases.

Conclusion
The gradient-based FDG-PET auto-contouring method reduced delineation time by 24%, but was sufficient in only 37.3% of the primary tumors and 42.6% of the involved lymph nodes; most notably at the tumor/bone and tumor/air interfaces segmented using the CT scan. The results suggest the FDG-PET auto-contour is currently primarily used for localization, and not so much for delineation. Multi-modal auto-contouring has the potential to reduce inter-observer variation when further developed in close collaboration with radiation oncologists.

Background
The use of CBCT is essential for precise treatment delivery of radiotherapy for lung cancer. The current work practice at many centres is to use bony landmarks to match on-treatment CBCT to the radiotherapy planning CT to verify treatment. To take full advantage of this imaging modality for lung cancer, soft-tissue matching is preferred as it ensures that the actual lung cancer is within the radiotherapy fields regardless of bony anatomy. However Radiation Therapists (RTs) are trained in bony matching and not soft tissue matching. The purpose of this study was to determine the level of inter-observer variability in lung cancer gross tumour volume (GTV) delineation on CBCT and alignment of the CBCT with a planning GTV between Radiation Therapists (RTs), a Radiation Oncologist (RO) and a Radiologist (RD)

Methods
Ten RTs, one RO and one RD independently delineated the lung cancer GTV for fifteen lung cancer patients on Elekta Synergy CBCT image datasets taken on the first treatment fraction. The window and level settings used by each observer were recorded. Each observer then performed an alignment of the CBCT GVT to the radiotherapy planning GTV and translational errors were recorded. The difference in the isocentre corrections for the alignment shifts and Centre of Volume, Volume and Concordance Index (CI) for the contoured volumes were calculated to determine the level of agreement between the RT’s and the RD and between the RTs and the RO, in comparison to the variation between the RD and RO. In an ideal setting the difference between the RTs and the RO and the RTs and the RD would be at least equivalent to the difference between the RD and RO.

Results
The difference between the RT’s and RO and RD was found to be not statistically equivalent to the difference between the RD and RO. The mean isocentre difference between the RO and RD was 0.40cm, compared with 0.42cm and 0.51cm between the RT’s and the RO and RD respectively. The mean CI between the RD and RO was 0.56 (0.44,0.69), which was smaller than the lower bound of the 95 % confidence intervals (95%) of the RT’s compared to the RD (0.5, 0.56) and RO (0.52,0.59). The mean log COV difference was -0.82cm between the RD and RO and -0.54 and -0.65cm between the RT’s and RO and RD respectively. The volume results showed that only 6 of thirty comparisons were equivalent. The mean volume difference between the RD and RO was 0.44cm[3] and 4.73 cm[3] and 5.7cm[3] between the RT’s and RO and RD respectively.

Conclusion
The variation between the RTs and the RO and RD was greater than the variation between the RO and RD. Advanced training is necessary to educate the RTs on soft-tissue matching on CBCT for lung cancer radiotherapy.

Background
Cone beam-CT (CBCT) guidance is routinely used for setup verification of lung cancer patients treated with radiotherapy. CBCT’s frequently show intra-thoracic anatomical changes (ITAC) during treatment. We developed a protocol as a decision support system to guide the radiation technologist in prioritizing these changes. The purpose of this study was to quantify these ITAC during the radiotherapy course and evaluate the current decision protocol.

Methods
The CBCT-scans (made the first 3 fractions and weekly thereafter) of all lung cancer patients treated in 2010 in our institute with radical radiotherapy were evaluated. Each CBCT-scan was visually compared with the planning-CT and all visible ITAC were scored. Additionally, our decision protocol called “traffic-light protocol” was retrospectively applied to all CBCT-scans. The traffic-light protocol has three urgency levels: 1) red: ITAC that likely have a considerable impact on the delivered dose to the primary tumor and/or involved lymph-nodes such as tumor shifts outside the high dose region, large in- or decrease of atelectasis; 2) orange: ITAC with likely moderate impact on the dose distribution such as tumor progression, minor in- or decrease of atelectasis, pleural effusion and post obstructive pneumonia; 3) green: ITAC with likely negligible impact on the dose distribution such as tumor regression without considerable centre of mass displacement or other anatomical changes. For level red changes, the radiation oncologist needs to be consulted immediately before the treatment fraction is delivered. For level orange, the radiation oncologist will be informed by email and a response is required before the next fraction. For level green, the radiation oncologist is informed but no response is required.

Results
In total 1500 CBCT-scans of 177 patients were evaluated. All patients received radical radiotherapy (≥50 Gy); 97 patients with concurrent chemoradiation, 23 with sequential chemoradiation and 57 with radiotherapy only. In 128 patients (72%) ITAC were observed with maximum level red, orange and green in 12%, 36% and 24% respectively. Fourteen patients (10%) required a new CT and treatment plan to account for the changed anatomy. Most ITAC occurred in the first week (55%). Of all patients with ITAC during treatment, 45%, 36% and 17% had 1, 2, and ≥3 ITAC respectively. Types of observed ITAC were evident regression (36%), considerable tumor baseline shift (28%), changes in atelectasis (15%), tumor progression (11%), pleural effusion (7%) and pneumonia (3%). Progression seen on the CBCT had a significant correlation with changes in week 1 (p<1e3), and level red changes (p=0.01).

Conclusion
ITAC have been observed in 72% of all lung cancer patients during radical radiotherapy. In 12% of the patients the radiation oncologist needed to respond immediately and in 10% of the patients a new planning-CT was made to mitigate the risk of tumor under dosing. Volumetric image guided radiotherapy in combination with a decision protocol is recommended for lung cancer patients treated with radical radiotherapy. In our institute we implemented daily CBCT guidance for accurate patient alignment and simultaneously capture ITAC as soon as possible.

Background
FDG-PET/CT based selective lymph node (LN) irradiation is the standard when using 3D-conformal techniques (3D-CRT) for locally advanced NSCLC. With 3D-CRT, adjacent LN not included in the target volume still receive a substantial radiation dose. With current new techniques (IMRT/VMAT), the radiation dose to non-involved LN decreases, which raises the question whether selective nodal irradiation based on PET/CT is still safe. We therefore evaluated the impact of adding EBUS-TBNA (endobronchial ultrasound guided transbronchial needle aspiration)-mapping of the mediastinal LN to PET/CT in avoiding geographical miss, and on the size of nodal GTV (gross tumor volume).

Methods
Consecutive NSCLC-patients referred for radiotherapy (RT) in 2012 who underwent EBUS-TBNA were included. False negative (FN) LN for different constellations of PET, CT and EBUS-TBNA based on literature data were calculated, to evaluate the safety of excluding LNs based on CT, PET and EBUS findings. A practical algorithm when to include LN in the GTV was made, and tested on our patients. Results are expressed as mean +/- SD and range.

Results
Twenty-five consecutive patients with a full EBUS-TBNA mapping before RT were included: 11 women, 14 men; 17 adenocarcinoma, 8 squamous cell carcinoma; 14 right-sided and 11 left-sided tumors. Mean age: 62.5 +/- 9.7 years. All patients had stage III-disease based on PET-CT. LN stations 1,2R,2L,3,4R,4L,5,6,7,8,9,10-11L,10-11R were analyzed on CT- and PET-scan (=325 LN). Sixty-seven were enlarged (≥10mm), of which 63 were PET-positive. Twelve normal-sized LNs were PET-positive. Fifty LNs were investigated with EBUS-TBNA (mean: 2/patient +/-0.96;1-5): 28 were malignant, 22 normal. EBUS-TBNA detected 1 cancer-containing normal-sized LN without FDG-uptake, thus 1/25 geographical miss (4%). The cancer prevalence, taking into account the FN rate of EBUS of 20%, was calculated (Fig.1). With addition of EBUS, in PET-negative patients FN decreases with 10% for enlarged LN, and with 5% for normal-sized LN. An algorithm when to include a LN in the GTV is proposed (Fig.1). According to this algorithm, in our population 3/79 (4%) enlarged or PET-positive LN would be excluded from the GTV. At patient level, this was a GTV decrease in 3 (12%) patients.

Conclusion
When incidental nodal irradiation is low such as in IMRT or VMAT, EBUS-TBNA should be added to FDG-PET/CT for mediastinal staging. This avoids geographical miss in 4% of patients, and decreases the radiation volume in 12% of patients. A practical algorithm is proposed.

Background
A modern treatment approach for non-resected NSCLC comprises radiation dose intensification and short overall treatment times. We report on patients treated within a prospective trial, correlating doses to tumor volume, combined with chemotherapy sequentially.

Methods
Radiation doses to primary tumors were aligned along increasing tumor size within 4 groups (<2.5 cm/ 2.5-4.5 cm/ 4.5-6.0 cm/ >6.0 cm; mean number of three perpendicular diameters). ICRU-doses of 73.8 Gy/ 79.2 Gy/ 84.6 Gy/ 90.0 Gy, respectively, were applied. Macroscopically involved nodes were treated with a median dose of 59.4 Gy, nodal sites about 6 cm cranial to involved nodes electively with 45 Gy. Fractional doses were 1.8 Gy twice daily (bid). 2 cycles chemotherapy were given before radiotherapy; the interval between chemotherapy and radiotherapy was preferentially shorter than 8 days. With a median follow up time of 56.1 months (range 43.2 – 97.1 ) for patients alive, mature results for locoregional tumor control, survival and toxicity are presented.

Results
Between 2004 and 2009,123 continuously referred, unselected patients with 127 histologically/ cytologically proven NSCLC were enrolled; Stage II: 6 pts.; IIIA: 70 pts.; IIIB: 47 pts. Weight loss >5%/ 3 months: 26%; Karnofsky Index ≤ 70%: 46% of the patients. The local tumor control rate at 2-/ 5 years is 73%/ 70%, respectively; the regional tumor control rate 91%/ 89%, respectively. The median overall survival time is 24.6 months, the 2- and 5-year overall survival rates are 52% and 19%, respectively. 2 treatment-related deaths (progressive pulmonary fibrosis) occurred in patients with pre-existing pulmonary fibrosis. Further toxicity was mild or moderate: Pneumonitis grade 2/ 3 (n=10/ 6); esophagitis grade 2/ 3 (n=16/ 7). Lung late grade 2 (n=13), esophagus late grade 3 (n=1).

Conclusion
Locoregional tumor control is high; as are survival times for this unselected patient cohort. In all outcome parameters DART-bid seems to compare favourably with simultaneous chemo-radiotherapies, at present considered ‘state of the art’; simultaneous treatments however are applicable only to a minority of referred patients, patients in good general condition.

Abstract not provided

Background
Sixty percent of all neoplasms and two-thirds of all deaths due to cancer occur in persons older than 65 years. More than 50% of patients with lung cancer are older than 65 years and 30% older than 70 years. With more persons surviving to older age treatment of the elderly with lung cancer has become an important issue.

Methods
All patients 70 years or older with non small cell lung cancer (NSCLC) seen at the Department of Respiratory Medicine and Allergy, Karolinska Hospital from 2003 to 2006 were retrospective reviewed. In all 659 patients were analyzed.

Results
The mean age was 78 years, 55.5 (%) were men. 93,2% of the males and 82.1% of the females were smokers or former smokers. There was a significant differences between smoking habbits among the genderas (P<0.0001). 77.2 (%) had PS 0-2. 38.4% adenocarcinoma, 9.8% with small cell lung cancer, 20.6% squamous cell carcinoma, 15.6% had clinical lung cancer and the others broncheoalveolar cell carcinoma or low differentiated carcinoma were 15.3%. 10.7% underwent radical surgery, 24% received chemotherapy only, 17.8% radiotherapy against the tumour (there of stereotactic 4.4%), and 3.7% concomitant chemo-radiotherapy. 7.4% received radiotherapy against metastases, and 32.1% had no therapy. Only 10% were given second-line chemotherapy. Median survival for patients 70-75, 76-80 and >80 years was 231, 250 resp 213. Median survival for patients with PS=0 was 810 days, those with PS=3 only 109 days. Median survival was 610 days for patients given second line chemotherapy. Survival among those who received only first line chemotherapy was 285 days.

Conclusion
Significant survival among patients given second line chemotherapy (p<0.003). Significant survival among patients between 70-80 versus > 80 years old (P<0.001). Treatment of elderly patients with lung cancer is feasible if they have a good PS and seems to result in prolonged survival.

Background
In 2004, the Italian Association of Medical Oncology (AIOM) created the RIGHT (Research for the identification of the most effective and highly accepted clinical guidelines for cancer treatment) program. The third step of the program, RIGHT3, aimed to evaluate the concordance between AIOM lung cancer guidelines and clinical practice in Italy. Description of treatment decisions for elderly patients with advanced non-small-cell lung cancer (NSCLC) was among the indicators. According to 2009 AIOM guidelines, single-agent chemotherapy with a third-generation agent was a reasonable choice for elderly patients with advanced NSCLC, whilst evidence about use of platinum-based treatment in the elderly population was judged potentially affected by selection bias and not conclusive.

Methods
RIGHT3 was a retrospective observational study conducted in a sample of 53 Italian lung cancer centers, representative of 230 AIOM centers. Patients with NSCLC diagnosis who had their first visit at the oncology center during 2010 and followed-up for at least 6 months were included. Proportion of elderly patients with stage IV disease receiving chemotherapy was among the 14 indicators evaluated.

Results
Overall, 306 pts with stage IV NSLSC were enrolled, and 299 were evaluable. Of these, 91 (30.4%) were older than 70. In the elderly subgroup, 81 pts (89%) were treated with first-line chemotherapy. In detail, a single-agent treatment was administered in 28 (34.6%) of cases, and a combination chemotherapy in the other 53 cases (65.4%). Among pts receiving platinum-containing doublets, carboplatin was more frequently used than cisplatin: carbo-gemcitabine (16 pts), carbo-pemetrexed (12 pts), cisplatin-pemetrexed (8 pts), cisplatin-gemcitabine (7 pts), carbo-vinorelbine (4 pts) were the 5 most frequently used regimens.Thirty pts (33%) received a second-line chemotherapy: single-agent in 23 cases, combination chemotherapy in 7 cases.

Conclusion
First-line platinum-based combination chemotherapy was commonly used in elderly patients with advanced NSCLC in 2010 by the Italian Lung cancer centers involved. First-line single-agent treatment, recommended by AIOM 2009 guidelines as the treatment choice with highest level of evidence, was used only in a minority of patients.

Background
Sixty percent of all neoplasms and two-thirds of all deaths due to cancer occur in persons older than 65 years. More than 50% of patients with lung cancer are older than 65 years and 30% older than 70 years. With more persons surviving to older age treatment of the elderly with lung cancer has become an important issue.

Methods
All patients 70 years or older with non small cell lung cancer (NSCLC) given chemotherapy at the Department of Respiratory Medicine and Allergy, Karolinska Hospital from 2003 to 2006 were retrospective reviewed. In all 149 patients were analyzed.

Results
The mean age was 75,5 years and median 74 years. 54.4 % were male. 96,3% of the males and 88.2% of the females were smokers or former smokers. There was a significant differences between smoking habitts among the genderas (P<0.05). 16.1% , 50.3% and 27.5% had PS 0 resp 1 resp 2. 57.7% and 30.9% with stage IV resp III . 32.9% adenocarcinoma, 24.8% squamous cell carcinoma, and the others broncheoalveolar cell carcinoma or low differentiated carcinoma were 24.2%. 18.1% of the patients had no histopathological diagnosis – clinical diagnosis. Almost all the patients were given carboplatin/gemcitabin as first line chemotherapy regardless of histology. Four cycles was given to almost all the patients. Only 27.5% were given second-line chemotherapy. Median overall survival was 285 days. Longer overall survival among 70-80 vs > 80 years old patients.

Conclusion
Significant survival among patients between 70-80 versus > 80 years old.. Treatment of elderly patients with lung cancer is feasible if they have a good PS and seems to result in prolonged survival.

Background
The number of seniors in Canada is expected to double by 2036 and 40% of new cancers are diagnosed in those ≥70 years. New data over the last decade suggests an increasing role for systemic treatment options for elderly lung cancer patients. However, age-related changes in organ function, co-morbid health problems, and a greater risk of death from other causes may impact on toxicity and expected survival gains. Historically, many oncologists excluded older patients from receiving chemotherapy. This study investigated trends in the treatment of NSCLC patients over the last decade contrasting patients ≥70 years to those <70 years old.

Methods
We conducted a retrospective cohort study of NSCLC patients (ICD-9 codes 162.2-162.9) residing in Ontario and diagnosed between January 1, 2000-December 31, 2010. Data including demographic, staging, treatment and outcome information were extracted by the Institute for Clinical Evaluative Sciences and de-identified before release. The primary outcomes were the proportion of elderly v non-elderly patients referred to an oncologist and receipt of chemotherapy. Standard statistical methods were used.

Results
Of 61,646 patients, 32,131 (52.1%) were ≥70 years. There was an increase in the number and proportion of cases diagnosed in the elderly over the time period. Fewer adenocarcinomas were diagnosed in the elderly (29.8 v 44%) and more elderly patients lacked microscopic confirmation of malignancy (20.1 v 6.2%). Charlson co-morbidity scores and the need for homecare services prior to diagnosis (12.6 v 4.7%) were higher in the elderly. Staging information was inconsistent prior to 2007. In 53.6% of patients, stage was unknown. Stage distribution in remaining patients was: I (18%), II (6%), III (28%), IV (48%). Referral to any lung cancer specialist (defined as medical oncologist, radiation oncologist, or thoracic surgeon) was significantly lower in the elderly population (80.6 vs 93.9%). This was true for each sub-specialty. Only 59.5% of elderly lung cancer patients were referred to a medical oncologist, compared to 78.5% of younger patients. The elderly were less likely to receive chemotherapy (18.3 v 46.7%), even after referral to medical oncology. Elderly patients had a shorter overall (5.8 v 9.6 months) and lung cancer specific survival (9.5 v 13.9 months). Among patients receiving chemotherapy, there was less difference in overall (13.6 v 14.9 months) and lung cancer specific survival (18.6 v 19.9 months). Receipt of chemotherapy increased only marginally among elderly patients between 2000 and 2010. P-values for all comparisons (p<0.001).

Conclusion
There is evidence of disparity in treatment of elderly lung cancer patients. Fewer patients ≥70 years old are referred to a lung cancer specialist and receive treatment. This trend is particularly evident for referral to medical oncology and receipt of chemotherapy. In those elderly patients who receive chemotherapy, their survival approximates that seen in younger patients. Published evidence supporting the use of chemotherapy in the elderly does not appear to have been implemented into practice.

Abstract not provided

Background
PARAMOUNT study confirmed the improvement of overall survival with continuation maintenance chemotherapy with pemetrexed (PEM) compared with placebo after 4 cycles of cisplatin plus PEM induction chemotherapy recently. JMEN study also showed the usefulness of switch maintenance with PEM after 4 cycles of platinum doublet without PEM. In this study, we conducted the randomized phase II study comparing switch or continuation maintenance chemotherapy with PEM after standard doublet regimen.

Methods
Histologically/cytologically confirmed stage IIIb or IV non-squamous NSCLC patients with mesurable disease, ECOG PS 0-1, age over 20 years and adequate organ function were eligible for the study. Randomization was stratified by gender and stage of disease. Patients received 3 cycles of PEM 500mg/m2 plus CB AUC6 (Arm 1) or PAC 200mg/m2 plus CB AUC6 (Arm 2). All patients with non-PD after induction chemotherapy continued PEM 500mg/m2 until PD. Primary endopoint is progression free survival (PFS).

Results
140 pts were enrolled and assigned to Arm1 or Arm2 randomly. The clinical data of 132 pts were used as full analysis set (median age 64.5 yrs (42-83), 85 male, 120 stage IV, 58 PS0, 127 adenocarcinoma, 46 never smoker). 42 pts had prior treatment including 9 sugery, 1 adjuvant chemotherapy, 24 radiotherapy and 8 others. In both arms, 50% of pts entered into the maintenance treatment with PEM after completion of 3 cycles induction chemotherapy. The median PFS was 113 days in Arm 1 and 143 days in Arm 2, respectively. Cox-proportinal Hazard ratio was1.047, and 95% HR confidential interval was 0.707-1.549. Stratified Log-Rank test showed no significant difference in both arms.

Conclusion
There was no significant difference for PFS in Arm 1(PEM plus CB followed by PEM) and Arm 2 (PAC plus CB followed by PEM).

Background
Continuous maintenance is defined as continuation of ≥ 1 first-line agents after 4-6 cycles of induction therapy in pts who have not progressed. In a pivotal phase 3 trial, first-line treatment to progression with nab-paclitaxel (nab-P, 130-nm albumin-bound paclitaxel particles) + carboplatin (C) vs solvent-based paclitaxel (sb-P) + C resulted in a 68% improvement in response rate (41% vs 24%; P < .001) and a trend toward improved survival (median, 10.7 vs 9.5 months; P = .808) in the subset of pts with SCC. This unplanned exploratory analysis examined outcomes in pts with SCC receiving > 4 cycles of nab-P/C to assess the feasibility of the nab-P/C regimen in the maintenance setting in SCC.

Methods
Pts with untreated stage IIIB/IV NSCLC were randomized 1:1 to nab-P 100 mg/m[2] on days 1, 8, 15 or sb-P 200 mg/m[2] on day 1 every 21 days; both arms received C AUC 6 on day 1. Overall response rate and progression-free survival (PFS) were determined by blinded centralized review. To allow comparison of the results of this analysis with maintenance studies, PFS is expressed from day 1 of cycle 5 (C5D1).

Results
229 pts with SCC received nab-P/C and 221 received sb-P/C in this study. In the nab-P/C arm, 60% (n = 138) of pts with SCC were progression-free at the end of cycle 4 and entered cycle 5 (the study population). In these pts, the median PFS was 3.4 months (range 2.8 – 4.2) from C5D1. The median OS from randomization in these pts was 13.8 months (range 12.4 – 16.8). Survival at 1year was 59% (51% – 67%). The median number of treatment cycles was 7 (range 5 – 31). A total of 125 (91%), 64 (46%) and 35 (25%) pts were treated for up to 6, 8 and 10 cycles, respectively, with a median weekly dose of 75 mg/m[2 ]for nab-paclitaxel in each group, and carboplatin AUC of 6, 4.75, and 4.5, respectively. Preliminary safety findings in this population revealed that the most common grade 3/4 treatment-related adverse events were neutropenia (49%), anemia (31%), and thrombocytopenia (27%). The overall rate of grade 3 peripheral neuropathy in the nab-P/C arm was 4% (with no grade 4); 1%, 3%, and 0% of pts had grade 3 peripheral neuropathy at cycle 6, 8, and 10, respectively.

Conclusion
Continued treatment with nab-P/C to progression was feasible, well tolerated, and effective in pts with advanced SCC who had not progressed after 4 cycles of first-line therapy. Future randomized, prospective studies are warranted to further evaluate the activity of nab-P/C as maintenance therapy in SCC pts.

Background
FRAME was a European non-interventional prospective observational study of patients with advanced or metastatic non-small cell lung cancer (NSCLC) initiating platinum-based therapies as first-line treatment (FLT).

Methods
Patients were enrolled between April 2009 and February 2011. Consenting adult NSCLC (Stage III/IV) patients initiating FLT with a platinum-based doublet chemotherapy, with or without an additional targeted agent, were eligible for the study. The choice of FLT was left to physician discretion, as per routine clinical practice. The primary objective of FRAME was to evaluate overall survival (OS) among different platinum-based treatment cohorts in patients with and without additional targeted therapy. Secondary objectives included the evaluation of OS in patients with different histological subtypes of NSCLC. Survival outcomes were assessed using Kaplan-Meier analysis, and unadjusted estimates are presented.

Results
A total of 1564 eligible patients from 11 EU countries were observed. Patient cohorts were: pemetrexed + platinum, gemcitabine + platinum, vinorelbine + platinum, taxanes + platinum and other therapy + platinum. Table 1 shows a subset of baseline patient characteristics, which varied across several parameters in the treatment cohorts, including age, performance status (PS), stage and histology. The median OS across the 4 main treatment cohorts was 10.3 months (95% CI: 9.5-11.2). A subset of overall survival estimates in the different treatment cohorts is shown in Table 1.

Table 1. Select baseline patient characteristics and overall survival

	Baseline Patient Characteristics				Overall Survival Estimates (unadjusted)
Treatment Cohort[a]	Age ≥70 Years (%)	ECOG PS of 2/3 (%)	Stage IV (%)	Non-squamous Histology (%)	All patients Median OS in Months (95% CI)	Non-squamous Median OS in Months (95% CI)	Non-squamous Cisplatin[b] Median OS in Months (95% CI)
Pemetrexed + Platinum[b ](n=569)	23	18	86	97	10.7 (9.4-12.3) [n=569]	10.6 (9.4-12.0) [n=553]	11.6 (9.9-13.8) [n=374]
Gemcitabine + Platinum[b] (n=360)	35	11	74	56	10.0 (8.4-11.8) [n=360]	8.4 (7.0-10.6) [n=201]	8.4 (6.7-10.8) [n=107]
Taxanes + Platinum[b ](n=295)	36	23	75	64	9.1 (8.0-11.3) [n=295]	8.1 (7.4-10.1) [n=189]	9.6 (7.1-14.1) [n=44]
Vinorelbine + Platinum[b] (n=300)	28	15	67	53	10.7 (8.9-12.8) [n=300]	10.1 (8.0-13.1) [n=160]	9.9 (7.2-13.4) [n=91]

[a]A fifth cohort, the ‘other’ + platinum cohort contained a small number of subjects (n=40) and it was not included in the analyses presented here [b]Cisplatin is the platinum agent in the EMA approved prescription drug label

Conclusion
This observational study of first-line treatment for advanced NSCLC provides data describing patients and their survival outcomes in a real-world European practice setting between 2009 and 2012.

Abstract not provided

Background
Despite the introduction of antiemetic treatments including corticosteroids, serotonin (5-HT3) receptor antagonists and neurokinin-1 receptor antagonist, chemotherapy-induced nausea and vomiting (CINV) remains major adverse toxicity of cancer chemotherapy deteriorating patient’s quality of life. It is recommended that these antiemetic treatments should be adopted according to the emetic risk classification of clinical practice guideline, however, the treatments are not so effective in delayed CINV comparing to acute CINV. The mechanism of delayed CINV is not clear so that effective antiemetic drug have not been developed yet. Iron poisoning in cases of blood transfusion or oversupply of iron supplement have various symptoms such as nausea, vomiting, gastroenteritis and liver injury caused by free radical iron, so-called Fenton reaction. We hypothesized that these symptoms are very similar to the adverse effects of cancer chemotherapy and that CINV may be related to the iron level of the patients receiving chemotherapy.

Methods
The patients with lung cancer received cytotoxic chemotherapy were included to this study if the serum level of iron, unsaturated iron binding capacity (UIBC ) and ferritin before the chemotherapy, on day 2, and day 8 were available. All chemotherapeutic regimens were administered as standard practice indicated by Japan governmental insurance. The treatment regimens were classified to highly emetogenic chemotherapy (HEC), moderately emetogenic chemotherapy (MEC) and low emetogenic chemotherapy (LEC) according to the clinical practice guideline of the American Society of Clinical Oncology to investigate the relationship between the change of serum iron level and CINV.

Results
A total of 37 patients (male26/femal11) were included. The number of patients of each classification were 18 in HEC (cisplatin+etoposide), 14 in MEC(caboplatin+gemcitabine, calboplatin+paclitaxel, calboplatin+etoposide, carboplatin+pemetrexed,irinotecan and amrubicin), 5 in LEC(pemetrexed). Serum iron level (μg/dl) of patients received HEC were 64.6±42.0 before treatment, 233.5±50.0 on day 2, and 235.5±41.3 on day 8. Those of MEC were 62.8±17.0 before treatment, 224.3±33.0 on day 2, and 175.7±87.6 on day 8. Those of LEC were 54.6±17.3 before treatment, 116.4±36.6 on day 2, and 40.7±33.5 on day 8. The serum iron levels of all patients markedly increased on day 2 and there were significant difference between LEC and the other two groups (p=0.01). The iron levels of LEC decreased to normal, on the contrary, those of other two groups remained abnormally high on day 8. With the increase of iron, the significant decrease of UIBC was observed implying that free radical iron appeared after the chemotherapy

Conclusion
Serum iron levels were closely correlated to CINV. This phenomenon may be a clue to new approach for antiemetic treatments.

Background
Chemotherapy-induced nausea and vomiting (CINV) is one of the major causes to deteriorate patient’s quality of life. Therefore, it is important to assess the current status of CINV nationwide for the appropriate treatment method to manage CINV. For this purpose, prospective multi-center observational study was performed in Japan.

Methods
Between 2011/Apr and 2012/Dec, 458 lung cancer patients who underwent systemic chemotherapy with high (HEC) or moderate emetogenic agents (MEC) were registered and the data in 429 patients were analyzed. CINV status was assessed in acute phase (within 24 hours from chemotherapy start) and late phase (after 24 hours) separately. Multivariate analysis was performed to clear the predictive factors in patient background for CINV.

Results
Patient background was as follows; median age 65, 318 male and 111 female patients, 190 patients treated with HEC and 239 with MEC. In acute phase, nausea and vomiting were observed in 5.6% (HEC 6.8%, MEC 4.6%) and 1.2 % (HEC 0.5%, MEC 1.7%) of all patients, respectively. In late phase, nausea and vomiting were observed in 40.1% (HEC 46.3%, MEC 35.2%) and 9.6 % (HEC 7.9%, MEC 10.9%) of all patients, respectively. The frequency of nausea in late phase is significantly higher in HEC than that in MEC. The predictive factors for nausea were a younger age in female patients, and younger age, no drinking history, decreased hemoglobin in male patients. The prediction of CINV by physician was relatively poor in late phase vomiting.

Conclusion
In this study, the current status of CINV and antiemetic therapy in lung cancer patients in Japan were elucidated. CINV was frequently observed in late phase and the appropriate management for late emesis is needed according to the guideline.

Background
POLI is one of the Y-family polymerases, which are considered as error-prone replicases with low fidelity and involved in translesion synthesis (TLS) pathway. Polymorphisms on POLI genes may affect efficiency of DNA damage tolerant repair, therefore affect the platinum-based chemotherapy tolerance in tumor tissue and maintain routine function of normal organs. Our study aimed to investigate the association of five SNPs of POLI at codon 731, 5’-upstream and 3’UTR with prognosis and severe toxicity in advanced NSCLC patients in eastern developed regions in China.

Methods
663 stage III-IV aNSCLC patients treated with first-line platinum-based chemotherapy were genotyped with MassARRY platform on the five polymorphisms.

Results
p.731Ala (G of rs8305) indicated protective tendency from severe grade III-IV gastrointestinal toxicity in a dominant genetic model (adjusted odds ratio for Ala/Ala+Ala/Thr: 0.51, 95% confidence internal, 0.28-0.93； P for trend = 0.028). Stratified analysis revealed that the protective effect was rather for cisplatin- than carbonplatin-based regiments (adjusted OR for Ala/Ala+Ala/Thr: 0.38, 95% CI, 0.18-0.81； P for trend = 0.012). As linked loci of rs8305, rs3730668 on 5’-upstream and rs513543 on 3’-UTR of POLI performed similar protective tendency to gastrointestinal toxicity. No significant association was discovered for these five SNPs with other hematological toxicity, progress-free survival and overall survival. Both haplotype and diplotype analysis revealed consistent result as single polymorphism analysis. Haplotype “AAA” (in the order of rs3730668-rs8305-rs513543) indicated a significant susceptibility to gastrointestinal toxicity (adjusted OR: 1.92; 95% CI, 1.19-3.10; P = 0.007).

Conclusion
For the first time, our study indicated error-prone replicase POLI was associated with gastrointestinal toxicity in aNSCLC patients accepting first-line platinum-base chemotherapy, especially for cisplatin-based regiments.

Background
To determine whether volumetric assessment has potential as a predictive biomarker and to assess relationship between longitudinal tumor data during treatment and prognosis in lung adenocarcinoma patients with sensitizing EGFR mutations treated with EGFR tyrosine kinase inhibitor (TKIs).

Methods
We retrospectively assessed patients with EGFR-mutant stage IV lung adenocarcinoma, who underwent EGFR TKIs as second-line therapy and this treatment was repeated every three weeks until disease progression. All 106 patients with at least one measurable lung lesions were quantitatively analyzed in terms of tumor size and volume based on the whole tumor volume, on baseline contrast-enhanced CT scans and on follow-up CT scans of every two treatment cycle. A quantify for tumor response was evaluated with growth tumor kinetics, followed by determining correlation with early tumor parameters including change of size, volume, and response rate. Cox-proportional hazard model and Log-rank test were also applied to predict the overall survival. Figure 1

Results
Percent of volume change after two cycles of TKI treatment had a strong correlation with progression rate based on growth tumor kinetics (P < 0.001). Responders based on percent of volume change after two cycles of TKI treatment had a higher overall survival rate than non-responders (P = 0.001). The velocity of progression was also a good potential parameter to predict overall survival (P < 0.001). Figure 1

Conclusion
Early radiologic parameters of the tumor helped predict treatment response and overall survival in EGFR mutant lung adenocarcinoma patients treated with TKIs. Longitudinal tumor data also showed potential as a predictive factor.

Abstract not provided