Virtual Library

Background
A projected 75% increase in cancer deaths are expected in Low and Middle Income Countries (LMIC) by 2020. As successful battles against infectious disease and malnutrition deaths are waged, the demands on poor healthcare systems to create affordable oncology infrastructure will become ever more acute. Effective and efficient collaborative technologies that permit presentation of cases from resource limited environments to healthcare professionals in the developed world can aid in decision making, treatment planning and education. In this trial a novel clinical platform was launched in Haiti and we present a case of a chest wall malignancy demonstrating the platform's capacity for collaboration and clinical management between a resource limited community hospital in Haiti and Academic Medical Centers in the United States.

Methods
An Extensible Markup Language (XML) based system was built according to specifications of clinicians in the Thoracic Oncology Service of University of California San Francisco Medical Center. In a community hospital in Saint Marc, Haiti 30 cases involving a variety of clinical conditions across adult and pediatric oncology and traumatic disease were presented to Academic Medical Center volunteer physicians in the United States on a web-based asynchronous clinical collaboration system. The infrastructure required transfer over a wireless network in Haiti followed by secure transmission via internet to the dedicated servers in the United States.

Results
Case 1: A 32 year old Haitian Male presented to the Hopital Saint Nicholas in Saint Marc, Haiti with posterior chest and shoulder pain and a chest wall mass extending to the scapula. X-rays revealed a destructive lesion of the chest wall without frank mass within the pulmonary parenchyma. An open biopsy was performed and the specimen transferred for pathologic evaluation at The University of California San Francisco. Clinicians from 3 medical centers in the US came to a consensus opinion regarding diagnosis (unicentric plasmacytoma of chest wall) and treatment strategy within 3 days. Digital images of Immunohistochemical staining, X-rays uploaded to the collaboration platform via a smartphone photo app and literature reviews of the case were transmitted to Haitian physicians including a treatment plan recommendations . 29 additional patients have been offered evaluation in a web based environment and will be discussed.

Conclusion
Oncology cases in the developing world are increasingly prominent in light of advances in combating infectious disease and poverty related malnutrition. However resource limited environments may not have access to clinical decision tools, diagnostic measures or treatments commonplace in fully developed countries. Inexpensive collaborative technologic tools as demonstrated in this pilot can serve as a bridge between developed and developing countries in combination with the will to improve health among the planet's poorest communities

Background
Lung cancer remains the United Kingdom's commonest cause of cancer death and accounts for 1 in 14 of UK deaths from cancers. Approximately 41,428 new cases of lung cancer and 2500 new cases of mesothelioma are diagnosed in the UK (CRUK : Cancer Research UK 2009.) Evidence shows eighty per cent of people will present with advanced disease and the majority of these will die within a year of diagnosis (CRUK 2009.) There is a large amount of evidence in existence to support end of life care but this is very generic in nature. Consensus opinion from the National Lung Cancer Forum for Nurses recognised the need for specialist guidance for lung cancer and mesothelioma patients to enhance their end of life experience and to inform health care professionals who are caring for this group of patients. The focus of the project was to develop guidance driven by evidence from patients and carers, to focus on issues highlighted by them that were important. Previous guidance produced had not had this direct focus.

Methods
This guidance has been developed over an eighteen month period by a dedicated working party with expertise in caring for lung cancer and mesothelioma patients and carers and incorporating current evidence and guidance which was reviewed extensively. The document provides detailed supportive and palliative care specialist interventions to assist any health care professional who is caring for a patient with advanced lung cancer or mesothelioma. The guidance is focused around nine key elements that were identified in work carried out by the Health Experience Research Group at the University of Oxford. Cancer patients identified nine key areas of their care that were important to them or that they found to be lacking. Holistic approach to care. Getting the bad news. Care co ordination. Responsiveness and ease of access to benefits and support. Pain control and symptom management. Staff attitudes and empathy. End of life choice and the actual experience. Carer focus. Each of these nine key elements are addressed within the guidance. Recommendations are made based on evidence and specialist experience. Good practice examples are included collected from a wide range of lung cancer services across the United Kingdom to assist users to develop their own practice.

Results
The guidance was completed and published in Novmber 2012. The guidance provides a usable document with evidence and practice examples to assist health care professonals to improve supportive and palliative care within their area. The document is being diseminated locally by specialist lung cancer nurses and nationally via the National Lung Cancer Forum for Nurses.

Conclusion
Although recently published and to date has not been formally evaluated, this guidance has been well received by health care professionals and organisations associated with the care of lung cancer and mesothelioma patients. References 1. Cancer Research UK (2009) : Incidences of Lung Cancer (online) Cancer Research UK. Available from 2. Health Experience Research Group (HERG) University of Oxford, GC Associates, Unpublished.

Background
Lung cancer is the leading cause of death from cancer in Australia with the majority of patients diagnosed with late stage incurable disease. Although there is evidence of patient benefit from early involvement with specialist palliative care, this may not translate into clinical practice. The aim of this study was to explore clinicians’ perceptions and attitudes to Palliative Care referral.

Methods
A modified validated self-report palliative care referral questionnaire (Johnson, 2008) was given to doctors and nurses working in the multi-disciplinary lung cancer teams at three teaching hospitals in metropolitan Melbourne. Participants were asked whether listed items had contributed to referral (9 triggers) or non referral (15 barriers) of their patients. Level of agreement with 22 attitudinal and perception items explored clinicians’ views about palliative care.

Results
55 questionnaires were distributed and 42 completed (76% response rate). Respondents had a median of 6 years (interquartile range 3-12) of experience practicing in their specialty. One-third (14/42) were doctors working in Medical Oncology, 26% (11/42) in Respiratory Medicine, 19% (8/42) in Radiation Oncology, and 12%, (5/42) in Surgical Oncology, plus two oncology nurses and one physician trainee.93% of respondents agreed that early referral to Palliative Care is beneficial to patients and 95% agreed that Palliative Care can benefit patients receiving active treatment. The majority (69%) of clinicians believe that their relationship with the patient continues when she/he elects to have specialist palliative care. 71% indicated that it is not difficult to refer a patient they have cared for a long time and have a close relationship with. Almost two-thirds (64%) disagreed that when they first bring up palliative care patients give up hope. However, only 60% of respondents agreed that all advanced cancer patients should be referred to Palliative Care. The most frequently cited reasons for referral were for physical symptoms. The majority reported that Palliative Care is either very important or important for patients with psycho-social issues or foreseeable future psycho-social issues, yet only half of respondents agreed that psycho-social issues would trigger a referral to Palliative Care. When asked for the main reasons for not referring to Palliative Care, 60% agreed they do not refer when the patient has no symptoms and 60% also agreed they do not refer if they can manage the patients’ symptoms themselves. However, only 38% of clinicians reported they were well trained to take care of the symptoms of advanced cancer patients. Issues related to patients not understanding or accepting their prognosis were cited as barriers to referral by more than a third of clinicians.

Conclusion
Clinicians involved in the care of patients with incurable lung cancer have positive perceptions and attitudes to Palliative Care but this may not translate into routine referral of all patients with incurable lung cancer. In order to make referral routine, we need education around the perception that only patients with unmanageable symptoms benefit from referral to Palliative Care. Furthermore, additional training of oncologists about symptom management appears desirable since a significant proportion reported a deficiency in this area.

Abstract not provided

Background
Palliative radiotherapy to the thorax is very effective at managing symptoms and improving quality of life but can also have significant toxicity. Dosing decisions are a balance between potential benefit and toxicity in patients whose prognosis and performance status is poor and who are likely to have multiple co-morbidities and complex causation of symptoms. Observations made by the members of the Uinted Kingdom National Lung Cancer Forum for Nurses (NLCFN) raised concerns that this group of patients may not be receiving optimal intervention and support following palliative radiotherapy. The NLCFN has therefore produced Guidance for the Assessment of Patients following Palliative Radiotherapy for Lung Cancer to aid Lung Cancer Nurse Specialists (LCNS) in the assessment and intervention of patients undergoing low dose palliative radiotherapy for symptoms related to lung cancer and side effects from treatment.

Methods
A NLCFN working group was created to analyse the observation of sub-optimal care following palliative radiotherapy. A literature review was undertaken to identify current best evidence and practice. A survey was undertaken to question LCNS, Clinical Oncologists, as well as Radiographers who could provide whether there was a need for such a guideline. 53 responses were received. Following analysis of the survey and discussion within the working group the Guidance for the Assessment of Patients following Palliative Radiotherapy for Lung Cancer was produced. The guidance aims to aid LCNS in the assessment and intervention of patients undergoing low dose palliative radiotherapy for symptoms related to lung cancer and side effects from treatment. Table 1 Figure 1Figure 2Figure 3

Results
Following the literature review, although there was significant evidence of toxicity profiles and effects of treatment, there were no examples of how to address the support needs of patients following palliative radiotherapy to the thorax. Of the 53 responses, 75% said that there was a need for the service, 54% were not aware of current practice in radiotherapy follow up support, with 55 % stating that a review should take place between 1 and 2 weeks after treatment. The working group produced the guideline following discussion in relation to these outcomes.

Conclusion
The Guidance for the Assessment of Patients following Palliative Radiotherapy for Lung Cancer aims to guide LCNS and the treating teams in the assessment and intervention of patients undergoing low dose palliative radiotherapy for symptoms related to lung cancer. The guideline contains flow charts with recommended interventions together with documentation proforma and Common Toxicity Criteria. In the UK patients are treated in Cancer Centres and often repatriated to secondary care for review and follow-up. The formal assessments provided in the Guidance can be implemented either in the clinic, telephone or home visit. The guideline could be adapted for use in other health care systems other than the UK and can be found at http://www.nlcfn.org.uk/NLCFN-guidelines.htm

Background
Between 01/01/2006 and 31/12/2011, 1070 cases of non-small cell lung cancer (NSCLC) were registered in the Illawarra Shoalhaven Local Health District (ISLHD) Clinical Cancer Registry (ClinCR); having been diagnosed and/or received a cancer directed treatment (including end-of-life palliative care) in an ISLHD public facility. A retrospective study was undertaken to determine the impact palliative care involvement had on the place of death for patients in this cohort who were known to be deceased.

Methods
A retrospective study was undertaken using data recorded in ClinCR. Data items include date of death, name of public facility where death occurred, palliative care status and date of referral to palliative care. Patients who did not die in public hospital had the place of death recorded in a free text box in ClinCR if it was documented in one of ISLHD’s electronic medical records: PowerChart, iPM, CHIME or MOSAIQ.

Results
Of the 1070 cases, 936 (87.5%) patients were known to be deceased, with 93% (872n) of those patients dying locally: palliative care facility 52% (454n); hospital 27.5% (240n); home 14.5% (127) and RACF 6% (51n). The remaining 7% died out of the Area (12n) or had “unknown” recorded for place of death (52n). 87% of those known to be deceased were referred to palliative care. Of the deceased patients not referred to palliative care, 45% died in an acute hospital, compared to 14% of those who were referred to palliative care. Home was the second most frequent place of death (15% 121n) for patients referred to palliative care.

Conclusion
This study shows the impact palliative care involvement had on the place of death for non-small cell lung cancer patients in ISLHD. Although more than 50% died in a dedicated palliative care ward/facility, the data shows that patients with palliative care intervention are more likely to die in their home, and less likely to die in an Acute Hospital. Patients with respiratory cancers may require hospital admissions due to local complications which may not occur in other cancers; making a comparison between this and another tumour stream a worthwhile exercise.

Background
Data from the Ontario Cancer System Quality Index demonstrate a high use of Emergency Department (ED) services by lung cancer patients in the last three months of life. There is a need to better understand the resource utilization of lung cancer patients during this time period.

Methods
A retrospective cohort study was undertaken to evaluate resource utilization in the last three months of life for new patients with lung cancer seen at the Juravinski and Walker Family Cancer Centres between January and June 2011and deceased prior to July 2012. Data abstracted from patient records included demographics, staging, treatment, referral to palliative care, use of community services, visits to the cancer centre and family doctor, visits to the emergency department and hospitalizations in the last three months of life. The primary outcome was the proportion of patients using the ED in the last three months of life. Secondary outcomes include the proportion of patients hospitalized, place of death, and the use of community and palliative care services.

Results
There were 323 new patients seen during the six month period and 162 were deceased at the time of data cut-off. There were 86 men (53%) and 76 women (47%), with a median age at diagnosis was 68.9 years (range 38-90). The majority were married (66%), but 20% were living alone. Twenty percent of patients had SCLC, 73% NSCLC and 7% did not have tissue diagnosis. Most patients (n=141, 87%) were treated with palliative intent from the outset. Chemotherapy was administered to 63 patients (39%) with 11 (7%) receiving chemotherapy within the last 2 weeks of life. A greater proportion of patients received radiation therapy (n=111, 69% [10% radical, 90% palliative]). The median overall survival was 4.1 months (95%CI 3.4-4.8m). The majority of patients (n=132, 82%) were referred to community care services (CCAC) and most of these received community palliative services (n=113, 70%). The median time from CCAC referral to death was 2.5 months (0.3 – 31 months). There was documentation about a change in goal from active treatment to supportive care in 38% of patients and documentation of end of life discussion in 66% of patients. Place of death was: hospital (51%), home (21%), hospice/palliative care institution (20%), unknown (8%). During the last three months of life 93% visited the cancer centre (median visits 2, range 0-10) and 67% made calls to the cancer centre (median 1, range 0-19). Visits to the ED were made by 118 patients (73%, median visits 1, range 1-9) and 36 patients were hospitalized (22%, median 1, range 1-5). Patients referred to CCAC were less likely to visit the ED (72% v 83%, p=0.2).

Conclusion
Lung cancer patients use considerable range of services during the last three months of life. Use of acute care services such as the ED and hospitalizations are common. CCAC referral has a small impact on the use of acute care services.

Abstract not provided

Abstract
ENDOBRONCHIAL ULTRASOUND The integration of ultrasound technology and flexible fiberbronchoscopy enables imaging of lymph nodes, lesions and vessels located beyond the tracheobronchial mucosa. Developed in 2002, the EBUS-bronchoscope looks similar to a normal bronchovideoscope, but is 6.9mm wide and has a 2mm instrument channel and a 30 degree side viewing optic. Furthermore, a curved linear array ultrasonic transducer sits on the distal end and can be used either with direct contact to the mucosal surface or via an inflatable balloon which can be attached at the tip. This allows a conventional endoscopic picture side-by-side with the ultrasonic view. US scanning is performed at a frequency of 7.5-12 MHz with tissue penetration of 20 – 50mm. An ultrasound processor processes the US image. Procedure: The actual TBNA is performed by direct transducer contact with the wall of the trachea or bronchus. When a lesion is outlined, a needle of 21 gauge (NA-201SX-4022; Olympus Corporation, Tokyo, Japan) can be advanced through the working channel and lymph nodes can be punctured under real-time ultrasound visualisation. At the same time colour Doppler can be used to identify surrounding vascular structures. Once the target lymph node or mass has been clearly identified with EBUS, the needle is inserted under real-time US guidance. Suction is applied with a syringe, and the needle is moved back and forth inside the lesion. Lymph node stations that can be reached via EBUS are the highest mediastinal (station 1), the upper paratracheal (2L and 2R), lower paratracheal (4R and 4L), the subcarinal (station 7), the hilar (station 10) as well as the interlobar (station 11) and the lobar nodes (station 12). The highest staging N should be biopsied first otherwise the needle needs to be changed each time. Results: In recently published meta-analysis EBUS-TBNA has been shown to have a high-pooled sensitivity of 93% and specificity of 100% . Multiple publications have shown that even in patients with lymph nodes under 1cm (which had been termed N0 by CT criteria), with the use of EBUS-TBNA a large percentage could still be shown to have N2/N3 disease (some despite also being negative on PET-CT). Complications such as bleeding or infection are very rare and have only been reported as case reports. Endoesophageal ultrasound Gastroenterologists have been using this technique for many years in the investigation of oesophageal and pancreatic malignancies. Mediastinal EUS-FNAs were first used in the early 1990s and have subsequently become a popular method to diagnose a variety of intra-abdominal and intrathoracic masses, including mediastinal lesion. Procedure The linear EUS-Scope (has the same basic architecture as the EBUS and uses a scanner of between 5 and 10 MHz. The penetrating ultrasound depth can be up to 8cm. Needles used for biopsy are 19 or 21gauge, again equipped with a stylet. The procedure is usually performed on an outpatient basis and takes approx 30min. However, EUS-FNA has limited access as only lymph node stations 2L, 4L, 7, 8 and 9 are accessible through a transesophageal approach. Lymph node station 5 is not routinely accessible via EUS, and may require transvascular FNA.. Results. EUS is especially useful in staging of the posterior mediastinum. Multiple publications and a meta-analysis on EUS-FNA have shown a high sensitivity and specificity. Even in patients without mediastinal lymph node enlargement on CT, EUS-FNA has been able to demonstrate metastases in 25% of lung cancer patients. Also, the left adrenal can be reached and identified in 97% of cases. It has a so-called ‘seagull’ shape on ultrasound and is particularly well visualised in cases of metastatic enlargement. Furthermore, the left lobe of liver can also be reached. The hilar and pre-carinal lymph nodes cannot be reached. EUS is also more accurate and has a higher predictive value than either PET scan or CT for posterior mediastinal lymph nodes. The procedure carries only a very small risk of mediastinitis or bleeding. . For both techniques it´s important to remember, however, that with EBUS and EUS the negative predictive value is limited and therefore samples which do not contain tumour cells require follow up with a more definitive procedure such as mediastinoscopy or VATS. Combining EBUS and EUS For tissue sampling of mediastinal lymph nodes after conventional TBNA, the present authors prefer minimally invasive methods such as EBUS-TBNA and EUS-FNA to more invasive procedures such as mediastinoscopy and VATS. EUS-FNA and EBUS-TBNA have been shown to prevent mediastinoscopies to a large extent. EBUS-TBNA and EUS-FNA have a complementary reach in analysing mediastinal nodes whereby EBUS has access to the paratracheal, subcarinal and hilar regions and EUS to the lower mediastinum and aortopulmonary window. As shown above, EUS and EBUS provide access to different areas of the mediastinum. In combining techniques, most lymph node stations as well as the left adrenal gland can be reached (apart from stations 5 and 6). In six recent series the accuracy of EUS-FNA and EBUS-TBNA used in combination for the diagnosis of mediastinal cancer was 95% . Using the EBUS-Scope for both endobronchial as well as endoesophagel sampling, the sensitivity for cancer detection could be shown to be as high as 96% (EUS 89%, EBUS 91%), specificity 100% and negative predictive value of 96% (EUS 82%, EBUS 92%). CONCLUSION Overall, EBUS and EUS are safe and effective techniques for the staging of the mediastinum. They are minimally invasive and reduce the number of invasive staging procedures. Currently, the main limitation for EBUS and EUS are that they are predominantly performed at centres of excellence and hence only on selected patients. Training of physicians and surgeons remains the issue and performance of an adequate amount of procedures per year is required in order to maintain competency. Reimbursement remains an issue in some countries as well as the actual implementation into cancer guidelines within the hospitals. Increasingly both techniques are being used in hospitals across the world improving the diagnostic yield. Combined EBUS and EUS ought to be regarded as the “first techniques into the mediastinum”, called “complete endo-echo staging”.

Abstract
There is a widely divergent clinical, radiologic, molecular and pathologic spectrum within lung adenocarcinoma. Remarkable advances in understanding of the genetic mechanisms that underlie lung adenocarcinoma have altered the diagnostic criteria that determine subsequent treatment. The use of the term bronchioloalveolar carcinoma (BAC) encompassed a broad spectrum of tumors ranging from solitary small peripheral lung tumors with a 100% 5-year survival to widespread advanced disease with a 10% 3-5 year survivals, with widely varying use of terminology even after publication of the 2004 WHO Classification. There are also clinical, radiologic, immunohistochemical, and molecular differences that are distinguishable among the subsets of mucinous and non-mucinous types of adenocarcinoma. In 2011, a new Classification of Lung Adenocarcinoma was therefore proposed by the International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society. The 2011 classification addressed three important weaknesses in the previous classification. First, it eliminated the term BAC. Second, it added new terminologies of carcinoma-in-situ, and minimally invasive adenocarcinoma to recognize that minimal invasion (< 5mm). Third, it replaced the terminology of mixed adenocarcinoma. The widespread availability of MDCT and abundance of new information obtained especially from low-dose CT lung cancer screening programs, have increased our understanding of the types and management of small peripheral lung nodules encountered in daily clinical practice, in particular, the importance and prevalence of subsolid pulmonary nodules (atypical adenomatous hyperplasia (AAH), ground glass nodules (GGN) and part-solid nodules). Thin section CT has emerged as a new biomarker for lung adenocarcinoma subtypes. The staging system is based solely on the anatomic extent of the disease. Other factors, such as clinical symptoms or molecular biological characterization of the tumor or attenuation of nodules on CT are not factored in the new TNM classification. Increasing T status reflects tumors that are larger or invasive. In lung cancer nodal staging depends on the location of involved nodes (as opposed to the number of nodes). The M descriptor defines the presence or absence of distant metastatic disease. In 2007, The International Association for the Study of Lung Cancer (IASLC) revised the lung cancer stage groupings based on newer survival data. In the 7[th] edition of TNM classification of lung cancer, following modifications were made: (a) Size cut points, in addition to the 3 cm cut point that traditionally separated T1 and T2 tumors, was introduced at 2, 5, and 7 cm. T1 tumors were now subdivided into T1a and T1b around the 2 cm cut point. T2 tumors were subdivided into T2a and T2b around the 5 cm cut point, and tumors larger than 7 cm. were classified as T3. (b) Cases in which additional tumor nodules are found were reclassified. Those in the same lobe as the primary tumor are now classified as T3, those in the other ipsilateral lobes are T4 and those in the opposite lung are now M1a. (c) Cases associated with pleural or pericardial nodules or effusions were reclassified from T4 to M1a. M1 disease due to distant metastasis was reclassified as M1b. A new IASLC nodal chart, with precise definitions was also agreed, reconciling the previous differences between the Japanese and Mountain-Dresler charts. The concept of nodal zones was introduced to make such classification relevant to those dealing with bulky nodal deposits that transgress the boundaries of individual nodal stations. Further improvements in stage discrimination and management of lung cancer could be expected in the future, as more robust data related to genetic make-up and biological behavior affecting survival of tumors becomes available.

Abstract
Background The origin of the International Association for the Study of Lung Cancer (IASLC) Lung Cancer Staging Project took place during an international workshop on intrathoracic staging organized at the Royal Brompton Hospital, London, UK, in 1996. (1) At that time, the 6[th] edition of the tumour, node and metastasis (TNM) classification was in press, but its limitations and weaknesses were discussed in an international and multidisciplinary forum. The main conclusion was the need for a large international database that could be used to refine and update the TNM classification of lung cancer. Two years later, the IASLC Board approved the creation of an International Staging Committee (ISC), whose first co-chairs were Mr. Peter Goldstraw and the late Dr. Robert Ginsberg. An international call was made to promote participation and data sharing, and potential participants were summoned to subsequent meetings and workshops. Data on lung cancer patients diagnosed from 1990 to 2000 were collected from 46 different sources in 20 countries around the world. Data were stored, managed and analysed at Cancer Research And Biostatistics (CRAB), a biostatistics agency based in Seattle, WA, USA. By the end of 2005, 100,869 cases had been registered and 81,495 were analyzable: 68,463 non-small cell lung cancers (NSCLC) and 13,032 small cell lung cancers (SCLC). (2) The analyses of these cases allowed the IASLC to issue recommendations for changes to the 6[th] edition of the TNM classification. The recommendations were accepted by the Union for International Cancer Control (UICC) and by the American Joint Committee on Cancer (AJCC), and were introduced in the 7[th] edition of the TNM classification. (3, 4, 5) With the revision undertaken for the 7[th] edition, a new period of data-based revisions started, with the IASLC leading the revision process and informing the UICC and the AJCC of the potential changes in the classification based on the analyses of its growing international databases. The analyses of the retrospective IASLC database showed that a more detailed database, containing specific information on T, N and M descriptors, would be necessary to continue the revision process. Therefore, in 2009, a call was made for international participation in the prospective collection of data to inform the 8[th] edition of the TNM classification of lung cancer, due to be published in 2016. (6) The IASLC Prospective Phase of the Lung Cancer Staging Project This prospective phase of the project included a new retrospective collection of data from 1999 to 2010. 94,684 patients were collected: 78,640 analyzable cases of NSCLC and 5,912 analyzable cases of SCLC. These cases will be used to inform the 8[th] edition of the TNM classification and are now being analysed at CRAB. Expansion to Other Thoracic Malignancies The ISC incorporated mesothelioma in 2008 and thymic malignancies and oesophageal cancer in 2009. The structure of the ISC was modified to accommodate more tumours and members. Four domains were created: lung cancer domain (chaired by this writer), mesothelioma domain (chaired by Dr. Valerie Rusch), thymic malignancies domain (chaired by Dr. Frank Detterbeck) and oesophageal cancer domain (chaired by Dr. Tom Rice). To increase the participation of more specialists without increasing the number of ISC members and the budget, advisory boards for mesothelioma, thymic malignancies and oesophageal cancer were created. The retrospective database of mesothelioma contains 3,101 surgically treated patients, and its first analysis has been already published. (7) The International Mesothelioma Interest Group (IMIG) and the Mesothelioma Applied Research Foundation (MARF) collaborate with the IASLC Mesothelioma Staging Project. The prospective collection of cases is now ongoing, includes surgically and non-surgically treated patients, and is intended to inform the 8[th] edition of the TNM classification. A side-project on volumetric computerized tomography for clinical staging is also underway. The retrospective database of thymic malignancies has data on more than 10,000 cases, and the prospective collection of data is ongoing. The ISC works closely with the International Thymic Malignancies Interest Group (ITMIG) (8) and with thymic working groups of scientific societies, such as the European Society of Thoracic Surgeons, the European Association for Cardiothoracic Surgery, etc. The main objective is to device a data-driven, internationally acceptable TNM classification for thymic malignancies, both thymomas and thymic carinomas. The retrospective database of the oesophageal cancer is kept at the Cleveland Clinic, Cleveland, OH, USA, and contains data on more than 10,000 patients. Cases are provided by members of the Worldwide Esophageal Cancer Collaboration (WECC). (9) The revised 7[th] edition of the TNM classification of oesophageal cancer was based on the analyses of the surgically treated patients of this database. (10) Expansion to Prognostic Factors Given the importance of more precise prognostication, besides that provided by the TNM classification and staging system, the IASLC Board decided to expand the activities of the Committee to prognostic factors. To make this activity more patent, the name of the Committee was changed to Staging and Prognostic Factors Committee in February 2013. References 1. Goldstraw P. Report on the international workshop on intrathoracic staging, London, October 1996. Lung Cancer 1997;18:107-111. 2. Goldstraw P, Crowley JJ . The International Association for the Study of Lung Cancer international staging project on lung cancer. J Thorac Oncol 2006;1:281-286 3. Goldstraw P, ed. Staging manual in thoracic oncology. Orange Park, FL: Editorial Rx Press; 2009. 4. Sobin L, et al., eds. TNM classification of malignant tumours. 7[th] edition. Oxford: Wiley-Blackwell; 2009;138-146. 5. Edge SB et al., eds. Cancer staging manual. 7[th] edition. New York: Springer; 2010;253-270. 6. Giroux DJ et al. The IASLC lung cancer staging project. Data elements for the prospective project. J Thorac Oncol 2009;4:679-683. 7. Rusch VW et al. Initial analysis of the International Association for the Study of Lung Cancer mesothelioma database. J Thorac Oncol 2012;7:1631-1639. 8. Detterbeck FC, Huang J. Overview. J Thorac Oncol 2011;6(Suppl 3):s1689-1690. 9. Rice TW et al. Worldwide esophageal cancer collaboration. Dis Esophagus 2009;22:1-8. 10. Rice TW et al. 7[th] edition of the AJCC Cancer Staging Manual: esophageal and esophagogastric junction. Ann Surg Oncol 2010;17:1721-1724.

Abstract
Tumor diagnosis, tumor staging, and patient treatment in clinical oncology depend on morphological and molecular imaging procedures, such as magnetic resonance imaging (MRI), computed tomography (CT), and positron emission tomography (PET). Radiological and functional imaging studies, however, have well-known, inherent limitations that limit their diagnostic accuracy in assessing tumor stage and therapeutic response. Both CT and MRI provide mainly morphological information on the tumor and potential metastasis. However, the lack of functional information frequently limits the value of these studies when assessing lymph nodes metastasis. Accurate staging of patients with non-small cell lung cancer (NSCLC) is of paramount importance because stage significantly affects both treatment options and prognosis. The management of NSCLC often requires a multimodality approach for accurate diagnosis and staging and for patient treatment. Some of the most important advances in the treatment of lung cancer have been the development and implementation of accurate and functional imaging. In numerous studies the diagnostic capability of whole-body MRI, PET and PET/CT for cancer staging has been evaluated and compared. In the primary evaluation of pulmonary lesions, fluorodeoxyglucose (FDG)-PET scans are useful for distinguishing benign from malignant etiologies. Several studies investigating the accuracy of FDG-PET in diagnosing malignant pulmonary lesions have estimated its sensitivity and specificity to be 96.8% and 77.8%, respectively. In the same analysis, FDG-PET was found to be superior to CT for evaluating nodal and distant metastases and changed therapeutic management in 18% of the cases studied. However, PET has been shown to be less sensitive for characterizing smaller lung lesions. The positive predictive value (PPV) of FDG-PET is significantly lower for lesions smaller than 1 cm than for larger lesions (0.36 vs 0.90, p=0.015). The lower PPV for smaller lesions reflects a higher rate of false-positive FDG-PET scans. A comparison of the characteristics of PET-negative and PET-positive tumors has shown significant differences in lesion size (p < 0.001), histopathological type (p < 0.001), and pathological stage (p = 0.028). Both lesion size (p < 0.001) and histopathological tumor type (p < 0.001) were significant factors for determining whether PET results were negative or positive. This study established that negative PET findings were likely for lesions 2 cm or smaller and for adenocarcinomas (i.e., adenocarcinoma in situ and well-differentiated adenocarcinomas). A meta-analysis of 59 studies has shown that PET/CT is useful for detecting lymph node metastasis and extrathoracic metastasis. PET/CT is significantly more sensitive and specific than conventional CT alone and more sensitive than PET alone for staging NSCLC. Furthermore, PET/CT demonstrates excellent sensitivity (0.91) and specificity (0.98) for bone metastasis. However, PET/CT has high specificity but low sensitivity for detecting brain metastasis. The question of bone metastasis was most thoroughly answered by a recent meta-analysis of 17 studies comparing FDG-PET/CT, FDG-PET, MRI, and bone scintigraphy. The pooled sensitivity of each of the modalities in the detection of metastasis was 92%, 87%, 77%, and 86%, respectively, and the specificity was 98%, 94%, 92%, and 88%, respectively. When compared with other imaging modalities, FDG-PET appears to offer no additional information regarding the presence of metastatic disease in the brain. The current standard of care is to evaluate the brain metastasis with MRI in all patients, except those with clinical stage IA disease. A recent study of 1122 patients with PET-CT–determined stage I (T1-2N0) NSCLC suggests that invasive staging is not indicated for such patients, especially if a PET scan of the mediastinum is negative. Several studies have assessed the prognostic implications of mediastinal PET findings in patients undergoing curative resection of NSCLC. The rates of locoregional and distant recurrence are higher in patients with positive mediastinal PET findings than in patients with negative findings for the N0/N1 subset. The higher rate of locoregional failure in patients with positive preoperative PET findings in the mediastinum might lead to postoperative radiation therapy. Although chemotherapy is recommended for most patients with N1 disease, chemotherapy is generally not recommended for patients with N0 disease. The higher rate of distant failure in patients with positive preoperative mediastinal PET findings might lead to chemotherapy being recommended. On the other hand, pathologic confirmation with invasive mediastinal staging, either by mediastinoscopy alone or by mediastinoscopy combined with thoracotomy, is recommended if mediastinal lymph node abnormalities are detected with PET-CT. Several recent studies have shown that diffusion-weighted magnetic resonance imaging (DWI) has a higher specificity for N staging of NSCLC than does FDG PET/CT and has the potential to be a reliable alternative noninvasive imaging method for the preoperative staging of mediastinal and hilar lymph nodes in patients with NSCLC. Short inversion time inversion-recovery (STIR) turbo spin-echo (SE) MRI may be useful for distinguishing metastatic lymph nodes from nonmetastatic lymph nodes in patients with NSCLC. This imaging method might be more sensitive and accurate than CT, conventional T1-weighted MRI, FDG PET, or FDG PET/CT. We can prospectively compare the diagnostic capabilities of STIR turbo SE imaging, DWI, and FDG PET/CT for N staging in patients with NSCLC. In patients with NSCLC, quantitative and qualitative assessments of N staging obtained with STIR turbo SE MR imaging are more sensitive and more accurate than those obtained with DWI or FDG PET/CT. A new technology, PET-MRI, is now being established. To guarantee the clinically valuable, time- and cost-efficient use of PET/MRI, it is essential that appropriate indications be chosen, that cross-modality training be performed, that the acquisition protocols be optimized, and that the images be carefully reviewed, taking into account potential artifacts. Additional studies are needed to determine how PET/MRI might best be used clinically and to prospectively verify its clinical abilities. The increased use of FDG-PET will help clinicians to select the most appropriate treatments for each patient and thereby improve outcomes and avoid toxic therapies that are unlikely to be beneficial.

Abstract
Introduction: Excellent cure rates for central lung cancer can be achieved with local endobronchial therapy if lesions can be detected at a pre-invasive stage. Flexible white light bronchoscopy is the most commonly used imaging tool to evaluate the central airways but it has a limited ability to detect small pre-invasive central lung cancers. Screening with low dose thoracic CT (LDCT) has been shown to be useful in the early detection of lung cancer, but it largely detects peripheral lesions. Despite advances in CT technology, LDCT cannot detect early pre-invasive central lung cancers due to limitation of resolution. Method: Optical imaging modalities that are both established and in development will be reviewed and discussed. These include techniques such as autofluorescence bronchoscopy, narrow band imaging, optical coherence tomography, confocal microendoscopy, endocystoscopy and raman spectroscopy. Results: Autofluoresence imaging is the most well proven imaging tool to be used in conjunction with white light bronchoscopy to rapidly detect small preinvasive lesions. Narrow band imaging may also be useful but further comparative studies are needed. Optical coherence tomography and raman spectroscopy are promising techniques that can be easily applied via small probes during flexible bronchoscopy to further evaluate abnormal lesions. Further development of in-vivo microscopic evaluation of abnormal lesions is ongoing using confocal microendoscopy and endocystoscopy although tissue staining and direct contact is currently required. Conclusion: The detection of early central lung cancers requires more sophisticated tools than conventional white light bronchoscopy. The future utilisation of other imaging tools as part of a minimally invasive flexible bronchoscopic procedure appears promising. A multimodality approach will enable the rapid detection and diagnosis of early curable central lung cancers in selected high-risk populations.

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Abstract
Stereotactic ablative radiotherapy (SABR) is an established treatment modality in the curative treatment of early stage peripheral non-small cell lung cancer (NSCLC). The local control rates of SABR in many publications have exceeded 90% when tumors of up to 5 cm were treated, with corresponding regional nodal failure rates of approximately 10%. SABR has been reported in many series to have only modest early and late toxicity, generally maintaining pulmonary function and preserving health-related quality of life. Following the publication of an phase II study, which showed an 11-fold increase in severe toxicity in the subgroup of patients with centrally located lung tumors that had been treated with a high dose per fraction, these central locations had been considered to be a ‘no fly zone’ for SABR [Timmerman 2006]. Although several subsequent single center studies have shown that SABR performed with an adapted fractionation scheme using daily fractions of 6.0–7.5 Gy to total doses of 48–60 Gy has been both effective and safe, the results of the ongoing Radiation Therapy Oncology Group (RTOG) phase II trial (0813) for SABR in central tumors, have to be awaited to determine the maximum tolerated dose which can be delivered in five fractions. A recently published systematic review of the literature identified a total of 20 studies reporting on the outcome of SABR in 315 patients with centrally located early stage NSCLC, including two phase II studies [Senthi 2013]. The overall survival rates reported for centrally located tumors appeared to be similar to those of peripheral tumors. Similar to what has been described for peripheral lesions, central tumors showed a dose–response relationship for local control, with four studies reporting improved outcomes with a biological effective dose of 100 Gy~10~ or higher compared to lower doses. In those studies where fractionation schedules with a biological effective dose of 100 Gy~10~ or higher were used, the local control rates exceeded 85%. Post-SABR grade 3 or 4 toxicity occurred in 8.6% of central tumors treated with SABR, and the risk of treatment-related mortality was less than 1% if the biological effective dose for late responding tissues (BED Gy~3~) remained below 210 Gy~3~. In conclusion, SABR for central tumors has been shown to be both effective and safe, provided that appropriate risk-adapted fractionation schemes are used and careful contouring of organs at risk with quality assurance of all aspects of treatment planning and delivery are taken into account. The results of the RTOG dose-finding phase II study 0813, in which already 120 patients are entered, will further strengthen the data on the use of SABR for centrally located tumors.

Abstract
Lung cancer risk models and screening protocols are becoming more precise and, consequently, there is an increasing interest in developing new chemoprevention strategies for lung cancer. A number of compounds, among them several phytochemicals, have been proposed as potential lung cancer chemopreventive agents based on studies using rodent models. New preclinical studies involving novel chemopreventive compounds or more efficacious dosing strategies are required and their success will depend in part on the quality of the experimental models. In our presentation we will give an update of the available and newly emerging rodent models for the preclinical study of potential chemopreventive interventions for lung cancer. In order to fully recapitulate the complexities of human lung cancer, different animal models have been developed. These models can be divided into chemically-induced lung cancer and genetically engineered mouse models (GEMMs). Most chemoprevention studies have been performed on mouse models of lung adenocarcinoma (ADC) induced by a number of chemical carcinogens found in tobacco combustion products. The A/J mouse strain has been utilized primarily for these studies since these mice develop lung tumors rapidly after treatment with certain carcinogens such as anthracene, urethane, nicotine-derived nitrosamine ketone (NNK), other nitrosamines, benzo(a)pyrene (BaP), or vinyl carbamate. There are several well established chemically induced mouse ADC models which have been most frequently used in the assessment of the preventive potential of various types of agents: Genetic differences between ADC and squamous cell carcinoma (SCC) are also paralleled in the development of animal models. Skin painting with nitroso-tris-chloroethylurea (NTCU) is the best established protocol to produce lung SCC in susceptible mice and it has already been used for chemoprevention studies. In our lab, we have studied some phenotypic and genetic traits of the NTCU induced SCC, and we have used this model to analyse SCC-specific drug efficacy. GEMMs of lung cancer, mainly leading to adenomas or ADCs have also been used in chemopreventive preclinical studies. A plethora of GEMMs for lung carcinogenesis are available with single or combined genetic alterations in oncogenes or tumor suppressors. Several mouse models of lung cancer have been developed with mutation of Kras as the initiating oncogenic event. In the Kras[LSLG12D/+ ]knock-in mouse model, expression of oncogenic Kras is achieved by intratracheal inoculation with adenoviruses carrying Cre-recombinase The Kras[LSLG12D/+ ]model represents a highly relevant GEMM as it recapitulates many aspects of human ADC oncogenesis, including the full spectrum of lesions from early atypical adenomatous hyperplasia (AAH) to adenocarcinoma, and expresses human NSCLC gene signatures. Interestingly, combined mutant KRAS expression with additional genetic alterations such as p53, PTEN or LKB1 loss results in advanced stages of lung cancer including metastasis. To date, there is only one GEMM leading to pure squamous histology with many human SCC traits, recently developed in kinase-dead IKKα knock-in mice. Some years ago a mouse model for SCLC was developed by conditional inactivation of Rb1 and Trp53 in mouse lung epithelial cells. A newly developed model of SCLC incorporates p130 knockout and accelerates the formation of SCLC. Finally, mouse models for inflammation-driven lung carcinogenesis are helping to understand the role of smoking induced inflammation in lung cancer. We recently found that silica-induced chronic lung inflammation markedly increases the incidence and multiplicity of mouse lung adenomas and ADCs following N-nitrosodimethylamine (NDMA) treatment. These results are in concordance with other animal models that explore the effects of different inflammatory agents in chemically-induced lung tumor promotion. One of the key practical points regarding the relevance of these animal models in developing new chemoprevention strategies is the extent to which they recapitulate human lung cancer multistep progression at the cellular and molecular levels.. The pathological and molecular likes and dislikes between human lung cancer and the most frequently used animal models will be discussed during the presentation. The quantitative assessment of tumor volume progression in cancers affecting internal organs such the lung is more difficult than the assessment of lesions that are superficial (for example, breast or skin). New imaging technologies such as respiratory-gated micro-CT scans for small animals allow performing longitudinal studies on animal models of lung cancer. Micro-CT has been mainly used to monitor tumor growth and to assess the response or the resistance to therapeutic drugs. The potential of micro-CT imaging in lung cancer chemoprevention studies has been already highlighted. Standardization of protocols, improved resolution, more robust and faster image acquisition and, fully automatic and properly validated quantification algorithms need to be implemented before micro-CT imaging can show its full potential in the assessment of chemoprevention therapies.

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Abstract
The goal of lung cancer chemoprevention is to prevent the development of invasive cancer, but designing early phase intermediate efficacy clinical trials to demonstrate that a strategy is effective remains a “work in progress”. Phase III prevention trials focus on individuals at high risk for cancer and have a lung cancer endpoint. By contrast, phase II trials depend on intermediate endpoints that are surrogates for cancer incidence, in a fashion analogous to shrinkage in tumor size being a surrogate for survival in phase II cancer treatment trials. Examples of such endpoints include premalignant lesions, proliferative indices, and various biomarkers of risk or malignant potential. To be useful, intermediate endpoints should be integrally involved in the process of carcinogenesis, differentially expressed in at-risk vs. normal epithelium, and modulated by effective interventions with little spontaneous fluctuation in expression. Although no intermediate endpoints have been validated as replacements for cancer incidence thus far, the assessment of a variety of such markers can significantly inform drug development and help make decisions regarding subsequent phase III trials. Lung cancer consists of a heterogeneous set of malignancies that presents with diverse molecular and histologic characteristics. The molecular evolution of tobacco related carcinogenesis is not well understood, but histologic evolution of squamous carcinogenesis, with progression from metaplasia through increasing grades of dysplasia and carcinoma in situ, is well described. This allows for a clinical trial design based on pre- and post-treatment bronchial biopsies to assess the response to chemopreventive interventions. Since the rate of progression of dysplasia to invasive cancer is variable, with higher progression rates associated with higher grades of dysplasia, studies assessing dysplasia as an endpoint need to be randomized such that the “spontaneous” reversion rate in the placebo arm can be used as a comparison to account for the effects of the biopsies and for true biologic reversion. This model has been successfully used to study a variety of interventions, including a recent trial of the prostacyclin analogue iloprost that showed improvement in bronchial histology after 6 months of treatment (Keith R et al., Cancer Prev Res 2011;4:793-802). In contrast, the study of the development of adenocarcinomas has been more difficult due to the inability to access tissues from the peripheral lung. The demonstration that helical CT screening reduces lung cancer mortality opens the opportunity to assess the peripheral lung for adenocarcinoma precursor lesions. Veronesi and colleagues (Veronesi G et al., Cancer Prev Res 2011;4;34-42) examined the effect of an inhaled steroid, budesonide, on CT-detected lung nodules, showing nonsignificant modulation of nonsolid lesions only. As persistent nonsolid (ground glass) lesions are more likely to represent lung cancer precursor lesions such as atypical adenomatous hyperplasia or early cancers than solid nodules, future studies should focus on nonsolid lesions only. Alternative designs for trials include a focus on individual biomarkers, panels of biomarkers, or pathways that are deregulated during carcinogenesis. As an example, Gustafson et al. demonstrated that the PI3K pathway is upregulated early during lung carcinogenesis and that an intervention with the drug myo-inositol that resulted in regression of bronchial dysplasia also inhibited PI3K activation in the bronchial epithelium (Gustafson AM et al., Science Trans Med 2010;2:26ra25). These data suggest that upregulated PI3K signaling could potentially identify smokers at increased risk for lung cancer and that pathway inhibition could serve as an endpoint for assessing treatment effect, a hypothesis that requires further testing. The rapidly increasing understanding of the pathogenesis of lung cancer provides an unprecedented opportunity to intervene in the process. Optimization of clinical trial design is required to translate the basic knowledge into clinical realities.

Abstract
Smoking exposes the respiratory mucosa to carcinogens in a “field cancerization” process. Smokers develop bronchial lesions, at the pre-invasive stages, preceding the development of invasive lung cancer. Because of the field of cancerization, these lesions are multiple and occur throughout the bronchial airways, which make complete resection of bronchial premalignant lesions impractical. Chemoprevention aims to prevent the development of lung cancer. The administration of chemopreventive agents may be effective, alone or in association with local treatment, in reducing the risk of developing lung cancer. So far no phase III trial testing chemopreventive agents for lung cancer has shown a consistent and reproducible benefit. Therefore no agent can be recommended currently for the chemoprevention of lung cancer (Szabo et al, Chest, 143 (5), Supplement, 2013, e40S-e60S). Future chemoprevention trials should be conducted based on the knowledge of lung carcinogenesis drivers and pathways (Keith et al, Nature Reviews, 10, 2013, 334-343). This would allow the choice of drugs with a better chance of benefit and the customization of the chemoprevention agents. Personalized approaches based on prediction of response to therapy by biomarkers are integrated in lung cancer treatment, with much higher success rate and reduced useless toxicity. In the context of chemoprevention, no or minimal sides effect must be obtained in the high risk population receiving the drug because of the absence of active disease, the fact that the treatment might have to be taken for many years by a large population at high-risk and consequently, the potential huge impact on public health. Therefore biomarkers could play crucial roles as surrogate intermediate endpoint and as predictors of response to targeted treatment. Lung cancers express lower levels of prostacyclin than normal lung tissues. Prostacyclin prevents lung cancer in a variety of mouse models. A randomized phase II trial comparing oral iloprost (a prostacyclin analogue) to placebo in high-risk subjects demonstrated improvement in bronchial histology but only in former smokers (Keith et al, Cancer Prev Res, 4 (6), 2011, 793-802). This placebo-controlled study offered the opportunity for investigation of other potential intermediate endpoints and predictive biomarkers to incorporate into chemoprevention trials. Matched biopsies (baseline-BL and the same site at follow-up-FU after 6 months of Iloprost or placebo) were obtained in 125 high-risk individuals who completed the trial: 40/35 and 25/25 current/former smokers in the Iloprost and placebo arm, respectively. We analyzed 496 biopsies including 4 matched biopsy pairs per patient: the best and the worst histology at BL and the 2 biopsies from same site at FU. Total RNA was extracted from formalin fixed paraffin embedded sections adjacent to the diagnostic section and 14 selected miRNA previously identified in high-grade bronchial preneoplasia were analyzed by qRT-PCR (Mascaux et al, Eur Respir J, 33, 2009, 352-359). The expression of seven miRNAs was significantly correlated with histology at BL. The expression of miR-34c was inversely correlated with histology at BL (p<0.0001) and with change in histology at FU (p=0.0003), independent of treatment or smoking status. Several miRNAs were also found to be differentially expressed in current smokers as compared with former smokers. In current smokers, miR-375 was up-regulated at BL (p<0.0001) and down-regulated after treatment with iloprost (p=0.0023). No miRNA at baseline reliably predicted a response to iloprost. Thus, miR-34c was inversely correlated with BL histology and with histology changes. Mir-34c changes at FU could be used as a quantitative biomarker to assess histological response in formalin-fixed bronchial biopsies in future lung cancer chemoprevention studies (Mascaux et al, Canc Prev Res, 6 (2), 2013, 100-108). This utility of miR-34c to assess the histological response to chemoprevention needs to be further demonstrated prospectively in other chemoprevention trials. The high-throughput gene expression profiling of bronchial epithelium (Gustafson et al, Sci Transl Med, 2 (26), 2010, 26ra25) and in lung preneoplasia (Mascaux et al, J Thor Oncol, 4 (suppl to 9), 2009, abstract PRS.2, page S282) could allow the discovery of new targets for chemoprevention and the possibility of customized lung cancer chemoprevention, by selecting the agents based on the different molecular profile of the individuals at high risk. Thus future chemoprevention trials should be undertaken based on the biological drivers and pathways of lung carcinogenesis. The chemoprevention trials should include the collection of biological samples to allow testing biomarker for their role as surrogate intermediate endpoint, for the selection of the patients who are at higher risk and for the personalization of the chemoprevention approach, with the purpose of optimizing the benefit and avoiding useless toxicity in high-risk but cancer-free individuals.

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Abstract
1. Introduction Lung cancer has remained to be the leading cause of cancer-related death in many countries. Most patients are diagnosed at an advanced stage, stage III or IV. A way to improve surgical outcome would be the administration of chemotherapy before or after the surgical procedure. 2. Neoadjuvant therapy The preoperative induction therapy offers several benefits: (1) an increased percentage of patients completing the planned dose of chemotherapy, (2) the probability to treat micrometastatic tumor dissemination preoperatively, (3) the ability to assess response to the chemotherapy as a prognostic indicator, and (4) the probability to increase resectability by the tumor regression. 2.1. Induction chemotherapy Numbers of phase II trial using induction chemotherapy can be found in the previous literatures. Phase III neoadjuvant trial results including stage IIIA disease are summarized in Table1. Two studies reported by Roth (1994) and Rosell (1994) suggested that induction therapy followed by surgery could lead to improved outcomes, however, recent large scale studies did not show the improvement of survival in stage IIIA patients received neoadjuvant chemotherapy.　 2.2. Induction chemotherapy with third-generation agents Results of previous studies, all of them are phase II study, evaluating the efficacy of induction chemotherapy with third-generation agents are shown in the table 2. These trials showed the feasibility and potential benefit of induction chemotherapy with combination or cisplatin and third-generation agents for stage III patients. Since the data of phase III trial with large sample size are lacking, the adequate regimen of induction chemotherapy has yet to be defined. 2.3. Induction chemotherapy or induction chemoradiotherapy? Whether induction radiotherapy adds benefit when surgery is planned is an important clinical question, because the addition of each modality increase the possibility of morbidity and mortality of treatment. To investigate the benefit of neoadjuvant radiation therapy, Shah (2012) conducted systematic review and meta-analysis. None of the studies demonstrated a survival benefit to adding induction radiotherapy to induction chemotherapy versus induction chemotherapy alone. The meta-analysis performed on randomized studies demonstrated no benefit in survival from adding radiation (HR: 0.93; p=0.81), nor did the meta-analysis performed on retrospective studies (HR: 0.77; p=0.24). The most promising use of induction chemoradiotherapy is to treat the superior sulcus tumor (SST) where preoperative local tumor regression is a key to achieving complete resection. Rush (2007) reported the results of SWOG 9416 (Intergroup 0160) phase II trial, which tested the feasibility of induction chemoradiotherapy for SST, on the basis of improved outcomes in other subsets of stage III NSCLC. Pathologic complete response (CR) or minimal microscopic disease was seen in 61 (56%) resection specimens. Five-year survival was 44% for all patients and 54% after complete resection, with no difference between T3 and T4 tumors. Kunitoh (2008) reported the similar results of Japan Clinical Oncology Group (JCOG) phase II trial (JCOG 9806), which was conducted for testing the feasibility of induction chemoradiotherapy for NSCLC-SST patients. There were 12 patients with pathologic CR. The disease-free and overall survival rates at 3 years were 49% and 61%, respectively; at 5 years, they were 45% and 56%, respectively. They concluded that the trimodality approach was safe and effective for the treatment of patients with SST 3. Adjuvant therapy 3.1. Adjuvant chemotherapy The NSCLC Collaborative Group (1995) reported a meta-analysis of 14 clinical trials addressing the role of adjuvant chemotherapy for resected NSCLC. There was no statistically significant survival benefit in group of patients received adjuvant chemotherapy, but a trend toward better survival prompted further studies. Subsequently, the Lung Adjuvant Cisplatin Evaluation (LACE) meta-analysis based on individual patient data collected from the 5 largest trials (4,584 patients) of cisplatin-based adjuvant chemotherapy in completely resected patients with NSCLC was performed. This analysis also showed a significant survival benefit with adjuvant chemotherapy, with an overall hazard ratio (HR) of 0.89, translating into a 5-year absolute survival benefit of 5.4%. Then in 2010, the NSCLC Meta-analyses Collaborative Group reported a meta-analysis of 34 clinical trials with 8,447 patients (3,323 deaths) addressing the benefit of adjuvant chemotherapy for resected NSCLC. Among those, the overall hazard ratio to survival in patients received cisplatinum-based adjuvant chemotherapy by stage suggests absolute improvements in 5-year survival of 5% for stage III disease (from 30% to 35%). 3.2. Adjuvant radiotherapy In 1988, postoprative radiotherapy (PORT) Meta-analysis Trialists Group collected individual data on 2,128 patients from nine available randomized trials of PORT versus surgery alone. They reported a 21% relative increase in the risk of death, which was equivalent to an absolute detriment of 7% at 2 years, with PORT reducing overall survival from 55% to 48% after resection. Subgroup analysis suggested that the adverse effect on overall survival was most notable for patients with stage I/II (N0-N1) tumors, whereas there was no clear evidence of either adverse effect or benefit for stage III disease. The results of the PORT meta-analysis, however, are probably not applicable to current therapy because of recent major improvements in radiation treatment planning and delivery. 4. Neoadjuvant or adjuvant chemotherapy? Which is the better treatment, induction or adjuvant chemotherapy? Some concern has also arisen regarding adjuvant chemotherapy compliance, with most trials using cisplatin doublets reporting delivery of only 60% of planned treatment. Induction chemotherapy seems better tolerated, more than 80% of the patients received the full planned treatment at the difference of adjuvant chemotherapy. In the LACE meta-analysis, 33% of patients in the chemotherapy arm did not start or finish the planned chemotherapy regimen, reflecting the difficulty of adjuvant chemotherapy administering such taxing therapies to a postoperative population. 6. Conclusions Although definitive chemoradiation remains a standard of care for stage IIIA NSCLC, alternative approaches such as induction chemotherapy and surgery for a selective group of patients can be considered. When surgical resection after induction therapy can be performed with low risk and a good chance of complete resection, it might provide an optimal outcome. The decision to proceed with resection after induction therapy must include a detailed preoperative pulmonary function evaluation as well as a critical intraoperative assessment of the feasibility of complete resection. Figure 1Figure 2

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Abstract
There has been an explosion of studies, reports and clinical experience with Stereotactic Ablative Body Radiotherapy (SABR) for lung lesions (both primary and metastatic). Most of the experience and published literature focuses on peripheral lesions; the published and used SBRT dose/fractions are safe, associated with virtually no acute toxitxity and very low rates of subacute and late RT toxicity and high rates of local control. There is an emerging experience in treating central lesions, previous described as a "no-fly zone" . There is also an emerging appreciation about the multitude of organs at risk -- the intiial focus was on bronchi and spinal cord, but clinicians and researchers need to be midful of esophagus, great vessels, heart and brachial plexus as well. The presentation will review the current state of knowledge and highlight the methodological challenges of interpreting the current literature, and emphasize the importance of careful followup of patients with more centrally located lesions, treated with SABR.

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Abstract
Tumors evade immune system attack through various different mechanisms. One such mechanism is through coopting inhibitory immune checkpoints.(1) These inhibitory checkpoints cause compromised T cell activation and effector function. The two immune checkpoints best known are CTLA-4 and PD-1.(2) CTLA-4 is the receptor that is expressed earlier on in T cell activation and whose ligands are B7.1 and B7.2. Tumor cells have not been known to express the CTLA-4 ligands which are only known to be expressed on antigen presenting cells (APC). CTLA-4 deficient mice die early on of massive lymphoproliferative disorders.(3) Alternatively, the PD-1 receptor is expressed later on in T cell activation in the periphery and binds to two ligands, PD-L1(B7-H1) and PD-L2 (B7-DC). Both ligands are known to be expressed in peripheral tissues on APCs as well as tumor cells. Both ligands are upregulated by type 1 and 2 interferons, particularly gamma interferon.(4) PD-1 deficient mice develop strain specific autoimmune diseases later on in life.(5) Antibodies developed to block the binding between co-inhibitory receptor and its ligands cause T cell activation. While CTLA-4 blockade via the antibody, ipilimumab, has yielded an improvement in survival in patients with melanoma, PD-1 blockade is earlier on its development.(6,7) Several antibodies are in various stages of development. Of the antibodies designed to bind to the PD-1 receptor, Nivolumab (BMS-936558) is furthest along in development. In the first in human, single dose study of nivolumab, no maximum tolerated dose was found.(8) The pharmacokinetics of the antibody revealed a 14 day half-life, but the antibody was found to occupy T cell receptors for up to 3 months after treatment leading to prolonged pharmacodynamic effects. The toxicities were relatively mild and consistent with the immune mechanism of action. Early signs of clinical activity were seen in patients with melanoma, colon cancer, non-small cell lung cancer (NSCLC), and renal cell cancer (RCC).(9) Two patients remain in a complete response even up to almost 5 years after their last treatment. One patient’s response was maintained up to 18 months after stopping treatment and when the cancer progressed, the patient was retreated with nivolumab resulting again in a response. More recently, a multidose phase I study of Nivolumab was performed.(10) Again, no maximum tolerated dose was found up to 10 mg/kg every two weeks. Toxicities again tended to be manageable and consistent with the immune mechanism of action. Because of initial signs of significant clinical activity, expansion cohorts in NSCCLC, RCC, and melanoma were enrolled. Exciting responses in NSCLC (17%) were seen. These responses were durable with a median duration of response of 17 months. Based on these results, two phase III trials have been initiated in the second line treatment setting comparing nivolumab to docetaxel in both squamous cell and non-squamous cell carcinomas. Another anti-PD-1 antibody, MK-3475, recently reported similar toxicities consistent with the immune mechanism of action as well as initial clinical activity in melanoma (47% response rate).(11) Further expansion cohorts were enrolled in NSCLC and information is forthcoming. Antibodies blocking the ligand, PD-L1, have also been developed. Theoretically there may be differences in activity and toxicities between the two groups of antibodies. By blocking the PD-L1, the interaction between PD-1 and PD-L2 remains intact. It remains to be seen if this is meaningful, clinically. The first in human study of once every two week dosing of BMS-936559 reported initial tumor activity in several tumor types including NSCLC (10%) as well as a tolerable safety profile.(12) Another PD-L1 antibody, MPDL3280A, initial phase I trial was reported at ASCO in 2013. Toxicities were mild, no MTD was reached, and initial clinical activity was seen in multiple tumor type including NSCLC (22%).(13) These trials demonstrate that the PD-1 pathway is important in tumor immune evasion, and by blocking this pathway, immune activation occurs which in turn can cause durable tumor control. References 1. Zou W: Immunosuppressive networks in the tumour environment and their therapeutic relevance. Nat Rev Cancer 5:263-74, 2005 2. Chen L: Co-inhibitory molecules of the B7-CD28 family in the control of T-cell immunity. Nat Rev Immunol 4:336-47, 2004 3. Waterhouse P, Penninger JM, Timms E, et al: Lymphoproliferative disorders with early lethality in mice deficient in Ctla-4. Science 270:985-8, 1995 4. Keir ME, Butte MJ, Freeman GJ, et al: PD-1 and its ligands in tolerance and immunity. Annu Rev Immunol 26:677-704, 2008 5. Nishimura H, Nose M, Hiai H, et al: Development of lupus-like autoimmune diseases by disruption of the PD-1 gene encoding an ITIM motif-carrying immunoreceptor. Immunity 11:141-51, 1999 6. Hodi FS, O'Day SJ, McDermott DF, et al: Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 363:711-23, 2010 7. Robert C, Thomas L, Bondarenko I, et al: Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N Engl J Med 364:2517-26, 2011 8. Brahmer JR, Drake CG, Wollner I, et al: Phase I study of single-agent anti-programmed death-1 (MDX-1106) in refractory solid tumors: safety, clinical activity, pharmacodynamics, and immunologic correlates. J Clin Oncol 28:3167-75, 2010 9. Lipson EJ, Sharfman WH, Drake CG, et al: Durable cancer regression off-treatment and effective reinduction therapy with an anti-PD-1 antibody. Clin Cancer Res 19:462-8, 2013 10. Topalian SL, Hodi FS, Brahmer JR, et al: Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med 366:2443-54, 2012 11. Iannone R, Gergick K, Cong C, et al: Efficacy and safety of MK-3475 in patients with advanced melanoma, 9th International Congress of the Society for Melanoma Research. Los Angeles. California, 2012 12. Brahmer JR, Tykodi SS, Chow LQ, et al: Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med 366:2455-65, 2012 13. Herbst R, Gordon M, Fine J, et al: A study of MPDL3280A, an engineered PD-L1 antibody in patients with locally advanced or metastatic tumors, ASCO Annual Meeting 2013. Chicago, I.L., 2013

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Abstract
Surgical resection is the standard therapy for early stage NSCLC, but about half of the patients still develop a relapse and die of their cancer. In case of unresectable locally advanced disease, the combination of chemo- and radiotherapy may cure some patients, but the majority will relapse. Targeted agents have brought progress for patients with advanced NSCLC selected based on molecular factors such as EGFR or ALK mutation, but other novel approaches are needed. One is therapeutic cancer vaccination (TCV), which may become an important part in our future treatment armamentarium, especially for patients with local or locally advanced NSCLC. Cancer immunotherapy in a broad sense is any interaction with the immune system to treat cancer. A first approach is non-antigen-specific modulation of the immune system. Historical experience (BCG, C. parvum, interferon, interleukins, thymosin, etc.) was disappointing. Promising response rates in heavily pre-treated NSCLC patients were reported in recent phase I trials with agents acting on the interaction between antigen presenting cells, T-lymphocytes and tumor cells. Examples are antibodies against Cytotoxic T-lymphocyte Antigen 4 (CTLA-4) or against Programmed Death 1 receptor or its ligands. Antigen-specific immunotherapy aims at specific priming of immune system to recognize the tumor as foreign, thereby generating specific antibodies and/or cytotoxic T cells. This is “therapeutic cancer vaccination”. Conditions for optimal TCV are: 1/ specificity (well-defined target antigen in the tumor, not in other tissues); 2/ selectivity (use in the population expressing the target); 3/ immunogenicity (interaction with antigen leads to effective humoral and/or cellular response); 4/ tumor sensitive to immune kill in order to obtain improvement in patients’ outcome. Although the historical results of TCV for NSCLC were disappointing, knowledge from the last decades about the molecular pathology of tumors, of the immune system in general, and of tumor immunity in particular, has led to the introduction of several modern and more sophisticated TCVs. These vaccine formulations have shown encouraging data in phase II randomized clinical trials, and are now being studies in large phase III studies. Important examples are the MAGE-A3 vaccine in resected early stage NSCLC, the BLP-25 vaccine in locally advanced NSCLC after chemoradiotherapy, and e.g. belagenpumatucel-L and the TG4010 vaccine in advanced stage NSCLC. The MAGE-A3 protein is totally tumor-specific and present in about 35% of early stage NSCLC. In the hypothesis generating double-blind, randomized, placebo-controlled phase II study, 182 patients with completely resected MAGE-A3-positive stage IB-II NSCLC received recombinant MAGE-A3 protein combined with an immunostimulant (13 doses over 27 months) or placebo [1]. No significant toxicity was observed. There was a 24% - non-significant - improvement in disease-free survival (HR 0.76; 95% CI 0.48 to 1.21). Moreover, a predictive gene signature, initially described in advanced melanoma patients could be confirmed in early stage NSCLC [2].A large phase III study (n=2270) with MAGE-A3 vaccine is recruited and awaiting results (MAGRIT, NCT00480025). Mucins like the MUC1 protein are present in many epithelia, but MUC1 expression is altered (mainly by aberrant glycosylation) in many cancer types, including NSCLC. The tandem repeat MUC1-peptide liposomal vaccine BLP-25 has been studied in patients with stage IIIB-IV NSCLC [3]. Patients in disease control after conventional treatment with chemo(-radio)therapy were randomly assigned to BLP25 (8 weekly s.c. immunizations, followed by administration at 6-week intervals) plus BSC or BSC alone. While overall survival (OS) was not significantly different in the total group, a challenging effect was observed in stage IIIB patients (HR 0.524; 95%CI 0.261-1.052). No significant toxicity was observed. At the 2013 ASCO meeting, the double-blind, randomized, placebo-controlled phase III study was presented (START, NCT00409188) [4]. Patients not progressing after primary chemoradiotherapy for unresectable stage III NSCLC were randomized to BLP25 or placebo. In the primary analysis population (n=1239), OS was better with the vaccine (HR 0.88, 95%CI 0.75-1.03). In the predefined subgroup analysis in patients after concurrent chemoradiotherapy (n=806) there was a median OS difference of 10.2 months (HR 0.78, 95%CI 0.64-0.95). While the most obvious role for TCV is for patients with small residual disease after treatment, several compound are in phase III testing in advanced NSCLC as well. Belagenpumatucel-L is a vaccine based on a mixture of allogeneic tumor cells with TGF-β2 antisense blockade as adjuvant. In a phase II open trial, survival was related to the dose administered [5]. A phase III trial in patients with stage III-IV NSCLC in disease control after first-line therapy is now fully recruited (STOP, NCT00676507). TG4010 is a vaccine based on a recombinant viral vector (attenuated strain of vaccinia virus) expressing both the tumor-associated antigen MUC1 and interleukin-2. In a phase II randomized study, 148 patients with advanced NSCLC expressing MUC1 by immunohistochemistry received either up to 6 cycles of cisplatin-gemcitabine plus TG4010, or the same chemotherapy alone [6]. The primary endpoint, a 6-month progression-free survival more than 40% in the experimental arm was met. A confirmatory phase IIB-III trial is ongoing (TIME, NCT01383148). 1. Vansteenkiste J, Zielinski M, Linder A, et al. Adjuvant MAGE-A3 immunotherapy in resected non-small cell lung cancer: Phase II randomized study results. J Clin Oncol 2013; 31: 2396-2403. 2. Ulloa-Montoya F, Louahed J, Dizier B, et al. Predictive gene signature in MAGEA3 antigen-specific cancer immunotherapy. J Clin Oncol 2013; 31: 2388-2395. 3. Butts C, Murray N, Maksymiuk A, et al. Randomized phase IIB trial of BLP25 liposome vaccine in stage IIIB and IV non-small cell lung cancer. J Clin Oncol 2005; 23: 6674-6681. 4. Butts CA, Socinski MA, Mitchell P et al. START: A phase III study of L-BLP25 cancer immunotherapy for unresectable stage III non-small cell lung cancer. J Clin Oncol 31 Suppl, abstract 7500. 2013. 5. Nemunaitis J, Dillman RO, Schwarzenberger PO, et al. Phase II study of belagenpumatucel-L, a transforming growth factor beta-2 antisense gene-modified allogeneic tumor cell vaccine in non-small cell lung cancer. J Clin Oncol 2006; 24: 4721-4730. 6. Quoix E, Ramlau R, Westeel V, et al. Therapeutic vaccination with TG4010 and first-line chemotherapy in advanced non-small cell lung cancer: a controlled phase 2B trial. Lancet Oncol 2011; 12: 1125-1133.

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Abstract
Pleural neoplasms may be difficult to diagnose because they must be distinguished from metastatic malignancy involving the pleura, and from benign reactive processes causing pleural thickening. In contrast to primary lung neoplasms, primary pleural neo­plasms are uncommon, with secondary involvement being more frequent. A correct diagnosis is important, so that appropriate therapy can be delivered. Also, the diagnosis may affect the pateint’s prospects for compensation. The most common primary pleural neoplasm is mesothelioma, but compared to lung tumours even mesotheliomas are relatively rare. Mesotheliomas exhibit a wide variety of histologic patterns, which may be confused with other neo­plasms. Here we consider those other pleural lesions that must be differen­tiated from mesothelioma. Secondary Malignant Neoplasms Affecting the Pleura Secondary neoplasms represent the most common malignancy affecting the pleura, with lung carcinoma being the most common, followed by metastatic breast cancer, malignant lymphoma, (including Hodgkin and non-Hodgkin malignant lymphomas). Metastatic carcinomas of ovarian or gastric origin, malignant melanoma and sarcomas account for only a small percentage of cancer-associated pleural disease (about 5%). Some of these may show diffuse infiltration of the pleura in a pattern indistinguishable from pleural malignant mesothelioma macroscopically and radiologically. The majority of such so-called pseudomesotheliomatous neoplasms originate from the lung, but metastases from kidney, thyroid gland, larynx, stomach and cutaneous malignant melanoma as well as various sarcomas, including malignant phyllodes tumor, have also been described. Renal cell carcinoma (RCC) and amelanotic malignant melanoma may also metastasize to the pleura. RCCs with a sarcomatoid pattern can present a diagnostic problem. Labelling for RCC-related markers such as CD10 can also be seen in mesotheliomas and in sarcomatoid RCCs, the other RCC markers may be negative: correlation with imaging studies is imperative. Rare cases of sarcoma metastatic to the pleura may mascerade as mesothelioma and comprehensive clinical history is of highest imprtance. Other Neoplasms Arising in the Pleura Thymoma Affecting the Pleura Thymoma may spread into the pleura from an anterior mediastinal thymoma, but primary pleural thymomas are described and can present as localised masses or with diffuse pleural thickening. The concept of primary pleural thymoma has become accepted, but only about 25–30 cases have been reported to date. Spindle Cell Neoplasms Synovial sarcoma of the pleura Both biphasic and monophasic synovial sarcomas (SySa) are characterized by a distinctive t(X;18) chromosomal translocation and the production of the resultant alternative fusion genes, SYT-SSX1 or SYT-SSX2. SySa are well recognised as primary intrathoracic neoplasms in the pleura, where they can be confused with biphasic or sarcomatoid mesothelioma, carcinosarcoma /spindle cell carcinoma, or a biphasic pulmonary blastoma. Clinical features, immunohistochemistry and electron microscopsy are of limited usefulness and it is the detection of the t(X;18) chromosomal translocation and expression of the resultant SYT-SSX1 or SYT-SSX2 that is diagnostic of SySa. This can be done by FISH, but PCR is more sensitive and we consider molecular analysis of t(X;18) to be mandatory for discrimination between a genuine pleural SySa versus a biphasic or monophasic mesothelioma with histological appearances that mimic SySa. Solitary Fibrous Tumors (SFTs) Of Pleura Solitary fibrous tumors (SFTs) are uncommon localized spindle-cell fibroblastoid neoplasms. They most commonly arise in relation to the visceral pleura (~80%) or the parietal pleura, but they can occur in the mediastinum, lung parenchyma or related to pericardium or diaphragm. Terms such as submesothelial fibroma, fibrous mesothelioma and localized fibrous tumor have been used as synonyms in the past. Localized fibrous tumor might be the best term, because multiple simultaneous tumours have been described but 'SFT' is well established. Thoracic SFTs can vary greatly in size abd have a peak incidence between the 4[th] and 6[th] decade. SFTs are often incidental findings in asymptomatic patients, and the radiologic appearances may suggest the diagnosis, but a biopsy is always required. Symptoms can be related to the size and site of the tumor with compression of surrounding tissues. The histology ranges from the 'patternless pattern' of Stout to 'herringbone', cellular, myxoid and hemangiopericytic or angiofibromatoid areas. The mitotic index may be useful to predict malignant behaviour. Desmoid Tumors of the Pleura Desmoid tumors in the region of the chest wall are well recognized and can impinge upon the parietal pleura, but primary desmoid tumors of the pleura and lung are extremely rare. Benign and Malignant Nerve Sheath Tumors Neoplasms that have histologic and immunohistochemical features of nerve sheath tumors can occur as primary tumours in the pleural cavity. Benign ones typically show Verocay bodies and Antoni A and B areas. When malignant, these cells can cause major diagnostic confusion. Immunohistochemical staining with neural markers such as S100 protein is helpful to confirm a neurogenic origin. Inflammatory Myofibroblastic Tumors Inflammatory pseudotumors (plasma cell granuloma; inflammatory myofibroblastic tumor) may occasionally involve the pleura. They consist of of a proliferation of spindle cells with varying numbers of inflammatory cells, with prominene of plasma cells. Current thinking favours the concept that these are neoplastic lesions with the capacity in some cases for multicentricity, angioinvasion and metastasis (especially in older patients in whom IHC for anaplastic lymphoma kinsae (ALK) is negative). Epithelioid Hemangioendothelioma of the Pleura Epithelioid hemangioendothelioma is a malignant angioformative neoplasm, where the neoplastic endothelial cells are epithelioid and sometimes quite bland in appearance. The pattern in H&E-stained sections may be virtually indistinguishable from mesothelioma, and both may label for thrombomodulin and in some cases, cytokeratins. Labelling for endothelial markers such as CD31, CD34 or factor VIII-RAG aids in the diagnosis. Pleuropulmonary Blastoma Pleuropulmonary blastomas are rare in the pleura and mostly occur in early childhood. Tumours consist of primitive cells underneath an epithelium with a cambium layer-like appearance as seen in sarcoma botryoides. Rhabdomyoblasts may be found and anaplastic sarcomatous elements, such as embrynal rhabdomyosarcoma, fibrous sarcoma, chondrosarcoma and undifferentiated sarcoma, may be present. Pleural Lymphomas Primary pleural lymphomas are rare, with primary effusion lymphoma (PEL) and pyothorax-associated lymphoma being the most common. In our experience, most cases of pleural lymphoma represent secondary spread in cases of previously-diagnosed extrapleural lymphoma.

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Abstract
In this presentation, we describe the process that our laboratory followed that led to successful accreditation, by the Australian National Association of Testing Authorities (NATA), for medical use of NGS in clinical practice. First, we evaluated three different amplicon –based MPS technologies in order to choose the platform of choice for clinical use. We compared the performance of two commercial somatic mutation panels (Life Technology’s AmpliSeq cancer panel and Illumina’s TruSeq amplicon panel) and a customized panel (Agilent’s HaloPlex). The panels shared 31 genes in common. The AmpliSeq panel was sequenced using the Ion Torrent platform and the TruSeq and HaloPlex panels were sequenced using the Illumina MiSeq platform. In-house bioinformatics and variant annotation and reporting pipeline were developed to allow data from all three panels to be compared. A training set of 28 FFPET samples with known missense or deletion mutations in EGFR, KRAS, BRAF, NRAS, PIK3CA and KIT were tested by all three panels. These samples, previously tested using NATA - accredited Sanger sequencing, SNaPshot and fragment analysis performed on an ABI3730, were used to empirically determine the parameters required for accurate mutation detection by MPS. Sample acceptance criteria included samples with at least 1mg of extractable DNA following macrodissection from tumour areas with at least 70% purity. Library quality was assessed by BioAnalyser and libraries were sequenced to a median depth of 2000x. The panels and platforms were compared for % aligned reads, % on - target reads, median and range of coverage, input DNA quantity and quality requirements, data quality and variability, cost, turn around time, ease of use, and accuracy of mutation detection. There was marked variation in the number and types of variants identified across the three panels. With minimum variant calling criteria of depth >50x, variant depth >20x, variant frequency >5% and base quality >15, we identified 18557 variants with AmpliSeq, 15064 variants with TruSeq and 3326 variants with Haloplex. 14229 of the TruSeq variants were SNPs (9319 were C>T), indicating DNA polymerase errors, while 12370 of the AmpliSeq variants were small indels (mostly in homopolymeric tracts) indicating errors in calling repetitive sequences. In total, 59 variants were identified by all three panels. The TruSeq and Ampliseq panels detected all 31 known somatic mutations, where as the HaloPex panel missed four mutations due to patchy on - target coverage. In panels with adequate coverage of regions of interest, the assay sensitivity was 100%. The TruSeq panel was chosen for clinical use, despite the requirement for higher DNA input (150ng compared to 10ng for AmpliSeq), primarily due to ease of use and less hands - on time by laboratory staff. We then performed reproducibility, repeatability, robustness and limit of detection experiments using the TruSeq panel. Initially, there was poor reproducibility of all variants, particularly SNVs, especially in samples with low input DNA (<50ng) or poor quality DNA (fragment size <250 bp). Most of the identified variants were random and present at low frequency, most being present at <1-2% allele frequency. These showed characteristics suggestive sequencing and polymerase errors, formalin – induced artifacts and misaligned repetitive sequences. To reduced the great excess of false positives, we restricted variant calling by establishing minimum allele frequencies, by eliminating unreported variants and by limiting alignment to clinically- relevant or actionable mutations. Variant reproducibility was increased to 38% by only calling SNVS >5% and indels >1% allele frequency that were contained within the COSMIC database. This was further increased to 92% by restricting variant calling to known clinically - relevant mutations listed on the www.mycancergenome web site. Reproducibility was increased further by strict adherence to sample and library quality control criteria (DNA amount 150ng DNA fragment size at least 250bp, minimum library concentration of 1nM, and minimum of 400,000 reads per sample) and by only calling mutations if present with allele frequency above 5% for FFPET samples and 1% for AML samples. Notabily, non - reproducible “mutations” in clinically relevant genes (eg KRAS G12A) were not infrequently encountered below these cut off values. A second independent test set of 82 FFPET samples with known missense and deletion mutations in EGFR, KRAS, BRAF, NRAS, PIK3CA, KIT and PDGFRA were analysed by the TruSeq panel. By strict adherence to the above criteria and restricting variant calling to clinically relevant mutations, 100% sensitivity and 100% specificity was achieved in the samples that met the criteria. In all, only 71% of the samples tested passed all quality control criteria. 12% of the samples failed the library preparation and were not processed. 17% of the samples passed the library QC criteria but failed the sample QC criteria. In each case the known mutation was identified. In conclusion, by strict adherence to sample and library QC and by restricting analysis to clinically-relevant mutations, the TruSeq amplicon cancer panel was able to detect common somatic missense and deletion mutations with an allele frequency >5% in FFPET samples with 100% specificity and sensitivity without the need for confirmation by an orthogonal method. However, confirmation by an orthogonal methods would be required for suspected mutations present at an allele frequency <5%, for mutations not known to be of clinical – relevance and for samples with low tumour purity, low DNA input or poor quality DNA. This study showed that deep sequencing of tumour tissue from FFPETs generated many low frequency artifacts due to sequencing, polymerase, formalin – induced chemical modifications and well as frequent mapping and variant calling errors. These artifacts and errors mostly occur at low allele frequency and can be difficult to distinguish from low frequency somatic mutations. Strict adherence to sample and library quality control criteria, allele frequency thresholds and clinically relevant mutations allows highly accurate mutation calling without the need for confirmation by an orthogonal method.

Abstract
Over the past decade, significant progress has been made in the characterization of molecular and genetic abnormalities tumors from patients with non-small cell carcinoma (NSCLC) that are being used as molecular targets and predictive biomarkers to select patients for targeted therapy. Recent advances in expanding the available NSCLC targeted therapies require the analysis of a broad panel of molecular abnormalities in tumor specimens, including gene mutations, gene amplifications, gene fusions and protein expression by applying different methodologies to tumor tissue (biopsy) and cell (cytology) samples. The rapid development of technologies for large-scale sequencing (next-generation sequencing, NGS) has facilitated high-throughput molecular analysis holding various advantages over traditionally sequencing including the ability to fully sequence large numbers of genes in a single test and simultaneously detect deletions, insertions, copy number alterations, translocations, and exome-wide base substitutions (including known hot-spot mutations) in all known cancer-related genes [1,2]. Currently, NGS platforms, including whole genome, whole exome and targeted gene sequencing, represent emerging diagnostic methodologies for the detection of oncogenes fusions and mutations in tumor tissue specimens, including formalin-fixed and paraffin-embedded (FFPE) samples [3]. Technical challenges include sequencing samples of low quality and/or quality, reliable identification of structural and copy number variation, and assessment of intratumoral heterogeneity. In addition, the clinical use of the NGS sequencing data is not straightforward and there are several challenges related to data analysis, data storage and report generation [4]. There is growing consensus that tumor tissue specimens must represent the setting of the disease to be treated, and increasingly, more tissue samples are being obtained for molecular testing of advanced, metastatic and chemo-refractory NSCLC tumors (e.g., MD Anderson BATTLE Lung Cancer Program) [5]. However, the biopsy and cytology samples available for molecular testing in those metastatic refractory NSCLC tumors are likely to be more challenging samples for molecular testing, including NGS platforms. The role of the pathologist is becoming increasingly important to adequately integrate routine histopathology assessments and molecular testing, including NGS, with clinical pathology for the most accurate tumor diagnosis and subsequent selection of the most appropriate therapy. References: 1. Meyerson M, Gabriel S, Getz G: Advances in understanding cancer genomes through second-generation sequencing. Nat Rev Genet 11:685-96, 2010 2. Mwenifumbo JC, Marra MA: Cancer genome-sequencing study design. Nat Rev Genet 14:321-32, 2013 3. Ross JS, Cronin M: Whole cancer genome sequencing by next-generation methods. Am J Clin Pathol 136:527-39, 2011 4. Ulahannan D, Kovac MB, Mulholland PJ, et al: Technical and implementation issues in using next-generation sequencing of cancers in clinical practice. Br J Cancer 109:827-35, 2013 5. Kim ES, Herbst RS, Wistuba, II, et al: The BATTLE trial: personalizing therapy for lung cancer. Cancer Discov 1:44-53, 2011

Abstract
As molecular biomarkers are becoming routine in the clinical management of lung cancer patients, there is an increasing need to establish standards or guidelines for the reporting of molecular results. In the most ideal situation, reporting of tissue based molecular biomarker results should be integrated into the histopathology report of the tissue sample, to provide a more complete genotype-phenotype characterization of the tumor. This is particularly important for lung cancer as molecular profiling to date has clearly shown that many “driver” genomic aberrations are often closely associated with specific tumor histology. In fact, the current CAP/IASLC/AMP guideline on molecular testing in lung cancer recommends the use of histology (adenocarcinoma containing tumors) as a primary criterion to select lung cancer samples for EGFR and ALK testing. However, until reflex molecular testing becomes routine in pathology practice, molecular testing is often conducted at a laboratory that is separate from the one where the original tissue histopathological diagnosis was made. In such cases, it is important that the stand alone molecular report should also include some histopathological data that may be highly relevant to the interpretation of the results, or at the very least, refer to the relevant Pathology report. In the Pathology report, the data should include: (a) type of sample, whether it is paraffin embedded or fresh (e.g. fluid), (b) tumor diagnosis, subtypes and variants when applicable, (c) essential immunohistochemical markers that were assessed to support the diagnosis, (d) use of tissue processing solution or fixative that could adversely affect the quality of DNA for sequencing, e.g. acid and Bouin’s solution, (e) the approximate size of the tissue, (f) whether a tumor cell enrichment strategy was used, and (g) estimated tumor cellularity in the tissue area marked for isolation of DNA for testing. It is of utmost important that molecular reports are written in language that can be understood by the treating physicians and the pathologists, who are the end-users of the report. Typical laboratory reports should include patient identification codes, the date the sample was acquired (biopsy or resection) from the patient, the date the sample is received in the molecular testing laboratory, and the date the report is signed out. All this information provides not only important sample identification information, but also the real turnaround time of the reported results. Aside from a summary of the molecular results themselves, the report should include a concise but reasonable detailed methodological section, which also provides the performance features of the assay platform being used. It should specify the list of genes included in the assay, the type of aberrations that can be reliably detected, e.g. single nucleotide mutations, deletions, insertions, rearrangements, copy number changes, etc, and the sensitivity and specificity of the assay. The methodology section should also include the analytical software used for processing the data and identifying the genomic aberrations and the version of the normal reference sequence used for comparison with the sequence in question. If the methodology used is fairly new or represent emerging technology, such as next generation sequencing (NGS), then information about mutation verification technology or process may also be required (1). While molecular aberrations are integral to the complete pathological diagnosis of a tumor, in lung cancer their main clinical relevance is for their ability to predict patient response to a specific therapeutic agent, or for patient prognosis. In this context, especially if there are a number of genetic changes being reported (as example with NGS); it may be useful if the aberrations (often called variants) are classified into categories, which reflect their clinical utility. Although there is as yet no universally acceptable classification framework for reporting genomic aberrations identified by NGS platforms, broad categories that establish prognostic, biological or treatment relevance to the aberrations have been proposed or used. These variants have been classified into several “Levels” or “Tiers”, depending on the level of evidence for their predictiveness of response to specific drug. These levels have been derived from widely accepted classification schemes, such as those published by the American College of Medial Genetics (ACMG) for use in diseases such as Breast Cancer. The “actionable” aberrations are those demonstrating proven evidence for their association with high response rates to a specific drug or treatment strategy. The “potentially actionable” alterations are those with strong rationale but as yet proven clinical evidence for being associated high response rate to a specific drug. This group also include aberrations that have demonstrated evidence for response to a specific drug in one type of cancer, yet of unproven response pattern in a different tumor being studied. However, as NGS enables the discovery of a large number of genetic aberrations that typically occur in sporadic adult cancers, many aberrations fall into the category of “unknown therapeutic or biological significance”. While some of these could potentially be predictive markers of drugs that are already available for other reasons, most may not even be pharmacologically targetable. An important risk of conducting comprehensive genomic profiling in patient samples is the identification of “incidental” aberrations, which require clinical management that is not originally planned or anticipated (2). These aberrations could involve genes/mutations with known hereditary roles in cancer or non-cancer conditions, with potentially significant implication on patient and/or other family members. For these reasons, the ACMG recently convened a working group of experts to publish recommendations for reporting of incidental findings in clinical exome and genome sequencing. While these recommendations have been provided primarily as educational resources for medical geneticists and other health care providers (and are still quite controversial), the issues discussed should be considered when deciding upon the reporting strategy for profiling cancer samples using NGS technology. References: 1. Rehm HL, Bale SJ, et al. ACMG clinical laboratory standards for next-generation sequencing. Genet Med. 2013 Jul 25. doi: 10.1038/gim.2013.92. [Epub ahead of print] 2. Green RC, Berg JS, et al. ACMG recommendations for reporting of incidental findings in clinical exome and genome sequencing. Genet Med. 2013 Jul;15(7):565-74. doi: 10.1038/gim.2013.73. Epub 2013 Jun 20.

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Abstract

Abstract
Formal prospective evidence of benefit from cancer treatments for patients with mesothelioma exists only for the small survival increment obtained from combinations of cisplatin and anti-folate agents in those with inoperable disease. Despite this absence of evidence of benefit, and some evidence of detriment, trimodality therapy including neoadjuvant chemotherapy, surgery and adjuvant radiotherapy continues to be regarded as a widespread standard of care in early disease. Only one very small randomised trial has addressed this question[1], and the evidence from that trial suggesting a substantial increase in mortality has been disputed by many believers in trimodality therapy. The surgical literature has recently been extensively reviewed, revealing the paucity of high level evidence for these treatments[2-3]. One Swiss trial investigated the role of radiotherapy in this combination, but closed last year because of poor accrual due to changes in surgical fashion (NCT00334594)[ 4]. The two major surgical approaches to early mesothelioma have been extrapleural pneumonectomy (EPP), first described over 30 years ago, and presented in 16 published reports of which 5 were prospective and only 1 randomised[2]. None of these studies directly compare radiation doses or techniques, and no firm conclusions are possible regarding dose response, or the superiority of techniques as variable as a simple opposed pair with or without electrons to intensity modulated radiotherapy (IMRT) or protons. It seems extremely unlikely that such data will ever exist, and what radiotherapy is used will continue to depend mainly on the expertise, technology and time available locally. There have been publications[5,6], reporting an unexpectedly high morbidity and mortality following IMRT and there may be an argument that simplest is best given the general lack of fatal outcomes with conventional radiotherapy, although dose coverage of certain areas is poor. One report suggested lower local failure with IMRT[7], but this may have related to the higher dose given (50.4 Gy vs 30 Gy) and it was unclear why the slightly higher dose (54 Gy)[ 8] normally used postoperatively was not possible. If IMRT is to be used then treatment times may be shorter with volumetric modulated arc therapy[9]. Whether as a result of the MARS trial, or the disappointing outcomes from prospective trials conducted by the EORTC and in the US[8, 10], surgical fashion has moved in the last few years from EPP to various extents of pleurectomy, where the underlying lung is preserved. This is not a conventional cancer operation involving en bloc resection of tumour with a defined margin, and adjuvant radiotherapy is rendered more difficult, if not impossible, by the residual lung. Attempts to spare the lung at least partially must of necessity involve sparing the pleura overlying the fissures, and significant rates of pneumonitis have been reported, albeit less than in the early reports of IMRT[11]. The doses achievable by these techniques remain relatively low by cancerocidal standards in the context of a disease believed to relatively radioresistant. Cao has also reviewed the 34 publications on pleurectomy, none of which are randomised and very few prospective[3]. Radiotherapy in most series, when it is described at all, seems to be at relatively low dose to the port sites, of questionable benefit since 2 randomised trials have shown no effect from this intervention at the time of diagnosis[12, 13]. The MARS group also plan to look at the benefits of pleurectomy, but radiotherapy is not currently included in the trial outline. Currently this is an area in which virtually no data exist to support decision making. Radiotherapy is likely to remain part of the trimodality recipe for those who continue to believe in EPP, at least until the postulated trial of 670 participants is completed[14], and single centre reports on small numbers of patients with more complex treatment techniques likely to continue. If the next generation of larger trials of radiotherapy looking at port site prophylaxis confirm the lack of utility of this intervention, it is difficult to see that there will be a role for radiotherapy after pleurectomy. Rather than assume such a role, it is to be hoped, but not expected, that randomised trials of the benefits of radiotherapy be instituted. 1. Treasure T et al, Lancet Oncol. 2011 Aug;12(8):763-72. 2. Cao CQ et al, J Thorac Oncol. 2010 Oct;5(10):1692-703. 3. Cao CQ et al, Lung Cancer. 2013 Jun 12. doi:pii: S0169-5002(13)00212-2. 4. http://clinicaltrials.gov/show/NCT00334594 5. Allen AM et al., Int J Radiat Oncol Biol Phys. 2006 Jul 1;65(3):640-5. 6. Patel PR et al., Int J Radiat Oncol Biol Phys. 2012 May 1;83(1):362-8. 7. Buduhan G et al., Ann Thorac Surg. 2009 Sep;88(3):870-5. 8. Van Schil PE et al., Eur Respir J. 2010 Dec;36(6):1362-9. 9. Scorsetti M et al., Int J Radiat Oncol Biol Phys. 2010 Jul 1;77(3):942-9. 10. Krug, LM et al., J Clin Oncol. 2009 Jun 20;27(18):3007-13. 11. Rosenzweig KE et al., Int J Radiat Oncol Biol Phys. 2012 Jul 15;83(4):1278-83. 12. Bydder S et al., Br J Cancer. 2004 Jul 5;91(1):9-10. 13. O’Rourke N et al., Radiother Oncol. 2007 Jul;84(1):18-22. 14. Weder W et al, Lancet Oncol. 2011 Nov;12(12):1093-4.

Abstract
Mesothelioma remains an incurable disease. Although there is compelling evidence that some patients can benefit from radical surgery, this modality remains surrounded by controversy and true Level I evidence in the form of a randomized prospective trial has yet to establish surgery as the standard of care. The driving principles behind utilizing surgery-based treatments for this cancer are that: these tumors are not curable with other modalities, they can reach enormous volumes where surgery is the only current modality that has expectation of achieving a significant response, as a general rule these cancers tend to progress locally to the point of patient demise without extrahemithoracic disease being present or of clinical significance. Because it is not possible to achieve completely negative margins in the overwhelming majority of pleural cancers, the realistic goal of any radical surgical procedure is to achieve a macroscopic complete resection. It is logical, therefore, to employ intraoperative adjuvant therapies in an effort to control the microscopic disease that remains after surgery. To date there are several different intraoperative adjuvants that have been employed with any regularity in the treatment of pleural mesothelioma: intraoperative radiation, heated perfusion with either chemotherapy or povidone iodine and photodynamic therapy. Each has its own advantages and disadvantages, from both oncologic and technical perspectives. Intraoperative radiation does not appear to be in active use at this time. The advantages of radiation are the established track record in treating mesothelioma and the penetrating nature of the modality with the disadvantages being damage to normal tissue, from the same penetrating nature. Employment of intraoperative radiation is likely the most expensive and logistically complicated of the intraoperative adjuvants. The technique that has been employed with heated povidone iodine has the advantages of logistical simplicity, with the treatment being delivered as sequential dwells, and low expense. In addition, there is the advantage of povidone iodine being an easy and safe material with which to work, with a high safety profile for both the patient and health care staff delivering the treatment. The disadvantages of this technique include the unclear benefit of povidone iodine as a therapeutic agent against this cancer and the certainty that unifom hyperthermia is not maintained during a dwell, working under the assumption that hyperthermia is an effective modality in and of itself. There is recent evidence, however, that mesothelioma may be resistant to hyperthermia. The common technique utilized for heated chemotherapy perfusion, typically platin-based, is significantly more involved than the dwell technique. In this situation a perfusion pump is employed. Disadvantages include increased expense and logistical complexity and utilization of an agent with a significant toxicity profile for both the patient and health care staff delivering the treatment. Advantages include assurance that hyperthermia is maintained, along with control of the temperature, and application of a perfusion agent that has an established track record in treating malignant pleural mesothelioma. With inflow and outflow catheters, this technique has the ability to simultaneously perfuse both the chest cavity and the abdomen, theoretically of benefit to treating occult peritoneal metastases or cells that are disseminated during surgery. Both perfusion techniques have the additional limitation that they are likely purely surface treatments, without any depth of penetration for the treating agent. Photodynamic therapy is a unique treatment modality and, as such, has unique advantages and limitations. Although it is simple to perform, it is likely the most logistically complex of the currently employed modalities. It requires delivery of visible laser light, pretreatment with a photosensitizing drug and employment of special “light precautions” for some period of time before, during and after surgery. Although the cost and availability of lasers has dropped dramatically, it is still a treatment that currently comes with a significant cost. The advantages are that the treatment works by a unique set of mechanisms, delivers treatment at and below the surface for short distance and is known to incite a significant immune response against treated cancers. Whether or not that tumor-directed immune response occurs with pleural mesothelioma is under investigation. Currently it is not possible to rigorously determine which, if any of these treatments is superior. Factors contributing to this dilemma are among the same that limit comparison of any surgery-based treatments. These include: small numbers of patients, colossal variability in patients not only between series but within series, lack of a highly effective staging system to allow rigorous analyses and comparisons, enormous variability in surgical techniques, lack of prospective randomized trials and the fact that essentially all patients suffer recurrence and overall survival may be greatly affected by subsequent treatments. This presentation will review the different intraoperative modalities, present current results and speculate about future directions.