Virtual Library

Background:
Diagnostic yield for routine unguided bronchoscopy for peripheral pulmonary lesion (PPL) is less than 20%. Hence, CT guided transthoracic needle aspiration (TTNA) is currently the preferred method with a high diagnostic yield of 90%, however running risk of pneumothorax of around 25%. Radial endobronchial ultrasound with guide sheath (R-EBUS-GS) for diagnosis of PPL is a novel technique with diagnostic yield of 70.6% with good safety profile. However, this advanced technique is not readily available in developing nations and were further limited by the availability of other supporting modalities such as thin section computed tomography (CT) scan, fluoroscopy, thin bronchoscope, availability of rapid onsite evaluation (ROSE) and a established cytology services. To the best of our knowledge, this is the first series of R-EBUS from Malaysia.

Method:
Retrospective review of our early experience with R-EBUS-GS in diagnosing PPL at Respiratory Medicine Unit, Sarawak General Hospital over six months duration from October 2016 to May 2017.

Result:
65 patients with 68 targets were enrolled. 48 (71%) male and 20 (29%) female patients with mean age of 60.5±13.2 years old. Up to 54 (79%) cases will undergone CT guided TTNA if without R-EBUS-GS. All procedures were performed as day case under conscious sedation with mean procedure time of 37 minutes. Mean PPL size was 3.87±1.2 cm and 53.1% located in the upper lobes. We were able to localize the lesion in 58 (85.3%) cases, failed to identify in 4 (5.8%) and 3 (4.4%) had endobronchial lesion. Overall diagnostic yield for PPL that could be localized was 63.8%. Diagnostic yield for patient who suspected malignancy was 57.5%. Higher diagnostic yield is associated if lesion was orientated within the radial probe rather than adjacent to it (85.2% vs. 20%, p<0.005). Fluoroscopic guidance, CT bronchus sign and lesion size did not contribute significantly to diagnostic yield. Overall complication rate was 3% with only 1 (1.5%) patient developed pneumothorax, which was self-limiting.

Conclusion:
Radial EBUS-GS is an effective tool to guide biopsy during peripheral bronchoscopy with low complication rate. Despite various resource constraints and challenges, our early experience with R-EBUS-GS shown promising result and our center anticipates further experiences with this technique in the future.

Background:
Radial probe endobronchial ultrasound (R-EBUS) is a novel technique in localizing peripheral lung mass with overall diagnostic yield of 70%. Conventional biopsy techniques using forcep or fine needle aspirates guided by R-EBUS occasionally resulted in small sample which may not be suitable for immunohistochemical or molecular studies. R-EBUS guided transbronchial cryobiopsies in peripheral lung mass is a feasible technique to obtain larger tissue samples without affecting safety. We described our initial experience with three consecutive patients who underwent R-EBUS guided transbronchial cryobiopsy in our unit in May 2017.

Method:
Therapeutic flexible bronchoscope with a 2.8mm working channel, 2.0mm 20 Hz ultrasound probe (UM-S20-20R, Olympus Medical) within a 2.2mm flexible guide sheath and 1.9mm flexible cryoprobe (1150mm ERBE, Medizintechnik, Germany) was used in all cases.

Result:
The mean age was 60±11.6 years (range 47-68 years). Two cases were performed under conscious sedation and one under total intravenous anaesthesia. Mean procedural time was 48.3±15.9 minutes. All lesions were located in right upper lobe. Two patients had non-diagnostic computed tomography (CT) guided biopsy prior. Mean lesion size was 2.6±0.4cm with mean distance to the pleural of 1.2cm. All lesions were able to be identified via R-EBUS with two lesions orientated within the radial probe while one adjacent to it. Cryobiopsy was obtained by freezing the tip of cryoprobe for 5 seconds. Three attempts were performed in Case 1 and 3, two in Case 2. First two cases were guided with fluoroscopy. All patients had minimal intra-procedure post biopsy bleeding which was easily managed. Mean specimen size was 10.6mm. All biopsies yielded adenocarcinoma of lung with immunohistochemistry positive for CK7 and TTF-1.

Conclusion:
Our initial experience shows that R-EBUS guided transbronchial cryobiopsy is safe and can potentially increase the diagnostic yield of peripheral lung mass. Our center anticipate further experience with this technique in the future.

Background:
Once there were mediastinoscopy and now there is EBUS TBNA. It started in 1997. the development of a real time Ultrasound guide TBNA system were proposed in 1997 and in Dec 2002 the first EBUS TBNA paper were published Then 1 in 2003, 2 in 2004 and 3 in 2005 describing the use of EBUS TBNA for staging of the mediastinum. All ready in 2006 the first paper describing the effectiveness in combining EUS FNA and EBUS TBNA using 2 different types of scopes. This combination was not widely used until Felix Herth and his group demonstrated the usefulness of the EBUS TBNA scope in the esophagus. In 2007 the first paper on the use of EBUS TBNA in sarcoidosis was published, the first review and the use of cytology and EGF. 2008 was the year when the issue of diagnosing lymphoma was raised and the diagnosing metastases in the mediastinum from other organs and mediastinal tumors was shown feasible. 2009 was the year of the first metaanalysis and the first randomized study. The first complication was mentioned. The chemosensitivity and cell receptors were discussed. In 2010 the number of papers exploded. Restaging, TB, the number of stations punctured, one scope in esophagus and trachea, cost benefit, learning curves, sedation, elastography were the main topics. Mediastinoscopy was still the golden standard 2011 another randomized study. More papers on hematological diseases and more receptors were demonstrated in cytology and a biopsy forceps were introduced and more complications were described 2012 the 19 G needle and cell block and ROSE were introduced. The first paper using the EBUS TBNA in treatment was described. And it was the year of the ASTER trial 2013 is the year of molecular biology and EBUS TBNA. The literature from this year was characterized by the establishment of EBUS TBNA’s role in the staging and diagnostic process of cancer in the lung and mediastinum 2014 is the year of the acceptance of EBUS TBNA with the new ESTS guidelines 2015-16 is characterized of different metaanalysis and many reviews on a wide spectrum of topics using the EBUS TBNA in diferent areas of pulmonology

Method:
A review of the literatur

Result:
Section not applicable

Conclusion:
EBUS TBNA have in a very short time revolutionized the diagnostic of chest diseases and the staging og lung cancer. There is still room for improvement of the system and the role of EBUS TBNA is stil developing

Background:
Flexible Bronchoscopy was developed in 1976 by Shigeto Ikeda and has become the mainstay investigation in the evaluation of patients suspected of lung cancer. It is an indispensable tool for diagnosis and therapeutics. It is convenient to perform, safe and well tolerated. The British Thoracic Society guidelines recommended biopsies, brushings and washings for sampling. However, reported diagnostic yield from bronchoscopies in patients with lung cancer varies greatly. Due to the lack of data regarding the lung cancer detection rate of conventional bronchoscopic techniques available in our institution, our study is mainly intended to present the experience gathered in 200 cases in the use of bronchoscopy.

Method:
We retrospectively reviewed all patient data that underwent conventional bronchoscopic techniques at Perpetual Succour Hospital, Cebu City, Philippines between June 2011 and December 2016. Incluscion criteria includes 1. all bronschopies performed with conventional bronschopic techniques; 2. final histopathologic diagnosis of malignant lung disease obtained during bronchoscopy. Figure 1



Result:
A total of 200 patients have undergone bronchoscopy,154 patients undergone conventional bronchoscopic techniques. Majority were males, the main indication was diagnostic and done via conscious sedation. Endobronchial biopsy had the highest rate of positive yield for malignant lung disease with 34%. The most common histopathological result is Squamous Cell CA for both endobronchial biopsy and brushing while Adenocarcinoma and Small Cell for bronchial lavage and washing. The presence of endobronchial lesion was associated with malignant lung disease.

Conclusion:
It can be concluded that majority of our patients are males whose main indication was diagnostic. Endobronchial biopsy was the technique with the highest rate of positive yield for malignant lung disease. Endobronchial visibility is a predictor of a positive rate for malignancy.

Background:
Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is a minimally invasive modality for sampling of mediastinal and hilar lesions. Two dedicated aspiration needles are used for EBUS-TBNA. The relative utility of 21- versus 22-gauge needles remains controversial. The aim of this study was to evaluate the two needles in terms of the adequacy of histological specimens and cellularity of cytological specimens in patients with lung cancer.

Method:
Sixty-eight patients with metastatic hilar/mediastinal lymphadenopathy with lung cancer or tumors adjacent to the central airway (115 lesions in all) underwent EBUS-TBNA using 21- or 22-gauge needles between September 2014 and April 2016. Samples were assessed by an experienced pathologist blinded to the needle gauge used; rapid on-site cytological evaluation was not performed. The adequacies (in terms of histopathology and cellularity) of aspirates were evaluated.

Result:
We found no significant difference between the two groups in terms of sex, age, the characteristics of primary malignancy, lesion size, location of the evaluated lesions, or number of needle passes. For samples obtained using 21- and 22-gauge needles, the histological adequacies were 82.5% and 79.4% (p=0.81), and the cytological adequacies 77.1% and 55.2% (p=0.018), respectively. No significant complication was associated with either procedure.

Conclusion:
The 21-gauge needle afforded better specimen cytology but the needles did not differ in terms of adequacy of the histological specimens in patients with lung cancer.

Background:
Dedicated 22G needle is usually used for EBUS-TBNA, which is a main diagnostic tool for nodal staging in lung cancer. Recently new 25G needle is developed and expected less invasive nodal biopsy. Although, diagnostic yield and complication of the EBUS-TBNA using 25G needle are still unclear.

Method:
From September 2016 to May 2017, 39 hilar or mediastinal lymph nodes in 25 patients were consecutively biopsied using both 22G (Olympus, Tokyo, Japan) and 25G (Boston Scientific, MA) needles for diagnosis or staging of lung cancer. Concordance rates of rapid on-site cytologic evaluation and cytological and pathological diagnosis between the EBUS-TBNAs using the two types of needles were evaluated. And also, bleeding score of cytological specimen (0-3: higher is more contaminated) and calculated area of histological core (the number of high-power field microscopically in paraffin-embedded slides) were compared for evaluating sample qualities. The results obtained from EBUS-TBNA using 22G needle were regarded as control to evaluate the diagnostic ability of that using 25G needle in this analysis.

Result:
No complication was recorded during the study period. Thirty three Mediastinal nodes (#2(n=2), #3(n=1), #4R(n=16), #4L(n=2), #7(n=12)) and 6 hilar nodes (#10(n=1), #11(n=3), #12(n=2)) were biopsied and concordance rate between 22G and 25G was 87% (34/39) in the rapid on-site cytologic evaluation, 95% (37/39) in the cytological diagnosis and 85% (35/39) in the histological diagnosis. Final decision whether metastatic or not according to the combined cytologic and histologic diagnosis in the EBUS-TBNA using 22G needle was 19 metastases and 20 benign nodes, and the concordance rate with the two types of needles was 92% (36/39). In the 3 nodes with discrepancy, 2 nodes were diagnosed as lung cancer metastasis by the 25G needle sampling. Both bleeding score and calculated area of histological core showed no significant difference (p=0.3 and 0.7) between 22G and 25G, with respective values of 1.8±0.9 vs. 2.0 ±0.7, and 20±2.2 vs. 21±2.2.

Conclusion:
EBUS-TBNA using 25G needle is feasible and as useful as that using conventional 22G.

Background:
Endbronchial ultrasound guided-trans-bronchial needle aspiration is useful methods for the diagnosis of lung cancer and benign disease. In EBUS-TBNA, we should pay attention for complication and fail. Mediastinitis is a sever complication by EBUS-TBNA. Some reports were paid attention to necrosis findings by EBUS, for example coagulation necrosis sign, heterogeneous echogenicity, and blood poor finding. And then, we couldn’t collect lesion with EBUS-TBNA, because of size and bronchus artery. We should avoid bronchus artery. If bronchus artery was punctured, Bleeding was failed sampling.

Method:
In this study, we revealed CT finding is enhanced LN size and necrosis. 43 lesions were enrolled retrospectively from Jan 2015 to May 2017.

Result:
Malignancy were 23. In CT finding, aspiration axis’s means were 34.4±12.3 mm. In plain CT, low intensity area was detected 36.6% (14/43). In enhanced CT, low density area was detected 47.2% (17/36). CT size was enhanced EBUS size (r2=0.45, p<0.001). Indeed, we avoided sampling for 10mm or less in EBUS. CT low density area wasn’t enhanced EBUS necrosis sign’s. These CT findings were low sensitivity and specificity. We avoided sampling from necrosis leions in EBUS.

Conclusion:
CT size were enhanced EBUS sampling axis diametter. However, CT low density area wasn't reflect necrosis finding in EBUS.

Background:
Cancer stem cells (CSCs) have been proposed to be responsible for tumor initiating, drug resistance, metastasis, and recurrence. Many novel therapeutic strategies have been designed to target and eliminate CSCs. According to our previous study, we have established a model of CSCs and cancer associated fibroblasts (CAFs) co-culture system for anti-CSCs drug screening. Here, we report one of the potential hits screened via this platform and the anti-CSCs activity was further investigated both in vitro and in vivo.

Method:
Human lung CSCs and CAFs were primary cultured from patient with lung adenocarcinoma according to our previous study. Image–based high content screening system was used to analyze different parameters after drug treatment. Tumorogenicity and self-renew ability are examined by sphere forming ability. Aldehyde dehydrogenase (ALDH) activity was used to analyze stem cell population by flow cytometry. The expression level of stemness-related genes, Nanog, Oct3/4 and Sox2 were validated by real-time reverse transcriptase Q-PCR. The efficacy of the lead on tumor growth was examined by the xenograft model. Lung cancer stemness markers of the xenograft tumor tissues were also evaluated by immunohistochemistry.

Result:
Using the CSC/CAF co-culture model with the image–based high content screening system to screen over one thousands of compounds, we have identified aloe-emodin (AE), an anthraquinone isolated from traditional herbs (e.g., Aloe vera), shows higher potency on lung CSCs (under 1 µM dosage) and relative selection for targeting on the cancer cell lines with the IC~50~ less twenty µM; compared to normal human bronchial epithelium cells and human normal fibroblast represented by IC~50~ (26.77 µM v.s. 39.13 µM). The level of stemness markers, Nanog, Sox2 and Oct3/4 were significantly down-regulated after AE treatment compared to cisplatin treatment. AE could suppress tumor initiating abilities and self-renew capacities by inhibiting the tumorous sphere forming in CL152 ALDH[+] cells. Besides, AE could inhibit ALDH population in CL152 cells (40% reduced). Also, the AE can inhibit the cisplatin-induced ALDH population as well. Furthermore, we found that the combination treatment of AE and cisplatin could inhibit tumor growth as comparing to cisplatin treatment in subcutaneous xenograft models in NOD/SCID mice, whereas, AE can significantly inhibit the level of Nanog in mice tumor tissues.

Conclusion:
According to these results, AE is a potential lead targeting on lung CSCs. To discover the pharmacological mechanism of AE on CSCs will be helpful to develop new strategy for lung cancer therapy.

Background:
Low-dose CT (LDCT) screening for lung cancer is currently recommended in the USA but not in Australia, as there remain important knowledge gaps. We aimed to evaluate the feasibility of lung cancer screening in the Australian healthcare setting using the PLCO~m2012~ model to identify high-risk participants and the PanCan nodule malignancy risk-calculator to guide management of detected pulmonary nodules.

Method:
Current/former smokers, aged 55-74 years, were recruited from the community. Eligibility for LDCT-screening was defined as PLCO~m2012~ ≥1.51% over 6 years. Participants underwent interview, spirometry and LDCT. Detected nodules were managed with a risk-based algorithm using the PanCan nodule calculator (highest-risk nodule score used if multiple nodules present). If risk-score <1.5%: repeat LDCT at 24 months; 1.5-6%: LDCT at 12 and 24 months; 6-10%: LDCT at 3, 12 and 24 months; >10%: consider immediate investigation. If no nodules detected, no further LDCT arranged. We report results after 24-month follow-up.

Result:
We received 104 enquiries – 54 were eligible and 49 underwent screening LDCT. Results are summarised in Table 1. In participants with pulmonary nodules (n=26), the PanCan risk-score was <1.5% in 12 (46.2%), 1.5-6% in 5 (19.2%), 6-10% in 6 (23.1%) and >10% in 2 (7.7%). Of note, 65% of nodule-positive participants did not require further investigation within the first year of screening. Lung cancers were identified in 2 (4.1%) participants – 1 underwent surgical resection of a Stage 1b adenocarcinoma, the other had an enlarging nodule treated with stereotactic radiotherapy (no biopsy due to surrounding emphysema). A further participant is due surgery for a 53mm[3] slow-growing nodule with growth between 12 and 24 month scans. Table 1. Characteristics and LDCT findings of screened-individuals. Figure 1



Conclusion:
A targeted, algorithmic approach to lung cancer screening is feasible and identifies early-stage lung cancers. Use of the PanCan nodule risk calculator simplifies downstream investigation after baseline LDCT.

Background:
The incidence of lung cancer among never-smokers has been increasing rapidly. The US National Lung Screening Trial study showed that screening using low-dose chest computerized tomography (LDCT) effectively reduced lung cancer mortality among heavy-smokers. However, its effectiveness in never-smokers has not been studied. Therefore, this study investigated the role of LDCT in lung cancer screening among never-smokers.

Method:
In this single-center, retrospective, cohort study, we identified 4,054 (13.5%) non-smokers (age range: 40-75 years) among 30,080 patients who underwent LDCT for lung cancer screening at Seoul National University Bundang Hospital Health Promotion Center, between May 2003 and June 2016. We analyzed patients with abnormal LDCT findings and cancer rates. Abnormal LDCT findings, such as nodules, were classified according to the Lung-RADS criteria and the final pathologic outcomes were further analyzed. If multiple nodules were found, we selected one dominant nodule.

Result:
Among the 4,054 never-smokers, 2,519 (62.1%) were women. Among the 846 patients (20.8%) with lung nodules, 636, 112, 56, 34, and 8 had nodules categorized as 2, 3, 4A, 4B, and 4X, respectively, according to the Lung-RADS criteria. Among these, 315 (37.2%), 95 (11.2%), and 436 (51.5%) nodules were solid, part-solid, and non-solid, respectively. Moreover, 448 (52.5%) patients underwent further diagnostic work-up, including follow-up CT or diagnostic procedures. Finally, 38 (0.9%) patients were pathologically diagnosed as lung cancer. Among these patients, 34 (89.5%) were in stage I, and 33 (86.8%) had adenocarcinoma. No cancer-related death occurred, and the diagnostic work-up did not cause significant morbidity.

Conclusion:
In the never-smoker population, LDCT screening helped detect a significant number of lung cancers. Most of these lung cancers were detected at a very early stage.

Background:
African Americans have been underrepresented in trials showing survival benefit to lung cancer screening. We implemented a multidisciplinary lung cancer screening program in an African American population. We hypothesize that lung cancer screening in an African American population will lead to safe detection and treatment of lung cancer.

Method:
In an urban, academic medical center, we prospectively gathered information on African American patients referred to a multidisciplinary lung cancer screening program from October 2015 to December 2017 with a 6 month follow up. We studied, age, gender, smoking history and level of education. We measured lung cancer screening results using Lung-RADs categorizations, diagnosis of cancer, treatment modality and complications.

Result:
Of 160 African Americans undergoing lung cancer screening, the average age was 64.2 (SD 5.75), 95 (59.3%) were women, 111 (69.3%) were current smokers, average pack years was 47.2 (SD 17.1) and level of education was less than high school in 52 (32.5%), high school in 53 (33.1%), advanced education in 45 (28.1%) and 10 (6.2%) declined to report. LDCT results were 1 (0.6%) with Lung-RADs 0; 69 (43.1%) with Lung-RADs 1; 73 (45.6%) Lung-RADs 2; 7 (4.3%) Lung-RADs 3; 10 (6.3%). Of the 6 people undergoing invasive procedure for biopsy (3 CT guided needle biopsy, 1 transbronchial needle biopsy, 2 surgical resection) 4 were diagnosed with stage I non-small cell lung cancer. Three of these underwent surgical resection for treatment, and one underwent radiation treatment.

Lung Cancer Screening in an African American Population

	Number	Percent
Total	160	100%
Average Age	64.2
Average Pack Years	47.2
Active Smokers	111	69.4%
Former Smokers	49	30.6%
Gender
Women	95	59.4%
Men	65	40.6%
Education
Less Than High School	52	32.5%
High School	53	33.1%
Advanced Education	45	28.1%
Declined to Answer	19	6.3%
Lung-RADs Category
Lung-RADs 0	1	0.6%
Lung-RADs 1	69	43.1%
Lung-RADs 2	73	45.6%
Lung-RADs 3	7	4.4%	1 diagnosed with stage I lung cancer with CT guided biopsy
Lung-RADs 4	10	6.3%	3 diagnosed with stage I lung cancer, 1 with CT guided biopsy, 2 with surgical biopsy
Total Receiving Biopsy	6	3.8%
CT Guided	3	1.9%	2 diagnosed with stage I lung cancer
Transbronchial	1	0.6%
Surgical Resection	2	1.3%	2 diagnosed with stage I lung cancer
Lung Cancer Diagnosis	4	2.5%
Stage I	4	2.5%
Stage II	0	0%
Stage III	0	0%
Stage IV	0	0%
Adenocarcinoma	4	2.5%
Squamous Cell	0	0%
Treatment
Surgical Resection	2	1.3%
Radiation	1	0.6%
Complications	0	0%

Conclusion:
Implementation of a multidisciplinary lung cancer screening program enrolling African Americans at high risk of lung cancer led to detection and treatment of lung cancer in 2.5%. Only 10.7% had positive screens (lung-RADs 3 or 4), 3.8% had an invasive biopsy and no one had complications from diagnostic procedures or treatment. Further study is necessary to understand long-term survival benefit of lung cancer screening.

Background:
Lung Cancer Screening with low dose CT (LDCT) can reduce lung cancer death, but only if those found to have lung cancer proceed with lung cancer treatment. When implemented into diverse populations, lung cancer screening may prove less effective if patients are unwilling or unable to undergo lung cancer treatment. We employed an enhanced shared decision making (SDM) model to address willingness and ability to undergo lung cancer treatment before low dose CT (LDCT) scanning. We hypothesized that enhanced SDM was feasible and did not discourage patients or providers from proceeding with lung cancer screening.

Method:
We performed a prospective study of patients referred for lung cancer screening between October of 2015 and May of 2017. We measured race, gender, adherence to the consent process and questions regarding willingness and ability to undergo lung cancer treatment. Subsequent uptake of LDCT, outcomes of cancer diagnosis and failure to follow up were also studied.

Result:
Of 363 enrolled study participants, 59% were African American, 12% were Caucasian, 12% were Hispanic and 2% were Asian. The gender distribution was 186 male (51.2%) and 177 female (48.8%). All 363 patients had a documented SDM visit addressing the risks and benefits of lung cancer screening and consented to discuss lung cancer treatment if lung cancer is diagnosed. When asked if they were willing to undergo lung cancer treatment, 15 (4.1%) people responded “no”, 4 (1.1%) people responded “unknown” and 8 (2.2%) did not have a documented answer. When asked if they were able to undergo lung cancer treatment 10 (2.8%) people responded “no”, 2 (0.5%) people responded “unknown” and 8 (2.2%) people did not have a documented answer. Overall, 6 (1.7%) people were diagnosed and treated for lung cancer. Only 1 person declined screening despite being willing and able to undergo lung cancer treatment. One (0.2%) person failed to follow up on a suspicious nodule found on lung cancer screening despite reporting being willing and able to undergo lung cancer treatment.

Conclusion:
Though SDM is essential to lung cancer screening, there are few guidelines on how to conduct this process. This study demonstrated that an enhanced SDM experience, including questions about willingness and ability to undergo lung cancer treatment, is a feasible practice that did not deter patients or providers from proceeding with lung cancer screening. Our enhanced SDM experience gave clinicians and patients a framework to emphasize the importance of appropriate follow up of positive screens.

Background:
In low-dose computed tomography (LDCT) lung cancer screening new nodules are frequently found after baseline. Currently, there is no evidence concerning the relationship between a participant’s number of nodules and the lung cancer probability of new nodules.

Method:
This study is part of the ongoing Dutch-Belgian Randomized Lung Cancer Screening (NELSON) Trial. Participants with solid and sub-solid nodules detected after baseline and registered as new by the NELSON radiologists were included. Three nodule counts were calculated: The participant’s total number of new nodules present at new nodule detection, the participant’s overall number of nodules detected before new nodule detection, and the participants overall number of calcified nodules detected until new nodule detection. The discriminative performance of the nodule counts for prediction of lung cancer was assessed through the area under the receiver operating characteristic curve (AUC). On participant level, a multivariable logistic regression analysis with eventual lung cancer diagnosis in a detected new nodule as outcome was performed, including the nodule count and participant’s largest new nodule size (categorized as <50mm[3], 50-<500mm[3], ≥500mm[3]). On nodule level, the equivalent analysis was performed, including the nodule count and nodule size while adjusting for clustering of data within participants using Huber-White robust estimators.

Result:
A total of 706 participants with 964 new nodules (median 1, range 1-12) were included. Eventually, 9% (65/706) of the participants had lung cancer in one of the new nodules. The lung cancer probability was 10% (56/552) for participants with 1 new nodule, 7% (7/100) with 2 new nodules, and 4% (2/54) with ≥3 new nodules (P=0.21). On nodule level, the number of new nodules provided moderate discrimination for lung cancer (AUC: 0.67, P<0.001) and remained a significant predictor after adjusting for nodule size (odds ratio [OR] 0.42, 95% confidence interval [CI] 0.26-0.68, per additional new nodule present). On participant level, the number of new nodules provided poor discrimination for eventual lung cancer diagnosis in a detected new nodule (AUC: 0.55, P=0.22), but was significantly associated with lung cancer when corrected for largest new nodule size (OR 0.61, 95%CI 0.39-0.98 per additional new nodule present). The participant’s overall number of nodules before new nodule detection and the number of calcified nodules were not associated with lung cancer.

Conclusion:
While an increased number of detected new nodules signifies a reduced lung cancer probability of each individual new nodule, the impact on the participant’s overall lung cancer probability in the new nodules is limited.

Background:
The landmark Lung Cancer Screening (LCS) Trial demonstrated a significant reduction in mortality. However, European LCS trials have not confirmed such benefit. We examined the impact of LCS-led diagnosis on the mortality of newly diagnosed lung cancer patients at an urban medical center.

Method:
Medical records of patients diagnosed with primary lung cancer for the period 2013-2015 (n=638) were reviewed to identify those who had an established primary care provider (PCP), were LCS-eligible/ non LCS-diagnosed, and LCS-eligible/LCS-diagnosed as per the United States Preventative Services Task Force (USPSTF) guidelines. Baseline characteristics between LCS-eligible/non-diagnosed patients and LCS-eligible/diagnosed patients were analyzed using chi-squared and Wilcoxon-Mann-Whitney tests. Kaplan-Meier curves were generated, and predictors of overall survival were evaluated using Cox proportional hazards modeling.

Result:
134 primary lung cancer patients had an established PCP and were LCS-eligible; 19/134 (14%) were LCS-diagnosed. LCS-eligible/LCS-diagnosed patients were of younger age (p=0.03), English-speaking (p=0.03), of higher socioeconomic status (p=0.02), active smokers (p<0.01), and had earlier disease stages (p=0.02) than LCS-eligible/non-diagnosed patients. All-cause mortality was significantly lower in LCS-eligible/diagnosed patients compared to LCS-eligible/non-diagnosed patients (p=0.03). Disease stage was found to be the main factor associated with higher mortality by multivariate regression analysis (HR: 6.13, stage 4 vs. stage 1-2, p<0.01).

Conclusion:
To our knowledge, this is the first report of lung cancer mortality differences in LCS eligible patients as a function of them undergoing or not LCS in a single-center setting since the inception of the USPSTF guidelines. Patients with an LCS-led diagnosis had a reduced mortality, probably as a result of having an earlier disease stage, which echoes the findings of large prospective LCS trials. LCS-led diagnosis rates remain low among lung cancer patients. Fully implementing the USPSTF guidelines constitutes a great unrealized opportunity to decrease lung cancer mortality.

Background:
Since the National Lung Screening Trial (NLST), doubt has been expressed as to whether the results could be replicated in a community setting. We aim to document our experience over 3.5 years and over 3000 CT scans.

Method:
The Providence Cancer Center in Portland Oregon initiated a lung cancer screening program in 2013 that included 7 hospitals (2 non-university tertiary medical centers and 5 community hospitals). Lung cancer screening candidates were referred by primary care providers from Noverember 2013 through May 2017. Candidates were screened using NLST criteria. Initially, shared decision making was provided by the team, but in 2015 transitioned to the PCP. Dedicated radiologists at the tertiary centers read all CTs and assigned Lung-RADS assessment categories. All Lung-RADS category 4 scans were reviewed by a multidisciplinary team of thoracic surgery, pulmonary, radiology and oncology to generate management recommendations. The navigator recorded all imaging, procedures, pathology, staging and complications. This individual ensured follow-up scans were completed.

Result:
2983 patients were referred. 353 were not eligible and 529 declined participation. 1950 underwent initial CT screening. 178 were presented at the multidisciplinary conference. Additional imaging included 1160 follow CT scans and 75 PET scans. Invasive diagnostic procedures included bronchoscopy (27) and CT-guided biopsy (19). Thoracic surgical procedures included pneumonectomy (1); lobectomy (21); segmentectomy or wedge resection (10). 55 cancers were diagnosed. 40 non-small cell lung cancers were found including 26 stage I; 5 stage II; 4 stage III and 5 stage IV. 6 small cell lung cancers were diagnosed including limited stage (3) and extensive stage (3). Lung cancer rate was 2.4%. 9 extra-thoracic malignancies were diagnosed including thyroid, renal cell (4), breast, colon, liver and prostate. The intervention rate was 5.6% with 46 major procedures (surgery) and 64 minor procedures (bronchoscopy, CT-guided biopsy, EUS, EGD). Adverse event rate was low and included pneumothorax (8) with 4 requiring chest tube, intra-operative bleeding requiring thoracotomy (1) and post-operative bleeding requiring repeat thoracoscopy (1). There was one death in a post-operative lobectomy patient.

Conclusion:
Low-dose CT screening for lung cancer can be done with low intervention and complication rates in a non-university setting using a systematic, multidisciplinary approach. This large group of screened patients demonstrates a stage shift toward early stage lung cancers with complication rates approximating those of the NLST. Our data contradict the argument that lung cancer screening cannot be done successfully and safely in the community.

Background:
According to the World Health Organisation’s report published in 2010, neoplasms, cardiovascular diseases (CVD), diabetes and chronic obstructive pulmonary disease (COPD) are responsible for over 75% of all deaths in the world and they have the same modifiable risk factors - smoking, bad dietary habits, lack of activity and alcohol abuse. Lung cancer screening participants that represent a high risk population of developing a lung cancer constitute the group that exactly matches these criteria, being simultaneously exposed for CVD, diabetes and COPD.

Method:
Between 2009 and 2011, 8649 individuals participated in the Gdańsk Lung Cancer Screening Programme (Poland), where 107 neoplasms (1,24%) were detected. Eligibility criteria included age 50 to 79 and significant, accumulated exposure to smoking (>20 pack-years). Every participant underwent a low-dose computed tomography (LDCT) followed by a standard evaluation protocol and blood sampling for the molecular studies. In order to find the incidence of lung cancer, CVD, diabetes and COPD in the lung cancer screening cohort during a 5-year-long follow-up, the records of all screenees were checked and collected from the Polish National Health Service - the only healthcare provider in the country.

Result:
Out of 8649 patients, after the programme’s termination, 459 (5,3%) new cases of lung cancer were detected in a 5-year-long follow-up. Two thousand seven hundred sixty five (31,9%) patients developed one of the cardiovascular diseases - in 2418 (28%) cases a coronary artery disease and in 309 (3,6%) a stroke were registered, while 38 (0,4%) had an episode of the acute coronary syndrome. One thousand and seven hundred forty (20,1%) patients developed COPD. There were 2104 (24,3%) patients registered with diabetes - 460 (5,3%) had an insulin-dependent and 1644 (19%) non-insulin-dependent type.

Conclusion:
Accumulated lung cancer detection rate in the Polish lung cancer screening programme after a 5-year-long follow-up was 6,5%. Lung cancer screening programme offers a great potential for joint screening of lung cancer, CVD, diabetes and COPD, which enhances a social significance of such an effort.

Background:
Lung cancer screening programs with low dose computed tomography (LDCT) could be economically viable if they targeted high-risk people. The optimal selection criteria have not been defined in prospective clinical trials. The goal of this prospective study is to test the hypothesis that lung cancer screening based on a highly predictive risk model: The Prostate, Lung, Colon, Ovarian (PLCO~m2012~) is superior to applying National Lung Screening Trial (NLST)-like criteria.

Method:
Participants were enrolled through three screening studies, two in Canada (Vancouver and Alberta) and one in London, UK. Eligibility included a PLCOm2012 6-year lung cancer risk ≥1.5% or NLST-like criteria (≥30 pack-years smoking history and quit ≤15 years with some variation in age limits – 55 to 80 years in BC, 55 to 74 in Alberta and 60 to 75 in UCL). The proportion of participants who have been found to have lung cancer or high risk lung nodules, requiring repeat imaging studies or biopsy prior to the next scheduled annual screening were compared between the two selection methods.

Result:
The demographics of participants are shown in Table 1. To date, 1,533 received a LDCT, of these, 341 met the PLCOm2012 criteria alone, 169 met NLST-like criteria and 1023 met both criteria. Twenty-seven participants have been found to have lung cancers. All 27 met the PLCOm2012 selection criteria alone while 62% met NLST- like criteria. No lung cancer was found in participants who met NLST-like criteria alone. There are 129 participants with suspicious lung nodules under close surveillance or scheduled for biopsy. Among these, 97% met the PLCOm2012 criteria and 74% met NLST-like criteria.

Table 1. Clinical and Demographic Features of Study Cohorts

Study Site	British Columbia	Alberta	London	Total
No. Contacted	802	1661	1990	4453
No. Eligible	364	741	812	1917
No. Screened	241	688	604	1533
Age (yrs)	65+/- 6.3	63.5 +/- 4.2	66+/-4.2	64.8+/- 5.7
Sex (female/Male)	91F:150M	342F:346M	273F:331M	706M;827M
Current:Former Smoker	103CS:138Ex	341CS:347Ex	443CS:161Ex	887CS:646Ex
Pack Years (Mean +/-SD)	47.3+/-22	42.4+/-15.8	47.7+/-22.3	45.3+/-19.8
Median Follow-up(months)	7.5	9.7	9.7
No. of lung Cancers	3	7	17	27
Participants with suspicios nodules	21	41	67	129

Conclusion:
Our preliminary results show that fewer people are eligible for screening using NLST-like criteria compare to a highly predictive risk model such as PLCOm2012. Thirty-seven percent more participants with lung cancer are identified by PLCOm2012.

Background:
The efficiency of a lung cancer screening program with low dose computed tomography (LDCT) is influenced by the screening uptake. The most efficient method to improve participation rate of individuals in the general population who are eligible for screening has not been determined. We evaluated different methods of recruitment on the participation rate.

Method:
The BC lung screening trial is part of the International Lung Screen Trial (ILST) in Canada, Australia, the UK and Hong Kong. ILST aims at defining the optimal selection criteria for LDCT by comparing the relative sensitivity of the US Preventative Services Task Force criteria versus the PLCOm2012 prediction model with 6-year lung cancer risk>=1.5%. Individuals with a chest CT within 2 years are excluded from the screening study. Different methods [social media, radio, newspaper, QuitNow smoking cessation program, BC Lung Association and referrals by general practitioners (GP)] to recruit eligible individuals are compared.

Result:
Of the 802 participants referred or self-referred to the study, 364 (41% female, 59% males, 53% ex-smokers and 47% current smokers) were eligible. The largest draw was radio which reached 64% of respondents, however only 29% of these were eligible. General practitioners (GP) reached only 24% but of these 70 % were eligible. 13% had a CT scan within 2 years, and but only 40% would have been eligible via risk criteria (Table 1). Table1. Figure 1



Conclusion:
The largest number of eligible participants were referred by their GPs. Media (radio) reached a larger number of participants but many were ineligible. A combined approach of media publicity and GP referrals may be the best way to reach the target the population. Ad hoc screening is likely occurring in the absence of a publicly funded screening program inappropriately exposing participants outside of the criteria.

Background:
Tumor associated (TA) autoantibodies are present during early stage lung cancer and have been detected up to five years before diagnosis. However the detection lead time provided by their measurement has never been accurately determined due to a lack of suitable patient samples. The United Kingdom Collaborative Trial of Ovarian Cancer Screening (UKCTOCS) recruited 202,638 postmenopausal women. Annual blood samples were collected for over 10 years during which time a number of lung cancer cases were diagnosed. The primary aim of this study was to determine the detection lead time of tumor associated autoantibody assays for a subset of the UKCTOCS cohort.

Method:
A set of 142 primary lung cancer cases (NSCLC 83%, SCLC 12%) with 7 serial samples over a pre-diagnosis period of 10 years were randomly split into Training (n=100) and Validation (n=42) cohorts and matched to healthy controls by age-at-diagnosis, age-at-first sample and smoking history. TA autoantibody profiles were produced for each patient by measuring autoantibody levels against a panel of tumour associated antigens ( p53, SOX2, CAGE, NY-ESO-1, GBU4-5, MAGE A4, HuD, CK8, CK20, LMYC, SSX1, p53-95, p16 and p62) using ELISA. The profiles for each patient were compared to those for the preceding time point using a multivariate distance measure to determine if a statistically significant positive change had occurred. Comparison against a population based cut-off for the earliest time point sample for each patient was used to determine initial positivity. An optimised algorithm was developed on the Training cohort and then applied to the Validation cohort.

Result:
There were 49 positive patients in the training cohort: 11 at the earliest time point and 38 during serial sampling. For the Validation cohort there were 14: 3 at the earliest and 11 during serial sampling. The median detection lead time for the Training cohort was 4.0 years (0.3 to 9.4 range) and for the Validation cohort 4.3 years (0.1 to 9.0 range) before clinical diagnosis. The median was 4.1 years (0.1 to 9.4 range) for the entire cohort.

Conclusion:
This is the first time statistically sound estimates of detection lead time have been reported for tumor assoicated autoantibody tests run on such a large cohort of pre-diagnostic serial samples. These cancer biomarkers can be detected on average 4 years before diagnosis. Monitoring autoantibody profiles could be hugely beneficial by enabling earlier detection and stratification of screening populations for cancer. This could lower mortality rates and reduce healthcare costs.

Background:
In the National Lung Screening Trial (NLST), indeterminate pulmonary nodules were detected in 40% of high-risk individuals screened by low dose high-resolution computed tomography (HRCT). However 96% of these nodules were benign indicating that overdiagnosis represents a major challenge for the clinical implantation of CT based lung cancer screening. While current clinical-radiological risk prediction models are very valuable, optimization of the clinical management of larger (≥ 7 mm) screen-detected nodules to avoid unnecessary diagnostic interventions including futile thoracotomies better strategies are needed. Herein we demonstrate the potential value of a novel radiomics based approach for the classification of screen-detected indeterminate nodules.

Method:
Independent quantitative variables assessing various radiologic nodule features such as sphericity, flatness, elongation, spiculation, lobulation and curvature, using 726 nodules (all ≥ 7 mm) were developed from the NLST dataset (benign, n=318 and malignant, n=408). Multivariate analysis was performed using least absolute shrinkage and selection operator (LASSO) method for variable selection and regularization in order to enhance the prediction accuracy and interpretability of the multivariate model. To increase the stability of the modeling, LASSO was run 1,000 times and the variables that were selected in at least 50% of the runs were included into the final multivariate model. The bootstrapping method was then applied for the internal validation and the optimism-corrected AUC was reported for the final model.

Result:
Eight radiologic features were selected by LASSO multivariate modeling out of 57 quantitative radiological variables considered for inclusion. These 8 features include variables capturing vertical location (centroid_Z), volume estimate (Min Enclosing Brick), flatness, texture analysis (SILA_Tex), surface complexity (Max_SI and Avg_SI), and estimates of surface curvature (Avg_PosMeanCurv and Min_MeanCurv), all with P<0.01. The optimism-corrected AUC is 0.939.

Conclusion:
Our novel radiomic HRCT-based approach to non-invasive screen-detected nodule characterization appears extremely promising. Independent external validation is needed.

Background:
As lung cancer screening has become more mainstream in the US, increasing attention has been paid to appropriate referral and follow up to minimize harms. This has been particularly focused on community-based programs as concerns have been voiced about the dearth of RCT evidence to support screening implementation in that setting. In addition, with the release of the US Preventive Services Task Force (USPSTF) and Centers for Medicare/Medicaid Services (CMS) recommendations for screening, more of the decision-making has been shifted to the primary care community. Primary care providers (PCPs) are expected to increase awareness of screening with their high-risk patients, perform counseling and shared decision-making (SDM), and manage screening outcomes more than ever before.

Method:
In a sample of mostly hospital-based lung cancer screening programs, program managers completed an application update as required for their continued participation in a national network. The applications were completed between March-June 2017 and covered areas of requirement for the designation, including: eligibility criteria, screening protocols, smoking cessation resources, multidisciplinary team make-up, SDM, and results reporting. 222 health systems responded, which represents 473 individual health care facilities out of 549 facilities that received the application (an 86% response rate).

Result:
Regarding counseling and SDM – required by CMS prior to generation of a written order - 82% of respondents reported that patients accessed SDM via the PCP. However, the majority of these respondents also indicated that the patient accessed SDM via a member of the screening team in addition to the PCP. Academic programs were less likely to see screening patients who received SDM through the referring provider and screening team (59%) compared to community/non-academic programs where 75% of patients received SDM through a referring provider and the screening team. We also examined the make-up of multidisciplinary clinical teams. 36% of respondents reported primary care as a team member. This was more common with community/non-academic programs when compared to academic programs.

Conclusion:
Data collected from screening program self-reporting indicates interesting trends in how primary care is incorporated into the lung cancer screening process prior to the referral through shared decision-making and during the review of screening results through the multidisciplinary care team. With patient awareness of lung cancer screening still reported to be low and PCP awareness and buy-in for lung cancer screening still considered to be inconsistent, supporting the integration of primary care into the workflow may help increase uptake of screening in a high risk population.

Background:
Despite approval and coverage for lung cancer screening in the US for a high-risk population, recent research indicates that screening rates are still far lower than anticipated. Jemal and Fedewa (2016) looked at rates during 2011-2015 and found only a 3.9% screening rate in the eligible population. While some of that low rate may be due to lack of insurance coverage in both private and Medicare populations during the bulk of the study time period, screening programs continue to report challenges that may be barriers to increasing screening rates even though it is covered by most insurance plans and Medicare.

Method:
In a network of mostly hospital-based lung cancer screening programs in the US, 152 programs representing both academic and community programs completed a survey on practices and statistics, achieving a 61% response rate. The survey was completed using SurveyMonkey between March-June 2017 and asked a range of questions based on the 2016 program experience, including program statistics, current smoking cessation referrals, participation in research and programmatic barriers. The reported data here represent screening program managers’ perceptions of continued challenges to screening as captured through two specific questions: “What barriers continued to cause problems for you in 2016?” and because insurance/billing issues constitute a broader category, “What was the nature of the insurance/billing issues you faced in 2016?”

Result:
The majority of respondents indicated that insurance/billing issues, lack of patient awareness, internal workflow challenges, and lack of support from referring providers were barriers that continued to cause problems in 2016. Only 30% of respondents indicated that lack of patient interest in screening was a barrier and 41% indicated that staffing/time limitations was a barrier. Other barriers identified by respondents included lack of provider awareness and challenges (often technical) with complying with the Medicare requirement for submission of registry data. Because insurance/billing issues continue to be significant, respondents provided more detail about the nature of these issues, including claims denials, coverage co-pays or deductibles, coding errors, and receiving prior authorizations.

Conclusion:
Despite widespread insurance coverage in the eligible screening population in the US, screening programs are still facing barriers to increasing screening service usage. It is clear that communities and professionals supportive of screening need to focus attention in increased patient and provider education around lung cancer screening. However, insurance and billing issues remain a major challenge, even though coverage is theoretically in place.

Background:
Lung screening with LDCT has demonstrated a significant improvement in lung cancer specific overall survival including the National Lung Screening Trial (NLST) comparison of LDCT vs chest x-ray. LDCT is recommended by the USPSTF and covered by Medicare, prompting the development of lung screening programs. In January, 2012, Lahey began a program for lung screening by low dose CT scan.

Method:
All individuals enrolled in the Lahey screening program fulfilled the National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology: Lung Cancer Screening v1.2012 (NCCN Guidelines®) high risk criteria for lung cancer and had a physician order for CT lung screening. Patients qualifying by NCCN Group 2 criteria were included in our free program from 2012-2015.

Result:
More than 11,000 LDCT lung screening scans have been performed in the Rescue Lung Rescue Life program on about 4500 patients. As of June, 2017 the program has diagnosed 135 cancers, of which approximately 70% are early stage non-small cell lung cancers. The rate of positive scans in year 1 of patient enrollment is about 15% and decreases substantially in following years. About 84% of patients continued in the program with recommended follow up scans. A very small number of patients undergo an invasive intervention without ultimately having a cancer diagnosis. We will present updated numbers.

Conclusion:
The reported numbers from screening trials have impacted the discussion about lung cancer screening program development and expectations. Our single institution data set of more than 11,000 scans shows a lower rate of positive screening tests with a higher positive predictive value than that reported in NLST, in part due to evolution of the recommended nodule size categorization. The high rate of patient retention in the program suggests follow up scans and regular screening are feasible. Our data showing limited intervention in patients with benign nodules, and about 70% of patients diagnosed with early stage disease, further demonstrates the importance of lung screening and limited risk associated with lung screening in an established program. The largest lung screening study performed to date, NLST, evaluated low dose CT chest vs chest x-ray yearly for 3 years. We provide data from an established lung screening program over more than 4 years.

Background:
Although LDCT lung screening has demonstrated improvement in overall survival, some have worried that indolent BAC-like adenocarcinomas (ADCA) may be over-detected/treated. We previously reported comprehensive and detailed pathologic comparison of stage I/0 lung ADCAs detected by LDCT screening vs incidentally discovered ADCAs stratified by NCCN risk criteria, demonstrating the presence of high grade invasive disease and high risk features in the LDCT group similar to incidentally discovered cancers. We now report clinical outcomes from a single institution LDCT program with associated pathology details.

Method:
Comprehensive histologic subtyping was performed on 54 consecutive stage I/0 LDCT screen detected ADCAs in patients meeting NCCN group 1/2 high risk (HR) criteria and compared to 77 incidentally detected stage I/0 ADCAs meeting HR criteria. We evaluated clinical outcomes in relation to details from pathologic evaluation.

Result:
We provide clinical data including disease free interval and recurrence in patients treated with curative intent for stage I adenocarcinoma detected by lung cancer screening vs incidentally discovered in HR patients with associated detailed pathologic evaluation. Screen detected and incidentally detected ADCAs show an equally low-rate of indolent, non-invasive/minimally invasive ADCAs. A collection of lepidic predominant (BAC-like) ADCAs associated with aggressive non-predominant cribriform and/or solid patterns and high proportion of lymphatic invasion were more frequently observed in the screen-detected group. Subgroup analysis of screen detected NCCN group 1 vs. 2 shows group 2 tumors exhibit histologic features which are at least as aggressive as group 1 tumors. Updated numbers with a larger cohort than previously reported and associated clinical data will be presented.

Conclusion:
We have demonstrated that many BAC-like tumors in LDCT screen detected patients bear histologic features of aggressive ADCAs, including among those still in a lepidic predominant phase. We provide the clinical data associated with updated numbers of the first detailed pathologic comparison of LDCT screen and incidentally detected ADCA of NCCN HR tumors.

Background:
Community-wide lung cancer screening has the potential to significantly impact lung cancer mortality. Thus, much emphasis has been placed on program development and recruitment of high-risk individuals. Lung cancer screening is a continuum, and shared decision-making focuses on the need for participants to remain engaged. Currently, little is known about screening follow-through in the community setting outside of clinical trials. Thus, we aimed to quantify the rate of attrition in our Lung Cancer Screening Program (LCSP) and identify contributing factors.

Method:
We reviewed all individuals enrolled in our LCSP, which is led by an independently practicing nurse practitioner within a multidisciplinary team, from 2012-2016. We identified all individuals who were closed out of the program, the closure date, and reason for closure. Of these, attrition was defined as declined further screening or lost to follow-up. A formal process for documentation of attrition included failure to respond to a written communication, a minimum of three contact attempts, and a clinical note forwarded to the referring provider.

Result:
Of the 520 individuals enrolled in the LCSP, 23% (122) were officially closed out. Thirteen percent (67/520) were closed out for clinical, geographic, or other identifiable reasons. Attrition from the program was identified to be 11% (55/520). Of the individuals that dropped out, 69% (38/55) were smoking upon enrollment compared to 52% (205/398) of retained individuals (p=0.014). In addition, 78% (43/55) had only one CT scan prior to attrition (Figure). Figure 1



Conclusion:
We identified an 11% attrition rate in our community-based LCSP. Individuals who failed to follow-up with the LCSP were more likely to be current smokers. The majority of individuals who failed to follow-up did not return after the initial CT scan. Future work needs to focus on promoting the continuum of screening and support the highest risk communities to minimize attrition.

Background:
Lung cancer is the leading cause of cancer death in the world. Screening has proved effective in reducing mortality in one major trial. In countries where granulomatous disease is prevalent, CT-screening false positive results may increase, even when Lung-RADS is used in the screening-CT analysis. Purpose: To analyze the outcomes of low-dose computed tomography (LDCT) lung cancer screening using Lung CT Screening Reporting and Data System (Lung-RADS) at a Brazilian cancer center.

Method:
Medical records of 552 patients initially selected to baseline LDCT- lung-cancer-screening program between May/2016 and April/2017 were analyzed. Only 287 patients complied NLST[1 ]inclusion criteria and were included in the study. These had a mean age of 61.8 years and a history of smoking of a mean of 45.3 pack-year. Mean Dose Length Product (DLP) of LDCT was 21.3 mGy/cm[2] with a mean effective dose of 0.30 mSv. LDCT findings were classified according to Lung-RADS[2] assessment categories.

Result:
Most patients (n=207; 72.1%) had a negative screening CT (Lung-RADS categories 1 or 2), 55 (19.2%) had probably benign findings (Lung-RADS category 3) and 25 (8.7%) had suspicious findings (Lung-RADS categories 4A [5.6%], 4B [2.1%] and 4X [1.0%]). The most common finding was a solid nodule (64.1%), followed by non-solid nodule (8.7%) and then by part solid nodule (2.8%). One patient classified as Lung-RADS category 3S had an incidental diagnosis of chest wall lymphoma, confirmed after biopsy. Patients in Lung-RADS category 4A (n=9) had a CT follow-up and most of them (n=7) showed stable findings and in two patient the nodules increased in size on follow-up CT. Histologic results confirmed lung cancer in 2 cases (prevalence of 0.7% of all screened patients).

Conclusion:
Lung cancer prevalence in our sample was compatible with the literature. However, we had a higher prevalence of Lung-RADS categories 3 and 4A than expected[3]. This may be associated with the higher incidence of granulomatous disease, especially tuberculosis, in the Brazilian population. 1.National Lung Screening Trial Research Team, et al. Reduced lung-cancer mortality with low-dose computed tomographic screening. N Engl J Med. 2011 Aug 4;365(5):395-409. doi: 10.1056/NEJMoa1102873. 2.American College of Radiology. Lung CT Screening Reporting and Data System (Lung-RADS) 3.Pinsky PF, et al. Performance of Lung-RADS in the National Lung Screening Trial: a retrospective assessment. Ann Intern Med 2015 Apr 7;162(7):485-491 doi: 10.7326/M14-2086.

Background:
The National Lung Screening Trial (NLST) demonstrated a 20% reduction in lung cancer mortality. However, it’s study centers may not have represented remote populations with low socioeconomic status and/or health care access. Previous reports on other cancers have demonstrated higher rates of screening in urban populations, with lower adoption in underserved and geographically remote communities. We aimed to quantify the proportion of screened individuals from medically underserved and geographically remote areas represented in our multi-state hospital network lung cancer screening programs (LCSPs).

Method:
We performed a multi-institution review using data from individuals enrolled in Pacific Northwest LCSPs, which form part of a multi-state hospital network. Individuals from programs spanning Washington State, Oregon, Montana, and Alaska from 2012-2016 were included. Definitions include: medically underserved area [MUA; healthcare resources deficient region], medically underserved population [MUP; area with economic/cultural/linguistic barriers to primary care services], health professional shortage area [HPSA; primary care physician shortage].

Result:
We identified a total of 2,379 screening participants. Of these, 22% (529) resided in a medically underserved area and 5% (108) were from a medically underserved population. Only 9% (216) resided in a HPSA, compared to the combined state data reporting a rate of 20% HPSA residents. Individuals lived a median of 6 miles from the screening site. Data stratified by state is shown in the figure, and demonstrates a high capture rate of individuals residing in MUAs in Montana. Figure 1



Conclusion:
All sites showed poor penetration into communities identified as MUPs and HPSAs. All sites also had poor penetration into MUAs; except for Montana, likely due to its overwhelming rural nature. However, the vast majority of screening participants lived in close proximity to screening centers. Therefore, novel approaches such as telemedicine and mobile screening clinics may be needed to reach underserved populations for LCS.

Background:
Screening program for lung cancer are leading for more incidental lung nodules diagnosis.This study aimed to address the lung nodule management from different specialty perspective working in different settings. This is the first survey uniting national societies in Brazil and in Latin America.

Method:
A web-based survey was developed by thoracic surgeons, pulmonologists and radiologists to evaluate lung nodule perception and management. This survey was sent to their respective national societies members and answers collected between August and December 2016. That included multiple choice questions regarding age, specialty, lung nodule management, accessibility to exams and interventional procedures characterizing public (SUS) and supplementary(SHS) working settings.

Result:
A total of 461 questionnaires were answered. More than half of participants live in cities with over one million population. Specialties were reasonable equilibrated with 43.5% radiologists, 33.5% thoracic surgeons, 20.3% pulmonologist and 2.6% others. Most of the respondents work in both public and private sector (72.7%). SHS has a similar reality compared to well developed nations regarding exams accessibility and interventions. SUS setting has a significant difference according to the participants. CT is only easily available in 31.9% of cases, PET-CT is easily available in 24.4%(graphic1), bronchoscopy is unavailable and almost unavailable for 33.1%, IR biopsy is unavailable in 38.2% and video-assisted thoracic surgery (VATS) biopsy is easily available in 42.8%. When there is a probability of malignancy of 50% or higher, 46.5% of participants would be comfortable recommending surgical biopsy. When the probability higher than 10%, only 36.9% would be comfortable following up radiologically. Figure 1



Conclusion:
Brazil has a very different setting for SUS and SHS patients regarding exams availability and management options. That might explain why participants have a higher tendency to choose interventional diagnosis and explains why current guidelines may not be applicable to developing countries reality.

Background:
Computed Tomography Coronary Angiography (CTCA) is frequently performed for non-invasive coronary artery assessment. Extracardiac findings are frequent, with indeterminate pulmonary nodules the commonest incidental finding. Given the established efficacy of lung cancer screening with low dose CT (LDCT), CTCA has been suggested to be an opportunity for “opportunistic” lung cancer screening. This rationale has been used to justify full field of view imaging, despite limited field of view significantly reducing prevalence of nodules detected and therefore reduce downstream healthcare costs. Distribution of lung cancer risk of patients undergoing Cardiac CT has not previously been reported. We performed a cross-sectional survey to determine the proportion of patients undergoing CTCA who would be eligible for lung cancer screening, and to determine the lung cancer risk profile of eligible patients.

Method:
Patients attending two tertiary hospitals in Melbourne, Australia, for clinically indicated out-patient CT coronary angiography were screened for inclusion in the study. Patients eligible for Lung Cancer screening according to the US Preventive Services Task Force (USPSTF) recommendations were invited to complete a questionnaire including smoking history and demographic details, to determine 6-year lung cancer risk, according to the PLCO~m2012~ risk prediction model. A threshold PLCOm2012 risk at least 1.5% was used to identify a sub-group in whom LDCT screening is most likely to be cost-effective and reduce lung cancer mortality.

Result:
In a four month period, 216 patients (60% male) were screened prior to CTCA across both sites. Only 57 patients (26%) were potentially eligible for lung cancer screening according to USPSTF guidelines: 126 (58.3%) were never-smokers, with a further 33 patients (15.3%) outside the reccomended 55-80 years age range. Of 57 eligible patients, 48 (84%) consented to the questionnaire. Thirty-four were male (71%), with mean age 65.6+/-6.0 years. Median (IQR) PLCOm2012 risk was 1.30% (0.45–2.19%). Only 22 patients (45.8% of patients completing the questionnaire, estimated 12% of total cohort)had a PLCO~m2012~ risk score >1.5%, and just 18 of 48 (37.5% of patients completing the questionnaire) had a PLCOm2012 risk > 2.0%

Conclusion:
A majority of patients undergoing CTCA were never-smokers. Only 26% would be eligible for screening according to USPSTF criteria. Therefore routine use of Cardiac CT for “opportunistic” lung cancer screening is likely to result in net harm and is not appropriate A small proportion of patients undergoing CTCA have high risk for lung cancer and may benefit from full thoracic imaging at the time of CTCA

Background:
The application of risk prediction models for the selection of individuals for lung cancer (LC) screening requires risk thresholds to distinguish between individuals eligible and ineligible for screening. However, little is known about the performance of risk prediction models across different risk thresholds. The UKLS trial utilised the Liverpool Lung Project risk model (LLP~v2~) with a risk threshold of 5% for 5-year LC incidence as the selection criteria in the trial. The UKLS yielded a 1.7% LC detection rate at baseline, which was higher than the NLST or NELSON trials. This study evaluates the performance of different risk thresholds for the selection of individuals for lung cancer screening utilising the LLP~v2~ model.

Method:
The performance of the LLP~v2~ risk model to predict 5-year LC incidence was evaluated in ever-smokers from the PLCO. The sensitivity (the proportion of LC in the total population that occur within those selected for screening), specificity (the proportion of individuals excluded from screening which do not develop LC), and proportion of individuals eligible for screening was assessed across a wide range of risk thresholds. In addition, the trade-off between the sensitivity and the proportion of individuals eligible for screening was assessed.

Result:
Applying low risk thresholds yielded high sensitivities, at the cost of low specificities and higher ratios of persons eligible per LC included within the eligible population. For example, a LLP~v2~ risk threshold of 1.0% would yield a sensitivity of 91.5% at the cost of a specificity of 37.2% and a ratio of 39 eligible individuals per LC. In contrast, a LLP~v2~ risk threshold of 5.0% would only yield a sensitivity of 36.5%, but had a specificity of 88.8% and a ratio of 18 eligible individuals per LC. A LLP~v2~ risk threshold of 2.03% yielded a similar sensitivity, but higher specificity and a more favourable ratio of eligible individuals per LC compared to the NLST criteria. LLP~v2~ risk thresholds between 2.0-3.0% may provide an advantageous balance between sensitivity and the ratio of eligible individuals per LC.

Conclusion:
The level of the risk threshold applied to select individuals for screening has an inverse relationship between the efficacy and efficiency of LC screening. Implementing LC screening programs which use risk prediction models to determine screening eligibility require further assessment of the trade-off between these aspects with regards to the long-term benefits, harms and cost-effectiveness to ascertain the optimal risk threshold.

Background:
The current lung cancer screening recommendation of the United States Preventive Services Task Force (USPSTF) is to perform annual low-dose computed tomography (CT) scans for high risk current smokers (at least 30 pack-years), or quitters in the past 15 years, age 55-80 years. Our study aims to assess if early detection of lung cancer by screening decreases the lung cancer mortality burden and, if so, how drastically for those considered at highest lung cancer risk.

Method:
Lung cancer screening prevalence was calculated from the 2010 to 2015 National Health Interview Surveys (NHIS). Probability of screening was derived from logistic regression models using race, age, gender, smoking and health insurance status as predictors. Beta values for these covariates were then used to estimate the probability of screening in the 1999-2004 National Health and Nutrition Examination (NHANES) cohort, for which lung cancer mortality information was available through linkage with the National Death Index. Using the predictor values generated in the NHIS dataset, probability of screening was estimated for the at risk NHANES participants, to make inferences about the effects of screening on lung cancer mortality.

Result:
Of the 60829 NHIS study participants, 2296 met the definition for being at high for lung cancer. The overall screening prevalence for this at-risk population was 10.4%; 7.7% had chest radiography while 5.7% had CT scans. Screening occurred more frequently in former smokers (p=0.0474), people who had health insurance coverage (p= 0.0017), and those older than 68 years (p = 0.0439). In the NHANES cohort, out of 31126 participants, 668 met the USPSTF recommendation for screening and 25 of them died of lung cancer. Lung cancer mortality was significantly higher in the high-risk group than in the low-risk group (HR~adj~ 8.59, 95% CI: 5.12-14.41). Based on the screening predictors obtained from NHIS data, 347 (51.95%) of the 688 high risk individuals would undergo a screening; 16 of them (4.6%) have died of lung cancer. If screening had occurred, overall lung cancer mortality would have potentially been reduced by 64%, provided that individuals had screening-detected early stage operable tumors.

Conclusion:
Increasing CT screening among those at high-risk for lung cancer should significantly reduce deaths from lung cancer in this population. Screening needs to be combined with continued smoking cessation efforts.

Background:
Lung cancer screening will become an important way of reducing lung cancer mortality. Identifying high-risk population based purely on age and pack years may leave out 3/4 of high-risk individuals. There is an urgent need for validated, accurate risk-prediction models for all ages and types of smokers.

Method:
In the prospective cohort of 65 237 people aged 20-100 years participating in the HUNT2 study in Norway in 1995-97 (70% of the regional adult population), median follow-up time of 15·2 years (800 845 person-years), 583 incident lung cancer cases were diagnosed (cumulative incidence 0·9%). Thirty-six candidate risk variables for lung cancer were examined using univariate and multivariate analyses and backwards feature selection using multiple imputation. The model was validated in ten comparable Norwegian population studies of 44 600 ever-smokers (CONOR), with a median follow-up time of 11·6 years and 675 incident lung cancer events.

Result:
In the total HUNT2 cohort at base-line, the smokers were light smokers (median 10·3 pack-years). Among the lung cancer cases 94·7% were ever-smokers (median 22·5 pack-years) and 70% of lung cancer cases had reported smoking <30 pack-years at base-line. There were only seven risk variables selected in the final model; age, pack-years, smoking intensity (number of cigarettes daily), years since quitting, body mass index, daily cough and hours of daily exposure to cigarette smoke. The model for ever-smokers had a concordance index of 0·869 (interquartile range 0·868-0·870). A nomogram was made to calculate the personal 5, 10, and 15-year risk of lung cancer. External validation of the model in CONOR on 44600 ever-smokers showed a similar concordance index of 0·867 ([0·854, 0·880]95% CI). Selecting a threshold of median risk one would need to screen only 22·7% of ever-smokers to identify 78% of all lung cancers.

Conclusion:
The resulting Lung-HUNT model is simple, robust and accurate, and identify lung cancer risk individuals of all ages and smoking patterns. This model is useful for prospective screening studies for lung cancer and can motivate smokers to quit smoking. ​

Background:
Assessing CT image quality is becoming of increasing concern in the domain of quantitative imaging. Current calibration devices tend to be time-consuming to use and often require special expertise for analysis. We have developed a novel approach for measuring image quality on CT scanners that is automated and inexpensive.

Method:
Three new rolls of 3M 3/4x1000 Inch Scotch Magic tape($1.50 each) were placed radially out from iso-center and CT scanned using standard head, body,and low dose lung protocols on a GE VCT and a Siemens Somatom Definition AS scanner. A Gammex 464 ACR CT Accreditation phantom was also scanned on the same scanners with identical protocols. GE and Siemens scans were reconstructed with 0.625, 1.25,and 2.5mm and 0.6, 1.0,and 2.0mm slice thickness and spacing, respectively. A total of 36 3D CT scans(36=2 objects x 2 scanners x 3 protocols x 3 thicknesses) were used for this study. Automated analysis was performed using Radia Diagnostic Software(Radiological Image Technology, Inc.) for the Gammex scans and Accumetra software for the tape scans. Both software tools produced measurements for CT linearity(air and acrylic HU), in-plane resolution, slice thickness,and image noise. Mean, standard deviation,and difference in measurements was used to evaluate performance.

Result:

	Gammex Mean, SD	Tape Mean, SD	(Tape-Gammex) Mean, SD
Air (HU)	-988, 10.4	-995, 4.6	-6.97, 6.38
Acrylic (HU)	130, 2.0	121, 12.3	-8.90, 12.75
In-plane Resolution (LP/cm)	6.32, 0.31	6.09, 0.67	-0.23, 0.91
Slice Thickness (mm)	1.88, 1.13	1.42, 0.57	-0.46, 0.63
Image Noise (HU SD)	13.39, 9.93	7.05, 2.65	-6.35, 8.47

Given that mean tape measurements differed from Gammex phantom measurements by <10 for HU density,<0.25 for LP/cm of in-plane resolution,<0.5 for mm of slice thickness, and <10 for HU SD of image noise, scotch tape has the potential to be used as a fast, accurate, and inexpensive tool for assessing CT scanner and protocol image quality.

Conclusion:
A new automated and inexpensive method for CT scan image quality assessment that relies on advanced image processing techniques provides results comparable to standard calibration methods thus allowing CT scan calibration to be performed rapidly and inexpensively allowing for more comprehensive integration of quality standards into daily practice.

Background:
The creation of an effective management plan for non-small cell lung cancer (NSCLC) requires clinical and functional evaluation, a series of diagnostic and staging investigations and an evaluation of suitability for treatment. This process requires diverse multidisciplinary input and modern clinical guidelines therefore recommend presentation of all new lung cancer diagnoses to a multidisciplinary meeting (MDM) to facilitate evaluation and the development of an informed multidisciplinary management plan

Method:
We sought to evaluate the characteristics of patients presented to the lung cancer MDM and to evaluate the impact of MDM presentation on (i) management related outcomes including timeliness, supportive care screening, receipt of treatment and clinical trial participation, and (ii) patient related outcomes including survival and quality of life (QoL) in a metropolitan university teaching hospital.

Result:
In this cohort of cancer patients we found that just 59.6% of all new cancer diagnoses were presented to the lung cancer multidisciplinary meeting for clinical assessment and treatment planning despite the recommendation that all patients with lung cancer receive treatment in the context of a multidisciplinary setting. The likelihood of presentation was doubled for those with early clinical stage IA and halved for those with stage IV. Measures of quality of life (vitality and role emotion domain scores from the SF12v2) improved for those presented to the MDM between 3 and 12 months following presentation compared to those not presented. Advanced clinical stage was a strong predictor of mortality for all patients. MDM presentation conferred a significant crude protective effect on mortality for all patients (HR 0.63, 0.49-0.81; p<0.001) which was diminished when adjusted for confounding factors (0.79, 0.56-1.10;p=0.16), although this benefit was sustained for those with clinical stage IIIA (adjusted HR 0.31 0.12—0.79; p=0.01). The referral source for MDM presented patients were approximately one third from respiratory medicine, one third from lung cancer specialities and one third from medical and surgical specialty units with mortality risk increased for those referred by general medicine and surgical specialties.

Conclusion:
We found significant disparities in the utilisation of lung multidisciplinary meeting presentation which was associated with significant differences in uptake of active cancer therapy and ultimately survival. This study identifies significant benefit to those being presented to a lung cancer MDM and provides evidence to support multidisciplinary evaluation.

Background:
To assess the utility of four-dimensional (4D) ventilation/perfusion (V/Q) PET/CT lung imaging to facilitate mid-radiotherapy treatment adaption with volumetric modulated arc radiotherapy (VMAT).

Method:
In a prospective clinical trial, patients with non-small cell lung cancer (NSCLC) underwent [68]Ga-4D-V/Q PET/CT scanning before and during a six-week (60Gy) course of definitive chemoradiation. Functional lung volumes were delineated on both datasets as ‘highly perfused’ (HPLung) and ‘highly ventilated’ (HVLung), using a 70[th] centile SUV threshold. Three VMAT plans were created on the mid-treatment datatsets: optimised to anatomical lung, HPLung, and HVLung volumes, respectively. Functional dose volumetrics were assessed using the parameters of mean lung dose (MLD), and lung volume receiving 5, 20 or 30Gy, (V5, V20, and V30). Plan quality was assessed for consistency with respect to conformity indices, and doses to critical structures.

Result:
The study cohort consisted of 10 patients resulting in a total of 30 VMAT plans. PTV volumes reduced by a mean of 5.5% between scans. HVLung volume increased between scans by a median value of 39.2%. Subsequent volumetric and spatial changes were reflected in varying DICE similarity coefficients, or DSC (ranging from 0.336-0.923). HPLung decreased by a median value of 4.5% with spatial discrepancy represented by DSC of 0.568-0.805. Increase in ventilated function was most prevalent adjacent to the target, limiting the benefit of adaptive planning (Fig 1). Plan quality was consistent with the median PTV D95 ranging from 60.6-61.3Gy, and mean conformity index ranging from 1.23-1.25. Functional MLD of HPLung decreased by a mean of 7.3%, p=0.02. Plans optimised to HPLung resulted in a reduction of perfused lung V5 by a mean of 13.2%, p<0.01, with HVlung plans yielding a decrease in ventilated lung V5 of 9.6%, p=0.02. Fig 1 Figure 1



Conclusion:
To achieve reduced irradiation of functional lung, radiotherapy adaptation is more effectively facilitated by perfusion rather than ventilation imaging.

Background:
Recent randomized and observational studies suggested that pre-existing cardiac disease and higher radiation heart doses were associated with more cardiac events and worse overall survival (OS) in locally-advanced non-small cell lung cancer (NSCLC) treated with definitive chemoradiation. Post-operative thoracic radiotherapy (PORT) delivered via non-modern radiation techniques had also been shown to increase cardiac mortality. Hence we performed this study to determine the impact of pre-existing ischaemic heart disease and radiation heart dose on OS in NSCLC patients treated with PORT using contemporary radiation techniques.

Method:
Study eligibility criteria included stage I to III NSCLC treated with PORT at two institutions from 2007 to 2014. Clinical data and dosimetric parameters affecting overall survival were collected from the institutional electronic medical records as well as the national death and acute myocardial infarction registries. Univariate cox regression was performed using Stata version 13.

Result:
Twenty eligible patients were identified. Median follow-up duration was 30.4 months (2.3- 81.9). Median age was 59 years. Median prescription dose was 57 Gy. Median mean heart dose was 12Gy. 10% had pre-existing ischaemic heart disease. 75% underwent lobectomy. 60% had pathological stage III disease. 40% had left-sided disease. 70% received chemotherapy. The 1- and 2-year OS were 75% and 60% respectively. Univariate analysis showed that pre-existing ischaemic heart disease was significantly associated with worse OS (hazard ratio 7.13, 95% confidence interval 1.17-43.47, P value < 0.03). Mean heart dose and the other cardiac dosimetric parameters (volume of heart receiving ≥ 5, 25, 30, 40, 50Gy, and dose to ≥ 30% of heart volume) were not associated with OS.

Conclusion:
Pre-existing ischaemic heart disease was a significant predictor for worse OS in NSCLC patients treated with modern PORT. We plan to expand the cohort to confirm these findings. Patients should be screened for ischaemic heart disease and cardiac function optimised prior to PORT and on follow-up.

Background:
Stereotactic body radiation therapy (SBRT) has emerged as a treatment option for patients with early-stage lung cancer, especially in the medically inoperable population. As most reported data are from developed countries, the purpose of this study was to report clinical outcomes and toxicity for SBRT in these patients from a single academic institution from Brazil.

Method:
Between January 2007 and September 2015, 102 consecutives lung lesions at Hospital Sírio–Libanês, São Paulo, were treated with SBRT, of which 59 primary non-small cell lung cancer (NSCLC) (biopsy-proven) lesions from 54 inoperable patients were reviewed from a specific registry (43 lesions were excluded: metastatic or with no biopsy). For patient immobilization, semi-rigid (vaclok based) system was used. The CTV was delineated based on CT data from 3 phases superimposed on 3-dimensional radiation treatment planning systems to obtain an internal target volume (ITV). A median dose of 54Gy (45-60Gy) was prescribed in 3 – 5 fractions per lesion and image guidance was mandatory. Treatment outcomes for in-field local control (LC) per lesions, progression free survival (PFS) and overall survival (OS) were assessed with Kaplan-Meier estimates. Toxicities were graded according to Common Terminology Criteria for Adverse Events version 4.0

Result:
Of the 54 patients analyzed, the majority were elderly (average age 75.7 years; SD ±8.8 years). More than 90% were PET/CT staged with Stage IA 40 (68%) and adenocarcinoma 46 (78,0%) representing the most common stage and histology, respectively. Median follow-up was 21,3 months (4 -55 months) for LC, 22.3 months (4 -55,8 months) for PFS, and 18.7 months (4.2 - 56,4 months) for OS. The 2-year rates of LC, PFS and OS were 89.1%, 79%, and 80.3%. Median LC, PFS, OS was 48.5 months, not reached, 41,8 months, respectively. Histology, size and stage of the primary were not a significant predictor for LC (P = 0.58; P = 0.26; P= 0.64, respectively), PFS (P = 0.81; P = 0.86; P = 0.64, respectively), or OS (P=0.21; P = 0.62; P = 0.94, respectively). Grade 3+ toxicities were observed in 2 patients (3.7%), of which 1 was grade 3 pneumonitis and one was grade 4 skin toxicity.

Conclusion:
Our data also show that SBRT is effective and feasible in a predominantly elderly and medically inoperable patient population in Brazil.

Background:
The optimal radiation schedule for small cell lung cancer (SCLC) has not yet fully established. This study was designed to compare the clinical outcomes between twice- and once-daily radiotherapy in the treatment of SCLC.

Method:
One hundred and twenty-four consecutive patients diagnosed with extensive stage SCLC and treated with chemoradiotherapy were retrospectively reviewed. Either twice-daily hyper-fractionated irradiation (45 Gy/30 fractions/BID), or alternative schedules, including hypo-fractionated (45 Gy/15 fractions/QD) or conventionally fractionated (50 Gy/25 fractions/QD or 60 Gy/30 fractions/QD) radiation was delivered, with etoposide and platinum prescribed concurrently or sequentially. Local controls and overall survivals were calculated and compared between twice- and once-daily schedules based on Kaplan-Meier method. Toxicities were record according to Common Terminology Criteria Adverse Events.

Result:
There were 67 and 57 patients received twice- and once-daily chest radiotherapy, respectively. With a median follow-up of 27 and 24 months, the local control rates were reported 64.2% and 63.2%. The 2-year estimated local progression-free survival rates were similar (61.6% vs 61.0%, p=0.90). Progressive disease identified three months after radiotherapy was correlated to increased local failure (p=0.026). There was no difference between the incidences of grade 3-4 toxicities between twice- and once-daily schedules (23.9% vs 12.3%, p=0.16).

Conclusion:
Either twice- (45 Gy/30 fractions/BID) or once-daily (45 Gy/15 fractions/QD, 50 Gy/25 fractions/QD, 60 Gy/30 fractions/QD) radiation schedule could be considered in the treatment of SCLC, resulting in comparable local control and toxicities.

Background:
[18]F-Fluorodeoxyglucose positron emission tomography-computed tomography ([18]F-FDG-PET-CT) has the potential to increase the precision in contouring of gross tumour volume (GTV). However, detection of tumour edge in the halo around the tumour has been a problem. A surgical histopathological examination is the current gold standard for tumour size estimation in NSCLC. The aim of this study was to determine an optimal cut-off of standardized uptake value (SUV) on FDG-PET-CT images that correlates best with tumour size on surgical histopathology examination.

Method:
From January 2013- July 2014, 25 consecutive patients with diagnosed early NSCLC (pT1-pT3,N0M0) who underwent surgical resection (either a lobectomy or pneumonectomy) were accrued. GTVs were delineated on a preoperative FDG-PET-CT scan (acquired within 8 weeks before surgery) by automatic delineation using % threshold SUV at 20%, 30%, 40%, 50% of maximal uptake and threshold as absolute SUV 2, 2.5, 3, 3.5 and 4. The maximum tumour size was recorded from the surgical histopathology reports. First order linear regression was used to obtain values of optimal cut off SUV for each patient at which maximum size of GTV on FDG-PET-CT matched with maximum tumor size on histopathology. Different SUV thresholds of GTV delineation were compared with histopathology with respect to the estimation of maximum tumour size using Bland-Altman plots. The above methodology was carried out in 25 patients in test set. 12 additional patients were used to validate the results of the test set.

Result:
On analysis of 25 patients in the test set using first order linear approximation, the mean optimal cut-off values for GTV delineation on FDG-PET-CT images were 35.6 % ± 18.6 for % threshold SUV and a 4.35 ± 1.7 for absolute SUV. On analysis of 12 more patients in the validation set, the mean optimal cut-off values for GTV delineation on FDG-PET-CT images were 36.9 ± 16.9 % threshold SUV and a 4.1 ± 1.6 absolute SUV. After combined analysis of all 37 patients, the mean optimal cut-off values for GTV delineation on FDG-PET-CT images were 36 ± 17.9 % threshold SUV and a 4.27 ± 1.7 absolute SUV. On comparing various methods of delineation by Bland-Altman plots, auto-contouring with percentage threshold of 40% and absolute SUV 4 were in greater agreement with the histopathological tumour size.

Conclusion:
Auto-contouring of GTV in NSCLC with the help of optimal cut-off SUV in FDG-PET-CT will improve precision in delineation, reduce inter-observer variability and importantly will save time.

Background:
We report the results of a randomized, placebo-controlled pilot study for measuring the effect of lisinopril, an angiotensin-converting enzyme (ACE) inhibitor, on pulmonary distress in patients receiving thoracic radiotherapy (TRT) with or without chemotherapy. We aimed to evaluate the practicality for developing a larger-scale, randomized phase III study in the future.

Method:
Twenty-three (23) eligible patients receiving TRT (≥45 Gy) for predominantly non-small cell lung cancers were enrolled; an ECOG performance of 2 or better was required. The patients were randomized to receive either 20 mg of lisinopril or placebo once daily during and up to 3 months post-RT. The trial stopped early due to lower accrual than anticipated. The baseline and weekly during RT patient-reported outcome (PRO) results for Symptom Experience Questionnaire (SEQ), Lung Cancer Symptom Scale (LCSS), the EORTC for Lung Cancer Questionnaire (EORTC-QLQ-LC13), and Function Assessment of Cancer Treatment were analyzed. Adverse events (AE) were measured according to CTCAE v4.0. Our primary endpoint was safety and AE profile of lisinopril, followed by PRO comparisons; multiple comparisons for secondary analyses were not adjusted.

Result:
There were 11 and 12 eligible patients on the placebo and lisinopril arms, respectively. Mean age was 63.5 years; 13 (62%) were male. Eighteen (86%) were either former or current smokers. All baseline characteristics were balanced. All baseline PRO results were balanced except for more shortness of breath by SEQ/LCSS which were slightly worse in the placebo arm. The placebo patients reported more dyspnea on climbing stairs at baseline on EORTC-QLQ-LC13. The incidences of grade 2 hypotension were 2 vs. 4 patients for placebo and lisinopril, respectively (P=0.26). One (1) patient taking lisinopril had grade 2 acute kidney injury (P=0.20). One (1) patient developed grade 4 dyspnea on placebo arm. No patients experienced grade 5 toxicities. Patients taking lisinopril did not have more cough or allergic reaction. Acute respiratory distress as measured by worst dyspnea score was poorer in placebo vs. lisinopril patients (42.0 vs. 77.5 respectively, P=0.006). The rest of the PRO indices were with no clinically meaningful differences between arms.

Conclusion:
Although this novel trial was underpowered which was not intended, the results provided a strong signal for safety and perhaps even efficacy, by PRO, in concurrently administering lisinopril, an ACE inhibitor, for advanced lung cancer patients who require RT-based therapies. Using lisinopril for mitigating or preventing radiation-induced pulmonary distress or pneumonitis will require future trial testing. Support: UG1CA189823.

Background:
[Background] Chemoradiotherapy is the standard treatment for locally advanced non-small cell lung cancer. Histological difference has not been taken into account in the chemoradiotherapy unlike in chemotherapy for metastatic disease. The purpose of this study is to evaluate the results and relapse pattern difference between squamous cell carcinoma (Sq) and adenocarcinoma (Ad) histology.

Method:
[Methods] We retrospectively analyzed the outcomes and relapse pattern in patients who received definitive chemoradiotherapy for locally advanced non-small cell lung cancer in our institute between 2003 and 2012

Result:
[Results] There were 74 Sq patients and 36 Ad patients. Sq patients had more advanced T Stage, and less female ratio. Other factors were well balanced. Median follow-up time in all patients and surviving patients were 21.3 and 79.6 month, respectively. Median survival time was not significantly different between Sq and Ad patients (P=0.61; 20.8 and 26.7 month, respectively). Relapse pattern was different between the two histologies (P=0.0149). Locoregional, distant, and simultaneous relapse of locoregional and distant sites were observed in 32 (55.2 %), 23 (39.8 %) and 3 (5.2 %) for Sq patients; and 7(22.6 %), 20(64.5 %) and 4(12.9 %) for Ad patients, respectively. The time from relapse to death in Sq patients were shorter than Ad patients (median, 8.9 months and 14.9 months; P=0.046). Numbers of patients surviving without any relapse for 5 years or more were 9 (12.2 %) in Sq and 1 (2.8 %) in Ad. Figure 1



Conclusion:
[Conclusion] More than 10% of Sq patients could achieve relapse-free survival longer than 5 years. However, in relapsed patients, prognosis was poorer in Sq patients compared to Ad patients. Dominant pattern of relapse was locoregional in the Sq patients. More aggressive local treatment such as combination with surgery or dose escalation of radiotherapy may improve survival in Sq patients.

Background:
Three dimensional conformal radiation therapy (3DCRT) with 10-15 static fields is the most common technique used to create the desired conformal dose distribution for SBRT. The main drawback of 3DCRT planning is the lengthy treatment time relating to patient setup and radiation delivery resulted from many fields needed to create an acceptable treatment plan. The capability of VMAT to increase the sparing of organs at risk (OARs) without compromising conformal dose distributions in a shorter treatment time compared to IMRT and 3DCRT has been demonstrated for both conventional fractional radiotherapy and SBRT in the treatment of lung cancer. The purpose of this study is to investigate the feasibility of partial arc volumetric modulated arc therapy (VMAT) in lung cancer stereotactic body radiotherapy (SBRT), as well as the volumetric and dosimetric effects of different internal target volume (ITV) definitions with 4D CT.

Method:
Fourteen patients with primary and metastatic lung cancer underwent SBRT were enrolled in this study. Full and partial VMAT plans were generated with four different ITVs: ITVall, ITV~MIP~, ITV~AIP~ and ITV~2phases~, representing ITVs generated from all 10 respiratory phases, maximum intensity projection (MIP), average intensity projection (AIP), and 2 extreme respiratory phases. Volumetric and dosimetric differences, as well as MU and delivery time were investigated.

Result:
Full arc VMAT irradiated less dose 2 cm away from the PTV compared with partial arc VMAT (P=0.002), other than this, there was no significant difference on target coverage between partial and full arc VMAT plans. However, partial arc VMAT irradiated less MLD and V5 compared with full arc VMAT. Partial arc VMAT also achieved better protection on spinal cord, heart and esophagus compared with full arc VMAT. The average MU and delivery time of full arc VMAT plans were 240 and 1.6 min more than those of partial arc VMAT. No other significant difference was observed between these two planning schemes. There were no significant differences on target coverage and organ at risks (OARs) sparing among four ITVs. The average percent volume differences of ITV~MIP~, ITV~AIP~ and ITV~2phases~ to ITV~all~ were 8.6%, 13.4%, and 25.2%, respectively.

Conclusion:
Partial arc VMAT was feasible and more efficient for lung SBRT. Although ITV~MIP~, ITV~AIP~ and ITV~2phases~ were smaller than ITVall, no significant dosimetric differences resulted due to a relative small target volume of lung SBRT.

Background:
As the use of radiotherapy (RT) in lung cancer patients in the ICU is poorly described; we evaluated characteristics, outcomes, RT utilization and costs in a population-based cohort of ICU lung cancer patients in Ontario, Canada.

Method:
Eligible patients between April 1, 2007 and March 31, 2014 were identified through provincial administrative healthcare databases. Given that a patient could receive multiple RT deliveries, each ICU stay was analyzed separately as an episode of care. Significant differences in patient, treatment, institution and tumor characteristics between RT and non-RT groups were compared with t-tests and chi-square tests, as appropriate. Pre-ICU disposition was by ER admission, same institution admission or different institution transfer. The Kaplan-Meier method was used to estimate overall survival (OS), measured from index ICU admission to death, censoring at the end of the observation period. Differences in OS between the RT and non-RT groups were compared using the log-rank test. Univariable and multivariable Cox proportional hazard modeling were performed to assess the effect of RT on OS. Daily costs were calculated in 2015 Canadian dollars (converted using consumer price indices) for RT patients only, based on acute hospitalizations, ER visits, cancer clinic visits, same-day surgeries, and physician billings. For all analyses, a p-value threshold of <0.05 was used to define statistical significance.

Result:
In 13,739 unique lung cancer ICU patients, RT was delivered in 133 episodes to 1.0% (n=131) of patients. The RT group tended to be younger (median age 65 vs. 68, p<0.001), on some form of ventilation (79.8% vs. 38.2%, p<0.001) and with longer ventilation durations ((median [IQR]) 6 [1-11] vs. 0 [0-2] days, p<0.001). RT patients were more likely to present from the ER (28.2% vs. 21.9%, p=0.002) or via transfer (35.3% vs. 9.7%, p<0.001). While ICU discharge was common in both RT (56.4%) and non-RT (71.4%) cohorts, 1-year OS was poor with both groups, but most notably in the RT group (11.3% vs. 42.4%). RT was associated with inferior 1-year OS on unadjusted modeling (HR=1.99, 95% CI:1.65-2.38, p<0.001), with ventilation status and pre-ICU disposition adjusting this finding towards the null on multivariable modeling (HR=1.17, 95% CI:0.97-1.40, p=0.095). The median daily cost of medical care in RT patients was $2771 (IQR $1757-$3753), with acute hospitalization accounting for more than half (median $1723) of calculated costs.

Conclusion:
The use of RT needs to be considered judiciously for lung cancer patients in the ICU, given the poor prognosis and increased costs incurred.

Background:
Stereotactic Body Radio Therapy (SBRT) is a curative treatment option for patients diagnosed with primary lung cancer, who are deemed unsuitable for surgical resection. Currently, the most commonly used contouring method utilises 4D-CT delineated Internal Target Volumes (ITVs). This takes into account the tumour positions throughout all phases of the respiratory cycle but can result in unnecessarily large Planning Target Volumes (PTVs). The time-weighted mid-ventilation (TWMV) method is an alternative contouring method in which the gross tumour volume (GTV) is contoured on a single 3D-CT structure from the 4D dataset at the phase closest to its time-weighted average position. We hypothesise that the TWMV method will result in significantly smaller PTV and treated lung volumes when compared with the ITV method

Method:
5 consecutive lung SBRT patients who participated in a Phase 2 Clinical Trial were contoured with the ITV method using Velocity Advanced Imaging software (v.3.2.0). The PTVs and irradiated lung volumes were recorded. The GTVs were then re-contoured both manually on each phase of the 4D-CT and automatically using deformable image registration (DIR). The time-weighted average tumour position was determined and PTV volumes generated from the phase closest to this position using patient-specific margins described by Wolthaus et al. Finally, PTVs and treated lung volumes were recorded and compared with those from the ITV plans.

Result:
There was close agreement in both manual and automatic contouring methodologies for the time-weighted average position, with a three-dimensional vector error between the GTV centroids of 1.6mm ± 0.8 mm (1 SD). The manual contouring methods resulted in the same phase from the 4DCT being used for the mid-ventilation approach for all 5 patients. Using the mid-ventilation approach, the PTV volumes decreased by an average of 24.5% (range 19.8% - 33.7%), corresponding to an average decrease in irradiated healthy lung of 17.1cc ± 6.5cc. The decrease in PTV volume was greater for patients with a larger cranio-caudal tumour motion, with a linear relationship found between the two (R[2] = 0.995).

Conclusion:
For patients undergoing lung SBRT, contouring using the TWMV method resulted in a significant decrease in both PTVs and irradiated lung volumes compared with the ITV method. DIR for implementation of the mid-ventilation technique was feasible and reproducible. Application of this technique may improve the therapeutic ratio, and enable dose escalation for treatment of patients with unfavourable lung function to reduce lung toxicities.

Background:
Recombinant human endostatin (Endostar) is an angiogentic medicine with mild toxicity and strong efficacy in systematic treatment of NSCLC. Recently, several studies proved that Endostar combined with radiotherapy could enhance NSCLC treatment efficiency according to mechanism of microenvironment normalization. However, this combination therapy has not tested in elderly population up to now. In this trial, we observed the efficacy and safety of Endostar combined with concurrent intensity modulated radiation therapy (IMRT) for inoperable elderly local advanced NSCLC.

Method:
This trial was perspective, open‐labeled study. A total of 40 inoperable elderly local advanced NSCLC were randomly assigned into two arms. Twenty patients received IMRT alone in control arm, the dosage of primary tumor and mediastinal lymph node metastasis was DT 60 66 G/30 33/6‐ 7w. Intravenous infusion of Endostar concurrently inducted with IMRT in experimental arm. Endostar is administrated in 15mg once daily for two weeks followed by one week interval, repeated twice. The efficacy was evaluated according to RECIST 1.1 criteria and recorded ORR, DCR, mDFS and mOS. Safety and efficacy evaluation were performed based on NCI CTC v4.0 criteria.

Result:
In the experimental arm, 15 cases were PR and 5 cases were SD. Although a superiority of patient number showed comparing to the control group, there is no statistical difference between two arms either ORR (75.0% vs. 80.0%, p=0.326) or DCR (100% vs. 90.0%, p = 0.031). The mDFS (9.4M vs. 6.8M, p=0.286) and mOS (17.5M vs. 14.1M, p=0.052) in the two groups were not significantly different. One year survival rate were 79.4% vs 61.1%, and 2 year survival rate was 9.0% vs 0% in experimental arm and control arm, respectively. In the experimental arm, risk of disease progression decreased by 35% by using Endostar plus IMRT, HR = 0.649 (95% CI, 0.288 to 1.464), meanwhile the risk of death decreased by 66%, HR = 0.435 (95% CI, 0.184 to 1.030) . Most toxicities occured in two arms were grade 1/2, there is no grade 3/4 adverse events occured. In contrast to the control arm, no difference in safety events was found in the Endostar plus IMRT group.

Conclusion:
Endostar combined with concurrent IMRT for inoperable elderly local advanced NSCLC had a good safety and activity profile. One and two year survival rates were all increased, with a tendency of prolonging median survival time. Therefore the conclusion is worth to further confirmed in similar clinical study but with larger sample size.

Background:
SABR is a definitive treatment option in patients diagnosed with an early stage lung cancer. It is a suitable alternative for patients of poor performance status who may be medically inoperable. The Cyberknife (CK) machine delivers high dose, hypofractionated regimes using extensive non-coplanar beams of radiation. This enables lesions to be treated with radiobiologically higher doses, maximising local tumour control. University Hospital Birmingham has delivered the most CK-based lung SABR for any stage lung cancer in the UK. Limited data exists for outcomes following CK treated lung cancers. At our institute we reviewed a cohort of patients with early stage lung cancer treated with CK over a 30 month period looking at overall survival and local control rates to ensure this was comparable to accepted SABR outcome statistics.

Method:
A retrospective analysis was performed on 88 patients with primary lung cancer treated with CK from June 2014 to December 2016.

Result:
From the 88 patients reviewed, 1 was excluded due to lack of follow-up data. Demographic data is presented in table 1. Median follow-up was 14 months (range 0.5 to 36). Local control (LC) was achieved in 93% of patients. The median progression free survival (PFS) interval was 15 months. Overall survival (OS) at 1 year was 90% and at 3 years 72%. The median overall survival was 14 months (range 0.5 to 36). During follow-up, 14 patients progressed. However, only 6 of these progressed within the treated lesion. There were no treatment-related deaths, nor grade 3 or 4 adverse toxicities documented. Table 1 Demographics

SEX	Male 52 (59%) Female 36 (41%)
AGE	Mean: 72 Years Range : 55- 87
ECOG PERFORMANCE STATUS	1 : 21 2: 33 3: 2 Not available: 32
TNM STAGING	T1aN0M0 : 4 T1bN0M0 : 32 T2aN0M0 : 46 T2bN0M0 : 6
HISTOLOGY	Adenocarcinoma : 8 Squamous: 9 NSCLC not differentiated: 2 Radiological diagnosis: 69
DOSE FRACTIONATION	50Gy/ 5# : 2 51Gy/ 3# : 1 54Gy/ 3# : 15 54Gy/ 5# : 1 55Gy/ 5# : 58 60Gy/ 8# : 11

Conclusion:
These results have proven Cyberknife radiotherapy to be a safe and effective treatment for acquiring local disease control in early lung cancers. LC rates are in line with previously published outcomes for lung SABR. OS appears better at 3 years, but this does warrant further follow up.

Background:
Surgical resection is generally accepted as the gold standard for managing early stage lung cancer. There remains, however, a subset of patients who do not proceed to surgery. Many of these patients are ‘medically inoperable’ due to comorbidities. Others may decline surgery or their tumour is deemed inoperable due to technical difficulties. In this subset, SABR has been shown to be an effective alternative treatment option. SABR involves multiple beams, which together deliver an ablative dose of radiation to a precise area. There is rapid dose fall-off which ensures sparing of nearby structures. Evidence suggests that SABR is not associated with a clinically relevant deterioration in quality of life (QoL). The negative impact on pulmonary function is also minimal. This audit aims to assess the effect of SABR on both pulmonary function and QoL of a cohort of patients undergoing treatment in the West Midlands.

Method:
The Queen Elizabeth Hospital, Birmingham delivers SABR to patients across the West Midlands. We followed a cohort of 45 patients who received SABR between September 2016 and April 2017 for early stage lung cancer. If patients had baseline PFTs, these were repeated between 3-13 weeks post treatment. Patients had their QoL assessed using the EORTC Quality of Life Questionnaire (QLQ-C30 version 3). This was recorded at baseline, early and late follow up (defined as 13-28 days and 30-75 days post treatment respectively).

Result:
To date, twenty patients have had baseline FEV1 and FVC which was repeated post treatment. Median baseline FEV1 was 1.52 (range 0.56-2.92) and median baseline FVC was 2.63 (range 1.25-4.89). Post treatment median FEV1 was 1.34 (range 0.60-2.61) and median FVC was 2.42 (range 1.40- 3.95). Using a Wilcoxon Signed Ranks test, there was no significant difference between pre and post treatment FEV1 or FVC (Z=-0.78,p=0.43 and Z=-1.0,p=0.31 respectively). Similarly, there was no difference in DLCO pre and post treatment (Z= -0.27,p=0.79) Thirty nine patients had their baseline QoL assessed. Of these, 36 had this repeated at early follow-up and 31 at late follow up. Median QoL score at baseline, early and late follow up was 66/100, 54/100 and 50/100 respectively. There was no significant difference in either early or late QoL compared to baseline (Z=-0.49,p=0.63 and Z=-0.15,p=0.88).

Conclusion:
Overall this study shows no significant difference in either PFTs or QoL in this cohort of patients undergoing SABR in Birmingham. These results compare favourably with other published data and are reassuring for our practice

Background:
The majority of patients offered lung SABR have a radiological diagnosis of primary lung cancer only. This is commonly due to poor performance status, multiple co-morbidities, poor lung function or medical inoperability rendering them unsuitable for lung biopsy. Local control rates (LCR) for SABR-treated lung lesions are in the order of > 90% at 12 months. Little data exists on whether histological subtype affects this or overall survival (OS).

Method:
We retrospectively analysed local control and survival data on all patients treated for primary lung cancer with SABR (using volumetric modulated arc therapy (VMAT) technique) at our tertiary centre over a 4-year period from May 2013 until February 2017.

Result:
153 patients in total were treated, with follow-up data available for 135 patients. Baseline demographic data and analysis are presented in table 1. Median follow-up was 13 months (range 0.5 to 45). The LCR in treated lesions for all patients was 95.2%. Squamous cell carcinomas (SCC) had a better LCR when compared to adenocarcinomas (100% vs 92.8%). Median OS for all patients was 13 months (range 0.5 to 45). By histological subtype, SCC had better OS when compared to adenocarcinomas (15.5 months vs 12.5 months). 35.7% of adenocarcinomas progressed either within the thorax or at distant sites compared to only 12.5% of SCC. However, in 93% of adenocarcinomas and 100% of SCC the original treated lesion did not progress. Those with no histology had LCR of 95% with a median OS of 12 months respectively.

Table 1

SEX Male – 82 (53.6%) Female – 71 (46.4%) AGE Mean – 73 Range – 48-92 PERFORMANCE STATUS (PS) PS 0 – 4 (2.6%) PS 1 – 66 (43.1%) PS 2 – 60 (39.2%) PS 3 – 6 (3.9%) Not recorded – 17 (11.1%) DISEASE T-STAGE T1a – 100 (63.4%) T1b – 29 (18.9%) T2a – 24 (15.7%) HISTOLOGY Adenocarinoma – 15 (9.8%) Squamous cell – 8 (5.2%) NSCLC not specified – 2 (1.3%) Large cell – 1 (0.7%) Carcinoid – 1 (0.7%) No histology – 126 (82.3%) DOSE/FRACTIONATION 54Gy/3 – 38 (24.9%) 55Gy/5 – 103 (67.3%) 60Gy/8 – 12 (7.8%) MEDIAN OVERALL SURVIVAL BY HISTOLOGY Adenocarcinoma – 12.5 months (range 3 to 38) Squamous cell – 15.5 months (range 1 to 43) NSCLC not specified – no follow-up data available Large cell – 18 months (1 patient only) Carcinoid – 14 months (1 patient only) No histology – 12 months (range 0.5 to 45) LOCAL CONTROL RATE BY HISTOLOGY Adenocarcinoma – 92.8% Squamous cell – 100% NSCLC not specified – no follow-up data available Large cell – 100% Carcinoid – 100% No histology – 95.0%

Conclusion:
Our data suggests a trend towards slightly better OS and LCR with SCC over adenocarcinomas. More adenocarcinomas progressed both locally and at distant sites than SCC did. This information may be useful prognostically and it suggests adenocarcinomas may need closer follow-up post-SABR. Overall, our LCR is in line with published data.

Background:
SABR has become a commonly used treatment for early stage lung cancers, particularly in patients not suitable for radical surgery. It provides excellent local tumour control and is well-tolerated. At our institute, we have two platforms to deliver SABR; Linac-based volumetric modulated arc therapy (VMAT) and Cyberknife (CK). Little data exists directly comparing these two in terms of local control (LC) and overall survival (OS), thus, we performed an analysis to ascertain whether one platform outperforms the other. We have conducted lung SABR using VMAT since June 2013 and CK since June 2014.

Method:
We retrospectively analysed data on all early stage primary lung cancer patients treated with lung SABR from June 2013 to February 2017. Demographic and survival data was collected.

Result:
241 patients were treated in total, 153 using VMAT and 88 using CK. 19 patients were excluded from analysis due to lack of follow-up data (18 VMAT, 1 CK). Median follow-up for all patients was 13 months (range 0.5 to 45). Age, sex and histological breakdown were similar for the two groups. The majority in both groups were treated based on a radiological diagnosis. In terms of staging, there were more T1 tumours treated with VMAT than CK due to our local departmental policy excluding tumours less than 2cm being considered for CK. LC was 95.2% for VMAT compared to 93% for CK at median follow-up. Median OS was 13 months for VMAT compared to 14 months for CK. We saw a higher proportion of disease progression (local or distant) in the VMAT group (25.8% versus 17.0%). Lung cancer related deaths were equal in both groups (8.9% VMAT versus 8.0% CK). Neither platform had any grade 3 or higher toxicities reported.

Conclusion:
We demonstrated both treatment modalities were well tolerated by patients and produced similar LC and OS outcomes. In those where the disease progressed, within the CK group a higher proportion of them progressed within the treated lesion, whereas in the VMAT group it was at other sites (ie new lung nodules or distant metastases). This could be due to staging and the fact the CK group featured significantly more T2 tumours. Overall, both treatment modalities gave comparable outcomes to surgery when looking at LC.

Background:
In this study, we aimed to investigate the validity and clinical outcomes of lung resection after curative intent chemoradiation for locally advanced NSCLC.

Method:
The retrospective review of the prospectively recorded data of patients with NSCLC that was treated with curative intent induction chemoradiation followed by surgery between 1996 and 2016 was carried out. The patients undergoing segmentectomy or bigger resection with lymph node dissection after chemoradiotherapy were included into study. Patients received 2-6 cycles of chemotherapy and 45-70 Gy radiotherapy and were divided into two groups; Group 1: patients who received 60 Gy radiotherapy or less; Group 2: patients who received 61 Gy radiotherapy or more. We compared the chemotherapy drugs, doses, cycles, body mass index and performance status, type of lung resection, 90-day postoperative complications, mortality and long term survival between the two groups.

Result:
One hundred and forty two patients were included into study (group 1 n=88, group 2 n=54). All but 17 patients were male with a mean age of 56.5y (31-85y). Twenty patients underwent pneumonectomy and 122 patients received lobectomy (55 patients with extended resection, chest wall resection and sleeve etc). Complete pathological response was observed in 44(31%) patients (group 1= 29.5% (26/88), group 2= 33.3% (18/54), p=0.63. Postoperative morbidity rate was 42.2% (group 1=47.7% (42/88), group 2=33.3% (18/54), p=0.09. In addition, 90-day mortality rate was 6.3% (group 1=5.6%, group 2=7.4%, p=0.68). The overall survival 5-year survival rate was 54.1% that was 61% in Group 1 and 43.6% in Group 2, respectively (p=0.14). We found no relationships between the radiotherapy dose and the complete response rate, mortality, morbidity and survival.

Conclusion:
These findings reveal that lobectomy or pneumonectomy can be safely performed following high-dose chemoradiotherapy without affecting surgical outcomes. However, the positive or negative effect of high-dose radiotherapy on complete response and survival has not been proven.

Background:
Use of postoperative radiotherapy (PORT) in completely resected (R0) pathologic stage IIIA-N2 non-small cell lung cancer (NSCLC) remains controversial. To assess the impact of PORT, we analyzed on the patterns of failure and survival difference in these patients.

Method:
Consecutive 50 patients with pathologic stage ⅢA-N2 NSCLC who underwent surgery with complete resection (R0) between Apr. 2004 and Dec. 2013 were retrospectively reviewed. Thirty-five(70%) patients were male and median age was 63 years (range, 35 - 82 years). Thirty-nine(78%) patients underwent lobectomy, 7(14%) bilobectomy, and 4(8%) pneumonectomy. Postoperative adjuvant therapy consisted of chemotherapy (ChT) alone in 26(52%) patients, ChT + PORT in 10(20%), PORT alone in 4(8%), and none in 10(20%). Radiation dose was ranged from 34 to 60 Gy with the median 55 Gy. Follow-up period was ranged from 4 to 132 months with median 42 months. Survival was calculated from the date of surgery. Kaplan-Meier method was used for survival calculation and their comparison was done using log-rank test.

Result:
The 3 and 5-year overall survival (OS) rate of all 50 patients was 70% and 58%, respectively and the median survival time was not yet reached. Both univariate and multivariate analysis showed age (> 70 yrs old) and ratio of node positive (LNR > 17%) were correlated with the poor OS. The locoregional recurrence was appeared in 19(38%) patients and distant metastasis in 27(54%). The median time to recurrence was 16 months (range, 1 - 87 months) in locoregional failure and that of distant metastasis was 20 months (range, 6 - 60 months). Lymphovascular space invasion (LVSI) was the only statistically significant factor correlating to the locoregional recurrence-free survival (LRFS) both in univariate and multivariate analysis. PORT did not improve both OS and LRFS. Three and 5-years OS in patients with PORT were 56% and 40%, in a while 76% and 68% in patients without PORT (P=0.166), respectively. Three and 5-years LRFS in patients with or without PORT was 80% and 80% versus 54% and 50% (P=0.105), respectively. We could find that the LNR over 17% (p=0.003), tumor extension (p=0.006), and LVSI (p=0.01) were more prevalent in patients group with PORT.

Conclusion:
In this analysis, the most important prognostic factor in the pathologic stage IIIA-N2 (R0) NSCLC patients was the age and positive lymph node ratio. Risk of locoregional recurrence was decreased with the use of PORT. However, this benefit was not leaded to the overall survival benefit.

Background:
Volumetric-modulated arc therapy (VMAT) has demonstrated the ability to deliver radiation dose precisely and accurately with a shorter delivery time and less MU compared to conventional intensity-modulated fixed-field treatment (IMRT) in the treatment of inoperable non–small-cell lung cancer (NSCLC). However, published data on clinical outcome and lung toxicities of VMAT in the treatment of NSCLC are scarce. The purpose of the present retrospective cohort study was to evaluate clinical outcome, acute and late pulmonary toxicities using VMAT (sequential/concurrent chemo) radiotherapy in inoperable NSCLC.

Method:
The clinical outcome, acute and late pulmonary toxicities of 134 consecutive inoperable NSCLC patients treated by VMAT with or without concurrent chemotherapy were retrospectively reviewed. Univariate and multivariate analysis on the dosimetric and characteristic factors associated with acute radiation pnuemonitis (RP) and pulmonary fibrosis were evaluated.

Result:
The average prescriptions dose to these patients were 5736.38±649.11 cGy (range from 5200 to 6400 cGy) with a median follow-up of 18.6 months (range, 2–45 months) for the enrolled 134 patients. The two-year progression-free survival (PFS) and overall survival (OS) for all patients was 18.2% and 38.4% with a median PFS and OS of 7.6 months and 18.6 months, respectively. There were 14 and 12 out of 134 patients experienced grade III/higher RP (10.45%) and pulmonary fibrosis (8.95%), respectively. Age, chemotherapy exposure, dose prescription, V10, V13, V20 and V30 were significantly associated with acute RP. Dose prescription was related to pulmonary fibrosis. Only V13 (p=0.02) and age (p=0.02) were independently associated with acute RP according to multivariate analysis. Based on regression analysis, the threshold for lung dosimetric metrics V10,V13,V20 andV30 were 50%,40%,28% and 18% in VMAT treatment of NSCLC to limit the RP rate <10%.

Conclusion:
VMAT can be delivered safely with acceptable acute and late toxicities for NSCLC. Lung dosimetric metrics were valuable in predicting acute RP. A threshold of 40% of Lung V13 in VMAT treatment of NSCLC was helpful to limit the RP rate <10%.

Background:
Stereotactic ablative radiotherapy (SABR) can result in high local control rates for adrenal metastases when biological doses of at least 100 Gy~BED10~ are delivered [Chance WW, 2017]. SABR is technically challenging due to respiration-induced displacements of the adrenals and adjacent organs at risk (OAR), both of which are poorly visualised using imaging techniques currently available at linear accelerators. MR imaging enables superior anatomical imaging of both the adrenals and OAR’s. We implemented stereotactic MR-guided adaptive radiotherapy (SMART) using daily on-table re-optimization of pretreatment SABR plans using the anatomy-of-the-day. We studied the impact such daily plan re-optimization for adrenal metastases.

Method:
Since mid-2016, 13 patients with adrenal metastases from lung cancer have undergone video-assisted, respiratory-gated SMART delivery on the MRIdian system (ViewRay Inc.). This entails using visual feedback involving projection of both target volume and safety margins onto a monitor visible to patients. The radiotherapy system automatically shuts-off delivery when the target is outside pre-specified safety margins (3mm). The commonest fractionation scheme delivered was 5-fractions of 10 Gy (in 9 patients). Prior to each fraction, a 17-second MR scan in shallow breath-hold was performed with patient in treatment position, in which the GTV was rigidly registered to that on the baseline MR scan. Setup was performed on the gross tumor volume (GTV), and contour deformation was used to automatically generate OAR’s according to the anatomy-of-the-day. Baseline SABR plans were recalculated on the anatomy-of-the-day (defined as ‘predicted plans’), before being routinely re-optimized.

Result:
The median planning target volume (PTV = GTV + 3mm) was 35.1 cc (range 6.5 – 69.8 cc). Online plan adaptation improved PTV coverage in 78% of all fractions. Re-optimized plans exhibited significantly better sparing of OAR and achieved a reduction in volumes of stomach, bowel and duodenum receiving 33Gy, with respect to predicted plans. All patients completed the planned treatments using repeated breath-holds. The total on-table duration was approximately 50 minutes for each fraction.

Conclusion:
Breath-hold SABR delivery under MR-guidance is advantageous for adrenal tumors. Substantial variations in OAR’s positions were observed at imaging prior to delivery of each fraction, leading to improved target coverage and OAR sparing when on-table plan re-optimization was performed.

Background:
Concurrent chemoradiation (CCRT) is the preferred treatment approach in inoperable non-small cell lung cancer (NSCLC) patients. However, CCRT increases the risk of acute esophagus toxicity (AET) compared to radiotherapy alone or sequential chemoradiation. To minimize the risk of AET, an international RT-dose constraint of either V50Gy or V60Gy <50% is used. However, clinical applicability of those models is not evident since assessment of the model accuracy and validity should be performed before generalizing to other populations. Therefore, the aim of this study was to clinically validate the two NTCP-models to predict acute esophagus toxicity in NSCLC patients treated with CCRT.

Method:
To validate the NTCP-models, clinical data of 274 inoperable NSCLC patients receiving CCRT using IMRT was used. The planned V50Gy and V60Gy and the prospectively scored grade ≥2 AET (CTC-AE) were retrieved and independently reviewed. The grade ≥2 AET probability for the V50Gy and V60Gy was calculated as; [1/1+[exp][[-0.515 + (0.027*V][50]] and [1/1+[exp][[-0.701 + (0.029*V6][0]]]. Validity of the model was assessed with the ability to predict the number of grade ≥2 AET events (calibration) and the ability to distinguish between those who develop grade ≥2 AET from those who do not (discrimination, area under the curve (AUC)). Furthermore, sensitivity and specificity for different cut-off points were determined.

Result:
From the 274 NSCLC patients, 125 (45.6%) patients developed grade ≥2 AET (93.8% grade 2, 6.2% grade 3), median V50Gy 23% (interquartile range 10.1-35.6%), median V60Gy 4.3% (interquartile range 0-20.5%). Calibration showed that the V50 overestimated the risk of developing grade ≥2 AET in low-risk patients while the V60 underestimated the risk of developing grade ≥2 AET in high-risk patients. Discrimination of both algorithms demonstrated a similar moderate fit (AUC 0.70 95%CI 0.64 to 0.76 and AUC 0.69 95%CI 0.63 to 0.76 for the V50Gy and V60Gy, respectively). For V50Gy, a cut-off point of more than 40% probability of developing grade ≥2 AET resulted in the most favorable sensitivity of 95.8% for grade ≥2 and 100% for grade 3, with specificity scores of 54.6% and 40.7% respectively. For V60Gy, a cut-off point of more than 60% resulted in the most favorable sensitivity of 95.1% for grade ≥2 and 100% for grade 3, with remarkably low specificity scores of 9.1% and 18.8%, respectively.

Conclusion:
The NTCP-models to predict acute esophagus toxicity in NSCLC patients both showed good predictive accuracy. For clinical practice, the V50Gy seems to be the most sensitive without compromising safety and efficacy.

Abstract not provided

Background:
Despite recent advances in combined chemoradiotherapy for the management of locally advanced, unresectable, stage III non-small cell lung cancer, the majority of patients treated ultimately relapse from their disease. Identifying prognostic factors that predict outcome may improve patient selection for definitive therapy and provide relevant clinical information for their future care.

Method:
This retrospective analysis assessed survival data for a consecutive series of patients with stage III non-small cell lung cancer treated with 6 weeks of curative-intent carboplatin (AUC 2) - paclitaxel (45mg/m[2]) plus radiotherapy at the Princess Alexandra Hospital, Brisbane, between January 2009 and December 2015. Kaplan-Meier analysis on an intention-to-treat basis was used to assess survival data, with attention to a number of clinicopathologic subgroups. Cox proportional hazards regression was performed on continuous and discrete patient covariates to identify those with an independent association with survival.

Result:
The study included 171 patients, with a median follow-up time of 30.5 months. Median overall survival (mOS) was 27.3 months (95% CI = 22.6 - 33.0) for the entire cohort. An improved mOS was seen in stage IIIA (34.3mo) vs IIIB (13.1mo, p<0.001) patients, and with non-squamous compared to squamous histologic subtype (35.5mo vs 22.7mo, p = 0.022). A longer mOS in females compared to males did not meet statistical significance (27.7mo vs 23.2mo, p = 0.21). Multivariate analysis revealed four factors most strongly and independently associated with poor survival: serum neutrophil:lymphocyte ratio (HR 1.15 for each unit increase, p <0.001), lactate dehydrogenase (HR 1.28 for each 50 U/L increase, p = 0.005), alkaline phosphatase (HR 1.1 for each 20 IU/L increase, p = 0.045), and albumin (inverse relationship, HR 0.76 for each 5 g/L increase, p = 0.047).

Conclusion:
This analysis confirms that outcomes for our cohort of stage III non-small cell cancer patients are consistent with international best practice. Our subgroup analyses were also in keeping with recognised clinical factors asociated with improved survival including earlier stage tumours and non-squamous histopathology. A number of pre-treament blood parameters, less well established as prognostic factors, independently influenced survival including the neutrophil:lymphocyte ratio, and lactate dehydrogenase, alkaline phosphatase and albumin levels. Analysis of oncogenic driver mutation status, PD-L1 expression and degree of tumor-infiltrating lymphocytes in available tumor samples is planned, with the goal of establishing a prognostic model to stratify and direct treatment options in this cohort of potentially curable patients.

Background:
Small molecule inhibitors targeting bromodomain and extraterminal domain (BET) protein is promising for cancer therapy. According to our previous study, BRD4 was highly expressed in small cell lung cancer (72%) and correlated with poor prognosis.

Method:
Series small molecular compound NHWD which design and modify by ourselves is a potent and selective BET family bromodomain inhibitor and only binds bromodomains of BRD2/3/4/T. We use the MTT in small cell lines to evaluate the activity and selected the best. And then potential pathway was demonstrated with Western blot and low cytometry. Finally, the activity of small compounds was conducted by xenograft and Patient Derived Xenograft (PDX).

Result:
Compare with JQ1 and other molecular compounds, NHWD-870 has the best effectiveness and powerful anti-cancer, and the IC50 was 1.579nM (figure 1). NHWD-870 exhibited robust single agent activity in cell viability assay across cell lines in vitro and xenografts of small cell lung cancer in vitro by downregulating the PDGFRβ, MEK1/2 and STAT1/MYC pathway (figure 1). Consistent with its broad spectrum of activities in invo, NHWD-870 has potent tumor suppressive efficacies in PDX model of small cell lung cancer (figure 2).Figure 1Figure 2





Conclusion:
Further research will be conducted about series small molecular compounds from bench to beside.

Background:
Neuroendocrine tumors of lung are classified into four histological types (WHO-2015): typical carcinoid, atypical carcinoid, small-cell lung cancer (SCLC) and large cell neuroendocrine carcinoma (LCNEC). The Pulmonary LCNEC is considered as an orphan disease due to its low incidence. Our aim was to evaluate the clinical presentation and outcome of standard chemotherapy for LCNEC. All India Institute of Medical Sciences, Bhubaneswar, is an institute of national importnace situated in eastern India. No case of LCNEC has been reported from this part of India till date.

Method:
We retrospectively analysed data of patients from June 2014 June to May 2017 with special focus on pulmonary neuroendocrine tumors. We examined incidence of different histological types of pulmonary neuroendocrine tumors. We also analysed clinical characteristics of patients with pulmonary LCNEC and their treatment outcomes.

Result:
In this new Institution 263 Lung Cancer patients were diagnosed by bronchoscopic and transthoracic biopsies. There were 26 (10%) patients with pulmonary neuroendocrine tumors(NEC). Seven(2.7%) of them were LCNEC, 3(1%) carcinoid and 17 (7%) were SCLC. Median age of pulmonary LCNEC was 60 years with M:F ratio 5:2. Four of them were smokers. Median performance status (ECOG) was 2.5. Three patients presented with superior vena cava obstruction and 5 patients had central mass lesions. All the elligible patients with LCNEC were offered chemotherapy with Cisplatin 60 mg/m [2] IV on day-1 plus etoposide 120 mg/m [2] IV on days 1 to 3 in every 21days for initial 4 cycles as a standard treatment in addition to other supportive care. Two patients could not complete initial 4 cycles of chemotherapy due to progression of the diseases and drug intolerance. Four (57%) of the patients had partial response in initial chemotherapy and subsequent progression of disease. Two patients were offered Topotecan as second line chemotherapy but no significant response was observed. Overall survival of patients of LCNEC was 7 months (4-11).

Conclusion:
Incidence of pulmonary LCNEC is low but is increasingly encountered. Most of the patients were diagnosed at advanced stages. Overall survival was poor despite chemotherapy. There is no definite second line regimen recommended for LCNEC. There is a need for clinical trial with alternative modalities including targeted and immunological treatment for these types of lung cancer.

Background:
Small cell lung cancer (SCLC), which accounts for approximately 15% of lung cancer, is one of the most malignant diseases world-wide, with a high mortality. Despite progress in treatment of small cell lung cancer (SCLC), the biology of the tumor still remains poorly understood. Recently, we globally investigated the contributions of lncRNA in SCLC with a special focus on sponge regulatory network. Here we report lncRNA HOTTIP, which is specifically amplified in SCLC, is associated with SCLC proliferation and poor prognosis of patients.

Method:
RT-qPCR was used to investigate the expression of HOTTIP in SCLC tissues and cell lines. The role of HOTTIP in SCLC cell proliferation was demonstrated by CCK8 assay, colony formation assay, flow cytometry analysis and in vivo models of transplant tumor in mice through HOTTIP loss- and gain-of function effects. Western blot assay was used to evaluated gene expression in cell lines at protein level. RNA pull-down, Mass spectrometry and RNA binding protein immunoprecipitation (RIP) were performed to confirm the molecular mechanism of HOTTIP involved in SCLC progression.

Result:
We found that HOTTIP was overexpressed in SCLC tissues, and its expression was correlated with the clinical stage and the shorter survival time of SCLC patients. Moreover, HOTTIP knockdown could impair cell proliferation, affect the cell cycle and inhibit tumor growth of mice, while HOTTIP overexpression might enhance cell proliferation and cell cycle in vitro and in vivo. Mechanistic investigations showed that HOTTIP functions as an oncogene in SCLC progression by sponging miR-574-5p and affecting the expression of several protein-coding cancer driver genes, such as polycomb group protein EZH1 and EZH2. By in-depth study of mechanism, we identified Ago2 as an RNA-binding protein that binds to HOTTIP, which confirmed miRNAs interact with HOTTIP by the RNA-induced silencing complex (RISC).


Conclusion:
Our findings not only illuminate how HOTTIP confers an oncogenic function in SCLC pathogenesis, but also underscore a novel gene expression governing hallmarks in the disease.

Background:
Since December 2013, we initiated a phase II/III trial [Japan Clinical Oncology Group (JCOG) 1201/Thoracic Oncology Research Group (TORG) 1528: UMIN000012605] for elderly patients with extensive-disease small-cell lung cancer (ED-SCLC). Aim of the study is to demonstrate that a carboplatin plus irinotecan regimen is superior to carboplatin plus etoposide in elderly patients with ED-SCLC. However, the patient accrual rate did not satisfactorily match our expectations a year from the time of initiation of our study. To define factors related to low accrual, we searched institutional records and analyzed.

Method:
We collected data of elderly patients with ED-SCLC from each institution and investigated the total number of elderly patients with ED-SCLC, number of patients eligible/ineligible for the study, numbers of patients registered for the study, and the reasons for non-registration of even eligible patients. Doctor-reported questionnaires concerning elderly (≥71 years old) ED-SCLC patients diagnosed in their institutions were sent to chief or coordinate doctors at each institution in December 2014.

Result:
We received a response from 32 (84%) of 38 institutions. Approximately 260 patients were diagnosed as elderly patients with ED-SCLC in the last year. Only 100 patients (38%) were eligible for the JCOG 1201/TORG1528 trial. Reasons for ineligibility primarily included poor performance status (PS) (25%), low organ functions (25%), interstitial pneumonitis (19%) and double cancer (18%). Only 23 patients among the 100 eligible candidates accrued to the study. The primary reasons for non-accrual were delayed approval from the Institutional Review Board (IRB) of the individual institution (24%), physician preferences (23%), patient refusal (18%), and registration for other trials (12%).

Conclusion:
Our data demonstrated that 62% of ED-SCLC patients were ineligible for the protocol due to frailty with the most frequent reason being comorbidities such as poor PS and low organ functions. However, inactive institutions need to increase their efforts to register a greater number of eligible patients in addition to obtaining quicker IRB approval of protocol. Based on responses to questionnaires sent out as part of our investigation, in January 2016, the protocol was revised in terms of eligibility criteria to enhance patient accrual. Eligibility criteria for participation of elderly patients with ED-SCLC need to be formulated prudently so that patients are benefitted in routine clinical practice.

Background:
The benefits of second-line chemotherapy on the overall survival (OS) of small-cell lung cancer (SCLC) patients might be confounded by subsequent therapies. In this study, we aimed to determine the influence of progression-free survival (PFS) and of post-progression survival (PPS) on OS after second-line chemotherapy in patients with refractory SCLC treated with amrubicin monotherapy.

Method:
We analyzed the data of 35 patients with refractory SCLC who were treated with amrubicin monotherapy as second-line chemotherapy between July 2005 and December 2015. The correlations of PFS and PPS with OS were statistically analyzed at the individual level using Spearman rank correlation and linear regression analyses.

Result:
The correlation between PPS and OS was strong (r = 0.88, p < 0.05, R[2 ]= 0.87), while that between PFS and OS was weak (r = 0.60, p < 0.05, R[2] = 0.15). The number of regimens administered after disease progression post-second-line chemotherapy was significantly associated with PPS (p = 0.003).

Conclusion:
OS is more strongly linked to PPS than to PFS in refractory SCLC patients who undergo amrubicin monotherapy as a second-line treatment. Moreover, receiving additional regimens after second-line treatment is a significant independent prognostic factor for PPS. Taken together, our results indicate that additional treatments administered after second-line chemotherapy favorably affect the OS of refractory SCLC patients treated with amrubicin monotherapy.

Background:
Small cell lung cancer (SCLC) accounts for about 15% of all lung cancer cases. SCLC is characterized by frequent relapse, and current treatments lack tumor specificity. Arginase is an important enzyme in human, but it is deficient in some tumors. Arginine deprivation has become a potential therapeutic option in selected tumors. BCT-100 is a pegylated arginase which has demonstrated anticancer activity in arginine auxotrophic tumors, such as melanoma, hepatocellular carcinoma and acute myeloid leukemia. One of resistance mechanisms to arginase is overexpression of argininosuccinate synthetase (ASS1) and ornithine transcarbamylase (OTC). The aim of this study is to determine the effects of BCT-100 on SCLC in vitro and in vivo.

Method:
3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay was used to detect cell viability of different SCLC cell lines after BCT-100 treatment. Western blotting was employed to evaluate the protein expression. Knockdown of OTC was performed using specific siRNA. Xenograft models were established in nude mice for testing the anticancer effect of BCT-100.

Result:
The IC~50~ values of BCT-100 in H69, DMS79, H187, H209, H446, H510A, H526, H841 and SW1271 cells were 462.9±112.2, >1000, 24.9±6.4, 8.6±0.8, 18.0±0.7, 18.2±4.0, 10.1±0.7, >1000 and 49.2±7.4 mU/mL respectively. Knockdown of OTC increased sensitivity to BCT-100 in H841 cells, partially mediated via apoptosis. Mitochondrial membrane depolarization was observed in BCT-100 treatment and cytochrome c and SMAC were released from mitochondria to cytosol. N-acetylcysteine (NAC), the reactive oxygen species (ROS) scavenger, could reverse the apoptosis induced by BCT-100 significantly. Besides, cell cycle specific proteins, cyclin A2, cyclin B1 and CDK4, were downregulated in a time-dependent manner. The tumor growth was inhibited and median survival of mice was prolonged in BCT-100 group in H446 and H510A xenograft models. Serum and intratumoral arginine level was sharply decreased, associated with G1 arrest and apoptosis in H446 and H510A xenografts.

Conclusion:
The SCLC cell lines with low expression of ASS1 and OTC were susceptible to BCT-100 treatment. ROS was involved in BCT-100 induced-apoptosis. BCT-100 showed potential anticancer activity in SCLC xenograft models.

Background:
Survival outcomes for extensive stage small cell lung cancer (ES-SCLC) remain poor. The standard management of ES-SCLC is chemotherapy. For those achieving a good response consolidation thoracic radiotherapy and prophylactic cranial irradiation (PCI) is considered. This retrospective audit analysed patterns of care and survival for all patients with ES-SCLC treated at Prince of Wales Hospital (POWH) over 15 years. Factors correlating with survival were also analysed. A literature review was performed to benchmark our results.

Method:
We identified ­­187 patients diagnosed with SCLC at Prince of Wales Hospital between 2000 and 2014 from the departmental electronic patient information system (MOSAIQ, Elekta). Eligibility criteria were: age >18 years, histopathologically confirmed diagnosis of SCLC, extensive stage according to the two-stage Veterans’ Affairs Lung Study Group staging criteria, and treatment at POWH. Median progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method and log-rank test (IBM SPSS version ­24).

Result:
Eighty-three patients fulfilled the eligibility criteria. Median age was 70 years. 42% of patients were female and 63.9% had an Eastern Cooperative Oncology Group performance status (PS) of 0-1. Median PFS and OS were 5.0 and 8.2 months respectively, comparable with published literature. There was correlation between PS (0-1 versus >2) and OS (p=0.025) but not PFS (p=0.16). 79.5% of patients received initial chemotherapy, 48.5% of these patients received 6 cycles, of which 89.4% was carboplatin and etoposide. Median time from date of diagnosis to start of chemotherapy was 12 days, with correlation between time to chemotherapy and OS (p=0.006) and PFS (p=0.003). 75.9% patients received radiotherapy of any kind, but only radiotherapy directed at the thorax was associated with improved OS (p=0.01) but not PFS (p=0.5). Five (6%) patients underwent consolidation thoracic radiotherapy, while 32.5% underwent palliative thoracic radiotherapy. Palliative whole brain radiotherapy was given to 11 (13.3%) patients and only 2 patients received PCI. 78.3% of patients had documented progression after treatment, with simultaneous loco-regional and distant progression the most common pattern. 66.2% of patients had treatment at progression, with most (86%) receiving palliative radiotherapy.

Conclusion:
Our current analysis demonstrates an association between survival outcomes and baseline PS, time to initiation of chemotherapy and receipt of thoracic radiotherapy for patients with ES-SCLC. The survival outcomes are comparable to the reported literature. This highlights the importance of early referral and treatment commencement for improved outcomes in ES-SCLC.

Background:
Pulmonary neuroendocrine carcinoma, including small cell lung cancer (SCLC), large cell neuroendocrine carcinoma (LCNEC), and carcinoid tumor, is a highly malignant cancer with poor prognosis. Because of its rarity, the molecular information available to investigate suitable therapeutic targets is insufficient, and little advancement has been made in the development of molecular-targeted therapies for these patients. This study aimed to determine a molecular signature of pulmonary neuroendocrine carcinoma by genomic analysis to explore therapeutic targets.

Method:
Surgically resected primary tumor specimens obtained between January 2014 and June 2016 from 15 patients with neuroendocrine carcinoma [SCLC, 8; LCNEC, 6; typical carcinoid (TC), 1; categorized based on WHO classification] were subjected to whole-exome sequencing (WES) and gene-expression profiling (GEP). Corresponding peripheral blood samples were collected as controls to identify tumor-specific genetic alterations in WES. Written informed consent was obtained from all patients. WES was performed on an Ion Proton system. An Agilent SurePrint G3 Human Gene Expression 8×60K v2 Microarray was used to detect tumor-specific gene expression. Oncogenic fusions were detected by targeted RNA sequencing. Copy number alterations were detected by integrating copy numbers resulting from WES and GEP. Promising oncogenic genetic alterations were selected using the OncodriveFML and Cancer Genome Interpreter.

Result:
Patient characteristics were: median age, 67 years; men, 67% (10/15); smokers, 93% (14/15); ratio of stage I/II/III/IV (%), 40/47/13/0. The median tumor mutational burden (TMB) in SCLC and LCNEC was 7.6 mutations (mt)/Mb (1.1–11.3) and 8.0 mt/Mb (3.5–12.6), respectively, which were significantly higher than that in lung adenocarcinoma (1.6 mt/Mb; p = 0.0025, p = 0.009), but not in lung squamous cell carcinoma (5.6 mt/Mb). One patient with TC showed low TMB (0.7 mt/Mb) and harbored a truncating mutation in MEN1, indicating a typical molecular signature of carcinoid tumor. The commonly altered genes (≥ 20%) were TP53 [60%, mut, 8; downregulation (down), 1], RB1 (53%, mut, 6; down, 2), CCNE1 [27%, amplification (amp), 4], APC (27%, mut, 3; down, 1), and BCL2 (20%, amp, 3). All genetic alterations detected in TP53, RB1, and APC were putative loss-of-functions. We observed no significant differences in frequency of alterations in the commonly altered genes between SCLC and LCNEC. One patient with LCNEC harbored EGFR-activating mutation, indicating possibility that this tumor was combined LCNEC with adenocarcinoma.

Conclusion:
This study revealed a molecular signature in Japanese patients with pulmonary neuroendocrine carcinoma, which could contribute to the development of novel molecular-targeted therapies.

Background:
Small cell lung cancer (SCLC) that constitutes of 15-18% of all lung cancers is a highly lethal malignancy. The functional effects of long noncoding RNAs(lncRNAs) in cancer have been widely recognized. Long intergenic non-protein coding RNA 173(Linc00173) was first identified in SCLC, and was found to be involved in chemoresistance. We aimed to explore the regulatory mechanisms of Linc00173 using drug-resistant cell lines and human tissues.

Method:
We used microarrays to compare expression profiles of lncRNAs in SCLC cell line and the drug-resistant subline and Linc00173 was identified. Linc00173 was examined in 60 SCLC patient samples by qRT-PCR assay. The functional roles of Linc00173 in SCLC were studied by overexpression and RNA interference approaches in vitro and in vivo. The localization of the genes were involved in competitive endogenous RNAs(ceRNAs) regulatory network was studied by separating cytoplasmic and nuclear RNA fractions from SCLC. Bioinformatic analysis, luciferase assays, RNA immunoprecipitation and pull-down assays were performed to elucidate the role of Linc00173 in mechanism of ceRNA. The positive Linc00173/Etk correlation was further verified by qRT-PCR assay and bivariate correlation analysis in clinical tissues and blood samples.

Result:
We found that Linc00173 expression was significantly associated with chemoresistance and the shorter survival time in SCLC patients. Downregulation of Linc00173 expression could impair cell proliferation and increased cell sensitivity to anticancer drugs, while upregulation of Linc00173 promoted the proliferation and induced multidrug resistance both in vitro and in vivo. Linc00173 overexpression enhanced the expression of Etk through competitively ‘spongeing’ miRNA-218 resulting in the activation of STAT3. Particularly, the ceRNA regulatory network of above genes was occurred in nucleus. Finally, the positive Linc00173/Etk correlation was found in SCLC tissues and blood samples.

Conclusion:
Figure 1Linc00173 was first identified to promote proliferation and chemoresistance of SCLC. It regulates levels of Etk by acting as ‘sponger ’of miR-218. These genes may be novel indices for clinical diagnosis of tumor growth and chemoresistance in SCLC.

Background:
Epithelial and endothelial tyrosine kinase(Etk), also known as Bone marrow X kinase (Bmx), was found to be critical in modulating chemoresistance of small cell lung cancer(SCLC) in our preliminary study. However, the molecular mechanisms of Etk leading to chemoresistance in SCLC remain obscure.

Method:
Knockdown of Etk by siRNAs was performed to evaluate autophagy change in SCLC. Subsequently, a microarray analysis identified PFKFB4 as a downstream molecule of Etk, and CoIP and GST-pull down was used to test protein interaction. We then explored whether PFKFB4 affected autophagy of SCLC. Gain or loss-of-function in vitro or in vivo was used to evaluate the effects PFKFB4 on chemotherapy sensitivity. The expression of PFKFB4 in SCLC tissues were measured by immunohistochemistry(IHC). Besides, luciferase assays, Western blot and CCK8 assay were performed to confirmed whether miR-218 regulates Etk and its effect on chemoresistance. As Etk shares conserved domains with Btk(Bruton’s tyrosine kinase) family, we also explored whether ibrutinib, a Btk inhibitor used in leukemia, affected chemotherapy sensitivity of SCLC.

Result:
Etk affected autophagy in SCLC, and directly inhibition of autophagy sensitized cells to chemotherapy. PFKFB4 was found as a downstream molecule of Etk and they interacted with each other in protein level directly. Moreover, knockdown of PFKFB4 suppressed autophagy of SCLC. PFKFB4 affected chemoresistance of SCLC in vitro and in vivo, and high level of PFKFB4 was associated with poor therapeutic response and prognosis. Furthermore, miR-218 directly modulated Etk expression as a novel regulator and it affected chemoresistance in SCLC. We demonstrated that ibrutinib exhibited a synergistic effect with chemotherapy in SCLC.

Conclusion:
Figure 1 Our results demonstrated for the first time that Etk interacts with PFKFB4 to modulate the chemoresistance of SCLC by autophagy and Etk is a direct target of miR-218. These genes may be predictive factors for the chemotherapy response as well as potential therapeutic targets in SCLC.

Background:
Small cell lung cancer (SCLC) and large cell neuroendocrine carcinoma (LCNEC) of the lung are highly malignant tumors and classified as variants of endocrine carcinoma and subdivided into pure or combined type. Clinical benefit of this stratification and strategy for target therapy has not been established in these tumors.

Method:
This study aimed to compare genetic and clinicopathological features between SCLC and LCNEC or pure and combined types, evaluate the usefulness of classification methodology, and explore the possibility of target therapy using next-generation sequencing (NGS). NGS custom panel was designed to cover 36 genes with median coverage percentage of 99.57% (80.89-100). As clinicopathological features, patients’ characteristics and immunohistochemistry using 8 antibodies were evaluated.

Result:
In 13 SCLC and 22 LCNEC cases, 72 point mutations, 19 deletions, and 3 insertions were detected. As therapeutically targetable variants, mutations in EGFR (L858R), KRAS (G12D, G12A, G12V), and PIK3CA (E545K) were detected in 5 cases. One combined LCNEC cases harboring EGFR mutation (L858R) showed response to EGFR-tyrosine kinase inhibitor. However, these therapeutically targetable cases were not accompanied by specific features in immunohistochemistry or histology. And there was no significant genetic feature between SCLC and LCNEC or pure and combined types.

Conclusion:
Although even SCLC and LCNEC cases harbored therapeutically targetable mutations and potentially include the benefit for target therapy, they were not identifiable by clinicopathologic background. And there was not significant genetic difference between SCLC and LCNEC, including between pure and combined types. Classifying SCLC and LCNEC in same category is reasonable. However, distinguishing the pure type from combined type was not validated. Comprehensive genetic analysis should be performed to detect targetable variants in any type of SCLC and LCNEC.

Background:
Section not applicable

Method:
The clinical data of 15 patients with small cell lung cancer(SCLC) combined with paraneoplastic limbic encephalitis(PLE) from 1980 to 2017 were collected from Peking Union medical college hospital. Their symptoms and laboratory data were analyzed and the prognosis of the patients was followed.

Result:
1. PLE is a rare disease, the incidence rate in small cell lung cancer is about 0.842%.The data may be underestimated because of misdiagnose or missed diagnosis. 2. High incidence crowd of the disease is the middle-aged male smoker, The TNM stages of them are later than others. 3. Typical neurological symptoms include varying degrees of short-term memory loss, seizures and varying degrees of mental disorders; neurological symptoms usually occur before the onset of cancer or respiratory symptoms appear, an average of about 2 months be taken from onset to diagnosis. 4. Serum antibody (anti-Hu, GABA-R-Ab), cerebrospinal fluid, head MRI and EEG of the patients has abnormalities; Videography, especially CT is a good means of screening the primary tumor, pathology diagnosis mainly rely on bronchoscopy. 5. The treatment of primary tumors can be more effective in alleviating the nervous system symptoms than immunotherapy.

Conclusion:
Paraneoplastic limbic encephalitis is a rare paraneoplastic syndrome in nervous system caused by malignant neoplasms often characterized by facial neurological symptoms. The disease are usually associated with lung cancer (especially small cell lung cancer) .Its nervous system symptoms occur earlier than the tumor diagnosis. Early diagnosis and treatment for primary tumors will increase the benefit.

Background:
Relapsed or refractory small cell lung cancer (SCLC) has a poor prognosis, with no good therapeutic options. Topotecan, a topoisomerase I inhibitor, and doxorubicin, a topoisomerase II inhibitor, are both active drugs in SCLC. We evaluated the safety and efficacy of a novel combination of oral topotecan and weekly doxorubicin, providing sequential topoisomerase I and II inhibition, in this setting.

Method:
Adult patients (>19 years) with relapsed or refractory SCLC who had received at least one prior chemotherapy regimen were included in the study. Patients received escalating doses of oral topotecan for five days (Days 1-5 of each cycle) every three weeks for a maximum of 5 cycles. The dosing cohorts were: DL1: 0.85 mg/m[2], DL2: 1.05 mg/m[2], DL3: 1.35 mg/m[2], DL4: 1.65 mg/m[2] and DL5: 2.30 mg/m[2]. All patients received weekly doxorubicin 20 mg/m[2] intravenously starting Day 6 of the first cycle and continued weekly for the duration of the study (maximum 15 weeks). The study design involved a standard 3+3 approach. In the absence of pre-specified criteria for dose limiting toxicities (DLT), patients were enrolled serially to escalated dose level cohorts. Patients received therapy until disease progression, undue toxicity or completion of the study. Primary objectives were safety and efficacy, dose limiting toxicity and response rate.

Result:
A total of 22 patients were enrolled in the study, of which 18 were evaluable for toxicity. Median age was 60.5 years, 72% were male and 95% were Caucasian. Most common adverse events observed were hematological toxicities. Grade 3/4 adverse events included: anemia (44%), thrombocytopenia (50%), neutropenia (44%), lymphopenia (33%), leucopenia (39%), transaminitis (17%), hypokalemia (11%), hypotension (5%) and dehydration (5%). There were no therapy-related Grade 5 toxicities. Incidence of DLT based on cohorts were: DL1: 0/3, DL2: 1/6 (Grade 4 Thrombocytopenia), DL3: 1/6 (AST Elevation) and DL4: 2/4 (Grade 4 Thrombocytopenia). Response rate was 16.6% (3/18) and disease control rate (SD + PR) was 33%. The median progression free and overall survival were 3.4 months and 5.8 months, respectively.

Conclusion:
The novel combination of oral topotecan and weekly doxorubicin was safe and showed promising efficacy in relapsed/refractory SCLC. The maximum tolerated dose of oral topotecan was 1.35 mg/m[2] when given concurrently with weekly doxorubicin. A phase 2 trial using this regimen is being developed.

Background:
Currently the chemotherapy protocol for extensive stage small cell lung cancer at Auckland Regional Cancer and Blood Service does not include a recommendation for the use of growth colony stimulating factor (G-CSF) support as either primary prophylaxis or in the secondary setting. The protocol does provide guidelines for treatment delay and dose reduction in the setting of haematological toxicity. Access to publicly funded pegfilgrastim (Neulasta) became available in New Zealand in May 2013. Individual physicians may choose to prescribe G-CSF prophylaxis for any patient they believe fits the funding criteria. We therefore reviewed current clinical practice and outcomes in this patient population.

Method:
A retrospective audit of patients 18 years and over with a histologically confirmed diagnosis of extensive stage small cell lung cancer who were schedule to receive carboplatin with or without etoposide chemotherapy, from 1 January 2015 to 31 December 2015 was undertaken. Primary end point was rate of febrile neutropenia (FN) with secondary end points of G-CSF use, patient related risk factors for FN and dose reductions / delays.

Result:
32 patients met the inclusion criteria, 29 of these received chemotherapy. The rate of FN in the entire population was 14% (4 episodes in 29 patients). One patient had 2 episodes of FN. The rate of FN in patients not receiving primary G-CSF was 13% (3 episodes in 23 patients). Six patients were administered G-CSF in the primary setting (20%, 6/29). One patient treated with primary G-CSF had FN (20%, 1/6). Two patients received G-CSF in the secondary setting. Risk factors for FN were commonly seen, including age >65 years (63%) chronic obstructive respiratory disease (41%) and multiple co-morbid conditions (22%). Treatment delays were experienced by 14 patients (48%) at some stage throughout their chemotherapy primarily due to haematological toxicity. Dose reductions occurred in 17 patients (58%).

Conclusion:
This retrospective audit confirms an overall rate of FN of 14%, in keeping with published data of moderate risk of neutropenia with carboplatin etoposide chemotherapy. In this retrospective study, primary G-CSF did not decrease this risk, but numbers are small. This population of patients commonly have risk factors for FN and many patients experience treatment delays. Given this and the importance of dose intensity in the treatment of small cell lung cancer, consideration for primary G-CSF support is warranted.

Background:
The biological and clinical significance of thyroid transcription factor 1 (TTF-1) remains unclear in small cell lung cancer (SCLC). The purpose of this study was to clarify the clinicopathological characteristics of TTF-1-negative SCLC.

Method:
We retrospectively studied the associations between survival and the expression of TTF-1, and examined the association between the expression of TTF-1 and neuroendocrine markers (Synaptophysin, Chromogranin, and CD56), neuroendocrine cell-specific transcription factor (ASCL1, BRN2), and NF1B, which is an oncogene for SCLC. Formalin fixing and paraffin embedding (FFPE) and clinical data in SCLC patients were collected and used. The study was approved by the institutional review board.

Result:
Thirty-five patients were examined. Eleven patients were negative for TTF-1, and twenty-four patients were positive for TTF-1. The analysis demonstrated that overall survival was not statistically significant between patients with TTF-1-negative and those with TTF-1-positive SCLC. However, frequency of negativity of Synaptophysin and Chromogranin was greater in patients with TTF-1-negative SCLC than in those with TTF-1-positive SCLC based on immunohistochemical expression, and the difference was statistically significant. mRNA expression of ASCL1, NF1B, and serum ProGRP were significantly lower in patients with TTF-1-negative SCLC than in those with TTF-1-positive SCLC. We showed that TTF-1-negative SCLC showed less neuroendocrine differentiation. It is suspected that TTF-1-positive and -negative SCLC have different biological characteristics.

Conclusion:
TTF-1-negative SCLC was different in terms of aspects of neuroendocrine differentiation (negativity of Synaptophysin and Chromogranin, lower expression of ASCL1 and NF1B) compared to TTF-1-positive SCLC.

Background:
Amrubicin (AMR) monotherapy is one of treatment options in patients with relapsed high grade neuroendocrine carcinoma (HGNEC) of the lung. Although topoisomerase-II (Topo-II), a target of AMR, has been reported to be a predictive or prognostic marker for chemosensitivity and clinical outcomes in various types of malignancies, its role remains unknown in this population.

Method:
Eighty-four patients with relapsed HGNEC (consisting of small cell lung cancer [SCLC] and large cell neuroendocrine carcinoma [LCNEC]) who received AMR monotherapy between 2003 and 2015 were enrolled into this study. We retrospectively collected clinical data including histological type, anti-tumor effect, and survival data from medical records. The expression levels of Topo-II were examined by immunohistochemical staining in tumor specimens obtained from surgical resection or biopsy.

Result:
The majority of enrolled patients were men (89%) and had a histological type of SCLC (92%) with a median age of 70 years (range, 49-83 years). Twenty-three percent of patients had poor performance status of 2 to 4. Sixteen percent of patients exhibited Topo-II overexpression in the tumors. The overall response rates in patients with high and low expression of Topo-II were 38.5% and 25.7%, respectively (p = 0.34). In multivariate analysis, patients with high expression of Topo-II had significantly longer progression-free survival (Hazard Ratio [HR] 0.39, p < 0.01) and overall survival (HR 0.48, p = 0.04).

Conclusion:
Our findings suggest that Topo-II expression is associated with clinical outcomes in patients with relapsed HGNEC receiving AMR monotherapy.

Abstract not provided

Background:
Intercostal nerve blocks with a liposomal Marcaine formulation (Exparel) was reported to provide pain relief equivalent to an epidural in the immediate post operative period following a thoracotomy. We compared pain relief of thoracotomies that received an Exparel block to minimally invasive procedures in the immediate and extended post-operative period.

Method:
We reviewed the records of 166 patients who underwent thoracic surgery procedures with a thoracotomy or a video-assisted thoracoscopic surgery (VATS) and who received multilevel paravertebral nerve blocks with either Exparel or 1 % Marcaine with epinephrine. Pain scores and opiate use were routinely recorded by nurses for the first 48 hours as well as opiate use in the postoperative days (POD) 5 to 13 (by patients). Clinical variables, atrial fibrillation, pulmonary complications, and hospital length of stay (LOS) were also examined. Statistics included t-test for means, and Fisher exact for proportions.

Result:
Fifty patients underwent a VATS wedge resection with a paravertebral block with Exparel (VATS-E) and 53 patients underwent a VATS wedge resection with a paravertebral block with Marcaine (VATS-M). The pain score were lower for the VATS-E vs. the VATS-M patients (p< 0.001). 32 patients underwent a thoracotomy with an Exparel block (Thor-E) (30 lobectomies) and 15 patients had a VATS lobectomy with a Marcaine block (VATS-lobe-M). Thor-E patients expressed lower pain scores compared to VATS-M and VATS-lobe-M in the first 48 hours after surgery (p<0.001). Opiate use was also lower in the Thor-E patients compared to VATS-lobe-M patients, with 25% of the Thor-E patients not taking opiates by POD 5. Opiate use was not significantly different between Thor-E and VATS-E patients from POD5 to POD 13. The LOS was 3.2 days for Thor-E and 5.7 days for historic control thoracotomy lobectomy patients who received a Marcaine nerve block.

Conclusion:
Our study suggests that the pain relief provided by an Exparel block in thoracotomy patients compares favorably to that of VATS procedures in the immediate and extended postoperative period, and that Exparel paravertebral nerve blocks may also improve hospital length of stay.

Background:
Current practice guidelines by the National Comprehensive Cancer Network (NCCN) recommend the complete dissection of at least three mediastinal nodal stations during lobectomy for lung cancer. Controversy exists concerning the adequacy of lymph node sampling (LNS) achieved by video assisted thoracic surgery (VATS) lobectomy for lung cancer and furthermore whether or not small volume centers could compare to the national benchmarks. Several large studies have shown conflicting evidence concerning the LNS yield in VATS vs thoracotomy. For thoracic surgeons in a rural community setting there may be warranted concern about the adequacy of lymph node dissection during VATS. This study aimed to assess the adequacy of lymph node sampling by VATS at our institution, a rural 300 bed community teaching hospital in western Massachusetts.

Method:
Retrospective review of clinical and pathological data were reviewed for 103 hospital admissions in patients undergoing lung Lobectomy performed from 2010-2016. Variables included age, sex, number of mediastinal nodes and node stations dissected.

Result:
103 patients with 103 VATs Lobectomies, 49 males (ave age 64.6 yrs) and 55 females (ave age 67.5), had a mean number of mediastinal lymph nodes (MLD) of 10.98 and the mean number of dissected N1+N2 stations was 3.47. The mean N2 station yield averaged 2.93 stations. S1 was resected in 2/103cases (2%); S2, 10/103 (10%); S3, 0/103 (0%); S4, 62/103 (64%); S5, 29/103 (30%); S6, 25/103 (25%); S7, 79/103 (81%); S8, 7/103 (7%); S9, 37/103 (38%); S10, 51/103 (53%); S11, 33/103 (34%); S12, 22/103 (23%); S13, 1/103 (1%).

Conclusion:
Recent data presented at Annual Meeting of the American Association for Thoracic Surgery (AATS) suggests VATS lymphadenectomy is inadequate 60% of the time. It was postulated that small volume centers and/or inexperienced general surgeons are contributing to this high percentage. This study agrees with previous data affirming the lymph node yield is adequate with VATs lobectomy. When compared to the current NCCN recommendations our institutions mean number of MLN and MLN stations dissected is similar or better to that of many larger volume centers across the nation and supports the adequacy of VATs Lobectomy in rural community hospitals.

Background:
For tissue diagnosis of an indeterminate lung tumor with a strong suspicion of lung cancer, wedge resection is sometimes difficult because of tumor size or location. Intra-operative needle aspiration biopsy can be considered when tumor biopsy via flexible bronchoscopy (FB), or using transthoracic needle aspiration biopsy (TTNA), fails to prove malignancy in tumors with a high rate of false negatives. There are numerous lesions where an easy wedge resection or TTNA cannot be carried out, and lobectomy followed by thorough pathological examination is required.

Method:
From April in 2010 through December in 2015, 30 patients with indeterminate lung tumors who underwent lobectomy (including 2 upper segmentectomy in the left upper lobe) followed by thorough pathological examination were reviewed. Right middle lobe lesion was excluded in this study.

Result:
Sixteen were men and 14 were women. The median age of the patients was 67 years with a range of 24 to 85 years). According to the size and location of the lesion, each case was classified in two patterns: deep nodule (18 patients, locates centrally, inner two thirds from the lung surface) or mass (12 patients, greater than 30mm in diameter). Tumor located in the right upper lobe/ right lower lobe/ left upper lobe/ left lower lobe in 13 (deep nodule/mass: 8/5) / 4 (deep nodule/mass: 3/1) / 7 (deep nodule/mass: 4/3) / 6(deep nodule/mass: 3/3) patients, respectively. Preoperative examination was chest computed-tomography/F-18 FDG PET/transbronchial biopsy through bronchofiberscopy in 30/24/19 patients, respectively. Pathological diagnosis were as followings: 25 primary lung cancer (13 adenocarcinoma, 1 adenosquamous cell carcinoma, 1 mucoepidermoid carcinoma, 4 bronchiolo-alveolar varcinoma, 1 pleomorphic carcinoma, 1 small cell carcinoma, 4 squamous cell carcinoma) / 1 inflammatory myoblastic tumor/ 1 metastatic carcinoma/ 1 organizing pneumonia/ 1 caseous granuloma/ 1 Non Tuberculous Mycobacteriosis(Mycobacterium xenopi). Pathological stages of primary lung cancer were stage IA/IB/IIB/IIIA/IV in 6/1/3/2/1/3 patients, respectively. Operative time was 110~304 minutes (median: 182.5 min), and intra-operative blood loss was 0~530ml (median: 60 ml). Post-operative drainage were 2~18 days (median: 3 days) and post-operative hospital stay was 5~23 days (median: 10 days). Post-operative complications of Clavien-Dindo grade grater than or equal to II occurred in 6 patients (II/III: 3:3), all of them resolved conservative therapy.

Conclusion:
Diagnostic lobectomy followed by thorough pathological examination were carried out safely with acceptable range of postoperative complications.

Background:
Pulmonary lymph flows are predominantly regarded to run along bronchi. In addition, limited resections such as segmentectomy are increasing recently. However there are some cases suggesting alternative lymph pathways, such as the skip metastases. We herein observed pleural lymph flows by the indocyanine green (ICG) fluorescence method with a near-infrared camera device in patients who underwent lung resections.

Method:
After thoracotomy, we injected ICG to subpleural spaces of the lung lobe that planned to resect in 100 cases. Intraoperative fluorescence images were observed in real time using a near-infrared camera. Patients with pleural involvement were excluded.

Result:
In 58 out of 100 cases, ICG movements were observed in subpleural space. In 18 cases, ICG flowed into adjacent lobes over the interlobular line. In 5 cases, ICG flowed into the mediastinum directly. Subpreural lymph flow detection rates were significantly lower in patients with smoking pack-year >40 than those with pack-years <40.

Conclusion:
In our study, in more than half of the cases, pleural lymph flows were observed and there were lymph flows that flowed into the mediastinum directly. In addition, the reduction of subpleural lymph flows in smokers with >40 pack-year suggests that smoking might modify lymph flow patterns. In the future, these findings may help us to select appropriate procedures for patients with possible skip metastasis.

Background:
Preoperative trans-bronchial biopsy and/or computed tomography (CT)–guided biopsy inevitably disrupt lung structure and might disseminate tumour cells into airway, vessels or the pleural cavity. Because preoperative diagnostic intervention may potentially disperse tumour cells, it may affect relapse and/or prognosis.

Method:
The data from the consecutive patients with cTanyN0M0 lung cancer who underwent surgery between January 2006 and December 2012 at our institute were extracted by chart review and analysed retrospectively. Prognostic factors of overall and recurrence-free survival were compared among the groups (the trans-bronchial biopsy group, the CT-guided biopsy group and the intra- or postoperative-diagnosis group) by using the univariate and multivariate Cox proportional hazard model. A stepwise backward elimination method with a probability level of 0.15 was used to select the most powerful sets of outcome predictors. A p-value <0.05 was considered statistically significant.

Result:
Data from 397 patients were available for analysis (the trans-bronchial biopsy group: 221, the CT-guided biopsy group: 71 and the intra- or postoperative-diagnosis group: 105). Solid tumour size was larger in the trans-bronchial biopsy and/or the CT–guided biopsy than the intra- or postoperative-diagnosis group (p = 0.0001). In the crude analysis, the trans-bronchial biopsy group and the CT-guided biopsy group showed higher probability of pleural dissemination (p = 0.048) and showed worse prognosis than the intra- or postoperative-diagnosis group (overall survival: p = 0.0458, recurrence-free survival: p = 0.0101). However, the method of diagnosis was not identified as an independent risk factor for pleural dissemination and overall and recurrence-free survivals by multivariate analyses. Figure 1



Conclusion:
Preoperative diagnostic intervention did not affect relapse and/or prognosis in this study cohort. Preoperative diagnostic intervention is recommended if necessary.

Background:
Locking of scapula is rare complication of rib resection or thoracotomy. The patients experience severe pain and restriction of movement in their shoulder, and they are treated conservatively or surgically.

Method:
A 72-year-old woman underwent right upper lobectomy and extended combined resection of the posterior chest wall (via a standard posterolateral thoracotomy and resection of the 2nd to 4th ribs), to treat a stage3A lung cancer. Chest wall reconstruction was not performed. Her immediate postoperative course was uneventful, she was discharged from our hospital on 7th operative day. One year after operation, severe pain appeared in her right shoulder while she put on her underwear. She was referred to our hospital.

Result:
Physical examination revealed that resting pain was not so severe, but the range of shoulder motion was restricted due to severe pain. We suspected that the inferior angle of the scapula was caught inside the 5th rib. Chest x-ray showed that scapula prolapsed into the intrathoracic cavity through the resection site in the right chest wall (figure). The manipulative closed reduction was successful, then her symptoms were resolved. We advised her to pay attention to her right shoulder movement especially in over 90 degrees abduction. Five month later, no recurrences were observed. Figure 1



Conclusion:
As to rib defects like this case, the necessity of the reconstruction is controversial because the defect is completely covered by scapula. Moreover scapular prolapse into the intrathoracic cavity is rare and implants have a potential to infection. We conclude that the partial resection of the inferior angle of the scapula should have been performed at her operation in order not to be caught inside the rib.

Background:
We report two rare cases of complete resection for endobronchial protruded tumors.

Method:
Case 1; a-46-year old man with a history of several pneumoniae consulted us because of chest X-ray abnormality. A chest-CT showed atelectasis at medial segment of the right lung with bronchial obstruction. Case 2; a-68-year-old woman was referred to our hospital for persistent couch. Enhanced CT scan showed an endobronchial tumor at basal segment of the right lung with peripheral atelectasis.

Result:
In case 1, bronchoscopic findings showed a smooth-surfaced polypoid tumor which occluded the medial bronchi of the right lung. An endobronchial biopsy was performed, and it suspected mucoepidermoid carcinoma. He underwent a right middle lobectomy with VATS. The tumor grew as an endobronchial polyp with 25mm in a diameter. On Histopathological findings, the tumor consisted of epithelial cells and myoepithelial cells with tubular or alveolar formation, and it diagnosed epithelial-myoepithelial carcinoma. In bronchoscopy in case 2, the basal segment bronchi were obstructed by a whitish endobronchial tumor, and it caused obstructive pneumonia. A biopsy from the tumor showed no evidence of malignancy. A right lower VATS lobectomy was performed. The tumor showed endobronchial growth without fibrous capsules. Spindle cells with mild atypia were scattered in the tumor. With immunohistological examinations (positive for smooth muscle actin and desmin, negative for estrogen receptor), the tumor was diagnosed as bronchial leiomyoma.

Conclusion:
Epithelial-myoepithelial carcinoma belongs to carcinomas of salivary-gland-type. Bronchial leiomyoma, arising from bronchial smooth muscle, should be distinguished from benign metastasizing leiomyoma. These tumors are usually covered with normal bronchial epithelium. Endobronchial biopsy is necessary for histological diagnosis. Bronchoscopic examination followed by surgical resection is recommended for endobronchial protruded tumors.

Background:
The lung is still pneumatized and we cannot take a broad view of the chest cavity. As for surgeons, the prediction of lung prolapse is valuable for surgical manipulations. We estimated the degree of the collapsed lung ten minutes after thoracotomy (collapsed lung index; CLI). We also evaluated the relationship between CLI and pre-operative pulmonary function test.

Method:
From December 2016 to June 2017, we included 38 patients undergoing video-assisted thoracoscopic surgery (VATS) without pleural adhesion. CLI was determined as the degree of collapse of the lung ten minutes after opening the first thoracic port. CLI definition was as follows; Grade 1: the distance between visceral pleura and chest wall was less than 1cm, Grade 2: the distance was less than 3cm, Grade 3: the distance was less than 5cm, Grade 4: the distance was more than 5 cm and the lung parenchyma was partially deflated, and Grade 5: the lung was completely collapsed.　We also checked the relationship between CLI and pre-operative pulmonary function test of the patients.

Result:
The patients are 47 years old to 83 years old. They consist of 25 males and 13 females. The numbers of CLI Grade 1 were 0 cases, Grade 2 were 4 cases, Grade 3 were 18 cases, Grade 4 were 14 cases, and Grade 5 were 2 cases. VATS were easily undergone with broad surgical view Grade 4 and Grade 5. The 42% of the cases are included in CLI Grade 4 and Grade 5. The mean value of %VC was 102.6 %, FEV1.0G was 76.8 %, and FEV1.0% was 100.3 % in Grade 4 and Grade 5 patients. The preoperative pulmonary function tests were better in Grade 4 and 5 than the other Grades.

Conclusion:
We proposed CLI to estimate the surgical views at the beginning of VATS. The preoperative pulmonary function will predict the surgical field. We are waiting for some methods to deflate the lung in CLI Grade 1, 2, and 3 to Grade 4 or 5. The complete collapsed lung should make a good contribution for Single port VATS.

Background:
No large series of oncologic emergencies in thoracic surgery has been reported. Such patients are usually in critical condition and need immediate intervention of various types. Here, we present the surgical interventions that have occurred in our experience with oncologic emergencies.

Method:
We retrospectively analyzed 28 patients with oncologic emergencies who underwent surgical intervention at our hospital in 2002‒2016. The mean patient age was 76 years, and there were 19 (68%) males and 9 (32%) females. The primary disease was primary pulmonary carcinoma in 13 cases, including adenocarcinoma and squamous cell carcinoma in 4 and 6, respectively, other-organ carcinomas in 12, and mediastinal tumors in 3. Airway stenosis was the complaint in 19 (68%), including hemoptysis in 2, superior vena cava syndrome in 3 (11%), infectious diseases in 2 (7%), tumor bleeding in 2 (7%), and pneumothorax in 2 (7%).

Result:
The goal of surgery was a radical operation in 8 (29%), biopsy in 3 (11%), and palliative therapy in 17 (60%) patients. The surgical procedure was lobectomy in 4 patients, bronchoplasty in 4, wedge resection in 3, pneumonectomy in 1, tumor removal in 2, pleural decortication in 1, excisional biopsy in 4, airway intervention (stent or laser cauterization) in 11, and tracheostomy in 6. The mean hospital stay was 32±39 (range 3–155) days. The outcome was hospital death in 7 (25%) and discharge in 21 (75%). Of the discharges, 3 (11%) patients were transferred to another hospital, and 18 (64%) were sent home. The mean survival was 743±743 (range 3–3798) days. Of the 21 discharges, 7 (25%) patients are alive, including 4 (14%) who are cancer-free and 3 (11%) with cancer. As treatment, radical surgery was more effective than conservative therapy.

Conclusion:
The oncologic emergencies experienced in thoracic surgery included obstruction/stenosis, bleeding, infection, and rupture. Stenosis comprised the majority and was caused by tumor growth in the airway and compression and invasion by tumors. Good outcomes were expected in patients with slow-growing tumors who underwent laser cauterization or airway stent placement.

Background:
Postoperative chest tube drainage is essential in pulmonary surgery. After chest tube removal, the patient can be discharged from the hospital promptly. Therefore, it should be a close relationship between hospital stay and drainage duration. Removing chest tube in the early postoperative period leads to reduction of pain and early discharge from the hospital. However, there are few reports about removal chest tube on the first day after surgery. In this study, we examined cases where chest tube was removed on the first day after surgery.

Method:
From January to December 2016, 48 patients with lung cancer underwent lobectomy in our institute. They were consisted of 35 males, 13 females, and median age was 72 (53-87) years old. Among them, chest tube was removed on the postoperative day (POD) 1 in 24 patients (Group 1) and on the POD2 in 24 patients (Group 2). Patients complicated of postoperative lung fistula and infection were excluded.

Result:
Patients were discharged from the hospital on 5.4 days after surgery in Group 1 and on 5.6 days in Group 2. There was no significant difference between them (p=0.48). The CRP values on POD1, 2, and 3 were 5.49±2.38, 12.0±4.71, and 11.6±6.12 mg/dl in Group 1, and 7.27±3.28, 15.5±6.31, 12.9±5.87 mg/dl in Group 2, respectively (p=0.03, p=0.03, p=0.46). In addition, the period until CRP peaked out was 2.5 days in Group 1, and 2.1 days in Group 2. Group 2 showed obviously short period until CRP peaked out (p=0.03).

Conclusion:
Removing the chest tube on the first day after surgery will not lead to an early hospital discharge, conversely it will prolong the inflammatory response such as CRP.

Background:
Isolated fibrinogen deficiency is rare disease in Korean; especially extremely rare in patient with preoperative normal level of PT/aPTT.

Method:
I present a 62-year-old female patient who was admitted with lung cancer (adenocarcinoma, RUL, cT2aN0M0). She underwent VATS right upper lobectomy with mediastinal lymph node dissection. During operation, there was no need for transfusion (EBL 200cc) and no evidence of hemodilution.

Result:
On the first postoperative day (POD), PT was prolongated over 100 seconds (INR was over than 10). Coagulating factors were evaluated and isolated fibrinogen deficiency was diagnosed. As serum level of fibrinogen was fallen below 40mg/dL, spontaneous bleeding such as subcutaneous hemorrhage on trunk and persistent minor air leakage was observed. Bleeding tendency and air leak was improved since repeated transfusion of cryoprecipitate made the serum level of fibrinogen over 60 mg/dL. On POD 24, she was discharged without complication, however, she still had low level of fibrinogen. Although she was stable without any signs of spontaneous bleeding and prolongation of PT, the serum level of fibrinogen was still low around 60mg/dL at last visit in out-patient clinic which needed intermittent transfusion of cryoprecipitate. Figure 1



Conclusion:
She refused genetic evaluation for fibrinogen deficiency and I still don’t know what caused isolated fibrinogen deficiency in this patient, which could lead to a critical situation. To prevent any other disaster caused by this, I think there needs countermeasure for this.

Background:
The lung contains a large volume of air and have thus been unsuitable for observation with ultrasound. However, recent advancements in ultrasound have enabled the diagnosis of pneumothorax and tumor invasion of the chest wall, and fine-needle aspiration of tumors abutting the pleura can now be performed using ultrasound. Here, we investigated whether ultrasound is capable of predicting internal tumor properties.

Method:
TOSHIBA aplio 400 was used. Of 64 patients with tumor lesions undergoing preoperative ultrasound at our hospital between June 2015 and April 2017, we investigated 42 patients in whom internal tumor properties were visualized before surgery. There were 27 men and 15 women; 37 patients had malignant and 5 had benign lung tumors. Solid components were present in the tumor in 25 patients, liquid components in 3, a cavernous lesion in 9, a ground-glass opacity (GGO) lesion in 4, and pulmonary sequestration in 1. The tumor diameters ranged from 0.7 to 10.4 cm (median, 2.4 cm), and the distances from the lung surface ranged from 0 to 8.9 cm (median, 0.57 cm).

Result:
Ultrasound was useful for identifying an anomalous vessel originating from the aorta in a case with pulmonary sequestration. According to internal tumor properties, lesions containing a large volume of air (cavernous or GGO lesions) were visualized as hyperechoic areas, while many solid lesions appeared hypoechoic with a hyperechoic periphery on images. The posterior echo was enhanced in tumors containing liquid components and also in many cases with benign tumors. Thus, ultrasound is potentially useful for determining whether tumors are malignant or benign before surgery.

Conclusion:
Although ultrasound was not capable of visualizing the internal tumor structures in all cases, the internal tumor structure, if visualized by ultrasound, could be assessed. Moreover, ultrasound has the potential for differentiating benign from malignant tumors. Our results suggest that ultrasound merits future study, with further accumulation of cases.

Background:
“Peripheral” is ubiquitously used in thoracic surgery literature, but definitions differ. Our purpose was to ascertain opinions of thoracic surgeons on CT images and assess the frequency of peripheral nodules according to their definitions.

Method:
We developed a survey and obtained an IRB exemption. Surgeons were asked to choose one of methods A-D to define the peripheral pleura: A=costal pleura, B=costal and mediastinal pleura (diaphragmatic pleura also on coronal and sagittal views), C=costal and fissural pleura, D=any pleural surfaces on: Question#1) axial images, Question#2) coronal images, Question#3) sagittal images. Question#4 asked whether the peripheral lung was: 1, 2, or 3 cm, outer 1/3, outer 1/2 or outer 2/3. Question#5 asked whether the measurement from the nodule to the pleura started at the inner edge, center, or outer edge of the nodule. By applying the possible choices to a database of 76 patients with documented lung cancer we determined the frequency of peripheral cancers for each combination.

Result:
Ten thoracic surgeons participated, all had different answers. The most frequent response to Question#1 was Method A (n=4), Question#2 Method A (n=5), and Question#3 Method B (n=4). The most frequent answer for Question#4 was the outer 1/3 of the lungs (n=6), and for Question#5, the outer border of the nodule, closest to the relevant pleura (n=5). The frequency of nodules classified as peripheral according to these answers ranged from 13% (10/78) to 91% (71/78).

Conclusion:
There was no consensus. Standardization and rationale for this would be highly useful.

Background:
With the increase in number of individuals undergoing CT screening, lung cancers are now being detected at an earlier stage. Curative treatment can thus be performed on these patients, resulting in better lung cancer survival. Effective surgical decision making depends upon the degree of knowledge and experience the treating surgeon has about the outcome of actions, ability to assess risk and its subsequent impact. Use of a gnostic expert system would increase cost-effectiveness and efficiency. Our objective is to garner experts’ tacit knowledge about surgical decision making in a form of probability function.

Method:
Nine surgeons with extensive experiences in thoracic surgery were presented with a set of hypothetical cases, specified by indicators for surgical treatment (lobectomy or limited resection). Their choice of surgery and probability of performing limited resection were recorded for each case. Probabilities were translated into a logistic probability function for limited resection by 1) taking logits of the probabilities: Y=log[P/(1-P)], then 2) applying a general linear model for the mean of Y, Ŷ=β~1~+ β~2~X~2~+ β~3~X~3~+ β~4~X~4~+ β~5~X~5~+ β~6~X~6~+ β~7~X~7~ + ε. Standardized coefficients were computed and ranked to determine the effect of each indicator on limited resection.

Result:
Across the 24 cases, the median probabilities of limited resection among experts ranged from 0.0% to 100.0%, their case-specific IQR had values from 5 to 90 (Q3-Q1) percentage points, and ranges had values from 10-100(max-min) percentage points. Considering the expert-specific median probabilities, five out of eight experts favored lobectomy (median probabilities of limited resection ≤12.5%). Two other experts had median probabilities of 42.5% and 49% while the remaining expert favored limited resection (median probability 65%). The effect of each indicator on preferring limited resection over lobectomy varied between surgeons. Overall, distance from relevant pleura and nodule size were important factors for considering limited resection.

Conclusion:
There was great inter-surgeons variability on surgical decision making. Garnering experts’tacit knowledge on surgical decision making will enhance efficiency of health care and potentially change surgical practice.

Background:
Digital drainage system (DDS) has been recently recognized as a useful device in postoperative chest drainage. However, there is no past study predicting the efficacy of pleurodesis using DDS for postoperative air leak. The aim of this study is to identify predictive factors of the efficacy of pleurodesis including the observed data in DDS log.

Method:
The 857 patients underwent pulmonary resection and were made use of DDS for chest drainage postoperatively from January 2015 to December 2016. We retrospectively reviewed clinical database and log data of DDS, and compared the patient who stopped postoperative air leak by single pleurodesis with the patient who needed two or more pleurodesis. Fisher’s exact test was used to compare categorical values, and Mann-Whitney U test was used to analyze continuous values. The cut-off values were decided by receiver operating characteristic curve.

Result:
The 40 patients underwent pleurodesis for postoperative air leak. The median age was 70 years (range, 51 to 86), and 83% of patients were men. The most common type of surgery was lobectomy (90%). Postoperative air leaks in the 23 patients (58%) were stopped by single pleurodesis, and those in the 17 patients (42%) needed pleurodesis more than two times to stop air leak. The predictive factors to stop air leak by single pleurodesis were lower air leak flow at the time of pleurodesis (P = 0.02), and lower average of air leak flow for 24 hours before pleurodesis (P = 0.05). The cut-off value of air leak flow was 100 ml/min, and average of air leak flow for 24 hours was 130ml/min.

Conclusion:
Air leak flow at the time of pleurodesis and the average for 24 hours in DDS log were useful predicters of stopping air leak by single pleurodesis.

Background:
Recently, the improvement of ability of Computed tomography (CT) scans permits us to identify a large number of small peripheral, undefined pulmonary lesions that require a diagnosis. Although the large majority of these cases are benign, diagnostic approaches to discriminate benign nodules from malignant nodules remain most-unsatisfactory.　 So we often have to perform thoracoscopic resection with the primary objective of diagnosis. In this study, we examined the clinicopathological findings in the cases of indeterminate pulmonary nodules in which thoracoscopic or open excisional biopsy was performed.

Method:
From a single institutional database, a total of 253 patients diagnosed with lung cancer or suspected lung cancer underwent resection between January 2014 and March 2017. In 155 patients, a histological diagnosis was not obtained preoperatively. This study was intended for 108 patients diagnosed with lung cancer after surgery among the 155 indeterminate pulmonary nodules.

Result:
Out of 155, 108 patients were diagnosed as primary lung cancer by intraoperative frozen section or postoperative pathological examination. Twenty-six patients were diagnosed as metastatic lung tumors, and 21 patients were diagnosed as other, such as benign inflammatory changes. Surgical resection of indeterminate　lung　nodules (mean diameter 20.6mm, range 3 to 53 mm) were performed in 108 primary lung cancer cases, which represented 52.4% of the 206 resections for lung cancer performed during the study period. There were 57 men and 51 women with an average age of 70.6 years old (47-91 years old). A biopsy needle (13cases) or wedge resection (61cases) was used to the methods of intraoperative diagnosis. The remaining 34 cases performed a final pathological examination after surgery without intraoperative diagnosis. Nineteen small pulmonary nodules that include ground-glass attenuation required preoperative computed tomography-guided lipiodol marking to identify the position of a nodule. The postoperative stage was 0 in 17 patients （16％）, IA in 66 （61％）, IB in 11 （10％）, IIA in 1 （1％）, IIA in 3 （3％）, IIIA in 8 （7％）, and IV in 2 （2％）.

Conclusion:
The small pulmonary nodules that include ground-glass attenuation are tricky to diagnose. When CT findings are highly suggestive of lung cancer, we think that positive lung biopsy under thoracoscopic surgery is necessary to detect lung cancer.

Background:
Pulmonary carcinoids (PC) are rare malignant neuroendocrine tumors with indolent course. It is estimated that PC overall encompass 1% to 5% of all lung neoplasms. The surgical resection is the preferred treatment modality but the indolent nature of the disease makes interpretation of survival numbers problematic.

Method:
Aims: We report a single institution experience with PCs over a 17-year period to gain a better understanding of prognostic factors related to the management of these rare tumors. Material and Methods: Patients who underwent operations for primary pulmonary carcinoid tumor at National Tuberculosis and Lung Diseases Research Institute in Warsaw, Poland between 1998 and 2015 were identified from the database. Their medical records were reviewed for clinical presentation, tumor spread, pathology, treatment modalities, and survival.

Result:
There were 329 cases of PCs: 217 (66%) typical (TC) and 112 (34%) atypical (AC) carcinoids, with a median follow-up time of 7,6 years. There were 230 females (69,9%) and 99 males (30,1%). The most common symptoms were cough (38,7%), dyspnea (15,9%) and hemoptysis (14%). No patients showed a carcinoid syndrome. There was no correlation between smoking status and PCs. The majority of patients were in stage I disease (67,4%), only 6,4% in stage III and IV (6,4%). Involvement of lymph nodes was present in 49 cases (14,9%), N1 -34 (10,3%) and N2 – 15 (4,6%). Infiltration of bronchial or vessel margin (R1) was revealed in 10 cases (3%). Surgical treatment consisted of: 247 lobectomies (75,1%), 30 pneumonectomies (9,1%), 36 bilobectomies (10,9%), 5 anatomic segmentectomies (1,5%), 8 wedge resections (2,4%), 3 – bronchoplastic procedures without lung resection (0,9%). Radical mediastinal lymphadenectomy was added in all cases. The number of death among the patients with TC and AC was 7 (6,3%) and 31 (14,3%) respectively. Kaplan-Meier 1-, 5-, 10- and 15-year overall survivals for the entire group were 98,8%, 92,8%, 86,8% and 78,6% respectively.

Conclusion:
• PCs are tumors with an excellent prognosis, even in the presence of metastases in lymph nodes and positive surgical margin. • None of the symptoms and stage of tumors as well as the distance of the tumor from the surgical margin did not affect significantly the overall survival. • The age of patients, the type of operation and performance status (ECOG score) had vital importance for overall survival. • Surgical resection is the best and adequate therapy for PCs with high overall survival and disease-free survival but long-time observation is necessary.

Background:
Inadvertent phrenic nerve injury (PNI) during lung cancer surgery is not well-studied. It is not always easy to make a clear-cut diagnosis with routine methods. Very few cases have been reported in literature. The aim of our study is to find an easily accessible and precise way to diagnose PNI and then to evaluate the incidence and its impact in early-stage lung cancer patients undergone minimally invasive surgery.

Method:
The first step was to examine the extent of diaphragm elevation in patients with invasive thymomas in whom phrenic nerve was certainly divided. The distance between the diaphragm and the apex of the chest was calculated on chest X-Ray before (DB: Distance before) and after (DA: Distance after) surgery. The following formula was used: [(DB-DA)/DB]x100. The result (mean+SD) was used as criteria for diagnosing PNI. The second step was to study PNI in early-stage lung cancer patients undergone VATS lobectomy using the above criteria.

Result:
Diaphragm elevation was found to be 24.24 +/- 6.2% in 22 invasive thymoma-patients and therefore, 30% was adopted as criteria for the diagnosis of PNI. Among 567 consecutive patients with early-stage lung cancer recruited from January 2014 to December 2016, 43 (7.6%) were diagnosed to have PNI (Table 1). No correlation was detected between PNI and location of the lesion or extent of lymph node dissection. Neither was there any difference in post-operative complications or length of hospital stay. But comparing spirometry data before and 6 months after surgery, reduction in FEV1, FVC, and DLCO was significantly greater in patients with PNI.Figure 1



Conclusion:
We found an easily accessible way to diagnose precisely PNI in lung cancer patients receiving VATS lobectomy. Inadvertent PNI during minimally invasive surgery seems to be underestimated, and it is associated with significant reduction in pulmonary function of the patient.

Background:
Poor pathologic nodal staging impairs overall survival (OS) after curative-intent surgical resection of NSCLC. We implemented a LN collection kit and previously demonstrated how it improves pathologic nodal staging. We now report its survival impact.

Method:
Using a prospective step-wedge design, kits were implemented for curative-intent surgical resections from 2009-2017 in 11 hospitals within 4 contiguous US Dartmouth Hospital Referral Regions. OS was analyzed with the Kaplan-Meier method. Crude (HR) and adjusted (aHR) hazard ratios with 95% confidence intervals (CI) are presented from Proportional Hazards Models adjusted for clustering by surgeon. Covariates in adjusted models include: age, sex, histology, tumor grade, extent of resection, T and M categories, and number of comorbidities.

Result:
The LN kit was used in 734 of 2,547 (29%) resections. All demographic and clinical characteristics, including age, sex, race, health insurance coverage and preoperative stage distribution were similar between kit and non-kit cases. Aggregate 1, 3, 5-year OS: 89%, 74%, 66%(kit) vs. 83%, 65%, 53% (non-kit) (p< 0.0001, Fig.1). Clinical stage stratification (kit v non-), 5-year OS: I, 68% vs. 58%, (p-value=0.0038); II, 68% vs. 40%, (p=0.0045); III, 57% vs. 42%, (p=0.0412). Pathologic stage stratification (kit v non-) 5-year OS: I, 72% vs. 59% (p=0.0082), II, 60% vs. 44% (p=0.0403); III, 48% vs. 36%, p =0.0179). For both clinical and pathologic Stage IV, survival did not differ. Kit cases had a 30% lower hazard of death compared to non-kit cases: HR 0.67 (CI[0.55,0.80], p<0.0001) and aHR: 0.70 (CI[0.54,0.92], p<0.0001). Results remained statistically significant after multiple sensitivity analyses excluding sub-lobar resections, 60-day mortality, non-adopting surgeons, and excluding the 48 months of retrospective baseline control data (aHR: 0.28 to 0.73). Operating time, perioperative complication rates, and duration of hospitalization were similar between groups. Figure 1



Conclusion:
Intraoperative specimen collection with a LN kit improves long-term NSCLC survival.

Background:
With the recent advances of diagnostic imaging modalities such as high-resolution computed tomography (HRCT), the detection rate of multiple synchronous lung cancer with ground-glass opacity (GGO) has increased. In clinical practice, preoperative pathological diagnosis of GGO lesions by transbronchial biopsy is difficult. It is necessary to develop the optimal surgical strategy that achieves both accurate diagnosis and curative resection. We recently encountered three cases of synchronous multiple lung cancer with GGO.

Method:
Case 1: A 68-year-old male had abnormal shadows detected on chest computed tomography (CT). HRCT showed a 3.5cm-in-diameter part-solid nodule in the right upper lobe (RUL), a 2.5cm-in-diameter part-solid nodule in the right lower lobe (RLL), and a 1.5cm-in-diameter pure ground-grass nodule (GGN) in the left lower lobe (LLL). Thoracoscopic right upper lobectomy and right S6 segmentectomy was performed. The histopathological diagnosis of the RUL tumor was well-to-moderately differentiated adenocarcinoma and RLL tumor was well differentiated adenocarcinoma. These tumors were found to harbor different epidermal growth factor receptor (EGFR) gene mutation. The LLL tumor is followed up by CT scan. Case 2: A 71-year-old female had an abnormal shadow incidentally detected on chest radiography. HRCT showed a 1.0cm-in-diameter pure GGN in RUL and a 3.0cm-in-diameter part-solid nodule in left upper lobe (LUL). To achieve a minimal invasive approach for bilateral lesions, we planned to perform staged bilateral surgery that the limited resection precedes the anatomical resection. Thoracoscopic wedge resection of RUL was performed as the first operation, then thoracoscopic left upper lobectomy was performed as the second. The histopathological diagnosis of both tumors were well-to-moderately differentiated adenocarcinoma with different EGFR mutation status. Case 3: A 68-year-old female had abnormal shadows detected on chest CT. HRCT showed a 1.5cm-in-diameter pure GGN in RUL and a 1.0cm-in-diameter pure GGN in LLL. Thoracoscopic wedge resection of LLL was performed as the first operation, then thoracoscopic right S3 segmentectomy was performed as the second. The histopathological diagnosis of the LLL tumor was well-to-moderately adenocarcinoma and the RUL tumor was well differentiated adenocarcinoma.

Result:
All three cases had an uneventful postoperative course with no evidence of recurrence.

Conclusion:
In case of multiple tumors, we decide surgical procedures based on the size, number, location, and radiological findings of the tumors. We select combination surgery with anatomical resection and limited resection, and avoid bilobectomy if possible. Additionally, the thoracoscopic approach for multiple lung cancer seems to be a good option to perform minimally invasive surgical procedures.

Background:
Malignant melanocytic neoplasm is a highly malignant tumour derived from melanocytes. It occurs most commonly in the skin and mucous membranes while occurrence in the mediastinum is extremely rare.

Method:
Section not applicable

Result:
Section not applicable

Conclusion:
We report a case of a young female who presented with shortness of breath and chest tightness. Further imaging revealed a large anterior mediastinal mass with compression of the pulmonary vessels and a few lung nodules. A Chamberlain procedure was performed and showed a highly pigmented lesion. The histology returned as malignant melanocytic neoplasm. She was then started on pembro.

Background:
We have initiated a new multi-center, international collaborative cohort study, the Initiative for Early Lung Cancer Research for Treatment (IELCART), which focuses on identifying optimal treatment for early stage lung cancer An issue under discussion is the extent of surgery (i.e., sublobar resection and no mediastinal lymph node resection) in order to decrease the length and morbidity of the surgical procedure, preserves pulmonary function, and increases the likelihood of resection of future new occurrences of lung cancers. The role of Stereotactic Body Radiation (SBRT), and for certain cases, Watchful Waiting (WW) also needs to be better delineated. Increasingly, the power of large prospective databases collected in the context of clinical care is being recognized as providing important information.

Method:
Based on an extensive literature review, scientific articles, and a series of focus sessions with patients and treating physicians, a common protocol has been developed. Relevant data forms were developed for both physicians and patients, both for pre- and post-surgery to account for potential confounders. These forms have been tested and entered into a web-based data collection system that also includes relevant imaging data. Initial enrollment focused on surgery.

Result:
Initial enrollment was limited to surgical clinics of 8 surgeons and a total of 174 patients (94 women, 80 men) agreed. Average age was 67.5 years and pack-years of smoking was 31.4. Patients stated that the internet was the most frequent source of information (35%), while family/friends, medical literature were used much less frequently (each <20%). Factors influencing the patient pre-treatment choice was that the physician thought it was best (93%) or what would provide the best outcome (87%); only 38% got a second opinion. The surgeon’s choice of procedure depended mainly on the location (75%), size of the nodule (64%), and the ability to have negative parenchymal margin (40%), with other considerations being much less likely (<26%). There was good agreement between patients’ and surgeons’ perceptions of the procedure, although the patients not fully prepared about the post-treatment consequences of surgery. Patients also thought that support groups were important in patients’ decisions on what was the best surgery.

Conclusion:
These results together with quality of life information and focus sessions suggest that more support in the post-operative phase of the treatment would be beneficial. Within the next 3 years, we anticipate to have statistically meaningful results to start to compare outcomes of alternative treatments.

Background:
Radiologists focus on the anatomic changes in the lung itself when interpreting postoperative surveillance CT scans, but the anatomic and physiologic effects of lung resection on the other organs of the thorax, specifically the pulmonary artery (PA), have not been well studied. Potential variations in PA size over time have been recognized as predictors of post-surgical complications and the development of pulmonary hypertension.

Method:
The International Early Lung Cancer Action Program (I-ELCAP) database was queried for lung cancer patients who underwent lobectomy and had both preoperative and postoperative CT imaging. Case-specific details were previously recorded in the database as per I-ELCAP protocol. All surgeries were performed by general thoracic surgeons. All CT imaging for each patient was reviewed by a fellowship-trained chest radiologist. Figure 1



Result:
Among the 142 subjects who underwent lobectomy, the median follow-up time from the pre-surgical CT to the last reviewable CT was 53.2 months (IQR: 27.9-100.4 months). The average increase in the size of the main pulmonary artery (mPA) was 1.5 mm (19.9 mm to 21.4 mm, P < 0.0001). There was also a significant increase between the pre-surgical CT and the initial postoperative CT which was on average 12.6 months later from 19.9 mm to 20.7 mm (P = 0.0002). Considering patients with and without CT evidence of emphysema, the 82 with emphysema had a smaller average change of the main PA between the pre-surgical and the last reviewable CT than the 60 without emphysema (1.0 mm vs. 1.8 mm, P = 0.08).

Conclusion:
Patients undergoing lobectomy appear to be at increased risk for enlargement of their pulmonary artery diameters after surgery. These results show that a focus on all the organs in the thorax, not just the lungs themselves, is important when evaluating postoperative lung resection CTs.

Background:
The anatomic and physiologic effects of lung resection for early stage lung cancer patients have not been extensively reported. We hypothesize that patients who have undergone lobectomy or wedge resection will have reduced lung volume on the affected side immediately after surgery while the lung volume on the opposing side may increase to compensate.

Method:
The Mount Sinai database was queried for stage 1 lung cancer patients who underwent lobectomy or wedge resection and had both pre-operative and postoperative CT imaging. Surgeries were performed by thoracic surgeons. The lung volumes on all CT scans were measured using previously published research software including actual volumes for each lung (left and right) at each time point as well as a set of volumes normalized to the overall chest volume in order to compensate for differences in inspiration.

Result:
In the cohort of 21 patients who met the above criteria, the median follow-up time from the date of surgery to the most recent CT was 44.6 months (IQR: 23.5-94.7 months). The median age was 63 and the median pack years was 40. There were 2 patients for which only one post-op scan was successfully analyzed; the remaining cases all had two postop scans. In 20 of the 21 patients, the lung volume on the side where the surgery occurred was reduced in the first postop CT scan (average reduction in volume of 5.6%). The change in volume of the contralateral side (not undergoing surgery), was highly variable, with 11 cases showing an increase in volume on both post-op scans, 2 cases showing a decrease, and 8 cases showing an increase in volume at the first postop scan followed by a decrease in volume on the second post-op scan.

Conclusion:
Stage 1 lung cancer patients undergoing resection have reduced lung volume on the side of surgery, however there was marked variability in the contralateral lung suggesting that the extent to which patients compensate post operatively is complex and dependent on many factors.

Background:
A solitary pulmonary nodule (SPN) is a common and increasing clinical problem, mainly due to the lung cancer (LC) screening programs and easier access to complementary diagnostic tests. Differential diagnosis is broad and often challenging for decision making, particularly in small and not accessible lesions. The process of selecting the right strategy must address the probability of malignancy, nodule characteristics observed on CT/PET-CT, patient preferences and institutional-related expertise. The aim of this study was to evaluate the accuracy of the multidisciplinary lung cancer tumour (MLCT) board team in the management of SPN.

Method:
We retrospectively reviewed all SPN patients who underwent surgical resections between January 2015 and March 2017. All patients were evaluated at a MLCT meeting. We characterised demographic, clinical and radiological features, surgical procedure, histology and outcomes.

Result:
We included 73 patients, 37 male (50.7%), with a mean age of 63.3±10.2, 64.4% smokers (current or former) and none with asbestos/radon exposure. Twenty-five patients (34.2%) had previous history of cancer and 5 (6.8%) of tuberculosis. Emphysema was present in 21 patients (28.8%). Fifty-six were solid SPN (6–20 mm) and 17 subsolid SPN (9-18 mm): 15 with solid component (2-13.5 mm) and 2 pure ground glass nodules (10 and 12.3 mm). Of the 73 patients, 11 (15.1%) had a definitive histological result before the surgical intervention: 10 LC and 1 metastasis. Among patients without diagnosis (n=62), frozen section was performed in 45 patients (61.6%): 31 of these (70%) were malignant disease (25 LC and 6 metastasis) and 14 were benign lesions. In this group, we performed 17 lobectomies, 15 anatomic segmentectomies and 13 wedge resections. All patients with LC underwent mediastinal lymph node dissection (MLND). Among the 25 patients with LC, 7 were adenocarcinoma in situ and 18 invasive lesions (17 in stage I). In the other 17 cases without previous diagnosis, a direct surgery was performed, based either on the location of the lesion, size or clinical suspicion. Twelve of these patients (70.6%) were confirmed to have LC in the final pathology evaluation (all invasive LC in stage I). They underwent an upper bilobectomy, 10 lobectomies, 3 anatomic segmentectomies, all with MLND, and 3 wedge resections. No major complications were reported.

Conclusion:
This study suggests that surgery is a safe strategy in the diagnosis and treatment of SPN without previous diagnosis.

Background:
Sarcomas are known to be malignant and aggressive tumors, and often develop multiple pulmonary metastasis. Although systemic therapy is a treatment of choice for metastatic lung tumors, effective treatments have not yet been established. Surgical resection for metastatic lung tumors is a therapeutic option to control the disease, while it is not a curative therapy.

Method:
Between 2006 and 2014, 129 sarcoma patients who underwent pulmonary metastasectomy in Okayama University Hospital were retrospectively reviewed. In total, 229 pulmonary resections were performed. We analyzed the following factors: age, sex, site of primary lesion, histology, operative procedures, size of the largest lesions resected, maximum number of the resected tumors, postoperative complications, and survival rate.

Result:
In total, 939 metastatic nodules were resected. Average number of tumors per intervention was 4.1 (range 1-19). These sarcoma patients consisted of 31 males and 98 females, and their average age was 53.6 years (range 14-80 years). Leiomyosarcoma was the most common histological subtype (n = 72, 55.8%) and uterus was the most common location of the primary disease (n = 55, 42.6%). Operative procedures were composed of 173 partial resections, 31 segmentectomies with or without partial resections, 24 lobectomies with or without partial resections, and 1 basal segmental auto-transplantation after pneumonectomy. The postoperative complications were limited, showing that pulmonary metastasectomies for sarcomas are acceptable. Overall 3-year survival after the first pulmonary metastasectomy was 49.5%, and the survival was significantly better for the group with disease-free interval of more than 2 years or the size of the largest resected lesion less than 30 mm.

Conclusion:
Surgical resections for metastatic lung tumors of sarcoma were performed without major complication, indicating acceptable feasibility. If disease-free interval is more than 2 years and the size of the largest resected lesion is less than 30 mm, patients may maximally benefit from surgical resection.

Background:
After pulmonary resections, one or two chest tubes are used, and the choice is based mainly on local habits rather than on evidence. The aim of the study was to evaluate the efficacy of chest drainage after lung resection using single chest tube versus two chest tubes in patients with non-small cell lung cancer (NSCLC).

Method:
Single-centre prospective randomized trial including patients who underwent anatomical lung resection for NSCLC between February 2016 and may 2017. At the end of the operation, patients were randomized in a 1:1 ratio, to the single tube group or to the two tubes group. On the day of surgery, controlled suction of -20 mmHg was used, switched on the 1st postoperative day to -8 mmHg. Chest tubes were removed in the absence of air leak for more than 24 hours, and the chest tube output <250 mL/day.

Result:
There were 357 patients enrolled, including 219 men, mean age 64.43 years (range: 22-84) and 138 women, mean age 64.06 years (range: 24-85). One chest tube was used in 176 patients, including 50 cases of VATS lobectomy and 126 cases of open lobectomy. Two chest tubes were used in 181 patients, including 35 patients after VATS lobectomy and 146 after open lobectomy. In the single chest tube group there was significantly shorter air leak time (4.25 vs. 4.5 day; p = 0.001, drainage time (3.6 vs 4.7 day; p = 0.0001), and postoperative hospital stay (6.15 vs 7.5 day; p <0.0011. Multivariate regression analysis demonstrated that time of chest tube drainage after cessation of the air leak depends on the volume of chest tube output in the first 6 hours (p = 0.00001) and the time of air leak (p = 0.0014), regardless of the number of drains.

Conclusion:
Single chest tube after anatomical lung resections is associated with shorter air leak, shorter drainage time, shorter hospital stay compared to two chest tube drainage. Routine use of single chest tube is safe and effective treatment.

Background:
The ability to constantly metastasize remains a truly challenging obstacle for cancer patients . Historically in the past , any local surgical treatment in patients with systemic malignant disease is considered without any prognostic benefit , this has since evolved with many studies confering huge success rates with excellent prognostic benefits . We hereby report our experience over the last 5 years at Wellington Regional Hospital , Cardiothoracic unit .

Method:
A retrospective study was undertaken in series of cancer patients with colorectal , melanoma , breast , sarcoma & renal metastatic disease undergoing pulmonary metastasectomy , from year 2011 to 2015 . These data was identified & stratified into groups using hospital patient database & ORSOS theatre database

Result:
Total of 61 patients had pulmonary metastatectomies in 5 years , of which 14 were done via VATs wedge resection .Population age between 34 to 86 years old with a M: F ratio of 2:1 . Average age was 63 years . A further 4 patients had multiple metastatectomy on ipsilateral side . 45 patients were non-smoker in this cohort . Average in-hospital stay was 7.83 days , with 3 patients requiring post op ICU admission . 47 patients had pre-op epidural catheter for pain management . Complications include 6 patients needing to return to theatre for suspicion of lung torsion , bronchopleural fistula , haemothorax and 3 patients had torrential air leaks .No major complications noted . Majority had colorectal & melanoma metastases . No mortality at 30 days . 87% survived at 1 year . Total of 38 patients are still alive at present .

Conclusion:
Using MDM as a tool , these carefully selected surgical patients underwent pulmonary metastasectomy for metastatic diseases which confers continual prognostic & survival advantage in this group . Overall 1 year survival seems resonable & surprisingly excellent given the overall bad prognosis of metastatic disease in general .

Background:
Lung cancer is the leading cause of cancer death in New Zealand, resulting in over 1600 deaths per year. Indigenous New Zealanders (Māori) have a higher lung cancer mortality rate than non-Māori (Female RR 4.3, Male RR 2.8). Data from our local thoracic multidisciplinary meetings (MDM) was presented to our regional cancer network (Northern Regional Alliance) and identified that only 9% of Māori lung cancer patients received curative intent surgery compared to 18% of New Zealand Europeans. The Treaty of Waitangi is a founding document of New Zealand that defines the relationship between Māori and the British Crown and gives responsibility to the New Zealand government to reduce inequities in health. The aim of this audit was to review the documented reasons for not proceeding to surgery in Māori lung cancer patients.

Method:
Electronic clinical records were retrospectively reviewed for the 100 identified Maori patients in the Auckland/Northland region who were presented at the thoracic multidisciplinary meeting between January and December of 2014. Patients were included if clinical records were available, Māori ethnicity was documented and treatment recommendations were made locally. Descriptive analysis is presented.

Result:
87 of 100 patients met criteria for inclusion. 65% were female with a median age of 65(47-83). 48% were current smokers, 63(72%) had pathologically confirmed NSCLC and the majority had advanced stage disease (IASLC 7[th] Edition TNM staging: I 24%, II 6% , IIIa 18%, IIIb 11%, IV 40%).Fourteen (16%) were recommended to have surgery by the MDM, with 9 (10%) completing surgery. Of the 5 who did not complete recommended surgery, two patients were found to have advanced disease intra-operatively and three declined surgery.Of the 78 not undergoing curative intent surgery, the documented reason was advanced disease (64%), comorbidities (21%), small-cell lung cancer (8%), declined by patient (4%) and one patient was recommended stereotactic radiotherapy. Analysis will be updated to include, and compare to, 100 age/sex matched New Zealand European patients.

Conclusion:
Presentation with advanced disease and comorbidities were documented as the reason for not proceeding to surgery in the majority of Māori patients with lung cancer discussed at the thoracic MDM. Within the limits of retrospective analysis, these findings suggest that addressing comorbidities and earlier detection of lung cancer may best improve access to curative treatment options for Māori.

Background:
ALK is a receptor tyrosine kinase that was discovered in anaplastic large cell lymphoma in the form of a fusion protein. To pick-up the patients with ALK-rearrangements is important to select the individual therapy as ALK inhibitor for mainly lung adenocarcinoma. There are several fusion partners with ALK 3’ region.

Method:
A 35-year-old woman with a short-breath and cough was referred and admitted taking a therapy for lung tumor in our hospital. By the bronchoscopic biopsy, she was suspected pulmonary IMT, but correct diagnosis was not indicated. Right upper wedge lobectomy was done. By the pathological examination of the permanent surgical resected tissue, the final diagnosis was pulmonary IMT.

Result:
The immunohistochemistry of ALK by using the iAEP method was positive. We extracted the RNA from frozen surgical resected tumor tissue, and prove the TPM4-ALK by 5’ RACE and RT-PCR. The preoperative bronchial biopsy specimen was also found positive for anti-ALK immunohistochemistry with iAEP method.

Conclusion:
The molecular therapeutic drug was expected as personalized therapy for the tumor with ALK translocation as oncogenic driver. We should examine the ALK protein expression and translocation about the cases of lung cancer and IMT by using adequate ALK immunohistochemistry system. We experienced a case of pulmonary IMT with TPM4-ALK translocation.

Background:
Tumors originating from chromaffin cells are located in 90% of cases in the adrenal gland and called pheochromocytomas, while in 10% of cases have an extra-adrenal origin (paraganglionic cells scattered throughout the body) and are termed paragangliomas. Endothoracic paragangliomas can arise in the lung and mediastinum, may have neuroendocrine activity, secreting catecholamines, or be non-functional, incidental, in asymptomatic patients or causing mass effect symptoms. Even if rare and with low grade of malignancy, they can present an aggressive behaviour, developing local infiltration of surrounding organs and distant metastases. A correct pathological diagnosis and radical surgical treatment are fundamental to obtain clinical recovery. We report our experience with three cases of endothoracic paragangliomas, in order to point out difficulties in diagnosis and problems related to surgical treatment.

Method:
From January 2009 to December 2016, we treated 3 patients (2 women, 1 man), mean age 67 years, with histological diagnosis of paraganglioma: 2 pulmonary, 1 mediastinal. All patients were asymptomatic for catecholamine-secreting syndromes; the two cases with pulmonary localization showed no other symptoms, while the mediastinal one had cough and dyspnea, due to compression by the mass, and blepharospasm. Imaging diagnosis was based on chest CT scan in pulmonary cases, chest CT and MRI scan for the mediastinal mass, which allowed to define vascularization and relationships with adjacent structures. No patient had preoperative histological diagnosis. Intraoperative pathological examination of the two pulmonary forms was suggestive for malignancy (extensive necrosis, high proliferative index, hypervascularization), thus a right pulmonary wedge resection was performed in one case, a right upper lobectomy in the other one. The hypervascularized mediastinal lesion, located in the middle mediastinum, tenaciously adherent to the superior vena cava, the aortic arch, the right branch of the pulmonary artery and the trachea, was completely removed after challenging isolation and section of numerous vascular pedicles.

Result:
Postoperative course was uneventful in all cases. No patient received adjuvant treatments. At a median follow-up of 35 months (range: 6-90 months), two patients are alive, without local or distant recurrence; one patient (with pulmonary involvement) died 6 months after surgery, due to disease progression.

Conclusion:
Endothoracic paragangliomas, rare and often asymptomatic tumors, are of difficult diagnosis and should be considered malignant tumors, due to the potential aggressive behaviour of cases with high mitotic index and the frequent possibility of recurrence. After complete excision, long-term prognosis is generally good. However, even after surgical removal, a close and periodical follow-up is mandatory.

Background:
Surgical resection for mediastinal germ cell tumors is one of important modality to cure. But it sometimes shows severe adhesion to greater vessels, complete resection without vessel replacement is difficult. But, no viable cells are found in the resected specimen in many cases. Is vessel replacement really needed for this situation? The aim of this study is to confirm whether complete resection is really needed for mediastinal germ cell tumor.

Method:
The data of 13 patients with resected mediastinal germ cell tumor were retrospectively analyzed for recurrence.

Result:
Median follow up period was 72.2 months. All cases were male. Mean age was 33.1 years old. Pathological diagnosis was mature teratoma in 5 cases, seminoma in 5 and non-seminomatous malignant germ cell tumor in 3. Seven cases received preoperative chemotherapy. Mean tumor size before surgery was 7.1cm. Median sternotomy was performed in 10 cases and posterolateral approach in 3 cases. Mean operative time was 225 minutes and blood loss was 228 g. Mean postoperative in-hospital duration was 8.2 days. There were not any life-threatening postoperative complications. Macroscopic residual tumor (R2) was found in 5 cases; 2 mature teratoma and 2 seminomas and a germ cell tumor because of severe adhesion to aorta. Four cases received adjuvant therapy. But in R2 case; 2 of mature teratoma and a seminoma without viable cell did not receive adjuvant therapy. Only a case of non-seminoma with complete resection, which did not achieve negative tumor marker preoperatively, showed distant metastases 4 months later after surgery.

Conclusion:
The surgery for mediastinal germ cell tumor in selected situation can show good survivability without recurrence. To balance the invasiveness and curability, minimizing the extent of surgery; not performing greater vessel replacement is one of choice.

Background:
Germ cell tumors of testicular origin are the most common malignancy in young males. The lungs and the retroperitoneal space are frequently the initial sites of metastatic disease. Salvage surgery is an important treatment modality for residual post-chemotherapy pulmonary masses. We analyzed the prognostic predictors of survival in the patients after pulmonary metastasectomy.

Method:
Between September 1989 and December 2015, 32 patients underwent pulmonary resection of thoracic metastases following cisplatin-based chemotherapy. Germ cell tumors of mediastinal origin were excluded. These patients’ records were subsequently reviewed.

Result:
All patients underwent high orchidectomy and cisplatin-based chemotherapy.　　The primary tumor histology demonstarated 2 seminomas and 30 nonseminomatous germ cell tumors. Twenty-three patients (72%) received two or more chemotherapy regimens. International Germ Cell Cancer Collaborative Group classification, TNM factors, and serum tumor marker level at diagnosis were not associated with prognosis after pulmonary metastasectomy. The mean age at pulmonary surgery was 31.9 years. The surgical procedures included wedge resection in 23 (72%) and segmentectomy/lobectomy in 9 (28%). There were no perioperative deaths and major postoperative complications. The overall 5-year survival rate was 73% after an average follow-up of 55 months. The pathology of residual pulmonary masses revealed viable tumor cells in 12 patients (38%), necrosis alone in 18 patients (56%), and mature teratoma alone in 2 patients (6%). Preoperative increased lactic dehydrogenase (LDH) levels were significantly associated with the viable tumor cells of residual masses. The size of pulmonary metastases has not been found to be statistically related to malignant tumor cells. A significantly poor survival was observed using univariate analysis in patients with preoperative high free-βHCG (p=0.012), high intact HCG (p=0.031), high LDH (p<0.001), removing 5 or more lung metastases(p=0.012), and viable tumor cells of residual masses (p=0.026).

Conclusion:
We conclude that pulmonary resection in metastatic testicular tumors is a safe and effective treatment strategy. Increased tumor marker levels, free-βHCG/intact HCG or LDH, removing 5 or more lung metastases, and viable tumor cells of residual masses were identified as prognosis-related criteria for a poor prognosis.

Abstract:
Aberrations of oncogenes, such as EGFR mutation; and ALK and ROS1 fusions, function as a driver in the development of lung adenocarcinoma (LADC) and are established therapeutic targets. We previously identified RET fusion present in 1-2% of LADC (Kohno, Ichikawa, Nat Med, 2012). Its activity as an oncogenic driver in lung carcinogenesis was validated by a study of transgenic mice expressing KIF5B-RET cDNA in their lungs (Saito, Carcinogenesis, 2014). RET fusion is likely to be another target of therapy using tyrosine kinase inhibitors, as represented by a high response rate of RET-fusion positive LADC to vandetanib (LURET study, Yoh et al., Lancet Resp Med, 2016). Our genome-wide sequencing study revealed that ALK, RET and ROS1 oncogene fusion-positive LADCs carry less numbers of mutations in cancer-related genes than others (Saito, Cancer Res, 2015), indicating a small mutation burden in the development of the formers. On the other hand, >30% of LADC and most of other types of lung cancers are negative for the oncogene aberrations above, therefore, other therapeutic targets are needed for precision lung cancer medicine. We have revealed frequent inactivation of chromatin-regulating genes, such as SMARCA4/BRG1 and CREBBP, in lung cancers negative for oncogene aberrations (Ogiwara et al, Cancer Discovery, 2016). We propose a synthetic lethal therapeutic method for chromatin regulator-deficient lung cancers based on inhibition of paralog proteins. LADC driven by somatic EGFR mutations is more prevalent in East Asians (30-50%) than in European/Americans (10-20%). We recently revealed that variations in HLA-class II loci underlie the risk of the disease, by conducting a genome-wide association study of 3,173 EGFR-LADC patients and 15,158 controls (Shiraishi et al., Nature Comm, 2016). The result indicates that LADC develops in vivo through interaction between somatic oncogene mutations and germline variations that modulate immune reaction. We would like to discuss here precision lung cancer medicine based on information on cancer and the host genomes.

Abstract:
The implementation of mutation-directed therapy has revolutionized systemic treatment of non-small cell lung cancer (NSCLC). In particular in lung adenocarcinoma targetable driver mutations can be found in a substantial proportion of patients allowing therapy with specific tyrosine kinase inhibitors (TKI) with higher efficacy and better tolerability compared to chemotherapy. Such personalized treatment approaches partly have already become first line standard therapy (EGFR, ALK, ROS1, BRAF V600), other driver mutations are currently evaluated in clinical trials (MET, RET, HER2, NTRK). Also with these new treatment options, however, we are still far away from cure and, mostly after a median progression free survival (PFS) of 10 – 12 months, resistance develops and the patients suffer from relapse. Different mechanisms may underlie primary as well as secondary resistance, which can be subdivided in two major groups: (I) pharmacological resistance, caused by reduced absorption or increased metabolism of the drug or, as a particular challenge in patients with CNS-metastases, by inadequate CNS penetration; (II) biological resistance by molecular changes in the target molecule (resistance mutations or gene copy number gain) or by activation of oncogenic bypass pathways (1). Impressive progress in treating NSCLC patients resistant to TKI therapy has been achieved by a deep understanding of the molecular mechanisms underlying biological resistance, in particular in EGFR mutated and ALK positive NSCLC. In about 60% of patients with acquired resistance (AR) to first- or second generation EGFR-TKIs resistance is caused by the secondary EGFR point mutation T790M leading to reduced TKI binding affinity and conferring growth advantage to the cancer cells. The resistance mechanisms include activation of bypass pathways e.g. by amplification of CMET or HER2 and transition to small cell carcinoma (2). Osimertimib, a third-generation EGFR-TKI, can overcome resistance caused by the T790M mutation and, based on its high clinical activity and favorable tolerability, now has become standard treatment for patients with T790M positive AR to EGFR-TKIs (3). However, resistance also occurs under osimertinib therapy and the molecular mechanisms, which are partly different to those conferring reistance to first generation EGFR inhibitors, are increasingly understood on the molecular level. They include occurrence of the EGFR C797S mutation, activation of the RAS/RAF/MEK/ERK pathway, CMET amplification and HER2 amplification (4,5). Dependent on the molecular mechanism underlying resistance to third generation EGFR inhibitors treatment strategies include the development of next generation inhibitors with activity against C797S positive cancer cells (6) as well as the evaluation of combination therapy approaches e.g. EGFR-TKI plus MET- or MET-inhibitors. These combination approaches are evaluated in the clinical setting of manifest relapse (to overcome resistance) but also as first line treatment (to prevent or postpone relapse). Similarly, also osimertinib is being evaluated in the first line setting and a substantial higher PFS has been reported in this clinical situation. A particular challenge for molecular diagnostics as well as for the development of resistance-overcoming therapeutic strategies is clonal heterogeneity, i.e. the occurrence of different driver mutations within the same patient (7). Also in ALK positive patients substantial progress has been achieved in understanding and overcoming the molecular mechanisms underlying resistance to therapy with ALK-directed TKIs. Similarly to AR to EGFR-TKIs also in AR to ALK-TKIs resistance can be caused by resistance mutations in the ALK receptor itself or by the activation of transforming bypass pathways. A series of resistance mutations has been identified and several next-generation ALK-inhibitors are either already approved or in clinical evaluation. These ALK inhibitors differ in their activity against distinct ALK mutations providing a basis for moleculary guided sequential therapy (8). Already now, impressive prolongation of survival has been reported by the sequential use of the first generation ALK inhibitor crizotinib and the next generation ALK inhibitors alectinib and ceritinib (9,10). Also for other driver mutations like ROS1, BRAF V600 or CMET resistance to TKI therapy is increasingly understood on the molecular level enabling the development of resistance-overcoming treatment strategies for these patients. The development of molecularly guided treatment strategies in AR to TKIs also poses a challenge to molecular diagnostics. In view of the numerous mechanisms which might underly resistance, the implementation of rebiopsies and molecular multiplex diagnostics using next-generation-sequencing (NGS) technologies in clinical routine becomes increasingly important. In addition, the particular challenge of clonal heterogeneity might be addressed already in the near future by the development of highly sensitive NGS-based liquid biopsy diagnostics. References Camidge R et al. Nat Rev Clin Oncol 11, 473-481 (2014) Yu HA et al. Clin Cancer Res 8, 2240-2247 (2013) Mok TS et al. NEJM 7, 629-640 (2017) Thress KS et al. Nat Med 6, 560-562 (2015). Ortiz-Cuaran et al. Clin Cancer Res 19, 4837-4847 (2016) Jia Y et al. Nature 534, 129-132 (2016) Scheffler et al. J Thorac Oncol 10, 40-43 (2015) Gainor et al. Cancer Disc 10, 1118-1133 (2016) Gainor et al. Clin Cancer Res 21, 2745-2752 (2015) Duruisseaux et al. Oncotarget 8, 21903-21017 (2017)

Abstract:
Heterogeneity is a universal phenotype across different cancer types, including non-small cell lung cancer (NSCLC). Tumor heterogeneity is present not only between different tumors from different patients or within the same patients (inter-tumor heterogeneity), but also between different cells within the same tumor (intra-tumor heterogeneity, ITH). ITH results from tumor evolution and in the meanwhile servers as a substrate for tumor evolution. ITH may be influenced by the host antitumor immune surveillance as well as anticancer therapies. Delineating cancer evolution and ITH may provide pivotal insight to our understanding of cancer development, progression and therapeutic resistance, and may eventually help us design more effective preventive and therapeutic strategies. Pioneering studies by multi-region profiling and by comparing paired primary and relapsed tumors have shed light on cancer genomic evolution and suggested the potential impact of genomic ITH on cancer biology and patient outcome. Tracking Non-Small Cell Lung Cancer Evolution through Therapy (TRACERx) is by far the largest study on genomic ITH of NSCLC using multi-region sequencing approach. The results from the first 100 patients enrolled in TRACERx were recently published in the New England Journal of Medicine. In this elegant study, 327 tumor regions from 100 tumors were subjected to high-depth whole exome sequencing (WES). Extensive genomic ITH was demonstrated at both nucleotide and chromosomal levels: a median of 30% of somatic mutations and 48% of copy number alterations (CNAs) were subclonal. Early clonal mutations were associated with smoking signatures in the majority of tumors, while subclonal mutations were significantly enriched for genomic signatures related to spontaneous deamination of methylated cytosines and APOBEC suggesting different mutational mechanisms in play at different times during cancer progression. A high proportion of subclonal CNAs was associated with an increased risk of recurrence and shorter disease free survival (DFS). However, no significant association with DFS was observed between the groups when stratified by proportion of subclonal mutations. The rich data from TRACERx and previous studies are provocative for the future translational and clinical research. Herein, we outline some of the concepts. First, TRACERx provided another piece of evidence that genomic heterogeneity is associated with survival of patients with localized NSCLC. However, it is somewhat surprising that more commonly regarded ITH in point mutations was not found to be associated with survival in this patient cohort, which is in contrast with previous reports in NSCLC and other malignancies. Given the relative small sample size, short postsurgical follow up (median follow up of approximately 18 months with 80% patients less than 2 years) and only 20 relapses, any imbalance in major prognostic factors such as stage, age, histology, smoking, and adjuvant therapy may have masked an actual association between mutational ITH and survival. Our group has recently completed multi-region deep WES on 30 stage IA NSCLC -15 patients relapsed within 3 years post-surgery (cases) and 15 patients have not relapsed with a minimum of 5-year postsurgical follow up (controls). Cases and controls are matched for stage, tumor size, gender, age, histology, smoking history etc. and none of the patients received neoadjuvant or adjuvant therapy. In this well-balanced case-control study, higher degree of point mutation ITH was found to be associated with shorter overall survival and shorter DFS. Nevertheless, the association between CNA ITH and DFS reported in the TRACERx study remained significant after adjusting for known prognostic factors suggests that chromosomal ITH may have greater impact on patient outcome than somatic mutations. This is probably because gain or loss of chromosomal segments or even whole chromosomes could affect hundreds or thousands of genes that may thus disrupt multiple key molecular processes, while point mutations usually affect single genes or pathways. Second, subclonal driver mutations are often detected by multi-region sequencing, which introduces a challenge to our current personalized oncology approach based on sequencing driver genes from single biopsies. Multi-region sequencing is not practical for patients with metastatic diseases or unresectable tumors. However, ctDNA is not spatially limited to certain tumor regions and may have the advantage in detecting subclonal mutations compared to single biopsies. With the rapid progress being made in liquid biopsy and sequencing technologies, sequencing ctDNA could become a practical alternative for multi-region tumor sequencing. Third, majority of studies on NSCLC ITH are based on primarily resected tumors. How chemotherapy, targeted therapy, radiation or immune therapy would impact ITH architectures remains unknown. One can hypothesize that residual tumor cells that survive neoadjuvant therapies could represent the subclones resistant to the these therapies. Therefore, investigating the residual tumors post-neoadjuvant treatment may provide valuable information on mechanisms of drug resistance. As such, well-designed window-of-opportunity neoadjuvant clinical trials would be invaluable for studying drug resistance. Forth, in addition to serving as a potential prognostic biomarker, ITH itself could become a potential therapeutic target. Given the important role of genomic instability in tumor evolution, modulating genomic stability such as targeting APOBEC family, a common cause of subclonal diversification of NSCLC, or inhibiting DNA repair pathways could become a novel therapeutic strategy. This strategy has been recently highlighted by the efficacy of PARP inhibitors in homologous recombination-deficient tumors. Last but not least, the majority of studies on ITH have mainly focused on the genomic ITH. However, ITH can be present at different molecular levels (genetic, epigenetic, gene expression etc.) of cancer cells and also of tumor microenvironment constituting of epithelial cells, blood and lymphatic vessels, cytokines, infiltrating immune cells etc. ITH of any of these components may impact tumor evolution and patient outcome. Our pilot study has demonstrated that a higher level of methylation ITH was associated with larger tumor size, advanced patient age and increased risk of postsurgical recurrence in NSCLC patients. Furthermore, we recently reported substantial T cell repertoire ITH in NSCLC with the majority of T cell clones restricted to individual tumor regions and that a higher degree of T cell repertoire ITH was associated with an increased risk of postsurgical recurrence and shorter DFS. Tumor evolution is a complex process, during which cancer cells accumulate molecular alterations that change their phenotypic features by interacting with the tumor microenvironment. In order to systematically understand the tumor ITH and evolution, future studies are required to depict the overall molecular (genetic, epigenetic, gene and protein expression) ITH of cancer cells as well as the tumor microenvironment components, ideally from longitudinally collected samples with or without treatments to dissect the evolutionary history of NSCLC and other malignancies leading to novel diagnostic, preventive and therapeutic strategies.

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Abstract:
Clinical development and approval of immune-checkpoint inhibitors have transformed the treatment of many types of tumors. In recent years, three anti-PD-1 or –PD-L1 antibodies have been approved for advanced NSCLC, including nivolumab, pembrolizumab, and atezolizumab. These antibodies have entered into the routine practice of treatment for patients with advanced NSCLC. In addition, all clinical trials, which compared the efficacy of anti-PD-1 or PD-L1 antibodies with chemotherapy, demonstrated that these antibodies are less toxic than chemotherapy (1-4). However, these immunomodulatory antibodies have led to the emergence of unusual autoimmune toxicities, also called immune-related adverse events (IrAEs). IrAEs management is challenging because they may concern many organ systems, including the skin, hepatic, gastrointestinal, endocrine, and pulmonary systems. Furthermore, given the recent success of immunotherapy, the incidence of immunotoxicity will likely continue to rise as these therapies become more widely used not only in advanced diseases but also in early stage diseases (5). Treatment-related toxicities have correlated with better response in some cases, and it is probable that serious adverse events from immune-mediated reaction will increase as immunotherapeutic approaches become more effective (6). Adding more complexity, the natural history of certain irAEs is unpredictable. The onset of clinical disease manifestation can vary from weeks to decades after the appearance of autoantibodies (7). Thus understanding irAEs is critical for early detection and appropriate management of patients. We will discuss the mechanisms that might be related with the induction of anutoimmunity from immunotherapy. References: Lancet. 2016; 387(10027):1540-50. N Engl J Med. 2015;373(2):123-35. N Engl J Med. 2015; 373(17):1627-39. Lancet. 2016;387(10030):1837-46. Eur J Cancer. 2016 ;54:139-48. Blood. 2011;118(3):499-509. Nat Med. 2017 ;23(5):540-547.

Abstract:
Checkpoint protein inhibition is associated with on- and off-target, cell and metabolic toxic effects that need to be carefully monitored and managed during and after treatment[1]. Despite important clinical benefits, immunotherapy is associated with a unique spectrum of side effects termed immune-related adverse events (irAEs) or, occasionally, adverse events of special interest. IrAEs include dermatologic, gastrointestinal, hepatic, endocrine, and other less common inflammatory events. Most irAEs remain mild in intensity but approximately 10% of patients treated with immune checkpoint blockade agents will develop severe, sometimes life-threatening, grade 3–4 dysimmune toxicities. Before prescribing immune checkpoint blockade agents to patients, oncologists need to be aware of the toxicity spectrum and must identify potential risk factors that could favor the emergence of irAEs[2]. Patients should be informed that most of these irAEs are mild and reversible if detected early and specifically addressed. Therefore, patients should be educated about signs of organ inflammation that would require prompt referral such as diarrhea, blood or mucus in the stool, severe abdominal pain, fatigue, weight loss, nausea, vomiting, thirst or appetite increase, polyuria, extensive rash, severe pruritus, shortness of breath, coughing, headache, confusion, muscle weakness, numb-ness, arthralgia or swelling joints, myalgia, unexplained fever, hemorrhagic syndrome
and severe loss of vision in one or both eyes. Any new symptom or deterioration of pre-existing symptoms must at least be monitored attentively and if necessary be explored to determine its etiology and rule out any dysimmune cause that could be worsened by immunotherapy continuation. Although early recognition and treatment improves symptoms and severity, a broad differential diagnosis should be entertained. It is recommended that all patients receiving these agents routinely have thyroid function studies, complete blood counts, and liver function and metabolic panels at each treatment and at intervals of 6 to 12 weeks for the first 6 months after finishing treatment. Adrenocorticotropic hormone, cortisol, and in men, testosterone should also be checked in patients who develop fatigue and nonspecific symptoms. Follow-up testing may need to increase in frequency based on individual response and adverse events that occur[3]. It is challenging to differentiate between infection, early pulmonary edema, alveolar hemorrhage, immune-mediated pneumonitis, immune-related tumor inflammation, and tumor progression (figure 1). Infections, thromboembolism, congestive heart failure, and COPD are among the many diagnoses to consider before committing patients to a long course of steroid therapy with additional consideration of prophylaxis for opportunistic (i.e., pneumocystis with or without fungal) infections. Pulmonary specialty consultation and consideration of bronchoscopic evaluation with lavage to assess for infections alongside biopsies of lung tissue can help narrow the diagnosis. IrAEs can develop at any time: at the beginning, under treatment and after immunotherapy termination. As shown with nivolumab, the majority of irAEs occur within the first 4 months[4]. On the basis of this median time to onset, irAEs could be classified as early (median time to onset <2 months) and late toxicities (median time to onset >2 months). Early toxicities include skin (5 weeks), gastrointestinal (7.3 weeks) and hepatic (7.7 weeks), whereas late toxicities include pulmonary (8.9 weeks), endocrine (10.4 weeks) and renal (15.1 weeks). However, clinicians should keep in mind that all toxicities can develop at any time since confidence interval may vary widely among organs: 0.1–57 weeks for skin; 0.1–37.6 weeks for gastrointestinal. Rarely, other irAEs may occur after week 24 with any checkpoint-blocking antibodies. In trials including maintenance ipilimumab, colitis has been seen 47 months from initiation of treatment[5]. Patients with prior autoimmune diseases or a history of viral hepatitis have been excluded from receiving ipilimumab on trials, but recent data suggest that the drug can be given safely to those patients. Nonetheless, extreme caution should be taken in treating patients with recent or ongoing autoimmune conditions, particularly any type of inflammatory bowel disease[6]. Management algorithms have been established for patients treated with immunotherapy, which may be useful in helping to manage irAEs but they are based upon clinical experience, since no prospective trials have been conducted to guide the treatment of irAEs. Resolution of irAEs usually follows a temporal pattern: 2 weeks for gastrointestinal, 4 weeks for hepatic, 6 weeks for skin, and 20 weeks for endocrine irAEs[7]. The key to successful management of checkpoint protein antibody toxicities is early diagnosis, high suspicion, excellent patient-provider communication, and rapid and aggressive use of corticosteroids and other immune suppressants for irAEs. Effective biomarkers to predict toxicity could be valuable in the development of these agents. Figure 1 FIGURE 1: CT scan of a patient with non-small cell lung cancer presenting with cough, dyspnea, and hypoxia on an immunotherapy drug. References: Fecher LA, et al: Ipilimumab and its toxicities: A multidisciplinary approach. Oncologist 18:733-743, 2013 Champiat S. et al., Management of immune checkpoint blockade dysimmune toxicities: a collaborative position paper Annals of Oncology Volume 27, No. 4, 559-74, 2016 Weber JS et. al. Toxicities of Immunotherapy for the Practitioner, J of Clin Oncol., volume 33, No 18, 2092-2099, 2015 Weber JS et al. Safety profile of nivolumab (NIVO) in patients (pts) with advanced melanoma (MEL): a pooled analysis. J Clin Oncol 2015; 33 (suppl): abstr 9018 Sarnaik AA et al: Extended dose ipilimumab with a peptide vaccine: Immune corre- lates associated with clinical benefit in patients with resected high-risk stage IIIc/IV melanoma. Clin Cancer Res 17:896-906, 2011 Hodi FS, et al: Ipilimumab plus sargramostim vs ipilimumab alone for treatment of metastatic melanoma: A randomized clinical trial. JAMA 312:1744-1753, 2014 Weber JS, et al. Management of immune-related adverse events and kinetics of response with ipilimumab. J Clin Oncol. 2012;30:2691-2697

Abstract not provided

Abstract not provided

Abstract:
Checkpoint inhibitors have changed the outcome of patients with metastatic non-small cell lung cancer (NSCLC). Radiotherapy has consistently been shown to activate key elements of the immune system that are responsible for resistance for immune therapy. Radiation upregulates MHC-class I molecules that many cancer cells lack or only poorly express, tumor-associated antigens, provokes immunogenic cell death, activates dendritic cells, decreases regulatory T-cells (Tregs) in the tumor, broadens the T-cell repertoire and increases T-cell trafficking, amongst many other effects. Radiation may convert a completely or partly poorly or non-immunogenic tumor immunogenic. Radiotherapy in combination with different forms of immune therapy such as anti-PD-(L)1, anti-CTLA4,immunocytokines, dendritic cell vaccination and Toll-like receptor agonists improved consistently local tumor control and very interestingly, lead to better systemic tumor control (the “abscopal” effect) and the induction of specific anti-cancer immunity with a memory effect. At the time of writing, the most compelling data in human studies come from Shaverdian et al. (Lancet Oncol 2017). In 97 patients with advanced NSCLC treated on the phase 1 KEYNOTE-001 trial it was shown that patients having received prior radiotherapy, the six-month PFS rate was 54.3% vs. 21.4% among never irradiated patients. The median OS was 11.6 months and the six-month OS estimate was 75.3% among patients who previously received extra-cranial radiation therapy vs. a median OS of 5.3 months and a six-month OS estimate of 45.3% among patients who did not receive extra-cranial radiation therapy. Patients with prior thoracic radiotherapy had more overall pulmonary toxicity compared to never irradiated patients: 12.5% vs. 1.4%. Unfortunately, no dose-volume parameters such as the mean lung dose are available of these patients. The biggest concern of combining radiotherapy and immune treatment is indeed a higher incidence of pneumonitis. Many studies are investigating the combination of radiotherapy, chemotherapy and immune therapy in lung cancer, including the PACIFIC, the STIMULI and the NICOLAS studies. The results of these studies have not been reported at the time of writing, but none of the trials have been closed prematurely. Moreover, as radiotherapy is used to stimulate the immune system, classical concept in dose and volume will have to be investigated again. Less dose in a few fractions may suffice, and margins may be reduced, which in turn will lead to less side effects. When studied meticulously, radiotherapy and immune therapy may well turn out to be efficacious and with few side effects and additional costs.

Background:
The Kent Oncology Centre has been instrumental and innovative in the development of nurse-led services since 2005. The Lung CNS’s have been conducting oncology clinics since 2009 reviewing patients on TKI’s and chemotherapy. With Immunotherapy now available to some lung cancer patients, the Lung CNS's needed to incorporate immunotherapy review into their established clinics. The Lung CNS's worked collaboratively to develop a patient-centred electronic assessment tool. The tool would ensure standardised practise, patient safety and assess toxicities whilst on Immunotherapy. The aim is for the Lung CNS’s to utilise the electronic tool and roll out through an educational programme thus increasing knowledge and confidence and empowering nurses to safely review patients on immunotherapy.

Method:
To incorporate immunotherapy patients to an established CNS Nurse-led review clinic: Agreement between Consultant and Senior Nurses. Discussions with Computer Sciences, Lung Cns's, Oncologists, Chemotherapy Lead Nurse. Educational Requirements - Consultation and Physical Examination Skills, Non-Medical Prescribing, Chemotherapy Competence, IRMER. Protocols - Agreed for the Nurse Led Oncology review clinic. Competence - The Lung CNS requires a set of practice and competence in judgement and decision making. How the clinic works Consent by the consultant. Consultant toxicity assessment pre cycle 2. Reviewed thereafter by lung CNS or Chemotherapy Nurse prior to each treatment. Electronic Toxicity assessment completed. Weight/Observations recorded. Bloods FBC, U&E's, LFT's. Thyroid 8 weekly. 9am cortisol LH and FSH Direct access to consultant. Consultant review with CT scan.

Result:
Figure 1 Reported Toxicities. Adisonian Crisis Hypothyroidism Diarrhoea/Colitis Fatigue Hepatitis Skin Reactions Pneumonitis



Conclusion:
The number of patients on Immunotherapy treatment is set to rise. Incorporating the review of Immunotherapy into an established Lung CNS Nurse-led Review clinic enabled standardised practise, enhanced patient safety and provided continuity of care. Through education and training and by using an electronic assessment tool; chemotherapy nurses can be empowered to review patients on Immunotherapy.

Background:
Cisplatin, a systemic treatment component for many lung cancer types, is highly emetogenic (HEC). The guideline-recommended antiemetic combination for patients receiving HEC includes a NK~1~ receptor antagonist (NK~1~RA), a 5-HT~3~RA, and dexamethasone (DEX). NEPA is the first oral fixed combination of an NK~1~RA (netupitant) and a 5-HT~3~RA (palonosetron). The approval of oral NEPA was based on studies demonstrating superior prevention of chemotherapy-induced nausea and vomiting (CINV) over oral palonosetron; an intravenous formulation of NEPA is under FDA evaluation. A new Phase 3 study in Asia has reached its primary objective: a single day oral dose of NEPA is non-inferior to a 3-day regimen of aprepitant (APR) and granisetron (GRAN) [both combined with DEX] in preventing CINV in patients receiving cisplatin. This post-hoc analysis explores the efficacy of NEPA vs APR/GRAN within the lung cancer subset of that study.

Method:
Chemotherapy-naïve lung cancer patients in this double-blind, parallel group study received either a single oral dose of NEPA prior to cisplatin-based HEC or a 3-day regimen of APR/GRAN, both with oral DEX on days 1-4. Efficacy endpoints were complete response (CR: no emesis/no rescue medication), no emesis, and no significant nausea (<25 mm on 100 mm visual analog scale) during the acute (0-24h), delayed (25-120h) and overall (0-120h) phases post-chemotherapy. The risk difference for NEPA – APR/GRAN and associated 95% confidence intervals (CIs) were analyzed for each endpoint using the Cochran-Mantel-Haenszel test.

Result:
542 (65%) of the 828 patients had lung cancer. Mean age was 56.1; 73% males. Response rates were comparable for both arms during the acute phase, and favored NEPA in delayed phase (Table). Figure 1



Conclusion:
As a fixed oral combination of an NK~1~RA and 5HT~3~RA in a single capsule/cycle, NEPA offers a convenient and effective prophylactic antiemetic in lung cancer patients receiving cisplatin-based HEC regimens.

Background:
Increasing numbers of patients are being treated with potentially curative surgery for lung cancer. Pathological staging gives an indication of 5-year survival and whether further treatment is recommended. Patients undergo a period of post-operative clinical surveillance to monitor for potential recurrence of cancer. The process of discussing potential recurrence and its early warning signs has not been well researched. This study examines how clinical teams and patients manage information disclosure about possible cancer recurrence following lung cancer surgery. The aim is to identify some of the practice implications for lung cancer teams.

Method:
This qualitative project used case study methodology to explore how information regarding possible recurrence was presented to patients. Twelve patients were recruited at two thoracic surgical centres. Observation of the first post-operative surgical and subsequent oncology or follow-up clinic was conducted and consultations audio recorded. In-depth, one-to-one interviews were completed with clinical staff (surgeon, oncologist, physician and/or nurse specialist) who saw the patients to ascertain their perspective and understand rationale for particular information giving. Framework Analysis methods were used to identify key themes.

Result:
Staff varied in the extent and explicitness that long-term surgical outcomes were communicated to patients. Explicit information was presented in terms of recurrence risk or survival and the terms were frequently used interchangeably. Clinicians were often reluctant to give a numerical estimate of risk of recurrence or survival at the post-operative clinic. Information about early warning signs of recurrence was sporadic, with some clinicians preferring to delay such discussions until later on in the follow-up pathway, due to fear of damaging patients’ perceived fragile hope for cure. Information was aimed at supporting hope, aiding treatment understanding, or facilitating decision-making. Choices made by staff regarding information giving were complex and largely tacit, but appeared to be linked to individual professionals’ underlying optimistic or realistic approach. Staff talked about the importance of balancing hope and realism.

Conclusion:
These findings give unique insight and reveal how challenging and complex it is for clinicians to discuss recurrence following lung cancer surgery. The next stage of the project will examine the patient’s perspective of this process. These data will then be combined to identify ways to improve communication of recurrence

Abstract not provided

Background:
Using evidence based follow up guidelines, our nurse led follow-up clinic was established in December 2012. All post-operative thoracic surgery patients are seen, including patients with primary lung cancer. We evaluated problems and issues patients identified related to their post-operative recovery and follow-up period

Method:
Data was collected prospectively from December 2012 to March 2017. This included information for each patient on surgery, pathology, TNM stage, follow-up plan and smoking status. We recorded additional issues raised by patients. Data was analysed to generate descriptive statistics of post-operative problems. There were 546 patient episodes in 189 clinics for 285 patients with primary lung cancer

Result:
Of the 285 patients 70 (25%) were smokers in the 6 weeks prior to surgery. 171 (60%) were ex-smokers and 44 (15%) had never smoked. 32 (11%) patients smoked after surgery, all except one were pre-operative smokers. Smoking cessation was a concern after surgery with 44% of the pre-operative smokers restarting smoking post-operatively. The number of patients seen at each follow-up interval and the issues identified are shown in the table below. The most frequent issues reported by patients after thoracic surgery are pain, respiratory issues and anxiety. 80% of patients report problems at their first follow-up appointment after surgery, decreasing to 59% at five years. Respiratory issues are common in this group of patients who often have co-existing lung disease. Anxiety, most commonly associated with fears about recurrence of disease, remains a problem throughout the follow-up period. 31% of patients had abnormal imaging at one or more appointments.

Issues identified in the nurse led thoracic surgery follow-up clinic

	Number of patients % of the total patients seen in each survillance period
Time since surgery	Total	Pain	Respiratory issues	Anxiety	Imaging issues	Other issues	No issues
1st follow-up	120	33 27.5%	23 19%	24 20%	18 15%	16 13%	24 20%
6 months	118	21 18%	20 17%	11 9%	33 28%	14 12%	31 26%
12 months	79	10 13%	20 25%	8 10%	19 24%	8 10%	14 18%
18 months	66	9 14%	15 23%	8 12%	14 21%	7 11%	22 33%
2 years	65	9 14%	12 18%	7 11%	10 15%	10 15%	19 29%
3 years	48	7 15%	7 15%	7 15%	11 23%	8 17%	13 27%
4 years	28	0	7 25%	5 18%	5 18%	8 29%	7 25%
5 years	22	0	6 27%	2 9%	4 18%	2 9%	9 41%
Totals	546	89 16%	110 20%	72 13%	114 21%	71 13%	139 25%

Conclusion:
The findings indicate the extent of physical, psychological and lifestyle (e.g. smoking) concerns in post-operative follow-up. A new telephone follow-up clinic has recently been introduced to address these needs. Further investigation with objective assessment and scoring of symptoms would improve the quality of the data collected.

Background:
Research shows people diagnosed with lung cancer have greater unmet supportive care, physical and emotional needs compared to those diagnosed with other cancers. Much of this research is older and primarily focused on small numbers of newly diagnosed patients. Other research has focused on the relative lack of treatment options and does not address practical and psychosocial needs.

Method:
To more fully understand the current unmet needs of lung cancer survivors, an online survey was distributed between 11/9/2015 and 2/8/2016. Of 820 respondents, 471 were lung cancer patients/survivors with 349 loved ones. Queried on treatment histories, respondents were asked to identify the most prevalent and problematic symptoms and side effects experienced during treatment, shortly after treatment ended and at 5+ years post-diagnosis. They were also asked which were most problematic during each time period.

Result:
The survey had an overall 72% completion rate with 21% of survivor-respondents indicating a diagnosis 5+ years prior. Patients/survivors rated anxiety, fatigue and shortness of breath as most challenging in the immediate, post-treatment, and long-term. During treatment, gastrointestinal issues including constipation, diarrhea and nausea were also highly problematic. All groups reported physical effects were significantly more problematic during treatment but deemed emotional effects more difficult to manage post-treatment and in the long-term. In open-ended questions, nearly 25% of respondents indicated they received inadequate information/assistance to manage physical and emotional reactions, both during and after treatment. Only 27% of respondents had a discussion about palliative care with just over 20% having received it. The survey affirmed that assistance to manage lung cancer’s symptoms and treatment side effects is an unmet need in the lung cancer community. In response, a four-part educational series, including webinars and accompanying print materials, was developed. The series is the only to focus specifically on lung cancer and helps participants understand the causes of the top four reported symptoms and side effects, including potential medical interventions and holistic, practical tips that can used immediately.

Conclusion:
Those diagnosed with lung cancer are the experts and we can only understand their unmet needs by asking them. This large, extensive survey provided insight into their needs during, immediately after and long after treatment. Our initial four-part webinar series is only the beginning--through our results and querying webinar participants, we are developing additional educational programming to help those diagnosed with lung cancer and their loved ones understand and manage their specific disease and treatment-related challenges.

Background:
The National Lung Cancer Audit 2015 reported 40% of patients with Lung cancer are diagnosed following an emergency admission. The National Lung Cancer Forum for Nurses Workshop 2016 undertook a review of how the Lung Cancer CNS’s (LCNS) early intervention can have a positive impact on the reduction in the length of stay for those patients admitted via the emergency route at their first presentation.

Method:
A prospective and a retrospective review of a cohort of patients admitted by the emergency route was undertaken, n=51 in both cohorts, across 13 UK sites over a 2 month period. A standardised Data Collection Tool was developed to ensure consistency and avoid bias. In the prospective cohort the LCNS actively identified patients at an early stage following their admission, whereas the retrospective cohort was a random sample of patients admitted and diagnosed via the emergency route irrespective of the LCNS involvement.

Result:
Demographics and baseline characteristics were found to be similar in both cohorts. 31% of patients were never seen by the LCNS in the retrospective cohort whereas all patients were seen in the prospective cohort 76% of patients in the prospective cohort were seen within 0-5 days following admission by a LCNS compared with 43% in the retrospective cohort Average length of stay in the prospective cohort was 9.7 days V 17.6 days in the retrospective cohort.

Conclusion:
This review suggests the early intervention of a LCNS is associated with a reduced length of stay following an emergency admission when Lung Cancer/Mesothelioma is diagnosed.

Abstract not provided

Background:
Video-assisted thoracoscopic surgery (VATS) is now increasingly performed and recommended in early-stage NSCLC resection. Early postoperative mobilisation, rehabilitation and physiotherapy can improve subsequent reduction in lung volumes, aid clearance of secretions and independent mobility, although there is much variation in how lung cancer patients are currently managed in this respect. The objective of this study was to observe capability for early mobility and frequency of issues potentially amenable to physiotherapy rehabilitation following VATS lobectomy for lung cancer. Any preoperative factors associated with increased rehabilitation needs were also identified, thus enabling early recognition of lung cancer patients needing rehabilitation.

Method:
A prospective observational study was performed including all consecutive cancer patients undergoing VATS lobectomy in a regional centre over 4 years (2012-2016). Standard postoperative care included early mobilisation where patients were sat out by nursing staff from postoperative day 1 (POD1) and assisted to mobilise as able. Physiotherapy assessment of all patients on POD1 determined presence of issues potentially amenable to rehabilitation, and this was commenced as deemed necessary. Outcome measures included development of postoperative pulmonary complication (PPC), hospital and high dependency unit (HDU) length of stay (LOS) and intensive therapy unit admission (ITU).

Result:
285 lung cancer patients were observed; 76 (27%) patients did not requiring specialised rehabilitation or physiotherapy, and engaged with nursing staff successfully in early mobility and becoming independently mobile. These patients had a significantly lower hospital and HDU length of stay (p<0.001), reflecting uncomplicated recovery. The remaining 209 patients (73%) received physiotherapy rehabilitation to assist/improve reduced mobility. Of these patients 23 (8%) also received chest physiotherapy for sputum clearance and 65 (23%) for lung volume loss. amongst those requiring this therapy were all patients who developed PPC, and all those admitted to the ITU. Despite surgery being non-invasive the frequency of development of PPC was higher than that for other VATS surgery at 7%, and this was associated with poorer outcomes. Logistic regression identified that COPD, BMI, preoperative mobility and age were associated with increased postoperative rehabilitation needs for mobility or respiratory issues (p=0.013).

Conclusion:
We recommend that all lung cancer patients receive early mobilisation and routine postoperative rehabilitation following this surgery ensuring issues amenable to physiotherapy and the need for rehabilitation is detected early. Associated preoperative baseline factors included COPD, poor preoperative mobility, and increasing BMI and age; such patients may benefit from preoperative rehabilitation as well as routine physiotherapy for better postoperative outcome.

Background:
Early-palliative care (EPC) after lung cancer diagnosis is essential for a better quality-of-life (QoL), and even offers a substantial improvement in survival outcomes. We prospectively assessed the effect of EPC in overall survival (OS) and patient-reported outcomes in non-small cell lung cancer (NSCLC) patients.

Method:
Newly-diagnosed and treatment-naïve NSCLC patients were included and randomly assigned (1:1) to receive either EPC with oncologic, nutritional, and psychological care, or standard oncologic care alone. Assessments were performed at baseline, second, fourth and sixth cycle of chemotherapy, with evaluations including: QoL, evaluated by The European Organization for Research and Treatment of Cancer Quality of Life Questionnaire, depression and anxiety which were evaluated using the Hospital Anxiety and Depression Scale, and oncologic symptomatology, which was evaluated with the Edmonton System Assessment Scale. NCT01631565 [013/020ICI(CV773/13)].

Result:
Ninety-six NSCLC patients were enrolled; 42 patients were allocated to EPC while 54 patients were allocated to standard-care. Overall, patients receiving EPC have lower self-reported symptoms, depression and anxiety. Median OS of patients with EPC was 11.1 months (95% CI: 8.4–13.9), while in patients with standard-care was 5.9 months (95% CI: 4.8 – 7.1); p=0.049. In the multivariate analysis, factors associated with worse OS were: patients in standard-care arm (HR, 95% CI 1.6 (0.9 – 2.7); p=0.05), male patients (HR, 95% CI 1.8 (1.1 – 3.0); p=0.028) and worse ECOG performance status (≥2) (HR, 95% CI 1.9 (1.0 – 3.5); p=0.039).In a subgroup analysis, patients who reaped the most benefit from EPC included those with better ECOG performance status (<2) (8.9 vs. 5.7 months; p=0.05); those without depression at baseline (14.8 vs. 6.5 months; p=0.05) and those Corroborar que si sea mayor ansiedad basal-mayor beneficio Figure 1



Conclusion:
EPC might provide benefit in the clinical symptomatic burden and OS of NSCLC patients. Benefits from EPC in OS might be associated to favorable global clinical status.

Background:
While many thousands of patients per year receive chemotherapy for advanced NSCLC with first-line or subsequent chemotherapy, little is known about patients’ views on their decision to receive that treatment. In that median survival results generally do not exceed one year, there are many potential risks for regret. Given the highly symptomatic nature of NSCLC coupled with patient, family and oncologist desires to decide rapidly on treatment, many challenges exist affecting quality decision making for patients and their supporters facing treatment. Among 59 studies dealing with regret in a recent systematic review (Becerra Perez 2016), none analyzed patients with lung cancer (66% of studies were in oncology). A clinical profile of the extent of regret, and factors contributing to that regret is lacking in those undergoing chemotherapy for lung cancer.

Method:
All patients were entered into a phase III, two-arm, prospective, randomized trial in patients receiving chemotherapy for lung cancer. Patients were randomly assigned to either usual care (UC), or enhanced care (EC) using the DecisionKEYS decision aid coupled with every 3 week PRO assessment using the electronic LCSS measure. All patients were offered the Decision Regret Scale (“DRS,” O’Connor 1999), at 11 weeks (+/- 2 weeks) after starting treatment. The DRS is a categorical scale with 5-items in 5 categories (ranging from “strongly disagree” to “strongly agree”). Patients completed assessment for decisional conflict; the patients’ supporters completed similar measures.

Result:
164 patients were entered, 160 received chemotherapy. Characteristics: 43% women; 92% Stage IV; 73% first-line therapy. Means: age 63; KPS 81. ECOG 1 = 56%; ECOG 2 = 42%. 46% represented minority groups. 22 different chemotherapy regimens were used. First-line patients received combination regimens with the majority being platinum-based with 2 or 3 drugs. 128 patients (80%) completed the DRS. Results combined the two top categories indicating the greatest extent of regret. Only 9 patients (7%) expressed regret as the maximum of the 5 DRS questions. 94% expressed that the decision for chemotherapy was a wise one. This low degree of regret did not differ by first-line or subsequent chemo or by EC versus UC groups.

Conclusion:
Patients receiving chemotherapy for advanced NSCLC, at 3 months after starting treatment, rarely (7%) have regret, and 98% expressed that they made the right decision. Other factors associated with the few patients with regret, such as decisional conflict or reduced quality of life, will also be presented. Support: NIH/NCI R01 CA-157409

Abstract not provided

Background:
Lobectomy is the preferred treatment for patients with early stage non-small cell lung cancer (NSCLC). However, stereotactic body radiation therapy (SBRT) is an attractive option due to its promising efficacy reported recently. Given that prospective comparative data on lobectomy and SBRT are limited, we compared the two treatments for early stage NSCLC.

Method:
All patients undergoing treatment with lobectomy or SBRT for clinical early stage (T size≤5cm) NSCLC between January 2012 and June 2017 were reviewed. Age, gender, tumor characteristics, Charson Comorbidity Index, pulmonary function, local control rate (LCR), recurrence-free survival (RFS), overall survival (OS) data were collected and propensity matching performed.

Result:
For the entire lobectomy cohort, 3-year OS, DFS, and LCR were 87.9%, 84.9%, and 96.4% respectively. For the entire SBRT cohort, 3-year OS, RFS and LCR were 84.4%, 60.7% and 93.4%, respectively. A total of 246 patients underwent surgery, and 117 received SBRT. There were statistically difference between surgical patient and SBRT patients in tumor histology(P<0.000). Surgical patients had tendency that have longer tumor size than SBRT patients (2.4±1.0 vs. 2.1±0.8, P=0.092). There were no statistically difference between lobectomy and SBRT group with age (68.9±6.6 vs.69.0±9.2, P=0.980), Eastern Coorperative Oncology Group performance scores, Charlson comorbidity Index, pulmonary function test result (FEV1 and predict FEV1), gender, T stage, and tumor location. A propensity matched comparison in a blinded manner (1:1 ratio, caliper distance=0.0025) based on age, gender, WHO performance status score, pulmonary function (forced expiratory volume in 1 second [FEV1] % and FEV1), and T stage resulted in 49 matched pairs. The follow-up period ranged from 0.3 to 60.0 months, with a median of 21.4 months. There were no differences between lobectomy and SBRT in LCR, respectively 97.1% and 100% (p=0.355) at 4 year. Also the 4-year RFS was comparable between groups, as 68.6% after lobectomy, versus 81.9% at 4 year after SBRT (p=0.963). The 4-year OS was similar in both groups, with 58.1% vs. 75.2% for lobectomy and SBRT (p=0.774). No patient experienced treatment-related death in both groups.

Conclusion:
This retrospective analysis found no significant difference in LCR, RFS and OS between lobectomy and SBRT. This study indicated matching these disparate cohorts of patients remains challenging. Participation in clinical trials is essential to define the indications and relative efficacy of lobectomy and SBRT in a high-risk population.

Background:
Stereotactic body radiotherapy of “ultra-central” (UC) lung tumours, PTV directly abuts/overlaps the proximal bronchial tree (PBT), trachea, esophagus, pulmonary vein/artery, are considered to be at higher risk of toxicity. The purpose of this study is to review the outcomes and toxicities of Ultra-central lung tumours, compared to central tumours.

Method:
A retrospective review based on a prospective database of patients treated with lung SBRT from January 2006- December 2015 was conducted. Patients with central tumours defined using RTOG 0813 criteria and ultracentral tumours were included. 115 patients (53%) received 60Gy/8 and 61 (28%) received 48Gy/4. At our institution, the recommended Dmax for esophagus is 45Gy and 40Gy for 8 and 4 fractions, respectively. The Dmax and D10cc constraints for trachea, proximal bronchial tree, heart, and major vessels (including pulmonary artery and vein) are 48Gy and 40Gy for 4 fractions and 64 and 60Gy for 8 fractions. Toxicity was graded using CTCAE v3.0. Log-rank test was used to compare overall and cause-specific survival. Local, regional, and distant recurrence were compared using Gray’s test.

Result:
215 tumours were analyzed (189 C and 26 UC). The median age for C and UC were 75 years and 72.5 years. Median tumour size and PTV volume were 2.2 cm (range 0.9-5.7) and 41.7 cm3 (range 9.7-246.3) (C group) and 2.5 cm (0.8-5.5) and 58.2 cm3 (16.8-238.3) (UC group). The percentage of squamous cell carcinoma was higher in the UC group (15%, n=29 in C; 38%, n=10 in UC). The median follow-up was 20.3 months (24.5 mo for patients still alive). Median overall survival (OS) and cause-specific survival (CSS) was 34 mo and 53.8 mo for C and 20.1 mo and 28.2 mo for UC, respectively. Differences in OS and CSS between the two groups did not meet statistical significance (p=0.24 and p=0.14, respectively). Local, regional, and distant failure rates were 3%, 8% and 18% in the central tumour group and 0%, 9% and 25% in the ultra-central tumour group at 2 years. There was no statistically significant difference found in the rates of recurrence between the two groups. The rates of any grade 2 or higher toxicity (hemoptysis, esophageal toxicity, cough, dyspnea, pneumonitis) was 9% (n=17) in the C and 7.7% (n=2) in UC group (p=0.89). There were no known grade 4 or 5 toxicities.

Conclusion:
In our experience, SBRT to ultra-central tumours resulted in effective local control and no excessive risk of toxicity compared to central tumours.

Abstract not provided

Background:
We hypothesized that impaired pulmonary functions tests might predict for altered lung density which would interfere with the efficacy of radiotherapy. We therefore sought to determine if there are associations between pre-treatment [preTx] forced expiratory volume in 1 second (FEV1, in L and as % predicted [%p]) and diffusion capacity (DLCO, as %p) with local failure (LF) rates seen with lung stereotactic body radiotherapy (SBRT) for medically inoperable lung cancer.

Method:
From an IRB-approved institutional prospective SBRT registry of 1330 patients, we identified 557 treated definitively for medically inoperable early stage T1-T3N0M0 non-small cell lung cancer (NSCLC) between 2003 and 2016 for whom both preTx FEV1 and DLCO were available. Lung SBRT dose/fractionation for a given pt was at the discretion of the treating physician. LF was defined as progressive and increasing CT scan abnormalities confirmed by progressive and incremental increases in lesion SUVs on serial PET imaging, with or without biopsy. Predictors of LF were determined using competing risks regression and rates of local control were determined from cumulative incidence analysis.

Result:
Pt characteristics included: female gender (52.6%); median age 74 years (range 42-95); median KPS 80 (range 50-100); median preTx FEV1 and DLCO: 1.39L (range 0.26-3.87), 60 %p (range 13-151) and 52 %p (range 10-143), respectively. Tumor characteristics included: median diameter 2.2 cm (range 0.7-7.2); median PET SUVmax 7.7 (range 0.8-56); % as T stage 1a, 1b, 2a, 2b, 3: 40.2; 35.5; 18.9; 4.5; 0.9, respectively; “central” location (per RTOG 0813) 22.6%. Median follow up was 18.3 months. At analysis, 46.9% pts were alive. Treatment characteristics included 50 Gy/5 fractions (fx) for 235 pts (42.2%), 60 Gy/3 fx for 167 pts (30%), and other schedules for 155 pts (27.8%), with the latter excluded from analysis due to variability in schedules, leaving 402 pts (72.2%). Only dose was significantly associated with LF on multivariable analysis [p=0.0057; HR =3.416, 95% CI 1.429-8.166]. Three-year cumulative incidence of LF post-SBRT for 50 Gy/5fx and 60 Gy/3 fx was 15.2% and 2.3% [p=0.024], respectively. In subset analysis of the 50 Gy/5 fx, DLCO was significant for LF both as a continuous variable and as a categorical variable. The significant cut-off for DLCO was 45%p, such that 3-year LF at <45 was 24.7% (95% CI 13.6-35.8) and at > 45 was 10.6% (95% CI 5.3-16.0), [p=0.0234; HR =0.441, %95 CI 0.217-0.895[CR1] ]. There were no significant associations between LF and pulmonary functions tests for 60 Gy/3 fx.

Conclusion:
As preTx DLCO drops below 45 %p, our findings suggest local failure increases when lung SBRT is delivered as 50 Gy/5 fx for early stage NSCLC. This warrants validation in prospective series.

Background:
Central nervous system (CNS) metastases, including brain metastases (BM) and leptomeningeal metastases (LM) represent a frequent complication of non-small cell lung cancer (NSCLC). Patients with CNS metastases comprise a heterogeneous group, with a median survival that ranges from 3 to 14 months. Local therapies, such as whole brain radiotherapy (WBRT), stereotactic radiosurgery (SRS) or surgical resection, are available treatment strategies for BM. Introduction of tyrosine kinase inhibitors (TKIs) in clinical practice has led to individualization of therapy based upon the presence of the exact abnormality, resulting in a major therapeutic improvement in patients with NSCLC who harbor epidermal growth factor receptor (EGFR) activating mutations or anaplastic lymphoma kinase (ALK) gene rearrangements, respectively, but their role in combination with radiotherapy is controversial

Method:
We performed a systematic literature review of published data in PUBMED, SCOPUS and COCHRANE databases, as well as a manual search of reported data in major congresses, using the terms "EGFR-TKIs", "ALK-TKIs", "CNS", "BM" or ""LM" and "concurrent radiotherapy" or "stereotactic radiotherapy" from January 2000 through May 2017. Only prospective or retrospective clinical trials and meta-analyses reported in English language were included

Result:

Author/year	Phase	No of pts	EGFR status	Treatment groups	Control	Outcomes
Lind et al 2009	I	11	NA	Cohort 1: Erlotinib 100 mg +WBRT Cohort 2: Erlotinib 150 mg +WBRT		-Grade 3-5 toxicity in cohort 2 -High IDCR
Welsh et al 2013	II	40	EGFR mutant: 9 of 15 pts tested	Erlotinib 150 mg + WBRT		-ORR 86%, -Median OS 11.8 m -Median OS 19.1 m in EGFR mutant
Sperduto et al 2013	III	126 (closed early)	NA	Arm 2:TMZ+WBRT+ SRS Arm 3: Erlotinib 150 mg + WBRT+SRS	Arm 1: WBRT +SRS	OS not improved with addition of drugs -No difference in CNS-TTP between the three arms -49% grade 3-5 toxicity in arm 3
Lee et al.2014	II	80	EGFR mutant 1 out of 35 pts tested	WBRT + Erlotinib	WBRT	No difference in OS
Ma et al. 2009	II	21	NA	WBRT +Gefitinib		ORR 86% -Median OS 13 m -No significant grade 3 toxicity
Pesce et al 2012	Randomized Phase II	59	NA	WBRT + Gefitinib vs WBRT+ TMZ		Median OS 6.3 m (Gefitinib arm), 4.9 m (TMZ arm) -No relevant toxicity
Zeng et al 2012	Retrospective	90	NA	WBRT +Gefitinib	Gefitinib	Higher ORR and OS with WBRT+ Gefitinib
Luo et al 2015	Metaanalysis	980 (8 trials)	NA	Radiotherapy + TKI (TKI group)	Radiotherapy or Radiotherapy+ chemotherapy (non-TKI group)	-Higher RR, CNS-TTP and OS in radiotherapy +TKI group -No difference is serious AEs
jiang et al 2016I	Metaanalysis	1552 (15 trials)	NA	Radiotherapy + TKI	Radiotherapy or Radiotherapy+ chemotherapy	Higher RR, DCR, CNS-TTP and OS in radiotherapy +TKI group -Increased rate of any grade AEs

Conclusion:
At this time, concurrent use of TKIs with radiotherapy, although appearing to be safe, is not recommended outside of a clinical trial. Interestingly, data in EGFR mutant patients treated with an EGFR-TKI alone prompt the question whether this could be a front line approach in patients with asymptomatic BM, reserving WBRT for symptomatic cases. In clinical practice, burden of extracranial disease might also guide treatment decisions; physicians might select not to discontinue a TKI during WBRT in case of extensive extracranial organ involvement Ongoing clinical trials are currently evaluating the effectiveness of concomitant use of radiotherapy and TKIs.

Background:
The treatment outcomes of patients with pulmonary oligometastases treated by SBRT were evaluated; the oligometastases were classified into three groups (oligo-recurrence, sync-oligometastases, and unclassified oligometastases) and the outcomes compared.

Method:
This study was limited to patients who had a BED10 ≥75 Gy. Oligo-recurrence was defined as a primary lesion that was controlled, the number of metastases or recurrences in the lung was one to five, and the disease-free interval (DFI), the interval between initial therapy of the primary lesion and the date of recurrence in the lung, was ≥6 months. Sync-oligometastases were defined as: the primary lesion was active; the number of metastases or recurrences in the lung and the active primary lesion was one to five; and the DFI was zero. The definition of unclassified oligometastases was similar to that of oligo-recurrence, but the DFI was <6 months. All oligomtastases in this study were treated by local therapy for all active lesions including primary and metastatic lesions.

Result:
Between 2004 and 2015, 1378 patients (male/female = 893/485; PS 0/1/2/3 = 746/474/85/17) meeting the study definition of pulmonary oligometastases were treated by SBRT in 68 institutions in Japan. Their median age was 72 years (16-93 years). The primary region was lung in 421, colorectal in 348, head and neck in 113, and others in 618. Histopathology showed adenocarcinoma in 761, squamous cell carcinoma in 358, and others in 186. Oligostatus was oligo-recurrence in 1013, sync-oligometastases in 118, and unclassified oligometastases in 122. The median maximum tumor diameter (MTD) was 1.5 cm (0.3-6.5 cm). The number of target tumors was solitary in 1037 and multiple in 341. The median BED10 was 105.6 Gy (75-289.6 Gy). The median DFI was 17.9 months (0-424 months). The median follow-up time was 24.3 months (0.1-143.7 months). The 3-year overall survival (OS), relapse-free survival, and local control rates were 60.3% (95%CI: 57.1-63.3%), 32.6% (95%CI: 29.7-35.5%), and 81.4% (95%CI: 78.8-83.7%). Univariate analysis showed only oligostatus, sex, PS, DFI, MTD, primary region, and histopathology were significant. The 3-year OS was 64.0% (95%CI: 60.4-67.5%) for oligo-recurrence and 50.6% (95%CI: 42.9-57.8%; p<0.001) for the others. Multivariate analysis of OS showed that only oligostatus (others/oligo-recurrence: HR 1.43), MTD (>2 cm/<2 cm, HR 1.45), histopathology (others/adenocarcinoma: HR: 1.47), and sex (male/female: HR 1.38) were significant.

Conclusion:
Pulmonary oligometastases, oligo-recurrence, female sex, adenocarcinoma, and small-sized tumor could be factors associated with longer survival.

Abstract not provided

Background:
Immune-related pneumonitis (IR-pneumonitis) is a potentially fatal toxicity of anti-PD-1/PD-L1. This study investigates the role of chest radiotherapy (RT) and the development of IR-pneumonitis in NSCLC patients treated with anti-PD-1/PD-L1.

Method:
Between January 2011 and April 2017, NSCLC patients treated with anti-PD-1/PD-L1 either as part of a clinical trial or as standard-of-care at a tertiary academic cancer center, were identified. Patient demographics, treatment, adverse event and RT data including type of RT (SBRT, 2D/3D conformal RT, IMRT, multiple), timing of RT (pre or post PD-1/PD-L1), location of RT (chest/non-chest), and number of courses of chest-RT, were collected in an IRB-approved institutional database. IR-pneumonitis was diagnosed clinically by the treating investigator; patients with confirmed RT pneumonitis, progressive NSCLC, or active infection were excluded. Associations between patient, treatment and RT parameters, and development of any grade IR-pneumonitis were evaluated using Student’s t-test and Fisher’s exact tests.

Result:
Of 184 NCSLC patients identified: median age was 67 years (range: 39-88); 57% (n=105) were male, 75% (n=137) were former/current smokers, 64% (n=118) had adenocarcinoma histology, and 59% (n=109) had advanced NSCLC at diagnosis. Anti-PD-1/PD-L1 monotherapy was received in 74% (n=136, nivolumab: 107, pembrolizumab: 14, durvalumab: 7, other: 8) and combination therapy in 26% of patients (n=48, PD-1/CTLA-4: 13, PD-L1/CTLA-4: 5, PD-1/chemotherapy: 4, PD-1/other: 25, PD-L1/other; 1). Any RT was received by 129 patients (70%), and 96 patients received chest-RT (52%). Thirty-eight (21%) patients developed IR-pneumonitis of any grade. IR-pneumonitis incidence was numerically higher in patients receiving combination therapy compared with monotherapy (29%, n=14/48 vs. 18%, n=24/136, p=0.1). Former/current smokers had a higher incidence of pneumonitis compared with never smokers (25% vs. 12%, p=0.03). IR-pneumonitis incidence was numerically higher in patients receiving chest-RT compared with non-chest/no RT (25%, n=24/96 vs. 16%, n=14/88, p=0.15). Of 129 patients who received any RT, there was a trend towards increased IR-pneumonitis in patients who received chest RT compared with those who received non-chest RT (25%,n=24/96 vs 9%, n=3/33; p=0.08). Overall, there were no significant associations between chest-RT type, chest-RT timing, nor receipt of more than one chest-RT course, and development of IR-pneumonitis (p>0.05).

Conclusion:
IR-pneumonitis incidence is 21% and may be higher than reported in clinical trials. Smoking status is associated with the development of IR-pneumonitis. Receipt of chest-RT was numerically higher, but not statistically associated with, development of IR-pneumonitis after receipt of anti-PD-1/PD-L1 in patients with advanced NSCLC. Radiation parameters did not associate with the development of IR-pneumonitis.