Virtual Library

Background
Thymic epithelial tumor, consisting of thymoma, thymic carcinoma and thymic neuroendocrine carcinoma, is a relatively rare neoplasm, and there is not a satisfying consensus in the treatment strategy. Because of lack of TNM staging system and global consensus on pathological classification, global research in these research has been difficult. To participate in movement of establishing the global database, Japanese Association for research of the Thymus (JART) conducted the project of Japanese nation-wide database in 2012.

Methods
Patients undergoing surgical treatment during 20 years between 1991 and 2010 in Japan were collected from 32 institutes. 3182 patients were first enrolled, but after exclusion of cases with insufficient information, 3033 cases remained for analysis finally.

Results
1435 patients (44%) were male, and 1595 were female (not identified in 3 patients). The age at operation was 13 to 88 years (mean 57 years old). Pathological diagnosis was thymoma in 2505 patients (Type A: 203, Type AB: 710, Type B1: 599, Type B2: 669, Type B3: 329), thymic carcinoma in 381 patients (Squamous cell carcinoma: 223, neuroendocrine carcinomas 66), and unclassified or unknown in 147 patients. According to Masaoka staging system, 1063 patients were in stage I, 1084 were in stage II, 477 in stage III, 197 in stage IVA, 57 in stage IVB (undetermined in 155 patients). Complete resection was achieved in 2753 patients (92%), subtotal resection (mass reduction of more than 80%) in 157 patients (5%), partial resection including biopsy in 86 patients (unknown in 37 patients). 249 patients were alive with tumor. 316 patients were dead during the observation period, and 161 patients died from tumor. Among 2557 patients who underwent complete resection (R0), 269 patients (10.5%) had tumor recurrence. In the patients who underwent complete or subtotal resection, 10-year overall survival rate was 89% in thymoma, 56% in squamous cell carcinoma, 30% in non-squamous thymic carcinoma, 72% in well-differentiated neuroendocrine carcinoma and 29% in poorly-differentiated neuroendocrine carcinoma. According to Masaoka stage, 10-year overall survival rate was 94% in stage I, 93% in stage II, 74% in stage III, 59% in stage IVA and 44% in stage IVB. In thymoma patients who underwent complete resection, recurrence-free survival rate at 10 years was 96% in type A, 99% in type AB, 92% in type B1, 80% in type B2, 72% in type B3. By Cox’ proportional hazard model, involvement of the mediastinal pleura (p=0.01), involvement of the lung (p=0.01), pleural dissemination (p=0.0009), distant metastasis (p=0.01) and WHO histological subtype (p<0.0001) were found to be independent factors for tumor recurrence after complete resection, while nodal metastasis, intrapericardial dissemination, involvement of pericardium, pulmonary artery, SVC, brachiocephalic vein, aorta, or brachiocephalic artery were not.

Conclusion
Japanese nation-wide database revealed the oncological difference among thymoma, thymic carcinoma and thymic neuroendocrine carcinoma. In thymoma, involvement of pleura and lung, pleural dissemination, distant metastasis and WHO histological classification were significant factors of tumor recurrence. These results are supposed to contribute to clinical practice for tumor treatment as well as establishment of global TNM classification.

Background
Stage III thymoma has a variety characteristics in terms of involved organs, complex surgery and multimodal strategy, and a careful consideration is required in choices of treatments. Recently the Japanese Association for Research on the Thymus (JART) conducted a nationwide large cohort analysis for thymic epithelial tumors. The aim of this study is to clarify clinical characteristics and therapeutic outcome of patients who underwent surgical resection for stage III thymoma using this database.

Methods
Clinical data of 3,033 thymic epithelial tumor patients of 1991 to 2010 were collected rom 32 Japanese institutes. Medical information registered included patients’ characteristics, types of surgery, pathological diagnosis, perioperative therapy, and clinical outcomes were registered. In this study, stage III thymoma patients who underwent surgery were extracted from the database, and retrospectively analyzed for clinical characteristics and surgical outcome.

Results
A total of 340 records of patients were analyzed in this study, which comprised 186 males (54.7%) and 153 females (45.0%), 83 (24.4%) with myasthenia gravis, 42 (12.4%) with induction chemotherapy, 18 (5.3%) with preoperative radiotherapy, and 29 (8.5%) with adjuvant chemotherapies. WHO histologic types comprised 16 A (4.7%), 40 AB (11.8%), 47 B1 (13.8%), 118 B2 (34.7%) and 97 B3 (28.5%). Involved organs were lung in 209 (61.4%), pericardium in 167 (49.1%), chest wall in 7 (2.1%), phrenic nerve in 88 (25.9%) and great vessels in 134 (39.4%). Completeness of resection was R0 in 268 (78.8%), R1 in 35 (10.3%) and R2 in 20 (5.9%). Complications were observed in 85 (25.0%) including arterial fibrillation, phrenic nerve palsy, bleeding and crisis of myasthenia gravis, and 30-day mortality rate was 1.8% (6 cases). Tumor recurrence was experienced in 96 (28.2%), and 39 (11.5%) died during the observation. Overall and disease-free 10-year survival rates were 81.0% and 56.7%, respectively. Involved organs except for chest wall, completeness of resection or myasthenia gravis did not affect the survivals. Number of involved organs (1 vs. >2) and tumor length (<7cm vs. >7cm) affected disease-free survival but not overall survival. Among factors suggested to affect overall survival by univariate analyses such as male, surgical complication, WHO histologic type B1-3, chest wall invasion, induction treatments, and recurrence, independent adverse predictors were revealed by a multivariate analysis to be male (p=0.031, HR=2.47), induction chemotherapy (p=0.034, HR=2.39), postoperative complication (p=0.018, HR=2.41) and recurrence of disease (p=0.041, HR=2.15). Of 96 patients with recurrence, 47 patients who underwent salvage resection showed better prognosis than 49 patients who did not (p=0.009).

Conclusion
This nationwide registry study exhibited favorable surgical outcome in Japanese patients with stage III thymoma. Effectiveness of multimodal treatments need to be further investigated in prospective controlled trials.

Background
RYTHMIC (Réseau tumeurs THYMiques et Cancer) is a nationwide network for thymic malignancies, which was appointed in 2012 by the French National Cancer Institute, as part of its rare cancer program. The objectives of the network include a territorial coverage by regional expert centers, the dissemination of highest standards for the diagnostic and therapeutic management of patients, and the promotion of collaborative research. Registration in RYTHMIC of all patients diagnosed with thymic malignancy is recommended as part of good clinical practice for oncologists.

Methods
Starting January 2012, the management of all patients diagnosed with thymic malignancy in France has been discussed on a real-time basis at a reference national multidisciplinary tumor board (MTB), which is organized twice a month using a web-based conferencing system. Decision-making is based on consensual recommendations, that were originally established using available evidence, and are updated and approved each year by all members of the network. A prospective database of all patients is hosted by the French Thoracic Cancer Intergroup. We report the characteristics and treatment modalities of patients included during the first year.

Results
From January to December 2012, 257 patients were enrolled in RYTHMIC. There were 126 (49%) men and 131 (51%) women; mean age at diagnosis was 54.5 years. Among 214 cases, histology was thymoma for 146 (56%) patients (11 (5%) type A, 28 (13%) type AB, 22 (10%) type B1, 35 (16%) type B2, 24 (11%) type B3, 26 (12%) mixed type), and thymic carcinoma for 33 (15%) patients, 8 of which were neuroendocrine carcinomas; other histologies were diagnosed for 35 (16%) patients. Among 144 cases, Masaoka-Koga stage was I, IIA, IIB, III, IVA, and IVB in 34 (24%), 19 (13%), 20 (14%), 22 (15%), 35 (24%), and 14 (10%) patients, respectively. 44 (17%) patients presented with autoimmune disorder, consisting of myasthenia gravis in 28 cases. Surgery was performed for 166 patients, mostly using a median sternotomy approach (52% of cases). Postoperative radiotherapy was delivered to 42 patients; 71 patients received perioperative chemotherapy. Exclusive chemotherapy/radiotherapy was administered to 20 and 4 patients, respectively. Mature data will be presented at the meeting.

Conclusion
This first analysis of the RYTHMIC prospective cohort demonstrates the feasibility of a national MTB for thymic malignancies, that, besides ensuring all patients an equal access to highly specialized treatment, provides with a comprehensive tool to monitor dedicated actions to improve the management of patients in the future, increase the quality-of-care, and screen patients for future translational research and clinical trials. Supported by Institut National du Cancer

Background
Thymic epithelial tumors sometimes metastasize to lymph nodes (LNs). The frequency of lymph node metastasis, the pattern of node metastasis and the relationship between prognosis and node metastasis are still unclear.

Methods
We registered patients with thymic epithelial tumors who had undergone resection between 1991 and 2010 from 29 institutes in Japan by the Japanese Association for Research on the Thymus (JART). We investigated the collected data according to the site of lymphatic metastasis. Yamakawa-Masaoka's paper (Cancer 1991;68:1984–7.) tentatively classified the N factor to 3 groups: metastasis to anterior mediastinal lymph nodes around the thymus were defined as N1, metastasis to intrathoracic lymph nodes other than anterior mediastinal lymph nodes as N2, and metastasis to extrathoracic lymph nodes as N3.

Results
The rate of lymphatic metastasis in thymoma was 1.75% (44 cases of 2508). Most of metastatic nodes were located in anterior mediastinal lymph nodes (N1, 78%). There is a significant difference of overall survival between thymomas with LN metastasis and those without LN metastasis (p<0.0001, 10-year survival: 89.8% vs 63.6%). Thymomas with N1 metastasis showed a good prognosis than those with other node metastasis, although there is no significant relationship (5-year survival: 64.4% vs 52.5%). The rate of lymphatic metastasis in thymic carcinoma including thymic carcinoid was 22% (84 cases of 380). Most of metastatic nodes were located in anterior mediastinal lymph nodes (N1, 69%). There is a significant difference of overall survival between thymic carcinomas with LN metastasis and those without LN metastasis (p<0.0001, 10-year survival: 59.5% vs 18.4%). Thymic carcimomas with N1 metastasis showed good prognosis than those with other node metastases, although there was no significant relationship (5-year survival: 55.5% vs 27.5%).

Conclusion
The rate of lymphatic metastasis in thymoma and thymic carcinoma was 1.75% and 22%, respectively. Both tumors frequently metastasized to the anterior mediastinal nodes. There was a significant difference of overall survival between tumors with LN metastasis and without LN metastasis in both tumors. And both tumors with N1 metastasis showed good prognoses than those with other node metastases, although there was no significant relationship. We think that it may be reasonable to consider the anterior mediastinal lymph node group (N1) to be a primary lymph node of thymic epithelial tumor.

Background
Thymomas are uncommon tumors of thymic epithelial cells. Thymomas display significant heterogeneity from morphologic point of view, clinical behaviour, expression of immunohistochemical markers and molecular profiling. Improving our understanding of the molecular biology of thymic malignancies represents a key challenge in the treatment of these rare tumors.

Methods
The genomic DNA of 57 consecutive patients (31 females and 26 males; 43 thymomas and 14 thymic carcinomas) submitted to total thymectomy at our Institution was extracted from paraffin-embedded tissue. We selected polymorphisms in the following genes: Hypoxia Inducible Factor-1 alpha (HIF1a: rs2057482T>C, rs1951795A>C, rs2301113C>A, rs10873142C>T, rs11158358G>C, rs12434438G>A, rs11549465C>T, rs11549467G>A), Vascular Endothelial Growth Factor-A (VEGF-A: rs2010963G>C, rs699947A>C), VEGF Receptor 2 (VEGFR-2: rs2305948C>T, rs1870377T>A), VEGFR-3 (rs307826T>C, rs307821C>A), Platelet-Derived Growth Factor-A (PDGFR-A: rs35597368C>T) and Excision Repair Cross-Complementing 1 (ERCC1: rs11615A>G). Gene polymorphisms were determined by Real-Time PCR using TaqMan assays.

Results
The allele frequency of PDGFR-A rs35597368 T (95.24%) was significantly higher than general population (86%, p=0.012), while the frequency of alleles HIF1-A rs2057482C (76.98%), rs1951795C (68.25%), rs2301113A (68.55%), rs10873142T (68.85%), rs11158358C (74.6%), rs12434438A (65.87%), rs11549465C (83.33%) were significantly lower than those of the control group (90%, 87%, 82%, 87%, 86%, 84%, 92%, respectively, p<0.01). VEGFR-3 rs307821C was significantly higher in thymomas vs. thymic carcinomas (79.5% vs 72%, p=0.0371). The following factors were significantly correlated with a better overall survival: VEGFR-3 rs307826C, VEGFR-2 rs1870377A, PDGFR-A rs35597368T/C, HIF1a rs2301113C, rs2057482C/T, rs1951795C, rs11158358G/C and rs10873142T/C, ERCC1 rs11615A (p<0.05).

Conclusion
To the best of our knowledge this is the largest monocentric study analyzing the angiogenetic variants in thymic tumors representing a further asset in the definition of high-risk patients after curative resection. The selection tool deriving from this analysis may allow an optimal use of innovative treatment strategies including targeted agents such as sunitinib, sorafenib or pazopanib.

Abstract not provided

Background
There are no standard treatments for patients with advanced thymic epithelial tumors (TET) in whom chemotherapy has failed. A subset of TETs over-express and harbor activating mutations of KIT. Moreover, expression of angiogenic markers correlate with invasiveness of TETs. This two-center phase II study was conducted to evaluate efficacy of sunitinib, a multi-targeted tyrosine kinase inhibitor that blocks angiogenic and other growth factors in TETs.

Methods
Patients with TET who had progressive disease following at least one platinum-based chemotherapy were enrolled. Sunitinib was administered orally at 50 mg once daily in 6 week cycles for 4 weeks followed by 2 weeks off until disease progression. Tumor response was assessed by computed tomography scans every 6 weeks. KIT mutations were assessed in archival tissue. Primary end-point was objective response rate in parallel cohorts (thymoma, thymic carcinoma).

Results
Between May 2012 and June 2013, 22 patients with thymic carcinoma [median age 58 (40-81); males 59%] and 16 with thymoma [median age 54 (31-74); males 44%] enrolled. Median of 4 (range, 1-7) and 3 (range, 1-8) cycles were administered in patients with thymic carcinoma and thymoma respectively. Among 19 evaluable patients with thymic carcinoma, there were three partial responses (16%) and 10 minor responses (50%) (Figure). Thirteen patients had stable disease (68%) and three progressive disease (16%). After median follow up of 7.8 months, the median progression-free survival was 6.2 months and 6-month survival probability 85%. In contrast, only one out of 16 patients with thymoma had a partial response (6%). Twelve patients had stable disease (75%) and three progressive disease (19%). After median follow up of 6.4 months, median progression-free survival was 5.5 months and 6-month survival probability 90.9%. Grade 3 or 4 sunitinib-related adverse events which occurred in >10% of patients included neutropenia (18%), thrombocytopenia (23%), leucopenia (18%), lymphopenia (45%), fatigue (36%), mucositis (32%) and hypertension (18%). Three patients (14%) has symptomatic decline in left ventricular ejection fraction which improved with medical management and discontinuation of sunitinib. KIT mutations were absent in tumors of 20 patients who underwent mutational analysis.Figure 1

Conclusion
In this phase II trial, sunitinib demonstrated anti-tumor activity unprecedented for a targeted agent in previously treated patients with thymic carcinoma. Activity was modest in thymoma. These results are intriguing as response rates of thymic carcinomas are usually lower than that for thymomas. KIT mutations did not predict responses. Ongoing exploratory analyses are evaluating biologic determinants of activity and mechanisms of resistance.

Background
Thymoma is a rare malignancy with a paucity of data on biology. Thymic epithelial tumors are often admixed with developing T-lymphocytes in the microenvironment. Galectin-1 (gal-1) is a beta-galactosidase binding protein involved in T-cell development via thymic stromal and thymocyte interaction as well as thymocyte development through negative selection. Gal-1 also induces apoptosis of effector T-lymphocytes, promotes angiogenesis, and is a poor prognostic indicator when overexpressed in several tumor types. To our knowledge expression of gal-1 has not been examined in thymic epithelial tumors.

Methods
A TMA was constructed from 68 patients with thymic malignancies and 8 benign thymic controls at Stanford University School of Medicine (Stanford, CA). Immunohistochemical stains for galectin-1 (1:200 dilution; citrate pre-treatment; mouse monoclonal; Novocastra) were performed on 4 µM-thick TMA sections. Galectin-1 cytoplasmic staining of the epithelial cell component was scored as negative (0), focal positive (1+), or strong positive (2+) by a Stanford pathologist, who was blinded to the clinical data. Gal-1 expression was averaged for each patient sample. Statistical analysis was performed using SAS Enterprise Guide v5.0 (Cary, NC). Non-parametric statistical analyses were used to compare average patient gal-1 expression between thymic tumors and benign thymic controls. Stable gal-1 knockdown was achieved in IU-TAB1, a human thymoma WHO type AB cell line, using the pLKo.1 vector with gal-1 shRNA (Open Biosystems). Lentivirus was produced using the Trans-Lentiviral Packaging System (Thermo Scientific). In vitro proliferation cell counts were performed by hemocytometer. After hypoxia exposure (0.5% O~2~), apoptotic cells were labeled using the APO-Direct kit and quantified by flow cytometry (BD Biosciences).

Results
Demographics for 68 patients: M:F (53%/47%), Mean age at diagnosis: 55 years, WHO Histology: A (10%), B (57%), AB (24%), C (4%), unclassified (4%), Pathologic Maseoka Stage: I (46%), IIa (18%), IIb (4%), III (18%), IVa (9%) IVb (6%). Gal-1 expression was increased among thymic tumor tissue compared to unpaired controls (mean avg gal-1 expression 1.5 vs. 0.125, p=0.0012, Kruskal-Wallis test). Logistic regression of tumor vs. control thymus by gal-1 generated a C-statistic of 0.845. A significant increase in gal-1 expression was noted across all WHO thymoma subtypes except thymic carcinoma (type C) (p < 0.05, non-parametric ANOVA with post-hoc ranked Dunnett’s t-test). Among 11 thymic tumors analyzed with paired adjacent resected benign thymus tissue from the same patient, a significant increase was noted in gal-1 expression among tumor compared with adjacent resected normal benign thymus (mean avg gal-1 1.82 vs. 0.35, p=0.004, sign-rank test). In vitro, gal-1 knockdown did not affect IU-TAB1 proliferation. Preliminary results showed gal-1 knockdown increased apoptosis under hypoxia compared to scramble control.

Conclusion
Gal1 expression was increased among thymoma compared with benign thymus controls and paired adjacent resected benign thymus. A robust C-statistic of 0.845 indicates that gal-1 expression may discriminate tumor from benign thymus. Increased gal-1 expression was conserved across WHO histologic subtype except for thymic carcinoma—whose analysis was limited due to small sample size. Gal-1 knockdown might increase apoptosis under hypoxia. We are continuing to investigate the biologic and clinical significance of increased gal-1 expression in thymoma.

Background
Thymomic pathologies are associated with the autoimmune disease myasthenia gravis (MG). The thymomagenesis have been studied extensively but the etiology of human thymoma remains poorly understood. Based on the consistent finding that murine polyomavirus induces thymomas in mice we tested the presence of Human Polyomavirus 7 (HPyV7) in human thymic epithelial tumors.

Methods
We applied HPyV7 DNA Fluorescence in situ hybridization (FISH), DNA PCR and immunohistochemistry (IHC) in 37 thymomas (19 female, 18 male; mean age 58.3 years; range 34 – 82 years). Of these, 26 were previously diagnosed with MG. In addition, 2 thymic carcinomas, 20 follicular hyperplasia and 20 fetal thymus tissues were tested for HPyV7.

Results
HPyV7 FISH revealed specific nuclear hybridization signals within the thymoma cells of 23 thymomas (62.2%). Fifteen thymomas revealed strong to very strong hybridization signals, whereas 8 revealed only weak positivity. With one exception the HPyV7 FISH data highly correlated with the HPyV7 DNA-PCR data. IHC showed the presence of HPyV7 on the translational level and immunohistochemical double stainings confirmed the presence of HPyV7 in the epithelial thymoma cellular compartment. One thymus carcinoma was HPyV7 positive the other negative. All fetal thymus tissues were tested HPyV7 negative. The follicular hyperplasia results are pending.

Conclusion
We conclude that HPyV7 is frequently present in human thymic epithelial tumors and absent in fetal thymic tissues. No convincing association on HPyV7 and MG could be found. In as much HPyV7 is of relevance to human thymomagenesis remains to be established.

Background
Thymic carcinoma (TC) is a rare malignant tumor originated within the thymus gland and is associated with a poor prognosis, differing from thymoma which is the most common type of thymic malignant neoplasm. No results of clinical trials focusing on TC have been reported. This single-arm study evaluated carboplatin and paclitaxel (CbP) in previously untreated patients (pts) with advanced TC.

Methods
Pts with Masaoka’s stage III to IVb TC, ECOG PS 0 to 1, and more than 20 years old were eligible. The study treatment consisted of carboplatin (AUC 6) and paclitaxel (200 mg/m2) every 3 weeks for a maximum of 6 cycles. The primary endpoint was objective response rate (ORR) by extramural assessment. Secondary endpoints included overall survival (OS), progression-free survival (PFS), and safety. All pts were followed-up until 24 months (mo) after last enrollment. Based on the SWOG 2-stage design, the planned sample size of 40 pts was determined to reject the ORR of 20% under the expectation of 40% with a power of 0.85 and a type I error of 0.05.

Results
From May 2008 to November 2010, 40 pts were enrolled from 21 centers. Of 39 evaluable for analysis, the median age was 62 years (range, 36–84); 23/16 males/females; 3/10/26 with Masaoka’s stage III/IVa/IVb; 9/11/19 with squamous cell carcinoma/poorly differentiated neuroendocrine carcinoma/other types. The median number of cycles was 6. There was 1/13 complete/partial responses with an ORR of 36% (95% confidence interval [CI], 21-53%; P = 0.031). The median PFS was 7.5 mo (6.2-12.3 mo) while OS did not reach the median value. The 1-year and 2-year survival rates were 85% (95% CI, 69-93%) and 71% (95% CI, 54-83%), respectively. Major adverse event was grade 3-4 neutropenia in 34 pts (87%). Two cases (5%) of grade 3 febrile neutropenia, neuropathy, and arthralgia were observed, respectively. There was no treatment-related death.

Conclusion
CbP showed high efficacy in advanced TC. Our results established that CbP, one of the standard treatments for non-small cell lung cancer, also serves as a key chemotherapy regimen for TC.

Abstract not provided

Background
Customization is feasible in adjuvant setting (tissue availability). SCAT trial has completed planned recruitment with 500 p. For resected NSCLC with nodal involvement adjuvant platinum-based CT improves outcomes but survival remains suboptimal. Compliance may be a key issue for efficacy in adjuvant setting. mRNA BRCA1 levels are prognostic in early NSCLC and could be a predictive marker for CT activity. In advanced disease patients with low BRCA1 benefit from cisplatin doublets meanwhile p with high levels attained longer survival with taxanes.

Methods
Phase III trial testing 4 cycles non-selected vs customized adjuvant CT. Entry criteria: NSCLC, R0 resection, pN1 or pN2, KI > 70, recovered from surgery, adequate hematologic, renal and liver functions, no prior CT or RT, age > 18 y, informed consent. Stratification: N1 vs N2, histology (squamous vs non-squamous), resection (lobectomy vs pneumonectomy). Central lab mRNA BRCA1 levels and quartile distribution. Primary end-point: OS. Secondary end-points: DFS, toxicity, recurrence pattern. Design: R: 1:3. Control treatment: Cis-Docetaxel (CD). Experimental arm: Q1: Cis-Gemcitabine (CG); Q2-3: Cis-Docetaxel; Q4: Docetaxel (D). PORT in pN2 patients. Compliance treatment and toxicity profile analyzed by arm and correlation with potential prognostic factors explored

Results
500 included p; 108 control arm, 392 experimental arm. Median follow-up 18.6 m (2-59 m). Median mRNA BRCA1 levesl 15.78 (0.73-132) Q1 212 (42.4%), Q2-3 150 (30%), Q4 138 (27.6%). Mean BRCA1: Adenocarcinoma: 8.45 vs Squamous 19.6 (p< 0.001). Overall low levels BRCA1: 43.8%. EGFR mut 5.6% 297 p evaluated for compliance planned adjuvant treatment: M/F ratio: 82.5/17.5%. Median age: 62 (range 36-80). PS 0/1/2: 55.9/43,1/1%. Histology: Adenocarcinoma 47.5%, Squamous 44.1%. Stages: IIA/IIB/IIIA: 11.1/38.4/50.2%. Surgical procedure: Lobectomy 72.1%; Pneumonectomy 27.9%.. Toxicity. G3-4 AE: Neutropenic fever: CD 10% vs D 4.4% vs CG 0%. (p=0.0056); Nausea/vomits: CG 11.1% vs CD 10.4% vs D 0%. (p=0.0198); Hypersensitivity: D 5.97% (NS). Dose-reduction: 34.24% control vs 18.30% experimental (p=0.0044). Full 4 cycles CT compliance: CD control 80.83%, CG 91.2%, CD experimental 79.2%, D 88.1% (p=0.052). No differences in dose-reductions. CT compliance lobectomy 86.4% vs 85.5% pneumonectomy (NS). CT compliante < 70 y 91.1% vs 66.6% > 70 y (p<0.01)PORT compliance 55.31% of planned cases.

Conclusion
Planned trial recruitment achieved with median f-u 18.6 m. Majority of resected NSCLC showed low levels expression BRCA1. Adenocarcinoma lower levels than Squamous. Safety profiles differences observed between treatment schedules: neutropenic fever (CD), nausea/vomits (CG). Customized treatment requires less dose-reductions. Trend to poor compliance with Cis-Doc. No relation between extensión of surgery and adjuvant Tx compliance . Compliance CT significantly lower for age > 70 y. Low compliance for PORT.

Background
Although UFT is approved in eastern countries, most guidelines do not recommend any adjuvant treatment in resected Stage I NSCLC. Pazopanib (P) is a potent, orally active multi-target receptor tyrosine kinase inhibitor of VEGFR-1, -2, -3, platelet derived growth factor (PDGFR) type-α and –β, approved in metastatic renal cell carcinoma and sarcoma. Neoadjuvant P demonstrated single-agent activity in patients with early stage NSCLC. We report the feasibility and tolerance of adjuvant P in stage I NSCLC.

Methods
In this double-blind randomized multicenter phase II/III trial, completely resected patients (pts) with stage I NSCLC (7[th] TNM edition) were randomized to receive either placebo or P 800 mg/d during 6 months. The Fleming’s two stage phase II primary endpoint was compliance (i.e. % of pts able to receive at least 3 months of P, whatever the dose). After 64 pts included (interim analysis), IDMC recommended to start with P 400 mg/d because of initial insufficient compliance. A one-step Fleming design was used with the new dose. Phase II design was not comparative.

Results
143 pts were randomized in 29 centers between March 2009 and August 2012, 71 and 72 in the placebo and P arms respectively. Most pts were male (61%) and smokers (91%), median age was 60. Pathological stage was IA in 111 pts (78%) and 16% were squamous cell carcinomas. Compliance for P800 was adequate in 38% (95% confidence interval [21-56]) vs. 87% [71-96] in placebo; for P400 in 69% [50-84] (p=0.01, compared to P800) vs. 93% [77-99] in placebo. Dose modifications were seen in 44% and 34% of P800 and P400 groups. The proportion of patient with at least one grade 3/4 toxicity was 53% [35-71] in P800 (13% [4-29] for placebo) and 38% [21-56] in P400 (27% [12-46] for placebo). No toxic deaths were observed. Only 2 pts has grade 4 toxicities in P800 (fatigue in P arm, GGT in the placebo arm). Most common toxicities G3 in P800 were diarrhea (9%), hypertension (9%), and increased transaminases (16% vs. 0% in P400); in P400 gastro-intestinal disorders (16%, 6% diarrhea) and hypertension (6%).

Conclusion
IFCT-0703 is the first feasibility study demonstrating that full dose of P is safe but not feasible in the adjuvant setting in NSCLC. Compliance and tolerance with reduced dose appeared acceptable for adjuvant settings.

Background
In general thoracoscopic lobectomy (VATS) is considered being associated with advantages compared to conventional thoracotomy when it comes to postoperative outcomes such as pain, duration of hospitalization and overall complications. It is also believed that a reduction in these complications leads to better patient compliance with adjuvant chemotherapy. However, this assumption is based on single-institution case-control studies and selection bias is possible. This is a study on the differences in patient compliance with adjuvant chemotherapy following lobectomy by VATS or thoracotomy. Data are obtained from a complete national registry on lung cancer patients.

Methods
To investigate if the surgical approach alone had an impact on patient compliance to adjuvant chemotherapy we investigated patients who underwent lobectomy for clinical stage I non-small cell lung cancer. The patient population in this study had; however, unsuspected nodal involvement and adjuvant chemotherapy was indicated. Patients were analyzed for type of adjuvant chemotherapy as well as failure to begin or complete full treatment. A clinical oncologist who was blinded for surgery approach reviewed all patient files in order to investigate the data on chemotherapy.

Results
From 2007-2011 lobectomy for clinical stage 1 disease was performed in a total of 1513 patients by VATS (N=718/ 47.5%) or thoracotomy (N=795/ 52.5%). Unsuspected nodal disease was diagnosed in 278 (18.4%) patients, 11 patients were excluded. They had either distant metastasis or radiotherapy due to nonradical resection. This left 267 patients for further analyses, adjuvant chemotherapy was delivered to 155 (58.1%) and 98 (36.7%) completed 4 cycles as planned. There was no significant difference in patient compliance with chemotherapy and surgical approach (p=0.35). Survival was significantly influenced by comorbidity, histology and compliance with chemotherapy (p<0.001) in a Cox proportional hazard analysis; Survival was not influenced by sex, age or surgical approach.

Conclusion
In this study with complete national data we did not confirm the assumption that patient compliance with adjuvant chemotherapy was better after thoracoscopic lobectomy compared to conventional lobectomy. Survival was significantly influenced by compliance with chemotherapy but not surgical approach.

Background
Most patients with early-stage lung cancer will die of recurrent disease despite multimodality therapy with curative intent. KRAS is the most commonly mutated oncogene in lung adenocarcinomas, and patients with resected disease are a unique population amenable to a personalized clinical trial approach. GI4000 is a vaccine created from whole, heat killed recombinant Saccharomyces cerevisiae yeast, overexpressing KRAS Q61L plus Q61(R or H) and either a G12C, G12D, G12V, or G12R mutation. This study aimed to assess the feasibility and immunogenicity of the GI4000 vaccine in patients with KRAS-mutant lung cancers and to compare the outcomes of patients to matched controls.

Methods
Patients with Stage I-III KRAS-mutant lung cancers who completed curative therapy were enrolled. Each patient was routinely administered the genotype-matched vaccine from the GI4000 series subcutaneously starting 1-4 months after standard treatment completion: weekly x 3, monthly x 6 and every 3 months for a total of 3 years (19 doses). KRAS-antigen T-cell response was assessed by interferon-γ ELISpot assay in peripheral blood mononuclear cells. The study was powered to detect an immune response rate of ≥25% (N=24 patients). A comparison group matched for age, sex, KRAS genotype and stage was used to compare recurrence and survival using the Kaplan-Meier method with a hazard ratio for survival adjusted for age, sex and stage.

Results
In 28 months, 33 patients were screened and 24 patients enrolled. The study met its primary endpoint with 63% of evaluable patients (50% of all patients) developing an antigen-specific immune response. 19 patients had evaluable baseline samples, 9/13 with a negative response at baseline developed a treatment emergent response and 3/6 with a pre-existing baseline response had an increased response over baseline that met pre-specified immunologic criteria. There were no treatment-related Grade 3/4 or severe AEs. The median number of vaccinations received was 15 (range 1-19). 1 patient withdrew consent due to local injection site reaction and 2 died of recurrent disease during study. The baseline characteristics and clinical outcomes of the trial patients and a group of matched controls is presented in the Table below.

Conclusion
The GI4000 vaccine is safe, feasible and immunogenic after completion of curative-intent therapy in patients with KRAS-mutant lung cancers. Recurrence rates are equivalent but overall survival trends favorably when compared to matched controls. Exploratory analysis of survival in the immune responders versus matched controls is underway. A randomized study with prospective biomarker analyses is warranted.

Background
Postoperative adjuvant chemotherapy is extensively received due to its extension of the time to recurrence and enhancement of survival rate in non-small cell lung cancer (NSCLC). However, it has reached the plateau at current, the beneficial cases are few, and drug-resistance and over-treatment phenomena are present in most of patients, hence it is necessary to seek a new postoperative adjuvant chemotherapy to improve the survival rate. Angiogenesis is one premise of malignant tumors to occur, develop and metastasize, but vascular endothelial growth factor (VEGF) is one of the most important tumors in the process of neovascularization. Under normal conditions, VEGF is hardly expressed in a lot of normal tissues in vivo, while highly expressed in the tumors like osteosarcoma, bladder cancer, breast cancer and colorectal cancer. Recombinant human endostatin (endostar) can significantly intervene the angiogenesis-promoting effect to block the nutritional supply of tumors and inhibit tumor proliferation or metastasis. We compare the curative effect of endostar plus adjuvant chemotherapy and adjuvant chemotherapy alone in the treatment of patients with completely resected NSCLC at stage IB-IIIA.

Methods
This is an open, multicenter, randomized (1:1) study, stratified by gender, stage and histology. Completely resected pts (stage IB to IIIA) were randomized to receive adjuvant NP plus Endostar (Vinorelbine 25mg/m2 on d1 and d8 plus Cisplatin 75 mg/m2 on d1, and iv plus Endostar 7.5mg/m2 per day iv for consecutive 14 days. Every 21 days as one cycle for 4 cycles) or NP regimen alone. The primary endpoint was disease-free survival (DFS). Secondary endpoints included tumor response rate, overall survival and safety.

Results
250 pts (1:1) were included between 07/2007 and 06/2009. Two arms were well-balanced with regard to age, gender, histology, staging, and resection type. The follow-up time is 42 months. The two groups had no significant difference in the incidence of toxicity reaction. Endostatin plus NP can prolong the DFS of patients with complete resectable NSCLC at stage IIIA (19.33±3.73m vs 17.10±9.68m) with high security, but no statistical difference. Cases with high expression of VEGF showed a better DFS than cases with low expression in Endostatin plus NP group (48.45±3.52m vs 40.18±4.54m, P < 0.05). The level of peripheral circulating endothelial progenitor cells (EPCs) in NSCLC patients is significantly higher than that in healthy volunteers. EPCs level was associated with NSCLC stage. The EPCs levels after treatment significantly decreased than that before treatment (P=0.014) in beneficiaries of NP or NP plus with endostar. The time to progression (TTP) was longer in patients with lower levels of EPCs (<0.35%) before chemotherapy or endostatin treatment (P<0.001).

Conclusion
This preliminary result showed vascular targeted therapy in postoperative adjuvant therapy of lung cancer has a good application prospect. VEGF and EPCs play important roles in the development of lung cancer. Deep studies should be taken for the other related molecular targets in the future.

Abstract not provided

Background
We conducted a phase III randomized controlled study to investigate the efficacy of post-surgical adjuvant chemo-immunotherapy using activated killer T cells and dendritic cells (AKT-DC) obtained from regional lymph nodes of lung cancer patients. The target of immunotherapy is the residual micrometastases after surgery and the resistant clones to chemotherapy.

Methods
Between April 2007 and July 2012, 103 patients with post-surgical non-small cell lung cancer were randomly assigned to receive either chemo-immunotherapy (group A) or chemotherapy (group B). Immunotherapy was consisted of adoptive transfer of autologous activated killer T cells and dendritic cells (AKT-DC) obtained from regional lymph nodes of lung cancer patients. The primary end point of this study was overall survival. Secondary end points were recurrence free survival, toxicity, and adverse effects of immunotherapy.

Results
Two and five years over all survival were 93.4% and 81.4% in group A and 66.0% and,48.3% in group B respectively. The difference was statistically significant (log-rank test p=0.0005, generalized Wilcoxon test p=0.0005) in favor of chemo-immunotherapy group A. Hazard ratio was 0.229 (95% CI 0.093 to 0.564).Two year recurrence free survival was 68.5%(53.2 to 79.7%: group A) and 41.4% (27.5 to 54.7: group B). The difference was statistically significant (log-rank test p=0.0020 and HR 0.423(95% CI 0.241 to 0.743) in favor of group A. [Adverse effects of immunotherapy.] Chill and shiver: Out of total 762 courses, 52 courses (6.8%) were accompanied with chill and shiver and 47 courses (6.2%) fever (>38) thereafter. Out of 50 cases treated by immunotherapy, 28 cases had no side effect and 22 cases had at least more than one side effect of chill, shiver and/or fever.

Conclusion
Immunotherapy using this modality is effective in recurrence control of post-surgical lung cancer patients by inhibiting the growth of disseminated micrometastases.

Background
The NCIC CTG JBR.10 trial demonstrated that adjuvant chemotherapy (ACT) improves survival in resected stage IB/II non-small cell lung cancer (NSCLC) compared to observation. A 15-gene expression signature was developed from the trial population and subsequently validated to stratify patients with resected NSCLC into low and high risk prognostic groups. The signature may also be predictive for greater benefit from ACT in high risk patients (Zhu et al. JCO 2010), but this has not yet been validated. This gene expression signature may offer a risk stratification strategy to identify patients most likely to benefit from ACT. We conducted an exploratory economic analysis to assess the impact of the use of this gene signature compared to current clinical staging to guide ACT decisions in resected early stage NSCLC.

Methods
We developed a decision analytic model populated by the NCIC CTG JBR.10 trial cost and outcome data, including direct medical costs and overall survival (OS). Utility for each health state was estimated from quality of life data to generate quality-adjusted survival. The analysis was performed over a lifetime horizon from the perspective of the Canadian public health care system, expressed in 2013 Canadian dollars. Survival and costs were discounted at 5% per year. We determined the incremental cost-effectiveness ratio (ICER) and incremental cost-utility ratio (ICUR) of ACT versus observation in resected stage IB/II NSCLC in the following two scenarios: (1) gene signature-directed ACT, where patients classified as having high risk of recurrence receive ACT and those at low risk are observed; and (2) clinical stage-directed ACT, where gene signature profiling is not performed – those with stage IB tumours >4cm or stage II NSCLC receive ACT, and those with stage IB tumours <4cm are observed. Nonparametric bootstrapping to estimate 95% confidence intervals (CI) and multi-way sensitivity analyses were performed.

Results
The analysis included 52 patients in the gene signature-based strategy and 125 patients in the stage-based strategy with available direct medical costs and gene signature data. The mean survival gain of ACT versus observation was 2.28 years using gene signature-directed selection, and 1.59 years using stage-directed selection. The discounted ICER of ACT versus observation was $8,327/life-year gained (LYG; 95% CI, $395 to $19,590) using the gene signature-directed approach, and $5,623/LYG (95% CI, -$2,161 to $14,354) for the clinical approach. There was no significant difference in the ICER between the two strategies (p=0.52). The discounted ICUR was $11,315/quality-adjusted life-year (QALY; 95% CI, $211 to $27,314) using the gene signature-directed approach, and $7,728/QALY (95% CI, -$3,080 to $19,825) for the clinical approach. Sensitivity analyses showed that the ICER was most sensitive to changes in the survival hazard ratio (i.e. treatment benefit) and utility, but less sensitive to the cost of the gene signature (range $0 to $10,000 per case, with corresponding ICER $15,794 to $28,194/LYG, respectively).

Conclusion
This exploratory analysis suggests that use of the 15-gene expression signature to guide decisions for ACT in resected stage IB/II NSCLC patients could be highly cost-effective. Further validation of the signature’s impact on ACT outcomes is needed.

Background
Mediastinal lymph nodes staging in NSCLC is of paramount importance. Although relatively precise, diagnostic modalities still employ certain level of invasiveness. Artificial Neural Network (ANN) is a well established predictor tool which, due to underlying distribution and relationship among the given variables, allow for construction of multidimensional models trained in prognosis of given outcome. Their performance in mediastinal staging based on radiological data only, currently remains unknown.

Methods
Samples from 467 lymph nodes were obtained from 160 patients with primary NSCLC by means of endobronchial ultrasound guided-transbronchial needle aspiration (EBUS-TBNA), mediastinoscopy or lymphadenectomy during thoracotomy and microscopically analyzed. ANN models were created and prospectively validated on unmatched cohort of 50 consecutive patients (158 groups of lymph nodes). To identify factors correlated with nodal involvement single factor tests and logistic regression analysis were performed.Figure 1 Figure 1. The multilayer perceptron (MLP). Artificial Neural Network (ANN) structure for predicting metastatic involvement of mediastinal lymph nodes in NSCLC patients.

Results
Size and standard uptake value (SUV) of the node along with primary tumour T characteristics were identified as the most sensitive variables regardless of the analysis conducted. Two ANN models predicted metastatic involvement with 89% and 92% accuracy. Single factor tests maintained high accuracy only for 2 out of 4 most sensitive variables (SUV >2.8 and length >15mm) in prospective validation. Additionally, logistic regression analysis allowed for construction of scoring model with certain parameters corresponding to risk thresholds of metastatic disease.Figure 1 Figure 2. Artificial Neural Network (ANN) characteristics. ROC curves for 2 manually designed ANNs (A); Sensitivity analyses of coefficients (B) and overall characteristics of ANNs performance (C).

Conclusion
ANN is a repeatable and accurate diagnostic tool in mediastinal staging in NSCLC patients. Before its role in clinical practice will be established in large multi-centre study, findings of this preliminary report should be considered as exploratory only.

Background
Pleural lavage cytology (PLC) is considered to be a prognostic factor for non-small cell lung cancer (NSCLC) patients. There has been no report describing the relationship between adjuvant chemotherapy and the presence of PLC.Backgroud: Pleural lavage cytology (PLC) is considered to be a prognostic factor for non-small cell lung cancer (NSCLC) patients. There has been no report describing the relationship between adjuvant chemotherapy and the presence of PLC.

Methods
From January 2000 to December 2009, we retrospectively reviewed the medical record of lung adenocarcinoma patients who underwent tumor resection and were positive for PLC immediately after thoracotomy.

Results
There were 53 patients (4.8%) out of 1114 lung adenocarcinoma patients had PLC positive findings, including 31 male and 22 female patients, with a mean age of 66.6 years. Median follow up period was 33.6 months. Adjuvant chemotherapy was administered intravenously to 24 patients and they were classified as adjuvant chemotherapy group. The rest of 29 patients were classified as surgery alone group. Pathological stage of I / II / III was 12 (41%) / 8 (28%) / 9 (31%) in surgery alone group and 7 (36%) / 8 (30%) / 9 (38%) in adjuvant chemotherapy group. The regimen of chemotherapy was as follows; 8 patients received cisplatin plus gemcitabine, 7 patients received carboplatin plus paclitaxel, 7 patients received gemcitabine, and 2 patients received others. 5-year survival rate was 50.3% and 29.7% (p=0.09) and 5-year recurrence free survival rate was 34.6% and 15.7% (p<0.01) in adjuvant chemotherapy group and surgery alone group. Even in stage I cases, there was a tendency that adjuvant chemotherapy group had better 5-year recurrence free survival than surgery alone group (60.1% and 29% p=0.11). In the COX proportional hazard multivariate analysis for recurrence free survival revealed that adjuvant chemotherapy (hazard ratio (HR) 0.45, p=0.03), tumor size >30mm (HR 2.23, p=0.02), and lymph node metastasis (HR 2.67, p<0.01) were significant independent prognostic factors.Figure 1

Conclusion
Adjuvant chemotherapy was considered to be effective for PLC positive lung adenocarcinoma patients. Even in stage I cases, our results implicated that adjuvant chemotherapy was beneficial.

Background
Non-small cell lung cancer (NSCLC) with postoperative recurrence (POR) is generally believed to have an incurable disease. However, several studies have indicated that only a limited number of distant recurrences (oligorecurrence) may benefit from local therapy to the distant site of disease. We investigated factors associated with postrecurrence survival (PRS) in recurrent NSCLC, and particularly the role of local therapy to the metastatic site.

Methods
From 2000 through 2009, a total of 1542 patients with NSCLC underwent complete surgical resection. Of those, we reviewed the records of 356 patients with POR.

Results
Type of POR included locoregional only in 114 (32%), distant in 242 (68%). Of the 242, there were 65 oligorecurrences. Initial recurrence therapy found local treatment for 68 (surgery 5, radiation 12, surgery with chemotherapy and/or radiation 12, chemoradiotherapy 39). Multivariate analysis demonstrated that older age (HR1.522), advanced stage (HR1.371), shorter disease-free interval (DFI; HR1.733), non-adenocarcinoma (HR1.442), systemic treatment (-) (HR1.481), EGFR-TKIs (-) (HR1.563), local treatment (-) (HR1.705) and bone metastases (HR2.140) had a significant association with poor PRS, and oligorecurrences state appeared as an independent PRS factor in patient with distant recurrence (HR1.836). Median PRS times were 36.3 months for 37 patients with DFI > 16 months and receiving local treatment, and 16.0 months for other (p<0.001) in all patients (Fig.1), and 36.5 months for 29 patients with DFI > 16 months and oligorecurrence, and 14.6 months for other (p<0.001) in patient with distant recurrence (Fig.2). There was no significant difference in survival for the patients with oligorecurrence according to whether or not receiving local treatment. Figure 1Figure 2

Conclusion
This study showed that local therapy improved PRS in patients with POR. Optimization of personalized systemic treatment depends on patient selection, and therapeutic strategy for adding an aggressive local treatment options based on a careful follow-up is important.

Abstract not provided

Background
Radical pleurectomy is our standard approach for achieving a macroscopic complete resection in patients with malignant pleural mesothelioma undergoing surgery-based treatment. This procedure, not pneumonectomy, is performed even in the setting of advanced stage disease, bulky tumors and/or extensive involvement of the pulmonary fissures. Although the majority of patients subjectively rate their breathing as “good” after this operation we recently started measuring postoperative pulmonary function, reported herein.

Methods
We examined pre and postoperative FEV~1~ levels among 27 patients undergoing radical pleurectomy: 2 stage I, 3 stage II, 17 stage III, 5 stage IV.

Results
The figure shows pre/postoperative FEV-1. Median preoperative levels did not differ significantly between stages (P=0.25): 2.47 (Stage I/II) 2.19 (Stage III) and 1.68 (Stage IV) liters/second. Post-operative median values were 2.16 (Stage I/II), 1.97 (Stage III) and 1.05 (Stage IV) liters/second. The median (interquartile range) decrease in FEV-1 was 0.28 (0.12, 0.51) liters/second, which corresponds to a median (interquartile range) decrease in percent predicted FEV-1 of 7% (4.5%, 16.0%), neither change being statistically significant between stages. Figure 1

Conclusion
These operations were conducted in an advanced stage cohort of patients, 81% stage III or IV. The nominal decrease in FEV1 corresponds with the subjective impression of the patients regarding their pulmonary function. While lung parenchyma is preserved with radical pleurectomy, we conjecture the decrease in FEV1 is likely related to compromise in breathing mechanics. Further studies are ongoing to better quantify and characterize the decrease in pulmonary function observed with this operation and to more rigorously integrate this information with formal quality of life assessments.

Background
Surgery for malignant pleural mesothelioma (MPM) is typically restricted to patients without intraperitoneal or contralateral pleural spread. Imaging studies are accompanied by both false positive and false negative errors for both types of spread. To avoid these errors our group has routinely performed laparoscopy and selective contralateral video-assisted thoracoscopy (VATS) since 1997.

Methods
168 patients with MPM were evaluated for surgery as part of a multimodal treatment protocol. Radiographic staging studies included CT Chest with contrast for all 168 patients, PET Scan (112 patients) and MRI Abdomen (17 patients) for concerning findings on CT and/or PET. 150 patients underwent laparoscopy (two 5mm ports) with both peritoneal biopsy and lavage for cytology. 130/150 laparoscopies were performed in virgin abdomens with the remainder being reoperative procedures. 18 patients also underwent contralateral VATS, based upon any suspicious radiographic findings by either the interpreting radiologist or as reviewed by a multidisciplinary panel of treating physicians. All VATS were performed through a single 1 cm incision. Laparoscopies were performed as outpatient procedures. Patients undergoing combination VATS/laparoscopy were scheduled as same day admissions.

Results
There were no operative complications for either procedure. 5/132 (4%) laparoscopy patients scheduled as outpatients required overnight hospitalization – the most common reason being urinary retention. Laparoscopy revealed inaccuracies in radiographic staging in 13/150 (9%) patients- 6 false positive studies (1 interpretation of diaphragm transgression that was not through the diaphragm and 5 metastases that were not present) and 7 false negative studies (3 detected by lavage and 4 by biopsy). All of the false positive and all of the false negative studies occurred in patients who had PET scans. 2/18 (11%) patients who underwent VATS were positive for mesothelioma in the contralateral pleura, only one of whom had a positive PET scan finding.

Conclusion
Routine laparoscopy was performed safely and revealed inaccuracy in radiographic staging in 9% of the patients, all of whom had both CT and PET scans. Selective contralateral VATS was performed safely and revealed cancer in 11% of patients with suspicious findings, as determined by the interpreting radiologists and/or the treating clinicians and with PET only being accurate in one of the two positive findings. We conclude that prior to offering patients surgery-based treatment for MPM routine laparoscopy and VATS, based upon any suspicion, are indicated.

Background
Malignant pleural mesothelioma (MPM) is an aggressive disease of the pleural lining with a dismal prognosis of 6 – 12 months from the time of diagnosis. Surgical treatment of MPM includes extrapleural pneumonectomy and pleurectomy/decortication (P/D). Recently, IASLC has reclassified P/D according to therapeutic intent and surgical technique into partial P/D, P/D, and radical P/D. The present meta-analysis aimed to compare the perioperative and long-term outcomes of EPP and radical P/D for patients with resectable MPM.

Methods
A systematic review of the literature was performed on five electronic databases to identify all relevant data on comparative outcomes of radical P/D and EPP. Endpoints included perioperative mortality and overall morbidity, as well as long-term overall survival.

Results
Six relevant studies with comparative data of EPP (n= 601) versus radical P/D (n=493) were identified from the current literature. Comparison of these two groups demonstrated significantly lower perioperative mortality (3.0% vs 6.5%, p=0.04) and overall morbidity (30.4% vs 64.3%, p<0.0001) for patients who underwent radical P/D compared to EPP. Median overall survival ranged between 13 – 29 months for radical P/D and 12 – 22 months for EPP, with a strong trend favouring radical P/D. Figure 1Figure 2

Conclusion
Although it must be emphasized that patient selection and treatment strategies differ between EPP and radical P/D, a number of comparative studies have recently been conducted to compare these two surgical techniques for patients with resectable MPM. The present study indicated that appropriately selected patients who underwent radical P/D had lower perioperative morbidity and mortality with similar, if not superior, long-term survival compared to EPP.

Background
Pleurectomy/decortication (P/D) in the treatment of malignant pleural mesothelioma includes a number of procedures with different clinical indications and therapeutic intents. To unify the nomenclature, IMIG and IASLC recently defined P/D-related procedures according to surgical technique, including ‘extended P/D’, ‘P/D’ and ‘partial pleurectomy’. The present systematic review aimed to assess the safety and efficacy of these techniques.

Methods
A systematic review of relevant studies was performed by electronic search of five online databases from 1985 to 2012 by two independent reviewers according to predefined selection criteria.

Results
Thirty-four studies involving 1916 patients who underwent pleurectomy were included for quantitative analysis. These included 12 studies on ‘extended P/D’, 8 studies on ‘P/D’ and 14 studies on ‘partial P/D’. Perioperative mortality ranged from 0% - 11% and perioperative morbidity ranged from 13% - 43%. Median overall survival ranged from 7.1 – 31.7 months and disease-free survival ranged from 6 – 16 months. One study reported on quality-of-life outcomes using a standardized questionnaire suggesting superior outcomes for ‘extended P/D’ compared to extrapleural pneumonectomy. Figure 1Figure 2

Conclusion
Results of the present systematic review suggested similar perioperative mortality outcomes between different P/D techniques but a trend towards higher morbidity and length of hospitalization for patients who underwent ‘extended P/D’. However, overall and disease-free survival appeared to favour ‘extended P/D’ compared to less aggressive techniques. Future studies on P/D should adhere to recent definitions to enable accurate analysis of similar procedures. Direct comparisons of pleurectomy to extrapleural pneumonectomy remain challenging, and should be restricted to ‘extended P/D’ procedures only.

Background
Local mesothelioma recurrence remains a challenge even after multimodal therapy. Intracavitary chemotherapy is a promising approach to improve local tumor control. In preclinical studies we observed improved pharmacokinetic characteristics when cisplatin was loaded to a fibrin carrier and applied to the chest wall after surgery while effectiveness remained the same compared to cisplatin applied as a solution. We will present the first results of a phase I –dose-escalation-clinical study.

Methods
Since 11/2012 3 patients were included in the study. Cisplatin-fibrin was applied after pleurectomy/decortication (P/D) to the chest wall in a concentration of 11 mg/m[2] BSA. Blood samples were taken at several time points after the application (2, 6, 10, 24, 48 and 120 hours) to assess serum cisplatin levels and to test toxicity in the early phase until 14 days postoperatively. The concentration of total platinum was quantified by means of inductively coupled plasma sector field mass spectrometric detection. Adverse events were graded according to the CTCAE.

Results
Between November 2012 and March 2013 three patients (2x epithelioid, 1x biphasic) in stage II, III and stage IV were included and received P/D plus Cisplatin-Fibrin in a concentration of 11 mg/m[2]. The maximum concentration of cisplatin in the serum was below 0.3 µg/g at 2 h after application and continued to decrease over a period of 5 days (see image 1). No severe adverse events were observed. The adverse events documented were not related to cisplatin (table 1):

Conclusion
Our preliminary results show, that cisplatin-fibrin application to the chest wall and the lung surface after P/D is safe on a dose level of 11mg/m2 BSA. As no treatment related mortality and no drug related toxicity was observed we escalate the dosage to 22 mg/m2 BSA, further results including chest wall concentrations of cisplatin will be available in October.

Abstract not provided

Background
Malignant pleural mesothelioma (MPM) is an aggressive cancer with a median survival of around one year and a 5 year survival rate of less than 10%. A selected group of patients with a potentially resectable tumour mass and good performance status may be considered for extrapleural pneumonectomy (EPP). However the results of this form of treatment are variable. Several prognostic markers have been explored to assist with patient selection including histological subtype, neutrophil-to-lymphocyte ratio (NLR), calretinin and microRNA miR-29c* expression in tumour tissue. In the present study we used microarray profiling to identify other microRNAs which might have the potential to serve as a prognostic biomarker.

Methods
The study used 60 formalin-fixed paraffin embedded (FFPE) tumour tissues from MPM patients who underwent EPP and had sufficient tumour for RNA extraction, a series which had been previously used to assess the prognostic value of the NLR. MicroRNA microarray profiling was performed on RNA from the 8 patients with longest (median: 53.7 months) and the 8 patients with shortest (median: 6.4 months) survival. Candidate microRNAs were selected on a basis of biological (>2-fold difference) and statistical (p<0.05) significance, and selected candidates were independently validated in the initial profiling samples using TaqMan assay-based microRNA-specific RT-qPCR. Levels of validated candidates were then assessed by RT-qPCR in 44 additional tumour samples. Overall survival (OS) was calculated from date of EPP and date of death or last follow-up, with patients still alive at last follow-up censored. The median relative expression level of each candidate was used as cut-off to determine high and low expression for examination using the Kaplan-Meier method. Individually significant (p<0.05) variables were entered into a multivariate model together with the established risk factors age, gender, histological subtype, NLR.

Results
Microarray profiling identified 12 microRNAs with lower expression in long-term survivors and 4 microRNAs with higher expression in long-term survivors. None of the microRNAs with higher expression in long-term survivors could be validated using RT-qPCR. Of the microRNAs with lower expression in long-term survivors, miRs-30e, -93, -106b, -210, and -222 were validated by RT-qPCR in the same samples used for the profiling and found to be significantly different between long-term and short-term survivors. The expression levels of miR-30e and miR-210 showed a significant association with survival. MiR-30e: median OS of 24.2 months for low expression vs 13.3 months for high expression (p=0.03); miR-210: median OS of 24.2 months for low expression vs 13.7 months for high expression (p=0.008). In addition, both gender and histological subtype were significant prognostic factors using a univariate model. Multivariate analysis with age, gender, histological subtype, NLR and microRNA expression included as variables revealed that miR-210 was the only factor remaining significant (p= 0.006; hazard ratio: 0.41; 95% CI: 0.2-0.85).

Conclusion
This study has identified expression of miR-210 as a potential new prognostic factor for patients undergoing EPP. Further validation is needed, but this marker has the potential to assist in better selection of patients considered for radical surgery of MPM.

Background
We previously introduced a 3-level risk assessment algorithm based on tumor volume, gender and hemoglobin level (JTO 6:S486-7). Its applicability was limited to patients with epithelial disease undergoing surgery. We now report an expanded 4-level risk algorithm incorporating histologic subtype determined by pleural biopsy and interlobar septum thickness as additional predictors. We test its ability to stratify outcome among patients treated on a prospective phase I trial (protocol 07-091) of primary surgery and hyperthermic intraoperative intracavitary cisplatin plus dose-escalated gemcitabine.

Methods
All patients who underwent primary extrapleural pneumonectomy (EPP) or pleurectomy (PDC) between 2001-2012 with preoperative CT scan available for retrospective review were included. Patients enrolled on 07-091 were reserved for validation; the remaining patients were used to train the model. Maximal thickness among measurable interlobar septae was measured on CT and binned into 2 categories (≤5mm, >5mm). Kaplan-Meier estimates of overall survival functions were used to define risk strata. Cox regression was used to assess algorithm stratification of overall survival and time to recurrence.

Results
The model cohort comprised 308 patients (221 EPP, 87 PDC; 241 male; 244 epithelial histology on biopsy; median age 63). The validation cohort comprised 90 patients (53 EPP, 37 PDC; 70 male; 53 epithelial histology on biopsy; median age 66). Alignment of survival functions after stratification of 3-level risk by septum thickness and biopsy histology in the model cohort suggested 4 risk strata (A-D). The expanded algorithm stratified both model and validation cohorts into balanced groups with distinct overall survival and time to recurrence (Table).

Conclusion
This expanded risk stratification algorithm is based on information available preoperatively for the majority of patients with pleural mesothelioma being considered for surgical resection. It provides important prognostic information that is not reflected in conventional clinical stage regarding the risks and potential benefits of aggressive management for individual patients.

Background
Our experience in tri-modality therapy for MPM with induction chemotherapy followed by EPP and high dose hemithoracic radiation demonstrated that completion of EPP and radiation provided the best results. We therefore developed a new protocol of accelerated induction hypofractionated hemithoracic IMRT followed by EPP to deliver optimal radiation to the whole tumor bed in a short period of time. EPP is performed approximately one week after completion of radiation to limit the risk of pneumonitis. The results of Surgery for Mesothelioma After Radiation Therapy (SMART) was reviewed and compared to our previous cohort of patients undergoing induction chemotherapy followed by EPP and adjuvant hemithoracic radiation.

Methods
All patients undergoing EPP in our institution between 01/2001 and 06/2013 were reviewed. The SMART protocol (25 Gy in 5 daily fractions over 1 week delivered to the entire ipsilateral hemithorax by IMRT with concomitant boost of 5 Gy to volumes at high risk based on CT and PET scan findings) was started in 2008. EPP was performed 6±2 days after radiation therapy. The results of the SMART protocol were compared to the group of patients undergoing induction chemotherapy followed by EPP as part of a trimodality approach.

Results
A total of 111 patients underwent EPP between 01/2001 and 06/2013 with a hospital mortality of 4.5% (n=5). A total of 64 patients (81% men, 59±9 years old, 81% with epithelial histologic subtype) underwent induction chemotherapy, while 39 (82% men, 62±9 years old, 69% with epithelial histologic subtype) underwent SMART. Seven patients had no induction therapy and one had pre-operative chemo- and radiation therapy. Since 2008, the number of surgical patients undergoing SMART progressively increased from 14% in 2008 to 100% in 2013. None of the patients undergoing SMART died in hospital or within 30 days of surgery, while 4 of the 64 patients (6.4%) undergoing induction chemotherapy died in hospital after EPP (p=0.1). Patients undergoing SMART tended to have a greater proportion of ypN2 disease on final pathology than patients completing induction chemotherapy before EPP (58% vs 41%, respectively; p=0.09). After a median follow-up of 16 months after the start of therapy, the 3-year survival was significantly better in patients with epithelial disease undergoing SMART (n=27) compared to patients with epithelial disease undergoing induction chemotherapy and EPP (n=52) (79% 3-year survival vs 30% 3-year survival, respectively; p=0.04). In contrast, the 3-year survival of patients with biphasic disease was similar between patients undergoing SMART (n=12) or induction chemotherapy and EPP (n=12) (20% vs 8%, respectively; p=0.8). Multivariate survival analysis using Cox regression model demonstrated that epithelial histologic subtype (p=0.0003), the absence of ypN2 disease (p=0.007) and SMART (p=0.03) were predictors of better survival.

Conclusion
Over the past 5 years, accelerated hemithoracic IMRT followed by EPP has become our preferred approach for surgically resectable MPM. Surgery for mesothelioma after radiation therapy was feasible with no operative mortality in 39 patients. Although comparison with our historical cohort of patients has limitations, our current protocol provides very encouraging results in patients with epithelial disease with a 3 year survival of 79%.

Background
Pleurectomy/decortication (P/D) is increasingly used for the surgical management of MPM. The presence of the remaining ipsilateral lung poses a challenge when delivering adjuvant radiation therapy, as the risk for radiation pneumonitis (RP) is high. We developed an IMRT technique targeting the entire pleura of the involved hemithorax, with promising early results. Here, we present the interim results of a prospective phase II study to determine the safety and toxicity profile of pleural IMRT following induction chemotherapy and P/D.

Methods
Twenty-nine patients with locally advanced MPM have been enrolled to date. All patients received up to four cycles of pemetrexed/platinum chemotherapy. P/D was performed for all resectable patients. Sequential hemithoracic pleural IMRT was then administered with the intent of achieving a total planned dose of 50.4Gy in 28 fractions, as previously described (Rosenzweig et al., IJROBP 2012). All patients were simulated with a 4D-CT scan. A PET scan for image fusion and radiation planning was available for all patients. A Simon two-stage design was applied. A safety analysis after the first 9 patients led to the identification of only one case with ≥grade 3 RP in the first 3 months. The cohort was therefore expanded to 28 evaluable patients, defined as having initiated RT. The primary endpoint is the incidence of ≥grade 3 RP defined per Common Terminology Criteria for Adverse Events, v4.0. Steroids are typically initiated for ≥grade 2 RP.

Results
To date, 21 out of 29 patients total are evaluable. The median follow-up is 10 months. The median age at diagnosis is 66 years (range 38-79). Median KPS was 90% (range 70-90%). Three patients had sarcomatoid, 3 had biphasic and 23 had epithelioid MPM. All patients received chemotherapy. Eight patients (28%) had a partial response, nine patients (38%) progressed, and all others had stable disease. Twenty-four patients (83%) underwent surgical exploration. Five patients underwent an extended P/D or P/D, 11 had a partial P/D, and 8 were found to be unresectable. Eight patients were removed from the study prior to receiving IMRT (7 due to disease progression and 1 due to grade 4 pulmonary embolism after one cycle of chemotherapy). To date, nineteen patients have completed IMRT [median dose 4680cGy (range 4500 to 5040cGy)]; one patient had distant disease progression after 16 fractions; one patient is currently on treatment. Five patients experienced grade 2 RP that was successfully controlled with steroids. One patient experienced grade 3 RP requiring supplemental oxygen, but quickly improved after steroid initiation. Other commonly observed ≥grade 2 radiation-related toxicities included fatigue (37%), dyspnea (47%), nausea (42%), esophagitis (26%), and cough (11%). No grade 4 or 5 radiation-related toxicities were observed.

Conclusion
Hemithoracic pleural IMRT appears to have an acceptable toxicity profile in this ongoing phase II study. Early intervention with steroids is effective in controlling RP. This novel radiation technique has great promise as a component of lung-sparing multi-modality therapy in locally advanced MPM.

Background
Management of malignant pleural mesothelioma (MPM) remains controversial. After extra-pleural pneumonectomy (EPP) and adjuvant radiotherapy, many fail distantly (peritoneal cavity, contralateral lung), possibly due to inadvertent tumour spillage at time of EPP. We hypothesize that neoadjuvant radiation followed by planned imminent EPP can limit the proliferation of clonogens spilt intraoperatively. The radiotherapy technique developed for the Surgery for Mesothelioma After Radiation Therapy (SMART) study is described.

Methods
We conducted a phase II prospective REB approved single cohort clinical feasibility study on surgically resectable stage T1-3N0M0 MPM. The pre-operative clinical target volume (CTV) was defined as the ipsilateral hemithorax, , including biopsy and drainage tract sites. The gross tumour volume (GTV) was defined as any tumour seen on imaging. The dose prescription to the CTV was 25 Gy in 5 daily fractions over approximately 1 week with a concomitant boost of 5 Gy to the GTV and tract sites. All patients underwent EPP within 1 week of completing the neoadjuvant RT. If ypN2 found, patients were offered adjuvant chemotherapy. Treatment related toxicity was defined by the CTCAE v3.

Results
The accrual goal of 25 patients was completed between Nov 2008 and Oct 2012. All completed their intended RT and EPP. IMRT was well tolerated with only grade 1-2 toxicities noted (fatigue, nausea, and esophagitis). EPP was performed 6±2 days after completion of IMRT. Dosimetric values are shown in the table below.

Conclusion
Short neoadjuvant hemithoracic radiotherapy (30 Gy in 5 daily fractions over 1 week) using the SMART protocol constraints are well tolerated. The SMART protocol is technically demanding, requiring very close and careful coordination and planning between the multiple disciplines.

Abstract not provided

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Abstract not provided

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Abstract not provided

Abstract
In the 1970s, pulmonary neuroendocrine tumors were classified into three histologically defined categories: typical carcinoid (TC), atypical carcinoid (AC) and small cell lung carcinoma (SCLC) [1)] . Later, a fourth high-grade neuroendocrine tumor of the lung, large cell neuroendocrine carcinoma (LCNEC) was recognized [2)] , and in 1999, the World Health Organization (WHO) classified LCNEC as a variant of large cell carcinoma [3)] . To date, in neuroendocrine tumors of the lung, the major categories of morphologically identifiable neuroendocrine tumors are TC, AC, LCNEC, and SCLC. Lung tumors with neuroendocrine morphology by light microscopy encompass a three-grade spectrum of low grade TC, intermediate-grade AC, and high-grade LCNEC and SCLC. WHO criteria show that the mitotic range for TC was less than two mitoses per 2 mm[2] (10 high-power field [10 HPF]), and that for AC was between two and ten mitoses per 10 HPF. A mitotic count of eleven or more mitoses per 10 HPF is the main criterion for distinguishing LCNEC and SCLC from AC. A criterion for distinguishing AC from TC is necrosis. Therefore, we classify TC as a tumor with carcinoid morphology, lacking necrosis with less than two mitoses per 2 mm[2]. Tumors with carcinoid morphology, areas of necrosis and/or 2-10 mitoses per 2 mm[2 ]are classified as AC [4)] . Immunohistochemically, neuroendocrine markers such as chromogranin, synaptophysin, and N-CAM are typically positive in TC [4)] . Analyses of molecular markers revealed that low-grade TC and intermediate-grade AC exhibit a low proliferative rate compared with high-grade LCNEC and SCLC [5)] , and TC and AC have different genetic alterations from high-grade LCNEC and SCLC [6)] . Analyses of their genetic alterations show that neuroendocrine lung tumors may represent a spectrum ranging from low-grade TC and intermediate-grade AC to highly malignant LCNEC and SCLC tumors [6)] . Carcinoid tumors can be diagnosed by cytology of bronchoscopic fine needle aspiration or bronchoscopic biopsy specimens. Distinguishing TC from AC requires examination of a surgical specimen, unless mitoses between two and ten per 10 HPF and/or necrosis are seen on a bronchoscopic biopsy [4)] . Preoperative FDG-PET imaging is frequently positive in carcinoid tumors [7)] . TC and AC occur equally in males and females, and patients with TC and AC are younger than those with LCNEC and SCLC. TC is classified as a malignant epithelial tumor of the lung [3,4)] . However, the overall survival rate is better for TC than for AC [4,8)] , and the frequency of lymph node metastases in TC is lower than in high-grade LCNEC and SCLC [8)] . Therefore, some investigators have advocated limited resection in patients with carcinoid [9, 10)] . Some reports revealed that sublobar resection was noninferior to lobectomy for survival in patients with carcinoid tumor [10)] . However, other reports advised that radical oncologic surgery with radical node dissection was needed, and segmental and other limited procedures had to be avoided because of the high frequency of lymph node involvement and multicentric forms[11,12)] . A randomized controlled trial is the best method to compare surgical efficacies. However, it may be impractical due to the rarity of carcinoid tumors. Moreover, AC has a poorer prognosis and a higher frequency of lymph node metastases than TC, and preoperative diagnoses and/or diagnoses of intraoperative frozen sections are often difficult for differentiating AC from TC because small amounts of necrosis or few mitoses are sometimes unclear in those specimens. Therefore, sublobar resection for TC might be the optimal surgical method because of lung preservation and lower mortality than lobectomy; however, limited resection for TC remains an area of controversy. References 1) Arrigoni MG, Woolner LB, Bernatz PE. Atypical carcinoid tumors of the lung. J Thorac Cardiovasc Surg 1972;64:413-21 2) Travis WD, Linnoila RI, Tsokos MG, et al. Neuroendocrine tumors of the lung with proposed criteria for large-cell neuroendocrine carcinoma. Am J Surg Pathol 1991;15:529-53 3) Travis WD, Colby TV, Corrin B, Shimosato Y, Brambilla E, editors. Histological Typing of Lung and Pleural Tumours. World Health Organization International Histological Classification of Tumors, XIII, 3rd ed. Berlin/Heidelberg: Springer-Verlag; 1999 4) Travis W.D, Brambilla E, Müller-Hermelink H.K, Harris C.C (Eds.): World Health Organization Classification of Tumours. Pathology and Genetics of Tumors of the Lung, Pleura, Thymus and Heart. IARC Press:Lyon 2004 5) Rusch VW, Klimstra DS, Venkatraman ES. Molecular markers help characterize neuroendocrine lung tumors. Ann Thorac Surg 1996;62:798-810 6) Onuki N, Wistuba II, Travis WD, et al. Genetic changes in the spectrum of neuroendocrine lung tumors. Cancer 1999;85:600-7 7) Moore W, Freiberg E, Bishawi M, Halbreiner MS, Matthews R, Baram D, Bilfinger TV. FDG-PET Imaging in Patients With Pulmonary Carcinoid Tumor. Clin Nucl Med. 2013;38:501-5 8) Iyoda A, Hiroshima K, Baba M, Saitoh Y, Ohwada H, Fujisawa T. Pulmonary large cell carcinomas with neuroendocrine features are high-grade neuroendocrine tumors. Ann Thorac Surg. 2002 ;73:1049-54 9) Afoke J, Tan C, Hunt I, Zakkar M. Is sublobar resection equivalent to lobectomy for surgical management of peripheral carcinoid? Interact Cardiovasc Thorac Surg. 2013;16:858-63 10) Fox M, Van Berkel V, Bousamra M II, Sloan S, Martin RC II. Surgical management of pulmonary carcinoid tumors: sublobar resection versus lobectomy. Am J Surg. 2013;205:200-8 11) Daddi N, Ferolla P, Urbani M, Semeraro A, Avenia N, Ribacchi R, Puma F, Daddi G. Surgical treatment of neuroendocrine tumors of the lung. Eur J Cardiothorac Surg. 2004;26:813-7 12) Chen F, Sato T, Fujinaga T, Sakai H, Miyahara R, Bando T, Date H. Surgical management of bronchopulmonary typical carcinoid tumors: an institutional experience. Interact Cardiovasc Thorac Surg. 2010;11:737-9

Abstract not provided

Abstract
INTRODUCTION Mediastinal Neuroendocrine Tumors occur most frequently in the thymus. Primary Thymic Neuroendocrine Tumors (NETs) are rare and highly aggressive neoplasms; a little more than 350 cases have been described in the literature, many of which are single case reports. We collected one of the largest series ever reported through a multicenter International study, with the aim to evaluate factors influencing survival and recurrence development in patients with Thymic NETs. MATERIAL AND METHODS A multicenter retrospective study of patients operated for NETs between 1989 and 2012 in 9 high-volume International Thoracic Surgery Institutions, was conducted. According to the International Thymic Malignancy Interest Group (ITMIG) outcome measures, primary and secondary outcome were Cause Specific Survival (CSS) and Disease Free Survival (DFS). Competing-risks regression models (Fine and Gray method), taking into account death by any causes as competing event, were used to identify the association between individual factors and tumor related death. Cox proportional hazards regression models were used to define association between individual factors and DFS, considering R0 cases only. Univariate and multivariate analyses were also performed. RESULTS There were 52 patients (41 males –79%-, median age 49 years). The tumor was asymptomatic in 22 cases (42%). Endocrine paraneoplastic syndromes were observed in 23 cases (44%): 13 Cushing’s syndrome and 10 MEN-1 syndrome. Well differentiated neuroendocrine carcinoma (Typical and Atypical Carcinoid) was the commonest histological subtype (30 cases –58%-). Eight patients (15%) received induction therapy (3 chemotherapy, 2 chemo+radiotherapy, 2 biological therapy and 1 chemo+radio+biological therapy), because of their radiological invasiveness. Median sternotomy was the commonest surgical approach (29 cases). The median tumor size was 8 cm (range 1 – 31 cm); a complete resection (R0) was achieved in 48 cases (92%). Advanced Masaoka-Koga stage (III-IV) was observed in 35 patients (67%). Postoperative treatment was offered to 26 (50%): radiotherapy in 17, chemotherapy in 1, chemo+radiotherapy in 5 and chemo+radio+biological therapy in 3 patient, respectively. Three, 5 and 10-year survival rates were 89%, 76% and 51% (Figure 1). Recurrences were observed in 32 cases (62%): 11 local, 10 intrathoracic and 11 distant. Cumulative incidence of recurrence was 41% at 2 years and 70% at 3 years (Figure 2). Variables influencing survival were: tumor size (p< 0.00) and recurrences (p=0.01). Independents DFS predictors were: age > 50 (p= 0.02), paraneoplastic syndromes (p=0.02), symptoms at presentation (p= 0.01) and poor differentiated histology (p= 0.04). CONCLUSIONS We have confirmed that Thymic NETs are rare mediastinal tumors presenting with an aggressive biological behavior; surgery remains the mainstay of treatment and it should be proposed whenever possible, even in case of advanced diseases. Recurrences are frequent, especially in the first years after operation. Survival is statistically related to the tumor size and to the presence of recurrences, whereas, surprisingly, it is not influenced by induction/adjuvant treatment. A global International effort is needed to collect larger series and to confirm these conclusions. Figure 1: Thymic NETs overall survival curveFigure 1Figure 2: Thymic NETs: cumulative incidence of tumor recurrencesFigure 2

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

Abstract not provided

Abstract
Approval of most new agents for advanced non-small-cell lung cancer (NSCLC) has been based on prolongation of OS, representing a direct measure of clinical benefit, in randomized clinical trials. Recently, however, as we have more opportunity to obtain trial results showing “significant improvement in PFS without any OS benefit”, most investigators feel that the assessment of OS may become of limited use and that PFS must be surrogate endpoint for assessing the efficacy of an experimental agent in NSCLC. Originally, PFS is quite different from OS since it is subjective, but not a direct measure of clinical benefit. Progression is often asymptomatic, and it is not always clinically relevant. To use PFS as surrogate endpoint, its validity should be statistically evaluated. In the pooled analysis using individual patient data of randomized trials comparing first-line docetaxel with vinca-alkaloids, Buyse et al. showed relatively weak PFS-OS correlation [BMJ open 2013;3:e001802]. So far, there seem no other large-scaled validation studies investigating the surrogacy of PFS for OS endpoint with formal statistical approach. Thus, PFS has not yet been a statistically acceptable surrogate endpoint for OS in patients with metastatic NSCLC. Now, what could we interpret “significant improvement in PFS without any OS benefit”? Also, what would be the clinically meaningful endpoint in advanced NSCLC? The literature-based study was conducted to assess the PFS-OS relationship with the data of the phase III trials investigating molecular-targeted agents in advanced NSCLC [Lung Cancer 2013;79:20]. It showed a strong PFS-OS correlation only in trials where subsequent therapy was conducted less frequently, whilst trials with a higher proportion of use of subsequent therapy had weaker association. The study concluded that 1) the relationship between PFS and OS is originally strong enough to support potential surrogacy of PFS, but that 2) given the observation that increasing use of effective salvage therapies could affect the PFS-OS association, improvement in PFS without any OS benefit does not mean the experimental agent fails to have a true clinical benefit. That is, a potentially true OS benefit by an experimental agent would have been seen without any confounding if no subsequent therapy had been given. This theory is called “explanatory approach”, supporting the use of PFS as a clinically meaningful outcome. Rather, there is an opposite opinion, suggesting the observed difference in OS would be considered the measure of clinical benefit, regardless of subsequent therapies, provided that they follow the current standard of care. This is the pragmatic approach [JCO 2011;29:2439]. The observed difference in OS, of course, will be expected smaller by the subsequent therapy than one would see if it was not available, leading to the need of a large sample size to detect such differences. But, according to the pragmatic approach, such potentially attenuated but actually observed OS difference should be used for assessing the true clinical benefit of the experimental agent in the given clinical setting under reflecting the clinical reality of available subsequent treatments. Recently, ASCO discussed what would be clinical meaningful outcome in advanced NSCLC without EGFR or EML4-ALK mutations, and provided draft recommendations as follows: 1) survival after first line therapy is relatively short, and OS is a feasible endpoint although the effects of the experimental agent on OS can be clouded by treatments administered after the period of therapy, and 2) clinical trials should aim to improve OS by a minimum of 25% as compared with standard therapy. ASCO seems to support the importance of measuring OS rather PFS, in favor of the pragmatic approach. Even in the first-line metastatic colorectal cancer, though PFS has already been established as a surrogate for OS in the 90’s, its surrogacy was reappraised using individual patient data between 1997 and 2006 because of the advance in the treatment during the last decade and recent improvement of OS [JCO 2013 (suppl;abstr 3533)]. Surprisingly, the PFS-OS relationship was not as strong as was seen in the 90’s. The study concluded that in modern metastatic colorectal cancer trials where SPP exceeds time to first progression, the treatment effects on PFS do not reliably predict those on OS. It seems that even though PFS was once accepted as a suitable surrogate for OS, its validity should be assessed repeatedly along with the advances especially in the post-progression treatment, which also supports the concept of the pragmatic approach. Regarding the regulatory considerations, the FDA stated OS should be considered the standard clinical benefit endpoint and that it should be used to establish the efficacy of a treatment in metastatic NSCLC, although it can also consider PFS for regulatory decision of drug approval based on the population. Some of the abovementioned findings potentially support the rationale of the pragmatic approach, stressing the importance of a possibly attenuated, but actually observed OS difference. However, this theory is unlikely to be applied in more recent trials investigating specific targeted therapies including EGFR-TKIs or ALK inhibitors, because no OS difference would be arguably obtained due to a quite high level of crossover inevitably for the ethical reason. Thus, under the special situation where i) an experimental agent has theoretically been considered to target specific molecules, and ii) the earlier trials showed dramatic effect, this possibly high proportion of crossover can compromise the ability to assess clinical benefit, and also lead to the unrealistic sample size to detect significant OS difference. Rather, in this condition, whether both large magnitude of PFS advantage and great OS advantage compared with historical control can be obtained would be more important than the conventional assessment of OS difference between the arms. In conclusion, the goals of any new cancer treatment are to offer patients a true clinical benefit. PFS has not yet been formally accepted as a valid surrogate for the OS endpoint in advanced NSCLC, and its surrogacy will be addressed by each drug mechanism of action and patient population. Finally, OS remains the primary endpoint of clinical trials, except in a situation where agents targeting specifically driver oncogenes are being evaluated with anticipation of high level of crossover.

Abstract
A screening programme is a set of procedures that can be applied to an asymptomatic population to enable early detection and treatment of disease. The success of the programme is dependent on this early intervention reducing morbidity and mortality associated with the disease. There has been much research to develop and assess potential screening programmes for lung cancer. In particular, there are a number of major clinical trials such as the National Lung Screening Trial in the United States, the United Kingdom Lung Cancer Screening Trial and the Dutch-Belgian NELSON trial, that assess the effectiveness of screening a high risk population with low dose computed tomography scans to reduce mortality from lung cancer. The key elements of any screening programme are: (i) identification of the target population for screening, (ii) the screening test that will be used to classify patients as likely or unlikely to have the disease, (iii) the frequency of applying the screening test, (iv) the diagnostic test that will be used to determine whether people are truly diseased or not, (v) the treatment that will be available for those diagnosed early. These choices will impact on the statistical design. The research question may be whether to introduce screening, to determine the frequency of screening, to identify the appropriate target population for screening or whether to add an additional screening tool to an existing screening modality. Randomised controlled trials are the gold standard for assessing a screening programme as they overcome major biases specific to screening namely lead-time bias, length bias, over-diagnosis bias and selection bias. The usual trial design parameters are important but special statistical issues arise in relation to screening trials. Statistical inferences should only be made back to the eligible population defined for the trial so the choice of eligibility criteria is important. Screening interventions can cause harm to individuals that are potentially disease-free so the target population is usually those who are at high risk of disease. Interventions such as CT scans which have both a relatively high risk and high level of harm should be targeted at a high risk population whilst those that are low risk to the individual such as sputum cytology could be targeted at a wider population. Harms also include the inconvenience and psychological effects of a false positive result. A high risk population is usually defined in terms of pack-years of smoking and time since quitting and simple patient characteristics such as age. Statistical models that predict risk of disease could enhance the identification of a high risk population but the accuracy of prediction should be considered in relation to its impact on the trial. The primary outcome measure to assess benefit of a lung cancer screening programme should be lung cancer specific mortality. Duration of follow-up is an important design parameter. It needs to be long enough to allow for the time lag before the impact of screening becomes apparent and not so long after the cessation of screening as to include a period of time when screening would have lost its impact. Appropriate statistical analysis of the primary outcome measure is essential to properly evaluate the benefits of screening. Typically the screening intervention will be compared to the control arm in terms of its ability to reduce cumulative mortality. If this is calculated over the entire period of screening and follow-up then the benefit may be underestimated. Comparing time-specific mortality rates is the recommended approach [1]. The analysis is also complicated by the problems of non-attendance and contamination but methods have been proposed to adjust for these [2]. Sample size calculations involve key design parameters including hypothesised mortality reductions, expected compliance and contamination, number of screening rounds and length of follow-up [3]. The accuracy of the screening test to predict disease in asymptomatic people is not only important for the feasibility and ethics but will also impact on sample size as inaccurate predictions will dilute the potential benefit of screening. Screening tests, such as those that involve biomarkers measured on a continuous measurement scale, should be rigorously developed and validated before assessing their clinical utility within a randomised controlled trial environment. References [1] Hanley JA; Measuring mortality reductions in cancer screening trials; Epidemiologic Reviews 2011; 33: 36-45. [2] Baker SG, Kramer BS, Prorok PC; Statistical issues in randomised trials of cancer screening; BMC Medical Research Methodology 2002; 2: 11. [3] Prorok PC, Marcus PM; Cancer screening trials: nuts and bolts; Seminars in Oncology 2010; 37(3): 216-223.

Abstract
The growing number and rising costs of modern lung cancer therapies have brought the issue of cost and cost effectiveness to the forefront of clinical practice. While personalized medicine improves outcomes in specific subgroups, sparing others from ineffective costly treatment and toxicity, it can be challenging to incorporate into economic analyses. Defining the target population for the new treatment is key, and then evaluating the costs and benefits of the new intervention compared to the previous standard. However, the definition of molecular populations for targeted therapies has emerged as an important consideration when considering whether or not to adopt a new targeted therapy. The cost of biomarker testing can have a major impact on healthcare costs, and many countries are struggling with how to best incorporate the "hidden" costs of personalized medicine into adopting new targeted therapies. Focusing only on the target population, comparing the new treatment with standard comparators does not incorporate the costs of biomarker testing, or need for repeat biopsies for successful testing, but will be a better reflection of the benefit of the new treatment in that population. Comparing a test-and-treat strategy to a strategy without testing or the new therapy allows incorporation of the costs of testing, but has some important challenges. Biomarker frequency is a key driver in these analyses, with smaller populations as a particular challenge, such as ALK positive nonsmall cell lung cancer. Presenting the cost of both a test-and-treat strategy alongside an evaluation of the cost effectiveness of therapy in the target population may be a better way to illustrate the impact of a novel treatment, especially when the target population is small, while acknowledging the incremental financial burden of biomarker testing in cancer. This may allow new therapies to compete with current alternatives on a comparable footing, and not underestimate the impact of a new treatment in a small subgroup. It would also permit the development of more effective and cost-efficient screening methods for the desired target population. It is important to recall that technological methods and costs involved in biomarker testing and molecular analysis are rapidly changing, and should be revisited over time. The technological methods used to identify molecular abnormalities in cancer, such as sequencing and antibody development, are changing rapidly along with associated costs. Thus less expensive or more efficient methods (e.g. multiplex testing) may be more affordable compared to more labor-intensive methods used in initial clinical trials. For example, immunohistochemical techniques may replace more expensive methods, allowing more jurisdictions to take up testing and treatment of new therapies.

Abstract
Over the last several years, there have been a number of new classes of drugs approved for the management of lung cancer. Regulatory pathways are evolving in many ways – for example, to recognize that targeted therapies, such as the EGFR inhibitors, will require evaluation of the drug alongside a diagnostic test; or that the increasing specificity of targets may result in smaller and shorter trials with different endpoints; or that regulatory authorities might identify potential significant advances in therapy by the use of special evaluation pathways, such as the ‘breakthrough’ therapy designation from the US FDA. Sometimes the trials now also measure quality of life outcomes or patient preferences. But these trials are still fundamentally designed to ask the ‘regulatory’ question – can the new product work – as well as assessing the risk-benefit ratio. But where does this changing regulatory environment leave payers? The information set that is available to guide assessments of value of money generally seems to becomes more limited as the regulators increase the pace of their decision-making. Trials are truncated or treatment groups are crossed over to the new treatment at the earliest possible opportunity, often before there is a confident estimate of the effect size in terms of final clinical outcomes. The ethical imperative to offer access to possibly effective treatments outweighs ensuring adequate trial design to be confident in the estimate of effect. Statistical techniques to ‘adjust’ for limitations in design become more and more complex, and more prone to uncertainty. And at the same time, most countries are still struggling with faltering economies and diminishing health budgets. Patients still want access to the latest treatments, but are less and less willing to pay increasing prices. Payers then have to compare the limited information set available for new drugs with what is known about current treatments. Arguments over the value of differences such as a 1.4 months gain in overall survival compared to existing treatment become conflated with the cost of this gain. That is assuming, of course, that there is a gain in overall survival, which has not been often shown to date in the trials of the new drugs for lung cancer. When high prices and high prevalence are combined, the value-for-money question is rightly raised – why pay so much more for so much uncertainty? Arguments about incremental advances in therapy, innovation and technological developments then dominate the discussion, rather than the appropriate focus on health gain for communities and individuals. So what is the solution? Options suggested include ‘managed entry’ of new products with additional data collection as a condition of price negotiation, ‘paying for performance’ with outcome data collection, or ‘value-based pricing’ that allows a premium for ‘innovation’. However, given the high clinical need for effective treatments, the emphasis should be on getting the best health outcomes for an affordable price, to the community and for individuals.

Abstract
The United States Preventive Services Task Force (USPSTF) has released a draft recommendation, a “B”, for lung cancer screening. This means that the USPSTF concluded with moderate certainty that there was substantial net benefit for screening healthy individuals (i.e. those able to withstand surgical intervention) with a 30 pack-year of more history of smoking, ages 55 to 79 years of age who have smoked within the past 15 years. This recommendation is based primarily upon the results of the National Lung Screening Trial (NLST)with some consideration of the emerging results from much smaller trials in Europe. While this “B” isreasonable, the criteria for whom to screen may need revision. Tammemagi et al (NEJM 2013; 368:728-736) have serially refined an incidence-based risk model. In the most recent model, PLCO~M2012~, lung cancer risk increases with age, African American race/ethnicity versus white, lower socioeconomic status (education), lower BMI, self-reported history of COPD, personal history of cancer, family history of lung cancer, being a current smoker, increased smoking intensity and duration, and shorter quit-time in former smokers. Applying the NLST criteria to the PLCO intervention arm smokers, 14,144 of 37,332 (37.9%) were eligible. To obtain an equal number of individuals using the PLCO~M2012~, individuals with a lung cancer risk >1.3455% were regarded as positive. Overall the PLCO~M2012~ risk method identified 81 more of the 678 lung cancers (11.9%) than did the NLST criteria (41.3% fewer lung cancers were missed: 115 versus 196). To include 80% of lung cancers in the PLCO control smokers, a PLCO~M2012~ risk probability of 0.016082 or higher would be used (specificity = 67.3%; PPV = 4.1%) and the proportion of smokers to be screened would be 33.6%. A spreadsheet calculator is available online, which calculates lung cancer risk according to PLCO~M2012~ given an individual’s predictor levels. http://www.brocku.ca/lung-cancer-risk-calculator An alternative approach looking at lung cancer mortality was developed by Kovalchik et al (NEJM 2013; 369:245-254). This analysis was limited to individuals who met the NLST entry criteria and used the NLST data for risk development with similar factors as Tammemagi et al. Five-year risk of lung cancer mortality ranged from 0.15-0.55% in the lowest risk group (Q1) to greater than 2% in the highest risk group (Q5). Sixty percent of NLST participants with the highest risk of lung cancer mortality accounted for 88% of LDCT-prevented lung cancer deaths. Sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of LDCT screening across rounds have now been reported. There is little variation across the rounds. At T0, the sensitivity and specificity were 93.8% and 73.4% for LDCT. In the LDCT arm, the PPV was 52.9% (265/501) for any positive finding that led to a biopsy procedure but only 3.8% (270/7,181) for positive findings overall Overall NPV was 99.9% (19,043/19,061). Among LDCT positive screenees undergoing thoracotomy at T1 and T2, 18.9% and 15.9% did not result in a lung cancer diagnosis, respectively. The frequent need for evaluation of positive screens increases the burdens of LDCT screening. Increasing the minimum size threshold for screen positivity can reduce the frequency of diagnostic work-up. Nodules 4-6 mm diameter accounted for roughly half of LDCT positive screens at T1 and T2, but were associated with lung cancer in less than 1% of cases. The variability in radiologists' interpretations of computed tomography (CT) studies in the NLST (including assessment of false-positive rates [FPRs] and sensitivity), was characterized and factors that contributed to variability, and trade-offs between FPRs and sensitivity among different groups of radiologists were evaluated. One hundred twelve radiologists at 32 screening centers each interpreted 100 or more NLST CT studies, interpreting 72 160 of 75 126 total NLST CT studies in aggregate. The mean FPR for radiologists was 28.7% ± 13.7 (standard deviation), with a range of 3.8%-69.0%. Aggregate sensitivity was 96.5% for radiologists with FPRs higher than the median (27.1%), compared with 91.9% for those with FPRs lower than the median (P = .02). In adjusted analyses, smoking cessation was strongly associated with the amount of abnormality observed in the previous year’s screening (P<0.0001). Compared to those with a normal screen, individuals were less likely to be smokers if their previous year’s screen had a major abnormality that was not suspicious for lung cancer (odds ratio (OR) = 0.790, P<0.001), was suspicious for lung cancer but stable from previous screens (OR = 0.777, P<0.001), or was suspicious for lung cancer and was new or changed from the previous screen (OR 0.593, P<0.001). Integration of effective smoking cessation programs within screening programs should lead to further reduction in smoking-related morbidity and mortality. Estimates suggest that the risk of radiation-induced lung cancer from three annual lung CT screens (average lung dose from a single LDCT estimates at 4 mGY) for older current smokers is likely to be in the range 1-10 deaths per 10,000 screened. However, because of the high probability of a positive screen (>20%) the follow-up procedures could double the risk of radiation-related lung cancer. The observed reduction in lung cancer mortality in the trial due to lung CT screening was 31 deaths prevented per 10,000 screened. The estimated radiation-related risks are therefore considerably smaller than the observed benefit. However, when the follow-up scans are included the benefit for current smokers is reduced by about 30% from 31 to about 20 lung cancer deaths per 10,000 screened. The impact on life-expectancy will be smaller, however, because the lung cancer deaths prevented occur at a younger age than the radiation-related cancer deaths. Estimates of the reduction in life-expectancy from radiation-related cancer were on average only 1-5 days. The advent of improved risk models demonstrates that more efficient criteria for selection of individuals for lung cancer screening than the NLST are feasible and effective. The various medical groups that have developed recommendations for lung cancer screening have primarily settled upon the NLST criteria. These groups should re-evaluate their criteria in light of the findings of these new risk models. This would have the salutary effect of making lung cancer screening more efficient and save more lives.

Abstract not provided

Abstract
Background Standard treatment for stage IIIA or IIIB non-small cell lung cancer (NSCLC) is chemoradiotherapy (CRT). In patients with infiltrative stage III (N2) NSCLC and PS 0-1 being considered for curative-intent treatment, platinum-based chemotherapy and radiotherapy (60-66 Gy) are recommended based on the revised American College of Chest Physicians (ACCP) guidelines for lung cancer. This guideline adopted new criteria for clinical N2 status, discrete and infiltrative N2 status. Infiltrative N2 means no radiolucency between nodes and surrounding organs, and usually considered to be unresectable unless combined resection not performed. Discrete N2 was defined as nodes having surrounding radiolucency on computerized axial tomogram (CAT). Surgery alone is not recommended for both clinical N2 diseases, based on several retrospective studies reported in 1990’s. Some cases would be candidates for upfront surgery followed by adjuvant chemotherapy, but approximately 40% of patients with resected lung cancer cannot tolerate postoperative adjuvant chemotherapy. ACCP guideline does not recommend surgery followed by chemotherapy, if N2 was verified preoperatively, which is reasonable for considering Thus preoperative treatment should be suitable for most clinical N2 NSCLC, if trimodal treatment is taken into consideration. As to a suitable preoperative treatment, induction chemotherapy is generally preferred to CRT, for pulmonary resection following CRT is believed to be more difficult and higher complication rate. However one of the major disadvantages for induction chemotherapy should be incomplete resection, which means losing local control for patients with N2 disease. In this respect induction treatment should include radiotherapy for infiltrative or discrete N2 NSCLC. The significance of surgery in N2 NSCLC is controversial. Randomized controlled trial definitive CRT vs induction CRT followed by surgery, i.e. “Intergroup 0139 trial”, resulted in negative. Overall survival was not improved for surgery group. While in subset analysis lobectomy appeared to improve survival, pneumonectomy did not. This is partly due to a high mortality rate in pneumonectomy group, which is a matter of debate. Some authors insisted that pneumonectomy is feasible following CRT with a low surgical mortality rate. Lessons from “Intergroup 0139 trial) were described in the recent ACCP guidelines as follows; 1) patients preferences and characteristics should be considered; 2) highlight the importance of minimizing harms, and surgery should be undertaken in a center with experience; 3) if there are reasons to be concerned about the ability of radiotherapy to achieve local control, surgery may have a benefit provided R0 resection is likely to be achieved; 4) lobectomy is preferred to pneumonectomy following induction CRT. Dose of irradiation in surgery group is 45Gy, and in the other side of definitive CRT group 61Gy. Considering tumor biology under radiotherapy, the difference of the doses cannot be negligible. Cancer cells tend to response in the late phase of radiation rather than early phase. Thus ideal radiation dose would be 60 to 66Gy, and lobectomy rather than pneumonectomy should be performed in trimodal treatment for stage IIIA N2 NSCLC. In this setting surgery is performed following definitive CRT, and called as “salvage surgery.” There are few reports on the significance and feasibility of salvage surgery for lung cancer, and the indications should be limited. On the other hand, definitive CRT can control local disease at most 40% resulting in approximately 20% of long-term survival. Not a few patients die due to local disease without distant metastasis. Recent randomized study on the feasibility of very high dose radiotherapy, RTOG 0617, showed inferiority of 74Gy to 66Gy, and better local control should be obtained only with additional surgical resection, i.e. salvage surgery. Methods Comprehensive review of the literature will be presented. Experience of salvage surgery at Juntendo Hospital was investigated and presented. Between February of 2008 and July of 2013, 1240 patients with lung cancer underwent surgical resection, which includes 20 salvage surgeries. Salvage surgery was performed in 10 patients following chemotherapy, and 10 CRT. Majority of the mode of surgery was 6 pulmonary lobectomies, including 3 sleeve resection, and 3 pneumonectomies, including 1 sleeve pneumonectomy. The dose of radiation was 60Gy in 8 patients, 45Gy in 1 patient, and 140Gy in 1 patient who underwent proton and heavy particle radiotherapy. All cases underwent irradiation to the primary tumor and hilar and mediastinal region. Surgical outcome was investigated. Results There were no surgical mortality. There were 3 postoperative morbidity including empyema, pneumonia and bronchopleural fistula (BPF). BPF developed following right side pneumonectomy following proton and heavy particle radiation for the primary and hilar region. This patient underwent open window and remain alive without evidence of disease for 19 months. Sleeve bilobectomy of right middle and lower lobectomy following 45Gy radiation was performed in 1 patient, sleeve right upper lobectomy combined resection of the superior vena cava following concurrent CRT with 60Gy was performed in 2 patients. Postoperative course for those patients were no problems at all. Postoperative bronchial healing was excellent. Conclusion Salvage lobectomy following high dose radiation could be feasible even performing radical resection of the superior vena cava or pulmonary artery.