bluuebunny/crossref_metadata_2025_split huggingface dataset:
The role of adjuvant therapy in the management of resected large cell neuroendocrine carcinoma (LCNEC) of the lung: A National Cancer Database (NCDB) analysis.
Authors: Kujtan Lara Ann , Muthukumar Varsha , Toor Muhammad , Kennedy Kevin F , Masood Ashiq , Davis J Russell , Subramanian Janakiraman 
Published: September 2018

8529 Background: Large cell neuroendocrine carcinoma (LCNEC) is characterized by aggressive behavior and poor outcomes compared with other non-small cell lung cancers (ONSCLC). Methods: The National Cancer Database (NCDB) was used to identify patients diagnosed with early stage NSCLC (pathologic stage I, II, IIIA) from 2004-2012 who underwent surgical resection. Patients were divided into two groups: LCNEC and ONSCLC. One-way ANOVA was used to compare continuous variables, and chi-squared testing was used to compare categorical variables. Multivariate logistic regression analyses were used to obtain hazard ratios. Results: We identified 1672 patients with resected LCNEC and 134139 with resected ONSCLC. A higher proportion of patients with ONSCLC had a Charlson-Deyo co-morbidity score of 0 compared to LCNEC patients (50.6% vs. 43.8%; p < 0.001). No other significant differences in clinical and demographic characteristics were identified. Overall survival was lower for LCNEC patients across all stages when compared to patients with resected ONSCLC (46 months versus 74 months; 5-year survival 45% versus 57%; p <0.001). Multivariate analysis confirmed the survival benefit for adjuvant chemotherapy in resected LCNEC across all stages, including stage IA, although it did not reach statistical significance (hazard ratio 0.72 (0.51-1.02), p= 0.64; Table). Conclusions: Adjuvant chemotherapy significantly improves survival for stage IB, II and IIIA LCNEC compared to surgery alone. Patients with stage IA LCNEC appear to benefit from adjuvant chemotherapy although it did not reach statistical significance. The overall magnitude of benefit from adjuvant chemotherapy appears to be higher for patients with LCNEC compared to ONSCLC. [Table: see text]
Randomized trial of thoracic radiotherapy with or without concurrent daily low-dose carboplatin in elderly patients with locally advanced non-small cell lung cancer (NSCLC): Long-term follow-up of Japan Clinical Oncology Group (JCOG) Study JCOG0301.
Authors: Atagi Shinji , Mizusawa Junki , Ishikura Satoshi , Takahashi Toshiaki , Okamoto Hiroaki , Tanaka Hiroshi , Goto Koichi , Nakagawa Kazuhiko , Harada Masao , Takeda Yuichiro , Nogami Naoyuki , Fujita Yuka , Kasai Takashi , Kishi Kazuma , Sawa Toshiyuki , Takeda Koji , Tomii Keisuke , Satouchi Miyako , Seto Takashi , Ohe Yuichiro 
Published: September 2018

8532 Background: In the phase III JCOG0301 trial, concurrent chemoradiotherapy (CRT) was compared with radiotherapy (RT), demonstrating clinically significant survival benefits in elderly patients with locally advanced NSCLC after a median follow-up of 19.4 months. However, the long-term patterns and cumulative incidences of toxicity associated with CRT and RT are poorly understood for elderly patients. We report long-term survival data and late toxicities after a minimum follow-up of 6.4 years. Methods: Eligible patients were older than 70 years and had unresectable stage III NSCLC. They were randomly assigned to RT alone (RT arm: irradiation with 60 Gy in 30 fractions) or CRT (CRT arm: the same RT with additional concurrent use of carboplatin 30 mg/m2 per fraction up to the first 20 fractions). The primary endpoint was overall survival (OS). Prognosis and adverse events data were collected beyond those in the initial report of this trial. Kaplan-Meier survival curves and 3- and 5-year survival proportions were calculated. Late toxicities were defined as occurring later than 90 days after RT initiation. Results: From September 2003 to May 2010, 200 patients (RT arm, n = 100; CRT arm, n = 100) were enrolled. Consistent with the initial report, the CRT arm had better OS than the RT arm (HR = 0.743, 95% CI = 0.552 – 0.998, one-sided p = 0.0239 by stratified log-rank test). In the RT and CRT arms, median OS was 16.5 and 21.7 months, 3-year survival was 16.3% and 34.3%, and 5-year survival was 9.2% and 15.2%, respectively. %Grade 3/4 late toxicities were 7.4% (heart 2.1%, lung 5.3%) in the RT arm (n = 94) and 7.5% (esophagus 1.1%, lung 6.5%) in the CRT arm (n = 93). No additional cases of late toxicity (Grade 3/4) were seen since the initial report. There were 7 treatment-related deaths, all of which were recorded in the initial report: 4 (4.0%) in the RT arm and 3 (3.0%) in the CRT arm. Conclusions: Long-term follow-up confirms the survival benefits of CRT for elderly patients with locally advanced NSCLC. There was no observed increase in late toxicity with CRT, as compared with RT alone. Clinical trial information: 00132665.
Feasibility of endobronchial ultrasound fine-needle aspiration for massively parallel next-generation sequencing in cancer patients.
Authors: Turner Simon R. , Buonocore Darren , Rekhtman Natasha , Dogan Snjezana , Desmeules Patrice , Lin Oscar , Arcila Maria E. , Jones David Randolph , Huang James 
Published: September 2018

8535 Background: Next generation sequencing (NGS) is an important emerging tool in precision oncology, allowing identification of a growing number of clinically validated and investigational therapeutic molecular targets. A potential limitation is that some NGS assays require more DNA input than more limited molecular assays. Endobronchial ultrasound fine-needle aspiration (EBUS-FNA) is a minimally invasive procedure for sampling mediastinal and pulmonary lesions, but it is unknown if it provides adequate material for NGS. Methods: An IRB approved, retrospective review was performed of patients undergoing EBUS-FNA by thoracic surgeons at our institution 3/1/14 - 9/28/16. NGS was performed using an assay developed at our institution that detects mutations in up to 410 genes (MSK-IMPACT). Samples diagnostic for malignancy and with MSK-IMPACT requested were identified. Pathology and clinical data were drawn from the medical record and MSK-IMPACT results were examined. Results: 784 EBUS-FNA were done in the study period. MSK-IMPACT was requested on 115 positive samples. MSK-IMPACT was successful in 99 samples (86.1%), identifying an average of 12.7 mutations at a mean coverage depth of 806X. In 17 (17.2%) samples, tumor content was suboptimal ( < 20% of nucleated cells), with fewer identified mutations than in cases with higher tumor content (6.8 vs 13.9, p = 0.01). NGS was performed on paraffin-embedded cell blocks in 93 cases (93.9%), and in 6 cases DNA extraction was performed from residual cytological material isolated from supernatant including cell-free DNA. Failures were attributable to low cell content (7), high contamination by benign cells (4) or both (1) and processing issues (4). No difference in surgical or radiologic parameters were identified for failed or suboptimal samples. Conclusions: In our practice, EBUS-FNA has a high rate of success for obtaining adequate tissue for NGS. Ability to utilize cell-free DNA for molecular studies – a new process in our lab – allows increased success of molecular testing in scant samples. Further studies may identify factors contributing to NGS failure and to improving success for samples with minimal cellularity.
Retrospective analysis of clinical outcomes of early stage ALK-positive (ALK+) non-small cell lung cancer (NSCLC).
Authors: Dagogo-Jack Ibiayi , Santini Fernando , Eng Juliana , Yeap Beow Y. , Izar Benjamin , Chin Emily , Litvak Anya , Jones David Randolph , Kris Mark G. , Shaw Alice Tsang , Gainor Justin F. , Chaft Jamie E. 
Published: September 2018

8536 Background: ALK rearrangements are important oncogenic drivers in NSCLC. However, the prognostic implications of these rearrangements are unclear due to 1) conflicting results from small series of patients (pts) with early-stage ALK+ NSCLC, and 2) use of highly effective ALK tyrosine kinase inhibitors (TKI) in the metastatic setting. To assess the prognostic significance of ALK rearrangements in resected NSCLC, we performed a retrospective analysis of survival outcomes among pts with resected ALK+, EGFR+, or KRAS+ NSCLC treated at two institutions. Methods: We reviewed charts of pts that underwent resection for stage 1-3 NSCLC at Massachusetts General Hospital or Memorial Sloan Kettering Cancer Center between 1/2009 and 12/2012. Recurrence-free survival (RFS) was estimated for each genotype. Results: Among 764 pts (480 KRAS+, 255 EGFR+, 29 ALK+), we identified 555 (73%), 101 (13%), and 108 (14%) pts with stage I, 2, and 3 NSCLC, respectively. ALK+ pts were distributed across all stages: 10 (34%) stage I, 6 (21%) stage 2, and 13 (45%) stage 3 NSCLCs. Chemotherapy was administered to 14 ALK+ ( 0% stage 1, 67% stage 2, 77% stage 3), 45 EGFR+ (3% stage 1, 44% stage 2, 81% stage 3), and 96 KRAS+ pts (4% stage 1, 56% stage 2, 71% stage 3), respectively, for early-stage NSCLC. Thirteen (7%) stage 1 EGFR+ patients received adjuvant EGFR TKI. Although median RFS was not reached for EGFR+ pts, it was 24.3 months (95%CI 11.4 to 65.3) for ALK+ pts and 72.9 months (95%CI 59.7 to undefined) for KRAS+ pts. RFS for ALK+ NSCLC was significantly shorter than the other groups (HR 2.9, 95%CI: 1.75-4.89 vs. EGFR and HR 1.8, 95%CI: 1.12-2.93 vs. KRAS). When adjusted for stage, ALK+ NSCLC remained associated with worse RFS compared to EGFR+ NSCLC (HR 1.8, 95%CI: 1.09-3.12), but not when compared to KRAS+ NSCLC (HR 1.30, 95%CI: 0.79-2.12). Conclusions: Early stage ALK+ NSCLC is associated with shorter RFS than EGFR+ NSCLC. The propensity for relapse and the significant anti-tumor activity of ALK TKIs in pts with metastatic NSCLC suggest that enrollment of patients on trials of adjuvant ALK TKIs should be prioritized.
Interplay between immune infiltration and tumor progression and survival in non-small cell lung cancer: An analysis of institutional and public data.
Authors: Jalali Ali , Wang Jing , Lee Won-Chul , Zhang Jianhua , Wu Chia Chin , Gibbons Don Lynn , Tang XiMing , Kalhor Neda , Izzo Julie , Behrens Carmen , Fossella Frank V. , Tsao Anne S. , Lee J. Jack , Swisher Stephen , Heymach John , Futreal Andrew , Wistuba Ignacio Ivan , Herbst Roy S. , Papadimitrakopoulou Vassiliki , Zhang Jianjun 
Published: September 2018

8538 Background: In many types of cancer, infiltration of tumor by immune cells, as a reflection of the immune response against the tumor, is thought to play a critical role in clinical outcome. Tumors, however, tend to evade the immune response as they progress. In this study, we characterize the interplay between immune infiltration and tumor progression and survival in non-small cell lung cancer (NSCLC). Methods: We performed histologic immune profiling and microarray expression analysis on primary tumor specimens from 275 NSCLC patients (PR: PROSPECT trial) as well as RNA-Seq expression analysis on biopsy specimens from 50 patients with advanced NSCLC (B2: BATTLE-2 trial). RNA-Seq data from the TCGA lung cancer project was also analyzed. Immune Infiltration Score (IIS) was computed from the expression data using the Estimate package in R. Immune Suppression Score (ISS) was defined as the difference between the mean of CD3, CD4, CD8, FOXP3, and PD1 counts in the periphery and core of the tumor. Results: Tumor IIS is correlated (all p < 0.0005) with tumor immune infiltration as measured by inflammatory cell count on frozen tumor or several immune marker counts in tumor core. IIS is positively associated with survival (p = 0.04) independently of age (p = 0.008) and stage (p = 8e-10). IIS in the top half is associated with higher median survival vs. bottom half (10.2 vs 2.2 months, p < 0.0001) in B2. In TCGA lung adenocarcinoma samples, IIS is higher in stage I/II disease vs stage III/IV (p = 0.003). For all immune markers in PR samples, periphery of the tumor on average has higher counts vs tumor core (p < 0.0011), and this difference (suppression score) is higher in stage III/IV samples vs stage I/II for CD3, CD4, and CD8 (all p < 0.04) and for FOXP3 and PD1 (p < 0.1). ISS is negatively associated with survival (p = 0.02) independently of age (p = 0.06) and stage (p < 0.0001). Conclusions: As NSCLC tumors progress, immune infiltration in the periphery of the tumor increases while infiltration in the core decreases, reflecting increasing immune suppression. Tumor immune infiltration and suppression, as measured by IIS and ISS, are significant predictors of survival, independently of age and stage.
Lobectomy with mediastinal nodal dissection versus partial lobectomy in patients with bronchial carcinoid tumors: A NCDB analysis.
Authors: Westin Gustavo Figueiredo Marcondes , Alsidawi Samer , Leventakos Konstantinos , Halfdanarson Thorvardur Ragnar , Molina Julian R. 
Published: September 2018

8549 Background: Bronchial carcinoid tumors are a rare group of neoplasms that usually have an indolent clinical behavior. Surgical resection is the main treatment modality for patients with early stage disease, however it is unclear if lobectomy with mediastinal lymph node dissection (L) is superior compared to partial lobectomy (PL). Methods: Utilizing the National Cancer Database from 2004-2012, 1551 patients diagnosed with T1N0 or T2N0 typical carcinoid tumors (CT), and 167 atypical carcinoid tumors (ACT), who underwent L or PL (segmental or wedge resection) as initial treatment strategy, and did not receive chemotherapy or radiation were identified. All patients had pathologically confirmed diagnosis, negative surgical margins, and complete follow up data. Overall survival (OS) was analyzed utilizing Kaplan-Meier curves, and log-rank tests were used for statistical comparisons. Cox proportional hazards were performed to control for age, sex, race, grade, year of diagnosis, Charlson/Deyo Score, insurance, income, and facility type. T-test was used to compare post-surgical hospital stay. Results: The entire cohort median age was 61 years (range 18-90), and male to female ratio was 0.43. 75% of patients with CT and 78% of ATC underwent L. The 90 day mortality following surgery was < 1 % in both surgical groups. Patients who underwent L had longer post-operative hospitalization stay (mean 5.3 vs. 4.3 days; p < 0.001). The 5 year survival for patients with CT was 95% in the L versus 93% in the PL group (p = 0.62), and for ACT 89% in the L versus 81% PL group (p = 0.28). In a multivariate analysis increasing age was the only prognostic factor, and was associated with inferior survival. The HR for death comparing PL to L was 1.09 (95% CI: 0.65-1.78; p = 0.71) for CT and 1.25 (95% CI: 0.45-3.23; p = 0.65) for ACT. Conclusions: Patients with localized node-negative CT and ACT have excellent 5 year survival. Performing a lobectomy with mediastinal node dissection may not provide additional benefit compared to partial lobectomy, but this may increase the length of hospital stay.
The correlation between mutation burden and disease free survival in patients with lung adenocarcinomas.
Authors: Wang Changzheng , Xin Shuang , Shi Xulian , Zhao Xin , Wu Kui , Zhang Li , Zhang Xiuqing 
Published: September 2018

8550 Background: Lung cancer is one of the leading causes of cancerous deaths globally. High mutation burden is a special character in lung adenocarcinoma patients. Mutation burden is usually based on the number of non-synonymous mutations implying the instability of genome. We hypothesize genome-wide mutation burden indicates mutation degree and is correlated with prognostic in lung adenocarcinoma. Methods: Whole-exome sequencing was performed on 98 Chinese lung adenocarcinoma patients with tumor and normal tissue to a mean depth of 49.6ⅹ. The total number of non-synonymous somatic mutations was calculated from the sequencing data of each patient. Patients were divided into high mutation burden and low mutation burden groups in accordance with the mean mutation burden and Kaplan-Meier analysis was performed for survival analysis between these two groups. The association between mutation burden and age or smoking status was analyzed by Wilcoxon rank-sum test. Results: Among these 98 patients, the values of mutation burden varied from 5 to 1121 with mean value 161.8, 36 (36.7%) patients with smoking history and 34 (34.7%) patients were older than 65 years; the numbers of patients in I, II, III stage were 19 (19.4%), 16 (16.3%) and 63 (64.3%) respectively. 32 patients were classified into high mutation burden group, the other 66 patients classified into low mutation burden group. Survival analysis showed a significantly longer disease free survival (DFS) in low mutation burden group (p-value = 0.0133).Mutation burden was significantly associated with age ( < 65 vs ≥65, p-value = 0.0208) and smoking status (p-value = 8.67ⅹ10-4). Conclusions: The association between mutation burden and age or smoking status suggested the high risk for mutation burden accumulation. The significant difference of DFS between high mutation burden and low mutation burden groups reveals the potential of mutation burden as one of the prognostic factors in patients with lung adenocarcinomas.
Association of PD-L1 expression with tumor infiltrating immune cells and mutation burden in the high grade neuroendocrine carcinoma of the lung.
Authors: Kim Hye Sook , Han Ji-Youn 
Published: September 2018

8564 Background: Large cell neuroendocrine carcinoma (LCNEC) and small cell lung cancer (SCLC) are recognized as high grade neuroendocrine carcinoma of the lung and remain among the most fatal malignancies. Programmed death-ligand 1 (PD-L1) is expressed in a group of cancers that may be suitable for specific immunotherapy. We retrospectively investigated PD-L1 expression in tumor cells (TC) and tumor infiltrating immune cells (IC) and correlated this with mutation burden and clinical outcome. Methods: A total of 192 patients with LCNEC (n = 72) and SCLC (n = 120) were explored. PD-L1 expression was scored by immunohistochemistry in TC and IC. We used the Ion AmpliSeq Comprehensive Cancer Panel to identify mutation in all exons in 409 cancer-related genes. Results: The overall prevalence of PD-L1 expression on TC was 15.1 % (29/192). No significant difference was observed between LCNEC and SCLC (16.7% vs. 14.2%, p = 0.365). Tumor-infiltrating IC and PD-L1 positive immune cells (IC) were observed in 34.4% (66/192) and 31.3% (60/192), respectively. The prevalence of tumor-infiltrating IC and PD-L1 expression on IC were significantly higher in LCNEC compared to SCLC (57.6% vs. 23.3%, p < .001; 45.8% vs. 22.5%, p = .001, respectively). Tumor-infiltrating IC and PD-L1 expression on IC were correlated with higher nonsynonymous mutational load (p = 0.048 and 0.038, respectively). Tumor-infiltrating immune cells (median 11.3 vs. 6.8 months, p = 0.005), and its correlated PD-L1 expression on IC (median 11.3 vs. 7.0 months, p = 0.024) were related with better progression free survival. There was no relevance between biomarker status and overall survival. Conclusions: These findings suggest that the PD-1/PD-L1 pathway is activated in a fraction of HGNEC of lung with correlating higher mutational burden. Further studies are needed to determine the PD-L1 expression and correlated clinical features to refine role of anti-PD1 treatments in these patient population.
Evolution and clinical impact of genomic alterations detectable in circulating tumor DNA of 1150 advanced EGFR-mutant (mt) lung cancer patients.
Authors: Blakely Collin M. , Wu Wei , Gubens Matthew A. , Rotow Julia , Wang Victoria , Banks Kimberly , Lanman Richard B. , Mack Philip C. , Husain Hatim , McCoach Caroline Elizabeth , Doebele Robert Charles , Riess Jonathan , Bivona Trever Grant 
Published: September 2018

9009 Background: Advanced EGFR-mt lung adenocarcinomas (LUAD) frequently harbor additional genetic alterations. The clinical significance of these concurrent alterations and how they evolve with treatment are unclear. Methods: We performed next-generation sequencing (NGS) of ~70 cancer related genes from the circulating tumor DNA (ctDNA) of 1150 consecutive advanced LUAD patients (pts) with detectable EGFR mts. The analysis included 113 samples from 81 pts for whom clinical outcome data were known. Clinical response to EGFR TKI treatment was correlated to mutational status in 12 cancer-related pathways. Results: EGFR-mt cases contained an average of 3.6 genetic alterations (range 1-18). There was enrichment for co-alterations in TP53, CDK6, CTNNB1 and SMAD4 in EGFR-mt cases compared to a control cohort of 1008 EGFR WT cases. Enrichment for the EGFR T790M mutation was found upon progression to first-line EGFR TKI treatment, as expected. Analysis of 450 T790M-mt cases showed enrichment for co-alterations in genes controlling the cell cycle (28% vs. 21%, p = 0.01), DNA repair (12% vs. 8%, p = 0.03), and WNT (16% vs. 11%, p = 0.03) signaling. The number of genetic alterations increased during progression on each line of therapy in a manner unlinked to age, gender, or tobacco exposure (mean 3.2 pre-TKI vs. 6.4 after 2nd line, p = 0.001). Upon progression to second-line treatment, analysis revealed further selection for co-alterations in TP53, CCNE1, MYC and PIK3CA and the associated pathway-level classifications. We found an increased frequency of co-alteration in cell cycle genes in EGFR TKI non-responders versus responders (33% vs. 0%, p = 0.0005). Conclusions: Within the landscape of advanced EGFR-mt LUAD, we uncover features of evolutionary selection for multiple concurrent oncogenic pathway alterations including TP53, WNT, PI3K, MYC, and cell cycle genes. This large clinical and genetic dataset prompts a re-evaluation of the prevailing paradigm of monogenic-based molecular stratification to monotherapy, and highlights an alternative model of genetic collectives as a previously underappreciated determinant of lung cancer progression and therapy resistance.