bluuebunny/crossref_metadata_2025_split huggingface dataset:
Malignant mesothelioma in 91 danish women: The environmental asbestos exposure.
Authors: Panou Vasiliki , Vyberg Mogens , Meristoudis Christos , Omland Øyvind , Weinreich Ulla Møller , Hansen Johnni , RÃ¸e Oluf D. 
Published: September 2018

8560 Background: Malignant Mesothelioma (MM) is an asbestos-related malignancy that presents mainly in the pleura (MPM) and peritoneum (MAM). In a densely populated area of Aalborg city in North Jutland, Denmark, a large Eternit asbestos factory that was active for 60 years until 1986 and two shipyards were situated. The Region of North Jutland, Denmark has a high mm incidence in women of 1.0/100,000. Methods: From 1974-2015, 101 histological and cytological samples of women diagnosed with mm in Aalborg University Hospital were identified re-evaluated by modern immunohistochemistry. Patient information regarding asbestos exposure was retrieved from medical records and selected Danish registries. Asbestos exposure was classified as primary for asbestos workers; domestic, for women living with an asbestos worker; environmental, when living or working within 10.000 meters from an asbestos emitting location; unknown, where no source of asbestos exposure could be identified. Results: Clinical and histopathological mm diagnosis was certain for 91 women. Potential asbestos exposure is summarized in Table 1. The employment of the women and their relatives include work at the asbestos cement factory, shipyard, construction, laboratory, pipe factory, electrician and insulator. The women with domestic and combined domestic and environmental (secondary) exposure to asbestos were most prone to develop MPM rather than MAM while women primary exposed to asbestos developed MAM rather than MPM (p=0.016). Conclusions: This study showed that the vast majority (64%) of the women diagnosed with mm had documented non-occupational asbestos exposure and almost 1/5 had a sole environmental exposure, by living in proximity to asbestos industry. Environmental asbestos exposure is a serious risk factor for mm in women. Primary asbestos exposure, inferring more intense exposure through occupation, may predispose to peritoneal mesothelioma in women. [Table: see text]
Small cell lung cancer: The immune microenvironment and prognostic impact of checkpoint expression.
Authors: Rivalland Gareth , Walkiewicz Marzena , Wright Gavin Michael , John Thomas 
Published: September 2018

8569 Background: To date, immunotherapy has had limited success in small cell lung cancer (SCLC), despite the tumor’s high mutation load. Little is understood of the immune tumor microenvironment in SCLC due to a paucity of resected tumor. We present a SCLC cohort and describe the prognostic impact of checkpoint expression. Methods: SCLC tissue microarrays with triplicate cores from 105 SCLC specimens underwent IHC assessment for PD-L1, PD-L2, LAG3, TIM3, FoxP3, CD4 and CD8 on tumor and/or tumor infiltrating lymphocytes (TILs). Checkpoint positivity was defined > 5% tumor expression or TIL expression in > 5% of the total core area. Associations with clinicopathologic characteristics and survival were assessed. A Cox model was used for univariate and multivariate survival analysis. Results: Tumor expression of PD-L1 was positive (+) in 17/95 (18%), PD-L2+ in 2/96 (2%), and TIM3+ or LAG3+ in no cases. TILs expressed PD-L1+ in 64/95 (67%), PD-L2+ in 22/96 (22%), TIM3+ in 57/96 (59%) and LAG3+ in 43/96 (45%). FoxP3+ lymphocytes were found in all samples (range 0.02 – 2.98% of total core). TIL expression of PD-L1, PD-L2, TIM3 and LAG3 were all significantly correlated (p value ≤0.001 for all comparisons), and were associated with high FoxP3+ expression. All four checkpoints were expressed on TILs in 20/105 (19%) patients. PD-L1+ and PD-L2+, but not TIM3 or LAG3, on TILs were significantly higher in limited stage compared with extensive stage SCLC (76% v 52%, p 0.045 and 28% v 7%, p 0.02 respectively). There was no association between stage and tumor expression. TIL expression of PD-L1, PD-L2, TIM3 and LAG3 were all associated with improved prognosis. PD-L1+ median OS: 17.2 v 7.9 months (HR 0.36; 95%CI 0.22 – 0.6; p < 0.001). Univariate analysis showed stage and TIL expression of PD-L1, PD-L2, TIM3 and LAG3 were associated with improved survival, but only stage and PD-L1+ TILs remained significant on multivariate analysis (p < 0.01). Conclusions: Immune checkpoint molecules are frequently expressed in SCLC-associated TILs, but not the tumor itself. TIL expression of checkpoint molecules is associated with improved survival. Limited tumor expression of PD-L1 and an exhausted immune cell phenotype may contribute to immunotherapy failure.
Postoperative radiation for tumor control and overall survival in thymic epithelial tumors (TET): A matched-pair analysis.
Authors: Kong Feng Ming , Zang Yong , Wang Weili , Zhang Hong , Smith Jessica , Badve Sunil S. , Kesler Kenneth , Loehrer Patrick J. 
Published: September 2018

8572 Background: Due to lack of randomized trials, the role of postoperative radiation therapy (PORT) in thymic epithelial tumors (TET) remains controversial. This study aimed to evaluate whether PORT improves tumor control and overall survival (OS) in patients with resected TET in a large single institution database. Methods: This is a retrospective study of all TETs seen at Indiana University between 1975 and 2016. Patients with resected thymoma (T) or thymic carcinoma (TC) were eligible disregarding their margin status or stage. Study endpoints were progression free survival (PFS) and OS. Age, gender, race, tumor size, stage, pathology, grade, completeness of resection and adjuvant treatment modality were analyzed for significance on PFS and OS. Multivariate Cox model was used to identify significant factors for propensity score matching. Differences between the PORT and surgery alone group were estimated using stratified log-rank test. Results: A total of 478 patients with previous surgical resection were eligible. Masaoka Stage was: I-86 (22%); II-87 (23%); III-107 (28%); and IV-106 (27%), respectively. Multivariate analysis demonstrated that gender (HR = 1.4, p = 0.03), stage (HR = 1.3, p = 3×10-3), TC (HR = 1.6, p = 0.03) and PORT (HR = 1.6, p = 0.002) were significantly associated with PFS. Age (HR = 1.1, p = 4×10-7), TC (HR = 3.2, p = 3×10-5), stage (HR = 1.4, p = 0.003) were associated with OS. PORT was given to 126 (26%) patients. Propensity score matching based on independent prognostic factors identified 99 patients for PORT, matched to 285 patients without. The 5-/10-year intra-thoracic progression free rates were 77%/69% and 85%/68%, for patients with and without PORT (p = 0.009), respectively. The 5-/10-year PFS rates were 39%/18% and 61%/32%, for patients with and without PORT (p = 0.002), respectively. The median survival, 5-/10-year OS rates for patients treated with PORT were 150 (95%CI 111~277) months, 87%/57% and respectively, compared to 192 months (95%CI 167~279), 88%/69% for patients receiving surgery alone ( p = 0.13). Conclusions: This matched-paired analysis from a single institution suggests that PORT does not impact the PFS or OS in a selected population of resected TET.
Pembrolizumab in patients with recurrent thymic carcinoma: Results of a phase II study.
Authors: Giaccone Giuseppe , Thompson Jillian , McGuire Colleen , Manning Maria , Kallakury Bhaskar , Chahine Joeffrey J , Subramaniam Deepa Suresh , Liu Stephen V. , Gibney Geoffrey Thomas , Kim Chul , McCutcheon Justine N 
Published: September 2018

8573 Background: There are few treatment options for thymic carcinoma after chemotherapy. We completed a single institution phase II study of pembrolizumab (P) in patients with recurrent thymic carcinomas. Methods: Main eligibility criteria included: progression after ≥ 1 chemotherapy line, ECOG PS 0-2, no history of autoimmune disease, and adequate organ function. P was given at 200mg IV every 3 weeks. The primary objective of the study was response rate (RR) by RECIST v1.1 criteria; secondary objectives were PFS and OS, and safety. Results: From 3/2015 to 12/2016 we accrued 41 patients. Of 40 eligible patients, 29 were male, 19 Caucasians, median age was 57 years (range 25-80), 14 had squamous carcinoma histology, and 19 ECOG PS 0. Median number of cycles delivered was 6 (range 1-31). The most common side effects were mild fatigue (10), diarrhea (4) and rhinorrhea (4). Six patients developed multiple grade 3-4 immune-relates AEs (irAEs): myocarditis/myositis (1), myositis/myocarditis/hepatitis/myasthenia gravis (1), myositis/hepatitis (1), bullous pemphigoid (1), hepatitis (1), hepatitis/pancreatitis/diabetes mellitus type 1 (1). There were no treatment related deaths. The 2 patients who developed myocarditis required a pacemaker. Three patients interrupted treatment because of irAEs (all responders) and 3 because of progression around the time of the irAE. irAEs were more frequent in females (4/6; p = .026). Five patients developed hypothyroidism and 1 hyperthyroidism. RR assessed in all 40 eligible patients was 22.5%: 1 complete response, 8 partial responses (plus 1 unconfirmed), 20 stable disease and with 11 progressions. Two partial responses show minimal residual disease with no PET uptake. Two responders have progressed and 5 responses are beyond 12 months duration. Of 29 cases tested for PD-L1 staining (Dako 22C3), high PD-L1 (≥50% tumor cells positive) was seen in 8 (28%); 6/9 responders had high PD-L1 expression. Targeted NGS in 15 cases did not show correlation between mutational burden and response. Conclusions: P has activity in patients with thymic carcinoma. irAEs are more frequent than in other tumors. Further analysis of NGS, Nanostring and PD-L1 expression and updated survival will be presented. Clinical trial information: NCT02364076.
Paraneoplastic syndrome and survival in thymic epithelial tumors (TET): The Indiana University experience.
Authors: Wang Weili , Zhang Hong , Lu Ray , Smith Jessica , Conces Louise , Badve Sunil S. , Kesler Kenneth , Nelson Robert P , Kong Feng-Ming (Spring) , Loehrer Patrick J. 
Published: September 2018

8574 Background: Paraneoplastic syndromes (PNS) are commonly associated with thymic epithelial tumors (TET), especially thymoma. The purpose of this analysis is to examine the clinical impact of PNS in TET. Methods: Patients with pathologically diagnosed TET at a single institution were reviewed retrospectively. The primary and second endpoints for this study were overall survival (OS) and recurrence rates. Clinical factors included age, gender, race, performance score, histology, WHO classification, Masaoka stage, post-operative status, tumor size and number of positive lymph nodes. Cox proportional hazards model was used to identify significant prognostic factors for OS between different PNS groups. Results: From 1975 to 2016, 733 patients with TET (thymoma (T) -71%, thymic carcinoma (TC) -26% and neuroendocrine tumor (NET)-3%) were seen at Indiana University. Of these, 203 (28%) had PNS including myasthenia gravis (n = 130), red cell aplasia (n = 20), hypogammaglobulinemia (n = 14), systemic lupus erythematosus (n = 12) or other PNS (n = 64). Among these, 37 (18%) had two or more types of PNS. PNS were seen in 35% (183/523) of T, 9% (16/187) of TC and 15% (3/20) of NET ( p < 0.001), respectively. Recurrence rates and mortality at 5 year were 8% and 10% in PNS (+) group compared to 13% and 16% in PNS (-) group ( p < 0.05). Intrathoracic recurrences were more common in PNS (+) patients (89% vs 77%; p = 0.016). In both groups, adverse factors for survival included: older age, advanced stage, number of positive lymph nodes and TC histology (all p-values < 0.05). However, post-operative R1/2 status was adverse prognostic factor only in the PNS (-) group ( p = 0.001). Conclusions: PNS is common in TETs. Patients with PNS have lower risk of recurrence and mortality compared to patients without PNS, but may have a higher risk of intrathoracic recurrence.
Complete clearance of plasma EGFR mutations as a predictor of outcome on osimertinib in the AURA trial.
Authors: Thress Kenneth Stephen , Markovets Aleksandra , Barrett J Carl , Chmielecki Juliann , Goldberg Sarah B. , Shepherd Frances A. , Vowler Sarah , Oxnard Geoffrey R. 
Published: September 2018

9018 Background: Osimertinib, an EGFR T790M-selective tyrosine kinase inhibitor (TKI), provides high and durable response rates in patients (pts) with T790M positive advanced NSCLC whose disease has progressed following EGFR-TKI therapy. We investigated whether changes in the levels of plasma EGFRmutations post-osimertinib treatment are associated with clinical outcome. Methods: We studied pts from the AURA Phase I study (NCT01802632) with acquired resistance to EGFR-TKIs, T790M positive baseline genotyping (in tumor or plasma), and plasma samples collected at baseline and 6 weeks (wks) post- osimertinib (20–240 mg daily) treatment. Plasma samples were analyzed for the presence of detectable EGFR mutations (Ex19del, L858R and T790M) using BEAMing digital PCR (Sysmex/Inostics). In pts with detectable plasma EGFR mutations at baseline, clinical outcomes (by investigator, per RECIST 1.1) were compared for pts with or without detectable plasma EGFRmutations at 6 wks. Results: Evaluable baseline and 6 wk plasma samples were collected from 160 pts with T790M positive genotyping, of whom 143 had detectable EGFR mutations at baseline (median allelic fraction for Ex19del: 7.09%; L858R: 3.81%; T790M: 2.12%). In this cohort, the overall median progression-free survival (mPFS) was 9.3 months (m; 95% CI 8.2, 9.7). Clearance of plasma EGFRmutations at 6 wks was seen in 92/143 (64%) pts. mPFS was longer in pts with plasma clearance (10.9 m; 95% CI 9.5, 15.2) compared with pts without (5.5 m; 95% CI 3.9, 6.7), as was objective response rate (ORR; 70%; 95% CI 59%, 79% vs. 35%; 95% CI 22%, 50%). Conclusions: Clearance of plasma EGFR mutations after 6 wks of osimertinib therapy appears to be associated with improved ORR and mPFS in pts with T790M positive NSCLC. Evidence or lack of such a “plasma response” measured at 6 wks could, potentially, be used to predict subsequent outcomes on therapy. Further research is needed to better understand whether continued detection of plasma EGFR mutations at 6 wks may indicate the presence of heterogeneous resistance mechanisms, which could, potentially, be targeted by combination therapies. Validation of these results in an independent cohort of pts is ongoing. Clinical trial information: NCT02228369.
Pulse-continuous dose erlotinib as initial targeted therapy for patients with EGFR-mutant lung cancers with untreated brain metastases.
Authors: Kris Mark G. , Arbour Kathryn Cecilia , Riely Gregory J. , Ni Ai , Beal Kathryn , Daras Mariza , Hayes Sara A. , Young Robert J. , Rodriguez Christopher R , Pao William , Yu Helena Alexandra 
Published: September 2018

9039 Background: Clarke (Neurooncol 2010) reported responses with intermittent high pulse doses of erlotinib (leading to higher concentrations in CSF) given to patients with EGFR-mutant central nervous system metastases developing on standard erlotinib doses. In a phase 1 study of pulse-continuous dose erlotinib, no patient developed progression in existing or new brain or leptomeningeal metastases (Yu Ann Oncol 2016). This phase 2 trial tested pulse-continuous dose erlotinib in patients with lung cancers with EGFRmutations with brain metastases. Methods: Patients had no prior EGFR TKI or radiation to the brain and at least 1 target brain metastasis. All received initial daily "pulse" doses of erlotinib 1200 mg days 1&2 and "continuous" 50 mg doses days 3-7 (doses and schedule from the Yu Phase 1 study), weekly until progression. The co-primary endpoints were overall and brain metastasis response by RECIST 1.1. Results: We enrolled 19 patients with EGFR-mutant lung cancers: median age 61yrs (range 45-80), 74% women, 95% Karnofsky PS ≥80%, 1 leptomeningeal disease, 33% prior pemetrexed-based chemotherapy. The median size of target brain metastases was 13 mm (range 10-19 mm). 32% were on dexamethasone for cerebral edema. The partial response rate overall was 74% (95% CI 51-89%) and also 74% in brain metastases. Of 10 patients with progression, 9/10 occurred in non-brain sites (4 EGFRT790M, 1 with progression in brain as well), 1 with leptomeningeal. The median progression free survival was 10 mo (range 7-NR mo). Pulse doses were reduced in 68% (median delivered pulse dose 1050 mg days 1&2, range 600-1200 mg). Incidences of any gradeof rash and diarrhea were 84% and 63% respectively. There were no grade 4 or 5 toxicities. Conclusions: Pulse-continuous dose erlotinib alone controlled brain and leptomeningeal metastases in 89% (95% CI 67-98%) of patients with EGFR-mutant lung cancers with central nervous system spread pretreatment, with an overall response rate of 74% and progression free survival and rates of rash and diarrhea comparable to series with erlotinib 150 mg daily. Supported by Astellas, CA 129243, CA 008748. NCT01967095 Clinical trial information: NCT01967095.
Genetic subtypes of large cell neuroendocrine carcinoma (LCNEC) to predict response to chemotherapy.
Authors: Derks Jules , Leblay Noémie , van Suylen Robert Jan , Thunnissen Erik , den Bakker Michael , Groen Harry J.M. , Smit Egbert F. , Damhuis Ronald , van de Broek Esther , Chabrier Amélie , Foll Matthieu , McKay James , Fernandez-Cuesta Lynnette , Speel Ernst-Jan M. , Dingemans Anne-Marie C. ,   PALGA Group Coauthors
Published: September 2018

9061 Background: To treat LCNEC with non-small cell lung carcinoma type chemotherapy (NSCLC-ct, i.e. gemcitabine/taxanes or pemetrexed) or small cell lung carcinoma type (SCLC-ct, i.e. platinum-etoposide) is subject of debate. Molecular studies have identified two mutually exclusive subtypes in LCNEC, the co-mutated TP53 and RB1and the STK11/ KEAP1 (predominantly RB1 wildtype(wt)) group. We investigated if overall survival (OS) and progression free survival (PFS) correlates with targeted next-generation sequencing (TNGS) results in LCNEC treated with NSCLC-ct or SCLC-ct. Methods: For this population based retrospective cohort study all diagnoses of stage IV ct treated high grade neuroendocrine carcinomas (NEC, not being SCLC) were retrieved from the Netherlands Cancer Registry and Pathology Registry (PALGA) (2003-2012). Panel-consensus pathology revision of original tumor slides was performed on (N = 230) and TNGS for genes TP53, RB1, STK11 and KEAP1 analyzed with a multi-sample variant caller (Needlestack). Results: LCNEC was consensus diagnosed in 146/230 and 77 passed quality control for TNGS. Mean coverage was 2832x, a mutation(mt) in TP53 was present in 87%, RB1mt in 46%, STK11mt in 13% and KEAP1mt in 18% of sequenced LCNEC. RB1 was co-altered with TP53 in 94% of LCNEC; mutually exclusive to STK11mt (100%) but not KEAP1mt (57%). NSCLC-ct or SCLC-ct was specified in 92% of patients and RB1wt LCNEC treated with NSCLC-ct (n = 22) showed a trend to better OS compared to SCLC-ct (n = 13) (8.5 months (95% confidence interval (CI): [6.3-10.6]) vs. 5.8 [5.5-6.1] months, p = 0.055). Due to reported resistance in NECs we analyzed NSCLC-ct without pemetrexed-ct; OS was significantly longer for NSCLC-ct (n = 15) compared to SCLC-ct (9.6 [7.7-11.6] vs. 5.8 [5.5-6.1] months, p = 0.026). PFS of RB1wt NSCLC-ct treated patients was significantly longer than SCLC-ct (p = 0.044), without pemetrexed (p = 0.018). In patients with RB1mt LCNEC OS/PFS was not significantly different for NSCLC-ct vs. SCLC-ct. Conclusions: In LCNEC with RB1wt, NSCLC-ct correlates with a more favorable outcome compared to SCLC-ct. However, RB1mt LCNEC treated with NSCLC-ct do similarly worse as SCLC-ct. Prospective studies should be initiated.
Nivolumab-induced interstitial lung disease (ILD) in Japanese patients with non-small cell lung cancer: A study on risk factors for fatal outcome.
Authors: Kato Terufumi , Sakai Fumikazu , Baba Tomohisa , Kusumoto Masahiko , Kenmotsu Hirotsugu , Sugiura Hiroaki , Tominaga Junya , Oikado Katsunori , Sata Masafumi , Endo Masahiro , Yanagawa Noriyo , Sasaki Shinichi , Iwasawa Tae , Saito Yoshinobu , Fujiwara Yutaka , Ohe Yuichiro , Ito Yoshihiko , Tahara Yasuhiro , Kuwano Kazuyoshi 
Published: September 2018

9077 Background: We investigated case reports of nivolumab-induced ILD in patients with non-small cell lung cancer to identify risk factors for poor prognosis of ILD. Methods: Among data obtained during post-marketing surveillance of nivolumab, case reports of ILD with detailed clinical course and chest imaging (CT) findings were assessed by the ILD Expert Review Committee, which consists of respiratory medicine specialists and expert chest radiologists. The imaging findings were examined and classified into those with typical or atypical patterns. Atypical patterns included shadows limited to surrounding tumors designated as “peritumoral infiltration”, relapse of radiation pneumonitis, worsening of underlying infection, and predominant shadow in diseased side. CT pattern was classified as DAD (diffuse alveolar damage) or non-DAD. Data were analyzed using a multivariate stepwise logistic regression analysis. Results: Among 160 reported cases of ILD, 140 cases were considered to be induced by nivolumab. Imaging findings showed typical patterns in 92 patients, and 23 (25.0%) died of ILD. Atypical patterns were noted in 48 patients, and 5 (10.4%) died of ILD. The following table summarizes the results of univariate and multivariate analyses of risk factors for poor prognosis of ILD. See table. DAD pattern was observed in 20, 14 (70%) among them showed fatal outcome, whereas non-DAD pattern showed it in 14/120 (11.7%). Male and pretreatment CRP level were significant risk factors for fatal outcome. Conclusions: Nivolumab-induced ILD may show some atypical pattern that was not seen in conventional chemotherapy or EGFR-TKI. Outcome of patients with atypical patterns was better than those with typical patterns. DAD pattern at CT, male, and pretreatment level of CRP were identified as risk factors of fatal outcome. [Table: see text]