tbuckley/cabot-search huggingface dataset:
Surgical management of pulmonary typical carcinoids: A population-based analysis.
Authors: Muhammad Furqan, Yu-Yu Tien, Taher Abu Hejleh, Jun Zhang, Gerald H. Clamon, Alexandra Thomas, Kalpaj Parekh, John Keech, Bryan G. Allen, Mary Chen Schroeder
Journal: Journal of Clinical Oncology (2016)

8540 Background: Surgical resection is the preferred treatment modality for pulmonary typical carcinoids (TCs). However, the extent of surgery, e.g. lobar resection (L-R) vs sublobar resection (SL-R), remains controversial. In this population-based analysis, outcomes for TCs were compared by type of therapy: no surgery (NS), L-R and SL-R. Methods: Data from the Surveillance, Epidemiology, and End Results (SEER) Program was used to select patients (pts) ≥ 66 years old, and newly diagnosed between 2000 and 2012 with a microscopically confirmed typical carcinoid tumor of the lung. Those who received pneumonectomy or presented with distant disease were excluded. A similar cohort was developed using the SEER-Medicare database (diagnosed from 2000-2007) to identify chemotherapy use and co-morbidity. Five-year relative survival and cause-specific death were calculated. Cox models were generated, controlling for age, sex, race, stage, radiation therapy, chemotherapy, and comorbidity. Results: Our final sample size included 1,506 SEER pts and 512 SEER-Medicare pts. In the SEER cohort, 49%, 29% and 21% received L-R, SL-R, and NS, respectively. Those who received NS were older (p < 0.001), diagnosed with higher stage disease (p < 0.001), had greater comorbidity (p = 0.001), and were more likely to receive radiation therapy (p < 0.001) and chemotherapy (p = 0.004). Relative survival was ≥ 100% for those who received L-R or SL-R as opposed to 72% for those pts who received NS (p < 0.001). Cause-specific death was 22.9% for pts who received NS, compared with 4.2% and 5.1% for those who received SL-R and L-R (p < 0.001). Cox models showed no difference in survival for those who received L-R vs SL-R (HR = 1.1, p = 0.724) but substantial detriment in survival for those who received NS vs L-R or SL-R (HR = 3.4, p < 0.001), even after controlling for covariates. Conclusions: For pulmonary TCs, there was no significant difference in observed patient characteristics or survival by extent of surgery (L-R versus SL-R). Prospective studies will be needed to assess whether SL-R should be considered standard of care, given its lower morbidity. In contrast, NS was associated with far greater cause-specific death than those who received surgery.
Phase 2 multi-center study of tazemetostat (EPZ-6438), an inhibitor of enhancer of zeste-homolog 2 (EZH2), in patients with relapsed or refractory B-cell non-Hodgkin lymphoma (NHL).
Authors: Franck Morschhauser, Gilles A. Salles, Steven Le Gouill, John A. Radford, Pamela McKay, Guillaume Cartron, Patricia J. Pimentel, Maria Roche, Stephen J Blakemore, Alice McDonald, Natalie Warholic, Shelley Knight, Peter T.C. Ho, Vincent Ribrag
Journal: Journal of Clinical Oncology (2016)

TPS7582 Background: The histone transferase EZH2 is the catalytic subunit of the polycomb repressive complex 2 (PRC2) responsible for methylating lysine 27 of histone H3, a mark associated with repressed transcription when trimethylated. Aberrant EZH2 activity has been implicated as an oncogenic driver in NHL. In line with preclinical observations of cell line sensitivity to EPZ-6438 exposure, objective responses have been observed in phase 1 in patients with both wild-type and mutated EZH2 tumors. This phase 2 study is enrolling subjects with either EZH2 mutated or EZH2 wild-type relapsed/refractory diffuse large B-cell lymphoma (DLBCL) or follicular lymphoma (FL) to determine efficacy and safety in 5 separate cohorts determined by centrally confirmed histology, cell of origin (COO) and EZH2 mutation status. Methods: Tazemetostat 800 mg is administered orally twice daily to 5 cohorts: DLBCL with GCB subtype and EZH2 mutations; DLBCL with GCB subtype and wild-type EZH2; DLBCL with non-GCB subtype (including PMBCL); FL with EZH2 mutations; and FL with wild-type EZH2. Archival tumor tissue is analyzed prospectively for EZH2 hot spot mutations Y646X, A682G and A692V using a cobas EZH2 mutation test (in development) and COO as determined by immunohistochemistry using the Hans’ algorithm. Next generation sequencing will be used retrospectively to analyze somatic mutations in a panel of 60 genes commonly mutated in NHL (including EZH2). Key inclusion criteria include: ≥ 18 yrs of age; histologically confirmed DLBCL or FL; relapsed/refractory disease following at least 2 prior treatment regimens including at least 1 alkylator and anti-CD20-based regimen; unable to benefit from autologous hematopoietic stem cell transplantation (DLBCL only); measurable disease; and adequate organ function. The primary endpoint is objective response rate with response assessments performed every 8 weeks. This trial is open to enrollment in France, UK and Australia with additional sites to be opened in Canada, US and EU. (NCT01897571) Clinical trial information: NCT01897571.
Initial results of the phase ib/II, I-START trial: Isotoxic accelerated radiotherapy for the treatment of stage II-IIIb NSCLC.
Authors: Jason Francis Lester, Nicholas Courtier, Chinnamani Eswar, Nazia Mohammed, John Fenwick, Gareth Griffiths, Lisette Sheena Nixon
Journal: Journal of Clinical Oncology (2018)

e20551 Background: Clinical development of radical Radiotherapy (RT) in NSCLC is currently constrained by a paucity of data on the oesophageal maximum tolerated dose (MTD) when treating with a 20 fraction (#) regimen. Phase I was designed to establish the oesophageal MTD. The primary objective of phase II was to investigate whether this RT regimen is tolerable, safe and sufficiently active to justify inclusion as an experimental arm in future trials. We report toxicity data from the trial. Methods: Patients were sequentially allocated to cohorts of 58Gy, 61Gy and 63Gy to the oesophagus where the oesophagus was within the Planning Target Volume (PTV). Phase I and II recruited concurrently from centres across the UK who had undergone a national RT Quality Assurance process. Patients received 52Gy to 65Gy in 20# over 4 weeks to the PTV, planned according to predefined organ at risk (OAR) constraints (normalised mean lung dose ≤ 17Gy, spinal cord maximum 48Gy to 0.1cm3, Heart 100% < 36Gy, brachial plexus maximum 55Gy to 0.1cm3). Results: Data reported have been grouped according to oesophageal dose. Group Y (48 patients) had an oesophageal dose of ≥55Gy and Group Z (32 patients) < 55Gy (55Gy is a standard UK NSCLC prescription dose). Rates of Grade 3/4 toxicities were highest following treatment in both groups (Y = 6 patients, Z = 2 patients). Fatigue, Cough and Dyspnoea were the most common reported toxicities. One G3 oesophagitis occurred at the end of treatment (patient received 62Gy to the PTV, 61Gy to the oesophagus). 3/80 (3.8%) patient reported pneumonitis (2 at G3, one G5 in a patient with interstitial lung disease diagnosed post enrolment/treatment). Conclusions: Escalation of the prescription dose to 65Gy is safe and feasible if dose volume constraints are met. The rates of G3+ oesophagitis and G3+ pneumonitis were very low. We conclude that the dose to oesophagus is not a limiting factor when considering dose prescription in this setting and this treatment strategy warrants further investigation in a future randomised trial. I-START was developed on behalf of the NCRI Lung CSG, funded by Cancer Research UK (A11535), sponsored by Velindre NHS Trust and run by the Centre for Trials Research, Cardiff University. Clinical trial information: ISRCTN74841904.
The MAP4 Kinase SIK1 Ensures Robust Extracellular ROS Burst and Antibacterial Immunity in Plants
Authors: Meixiang Zhang, Yi-Hsuan Chiang, Tania Y. Toruño, DongHyuk Lee, Miaomiao Ma, Xiangxiu Liang, Neeraj K. Lal, Mark Lemos, Yi-Ju Lu, Shisong Ma, Jun Liu, Brad Day, Savithramma P. Dinesh-Kumar, Katayoon Dehesh, Daolong Dou, Jian-Min Zhou, Gitta Coaker
Journal: Cell Host & Microbe (2018)
Third-line therapy in glioblastoma: Analysis of a single centre database.
Authors: Enrico Franceschi, Giuseppe Lamberti, Alexandro Paccapelo, Stefania Bartolini, Santino Minichillo, Antonella Mura, Giovanni Tallini, Annalisa Pession, Dario De Biase, Raffaele Agati, Chiara Scafati, Maria Francesca Currà, Monica Di Battista, Laura Lombardo, Giovenzio Genestreti, Michela Visani, Alba Ariela Brandes
Journal: Journal of Clinical Oncology (2018)

e14057 Background: About 21-62% of GBM patients (pts) access to 3rd line therapy. In this setting, there is no defined standard. In this study we evaluated the outcome of pts who received 3rd line therapy for recurrent GBM. Methods: We analyzed data from our Institutional data warehouse from consecutive GBM pts who received 3rd line therapy between 2005 and 2016. Disease assessment was reviewed according to RANO criteria. Survival was calculated from diagnosis to death from any cause (OS) and from the beginning of 3rd line therapy to death from any cause (OS3). Progression-free survival was calculated from the beginning of 3rd line therapy to progression (PFS3). Results: 1552 GBM pts underwent standard RT/TMZ. 184 pts (11.9%) received 3rd line therapy and were included in the study. Median age was 50.5 years (range: 20 to 72). Treatments administered in 3rd line were nitrosourea-based (NU) in 81 pts (44.0%), TMZ in 43 (23.4%), Bevacizumab (BEV) in 25 (13.6%) and carboplatinum-etoposide (CE) in 35 (19%). mOS from GBM diagnosis was 30.3 months, median PFS3 was 2.7 months and median OS3 was 7.0 months. In univariate analysis, the BEV group showed longer mPFS3 (4.6 vs 2.4 months, p = .014) and mOS3 (8.0 vs 7.0 months, p = .038) with respect to NU (table 1). In multivariate analysis age < 65 years (HR 0.50, 95%CI 0.30 – 0.84, p = .008) and mMGMT (HR 0.62, 95%CI 0.43 – 0.89, p = .01) significantly improved OS3, whereas previous BEV therapy was a negative prognostic factor (HR 2.08; 95%CI 1.40 – 3.10, p < .001) for OS3. Conclusions: Favorable prognostic factors for pts who received 3rd line treatments are younger age and methylated MGMT promoter, whereas 2nd line therapy with BEV seems to negatively affect outcome. Third line therapy with BEV was associated with longer PFS3 and OS3. Table 1. n mMGMT (%) PFS3 (mos) OS3 (mos) OS (mos) BEV 25 41.2 4.6 8.0 30.1 CE 35 48.3 2.6 6.0 23.6 NU 81 47.5 2.4 7.0 28.6 TMZ 43 71.4 3.0 6.0 38.1
Abstract 13392: Clinical Significance of Hematuria in Patients With Atrial Fibrillation Receiving Oral Anticoagulation Therapy
Authors: Hee Tae Yu, Tae-Hoon Kim, Jae-Sun Uhm, Hui-Nam Pak, Moon-Hyoung Lee, Boyoung Joung
Journal: Circulation (2015)

Introduction: The presence of hematuria is frequently related with underlying genitourinary pathologies such as urolithiasis or malignancies. Although hematuria is an important and common complication in atrial fibrillation (AF) patients taking oral anticoagulation therapy (OAT), its clinical implication is not fully elucidated. Objectives: We evaluated the clinical significance of hematuria and its relationship with genitourinary disease in patients with AF. Methods: This study included 18,086 consecutive AF patients with (OAT+, n=11,432) or without OAT (OAT-, n=6,654) who visited to a tertiary Hospital from January 2005 to April 2015. The degree of urinary red blood cells (RBC) was reported to range from 0 to 3+ on random urinalyses. The incidence of cancer or stone in the genitourinary tract (kidney, ureter, and bladder) was evaluated. All data were obtained from the Clinical Data Repository System. Results: Overall, 144 (0.8%) patients had malignancies and 164 (0.9%) patients had stones in the genitourinary tract. Hematuria was observed in 3,737 (32.7%) and 2,017 (30.3%) in patients with and without OAT (p=0.001), and the large (≥ urine RBC 3+) hematuria was observed in 1,382 (12.1%) and 666 (10.0%) patients with and without OAT, respectively (p&lt;0.001). While 39 (2.8%) OAT+ patient with large hematuria had malignancies, 8 (1.2%) OAT- patient had (p=0.026). However, if the patients had small hematuria (urine RBC 1+ or 2+), the incidence of genitourinary cancer was not different between OAT+ and OAT- groups (p=0.266). The incidence of genitourinary tract stone in patients with large or small hematuria was comparable between OAT+ and OAT- groups. Conclusions: Large hematuria was associated with higher incidence of cancer in the genitourinary tract in OAT+ group, but not in OAT- group. A meticulous evaluation of the cause of hematuria is needed, if AF patients receiving OAT had large hematuria.
Subgroup analysis by prior lines of metastatic therapy (mtx) in NAPOLI-1: A global, randomized phase 3 study of liposomal irinotecan (nal-IRI) ± 5-fluorouracil and leucovorin (5-FU/LV), vs. 5-FU/LV in patients (pts) with metastatic pancreatic ductal adenocarcinoma (mPDAC) who have progressed following gemcitabine-based therapy.
Authors: Teresa Mercade Macarulla, Jens T. Siveke, Andrea Wang-Gillam, Chung-Pin Li, Gyorgy Bodoky, Andrew Peter Dean, Shan Yanshen, Gayle S. Jameson, Kyung-Hun Lee, Jean-Frédéric Blanc, Chang-Fang Chiu, Gilberto Schwartsmann, Fadi S. Braiteh, David Cunningham, Li-Tzong Chen, Daniel D. Von Hoff, Khalid Kevin Mamlouk, Parul Bhargava, Floris A. de Jong, Richard Hubner
Journal: Journal of Clinical Oncology (2017)

4127 Background: In the NAPOLI-1 study, nal-IRI+5-FU/LV significantly increased median OS vs. 5-FU/LV control (6.1 vs. 4.2 mo; unstratified HR = 0.67 [0.49–0.92]; p = .012). This is a subgroup analysis by prior lines of mtx. Methods: Study methodology has been published (Wang-Gillam; Lancet 2016). This exploratory subgroup analysis compares outcomes in pts with 0–1 vs. ≥2 prior mtx lines, based on primary survival analysis data (cut-off February 2014) of the ITT population. Results: OS, PFS and CA19-9 response rates in pts with 0–1 (65.8% of pts) or ≥2 (34.2%) prior mtx lines are shown (see Table). Median OS for nal-IRI+5-FU/LV improved vs. 5-FU/LV by 2.1 mo to 6.2 mo (HR = 0.66; p = .03) in pts with 0–1 prior mtx lines and by 1.1 mo to 5.4 mo (HR = 0.68; p = .18) in pts with ≥2 prior mtx lines. The safety profile was similar between subgroups with nal-IRI+5-FU/LV (≥grade 3 drug-related AEs: 43 [55%] with 0–1 and 20 [51%] with ≥2 prior mtx lines). Conclusions: This post-hoc subgroup analysis shows significant increases for nal-IRI+5-FU/LV over 5-FU/LV in OS, PFS and CA19-9 response in pts with 0–1 prior mtx lines. Median OS benefit was less prominent in later lines, but conclusions are restricted by limited pt numbers. Clinical trial information: NCT01494506. [Table: see text]
A phase Ib study combining irinotecan with AZD1775, a selective WEE 1 kinase inhibitor, in RAS/RAF mutated metastatic colorectal cancer patients who progressed on first line therapy.
Authors: Deirdre Jill Cohen, Elda Grabocka, Dafna Bar-Sagi, Robert Godin, Lawrence P. Leichman
Journal: Journal of Clinical Oncology (2017)

TPS3627 Background: Mutant KRAS tumors show a dependency on WT-H/N-Ras for activation of ATR/Chk1-mediated G2 DNA damage response (Grabocka, Cell, 2015). We have shown in vitro that the Wee1 kinase inhibitor AZD1775, which acts to abrogate the G2 DNA damage checkpoint and induces replication stress during S-phase, selectively sensitizes RAS/RAF mutant cells to the DNA damaging agent irinotecan. Up to 65% of metastatic colorectal cancers harbor RAS or BRAF mutations and these patients have limited treatment options following first line therapy. Methods: This is an open label, single-arm, phase Ib study using a modified 3+3 dose-escalation schedule with expansion cohort. Primary objective is to determine the MTD of AZD1775 in combination with irinotecan as 2 nd -line therapy in patients with metastatic KRAS, NRAS or BRAF mutated colorectal cancer. Up to 18 patients will be enrolled in the dose escalation portion. Standard dose irinotecan is given on day 1 of every 2 week cycle. AZD1775 is administered PO twice daily for 3 to 5 days of each cycle, starting cycle 2. The maximum tolerated dose (MTD) is defined as the highest dose level at which ≤1 of 6 patients experience a dose limiting toxicity. Once the MTD is reached and/or recommended dose for expansion is determined, a dose expansion cohort of 14 patients will be enrolled. Secondary endpoints include characterizing the safety profile at the MTD, obtaining a preliminary estimate of efficacy for the combination (measured by overall response rate, progression-free and overall survival rates), and obtaining pharmacokinetic parameters. Pre- and on-treatment biopsies will be collected from the expansion cohort to determine: adequate target engagement of Wee1, changes in markers of DNA damage, TP53 mutation status, and changes in gene expression profiles in order to identify potential biomarkers of response. At February 2017, 2 patients have been enrolled on this study. Clinical trial information: NCT02906059. [Table: see text]
Screening of neoantigen-specific T cells and establishment of T-cell receptor-engineered T cells: Implications for head and neck squamous carcinoma.
Authors: Lili Ren, Tatsuo Matsuda, Boya Deng, Kazuma Kiyotani, Taigo Kato, Jae-Hyun Park, Tanguy Y. Seiwert, Everett E. Vokes, Nishant Agrawal, Yusuke Nakamura
Journal: Journal of Clinical Oncology (2018)

3048 Background: Due to the high immune-suppressive condition in tumor microenvironment in growing tumors, the numbers of neoantigen-specific T cells is in general very limited. To improve adoptive T cell transfer (ACT) immunotherapy targeting neoantigens, we attempted to rapidly identify neoantigen-specific T cell receptors (TCRs) and establish T-cell receptor-engineered (TCR-engineered) T cells. Methods: To screen the neoantigen-specific T cells, we performed whole exome sequencing (WES) and transcriptome analysis, and selected candidate neoantigen epitopes to induce cytotoxic T lymphocytes (CTLs) in 20 patients with squamous head and neck cancer. 64 potential neoantigen peptides as well as 16 minigenes, each of which were designed to express peptides carrying 20 somatic missense mutations, were examined for induction of neoantigen-reactive cytotoxic T cells in vitro using patient-derived dendritic cells and peripheral blood, or expanded TILs isolated from corresponding tumors. Neoantigen-specific T cells were screened by 4-1BB expression levels as well as ELISPOT assay and TCR sequences were determined using isolated T cell clones. We then cloned TCR cDNAs into T lymphocytes and generated the neoantigen-reactive TCR-engineered T cells. Results: We have so far confirmed 8 neoantigen-reactive T cells and established 6 TCR-engineered T cells which showed HLA-restricted neoantigen-reactive cytotoxic activity in vitro. We also tested HLA A*02:01 restricted engineering T cells with the antigen-negative humanized mice model we generate previously, which showed very specialized antigen reactivity in vivo. Conclusions: We here demonstrate the establishment of a more effective and rapid protocol to generate neoantigen-specific T cells, identify neoantigen-specific TCRs for individual patients, and establish TCR-engineered T cells applicable for the clinical use.
Genomic alterations in the homologous recombination pathway in soft-tissue sarcomas.
Authors: Nathan David Seligson, Esko Antero Kautto, Edward N Passen, Colin W Stets, Amanda Toland, John L. Hays, James Lin Chen
Journal: Journal of Clinical Oncology (2018)

11549 Background: Soft-tissue sarcomas (STS) describe a heterogeneous group of tumors with limited treatment options available to patients. Targeted therapy exists for tumors with alterations in BRCA1/2 as well as other homologous recombination (HR) pathway genes; however, their prevalence has yet to be fully described in STS. We hypothesized that tumors with these alterations may represent a targetable cohort with the advent of poly (ADP-ribose) polymerase (PARP) inhibitors. Here we assess the frequency of BRCA1/2 and HR alterations in STS. Methods: DNA sequencing data was aggregated from The Cancer Genome Atlas (n = 255), Genomics Evidence Neoplasia Information Exchange (n = 583), and The Ohio State Sarcoma Registry (n = 398). Deleterious genomic alterations were defined as in ClinGen. Clinical data from three patients with somatic BRCA2 loss who were treated with PARP inhibitors were collected for analysis. Results: BRCA1 and HR somatic alterations were more common in leiomyosarcoma (LMS) subtype compared to other STS (LMS 17%, liposarcoma 9.8%, other 8.9%, p = 0.001). A disproportionate number of BRCA2 losses were detected in uterine LMS (uLMS) with 85.7% of tumors harboring BRCA2 loss identified in this STS subtype (p < 0.001). When considering uLMS, 9.8% of tumors had a loss of BRCA2 (0.9% in non-uterine LMS, 0.5% in all other STS). Tumors with BRCA2 loss often exhibited a poor differentiated histology (57.1% of BRCA2 loss vs 38.8% BRCA2 intact; p = 0.59) and tended to have a higher mitotic count (10.7 count/HPF BRCA2 loss vs 3.3 count/HPF BRCA2 intact; p = 0.10). Retrospective evaluation of three uLMS patients with somatic BRCA2 loss treated with PARP inhibitors demonstrated a median progression-free survival of nine months highlighting the potential targetability of BRCA2 loss in uLMS. Conclusions: Here we assess the frequency of BRCA1/2 and HR alterations and their clinical phenotype in STS. We identify somatic BRCA2 loss in a subset of patients with uLMS and describe three patients with uLMS harboring BRCA2 loss who were treated with PARP inhibitors. Our data suggests that patients with uLMS should be screened for BRCA2 alterations. Prospective trials are needed to confirm the efficacy of PARP inhibition in this cohort of patients.