bluuebunny/crossref_metadata_2025_split huggingface dataset:
Survival impact on regorafenib (REG) and trifluridine/tipiracil hydrochloride (FTD/TPI) for patients with metastatic colorectal cancer: Single institutional experience.
Authors: Chida Keigo , Kotani Daisuke , Sawada Kentaro , Nakamura Yoshiaki , Kawazoe Akihito , Kuboki Yasutoshi , Shitara Kohei , Kojima Takashi , Taniguchi Hiroya , Yoshino Takayuki 
Published: February 2020

43 Background: Regorafenib (REG) and trifluridine/tipiracil hydrochloride (FTD/TPI) demonstrated overall survival (OS) benefit in patients (pts) with metastatic colorectal cancer (mCRC) in the CORRECT and RECOURSE phase III trials. In Japan, REG and FTD/TPI have been approved in 2013 and 2014, respectively. However, little is known about survival impact on these agents in the real-world setting. Therefore, the aim of this retrospective study was to evaluate the effects of REG and FTD/TPI in pts with mCRC. Methods: We collected medical records from consecutive 1142 pts who had been initiated with first-line chemotherapy for mCRC from 2008 to 2016 at National Cancer Center Hospital East. The survival outcomes were compared between pts from 2008 to 2011 (cohort A) and those from 2012 to 2016 (cohort B). This study excluded pts who have not been refractory or intolerant to standard chemotherapy including fluoropyrimidine, oxaliplatin, irinotecan, and anti-EGFR antibody if KRAS exon 2/ RAS wild-type tumors. Results: A total of 590 pts were analyzed (cohort A; N = 236 and cohort B; N = 354). More patients received at least one of REG or FTD/TPI in cohort B (16.1% vs. 59.9%, p < 0.001). The time from initiation to end of standard chemotherapy was comparable between the two cohort (20.0 vs. 17.5 months, p = 0.266). With a median follow-up period of 34.9 months, salvage-line OS (sOS) after standard chemotherapy was significantly longer in cohort B (4.8 vs. 6.6 months, p = 0.001), while there was only a favorable trend in cohort B in terms of OS from start of first-line treatment (27.3 vs. 28.5 months, p = 0.516). In cohort B, pts who sequentially received both of REG and FTD/TPI showed longest sOS (median, both of REG and FTD/TPI; 11.3 months, either REG or FTD/TPI; 7.0 months, neither REG nor FTD/TPI; 3.1 months). Conclusions: Our study showed that REG and FTD/TPI led to prolongation of sOS in the real-world setting, indicating the importance of strategies which make all active agents available to pts with mCRC.
Pembrolizumab (pembro) in microsatellite instability-high (MSI-H) advanced gastric/gastroesophageal junction (G/GEJ) cancer by line of therapy.
Authors: Chao Joseph , Fuchs Charles S. , Shitara Kohei , Tabernero Josep , Muro Kei , Van Cutsem Eric , Bang Yung-Jue , De Vita Ferdinando , Landers Greg A. , Yen Chia-Jui , Chau Ian , Elme Anneli , Lee Jeeyun , Ozguroglu Mustafa , Catenacci Daniel V.T. , Li Xiaodong , Shih Chie-Schin , Shah Sukrut , Bhagia Pooja , Wainberg Zev A. 
Published: February 2020

430 Background: Pembro has demonstrated promising antitumor activity in patients (pts) with advanced G/GEJ cancer with PD-L1 CPS ≥1 and CPS ≥10 irrespective of MSI-H status. Here, we examine the antitumor activity of pembro monotherapy vs chemo in pts with MSI-H, advanced G/GEJ cancer in KEYNOTE (KN)-059 (NCT02335411), KN061 (NCT02370498), and KN062 (NCT02494583). Methods: Eligible pts with advanced G/GEJ cancer with ≥2 prior therapies (KN059 cohort 1; 3L+), 1 prior therapy (KN061; 2L), or no prior therapy (KN062; 1L) were enrolled. In KN059 cohort 1, pts received pembro only. In KN061 pts were randomized to pembro or paclitaxel (chemo), and in KN062 to pembro, pembro + cisplatin+5-FU/cape (chemo), or chemo. Pts received pembro 200 mg Q3W for up to 2 y. MSI-H status was determined centrally by PCR. Endpoints included OS, PFS, ORR, and safety. Data cutoff dates were Aug 8, 2018 (KN059), Oct 26, 2017 (KN061), and Mar 26, 2019 (KN062). Results: At data cutoff, 259 pts (n = 7 [3%] MSI-H) had enrolled in KN059 cohort 1 (3L+), 592 (27 [5%] MSI-H]) in KN061 (2L), and 763 (50 [7%] MSI-H] in KN062 (1L). Median follow-up was 5.6 mo, 7.9 mo, and 11.3 mo, respectively. For the overall study populations, median OS was 5.5 mo for pembro (3L+), 6.7 mo vs 8.3 mo for pembro vs chemo (2L), and 10.6 mo vs 11.0 mo for pembro vs chemo (1L). Median PFS was 2.0 mo (3L+), 1.5 vs 4.1 mo (2L), and 2.0 vs 6.4 mo (1L). ORR was 11.6% (3L+), 11.1% vs 12.5% (2L), and 14.8% vs 37.2% (1L), with median DOR of 16.1 mo, 18.0 vs 5.5 mo, and 13.7 vs 6.8 mo. In pts with MSI-H tumors, OS and PFS were prolonged with pembro vs chemo, with higher ORR (Table). Conclusions: As with PD-L1 expressers, MSI-H status is a predictive biomarker for pembro monotherapy in advanced G/GEJ cancer irrespective of line of therapy. Clinical trial information: (KN)-059 (NCT02335411), KN061 (NCT02370498), and KN062 (NCT02494583). Merck & Co., Inc., Kenilworth, NJ, USA.[Table: see text]
Gastric Cancer Registry: A comprehensive patient-reported resource for multidisciplinary and translational genomic approaches to gastric cancer.
Authors: Almeda Alison Figueroa , Hooker Anna , Lee Hojoon , Mills Meredith , Van Hummelen Paul , Ford James M. , Ji Hanlee 
Published: February 2020

432 Background: Gastric cancer (GC) is the fifth leading cancer diagnosis and third frequent cause of cancer death globally. GC results from a cascade of molecular and genetic changes owing to environmental and genetic factors. While there are known risks to GC, more is to be learned about its development so to establish effective screens for early stages of cancer. Methods: The Gastric Cancer Registry (GCR) was built to investigate GC and discover informative genomic biomarkers. The GCR comprises medical, family, and social history and genomics data from patients with GC, a family history of GC, and/or a known mutation in the gene CDH1. Samples of saliva and gastric tumors are collected when available. The GCR allows us to leverage several genome sequencing datasets to construct a complete molecular landscape of GC. Early analysis of GC tissue includes whole exome sequencing (WES) to identify mutations, whole genome sequencing (WGS) for copy number variation, and RNA sequencing (RNAseq) for expression profiling. Results are used to inform of clonal neoantigens, microbiome, and immune cell populations. Saliva will be analyzed with linked reads sequencing to unearth germline mutations not picked up in standard clinical gene panels. Results: Datasets from 455 patients and samples from 159 patients have been collected. In a pilot study, we pinpointed specific mutations using WES and revealed extensive changes in genome copy number involving clinically actionable genes through WGS. Most tumors had a high degree of genomic instability and exhibited candidate markers for treatment decisions and response. Additionally, we found that RNAseq revealed tumor subgroups through gene expression signatures. Conclusions: The GCR is an informative resource enabling the identification of biomarkers for GC. With the GCR we are integrating expertise in translational cancer genomics with molecular biology, statistics, and bioinformatics to build a platform for discovery and the development of tools that will ultimately improve the detection, treatment, and prevention of GC.
MT-5111: A novel HER2 targeting engineered toxin body in clinical development.
Authors: Waltzman Roger J. , Sarkar Asis , Williams Eric T , Iberg Aimee T. , Higgins Jack T. , Willert Erin K. 
Published: February 2020

433 Background: Engineered toxin bodies (ETBs) are comprised of a proprietarily engineered Shiga-like Toxin A subunit genetically fused to antibody-like binding domains. MT-5111 is a de-immunized ETB targeting HER2 for solid tumors. MT-5111 works through a novel mechanism of direct cell-kill, via enzymatic ribosome inactivation, and may not be subject to resistance mechanisms that exist for TKI, ADC, or antibody modalities. MT-5111 binds an epitope on HER2 distinct from trastuzumab or pertuzumab, that may provide for combination potential with other HER2 targeting agents. MT-5111 is a 55 kilodalton protein and may have improved tumor penetration capability in solid tumor settings. Methods: HER2 expression and activity of MT-5111 was assessed in vitro by flow cytometry and cell viability assays. Serum exposure and tolerability of MT-5111 was measured in non-human primate (NHP) studies. Results: MT-5111 effectively kills 8/9 cell lines (2 gastric) with moderate to high HER2 surface expression, as well as two additional gastric cell lines with lower HER2 expression. No cytotoxicity is observed on multiple HER2- cell lines. As a protein, MT-5111 is not a substrate of drug efflux transporters that limit efficacy of ADCs. MT-5111 demonstrates effective cell-killing in vitro against cell lines expressing HER2 but resistant to trastuzumab (HCC1954) or T-DM1 (JIMT-1 and gastric SNU-216), highlighting the benefit of a novel mechanism of action to treat resistant disease. MT-5111 binds human and NHP HER2 protein. Based on serum exposure of MT-5111 in NHPs used to model pharmacokinetics, planned MT-5111 dosing in humans is above the IC50 required for HER2-specific cellular cytotoxicity in vitro. MT-5111 has a short half-life that, while allowing for efficient tumor cell targeting, minimizes serum exposure to avoid systemic effects over time. Conclusions: A Phase 1, first in human, open-label dose escalation and expansion study of MT-5111 (NCT04029922) in subjects with HER2+ solid tumors whose disease has progressed after treatment with other approved therapies is open for enrollment. MT-5111 represents a novel HER2 targeted therapy for patients with HER2+ cancers with potential to overcome mechanisms of tumor resistance to existing therapies.
A novel gene signature for predicting response to chemoradiotherapy in esophageal adenocarcinoma.
Authors: Ghatak Souvik , Omstead Ashten N. , Jobe Blair A , Kreft Rachael , Gorbunova Anastasia , Salvitti Madison , Kelly Ronan Joseph , Zaidi Ali Hussainy , Goel Ajay 
Published: February 2020

445 Background: While neoadjuvant chemoradiotherapy (CRT) has emerged as an important treatment modality in patients with locally advanced esophageal adenocarcinoma (EAC), ~60%-70% of patients do not respond to such treatments; but are exposed to their toxicity nonetheless. This highlights the clinical need for the development of biomarkers that can robustly predict response to CRT and spare others from the toxicity and expense associated with these treatments. Herein, we systematically identified a biomarker signature that predicts response to CRT in EAC patients. Methods: Using a clinical-trial driven cohort of 25 EAC patients treated with 5- fluorouracil plus carboplatin and concurrent radiation therapy, we performed whole-exome sequencing (WES) in paired biopsy specimens obtained at baseline and 3-6 weeks post-treatment. In addition, we also analyzed the predictive potential of a panel of immune-related genes (TIM3, LAG3, IDO1 and CXCL9) in these matched tissues. Results: In our cohort, based upon RECIST criteria, 14 EAC patients were categorized as non-responders, while 11 were deemed as responders to CRT. Among responders, the most frequently mutated genes were NOTCH1, NOTCH2, NOTCH3, and MLL2; and the overall tumor mutation burden (TMB) was significantly reduced for these genes in post-treatment specimens (P<0.001). In contrast, in non-responders, NFE2L2, KEAP1, FAT1, FAT2, FAT3 and PIK3CA, harbored frequent mutations. Similarly, all four immune-related genes were significantly up-regulated in post-treatment specimens (p<0.05-0.001). Interestingly, the progression-free survival was significantly greater in patients with lower TMB (64.1%, p=0.04) and increased immunogenic scoring (62.7%, p=0.01). We finally constructed a risk-stratification model that comprised of mutational scores from 10 most frequently mutated genes, together with 4 immune-related genes, which achieved an AUC of 0.83 in predicting response to CRT in EAC patients. Conclusions: Using a systematic biomarker discovery approach, we have developed a novel biomarker signature that robustly predicts response to CRT in EAC patients and has a significant potential for personalized management of EAC patients.
Clinicopathological features of multifocal gastric carcinoma: A retrospective study.
Authors: Zou Xi , Zhang Runfeng , Lei Qi , Zhou Aiping , Du Chun-Xia 
Published: February 2020

453 Background: The occurrence of multifocal gastric carcinoma (MGC) is growing in China, while relevant study remains limited. This study aimed to collect more information of MGC for further research. Methods: Patients with MGC treated at China National Cancer Center from January 2010 to December 2017 were enrolled in this retrospective study. A 6-month interval was used to separate synchronous and metachronous foci. Results: 103 patients were included. 88 (85.4%) were males. 96 (93.2%) patients had two foci and 7 (6.8%) had three or more foci, contributing a total of 216 tumor foci. 185 (85.6%) foci were adenocarcinoma, 18 (8.3%) were intraepithelial neoplasia, 2 (0.9%) were lymphoepithelioma-like carcinoma and 1 (0.5%) was small cell carcinoma. Intestinal, diffuse, and mixed type accounted for 49.7%, 14.6% and 11.4% respectively, with 24.3% unknown.In 96 patients with 2 foci, 56 (58.3%) patients had synchronous diseases, and 40 (41.7%) had metachronous diseases. The median age at the diagnosis of first tumor was 62 (55-71) years. The median diagnosis interval of metachronous tumor foci was 41.4 (23.5-88.3) months. The locations and sizes of foci are shown in Table. In synchronous cases, 6 foci of accessory tumor were less than 1cm including one being 0.4 cm. In metachronous cases, 4 foci of second tumor were less than 1 cm. 51 (49.5%) patients were current smokers or ex-smokers, and 44 (42.7%) were regular alcohol consumers. 26 (25.2%) patients had a first-relative family history, including 14 (13.6%) having a family history of gastrointestinal carcinoma. Conclusions: The second gastric tumor should be thoroughly detected to avoid missed diagnosis, since the accessory tumor might be rather small. Further genetic research is warranted to explore the potential pathogenesis of MGC. [Table: see text]
Prognostic implications of tumor sidedness in colorectal cancer patients in South Dakota, 2006-2015.
Authors: Bleeker Jonathan Scott , Atiq Muslim , Nelson Morgan , Dosch Kay 
Published: February 2020

46 Background: Tumor “sidedness” is emerging as an important prognostic and predictive factor in patients with metastatic colorectal cancer (CRC), with right sided colon cancer (RC) associated with poorer overall survival (OS) than left sided colon cancer (LC). This distinction has been noted in clinical trials and large databases, where American Indian (AI) populations are generally underrepresented. This project aims to investigate the prognostic implications of CRC sidedness in the state of South Dakota, focusing on the AI population. Methods: Data from patients diagnosed with CRC in the South Dakota cancer registry from January 1, 2006 to December 31, 2015 were analyzed for demographic and presenting features as well as survival outcomes. A total of 3,637 cases were included in the analysis, of which 191 (5%) were AI. Tumors arising from the cecum, ascending colon, hepatic flexure and transverse colon were considered RC while those arising from the splenic flexure, descending colon, sigmoid colon and rectum were considered LC. Results: In all patients, 47.1% of cases were RC; Caucasians (C) were significantly more likely to have RC, as 47.7% of cases in Caucasians were RC, whereas in the AI population, 35.6% cases were RC (p=0.005). Patients with RC were more likely to be female and older and less likely to present with metastatic disease than LC. Tumor sidedness was not associated with OS when analyzing all patients regardless of stage or in patients with non-metastatic disease. In patients with metastatic disease, RC was associated with inferior OS compared to LC [Median OS (mo): 9.9 v. 23.6, p<0.001]. When analyzed by race, RC was associated with inferior OS in C [Median OS (mo): 9.6 v. 23.6, p=0.002] but not in AI [Median OS (mo): 10.2 v. 10.4, p=0.082]. Conclusions: Although limited by small sample size, this analysis is hypothesis generating, as AI patients with CRC were more likely to have LC than Caucasians and the well described prognostic implications of RC were not noted in the AI population. Larger population studies and further investigation as to potential explanations for this finding are recommended.
A United States Rectal Cancer Consortium study of inferior mesenteric artery versus superior rectal artery ligation: How high do we need to go?
Authors: Turgeon Michael K. , Gamboa Adriana C. , Lee Rachel M. , Maniko Jeffrey , Maguire Lillias , Mohammed Maryam , Holder-Murray Jennifer , Abdel-Misih Sherif , Kimbrough Charles , Wiseman Jason T. , Edwards-Hollingsworth Kamren , Hawkins Alexander , Bauer Philip , Silviera Matthew , Maithel Shishir K. , Balch Glen C. 
Published: February 2020

47 Background: The optimal level of pedicle ligation during proctectomy for rectal cancer, either at the origin of the inferior mesenteric artery (IMA) or the superior rectal artery (SRA), is still debated. Reasons for IMA ligation include facilitating a tension-free anastomosis and improved clearance of regional lymph nodes. Our aim was to determine if SRA ligation portends inferior outcomes. Methods: The US Rectal Cancer Consortium database (2007-2017) was reviewed for pts with primary, non-metastatic rectal adenocarcinoma who underwent treatment with low anterior resection or abdominoperineal resection. Primary outcomes were anastomotic leak rate and lymph node (LN) harvest. Secondary outcomes were locoregional recurrence-free survival (LRFS), recurrence-free survival (RFS), and overall survival (OS). Results: Of 877 pts, median age was 59 years (IQR52-67) and 62% were male (n = 541). 86% received an IMA ligation (n = 755) while 14% SRA (n = 122). 12% were pathologic stage 0 (n = 101), 33% stage I (n = 281), 24% stage II (n = 206), and 31% stage III (n = 269). Median follow-up was 34 mos. SRA ligation was more common in stage III disease (43vs30%, p = 0.005) while IMA ligation was more often performed with a minimally invasive approach (70vs42%, p < 0.001). SRA ligation was associated with a nearly identical anastomotic leak rate compared to IMA (9vs8%, p = 1.0). Similarly, the median number of LNs removed was the same between both ligation groups (15vs15, p = 0.38). On multivariable analysis accounting for an open approach, advanced pathologic stage, and positive resection margin status, SRA ligation was not associated with increased anastomotic leak rate or reduced LRFS, RFS, or OS (all p > 0.1). Conclusions: If a tension-free anastomosis is feasible, SRA ligation is not associated with either a worse technical outcome or inferior lymph node harvest. Furthermore, all cancer survival metrics are similar between SRA and IMA ligation. Given that either approach is safe and feasible from both a technical and oncologic standpoint, this study questions the routine practice of IMA ligation.
Ramucirumab (RAM) or merestinib (MER) or placebo (PL) plus gemcitabine (GEM) and cisplatin (CIS) as first-line treatment for advanced or metastatic biliary tract cancer (BTC): A randomized, double-blind, phase II study.
Authors: Valle Juan W. , Bai Li-Yuan , Orlova Rashida , Van Cutsem Eric , Adeva Alfonso Jorge , Chen Li-Tzong , Obermannova Radka , Ettrich Thomas Jens , Chen Jen-Shi , Wasan Harpreet Singh , Denlinger Crystal S. , Vogel Arndt , He Aiwu Ruth , Bousmans Nathalie , Girvan Allicia C , Zhang Wei , Walgren Richard A. , Carlesi Roberto , Oh Do-Youn 
Published: February 2020

477 Background: We assessed RAM or MER plus standard of care GEM+CIS as first-line treatment for BTC. Methods: Patients (pts) with BTC, ECOG PS 0/1, and measurable disease were randomized 2:1:2:1 to oral MER 80 mg QD, oral PL QD, IV RAM 8 mg/kg days 1 and 8 Q3W or IV PL days 1 and 8 Q3W. Pts also received up to 8 cycles IV GEM 1000 mg/m2 + CIS 25 mg/m2 days 1 and 8 Q3W. RAM, MER, or PL could continue until disease progression. Primary endpoint: progression-free survival (PFS). Secondary endpoints: overall survival (OS), objective response rate (ORR), and safety. PFS and hazard ratios (HRs) were compared using stratified log-rank tests and Cox regression models, respectively. NCT02711553. Results: 309 pts were randomized to RAM (106), MER (102), or pooled PL (101). More pts in the RAM (54.7%) and MER (49.0%) groups had baseline ECOG PS 1 vs PL (38.6%). Efficacy endpoints are in Table. Fewer pts received post-discontinuation systemic therapy in the RAM group (RAM 37.5%, MER 50.0%, PL 52.0%). The most common grade ≥3 treatment-emergent adverse events were: RAM vs PL: neutropenia (49.0% vs 33.0%), thrombocytopenia (34.6% vs 17.0%), and anemia (26.9% vs 19.0%); MER vs PL: neutropenia (47.1% vs 33.0%), thrombocytopenia (18.6% vs 17.0%), and alanine aminotransferase increased (10.8% vs 5.0%). Conclusions: PFS, OS, and ORR were not improved with the addition of RAM or MER to GEM+CIS. Treatment was well tolerated, with safety profiles consistent with known profiles for RAM, MER, and GEM+CIS. Translational studies are ongoing. Clinical trial information: NCT02711553 . [Table: see text]
Immune checkpoint blockade (ICB) response evaluation with MRI/MR elastography (MRE) in surgical and nonsurgical patients with HCC.
Authors: Qayyum Aliya , Avritscher Rony , Aslam Rizwan , Ma Jingfei , Pagel Mark David , Sun Jia , Abugabal Yehia I. , Hassan Manal , Amin Hesham M. , Rashid Asif , Lee Sunyoung S. , Wolff Robert A. , Yao James C. , Ehman Richard , Duda Dan G. , Kaseb Ahmed Omar 
Published: February 2020

480 Background: Currently, there is a lack of imaging biomarkers of immunotherapy outcome in hepatocellular carcinoma (HCC). The study aim was to determine if HCC enhancement on MRI and stiffness change measured by magnetic resonance elastography (MRE) can predict immunotherapy response. Methods: This was a prospective, Institutional Review Board approved study of 38 patients with HCC treated with immune checkpoint blockade (ICB) therapy. All patients had liver MRI/MRE and HCC biopsy at baseline, and MRI/MRE with biopsy or resection after 6 weeks therapy. HCC stiffness (kPa) was measured on MRE elastograms (liver stiffness maps). HCC enhancement and change in stiffness were compared with treatment response to ICB in 1) non-surgical patients (pembrolizumab), and 2) surgical patients (nivolumab +/- ipilimumab). For non-surgical patients, treatment response was defined as overall survival >1 year. For surgical patients, treatment response was defined as <50% viable tumor at time of resection. Analysis was performed using descriptive statistics and Spearman correlation; p-value <0.05 was considered statistically significant. Results: Twenty-five patients were evaluable. Median age was 67 years (32, 78). Etiology of liver disease was NASH (n=8), HCV (n=8), HBV (n=2) and unknown (n=7). Treatment response occurred in 11/25 (44%) patients. Median HCC size and change in size were 4.7 cm (1.2, 14.0) and –0.32 cm, respectively. Median baseline HCC stiffness and change in stiffness were 5 kPa (2.2, 12.4) and –0.1 kPa (–2.2, 1.5), respectively. Median change in HCC size for responders and non-responders was –1.2 cm (–4.8, 0.4) and 0 cm (–1.5, 1.1), respectively (p = 0.02). Treatment response was associated with absence of portal venous phase capsular enhancement and increase in HCC stiffness, (p<0.001). Conclusions: Capsular enhancement and MRE stiffness change may be useful biomarkers of immune cell activated response to ICB therapy.