bluuebunny/crossref_metadata_2025_split huggingface dataset:
Activity of tepotinib in hepatocellular carcinoma (HCC) with high-level MET amplification (METamp): Preclinical and clinical evidence.
Authors: Faivre Sandrine J. , Blanc Jean-frederic , Pan Hongming , Grando Véronique , Lim Ho Yeong , Cubillo Gracián Antonio , Isambert Nicolas , Johne Andreas , Schumacher Karl , Stroh Christopher , Friese-Hamim Manja , O'Brate Aurora , Zhou Dongli , Qin Shukui 
Published: January 2021

329 Background: Tepotinib, a potent and highly selective MET inhibitor, showed promising activity in advanced HCC with MET overexpression in two Phase Ib/II trials, which both met their primary endpoints. One trial enrolled Asian patients (pts) without prior systemic therapy (first line [1L]; NCT01988493) and one enrolled US/European pts with prior sorafenib (second line [2L]; NCT02115373). By investigator assessment, objective response rates and disease control rates with tepotinib in Phase II were 15.8% and 60.5% in 1L (n = 38), and 8.2% and 57.1% in 2L (n = 49). Outcomes appeared better in pts with METamp. Thus, we further investigated the preclinical and clinical activity of tepotinib in HCC, focusing on high-level METamp, which could be an oncogenic driver in this tumor type. Methods: Preclinical activity was assessed in 37 HCC pt-derived xenografts (PDXs) in nude mice treated with tepotinib (100 mg/kg, Days 1–5, every 7 days for five cycles; 6–12 replicates per PDX). Clinical activity was assessed by analyzing pts with METamp or high-level METamp (defined as mean MET gene copy number [GCN] ≥5 and ≥10, respectively; by fluorescence in situ hybridization), who received tepotinib 500 mg in Phase Ib or II of the 1L and 2L trials (n = 121). In the Phase Ib part of the 1L trial, pts could have received prior treatment. Results: Molecular profiling revealed high-level METamp in two of 37 HCC PDXs: LIM612 ( MET GCN 47.1) and LIPF210 ( MET GCN 44). Tepotinib induced significant tumor regression in both of these high-level METamp HCC PDX models (mean tumor volume reduction: 97% and 96%, respectively). Across the two trials, 15 pts treated with tepotinib 500 mg had METamp, of whom five had an objective response (one complete response [CR] and four partial responses [PRs]) and six had stable disease (SD) as best overall response. Four pts had high-level METamp (mean MET GCN 14.3, 18.1, 30.2, and 36.2), with best overall response of CR in one pt, PR in two pts and SD in one pt (Table). One pt with high-level METamp (mean MET GCN 14.3) treated with 1L tepotinib was still receiving treatment as of Sept 2020 (total tepotinib treatment duration: > 45 months). Conclusions: High-level METamp may be an oncogenic driver in HCC that sensitizes tumors to MET inhibition with tepotinib. Compared with MET overexpression, high-level METamp could be a better predictive biomarker for MET inhibitors in this setting. Clinical trial information: NCT01988493, NCT02115373. [Table: see text]
Development of a pancreatic cancer prediction model using a multinational medical records database.
Authors: Appelbaum Limor , Berg Alexandra , Cambronero Jose Pablo , Dang Thurston Hou Yeen , Jin Charles Chuan , Zhang Lori , Kundrot Steven , Palchuk Matvey , Evans Laura A. , Kaplan Irving D. , Rinard Martin 
Published: January 2021

394 Background: Previous work by our group has demonstrated that leveraging Machine Learning on diagnostic codes from Electronic Health Records (EHRs), can identify individuals at high-risk for Pancreatic Duct Adenocarcinoma (PDAC), as early as 1 year before current cancer diagnosis. We aim to improve the performance of our existing PDAC risk stratification model, by using an independent, multi-center dataset, and adding lab test features. Methods: EHR data from TriNetX, a federated global health research network, was utilized to develop Logistic Regression (LR) models. Diagnoses and lab test data from 32 different Health Care Organizations in the United States from 2015-2020 was used. PDAC patients ages 60-80 years, were identified using ICD codes, and cross-checked with tumor registry and pathology data to decrease false positives. Only patients with one or more clinical encounter/s, at least 6 months prior to cancer diagnosis, were included. Prediction time cutoffs of 180, 270, and 360 days before PDAC diagnosis were used. Preliminary basic data analysis was initially performed to explore potential lab test features that could be used to improve model performance. The discriminatory capabilities of the LR models were compared using Area Under the Receiver Operating Characteristic Curve (AUC) and 95% Confidence Interval using empirical bootstrap over test data were computed. We used L2-regularized LR, and performed evaluation using cross-validation. We report cross-validation performance. In contrast to prior published work that used predefined feature sets for model development, we incorporated a wide range of indicators, and relied on regularization to address potential overfitting risk. Results: The LR models were trained and evaluated on diagnoses and labs for 25,644 patients (cases= 1352; age-sex paired controls). Lab test administration per patient (i.e., for a given patient, what lab tests were administered and how frequently), was found to be the most valuable feature for improving discrimination. For almost every type of lab test, the average number of administrations per patient was higher for PDAC patients than controls. The top lab tests with highest discriminatory coefficients included glucose, potassium, hematocrit, hemoglobin, sodium, chloride and creatinine. With a 365-day lead time, the diagnoses-based LR obtained a test AUC of 0.58, the lab-test based LR obtained a test AUC of 0.72. The combined diagnoses and lab-test model (“concatenated LR model”) outperformed both of these models, obtaining a test AUC of 0.73. Conclusions: Our findings demonstrate that LR models based on concatenated lab test and diagnoses feature sets (“concatenated LR models”), can outperform both diagnoses-based LR models and lab-test-based LR models, and can be utilized in early prediction of PDAC development.
Efficacy and safety of 5-fluorouracil (5-FU) / levofolinate / irinotecan (FOLFIRI) for previously treated advanced pancreatic cancer (APC).
Authors: Shirasu Hiromichi , Kawakami Takeshi , Hamauchi Satoshi , Tsushima Takahiro , Todaka Akiko , Yokota Tomoya , Yamazaki Kentaro , Fukutomi Akira , Onozawa Yusuke , Yasui Hirofumi 
Published: January 2021

407 Background: 5-fluorouracil (5-FU) / levofolinate / irinotecan (FOLFIRI) is one of the preferred regimens for patients (pts) with advanced pancreatic cancer (APC) who received prior gemcitabine-based therapy in the National Comprehensive Cancer Network Guidelines. However, its survival benefit or safety in clinical practice is unclear. Methods: We retrospectively assessed the data of consecutive pts with APC who received FOLFIRI as a second or later-line treatment after gemcitabine-based therapy at Shizuoka Cancer Center between May 2014 and March 2020. Results: The characteristics of 102 pts included in this analysis were as follows: median age (range), 67 (39-78) y; male/female, 55/47; ECOG PS0/1/2, 21/72/9; the number of metastatic sites 0/1/2/3/4, 7/48/35/8/4; unresectable/recurrent, 84/18; UGT1A1 status wild/*6 or*28 heterozygous/homo or double-heterozygous/unknown, 40/40/5/17; treatment line of FOLFIRI 2nd/3rd/4th, 64/32/6. Previous treatment history according to the treatment line of FOLFIRI was as follows: 2nd-line, all patients received GEM-based regimen, GEM plus nanoparticle albumin bound paclitaxel in 63 pts (98.4%) and GEM in 1 (1.6%); 3rd, GEM-based and S1 in 20 (62.5%), GEM-based and 5-FU/levofolinate/oxaliplatin (FOLFOX) in 12 (37.5%); 4th, GEM-based, FOLFOX and S-1 or other agent in 5 (83.3%), 2 GEM-based regimens and S1 in 1 (16.7%). The median treatment cycle was 5 (range 1-55). The median treatment cycle according to the treatment line was as follows: 2nd-line, 7(1-55); 3rd, 4(1-14); 4th, 3.5(1-10). The initial dosage for each cytotoxic agent was as follows: bolus 5-FU injected/omited 72/30; continuous 5-FU 2400/2000/1200 mg/m2, 88/13/1; irinotecan 180/150/120/less than or equal to 100mg/m2, 27/59/13/3. The overall response rate (ORR) and disease control rate (DCR) were 5.9% and 52.9%, respectively. ORR and DCR according to the treatment line were as follows: 2nd-line, 9.3/64.1%; 3rd, 0/68.8%; 4th, 0/50.0%. At the median follow up 6.5 M, the median overall survival (OS) and progression free survival (PFS) were 6.6M and 3.1M, respectively. The median OS and PFS according to the treatment line were as follows: 2nd-line, 8.1/3.6M; 3rd, 5.1/2.1M; 4th, 6.6/2.0M. Adverse events (AEs) were observed in 70.8% pts. Grade 3 or higher AEs occurred in 27.2% pts [neutropenia in 26 (25.2%) pts, febrile neutropenia in 4 (3.9%) pts, nausea in 4 (3.9%) pts, decreased appetite in 3 (2.9%) pts]. No treatment related deaths were observed. Conclusions: FOLFIRI is well tolerated and effective especially in the second-line treatment for pts with gemcitabine-refractory APC.
Phase II randomized, double-blind study of mFOLFIRINOX plus ramucirumab versus mFOLFIRINOX plus placebo in advanced pancreatic cancer patients (HCRN GI14-198).
Authors: Shaib Walid Labib , Rupji Manali , Khair Tina Ashley , Robin Erwin L. , El-Rayes Bassel F. , Huyck Timothy K. , Liu Yuan , Sonbol Mohamad Bassam , Bekaii-Saab Tanios S. 
Published: January 2021

413 Background: Vascular endothelial growth factor (VEGF) and VEGF receptor (VEGFR)-mediated signaling and angiogenesis contribute to the pathogenesis and progression of pancreatic adenocarcinoma (PCA).VEGF is expressed in all PCA tumors. VEGF-A/VEGFR-2 signaling plays an important role in inducing invasion and migration of PCA cells. The pVEGFR-2 is significantly associated with invasion of the anterior capsule of pancreas and arteries. In preclinical studies, the anti-tumor activity of fluoropyrimidines, but not that of gemcitabine, caused the release of bone marrow derived circulating endothelial progenitor cells (CEPs) and Tie-2 expressing monocytes (TEMs) as well as the induction of pro-angiogenic growth factors. Methods: This phase II randomized, multi-center, and double-blinded trial was designed to compare the efficacy and safety of mFOLFIRINOX/ramucirumab (Arm A) versus mFOLFIRINOX/ placebo (Arm B) as front-line therapy in recurrent or metastatic PCA patients. The primary endpoint was progression free survival (PFS) at 9 months, and the secondary endpoints included overall survival (OS) and response rate. Results: A total of 86 subjects were enrolled, 82 were eligible (42 in Arm A v. 40 in Arm B). The mean age of the subjects in the two arms were comparable (61.7 v. 63.0, respectively); 43 male, 69 Caucasian. On the univariate analysis, there was no difference in distribution between the 2 arms for age, gender, race and ethnicity. The median PFS was 5.6 in Arm A compared to 6.7 months in Arm B (one-sided log-rank, p = 0.322). At 9 months, the progression free rates were 25.1% v. 35% for Arms A and B, respectively. The mFOLFIRINOX/ramucirumab combination was well tolerated. Patients in Arm A reported a slightly higher number of adverse events (AEs) encounters, most commonly diarrhea (29 vs 28), fatigue (25 v. 25), vomiting (24 v. 14), weight loss (23 v. 17), and abdominal pain (20 v. 15). Arm A had more SAEs than Arm B (43 v. 25), with sepsis most commonly reported in both arms (3 in each), vomiting (3 v. 2), diarrhea (3 v.1) and duodenal obstruction (3 v. 0). Arm B had a slightly higher response rate (22.58%) compared to Arm A (17.65%) that was not statistically significant. The median OS in Arm A was 10.3 compared to 9.7 months for Arm B (one-sided log-rank, p = 0.094). Conclusions: In this randomized phase 2 study, the addition of ramucirumab to mFOLFIRINOX did not improve PFS, response rate, or OS as initial therapy for metastatic pancreatic cancer. FOLFIRINOX/Ramucirumab combination was well tolerated in the treatment of PCA. Clinical trial information: NCT02581215.
Microbiomic profiles of bile in patients with benign and malignant pancreaticobiliary disease.
Authors: Poudel Shyam K. , Padmanabhan Roshan , Guinta Kathryn , Stevens Tyler , Sanaka Madhusudhan , Chahal Prabhleen , Sohal Davendra , Khorana Alok A. , Eng Charis 
Published: January 2021

417 Background: In pancreaticobiliary (PB) cancers, there is a paucity of data on predictive and pathophysiologic role of the biliary microbiome. We analyzed bile collected from patients with benign and malignant PB diseases to identify microbiomic signatures associated with malignancy. Methods: We collected bile samples from consenting patients during routine endoscopic retrograde cholangiopancreatography at the Cleveland Clinic, approved by the Institutional Review Board. DNA was extracted from bile specimens using PowerViral RNA/DNA Isolation kit. Bacterial 16S rRNA gene amplification and library construction were performed according to the 16S Metagenomic Sequencing Library Preparation guide from Illumina. Post-sequencing analysis was done using QIIME (Quantitative Insights Into Microbial Ecology), Bioconductor phyloseq, microbiomeSeq and mixMC packages. Results: Of 46 enrolled patients, 32 had PB cancers including pancreatic (N = 25), cholangiocarcinoma (N = 6), and gallbladder (N = 1). The rest (N = 14) had benign PB diseases including acute and chronic pancreatitis, and gallstones. Using multivariate approach in mixMC to classify Operational Taxonomic Units (OTUs), we found a predominance of genera Dicekeya (p = 0.0002), [ Eubacterium] hallii group (p = 0.0007) , Bacteroides (p = 0.00099) , Faecalibacterium (p = 0.007) , Facklamia (p = 0.013) , Peptococcus (p = 0.013) , Bergeyella (p = 0.0024) , Lachnospira (p = 0.026) , and Lactobacillus (p = 0.025) in bile samples from PB cancers as compared to benign PB diseases. Furthermore, bile samples from patients with pancreatic cancer showed an increased abundance of genera Enterobacter, Parabacteroides, Atopobium, Alloprevotella, Prevotella 7, Acinetobacter, Bergeyella, Clostridium sensu stricto, Lactobacillus, and Rothia; and a decreased abundance of genera Tannerella, Peptococcus, Colinsella, Capnocytophaga, Achromobacter, Ruminococcus 2, Bacteroides, Alistipes, Barnesiella,, Lachnoclostridium, Lautropia, Akkermansia, and Christensenellaceae R-7 group as compared to bile samples from patients with cholangiocarcinoma. Conclusions: Distinct microbiome signatures are associated with benign and malignant PB diseases. There is a difference in the relative abundance of OTUs in bile samples between patients with benign PB diseases vs PB cancers, and between pancreatic cancer vs cholangiocarcinoma. Our findings raise the possibility that either these OTUs have a role in carcinogenesis, or that changes in the microenvironment of benign PB diseases differ from PB cancers leading to distinct separation of the OTU clusters. Further studies to explore and validate our findings are needed.
A delayed path to diagnosis: Findings from young-onset colorectal cancer patients and survivors.
Authors: Newcomer Kim Lynn , Porter Laura Diane 
Published: January 2021

5 Background:Colorectal cancer (CRC) is the second-leading cause of cancer-related death among males and females in the US. Despite a decrease in overall incidence and mortality, there has been an alarming increase of CRC diagnosis among young adults (20-49 years old). In an article from 2014, authors predicted an increase in colon cancer diagnosis in people under the age of 50 with the largest increase in the 20-34-year age group of 37.8% and 90.0% by 2020 and 2030, respectively. The increase for rectal cancer is higher in the 20-34-year age group by 2020 and 2030 it is estimated to increase by 49.7% and 124.2% respectively. The Colorectal Cancer Alliance launched a comprehensive survey for Young-Onset Colorectal Cancer (YO-CRC) patients and survivors to capture self-reported experiences of this often overlooked population. Methods:The survey was completed by 1089 patients, survivors and caregivers. Questions were designed based on several established and validated instruments, including AYA-HOPE, EORTC-QOL-30, EORTC-CR-29, EORTC-SHC-22, PROMIS-29, FACT-C, and COH-47. The final survey instrument and study plan were reviewed and approved by the Aspire, Inc. Institutional Review Board. Results:Most respondents (62%) waited 3-12 months before visiting a doctor after they noticed symptoms. Furthermore, when patients visited their doctors, most indicated that they were initially misdiagnosed. Many patients reported they had to see multiple doctors and had multiple appointments before they were correctly diagnosed with YO-CRC. The majority of the respondents (75%) saw at least 2 physicians, and about 20% saw 4 physicians or more, prior to their diagnosis. Patients who saw 3 or more physicians prior to diagnosis were more likely to be diagnosed with advanced disease. Conclusions:The findings expose a critical issue of YO-CRC patients being diagnosed at late stages. This is often due to multiple challenges around misinformation and medical providers dismissing symptoms and not trusting the patients' self-knowledge. Medical professionals need to be aware of the possibility of colorectal cancer more readily and screen patients regardless of age. The Colorectal Cancer Alliance is dedicated to working with all stakeholders and is committed to supporting researchers who are leaders in the field to better understand YO-CRC, as well as research that looks at improved therapies for those in treatment to improve outcomes.
Initial experience of TAS-102 chemotherapy in Australian patients with chemorefractory metastatic colorectal cancer.
Authors: Jalali Azim , Wong Hui-Li , Wong Rachel , Lee Margaret , Gately Lucy , Loft Matthew , Shapiro Jeremy David , Kosmider Suzanne , Tie Jeanne , Ananda Sumitra , Yeung Justin , Jennens Ross , Lee Belinda , McKendrick Joseph James , Lim Lionel , Khattak Muhammad Adnan , Gibbs Peter 
Published: January 2021

71 Background: For patients with refractory metastatic colorectal cancer (mCRC) treatment with Trifluridine/Tipiracil, also known as TAS-102, improves overall survival. In Australia, TAS-102 was initially made available locally through patients self-funding, later via an industry sponsored Medicine Access Program (MAP) and then via the Pharmaceutical Benefits Scheme (PBS). This study aims to investigate the efficacy and safety of TAS-102 in real world Australian population. Methods: A retrospective analysis of prospectively collected data from the Treatment of Recurrent and Advanced Colorectal Cancer (TRACC) registry was undertaken. The characteristics and outcomes of patients receiving TAS-102 were assessed and compared to all TRACC patients and those enrolled in the registration study (RECOURSE). Results: Across 13 sites, 107 patients were treated with TAS-102 (non-PBS n = 27, PBS n = 80), The median number of patients per site was 7 (range: 1-17). The median age was 60 years (range: 31-83), compared to 67 for all TRACC patients and 63 for RECOURSE. Comparing registry TAS-102 and RECOURSE patients, 75% vs 100% were ECOG performance status 0-1, 74% vs 79% had initiated treatment more than 18 months from diagnosis of metastatic disease and 39% vs 49% were RAS wild type. Median time on treatment was 10.4 weeks (range: 1.7-32). Median clinician assessed progression-free survival was 3.3 compared to RECIST defined PFS of 2 months in RECOURSE study, while median overall survival was the same at 7.1 months. Two patients (2.3%) had febrile neutropenia and there were no treatment-related deaths in the real-world series, where TAS102 dose at treatment initiation was at clinician discretion. In the RECOURSE study there was a 4% febrile neutropenia rate and one treatment-related death. Conclusions: TRACC registry patients treated with TAS102 were younger than both TRACC patients overall and those from the RECOURSE trial. Less strict application of RECIST criteria and less frequent imaging may have contributed to an apparently longer PFS. However overall survival outcomes achieved with TAS102 in real world patients were comparable to findings from this pivotal trial with an acceptable rate of major adverse events.
Platform trial of BI 754091, an anti-PD-1 antibody, in patients with previously treated advanced solid tumors: Combination with BI 836880, a VEGF/Ang2-blocking nanobody.
Authors: Hussein Maen A. , Bendell Johanna C. , Arkenau Hendrik-Tobias , Chu Quincy S. , Hansen Aaron Richard , Erzen Damijan , Sun Zhichao , Lucarelli Anthony , Percent Ivor John 
Published: January 2021

TPS152 Background: Combining anti-programmed cell death protein 1 (PD-1) antibodies with other immuno-modulatory or targeted therapies may improve outcomes. NCT03697304 is an open-label, Phase II, platform trial assessing BI 754091, an anti-PD-1 antibody, combined with other agents. Here, we describe Module C in which BI 754091 will be combined with BI 836880, a humanized bispecific nanobody, that targets vascular endothelial growth factor (VEGF) and angiopoietin2 (Ang2). VEGF and Ang2 play key roles in tumor angiogenesis and have an immunosuppressive effect in the tumor microenvironment. Combining anti-VEGF/Ang2 with an anti-PD-1 therapy promotes an immunopermissive state supportive of T-cell-mediated tumor cell death. Methods: Patients are being enrolled in 5 cohorts: 1) locally advanced/metastatic gastric or gastroesophageal adenocarcinoma with ≥1 prior treatment (anti-PD-[L]1 naïve); 2) any advanced/metastatic solid tumor (excluding NSCLC and melanoma) with prior anti-PD-(L)1 treatment, which progressed after achieving at least stable disease (SD) for 4 months; 3) advanced/metastatic solid tumors with no benefit from prior anti-PD-(L)1 treatment (SD <4 months); 4) locally advanced/metastatic microsatellite stable (MSS) colorectal cancer with ≥1 prior treatment (anti-PD-[L]1 naïve); 5) advanced MSS and mismatch-repair proficient endometrial carcinoma which progressed following 1 line of chemotherapy (anti-PD-[L]1 naïve). Patients will receive BI 836880 (720 mg every 3 weeks [Q3W] intravenously [IV]) and BI 754091 (240 mg Q3W IV). Treatment will continue until progressive disease, unacceptable toxicity, consent withdrawal, or for a maximum of 1 year (treatment may be extended in case of clinical benefit). The primary endpoint is objective response (OR; complete or partial response per RECIST v1.1 as assessed by the investigator). Secondary endpoints are duration of OR, disease control and progression-free survival. Safety will also be assessed. Approximately 30 patients will be enrolled per cohort at sites in North America and the United Kingdom. Clinical trial information: NCT03697304.