bluuebunny/crossref_metadata_2025_split huggingface dataset:
Morphologic and molecular analysis of early-onset gastroesophageal adenocarcinomas.
Authors: Setia Namrata , Wang Cindy , Lager Angela , Maron Steven Brad , Peterson Bryan , Arndt Nicole , Misdraji Joseph , Ma Changqing , Kupfer Sonia , Hart John , Catenacci Daniel V.T. 
Published: May 2020

4547 Background: The incidence of early-onset gastroesophageal adenocarcinomas (EO-GEA) is increasing, and these tumors now constitute > 30% of all gastroesophageal cancers. Besides hereditary gastric cancer syndromes, which form ~3% of EO-GEA, the morphologic and molecular spectrum of these tumors is not well-studied. Methods: Next-generation sequencing (NGS) data obtained from routine clinical care from patients with EO-GEA, defined as age ≤50 years, from 3 tertiary care centers was evaluated and compared with tumor profiles of 2,081 patients with GEA from cBioPortal for Cancer Genomics. Available histologic slides were reviewed, and the tumors were classified into Lauren and WHO subtypes. Tumor-detected pathogenic variants of potential germline origin were identified from the NGS data. Results: The study cohort was formed by 79 patients with gastroesophageal (42%) and gastric (58%) adenocarcinoma. The most commonly mutated genes included TP53 (28.5%), CDH1 (10%), ARID1A (5%), KRAS (3.9%) and PIK3CA (3.9%). EO-GEA were less likely to harbor TP53 (28.5% vs. 57.5%, p 0.003) and ARID1A (5% vs. 20.6%, p 0.002) mutations when compared with cBioPortal data. Based on the Lauren scheme, the tumors were classified into intestinal (40%), diffuse (24%), mixed (12%), and indeterminate (15%) subtypes. Driver mutations in CDH1, TP53, FBXW7, BAP1 genes were seen in diffuse/mixed subtype, and TP53, ARID1A, KRAS, PIK3CA, APC, ATM, NBN, MUTYH genes in intestinal subtype. The indeterminate subtype showed TP53 mutations and additional alterations, including SMARCB1/ SMARCA4 loss leading to rhabdoid/undifferentiated morphology. ERBB2 amplification was more likely to be present in intestinal and indeterminate subtypes (p = 0.003). CD274 amplification/PD-L1 expression was more likely to be present in indeterminate subtype (p < 0.0001). Potential germline variants included mutations in gastric cancer susceptibility genes such as CDH1 (2.5%) and APC (1%), and other cancer susceptibility genes such as ATM (4%), NBN (1%), MUTYH (1%) and POLD1 (1%). Conclusions: The molecular profile of EO-GEA is distinct from traditional gastric cancers. Histologic subtypes of EO-GEA correlate with distinct genomic alterations. Our findings also support multigene germline panel testing in parallel for patients with EO-GEA.
Prediction of esophageal fistula from esophageal cancer CT images using multi-view multi-scale attentional convolutional neural network (MM-Atten-CNN).
Authors: Xu Yiyue , Cui Hui , Fan Bingjie , Zou Bing , Sun Xindong , Yu Jinming , Wang Linlin 
Published: May 2020

4553 Background: We aimed to propose a risk model based on MM-Atten-CNN for predicting esophageal fistula in patients with esophageal cancer (EC) from computerized tomography (CT) -based radiomics. Methods: EC patients who didn’t received esophageal surgery between July 2014 and August 2019 were collected. Of these, 186 patients (cases) who developed esophageal fistula were enrolled and compared with 372 controls (1:2 matched with the diagnosis time of EC, sex, marriage, and race). All 558 patients were divided into training set (n = 390) and validation set (n = 168) randomly. The MM-Atten-CNN risk model was trained over 2D slices from nine views of planes, where there were three patches of contextual CT, segmented tumor and neighbouring information in each view. In the training set (130 cases and 260 controls), data augmentation was performed including pixel shifting [-10, -5, +5, +10] and rotation [-10, +10]. In total, there were (130+260) *16*2 = 12480 subjects used for training. Finally, the risk model was validated in the validation set (56 cases and 112 controls) and measured by accuracy (acc), sensitivity (sen), and specificity (spe). Results: The developed risk model achieved (acc, sen, spe) of (0.839, 0.807, 0.926), which were more predictive for the occurrence of esophageal fistula when compared to CNN models using single coronal view (acc 0.763, sen 0.581, spe 0.837), multi-view 2D contextual CT slices (acc 0.779, sen 0.656, spe 0.896), and 3D CNN using contextual CT volumes (acc 0.781, sen 0.689, spe 0.852). Conclusions: MM-Atten-CNN CT-based model improved the performance of esophageal fistula risk prediction, which has the potential to assist individualized stratification and treatment planning in EC patients.
PET-directed chemoradiation (CRT) with induction FOLFOX compared to induction carboplatin/paclitaxel (CP) in patients with locally advanced esophageal adenocarcinoma (EA).
Authors: Carr Rebecca , Hsu Meier , Tan Kay See , Bains Manjit S. , Bott Matthew , Ilson David H. , Isbell James M. , Janjigian Yelena Yuriy , Maron Steven Brad , Park Bernard , Rusch Valerie W. , Sihag Smita , Wu Abraham Jing-Ching , Jones David Randolph , Ku Geoffrey Yuyat , Molena Daniela 
Published: May 2020

4554 Background: Induction chemotherapy with PET-directed CRT and surgery is the standard treatment for locally advanced EA at our institution. Following results of the CALGB 80803 trial, FOLFOX has recently replaced CP as the preferred induction regimen. Methods: We retrospectively evaluated patients with locally advanced EA treated with induction CP vs FOLFOX, followed by trimodality therapy between January 2010 and June 2019. Patients treated with CP with RT followed by surgery without induction chemo were also included. We compared pathological complete response (pCR) and near pCR (ypN0 with ≥90% response) rates in the induction FOLFOX group to the induction CP and no-induction groups. Univariable and multivariable analyses were used to adjust for confounding factors. Disease-free survival (DFS) was estimated by the Kaplan-Meier method and compared between groups using max-combo weighted log rank test. Results: 445 patients were included. Patients in the induction FOLFOX group had significantly higher pCR and near pCR rates vs induction CP patients. Notably, pCR rate was 38% among FOLFOX PET responders vs 19% in non-responders. In multivariable analysis, compared to induction CP, induction FOLFOX administration was an independent predictor of near pCR (OR: 2.22, 95%CI: 1.20-4.20, p = 0.012). Compared to 24% pCR rate among no-induction patients, induction FOLFOX pCR rate was slightly higher at 32%. DFS by 2-years was higher in induction FOLFOX compared to no-induction-treated patients (62% vs. 42%, p = 0.05). Postoperative complication rates were similar among the three groups. Conclusions: PET-directed CRT with FOLFOX instead of CP improves pCR and near pCR rates. Improved DFS was observed in the FOLFOX vs no-induction patients. Longer follow-up is needed to confirm any survival benefits. [Table: see text]
A phase II study of efficacy and safety of RC48-ADC in patients with locally advanced or metastatic HER2-overexpressing gastric or gastroesophageal junction cancers.
Authors: Peng Zhi , Liu Tianshu , Wei Jia , Wang Airong , He Yifu , Yang Liuzhong , Zhang Xizhi , Fan Nan-Feng , Luo Suxia , Gong Jifang , Li Zhen , Gu Kangsheng , LU Jin Wei , Xu Jianming , Fan Qingxia , Xu Rui-hua , Zhang Liangming , Fang Jianmin , Ba Yi , Shen Lin 
Published: May 2020

4560 Background: RC48-ADC is an antibody-drug conjugate (ADC) drug comprised of a novel humanized anti-HER2 IgG1, a linker, and a microtubule inhibitor, MMAE. The MoA included inhibition of HER2 signal pathway and cytotoxicity of MMAE. RC48-ADC has demonstrated promising anti-tumor activity in pre-clinical and early clinical studies. The current study is designed to evaluate the efficacy and safety of RC48-ADC in heavily treated patients with HER2-overexpressing (IHC 2+ or 3+) gastric or gastro-esophageal junction cancers. Methods: This is an open-label, multicenter, single-arm, phase II study. Eligibility criteria include: histologically confirmed gastric or gastro-esophageal junction cancers, HER2-overexpression (IHC 2+ or 3+), ECOG PS 0-1, post-to ≥2 prior systemic treatment. The patients received RC48-ADC, 2.5 mg/kg, q2w until disease progression, unacceptable toxicity, withdrawal, or study termination. The primary endpoint was ORR. PFS, OS, and safety were also evaluated. Results: Patient enrollment started in July 2017, and completed in November 2019. By the data cut-off date on 17-Dec-2019, 127 patients were enrolled. The median age was 58 years. At baseline, 59 patients (46.5%) had received ≥ 3 lines prior treatment. For the overall 127 patients, the investigator-assessed confirmed ORR was 18.1% (95% CI: 11.8%, 25.9%). Sub-group ORR was 19.4% and 16.9% for the patients post to 2 lines and ≥ 3 lines, respectively. For the 111 patients who were monitored for ≥ 2 cycles of efficacy assessments (i.e. 12 weeks), the ORR was 20.7% (95% CI: 13.6%, 29.5%). For the 127 patients, the mPFS was 3.8 months (95% CI: 2.7, 4.0, 89 events [70.1%]) and the mOS was 7.6 months (95% CI: 6.6, 9.2, 52 events [40.9%]). The most commonly reported treatment-related AEs were leukopenia (52.0%), alopecia (51.2%), neutropenia (48.0%), and fatigue (42.5%). Conclusions: RC48-ADC demonstrated a clinically meaningful response and survival benefit in the heavily treated patients with HER2-overexpressing gastric or gastro-esophageal junction cancers. The safety profile was in line with the previously reported data of RC48-ADC. RC48-ADC showed positive benefit/risk ratio for the target population. Clinical trial information: NCT03556345 .
Cabozantinib (cabo) combined with durvalumab (durva) in gastroesophageal (GE) cancer and other gastrointestinal (GI) malignancies: Preliminary phase Ib CAMILLA study results.
Authors: Saeed Anwaar , Phadnis Milind , Park Robin , Sun Weijing , Al-Rajabi Raed Moh'd Taiseer , Baranda Joaquina Celebre , Williamson Stephen K. , Collins Zachary , Firth-Braun Jeanette , Saeed Azhar , Foster Carolyn , Roberts Benjamin , Subramaniam Dharmalingam , Kasi Anup , Anant Shrikant 
Published: May 2020

4563 Background: Cabo targets multiple tyrosine kinases, including VEGFR, MET, and AXL, and has been reported to show immunomodulatory properties that may counteract tumor-induced immunosuppression, providing a rationale for combining it with PD-L1 inhibitors like durva. We conducted a phase Ib GI basket trial to evaluate the safety & efficacy of this regimen in advanced GE adenocarcinoma (GEA), colorectal cancer (CRC), & hepatocellular carcinoma (HCC). Methods: Patients received cabo and durva in 3+3 dose escalation then expansion to determine the dose limiting toxicity (DLT), Recommended Phase 2 Dose (RP2D), ORR, PFS & OS. Cabo was dosed at 20mg QD, 40mg QD, and 60mg QD in the first, second, and third cohorts respectively. Durva was dosed at 1500mg IV Q4W in all cohorts. DLT window was 28 days. Scans were obtained every 8 wks. Treatment beyond progression was allowed. Results: 23 Pts (16 M, 7 F), median age 60 yrs (range 33-79) were currently enrolled. 12 in the dose escalation cohort with cabo 20mg (6 pts), or 40mg (3 pts), or 60mg (3 pts). 11 pts enrolled in the dose expansion cohort with cabo 60mg. 8 pts had GEA, 13 pts had CRC, and 2 pts had HCC. Median number of prior chemotherapies was 3 (range 1-3). 3 pts were not evaluable for DLT due to missing ≥30% of DLT window doses, not related to DLT. No DLTs were observed. Drug-related Grade (G) 1&2 AEs included fatigue (83%), abnormal LFTs (39%), anorexia (26%), diarrhea (26%), nausea (13%), & hand foot syndrome (13%). One pt each developed drug related G3 hypertension, hyperthyroidism, thrombocytopenia, & thromboembolic event, all occurring outside the DLT window. 19 pts were evaluable for response: 4 PR (2 GEA & 2 CRC), 12 SD, 3 PD; ORR 21%; clinical benefit rate 84%; median time to PD 16 wks (range 8-40+). Conclusions: RP2D was determined to be Cabo 60mg QD and Durva 1500mg Q4W. Enrollment to phase I dose expansion is ongoing. RP2D may be adjusted based on additional experience & long-term tolerability. Early efficacy data was encouraging. This is an investigator-initiated trial funded by Exelixis & Astrazeneca. Clinical trial information: NCT03539822 .
HER2 heterogeneity in adenocarcinoma of the distal esophagus and stomach.
Authors: Butter Rogier , Hooijer Gerrit , van der Wel Myrtle , Bart Jos , ter Borg Susan , van Velthuysen Loes , van de Vijver Marc J. 
Published: May 2020

4567 Background: Patients with HER2 positive adenocarcinoma of the esophagus or stomach are eligible for HER2 targeted therapy, which can improve survival in selected patients. Previous research shows that HER2 gene amplification and HER2 overexpression is frequently heterogeneous within these tumors. Biopsies taken from heterogeneous tumors for predictive testing may therefore result in false-negative outcomes. The objective of this study was to assess HER2 amplification and expression in biopsies and paired resection specimens with adenocarcinoma of the esophagus or stomach, from patients who did not receive neoadjuvant systemic therapy. Methods: Paired biopsies and resection specimens of patients with adenocarcinomas of the esophagus or stomach were retrospectively selected. Immunostaining was performed on all samples using antibody 4B5 (Ventana Medical Systems) and Silver-In-Situ-Hybridization was performed in selected cases. Scoring for HER2 was performed according to the method described by Hofmann et al. (2008). Results: We included 378 cases for analysis. In both biopsies and resection specimens 14% of the cases were HER2 positive. Intratumor heterogeneity in HER2 positive tumors was present in 45% ( n= 24/53) in biopsies and 75% ( n= 39/52) in resection specimens. In HER2 positive resection specimens, 65% ( n= 34/52) of paired biopsies were also positive. In the 18 remaining discordant tumors (resection HER2 positive, biopsy negative), intratumor heterogeneity was present in 16/18 cases. For HER2 negative resection specimens all paired biopsies were also HER2 negative. SISH was performed in 110 tumors. Agreement of HER2 gene amplification between biopsy and resection specimens was observed in 86% (n = 95/110). Five HER2 negative biopsies were positive in the resection specimen. Conclusions: The results of this study indicate that predictive HER2 assessment in adenocarcinoma of the esophagus or stomach can lead to false negative results based on biopsies. As a result, patients with HER2 positive tumors can unintentionally be denied neoadjuvant HER2 targeted therapy. The set of patients investigated in this present study is unique because of the absence of any systemic and/or radiation therapy between the biopsy and the resection of the tumor. Hopefully these results can help in developing methods for improved patient selection for HER2 targeted therapy.
Identification of SLX4 as the most frequently mutated gene in homologous recombination deficiency in Asian gastric cancer.
Authors: Zhang Shi , Mu Tianhao , Dang Shiying , Huang Tanxiao , Duan Jingxian , Chen Shifu , Wang Guoqiang 
Published: May 2020

4570 Background: Gastric cancer is the third most common malignancy worldwide. Homologous recombination (HR) is a type of genetic recombination, and homologous recombination deficiency (HRD) is highly involved in multiple types of cancers and can predict response to anticancer therapies. However, homologous recombination deficiency is not well characterized in patients with Asian gastric cancer. Methods: 196 Asian patients with gastric cancer were analyzed in this study. A list of 102 genes related to HRD was compiled based on previous literature. Haplox 605-gene panel was used to capture the sequencing library. Mutations related to HRD were analyzed following next-generation sequencing. In addition, tumor mutational burden (TMB) was calculated by dividing the total number of mutations by the size of the coding region. The correlation analysis between HRD and TMB was also conducted. Results: In total, 43 (21.94%) of 196 Asian patients with gastric cancer harbored at least one HRD gene. The top 10 mutant HRD genes included SLX4 (3.57%), ATR (2.04%), RECQL (1.53%), NBN (1.53%), ERCC4 (1.53%), BAP1 (1.53%), ATM (1.53%), RAD54L (1.02%), BRCA1 (1.02%) and PARP1 (1.02%). In addition, the occurrence of HRD mutations was significantly correlated with a higher TMB. The median TMB of HRD group (8.28 muts/Mb) was significantly higher than that of the Non-HRD group (3.07 muts/Mb) (p < 0.01). The overall upper quantile value (4.80 muts/Mb) was used to screen patients with high TMB (TMB-H). The TMB-H in HRD group was significantly higher than the Non-HRD group (44.19% VS 17.92%, p < 0.01). Conclusions: Our study described that SLX4 was the most frequently mutated HR-related gene in Asian gastric cancer. Moreover, the positive correlation with homologous recombination deficiency (HRD) and tumor mutational burden (TMB) was observed in these patients.
A novel gene signature for predicting response to chemoradiotherapy in locally advanced esophageal adenocarcinoma.
Authors: Sahu Divya , Omstead Ashten N. , Gorbunova Anastasia , O’Meally Dennis , Salvitti Madison , Lam Vincent K. , Jobe Blair A , Kelly Ronan Joseph , Goel Ajay , Zaidi Ali Hussainy 
Published: May 2020

4571 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 and comprehensively identified a biomarker signature that predicts response to neoadjuvant therapy in EAC patients. Methods: A cohort of 31 EAC patients treated with chemotherapy or chemoradiotherapy was assembled, with a majority of patients receiving carboplatin, paclitaxel and concurrent radiotherapy. Specifically, we performed a capture based targeted sequencing 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 pre- and post-treatment tissues. Results: In our cohort, based upon pathologic response to neoadjuvant CRT, 8 EAC patients were categorized as non-responders, while 23 were deemed as responders to CRT. Among responders, the most frequently mutated genes were MKI67, SYNE1, PCLO, RECQL4, MSH3, NOTCH2, ILR7, CIITA, LRRK2 and EML4, and the overall tumor mutation burden (TMB) was significantly reduced for these genes in post-treatment samples ( P=5.73E-03). Similarly, in non-responders NLRP1, MAP3K1, ASMTL, and ALK harbored frequent mutations, and the TMB was significantly reduced for these genes in post-treatment samples ( P=5.57E-03). We compared responders and non-responders from the pre-treatment samples and identified differentially mutated genes including EPHA5, ZNF217, RELN, PALB2 and MYO18A. Similarly, responders had all four immune-related genes significantly up-regulated in post-treatment samples than pre-treatment samples. We constructed a risk-stratification model that comprised of mutational score from 5 differentially mutated genes, together with 4 immune-related genes, which achieved an AUC of 0.96 in predicting response to CRT in EAC patients ( P=1.03E-04). 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 locally advanced EAC patients.
Algorithm for blood-based panel of methylated DNA and protein markers to detect early-stage hepatocellular carcinoma with high specificity.
Authors: Chalasani Naga P. , Bhattacharya Abhik , Book Adam , Neis Brenda , Xiong Kong , Ramasubramanian T , Johnson Scott , Lidgard Graham P. , Roberts Lewis R. , Kisiel John B. , Reddy K Rajender , Singal Amit G , Olson Marilyn , Bruinsma Janelle J 
Published: May 2020

4577 Background: Hepatocellular carcinoma (HCC) is a leading cause of cancer-related deaths worldwide. Though biannual ultrasound surveillance with or without alpha-fetoprotein (AFP) testing is recommended for at-risk patients, its sensitivity for early-stage HCC detection is suboptimal. We therefore evaluated performance of a biomarker panel incorporating methylated DNA markers (MDMs) and proteins for early HCC detection in at-risk patients with chronic liver disease. Methods: In an international, multicenter, case-control study, blood specimens were collected from patients with HCC per AASLD criteria and controls matched for age and liver disease etiology. All patients had underlying cirrhosis or chronic HBV infection. Whole blood was collected in cell-free DNA stabilizing and serum-separation tubes and shipped to a central laboratory for processing. The levels of 5 MDMs, AFP, and AFP-L3 were assessed along with age and sex. We used 537 samples in a 5-fold validation for developing a LASSO regression algorithm to classify samples as HCC positive or negative. Model robustness was tested by perturbing the data in silico and analyzing results with the predictive algorithm. Algorithm performance was compared to AFP alone and the GALAD score (Gender, Age, AFP-L3, AFP, and DCP). Results: The study included 136 HCC cases (81 early-stage—BCLC stage 0/A) and 401 controls. With specificity set at 89%, we developed a model using sex, AFP, and 3 MDMs (HOXA1, TSPYL5, B3GALT6) with higher sensitivity (70%) for early-stage HCC compared to GALAD (54%) or AFP (31% at 20 ng/mL or 52% at ≥7.7 ng/mL) (Table). The AUC for the HCC marker panel was 0.91 (95% CI 0.89 – 0.94) compared to GALAD (0.88; 95% CI 0.85 – 0.91) or AFP (0.84; 95% CI 0.81 – 0.87). The panel performed similarly in viral (AUC = 0.94) and non-viral (AUC = 0.89) etiologies. Conclusions: The robust algorithm based on novel blood-based biomarkers presented here provides higher sensitivity for early-stage HCC compared to other available blood-based biomarkers and, therefore, could significantly impact HCC clinical management and patient outcomes. Further clinical studies to validate the algorithm are ongoing. Clinical trial information: NCT03628651 . [Table: see text]