bluuebunny/crossref_metadata_2025_split huggingface dataset:
Genomic profiling as a response predictor of second-line treatment in advanced gastric cancer patients: Post-hoc analyses of two phase Ib/II trials.
Authors: Lee Choong-kun , Che Jingmin , Kwon Woo Sun , Park Sejung , Kim Hyo Song , Jung Minkyu , Chung Hyun Cheol Cheol , Rha Sun Young 
Published: January 2022

351 Background: Targeted panel next-generation sequencing (NGS) is now actively performed in clinics to guide treatment decisions for advanced cancer patients. However, NGS profilings of advanced gastric cancer (AGC) do not provide relevant genomic biomarkers that could predict response to second-line treatment for AGC patients yet. Methods: Two paclitaxel-based phase Ib/II trials as a second-line treatment for AGC patients were included: GSK2636771 (PI3Kβ selective inhibitor) and paclitaxel for AGC patients with PI3K/Akt pathway alterations (PTEN trial, NCT02615730, presented at GI ESMO 2021) and nivolumab and paclitaxel for EBV-related, dMMR/MSI-H or PD-L1 positive AGC (K-umbrella-003 trial, NCT02951091, presented at AACR 2021). Pre-treatment tumor tissue samples from two trials were subjected to the in-house panel sequencing using CancerMaster Panel V2 (Kwon et al., GI ASCO 2021) that covers 524 genes for single nucleotide variants, 143 for copy-number variations, and 18 for fusions. Baseline genomic alterations were compared with each patient’s response and survival. Oncogenic signaling pathways were annotated manually according to previous reports. Tumor mutation burden (TMB) and Human leukocyte antigen (HLA) profilings were also performed. Results: Baseline tumor tissues from 54 patients (24 from PTEN trial, 30 from K-umbrella-003 trial) were available for NGS. In patients treated with GSK2636771 and paclitaxel, patients with PIK3R1 M326I mutation (n = 3) showed longer PFS (8.1 vs 2.8 months, P= 0.041), and patients without MYC Q48H (n = 13) showed better PFS (4.8 vs 2.6 months, P= 0.013). Genetic alterations in epigenetic pathway were found in 13 patients (54.2%) and showed worse PFS (2.8 vs 5.0 months, P = 0.04). In patients treated with nivolumab and paclitaxel, patients with RTK/RAS pathway alterations excluding deletions (n = 21, 70%) showed significantly longer PFS (4.1 vs 2.6 months, P = 0.0085), and patients with HLA-A02 supertype (n = 11, 36.7%) showed significantly longer PFS (12.4 vs. 2.7 months, P = 0.0068). In both studies, TMB-high was not related to the survival and there were no common predictive genomic alterations. Conclusions: We observed that specific NGS-based genomic alterations such as single gene mutations, altered signaling pathways and HLA genotyping were potential predictors of each targeted agent or immunotherapy as a 2nd line treatment of AGC patients, regardless of paclitaxel. Further correlative studies within AGC trials for exploring predictive biomarkers are warranted. Clinical trial information: NCT02615730; NCT02951091.
Systematic analysis of gene expression alteration of BIRC5/survivn in gastric cancer.
Authors: Wang Jianzheng , Li Qingli , Lv Huifang , Chen Xiaobing , Tu Shuiping 
Published: January 2022

353 Background: BIRC5/survivin gene is a member of the inhibitor of apoptosis (IAP) gene family, which encode negative regulatory proteins that prevent apoptotic cell death. Abnormal BIRC5/survivin expression is associated with carcinogenesis. Methods: We used sequencing data from The Cancer Genome Atlas database，Oncomine database and GTEx database, analyzed BIRC5/survivin expression and gene regulation networks in gastric carcinoma (STAD).Kaplan-Meier plotter database was used to assess the BIRC5/survivin prognostic potential. ULACAN was used to further analyze the relationship between the expression of BIRC5/survivin and the clinical stage of gastric cancer, and the methylation data of the promoter region of BIRC5/survivin. LinkedOmics was used to identify differential gene expression with BIRC5/survivin and to analyze Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathways. Gene enrichment analysis examined target networks of kinases, miRNAs and transcription factors. We investigated the correlation of BIRC5/survivin expression in gastric cancer with immune infiltration levels from TIMER database and TISID database. Results: We found that BIRC5/survivin is overexpressed in gastric cancer. The patient with high expression of this gene is associated with poor prognosis. The expression of BIRC5/survivin is positive with ERBB2 expression,TMB,MSI,MSH2,MSH6,PMS2.BIRC5/surviving expression is significantly positively correlated to tumor purity and has significant negative correlation with the immune cell infiltration level of B cells,CD8+T cells,CD4+T cells, Macrophage cells, Neutrophil cells and Dendritic cells. BIRC5/survivin expression is significantly positively correlated CD274，LAG3 and PDCD1. Our results show a detailed landscape map of BIRC5/survivin gene mutation in STAD. Our results showed the associations between BIRC5/survivin expression and six immune subtypes: C1 (wound healing); C2 (IFN-gamma dominant);C3 (inflammatory); C4 (lymphocyte depleted); C6 (TGF-b dominant) in STAD. Conclusions: Our results demonstrate that data mining efficiently reveals information about BIRC5/survivin expression and potential regulatory networks in gastric cancer, laying a foundation for further study of the role of BIRC5/survivin in carcinogenesis and tumor immunotherapy.
Improving survival prediction of patients treated with external beam radiotherapy for dysphagia in esophageal cancer using prediction models.
Authors: Kuijper Steven , Jeene Paul M. , van den Boorn Héctor G. , El Sharouni Sherif , Braam Pètra , Oppedijk Vera , Verhoeven Rob , Hulshof Maarten C.C.M. , Van Laarhoven Hanneke W.M. 
Published: January 2022

358 Background: The recently published POLDER trial investigated the effects of external beam radiotherapy (EBRT) on dysphagia caused by incurable esophageal cancer. As the effects of EBRT were presumed not to be immediate, an estimated life expectancy of minimally three months was required for inclusion. However, nearly a third of the included patients died within three months. The aim of this study was to investigate if the use of prediction models could have improved the physician’s estimation of the patient’s survival, and thus the eligibility for EBRT treatment. Methods: Data from the POLDER trial (N = 110) were linked to the Netherlands Cancer Registry to retrieve additional patient, tumor and treatment characteristics. Two published prediction models (the SOURCE model and Steyerberg model) were used to predict overall survival for all patients included in the POLDER trial. Predicted survival probabilities were dichotomized (predicted deceased/alive at three months) and the positive predictive value, negative predictive value, sensitivity, specificity and the area under the curve (AUC) were used to evaluate the predictive performance. DeLong’s test was used to test the difference between the AUCs of the SOURCE and Steyerberg models for statistical significance. Results: In the POLDER trial, 35 patients were unjustly presumed to survive three months. Predicting survival at three months, the SOURCE and Steyerberg model had an AUC of 0.76 and 0.60 respectively. The difference between the AUCs of the models was significant (p =.017). Under optimal survival cut-off scores, SOURCE would have incorrectly predicted 16 patients to survive three months. For the Steyerberg model this was 22 patients. Furthermore, using SOURCE under these cut-off scores, seven patients were incorrectly predicted to not survive three months compared to 18 patients using the Steyerberg model. Conclusions: Results showed that the SOURCE and Steyerberg models could have improved survival predictions compared to clinical judgement alone. The SOURCE model was found to be a more useful decision aid than the Steyerberg model as it was more accurate. Accepting that a small proportion of patients are incorrectly predicted not to survive three months and are not considered for EBRT treatment, we recommend using the SOURCE model for patients that are considered for palliative treatment of dysphagia caused by esophageal cancer.
Adjuvant S-1 versus observation in curatively resected biliary tract cancer: A phase III trial (JCOG1202: ASCOT).
Authors: Ikeda Masafumi , Nakachi Kohei , Konishi Masaru , Nomura Shogo , Katayama Hiroshi , Kataoka Tomoko , Uesaka Katsuhiko , Yanagimoto Hiroaki , Morinaga Soichiro , Wada Hiroshi , Shimada Kazuaki , Takahashi Yu , Nakagohri Toshio , Gotoh Kunihito , Kamata Ken , Shimizu Yasuhiro , Ueno Makoto , Ishii Hiroshi , Okusaka Takuji , Furuse Junji 
Published: January 2022

382 Background: Capecitabine is usually used for patients with curatively resected biliary tract cancer (BTC) in EU and US, but no clear survival benefit has been shown in phase III trials. S-1, an oral fluoropyrimidine derivative, has shown promising efficacy, with a mild toxicity profile, in patients with advanced BTC. The aim of this trial was to confirm whether adjuvant S-1 therapy might improve the overall survival (OS) in patients with curatively resected BTC. Methods: This open-label, multicenter, randomized phase III trial was conducted in 38 Japanese hospitals. Eligible patients were aged 20 to 80 years old, had undergone R0/R1 resection for histologically confirmed adeno(squamous) carcinoma of the extrahepatic bile duct, gallbladder or ampulla of Vater (T2-4, N0, M0 or T1-4, N1, M0) or the intrahepatic bile duct (T1-4, N0-1, M0) (7th UICC classification), and had an ECOG performance status (PS) of 0 or 1.The calculated sample size was 440 to detect hazard ratio for OS of 0.74 with one-sided alpha of 5% and a power of 80%. Patients in surgery-alone arm received no further anti-cancer treatment, while those in adjuvant S-1 arm received 4 cycles of oral S-1 chemotherapy at the dose of 40 mg/m2 twice daily for 4 weeks, followed by 2 weeks of rest. Primary endpoint was OS, and secondary endpoints were relapse-free survival (RFS), incidence of adverse events, and proportion of treatment completion. Results: A total of 440 patients (surgery-alone, n = 222; adjuvant S-1, n = 218) were enrolled from September 2013 to June 2018. The data cutoff date was June 23, 2021, and the median follow-up duration was 45.4 months. Of all randomized patients, OS was significantly longer with adjuvant S-1 than surgery-alone (hazard ratio [HR] 0.694, 95%CI, 0.514-0.935; one-sided p = 0.008; the 3-year OS, 67.6% [surgery-alone; 95%CI, 61.0-73.3%] and 77.1% [adjuvant S-1; 95%CI, 70.9-82.1%]). Adjuvant S-1 was also better for RFS (HR 0.797 [95%CI, 0.613-1.035], 3-year RFS, 50.9% [surgery-alone; 95%CI, 44.1-57.2%] and 62.4% [adjuvant S-1; 95%CI, 55.6-68.4%]). All preplanned subgroup analyses (PS, age, cancer type, cancer stage, R factor, and serum CA19-9) revealed favorable OS and RFS for adjuvant S-1 arm. The main grade 3-4 adverse events in adjuvant S-1 arm were biliary tract infection (7.2%), diarrhea (2.9%), appetite loss (2.9%), fatigue (2.9%), and the treatment was well-tolerated. Conclusions: Adjuvant S-1 therapy led to significantly longer survival than surgery alone and becomes the standard of care for resected BTC. Clinical trial information: UMIN000011688.
Real-world use of atezolizumab plus bevacizumab in patients with hepatocellular carcinoma and Child-Pugh A and B cirrhosis.
Authors: D'Alessio Antonio , Weinmann Arndt , Galle Peter R. , Fulgenzi Claudia Angela Maria , Bettinger Dominik , Bengsch Bertram , Vogel Arndt , Balcar Lorenz , Scheiner Bernhard , Navaid Musharraf , Naqash Abdul Rafeh , Personeni Nicola , Pressiani Tiziana , Sharma Rohini , Pinter Matthias , Cortellini Alessio , Rimassa Lorenza , Pinato David James 
Published: January 2022

393 Background: Atezolizumab plus bevacizumab (A+B) is the new standard of care for first-line treatment of advanced hepatocellular carcinoma (HCC). No evidence exists as to its use in routine clinical practice in patients (pts) with impaired liver function. Methods: This retrospective, multi-center observational study was conducted across 7 tertiary academic referral centres and collected 64 HCC pts consecutively treated with A+B. Efficacy outcome measures included overall (OS) and progression-free survival (PFS) calculated from time of A+B commencement and overall response rates (ORR) and disease control rates (DCR) defined by Response Evaluation Criteria in Solid Tumors (RECIST, v1.1). Safety outcomes included treatment-related adverse events (trAEs) graded (G) according to CTCAE v5.0. Results: Of 64 eligible pts, 54 had BCLC C stage HCC (84%), secondary to hepatitis C cirrhosis (n = 24; 37%), hepatitis B (n = 10; 16%), and non-viral etiologies (n = 40; 47%). Liver function was classified as Child-Pugh (CP) A in 46 patients (72%), B7 in 7 (11%), B8 in 8 (12%), and B9 in 3 (5%). Patients were of performance status (PS) ECOG 0 (n = 39; 61%) and 1 (n = 25; 39%). Pre-treatment upper-gastrointestinal endoscopy was performed in 44 patients (69%), with gastro-esophageal varices found in 18 pts (40%) and graded as 1 (n = 12, 27%), 2 (n = 4, 9%) and 3 (n = 2, 4%) respectively. After a median follow-up of 6.8 months (m) (95% confidence interval [CI], 5.5-8.0), median OS (mOS) was 11.7m (95% CI, 6.2-17.3) whereas median progression-free survival (mPFS) was 6.97m (95% CI, 2.9-11.0). ORR and DCR were 26% and 62% respectively. TrAEs of any grade were documented in 43 pts (67%): 12 pts (18%) had trAEs of G≥3: 7 (11%) atezolizumab-related and 5 (8%) bevacizumab-related. Toxicity led to treatment discontinuation in 3 pts (5%). Compared to CP-A, CP-B pts achieved shorter OS (11.7m [95% CI, 10.3-13.2] vs 6.5m (95% CI, 3.5-9.5), p = 0.029) and PFS (9.1m [95% CI, 5.4-12.8] vs 2.3m [95% CI, 1.7-2.9], p = 0.001) with no differences in ORR nor in DCR. The rate of trAEs did not significantly differ across CP classes. Median OS was significantly longer in patients achieving a radiologic response (12.7m [95% CI, not reached] vs 11.0m [95% CI, 5.5-16.5], p = 0.04). Presence and grade of varices was not associated to bevacizumab-related trAEs. Conclusions: This study confirms reproducible efficacy and safety of A+B in routine practice. Despite inferior OS and PFS compared to CP-A, A+B was associated with similar tolerability and radiologic response in CP-B patients, warranting prospective evaluation of A+B in this treatment deprived population.
Contemporary real-world evidence in unresectable HCC (uHCC) patients treated with regorafenib in Taiwan: Interim results from the observational REFINE study.
Authors: Lin Shi-Ming , Hsu Chih-Hung , Jeng Long-Bin , Lin Yih-Jyh , Lee Ming-Yang , Lee Teng-Yu , Huang Yi-Hsiang 
Published: January 2022

402 Background: The phase 3 RESORCE trial showed that regorafenib improved overall survival compared to placebo in uHCC patients (pts) who progressed on sorafenib. The characteristics of real-world pts are more diverse than those included in clinical trials. The global observational REFINE study was designed to evaluate the safety and effectiveness of regorafenib in pts with uHCC in a real-world setting. Methods: REFINE is an ongoing observational study of pts with uHCC who were treated with regorafenib in routine practice. The primary end point includes to assess treatment-emergent adverse events (TEAEs; NCI-CTCAE v4.03). Secondary endpoints include overall survival, progression-free survival, and tumor response. Tumor response and progression are assessed per investigator according to local standard. A planned interim analysis of 1008 pts in the global cohort has been reported (Lim, ILCA 2021). We describe interim results in pts from Taiwan. Results: A total of 137 pts were enrolled and 136 were valid for safety analysis (80% male). At study entry, median age was 65.5 years (Q1-Q3, 60-72); 51.5% pts had an ECOG PS 0 and 24.3% and 12.5% had an ECOG PS of 1 and, respectively (missing 11.8%); proportion of pts classified as Child–Pugh A/B/C were 46.3%/10.3%/0.7% (missing/not evaluable: 40.4%/2.2%). The initial daily regorafenib dose was 160 mg in 8% of pts and 120 mg/80 mg in 9%/78%; 5.1% started at 40 mg. 83.1% pts received regorafenib as a second line agent and 15.4% pts as third line or beyond. 132 pts had prior sorafenib treatment with last daily dose being 400mg in 53.8% of patients; 9 patients (6.6%) had received an immune checkpoint inhibitor. The most frequent TEAEs are shown (Table). Effectiveness results will be presented. Conclusions: The characteristics of real-world pts from Taiwan not only differ from those in the RESORCE trial but also from the global REFINE cohort, reflecting variation across countries. A higher proportion of patients from Taiwan initiated regorafenib at a lower dose. Clinical trial information: NCT03289273. [Table: see text]
The association of family history of primary liver cancer with cholangiocarcinoma: USA case-control study.
Authors: Eluri Madhulika , Hatia Rikita , Javle Milind M. , Hassan Manal 
Published: January 2022

403 Background: The incidence of cholangiocarcinoma (CCA), particularly intrahepatic cholangiocarcinoma (IHC) has exponentially increased in the United States since 2007. While cholangiocarcinomas share some common characteristics, increasing evidence suggests that different subtypes of CCA have divergent tumor microenvironments, pathobiology and distinct epidemiologic features and risk factors. The correlation between family history of cancer and cholangiocarcinoma remains to be determined. This study aims to address the connection between positive family history of primary liver cancer and development of cholangiocarcinoma, including intrahepatic cholangiocarcinoma (IHC) and extrahepatic cholangiocarcinoma (EHC), in USA. Methods: At The University of Texas M. D. Anderson Cancer Center, we studied 429 patients with pathologically confirmed cholangiocarcinoma (308 IHC, 121 EHC) and 1,075 healthy controls. All subjects were interviewed for their family history of cancer, including the number of relatives with cancer, the type of cancer, the subjects’ relationship with the relative, and the age at which the relative was diagnosed. Results: Independent of hepatitis B virus (HBV) and hepatitis C virus (HCV), a family history of cancer was significantly associated with IHC and EHC, the estimated ORs and 95% CI were 1.6 (1.2-2.2) and 1.6 (1.1-2.5) for IHC and EHC respectively. Primary liver cancer in first-degree relatives was significantly associated with EHC development (OR 9.4 [95% CI, 2.9-30.7]). No significant association was observed for IHC, (OR 1.7 [95% CI, 0.5-5.9]). The prevalence of family history of primary liver cancer in first-degree members was recorded in 6.6% of EHC patients and in 1.6% of IHC patients. Multiple relatives with primary liver cancer were observed in 5 patients (4.1%) among EHC subjects but less common in IHC (1%). All estimated ORs were adjusted for age, sex, race, smoking, alcohol, Hepatitis virus infection, diabetes, and obesity. Conclusions: First-degree family history of primary liver cancer is associated with EHC development in USA independent of known risk factors for CCA. Further research exploring the genetic–environment interactions associated with EHC is warranted. Focused efforts in identifying the population at increased risk for developing EHC are necessary and may lead to new screening and surveillance strategies.
Effectiveness of transarterial chemoembolization combined with lenvatinib plus sintilimab in unresectable hepatocellular carcinoma.
Authors: Cao Fei , Yang Yi , Si Tongguo , Luo Jun , Zeng Hui , Zhang Zhewei , Chen Yi , Zheng Jiaping 
Published: January 2022

414 Background: Combination therapies have been explored for the treatment of hepatocellular carcinoma (HCC) with favorable results, including PD-1 inhibitors plus lenvatinib and transarterial chemoembolization (TACE) plus lenvatinib. However, triple therapy with TACE combined with lenvatinib plus PD-1 inhibitors has not been investigated for patients with unresectable HCC. This study therefore aimed to investigate the effectiveness and safety of TACE combined with lenvatinib plus sintilimab in patients with advanced HCC. Methods: A single-arm retrospective study based on medical records and imaging data from 60 patients diagnosed with HCC using noninvasive methods or biopsy at the Cancer Hospital of the University of Chinese Academy of Sciences and the First Hospital of Medical University between January 2019 and March 2021. Eligible patients had received lenvatinib 12 mg (bodyweight >60 kg) or 8 mg (bodyweight <60 kg) orally once daily 2 weeks before TACE. Subsequently, sintilimab was administered at a dose of 200 mg intravenously on day 1 of a 21-day treatment cycle following TACE. The TACE procedure was repeated 4-6 weeks later and the chemotherapy regimens used included oxaliplatin (75 mg/m2) and iodized oil mixed with epirubicin (30-50 mg/m2). Objective response rate (ORR) and duration of response (DOR) were the primary endpoints and were assessed using the modified Response Evaluation Criteria in Solid Tumors (mRECIST). Results: The analysis included data from 52 patients; 86.4% were male, 76.7% were aged ≤65 years, 13.5% and 86.5% had an ECOG performance status (PS) of 0 and 1, respectively and 88.5% and 11.5% had a Child-Pugh score of A and B, respectively. All patients were diagnosed with Barcelona Clinic Liver Cancer (BCLC) stage B (25%) or C (75%) disease. After a median follow-up of 12.5 months (95% confidence interval (CI), 9.1–14.8), the ORR was 46.7% (28/60: complete response, n=4; partial response, n=24). Twenty-three patients had stable disease, and nine had progressive disease. The median DOR for confirmed responders was 10.0 months (95% CI, 9.0–11.0). The median progression-free survival and overall survival were 13.3 months (95% CI, 11.9–14.7) and 23.6 months (95% CI, 22.2–25.0), respectively. In total, 84.6% (n=44) of patients had adverse events (AEs) of any grade. The most common treatment-related AEs were fatigue (30.8%), hypertension (25.0%), diarrhea (19.2%), decreased appetite (23.0%), and palmar-plantar erythrodysesthesia (21.1%). Conclusions: TACE combined with lenvatinib plus sintilimab is a promising and tolerable therapeutic regimen for patients with unresectable HCC.