bluuebunny/crossref_metadata_2025_split huggingface dataset:
PD-L1 as a predictor of chemo-immunotherapy response in biliary tract cancers: A systematic review and meta-analysis.
Authors: Juarez Juan Jose , Osataphan Soravis Alm , Ponvilawan Ben , Charoenngam Nipith , Peters Mary Linton Bounetheau 
Published: January 2024

541 Background: Advanced biliary tract cancers (BTCs) are rare and aggressive malignancies with limited treatment options. Recently, immune checkpoint inhibitors in combination with chemotherapy (ICI-C) gained approval as first-line therapy for unresectable or metastatic BTCs. Two large phase III clinical trials of ICI-C in BTCs did not show a significant correlation between PD-L1 expression and therapeutic response. However, in a phase II study of single-agent nivolumab, there was an association. In light of these conflicting findings, we conducted a comprehensive systematic review and meta-analysis of clinical trials investigating ICI-C in BTCs to assess whether PD-L1 expression could predict treatment response. Methods: We searched PubMed, Web of Science, EMBASE, and Cochrane databases to identify relevant studies. Patient characteristics, method of PD-L1 assessment, and measures of treatment response including hazard ratio (HR), objective response rate (ORR), progression-free-survival (PFS), and overall survival (OS) were extracted. Pooled ORR and HR were calculated using random effect model and assessed for study heterogeneity. Results: Among the 4,882 studies screened, seven clinical trials evaluating the efficacy of ICI-C in BTCs were identified. Of these trials, two randomized phase III trials report HR between PD-L1 positive and negative patients, while five phase II clinical trials reported ORR based on PD-L1 expression. Out of the 1,069 patients included in these trials, 954 underwent assessment for PD-L1 expression. 66.4% (n=634) exhibited PD-L1 expression level ≥ 1% as determined by either tumor proportion score (TPS) or combined positive score (CPS), while 33.5% (n=320) were classified as PD-L1 negative. Notably, 115 patients were not tested for PD-L1 expression, a variety of PD-L1 assays were used across the studies, and only some studies reported multiple PD-L1 cutoffs. Pooled analysis of two-phase III trials demonstrated that PD-L1 expression ≥ 1% was associated with improved OS (pooled HR 0.83, 95% CI 0.72-0.95) compared to PD-L1 < 1% (pooled HR 0.85, 95% CI 0.67-1.07). Additionally, pooled ORR from five phase II studies showed a trend towards an improved response in patients with PD-L1 expression ≥ 1% (pooled ORR 64%, 95% CI 52-74%) compared to PD-L1 <1% (pooled ORR 46%, 95% CI 31-62%) with a subgroup difference p-value of 0.08. Conclusions: This meta-analysis suggests that BTCs patients with PD-L1 expression ≥ 1% may exhibit a more favorable response to chemo-immunotherapy, and that a majority of BTCs have this level of expression. These findings support further investigation of the use of PD-L1 as a biomarker, and in particular investigation of different PD-L1 levels, which may inform treatment for patients with relative contraindications to immunotherapy use.
The combination of CD8 and TIM3 expression to predict survival outcomes in hepatocellular carcinoma.
Authors: Shimada Mitsuo , Wada Yuma , Noma Takayuki , Saito Yu , Morine Yuji 
Published: January 2024

543 Background: CD8+ T cells have anti-tumor immunity in a variety of cancers including hepatocellular carcinoma (HCC). Tumor-infiltrating CD8+ T cells express immune checkpoint proteins and focus on a therapeutic targeting. T cell immunoglobulin and mucin domain protein 3 (TIM3) has been reported to be associated with suppression of anti-tumor immunity, poor prognosis, and tumor progression in HCC, resulting in up-regulation on exhausted CD8+ T cells. As the exhausted T cells showed a decrease of effector cytokine production and cytolytic activity, leading to the tumor progression, TIM3 is one of the most important exhaustion markers. In the present study, we investigated the role of CD8 and TIM3 as a prognostic biomarker in HCC. Methods: We analyzed 474 HCC patients with clinical and transcriptomic data from The Cancer Genome Atlas (TCGA: n=359) and GSE 76427 (n=115) to examine associations between CD8, TIM3, and programmed death receptor-1/programmed cell death ligand 1 (PD-1/PD-L1) expression and survival outcomes. Each gene was divided into low- and high-expression groups using the tertiles of gene expression. Results: The patients with high CD8 and low TIM3 expression were associated with better overall survival (OS) (P=0.021 and P=0.025, respectively) in TCGA, while PD-1/PD-L1 were not associated with OS (P=0.306 and P=0.318, respectively). Moreover, the patients with high CD8 and low TIM3 expression were validated in GSE dataset (P=0.014 and P=0.009, respectively). The patients with high CD8 and low TIM3 expression were associated with improved OS compared with the overall HCC patient (P=0.008). Among the patients with high CD8 expression, low TIM3 expression (non-exhausted CD8+ T cells) was associated with better OS (P=0.009), but PD-1/PD-L1 were not associated with OS (P=0.491 and P=0.772, respectively). Finally, multivariate analysis showed that the patients withnon-exhausted CD8+ T cells were significantly superior for the survival outcomes (Hazard ratio=2.80, 95% CI=1.27–6.19, P=0.01). Conclusions: High CD8 and low TIM3 expression is associated with better OS in HCC than PD-1/PD-L1, suggesting that CD8 and TIM3 are useful biomarkers for predicting HCC prognosis. Restoring exhausted T cells via the suppression of TIM3 is a promising strategy for cancer treatment, which become a breakthrough in the cancer immunotherapy.
Survival impact of homologous recombination deficiency in veterans with cholangiocarcinoma including mutual exclusivity with pathogenic KRAS and TP53.
Authors: Bergstrom Colin P. , Lin Ethan Samuel , Mehlhaff Eric G. , Lesnik Dyan M. , LoConte Noelle K. , Lubner Sam Joseph , Matkowskyj Kristina A. , Patel Monica Arun , Ronnekleiv-Kelly Sean , Uboha Nataliya Volodymyrivna , Wachsmann Megan , Wang David H. , Lin Albert Y. , Kratz Jeremy D. 
Published: January 2024

546 Background: Cholangiocarcinoma (CCA) has poor prognosis and limited treatment options. The US Veteran Health Administration’s (VHA) National Precision Oncology Program (NPOP) was established to characterize pathogenic drivers across the integrated VA network. Here, we summarize an important subgroup of CCA with homologous recombination deficiency (HRD) and its impact on overall survival (OS). Methods: Next-generation sequencing (NGS) was performed using FoundationOne CDx Analysis included clinicopathological, molecular alterations including, single nucleotide variants, gene amplification/loss, and gene fusion/rearrangements obtained from centralized data of the VHA’s Corporate Data Warehouse. Homologous recombination deficiency was defined by pathogenic variant mutations (MT) in ARID1A, ATM, ATR, BAP1, BRCA1, BRCA2, CDK12, CHEK2, FANC, NBN, PALB2, and RAD51. Statistical analysis was performed using Chi-squared test for concurrent gene enrichment and log-rank Kaplan-Meier analysis. Results: 483 CCA samples underwent tissue NGS as standard of care. Pathogenic variants in HRD genes included ARID1A (15.5%, n=75), BAP1 (9.5%, n=46), ATM (2.7%, n=13), PALB2 (2.3%, n=11) and BRCA (2.0%, n=10), representing 31.7% (n=153) of the population. HRD mutations were found in similar proportions of localized (31.8%) and metastatic (31.5%) clinical presentations at diagnosis. OS was not significantly different between CCA with HRD mutations (12.3 mo WT vs. 13.8 months with HRD MT, p=64). KRAS MT (n=77, 15.9% of population) did not impact OS (WT 12.3 mo v. MT 13.1 mo) including subgroup analysis stratified by HRD status. There was increased frequency in KRAS MT with HRD WT 18.5% versus HRD MT10.4% (p<0.03). Additionally, there was increased frequency in TP53 MT with HRD WT 54.8% versus HRD MT 28.1% (p<0.00001). TP53 MT (n=224, 46.3% of population) conferred inferior OS (WT 12.3 mo v. MT 13.1 mo) including subgroup analysis stratified by HRD status. Subgroup analysis of TP53 MT had worsened OS with concurrent HRD MT (n=39, 4.1 mo) v. HRD WT (n=158, 9.0 mo; p<0.04). Conclusions: Across a diverse integrated healthcare system of Veterans, mutations associated with HRD were found to be common, however, not prognostic in OS across a diverse patient population of CCA. Further work is needed to clarify exposure to platinum containing chemotherapy. TP53 MT CCA remains a critical unmet need that drives worsened outcomes including here in patients with mutations in HRD. Future analysis should consider mutation signatures of HRD, loss in heterozygosity of HRD, and platinum exposure to further define the subgroups of CCA with mutations in HRD. [Table: see text]
Actionable molecular alterations in veterans with advanced cholangiocarcinoma.
Authors: Lin Ethan Samuel , Mehlhaff Eric G. , Bergstrom Colin P , Lesnik Dyan M. , LoConte Noelle K. , Lubner Sam Joseph , Matkowskyj Kristina A. , Patel Monica Arun , Ronnekleiv-Kelly Sean , Uboha Nataliya Volodymyrivna , Wachsmann Megan , Wang David H. , Lin Albert Y. , Kratz Jeremy D. 
Published: January 2024

548 Background: Cholangiocarcinoma (CCA) requires integrated efforts to understand the heterogeneity in available molecular targets. Chemotherapy remains a non-selective standard of care, however defining distinct populations with molecular actionability remains a critical need. The Veteran Health Administration’s (VHA) National Precision Oncology Program (NPOP) was established to characterize comprehensive genomic profiles across the integrated VHA network. Methods: Veterans with CCA underwent next-generation sequencing (NGS) with FoundationOne CDx, which enhanced sensitivity in the reporting of gene fusions. Analysis included dedicated chart review for date of diagnosis and survival utilizing the VHA’s Corporate Data Warehouse. Molecular alterations included mutations(mut), amplifications (amp) and fusion/rearrangements (fus). Log-rank Kaplan-Meier survival analysis was stratified by primary tumor location, and actionable driver alterations defined by VA Clinical Pathways. Results: Veterans diagnosed with CCA (07/2008-04/2023) underwent tissue-based NGS (n=483) including 96 unique VHA sites with male predominant population (96.9%). There was a predominance of localized disease at clinical presentation (55.3%). A summary of common pathogenic variants is provided (see table). Actionable alterations defined as IDH1mut, FGFR2fus, ERBB2amp, BRAFmut (V600E), and MSI-H collectively represented 21.1% of all Veteran CCA. The largest population was intrahepatic CCA (n=327) with actionable alterations including IDH1mut (13.5%), ERBB2amp (4.3%), and FGFR2fus (4.3%). Data suggested improved overall survival (OS) in IDH1mut Intrahepatic CCA including median OS 19.8 months (mo) v. 10.7 mo (p<0.03). ERBB2amp (n=32) was enriched in extrahepatic (8.1%) and gallbladder cancer (17.2%), however did not improve OS including 7.1 mo in ERBB2amp v. 13.2 mo in wildtype (p=0.15). PIK3CAmut CCA (n=35) was found to confer inferior OS across the population with median OS of 7.5 mo v. 13.2 mo in wildtype (p<0.02). Additional pathologic mutations in genes of homologous recombination deficiency (31.7%), PIK3CA (7.2%), and amplifications in MDM2 (5.0%). Conclusions: Across an integrated healthcare system of Veterans, actionable molecular alterations from VA Pathways were seen in 21.1% of the population. Further data is needed to clarify the prognostic versus predictive value of integrated precision-based strategies in clinical practice. The Veteran population includes important molecular subtypes to consider in future prospective trial design. [Table: see text]
Developing a comprehensive cell-free DNA (cfDNA) epigenetic signature (ep-Sig) with diagnostic and prognostic value in hepatocellular carcinoma (HCC).
Authors: Manne Ashish , Jogi Soumya , Jeepalyam Sravan , Esnakula Ashwini K. 
Published: January 2024

553 Background: HCC is one of the deadliest tumors with poor outcomes often diagnosed in late stages. Current surveillance strategies (alfa-fetoprotein (AFP) plus ultrasound (USG)) for high-risk population (HRP) have poor sensitivity (SN) and reasonable specificity (SP) of 61% and 92%, respectively. Triple phase computed tomography (CT) imaging has good sensitivity and specificity (≈ 90% for both) but the evidence does not support its use for routine surveillance. All these modalities do not have prognostic (survival) value. We attempted to develop a non-invasive, cfDNA-based tests to improve the diagnostic value of the current standard of care modalities (AFP and USG) and help in predicting the outcomes at diagnosis. We hypothesized that RNA and gene expression in HCC tissues is a surrogate for epigenome (DNA-methylation changes). Methods: We curated a 21-gene cfDNA ep-Sig from the literature with a proven prognostic value. Evidence suggests epigenetic changes in every gene of this panel affect HCC outcomes influencing clinicopathological characteristics (large tumor size, vascular invasion, advanced staging) or early post-operative recurrence, and survival. We compared RNA and gene expression of the genes in the ep-Sig between normal (NT) and HCC tissues using a web-based tool, TNMplot.com that uses the data from the Gene Expression Omnibus of the National Center for Biotechnology Information (NCBI-GEO) or Cancer Genome Atlas (TCGA), Therapeutically Applicable Research to Generate Effective Treatments (TARGET), and The Genotype-Tissue Expression (GTEx) repositories was used create this tool. It uses Mann-Whitney or Kruskal-Wallis tests to compute statistical significance. Results: RNA expression of all the genes from the ep-Sig was significantly higher in HCC than NT (1.133, p=5.84e-15). Gene expression was 19/21 genes was higher in HCC tissues (1.15, p=1.3e-08). The other 2 genes were not detected in the tested samples. Conclusions: Our ep-Sig which has a proven prognostic value and reliable prevalence in HCC patients. This study is the first step in developing clinically useful blood-based test that can revamp the current diagnostic and screening practices when used alongside AFP and USG.
Impact of next-generation sequencing in biliary tract cancer treatment.
Authors: Goyal Priya , Ouf Mahmoud , Agarwal Seema , Kupfer Gary , Mukherji Reetu , Weinberg Benjamin Adam , Noel Marcus Smith , Marshall John , He Aiwu Ruth 
Published: January 2024

560 Background: Incorporating molecular profiling in BTC treatment has increased. With this study, we aimed to analyze the impact of molecular profiles on the survival of patients with BTC. Methods: This is the retrospective analysis of patients with biopsy-proven biliary tract cancer at our comprehensive cancer center GI oncology clinic from 2018-2022. Only patients with continued care at Lombardi Comprehensive Cancer Center were included in the study. Results: Of 217 patients screened; 160 patients were included in the final analysis. The mean age of the cohort was 63 years, and the majority were females (55%). In the order of frequency, intrahepatic cholangiocarcinoma (77.5%) was the most common type of cancer followed by extrahepatic cholangiocarcinoma (15.6%), and carcinoma of the Gallbladder (6.9%). Molecular profiling was performed in 49.4% of the patients and actionable mutations for FDA approved treatments or clinical trial enrollment were found in 42 patients (26.3%) of the patients. The spectrum of actionable mutations in decreasing order of frequency was KRAS (n=11), FGFR2 (n=9), IDH-1 (n=8), Her-2neu (n=5), BRCA1/2 (n=5), & PD-L1(n=4). Patients who underwent molecular profiling had significantly better survival (43±5 months vs. 25±4, p 0.013). Notably, patients with actionable mutations had even better survival as compared to the rest of the cohort (52±8 months vs. 26±7 months, p 0.019). Conclusions: BTC exhibits diverse genetic alterations. Patients who underwent molecular profiling as a part of the treatment plan had better survival. Identifying actionable mutations was associated with even better survival.
Preoperative risk factors related to relapse-free survival after R0 resection of gallbladder cancer.
Authors: Lee Sang Hun , Seol Yong Mi , Kim Dong Uk 
Published: January 2024

566 Background: Gallbladder (GB) cancer shows high prevalence in South Korea, and tends to be fatal. In surgically fit patients, radical resection aiming R0 margin combined with lymphadenectomy is the mainstay of curative-intent therapy. In spite of R0 resection, however, high recurrence rate is observed in GB cancer, demanding a need to find out risk factors related to recurrence after surgery. Methods: This is a single center, retrospective cohort study conducted on 148 patients with GB cancer who underwent R0 resection between January 1st, 2014 and December 31st, 2019. Several variables were analyzed with statistical tools to identify risk factors related to prognosis. Relapse free survival (RFS), defined as time from treatment of disease to any event, was analyzed with Cox regression analysis. Results: Based on statistical analysis, risk factors related to RFS were age over 65 (hazard ratio [HR] 3.82, 95% confidence interval [CI] 1.71 – 8.56, p= .001), glycated hemoglobin (HbA1c) level more than 6.5% (HR 2.72, 95% CI 1.31 – 5.66, p=0.007), surgical T stage more than T3 (HR 5.60, 95% CI 3.05 – 10.25, p<0.001), surgical N stage more than N1 (HR 4.07, 95% CI 2.25 – 7.36, p<0.001), pathologic differentiation of moderate or poor differentiation (HR 2.80, 95% CI 1.46 – 5.37, p=0.002), reversed albumin-globulin ratio (HR 0.16, 95% CI 0.06 – 0.40, p<0.001), and high gamma glutamyl peptidase (GGT) level (HR 1.00, 95% CI 1.00 – 1.00, p<0.001). Conclusions: Advanced pathologic stage and high inflammatory marker levels, reflecting high tumor burden, were related with poor surgical outcome. Interestingly, high HbA1c level was related to reduced RFS as well. In conclusion, active screening for early detection, reducing inflammatory conditions, and managing diabetes might enhance RFS after R0 resection of GB cancer. [Table: see text]
A novel image-guided laparoscopic liver resection with integrated fluorescent imaging and artificial intelligence: A preliminary study.
Authors: Tashiro Yoshihiko , Aoki Takeshi , Kobayashi Nao , Kumazu Yuta , Tomioka Kodai , Saito Kazuhiko , Yamazaki Tatsuya , Hirai Takahito , Shibata Hideki , Date Hiromi , Watanabe Ryohei , Matsuda Kazuhiro , Kusano Tomokazu , Yamazaki Kimiyasu , Watanabe Makoto 
Published: January 2024

568 Background: Technology innovations improve surgical techniques. ICG fluorescence imaging is beneficial for real time navigation tool during surgery and enables accurate surgery. Recently, the prediction of anatomical structures by artificial intelligence (AI) is expected to support surgeons as navigation tool. We developed a visual-support AI system to perform the laparoscopic liver resection (LLR) using ICG fluorescence imaging and AI technology. Methods: Procedure: ICG fluorescence imaging was used for liver mapping and securing surgical margin. AI model development and evaluation: Over 430 images extracted from 13 videos of LLR for hepatocellular carcinoma and colorectal liver metastasis was used to develop and evaluate the AI algorithm at Anaut Inc. The annotation was performed on video frames capturing a LLR performed by 2 surgeons for hepatic vein and Glisson sheath. The performance of AI on unlearned LH videos was evaluated quantitatively using Intersection-Over-Union (IOU) and Dice coefficients, and qualitatively on a five-point scale (from 1 to 5) by 10 hepato-biliary-pancreatic surgeons using 35 randomly extracted still images from the analyzed videos. Results: ICG fluorescence imaging could visualize the demarcation line and clarified the boundaries of the liver transected surface. The hepatic veins and Glisson sheath were appeared in the parenchymal transection plane during segmentectomy and securing surgical margin, and this AI system enabled to recognize and display these vascular structures through color-coding under bleeding and ICG fluorescent imaging without visual discrepancies. The AI model accurately recognized vascular structures of any size (IoU=0.33, Dice=0.44) in real-time (<0.12 s) In the qualitative evaluation by surgeons, the mean sensitivity score was 4.10 ± 0.92 (range 3.61–4.76). Additionally, this AI system also recognized vascular structures during robot-assisted liver resection. Conclusions: This is the first study demonstrating that AI can precisely identify vascular structures during LLR. Novel image-guided LLR using ICG fluorescent imaging and artificial intelligence is expected to provide safer and more accurate LLR, thereby contributing to reduce complications and improve survival rates.
Risk of relapse after surgical resection of localized appendiceal adenocarcinoma.
Authors: Fanaeian Mohammad Mahdi , Yousef Mahmoud M.G. , Yousef Abdelrahman M.G. , Foo Wai Chin , Taggart Melissa , Beaty Karen A. , Scally Christopher , Mansfield Paul F. , Fournier Keith F. , Helmink Beth A , Shen John Paul Y.C. 
Published: January 2024

58 Background: Appendiceal adenocarcinoma (AA) encompasses a heterogenous mix of histologic subtypes and frequently presents with peritoneal metastases. Data regarding the risk of relapse after surgical resection in patients with localized AA (stages I–III) is limited. More accurate evaluation of features predictive of relapse is critical to counsel patients, determine follow-up, and guide decisions regarding adjuvant therapy. Methods: The Foundry software platform was used to query the MD Anderson Cancer Center (MDA) Electronic Health Record database to identify and extract clinical information from AA patients presented to MDA from 2004 to 2023. Results: We identified 296 patients with localized AA, split into two cohorts: patients who underwent surgery at MDA (n=133) and patients with surgery at an outside institution later referred to MDA (n=163). The most common histologic subtypes were mucinous (n=124, 41.9%) and goblet (n=121, 40.9%) with less frequent colonic-type (n=42, 14.2%) and signet ring cell (SRC, n=9, 3%). With a median follow-up of 47 months, the relapse rate (RR) for the MDA surgical cohort was only 6% (n=8), with a median time to relapse of 24 months (range=8-74). Evaluating all 296 localized AA patients, histologic subtype was significantly associated with risk of relapse, with goblet AAs having lowest risk (6%, n=7), followed by colonic-type (12%, n=5), mucinous (27%, n=33), and SRC (44%, n=4; overall P< 0.001), with a median time of relapse of 26 months (range=3-96). Patients with a positive LN, higher grade, and/or higher T stage showed a higher RR (Table). Use of adjuvant chemotherapy (AC) was not associated with RR in our cohort, with odds ratio trending towards increased risk of relapse (14.4% vs 19.2%, OR=1.4, 95% CI=0.76-2.6; P=0.27). Restricting to only high-risk patients (poorly differentiated, LN-positive, and/or T4, n=205), similar results were observed with 18.4% (n=17) relapsed without AC vs 19.4% (n=22) relapsed with AC (OR=1.06, 95%CI=0.52-2.15; P=0.85). AC was also not associated with improved RFS (HR=1.2, 95%CI=0.63-2.2, P=0.59). Conclusions: Patients with localized AA who undergo surgical resection have a low risk of relapse, especially those with goblet AA. This retrospective analysis did not identify a benefit from adjuvant chemotherapy. Considering the clear histologic and molecular differences between AA and CRC, these data call into question the current practice of applying CRC data to guide AC decisions in AA. Prospective clinical trials of AC in AA, stratified by histologic subtype, are urgently needed. [Table: see text]