bluuebunny/crossref_metadata_2025_split huggingface dataset:
Clinical utility of immunotherapy hyperprogressive genes in hepatocellular carcinoma patients.
Authors: Wang Run , Lou Luyan , Guo Zhaoxia , Zhang Yanrui , Zhang Yun , Lou Feng , Cao Shanbo , Wang Huina 
Published: June 2022

e16126 Background: Hepatocellular carcinoma (HCC) is the most common liver malignancy associated with poor prognosis. With the rapid development of systematic therapy for liver cancer, immunotherapy has been widely used in therapy of liver cancer. Hyperprogression of tumor is a phenomenon of accelerated tumor growth, which occurs in patients with liver cancer and other solid tumors receiving systematic treatment, and is mainly related to immunotherapy hyperprogression genes. However, it is still unclear about the genes of immune hyperprogression in HCC patients. Therefore, we studied the molecular characteristics of HCC patients, including the genes related to immunotherapy hyperprogression. Methods: From June 2019 to August 2021, 102 patients with HCC were inculded in this study. Matched tumor/normal DNA from HCC patients (N = 102) were analyzed by whole exome sequencing (WES) or Acornmed panel with 808 cancer-related genes. Results: Overall, 86.3% (88/102) patients exhibited genetic alterations. TP53 (50%), TERT (23%), CTNNB1 (18%) and KMT2C (14%) were the most commonly mutated genes in HCC. In addition, 8.9% patinets harbored at least one immunotherapy hyperprogressive gene mutations, including CCND1 (7%), FGF19 (6%), FGF3 (5%), FGF4 (5%) and MDM4 (2%). In addition, CCND1 and FGF19 were frequently mutated genes in patients with liver cancer, ranking ninth and tenth, respectively. Compared with the TCGA data, there was no significant difference in immunotherapy hyperprogressive genes (25% vs 32.3%, p = 0.18). Interesting, CCND1, FGF19, FGF3 and FGF4 mutations occurred simultaneously in most patients and were mutually exclusive with MDM4 (p = 0.057). Conclusions: This study contributes to understand the molecular characteristics of patients with HCC, which will be useful to guide immunotherapy and promote the clinical management in this population. Furthermore, the study suggested that both Chinese and Western populations should pay attention to immunotherapy hyperprogression genes in immunotherapy selection.
Does acute cholangitis impact outcomes of cholangiocarcinoma? Insights from a nationwide database.
Authors: Lee Raymond , Franco Diana , Farooq Umer , Chattaraj Asmi , Rehman Mohammad Ebad Ur , Anwer Faiz 
Published: June 2022

e16138 Background: Cholangiocarcinoma is a malignancy associated with poor survival and outcomes. Structural abnormalities causing bile duct obstruction frequently lead to superimposed acute cholangitis (AC). We evaluated the impact of AC on hospitalized patients with cholangiocarcinoma. Methods: We investigated National Inpatient Sample 2019, employing International Classification of Diseases-10 (ICD-10) codes to include adult patients with cholangiocarcinoma. Analyses were performed using STATA (v 14.2), considering 2 sided P< 0.05 as statistically significant. Proportions were compared using Fisher exact test and continuous variables using Student’s t-test. Confounding variables were adjusted using multivariate logistic and linear regression analyses and included: gender, race, Charlson Comorbidity Index (CCI) score, median household income for patients’ zip codes, hospital location/region/ bedside, and insurance status. Results: A total of 36,900 patients were included in the analysis. Of those 15.26% (5,630) had AC on presentation (Table). Concomitant AC was associated with a higher adjusted length of stay (LOS) by 1.78 days and hospitalization cost by 3,028 USD in cholangiocarcinoma patients ( P< 0.01). There were higher adjusted odds of acute renal failure (Adjusted odds ratio (aOR) 1.31, P< 0.01) and lower odds of aspiration pneumonia while hospitalized in AC patients (aOR 0.37, P< 0.01). ERCP represented the primary technique of biliary drainage. No disparities were seen between the two groups undergoing ERCP or cholecystostomy tube, which resulted in comparable mortality trends ( P> 0.05). Rates of acute respiratory failure, mechanical ventilation, ICU admission, cardiac arrest, and sepsis were not different between the two groups ( P> 0.05). Conclusions: Unbiased and comparable biliary drainage via either ERCP or cholecystostomy resulted in observing no mortality differences between the two groups. However, superimposed AC in cholangiocarcinoma patients results in higher LOS driven by acute renal failure.[Table: see text]
Systematic literature review and meta-analysis of clinical outcomes for previously-treated patients with advanced biliary tract cancer.
Authors: Amonkar Mayur , Frederickson Andrew , Grira Torkia , Fox Grace , Gozman Alexander , Malhotra Usha , Malbecq William , Jin Fan , Abderhalden Lauren 
Published: June 2022

e16143 Background: There is no standard chemotherapy available for previously treated, advanced (unresectable and/or metastatic) biliary tract cancer (BTC). This systematic literature review and meta-analysis were conducted to assess clinical outcomes of chemotherapies in this patient population. Methods: A systematic literature search was conducted through mid-2021 to identify relevant studies using Embase, MEDLINE, and Cochrane Central Register of Controlled trials (January 1, 2000–July 6, 2021) with additional searches of recent ASCO and ESMO conferences. Eligible study designs included randomized controlled trials, controlled clinical trials, and non-randomized clinical trials in patients (≥18 years age, Eastern Cooperative Oncology Group performance score 0 or 1) previously treated for advanced BTC and who had progressed on prior treatment (i.e., ≥2L). The outcomes of interest were objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). A meta-analysis among chemotherapies was performed to obtain a pooled estimate of the efficacy of standard treatments in BTC. The ORR meta-analysis was performed using the Freeman-Tukey double arcsine transformation. For time-to-event outcomes, published Kaplan-Meier curves for OS and PFS were digitized to create pseudo- individual patient data. A meta-analysis of the resulting pooled survival curves for OS and PFS were conducted following the methodology of Combescure et al. (2014). Results: In total, 39 unique studies were identified. Seventeen studies representing 22 unique therapy arms evaluating chemotherapies among 903 patients were included in the meta-analysis for ORR. The random effects pooled estimate for ORR was 6.6% (95% confidence interval [CI]: 4.1-9.7%). Median PFS (12 studies; 16 survival curves) was 3.1 months (95% CI: 2.5-3.8) with PFS rates at 6 and 12 months of 26.7% (95% CI: 19.8-36%) and 6.9% (95% CI: 4.1-11.7%), respectively. Median OS (15 studies; 19 survival curves) was 6.8 months (95% CI: 5.9-7.5) with OS rates at 6, 12, and 24 months of 55.3% (95% CI: 49.9-61.3%), 24.6% (95% CI: 20.0-30.2%), and 2.0% (95% CI: 1.1-3.8%), respectively. Conclusions: The limited efficacy of clinical outcomes for chemotherapies used in the treatment of advanced BTC suggest an opportunity to explore the potential clinical benefits of newer treatments (e.g., immunotherapies).
Efficacy of camrelizumab and apatinib combination therapy versus apatinib only in treatment of advanced hepatocellular carcinoma: A meta-analysis.
Authors: Swed Sarya , Motawea Karam R , AbdelQadir Yossef Hassan , Gamal Mohamed , El-Sakka Amro A , Kandil Omneya A , Abdelazeem Basel , Abdelaziz Muhammad , Wahsh Engy A 
Published: June 2022

e16147 Background: Recent studies have assessed the efficacy of some therapeutics in advanced hepatocellular carcinoma. Our aim is to perform a meta-analysis to compare the efficacy of Camrelizumab and Apatinib combination therapy versus Apatinib only in treatment of advanced hepatocellular carcinoma. Methods: We searched PubMed, WOS, Embase and Scopus databases. Inclusion criteria were clinical trials and cohort studies that evaluated the efficacy of Camrelizumab and Apatinib combination therapy or Apatinib only in treatment of advanced hepatocellular carcinoma. We excluded case reports, conference abstracts, editorials and animal studies. CMA software (version 3) was used to perform the meta-analysis. Continuous outcomes were presented as (mean and SD) and dichotomous outcomes as event ratio(ER), with 95% confidence interval (CI). Results: After complete screening, 12 studies were finally included in our study. 4 studies for combination of Camerlizumab and Apatinib while 8 studies investigated the role of Apatinib in patients with advanced hepatocellular carcinoma. The total number of patients included in the study is 844; 172 in combination group and 672 in Apatinib group. By indirect comparison, combination therapy is associated with a relatively better pooled survival rate (ER = 0.532, 95% CI [0.446, 0.615]) compared to Apatinib only therapy (ER = 0.262, 95% CI [0.218, 0.313]). Combination therapy was also associated with higher pooled rates of disease control (ER = 0.755, 95% CI [0.683, 0.815]) compared with Apatinib only (ER = 0.683, 95% CI [0.644, 0.720]). While the Combination therapy was associated with lower pooled rate of stable disease (ER = 0.13, 95% CI [0.339, 0.491]) than Apatinib (ER = 0.531, 95% CI [0.492, 0.570]). The overall survival time was significantly higher in combination therapy (Mean = 14.375, 95% CI [14.101, 14.649]) compared to the pooled mean survival time from Apatinib only therapy (Mean = 10.390, 95% CI [9.925, 10.855]). Conclusions: This study showed that Camrelizumab and Apatinib combination therapy is associated with increased survival rate, disease control and overall survival time in advanced hepatocellular carcinoma patients compared with Apatinib only. It revealed also that combination therapy is associated with lower stable disease than Apatinib only. Further multicenter clinical trials are needed to support our results.
Characterization analysis of gut and bile microbiota for cholangiocarcinomas.
Authors: Zhu Wenwen , Zhang Ningning , Wang Zeyu , Zhang Shuwen , Yue Xiaofen , Sun Linlin , Sun Jiao , Gong Lan , El-Omar Emad M , Lu Wei 
Published: June 2022

e16150 Background: Cholangiocarcinomas (CCAs), which derive from the epithelial cells of the biliary tree, constitute a serious and growing health problem worldwide. Gut and bile microbiota have not been characterized in patients with CCA, and better noninvasive diagnostic approaches for CCA are essential to be established. CA19-9 was the most commonly used tumor marker for CCA; nevertheless, the forecasting performance of CA19-9 remains unsatisfactory. The aim of this study was to investigate the characteristics of gut and bile microbiota combined with CA19-9 in CCA patients. Methods: Fecal samples were collected from 42 CCA patients (16 of the total with Bile samples) and 16 healthy normal controls (HNC). 42 CCA patients were divided into three group according to CA19-9 levels: CCN (CA19-9 negative),CCP (CA19-9 positive: CPL (CA19-9 positive within 10 times) and CPH (CA19-9 positive over 10 times)) groups. DNA was extracted from fecal and bile samples and subjected to 16S rRNA gene analysis. The correlation between gut microbiota and clinical data in CCA group were further analyzed with Spearman rank correlation analysis. Results: Comparing with HNC group, the relative abundance of Firmicutes and Actinobacteriota were significantly decreased, whereas Proteobacteria and Bacteroidota were significantly enriched in CCA group at phylum level (all P < 0.01). Interestingly, Firmicutes/Bacteroidota (F/B) ratio significant decreased in CCA group compared to HNC group(P < 0.05). CA19-9 were inversely correlated with Bifidobacterium, which in turn was associated with Klebsiella in CCA patients. Especially the relative abundance of Klebsiella in CCP group was significantly enriched than CCN group(P < 0.05). Conclusions: Our findings provide evidence supporting Klebsiella may serve as a non-invasive intestinal microbiomarker for CCAs. Combinating with CA19-9, Klebsiella may improve the diagnosis of CCAs as non-invasive approach. Bifidobacterium is likely to be a potential protective factor for anti-tumorgenesis of CCAs.
Plasma cell-free DNA integrative analysis for early detection of hepatocellular carcinoma.
Authors: Nie Peiyao , Lv Fang , He Shuying , Han Tiancheng , Yang Shunli , Suxing Li , Liu Dan , Yang Ying , LI Yulong , Huang Yu S. , Hong Yuanyuan , Chen Weizhi , Yu Jianing , Tan Hai Dong 
Published: June 2022

e16173 Background: Cell-free DNA (cfDNA) methylation, fragmentation patterns, chromosome instability, and chromatin accessiblity have been previously shown to be valid plasma biomarkers for non-invasive cancer detection. However, conventional whole-genome bisulfite sequencing (WGBS) is unable to simultaneously profile all these biomarkers due to bisulfite-induced DNA damages. Here we developed a machine learning approach to comprehensively integrate multiple types of cancer genomic markers from enzyme-conversion-based low-pass whole-methylome sequencing (WMS) of plasma cfDNA to non-invasively detect hepatocellular carcinoma. Methods: Plasma cfDNA sampels from 127 cancer patients and 568 healthy individuals were collected and were split into the discovery and independent testing cohort. The discovery cohort includes 90 cancer patients and 398 healthy individuals and the independent testing cohort includes 37 cancer patients and 170 healthy individuals. Whole methylome sequencing (WMS) libraries were generated from enzymatically converted cfDNA and were subsequently paired-end sequenced at ̃2X coverage. The genome-wide methylation density, fragmentation fingerprints, chromosome instability, and chromatin accessibility were extracted from the WMS data and individually modelled via machine learning methods such as SVM, LR, GBDT, random forest. The final predictive model is an ensemble model integrating all uni-modal models. All models were trained and fitted on the discovery cohort. Results: Data of different modalities provide complementary information in separating the cancer patients from the healthy individuals. Unsupervised clustering of the individuals showed clear separation between cancer patients and healthy individuals. The final predictive model achieved AUC =0.979 in the discovery cohort and AUC =0.98 in the independent testing cohort. Under a specificity of 96.23%(CI: 86% - 87%), sensitivity was 86% (CI: 85% - 88%) in the independent testing cohort. Separating the cancer patients into different stages, we found that the detection power is usuaul lower for early-stage cancer patients. Conclusions: These results demonstrate the first proof of principle on the feasibility of integrating multiple genomic cancer markers to non-invasively detect hepatocellular carcinoma from WMS plasma cell-free DNA. A large prospective cohort study is planned to further validate its clinical performance.
Biomarker analysis of first-line sintilimab plus gemcitabine and cisplatin in patients with advanced biliary tract cancers: Results from a phase II study.
Authors: Yuan Zhen-gang , Zeng Tian-mei , Tao Chen-jie , Yang Guang , Xu He-ming , Wei Wei , Chen Xi-yun , Cheng Zhuo , Dong Yu-long , Shang Pei-pei , Lou Cheng , Han Qin , Chen Dong-sheng , Song Yunjie 
Published: June 2022

e16189 Background: The overall efficacy of immunotherapy for advanced biliary tract cancers (BTCs) was still poor, exploring the potential biomarkers associated with tumor response in advanced BTCs may further improve the clinical benefits from immunotherapy. Methods: Twelve patients from a phase 2 clinical trial (ChiCTR2000036652), which evaluated the efficacy and safety of sintilimab (anti-PD-1 antibody), plus gemcitabine and cisplatin as first-line treatment in advanced BTC patients, were included in the current biomarkers analysis. Exploratory points mainly focused on differentiated immune-related gene expression and immune pathway signatures using a 289-gene immune-related RNA panel sequencing on baseline tumor samples. Differential gene expression analysis was performed between responders (tumor regression) and non-responders (tumor extension) using Wilcoxon rank-sum test. Signature scores were calculated using the Gene Set Variation Analysis package with publicly available gene signatures. Results: Twelve patients (8 responders vs. 4 non-responders) who had available clinical response evaluations with RNA-sequencing data on baseline tumor samples were included in the current biomarkers analysis. Differential gene expression analysis revealed a significantly increased CXCL10, CXCL13 expression (p < 0.001) and decreased MAGEA12 expression (p < 0.001) in responder tumors compared with non-responder tumors. Differentiated genes were significantly enriched in cytokine-cytokine receptor interaction and interleukin-17 signaling pathway in responder tumors. Extensive analyses on immune pathway signatures showed that higher expression of IFN-γ-related genes (p = 0.048) and T cell-inflamed genes (p = 0.016) were associated with response to immunocombination therapy. Meanwhile, immune cell types score was also calculated, no notable differences were found between defined groups. Conclusions: Some differentially expressed genes were investigated in responder tumors compared with non-responder tumors. Higher expression of IFN-γ-related genes and T cell-inflamed genes could potentially predict the effect of immunocombination therapy. Potential biomarkers are needed to identify patients who respond to sintilimab plus gemcitabine and cisplatin in a larger validation cohort. Clinical trial information: ChiCTR2000036652.
Neutrophil-to-lymphocyte ratio (NLR), derived neutrophil-to-lymphocyte ratio (dNLR) and lymphocytes counts as a possible prognostic factor in neuroendocrine tumors of the gastrointestinal tract.
Authors: Androsova Alexandra , Orlova Rashida , Ivanova Anastasia , Beliak Natalia P. , Kutukova Svetlana 
Published: June 2022

e16207 Background: The aim of our study was to investigate the prognostic role of the neutrophil to lymphocyte ratio (NLR), derived neutrophil to lymphocyte ratio (dNLR), platelet to lymphocyte ratio (PLR), and lymphocyte to monocyte ratio (LMR) in PFS and OS of patients with neuroendocrine tumors (NETs) of the gastrointestinal tract. Methods: We analyzed medical records of 69 patients with stage I - IVB NETs of the gastrointestinal tract (25 men, 44 women; median age is 57 years [44.75-66.00]). All patients were treated according to the standard protocols from 2015 till 2020. We examined demographics, clinical stage, tumor morphology, and baseline levels of leukocytes, neutrophils, lymphocytes, monocytes, and PLT. We also analyzed the calculated value of NLR, dNLR, PLR and LMR. Results: The ROC analysis made it possible to determine that the factors, that have a significant impact on the PFS indicator are: absolute (cut-off: ≤2.26; p = 0.0274) and relative (cut-off: ≤30; p = 0.0158) lymphocyte count, NLR (cut-off: 1.85; p = 0.0230) and dNLR (cut-off: 1.40; p = 0.0209). The median PFS of patients whose baseline absolute lymphocyte count 2.26x109/l or less was 34.0 months and was significantly (61%) less than the median PFS in the group of patients with an absolute lymphocyte count greater than cut-off value (p = 0.0122; HR = 0.39: 95% CI 0.19-0.81). The median PFS of patients with relative lymphocyte count £30% was 25.0 months and was significantly (61%) less than the median PFS in the group of patients with lymphocyte count > 30% (p = 0.0082; HR = 0.39: 95% CI 0.20-0.79). The median PFS of patients with NLR > 1.85 was 26.0 months and was significantly (60%) less than the median PFS in the group of patients with NLR1≤.85 (p = 0.0095; HR = 0.40: 95% CI 0.21-0.80). The median PFS of patients with dNLR > 1.40 was 20.0 months and was significantly (60%) less than the median PFS in the group of patients with dNLR≤140 (p = 0.0120; HR = 0.40: 95% CI 0.20-0.82). In multivariant analyses, which contained all significance factors by univariate analysis, count of lymphocytes: lymphocytes≤30% significantly increased the risk of disease progression: p = 0.0344; HR = 0.97; 95% CI 0.94-0.99. Conclusions: Systemic inflammatory markers have demonstrated their diagnostic and predictive value in patients with neuroendocrine tumors of the gastrointestinal tract.
Anlotinib for the treatment of locally advanced or metastatic pheochromocytoma and paraganglioma: A retrospective study.
Authors: Tian Rui , Yao Xiaochen , Wang Jun , Fu Jingjing , Song Jieping , Shi Liang , Yu Fei , Zhang Pengjun , Ni Yudan , Wang Feng 
Published: June 2022

e16209 Background: Pheochromocytomas (PCC) and paragangliomas (PGL) are rare hyper-vascular neuroendocrine tumors derived from the adrenal medulla and paraganglia, respectively. In previous studies, the overall survival at 5 years for patients (pts) with metastatic disease was only 50% to 60% after the diagnosis of metastases. Anlotinib is a novel multikinase inhibitor targeting VEGFR, PDGFR, FGFR, and c-Kit. This study investigated the efficacy and safety of anlotinib monotherapy or in combination with other therapies in treating locally advanced or metastatic (LA/M) PCC and PGL. Methods: Pts with histologically or cytologically confirmed unresectable or progressive LA/M PCC or LA/M PGL were enrolled from March 2020 to October 2021. The inclusion criteria contained: (a) age 18 or older, (b) ECOG performance status 0–2, (c) adequate organ and marrow function. Eligible pts received anlotinib monotherapy or in combination with peptide receptor radionuclide therapy (PRRT) or 131I-MIBG. Anotinib was given orally 12 mg once daily (d1-d14, q3w) until the disease progression or the intolerable toxicities. Tumor response was assessed according to RECIST1.1. Results: 35 pts were enrolled (Table) and 25 were assessed for tumor response. Among them, 17 received anlotinib alone, others were treated with the combination regimen, including 6 with PRRT, and 2 with 131I-MIBG respectively. At the data cut-off date on January 15th, 2022, 4 pts progressed and 1 died. The median duration of treatment was 8.5 months. 10 pts (40%) achieved partial response (PR) and the stable disease (SD) was observed in 13 pts (52%). The objective response rate (ORR) for 25 pts was 40% and the disease control rate (DCR) was 92%. For pts with PCC and PGL, the ORR was 33.3% and 46.2%, respectively. All pts were assessed for safety. The most common adverse events (AEs) included: malaise (23 pts, 65.7%), palmar-plantar erythrodysesthesia syndrome (PPE) (23 pts, 65.7%), hypertension (22 pts, 62.9%) and oropharyngeal pain (17 pts, 48.6%). The most common grade 3 or worse AEs were hypertension (15 pts) and PPE (4 pts), which were claimed tolerable by the pts. Conclusions: This single-center retrospective study indicated that anlotinib monotherapy or in combination with radionuclide therapy showed promising efficacy and favourable safety profile in the treatment of LA/M PCC and PGL, which is worthy of further exploration.[Table: see text]