bluuebunny/crossref_metadata_2025_split huggingface dataset:
Epidemiology and patterns of care of intrahepatic cholangiocarcinoma (iCCA) in France: Real-life data from the French National Hospital‐Discharge Summaries Database System (PMSI).
Authors: Neuzillet Cindy , Emery Corinne , Teissier Clément , Bouée Stéphane , Lièvre Astrid 
Published: May 2020

e16624 Background: Little is known about epidemiology and patterns of care of iCCA in daily clinical practice. The aims of this study were to estimate from real-life data the incidence of iCCA in France and to describe the healthcare pathways of these patients (pts). Methods: A retrospective analysis was carried out using the nationwide prospective French PMSI database. All pts with a new diagnosis of "carcinoma of the intrahepatic bile duct" who had a 1st hospital stay in Medicine, Surgery and Obstetrics departments (MSO) between 2014 and 2015 with a 2-year follow-up were included. Data related to the 1st identified stay (S1) in MSO and on all subsequent stays in MSO, Aftercare and Rehabilitation (SSR) or Home Hospitalizations (HAD) were analyzed. Results: A total of 3,650 new iCCA cases were identified. At S1 (admission via emergency room [ER] in 28%), median age of pts was 73y, 57% were male and 35% had metastases. Jaundice/anemia/ascites/cholangitis were reported in 17%/16%/12%/7%, respectively. Pts care at S1 was mainly provided in general hospitals (CHG, 60%), rather than university hospitals (CHU, 15%), private (20%) or cancer centers (CLCC, 6%). 896 (24%) pts died during S1: they were more frequently hospitalized via ER (48% vs 23%), metastatic (52% vs 35%) and symptomatic. Subsequent stays were identified for 2,507 pts (69%). Similarly to S1, most pts were managed in CHG during their follow-up (70% vs 20% in CHU and 12% in CLCC). Based on the number of pts treated over the study period, centers were classified as low (≤5 pts, 68%), intermediate (5-20 pts, 26%) and high volume ( > 20 pts, 6%). 47% of the high-volume centers were CHU/CLCC. Three healthcare pathways were defined: surgery (n = 519; 14%), chemotherapy (CT) without surgery (n = 812; 22%) and best supportive care (BSC) (n = 2,319; 63%). CT, surgery and BSC were most frequently performed in CLCC, CHU and CHG, respectively. Pts who received CT (mean time between S1 and start of CT: 1.9 months) were younger, less frequently hospitalized via ER and less symptomatic at S1. A palliative care code was associated with S1 in 25% of pts and with a subsequent MSO/SSR/HAD stay in 60%. Conclusions: This real-life, medico-administrative study, covering all hospitalized patients in France, reveals a higher incidence of iCCA than that previously reported by cancer registries. It also highlights the severity of this disease, the central role of CHG in the management of pts and the expertise of CHU and CLCC for surgery and CT, respectively.
The mutation profiles of HBV or HCV infected hepatocellular carcinoma patients underlie the varied responses to second-line immunotherapy.
Authors: Duan Jingxian , Mu Tianhao , Chen Shifu 
Published: May 2020

e16629 Background: HBV and HCV infections facilitate the development of hepatocellular carcinoma (HCC) via different mechanisms, given that the DNA sequence of HBV but not HCV can integrate into the host genome. However, it remains unclear that whether the altered genomic landscape of HCC patients caused by HBV or HCV infection may result in different responses to treatments. Methods: The MSK panel sequencing results and treatment data of 127 HCC patients were downloaded from the TCGA database (MSK, Clin Cancer Res 2018). Profiles of HBV positive and HCV positive patients were extracted. Based on the treatment received, those patients were classified to sorafenib treated groups and sorafenib + immunotherapy (IT) groups. The progression-free survival (PFS, months) and overall survival (OS, months) were compared, and the mutational profiles of patients were analyzed. Results: Among patients who received sorafenib treatment alone, the mean PFS of HBV positive patients (n = 12, 4.9 ±1.1) is similar to that of the HCV positive patients (n = 21, 5.1±1.8). However, the mean OS of HBV positive patients (n = 12, 18.3 ±6.6) was longer than the mean OS of HCV positive patients (n = 21, 10.0 ±1.9). Among the patients who received immunotherapy following sorafenib treatment, the mean IT PFS of HBV positive patients was (n = 5, 4.4 ±1.8), which was longer than the mean IT PFS of HCV positive patients (n = 5, 2.5 ±0.5). Consistently, the mean IT OS of HBV positive patients (n = 5, 10.9 ±4.4) was longer than the mean IO PFS of HCV positive patients (n = 5, 4.6 ±1.0). Overall it seems that the HBV positive patients responded better to second-line immunotherapy, despite the fact that these comparisons did not reach statistical difference due to the limited sample size. By comparing the MSK panel sequencing results, mutations exclusive to the HBV or HCV infected groups were identified. Enrichment analysis showed that 7/35 mutations exclusively found in the HBV positive group are responsible for lymphocyte activation (p < 0.00001), which may underlie the better IT treatment outcome. Among the mutations restricted to the HCV infected group, 9/50 were involved in histone modification, 7/50 were involved in Hepatitis B pathways (p < 0.0001), suggesting that HCV infection may interfere with diverse molecular processes. Conclusions: HBV and HCV infected HCC patients may respond differently to second-line immunotherapy. This difference is perhaps related to the altered genetic landscape of the patients resulted from virus infections by HBV or HCV.
Safety and clinical activity of combination treatment with regorafenib and milciclib in liver transplant patients with hepatocellular carcinoma recurrence.
Authors: Pivetti Alessandra , Di Marco Lorenza , Bristot Laura , Milosa Fabiola , Critelli Rosina Maria , De Maria Nicola , Di Benedetto Fabrizio , Palejwala Vaseem , Jacob Jules , Shailubhai Kunwar , Villa Erica 
Published: May 2020

e16634 Background: Recurrence of hepatocellular carcinoma after liver transplant (LT-HCC), affects ~40% of patients. As LT-HCC drastically limits therapeutic options, combination of drugs with different mechanism of actions might be an attractive approach. Primary objective of this MiHRCO (Milciclib and Half Regorafenib CO-administration) protocol (87/2019/COMP/MiHRCO) is to evaluate safety and clinical activity of combination of Regorafenib (a tyrosine kinase inhibitor with higher clinical activity in aggressive HCC) with Milciclib (a pan cyclin dependent kinase inhibitor with clinical activities in refractory solid malignancy patients and HCC) in LT-HCC patients. Methods: Seven patients with LT-HCC are enrolled to date. Regorafenib administered at half the prescribed dose (80mg/day) for 3 weeks followed by 1 week Off and milciclib at 100 mg daily for 4 day On/3 day Off. Patients were maintained on this combination regimen until disease progression and/or unacceptable side effects. Primary endpoint was safety and secondary endpoints included progression free survival, time to progression, and clinical benefit rate. Results: This single-arm, single-center operative protocol in LT-HCC patients with extra-hepatic metastasis, not eligible to first line therapy with sorafenib (Todesca P. et al. Hepatology; doi: 10.1002/hep.30588), is currently ongoing. The combination treatment is well-tolerated with manageable toxicities (mostly related with regorafenib), i.e. moderate diarrhea, slight increase of hypertension in previously hypertensive patients and moderate hand and foot syndrome. Patients continuing with therapy are currently in 2 to 10 months of treatment period. All patients are exhibiting stable disease with reduced clinical symptoms. The mean AFP (□-fetoprotein) level (1310±200 ng/ml) at enrollment was reduced by 20% with in the first month of therapy. Importantly, AFP levels in 2 patients, treated for longer period, were reduced by 50%. Conclusions: Regorafenib and milciclib combination was well-tolerated. Most patients showed disease stabilization along with reduction in AFP levels within the first month of therapy. The encouraging clinical activity in difficult-to-treat patients with LT-HCC warrants continuation of this protocol and further evaluation in a larger controlled study. Clinical trial information: 87/2019/COMP/MiHRCO .
Predictors of immunotherapy (IO) response and subsequent tyrosine kinase inhibitor (TKI) response in hepatocellular carcinoma (HCC).
Authors: Armstrong Samantha Ann , Singh Bhavana Pendurthi , Kulasekaran Monika , Prins Petra , He Aiwu Ruth 
Published: May 2020

e16642 Background: Despite advances in understanding the molecular pathways of HCC, therapeutic options are limited and patient survival is dismal. IO is a promising HCC treatment and predicted to become first line therapy. Little is known about indicators predicting a prolonged response to IO or the effects of IO on subsequent TKI treatment. Methods: In this single-institutional retrospective analysis, pts received one of five IO containing regimens with nivolumab, pembrolizumab, atezolizumab plus bevacizumab, durvalumab or cemiplimab until disease progression (PD) or unacceptable toxicity. Relevant clinical factors including, but not limited to: stage, viral etiology, vascular invasion, tumor thrombus, multifocal disease, toxicity grade and additional therapies, were correlated to clinical outcome: progression free survival (PFS), overall survival (OS), response rate (RR), using Pearson’s chi-square test or student's t-test. Responses were assessed using RECIST v 1.1 criteria for stable disease (SD), partial response (PR) and PD were correlated with best response and PFS. OS was calculated by the Kaplan-Meier method. Results: Cohort demographics (n = 76) were: 72% male; 38% African American, 30% Caucasian and 16% Asian; 29% of pts had HBV, 41% had HCV, 1% had both HBV/HCV and 13% had no viral etiology (n = 64). The majority of pts were stage III (43%) or IV (38%). Best response to IO was SD in 65.7% of pts, PR in 25.7% and PD in 8.6%. Median OS was 13m (95% CI 7.9-18.1) from the start of IO and median PFS (n = 65) was 14m (95% CI 6.8-21.2). Median OS and PFS were significantly improved in pts with PR compared to PD (45 vs 8m, p < 0.0005, PFS 15 vs 3m p = 0.007). Both OS and PFS showed benefits for SD of ≥2 months compared to those with PD (11 vs 8m, p < .0005, PFS 5 vs 3m p = .007). Abnormal TSH anytime during IO treatment tended toward prolonged mOS (20 vs 9m p = 0.126). Thirty-five pts received additional lines of therapy after IO, 57% (N = 20) received a TKI and 14.2% (N = 5) received additional IO agents. Those who received TKI upon completion of IO had a significantly improved OS (p = 0.014) versus those who did not; median OS 22 m (95%CI 12.7-31.3) versus 10m (95%CI 5.4-14.6). Conclusions: PR and SD are independent predictors for prolonged PFS and OS in HCC pts receiving IO therapy. Abnormal TSH during IO treatment tended toward improved mOS. In addition data strongly indicates subsequent TKI therapy improves patient outcomes after IO.
Reliability of mRECIST criteria for HCC in the relationship between response and progression.
Authors: Sharma Manish , Bohnsack Oliver , Singareddy Anitha , Narang Jayant , O'Connor Michael , Bajpai Surabhi , Jarecha Rudresh , Kaja Rajesh 
Published: May 2020

e16645 Background: Response Evaluation Criteria in Solid Tumors (RECIST) guidelines consider the measurement of treatment response based on tumor shrinkage due to the antitumor activity of cytotoxic drugs. However, tumor response can be misleading when molecular-targeted therapies or locoregional therapies are used in Hepatocellular carcinoma (HCC). RECIST 1.1 does not specify for changes in tumor vascularity or necrosis. The modified RECIST (mRECIST) adapts the concept of viable (Enhancing) tumor and tumoral necrosis in the assessment of response. According to mRECIST, if a tumor that is solid at baseline becomes entirely necrotic, all the tumors are evaluated as complete response (CR). Edeline et al. evaluated the response of sorafenib in HCC and reported that 26.2% of the patients who were classified as having stable disease (SD) according to RECIST were reclassified as responding to treatment, according to the mRECIST. Takada et al. analyzed tumor responses with sorafenib in HCC according to RECIST 1.1 and mRECIST where 13.1 % of patients were assessed as responders by mRECIST and 7.8 % by RECIST 1.1. There was a significant difference in overall survival (OS) between responders and non-responders according to mRECIST ( p = 0.0117), but no significant difference in OS between responders and non-responders according to RECIST 1.1 ( p = 0.0722). Methods: A retrospective review of time points associated with HCC was performed for 3 clinical trials with a total of 1060 patients with 3998 time points and evaluated using RECIST and mRECIST guidelines. The responses: overall response rate (ORR), CR and partial response (PR) were compared using both guidelines and correlated with disease progression. Results: At a subject level, there are 128 responders by RECIST, of which 73 progressed (57%), 274 responders by mRECIST, of which 156 progressed (57%); while of 148 responders by mRECIST, which were non-responders by RECIST only 80 progressed (54%) within the stipulated study duration. At the visit level, there are 520 timepoints of response by both RECIST & mRECIST, while there are 509 timepoints of response by mRECIST, which are SD by RECIST due to necrosis related difference in criteria implementation. Conclusions: It can be concluded that subjects with response by mRECIST with response or no response by RECIST tend to have an excellent correlation with progression as well. The use of mRECIST improves the outcome of the response in HCC treatment. [Table: see text]
C5aR correlated with the dissemination capacity of circulating tumor cells in hepatocellular carcinoma by targeting INHBA-p-smad2/3-EMT/MMPs axis.
Authors: Dai Qian , Zhu Jie , Shen Minna , Jiang Huiqin , Pan Baishen , Zhou Jian , Fan Jia , Yang Xinrong , Guo Wei 
Published: May 2020

e16649 Background: Circulating tumor cells (CTCs) play important role in tumor dissemination and is an independent survival predictor in Hepatocellular carcinoma (HCC) patients. The aim of this study was to investigate C5a/C5aR, an important axis in complement pathway, which causes the difference capacity of the dissemination of CTCs between HCC patients. The influence of C5a/C5aR axis on recurrence and HCC cell functions was also explored. Methods: Expression microarray analysis was carried out to identify key molecule that cause the difference of CTC enumeration. Clinical significance of the key gene C5aR was evaluated by immunohistochemistry in 187 resectable HCC patients with CTC detection from March 2011 to October 2014. The function of C5a/C5aR axis to enhance the dissemination capacity of CTCs was confirmed first in HCC cell line and than validated in a mouse model. CTCs isolated from the animal circulation were identified by immunostaining for human EpCAM and nuclear counterstaining of red blood cell-lysed blood. Results: Analysis of 187 HCC patients undergoing curative resection showed that C5aR high expression patients were prone to developing vascular invasion, suffering higher AFP level as well as higher percentage of recurrence and death. Further, C5aR expression was also positive correlated with CTC number in HCC patients. In vitro, we observed that cell migration, invasive, proliferation, anti-apoptosis ability and EMT could be greatly inhibited after C5aR knockdown. Opposite results could be observed when C5aR is overexpressed. Further exploration indicated that C5a/C5aR axis could upregulate the expression of INHBA/Activin, and induce phosphorylation of smad2/3 which maintains the mesenchymal phenotype in HCC. Inhibition of the C5a/C5aR signal pathway could decrease circulating capacities of tumor cells and inhibit their colonization to distal organs such as lung in mouse model. Conclusions: Our research elucidated a new C5a/C5aR targeted INHBA-p-smad2/3-EMT/MMP axis to regulate the dissemination of CTC in HCC patients. And these molecules could be novel therapeutic targets for inhibiting the metastasis of tumor cell in the futures.
The landscape of MET mutations in Chinese biliary tract cancers.
Authors: Xu Shifeng , Rao Wei , Zheng Yuanwen , Wang Jianping , Hu Weiyu , Dong Guilan , Wang Jiangong , Ren Guibing , Shi Junping , Wang Yafei , Javle Milind M. , Yao Ming 
Published: May 2020

e16652 Background: Biliary tract cancers (BTCs) are malignancies with poor prognosis and limited treatment options. MET is recurrently altered in various cancers that confer susceptibility to targeted MET inhibitors. It has been reported that the MET mutation frequency is 2-7% in intrahepatic cholangiocarcinoma (ICC) and 3.7% in extrahepatic cholangiocarcinoma (ECC) in Western countries. However, the characterization of MET in Chinese BTCs are not clear. Methods: Next-generation sequencing (NGS) targeting 450 cancer genes was performed on formalin-fixed, paraffin-embedded (FFPE) tumor tissues and matching blood samples that collected from a cohort of 926 Chinese BTC patients. Genomic alterations, including single nucleotide variations (SNV), short and long insertions/deletions (Indels), copy number variations, and gene rearrangements/fusions, were analyzed. The testing was carried out by a College of American Pathologists (CAP) accredited and Clinical Laboratory Improvement Amendments (CLIA) certified laboratory. Results: MET mutations were detected in 4.1% of patients with BTCs, including 5.3% in ICC, 3.4% in hilar cholangiocarcinoma (HCCA), 3.0% in ECC, and 2.6% in gallbladder cancer (GBCA). Gene amplification was the most common type of MET mutation in BTC (2.6%) compared with gene rearrangements/fusions (1.1%) and SNV (0.9%). Novel MET fusion partners, including TNS3 and TRIM4, and MET exon 14 skipping mutation, were also detected. There was no difference in tumor mutational burden (TMB) between patients with and without MET mutation (average TMB: 6.5 vs. 5.6 muts/Mb, P= 0.213). Among these BTC patients, an advanced ICC patient (performance status [PS] 3) who harbored MET gene amplification, received crizotinib as the first-line treatment. Four months later, the patient had a complete response without obvious side effects. Conclusions: To our knowledge, this is the largest BTCs cohort and the first report of MET mutation profiling in the Chinese patients. MET mutations were detected in 4.5% BTCs, and MET inhibitors may be potential treatment options for BTC patients. All types of MET mutations, including gene amplification, SNVs, and gene fusions, were detected in BTCs, which demonstrated that NGS might be a powerful tool to detect MET mutations. Altogether, MET is a promising target in BTCs, and detection of MET mutations is important and essential for predicting the sensitivity of targeted therapy. Clinical trial information: NCT03892577 .
The role of ALBI and IGF-CTP score in refining prognostication of HCC.
Authors: Lee Sunyoung S. , Mohamed Yehia I. , Qayyum Aliya , Hassan Manal , Xiao Lianchun , Duda Dan G. , Hatia Rikita , Wolff Robert A. , Morris Jeffrey , Altameemi Lina , Yao James C. , Amin Hesham M. , Kaseb Ahmed Omar 
Published: May 2020

e16659 Background: Child-Turcotte-Pugh (CTP) score is widely used in the assessment of prognosis of HCC and CTP-A is the standard criterion for active therapy and clinical trials entry. Recently, ALBI and insulin-like growth factor-1 (IGF)-CTP scores have been reported to improve survival prediction over CTP score. However, comparative studies to compare both scores and to integrate IGF into Albi score are lacking. Methods: After institutional board approval, data and samples were prospectively collected. 299 HCC patients who had data to generate both IGF-CPG and Albi index were used. The ALBI index, and IGF score were calculated, Cox proportional hazards models were fitted to evaluation the association between overall survival (OS) and CTP, IGF-CTP, Albi and IGF, albumin, bilirubin. Harrell’s Concordance index (C-index) was calculated to evaluate the ability of the three score system to predict overall survival. And the U-statistics was used to compare the performance of prediction of OS between the score system. Results: OS association with CTP, IGF-CTP and Albi was performed (Table). IGF-CTP B was associated with a higher risk of death than A (HR = 1.6087, 95% CI: 1.2039, 2.1497, p = 0.0013), ALBI grade 2 was also associated with a higher risk of death than 1 (HR = 2.2817, 95% CI: 1.7255, 3.0172, p < 0.0001). IGF-1(analyzed as categorical variable) was independently associated with OS after adjusting for the effects of ALBI grade. Which showed IGF-1 ≤26 was significantly associated with poor OS, P = 0.001. Conclusions: Although ALBI grade and IGF-CTP score in this analysis had similar prognostic values in most cases, their benefits might be heterogenous in some specific conditions. We looked into corporation of IGF-1 into ALBI grade, IGF score with cutoff ≤26 which clearly refined OS prediction and better OS stratification of ALBI-grade.
IGF-Child-Turcotte-Pugh score as a predictor of treatment outcome in Child-Pugh A, advanced hepatocellular carcinoma patients undergoing sorafenib therapy.
Authors: Mohamed Yehia I. , Qayyum Aliya , Hassan Manal , Xiao Lianchun , Duda Dan G. , Hatia Rikita , Lee Sunyoung S. , Wolff Robert A. , Morris Jeffrey , Altameemi Lina , Yao James C. , Amin Hesham M. , Kaseb Ahmed Omar ,   Kaseb's
Published: May 2020

e16660 Background: Sorafenib is the first systemic therapy approved for advanced HCC treatment; with no accurate tool available to help predict survival and treatment outcome and to guide therapy decisions. Our novel blood-based insulin-like growth factor-1 (IGF)-Child-Turcotte-Pugh (CTP) score comprises levels of IGF-1, bilirubin, INR, and albumin. IGF-CP score significantly improved the prediction of HCC survival in our recently published studies. The current prospective study aimed to compare the overall survival (OS) and progression free survival (PFS) of 116 patients with CTP-A HCC treated with sorafenib whose score is reclassified as IGF-A (AA) to that of patients whose score is reclassified as IGF-B/C (AB/AC). Methods: After the approval of the institutional review boards and signing written informed consent, a total of 116 patients with HCC were prospectively enrolled and started on sorafenib and followed until progression or death. We calculated IGF-CTP scores, used Kaplan-Meier method and log rank test to estimate and compare time to event outcomes between subgroups of patients. Results: 116 patients were CTP class A, 87 of the patients with CTP class A were classified as IGF-CTP-A and had median OS of 13.16 ms (95% CI = 12.04 to 22.6 ms), and a median PFS of 5.82 months (ms) (95% CI = 4.34 to 9.14 ms), whereas 29 patients were reclassified as intermediate risk (IGF-CTP-B) and had had a higher risk of death with a shorter OS of 7.6 months (95% CI = 5.23 to 24.47 months) and shorter PFS of 3.49 months (95% CI = 2.53 to 5.26 months). There was higher overall rate of adverse events in the CTP-A patients reclassified as IGF-CTP B than IGF-CTP A especially in grade III-IV adverse events, upper GI Bleeding, lower GI Bleeding, nose bleeding, renal failure, liver failure, encephalopathy, fatigue, weight loss, anorexia, and vomiting. Conclusions: The results of this study support our biologically-driven hypothesis that among HCC patients with CTP-A class treated with sorafenib, those reclassified as IGF-CTP-B/C will have poorer prognosis in terms of shorter OS and PFS. Thus, our study provides an objective non-invasive strategy to better predict the outcome in HCC patients undergoing systemic therapy. Future validation of our IGF-1 score may lead to adopting it as a stratification tool in clinical trials as well as to predict HCC outcome and guide therapy decision in routine practice.