bluuebunny/crossref_metadata_2025 huggingface dataset:
Expression of the type 3 inositol 1, 4, 5-trisphosphate receptor according to the chronic liver disease etiology in hepatocellular carcinoma.
Authors: Diniz Paulo Henrique Costa , dos Santos Marcone Loiola , França Andressa , Filho Antônio Carlos Melo Lima , Vidigal Paula Vieira Teixeira , Ferrari Teresa Cristina de Abreu , Leite Maria de Fátima
Published: May 2020

e16604

Background: The expression of type 3 isoform of the inositol 1, 4, 5-trisphosphate receptor (ITPR-3), an intracellular calcium (Ca2+) channel reported in liver cancer cells, is important in the Ca2+ signalling. Thus, it may be involved in the many events of hepatocarcinogenesis. Here, we investigated the ITPR-3 expression in hepatocellular carcinoma (HCC) and its association with clinicopathological parameters and long-term outcomes, according to the etiology of underlying chronic liver disease (CLD). Methods: Clinical and laboratory data from patients (n = 53) who underwent orthotopic liver transplantation for HCC treatment in a Brazilian referral center were retrospectively collected. After pathological reviewing of their explanted liver samples, ITPR-3 expression in both tumor and underlying cirrhosis were assessed by immunohistochemistry, and quantified using density histograms in the ImageJ software. Event (tumor recurrence or death from any cause) occurrence and event-free survival (EFS) were analysed. Results: Hepatitis C virus (HCV) (n = 31), alcohol abuse (n = 16) and cryptogenic cirrhosis (n = 6) were the underlying CLD etiology, and the groups were, in general, well balanced regarding clinicopathological indices. Median EFS was 78.9 months (range, 63.6-94.1). The ITPR-3 expression profile was cytoplasmatic, predominantly perinuclear, and was stronger in tumor than in adjacent cirrhosis, considering all etiologies together (intensity 9.1% higher in tumors, p < 0.001) However, analyzing each etiologic group, the cryptogenic was the only one in which there was no difference between tumor and underlying CLD. Comparing the ITPR-3 expression only in tumors, there was no difference regarding the etiology of CLD. The tumor ITPR-3 higher intensity was correlated with higher serum aspartate alanine-transferases (ALT) levels (p = 0.018) and lower mitotic index ( < 5 per 10 high power fields) (p = 0.009). There was no association between receptor expression and event occurrence or EFS. Conclusions: The ITPR-3 was expressed in HCC, regardless of the underlying CLD etiology. Its correlation with mitotic index, a cell proliferation marker, was demonstrated, but there were no associations with clinical outcomes. Apart from cryptogenic cirrhosis, ITPR-3 expression was more intense in tumors than in underlying cirrhosis. These findings suggest that ITPR-3 could have a role in carcinogenesis. However, the prognostic and therapeutic implications need to be investigated.
Outcome of FOLFOX based chemotherapy in advanced pancreatobiliary cancers presenting with hyperbilirubinemia.
Authors: Batra Sandeep , Jha Sanjeev Kumar , Bahl Ankur , Chaturvedi Harit , Taneja Satyam
Published: May 2020

e16605

Background: Treatment of pancreatobiliary cancer patients with severe liver dysfunction including hyperbilirubinemia secondary to liver metastasis or biliary obstruction is challenging. A significant number of patients at presentation are in advanced/ locally advanced stage thus severely limiting chemotherapy options. FOLFOX (5 FU, Leucovorin, Oxaliplatin) represents a feasible option considering the pharmacokinetics. Clinical data on the dosage and tolerability of chemotherapy is limited and no recommendations are available to treat such patients in upfront setting with persistent hyperbilirubinemia. This observational study was done to find out safety and efficacy of FOLFOX based chemotherapy in these patients. Methods: Patients with advanced pancreatobiliary cancers with hyperbilirubinemia were treated with mFOLFOX6 based chemotherapy. Patients were treated till progression or 6 months or death (whichever occurred ealy) and assessed for toxicity and survival. Results: Only 13 out of 40 patients were able to complete all 12 cycle of chemotherapy. 12 patients were able to receive 2nd line chemotherapy of physician choice and 2 patients were able to received 3rd line chemotherapy. Total bilirubin of patients at start of chemotherapy ranged from 3 to 39.4 mg/dl with a mean value of 9.17±6.67 mg/dl and a median value of 7.5 mg/dl. Median progression free survival (PFS) of mFOLFOX6 was 5.97 months whereas median overall survival (OS) was 8.2 months. 6 patients were able to receive only one cycle of chemotherapy. 2 patients were able to receive only 2 cycles of chemotherapy. 26 patients completed 6 cycles of chemotherapy. Objective response rate was 45% after 6 cycles of chemotherapy. Of these 26 patients response assessment revealed progressive disease in 7 patients. 2 patient had complete metabolic response of which one of them had locally advanced disease. On laparotomy of this patient there were an extensive peritoneal disease curative surgery was not feasible. One patient successfully underwent Whipple’s procedure after 6 cycles of chemotherapy followed by adjuvant radiotherapy. Conclusions: FOLFOX based chemotherapy is a feasible option and a hope for patients of advanced pancreatobiliary cancers presenting with hyperbilirubinemia with a tolerable toxicity profile and providing comparable PFS and OS to other chemotherapy drugs/ regimens used in non hyperbilirubinemic patients.
Compliance to the American Association for the Study of Liver Diseases (AASLD) guidelines and its impact on overall survival in patients with hepatocellular carcinoma.
Authors: Manne Ashish , Mulekar Madhuri S , Escobar Daisy E , Prodduturvar Pranitha , Fahmawi Yazan , Henderson Phillip , Abdul-Rahim Osama , Hussain Zeiad , Liles Spencer , Fonseca Annabelle , Howard John Harrison , Mneimneh Wadad , Gilbert Robert , Pai Sachin Gopalkrishna , Nelson Cindy , Khushman Moh'd M.
Published: May 2020

e16609

Background: The Barcelona-Clinic Liver Cancer (BCLC) staging based management proposed by AASLD depends on baseline liver function and performance status of the patient in addition to tumor characteristics. Low adherence to AASLD guidelines, especially in advanced staged tumors, can be ascribed to suboptimal revision/updates of the guidelines reflecting the advancements in hepatocellular carcinoma (HCC) management. Here, in addition to the adherence rate, we explored the overall survival of patients with HCC according to first-line treatment modality compliance to AASLD guidelines. Methods: This is a retrospective study conducted at the University of South Alabama/Mitchell Cancer Institute. Between 2017 and 2019, 148 unique treatment-naïve patients with HCC were identified. Patients were staged according to the BCLC staging system and their compliance with suggested first-line treatment modality according to AASLD guidelines was noted. Overall survival was explored and differences between overall survival rates of compliant and non-complaint patients were compared using the log-rank Wilcoxon test. Results: In our cohort, the median age was 72.5 years (range 38-90). Males represented 80%. Caucasians, African Americans, and other ethnicities (e.g. Asians) represented 68%, 30% and 2% respectively. The overall adherence rate was 83%. The adherence rate according to BCLC stage 0, A, B, C and D was 100%, 97%, 77%, 77% and 38% respectively. Compliance vs. non-compliance to AASLD guidelines showed no significant difference in overall survival of patients with BCLC stage 0-A, B and C. In patients with BCLC stage D (N = 13), compared to patients treated in compliance to AASLD guidelines (N = 5), patients treated in non-compliance (N = 8) had better overall survival (2.2 vs. 5.2 months, p = 0.0012). Conclusions: In our cohort, the adherence rate to AASLD treatment guidelines in patients with BCLC stage D was very low at 38%. Lack of adherence in this group of patients translated into better overall survival. The current AASLD guidelines for the management of HCC have several limitations, especially for advanced stages. In the last few years, the FDA approved several tyrosine kinase inhibitors, immune checkpoint inhibitors and the monoclonal antibody, ramucirumab. This expansion generated the need for periodic updates/revisions of consensus guidelines.
Comparison of mutational landscape of non-alcoholic fatty liver disease, viral hepatitis, and alcohol consumption related hepatocellular carcinoma.
Authors: Qiu Jinrong , Wang Weifeng , Li Yingmei , Chen Shifu
Published: May 2020

e16614

Background: Hepatocellular cancer (HCC) is the seventh most common cancer and the fourth leading cause of cancer-related death worldwide. The most common risk factors of HCC have traditionally included hepatitis B virus (HBV), hepatitis C virus (HCV), and alcohol-related liver disease (ALD). Recently, Non-Alcoholic Fatty Liver Disease (NAFLD) has emerged as the fastest growing risk factor for the development of HCC. This study reports the mutation landscape of NAFLD-related hepatocellular carcinoma (HCC) versus other etiologies. Methods: Mutation data of 219 HCC samples were collected from TCGA database, including 13 NAFLD, 87 HBV, 37 HCV, and 82 ALD-related samples. We analyzed mutations for different type of HCC samples using GDC level 3 mutation data. Driver mutations were called by applying software MuSig2CV. Results: In 219 samples, a total of 32189 mutations were identified, including 3163 in NAFLD, 11430 in HBV, 6390 in HCV, and 11206 in ALD-related HCC samples. Driver genes shared by viral hepatitis and ALD-related samples were TP53 (32% for ALD, 33% for HBV, 42% for HCV) and CTNNB1(32 % for HCV, 26% for HBV,29% for ALD), while TP53 was not among the highest frequency of mutations in NAFLD-related samples. As lack of NAFLD-related HCC samples (n = 13), most frequently mutated genes in NAFLD-related HCC samples were computed instead of driver genes. Top 5 mutated genes in NAFLD-related HCC samples were TTN (36%), CACNA1B (27%), DSCAM (27%), GLI2 (27%), and BEB (27%). Conclusions: From our results, TP53 has a lower mutation frequency in NAFLD-related HCC samples than in other types of HCC. To further validate this finding, a larger size of NAFLD-related HCC samples is essential.
Mutational profile of hepatocellular carcinoma by liquid biopsy of Hispanics in central California.
Authors: Ali Mir , Chaudhary Uzair Bashir , Valliani Salimah , Kim Shirley , Moers Diana , Akabane Hugo , Fathi Amir
Published: May 2020

e16621

Background: Hepatocellular carcinoma (HCC) when localized to liver is typically diagnosed with Characteristic radiographic features while tumor tissue sampling is not warranted anymore. Recently, circulating tumor DNA (ctDNA) has been used to evaluate mutational profile in solid tumors in order to personalize treatments. However, it is not established well in HCC, specifically in Hispanic patients. This study aims to describe the mutational profile of Hispanic patients with ctDNA analysis as a single center experience. Methods: We enrolled 33 patients with diagnosis of HCC from 1/2016 to 12/2019. Diagnosis of HCC was based on Characteristic radiological features, defined by Liver Imaging Reporting and Data System (LI-RADS category 5). 18 patients self-identified as Hispanic while remaining were mainly Caucasians. FoundationOne Liquid genomic testing by Foundation Medicine was used for profiling of 77 most commonly mutated genes of sampled blood. Results: Baseline patient characteristics were similar between Hispanic and non-Hispanic population. Median age of diagnosis was 64 in this cohort with 23(70%) males and 10(30%) females. 30 patients had underlying cirrhosis with hepatitis C present in 19(58%) and heavy alcohol abuse in 15(45%) of cirrhotic. 32 patients had liver-only disease, while we had one patient with extrahepatic disease. 22 of these 33 patients had a single HCC lesion while 11 had multifocal HCC. 20 patients (60.6%) had at least 1 pathogenic mutation. 13 patients (39.4%) did not have any pathogenic mutations. The frequency of commonly mutated genes for our Hispanics versus non-Hispanics were following: CTNNB1(45.5% vs 44.4%), TERT (45.5% vs 55.6%), TP53(36.4% vs 55%), CNK2A (18.2% vs 0). Median of Allele frequency percentage was 0.81%. Mutations in TP53 was commonly detected at codon 249(R249S). Presence of these pathogenic mutations were associated with poor clinical features such as multifocal disease and higher AFP values > 59 as compared to 15 without mutations. Other mutations present at lower percentage include ERBB2, PIK3CA, DNMT3A, GNAS, KDR, RB1, PTEN and their frequency was similar in both Hispanic and non-Hispanic groups. Conclusions: Genomic profiling of ctDNA by liquid biopsy in our Hispanic patients with HCC appears similar to established mutational profile of HCC in Caucasian and Asian populations. These findings can be verified in heterogeneous populations in order to serve as a potential prognostic tool and help with personalized medicine.
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.
Association between serious immune-related adverse events and survival in patients with advanced HCC treated by nivolumab: A single-center experience.
Authors: Digklia Antonia , Diciolla Antonella , Hocquelet Arnaud
Published: May 2020

e16661

Background: Nivolumab received accelerated approval by the FDA in 2017 for the treatment of advanced hepatocellular carcinomas (HCC). This study is aimed at evaluating the relationship between serious irAEs leading to treatment pause and survival of patients treated with nivolumab in our center. Methods: we performed a retrospective analysis of the patients treated at our center. The Kaplan Meir method was used to evaluate overall survival(OS). Log-rank test was conducted to compare groups in terms of OS. Adverse events were assessed using NCI CTCAE version 4.03 criteria. Results: Twenty patients with advanced HCC received nivolumab as palliative therapy between 2017-2019. 12/20 received nivolumab as first line treatment, 7/20 as second line. 6/20 patients stopped nivolumab due to serious irAEs including pancreatitis, kidney dysfunction and colitis leading to definitively stop of the therapy. The majority of patients received nivolumab in second line (5/6). The 1 year OS was 44% at the non-serious irAEs group and 84% in the serious irAEs group (p value = 0.0166). Median overall survival for the entire cohort was 11.4 months. The median OS was 8.11 months in patients without serious irAEs and 18.2 months in the group with toxicity. Conclusions: the occurrence of serious irAEs was associated with longer OS at our single center review. These results are in line with reports in other diseases such as lung cancer and melanoma. These retrospective data warrant further evaluation.
Comprehensive molecular profiling of intrahepatic cholangiocarcinoms in Chinese population and therapeutic experience.
Authors: Wang Longrong , Wang Lu
Published: May 2020

e16663

Background: The genomic alterations of intrahepatic cholangiocarcinoma in Chinese population have not been fully revealed. Molecular profiling may provide reference to clinical management especially targeted therapy. Methods: A prospective study was conducted in 122 intrahepatic cholangiocarcinoma patients accepted chemotherapy with or without targeted therapy. All patients had results of next generation sequencing assay that analyzes 489 cancer-associated genes. Results: The most commonly mutated genes were TP53 (34%), KRAS (25%), ARID1A (17%), CDKN2A (12%), FAT1 (12%), and NOTCH3 (12%). ERBB2 alterations were found in 13 (11%) patients, 10 of 13 were gene amplification. Application of Trastuzumab achieved a disease control rate of 7/8 and response rate of 6/8. Twenty-two patients with wild type KRAS/NRAS/BRAF accepted Cetuximab combined chemotherapy. Disease control rate and response rate were 78% and 47% respectively. Fifty-four patients accepted anti-VEGF treatment combined chemotherapy. Disease control rate and response rate were 85% and 60% respectively. Better therapeutic efficiency (P = 0.001) and longer progress free survival (P = 0.04) were observed in Bevacizumab treated group than chemotherapy alone. Two patients (1.6%) had signatures of microsatellite instability (MSI-H), and both benefited from immunotherapy. Conclusions: This study provides an over view on genetic alterations in Chinese intrahepatic cholangiocarcinoma patients, and indicates the potential clinical implications for targeted therapies.
Classifying inpatient deaths among liver and intrahepatic bile duct cancer and the effect of palliative care utilization on overall health care burden.
Authors: Abbasi Saqib , Kasi Anup , Saeed Anwaar , Sun Weijing , Al-Rajabi Raed Moh'd Taiseer
Published: May 2020

e16673

Background: Liver cancer and bile duct cancer remain among of the most deadly cancers with a dismal 5 year survival of 2-15%. Patients often end up dying in an in-hospital setting as a result of acute complication of cancer progression. The purpose of this study is to identify annual trends in this sub-population, including cause of admission, palliative care utilization and economic impact on healthcare. Methods: From the years of 2002 to 2014, admissions for patients with a diagnosis of liver and bile duct cancer were identified using the National Inpatient Sample. Annual trends in incidence were compared to overall deaths via the SEER database. Trends were identified in hospital length of stay (LOS), total charges (TC), as well as utilization of palliative care. The effect of palliative care utilization on hospital length of stay and costs were also studied. Results: 73,833 (weighted) patient deaths were recorded from 2002 to 2014, 4,577 in 2002, compared to 6,595 in 2014. Signifying 33% (2002) to 32% (2014) of total deaths related to these cancers. The most common billed primary diagnosis was liver failure at 16.9%, sepsis (15.3%) and renal failure (6.7%). Overall LOS trended down from 5.9 days to 4.8 days (p < 0.001). Palliative consults increased from 8.2% in 2002 to 39.4% in 2014. In 2014, the mean TC for those who received palliative consults versus those who did not was $52,612 and $64,388 respectively (p < 0.001). LOS among these patients did not significantly change at 5.9 and 5.6 days (p = 0.13). When looking at patients with sepsis who did not die, a palliative care consult decreased costs from $87,564 to $75,223 (p < 0.001). LOS was not significantly different at 8.8 days to 8.5 days (p = 0.15). Conclusions: A third of patients with liver and bile duct cancers die in an in-hospital setting. More effort needs to be undertaken to identify these patients and establish appropriate goals of care prior to such an event. Nonetheless, palliative involvement decreased health care resource utilization. Even among patients with sepsis who did not die, a palliative care consult decreased total charges of admission.
The characterization of IDH1 mutations in Chinese biliary tract cancers.
Authors: Wang Kui , Xie Feng , Hu Mingtai , Zheng Yuting , Yuan Zhengang , Zhang Lei , Xue Hui , Liu Jianwei , Yang Zhao , Sui Chengjun , Xie Yanting , Liu Dan , Shi Junping , Hao Qing , Shi Xiaoliang , Liu Angen , Zhang Lin
Published: May 2020

e16674

Background: Next-generation sequencing (NGS) has been used to identify actionable mutations in biliary tract cancers (BTCs). IDH1 is an enzyme that catalyzes the conversion of isocitrate to alpha-ketoglutarate, and is involved in the tricarboxylic acid cycle. Mutations in IDH1 are associated with aberrant conversion of alpha- ketoglutarate to 2-hydroxyglutarate, which is an oncogenic metabolite. In addition, IDH1 showed an effective biomarker for cholangiocarcinoma targeted therapy in the ClarIDHy study. Therefore, the detection of IDH1 mutations is essential for predicting sensitivity to targeted therapy. Methods: Deep sequencing 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, including 469 intrahepatic (ICC), 203 extrahepatic (ECC), 195 gallbladder cancers (GC), and 59 hilar (HCCA) cholangiocarcinoma. Single nucleotide variations (SNV), short and long insertions/deletions (Indels), copy number variations, gene rearrangements, and 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: IDH1 mutations were detected in 3.9% patients, with a median age of 59 years old. The rate of IDH1 mutations was 7% in ICC, 1% in ECC, 0.5% in GC, and 0% in HCCA. IDH1 R132C (75.8%) substitution was the most common type of IDH1 mutation in ICC. In BTC patients, ARID1A (25%), TP53 (22%), and PBRM1 (22%) were the top-ranked co-mutation genes with IDH1. Compared with the IDH1 wild-type cohort, the frequencies of KRAS and TP53 mutations were significantly lower in the IDH1 mutated cohort (29.3% vs. 2.8%, p = 0.001; 56.6% vs. 22.2%, p < 0.001). In addition, IDH1 mutations were associated with a significantly lower TMB value compared to the wild-type cases (average TMB: 3.2 vs. 5.8 muts/Mb, p < 0.001). Conclusions: To date, this was the largest cohort used to study the characterization of IDH1 mutations in Chinese BTCs. The mutation frequency of IDH1 was lower in Chinese ICCs compared with non-Asian populations (7.0% vs. 16.5%). Consistent with the results from previous reports, IDH1 R132C substitution was the most common type of IDH1 mutation in ICCs (PMID: 31392056). TMB value and the frequency of TP53 and KRAS mutations were lower in patients with IDH1 mutation, which may provide clues for sensitivity to targeted therapy and prognosis.
Post-registration experience of nivolumab (nivo) therapy in patients with advanced hepatocellular carcinoma (HCC): An international study.
Authors: Fessas Petros , Kaseb Ahmed Omar , Wang Yinghong , Saeed Anwaar , Szafron David , Jun Tomi , Dharmapuri Sirish , Naqash Abdul Rafeh , Khan Uqba , Yu Bo , Paul Sonal D , Nimkar Neil satish , Bettinger Dominik , Hildebrand Hannah , Mohamed Yehia I. , Huang Yi-Hsiang , Rimassa Lorenza , Ang Celina , Marron Thomas Urban , Pinato David James
Published: May 2020

e16677

Background: Nivo is FDA-approved in sorafenib-experienced, advanced HCC. Post-registration data to portray treatment in a real-world setting is lacking. Methods: We describe safety and efficacy of nivo in patients (pts) from 8 centres (USA n = 181, Asia n = 47, Europe n = 5), documenting overall (OS), progression-free survival (PFS), overall response (ORR) and disease control rates (DCR) (RECIST). Results: We analysed 233 pts, mostly cirrhotic (n = 176, 75%) due to hepatitis C (n = 95, 54.0%) with Barcelona Clinic Stage (BCLC) C HCC (n = 178, 76.4%), Child-Pugh class (CP) A (n = 158, 67.8%) or B (n = 75, 32.2%), and AFP > 400 IU/mL (n = 132, 56.7%). Nivo was given as first (1L, n = 85, 36.5%), second line (2L, n = 130, 55.8%) or > 2L (n = 18, 7.7%), after local (n = 191, 82%) and systemic therapy (n = 148, 63.5%), mostly sorafenib (n = 142, 60.9%). Median duration of nivo was 6.0 months (mo, interquartile range [IQR] 2.6-11.9) and stopped due to progression (n = 109, 46.8%) or toxicity (n = 8, 3.4%). After median follow up of 7 mo (IQR 3.0-12.3), ORR was 22.4% and DCR was 52.1%. Best responses (n = 219, 94%) included complete and partial responses in 18 (7.7%) and 31 (13.3%) pts respectively, stable disease in 65 (27.9%) and progressive disease in 105 (45.1%), not dissimilar by CP (p = 0.26). Median OS was 12.2 mo (95%CI 8.4-16.0) and predicted by CP (CPA 16.3 mo 95%CI 11.7-20.8; CPB 7.3 mo 95%CI 4.2-10.4; hazard ratio [HR] 1.9, p = 0.01), nivo line (1L 16.3 mo 95%CI 8.0-24.5; > 1L 10.4 mo 95%CI 7.4-13.5; HR 0.68, p = 0.05), and PVT (PVT- 13.8 mo 95%CI 11.7-16.0; PVT+ 10.4 mo 95%CI 7.8-13.0; HR 1.8, p = 0.015) but not cirrhosis, AFP, BCLC or steroid use (p > 0.05). Median PFS was 10.1 mo (95%CI 6.1-14.2), predicted by BCLC (A-B 19.0 mo 95%CI 7.1-30.8; C 8.2 mo 95%CI 4.9-11.4; HR 2.8, p = 0.002) and line (1L 18.2 mo 95%CI 10.4-25.9; > 1L 8.2 mo 95% CI 6.2-10.2; HR 0.60, p = 0.021), but not cirrhosis, AFP, or steroid use (p > 0.05). 26 pts (11.2%) suffered > = Grade 2 toxicities, most commonly fatigue (n = 29, 24.7%). Conclusions: Real-world use of nivo in advanced HCC across line of therapy suggests reproducible clinical efficacy and safety compared to prospective trials.