bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effect of immune checkpoint inhibitor (ICI) treatment in hepatocellular carcinoma (HCC) based on underlying liver disease.
Authors: Wu Linda , Bagiella Emilia , Rudshteyn Michelle , Cohen Deirdre Jill 
Published: January 2022

396 Background: While treatment of unresectable HCC remains challenging, ICI either alone or in combination with bevacizumab, has become a standard therapy. Overall, HCC outcomes are improved with the use of ICI, but only a small percentage of patients respond. As a result, there remains a need for biomarker discovery for optimal patient selection. Emerging evidence suggests that patients with non-viral causes of HCC, including nonalcoholic steatohepatitis (NASH) and alcohol use, may not derive the same benefit from ICI as patients with viral causes of HCC. A recent study by Pfister et al. (2021) demonstrated in preclinical models that NASH-related aberrant T cell activation and impaired immune surveillance play a role in reducing responsiveness to ICI. Our study aimed to use real-world data to evaluate whether there is a difference in overall survival (OS) following treatment with ICI in patients with viral-induced compared to those with non-viral-induced HCC. Methods: We conducted a retrospective chart review of all patients with unresectable HCC at Mount Sinai Health System who received ICI from 1/2017 to 6/2021. The primary outcome investigated was OS of patients with viral etiologies compared to non-viral etiologies of HCC. Results: A total of 349 patients were included. The cohort was predominantly male (84%), with median age of 63 years. 86% of patients were cirrhotic. 246 (70%) patients had HCC with a viral etiology, with the majority (67.5%) due to hepatitis C infection. 103 patients (30%) had non-viral causes of HCC, with 47% due to NASH and 39% due to alcohol. At the time of ICI initiation, most patients (66%) had Child Pugh (CP) class A liver disease and performance status (PS) ECOG 0 (71%). Nivolumab was the most common ICI given (87%) and 79% of patients received ICI as first-line therapy. The viral and non-viral HCC groups were evenly matched in terms of sex, age, cirrhosis, ECOG PS, type of ICI, and line of therapy. With a median duration of follow-up of 10.5 months (range: 1.4-62.4 months), the median OS (mOS) of patients with viral HCC was 19.3 months (95% CI: 14.2-26.6) and mOS of patients with non-viral HCC was 11.4 months (95% CI: 9.3-17.7; P = 0.08). The hazard ratio, adjusted for CP class and stage, for viral HCC treated with ICI was 0.81 (95% CI: 0.583-1.127; P = 0.21). Conclusions: Patients with viral-induced HCC appear to have improved OS when treated with ICI compared to patients with non-viral-induced HCC, but the difference is not statistically significant. Further studies are required to better understand the mechanisms underlying response to ICI in HCC.
Outcomes of beta blockers (BB) in hepatocellular carcinoma (HCC) treated with immune checkpoint inhibitors (ICIs).
Authors: Wu Linda , Ozbek Umut , van Hyfte Grace , Reincke Marlene , Gampa Anuhya , Abugabal Yehia I. , Nishida Naoshi , Wietharn Brooke , Amara Suneetha , Balcar Lorenz , Pinter Matthias , Vogel Arndt , Weinmann Arndt , Saeed Anwaar , Rimassa Lorenza , Naqash Abdul Rafeh , Muzaffar Mahvish , Huang Yi-Hsiang , Pinato David James , Ang Celina 
Published: January 2022

399 Background: Portal hypertension increases intestinal permeability, dysbiosis, and bacterial translocation, leading to a pro-inflammatory state, which can in turn promote progression of liver disease. However, multiple studies have shown that BB use in patients with cirrhosis can reduce the risk of developing HCC, and in patients with HCC, BB can improve overall survival (OS). In recent years, ICIs have become first-line therapy for patients with unresectable HCC, and we aimed to evaluate whether BB use conferred survival benefits in patients treated with ICIs using real-world data. Methods: We conducted a retrospective chart review of HCC patients treated with ICI from 2017 to 2019 at 13 institutions across North America, Europe, and Asia in order to evaluate the association between BB use and OS, as well as BB use and overall response rate (ORR). Univariable and multivariable logistic regression models were used to evaluate associations, and survival analyses were performed using the Kaplan-Meier method. Results: A total of 578 patients were evaluated. The median age of the cohort was 65 years, and 80% of patients were male. The majority of patients (70%) were cirrhotic. The causes of underlying liver disease were as follows: HBV (22%), HCV (36%), alcohol (20.8%), and NASH (13%). Most patients (73.5%) had Child Pugh (CP) class A liver disease, and good performance status with ECOG score either 0 (52%) or 1 (45%). The majority of patients (75%) treated with ICIs received a PD-1 inhibitor alone. There were 360 deaths (62% of patients) with a median follow-up of 30.8 months (Quartiles: 17.2-40.3 months). Two hundred and three (35%) patients had BB use at any point during ICI therapy. Fifty-one percent of these patients were on a nonselective BB whereas 49% were taking a cardio-selective BB. BB use was not significantly correlated with OS (hazard ratio, 1.12; 95% CI, 0.9-1.39; P = 0.298) or ORR (odds ratio, 0.84; 95% CI, 0.54-1.31; P = 0.451) in univariate or multivariate analyses. Conclusions: Patients who used BB while on immunotherapy for unresectable HCC did not have statistically significant differences in OS or ORR compared to patients who did not use BB. More studies are required to elucidate the effect of beta blockade on the microbiome, immune activation, and HCC.
Provider- and system-level barriers to surveillance for hepatocellular carcinoma among patients with chronic liver disease.
Authors: Beal Eliza W. , Gorji Leva , Volney Jaclyn , Sova Lindsey , Tsung Allan , McAlearney Ann Scheck 
Published: January 2022

404 Background: Most cases of hepatocellular carcinoma (HCC) occur in patients with known risk factors. Expert society guidelines recommend HCC surveillance with ultrasound with or without serum alpha fetoprotein every 6 months for these patients, but less than 20% undergo recommended surveillance. The objective of this study was to identify provider- and system-level barriers to surveillance from the provider perspective and to examine the role of provider knowledge and attitudes. Providers’ suggestions for potential interventions to improve HCC surveillance were also elicited. Methods: Qualitative research methods were employed. Purposive sampling was used to invite providers from the Departments of Internal Medicine and Family and Community Medicine who provide primary care, and from the Department of Internal Medicine, Division of Gastroenterology, Hepatology and Nutrition to participate. A semi-structured interview guide was used. Transcribed interviews were analyzed to reveal emergent themes. Results: 22 providers were interviewed including primary care providers, general gastroenterologists and hepatologists. These providers spend a median of 70% (range 20% - 100%) of their time in clinical practice, versus research and administrative responsibilities, and have been in practice a median of 7 years (range 1.8 – 25 years). Provider-level barriers to HCC surveillance identified by participants included variable provider comfort managing chronic liver disease; relationships between primary care, gastroenterology, infectious disease and hepatology; if/how providers discuss HCC surveillance with high-risk patients; provider knowledge of guidelines and outcomes from HCC surveillance; and specific provider-level barriers including time in clinic, competing issues in clinic, deferral of responsibility to another provider, the provider-patient relationship, and time spent on patient education. System-level barriers to HCC surveillance included the absence of relevant technology tools, insurance denial of surveillance imaging, difficulty scheduling surveillance studies and the COVID-19 pandemic. Provider suggestions for interventions included patient navigation, use of technology, education for patients and primary care providers, partnering with primary care practices, and media campaigns. Conclusions: Important barriers to HCC surveillance and opportunities for intervention to improve HCC surveillance rates in high-risk patients were identified. Future research should focus on the design, testing and implementation of interventions to target provider- and system-level barriers.
Barriers for clinical trial enrollment in cholangiocarcinoma patients.
Authors: Pear Samantha , Bachini Melinda , Gardett Isabel , Lindsey Stacie , Delcorso-Ellmann Teresa , Abdel-Wahab Reham 
Published: January 2022

407 Background: Cholangiocarcinoma (CCA) is a rare and aggressive cancer, with most patients presenting at an advanced stage with few treatment options. In the past decade, the number of clinical trials available to CCA patients has increased significantly. Recent clinical trials for FGFR2 and IDH1 inhibitors showed significant improvement in patients’ overall survival and progression-free survival and led to the approval of three new targeted therapies over the last year and a half. Unfortunately, a small percentage of CCA patients were eligible for this treatment. As the standard treatment has limited efficacy, there is a critical need for CCA patients to have access to and enroll in clinical trials. Our study aims to evaluate the current clinical trial enrollment rate in CCA and barriers that limit patient enrollment. Methods: We surveyed CCA patients and caregivers during the 2021 CCA Virtual Annual Conference to leverage the large gathering of the CCA community as they learned about the clinical trial landscape and opportunities available to them. Results: A total of 204 attendees participated in this study. 62.3% were females, 89.2% identified as white, 72.5% of patients were diagnosed with intrahepatic CCA, followed by 13.2% Perihilar, and 8.3% distal CCA. 60.3% of patients were receiving active cancer therapy at the time of the survey. Out of those patients, 56.9% were receiving chemotherapy, 25.2% targeted therapy, and 6.5% immunotherapy. The remaining 11.4% received surgery+/- neoadjuvant therapy, liver transplantation, local therapy, radiotherapy alone or combined chemoradiotherapy. Only 1.5% of the current patients surveyed did not carry medical insurance. Some patients reported that financial hardship negatively impacted pursuing medical care; including their inability to secure a second opinion, to travel long distance to a comprehensive cancer center, and to access clinical trials. 27% had enrolled in clinical trials, with 25.5% of those enrolled in two clinical trials over the course over their treatment. Among patients who were told that they were not eligible for clinical trials enrollment, 34.8% reported it was due to not having actionable mutations, 17.4% did not have measurable tumors, 8.7% had insufficient tissue biopsy, and 40% of patients had other barriers, including no clinical trials in their treating cancer center, advanced age, prior chemotherapy, prior tumor resection, presence of brain metastasis, or other primary cancer. Conclusions: Although, more CCA clinical trials are now available, the number of patients enrolled in clinical trials is still low. Based on our analysis, there is a need to provide more clinical trials to CCA patients. Additionally, there is a need for a greater geographic diversity of trials sites, more expanded access programs, and designing clinical trials for patients who don’t have actionable mutations will provide treatment opportunities and hope for more diverse patients.
Feasibility of adjuvant S-1 chemotherapy after major hepatectomy for biliary tract cancers: An exploratory subset analysis of JCOG1202.
Authors: Kobayashi Shogo , Nakachi Kohei , Ikeda Masafumi , Konishi Masaru , Ogawa Gakuto , Uesaka Katsuhiko , Yanagimoto Hiroaki , Morinaga Soichiro , Wada Hiroshi , Shimada Kazuaki , Takahashi Yu , Nakagohri Toshio , Gotoh Kunihito , Kamata Ken , Shimizu Yasuhiro , Ajiki Tetsuo , Kawamoto Yasuyuki , Ueno Makoto , Okusaka Takuji , Furuse Junji ,   Hepatobiliary and Pancreatic Oncology Study Group of Japan Clinical Oncology Group (JCOG)
Published: January 2022

408 Background: JCOG1202 (UMIN000011688) is a randomized phase III trial conducted in patients (pts) with biliary tract cancers (BTCs) that showed the superiority of adjuvant S-1, in terms of the overall survival (OS). Previous reports have suggested that major hepatectomy (MH) may affect the dose intensity as well as frequency of adverse events (AEs) and reduce the treatment efficacy of chemotherapy, due to impaired liver function and drug metabolism. Therefore, we investigated whether MH might affect the feasibility of adjuvant S-1 chemotherapy. Methods: Among the 440 pts enrolled in the JCOG1202 study, 207 pts who received adjuvant S-1 were included in this analysis. We compared the rate of treatment completion, the frequency of AEs, and the dose intensity of adjuvant S-1 after MH versus non-major hepatectomy (NMH). MH was defined as right hemi-hepatectomy, right trisectionectomy, left trisectionectomy, and central bi-sectionectomy, with or without pancreatoduodenectomy. Results: Of the 207 pts, 42 pts had undergone MH and 165 pts had undergone NMH. The primary cancers in the MH group were mainly intrahepatic cholangiocarcinoma and hilar cholangiocarcinoma. The pretreatment characteristics of the pts were as follows: performance status 0 (MH vs. NMH: 81.0% vs. 89.1%), biliary reconstruction (performed: 81.0% vs. 82.4%), time from hepatectomy to initiation of adjuvant S-1 therapy (median: 60 vs. 57 days), platelet count (17.7 vs. 23.4 x 104/μL), and serum albumin (3.5 vs. 3.8 g/dL). The treatment completion proportion was lower in the MH group as compared to the NMH group (59.5% vs. 75.8%; treatment completion ratio, 0.786 (95% CI, 0.603-1.023), p = 0.0733), and the median dose intensity was lower in the MH group than in the NMH group (90% vs. 100%, p = 0.0358). The proportion of pts who discontinued adjuvant S-1 due to occurrence of AEs in the MH group vs. the NMH group was 23.8% vs. 10.3%. The major reasons for treatment discontinuation were biliary infection, nausea/vomiting, and diarrhea; these AEs were mainly observed in the first cycle; the frequency of grade 3-4 biliary infection during adjuvant S-1 therapy was 19.0% in the MH group versus 4.2% in the NMH group. Conclusions: In regard to adjuvant S-1 therapy for pts with resected BTC, the treatment completion proportion and dose intensity were lower in the MH group as compared to the NMH group. Caution should be exercised against the development of biliary infections during postoperative adjuvant S-1 therapy after MH in BTC pts.
Efficacy and safety of lenvatinib in patients with recurrent hepatocellular carcinoma after liver transplantation: A retrospective analysis.
Authors: Bang Kyunghye , Yoo Changhoon , Ryu Min-Hee , Park Sook Ryun , Kim Hyung-Don , Ryoo Baek-Yeol 
Published: January 2022

410 Background: Lenvatinib is approved for use in patients with metastatic or recurrent hepatocellular carcinoma (HCC); however, its clinical outcomes in patients experiencing HCC recurrence after liver transplantation (LT), remain unclear. Further, despite of immunotherapeutic advances (atezolizumab plus bevacizumab, pembrolizumab, and nivolumab) in the management of advanced HCC, patients with prior LT are not benefited because of the risk of allograft rejection, and they are also excluded in the most prospective clinical trials for novel agents. Thus, we investigated the efficacy and safety of lenvatinib treatment in patients with recurrent HCC after LT. Methods: This single center, retrospective study included 22 patients with recurrent HCC after LT who received lenvatinib at the Asan Medical Center, South Korea, between November 2019 and March 2021. Lenvatinib was given 12mg/day for bodyweight ≥ 60 kg or 8 mg/day for bodyweight < 60 kg. Response and adverse events (AEs) were graded according to RECIST v1.1 and NCI CTCAE v5.0. Results: The median age was 58 years (range, 20-69) and 95.5% (n = 21) were male. Most common etiology of HCC was hepatitis B (n = 18, 81.8%). The median time to recurrence after LT was 6.6 months (95% CI, 4.2-9.1 months). Prior to systemic therapy, transarterial embolization (TACE) (n = 12, 54.5%) was the most commonly used therapy for recurred HCC after LT. At the time of lenvatinib initiation, 95.5% (n = 21) of the patients were Child-Pugh A with 15 (68.2%) and 7 (31.8%) patients classified as ALBI grades 1 and 2, respectively. All patients were at BCLC stage C and lenvatinib was administered as first-line (n = 19) and second-line (n = 3) therapy. The objective response rate (ORR) was 13.6%. With a median follow-up duration of 5.2 months (range, 1.7-14.5 months), the median progression-free survival (PFS) was 6.6 months (95% CI: 3.6-9.5 months) and overall survival (OS) was 14.5 months (95% CI: not assessable). The 6-month PFS and OS rates were 59.8% and 88.8%, respectively. Patients with ALBI grade 2 showed significantly poorer OS [11.1 months (95% CI: not assessable)] compared to patients with ALBI grade 1 [14.5 months (95% CI: not assessable)] ( p= 0.011). AEs were hypertension (n = 8, 36.4%), thrombocytopenia (n = 7, 31.8%), and fatigue (n = 6, 27.3%). Conclusions: Lenvatinib was effective and showed manageable toxicities in patients with recurrent HCC after LT. These outcomes are comparable to those from the pivotal REFLECT trial where patients with LT were excluded. Better baseline liver function (ALBI grade 1) at lenvatinib initiation correlated with better survival outcomes.
Clinical outcomes in patients (pts) with previously treated advanced hepatocellular carcinoma (HCC) experiencing hepatitis B virus (HBV) DNA increases during tislelizumab (TIS) treatment in RATIONALE-208.
Authors: Cheng Ann-Lii , Hou Jinlin , Fang Weijia , Li Zhiwei , Hu Sheng , Pan Hongming , Chen Yajin , Hsu Chiun , Bai Yuxian , Meng Zhiqiang , Hou Ming-Mo , Xie Congying , Liu Yong , Wu John , Li Bai , Chica-Duque Sandra , Ren Zhenggang 
Published: January 2022

411 Background: The effect of checkpoint inhibitor therapy on HBV infection is uncertain. TIS, an anti-PD-1 antibody, was clinically active and well tolerated in pts with previously treated advanced HCC in the phase 2 RATIONALE-208 study (NCT03419897). Objective response rate by independent committee review (IRC) in pts with a history of HBV infection was consistent with the overall population (12.5% vs. 13.3%, respectively). We explored whether TIS treatment was associated with increased HBV DNA and the clinical significance of HBV DNA elevations. Methods: Pts with ≥ 1 prior systemic therapy for advanced HCC received TIS 200 mg IV Q3W. Pts with inactive, chronic, or active HBV were eligible if HBV DNA levels were < 500 IU/mL at screening (pts with detectable hepatitis B surface antigen [HBsAg] or detectable HBV DNA were required to be managed per treatment guidelines). HBV DNA testing was conducted every 4 cycles if HBV DNA was detectable at screening, or when clinically indicated. Results: Among 249 enrolled pts, 128 had a history of HBV infection. Of these pts, 114 were HBsAg positive at baseline (BL), 36 had detectable HBV DNA at BL, and 32 had detectable HBV DNA and HBsAg at BL. Clinically significant increases in HBV DNA levels from BL were reported in 7 pts, with no pattern relative to the time of TIS initiation (Table). All 7 pts were HBsAg positive at BL and had been receiving antiviral treatment for ≥ 3 months before the first dose of TIS. Six out of the 7 pts had increases in alanine transaminase (ALT) from BL during the study (Table), 4 of whom had ≥ 3-fold increases in ALT which were observed concurrently or soon after HBV DNA increases. IRC-assessed best overall response (BOR) was partial response (PR) for 1 pt with increased HBV DNA and progressive disease for the remaining 6. HBV-related treatment-emergent adverse events (TEAEs) were reported in 6 of the 7 pts (2 pts had a grade 3 TEAE of hepatitis B; 2 pts had a grade 2 TEAE of HBV reactivation; 2 pts had a TEAE of increased HBV DNA, with one grade 1 and one grade 3 event). All HBV-related TEAEs were non-serious and did not result in discontinuation of TIS. Conclusions: Clinically significant increases in HBV DNA from BL were reported in a small number of pts, which does not suggest that TIS is associated with increased HBV DNA. Tumor responses in these pts were consistent with the overall population and HBV-related TEAEs were manageable and did not require discontinuation of TIS, demonstrating that HBV DNA increases did not impact treatment. The effects of TIS in pts with HBV infection will be further investigated in an ongoing phase 3 trial (NCT03412773). Clinical trial information: NCT03419897. [Table: see text]
Liver-directed concurrent chemoradiotherapy versus sorafenib in hepatocellular carcinoma with portal vein tumor thrombus.
Authors: Kim Jina , Byun Hwa Kyung , Kim Tae Hyung , Kim Sun Il , Kim Beom Kyung , Kim Do Young , Seong Jinsil 
Published: January 2022

424 Background: This study aimed to investigate the efficacy of liver-directed concurrent chemoradiotherapy (LD-CCRT) compared with sorafenib in patients with liver-confined locally advanced hepatocellular carcinoma (HCC) with portal vein tumor thrombus (PVTT). Methods: Patients treated with sorafenib and LD-CCRT between 2005 and 2016 were reviewed. Patients with extrahepatic disease and those without PVTT were excluded, leaving 28 and 448 patients in the sorafenib and LD-CCRT groups, respectively. Propensity score matching was performed to balance the differences in clinical features between the two groups. Results: At baseline, the sorafenib group presented higher incidences of unfavorable clinical features, including type 3-4 PVTT (53.6% vs. 30.6%) and bilateral disease extent (64.3% vs. 31.5%), than the LD-CCRT group. A total of 27 patients from the sorafenib group and 52 patients from the LD-CCRT group were matched. At a median follow-up duration of 73 months (range, 11-110 months), the median overall survival (OS) was 4.0 and 8.7 months in the sorafenib and LD-CCRT groups, respectively (p = 0.001). The Cox proportional hazard model showed that LD-CCRT was a significant prognostic factor for OS. One patient from the sorafenib group and seven patients from the LD-CCRT group underwent surgical treatment (liver transplantation or liver resection). Patients who underwent surgical treatment had significantly longer OS than those who did not undergo surgery. Conclusions: LD-CCRT showed superior survival outcomes to sorafenib in HCC patients with PVTT. LD-CCRT could be an efficient means of local tumor control that can enable surgical treatment with a curative intent in selected patients.