bluuebunny/crossref_metadata_2025_split huggingface dataset:
Efficacy and safety of anlotinib with or without PD-1 blockades in the treatment of advanced primary hepatocellular carcinoma (HCC): A real-world exploratory study.
Authors: Chen Xiao-Qi , Zhao Yun-Xia , Zhang Chuan-Lei , Wang Xin-Ting , Yuan Chang-Wei , Ji Ai-Ying , Chen Xin-Ju 
Published: January 2022

432 Background: Half of the new cases and deaths of HCC was observed in China all over the world in 2020. However, the prognosis of traditional treatments for patients (pts) with HCC was dismal currently. Small-molecule anti-angiogenesis targeted drugs and PD-1 blockades were proved to demonstrate potential efficacy in advanced primary HCC. Anlotinib was a novel oral multi-targeted tyrosine kinase inhibitor for tumor angiogenesis and proliferation, which had been licensed for treatment of considerable malignancies in China. However, the real-world evidence of anlotinib and PD-1 blockades in HCC was still scanty currently. Consequently, the aim of this study was to investigate the efficacy and toxicity of anlotinib with or without PD-1 blockades in the treatment of advanced primary HCC in real-world. Methods: Pts with advanced primary HCC who received at least 2 cycles of anlotinib (8̃12mg, po, d1̃14, q3w) were recruited in this study. Clinical efficacy and survival data was summarized, adverse events were documented retrospectively. The tumor response was assessed by investigator according to RECIST version 1.1 using CT scans. The primary endpoint was objective response rate (ORR), secondary endpoints were disease control rate (DCR), progression-free survival (PFS), overall survival (OS) and safety. Results: From Jul 2019 to May 2021, a total of 28 eligible pts were screened. Among them, 12 pts received anlotinib as first-line treatment, 9 pts as second-line treatment and 7 pts as third-line treatment and above. In best overall response assessment, there were 5 CR (17.8%), 2 PR (7.1%), 13 SD (46.4%), 7 PD (25.0%) and 1 NE (3.5%). ORR was 25.0% (95%CI: 10.7̃44.9%) and DCR was 71.4% (95%CI: 55.3̃86.8%). At the data cut-off date, 15 pts discontinued treatment due to disease progression, the preliminarily prognostic results indicated that the median PFS of the 28 pts was 4.93 months (95%CI: 1.60̃8.26), and the median OS was 13.21 months (95%CI: 10.77̃15.65). Specifically, 14 pts combined with PD-1 blockades treatment, ORR was 28.6% (95%CI: 8.4̃58.1%) and DCR was 71.4% (95%CI: 41.9̃91.6%). The remaining 14 pts failed to receive PD-1 blockade combination therapy with the ORR of 21.4% (95%CI: 4.7̃50.8%) and DCR of 71.4% (95%CI: 41.9̃91.6%). The safety profile suggested that the most common drug-related adverse events were decreased appetite, fatigue, thrombocytopenia, hypertension, diarrhea, anemia, hand-foot syndrome, proteinuria and bleeding. The common grade 3 adverse event was bleeding (10.7%). Conclusions: Present study indicated that anlotinib-related regimens in the treatment of advanced primary HCC exhibited potential efficacy and manageable adverse events in real-world setting. The conclusion should be validated in more pts included subsequently.
Regorafenib in patients with unresectable hepatocellular carcinoma (uHCC) in routine clinical practice: Exploratory analysis of overall survival (OS) in the prospective, observational REFINE study.
Authors: Finn Richard S. , Kudo Masatoshi , Klümpen Heinz-Josef , Lim Ho Yeong , Merle Philippe , Ikeda Masafumi , Masi Gianluca , Frenette Catherine T. , Kim Yoon Jun , Gerolami René , Kurosaki Masayuki , Numata Kazushi , Pisarenko Julia , Ozgurdal Kirhan , Qin Shukui 
Published: January 2022

433 Background: Regorafenib improved OS versus placebo in patients with uHCC who progressed on prior sorafenib in the RESORCE trial (Bruix J, 2017). An interim analysis of the observational REFINE study supported the safety and effectiveness of regorafenib in patients with uHCC in real-world clinical practice (Lim HY, 2021). Here we present an exploratory analysis of OS in REFINE by prior treatment. Methods: REFINE is a multicenter study that enrolled patients with uHCC for whom a decision to treat with regorafenib is made by the treating physician prior to enrollment according to the local health authority approved label. The primary objective of this study is safety, including the incidences of treatment-emergent adverse events (TEAEs) and dose modifications due to TEAEs (NCI-CTCAE v4.03). The secondary endpoints include OS, progression-free survival, and treatment duration. Results: Of the 1,031 patients enrolled, 1,008 were evaluable for interim analysis. At baseline, median age was 66 years (range 21–94); 62% of patients were Barcelona Clinic Liver Cancer stage C; 62% had Child–Pugh A disease; and 83% had an Eastern Cooperative Oncology Group performance status of 0 or 1. In total, 99% of patients received prior treatment: 96% had prior sorafenib, 9% had ≥1 prior immunotherapy (most common: nivolumab [50%] and pembrolizumab [21%]), and 6% had a multikinase inhibitor other than sorafenib (lenvatinib [62%]). The majority of patients experienced TEAEs (91%) and drug-related TEAEs (73%). Median OS was 12.9 months (95% confidence interval [CI] 11.4, 14.6). Subgroup analyses of OS by prior treatment are shown (Table). Conclusions: REFINE reflects the changing treatment landscape and supports the safety and effectiveness of regorafenib in real-world patients with uHCC who had prior systemic treatment other than sorafenib, including immunotherapy. This interim analysis suggests that patients who received regorafenib in the second line had longer OS than patients who received regorafenib in the third line and beyond. Clinical trial information: NCT03289273. [Table: see text]
Indirect treatment comparison of futibatinib with chemotherapy and pemigatinib in cholangiocarcinoma with FGFR2 fusions/rearrangements.
Authors: Borad Mitesh J. , Paine Abigail , Wacheck Volker , He Yaohua , Kazerooni Reza , Salimi Tehseen , Bridgewater John A. 
Published: January 2022

440 Background: Futibatinib, an irreversible FGFR1–4 inhibitor, is being investigated for the treatment of advanced intrahepatic cholangiocarcinoma (iCC) with FGFR2 fusions/rearrangements. We conducted an indirect treatment comparison to evaluate efficacy outcomes with futibatinib for advanced iCC patients from the FOENIX-CCA2 trial (NCT02052778) relative to published data for chemotherapy and FGFR inhibitors. Methods: A systematic literature review was conducted to identify clinical trials for FGFR inhibitors published 01/2015-02/2021, with additional targeted searches for chemotherapy data. A simulated treatment comparison was conducted using individual-level patient data from FOENIX-CCA2 and published aggregate data from comparator trials, applying regression models to adjust for between-trial differences in baseline characteristics. Population-adjusted Cox regression models were used for base case time-to-event outcomes (progression-free survival [PFS], overall survival [OS], duration of response [DOR]) and binomial-logistic regressions for binary outcomes (objective response rate [ORR]). Results: Two studies of FGFR inhibitors among previously treated patients with FGFR2 fusions/rearrangements were identified with sufficient data for analysis: FOENIX-CCA2 (n=103) and FIGHT-202 (n=107, pemigatinib). Two studies were identified for chemotherapy in this setting (an analysis of prior systemic therapy in the FIGHT-202 cohort [n=53] and a natural history study using a clinicogenomic database [n=71]). Comparisons of futibatinib with chemotherapy showed significantly lower risk of progression or death with futibatinib (table). Comparisons of futibatinib with pemigatinib showed similar outcomes between treatments (table), however, there was a numerical advantage for futibatinib in all efficacy parameters. Conclusions: Data suggest that futibatinib provides longer survival vs chemotherapy among previously treated advanced iCC patients with FGFR2 fusions/rearrangements. No statistically significant differences were observed in efficacy outcomes between futibatinib and pemigatinib, although numerical trends favored futibatinib. Molecular detail such as improved activity against co-mutated tumours and resistance mutations may explain such trends. [Table: see text]
Phase II study of gemcitabine with oxaliplatin (GEMOX) in heavily treated patients with advanced hepatocellular carcinoma after failure of sorafenib treatment (PEACH).
Authors: Lee Choong-kun , Kim Han Sang , Choi Hye Jin 
Published: January 2022

456 Background: Recent advances in treatment of advanced hepatocellular carcinoma (HCC) includes novel immunotherapy and anti-angiogenic tyrosine kinases. However, there is no treatment option for the heavily treated HCC patients, and the role of cytotoxic chemotherapy regimens, such as oxaliplatin based doublets, are unknown. We aimed to investigate the antitumor activity of gemcitabine and oxaliplatin in advanced HCC patients who failed sorafenib treatment. Methods: This prospective single-arm, single-center phase II trial was conducted in Yonsei Cancer Center, Korea. Gemcitabine 1000mg/m2 IV D1 and oxaliplatin 100mg/m2 IV D1 were given every 2 weeks to Child Pugh Class A or B7 HCC patients who progressed after or cannot tolerate sorafenib treatment. Patients with HCC of >60% liver occupation or portal vein invasion at the main portal branch (Vp4) were excluded. The primary endpoint was progression-free survival (PFS) rate at 6months and the secondary endpoints included PFS, overall survival (OS), objective response rate (ORR), disease control rate (DCR), safety profile, and exploratory molecular biomarker analysis. Results: Total of 32 patients were treated between May 2015 and July 2019 with median follow up of 10.2 months. Most of the patients were ECOG PS 1 (93.8%), B-viral (90.6%), and BCLC-C (96.9%). Patients had multiple distant metastatic sites including lung (81.2%) and lymph node (34.3%). Patients were heavily treated with 25% of patients treated as fourth-line and 18.7% of patients treated as fifth-line or later. The PFS rate at 6 months was 15.6%. Median PFS was 3.87 months and median OS was 10.5 months. 9.4% of the patients achieved partial response, and DCR was 65.6%. Median number of treatment cycles were 6 (range, 3 to 25). Treatment-related AE (≥G3) occurred in 15 patients (46.9%) including 5 patients (15.6%) with asthenia, 5 patients (15.6%) with sensory neuropathy, and 4 patients (12.5%) with thrombocytopenia. Conclusions: Gemcitabine and oxaliplatin for sorafenib failed, heavily treated advanced HCC were tolerable and showed modest efficacy. Although novel agents are currently adopted in clinics to treat advanced HCC, gemcitabine and oxaliplatin could be considered as later-line treatment option for heavily treated HCC patients. Exploratory molecular biomarker analysis results will be presented.
Tumor treating fields (TTFields) in combination with sorafenib inhibit hepatocellular carcinoma in vitro and in vivo.
Authors: Potter Wyatt , Davidi Shiri , Jacobovitch Sara , Shteingauz Anna , Tempel-Brami Catherine , Zeevi Einav , Dor-On Eyal , Schneiderman Rosa S , Voloshin Tali , Tzchori Itai , Haber Adi , Giladi Moshe , Kinzel Adrian , Weinberg Uri , Palti Yoram 
Published: January 2022

464 Background: Hepatocellular carcinoma (HCC) is a highly malignant liver cancer and a leading cause of cancer related mortality. Sorafenib was the first approved systemic treatment for HCC, and remains one of few front-line treatments for this malignancy. Tumor treating fields (TTFields) are low intensity (1-3 V/cm), intermediate frequency (100-500 kHz), alternating electric fields that exert antimitotic effects on cancerous cells. Results of the phase 2 HEPANOVA study of TTFields (150 kHz) plus sorafenib for advanced HCC support investigation of TTFields in a randomized controlled phase 3 study. The current research aimed to describe the in vitro and in vivo efficacy of this combination and to elucidate details regarding the underlying mechanism of action. Methods: In vitro examinations were performed in HepG2 and Huh-7D12 human HCC cell lines, to which TTFields at a frequency of 150 kHz were applied using the inovitro system. Autophagy was examined by western blot and fluorescence detection of microtubule-associated protein light chain 3 (LC3) levels, an accepted autophagy marker. The effect of TTFields in combination with sorafenib was evaluated using cytotoxic, clonogenic, and apoptotic assays. In vivo, SD rats were inoculated orthotopically into the left hepatic lobe with N1S1 HCC cells. 7 days later, TTFields or sham (heat) were applied to the abdominal region of the rats, continuously for 6 days. Daily intraperitoneal injections of sorafenib (10 mg/kg/day) or vehicle were performed during this time. To determine tumor volume growth, MRI images were acquired before and after treatment. Levels of autophagy and apoptosis were examined in tumor sections by immunohistochemistry for LC3 and cleaved PARP, respectively. Results: Application of TTFields induced autophagy in HCC cells. TTFields delivery was cytotoxic to the cells, reduced their colony forming ability, and induced apoptosis while combination with sorafenib elevated these effects. In vivo, tumor volume increased 6-fold in control animals vs 1.6-fold in animals treated with TTFields plus sorafenib. This effect was accompanied by significantly elevated levels of cleaved PARP and LC3 within the tumors of treated relative to control rats. Conclusions: The results demonstrate induction of autophagy and apoptosis in HCC following treatment with TTFields. Concomitant application of TTFields with sorafenib enhanced efficacy via a mechanism that may involve overwhelming autophagy, in vitro and in vivo.
The CCK-B receptor: A novel target for therapy of hepatocellular carcinoma.
Authors: He Aiwu Ruth , Gay Martha D , Cao Hong , Chen Wenqiang , Kallakury Bhaskar , Smith Jill P 
Published: January 2022

466 Background: Today, the fastest growing cause of cancer-related death is hepatocellular carcinoma (HCC). Treatment with immune checkpoint antibodies has shown promise in HCC, but the response is still low at about 15%-20% as monotherapy. Our research laboratory discovered that the cholecystokinin-B receptor (CCK-BR) becomes over-expressed in the injured/ inflamed liver and is up-regulated in HCC. The primary aim of this study is to evaluate the effects of a CCK-BR antagonist, proglumide, alone and in combination with a PD-1 antibody (PD-1 Ab) on survival in HCC tumor-bearing mice and the tumor infiltrating T-cells. The secondary aim was to evaluate the frequency of CCK-BR expression in human HCC. Methods: RNA was extracted from murine RIL-175 HCC cells and subjected to qRT-PCR for gene expression of CCK-BRs, gastrin, and PD-L1. C57BL/6 mice (N = 40) were injected with RIL-175 HCC cells (100,000) subcutaneously. After one week when the mice had palpable tumors, they were divided into 4 groups (N = 10ea) of equal tumor size. Treatment included: controls-untreated drinking water; proglumide (0.1mg/ml) in drinking water; PD-1Ab (50µg, ip, days 7, 14, 21 with untreated water); and combination therapy with PD-1 Ab (as above) and proglumide water. Mice were euthanized when tumors reached a diameter of 20mm according to IACUC guidelines. Tumors were stained with a CD8 antibody to evaluate CD8+ tumor infiltrating T-cells. CCK-BR protein expression in human liver tissues and human HCC was evaluated by immunohistochemistry using a tissue microarray (US Biomax). Results: RIL-175 murine HCC cells exhibited increased expression of CCK-BR, gastrin, and PD-L1 by qRT-PCR. Survival of mice treated with the combination of proglumide and the PD-1 Ab was double that of the control mice and greater than proglumide or PD-1 Ab monotherapy. Compared to tumors of control mice, tumors of mice receiving proglumide monotherapy exhibited a 5-fold increase in CD8+ cells (P = 2.5x10-8), and there was a 12-fold increase in CD8+ T-cells in tumors of mice treated with the combination therapy (P = 4.7x10-17). In the human liver tissue microarray, immunoreactivity for the CCK-BR was negative in the normal human liver tissues and increased with the grade of HCC tumor (P = 0.0045) with 84.6% of grade-3 human HCC tissues staining positive for CCK-BR. Conclusions: The CCK-BR may provide a novel target for therapy in HCC. Treatment with the CCK-BR antagonist, proglumide, in combination with a PD-1 Ab appears to be synergistic improving the survival of mice by increasing the number of intratumoral CD8+ T-cells.
Molecular profiling to identify potential therapeutic targets in hepatocellular carcinoma.
Authors: Kundranda Madappa N. , Routh Josh , Kemkes Ariane C. , Turner Michelle , Therala Nishitha , Hall David W. , Flannery Cynthia A. , Evans Mark C. , De La O Jean-Paul , Thakkar Snehal Govind 
Published: January 2022

471 Background: Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer and is often diagnosed at an advanced stage with limited effective therapies. The advent of comprehensive genomic molecular profiling has the potential to identify novel therapeutic options in the treatment of HCC. In this descriptive clinical utility study, we evaluated the utility of the Oncotype MAP Pan-Cancer Tissue (MAP) test to identify potential therapeutic options, including clinical trials. Methods: Between October 2018 and October 2020, we identified 41 samples from patients with HCC submitted for MAP testing. The MAP test uses tumor tissue to identify single nucleotide variants, indels, copy number alterations, and select structural variants and fusions by next-generation sequencing (NGS) of a 257 gene panel. Tumor mutational burden and microsatellite instability are also determined. A custom immunohistochemical (IHC) panel is also performed. Results from NGS and IHC are run against a proprietary knowledgebase of genomic and proteomic data that includes FDA approvals, NCCN Recommendations and published biomarker data on potentially targetable alterations. Eligibility for ongoing clinical trials is determined using the NCI database. Results: Of the 41 samples, 37 (90%) met minimum tissue requirements (3mm2 and 15% tumor cellularity) for DNA sequencing. Of these 37 samples, 36 (97%) were successfully sequenced for NGS testing. Median turnaround time from the date of accessioning to the date of laboratory report was 5 days (interquartile range (IQR) 4-6 days). The most frequently identified genomic variants characterized as pathogenic, or unknown significance, were TP53, CTNNB1 and FAT1 genes. Thirty-two samples (86%) had a genomic alteration that could potentially direct treatment. Six samples (16%) had findings directing to an approved treatment for HCC, 4 (11%) had findings for an approved treatment of a different tumor type, and 22 (59%) had findings for one or more clinical trials. Conclusions: The Oncotype MAP Pan-Cancer Tissue test identified molecular variants that could be used to inform treatment decisions in 86% of HCC samples, including 16% to an approved HCC therapy. The Oncotype MAP test may be considered as another tool in the management of advanced HCC patients.
Plasma hPG80 (circulating progastrin) as a novel prognostic biomarker for hepatocellular carcinoma at early to intermediate stages (BCLC 0 to B).
Authors: Prieur Alexandre , Dupuy Marie , Iltache Sarah , Assenat Eric 
Published: January 2022

472 Background: Alpha-fetoprotein (AFP) is the most widely used biomarker for hepatocellular carcinoma (HCC) prognosis. However, AFP is not useful in establishing a prognosis for patients with a tumor in the early stages. hPG80 (circulating progastrin) is a tumor promoting peptide present in the blood of patients with various cancers including HCC, even at early stages. In this study, we evaluated the prognostic value of plasma hPG80 in patients with HCC at early and intermediate stages. Methods: A total of 79 HCC patients including 44 BCLC from 0 to A and 35 BCLC B managed with local or systemic treatments, (“Liverpool” biobank) were enrolled prospectively and analyzed retrospectively. hPG80 was quantified using DxPG80 Lab kit (ECS-Progastrin) with a limit of detection at 1 pM and AFP was quantified using Cobas E411 in the blood of HCC patients. An optimal cutoff value of hPG80 was identified at 4.5 pM by calculating the minimal p-value based on the log-rank method. For AFP, a cutoff of 100 ng/mL was used as for liver transplantation (Notarpaolo, 2016). The prognostic impact of hPG80 and AFP levels on patient overall survival (OS) was assessed using Kaplan-Meier curves and log-rank tests. Results: hPG80 was detected in 36 of 44 (81.8%) HCC patients at stages BCLC 0 to A and 29 of 35 (82.9%) at stage BCLC B by contrast to AFP present in only 5 (11.4%) and 9 (25.7%) patients respectively. The median of hPG80 was 5.7 pM (IQR: 1.7-22.4 pM) at stages BCLC 0 to A, 6.0 pM (IQR: 1.5-22.2 pM) at stage BCLC B and significantly different from a non-HCC age-range matched control group cohort (median value: 1.5 pM, IQR 0.6-3.2 pM, p < 0.0001). When combining BCLC 0 to B, the median OS for hPG80+ patients (n = 46) was significantly shorter than that of hPG80- patients (n = 33) (25 months versus undefined, HR: 3.07, 95% CI: 1.46-6.43; p = 0.0064). AFP+ patients were also significantly correlated with poorer OS (17.5 months versus undefined, HR: 3.16, 95% CI: 1.06-9.47; p = 0.0030). Then, we evaluated the prognostic significance of hPG80 in combination with AFP levels. hPG80+ patients with AFP > 100 ng/mL (n = 46) had a worse OS than that of patients with AFP < 100 ng/mL patients (n = 33) (15.8 months versus undefined, HR: 6.38, 95% CI: 1.74-23.41; p = 0.0052). Conclusions: Our findings show that hPG80 could serve as a new prognostic biomarker for HCC patients at early to intermediate stages. These results will need to be confirmed in a prospective study, but it opens the possibility to use hPG80 as a biomarker for HCC patients at early stage at a time they can be treated to be cured.