bluuebunny/crossref_metadata_2025_split huggingface dataset:
The impact of previous local therapy (LT) on overall survival (OS) in patients with advanced hepatocellular carcinoma (aHCC) treated with atezolizumab/bevacizumab (A+B) as first line systemic therapy.
Authors: Fierro Maria Elena , Alkadimi Munaf , Boyle Lauren Diaz , Lucero Kana , Mader Michael , Franklin Kathleen , Nooruddin Zohra 
Published: June 2023

e16129 Background: Treatment options for aHCC have drastically improved over the past few years with immunotherapy at the forefront. Ongoing studies aim to identify the benefit of immunotherapy in combination with local therapies, but there are no studies that analyze the impact of previous local therapy on OS in patients who later receive A+B for treatment of aHCC. This study aims to analyze the impact of previous local therapy on OS in patients with aHCC treated with first line A+B within the Veterans Health Administration (VHA). Methods: Patients with aHCC receiving first line systemic therapy with A+B at VHA between Dec 1, 2019 through Mar 1, 2022 were identified from the electronic medical record (EMR) using ICD-9 and ICD-10 codes. Abstractors reviewed the EMR and followed the patients from the date of diagnosis, date of local treatment and date of A+ B initiation until death or their last VHA visit with the study period ending on Jan 31, 2023. The Chi-Squared test was used to compare rates and the Mann-Whitney test was used to compare medians. Results: 332 patients with aHCC received A+B. 67% of patients received prior LT. Patients who received LT had better ECOG status, Child-Pugh classification, and BCLC staging at time of diagnosis. There was no difference in age at diagnosis, race/ethnicity, ALBI score at time of diagnosis or at time of starting A+B, or presence of extrahepatic spread at time of starting A+B. There was a statistically significant difference in time from HCC diagnosis to start of A+B, with patients who received LT having a longer interval time. There was a small but not statistically significant difference in median OS from the start of A+B, favoring people who received LT. Conclusions: Our unique retrospective study confirms that patients receiving LT have better OS from the time of diagnosis. Disease biology and LT response may be contributing to this survival benefit. However, the OS was similar from the time of initiation of A+B in patients receiving LT versus patients who did not receive any LT.[Table: see text]
Novel peptide binder to Glypican-3 for targeted radiopharmaceutical therapy of hepatocellular carcinoma.
Authors: Li Gary , Lin Fanching , Clift Renee , Ehara Takeru , Yanagida Hayato , Horton Steven , Salvador Katrina , Richardson Samantha , Guest Matt , Noncovich Alain , Bhat Abhijit , Han Guangzhou 
Published: June 2023

e16131 Background: Glypican-3 (GPC3) is a membrane-associated heparan sulfate proteoglycan primarily involved in embryonic development, and is barely detectable in normal adult tissues. Significant upregulation of GPC3 protein in hepatocellular carcinomas (HCC) has been observed in multiple immunohistochemistry (IHC) studies with up to 75% positivity rate, and is associated with poor prognosis. GPC3 is not expressed in healthy or non-malignant liver tissue. Targeting GPC3 could fulfill an unmet medical need for HCC, a leading cause of cancer-related deaths worldwide for which efficacious therapies are lacking. The differential expression of GPC3 between tumor and normal tissues provides an opportunity for GPC3-targeted radiopharmaceutical therapy (RPT) to treat HCC. Methods: RAYZ-8009 is comprised of a novel macrocyclic peptide binder to GPC3, a linker, and chelator DOTA that can be complexed with different radioisotopes. The affinity of peptide binders to GPC3 was determined by surface plasma resonance (SPR), as well as a radioligand binding assay in human HCC cell line HepG2. The cross-species binding was assessed by radioligand binding using recombinant mouse, cynomolgus monkey, and human GPC3 proteins. Target-mediated internalization in HepG2 cells was measured using Microbeta at various time points. In vivo biodistribution with 177Lu, and anti-tumor efficacy studies using 225Ac were performed in HepG2 tumor-bearing athymic nude mice. Results: RAYZ-8009 showed high binding affinity to human GPC3 with a KD of 0.7 nM as determined by SPR. Binding affinity was maintained across mouse, cynomolgus monkey and human GPC3. Potent cellular binding was confirmed in GPC3+ HepG2 cells, and was independent of choice of isotope. 177Lu-RAYZ-8009 showed fast and efficient internalization with 42% internalized by 20 minutes in HepG2 cells. In vivo biodistribution of 177Lu-RAYZ-8009 showed tumor uptake of 19.8, 16.6, 16.4, and 8.8 %ID/g at 2, 24, 48, and 96 hours, respectively. Renal uptake was 16.1, 4.7, 1.6, and 0.7 %ID/g at the same timepoints, with tumor/kidney ratios of 1.3, 3.7, 11.3, and 15.0, respectively. Minimal uptake was observed in other normal tissues. Tumor-specific uptake and retention were also observed when tumors were implanted orthotopically with no uptake in non-malignant liver tissue. Furthermore, significant tumor growth inhibition and survival benefit were achieved with 225Ac-RAYZ-8009 in GPC3+ HCC xenografts. Conclusions: Preclinical pharmacodynamic, pharmacokinetic, biodistribution and efficacy data demonstrate the potential of RAYZ-8009 as a RPT agent for the treatment of patients with GPC3-positive HCC.
TACE combined with the intra-arterial infusion of sintilimab and bevacizumab for advanced hepatocellular carcinoma: A prospective, single-arm, phase II study.
Authors: Mu Maoyuan , Fu Xiaobo , Qi Han , Jiang Weiwei , Chen Zixiong , Gao Fei 
Published: June 2023

e16133 Background: Combination treatment with an immune checkpoint inhibitor and an anti-VEGF antibody is recommended as the standard care for advanced hepatocellular carcinoma (HCC). However, the efficacy of systemic therapy is less than satisfactory in BCLC stage C. Transarterial chemoembolization (TACE) combined with systemic therapy may synergistically improve patients’ clinical outcomes and obtain survival benefits. Intra-arterial infusion of Sintilimab and Bevacizumab has not been assessed previously. This study aimed to evaluate the safety and efficacy of TACE combined with the intra-arterial infusion of Sintilimab and Bevacizumab in patients with BCLC stage C HCC. Methods: This prospective, single-arm phase II study recruited 16 patients with advanced HCC. Main inclusion criteria: aged ≥ 18 years; a confirmed HCC (BCLC stage C) based on the ALSLD with either pathological or imaging findings; no previous systemic/locoregional anticancer treatment; Child-Pugh score ≤7; ECOG performance status: 0-1. Patients were treated with TACE (30-40mg of pirarubicin, 30-40mg of lobaplatin, and lipiodol) plus Sintilimab (200mg, intra-arterial infusion, d1, Q3W) and Bevacizumab (7.5mg/kg, intra-arterial infusion, d1, Q3W) for four cycles, followed by maintenance therapy with Sintilimab (200mg, intravenously, d1, Q3W) and Bevacizumab (15mg/kg, intravenously, d1, Q3W) to a maximum total cycle of eighteen unless any evidence of disease progression or unacceptable side effects. The primary endpoint was objective response rate (ORR) (assessed with mRECIST v1.1) and the secondary endpoints included disease control rate (DCR), time to progress (TTP), progression-free survival (PFS), duration of response (DOR), overall survival (OS) and safety. Drug safety was investigated according to CTCAE (version 5.0). Results: From September 2021 to December 2022, 16 patients with a median age of 52 years (range:38 -73) were enrolled. 12 (75%) patients with HBV infection and 6 (38%) with extrahepatic metastasis. 14 (88%) patients were classified as Child-Pugh A class. With a median follow-up of 5.4 months (range 3.9-14.3), the ORR was 63% (95%CI, 36.4%- 84.8%) with 3 CR and 7 PR per mRECIST v1.1, and the DCR was 69% (95%CI, 41.3%-89.0%). The median PFS was not reached. Adverse events in 31% of 16 patients were hypertension (3, 19%), fatigue (1, 6%), and proteinuria (1, 6%). The most common adverse event of grade 3 was hypertension (2, 13%). There were no treatment-related serious adverse events. Conclusions: TACE combined with the intra-arterial infusion of Sintilimab and Bevacizumab as the first-line strategy for advanced HCC patients (BCLC stage C) demonstrated a promising value by improving ORR, with acceptable side effects. Clinical trial information: NCT04796025 .
Anlotinib combined with transarterial chemoembolization for unresectable hepatocellular carcinoma associated with hepatitis B virus: A retrospective controlled study.
Authors: Guo Wenbo , Chen Song 
Published: June 2023

e16138 Background: Hepatocellular carcinoma (HCC) has the third-highest cancer-related mortality rate in the world because most patients are diagnosed at an intermediate to advanced stage when surgery is not suitable. Transcatheter arterial chemoembolization (TACE) is currently considered a first-line therapy for unresectable HCC (uHCC), while the efficacy of TACE alone for uHCC patients still needs to be improved. Anlotinib has shown survival benefits in the treatment of uHCC as a kind of novel tyrosine kinase inhibitors (TKIs) in previous studies. Therefore, we aimed to compare clinical outcomes of TACE combined with anlotinib versus TACE monotherapy in patients with uHCC associated with hepatitis B virus (HBV). Methods: We retrospectively collected the data of 96 uHCC patients associated with hepatitis B virus who received either TACE only (TO group; n = 64) or anlotinib combined with TACE (TA group; n = 32) between January 2017 to January 2021. The clinical outcomes including overall survival (OS), progression-free survival (PFS), and tumor response according to mRECIST and RECIST 1.1 were compared between the two groups. Adverse events (AEs) were analyzed to assess the safety profiles. Results: The median OS in the TA group was 17.6 months (95%CI, 11.3 to 24.3) versus 9.4 months (95% CI, 7.8 to 16.3) in the TO group (hazard ratio, 0.59; 95% CI, 0.39 to 0.90; p= 0.018). The median PFS was also significant longer in the TA group (6.7 vs. 3.8months; hazard ratio, 0.46; p< 0.001). Additionally, the objective response rate (ORR) and disease control rate (DCR) numerically increased in the TA group (mRECIST: ORR 65.6% vs. 46.9%, p= 0.064; DCR 90.6% vs. 85.9%, p= 0.382. RECIST 1.1: ORR 46.9% vs. 15.6%, p= 0.001; DCR 90.6% vs. 85.9%, p= 0.382; respectively). No treatment-related mortality occurred. The most common AEs included elevated transaminases (56.3%), decreased appetite (46.9%) and abdominal pain (37.5%) in TA group. Though the incidence rate of grade 3/4 was higher in TA group, all of them were acceptable and controllable. Conclusions: Anlotinib combined with TACE may significantly improve outcomes for uHCC patients associated with hepatitis B virus comparing with TACE monotherapy with a controllable safety profile. Randomized controlled trials with a large sample are warranted to further validate the efficacy.
Efficacy and safety of transarterial chemoembolization in combination with lenvatinib and tislelizumab for patients with unresectable BCLC-B stage hepatocellular carcinoma classified as beyond up to seven criteria: A retrospective study.
Authors: Chen Song , Guo Wenbo 
Published: June 2023

e16147 Background: Transarterial chemoembolization (TACE) is the preferred therapeutic regimen for patients with intermediated-stage (BCLC-B stage) unresectable hepatocellular carcinoma (uHCC). However, selected patients with high tumor burden have shown improved survival with systemic treatment, including targeted therapy, immunotherapy, or combination of them. This study was to evaluate the efficacy and safety of combination therapy for BCLC-B stage uHCC beyond up to seven criteria. Methods: In total, 120 patients enrolled in the study during 2015-2021, which were divided into 3 groups according to receive different treatment, and each group just comprised 40 patients. One group received treatment with TACE only (T group), and the other two groups received TACE combined with Lenvatinib (T+L group) and TACE combined with Lenvatinib and tislelizumab (T+L+P group) respectively. We retrospectively compared the clinical outcomes including overall survival (OS), progression-free survival (PFS) and tumor response among the three groups. Both PFS and tumor response were based on the modified Response Evaluation Criteria in Solid Tumors (mRECIST). Besides, adverse events were collected to assess the safety as well. Results: The median duration of follow-up for all the patients was 28 months [95% CI, 22.8-34.2 months]. The median OS (mOS) was 24.2 months among patients in T+L+P group, as compared with15.0 months among patients receiving TACE alone (HR 0.32; 95%CI 0.19-0.55; P<0.001). The mOS was 20.6 months in T+L group (HR in comparison with TACE only, 0.54; 95%CI 0.34-0.85; P=0.008). The mOS was longer in T+L+P group comparing with T+L group (HR 0.49; 95%CI 0.29-0.85, P=0.011). The similar median PFS (mPFS) benefit was also detected among 3 groups (T+L+P vs. T HR 0.35; 95%CI 0.21-0.58; P<0.001. T+L vs. T HR 0.57; 95%CI 0.36-0.90; P=0.007. T+L+P vs. T+L HR 0.53; 95%CI 0.33-0.84; P=0.003). There was no significant statistic difference observed in objective response rate (ORR) and disease control rate (DCR) between each two groups ( P>0.05). Grade 3 or 4 adverse events (AEs) occurred more common in T+L group or T+L+P group, which was mainly due to target-related or immune-related AEs. There was no mortality happened related to treatment. Conclusions: TACE combined with lenvatinib and tislelizumab may significantly improve clinical outcomes both compared with TACE alone and TACE combined with lenvatinib with a manageable safety profile for BCLC-B stage uHCC beyond up to seven criteria. Nevertheless, it is necessary to be validated by means of prospective randomized control studies in future.
HER3 expression status following systemic chemotherapy treatment in biliary tract cancers.
Authors: Nishioka Mariko , Morizane Chigusa , Okada Mao , Satake Tomoyuki , Hiraoka Nobuyoshi , Nara Satoshi , Kakegawa Tomoya , Kobayashi Maki , Koyama Kumiko , Esaki Minoru , Okusaka Takuji 
Published: June 2023

e16153 Background: Erb-b2 receptor tyrosine kinase 3 (HER3) is frequently overexpressed in a variety of cancers. Activation of HER3 signaling serves an important role in promoting cell proliferation and is associated with chemoresistance. Thus, there is interest in exploring HER3 status of tumors as a potential prognostic and/or therapeutic target. Prior studies have reported HER3 status in various cancers after treatment with chemotherapy (CT). However, HER3 expression profile in biliary tract cancer (BTC) remains unknown. Here, we evaluated HER3 status of patients with BTC post CT. Methods: The medical records of patients (pts) who had been initially diagnosed with BTC and treated at the National Cancer Center Hospital (Tokyo, Japan), between January 2010 and June 2020, were retrospectively analyzed. Pts whose post CT specimens were available were included in this study. Immunohistochemical staining for HER3 was performed using HER3/ErbB3 (D22C5) XP Rabbit mAb (Cell Signaling Technology) as a primary antibody. IHC scoring (0, 1+, 2+, 3+) of membranous staining intensity was performed according to HER2 IHC gastric scoring guideline. Results: A total of 19 pts with BTC, with a median age of 59 (range 44-79) years, had specimens available after post CT and were evaluated for HER3 expression status. HER3 status was 3+ in 10 pts, 2+ in 3 pts, 1+ in 4 pts, and 0 in 2 pts. The specimens were obtained from liver in 17 pts, bone in 1 pt, and omental lymph node in 1 pt. The histological type was adenocarcinoma in all pts, and HER3 status according to primary tumor type is shown in the table below. Fourteen pts were treated with gemcitabine (GEM) plus cisplatin (CDDP), 1 pt with GEM plus CDDP plus S-1, 1 pt with GEM plus S-1 as first-line CT for advanced BTC, and 3 pts with S-1 as an adjuvant treatment. Fifteen pts were biopsied after CT to participate in clinical trial. The remaining 4 obtained specimens after CT during primary surgery or surgery for metastases or for cholangitis. The median overall survival of pts with advanced BTC was 23.6 months in HER3 3+, 17.1 months in HER3 2+, 27.7 months in HER3 1+, and 24.6 months in HER3 0. Four pts had specimens available from pre and post CT, all of which were intrahepatic cholangiocarcinoma with the treatment of GEM plus CDDP. HER3 status was upregulated in 3 pts (1 pt 1+ to 2+, 2 pts 2+ to 3+) and downregulated in 1 pt (1+ to 0) at post CT. Conclusions: HER3 expression (1+, 2+, 3+) was observed in 89.5% of previously treated pts with BTC, and HER3 status was upregulated after CT in some pts. These results suggest that HER3 might be a potential therapeutic target in BTC post CT. [Table: see text]
Real-world experience and outcomes of immune-checkpoint inhibitors (ICI) in hepatocellular carcinoma (HCC).
Authors: Paul Samuel , Min Eric , Benson Katherine K , Xu Menglin , Noonan Anne M. , Mittra Arjun , Malalur Pannaga G. , Roychowdhury Sameek , Jin Ning , Hays John L. , Elkhatib Rifat T. , Rahman Shafia , Miller Eric David , Diaz Pardo Dayssy Alexandra , Manne Ashish 
Published: June 2023

e16155 Background: Effective management of HCC needs concerted efforts of all the disciplines involved. ICI and its combinations have not improved the outcomes to the expected level outside clinical trials. This is a retrospective review of HCC patients treated with ICI in an academic institution. Methods: HCC patients who received at least one ICI dose between 1/1/2017 and 7/31/2021 at the Ohio State University were included in the study. The patient's baseline (BL) characteristics (at the first dose of ICI) were extracted with immune-related adverse events (irAE) details and survival outcomes. Descriptive statistics were used, Fisher exact test to compare categorical variables, log-rank test rank test for survival outcomes, and logistic regression model for categorical outcomes using JMP Pro 16 (SAS Institute Inc., Cary, NC). Results: Our cohort has 38 patients. The median age is 67 years (range 41-88), with 82% males and 90% Caucasians (7% African American and 3% other). Refer to the table for other BL characteristics. Median overall survival (OS) and progression-free survival were 6 months (m) (95% confidence interval [CI], 4-10) and 4m (95% CI, 3-6), respectively. The OS was better in patients with longer DoT (≤ 2m vs 3-6m vs ≥6m, 2m vs 5m vs 24m, p<0.001). Even though PFS was significantly better in patients with CP A-B9 (Vs B9-C, 6m vs 2.5m, p=0.03) and CP B (vs A vs C, 9m vs 5m vs 2m, p=0.02), OS was not different. Poor responders (<2 m vs ≥ 3m PFS) in this cohort had higher BL total bilirubin (TB) (p=0.03) and are more likely to have CPC (p=0.03) or CP B9-C (p=0.01) and BCLC D (p=0.04) patients. CP class (lower, p=0.0007), DoT (≥ 6m, p=0.0001), combination with bev (p=0.004), fewer liver lesions (≤2, < 0.001), no history of any LRT (p=0.01) or fewer LRTs (p=0.01), and non-metastatic disease (p< 0.001) are associated with better OS. PVTT, line of therapy, and ALBI G did not impact the OS. IrAE were reported just 4 (10%) patients. Conclusions: In this small retrospective cohort, lower volume of hepatic HCC lesions, use of ICI with bev, lower TB, longer DoT were associated with better OS, while more advanced disease, CPC, BCLC D, more LRTs and higher bilirubin resulted in worse survival. Our results suggest that prescribing ICI in line with FDA approval indications results in better outcomes. They must be validated in larger studies. [Table: see text]
Locoregional plus systemic therapy for unresectable intrahepatic cholangiocarcinoma: A systematic review and meta-analysis.
Authors: Qiu Zhenkang , Zhang Mengqi , Qiu Wensheng , Wang Song 
Published: June 2023

e16157 Background: The outcome of systemic therapy (ST) for unresectable intrahepatic cholangiocarcinoma (iCCA) is poor. This study aims to further evaluate the efficacy and safety of locoregional plus systemic therapy (LST) compared with only ST in unresectable iCCA by performing a systematic literature review and meta-analysis. Methods: A comprehensive search comparing LSTs and STs for unresectable iCCA was performed in PubMed, Web of Science, EMBASE, and the Cochrane Library up to November 3, 2022. The primary outcome was overall survival (OS), and the secondary outcomes were progression-free survival (PFS), objective response rate (ORR), and adverse events (AEs). Results: Ten cohort studies with 3,791 unresectable iCCA patients were enrolled in this study, including 1,120 who received ablation, arterially directed therapy (ADT), or radiotherapy (RT) combined with ST. The meta-analysis showed that the LST group had a longer OS ( HR = 0.51; 95% CI = 0.41–0.64; p value < 0.001) and PFS ( HR = 0.40, 95% CI = 0.22–0.71, p value = 0.002) and a better ORR ( RR = 1.68; 95% CI = 1.17–2.42; p value = 0.005). Subgroup analysis based on the type of locoregional treatment showed that both ST combined with ADT ( HR = 0.42, 95% CI = 0.31–0.56, p value < 0.001) and RT ( HR = 0.67, 95% CI = 0.63–0.72, p value < 0.001) could prolong OS. Combination with locoregional treatment does not result in additional severe AEs. Conclusions: Compared with only ST, LST improved survival outcomes for unresectable iCCA patients without increasing severe AEs, which can further provide a basis for guidelines.
Lenvatinib in combination with PD-1 inhibitor and hepatic arterial infusion chemotherapy (HAIC) for patients with potentially resectable hepatocellular carcinoma: A retrospective analysis.
Authors: Dong Wei , Zhang Songyan , Huo Zhuoni , Lu Junrong , Liu Haishi , Wang Ping , Zhang Yubao 
Published: June 2023

e16160 Background: Surgical resection is the primary radical treatment for hepatocellular carcinoma (HCC). However, the percentage of initially resectable HCC is only 15-30%, and most patients are unable to undergo surgical resection at the time of initial diagnosis. Lenvatinib combined with PD-1 inhibitor and transarterial intervention has demonstrated good efficacy and safety in unresectable HCC. The retrospective study was designed to explore the safety and conversion effects of lenvatinib + camrelizumab+ HAIC in potentially resectable HCC. Methods: In this single-arm retrospective study, investigators collected patients with potentially resectable HCC treated with lenvatinib + camrelizumab + HAIC from November 2020 to December 2022. The potentially resectable population was selected by the following screening criteria: acceptable liver function (Child-Pugh A-B), good ECOG PS (0-1), intrahepatic tumors confined to one lobe (left, right, or middle lobe), and unresectable by surgical or oncological causes. Results: A total of 64 patients with potentially resectable HCC were included in this analysis. The conversion rate was 31.25% (20), and 23.4% (15) patients underwent surgery. The ORR and DCR were 56.3% and 85.9% by RECIST 1.1. Progression had occurred in 8 patients by the data cutoff on November 1, 2022. The median follow-up time was 13.6 months (range: 2.9-23.7) and 8 patients died. The data was not yet mature, with 1-year survival rate of 90.7%, Overall, 65.6% of patients experienced at least one treatment emergent adverse event (TEAE) and 15.6% of patients had Grade 3/4 TEAE, the most common was hand and foot syndrome (7.8%, n=5). Conclusions: Lenvatinib combined with PD-1 inhibitor and HAIC was well tolerated and showed potential conversion efficacy in the treatment of patients with potentially resectable HCC.