bluuebunny/crossref_metadata_2025_split huggingface dataset:
Lenvatinib (LEN) combined with tislelizumab (TIS) plus transcatheter arterial chemoembolization (TACE) for unresectable hepatocellular carcinoma (uHCC): A single-arm, phase II clinical trial.
Authors: Nong Xiang , Zhang Yu-Mei , Liang Jing-Chang , Xie Jin-Long , Zhang Zhi-Ming 
Published: June 2023

4111 Background: uHCC still lacks effective treatments, combination of antiangiogenic targeted drugs and immune checkpoint inhibitors showed promising efficacy. TACE induces tumor necrosis and tumor antigen release, may synergize with immunotherapy. This study was to evaluate the efficacy and safety of TACE in combination with TIS and LEN in patients with uHCC. Methods: This study was a single-center, single-arm, open-label phase II exploratory clinical study (NCT05131698). Eligible patients were BCLC C stage and not candidates for surgical resection or liver transplantation, at least one target lesion evaluable, ECOG performance status of ≤ 1, and Child-pugh grade A or B. Enrolled patients received TACE treatment (loplatin + raltitrexed + iodine oil) followed by TIS (200 mg, IV, on Day 1 of a 21-day cycle) and LEN (body weight ≥ 60 kg: 12 mg/day; < 60 kg: 8 mg/day) daily. The primary endpoint was overall response rate (ORR) by mRECIST. The secondary endpoints included disease control rate (DCR), overall survival (OS), and progression-free survival (PFS) and safety. Results: As of December 28, 2022, 31 enrolled patients with uHCC were treated. Median follow-up time is 11.3 months. Among all patients with BCLC C, 28 patients (90.3%) had microvascular invasion and 17 (54.8%) had portal vein tumor thrombus. As assessed by mRECIST, the ORR and DCR were 71.1% and 87.1%, respectively (2 CR, 6.6%; 20 PR, 64.5%; 5 SD, 16.1%), 4 patients developed tumor progression (12.9%). As assessed by RECIST 1.1, the ORR and DCR were 67.7% and 87.1%, respectively (1 CR, 3.2%; 20 PR, 64.5%; 6 SD, 19.4%), 4 patients developed tumor progression (12.9%). The median PFS was 10.2 months（95% CI: 4.5-NA）, and the median OS was not reached. Any grade treatment-emergent adverse events (TEAEs) occurred in 64.5% (20/31) patients. The most common TEAEs were Increased γ-glutamyl transpeptidase (35%), Increased aspartate aminotransferase (32%), thrombopenia (25%). Only 2 patients experienced grade 3 TEAE (pneumonia). No serious adverse events (SAEs) were reported. Conclusions: In this study, TACE combined with TIS and LEN showed preliminary antitumor efficacy and tolerable safety profile in uHCC. Clinical trial information: NCT05131698 . [Table: see text]
Molecular subtypes from comprehensive clustering from multi-omics dataset to predict the therapeutic efficacy of immunotherapeutic agent-based treatments in advanced hepatocellular carcinoma.
Authors: Chon Hong Jae , Lee Sung Hwan , Kim Gwangil , Kang Haeyoun , Cheon Jaekyung , Kang Beodeul , Kim Chan 
Published: June 2023

4112 Background: In advanced hepatocellular carcinoma (HCC), combined treatment using anti-PD-L1 and anti-VEGF antibodies is a major therapeutic strategy in addition to using anti-PD-1 and anti-CTLA4 target agents. To identify clinically relevant molecular biomarkers for immunotherapeutic agents-based treatment in advanced HCC by comprehensive molecular profiling using genomics alterations and transcriptomic data. Methods: Multi-omics data from clinical tumor samples of patients treated with atezolizumab + bevacizumab (94 patients), nivolumab (40 patients), and ipilimumab + nivolumab (32 patients) were obtained from tumor biopsies or surgical resections in a single institution. The targeted panel sequencing was conducted via the Oncomine comprehensive assay (ThermoFisher, USA). QuantSeq mRNA sequencing (Lexogen, USA) was used to generate datasets for the genomic alterations and gene expression profiles. Results: A total of 166 target sequences for genomic alterations and 136 transcriptomic sequences were performed in patients with advanced HCC treated with immunotherapeutic agent-based treatment options. High tumor mutation burden was significantly associated with favorable therapeutic efficacy (disease control rate, P=0.036) and progression-free survival (P=0.037) in patients who had atezolizumab with bevacizumab treatment. The genomic alteration of CTNNB1 mutation correlated with the favorable therapeutic efficacy of nivolumab monotherapy (PFS, P=0.022), contrary to TP53 mutation (PFS, P=0.063) which demonstrated unfavorable outcomes. CD274(PD-L1) mRNA expression was significantly associated with a high drug response following nivolumab monotherapy (objective response rate, P=0.047) and oncologic outcomes (PFS, P=0.021). Interestingly, PLA2G4A, known as a downstream molecule of the VEGF signaling pathway, was highly correlated with unfavorable therapeutic efficacy of the combined atezolizumab with bevacizumab treatment (disease control rate, P=0.002) and related oncologic outcomes (PFS, P=0.003). We also identified the clinically relevant molecular subtypes from unbiased clustering using the ontologic pathway collection. We also used gene expression profiles to predict the therapeutic response and oncologic outcomes from immunotherapeutic agent-based treatment options. Conclusions: We identified clinically relevant molecular biomarkers from comprehensive clustering of a multi-omics dataset to predict the therapeutic efficacy and oncologic outcomes. Further prospective studies with clinical validation are warranted to confirm clinical implications.
Tracking the evolving ecosystem of recurrent hepatocellular carcinoma after liver transplantation.
Authors: Zhang Zijie , Wang Gaoyang , Ye Youqiong , Feng Hao , Xia Qiang 
Published: June 2023

4114 Background: Liver transplant (LT) contributes to the cure of hepatocellular carcinoma (HCC) by extending the conventional surgical margin, while removing the concurrent tumor-favoring conditions of the diseased liver. Over the past two decades, HCC has emerged as a preferable indication for LT, accounting for 22-45% of the cases globally. However, despite the stringent selection criteria, recurrence still occurs in a substantial proportion of patients, leaving 10-13 months of median survival after tumor relapse. To address this challenge, a thorough exploration of molecular mechanism behind HCC recurrence after LT is required. Here, for the first time, we performed a comprehensive analysis to depict the evolving and unique ecosystem of HCC in the context of LT and immunosuppressant (IS) administration. Methods: We retrospectively reviewed our biobank and collected 91 paired (primary tumors (PT) from the explant after LT and relapsed tumors (RT) from hepatectomy) FFPE tumor samples from 15 patients for whole exome sequencing (WES). Also, from Jan 2021, we prospectively collected surgical tumor specimens and their adjacent non-tumor tissues from 15 primary and 6 post-LT intrahepatic recurrence patients for single-cell RNA sequencing. Moreover, 6 paired samples from 3 patients were used for spatial transcriptomic analysis. Results: By analysing WES data, we confirmed that RT samples represent recurrent, instead of de novo tumors. Also, the phylogenetic analysis demonstrated strong clonal relationship between PT and RT based on shared SNVs. As to mutation landscape differences of PT and RT, we identified a significantly enriched mutation panel from RT, including MUC16, FAT3, APOB, COL6A3 and POTEC. And the accuracy of this panel for post-LT HCC recurrence surveillance using plasma derived cfDNA sequencing has been preliminarily validated in a prospective cohort of 17 patients. From the single-cell profiling, distinct immune microenvironment between PT and RT is identified. As predicted, proliferating T cells are decreased in RT due to IS. Pseudotime analysis of T cells revealed that T cells from PT mainly distribute at the terminal end of cytotoxic stage whereas T cells from RT mostly represent a naïve state, further confirming the T cell blocking effect of IS. In terms of myeloid cells, we surprisingly found that FOLR2+ tumor associated macrophages, which is conventionally considered as a favorable prognosis factor, is increased in RT. Spatial transcriptomics and IHC also confirmed their active interplay with tumor cells at invasive margin. We postulate that such increase might be a result of the healthy nature of liver graft. Conclusions: Our comprehensive dissection of the HCC ecosystem provides deeper insights into the tumor relapse after LT. Targeting novel mutations and strengthen the antigen presenting process between increased TAM and disabled T cells can be the future direction in this field. Clinical trial information: NCT04506398 .
Geographical and baseline clinical characteristics of participants enrolled in hepatocellular carcinoma (HCC) trials: Analysis of US FDA approvals.
Authors: Horiba M. Naomi , Gandhy Shruti U. , Casak Sandra J. , Lemery Steven , Kluetz Paul , Pazdur Richard , Fashoyin-Aje Lola A. 
Published: June 2023

4115 Background: Globalization of drug development is increasing, with reliance on data from patients accrued to large, randomized studies across continents. In addition to appropriate racial/ethnic representation, trials submitted to support FDA approvals should reflect the etiology and treatment patterns of HCC in the US. We conducted a pooled analysis of patient-level data from the HCC trials supporting approved marketing applications in the US to characterize geographical and baseline variables in clinical trials. Methods: Datasets from applications which received FDA approval for HCC between 2010-2022 were identified. The following data was abstracted: country, baseline disease characteristics (median age, HCC etiology, extent of tumor, and Child-Pugh score), and prior treatments received. Geographical region was recoded using categories observed by the United Nations M49 standard, based on country of enrollment reported in the datasets. Results: Variables that were defined differently across studies included region of enrollment, some categories of etiology, and prior therapy. Overall, the rate of HBV etiology was higher than that observed among patients with HCC in the US (20%), while the rate of HCV etiology was lower than in the US (50%). Conclusions: Variability in patient populations exist across trials submitted to FDA based on the regions that were targeted for enrollment and eligibility criteria. Global trials may be appropriate to support drug approvals for HCC; however, to ensure results are applicable to US patients, sponsors should select sites that represent a similar population with respect to racial/ethnic representation, disease etiology, and treatment patterns. [Table: see text]
Effect of MYC-targeting programmable epigenetic mRNA therapeutics on TME and immunotherapy responses.
Authors: Moore Yan , Senapedis William , Gallagher Kayleigh , Figueroa Elmer , Pacaro Madison , Yarar Defne , Lee Eugine , McCauley Thomas 
Published: June 2023

4116 Background: c-MYC is a master transcription factor (TF) critical for multiple cell physiologies. As a pleiotropic TF, MYC regulates the tumor microenvironment (TME) and impacts cancer cell initiation, growth, and survival. Although MYC expression is normally tightly controlled in normal cells, its activity is frequently dysregulated in cancer (e.g., HCC, NSCLC, Burkitt’s lymphoma). A direct MYC targeting anti-cancer agent has remained elusive, largely due the absence of a drug binding pocket and tight autoregulation. The MYC gene and its regulatory elements reside alone within an insulated genomic domain and represents a potential target for gene regulation via an epigenetic approach. Methods: We are developing programmable epigenetic mRNA medicines designed to controllably tune gene expression pre-transcriptionally with high specificity and durability. We have rationally designed MYC-targeted Omega Epigenomic (MYC-OEC: clinical candidate OTX-2002; MYC Lung OEC; mouse surrogate muMYC-OEC) to downregulate MYC expression, thereby selectively killing cancer cells while sparing normal cells. We investigated the role of MYC-OECs in the modulation of the TME and demonstrated in human and mouse tumor models that MYC-OECs enhanced the host immune response. Results: In HCC and NSCLC cell lines (Hep 3B, SKHEP1, H2009 and H460), treatment with MYC-OECs in vitro significantly inhibited PD-L1 surface expression. Using the muMYC-OEC in vivo, we demonstrated tumor growth inhibition (TGI) in Hepa1-6 liver cancer syngeneic tumor models with 70% of the mice exhibiting complete tumor response with good tolerability. Cancer cells used to rechallenge the cured mice failed to grow, demonstrating that muMYC-OEC monotherapy induced immune memory. In addition to inhibiting tumor growth with either muMYC-OEC or checkpoint blockade immunotherapy (CBI; anti-PD-1 or anti-PD-L1) treatment, combination therapy further enhanced TGI. Tumor-infiltrating lymphocyte profiling demonstrated an increase in activated T cells and a reduction in Tregs following combination treatment, resulting in an increased effector T cell to Treg ratio over monotherapy. Depletion of CD4+, CD8+ and NK cells in vivo prior to single agent or combination treatment demonstrated a requirement for both CD4+ and CD8+ T cell activity for TGI. NK cells were dispensable. Taken together, these data demonstrate that the improved CBI/MYC-OEC combination activity is mediated through the recruitment of activated T cells and reduction of immune suppressive Tregs. Conclusions: These efficacy and tolerability data support the combination of MYC-OEC and CBI treatment in patients with solid tumors. OTX-2002 is currently being evaluated in a Phase 1/2 clinical trial as a monotherapy and in combination with SoC (i.e., TKI and CBIs) for patients with HCC and other solid tumor types known for an association with MYC.
Camrelizumab in combination with apatinib as a perioperative treatment for patients with hepatocellular carcinoma at high risk of recurrence: A prospective, single-arm, phase 2 study.
Authors: Cui Yunlong , Bao Xu , Yu Ge , Li Huikai , Fang Feng , Li Qiang , Zhang Wei , Wu Qiang , Chen Lu , Liu Chen , Song Tianqiang 
Published: June 2023

4120 Background: Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide, and a rising cause of cancer-related mortality. To date, the optimal perioperative treatment strategy for HCC patients remains unclear. It is urgent to develop novel and reliable therapeutic interventions to reduce the risk of recurrence and improve survival in patients with locally advanced HCC. Methods: This prospective, exploratory, single-arm, phase 2 study enrolled patients with primary resectable HCC who had not received prior systemic therapy. Before surgery, patients received combination treatment with four cycles of camrelizumab (200 mg, Q2W) plus apatinib (250 mg, QD). Each cycle was two weeks. The feasibility of hepatic resection was assessed by radiographic imaging. After 4-8 weeks of surgery, patients continued combination therapy (camrelizumab [200 mg, Q2W] and apatinib [250 mg, QD]) for one year. Primary endpoint was major pathological response (MPR). Secondary endpoints were pathologic complete response rate (pCR), objective response rate (ORR), disease-free survival (DFS), and safety. Exploratory endpoint was microvascular invasion (MVI). This study is registered on Clinical Trials.gov, number NCT04701060. Results: Between Jan 12, 2021, and Aug 17, 2022, 31 patients with a median age of 54 years were enrolled. Among these, 21 patients (67.7%) had hepatitis B virus infection. Before surgical incision, two patients withdrew informed consent. Therefore, ORR based on RECIST 1.1 and mRECIST were 13.8% (4/29) and 48.3% (14/29), respectively. 26 patients underwent hepatic resection, R0 resection rate was 100%, 10 (38.5%) patients achieved MPR, and pCR rate was 7.7%. The reasons for patients not undergoing surgery were disease progression and serious adverse events (AEs). Among patients with MVI, M0 was found in 57.7% (15/26) patients, MI was found in 34.6% (9/26) patients, and M2 was found in 7.7% (2/26) patients. 1-year DFS rate was 77.4%, and median DFS was not reached. The most common AEs included increased aspartate aminotransferase (74.2%), increased alanine aminotransferase (70.1%), decreased platelet count (61.3%), anemia (58.1%), and decreased lymphocyte count (51.6%). Grade 4 AEs occurred in 7 of 31 patients, and there were no treatment-related deaths. Conclusions: Camrelizumab plus apatinib as a perioperative treatment is effective and tolerable in patients with HCC at high risk of recurrence. Preoperative neoadjuvant therapy has reduced the rate of MVI. Because of the short follow-up period, whether perioperative treatment can effectively reduce recurrence rates and improve long-term survival still needs further investigation. Clinical trial information: NCT04701060 .
Utility of circulating tumor DNA (ctDNA) as a predictive biomarker for disease monitoring in patients (pts) with cholangiocarcinoma (CCA) before and during adjuvant chemotherapy (ACT): Sub-analysis of the randomized phase 2 STAMP trial.
Authors: Yoo Changhoon , Laliotis George , Jeong Hyehyun , Jeong Jae Ho , Kim Kyu-Pyo , Lee Seonmin , Ryoo Baek-Yeol , Sharma Shruti , Dutta Punashi , Malhotra Meenakshi , Jurdi Adham A , Liu Minetta 
Published: June 2023

4123 Background: Detection of circulating tumor DNA (ctDNA) in blood is a powerful predictive biomarker for identifying molecular residual disease (MRD) post-surgery. Not much is known about the utility of identifying MRD using ctDNA in pts with resected CCA, despite its associated poor prognosis. The STAMP trial (NCT03079427), a randomized phase 2 study comparing adjuvant capecitabine (CAP) to gemcitabine plus cisplatin (GemCis) showed no difference in recurrence-free survival (RFS) and overall survival (OS) between the 2 arms. The goal of this analysis was to evaluate the feasibility of monitoring ctDNA to predict the risk of recurrence in pts with resected CCA. Methods: A total of 254 plasma samples were collected from a cohort of 89 CCA (hilar, N = 43; distal, N = 46) pts post-surgery at 3 separate time points; pre-ACT (baseline, N = 89), on-ACT C5D1 (after 5 cycles of treatment) (N = 88), and on-ACT C8D1 (after 8 cycles of treatment) (N = 77). Longitudinal ctDNA testing was performed using a personalized, tumor-informed ctDNA assay (Signatera, bespoke mPCR-NGS assay). ctDNA results were analyzed and evaluated for its correlation with RFS and OS. Results: At the MRD timepoint (baseline, pre-ACT), 24.7% (22/89) pts were ctDNA-positive, 90.9% (20/22) of whom recurred demonstrating a trend for shorter RFS (HR = 1.7, 95%Cl 0.98-2.8, p = 0.069) compared to ctDNA-negative pts. All pts who remained ctDNA-positive on-ACT at C5D1 (N = 17) and C8D1 (N = 15), recurred clinically with a significantly shorter RFS (HR = 8.1, 95%Cl 4.3-15, p < 0.0001 and HR = 5.0, 95%Cl 2.7-9.4, p < 0.0001, respectively). The primary cancer site (hilar vs distal) or type of ACT (CAP vs GemCis) had no impact on RFS irrespective of ct-DNA result. Pts who remained ctDNA-negative on ACT (N = 56) showed significantly better RFS compared to pts who remained positive (N = 10, HR = 6.6, 95%Cl 3.1-14, p < 0.001), or who turned positive (N = 11, HR = 5.2, 95%Cl 2.54-10.5, p < 0.001). In multivariate analysis including primary tumor site, sex, pathological grade and ACT regimen, positive ctDNA status at baseline (pre-ACT) remained significant for poor RFS (HR = 1.82, 95%CI 1.04-3.18, p = 0.035). Conclusions: Personalized monitoring of ctDNA both pre and on-ACT is feasible and predictive for recurrence in pts with resected CCA. To our best knowledge, this is one of the first reports presenting the clinical implication of ctDNA monitoring on ACT, in pts with CCA. Our findings suggest ctDNA monitoring may help optimize clinical decision-making in pts with resected CCA. Larger prospective studies would be needed to validate the findings of this study. Clinical trial information: NCT03079427 .
Development and validation of a non-invasive cfDNA targeted sequencing assay for early-stage hepatocellular carcinoma detection using cfDNA methylation and fragmentomics.
Authors: Liu Rui , Guo De-Zhen , Huang Ao , Ma Cheng-Cheng , Xu Min-Jie , Liu Yi-Ying , Su Ming-Yang , Chen Hua , Zhang Yun-Zhi , He Qi-Ye , Su Zhi-Xi , Yang Xin-Rong , Fan Jia , Zhou Jian 
Published: June 2023

4128 Background: Hepatocellular carcinoma (HCC) is one of the most common cancers in China, and one of the leading causes of cancer-related deaths in the country. With a 5-year survival rate of only 15-20%, early detection is crucial to improve the treatment and survival of HCC patients. Currently, alpha-fetoprotein (AFP) is commonly used as a serum marker for HCC, but it is not a sufficiently specific and can cause false positive readings due to elevated levels caused by other liver conditions. An alternative method is to use circulating free DNA (cfDNA) released by tumor cells as cancer-screening targets, which has been shown to be a more sensitive and specific biomarkers for HCC detection. This study aims to develop a non-invasive screening assay based on cfDNA features to improve the detection of early-stage HCC. Methods: Candidate methylation markers for HCC detection were collected and evaluated using GEO, TCGA and in-house datasets, 1601 of which were incorporated into a targeted sequencing panel named HcSeer. Multiple types of cfDNA features were constructed from the sequencing data, which included methylation-related features such as methylation haplotype blocks (MHBs) and methylated haplotype fraction (MHF), and fragmentomics features such as end motif and CNV. For model building, Cancer and healthy plasma samples were randomly divided into a training and a testing set at a 2:1 ratio. A two-step deep neural network model was built to classify HCC using selected features of both types. Results: We previously enrolled a total of 401 plasma samples (200 healthy, 201 HCC) for model construction and the performance of the HcSeer model have been documented. An independent validation cohort of 421 plasma samples (280 healthy, 141 HCC) was currently collected from different centers. In this independent validation, the HcSeer model achieved an AUC of 0.98 with a sensitivity of 96.5% at a specificity of 96.4%. Importantly, HcSeer maintained a high sensitivity for HCC across all stages: 94.3%, 96%, 100% and 100% for stage I – IV cases, respectively. When compared to AFP, HcSeer achieved a significantly higher sensitivity of 94% than AFP’s 55% in 137 HCC cases having AFP level tested. When AFP level was combined with the HcSeer model, the sensitivity for HCC further increased to 96%. Conclusions: This study demonstrated that the DNA methylation and fragmentomics patterns of cfDNA can accurately distinguish HCC and healthy plasma samples, particularly in the early stages of HCC. The combination of the HcSeer and AFP further improved the accuracy of the prediction. Although this study was limited in sample size, it clearly showed the potential of the HcSeer assay for accurate HCC detection in blood.