bluuebunny/crossref_metadata_2025_split huggingface dataset:
A prospective single-arm phase II study of blank-microsphere transarterial chemoembolization (bTACE) plus lenvatinib (LEN) and sequential microwave ablation (MWA) in patients with large hepatocellular carcinoma (L-HCC, ≥ 7 cm): The Talem trial.
Authors: Huang Zhimei , Han Xue , Jiang Yiquan , Gu Ling , Zhang Tianqi , Wang Jianwei , Huang Jinhua 
Published: January 2023

567 Background: Blank-microsphere transarterial chemoembolization (bTACE) has been demonstrated to have great efficacy, low toxicities and few adverse events. We report results of efficacy, safety and immunomodulatory effects from a phase II study of bTACE plus low-dose Lenvatinib (LD-LEN) and sequential microwave ablation (MWA) in patients with large hepatocellular carcinoma (L-HCC, ≥ 7 cm). Methods: Patients with large HCC with tumor number ≤ 3 and tumor diameter ≥ 7 cm (BCLC stage A/B) were treated with bTACE plus LD-LEN (4-8mg/day) and sequential MWA. bTACE was performed using blank microspheres and low-dose chemotherapeutic agents. Peripheral blood mononuclear cells (PBMC) were isolated before and after b-TACE plus LD-LEN for the evaluation of immunomodulatory effects. The primary endpoint was objective response rate (ORR) per modified-RECIST (mRECIST) criteria. Secondary endpoints included progression free survival (PFS), overall survival (OS), down-staging rate (DSR), complications and adverse events (AEs). Results: From November 2019 to March 2022, a total of 46 patients were enrolled in the study. The ORR per mRECIST was 93.02% (CR, n=26; PR, n=14) and DSR was 83.7 (36/43). Eight patients reached CR without MWA. The 1-year and 2-year OS rates were 89.4% and 67.5%, respectively. The 1-year and 2-year PFS rates were 57.8% and 34.8%, respectively. The median PFS were 16.7 months (95% CI, 8.6-not reached). The majority of the AEs observed were grade 1-2 (n = 21, 48.8%) and no treatment related death was observed. PBMC samples from 18 patients undergoing bTACE plus LD-LEN were investigated. Among myeloid cell populations, we observed a marked decline after treatment in CD11b+CD33+HLA-DR- MDSCs ( p <0.005). Increased numbers of activated CXCR5+CD8+ and CXCR5+CD4+ T cells were found after treatment ( p < 0.005), exerting anti-tumor immunity. Conclusions: From November 2019 to March 2022, a total of 46 patients were enrolled in the study. The ORR per mRECIST was 93.02% (CR, n=26; PR, n=14) and DSR was 83.7 (36/43). Eight patients reached CR without MWA. The 1-year and 2-year OS rates were 89.4% and 67.5%, respectively. The 1-year and 2-year PFS rates were 57.8% and 34.8%, respectively. The median PFS were 16.7 months (95% CI, 8.6-not reached). The majority of the AEs observed were grade 1-2 (n = 21, 48.8%) and no treatment related death was observed. PBMC samples from 18 patients undergoing bTACE plus LD-LEN were investigated. Among myeloid cell populations, we observed a marked decline after treatment in CD11b+CD33+HLA-DR- MDSCs ( p <0.005). Increased numbers of activated CXCR5+CD8+ and CXCR5+CD4+ T cells were found after treatment ( p < 0.005), exerting anti-tumor immunity. Clinical trial information: NCT05555316 .
Sorafenib plus tislelizumab as maintenance therapy for patients with advanced hepatocellular carcinoma treated with transarterial chemoembolization: A phase II study.
Authors: Cai Mingyue , Hong Xiaoyang , Huang Wensou , Guo Yongjian , Shi Wenbo , Liang Licong , Zhou Jingwen , Lin Liteng , Chen Ye , Zhu Kangshun 
Published: January 2023

574 Background: Tyrosine kinase inhibitor combined with immune checkpoint inhibitor has been reported to confer a survival benefit in patients with unresectable hepatocellular carcinoma (HCC). This phase II study (NCT04599777) aimed to evaluate the safety and efficacy of sorafenib plus tislelizumab (Sor-Tis) for patients with advanced HCC who received transarterial chemoembolization (TACE). Methods: The key inclusion criteria were: age ≥ 18 years; BCLC C stage HCC; no prior systemic therapy; Child-Pugh score ≤7; ECOG PS ≤1. The key exclusion criteria were: tumor thrombus involving the main portal vein or vena cava; central nervous system metastasis; history of malignancies other than HCC; history of organ and stem cell transplantation. Sorafenib (400 mg Bid) and tislelizumab (200 mg Q3W) was started at 3-7 days after the first TACE (TACE was repeated on demand). The primary endpoint was overall survival (OS). The secondary endpoints included treatment-related adverse events (TRAEs), progression free survival (PFS), objective response rate (ORR), and disease control rate (DCR). Results: Thirty patients were enrolled in this study. Among these patients, 27 (90.0%) had macrovascular invasion, 12 (40.0%) had extrahepatic metastasis and 14 (46.7%) had intrahepatic tumor number >3. The mean largest tumor diameter was 11.4±3.9 cm. Till cutoff date (September 15th, 2022), the mean follow-up for the patients was 16.6±3.8 months. The median OS was not reached. The ORR per RECIST 1.1 and mRECIST was 20.0% and 53.3%, respectively. The DCR per RECIST 1.1 or mRECIST was 86.7%. During follow-up, 29 patients (96.7%) experienced disease progression (per RECIST 1.1 or mRECIST). The median PFS was 6.8 (95% confidence interval [CI] 4.5-9.0) months. TRAEs occurred in 28 patients (93.3%) and ≥grade 3 TRAEs was observed in 11 patients (36.7%). There was no treatment-related death in these patients. Conclusions: Sor-Tis showed preliminary clinical benefits and was tolerated in advanced HCC patients treated with TACE. This study is still ongoing and further follow-up is required to obtain final survival results. Clinical trial information: NCT04599777 .
Discovery of novel interactions with LCK in cholangiocarcinoma using proximity-dependent biotinylation.
Authors: Tomlinson Jennifer L , Watkins Ryan D , Mun Dong-Gi , Conboy Caitlin , Pandey Akhilesh , Smoot Rory L 
Published: January 2023

575 Background: Cholangiocarcinoma (CCA) is a lethal hepatobiliary adenocarcinoma with increasing incidence and poor outcomes. Treatment success has been hindered by resistance, and new therapeutic strategies are necessary. The Src-family tyrosine kinase, LCK, activates Yes-associated protein (YAP), a known oncogene in CCA. While YAP has been historically difficult to target, we recently described LCK inhibition as a potential therapeutic option in CCA. We probed the LCK interactome employing biotinylation site identification technology (BioSITe) to discover molecular co-dependencies in the LCK-YAP axis. Methods: LCK-deficient HuCCT1, wild-type HuCCT1, and wild-type RBE cells were transfected with pEF-LCK-TurboID and used to reveal protein-protein interactions. Biotinylated peptides were enriched using anti-biotin antibodies followed by mass spectrometry analysis. Co-immunoprecipitation (Co-IP) was used to confirm interactions between LCK and identified interactors. Phosphoproteome profiling of human CCA tumors and patient derived xenografts was conducted to identify active kinase signatures in CCA. Tyrosine phosphorylated peptides were enriched using anti-phosphotyrosine antibody beads and analyzed by high-resolution mass spectrometery/liquid chromatography. Immunoblot analysis of HuCCT1 and LCK-deficient HuCCT1 cells was used to map the mechanistic interaction between LCK and epidermal growth factor receptor, EGFR. Inhibitors of EGFR and LCK, afatinib and NTRC 0652-0, respectively, were tested in vitro on human and murine CCA cell lines. Cell viability was determined with CellTiter-Glo; Calcusyn software was used to determine synergistic drug effects. Results: We discovered intracellular interactors of LCK in CCA using BioSITe. We identified both known and novel LCK interactors, including EGFR. Given that EGFR functions as a molecular driver of tumorigenesis and is increasingly recognized as a biomarker of resistance in a variety of tumors, we performed a phosphoproteomic evaluation of CCA tumors in which activated EGFR was identified by the presence of EGFR-Y1092, Y1197, and Y1172 phosphorylation. EGFR phosphorylation decreased under conditions of genetic LCK knock out and inhibition by NTRC 0652-0. Co-IP confirmed the interaction of EGFR with LCK. EGFR-Y1092 phosphorylation was downregulated with genetic knockout of LCK by immunoblot. Finally, EGFR inhibition was evaluated as a therapeutic strategy utilizing afatinib. Effects on cell viability were noted in both human and murine CCA cells. Afatinib and NTRC 0652-0 demonstrated a synergistic effect in vitro, with calculated combination indices of 0.007 – 0.790. Conclusions: A novel interaction between EGFR and LCK in CCA was identified using an unbiased proximity-dependent biotinylation technique. Dual blockade of LCK and EGFR is synergistic in CCA and may be a viable therapeutic approach for patients.
Atezolizumab plus bevacizumab versus lenvatinib for unresectable hepatocellular carcinoma: A large, real-life, worldwide population.
Authors: Rimini Margherita , Casadei-Gardini Andrea , Persano Mara , Tada Toshifumi , Suda Goki , Shimose Shigeo , Kudo Masatoshi , Cheon Jaekyung , Finkelmeier Fabian , Rimassa Lorenza , Presa Josè , Masi Gianluca , Yoo Changhoon , Lonardi Sara , Tovoli Francesco , Scartozzi Mario , Burgio Valentina , Cascinu Stefano , Cucchetti Alessandro 
Published: January 2023

579 Background: Atezolizumab plus bevacizumab and lenvatinib have not been compared in a randomized controlled trial. We conducted a retrospective multi-center study to compare the clinical efficacy and safety of lenvatinib and atezolizumab with bevacizumab as a first-line treatment for patients with unresectable HCC in the real-world scenario. Methods: Clinical features of lenvatinib and atezolizumab plus bevacizumab patients were balanced through inverse probability of treatment weighting (IPTW) methodology, which weights patients' characteristics and measured outcomes of each patient in both treatment arms. Overall survival was the primary endpoint. Results: The analysis included 1,341 patients who received lenvatinib, and 864 patients who received atezolizumab plus bevacizumab. After IPTW adjustment, atezolizumab plus bevacizumab did not show a survival advantage over lenvatinib HR 0.97 (p=0.739). OS was prolonged by atezolizumab plus bevacizumab over lenvatinib in viral patients (HR: 0.76; p=0.024). Conversely, OS was prolonged by lenvatinib in patients with NASH/NAFLD (HR: 1.88; p=0.014). In the IPTW-adjusted population, atezolizumab plus bevacizumab provided better safety profile for most of the recorded adverse events. Conclusions: Our study did not identify any meaningful difference in overall survival between atezolizumab plus bevacizumab and lenvatinib. Although some hints are provided suggesting that patients with NASH/NAFLD might benefit more from lenvatinib therapy and patients with viral etiology more from atezolizumab plus bevacizumab.
Final results of a phase 1b/2 study of tivozanib in combination with durvalumab in patients with advanced hepatocellular carcinoma in both previously untreated patients and patients progressing on atezolizumab and bevacizumab.
Authors: Li Daneng , Dayyani Farshid , Mahalingam Devalingam , Rowe Julie Haewon , Abrams Thomas Adam , Kasturi Vijay , Iyer Renuka V. 
Published: January 2023

585 Background: The approval of atezolizumab + bevacizumab for untreated advanced HCC was a significant benefit for patients, but with an increased risk of potentially severe bleeding complications. Tivozanib (a selective VEGFR 1, 2, & 3 tyrosine kinase inhibitor [TKI]) has been combined with durvalumab in the DEDUCTIVE study; preliminary results presented in January 2022 showed that this combination was well tolerated with comparable efficacy to other immune checkpoint and VEGF containing regimens in patients with previously untreated HCC ( J Clin Oncol 40, no. 4 suppl 462-462). We now report the final results of this cohort (cohort A) of patients as well as those with previously treated HCC, including safety results for all the patients. Methods: Major eligibility criteria included age >18 yrs with documented advanced HCC, Child-Pugh Class A, ECOG 0 or 1, and creatinine clearance >40 ml/min. Major exclusion criteria included co-infection with HBV and HCV and significant organ dysfunction. Patients were treated with 0.89 mg tivozanib p.o., 21 days on followed by 7 days off and 1500 mg durvalumab i.v. every 28 days. The primary objective was to determine the safety and tolerability of this combination in patients with advanced HCC; secondary objectives included assessing objective response rate (ORR), progression free survival, and overall survival (OS). The study was amended in 2021 to include a cohort of patients previously treated with atezolizumab and bevacizumab (cohort B). Results: 21 patients were enrolled in cohort A and 6 in cohort B; the median age was 67, 88% of patients were male, and 24% were Asian. The median follow-up time was 13.2 mos and 3.4 mos for cohorts A and B, respectively. Data were available for 25 of the 27 patients enrolled. For cohort A, the ORR was 25% (5/20) and 1-year OS was 76%. For safety analysis, 24 (96%) patients had at least 1 treatment-emergent adverse event (TEAE); 92% were attributed possibly to either tivozanib or durvalumab; 32% were serious TEAEs and there was 1 TEAE leading to death (unrelated). Of the 8 (32%) serious TEAE, 2 were coronavirus infection. 2 patients had serious (grade 3) treatment-related AEs: 1 pneumonitis and 1 with gastrointestinal hemorrhage and anemia. There were no grade 4 or 5 treatment-related AEs. Conclusions: Treatment with the combination of tivozanib and durvalumab in patients with either untreated advanced HCC or those previously treated with atezolizumab and bevacizumab was well tolerated; no severe bleeding events occurred in this study. Efficacy outcomes were comparable to other IO-TKI combinations in HCC. Data for PDL1 status, HBV/HCV status was collected and will be presented along with final safety and efficacy results for both cohorts. Clinical trial information: NCT03970616 .
Effect of AXL on cholangiocarcinoma survival and sensitivity to cytotoxic chemotherapy.
Authors: Takaichi Shohei , Tomlinson Jennifer L , Yu Mincheng , Abdelrahman Amro M , Werneburg Nathan W , Gores Gregory J , Smoot Rory L 
Published: January 2023

591 Background: Cholangiocarcinoma (CCA) is a lethal disease with limited therapeutic options. We have demonstrated the interaction of Src-family kinase LCK with AXL, a TAM receptor tyrosine kinase (RTK), by phosphoproteomic analysis in CCA ( J Hepatol 2022). AXL is reported to act as a mechanism of acquired drug resistance in solid cancers. However, the role of AXL in CCA remains to be elucidated. Here, we investigated the significance of AXL expression as a potential therapeutic target in CCA. Methods: We first evaluated the expression levels of AXL in CCA and the associations with patient outcome using publicly available data from The Cancer Genome Atlas (TCGA). Next, to evaluate whether AXL inactivation sensitizes CCA cells to gemcitabine and cisplatin (GemCis) therapy as a standard therapy. AXL downregulation was achieved via siRNA approach and the selective inhibitor bemcentinib. We examined 50% inhibitory concentration (IC50) value of HuCCT1, a well characterized CCA cell line, on GemCis therapy with and without AXL knockdown using CellTiter-Glo cell viability assay. Then we assessed the efficacy of the combinatorial therapy of GemCis and bemcentinib utilizing Calcusyn software. Finally, apoptosis was evaluated by Annexin V assay. In vivo efficacy was assessed using a SB-1 (murine CCA cell line) and syngeneic murine model of CCA in C57Bl/6J mice treated with vehicle, GemCis, bemcentinib, and the combination of GemCis and bemcentinib. Results: In the TCGA cohorts, AXL is significantly expressed in CCA (P < 0.01), and disease-free survival and overall survival in low AXL expression group are significantly longer than those in high AXL expression group (P = 0.04, 0.01). In in vitro study, IC50 value of GemCis was decreased from 685nM to 129nM after AXL knockdown. Synergy effect was observed with the value of CI = 0.17 and Fa = 0.50 in the combinatorial therapy. The combinatorial therapy caused significantly increased apoptosis compared to GemCis or bemcentinib alone (P < 0.01, P < 0.01). In in vivo study, the combinatorial therapy significantly suppressed the tumor growth compared to GemCis or bemcentinib alone (P = 0.04, 0.01). Conclusions: Targeting AXL sensitizes CCA cell lines and preclinical models to standard of care GemCis combinatorial therapy. Our study suggests that the addition of AXL targeted therapy to cytotoxic chemotherapy can increase the response in CCA patients and is a promising combination.
Effect of EGFR and ERBB2 amplifications and activating alterations on efficacy of lenvatinib in hepatocellular carcinoma.
Authors: Lim Mir , Yang Dong , Imperial Robin John Lester , Majeed Umair , Tsai Jill , Franses Joseph Wang , Hsieh David 
Published: January 2023

600 Background: Hepatocellular carcinoma (HCC) is the most common primary liver cancer and is associated with a high mortality burden. Lenvatinib is an effective frontline tyrosine kinase inhibitor for HCC but is associated with primary and acquired resistance in most patients. Molecular mechanisms of resistance to lenvatinib remain unclear. Methods: We retrospectively analyzed 227 patients with HCC who underwent baseline ctDNA profiling as a component of routine clinical care, including 46 patients who had serial ctDNA analysis done at baseline and after progression to lenvatinib or ICI. Clinical data including demographics, treatment history, tumor responses, and survival outcomes were abstracted from the electronic medical record. Tumor response was categorized according to RECIST 1.1. A national registry of HCC that underwent ctDNA testing using Guardant360 was analyzed to determine the prevalence of EGFR/ERBB2 alterations in HCC. Results: Nearly a third of patients who progressed on lenvatinib demonstrated a gain in EGFR/ ERBB2 amplifications or activating mutations. No consistent trend in EGFR/ ERBB2 amplifications and alterations was found among ICI refractory HCC. Disease control rates (including complete response, partial response, and stable disease) were 20% in EGFR/ERBB2 altered HCC treated with lenvatinib, 62.5% in EGFR/ERBB2 wildtype HCC treated with lenvatinib (p = 0.05), and 58% in EGFR/ERBB2 altered HCC treated with ICIs (p = 0.09). PFS was also longer in EGFR/ERBB2 wildtype HCC treated with lenvatinib (5.9 months) and EGFR/ERBB2 altered HCC treated with ICIs (7.1 months) compared to EGFR/ERBB2 altered HCC treated with lenvatinib (2.2 months, p = 0.002). In a national cohort of 1739 patients with HCC, EGFR amplifications and activating mutations occurred in 6.5% and 1.5% of cases, respectively, and ERBB2 amplifications and activating mutations occurred in 1.9% and 0.7% of cases, respectively. Among EGFR/ERBB2 mutations, we identified recurrent gatekeeper mutations, including multiple A547T and T790M mutations, in 31% of patients. Conclusions: Our study substantiates EGFR/ERBB2 amplifications and mutations as putative drivers of lenvatinib resistance in patients with HCC and identifies the genetic mechanisms for EGFR pathway activation in refractory cancers. EGFR/ERBB2 alterations may thus represent predictive and pharmacodynamic markers of lenvatinib resistance. These findings lend support to the use of EGFR inhibitors combined with lenvatinib in previously untreated or lenvatinib refractory cancers.
Concordance in oncogenic alterations between primary and recurrent/metastatic cholangiocarcinoma pairs using targeted next-generation sequencing.
Authors: McIntyre Sarah Margaret Helena , Preston William , Walch Henry S. , Sigel Carlie S. , Sharib Jeremy , Chen Wei , Lidsky Michael , Kundra Ritika , Cercek Andrea , Harding James J. , Abou-Alfa Ghassan K. , Balachandran Vinod P. , Drebin Jeffrey A. , Soares Kevin , Wei Alice Chia-chi , Kingham T. Peter , D'Angelica Michael Ian , Iacobuzio-Donahue Christine A , Schultz Nikolaus , Jarnagin William R. 
Published: January 2023

604 Background: The genetic background of cholangiocarcinoma (CCA) commonly involves alterations in kinase signaling, tumor suppression, oxidative stress modulation, and proto-oncogenic coupling pathways. Novel agents targeting such pathways have shown promise in systemic treatment; however, studies examining differences in the mutational landscapes between primary and recurrent, metastatic, or progressive disease after systemic therapy are lacking. The present study aimed to determine if recurrent, metastatic, or progressive disease genetically parallels the primary or not. Methods: Patients with biopsy proven CCA (primary tumor and paired recurrent/metastatic or progressive disease) from two institutions (MSKCC and Duke) were identified. Targeted next-generation sequencing (Integrated Mutation Profiling of Actionable Cancer Targets (IMPACT)) capturing single nucleotide variants, copy number alterations, and structural variants was used to compare driver alteration concordance across the paired samples. Subgroup analyses were performed based on exposure to systemic therapy in patients with disease progression and tumor type (intrahepatic versus extrahepatic). Results: Sample pairs from 65 patients with intrahepatic (ICCA, n=54) and extrahepatic CCA (ECCA, n=11) were analyzed. Median time between samples was 19.6 months (range 2.7 - 122.9). Some de novo alterations were identified in recurrent/metastatic samples, but overall concordance (70%) was demonstrated between patient pairs for common oncogenic driver genes (Table). Subgroup analyses of summative ICCA and ECCA mutations revealed concordance of 65% and 88%, respectively. Concordance was also demonstrated between pairs exposed to systemic therapy between sample collections (n=50, 71%). Conclusions: In this dataset of CCA patients, a concordance rate of 70% was identified in the genomic alterations between primary and recurrent/metastatic pairs, and this did not appear to be altered by prior treatment with systemic chemotherapy. While limited by sample size, concordance in ICCA pairs was lower than that seen in ECCA. [Table: see text]
CD34 immunostaining for microvascular invasion analysis in hepatocelullar carcinoma.
Authors: Diniz Paulo Henrique Costa , Gama Henrique Valladao Pires , Albuquerque Ronniel Morais , Wanderley David Campos , Xavier Marcelo , Osorio Fernanda Maria Farage , Couto Claudia Alves , Ferrari Teresa Cristina de Abreu , Lima Agnaldo Soares , Chaves Gabriela Freitas , Vidigal Paula Vieira Teixeira 
Published: January 2023

609 Background: Hepatocellular carcinoma is the most common primary neoplasia of the liver. Microvascular invasion predicts outcome and defines tumor staging. However, its diagnosis is still a challenge. The present study aims to evaluate inter and intraobserver agreement in identifying the presence of microvascular invasion using conventional and immunohistochemistry histology. Methods: Three pathologists performed the analysis of 76 hepatocellular carcinoma explants to characterize the presence of microvascular invasion using the hematoxylin/eosin stain and immunohistochemistry for CD34. The evaluations were made individually, in two distinct moments. Results were analyzed by the Kappa’s coefficient and ROC curves. Results: Our study demonstrated similar agreement for microvascular invasion between hematoxylin/eosin and CD34 methods. However, the intraobserver agreement values for both methods were higher than the interobserver ones. The accuracy of CD34 in relation to hematoxylin/eosin by ROC curves in intraobserver analysis tends to a high specificity, ranging from 82.1 to almost 100%, with sensitivity of 46.9 to 81.1%. In interobserver analysis, CD34 also has a high specificity (84.3 to 85.5%) while its sensitivity is a little shorter (81.2 to 84.3%). Conclusions: Intraobserver higher agreement allows us to suppose that pathologists employed own criteria to evaluate vascular invasion, reinforcing the need of standardization. ROC Curves analysis showed that the CD34 method is more specific than sensitive. Therefore, immunohistochemistry for CD34 should not be used routinely, but it could be useful to help confirming invasion previously seen by conventional histology.