bluuebunny/crossref_metadata_2025_split huggingface dataset:
Anti-PD1 antibody pucotenlimab in combination with bevacizumab or lenvatinib in a phase II study for the treatment of advanced hepatocellular carcinoma (aHCC).
Authors: Zhao Hong , Zhou Aiping , Tu Jianfei , Bai Yuxian , Mao Xianhai , Song Tianqiang , Li Bo , Dai Wenxiang , Lv Jing , Wang Jufeng , Che Xu , Liu Lianxin , Zhang Lianhai , Wu Wei , Cai Jianqiang 
Published: June 2023

e16180 Background: Immune checkpoint inhibitors plus anti-VEGFR agents have emerged as a powerful strategy for aHCC. This has been confirmed by several phase 3 trials: 1) atezolizumab + bevacizumab showed an ORR of 27.3%, mPFS of 6.8 months, and mOS of 19.2 months in IMbrave150; 2) sintilimab + IBI305 (bevacizumab biosimilar) showed an ORR of 21%, mPFS of 5.6 months and mOS of 22.1 months in Orient-32; 3) camrelizumab + Apatinib showed an ORR of 25.4%, mPFS of 5.6 months and mOS 22.1 months in SHR-1210-III-310. To our knowledge, data from a trial about PD-1 inhibitor plus different antiangiogenic drugs have not been reported. Here, we present the result of the Pucotenlimab (HX008) plus bevacizumab (B) or lenvatinib (L) as the first-line treatment for aHCC. Methods: This study is a single-arm, multiple-center trial. Eligible pts aged 18 to 75 years had 1) histologically or cytologically confirmed aHCC naïve to systemic treatment; 2) BCLC stage C or B not amenable to surgery and/or locoregional therapy or showed radiographic progression after treatment; 3) Child-Pugh class A/B7; 4) ECOG PS 0 or 1. Pts of C1 received HX008 200 mg IV Q3W plus B 15 mg/kg, IV, Q3W; Pts of C2 received HX008 (200mg IV Q3W) plus L (12mg/d for BM ≥60 kg or 8 mg/d for <60 kg). The primary endpoint was ORR. Secondary endpoints included PFS, OS, and safety. Results: Between Dec. 30, 2020, and Oct. 12, 2022, 75 pts were sequentially assigned to C1 (n = 28) or C2 (n=47). The pts characteristics are presented in table below. With a median follow-up duration of 15.2 and 12.5 months, investigator-assessed ORR per RECIST v1.1 showed a similar magnitude of benefit ( p=0.6150) between C1 (28.6%) and C2 (36.2%). Also, there were no statistically significant differences (p=0.4606) in median PFS, 7.5 and 9.6 months (HR:1.26 [0.674-2.373]). OS result is not mature, the 12-mo rate was 88.6% and 81.8%. The most common TEAEs were platelet count decreased (42.9%), and proteinuria (35.7%) in C1; and platelet count decreased (44.7%), proteinuria (42.6%), and hypothyroidism (40.4%) in C2. Grade ≥3 TEAEs were reported in 9 pts (32.1%) and 24 pts (51.1%) in C1 and C2, respectively, with hypertension (10.7% and 12.9%) being the most commonly reported. The most commonly SAE reported were abdominal infection (3.6%) in C1, and diarrhea (4.3%) in C2. Conclusions: Pucotenlimab plus bevacizumab or lenvatinib has demonstrated clinical efficacy in aHCC patients naïve to systemic therapy, and no unexpected safety signals emerged. The two cohorts are comparable in terms of effectiveness, but safety profiles presented some differences. The findings need to be confirmed by additional studies. Clinical trial information: NCT04741165 . [Table: see text]
Genomic profiles of chromosome remodeling pathway and their correlation with TMB, MSI, PD-L1, and immune microenvironment in biliary tract tumors.
Authors: Shen Ningjia , Shi Xintong , Zhang Yongjie , Zhong Xuefeng , Huang Mengli 
Published: June 2023

e16181 Background: Immunotherapy combined with chemotherapy has become a promising first-line treatment for biliary tract tumor (BTC) patients. A previous clinical trial with a small sample size revealed that impaired functions of chromatin remodeling genes might be a potential predictive biomarker of combined immunotherapy for BTC. However, genomic profiles of chromosome remodeling pathway and their correlation with tumor mutation burden (TMB), microsatellite instability (MSI), programmed death ligand-1 (PD-L1) and immune microenvironment in Chinese BTC patients remain unknown. Methods: A total of 2031 BTC patients (cholangiocarcinoma [CCA], N=1476; gallbladder carcinoma [GBC], N=555) were included in this study, and their tumor tissue samples were subject to next generation sequencing using a 733-gene panel. Multiple immunofluorescence using for immune microenvironment related markers (including PD-1, PD-L1, CD8, CD68, CD163, CD3, CD4, CD20, CD56 and FoxP3) detection was conducted in 49 patients. Prognostic survival data were obtained from two clinical sequencing cohorts (CCA: ICGC-2017, N=417; GBC: MSK-2022, N=233) and were used to explore the association between chromatin remodeling genes mutation and prognosis. Results: In total, 57.9% (1175/2031) of BTC patients harbored alternations in genes involved in chromatin remodeling pathway and the top three alteration frequency somatic genes were ARID1A (19%), KMT2C (11%), ARID2/KMT2D/PBRM1 (8% each), respectively. The commonly alternation types were missense (48%), frameshift indel (25%) and nonsense (17%), respectively. The TMB level of altered group was significantly higher than wild group (median TMB, mutant-type vs. wild-type = 6.145 vs. 3.352 Muts/Mb, P<0.0001), but no significant difference was found in the PD-L1 expression level between the two groups. A total of 43 patients were identified as MSI-high, all of whom harbored alternations in genes involved in chromatin remodeling pathway. Compared with the wild group, the infiltration level of CD20+ B cells in tumor parenchyma was significantly higher in the altered group. Furthermore, there was no difference in overall survival (OS) between altered group and wild group (median OS, 18.99 vs. 20.97 months; HR=1.164 [95%CI: 0.9048-1.498], P=0.2360) in two clinical sequencing cohorts without immunotherapy. Conclusions: The results revealed the molecular basis of chromosome remodeling genes as the predictive biomarker of combined immunotherapy for BTC and exclude its effect on prognosis.
Therapeutic outcomes of lenvatinib versus sorafenib in the primary treatment of advanced hepatocellular carcinoma: A systematic review and meta-analysis.
Authors: Naz Sidra , Hameed Maha , Jaiswal Vikash , Attia Abdelrahman M , Soliman Mostafa a , Kumar Vikash , Nath Supti Dev , Mukherjee Dattatreya , Jaiswal Akash , Koifman Michelle 
Published: June 2023

e16183 Background: Molecular-targeted agents such as Lenvatinib and Sorafenib have improved survival outcomes in patients with hepatocellular carcinoma (HCC). However, using these agents in the primary treatment for advanced HCC is still under debate, with limited literature comparing the therapeutic effects of Lenvatinib versus Sorafenib. Methods: We performed a systematic literature search using the PubMed, Embase, Scopus, and Cochrane libraries for relevant articles from inception until 10th February 2023. Results: A total of 8 studies with 1995 patients (955 Lenvatinib vs. 1040 Sorafenib) were included in our analysis. The mean age of the patients in both groups was comparable (65 vs. 66) years. The overall survival was also comparable between the groups (HR = 0.83; 95%CI: 0.67-1.02; p = 0.08). However, progression-free survival (HR = 0.83; 95%CI: 0.77-0.89; p<0.00001) and time to progression (HR = 0.69; 95%CI: 0.51-0.93; p = 0.02) were significantly improved in the Lenvatinib group compared to Sorafenib. The pooled analysis showed that the treatment response evaluated through the Objective response rate (OR = 7.37; 95%CI: 1.86-29.20; p = 0.004) and Disease control rate (OR = 3.03; 95%CI: 0.98-9.30; p = 0.05) of the Lenvatinib group were better than those of the Sorafenib group. However, the likelihood of severe adverse events (OR = 1.76; 95%CI: 1.38-2.24; p <0.00001) was significantly higher in the Lenvatinib group compared with Sorafenib patients. In addition, among common adverse events, hypertension (HR = 2.68; 95%CI: 1.48-4.83; p = 0.001) and fatigue (HR = 2.53; 95%CI: 0.90-7.13) were significantly higher among Lenvatinib group compared to Sorafenib. Conclusions: In the primary treatment of advanced HCC, Lenvatinib significantly improves progression-free survival, time to progressions, and objective response rate. However, the likelihood of severe and common adverse events such as hypertension and fatigue are significantly higher after using Lenvatinib than Sorafenib. [Table: see text]
The efficacy and safety of toripalimab combined with sorafenib for unresectable hepatocellular carcinoma: An open-label, prospective, single-arm phase II study.
Authors: Yang Xin-Rong , Cheng Jian-Wen , Wu Suiyi , Hu Bo , Qiu Shuang-Jian , Sun Hui-Chuan , Fan Jia , Zhou Jian 
Published: June 2023

e16184 Background: Hepatocellular carcinoma (HCC) is often diagnosed at an advanced stage, leaving patients ineligible for surgery. Sorafenib is a first-line therapy, but disease progression still occurs in most patients within a year. Toripalimab, an immune checkpoint inhibitor has demonstrated promising efficacy and safety in various solid tumors, and its combination with Sorafenib may alter outcomes in HCC patients. This study aims to assess the safety and efficacy of Toripalimab plus Sorafenib for the treatment of advanced HCC. Methods: This is a single-arm, open-label, prospective phase II clinical trial (NCT04926532) for patients with unresectable HCC. Participants receive Toripalimab (240mg, iv, d1) and Sorafenib (400mg, bid, po, d1-21) every 3 weeks until disease progression or unacceptable toxicity occurs. The primary endpoints are objective response rate (ORR) evaluated with RECIST v1.1 and safety. Secondary endpoints include progression-free survival (PFS), overall survival (OS), disease control rate (DCR), and duration of response (DOR). Exploratory endpoints comprise monitoring indicators for the efficacy and sensitivity of immunotherapy drugs. Results: As of January 17, 2023, 28 patients were enrolled, with a median age of 59.8 years and 85.7% were male. All patients had Child-Pugh A classification. The median follow-up time was 14.7 months (2.3-31.3). The distribution of patients by CNLC stage was as follows: Ib/IIa/IIb/IIIa/IIIb stage were 25.0%, 17.9%, 25.0%, and 32.1%, respectively. Among all patients, 6 (21.4%) had distant metastasis, 7 (25.0%) had portal vein tumor thrombus (PVTT), and 3 (10.7%) had hepatic vein invasion. The ORR was 35.7% and DCR was 71.4%. Of the 28 patients, 3 (10.7%) achieved complete response (CR), and 7 (25.0%) achieved partial response (PR). The median DOR was 2.7 months (95% CI: 0.9-16.9). The median PFS was 4.8 months (95% CI: 3.1-18.9), and the median OS was not reached (95% CI: NA-NA). 6 patients (21.4%) underwent surgical resection, and 3 of them (50.0%) experienced postoperative recurrence. The median PFS of patients who underwent surgery was 20.4 months (95% CI: 12.6-NA). 6 patients (21.4%) withdrew due to adverse events (AEs). Treatment-related adverse events (TRAEs) occurred in 26/28 patients (92.9%). Grade 1-2 TRAEs occurred in 10/28 patients (35.7%), Grade 3 TRAEs occurred in 11/28 patients (39.3%), and no grade 4-5 TRAEs were observed. This study is currently ongoing. Conclusions: Toripalimab combined with Sorafenib demonstrated encouraging efficacy and tolerable toxicity as a first-line option for patients with unresectable HCC, with some patients achieving tumor downstaging and surgical resection. This combination could be considered an optional regimen for the first-line treatment of unresectable HCC. Clinical trial information: NCT04926532 .
Liver directed therapies in primary and metastatic liver cancer: A rural academic institution experience.
Authors: Saeed Zabila , Burke Aidan Michael , Meyer David , Muzaffar Mahvish 
Published: June 2023

e16188 Background: Liver-directed therapies (LDT) are well established in the treatment of primary and secondary hepatic malignancies and are developed for potentially curative intent, bridging for definitive therapy or palliation. They are used either in isolation usually for hepatocellular carcinoma (HCC) or in combination with systemic chemotherapy and/or surgery. We conducted a retrospective study at our academic institution that serves ethnic minorities and patients with high BMI and multiple major co-morbidities. Methods: All patients who underwent liver-directed therapy at ECU Health Medical Center from the year 2010 to 2020 were included in this study. Total of 196 patients were identified of which 96 met the eligibility criteria. That criteria included all patients who have undergone any type of liver directed therapy in primary and mainly metastatic gastrointestinal liver cancer. We conducted descriptive univariate analysis, cox regression and Kaplan-Meier survival analysis. Results: The study cohort had 63% (n=60) with primary HCC and 38% (n=36) with metastatic liver cancer predominantly colorectal cancer. Median age at diagnosis was 68 yrs. (65.3-69.5), 58% were Caucasian, 38% were black and 2% were other ethnic groups. 68% of the patient were male and 31% were female. ECOG performance status of 1 in 60% of the cohort. 50% of the cohort had 3 major comorbidities other than cirrhosis and hepatitis. Mean body mass index (BMI) was >25 kg/m2. 43% of the patient (n=41) had multiple barriers to care. Patients with primary HCC, 45% had hepatitis C and 48 % had non-viral causes in 60 patients. Child- Pugh A in 67% (n=40), B in 30% (18) and C in 3% (n=3). 70% of non-HCC cohort has colorectal and cholangiocarcinoma. All patient in non-HCC group received chemotherapy and 52% of HCC cohort received systemic therapy. 55% (n= 43) of the patients underwent Y-90 and 55% (n= 53) underwent other types of liver directed therapies, most common being TACE. 62% of the patient underwent 1 treatment and 38% had >2 LDT. Multivariate analysis showed that age (p-value, 0.0229) and type of liver directed therapy ( p-value, 0.0212) are statistically significant in the HCC cohort. In the non-HCC cohort, patients with high BMI (P-value=0.0050) had poor outcome and was statistically significant. Conclusions: Liver directed therapy is a reasonable option for patients with HCC and non-HCC metastatic disease. According to our study, it improves median survival in non-HCC patients. It includes rural population with high BMI, major comorbidities and multiple barriers to care. In this study, 38% of patients were African Americans who are usually underrepresented in majority of studies. Limitations of the study include retrospective nature of the analysis and heterogenous group. In future clinical trials, ethnic minorities should be equally represented to advance health equity and to apply real word data to the populations we serve.
Prevalence of next generation sequencing testing and targetable mutations in cholangiocarcinoma.
Authors: Shah Anuj , Jones Patricia Denise 
Published: June 2023

e16194 Background: Cholangiocarcinoma (CCA) is an aggressive cancer with a poor prognosis. However, next-generation sequencing (NGS) of tumors and new mutation-targeted therapies have the potential to greatly improve treatment outcomes while reducing the systemic toxicities of traditional chemotherapy. In this study, we examined clinical characteristics, treatment outcomes and the use of NGS profiling in a diverse South Florida population of CCA patients to identify mutations as potential therapeutic targets. Methods: We included patients treated at Jackson and University of Miami Health Systems who were diagnosed with CCA between 2018 and 2021. Clinical and demographic characteristics were obtained through retrospective chart review and entered into a REDCap database. We analyzed the association between clinical characteristics, treatment outcomes, use of NGS and race/ethnicity using Pearson’s Chi-square and Kruskal Wallis tests. Results: The majority of our sample, n = 140, had intrahepatic CCA (iCCA), n = 97, followed by extrahepatic CCA (eCCA), n = 27, and perihilar CCA (pCCA), n = 16. Stage, based on AJCC 8th edition, was most advanced in iCCA and pCCA; 56% had stage III or higher, compared to only 26.2% of eCCA patients. In addition, the median size of the largest iCCA tumor, 7 cm, was significantly larger than that of pCCA, 2.4 cm, and eCCA, 2.2 cm, p = 0.001. NGS was performed in significantly more iCCA cases, 72.2%, compared to pCCA, 37.5%, and eCCA, 59.3%, p = 0.04. TP53 mutations were most common across all CCA subtypes. Other common mutations included CDKN2A, CDKN2B, ERBB2, KRAS, FGFR2, IDH1, and ARID1A, of which only IDH1 and FGFR2 are targetable mutations. There were no significant differences across CCA subtypes in receipt of targeted therapy; overall, 17.1% of patients received targeted therapy. There were no racial differences in stage at presentation or survival in any CCA subtype. While there were numerical differences in the proportion of patients receiving targeted therapy (13.6% of Black, 12.8% of White, and 21.3% of Hispanic), these differences were not statistically significant. Conclusions: There are significant differences in the presentation of CCA subtypes. Examination of NGS results in a larger sample of CCA patients will help expand knowledge on CCA’s mutational profile and permit examination of potential racial disparities in survival or rates of NGS. This work also highlights the need for further targeted therapies against other common mutations in CCA. [Table: see text]
Treatment patterns post atezolizumab plus bevacizumab for advanced hepatocellular carcinoma: Real-world analysis at Veterans Health Administration comparing lenvatinib vs. sorafenib.
Authors: Aldawoodi Tamarah , Alkadimi Munaf , Lucero Kana , Boyle Lauren Diaz , Fierro Maria Elena , Mader Michael , Franklin Kathleen , Nooruddin Zohra 
Published: June 2023

e16195 Background: Atezolizumab plus Bevacizumab (A+B) has been the standard first-line therapy for advanced hepatocellular carcinoma (HCC) patients. There needs to be more data on the efficacy and selection of optimal sequences following resistance to A+B. Our study aims to review treatment patterns for disease progression following A+B, focusing on the most common 2nd line treatment utilized by the Veterans Health Administration (VHA). Methods: Patients with advanced HCC receiving line A+B at the VHA between Dec 1, 2019, to Mar 1, 2022, were selected electronically using ICD-9 and ICD-10 codes. Abstractors reviewed EMR following each patient from their index date of A+B initiation, sequential therapies, until death, or their last VHA visit, with the study period ending on Jan 31, 2023. Results: Three hundred thirty-two patients received A+B during our study period, and 1/3rd (n = 107) of these patients went on second-line treatments. 87 % started Tyrosine Kinase Inhibitors with 52, 29,12, and 1 on Lenvatinib, Sorafenib, Cabozantinib, and Regorafenib, respectively. Two second-line cohorts were selected, A (52 on Lenvatinib) and B (29 on sorafenib). The median age was 66 yrs vs. 65 yrs in cohorts A and B, respectively. In both cohorts, 60% non-Hispanic White and 90% with ECOG ≤1, there were no statistically significant differences between both cohorts in overall and progression-free survival. The outcomes are shown. Conclusions: Despite minimal improvement in PFS and a lower discontinuation rate due to toxicity favoring Lenvatinib over Sorafenib, Sorafenib had slightly better overall survival. This study is one of the most significant projects that describes 2nd line treatment patterns post-A+B failure. Further studies are warranted to evaluate larger cohorts to study treatment sequencing in the second and third lines.[Table: see text]
Translational analysis of combination of 5-fluorouracil (FU), interferon (IFN)-alpha2, and nivolumab in unresectable fibrolamellar liver cancer.
Authors: Lee Sunyoung S. , Duan Fei , Chamseddine Shadi , Jindal Sonali , Basu Sreyashi , Yadav Shalini , Allison James , Sharma Padmanee , Abugabal Yehia I. , Kaseb Ahmed Omar 
Published: June 2023

e16198 Background: Fibrolamellar liver cancer (FLC) is a rare malignancy and involves multidisciplinary approaches including surgery, liver-directed, and systemic treatment. Combination of 5-fluorouracil (FU) and interferon (IFN)-a2 has long been used for FLC. We had a hypothesis that addition of anti-PD1 to 5FU+IFN-a2 may further improve clinical outcome and modulation of FLC tumor microenvironment. Methods: We treated 3 patients with 5FU+IFN-a2+nivolumab (N): 5FU 200 mg/m2 7-day-on/7-day-off and IFN-a2 (4 million U/m2 3 times/week while on 5-FU) for 8 weeks, followed by on-treatment biopsy and addition of N 480 mg every 4 weeks to 5FU+IFN-a2. Those who had conversion of unresectable disease to resectable one had the resected tumors analyzed. Gene expression profiling and immunohistochemistry (IHC) staining of immune cells were performed to investigate the evolution of tumor microenvironment on treatment. Results: 26 and 29 year-old patients had unresectable FLC with a 6.1 cm tumor in seg IV liver invading the common hepatic duct, and a 19.5 cm tumor, metastatic peritoneal nodules, and abdominal lymphadenopathy, respectively. After 9 and 5 months of therapy, unresectable tumors were converted to resectable ones with partial response (PR): the former had left hepatectomy and bile duct resection; the latter, left hepatectomy, resection of the omentum, spleen, left diaphragm, and lymph node dissection. A 20 year-old patient had multifocal liver tumors with peritoneal carcinomatosis and lymph nodes. He received treatment for 5 months and achieved stable disease, but hepatic tumor bleeding led to treatment discontinuation. 2 patients with PR had increased expression of genes related to T cells, CD8+T cells, Th1 cells, NK cells, cytotoxic cells, macrophages, dendritic cells, neutrophils, and B cells, subsequently on tumors before-treatment, on-treatment (5FU+IFN-a2), post-surgery (5FU+IFN-a2+N). IHC staining confirmed an increase in CD8+T cell infiltration after treatment with 5FU+IFN-a2 and 5FU+IFN-a2+N. The third patient whose disease was not converted to a resectable disease showed a decrease in genes related to Th1 cells, cytotoxic cells, dendritic cells, and neutrophils on-treatment biopsy (5FU+IFN-a2). This patient had a marginal increase in CD8+T cell infiltration on exposure to 5FU+IFN-a2. Conclusions: This clinical outcome of converting unresectable disease to resectable one suggests synergy of 5FU+IFN-a2 combined with N. The robust increased expression of genes related to immune system activation and increased infiltration of CD8+T cells on 5FU+IFN-a2+N may explain this clinical efficacy. Pro-inflammatory evolution of tumors on treatment could be used as predictive biomarkers. More prospective data are indicated to further confirm our hypothesis. Clinical trial information: NCT04380545 .