bluuebunny/crossref_metadata_2025_split huggingface dataset:
Stereotactic body radiation therapy combined with atezolizumab and bevacizumab for hepatocellular carcinoma with extrahepatic metastasis: Preliminary result of a single-arm study.
Authors: Wang Lu , Zhang Ti , Lin Zhenhai , Zhou Jiamin , Wan Juefeng , Pan Qi , Zhao Yiming , Zhu Weiping , Mao Anrong , Zhang Ning , Wang Longrong 
Published: July 2024

e16205 Background: IMbrave150 study confirmed the clinical benefit of atezolizumab and bevacizumab in patients with advanced hepatocellular carcinoma (HCC). However, patients with extrahepatic metastasis (EHS) had a poorer prognosis. Studies suggested “abscopal effect” of synchronous radiotherapy and immunotherapy may improve antitumor activity. This study aimed to evaluate efficacy and safety of stereotactic body radiation therapy (SBRT) combined with atezolizumab and bevacizumab in HCC patients with EHS. Methods: This single-arm study included HCC patients with EHS from January 2022 to November 2023 in Fudan University Shanghai Cancer Center. Prior tyrosine kinase inhibitor and/or immune checkpoint inhibitor treatment were eligible. After first dose atezolizumab and bevacizumab, SBRT was performed with a total dose of 25-50 Gy. The primary endpoint was objective response rate (ORR). The secondary endpoints included overall survival (OS), disease control rate (DCR), progression-free survival (PFS), time to progression (TTP), and duration of response (DOR). Results: Thirty-nine patients were included. Fourteen patients were treated as first-line therapy and 25 patients were treated as later-line therapy. The mean age was 56.69±11.21 years and 89.7% were male. Of these patients, 66.7% had hepatitis viral infection and 25.6% had vascular invasion. 53.8% of patients had ≥2 extrahepatic spread lesions. In addition, 33.3% of patients had received prior immunotherapy and 23.1% of patients had received tyrosine kinase inhibitor therapy. The median follow-up was 6.50 (range: 1.43-22.17) months. The ORR and DCR were 43.6% and 92.3%, respectively. The ORR was 57.1% and 36.0% in first-line subgroup and later-line subgroup, respectively. The 12-month OS rates was 54.7%. The median PFS, median TTP and median DOR were 6.73 months, 8.67 months, and 7.17 months, respectively. The incidence of all grade TRAE and grade ≥3 TRAE were 38.5% and 12.8%, respectively. The most common grade ≥3 TRAEs were decreased platelet count (7.7%), decreased white blood cell count (2.6%), pruritus (2.6%) and rectal bleeding (2.6%). No serious adverse events occurred. Conclusions: SBRT combined with systemic atezolizumab and bevacizumab showed encouraging efficacy with manageable safety profile for HCC patients with EHS regardless of prior treatment. Further studies are warranted. Clinical trial information: NCT05396937 . [Table: see text]
Predictors of poor response to immune-checkpoint inhibitor (ICI) treatment among patient with hepatocellular carcinoma (HCC).
Authors: Das Parthib , Paul Samuel , Min Eric , Elsaid Mohamed I. , Mittra Arjun , Malalur Pannaga G. , Manne Ashish 
Published: July 2024

e16212 Background: No established risk factors or toxicity biomarkers exist for HCCs treated with ICI, even though they are commonly used in clinical practice. The outcomes in real-world practice are worse than those reported in clinical trials. This retrospective review aims to identify HCC patients at high risk of failing ICI therapy. Methods: HCC patients who received at least one ICI dose between 1/1/2017 and 5/30/2023 (before tremelimumab/durvalumab approval) at the Ohio State University were included in this study. The patient's baseline (BL) characteristics (at the first dose of ICI) were extracted with immune-related adverse event (irAE) details and survival outcomes. We examined BL characteristics significantly different in poor (progression-free survival (PFS) ≤ median (m)) and worst (PFS ≤ 25% percentile) responders, and poor (overall survival (OS) ≤ m) and worst (OS ≤ 25% percentile) survivors. Chi-square test and logistic regression were performed using JMP Pro 17 (SAS Institute Inc., Cary, NC). Results: Our cohort included 53 HCC patients. The median age was 66 years (range 40-86), with 81% male and 85% White (13% African American and 2% other). The median OS and PFS were 19 months (m) (95% confidence interval [CI], 8-26) and 5m (95% CI, 2-9), respectively. The poor responders (PFS ≤5m, N = 30) had patients with significantly higher alcohol history (AHx, 90% vs. 70%) and mean alpha-fetoprotein (AFP, 44, 155 vs. 811 ng/mL) levels, a higher proportion of Child-Pugh (CP) C (A/B/C %, 53/27/20 vs. 53/47/0), and negligible bevacizumab (bev, 77 vs. 24) use, all (p < 0.05). The worst response group (PFS ≤2m, N = 16), furthermore, had significantly (p < 0.05) higher Albumin-bilirubin (ALBI) grade (G) 3 patients (50% vs. 16%), higher mean total bilirubin (2 vs. 1,2 ng/mL), lower tyrosine-kinase inhibitor (TKI, 7% vs. 46%), and lower mean albumin (Ab, 3 vs. 3.4) levels. A significantly (p < 0.05) higher fraction (fx) of poor survivors (OS ≤19m, N = 33) got ICI In the first or second line (85% vs. 45%) and did not receive any locoregional therapy (LRT, 66% vs. 35%). The worst survivors (OS ≤8m, N = 14) got ICI in the first line (100% vs. 59%, p = 0.04, and significantly (p < 0.05) lower Alb (3 vs. 3,4) and higher AFP (90620 vs. 3104) levels. The irAE group (N = 10, 19%) had higher AFP (115289 vs. 3482, p = 0.01) and a lower distant metastasis rate (20% vs. 58%, p = 0.02), and none of them received bev (0% vs. 30, p = 0.04). Conclusions: Response to ICI depends on BL liver function (AHx, ALBI, CP, Alb) and combination therapy (bev). Survival depends on HCC management up to the administration of ICI (LRT and TKI).
Targeting USP7 to induce ubiquitination degradation of oncogenic ATAD2 and effects on cholangiocarcinoma growth.
Authors: Zhang Peng , Zhang Chengsheng 
Published: July 2024

e16215 Background: Cholangiocarcinoma (CCA) is a highly fatal disease due to limited therapeutic targets. Deubiquitinase USP7 is an oncogene and has been suggested to be deeply involved in regulating tumor initiation and progression, but its abundance and role in CCA still remain unclear. Methods: USP7 mRNA expression was performed using TCGA and GEO database. Survival analysis in CCA patients with high- and low-USP7 mRNA expression was performed using NODE database. CCK8, colony formation, flow cytometry and shRNA interference assay were used to evaluate the biological function of USP7-ATAD2 axis on CCA cancer cells in vitro. 4D label-free quantification proteomics was used to analyze the targets and networks regulated by USP7. The molecular mechanism of USP7 and ATAD2 in CCA was determined by conducting Western blot, co-immunoprecipitation, IHC and quantitative real-time PCR (qPCR) analyses. The CCA PDX model was used to evaluate the efficacy of targeting USP7 in the treatment of cholangiocarcinoma. Results: Here, we found USP7 is highly expressed in CAA, and is associated with poor outcomes of CCA patients. We show that USP7 depletion induces S phase arrest, and suppresses CCA tumor cells proliferation. Next, we provide a comprehensive understanding of targets and networks affected by USP7 depletion by performing a 4D label-free quantification proteomics analysis. We show that ATAD2 is a USP7 target, and USP7 interacts with and deubiquitinates ATAD2 to stabilize ATAD2 protein level. Ectopic expression of ATAD2 in USP7-depleted cells rescues the cell proliferation phenotype. Further, pharmacological blocking the activity of USP7 by P5091 inhibits tumor growth in CCA patient-derived xenograft (PDX) mouse model. Conclusions: This study uncovers the role of USP7-ATAD2 axis in regulating tumor growth, and targeting USP7 may provide a novel therapeutic strategy for CCA.
A prospective study of radiofrequency ablation combined with systematic neoadjuvant therapy in the treatment of recurrent hepatocellular carcinoma (RANT study).
Authors: Feng Kai , Ma Kuansheng , Wang Qiang , Xia Feng , Bi Huaqiang , Chen Zhiyu , Zhang Leida 
Published: July 2024

e16240 Background: Radiofrequency ablation (RFA) is an important minimally invasive approach for recurrent HCC, but is hampered by the high recurrence rate and limited ablation volume for the tumor. This study aims to evaluate the efficacy and safety of systemic neoadjuvant therapy (tislelizumab combined with lenvatinib/bevacizumab) combined with RFA in the treatment of recurrent HCC. Methods: This prospective, single-arm, phase II trial enrolled patients with recurrent resectable HCC who has a history of liver resection or RFA (the number of lesions ≤ 3, the largest lesion ≤ 3 cm, as demonstrated by contrast enhanced CT/MRI). Prior to RFA, patients received tislelizumab (200 mg, q3w, iv) and lenvatinib (body weight≥60 kg, 12 mg; <60 kg, 8 mg, qd, po) or bevacizumab (15mg/kg) for two cycles. RFA was scheduled in one week after the systemic neoadjuvant therapy. After 4-8 weeks of surgery, patients continued to receive tislelizumab and lenvatinib /bevacizumab for 6 to 12 months. Primary endpoint was one-year relapse-free survival (RFS) rate and one-year overall survival (OS) rate. Secondary endpoints were objective response rate (ORR) by mRECIST, and adverse events (AE). Results: From November 2021 to October 2023, 20 patients (median age, 57 years) were enrolled, all Child-Pugh A and ECOG PS 0, mostly males (95%) and HBV infection (90.0%). 19 patients had received 2 cycles systemic neoadjuvant therapy and RFA was successfully performed, 1 patient achieved complete response after systemic treatment and didn't perform RFA. According to mRECIST, the ORR was 50% (95%CI: 27.20%-72.80%), and the DCR was 100 % (CR 1, PR 8, SD 11). After a median follow-up of 8.5 months (interquartile range 5-21 months), tumor recurrence was detected in 2 patients, 1 patient died of disease recurrence. The estimated 12-month RFS rate and OS rate were 76.9% (95%CI 31.2%, 94.3%) and 100%, respectively. Median RFS and OS were not reached. So far the safety of neoadjuvant treatment was satisfied, no grade 4 or above treatment-related-adverse events (TRAEs) were observed. Grade 3 TRAEs were reported in 3(13.04%) patients. Frequently occurring adverse eventswere grade 1-2, including total bilirubin increased (39.13%), elevated aspartate aminotransferase (30.43%), and elevated alanine aminotransferase (30.43%). Conclusions: Radiofrequency ablation combined with systematic neoadjuvant therapy exhibited promising efficacy and favorable safety for recurrent HCC. Clinical trial information: NCT05277675 .
Neoadjuvant tislelizumab combined with lenvatinib plus transcatheter arterial chemoembolization in resectable hepatocellular carcinoma with high-risk of recurrence: A prospective, single-arm, phase II trial.
Authors: Chen Zhiyu , Zhang Leida , Zhang Hui , Gong Yi , Feng Kai , Ma Kuansheng , Bi Huaqiang , Xia Feng , Dai Haisu 
Published: July 2024

e16242 Background: Currently, more than 55% of liver cancer patients have recurrence within 1 years after radical surgery. However,there is no standard treatment of neoadjuvant therapy for resectable HCC patients. This study aimed to explore the efficacy and safety of the triple therapy [Tislelizumab combined with lenvatinib plus transcatheter arterial chemoembolization (TACE)] as neoadjuvant therapy in patients with resectable HCC with high-risk of recurrence. Methods: This prospective, single-arm, phase II trial (ChiCTR2200059574) enrolled patients with primary resectable HCC who had not received prior anti-tumor therapy. The recurrence rate was predicted to be > 50% according to the risk predictor ( http://www.asapcalculate.top/Cal2_ch.html ) of early recurrence before surgery. TACE will be performed once on Day 1. Tislelizumab (an anti-PD-1 antibody, 200 mg) intravenously once every 3 weeks and lenvatinib (body weight ≥ 60 kg, 12 mg;< 60 kg, 8 mg) orally daily was initiated 3 days after TACE treatment. Surgery was performed after two cycles of neoadjuvant treatment. After 4-6 weeks of surgery, patients continued to receive tislelizumab and lenvatinib for 6 months to 1 year. Primary endpoint was adverse events (AE) and major pathological reactions. Secondary endpoints were objective response rate (ORR) by mRECIST, relapse-free survival (RFS) and overall survival (OS). Results: From April 2022 to August 2023, 19 patients (median age, 55 years) were enrolled, all Child-Pugh A and ECOG PS 0, mostly males (89.5%) and HBV infection (94.7%). According to mRECIST, the ORR was 94.7% (18/19, CR 2, PR 16), and the DCR was 94.7% too (18/19, CR 2, PR 16, SD 0). In 19 patients, 14 patients had received surgical treatment (R0 resection rates were 100%), 12 patients (12/14, 85.7%) achieved major pathological reaction (necrosis≥90%), and 2 patients (2/14, 14.3%) achieved complete pathological response. For those patients who did not undergo surgery, 3 of them refused surgery, and 2 patients lost the chance of surgery because of disease progression and high ICG R-15, respectively. At the end of the last follow-up (January 20, 2024), tumor recurrence was detected in 2 patients after surgery. The 12-month RFS rate and OS rate were 80.2%(95% CI: 40.4%-94.8%)and 94.7%(95% CI: 68.1%-99.2%), respectively. Median RFS and OS were not reached. No grade 3 or above AE were observed. Conclusions: Tislelizumab, lenvatinib, and TACE were safe and showed promising efficacy as a neoadjuvant therapy for resectable HCC with high risk of recurrence. Clinical trial information: ChiCTR2200059574.
The safety and short-term efficacy of selective internal radiation therapy combined with systemic treatment for unresectable malignant hepatic tumors in Chinese patients.
Authors: Zhang Hui , Kong Mingxin , Tan BinBin , Shao MingHua , Fu Ying , Liu Ping , Fan Chao , Chen HaiLei 
Published: July 2024

e16247 Background: There are many systemic treatment options for patients with unresectable malignant hepatic tumors. In China, selective internal radiation therapy (SIRT) with yttrium-90 (Y90) resin microspheres was approved until 2022. The aim of this retrospective study was to investigate the safety and short-term efficacy of SIRT with Y90 resin microspheres followed by systemic treatment in Chinese patients. Methods: The study analyzed patients who received SIRT with Y90 combined with systemic treatment at our center between June 2022 and October 2023. The study's primary endpoint was to determine the objective response rate (ORR), while safety was the secondary endpoint. Response was measured based on modified Response Evaluation Criteria in Solid Tumors criteria (mRECIST) up to 90 days after the initial therapy. Safety was evaluated using the Common Terminology Criteria for Adverse Events Version 5.0. Results: 21 patients wereincluded, of whom 22 times of SIRT were performed. 18 patients had HCC, and 3 had mCRC.The baseline characteristics of the patients are shown in Table. The median age was 54 years (IQR, 48-59 years) and 90.5% of patients were male. According to Eastern Cooperative Oncology Group performance status, grade 0 and grade 1 were 81% and 19%, respectively, whereas Child-Pugh A represented 90.5% of cases. The proportion of patients with hepatitis B virus infection was 95.2%. Thirteen (61.9%) patients received different treatments before SIRT. The median number of tumors was 2.5 (IQR, 1-4.3), whereas the median diameter of the largest lesion was 100.4 mm (IQR, 68.3-127.7 mm). PVTT was classified as follows: Vp1 (n = 3), Vp2 (n = 2), Vp3 (n = 2) and Vp4 (n = 1). Median AFP was 33.2 ng/mL (IQR, 5.9-401 ng/mL). The median total radiation activity administered was 1.4 GBq (IQR, 0.9-2.7 GBq) and the median target tissue dose was 205 Gy (IQR, 155-242 Gy). Nine (43%) patients were downstaged to surgery. Four (19%) patients had a complete response, fifteen (71.4%) had a partial response and two (9.5%) had a progressive disease. ORR and disease control rate were 90.5% and 90.5%, respectively. None of the patients experienced grade 3 and higher adverse events. The most common treatment-related adverse events were fever and abdominal pain, which required no special treatment. Conclusions: SIRT with Y90 resin microspheres combined with systemic treatment is safe and effective in patients with unresectable malignant hepatic tumors, which resulted in encouraging ORR (90.5%) and a downstaging rate (43%). Clinical trial information: ChiCTR2300077524. [Table: see text]
Effect of regulatory B cell expansion on tissue-resident TPH cells immune evasion in hepatocellular carcinoma.
Authors: Li Siqi , Yu Haoyuan , Shi Mengchen , Liang Zhixing , Li Kun , Hu Yongwei , Zhang Mingshen , Yang Yang , Ye Linsen 
Published: July 2024

e16252 Background: Within pathologically inflamed nonlymphoid tissues, TPH cells are uniquely positioned to stimulate B cell responses and antibody production. The phenotype, function and clinical relevance of TPH cells in hepatocellular carcinoma (HCC), however, are presently unknown. Methods: Flow cytometry was used to quantify the expression, phenotype and function of TPH cells. Log-rank tests were performed to evaluate disease-free survival and overall survival in samples from 39 patients and 101 patients with HCC. TPH cells, CD19+ B cells and TFH cells were cultured separately in vitro or isolated from C57/B6L mice in vivo for functional assays. Results: TPH cells highly infiltrated in tumor tissues, which influenced tumor sizes and early recurrence predictions and decreased survival times. The tumor-infiltrated TPH cells showed unique ICOShiCXCL13+IL-21-MAF+BCL-6- factors and triggered naïve B cell differentiation into regulatory B cells. Triggering PD-1 induced the production of CXCL13 by TPH cells, which then suppressed tumor-specific immunity and promoted disease progression. Conclusions: Our study reveals a novel regulatory mechanism of TPH cell-regulatory B cell mediated immunosuppression and provides an important perspective for the differentiation balance between protumorigenic TPH cells and antitumorigenic TFH cells in the HCC microenvironment.
Impact of preoperative frailty on outcomes of hepatic resection among elderly patients with hepatocellular carcinoma: A comprehensive multicenter cohort study.
Authors: Dan Li , Diao Yong-Kang , Wang Nanya , Yang Yi-Fan , Gu Wei-Min , Chen Ting-Hao , Li Jie , Wang Hong , Zhou Ya-Hao , Wang Xian-Ming , Zeng Yong-Yi , Pawlik Timothy M. , Fan Zhong-Qi , Lau Wan Yee , Shen Feng , Lv Guo-Yue , Yang Tian 
Published: July 2024

e16254 Background: With the increasing prevalence of hepatic resection for hepatocellular carcinoma (HCC) in the elderly, understanding the impact of preoperative frailty on surgical outcomes is crucial. This multicenter cohort study investigates the association between frailty and both short- and long-term outcomes post-hepatic resection in elderly HCC patients. Methods: This multicenter study involved elderly HCC patients (≥ 70 years) undergoing curative-intent resection at 10 hospitals in China from 2012 to 2021. Frailty was assessed using the Clinical Frailty Scale (CFS), with a score of ≥5 indicating frailty. The primary outcomes were overall survival (OS) and recurrence-free survival (RFS), while secondary outcomes included postoperative 30-day morbidity and mortality, and 90-day mortality. Comparisons were made between patients with and without preoperative frailty. Results: Out of 488 elderly patients, 148 (30.3%) were classified as frail. Frail patients had significantly higher rates of 30-day morbidity (68.9% vs. 43.2%), 30-day mortality (4.1% vs. 0.6%), and 90-day mortality (6.1% vs. 0.9%) compared to non-frail patients (all P < 0.05). Over a median follow-up of 37.7 months, frail patients showed markedly lower median OS (41.6 months [95% CI, 32.0-51.2] vs. 69.7 months [55.6-83.8]) and RFS (27.6 months [23.1-32.1] vs. 42.7 months [34.6-50.8]) than non-frail patients (both P < 0.01). Multivariable Cox regression analysis identified frailty as an independent risk factor for decreased OS (HR 1.61, P = 0.001) and RFS (HR 1.32, P = 0.028). Conclusions: Preoperative frailty is significantly associated with worse short-term and long-term outcomes following hepatic resection in elderly HCC patients. These findings underscore the importance of incorporating frailty assessment into the perioperative and postoperative care of elderly patients undergoing HCC resection.
Inpatient mortality outcomes of patients with hepatocellular carcinoma with congestive heart failure: A nationwide retrospective cohort study.
Authors: Adegbite Benjamin Olufemi 
Published: July 2024

e16256 Background: Chronic conditions create challenges in improving outcomes and treatment strategies for cancer patients. In the general population, for example, congestive heart failure (CHF) has been associated with poor cardiovascular health and thus increased mortality. However, its prognostic implications in patients with hepatocellular carcinoma (HCC) are less clear despite the physiological connection of the cardiohepatic system. This study aims to elucidate the relationship between CHF and mortality among HCC patients, offering insights that could inform clinical management strategies and improve care. Methods: The 2017 – 2019 versions of the National Inpatient Sample (NIS) database from the Healthcare Cost and Utilization Project (HCUP) were used to acquire the sample population. ICD-10 codes were used to identify diagnoses and procedures. The main sample population consisted of all patients diagnosed with HCC. A multivariate regression model was used (adjusted for age, sex, race, median household income based on patient ZIP code, Charleston Comorbidity Index score, hospital region, hospital teaching status based on rural/urban setting) to calculate the adjusted odds ratio (aOR) for outcomes. First, the association between CHF and inpatient outcomes was examined. Then mortality was calculated for HCC patients receiving therapeutic interventions (chemoradiation, liver transplant, radiation, or immunotherapy) based on CHF status. Results: There were 29,396 patients with HCC. Of this amount, 3,810 patients (13%) had CHF diagnoses. For inpatient procedures, 1,120 patients (3.8%) underwent a liver transplant, 265 (0.9%) received chemotherapy, 2 (0.01%) received immunotherapy, and 5 (0.02%) received radiation therapy. The cohort of CHF patients was found to be older than non-CHF patients (70.2 ± 0.3 years and 64.3 ± 0.2 years, respectively, with p < 0.001). The multivariate regression analysis for the entire sample showed that the adjusted odds of mortality for HCC patients with CHF was 0.92 times that of not having CHF but not significant (95% CI 0.8 – 1.07, p = 0.3). The analysis was then applied to HCC patients receiving one of the four treatments during their hospitalization. Results showed that the CHF cohorts had increased odds of mortality if they received a liver transplant (aOR 20.3, 95% CI 2.5 – 165.7; p = 0.005) or chemotherapy (aOR 338.4, 95% CI 10.0 – 11428.9; p = 0.001). Conclusions: Having CHF is not a significant predictor of mortality in patients with HCC. However, when considering HCC patients undergoing liver transplantation, having comorbid CHF significantly carried about a 20-fold odds in mortality. In addition, HCC patients receiving chemotherapy had a 338-fold odds of death if they have CHF. Thus, careful consideration and planning must be taken into account to optimize patients’ cardiac status when considering treatment options.