bluuebunny/crossref_metadata_2025_split huggingface dataset:
Salvage ipilimumab plus nivolumab in advanced hepatocellular carcinoma after prior anti-PD-(L)1 blockade.
Authors: Alden Stephanie Leigh , Lim Mir , Kao Chester , Shu Daniel , Singal Amit G. , Noonan Anne M. , Griffith Paige , Baretti Marina , Ho Won Jin , Kamel Ihab R. , Yarchoan Mark , Hsiehchen David 
Published: June 2023

4091 Background: Combination PD-(L)1/CTLA-4 blockade is approved in patients with advanced hepatocellular carcinoma (HCC) in the first line or after treatment with sorafenib, but it is unclear if combination therapy has efficacy after treatment with anti-PD-(L)1 alone or in combination with a multikinase inhibitor. We evaluated responses to ipilimumab plus nivolumab in patients with advanced HCC who previously received anti-PD-(L)1 to assess the efficacy and safety of this regimen. Methods: We performed a multi-center retrospective review of patients 18 years of age or older with a diagnosis of HCC based on histology or imaging who had received at least one dose of anti-PD-(L)1 therapy prior to receiving ipilimumab plus nivolumab as a subsequent line of therapy. All patients had imaging and/or laboratory monitoring to monitor for disease progression. Results: Our cohort contained 32 patients, with a majority being male (88%, n = 28) and a median age of 67 years. All patients were Child Pugh A (66%, n = 21) or B (34%, n = 11) at the start of treatment, with most having an ECOG performance status of 0-1 (84%, n = 27). The median number of prior lines of therapy was 2 (range 1-8). Prior anti-PD-(L)1 containing regimens included atezolizumab plus bevacizumab (50%, n = 16), other VEGF plus anti-PD-(L)1 combination (31%, n = 10), and anti-PD-(L)1 monotherapy (19%, n = 6). The objective response rate (ORR) was 22% (1 CR, (3%), 6 PR (19%)), with remaining responses including 8 SD (25%), 16 PD (50%), and 1 NE (3%). Among patients who had an objective response to ipilimumab plus nivolumab, none had an objective response to prior anti-PD-(L)1 treatments. Response rates were similar across major clinical (obese vs. non-obese) and etiological (viral vs. non-viral) subsets of HCC. Response to ipilimumab plus nivolumab was associated with improved PFS and OS: median PFS for PD/SD/NE 2.4 months (95% CI: 2.1-NR) vs. PR/CR not reached (NR) (95% CI: 7.5-NR), p = 0.004, and OS for PD/SD/NE 5.9 months (95% CI: 3.1-NR) vs. PR/CR NR (95% CI: NR-NR), p = 0.02. Immune related adverse events (irAEs) were reported in 13 patients (41%), and 6 patients experienced grade 3-4 irAEs (19%). One patient in our cohort experienced a fatal irAE (autoimmune hepatitis), and 5 patients discontinued therapy due to irAEs. Conclusions: This study demonstrates that ipilimumab plus nivolumab has clinical activity in patients with advanced HCC who previously received anti-PD-(L)1 therapy with an acceptable safety profile, supporting this regimen as second line immune checkpoint inhibitor therapy in advanced HCC. Further studies are required to determine the optimal sequence of therapies in advanced HCC.
Efficacy and safety of first-line treatments for patients with advanced hepatocellular carcinoma: A systematic review and network meta-analysis.
Authors: Li Danni , Li Jingyi , Liu Yunpeng , Qu Xiujuan 
Published: June 2023

4094 Background: In recent years, the first-line treatment options for advanced HCC has been increasingly abundant, including transarterial therapies, combination of the immune checkpoint inhibitors (ICIs) and the anti-vascular endothelial growth factor (VEGF) inhibitor, ICIs combined with ICIs, and tyrosine kinase inhibitors. However, it remains to be confusing which treatment pattern would benefit people most, especially for different subgroups. Methods: A systematic literature search was conducted on PubMed, Embase, Cochrane Central Register of Controlled Trials, and American Society of Clinical Oncology and European Society of Medical Oncology meeting proceedings for III phase randomized clinical trials (RCTs) investigating first-line treatments for HCC compared with sorafenib. The survival outcomes and toxic effects of RCTs should be reported, including overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and adverse events (AEs) of grade 3 or higher. This systematic review was performed in line with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Guidelines. The random-effects model was used to calculate the summary hazard ratios (HRs) of OS and PFS. The likelihood of ORR, and AEs of grade 3 or higher was performed by odds ratios (ORs) using a random-effects model. Results: A total of 13 phase III RCTs involving 8505 patients were included in this study. Hepatic arterial infusion of oxaliplatin combined with fluorouracil (FOHAIC-1) showed OS, PFS, and ORR benefit over all other first-line therapies, except for the regimen of sorafenib plus HAIC of FOLFOX (OS: HR, 0.88; 95% CI, 0.37-2.09; ORR: OR, 1.53; 95% CI, 0.29-8.13). More importantly, we found that sorafenib combined with FOLFOX was superior to other regimens in patients with HBV infection regarding OS except FOHAIC-1 (HR, 0.57; 95%CI, 0.21-1.52) and tremelimumab-durvalumab (HR, 0.42; 95%CI, 0.16-1.11). While in HCV-infected subgroup, ICIs combined with anti-VEGF inhibitor improved OS benefit compared with tremelimumab-durvalumab (HR, 0.31; 95% CI, 0.11-0.84) and sorafenib (HR, 0.38; 95% CI, 0.16-0.88). HAIC-FO also showed significant OS benefits to other therapies in patients with portal invasion or extrahepatic metastasis. The probability of adverse events of grade 3 or higher was significantly lower with HAIC-FO than with others except for nivolumab (RR, 0.96; 95%CI, 0.51-1.82) and tislelizumab (RR, 0.57; 95%CI, 0.30-1.08). Conclusions: This network meta-analysis supports arterial infusion as the first-line treatment for patients with HCC. In portal invasion and extrahepatic metastasis subgroups, HAIC-FO may be a preferred option, with sorafenib combined with FOLFOX as an additional option in those with HBV infection. Besides, novel combination therapy should be focused on in patients with certain subgroups.
A prospective, open-label, randomized, controlled trial of radiofrequency ablation versus stereotactic body radiation therapy for recurrent small hepatocellular carcinoma.
Authors: Zhang Yaojun , Xi Mian , Chen Minshan , Xu Li , Liu Shi-Liang , Liu Mengzhong ,   Collaborative Innovation Center for Cancer Medicine, State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center
Published: June 2023

4096 Background: Effective treatments are urgently needed to improve the prognosis of patients with recurrent hepatocellular carcinoma (HCC). Previous studies demonstrated that both radiofrequency ablation (RFA) and stereotactic body radiation therapy (SBRT) were promising therapies for recurrent small HCC. This trial was designed to compare the efficacy and safety of RFA versus SBRT in patients with recurrent small HCC. Methods: This is a prospective, open label, randomized controlled trial, in which patients aged between 18 and 75 years with recurrent small HCC (occurred more than 3 months after hepatectomy or RFA, a solitary HCC ≤5.0 cm in diameter without vascular invasion or extrahepatic metastasis), KPS score ≥90, Child-Pugh score ≤6, adequate organ function, and estimated life expectancy ≥6 months were considered eligible. All patients were assigned 1:1 to RFA or SBRT group, and stratification was performed according to tumor size (≤ 2.0 cm or 2.1-5.0 cm). The primary endpoint was 2-year local progression-free survival. Secondary endpoints were progression-free survival, locoregional control, overall survival, and safety. Results: A total of 170 patients were recruited during August 2019 to May 2022 (83 in RFA arm and 87 in SBRT arm). In the ITT population, median age was 56 (range, 33-75) and 15 were female. Baseline characteristics were well balanced between treatment arms. Adverse events occurred in RFA and SBRT were mainly grade 1 or grade 2 in severity, and were gastrointestinal and constitutional symptoms, or abnormal laboratory investigations. The most common adverse events were bilirubin increase（14.6%）and AST increase (13.3%) in RFA group vs ALT increase (20.0%) and AST increase (15.3%) in SBRT group. No Grade 3-4 adverse events or mortality were noted. Late adverse events were hardly observed after 3 months. The follow-up of survival data is ongoing. Conclusions: Both RFA and SBRT are tolerable and safe for patients with recurrent small HCC. This randomized controlled trial will report the survival outcomes in 2024, which will make an important contribution in clinical decision-making for recurrent small HCC. Clinical trial information: NCT04047173 .
A phase II study of olaparib and durvalumab in patients with IDH-mutated cholangiocarcinoma.
Authors: Tsang Erica S. , O'Kane Grainne M. , Knox Jennifer J. , Chen Eric X 
Published: June 2023

4099 Background: IDH1/2 mutations (m) occur in approximately 25% of cholangiocarcinomas (CCAs) (20% intrahepatic, < 5% extrahepatic) and result in the accumulation of R-2-hydroxyglutarate (R2HG). R2HG, suppresses homologous recombination repair and as a result IDH1/2m are hypothesized to predict PARP inhibitor sensitivity. PARP inhibition upregulates PD-L1 and the combination is thought to be synergistic. We conducted a phase II trial of olaparib with durvalumab for patients with IDH-mutated cholangiocarcinoma. Methods: Patients with advanced IDHm CCA were enrolled in this phase II open-label study (NCT03991832). Patients received olaparib 300 mg twice daily continuously and durvalumab 1500 mg IV every 4 weeks. Simon’s optimal two-stage design was used, with an interim analysis planned for efficacy. 10 patients were accrued in the first stage, with a plan for expansion if ≥2 responses were observed. The primary objective was to determine the overall response rate (RECIST 1.1) and disease control rate (DCR). Secondary objectives included progression-free survival, overall survival, and safety of the olaparib and durvalumab combination. Results: 10 patients with IDH1m were enrolled in this study between January 2020-August 2021. Median age was 63.5 years (range 49-78), and 50% were female. All patients had a baseline ECOG PS of 0-1. 40% of patients had prior surgical resections and subsequently developed recurrent disease. 20% of patients had ³2 lines of prior chemotherapy, with 90% receiving prior platinum. Median duration of treatment was 1.95 months (range 1.8-13.5). There were no treatment-related grade 3-4 toxicities. Any grade toxicities included fatigue (100%), nausea (60%), anemia (20%), hypothyroidism (20%), elevated liver enzymes (20%). We did not observe any complete or partial responses. The DCR was 30% with 3 patients demonstrating stable disease. One patient remained on treatment for 13.5 months, and was eventually taken off study due to clinical progression. The median PFS was 1.97 months (95% CI 1.73-3.93). Given that no responses were seen in the initial 10 patients, the study did not proceed to Stage 2. Conclusions: While the combination of olaparib and durvalumab was well-tolerated, this study was discontinued after Stage I due to lack of efficacy. IDH1/2m may not induce a BRCAness phenotype and further correlative studies are planned to evaluate this. Clinical trial information: NCT03991832 .
Ex-vivo analysis of programmed cell death on fibrolamellar carcinoma.
Authors: Ajay Olutani-Grace , Kent Paul , Nagourney Robert Alan , Stockwell Tom , Ellison Jessica , Swasey Susanne M. , Tasse Jordan C , Schadde Erik , Humar Abhinav , Kato Tom , Yamashiro Darrell 
Published: June 2023

4103 Background: Fibrolamellar carcinoma (FLC) is a rare liver cancer with surgery as the only established treatment. Relapse is common (>80%) and with 40% unresectable, there is a need for rationale systemic therapy. Empiric combinations, especially with lenvatinib (LEN) and gemcitabine (GEM), show promise, but are lacking a CLIA licensed laboratory rationale. Ex-Vivo Analysis of Programmed Cell Death (EVA-PCD), from Nagourney Cancer Institute, is an attempt to meet this need. Methods: Nagourney Institute analyzed FLC tissue (as previously described), with a panel of 34 single/26 combinations of available/promising agents from 18 drug classes. Drug concentration with 50% cell death (LC50), below, within, or above 1-standard deviation of the mean (n ≥ 15), define Highly-Sensitive/Intermediate/Resistant, respectively. Active/Moderate/Inactive are similarly defined but with n < 15. Actionable defines clinically available drug(s), not resistant/inactive and ≥ 6 assays. Results: Forty-four samples from 40 patients (17M,23F, age 6-56, 23 states/4 countries) were analyzed: 80% were viable and 69% of high quality for a total of 378 assays (avg 12/patient). However, all patients had actionable agents, and 78% of the assays showed activity in at least some patients. All the universally resistant/inactive assays (22%) were single agent. 76% of assays were actionable in at least one patient (100% for combinations compared to 62% for single agents). EVA-PCD replicate FLC studies and experience, such as the failure of monotherapy and the importance of LEN. Of 11 patients who had treatment that matched testing, 72% responded as predicted, including 6 with 100% response to LEN and/or QUE as predicted. Overall LEN/QUE, LEN/EVE, TRE, REG, QUE, 5FU/INF performed the best, while single agent ALP, CAB, LAR, VOR, GEM, DAS and IBR all showed 0% activity when tested > 5 times. The largest challenge is the need for an adequate amount of viable tissue to arrive within 24 hours. However our experience demonstrates that it is feasible from other countries and across the US. Conclusions: This is the first demonstration of CLIA approved human FLC tumor testing. Data are in line with literature and correlates clinically. Prospective data are needed to fully incorporate EVA-PCD testing into the clinic. [Table: see text]
Alteration of gut microbiota composition in patients with cholangiocarcinoma with non-responsiveness to first-line chemotherapy: A pilot study.
Authors: Ketpueak Thanika , Sriwichaiin Sirawit , Suparan Kanokphong , Kerdphoo Sasiwan , Charoentum Chaiyut , Suksombooncharoen Thatthan , Chewaskulyong Busyamas , Chattipakorn Nipon , Chattipakorn Siriporn 
Published: June 2023

4104 Background: Gut microbiota established crucial roles in host metabolism and several diseases, particularly cancers. Distinct bacterial profiles from intestine are found to be a potential factor in carcinogenesis, while some of those are associated with detrimental treatment to the responsiveness in various types of cancer. Association of gut microbiota and treatment outcome has been thoroughly investigated in intrahepatic cholangiocarcinoma (ICCA). The present study aimed to compare gut microbiota profiles between chemotherapy responder and non-responder in ICCA patients. Methods: Unresectable or metastatic ICCA patients were recruited in the study. The criteria of all patients were naïve to chemotherapy. All patients received first line combination of cisplatin 25 mg/m2 and gemcitabine 1000 mg/m2 at day1 and day 8 in every 21-day cycle and were given up to 8 cycles. The primary endpoint was to evaluate the association between gut microbiota and the objective response rate. Bacterial genomic DNA samples were extracted from the stool using a commercial genomic DNA isolation kit (Qiagen, Hilden, Germany) and then underwent next-generation sequencing. Data analyses were conducted by using QIIME2 and Analysis of Compositions of Microbiomes with Bias Correction (ANCOM-BC). Results: Seventeen ICCA patients were recruited. The objective response rate was 23.5% comparable to historical study. Chemotherapy responder group was defined as partial response patients (N = 4) and chemotherapy non-responder group included stable of disease and progressive disease (N = 13). Baseline characteristics were similar including age, sex, ECOG performance status, numbers of metastatic organ and CA 19-9 in two groups. Median Age were 63 years old (60-70) and 61 (45-73), respectively. Alpha-diversity and beta-diversity were not different between two groups. In chemotherapy non-responder group, some taxa were dominantly observed including Ruminococcaceae, Oribacterium, Oxalobacter, Peptostreptococcus, Aggregabacter, which had been previously reported increasing in ICCA patients. Interestingly, Ruminococcaceae, which was previously documented to be correlated with vascular invasion, was significantly increased abundance in non-responder group. Moreover, the median progression-free survival (PFS) was improved in chemotherapy responder group compared to non-responder group 11.8 and 6.6 month, respectively. Large sample sizes study to confirm this study result should be developed. Conclusions: Distinct bacteria from gut microbiota such as Ruminococcaceae has inversely associated with chemotherapy response in ICCA patients receiving first line cisplatin and gemcitabine combination, suggesting the possibility of the poorer PFS.
Application of the albumin-bilirubin (ALBI) grade as predictive marker of atezolizumab plus bevacizumab (A+B) treatment outcomes for patients with advanced hepatocellular carcinoma (HCC): Real-world retrospective analysis at Veterans Health Administration (VHA).
Authors: Alkadimi Munaf , Fierro Maria Elena , Boyle Lauren Diaz , Lucero Kana , Franklin Kathleen , Mader Michael , Nooruddin Zohra 
Published: June 2023

4107 Background: Most clinical trials use Child-Pugh (CP) for patient selection; this subjective scale was originally developed to assess liver function in cirrhosis, thus cannot be applied to HCC patients with non-cirrhotic background. Alternatively, ALBI grade is an objective and validated prognostic system that has demonstrated improved accuracy to predict survival and liver function decline in HCC patients. Our real-world study aims to assess the ALBI grade as a predictive marker of treatment response in patients with advanced HCC who received (A+B) within the VHA. Methods: VHA patients with HCC receiving 1st line therapy with A+B were identified through EMR using ICD-9 or ICD-10 codes between 1 Jan 2007 and 31 Dec 2021. Patients were followed from their A+B initiation date through the earliest of the last VHA visit, loss to follow up, death, or end of study on Jan 31, 2023. Structured electronic health record and chart review data were retrospectively collected to determine patient baseline characteristics, treatment response, overall survival (OS), and progression-free survival. Survival rates were based on patients with at least 6 months or 1 year of time (as indicated) from A+B initiation until the chart was reviewed; patients without a scan or known date of scan were excluded from PFS calculations. The Chi-Squared test was used to compare rates. Results: 332 patients were included in the study. The median age was 67 yrs, 99% were males, 63% non-Hispanic White, 26% Black, 86% with ECOG < 1, 84% had CPS class A, 16% had CPS class B and C, 56% had viral hepatitis-caused HCC, 20% had no cirrhosis present, and 60% had prior local therapies. There was a statistically significant difference in progression free survival (PFS) and over survival (OS) amongst different ALBI grades as shown. Conclusions: In our retrospective cohort, it was clear that patients with ALBI grade 1 had improved PFS and OS compared to ALBI score grade 3. Patients with ALBI score grade 2 also had a moderate response to treatment with modest OS and PFS compared to patients with ALBI score grade 3. Utilizing stratification ability ALBI grade in future clinical trials may improve prognostic power facilitating ideal patient selection. [Table: see text]
Adjuvant immune checkpoint inhibitors and association with recurrence-free survival in postoperative hepatocellular carcinoma (PREVENT): A prospective cohort study.
Authors: Li Le , Liang Xiu-Mei , Chen Kang , Zhang Guan-Lan , Huang Shan , Ma Liang , Zhong Jian-Hong 
Published: June 2023

4119 Background: Adjuvant therapy may improve survival of patients with hepatocellular carcinoma (HCC) after curative resection, yet no such therapy is universally recommended. This study compared safety and efficacy outcomes between patients at high risk of recurrence who received different types of adjuvant therapy or no such therapy after hepatic resection for HCC. Methods: Recurrence-free survival (RFS), overall survival, and adverse events were compared among patients who received adjuvant immune checkpoint inhibitors (ICIs) alone, ICIs with tyrosine kinase inhibitors (TKIs), or no adjuvant therapy at our medical center between 13 March 2019 and 19 March 2022. In some analyses, patients who received adjuvant therapy were matched based on propensity scores to patients who did not, in order to reduce confounding due to baseline differences. This study was registered on ClinicalTrials.gov (NCT05221398). Results: Of the 492 patients in our final analysis, 410 (83.3%) received no adjuvant therapy, 50 (10.2%) received ICIs alone, and 32 (6.5%) received adjuvant ICIs and TKIs. During median follow-up of 23.3 months (IQR 15.6 to 31.1 months), HCC recurred in 221 (53.9%) of patients who received no adjuvant therapy, compared to 22 (44.0%) of patients who received ICIs and 18 (56.3%) of patients who received ICIs and TKIs. RFS was significantly longer among patients who received either type of adjuvant therapy (23.9 months, 95%CI 14.0-33.7) than among those who received none (16.8 months, 95%CI 13.2-20.3), and this difference remained significant after propensity score matching (HR 0.61, 95%CI 0.39-0.94, P = 0.033). However, overall survival was unaffected by either type of adjuvant therapy, even after propensity score matching. The rate of grade 3 or 4 adverse events was similar between the two types of adjuvant therapy. Conclusions: ICIs alone or with TKIs may improve RFS of patients at high risk of recurrence after curative resection. Clinical trial information: NCT05221398 .