bluuebunny/crossref_metadata_2025 huggingface dataset:
Cholangiocarcinoma: A nationwide trend analysis from 2016 to 2020.
Authors: Ishaya Michelle , Litvin Rafaella , Pan Chun-Wei , Ibrahim Muhammad Bilal , Shah Mihir
Published: June 2023

e16177

Background: Cholangiocarcinomas (CCAs) are epithelial malignancies arising from the biliary ductal system, occurring with an incidence of 1/100,000 people per year in the US. Most patients present with advanced-stage disease and prognosis is very poor, with five-year mortality rates ranging from 2-24% depending on stage and subtype. This study was designed to determine the trends and adverse outcomes of CCA. Methods: This retrospective trend study analyzes data from the Nationwide Inpatient Sample (NIS) for the years 2016-2020 to identify adult hospitalizations with a diagnosis of cholangiocarcinoma and to highlight epidemiological trends. Inpatient mortality, mean length of stay (LOS), mean total hospital charge (THC), and rates of procedures and complications were estimated. Multivariate regression trend analysis was used to assess statistical significance and adjust for confounders. Results: There was an increase in the number of CCA hospitalizations per total hospitalizations from 8.49/100,000 in 2016 to 11.0/100,000 in 2020 (p < 0.01). Mean age remained around 67 years old, and male predominance remained constant throughout this period (52.7%). White patients made up the majority of the study population (65.6%). Inpatient mortality ranged from 6.8% to 7.1%, with no statistically significant trend. However, there was an increase in mean THC (P-trend <0.05) with no significant change in mean LOS (P-trend 0.76). We found a decrease in endoscopic retrograde cholangiopancreatographies (ERCPs) performed (1.6% to 1.2%, p=0.05), biliary duct stents placed (1.2% to 0.6%, p=0.003), and percutaneous biliary tract drains placed (4.2% to 3.4%, p=0.002) from 2016 to 2020. An increase was seen in rates of acute kidney injury (AKI) (22.9% to 28.6%, P<0.05), stent-related complications (2.0% to 2.6%, P=0.01), and peritoneal metastasis (7.7% to 9.3%, P<0.05). Biliary duct obstruction, stent-related infection, and palliative care utilization did not show any statistically significant change during this time. Conclusions: CCA hospitalizations increased from 2016 to 2020. Demographics remained unchanged, with a stable inpatient mortality rate but increased THC. The use of ERCPs, biliary duct stents, and percutaneous biliary tract drainage devices decreased, but rates of AKI, stent-related complications, and peritoneal metastasis increased. It is unclear what factors led to decreased procedure rates and increased complication rates. No significant changes were observed in biliary duct obstruction, stent-related infections, or palliative care utilization.[Table: see text]
A survey on the detection of hepatitis B virus (HBV) in blood samples of patients with hepatocellular carcinoma (HCC) in China.
Authors: Gao Biwei , Xu Ruilian , Hu Bo
Published: June 2023

e16178

Background: China is the country with the highest occurrence of HCC, accounting for about 45.3% of the new cases in the world. HBV can cause chronic infection and potentially leads to the occurrence of HCC. Generally, HBV genomic segments are able to be integrated into the host’s genome, then affect the expression of host genes, form carcinogenic proteins and cause chromosomal aberrations in host cells. HCC tumor tissue samples have more integration sites of HBV on the genome compared with para-cancerous tissues. It suggests that HBV is likely to be continuously enriched and integrated in the host genome during the development of HCC, and promotes the occurrence of HCC. There is plenty of tumor molecular information in the blood plasma of patients. Features of virus integration patterns and relatively quantitative level of virus DNA in the blood plasma should be intriguing to study. Methods: 216 blood samples of 178 HCC Chinese patients were collected. Circulating cell-free DNA (cfDNA) was processed by hybridization-based target enrichment and sequenced by next-generation sequencing (NGS) technique using Haplox HapOnco 680 panel. Results: In the blood of 178 HCC patients, the cfDNA of a total of 58 patients was detected with HBV genome fragments integration. These HBV genome fragments mainly belong to two subtypes, HBV-B and HBV-C, of which single HBV-B type was detected in 18 cases, accounting for 31% of HBV integrated infections, single HBV-C type was detected in 39 cases, accounting for 67.2% of HBV integrated infections. Additionally, HBV-B and HBV-C were co-integrated in 1 case. In the integrated host genome, the average number of breakpoints produced by HBV-B infection was 3.158, and the most frequent integration site was ANKRD26P1 (6 times). The average number of breakpoints produced by HBV-C integration was 3.65, and the most frequent integration site was TERT (15 times). There was no significant difference in the number of breakpoints produced between HBV-B and HBV-C groups (p=0.49). In the total of 58 HBV-B datasets and 64 HBV-C datasets, the average abundance of integrated HBV-B reads was 5.6e-05, and the average abundance of HBV-C was 5.04e-0.5, and there was no significant difference between them (p = 0.71). Conclusions: Approximately one third of the 178 HCC patients were detected positive for HBV integrationin their blood samples, with the ratio of subtypes HBV-B and HBV-C roughly 1:2. HBV-B is slightly lower than HBV-C in the number of average breakpoint, but the difference is not significant. Similarly, the overall abundance of HBV-B and HBV-C of integrated reads in blood is also quite similar. However, the hotspot integration sites of HBV-B and HBV-C on the host genome are quite different.
Trends in hepatocellular carcinoma rates by age, region, race, and ethnicity: A SEER database population study 2000-2019.
Authors: Schodowski Eve , Alkrekshi Akram , Al Zubaidi Anas , Al Armashi Abdul Rahman
Published: June 2023

e16179

Background: Liver cancer (LC) incidence has tripled over the past four decades, with hepatocellular carcinoma (HCC) being the most common type (72%). Further, LC mortality often coincides with incidence, as the disease is often fatal. To illustrate, the five-year survival rate (2012-2018) for LC is 21% at all stages, compared to lung cancer at 23% and colon cancer at 65%. While incidence and death rates of LC have stabilized in the past 5 years, troubling disparities have been identified when rates are stratified by region, age, race, and ethnicity. For example, HCC incidence in rural areas has increased by 5.7% annually, with rates approaching that of urban ones, despite a historically lower incidence. Consequently, as several inequalities in HCC have been established, the study herein aims to identify whether recognition of these disparities has helped to reduce their growth. Methods: We identified incidence rates of HCC from the Surveillance, Epidemiology and End Results Program database at 4-year time intervals from 2000-2019, stratified by age above (>) and below (<) 60, metropolitan (M) vs nonmetropolitan (NM) counties, race, and ethnicity. Next, we calculated percent change and percent difference in HCC rates across time intervals and groups to evaluate trends. Results: Percent change in rates of HCC has increased since 2000 in those >60 in both M and NM areas with larger growth observed in NM counties. Conversely, between 2010 and 2019 HCC rates have declined in those <60, with a steeper decline observed in M (-18.2%) vs NM (-10.0%) counties. Alarmingly, when 2015-2019 HCC rates are stratified by race/ethnicity, each minority group studied exhibited considerably higher rates of HCC when compared to whites and non-Latinos of the same age group and region (percent difference = >60 M; >60 NM; <60 M; <60 NM): Black (50.3%; 37.2%; 24.1%; 26.6%), American Indian (21.2%; 85.8%; 7.6%; 77.5%), Asian (17.3%; 17.8%; 21.1%; 28.1%), and Latino (39.0%; 45.6%; 40.0%; 36.1%). [Reference: white rates = 35.4; 31.7; 5.1; 4.9 and non-Latino rates = 36.5; 33; 2.4; 2.5, respectively, per 100,000 and age adjusted to the 2000 US Standard Population]. Conclusions: Recent data describes a stabilization in LC incidence and death rates over the past 5 years. However, when HCC incidence is stratified by age, region, race, and ethnicity, disconcerting trends continue to be revealed. As such, interventions should be targeted at those >60, living in NM areas, and in the minority groups studied to combat these disparities. [Table: see text]
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 .
A multicenter study on adjuvant chemotherapy of S-1 versus observation for resected perihilar cholangiocarcinoma.
Authors: Hosokawa Isamu , Higuchi Ryota , Homma Yuki , Takayashiki Tsukasa , Ome Yusuke , Matsuyama Ryusei , Takano Shigetsugu , Uemura Shuichiro , Yabushita Yasuhiro , Suzuki Daisuke , Miyake Kentaro , Honda Goro , Endo Itaru , Ohtsuka Masayuki
Published: June 2023

e16201

Background: The prognosis of perihilar cholangiocarcinoma (PHC) is poor even after curative resection. The efficacy of adjuvant S-1 chemotherapy for resected PHC is unclear. This study aimed to assess the efficacy of adjuvant S-1 chemotherapy after major hepatectomy for PHC. Methods: Consecutive patients with PHC who underwent major hepatectomy (hemihepatectomy or trisectionectomy extending to segment 1 with extrahepatic bile duct resection) at three high-volume centers in Japan from 2007 to 2020 were retrospectively evaluated. Patients with Clavien-Dindo grade V complications, pStage I or IVB disease, and those who underwent adjuvant radiation therapy were excluded from analysis. Propensity score matching analysis was performed to compare the disease-specific survival (DSS) of patients who underwent adjuvant S-1 chemotherapy with those who underwent observation. Results: Of 480 patients, 373 were eligible for the study, 81 of whom underwent adjuvant S-1 chemotherapy, and 146 underwent observation. In the global cohort, DSS in the S-1 and observation groups were similar ( P = 0.18). In the matched cohort as well (S-1: n=44, Observation: n=44), DSS was similar between the S-1 and observation groups ( P = 0.09). On multivariate analysis, performance of percutaneous biliary drainage, CA19-9 levels at operation ≥ 300 U/ml, and lymph node (LN) metastasis were independent predictors of poor survival following major hepatectomy for PHC. In subgroup analysis of patients with LN metastasis, DSS in the S-1 group was better than in the observation group ( P = 0.001). Conclusions: Adjuvant S-1 chemotherapy after major hepatectomy might be effective in PHC patients with LN metastasis.
Association between autologous transfusion and recurrence-free survival in patients with hepatocellular carcinoma after resection: A prospective nonrandomized controlled trial.
Authors: Zhong Jian-Hong , Xie Si , Huang Jian-Li , Yang Da-Long , Chen Zu-Shun , Ma Liang
Published: June 2023

e16206

Background: To investigate whether preoperative stored autologous transfusion has a significant effect on recurrence-free survival of patients with primary hepatocellular carcinoma (HCC). Methods: Recurrence-free survival (RFS), overall survival, and perioperative morbidity were compared among patients with or without autologous transfusion at our medical center between January 2019 and December 2021. Patients who received autologous transfusion 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 (NCT02654028). Results: Of the 618 patients in the analysis, 399 (64.6%) received autologous transfusion and 219 (35.4%) did not receive autologous transfusion. By 30 July 2022, the median RFS time had been achieved. Patients with or without autologous transfusion had similar RFS before (hazard ratio 1.01, 95%CI 0.82-1.24) or after propensity score analysis (hazard ratio 1.04, 95%CI 0.82-1.31). However, the median overall survival was not achieved. Patients with or without autologous transfusion also had similar overall survival before (hazard ratio 1.15, 95%CI 0.84-1.56) or after propensity score analysis (hazard ratio 1.26, 95%CI 0.88-1.79). Moreover, subgroup analyses found that patients with or without autologous transfusion had similar RFS or overall survival among those with early, intermediate, or advanced stage disease. The two groups also had similar rates of perioperative mortality and morbidity. Conclusions: Preoperative stored autotransfusion had no significant effect on survival in patients with HCC who underwent liver resection. Clinical trial information: NCT02654028 .
EGFR/ERBB2 aberrations in Chinese biliary tract carcinomas.
Authors: Wu Xiaobing , Zhao Yaping , Wang Chenxi , Ding Ran , Deng Wanglong , Bu Fanfeng
Published: June 2023

e16208

Background: Biliary tract carcinoma (BTC) accounts for 3% gastrointestinal cancers in China. BTCs are mainly classified as gallbladder cancer (GBC) and cholangiocarcinomas (CCA) with dismal prognosis. Current chemotherapy regimens for BTC yield poor outcomes. We aimed to describe the genomic landscape of a BTC patient cohort using next-generation sequencing (NGS), focusing on the EGFR/ERBB2 aberrations and exploring the possibility of therapeutic intervention. Methods: We analyzed BTC tissue/blood samples including GBCs and CCAs with targeted sequencing (NGS) for EGFR/ERBB2 activating mutations, copy number amplifications (copy number≥5) and rearrangements (containing the kinase domain). A cohort of 1033 Chinese BTC patients were analyzed including 783 GBC patients and 250 CCA patients. Results: Data analysis revealed EGFR/ERBB2 alteration rates were 9.0% in Chinese BTC patients. The majority of these alterations were in fact ERBB2 alterations at a rate of 15.8% in GBC and 6.4% in CCA（P<0.05). A further subanalysis of ERBB2 mutation types showed that 46.7% in GBC and 64.6% in CCA were activating mutations, 37.8% in GBC and 31.3% in CCA were gene amplifications, 8.9% in GBC and 2.1% in CCA were gene rearrangements and 6.7% of GBC and 2.1% of CCA cases had multiple ERBB2 alterations. The top activating ERBB2 mutation were p.S310F（10/45） followed by p.R678Q(4/45) in GBC and were p.S310F (11/48) followed by p.V777L(5/48) in CCA. EGFR alteration rates were 3.5% in GBC and 1.3% in CCA（P<0.05). Among these, 30% of the GBCs and 60% of the CCAs had an activating EGFR mutation, 70% of the GBCs and 30% of the CCAs had EGFR copy number amplification and 10% of the GBCs and no CCA case had an EGFR rearrangement. Three EGFR activating mutations detected in GBC were p.G719A, p.L861Q, p.A289V. Six EGFR activating mutations detected in CCA were p.G719D, p.E746_S752delinsV, p.L858R, p.N771_H773dup, p.D770_N771insG, p.R222C. Conclusions: We report characteristics of EGFR/ERBB2 alterations in Chinese GBC and CCA patients. In general, 19.4% of GBC and 7.7% CCA may benefit from EGFR/ERBB2 targeted therapy. EGFR/ERBB2 targeted therapies should be further explored in Chinese BTC patients.
Evaluating triple therapy with lenvatinib, PD-1 inhibitor and transarterial chemoembolization for unresectable intrahepatic cholangiocarcinoma: A retrospective study.
Authors: Tu Jianfei , Ying Xihui , Lai Lingqiang , Huang Chaoming , Liu Shuang , Chen Li , Zhang Dengke , Wu Jiahao , Chen Jie
Published: June 2023

e16210

Background: Cholangiocarcinoma has a poor prognosis and responds poorly to intravenous chemotherapy. This study evaluated the efficacy and safety of a triple therapy combining transarterial chemoembolization (TACE) with lenvatinib and programmed cell death protein (PD)-1 inhibitors for treating unresectable intrahepatic cholangiocarcinoma (ICCA). Methods: This retrospective study included a total of 15 patients with unresectable ICCA who were initially treated with TACE. One week later, they received lenvatinib 8 mg/day orally and PD-1 inhibitors for 21 days/cycle. The primary endpoint was the objective response rate (ORR); secondary endpoints included disease control rate (DCR), overall survival (OS), progression-free survival (PFS), and the incidence of treatment-related adverse events (TRAEs). Results: At 1-month post-treatment, the ORR was 73.3% and the DCR was 86.7%. The median PFS was 10.4 months (95% confidence interval [CI]: 6.73, not reached), and the median OS was 16.9 months (95% CI: 9.2, not reached). Compared with pre-treatment data, post-treatment levels of the tumor serum markers carcinoembryonic antigen and carbohydrate antigen 19-9 had decreased significantly (P<0.05). However, 13 patients experienced Grade 1–2 TRAEs, including decreased appetite (n=8 [53.3%]), fatigue (n=3 [20.0%]), weight-loss (n=3 [20.0%]), hypertension (n=2 [13.3%]), hand–foot syndrome (n=2 [13.3%]), diarrhea (n=1 [6.7%]), dysphonia (n=1 [6.7%]), and hypothyroidism (n=1 [6.7%]). No patient experienced Grade ≥3 TRAEs during treatment or follow-up. Conclusions: Triple therapy with TACE, lenvatinib and PD-1 inhibitors showed promising antitumor activity as well as a tolerable safety profile in patients with ICCA. Larger clinical studies investigating this treatment combination should be considered.
Huaier granules for hepatocellular carcinoma recurrence after ablation: A multicenter prospective cohort study.
Authors: Han Yue , Zheng Jiasheng , Wan Chidan , Li Zixiang , Zhai Bo , Li Jiaping , Li Yuliang , Li Hailiang , Ma Liwei , Liu Ruibao , Zhou Jun , Shi Lei , Song Lei , Wang Shuai , Han Juqiang , Zhang Bo , Li Qingdong , Ye Xin , Fan Weijun
Published: June 2023

e16216

Background: Clinical trials had confirmed the efficacy and safety of Huaier granules in the treatment of hepatocellular carcinoma (HCC), but real-world evidence is still lacking. This prospective study aimed to evaluate the real-world effectiveness and safety of Huaier granules for HCC recurrence after ablation. Methods: Post-ablation patients with no residual lesions confirmed by imaging were enrolled in this study and divided into the Huaier granule group and the control group based on receiving Huaier granules or not. Propensity-score matching was performed according to age, gender, TACE within 3 months before ablation, alpha-fetoprotein level, time interval between ablation and enrollment, and Child-Pugh Grade in 1-(up)-to-2 ratio. The primary outcome was progression-free survival (PFS), and the secondary outcomes were local recurrence-free survival (LRFS) and adverse events (AEs). Results: There were 340 patients in the Huaier granule group and 141 patients in the control group. After propensity score matching, 189 patients and 111 patients were selected for the Huaier granule group and the control group, respectively. There was no significant difference in baseline characteristics between two groups after matching. The median follow-up time of the Huaier granule group and the control group were 49.14 weeks and 73.29 weeks, respectively. The number of PFS events were 29 (15.34%) and 27 (24.32%) in the Huaier granule group and the control group, respectively. The 48, 72, and 96-week PFS rates were 87.4%, 79.4% and 75.2% in the Huaier granule group, and 79.9%, 70.1% and 66.5% in the control group, respectively ( P=0.1649). The number of LRFS events were 27 and 25 in the Huaier granule group and the control group, respectively. In the pre-matching Huaier granule cohort, the incidence of AEs, serious AEs, and grade ≥ 3 AEs were 54 (16.56%), 30 (9.20%) and 14 (4.30%), respectively. Conclusions: This study suggested potential benefit in PFS and RFS and favorable safety profile of Huaier granules in patients with HCC after ablation. Longer-term follow-up is needed to confirm this finding.[Table: see text]
Using machine learning-based boosting algorithm to predict hepatotoxicity after local therapy and association with survival in patients undergoing liver directed therapy.
Authors: Mo Allen , Velten Christian , Tang Justin , Ohri Nitin , Kalnicki Shalom , Mirhaji Parsa , Kaubisch Andreas , Soby Selvin , Peshansky Alexandre , Henninger Erin , Garg Madhur , Guha Chandan , Kabarriti Rafi
Published: June 2023

e16229

Background: Hepatocellular carcinoma typically arises in the setting of chronic liver disease. In carefully selected patients, liver directed therapy has been demonstrated to improve survival; however, this benefit from cancer specific survival may be offset by increased mortality from diminished hepatic functional reserve. Treatment-related hepatotoxicity also may vary between liver directed treatment modalities for a given tumor. Our aim was to determine if a machine learning approach could estimate hepatotoxicity prior to treatment. Methods: We identified all patients with hepatocellular carcinoma who underwent liver directed therapy at a large urban academic health system who also had post-treatment laboratory follow-up at 6 months. Patients were categorized as having worse liver function if they experienced a decline in albumin-bilirubin (ALBI) grade or more than 0.5 absolute decline in ALBI score at post treatment follow-up. A machine learning, extreme-gradient boosting (XGBoost) approach was employed to identify predictive features for hepatotoxicity using fine-tuned hyperparameters. Results: The study cohort consisted of 269 patients. 48 (18%) were categorized as having worsened hepatic function after liver directed therapy, with an average decline of -0.72 in ALBI score. Median survival after liver directed therapy was 5.8 years, with worsening hepatic function associated with a 5 month decline in overall survival. 158 (59%) patients received transarterial chemoembolization, 99 (37%) patients received stereotactic body radiotherapy and 12 (7%) patients received Y-90. A machine learning model was developed resulting in an Area Under the ROC Curve (AUC) of 0.894 in a 10-point decision tree model. On SHAP analysis, the features with the largest impact on hepatotoxicity prior to treatment was pretreatment T-stage followed by Child-Pugh Score. Conclusions: A machine learning model was developed to accurately classify patients who sustained treatment related hepatotoxicity. Significant decline in ALBI score or grade was associated with a worsening of overall survival. Future studies in larger prospective clinical trials utilizing this machine learning-based methodology of assessing liver dysfunction after focal therapy are required to validate these findings.
Survival outcomes with observation or adjuvant therapy in elderly patients with biliary tract cancer.
Authors: Gbolahan Olumide B. , Zhi Xiaojie , Botrus Gehan , Shah Mihir Maheshkumar , Sarmiento Juan , Russell Maria C. , Kooby David A. , Maithel Shishir K. , Alese Olatunji B.
Published: June 2023

e16230

Background: The impact of adjuvant therapy (AT) on overall survival (OS) for biliary tract cancer (BTC) is contested. The BILCAP study suggested an improvement in OS with adjuvant capecitabine compared to observation. This was not apparent in the intention to treat population. Importantly, none of the patients in the study was older than 70 years. Considering the toxicity of AT and conflicting results of efficacy, the role of AT in older adults with BTC needs to be thoroughly assessed. We hypothesized that AT is not associated with significant benefit in the elderly. Methods: We performed a retrospective review of patients with resected BTC; gall bladder cancer (GBC), intrahepatic cholangiocarcinoma (ICC), and extrahepatic cholangiocarcinoma (ECC) using the National Cancer Database (NCDB) PUFs (2004-2019). We limited analysis to patients aged >= 70 years. We compared clinical characteristics and outcomes in those who received AT (including chemotherapy and chemotherapy + radiation) within 6 months after resection, and those who did not (Obs). We performed propensity score matching analysis of both groups (matched for age, sex, race, Charleson-Deyo score, AJCC pathologic T stage among others) and assessed survival by Kaplan-Meier analysis. Results: We identified 8,091 elderly patients with T1-T3/N1-N2 resected BTC. The majority had GBC (76.7%), and 3, 041 (38%) were aged >= 80 years (median 78 years). Only 2, 632 (32.5%) received AT. Of these, 1,304 (50%) received chemotherapy and radiation. Median OS was higher in the Obs vs the AT group (24.3 months, vs 20.2 months, P < 0.0001) and the five-year survival was also higher in the Obs group (29.1% vs 22.6%, P<0.001). Survival also favored the Obs group in a propensity score matched cohort of 835 patients per group (median OS 33.1 vs 19.5 months, P <0.0001). On multivariable analysis AT was associated with a higher hazard of death (HR 1.21, CI 1.13-1.29, P <0.001). Age >=80 (HR 1.39, CI 1.32-1.47, P<0.001), GBC ( HR 1.29, CI 1.20-1.39, P<0.001) were also associated with worse survival. Compared to diagnosis between 2004-2009 diagnosis in 2010- 2015 (HR 0.83, CI 0.78- 0.89) and 2016- 2019 (HR 0.74 CI 0.67-0.8, P <0.001) were associated with improved OS. Conclusions: In patients >=70, AT for BTC was not associated with improved OS and was actually associated with a higher hazard of death compared Obs. Based on these results, the role of AT for BTC in the elderly needs to be examined prospectively.