bluuebunny/crossref_metadata_2025_split huggingface dataset:
The impact of CARE Frailty Index on overall survival in older adults with hepatocellular carcinoma.
Authors: Ozluk Ahmet Anil , Williams Grant Richard , Dai Chen , Malla Midhun , Siwakoti Krishmita , Outlaw Darryl Alan , Pywell Cameron , Gupta Garima , El-Rayes Bassel F. , Giri Smith , Akce Mehmet 
Published: January 2024

462 Background: Pre-treatment frailty is associated with unfavorable short and long-term outcomes among patients with hepatocellular cancer (HCC) post liver resection.However, there is a knowledge gap in identifying the subset of older adults with HCC at high risk for inferior survival outcomes. Methods: We evaluated the association between patient-reported geriatric assessment (GA)-based frailty index and overall survival (OS) among older adults (≥60y) diagnosed with HCC enrolled in a single institutional prospective registry (Cancer and Aging Resilience Assessment (CARE) registry). All patients underwent a patient-reported GA at enrollment that encompassed multiple health domains related to aging. To determine frailty, we utilized a 44-item CARE Frailty Index (CARE-FI) based on the principles of deficit accumulation (Giri S et al JAGS 2021). We categorized frailty into robust, pre-frail and frail. The primary outcome was OS from the time of GA. Comparison of survival between groups was made using log-rank statistic. A multivariable Cox regression model measured the independent association between frailty and OS adjusted for age, etiology, Child-Pugh score and cancer stage. Results: A total of 116 older adults with HCC were identified with a median follow-up 2.1 year, median age was 67y (63-72) with 82% males, 27% blacks, 64% with Child-Pugh-A and 78% with stage III/IV disease. Overall, 50.1% (n=58) were frail, 33.6% (n=39) pre-frail and 16.3% (n=19) robust. No significant clinico-demographic differences across the 3 frailty groups were observed. In univariable analysis, there was a marginally significant difference between the three frailty groups (p value 0.06). However, in multivariable analysis, being frail vs robust was associated with an increased risk of mortality (HR 2.6 [95% CI 1.03 – 6.56]; p=0.04) after adjustment for aforementioned confounders. Conclusions: Frailty status assessed by patient-reported GA using CARE-FI is associated with an increased risk of mortality in older adults with HCC. Frailty assessment should be encouraged and considered in prospective clinical trials to estimate the impact of treatment on the most vulnerable adults. [Table: see text]
Care delivery and patient self-management for people with primary liver cancer receiving 4R care sequence plans.
Authors: Therapondos George , Weldon Christine B. , Du Lingling , Mizrahi Jonathan , Palmer Carol , Medina Amanda , Sandow Tyler Allan , Gimenez Juan , Cohen Ari , O'Brien Michelle , Tan Amie , Trosman Julia R. 
Published: January 2024

465 Background: The 4R Oncology Model (4R=Right information/care/patient/time) supports patient self-management1 and quality improvement.2 Here we report the impact of using 4R Care Sequence plans for patients with primary liver cancer cared for by a multi-disciplinary liver cancer team. Methods: We tested the impact of 4R care sequence plans on patient self-management and care delivery referrals at a liver cancer program via patient surveys. 4R Plans were provided to patients with primary liver cancer from Jan – Aug ’23 (4R cohort). Patient-reported data were analyzed to compare the control cohort of patients who received care pre-4R, Jan - Dec ’22 (N=42) to the 4R cohort (N=17). Statistical analysis used Fisher’s exact test. Results: Patient survey response rates: Control cohort 54% (42/78), 4R cohort 55% (17/31). Comparing the control cohort to the 4R cohort respectively, patients were male (52%, 65%), White (64%, 64%), Black (26%, 18%), average age (63.2, 64.7), and reported income less than $30,000 (45%, 53%). The 4R cohort significantly improved care delivery in three metrics, and directionally improved in the other care delivery metrics as compared to the control cohort (table). All four patient self-management metrics significantly improved in the 4R cohort vs. the control cohort (Table). Conclusions: The use of 4R Care Sequence plans for patients with primary liver cancer facilitated improvements in care delivery and patient self-management metrics. While there were directional improvements in all metrics, there is opportunity and room for additional improvements. The team will continue to work on efforts to improve these metrics and optimize the use of 4R Care Sequence plans for patients with primary liver cancer. 1. Trosman, JCOOP 2021. 2. Liu, JCOOP 2022. [Table: see text]
Preoperative endoscopic biliary drainage procedures may affect intrahepatic recurrence of cholangiocarcinoma after surgical resection.
Authors: Kim Jin-Oh 
Published: January 2024

468 Background: To determine the impact of preoperative endoscopic nasal biliary drainage (ENBD) and/or endoscopic retrograde biliary drainage (ERBD) procedures on intrahepatic recurrence rate in patients with cholangiocarcinoma after surgical resection. Methods: Between January 2005 and January 2023, 143 patients diagnosed cholangiocarcinoma and received surgical resection. Among 143 patients, 99 patients were treated with preoperative ENBD and/or ERBD. We retrospectively analysed prognostic factors (age, gender, preoperative ENBD and/or ERBD, tumor differentiation, pT factor, lymph node metastasis, surgical margin, lymphovascular invasion, preoperative maximal total bilirubin, postoperative chemoradiation/chemotherapy/radiation therapy, CA19-9) for recurrence after surgical resection. Results: Intrahepatic recurrence after surgical resection was detected in 22 /99(22.2%) patients with preoperative ENBD and/or ERBD, and 5/44(11.4%) patients without preoperative ENBD and/or ERBD for median period of 12 months (range 0-48). On univariate analysis, intrahepatic recurrence rate of patients who underwent ENBD and/or ERBD (n=99) was higher than that of patients who did not (n=44) ( P=0.090) and and that of patients who had T3/T4 factor (n=74) was higher than that of who had T1/T2 factor (n=69) (P=0.168). Intrahepatic recurrence rateof patients who had elevated CA19-9 (> 200) (n=49) was higher than that of patients who had not (n=94) ( P=0.002). In multivariate analyses, preoperative ENBD and/or ERBD and elevated serum CA19-9 level (>200 ng/mL) were prognostic factors for intrahepatic recurrence, with hazard ratios (HR) of 2.154 (95% confidence interval (CI) 0.893-7.626, P = 0.080) and 3.647, (95% confidence interval (CI) 1.660-8.011, P = 0.001). Conclusions: Preoperative preoperative endoscopic nasal biliary drainage (ENBD) and/or endoscopic retrograde biliary drainage (ERBD) procedures may affect the intrahepatic recurrence of tumor in patient with cholangiocarcinoma after surgical resection. And serum elevated CA 19-9 level affected intrahepatic recurrence of tumor in patients with cholangiocarcinoma after surgical resection.
A phase 2, open-label, safety and efficacy study of telotristat ethyl plus first-line chemotherapy in patients with advanced biliary tract cancer.
Authors: Kim Richard D. , Joseph-Ridge Nancy , Du Jichang , North Janine , Warren Cathy , Iyer Renuka V. 
Published: January 2024

472 Background: Patients (pts) with unresectable biliary tract cancer (BTC) have a poor prognosis. In preclinical models of cholangiocarcinoma (CCA) telotristat ethyl (TE), a tryptophan hydroxylase inhibitor that reduces production of serotonin, enhanced the antiproliferative effects of gemcitabine and cisplatin (GC) chemotherapy. This trial assessed the safety and efficacy of adding TE to GC chemotherapy in pts with advanced BTC. Methods: This was a Phase 2 open-label study. Eligible pts had unresectable, locally advanced, or metastatic BTC, were treatment naïve and had plans to initiate GC chemotherapy. On Day 1, pts received Gem 1000mg/m2 and Cis 25mg/m2 with TE 250 mg orally three times daily (TID) for 7 days. Thereafter, pts received TE 500 mg TID continuously plus GC therapy on days 1 and 8 of each 21-day cycle. The study comprised of 2 stages: stage 1 would enroll 20 patients with a safety run-in cohort in the first 6 pts to monitor safety and tolerability of TE + GC treatment for 21 days. Stage 2 would enroll 33 patients if no significant/unresolved grade 3 or higher toxicities related to study drug occurred in stage 1. The primary endpoint was 6-month (mo) progression free survival (PFS) rate according to RECIST 1.1. If 60% of pts (≥34) in the safety population were alive and progression free at 6-mos, the study was considered successful. Secondary endpoints included overall response rate (ORR) and disease control rate (DCR). Restaging occurred every 9 weeks using RECIST 1.1 and toxicities were graded using CTCAE v 5.0. Results: Between 2019 and 2021, fifty-three pts were enrolled across 12 study sites and comprised the safety population. The majority of pts were female (62.3%) and median age was 66 yrs (range 33 to 79). Baseline mean plasma 5-HIAA was 11.1 µg/L (ULN defined as >10.8 µg/L). Thirty-one pts (58.5%) had plasma 5-HIAA levels ≤ULN and 22/53 (41.5%) had 5-HIAA levels >ULN. Majority of pts had metastatic BTC (85%) and liver was the most common primary tumor site (66%). The 6-month PFS rate was 22.6% (12/53). Based on blinded independent central review, the ORR was 13.2% and DCR was 62.3%. Mean reduction in plasma 5-HIAA at 6 mos was -1.735 µg/L (SD 8.69) in 24 patients with available data. There was no difference in 6-mo PFS rate based on pts baseline 5-HIAA status; 58% (14/24) pts had ≥30% decrease from baseline in 5-HIAA, however there was no correlation with 6-month PFS. The most common TE related TEAEs were constipation (43.4%), nausea (28.3%) and fatigue (28.3%). Conclusions: The study did not achieve its primary endpoint of 60% of patients on TE plus GC chemotherapy being alive and progression free at 6 months. TE did reduce 5-HIAA levels in a subset of pts; however, this did not correlate to improved clinical outcomes. No significant safety issues noted with TE in combination with GC chemotherapy. Clinical trial information: NCT03790111 .
First safety and efficacy data from phase Ib/IIa study of fostroxacitabine bralpamide (fostrox, MIV-818) in combination with lenvatinib in patients with hepatocellular carcinoma (HCC).
Authors: Reig Maria , Evans T.R. Jeffry , Chon Hong Jae , Lim Ho Yeong , Ryu Min-Hee , Kim Do Young , Macarulla Teresa , Gomez-Martin Carlos , Moreno Victor , Haugk Beate , Ness Thomas , Baumann Pia , Bhoi Sujata , Jensen Malene , Tunblad Karin , Wallberg Hans , Oberg Fredrik , Heo Jeong 
Published: January 2024

476 Background: Fostrox is an orally administered troxacitabine-based nucleotide prodrug in clinical development in combination with lenvatinib (NCT03781934). Fostrox is rapidly metabolized by human hepatocytes, directing high levels of the active metabolite to the liver. Phase I fostrox monotherapy demonstrated selective intra-tumoral activity in on-treatment liver biopsies. The anti-angiogenic activity of lenvatinib has the potential to synergize with fostrox by hypoxia-induced increase in the enzymatic generation of the active metabolite of fostrox in the tumor. Methods: In a phase Ib/IIa study with an inter-patient dose escalation 3+3 cohort design followed by a dose expansion phase, fostrox was administered orally QD for 5 days in 21-day cycles in combination with lenvatinib according to local prescription information. Patients (pts) with <2 prior lines systemic treatment for advanced, unresectable HCC were recruited at 10 sites in Spain, South Korea and UK. Pts with histologically, radiologically, or cytologically confirmed HCC, Child-Pugh A, ≥18 years, ECOG PS ≤ 1 and adequate organ function were eligible. The primary objective was to assess safety and tolerability. Key secondary endpoints were ORR based on RECIST 1.1 and mRECIST. Exploratory endpoints included pharmacokinetics (PK) and pharmacodynamic effects of fostrox in combination with lenvatinib. Results: At interim data cut-off 18 pts (6 pts in Ib and 12 pts in IIa) were enrolled at fostrox QD doses of 20mg (3 pts) and 30mg (15 pts) in combination with lenvatinib. Median age was 63 years (range: 42-82). No DLTs and only 1 discontinuation of fostrox due to AEs with a median FU of 3.8 months, were observed. Most common grade 3/4 AEs were transient neutrophil count decrease, platelet count decrease and hypertension. No febrile neutropenia, bleeding events or proteinuria were reported. The safety profile was consistent with each individual agent. In phase Ib, central independent review based on RECIST 1.1 showed SD in 5/6 pts, while mRECIST showed CR in 1 pt, PR in 2 pts and SD in 2 pts. Updated phase Ib data and efficacy data from phase IIa by central independent review, together with PK for fostrox and lenvatinib, and liver biopsy biomarker data, will be presented. Conclusions: Fostrox in combination with lenvatinib, in pts with HCC who progressed on previous systemic treatment, had an acceptable safety and tolerability profile with promising interim efficacy results from the completely enrolled phase Ib/IIa study. Clinical trial information: NCT03781934 .
Clinical impact on treatment effectiveness of immune-related adverse events in patients with hepatocellular carcinoma treated with atezolizumab plus bevacizumab.
Authors: Suzuki Keito , Yasui Yutaka , Tsuchiya Kaoru , Matsumoto Hiroaki , Yamazaki Yudai , Uchihara Naoki , Tanaka Yuki , Miyamoto Haruka , Yamada Michiko , Keitoku Taisei , Okada Risa , Higuchi Mayu , Takaura Kenta , Tanaka Shohei , Maeyashiki Chiaki , Tamaki Nobuharu , Nakanishi Hiroyuki , Takahashi Yuka , Kurosaki Masayuki , Izumi Namiki 
Published: January 2024

479 Background: Immune checkpoint inhibitors (ICIs) have emerged as the first-line therapy for unresectable hepatocellular carcinoma (HCC). However, their administration poses the risk of immune-related adverse events (irAEs). Recent data suggests that the occurrence of irAEs may be associated with a favorable prognosis. Nevertheless, limited studies have explored the relationship between irAE severity or specific symptoms and clinical outcomes. Therefore, the objective of this study was to investigate and analyze the association between these adverse events and the clinical benefits in patients with unresectable HCC treated with immune checkpoint inhibitors. Methods: We enrolled 130 patients with unresectable HCC treated with atezolizumab plus bevacizumab between November 2022 and January 2023 at a single center. We investigated the relationship between irAEs and both response rate and post-treatment outcomes. Results: Out of the 130 patients, 36 (27.7%) developed irAEs. Patients with irAEs exhibited a significantly longer progression-free survival (PFS) compared to the non-irAE group, with a median PFS of 8.9 months compared to 4.6 months (p < 0.01). There was no difference in overall survival with or without irAEs. The irAE group demonstrated significantly higher disease control rate (DCR) compared to the non-irAE group (97.0% vs 65.5%, p < 0.01). The analysis by the severity of irAE revealed that the grade 1/2 group exhibited significantly longer PFS (7.9 months vs 4.6 months, p =0.007) and higher DCR (100% vs 65.5%, p < 0.01) compared to the non-irAE group. Furthermore, hypothyroidism was correlated with a favorable PFS (8.9 months vs 5.4 months, p = 0.02), DCR (100% vs 71.3%, p = 0.03) and overall response rate (58.3% vs 18.5%, p = 0.005). Conclusions: The presence of irAEs is associated with prolonged PFS and higher DCR. Specifically, mild irAEs (Grade 1/2) and hypothyroidism displayed prolonged PFS and higher DCR.
Phase Ib trial of durvalumab plus tremelimumab in combination with particle therapy in advanced hepatocellular carcinoma patients with macrovascular invasion: DEPARTURE trial.
Authors: Ogasawara Sadahisa , Koroki Keisuke , Makishima Hirokazu , Wakatsuki Masaru , Takahashi Asahi , Kanzaki Hiroaki , Kobayashi Kazufumi , Inoue Masanori , Kiyono Soichiro , Nakamura Masato , Kanogawa Naoya , Kondo Takayuki , Nakamoto Shingo , Shiko Yuki , Ozawa Yoshihito , Inaba Yosuke , Kurokawa Tomoya , Hanaoka Hideki , Yamada Shigeru , Kato Naoya 
Published: January 2024

480 Background: The HIMALAYA study established the efficacy and safety of durvalumab combined with tremelimumab (STRIDE) as a first-line treatment for advanced hepatocellular carcinoma (HCC). Carbon ion radiotherapy (C-ion RT), a type of particle therapy, allows precise tumor targeting while sparing nearby normal tissue. In HCC, macrovascular invasion (MVI) signifies aggressive progression with poor outcomes. Our strategy used C-ion RT to target a key tumor with MVI for disease management and potential MVI control, complemented by STRIDE. Recognizing that radiation therapies, including C-ion RT, stimulate immune responses, notably releasing tumor antigens and DAMPs (immune priming), we posited that merging C-ion RT with STRIDE might enhance therapeutic effects. Methods: This is a Phase Ib, multicenter study evaluating durvalumab with particle beam radiotherapy in HCC patients with MVI (Cohort A) and STRIDE (Cohort B). Both cohorts began with patients resistant to standard treatments. After safety confirmation, the study expanded to include systemic therapy-naïve patients, totaling 15. C-ion RT begins after day 8 of the first cycle, following the initial drug dose. The relative biological effectiveness weighted dose is set at 60 Gy in four fractions over one week, targeting one representative intrahepatic nodule with MVI. The primary endpoint is adverse event rates, including dose limiting toxicity (DLT), with secondary endpoints on progression free survival (PFS) and overall survival (OS) (jRCT2031210046). Results: From July 2021 to January 2023, 15 advanced HCC patients were enrolled in our study (Cohort A: 3, Cohort B: 12). Four in Cohort B were systemic therapy-naïve. All cases confirmed MVI radiologically; with tumor invasion observed in the main portal vein for 4 patients and in the inferior vena cava for one. DLT evaluations in 3 from each cohort showed no incidents. While Cohort A had no adverse events, 4 patients in Cohort B (26.7%) experienced serious treatment-related adverse events. Cohort B's median PFS was a significant 2.79 months (95%CI, 1.12–6.64). The 6- and 12-month PFS rates stood at 38.1% and 12.7% respectively. The median OS is still undetermined, but promisingly, the 6- and 12-month survival rates both reached 87.5%. Conclusions: The safety of STRIDE in combination with particle therapy has been confirmed in advanced HCC with MVI. This combination, especially the irradiation of tumors with MVI using C-ion RT, holds promise in managing prognostic determinant tumors and potentially enhancing OS. Clinical trial information: jRCT2031210046 .
Treatment outcomes by stratifying the N-acetyl transferase 2 phenotype in pre-treated patients with advanced refractory biliary tract cancer treated with nanvuranlat, an L-type amino acid transporter inhibitor: An ad-hoc analysis of a randomized, double-blind, placebo-controlled phase 2 study.
Authors: Okano Naohiro , Nagashima Fumio , Nishioka Mariko , Kusaka Haruki , Yamamoto Kouji , Furuse Junji 
Published: January 2024

483 Background: L-type amino acid transporter 1 (LAT1, SLC7A5) is overexpressed in cancer cells, leading to aggressive proliferation and lymphatic metastases. In a placebo-controlled, randomized phase 2 trial involving patients with pre-treated, advanced, refractory biliary tract cancer (BTC), monotherapy with nanvuranlat (JPH203), a selective LAT1 inhibitor, demonstrated a significant improvement in progression free survival (PFS) as the primary endpoint compared to placebo. The safety profile was comparable between nanvuranlat and placebo treated patients, except for a higher rate of cholangitis in the nanvuranlat group. Nanvuranlat is metabolized to its main inactive, off-target metabolite, Nac-JPH203 by N-acetyl transferase 2 ( NAT2). Since the NAT2 unknown patients mislead the benefit and risk ratio of nanvuranlat treatment, an ad-hoc analysis was conducted in enriched NAT2 non-rapid (NR) phenotype patients who slowly produced Nac-JPH203 in plasma. Methods: Among 104 (full analytical set (FAS) - nanvuranlat:69 & placebo:35) enrolled patients, 25 with unknown NAT2 phenotype were enrolled prior to an amendment to only enroll NAT2-NR phenotype. Subsequently, further analysis was conducted to determine the NAT2 phenotypes of these 25 patients. Results: Among the 25 NAT2 unknown patients, 16 and 9 patients were assigned to nanvuranlat or placebo, respectively. NAT2 ad hoc analysis recorded those 9 patients in nanvuranlat and 5 in placebo as NAT2 NR, and 7 patients in nanvuranlat and 4 in placebo were NAT2 rapid (R). As a result, number of NAT2 NR patients was increased from 81 to 94. Efficacy analysis of this enriched population (FAS-NR-nanvuranlat:63 & placebo:31) revealed a significant improvement in PFS. With respect to cholangitis, 8 all-grade (12.7%) and 7 over grade 3 (11.1%) were documented in the FAS-NR population. In the FAS-R population, 2 all grades (28.5%) and 2 over grade 3 (28.5%) were observed (Table). Conclusions: By classifying BTC patients by NAT2 phenotype in this ad hoc analysis, the LAT1 inhibitor nanvuranlat further improved its clinical efficacy and safety in the NAT2 NR population. Therefore, selecting NAT2 NR for nanvuranlat treatment may improve the risk -benefit ratio. Clinical trial information: UMIN000034080 . [Table: see text]
Characterizing outcomes of ERBB2-amplified biliary tract cancer.
Authors: Fox Daniel Aaron , Haro-Silerio Jaime , Bhamidipati Deepak , Meric-Bernstam Funda , Pant Shubham , Ross Jeffrey S. , Hu Zishuo Ian , Koay Eugene Jon , Ludmir Ethan B. , Tran Cao Hop Sanderson , Tzeng Ching-Wei D. , Chun Yun Shin , Vauthey Jean-Nicolas , Newhook Timothy E. , Metwalli Zeyad , Habibollahi Peiman , Cox Veronica L. , Kang Hyunseon , Javle Milind M. , Lee Sunyoung S. 
Published: January 2024

492 Background: A subset of biliary tract cancers (BTC) feature amplification (amp) of the human epidermal growth factor receptor 2 ( ERBB2) gene. The prognostic role and treatment in these patients (pts) are poorly understood. This study aims to characterize the clinical outcomes and molecular profiles of ERBB2-amp BTC. Methods: We conducted a retrospective analysis of clinical outcomes data and next-generation sequencing (NGS) at MD Anderson (MDA) and Foundation Medicine (FMI) from 2009-2023 in pts with ERBB2-amp BTC including all classes of genomic alterations (GA) in other genes. Progression-free survival (PFS) and overall survival (OS) were assessed by the log-rank test. Results: 80 pts (MDA) were identified with ERBB2-amp BTC with documented treatment and NGS data. Pts (Table) who received ERBB2-directed therapy (22.4 vs. 12.0 m, p=0.004), surgery (21.0 vs. 12.0 m, p=0.002), local therapy with RT/ablation/Y90 (excluding surgical pts, 20.6 vs. 11.6 m, p = 0.0001) had significantly longer OS. Median PFS (mPFS) without ERBB2-directed therapy for 1st, 2nd, and 3rd line systemic therapy was 4.1, 3, and 2.2 m. mPFS with all ERBB2-directed therapy was 4.1 m, but that of gemcitabine (gem)-based plus trastuzumab (tt) and 5FU-based plus tt was 7.8 and 3.8 m (p=0.018). The most common concurrent-GA at MDA, any co-amps (72.7%; 19.2 vs. 20.3 m, p=0.69) and TP53 inactivating mutation (70.4%; 16.6 vs. 14.9 m, p=0.89), had no OS association; 3rd most common co-GA found, CDK12 amp (46.4%), had a trend toward a better OS (19.2 vs. 14.3 m, p=0.089). FMI database showed ERBB2 amp in 3.2%, 5.4%, and 8.9% in intrahepatic cholangiocarcinoma (iCCA), extrahepatic CCA, and gallbladder cancer. The most common co-GA included TP53, CDKN2A/B, and CCNE1. FGFR2 fusions (iCCA) were mutually exclusive with ERBB2 amp (0%, MDA/FMI); IDH1 (iCCA) with ERBB2 amp, 5.7 and 4.3% (MDA and FMI). Conclusions: ERBB2-amp BTC has shorter mPFS or mOS without ERBB2-directed therapy, surgery, or local therapy, suggesting clinical benefit from multi-disciplinary care and targeted therapy. Co-GA with ERBB2-amp did not demonstrate a significant association with survival outcomes. [Table: see text]