bluuebunny/crossref_metadata_2025_split huggingface dataset:
Primary percutaneous stenting above the ampulla for palliative biliary drainage of malignant hilar biliary obstruction.
Authors: Franssen Stijn , Van Driel Lydi M.J.W. , Moelker Adriaan , Groot Koerkamp Bas 
Published: January 2023

527 Background: Most patients with malignant hilar biliary obstruction (MHBO) are ineligible for surgical resection due to distant metastasis, locally advanced disease, or poor performance status. These patients mostly undergo biliary drainage with endoscopic stents or percutaneous drains that cross the ampulla. This approach causes bacterial colonization of the bile ducts, recurrent cholangitis, and biliary reinterventions. Few patients become eligible for palliative systemic chemotherapy, because of inadequate drainage and drainage-related complications. The solution is primary percutaneous stenting (PPS) with one or more fenestrated self-expandable metal stent (SEMS) across the biliary obstruction, without crossing the ampulla. After PPS, the percutaneous transhepatic puncture tract is sealed with glue without leaving an external biliary drain. The aim of this study was to assess the safety, feasibility, and effectiveness of PPS in patients with unresectable MHBO. Methods: A single center prospective study was performed from October 2020 till September 2022 including 35 patients with MHBO who underwent PPS. We made a comparison with a historical cohort of 90 consecutive patients treated with primary endoscopic biliary drainage at our center from 2011 till 2020. Results: All 35 patients had technical successful percutaneous SEMS placement. Perihilar cholangiocarcinoma was present in 15 patients (43%), intrahepatic cholangiocarcinoma in 14 patients (40%), and gallbladder cancer in 6 patients (17%). Two patients required two attempts because the stricture could not be passed at the first attempt. Two patients developed cholecystitis and one patient had melaena due to intrahepatic bleeding of a portal venous branch requiring blood transfusion. One patient (3%) developed cholangitis after the first biliary drainage procedure because the tumor extended up to the ampulla, requiring additional stenting. No cholangitis was seen in the other 34 patients. We made a comparison with a historical cohort of 90 consecutive patients treated with primary endoscopic biliary drainage at our center from 2011 till 2020. Only 3 patients (9%) required a readmission and 3 patients (9%) a reintervention. Palliative systemic chemotherapy was administered in 26 patients (75%) versus 18 patients (20%) after primary endoscopic biliary drainage. The median overall survival was 10.6 months (95% CI 8.1 – not reached) versus 4.3 months (95% CI 3.1 – 6.4) after primary endoscopic biliary drainage. After PPS, no patients died because of cholangitis or drainage-related complications. Conclusions: Primary percutaneous stenting with fenestrated SEMS without crossing the ampulla is safe, feasible, and effective for palliative treatment of patients with MHBO. These promising results need to be confirmed in a randomized controlled trial. Clinical trial information: NL9624 .
A study of pembrolizumab (pembro) in combination with Y90 radioembolization in patients (pts) with poor prognosis hepatocellular carcinoma (HCC).
Authors: Somasundaram Ashwin , Helft Paul R. , Harris William Proctor , Sanoff Hanna Kelly , Johnson Guy E. , Yu Menggang , Johnson Matthew , O'Neil Bert , McRee Autumn Jackson 
Published: January 2023

534 Background: HCC is an aggressive cancer as a sequela of cirrhosis. For pts with no extrahepatic metastases and well-compensated liver function, Y90 radioembolization is a therapeutic option. However, high-risk patients with macrovascular invasion (MVI) or multifocal disease treated with Y90 alone have a median time to progression of less than 6 months. Pembro is an anti-PD-1 monoclonal antibody that is FDA-approved for advanced HCC pts who have progressed on sorafenib. Given pre-clinical evidence that radiotherapy can increase PD-L1 expression and enhance tumoral T-cell recruitment, this study explored the safety and efficacy of pembro with Y90 radioembolization in pts with poor prognosis HCC. Methods: GI15-225 was a multi-center, single-arm study in poor prognosis HCC pts, defined as having multifocal disease, MVI, or diffuse disease. Eligible pts had disease amenable to 1-2 embolization procedures, Child Pugh A/B7 cirrhosis, no prior Y90 treatment; previous locoregional therapy and resection were allowed. Pts with extrahepatic mets were excluded. Treatment consisted of pembro 200mg every 3 weeks with standard dose Y90 performed 7-10 days after first dose of pembro. The primary objective was to estimate the progression free survival (PFS) rate at 6 months per RECIST 1.1; secondary endpoints included safety, time to progression (TTP), overall response rate (ORR) and overall survival (OS). Imaging was performed every 9 weeks. Results: A total of 29 pts were enrolled 10/23/17 to 11/24/20. Median age 66 years, 89% male, 7% Child’s Pugh B, and 47% with MVI. 27 pts were evaluable for primary endpoint having received Y90 and at least one dose of pembro. The 6-month PFS rate was 57.7% (95% CI 36.9 – 76.6). Median PFS was 9.95 months (95% CI 4.14 – 15.24) and median TTP was 9.95 months (95% 4.14 – 18.56). Median OS was 27.30 months (95% CI 10.15 – 39.52). The ORR was 30.8% (Table). Three patients (11%) have ongoing treatment response with one of these patients off treatment for 16 weeks. Most common treatment related grade 3-4 AEs were decreased lymphocytes (n=5), increased bilirubin (n=3), hypertension (n=3), ascites (n=2), and AST/ALT elevation (n=2). One pt experienced grade 5 toxicity of hepatic failure after receiving one dose of pembro and Y90 that was attributed to Y90 and disease progression. Conclusions: Concurrent administration of pembro with Y90 in pts with poor prognosis HCC demonstrated promising clinical activity with median TTP and OS that exceeds historical data with three patients having ongoing response. With a 6-month PFS rate of 57.7%, median OS of 27.30 months and an acceptable toxicity profile, the combination of checkpoint blockade and Y90 deserves further evaluation in larger randomized clinical trials. Clinical trial information: NCT03099564 .[Table: see text]
Risk factors for early relapse in patients with biliary tract cancers who underwent curative resection: An exploratory subgroup analysis of JCOG1202.
Authors: Yanagimoto Hiroaki , Nakachi Kohei , Ikeda Masafumi , Konishi Masaru , Ogawa Gakuto , Sano Yusuke , Nomura Tatsuya , Yanagibashi Hiroo , Shibuya Kazuto , Shirakawa Hirofumi , Takahashi Amane , Sakamoto Yoshihiro , Makino Isamu , Hatano Etsuro , Gotohda Naoto , Ozaka Masato , Terashima Takeshi , Okusaka Takuji , Furuse Junji , Ueno Makoto 
Published: January 2023

541 Background: Relapse after highly invasive surgery for biliary tract cancers (BTCs), especially in the early postoperative period, causes medical, psychological, social, and economic disadvantages to the patients. However, approximately 30% of patients with curatively resected BTCs experience relapse within the first 12 months. JCOG1202 (UMIN000011688) is a randomized phase III trial conducted in patients with resected BTCs showing the benefit of adjuvant S-1 for overall survival. This study aimed to investigate the risk factors for early relapse of resected BTCs in the JCOG1202 cohort. Methods: Of the 440 patients enrolled in the JCOG1202, 217 patients who received surgery alone (arm A) and 207 patients who received adjuvant S-1 (arm B) were eligible and included in this analysis. Early relapse was defined as relapse or death within 12 months after enrollment. Predictive factors for early relapse were assessed using logistic regression analyses. Results: Postoperative early relapse was observed in 59 (27.2%) and 38 (18.4%) of patients in arm A and arm B, respectively. In multivariable logistic regression analysis for the 424 eligible patients, postoperative CA19-9 levels >37 u/ml (odds ratio (OR): 2.790, 95% confidence interval (CI): 1.262-6.170), poorly differentiation (vs. well-differentiated/papillary) (OR: 4.746, 95% CI:1.927-11.688), moderate differentiation (vs. well-differentiated/papillary) (OR: 1.955, 95% CI:1.071-3.567), lymph node metastases > 4 (vs. 0) (OR: 3.991, 95% CI: 1.674-9.514), lymph node metastases 1-3 (vs. 0) (OR: 2.661, 95% CI: 1.471-4.814), and presence of residual tumor (OR: 2.171, 95% CI: 1.070-4.408) were independent risk factors for early relapse. Importantly, adjuvant S-1 chemotherapy significantly reduced early relapse (OR: 0.491, 95% CI: 0.290-0.833). Similar results were observed in arm B. Conclusions: Postoperative CA19-9 level, tumor differentiation, lymph node metastases, and the residual tumor significantly impact early relapse in patients with curatively resected BTCs. Although adjuvant S-1 chemotherapy was effective in reducing early relapse, similar factors tended to be the risk factors in patients receiving adjuvant S-1 chemotherapy. Patients at high risk of early relapse may need more intensive perioperative therapy. Clinical trial information: UMIN000011688 .
Clinical utility of comprehensive genomic profiling in patients with unresectable primary liver cancer.
Authors: Ishido Shun , Tsuchiya Kaoru , Suzuki Keito , Uchihara Naoki , Tanaka Yuki , Miyamoto Haruka , Yamada Michiko , Keitoku Taisei , Matsumoto Hiroaki , Nobusawa Tsubasa , Higuchi Mayu , Takaura Kenta , Tanaka Shohei , Maeyashiki Chiaki , Tamaki Nobuharu , Yasui Yutaka , Takahashi Yuka , Nakanishi Hiroyuki , Kurosaki Masayuki , Izumi Namiki 
Published: January 2023

542 Background: Comprehensive genomic profiling (CGP) using tissue and blood specimens is covered by national health insurance for patients who have already received standard systemic therapy in Japan. We investigated the clinical utility of CGP in patients with unresectable primary liver cancer in real-world practice. Methods: We retrospectively investigated the clinical outcome of the patients with unresectable primary liver cancer. All patients received CGP between February 2021 and May 2022 at our institution. Results: 17 patients with unresectable primary liver cancer were included. 10 patients had hepatocellular carcinoma (HCC) and seven had intrahepatic cholangiocarcinoma (ICC). In HCC patients, the treatment line at CGP was 4th (n=5), 5th (n=4), and 6th-line (n=1). The samples were from liver tumor biopsy (n=2), surgical specimens of bone metastases (n=2), and blood (n=6). Clinically meaningful oncogene mutations were detected in all HCC cases. Seven of 10 patients were candidates for clinical trials, and 1 patient showed TMB-high. Six of the 7 patients could not participate in clinical trials due to renal dysfunction, low platelet counts, the immune-related adverse event of past therapy, or HBV infection. One patient with TMB high started pembrolizumab. In ICC patients, the treatment line at CGP was 1st (n=6), and 2nd -line (n=1). The samples were from liver tumor biopsy (n=5), blood (n=1) and surgical specimens of lung metastases (n=1). Clinically meaningful oncogene mutations were detected in all ICC cases. Six of 7 patients were candidates for clinical trials, and 1 patient showed MSI-high. One patient with MSI high started pembrolizumab, and one patient with FGFR2 fusion could use pemigatinib as 3rd line. The Overall survival duration of this patient with ICC (StageⅣB) was 26 months. In total, 13 of 17 patients were candidates for clinical trials, and 4 of 17 patients could receive personalized therapy according to the results of CGP. Conclusions: CGP in patients with unresectable primary liver cancer was useful in real-world practice. However, most patients could not participate in clinical trials because of adverse events associated with previous therapies. The best timing of CGP should be discussed in the future to provide more personalized therapies.
Bevacizumab combined with atezolizumab or sintilimab as second-line treatment in patients with advanced hepatocellular carcinoma: A retrospective study.
Authors: Gan Leijuan , Li Huikai , Wu Qiang , Li Qiang , Cui Yunlong , Zhang Wei , Fang Feng , Lu Wei , Li Guangtao , Ren Shaohua , Liu Yayue , Lang Mengran , Han Ruyu , Song Tianqiang 
Published: January 2023

544 Background: The combination of bevacizumab and immune checkpoint inhibitors (ICI) has demonstrated promising efficacy and safety in the first-line treatment of advanced hepatocellular carcinoma (HCC). However, this combination has not been examined in patients with previous first-line treatment of ICI and tyrosine kinase inhibitor. This study aimed to investigate the effectiveness and safety of bevacizumab combined with atezolizumab or sintilimab as second-line treatment in patients with advanced HCC. Methods: The retrospective study included patients with advanced HCC who received combined therapy of bevacizumab and atezolizumab or sintilimab after failure of lenvatinib plus ICI between July 28, 2020 and March 7, 2022. Baseline patient characteristics were collected. Treatment response, overall response rate (ORR) and disease control rate (DCR) were evaluated according to response evaluation criteria in solid tumors (RECIST) version 1.1. Overall survival (OS) and progression-free survival (PFS) were analyzed by the Kaplan-Meier method. Treatment-related adverse events were graded according to Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0. Results: A total of 20 patients with advanced HCC were included, with a median follow-up time of 11.05 (5.03-20.63) months. Eleven patients died by the last follow-up on August 12, 2022. There were 18 males (90%) and two females (10%). The average age was 59.9±12.08 years. Seven patients (35%) had distant metastasis, and nine (45%) had vascular invasion. Liver function was classified as Child-Pugh grade A in 17 patients (85%) and grade B in three (15%). Patients with Barcelona Clinic Liver Cancer (BCLC) stages B, C and D were 1 (5%), 16 (80%) and 3 (15%), respectively. Eighteen patients (90%) had previous topical therapy. Of all patients previously administered lenvatinib plus ICI as first-line treatment, 14 (70%) had PFS longer than three months. ORR and DCR were 15% (95% confidence interval [CI], 3.2-37.9) and 55% (95% CI, 31.5-76.9), respectively. Median OS was 8.00 months (95% CI, 0.00-16.66), while median PFS was 3.80 months (95% CI, 2.41-5.19). Adverse events were observed in 14 patients (70%). Adverse events of grade 3 or worse occurred in six patients (30%). Conclusions: The combination of bevacizumab with atezolizumab or sintilimab had tolerable safety profile but poor response in the second-line treatment of HCC. Despite the satisfying efficacy as first-line therapy, this combination is not a cost-effective recommendation for advanced HCC cases who failed the first-line treatment of lenvatinib plus ICI. [Table: see text]
Randomized phase 2 study of nivolumab with or without ipilimumab combined with stereotactic body radiotherapy in pretreated patients with metastatic biliary tract cancer.
Authors: Markussen Alice , Johansen Julia S. , Larsen Finn Ole , Theile Susann , Hasselby Jane P. , Willemoe Gro Linno , Lorentzen Torben , Madsen Kasper , Wilken Eva E. , Geertsen Poul F. , Behrens Claus , Svane Inge Marie , Nielsen Dorte , Chen Inna Markovna 
Published: January 2023

545 Background: The treatment options for patients with biliary tract cancer (BTC) are limited. The aim of this study was to evaluate the clinical benefit of nivolumab with or without ipilimumab combined with stereotactic body radiotherapy (SBRT) in patients with BTC. Methods: In this phase 2 study with a Simon’s 2-stage optimal design, patients with BTC refractory to at least one line of prior chemotherapy were randomized 1:1 to receive SBRT of 15 Gy combined with nivolumab or nivolumab/ipilimumab stratified by performance status. Signed informed consent was obtained from all patients. The primary endpoint was clinical benefit rate (CBR) defined as the proportion of patients with stable disease, partial response (PR), or complete response according to RECIST 1.1. Decision on expansion independently for both arms was pending on CBR from the first stage. Secondary endpoints included overall response rate, progression-free survival (PFS), overall survival (OS), and safety. Results: Between September 2018 and January 2022, 61 patients (19 SBRT/nivolumab and 42 SBRT/nivolumab/ipilimumab) received at least one treatment. Forty-eight patients (79%) had cholangiocarcinoma (intrahepatic 41, perihilar 2, distal 4, unspecified 1) and 13 patients (21%) had gallbladder cancer. No responses were observed in SBRT/nivolumab arm and this cohort was closed for inclusion after first stage based on CBR of 11% (95% confidence interval (CI) 1-33). SBRT/nivolumab/ipilimumab resulted in CBR of 31% (95% CI 18-47) and an overall response rate of 11.9% (95% CI 4.0-25.6). Of the five patients that achieved a PR, the median duration of response was 4.4 months (95% CI 0.0-9.2). A median PFS of 1.7 months (95% CI 1.6-1.7) and 1.7 months (95% CI 1.6-1.8), and a median OS of 4.7 months (95% CI 3.2-6.2) and 5.0 months (95% CI 2.1-7.9) were observed for patients receiving SBRT/nivolumab and SBRT/nivolumab/ipilimumab, respectively. Treatment-related adverse events grade 3 or higher occurred in 3 (16%) patients in the SBRT/nivolumab arm and 13 (31%) patients in the SBRT/nivolumab/ipilimumab arm. One patient died due to hepatitis in the combination arm. Conclusions: The combination of SBRT/nivolumab/ipilimumab demonstrated anti-tumor activity and acceptable toxicities in patients with advanced BTC. Further studies are warranted. Clinical trial information: NCT02866383 .
Anlotinib plus toripalimab as first-line treatment for patients with unresectable hepatocellular carcinoma: Updated results of the ALTER-H003 trial.
Authors: Lin Haifeng , Ma Jie , Zhuo Manyun , Zhang Chengsheng , Luo Jingru , Zhuang Xiaohong , Zeng Zhiming , Yang Lihua 
Published: January 2023

568 Background: Anti-angiogenic plus anti-PD-1/L1 agents have shown superior efficacy over sorafenib in the first-line treatment for uHCC. Anlotinib, a multi-targeted tyrosine kinase inhibitor that targets VEGFR 1/2/3, FGFR 1-4, PDGFR α and β, and c-kit. Toripalimab is a humanized lgG4 mAb against PD-1. Preliminary results exhibited promising efficacy and tolerable safety of the combined regimen. Here we reported the updated results at the data cutoff of August 24, 2022. Methods: This single arm, multicenter, phase II trial of ALTER-H003 was planned to enroll 30 eligible pts to receive anlotinib (12mg, p.o., qd, d1-14, q3w) and toripalimab (240mg, iv, d1, q3w) until disease progression or unacceptable toxicity. Primary endpoint was ORR. Secondary endpoints included PFS, OS, DCR, DoR and safety. Results: From Jan, 2020 to Jul, 2021, 31 pts were enrolled. Pts characteristics were as follows: median age of 56y (range: 27-75); hepatitis B (29, 93.5%); BCLC B/C (23, 74.2%/8, 25.8%); macrovascular invasion (11, 35.5%); extrahepatic metastasis (19, 61.3%) and AFP>400 ng/ml (12, 38.7%). The median follow-up time was 19.9m (95%CI: 14.3–25.5). The confirmed ORR and DCR by mRECIST was 32.3% (95%CI: 14.8-49.7%) and 77.4% (95%CI: 61.8-93.0%), respectively. 10 pts achieved tumor response and the mDOR was 11.1m. The median PFS was 11.0m (95%CI: 3.5-18.4) and the median OS was 18.2m (95%CI: 15.9-20.5). Grade 3-5 treatment-related adverse events (TRAEs) were recorded in 20 pts (64.5%). The common ≥ grade 3 TRAEs included hand-foot skin reaction (3, 9.7%), hypertension (3, 9.7%) and impaired liver function (3, 9.7%). 2 pts had an irTRAE (pneumonitis; impaired liver function) that led to death. Conclusions: Anlotinib plus toripalimab showed hopeful efficacy and manageable toxicity in the first-line treatment for uHCC. Further studies are warranted. Clinical trial information: ChiCTR1900028295 .
The impact of relative dose intensity on overall and progression-free survival during cabozantinib therapy for unresectable hepatocellular carcinoma.
Authors: Nobusawa Tsubasa , Tsuchiya Kaoru , Yasui Yutaka , Uchihara Naoki , Suzuki Keito , Tanaka Yuki , Miyamoto Haruka , Ishido Shun , Yamada Michiko , Keitoku Taisei , Matsumoto Hiroaki , Higuchi Mayu , Takaura Kenta , Tanaka Shohei , Maeyashiki Chiaki , Tamaki Nobuharu , Nakanishi Hiroyuki , Kurosaki Masayuki , Izumi Namiki 
Published: January 2023

569 Background: Cabozantinib (CAB) has been approved as 2nd or later-line worldwide in patients with unresectable hepatocellular carcinoma (u-HCC). There is no data about the relationship between the relative dose intensity (RDI) of CAB and clinical outcome. We investigated the impact of RDI on overall survival (OS) and progression-free survival (PFS) during CAB in real-world practice. Methods: A total of 38 u-HCC patients who received CAB between Jan 2021 and Sep 2022 at our institution were enrolled. Tumor assessments in accordance with RECIST ver1.1 were done using dynamic CT or MRI within 4-8 weeks and every 8-10 weeks thereafter. The RDI of CAB for the first month (1M-RDI) was calculated. Results: The median age was 74 years, and 30 patients were Child-Pugh A. BCLC stage A/B/C were 0/ 11/ 27 patients, and 34 patients were previously received atezolizumab plus bevacizumab. As 2nd or 3rd-line, 20 patients received CAB. The median follow-up duration was 7.2 months, and the median PFS was 4.4 months in all patients. The median overall survival (OS) was 16.2 months from the administration of CAB. The objective response rate (ORR) and disease control rate (DCR) was 13.8% and 89.7%. Adverse events (AEs) were observed in all patients, requiring dose reduction in 26 patients (68%) and interruption of CAB in 21 patients (55%). The median 1M-RDI was 35%, and there was no significant difference in PFS between 1M-RDI ≧40% (high 1M-RDI, n=13) and <40% (n=16) (4.1 months vs. 4.7 months, p=0.89). There were no significant differences in age, pretreatment ALBI score, AFP, and major vascular invasion (MVI) between the patients with and without a high RDI. The induction rate of molecular targeted therapies after CAB was 60%. The only significant factor associated with PFS was MVI (HR 0.10, 95%CI 0.02-0.65, p=0.02). In a multivariate analysis, pretreatment ALBI score (HR 5.8, 95% CI 1.2-27.8, P=0.03) and hypertension as AE during CAB (HR 0.29, 95% CI 0.09-0.87, P=0.03) were the significant factors associated with OS. Conclusions: Maintaining a high 1M-RDI of CAB was not associated with OS and PFS in real-world practice. Dose modification is essential for CAB therapy in u-HCC patients.