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Introduction: The phase III IMbrave150 study established atezolizumab + bevacizumab as the global standard of care in patients with unresectable hepatocellular carcinoma (HCC). This exploratory analysis examined the impact of bevacizumab interruption due to bevacizumab adverse events of special interest (AESIs)., Methods: Patients in IMbrave150 who were randomized to atezolizumab + bevacizumab and received treatment for ≥6 months (to reduce immortal time bias) were included in group A-1 if bevacizumab had ever been skipped due to bevacizumab AESIs or to group A-2 otherwise. Efficacy analyses included overall survival (OS) and progression-free survival (PFS) by whether bevacizumab was skipped (group A-1 vs. A-2). PFS was evaluated per independent review facility (IRF)-assessed Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1 and HCC-modified RECIST (IRF-HCC mRECIST). Safety was also evaluated., Results: Of the 210 patients who received ≥6 months of atezolizumab + bevacizumab, 69 were assigned to group A-1 and 141 to A-2. At data cutoff (August 20, 2020), hazard ratio (HR) for OS was 1.04 (95% CI: 0.64, 1.69) for group A-1 versus A-2. HR for PFS was 1.07 (95% CI: 0.74, 1.55) per IRF-assessed RECIST 1.1 and 1.10 (95% CI: 0.76, 1.59; 15.5 vs. 9.7 months) per IRF-HCC mRECIST for group A-1 versus A-2. Safety profiles for atezolizumab and bevacizumab were largely similar between groups. More group A-1 patients had grade 3/4 adverse events. A separate analysis investigating the impact of immortal time bias in patients who received ≥3 months of atezolizumab + bevacizumab supported the appropriateness of the ≥6-month landmark analysis., Discussion/conclusion: Efficacy was similar between patients who skipped bevacizumab due to bevacizumab AESIs and those who did not. Although this comparison was nonrandomized and exploratory, results suggest that skipping bevacizumab due to bevacizumab AESIs did not considerably impact the efficacy and safety of atezolizumab + bevacizumab., Competing Interests: Masatoshi Kudo reports the following conflicts of interest: honoraria payment to self from Bayer, Chugai Pharmaceutical Co. Ltd., Eli Lilly, Eisai, and Takeda; research funding to institution from AbbVie, Chugai Pharmaceutical Co. Ltd., EA Pharma, Eisai, F. Hoffmann-La Roche Ltd, GE HealthCare, Gilead Sciences, Otsuka, Sumitomo Dainippon Pharma, Taiho, and Takeda; and Editor in Chief of Liver Cancer. Kaoru Tsuchiya reports the following conflicts of interest: advisory/consultancy fees to self from Chugai Pharmaceutical Co. Ltd. and Eisai; speakers bureau participation for Chugai Pharmaceutical Co. Ltd., Eisai, Eli Lilly, and Takeda; and research funding to institution from F. Hoffmann-La Roche Ltd. Yu-Yun Shao reports the following conflicts of interest: honoraria from AstraZeneca, Bayer, Bristol Myers Squibb, Eisai, Eli Lilly, F. Hoffmann-La Roche Ltd, Ipsen, Merck, and Ono. Richard S. Finn reports the following conflicts of interest: consulting fees to self from AstraZeneca, Bayer, CStone Pharmaceuticals, Eisai, Eli Lilly, Exelixis, F. Hoffmann-La Roche Ltd., Hengrui, Merck, and Pfizer; research funding to institution from Adaptimmune, Bristol Myers Squibb, Eisai, Eli Lilly, Merck, Pfizer, and F. Hoffmann-La Roche Ltd.; and Editorial Board Member of Liver Cancer. Peter R. Galle reports the following conflicts of interest: consulting fees to self from Adaptimmune, AstraZeneca, Bayer, Boston Scientific, Bristol Myers Squibb, Eisai, Eli Lilly, F. Hoffmann-La Roche Ltd., Guerbet, Ipsen, Merck Sharp & Dohme, and Sirtex Medical; honoraria payment to self from Adaptimmune, AstraZeneca, Bayer, Boston Scientific, Bristol Myers Squibb, Eisai, Eli Lilly, F. Hoffmann-La Roche Ltd., Guerbet, Ipsen, Merck Sharp & Dohme, and Sirtex Medical; advisory fees to self from Adaptimmune, AstraZeneca, Bayer, Boston Scientific, Bristol Myers Squibb, Eisai, Eli Lilly, F. Hoffmann-La Roche Ltd., Guerbet, Ipsen, Merck Sharp & Dohme, and Sirtex Medical; and research funding to institution from Bayer and F. Hoffmann-La Roche Ltd. Michel Ducreux reports the following conflicts of interest: honoraria, consulting fees, or advisory fees to self from Amgen, AstraZeneca, Bayer, Eli Lilly, F. Hoffmann-La Roche Ltd., Ipsen, Merck Serono, Pierre Fabre, and Servier; travel support from Bayer, Eli Lilly, F. Hoffmann-La Roche Ltd., Ipsen, Merck Sharp & Dohme, and Servier; speakers bureau participation for Amgen, Bayer, Eli Lilly, F. Hoffmann-La Roche Ltd., Ipsen, and Merck Serono; and research funding to institution from Bayer and F. Hoffmann-La Roche Ltd. Ann-Lii Cheng reports the following conflicts of interest: research funding to institution from F. Hoffmann-La Roche Ltd. Tatsuya Yamashita reports the following conflicts of interest: speakers bureau participation for Bayer and Chugai Pharmaceutical Co. Ltd. and research funding to institution from F. Hoffmann-La Roche Ltd. Hironori Koga reports the following conflicts of interest: research funding to institution from AbbVie, Chugai Pharmaceutical Co. Ltd., Daiichi Sankyo, and F. Hoffmann-La Roche Ltd. Ryosuke Take, Kyoko Yamada, Takashi Asakawa, and Yuki Nakagawa reports the following conflicts of interest: employment by Chugai Pharmaceutical Co. Ltd. Masafumi Ikeda reports the following conflicts of interest: honoraria to self from Bayer, Chugai Pharmaceutical Co. Ltd., Eisai, Eli Lilly, and Takeda; advisory/consulting fees to self from Chugai Pharmaceutical Co. Ltd., Eisai, Eli Lilly, Merck Sharp & Dohme, and Takeda; and research funding to institution from Bayer, Bristol Myers Squibb, Chugai Pharmaceutical Co. Ltd., Eisai, Eli Lilly, F. Hoffmann-La Roche Ltd., Merck Sharp & Dohme, and Takeda., (© 2023 The Author(s). Published by S. Karger AG, Basel.)

Introduction: Intratumoral administration of pexa-vec (pexastimogene devacirepvec), an oncolytic and immunotherapeutic vaccinia virus, given to patients with hepatocellular carcinoma (HCC), is associated with both local and distant tumor responses. We hypothesized subsequent treatment with sorafenib could demonstrate superior efficacy., Methods: This random phase III open-label study evaluated the sequential treatment with pexa-vec followed by sorafenib compared to sorafenib in patients with advanced HCC and no prior systemic treatment. The primary endpoint is overall survival (OS). Key secondary endpoints included time to progression (TTP), progression-free survival, overall response rate (ORR), and disease control rate (DCR). Safety was assessed in all patients who received ≥1 dose of study treatment., Results: The study was conducted at 142 sites in 16 countries. From December 30, 2015, to the interim analysis on August 2, 2019, 459 patients were randomly assigned (pexa-vec plus sorafenib: 234, sorafenib: 225). At the interim analysis, the median OS was 12.7 months (95% CI: 9.89, 14.95) in the pexa-vec plus sorafenib arm and 14.0 months (95% CI: 11.01, 18.00) in the sorafenib arm. This led to the early termination of the study. The median TTP was 2.0 months (95% CI: 1.77, 2.96) and 4.2 months (95% CI: 2.92, 4.63); ORR was 19.2% (45 patients) and 20.9% (47 patients); and DCR was 50.0% (117 patients) and 57.3% (129 patients) in the pexa-vec plus sorafenib and sorafenib arms, respectively. Serious adverse events were reported in 117 (53.7%) patients in the pexa-vec plus sorafenib and 77 (35.5%) patients in the sorafenib arm. Liver failure was the most frequently reported in both groups., Conclusion: Sequential pexa-vec plus sorafenib treatment did not demonstrate increased clinical benefit in advanced HCC and fared worse compared to sorafenib alone. The advent of the added value of checkpoint inhibitors should direct any further development of oncolytic virus therapy strategies., Competing Interests: Ghassan K. Abou-Alfa reports research support from Arcus, Astra Zeneca, BioNtech, BMS, Celgene, Flatiron, Genentech/Roche, Genoscience, Incyte, Polaris, Puma, QED, Silenseed, Yiviva, and consulting support from Adicet, Alnylam, Astra Zeneca, Autem, Beigene, Berry Genomics, Boehringer Ingelheim, Celgene, Cend, CytomX, Eisai, Eli Lilly, Exelixis, Flatiron, Genentech/Roche, Genoscience, Helio, Helsinn, Incyte, Ipsen, Merck, Nerviano, Newbridge, Novartis, QED, Redhill, Rafael, Servier, Silenseed, Sobi, Vector, Yiviva, plus patent PCT/US2014/031545 filed on March 24, 2014, and priority application Serial No.: 61/804,907; filed: March 25, 2013. Peter R. Galle reports research support from Bayer and Roche and consulting support from Bayer, Boston Scientific, AstraZeneca, Adaptimmune, BMS, Eisai, MSD, Sirtex, Lilly, Roche, Guerbet, and Ipsen. Joseph Erinjeri reports consulting support from AztraZeneca. Jeong Heo received grants/research support from Roche, Yuhan, and Gilead and participates on trials steering committee for Sillajen, Oncolys, Gilead, and AstraZeneca. Mitesh J. Borad report research support from Senhwa Pharmaceuticals, Adaptimmune, Agios Pharmaceuticals, Halozyme Pharmaceuticals, Celgene Pharmaceuticals, EMD Merck Serono, Toray, Dicerna, Taiho Pharmaceuticals, Sun Biopharma, Isis Pharmaceuticals, Redhill Pharmaceuticals, Boston Biomed, Basilea, Incyte Pharmaceuticals, Mirna Pharmaceuticals, Medimmune, Bioline, Sillajen, ARIAD Pharmaceuticals, PUMA Pharmaceuticals, Novartis Pharmaceuticals, QED Pharmaceuticals, Pieris Pharmaceuticals, and consulting support from ADC Therapeutics, Exelixis Pharmaceuticals, Inspyr Therapeutics, G1 Therapeutics, Immunovative Therapies, OncBioMune Pharmaceuticals, Western Oncolytics, Lynx Group, Genentech, Merck, Huya. James Burke is employed by CG Oncology and is consultant for Oncomyx, Kalivir, Western Oncolytics, Sonata, and Amped. Adina Pelusio is employed by Kalivir Immunotherapeutics and reports previous employment by SillaJen Biotherapeutics and Turnstone Biologics, Corp. Delphine Agathon reports previous employment by Transgene. Caroline Breitbach is an inventor on SillaJen patents. Edward Gane is a member of the Scientific Advisory Boards as an advisor and/or speaker for AbbVie, Abbott Diagnostics, Aligos, Arbutus, Arrowhead, Assembly, Dicerna, Gilead Sciences, GlaxoSmithKline, Janssen, Merck, Novartis, Roche, Surrozen, The Liver Company, Vaccitech, Virion Therapeutics, and Vir Bio and is on Speakers’ Bureau for AbbVie and Abbott Diagnostics. Yee Chao, Angelo Luca, Monika Lusky, and Shukui Qin report no conflicts of interest., (© 2023 The Author(s). Published by S. Karger AG, Basel.)

Introduction: Atezolizumab + bevacizumab showed survival benefit in patients with unresectable hepatocellular carcinoma (HCC) versus sorafenib in the Phase III IMbrave150 study. This exploratory analysis examined the prognostic impact of a baseline albumin-bilirubin (ALBI) score., Methods: Patients with treatment-naïve unresectable HCC, ≥1 measurable untreated lesion, and Child-Pugh class A liver function were randomized 2:1 to receive atezolizumab 1,200 mg + bevacizumab 15 mg/kg every 3 weeks or sorafenib 400 mg twice daily. Overall survival (OS) and progression-free survival (PFS) were assessed in the intention-to-treat population by ALBI/modified (m)ALBI grade. Time to deterioration (TTD; defined as time to 0.5-point increase from the baseline ALBI score over 2 visits or death) of liver function and safety were investigated., Results: Of 501 enrolled patients, 336 were randomized to receive atezolizumab + bevacizumab (ALBI grade [G] 1: n = 191; G2: n = 144 [mALBI G2a: n = 72, G2b: n = 72]; missing ALBI grade: n = 1) and 165 to sorafenib (ALBI G1: n = 87; G2: n = 78 [mALBI G2a: n = 37; G2b: n = 41]). Median follow-up was 15.6 months. OS and PFS improved with atezolizumab + bevacizumab versus sorafenib in patients with ALBI G1 (OS HR: 0.50 [95% CI: 0.35, 0.72]; PFS HR: 0.61 [95% CI: 0.45, 0.82]). In patients with ALBI G2 or mALBI G2a or G2b, PFS was numerically longer with atezolizumab + bevacizumab versus sorafenib, but no OS benefit was seen. Median TTD in the intention-to-treat population was 10.2 months (95% CI: 8.0, 11.0) with atezolizumab + bevacizumab versus 8.6 months (95% CI: 6.2, 11.8) with sorafenib (HR: 0.82 [95% CI: 0.65, 1.03]). Safety profiles of atezolizumab and bevacizumab were consistent with previous analyses, regardless of ALBI grade., Conclusion: ALBI grade appeared to be prognostic for outcomes with both atezolizumab + bevacizumab and sorafenib treatment in patients with HCC. Atezolizumab + bevacizumab preserved liver function for a numerically longer duration than sorafenib., Competing Interests: Masatoshi Kudo reports the following conflicts of interest: honoraria payment to self from Bayer, Chugai Pharmaceutical Co., Ltd., Eli Lilly, Eisai, and Takeda; research funding to institution from AbbVie, Chugai Pharmaceutical Co., Ltd., EA Pharma, Eisai, F. Hoffmann-La Roche Ltd., GE Healthcare, Gilead Sciences, Otsuka, Sumitomo Dainippon Pharma, Taiho, and Takeda; Editor-in-Chief of Liver Cancer. Richard S. Finn reports the following conflicts of interest: consulting fees to self from AstraZeneca, Bayer, CStone Pharmaceuticals, Eisai, Eli Lilly, Exelixis, F. Hoffmann-La Roche Hengrui, Merck, and Pfizer; research funding to institution from Adaptimmune, Bristol Myers Squibb, Eisai, Eli Lilly, Merck, Pfizer, and F. Hoffmann-La Roche Ltd; Editorial Board Member of Liver Cancer. Ann-Lii Cheng reports the following conflicts of interest: research funding to institution from F. Hoffmann-La Roche Ltd. Andrew X. Zhu reports the following conflicts of interest: consulting fees to self from Eisai, Eli Lilly, F. Hoffmann-La Roche Ltd., and Sanofi-Aventxis; research funding to the institution from F. Hoffmann-La Roche Ltd. Michel Ducreux reports the following conflicts of interest: honoraria, consulting fees, or advisory fees to self from Amgen, AstraZeneca, Bayer, Eli Lilly, F. Hoffmann-La Roche Ltd., Ipsen, Merck Serono, Pierre Fabre, and Servier; travel support from Bayer, Eli Lilly, F. Hoffmann-La Roche Ltd., Ipsen, Merck Sharp & Dohme, and Servier; speaker bureau participation for Amgen, Bayer, Eli Lilly, F. Hoffmann-La Roche Ltd., Ipsen, and Merck Serono; research funding to institution from Bayer and F. Hoffmann-La Roche Ltd. Peter R. Galle reports the following conflicts of interest: consulting fees to self from Adaptimmune, AstraZeneca, Bayer, Boston Scientific, Bristol Myers Squibb, Eisai, Eli Lilly, F. Hoffmann-La Roche Ltd., Guerbet, Ipsen, Merck Sharp & Dohme, and Sirtex Medical; honoraria payment to self from Adaptimmune, AstraZeneca, Bayer, Boston Scientific, Bristol Myers Squibb, Eisai, Eli Lilly, F. Hoffmann-La Roche Ltd., Guerbet, Ipsen, Merck Sharp & Dohme, and Sirtex Medical; advisory fees to self from Adaptimmune, AstraZeneca, Bayer, Boston Scientific, Bristol Myers Squibb, Eisai, Eli Lilly, F. Hoffmann-La Roche Ltd., Guerbet, Ipsen, Merck Sharp & Dohme, and Sirtex Medical; research funding to institution from Bayer and F. Hoffmann-La Roche Ltd. Naoya Sakamoto reports the following conflicts of interest: honoraria payment to self from AbbVie, Eisai, Gilead Sciences, and Otsuka; research funding to institution from Astellas Pharmaceutical, Bayer, Chugai Pharmaceutical Co., Ltd., Daiichi Sankyo, F. Hoffmann-La Roche Ltd., Gilead Sciences, Otsuka, and Takeda. Naoya Kato reports the following conflicts of interest: honoraria payment to self from Bayer and Chugai Pharmaceutical Co., Ltd.; research funding to institution from Bayer, Chugai Pharmaceutical Co., Ltd., and F. Hoffmann-La Roche Ltd. Michitaka Nakano reports the following conflicts of interest: employment by Chugai Pharmaceutical Co., Ltd. Jing Jia reports the following conflicts of interest: employment by F. Hoffmann-La Roche Ltd. Arndt Vogel reports the following conflicts of interest: consulting fees to self from AstraZeneca, Bayer, Böhringer Ingelheim, Bristol Myers Squibb, BTG Limited, Eisai, F. Hoffmann-La Roche Ltd., Imaging Equipment Ltd. (AAA), Ipsen, Merck Sharp & Dohme, Servier Laboratories, Sirtex Medical, and Terumo; honoraria payment to self from AstraZeneca, Bayer, Böhringer Ingelheim, Bristol Myers Squibb, BTG Limited, Eisai, F. Hoffmann-La Roche Ltd., Imaging Equipment Ltd. (AAA), Ipsen, Merck Sharp & Dohme, Servier Laboratories, Sirtex Medical, and Terumo; travel support from Bayer, Bristol Myers Squibb, and F. Hoffmann-La Roche Ltd.; advisory fees to self from AstraZeneca, Bayer, Bristol Myers Squibb, BTG Limited, Eli Lilly, Eisai, F. Hoffmann-La Roche Ltd., Imaging Equipment Ltd. (AAA), Ipsen, Merck Sharp & Dohme, Sirtex Medical, Servier Laboratories, and Terumo; research funding to institution from F. Hoffmann-La Roche Ltd., (© 2023 The Author(s). Published by S. Karger AG, Basel.)

Introduction: The literature on liver transplantation (LT) for cirrhosis-associated hepatocellular carcinoma (cirr-HCC) in elderly patients (≥65 years of age) is scarce. The aim of this study was therefore to analyze the outcome after LT for cirr-HCC in elderly patients in our single-center experience., Methods: All consecutive patients who underwent LT for cirr-HCC at our center were identified from our prospectively collected LT database and stratified into an elderly (≥65 years) and a younger (<65 years) cohort. Perioperative mortality as well as Kaplan-Meier estimations of overall (OS) and recurrence-free survival (RFS) were compared between age strata. A subgroup analysis was performed for patients with HCC only inside Milan criteria. For further oncological comparison, outcome in the subgroup of elderly LT recipients with HCC inside Milan was also compared to a group of elderly patients undergoing liver resection for cirr-HCC inside Milan extracted from our institutional liver resection database., Results: Out of 369 consecutive patients with cirr-HCC who underwent LT between 1998 and 2022 at our center, we identified 97 elderly (with a subgroup of 14 septuagenarians) and 272 younger LT patients. 5- and 10-year OS in elderly compared to younger LT patients was 63% and 52% versus 63% and 46% ( p = 0.67), respectively, while 5- and 10-year RFS was 58% and 49% versus 58% and 44% ( p = 0.69). 5-/10-year OS and RFS in 50 elderly LT recipients with HCC inside Milan were 68%/55% and 62%/54%, respectively, which compared to 46%/38% ( p = 0.07) and 26%/14% ( p < 0.0001) in elderly patients after liver resection for cirr-HCC inside Milan., Conclusion: Our results in almost 100 elderly patients after LT for cirr-HCC show that older age per se should not be considered a contraindication to LT and that selected elderly patients older than 65 and even 70 years benefit from LT as much as younger ones., Competing Interests: None of the authors has any conflict of interest to disclose with regard to this study. Arndt Weinmann received compensations as a member of scientific advisory boards for BMS, Wako, and Sanofi and received travel support from Merck and Servier. Roman Kloeckner consults and advises for Boston Scientific, Bristol-Myers Squibb, Guerbet, Roche, and SIRTEX and is on the speakers' bureau for BTG, Eisai, Guerbet, Ipsen, MSD Sharp & Dohme, and SIRTEX. PRG reports receiving consulting and lectures fees from Adaptimmune, AstraZeneca, Bayer, BMS, Eisai, Ipsen, Lilly, MSD, Roche, and SIRTEX., (Copyright © 2022 by The Author(s). Published by S. Karger AG, Basel.)

Introduction: The phase III IMbrave150 study established atezolizumab + bevacizumab as standard of care in patients with unresectable hepatocellular carcinoma (HCC). This exploratory analysis reports efficacy and safety results in patients with baseline Barcelona Clinic Liver Cancer (BCLC) stage B disease., Methods: Patients with systemic treatment-naive unresectable HCC and Child-Pugh class A liver function were randomized 2:1 to receive 1,200 mg of atezolizumab plus 15 mg/kg of bevacizumab or 400 mg of sorafenib. Co-primary endpoints were overall survival (OS) and progression-free survival (PFS) per independent review facility (IRF)-assessed Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1 in the BCLC stage B subgroup. Patients in this analysis had BCLC stage B disease at baseline per electronic case report form. Secondary efficacy endpoints included the objective response rate (ORR) and change in the sum of longest diameters (SLD) of target lesions from baseline per IRF RECIST 1.1 and modified RECIST (mRECIST) for HCC., Results: Of 501 enrolled patients, 74 (15%) had BCLC stage B disease at baseline (atezolizumab + bevacizumab, n = 49; sorafenib, n = 24). For this group, median follow-up was 19.7 months. A trend toward improved OS and PFS per IRF RECIST 1.1 was observed with atezolizumab + bevacizumab versus sorafenib (OS: hazard ratio [HR]: 0.63; 95% confidence interval [CI]: 0.29, 1.34; PFS: HR: 0.64; 95% CI: 0.36, 1.12). ORRs per IRF RECIST 1.1 and HCC mRECIST were 43% and 50% with atezolizumab + bevacizumab and 26% and 30% with sorafenib, respectively. Percentage change in SLD of target lesions from baseline per IRF RECIST 1.1 and HCC mRECIST showed durable responses with atezolizumab + bevacizumab treatment. Safety data were consistent with known profiles of atezolizumab and bevacizumab, as seen in the overall study population., Discussion/conclusion: Efficacy benefits were observed with atezolizumab + bevacizumab in patients with baseline BCLC stage B disease, consistent with the intention-to-treat population., Competing Interests: Masatoshi Kudo reports the following conflicts of interest: honoraria payment to self from Bayer, Chugai Pharmaceutical Co. Ltd., Eli Lilly, Eisai, Merck Sharp & Dohme, and Takeda; research funding to the institution from AbbVie, Chugai Pharmaceutical Co. Ltd., EA Pharma, Eisai, F. Hoffmann-La Roche Ltd., GE Healthcare, Gilead Sciences, Otsuka, Sumitomo Dainippon Pharma, Taiho, and Takeda; Editor-in-Chief of Liver Cancer. Richard S. Finn reports the following conflicts of interest: consulting fees to self from AstraZeneca, Bayer, CStone Pharmaceuticals, Eisai, Eli Lilly, Exelixis, F. Hoffmann-La Roche Ltd., Jiangsu Hengrui Pharmaceuticals, Merck, and Pfizer; research funding to the institution from Adaptimmune, Bristol Myers Squibb, Eisai, Eli Lilly, Merck, Pfizer, and F. Hoffmann-La Roche Ltd; Editorial Board Member of Liver Cancer. Peter R. Galle reports the following conflicts of interest: consulting fees to self from Adaptimmune, AstraZeneca, Bayer, Boston Scientific, Bristol Myers Squibb, Eisai, Eli Lilly, F. Hoffmann-La Roche Ltd., Guerbet, Ipsen, Merck Sharp & Dohme, and Sirtex Medical; honoraria payment to self from Adaptimmune, AstraZeneca, Bayer, Boston Scientific, Bristol Myers Squibb, Eisai, Eli Lilly, F. Hoffmann-La Roche Ltd., Guerbet, Ipsen, Merck Sharp & Dohme, and Sirtex Medical; advisory fees to self from Adaptimmune, AstraZeneca, Bayer, Boston Scientific, Bristol Myers Squibb, Eisai, Eli Lilly, F. Hoffmann-La Roche Ltd., Guerbet, Ipsen, Merck Sharp & Dohme, and Sirtex Medical; research funding to the institution from Bayer and F. Hoffmann-La Roche Ltd. Andrew X. Zhu reports the following conflicts of interest: consulting fees to self from Eisai, Eli Lilly, F. Hoffmann-La Roche Ltd., and Sanofi-Aventis; research funding to the institution from F. Hoffmann-La Roche Ltd. Michel Ducreux reports the following conflicts of interest: honoraria, consulting fees, or advisory fees to self from Amgen, AstraZeneca, Bayer, Eli Lilly, F. Hoffmann-La Roche Ltd., Ipsen, Merck Serono, Pierre Fabre, and Servier; speaker bureau participation for Amgen, Bayer, Eli Lilly, F. Hoffmann-La Roche Ltd., Ipsen, and Merck Serono; travel support from Bayer, Eli Lilly, F. Hoffmann-La Roche Ltd., Ipsen, Merck Sharp & Dohme, and Servier; research funding to the institution from Bayer and F. Hoffmann-La Roche Ltd. Ann-Lii Cheng reports the following conflicts of interest: research funding to the institution from F. Hoffmann-La Roche Ltd. Masafumi Ikeda reports the following conflicts of interest: honoraria to self from Bayer, Chugai Pharmaceutical Co. Ltd., Eisai, Eli Lilly, and Takeda; advisory/consulting fees to self from Chugai Pharmaceutical Co. Ltd., Eisai, Eli Lilly, Merck Sharp & Dohme, and Takeda; research funding to the institution from Bayer, Bristol Myers Squibb, Chugai Pharmaceutical Co. Ltd., Eisai, Eli Lilly, F. Hoffmann-La Roche Ltd., Merck Sharp & Dohme, and Takeda. Kaoru Tsuchiya reports the following conflicts of interest: advisory/consultancy fees to self from Chugai Pharmaceutical Co. Ltd., and Eisai; speaker bureau participation for Chugai Pharmaceutical Co. Ltd., Eisai, Eli Lilly, and Takeda; research funding to the institution from F. Hoffmann-La Roche Ltd. Ken-ichi Aoki reports the following conflicts of interest: employment by Chugai Pharmaceutical Co. Ltd. Jing Jia reports the following conflicts of interest: employment by F. Hoffmann-La Roche Ltd. Riccardo Lencioni reports the following conflicts of interest: advisory/consultancy fees to self from AstraZeneca, Bayer, Eisai, and F. Hoffmann-La Roche Ltd.; research funding to the institution from F. Hoffmann-La Roche Ltd., (Copyright © 2022 by The Author(s). Published by S. Karger AG, Basel.)

Introduction: In the Phase 3 IMbrave150 trial (NCT03434379), atezolizumab + bevacizumab demonstrated a clinically meaningful survival benefit over sorafenib in patients with unresectable hepatocellular carcinoma (HCC), including those with hepatitis B virus (HBV) or hepatitis C virus (HCV) infection. We used IMbrave150 data to investigate the safety and risk of viral reactivation or flare in infected patients treated with atezolizumab + bevacizumab or sorafenib., Methods: Patients with unresectable HCC not previously treated with systemic therapy were randomized 2:1 to atezolizumab + bevacizumab or sorafenib. In this exploratory analysis, safety was continually evaluated, including for hepatic adverse events. Patients were monitored for HBV and HCV reactivation and flare at screening, the beginning of Cycles 5 and 9, and at treatment discontinuation., Results: Of 501 enrolled patients, 485 were included in the safety population; 329 (68%) received atezolizumab + bevacizumab, and 156 (32%) received sorafenib. Overall, 150 (31%) and 58 (12%) patients had HBV and HCV infections, respectively. The safety profiles of atezolizumab + bevacizumab and sorafenib were consistent across patients, regardless of viral infection. Overall, hepatic serious adverse events occurred in 11% of patients receiving atezolizumab + bevacizumab and 8% receiving sorafenib. HBV or HCV reactivation occurred in 2% or 16% of atezolizumab + bevacizumab-treated patients, respectively, versus 7% or 14% with sorafenib. There were no instances of hepatitis flare with atezolizumab + bevacizumab., Conclusions: Atezolizumab + bevacizumab had a similar hepatic safety profile in patients with and without HBV or HCV infection. Viral reactivation rates were similar between arms. Overall, these data support the use of atezolizumab + bevacizumab in patients with HCC and HBV or HCV infection without any special precaution., Competing Interests: Chiun Hsu received research grants from Bristol Myers Squibb/ONO Pharmaceutical, F. Hoffmann-La Roche, and Ipsen and received honoraria from AstraZeneca, Bayer, Bristol Myers Squibb/ONO Pharmaceutical, Eisai, Eli Lilly and Company, Ipsen, Merck Serono, MSD, Novartis, F. Hoffmann-La Roche, and TTY Biopharm. Michel Ducreux reports a consulting or advisory role; has received honoraria from AstraZeneca, Bayer, F. Hoffmann-La Roche, Amgen, Pierre Fabre, Servier, Ipsen, Merck Serono, and Eli Lilly and Company; has been on a speakers bureau for Bayer, Ipsen, Lilly, Merck Serono, Amgen, and F. Hoffmann-La Roche; has received research funding from Bayer and F. Hoffmann-La Roche; and has received travel or accommodation expenses from Servier, Bayer, MSD, Ipsen, Eli Lilly and Company, and F. Hoffmann-La Roche. Andrew X. Zhu reports a consulting or advisory role for AstraZeneca, Bayer, Eisai, Exelixis, Gilead Sciences, Eli Lilly and Company, Merck, F. Hoffmann-La Roche/Genentech, and Sanofi and has received research funding from Bayer, Bristol Myers Squibb, Eli Lilly and Company, Merck, and Novartis; and is the associate editor for Liver Cancer. Shukui Qin declares no conflict of interests. Masafumi Ikeda is an advisor/board member at AstraZeneca, Eisai Co. Ltd., Eli Lilly Japan, and Takeda Pharmaceuticals; and received honoraria payment from Bayer, Bristol Myers Squibb, Chugai Pharmaceutical Co. Ltd., Eisai Co. Ltd., Eli Lilly Japan, MSD, and Takeda Pharmaceuticals; and is an editorial board member for Liver Cancer. Tae-You Kim reports grants and non-financial support from F. Hoffmann-La Roche, during the conduct of the study. Peter R. Galle reports a consulting or advisory role and received honoraria from AdaptImmune, AstraZeneca, Bayer, Bristol Myers Squibb, Eisai, Ipsen, Eli Lilly and Company, MSD, F. Hoffmann-La Roche, and Sirtex; has been on a speakers' bureau for AstraZeneca, Bayer, Bristol Myers Squibb, Eisai, Ipsen, Eli Lilly and Company, MSD, F. Hoffmann-La Roche, and Sirtex; has received research funding from Bayer and F. Hoffmann-La Roche; has provided expert testimony for Eli Lilly and Company; and has received travel or accommodation expenses from AstraZeneca, Bayer, Bristol Myers Squibb, Eisai, Ipsen, Eli Lilly and Company, and F. Hoffmann-La Roche. Richard S. Finn has served as a consultant with AstraZeneca, Bayer, CStone Pharmaceuticals, Eisai Co. Ltd., Eli Lilly, Merck, Pfizer, and F. Hoffmann-La Roche/Genentech; has received grant/research support to institution from Bristol Myers Squibb, Eisai Co. Ltd., Eli Lilly, Merck, Pfizer, and F. Hoffmann-La Roche/Genentech; and is an editorial board member for Liver Cancer. Ethan Chen is an employee of F. Hoffmann-La Roche. Ning Ma is an employee of F. Hoffmann-La Roche. Youyou Hu is an employee of Genentech. Lindong Li is an employee of Genentech. Ann-Li Cheng has served as a consultant with AstraZeneca, Bristol Myers Squibb, Eisai, Merck Serono, Novartis, Ono Pharmaceutical, Exelixis, Nucleix, IPSEN Innovation, Bayer Healthcare, Merck Sharp Dohme, Genentech, eiGene, CSR Pharma Group, F. Hoffmann-La Roche, and IQVIA; travel support from Bayer Yakuhin, Roche/Genentech, and IQVIA; reports receiving fees for serving on a speakers bureau from Bayer Yakuhin, Novartis, Eisai, Ono Pharmaceutical, and Amgen Taiwan; and is an associate editor for Liver Cancer., (Copyright © 2022 by The Author(s). Published by S. Karger AG, Basel.)

Background: Intermediate-stage hepatocellular carcinoma (HCC), as defined by Barcelona Clinic Liver Cancer (BCLC) stage B, is heterogeneous in terms of liver function and tumor burden. REACH and REACH-2 investigated ramucirumab in patients with HCC after prior sorafenib, with REACH-2 enrolling only patients with baseline α-fetoprotein (AFP) ≥400 ng/mL. An exploratory analysis of outcomes by BCLC stage was performed., Methods: A pooled meta-analysis of independent patient data (stratified by study) from REACH (AFP ≥ 400 ng/mL) and REACH-2 was performed. All patients had Child-Pugh A, Eastern Cooperative Oncology Group performance status 0-1, prior sorafenib treatment, and either HCC BCLC stage B (refractory/not amenable to locoregional therapy) or BCLC stage C. Patients were randomized to ramucirumab 8 mg/kg or placebo every 2 weeks. Median overall survival (OS) and progression-free survival were estimated by the Kaplan-Meier method. Treatment effects in BCLC stage B and C were evaluated by Cox proportional-hazards model; prognosis of BCLC staging for OS was evaluated by multivariate Cox proportional-hazards model. Tumor responses were evaluated according to Response Evaluation in Solid Tumors v1.1. Liver function was assessed with albumin-bilirubin score., Results: Baseline characteristics were generally balanced between treatment arms in each BCLC stage. BCLC staging trended as an independent prognostic factor for OS (B vs. C; hazard ratio [HR] 0.756 [95% CI 0.546-1.046]). Consistent treatment benefit was observed for ramucirumab versus placebo across BCLC stages. Median OS for ramucirumab versus placebo was 13.7 versus 8.2 months; HR (95%): 0.43 (0.23-0.83) and 7.7 versus 4.8 months; HR (95%): 0.72 (0.59-0.89) for BCLC stage B and C, respectively. Adverse events (AEs) were consistent with observations from both studies; hypertension was the most frequent grade ≥3 AE. Liver function was preserved throughout the study and similar between treatment arms in both BCLC stages., Conclusions: Ramucirumab provided a better survival benefit irrespective of BCLC stage and was well tolerated without compromising liver function during treatment., Competing Interests: M. Kudo is the Editor-in-Chief of Liver Cancer and reports grant and personal fees from Eisai and EA Pharma; grants from Gilead Sciences, Taiho, Sumitomo Dainippon Pharma, Takeda, Otsuka, and Abbvie; and personal fees from Roche, Ono, Eli Lilly and Company, BMS, and Bayer. R. Finn is an Editorial Board Member of Liver Cancer and reports personal fees from AstraZeneca and Cstone; grants and personal fees from Bayer, Eisai, Bristol-Myers Squibb, Roche/Genentech, Merck, Pfizer, and Eli Lilly and Company. M. Morimoto, K. Rau, H. Lim, and K. Liang have nothing to disclose. M. Ikeda is an Editorial Board Member of Liver Cancer and reports fees for honoraria, advisory board, & research funding from Eli Lilly and Company, Bayer, Eisai, AstraZeneca, Chugai, Takeda, & Novartis; honoraria and research funding from Bristol-Myers Squibb, MSD, & EA Pharma; fees for advisory boards and research funding from Nihon Servier and Aslan; fees for research funding from Merck Serono, Yakult, Ono, J-Pharma, Pfizer, Chiome Bioscience, & GlaxoSmithKline; honoraria fees from Taiho, Teijin Pharma, Astellas, Sumitomo Dainippon, Gilead, & Otsuka. C. Yen has nothing to disclose. P. Galle reports grants from Bayer as well as personal fees from Bayer, BMS, AstraZeneca, Sirtex, MSD, Eisai, Ipsen, and Roche. J. Llovet reports grants and personal fees from Bayer Pharmaceuticals, Eisai, Boehringer Ingelheim, & Ipsen, grants from Bristol-Myers Squibb, and personal fees from Eli Lilly and Company, Celsion, Merck, Genentech, Roche, Glycotest, Nucleix, Sirtex, Mina Alpha, AstraZeneca, Axis, & Medscape. B. Daniele reports personal fees and nonfinancial support from Ipsen, Sanofi, & Bayer as well as personal fees from Esiai, Eli Lilly and Company, AstraZeneca, MSD, Roche, & Amgen. D. McIlwain is an employee and stockholder of Eli Lilly and Company. R. Yoshikawa is a full-time employee and shareholder of Eli Lilly and Company. K. Nakamura is an employee of Eli Lilly Japan KK. C. Wang is an employee and stockholder of Eli Lilly and Company. P. Abada is an employee of Eli Lilly and Company. R. Widau is an employee and stockholder of Eli Lilly and Company. A. Zhu is an Associate Editor of Liver Cancer and reports personal fees from Roche, Lilly, Eisai, Bayer, Merck, Exelixis, & Sanofi., (Copyright © 2021 by S. Karger AG, Basel.)

Background and Aims: Inflammation affects progression of hepatocellular carcinoma (HCC). We therefore postulate that systemic inflammatory markers could help to predict prognosis in HCC patients receiving sorafenib therapy., Methods: Overall survival (OS) of HCC patients receiving palliative sorafenib treatment was correlated with the neutrophil to lymphocyte ratio (NLR), platelet to lymphocyte ratio (PLR), C-reactive protein to albumin ratio (CAR), Glasgow prognostic score (GPS) and the modified GPS (mGPS) along with clinicopathological parameters. Predictors of OS were assessed by multivariable Cox regression and receiver operating characteristics and area under the curve (ROC-AUC) analyses., Results: Patients receiving sorafenib ( n = 120) for advanced HCC (Barcelona Clinic Liver Cancer stage C) were explored by retrospective analysis. Findings were subsequently validated by a second HCC cohort ( n = 113) receiving sorafenib at two independent treatment centers. Multivariable assessment across these HCC cohorts confirmed a stable association of CAR ( p ≤ 0.001), GPS ( p ≤ 0.01) and mGPS ( p ≤ 0.004) with OS. This study also identified Eastern Cooperative Oncology Group (ECOG) performance score ( p < 0.001) and portal thrombosis ( p = 0.002) as prognostic factors and uncovered an inconsistent OS association of NLR and PLR in HCC patients. Additional combined analysis of ECOG, portal thrombosis and GPS within an extended score (GPS-EP) was associated with OS ( p = 0.021), which was confirmed within the validation cohort ( p = 0.001). In sorafenib-treated HCC, the ROC-AUC value for the prediction of 12-month survival was 0.761 (CAR >/≤0.37 cut-off, p < 0.001), 0.766 (GPS, p < 0.001) and 0.754 (mGPS, p < 0.001), respectively. In comparison to this, GPS-EP achieved a higher AUC of 0.826 (0.746-0.907) for the 12-month survival prediction, resulting in a 64.4% sensitivity and 83.3% specificity at a > 2 point cut-off., Conclusions: Inflammatory scores obtained before sorafenib treatment initiation are associated with OS in advanced HCC. Their combination with other risk factors improves prediction of 3- and 12-month survival, which could guide treatment decisions in selected patient subgroups., Competing Interests: M.F.S., M.-L.S., S.K., J.U.M., J.W.- M., C.D. and H.L. declare no conflict of interest regarding the content of this manuscript. M.-A.W., A.W. received travel and lecture fees from Bayer Healthcare, P.R.G. is consultant and speaker bureau member of Bayer Healthcare., (Copyright © 2018 by S. Karger AG, Basel.)

Background/aim: Individual components of the metabolic syndrome (MS) such as obesity or diabetes mellitus impair the prognosis of patients with hepatocellular carcinoma (HCC) following curative treatment approaches or transarterial therapies. The aim of this retrospective study was to assess the impact of these factors on the overall survival (OS) of patients with advanced HCC treated with sorafenib., Methods: Univariate and multivariate analyses were performed to assess the impact of individual components of the MS on the OS of 152 consecutive patients with advanced HCC treated with sorafenib., Results: The presence of overweight/obesity, type 2 diabetes mellitus, hypertension, dyslipidemia, and of the MS itself did not impair the median OS. Multivariate analysis showed that Eastern Cooperative Oncology Group Performance Status ≥1 (hazards ratio [HR] 2.03), presence of macrovascular invasion (HR 1.71), Child-Pugh score B/C (HR 2.19), tumor grading G3 (HR 2.17), no prior HCC treatment (HR 2.34), and the presence of 2 or more out of 5 individual components of the MS (HR 0.65) were independent prognostic factors regarding the median OS., Conclusions: Our investigations do not confirm a negative prognostic role of individual components of the MS or the MS itself for patients with advanced HCC treated with sorafenib., (© 2017 S. Karger AG, Basel.)

Background: Optical Enhancement technology (OE) combines bandwidth-limited light and image enhancement processing technology to enhance subtle mucosal and vascular details. This is the first study assessing the new technology for the diagnosis of gastroesophageal reflux disease (GERD)., Patients and Methods: Consecutive patients with GERD and controls were prospectively included. The distal esophagus was examined in all quadrants with high definition white-light endoscopy (HD-WLE) followed by OE and biopsies for histopathological analysis. Features observed only by OE were compared between controls and patients with GERD., Results: A total of 100 areas were evaluated. About 56% of patients had a diagnosis of GERD. The mean age of patients was 53 years (range 27-89 years), 60% were female. Compared to controls, patients with diagnosis of GERD showed significantly more often tortuosity (p = 0.042), dilation (p = 0.0003), and increased number (p = 0.001) of intrapapillary capillary loops (IPCLs). In addition, increased vascularity and mucosal breaks were significantly more often found in patients with GERD as compared to controls (p < 0.05). On multivariate analysis, increased number and dilation of IPCL were the best predictors of GERD., Conclusions: The newly introduced OE technology significantly improves the diagnosis of GERD compared to HD-WLE. The results should be confirmed in a multicenter trial., (© 2018 S. Karger AG, Basel.)

Hepatocellular carcinoma (HCC) is the third most common cause of cancer-related deaths worldwide. HCC represents more than 90% of primary liver cancers. There is growing incidence of HCC worldwide. In the western world, HCC arises in a cirrhotic background in up to 90% of cases, and cirrhosis itself is a progressive disease that affects patient survival. Thus, outcome in patients with HCC and the chances for anti-tumor treatment and it is results are dependent not only on tumor-associated factors but also on the liver function. Cholangio carcinoma is the second most common primary liver tumor with an estimated incidence of 1:100,000. Cholangiocarcinoma can be sub-classified as intrahepatic (iCCA), perihilar or distal where iCCA arises within the liver parenchyma. Overall, the incidence of iCCA seems to be increasing globally. This may be attributed to a global increase of risk factors shared between HCC and iCCA, such as viral hepatitis, liver cirrhosis, diabetes mellitus, obesity, NASH, and others., (© 2017 S. Karger AG, Basel.)

Hepatocellular carcinoma (HCC) is the third most common cause of cancer-related deaths worldwide. HCC represents more than 90% of primary liver cancers. There is a growing incidence of HCC worldwide. In the Western world, HCC arises in a cirrhotic background in up to 90% of cases, and cirrhosis itself is a progressive disease that affects patient survival. Thus, outcome in patients with HCC and the chances for anti-tumor treatment and its results are dependent not only on tumor-associated factors but also on liver function., (© 2016 S. Karger AG, Basel.)

Background: Malignant ascites is a frequent complication in gastrointestinal malignancy and is unresponsive to systemic therapies. Therapeutic options are limited, and repeated paracentesis is associated with increased loss of fluids and proteins, and impaired quality of life. The bi-specific trifunctional antibody catumaxomab has been approved for the treatment of refractory ascites. It has been proposed that repeated application leads to formation of human anti-mouse antibodies with a decrease in effectiveness and potentially hypersensitivity reactions., Case Report: Here we report on the repeated application of catumaxomab in 2 patients with advanced signet cell gastric cancer. Repeated application was safe and effective in decreasing the frequency of paracentesis in 1 patient. No hypersensitivity reactions beyond the immune-mediated side effects were observed with the application of catumaxomab. 1 patient experienced an inflammatory response with acute deterioration of kidney function during the first cycle but recovered quickly. Re-challenge with catumaxomab did not produce an inflammatory reaction in the 2 cases., Conclusion: Overall, the repeated treatment was associated with a beneficial effect on puncture-free survival in 1 patient, and appears to be a treatment option in selected patients with gastrointestinal malignancy., (© 2014 S. Karger GmbH, Freiburg.)

Familial amyloid polyneuropathy (FAP; also known as familiar amyloidosis and hereditary amyloidosis) is an autosomal dominant inherited disease due to mutations of the transthyretin (TTR) gene coding for the corresponding protein, consisting of 127 amino acids. The gene is located on chromosome 18q. More than 100 different mutations are known. Other mutant precursor proteins produced in the liver, such as apolipoprotein I and II, lysozyme and fibrinogen Aα, may be of etiological importance as well. Amyloidogenic mutations of the TTR gene lead to decreased stability of the corresponding protein and subsequently to extracellular deposition of amyloid in several tissues (peripheral and autonomic nerves, walls of the gastrointestinal tract, heart, etc.). The Val30Met mutation is the most prevalent cause of FAP worldwide. There are endemic regions in Portugal, Sweden and Japan. The onset of symptoms is usually between 25 and 35 years of age, but late-onset families are also known. The most common clinical symptoms are polyneuropathy of the lower limbs, rhythmological disturbances and diarrhea/obstipation. TTR amyloid is predominantly produced in the liver; only as few as 5% are synthesized in the retina and choroid plexus. Therefore, liver transplantation has become widely accepted as the ultimate curative treatment of this disease in order to prevent the ultimately fatal outcome and ameliorate disabling symptoms. Because of shortage of donor grafts, livers of FAP patients are used for domino liver transplantation. Last year, a new therapeutic option was approved by the European Medical Authority (EMA) for therapy of early-stage FAP. The first results of a multicenter-controlled trial have been published and show a benefit in patients with an early stage of disease regarding neurological symptoms as well as modified BMI. There are several other pharmacologic approaches that have been reported in the last years which may lead to stabilization of the TTR tetramer. Therefore, this might be the beginning of new therapeutic options with pharmacological therapies in patients with FAP., (Copyright © 2013 S. Karger AG, Basel.)

The epidemic occurrence of obesity has led to a rapid increase in the incidence of non-alcoholic fatty liver disease (NAFLD) in industrial countries. The disease spectrum includes hepatic steatosis, lobular inflammation with steatohepatitis (NASH) and varying degrees of liver fibrosis, which can progress to cirrhosis. Hepatocellular carcinoma can develop in patients with NASH, even in the absence of cirrhosis. The majority of patients with primary NASH exhibit risk factors that define the metabolic syndrome including insulin resistance and visceral obesity. However, only a minority of patients with NAFLD progress to end-stage liver disease and, so far, predictors to identify these patients are not available. The course of disease progression appears to be slow and develops progressively over years, modulated by genetic susceptibility, nutritional misbehavior and environmental factors. Although risk factors have been identified in epidemiological studies, little is known about disease initiation and progression. This review summarizes the existing animal models of NAFLD, focusing on genetic and dietary models, and discusses their applicability in studying signaling events involved in steatohepatitis. Despite the shortcomings inherent to all experimental models, research in this field has helped to identify potential therapeutic targets and, thus, contributed significantly to our understanding of this disease. The validation and search for new in vivo and in vitro models will propagate the understanding of NASH and help clinicians to develop new treatment modalities., (Copyright 2010 S. Karger AG, Basel.)

Hepatocellular carcinoma (HCC) is one of the most common and lethal malignant tumors worldwide in the human population. Due to late diagnosis and/or advanced underlying liver cirrhosis, only limited treatment options with marginal clinical benefit are available in up to 70% of patients. During the last decades, no effective conventional cytotoxic systemic therapy was available contributing to the dismal prognosis in patients with advanced disease. However, a better knowledge of molecular hepatocarcinogenesis provides today the opportunity for targeted therapy. Positive data from the pivotal phase III SHARP trial assessing the efficacy and safety of the multikinase inhibitor sorafenib broadened the horizon for patients with advanced disease. After years of therapeutic nihilism, sorafenib was the first agent to demonstrate a statistically significant improvement in overall survival for patients with advanced HCC. This article reviews the historical perspective of systemic therapy in HCC and provides a brief overview of molecular hepatocarcinogenesis and potential targets in HCC. Most promising molecular targeted agents tested within clinical trials in advanced HCC are summarized, with a special attention to sorafenib, sunitinib, bevacizumab, and erlotinib., (Copyright 2009 S. Karger AG, Basel.)

Despite surgical R0 resections, patients with gastric cancer stage UICC II-III have a high risk of recurrence and metachronic metastases. Preliminary evidence exists that adjuvant chemotherapy or neoadjuvant chemo(radio)therapy protocols may improve the prognosis of these patients undergoing surgery of gastric cancer with curative intention. As for palliative regimens, 5-fluorouracil and cisplatin are integral components of such (neo)adjuvant strategies. Upcoming cytostatic agents, i.e. irinotecan, docetaxel, oxaliplatin, and oral fluoropyridines are currently under investigation in new multimodality treatment regimens and may further increase R0 resection rates and may prolong disease-free and overall survival in the treatment of advanced localized gastric cancer., (Copyright (c) 2004 S. Karger AG, Basel.)

Introduction: More than half the patients with gastroesophageal reflux disease (GERD) show no endoscopic abnormality or minimal change esophagitis (non-erosive reflux disease, NERD). We investigated the value of endoscopic and histological markers for the prediction of NERD before and after treatment with 20 mg esomeprazole., Methods: Between July and October 2002, consecutive patients presenting for upper endoscopy were stratified into GERD and non-reflux patients (control group) with the help of a questionnaire. The endoscopist was blind to the presence of reflux symptoms. Using magnifying endoscopes minimal change esophagitis was defined by the presence of vascular injection or vascular spots above the Z-line, villous mucosal surface and islands of squamous cell epithelium below the Z-line. Targeted and random biopsies were taken below and above the Z-line. Patients with endoscopically visible classical signs of esophagitis (Los Angeles A-D) or histologically proven Barrett's esophagus were not further investigated in the study (drop out). The esophageal specimens were histologically evaluated for erosions, infiltration with leukocytes, hyperplasia of basal cells and length of papillae. Patients with NERD were treated with 20 mg esomeprazole/day for 4 weeks and reevaluated by endoscopy as described before., Results: 39 patients with heartburn and 39 patients without reflux symptoms (controls) were finally included in the analysis (per protocol). Patients with NERD significantly (p = 0.005) more often showed endoscopic signs of minimal change esophagitis (27/39) than the control group (8/39). An increased length of papillae (14/39 versus 2/39; p = 0.005) and basal cell hyperplasia (17/39 versus 4/39; p = 0.009) were significantly more common in the heartburn group. After treatment with esomeprazole, no significant endoscopic or histological differences between the NERD and control group could be observed., Conclusions: Minimal change esophagitis can be seen with high resolution magnifying endoscopy. By combining endoscopic and histological markers NERD can be predicted with a sensitivity of 62% and a specificity of 74%. Treatment with esomeprazole for 4 weeks reverses the slight alterations to normal., (Copyright 2004 S. Karger AG, Basel)

Gastroesophageal reflux disease (GERD) is common in the Western world. Upper endoscopy is needed to characterize the disease. Barrett's esophagus as a complication of GERD is an established precancerous condition which can lead to adenocarcinoma in the distal esophagus. This review summarizes recent advances in the endoscopic characterization of Barrett's esophagus using magnification endoscopy and chromoendoscopy. Methylene blue, indigo carmine and acetic acid are commonly used dyes to facilitate diagnosis of Barrett's esophagus. Methylene blue is absorbed in the specialized columnar epithelium, which is pathognomonic for Barrett's esophagus. Indigo carmine and acetic acid are used as contrast stains to highlight the surface architecture. Currently, different dyes are used in conjunction with magnifying endoscopes to characterize specific surface patterns of Barrett's epithelium. However, the current proposed classifications are too complex relative to their clinical value. Nevertheless, simplification of these systems will occur over time with increased use of magnifying chromoendoscopy. The value of magnifying chromoendoscopy for clinical practice is not determined yet and currently under investigation. However, these techniques have significant potential to improve diagnostic accuracy in patients with Barrett's esophagus., (Copyright 2004 S. Karger AG, Basel)

Objective: The proinflammatory cytokine interleukin (IL)-6 is involved in various chronic inflammatory processes. IL-6 is a predominant cytokine produced by lamina propria T cells in Crohn's disease and experimental colitis. This study was designed to examine the effect of a neutralizing IL-6-receptor (IL-6R) antibody on the programmed cell death of mucosal T cells in the CD62L+ CD4+ SCID transfer model of chronic experimental colitis in mice and to gain more insight into the pathogenesis of this transfer colitis model., Methods: For adoptive transfer, we isolated CD62L+ CD4+ double-positive T cells from wild-type BALB/c mice followed by intraperitoneal application of 1 million cells in CB17 SCID mice. The purity of the transferred T-cell population was tested by FACS analysis. Cytokine secretion was measured by ELISA. Western blot analysis was performed to detect phospho-STAT-3 in protein extracts of splenic cells. Cryo- and paraffin colon cross-sections were used to perform immunochemical or fluorescence TUNEL stainings., Results: We isolated CD62L+ CD4+ and CD62L- CD4+ T cells. In vitro studies showed an increased production of IL-4 by CD62L- CD4+ T cells compared to CD62L+ T cells. 8-10 weeks after transfer of CD62L+ CD4+ T cells in SCID mice, reconstituted mice developed wasting disease, anal prolapse and diarrhea, whereas mice reconstituted with CD62L- CD4+ did not, similar to anti-IL-6R-treated CD62L+ CD4+-reconstituted SCID mice. Anti-IL-6R-treated reconstituted SCID mice showed decreased levels of activated STAT-3. The previously described efficacy of anti-IL-6R antibody treatment on colitis activity appeared to be due to the induction of apoptosis, as many TUNEL-positive cells were detected in the lamina propria., Conclusions: These results suggest that the activation of the IL-6/STAT-3-signaling pathway plays a pivotal role in the pathogenesis of CD62L+ CD4+ transfer colitis. Moreover, the application of a neutralizing antibody to IL-6R induces apoptosis in transferred T cells. These data implicate the importance of anti-apoptotic pathways in chronic disease and might contribute to future therapies., (Copyright 2003 S. Karger AG, Basel)