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Background: There is an increasing interest for Notch signalling pathway and particularly Delta-like ligand 4 (DLL4) as potential therapeutic target to improve outcome for patients with pancreatic ductal adenocarcinoma (PDAC).Methods: Using immunohistochemistry (IHC) and tissue microarray (TMA), we assessed the expression patterns of DLL4, Notch1 and Notch3 in 151 patients from two independent cohorts of resected PDAC. We investigated the prognostic and the predictive significance of these proteins.Results: High IHC DLL4 expression in cancer cells was associated with worse overall survival (OS) and disease-free survival (DFS) than low DLL4 expression (median OS: 12.9 vs 30.4 months, P=0.004 and median DFS: 8.8 vs 17.4 months, P=0.02). High DLL4 expression remained a significant negative prognostic factor in multivariate analysis (HR for OS: 2.1, P=0.02 and HR for DFS: 2.0, P=0.02). Low DLL4 abundance was associated with a longer OS-only for patients who received an adjuvant gemcitabine-based chemotherapy (P<0.001) but not for patients who did not receive gemcitabine (P=0.72). Furthermore, the interaction test for adjuvant gemcitabine therapy was statistically significant (P<0.001). The validating cohort recapitulated the findings of the training cohort.Conclusions: Low DLL4 abundance in tumour cells may predict the benefit from adjuvant gemcitabine therapy after PDAC resection. [ABSTRACT FROM AUTHOR]

To assess the efficacy of the combination of long-acting release (LAR) octreotide and tamoxifen (TMX) for the treatment of advanced hepatocellular carcinoma (HCC). A total of 109 patients with advanced HCC were randomised to receive octreotide LAR combined with TMX (n=56) (experimental treatment group) or TMX alone (n=53; control group). The clinical, biological and tumoural parameters were recorded every 3 months until death. Primary end point was patient survival; secondary end points were the impact of therapy on tumour response, quality of life and variceal bleeding episodes. Univariate and multivariate analyses were performed for assessment of specific prognostic factors. The median survival was 3 months (95% CI 1.4–4.6) for the experimental treatment group and 6 months (CI 95% 2–10) for the control group (P=0.609). There was no difference in terms of α-foetoprotein (α-FP) decrease, tumour regression, improvement of quality of life and prevention of variceal bleeding between the two groups. Variables associated with a better survival in the multivariate analysis were: presence of cirrhosis, α-FP level <400 ng ml−1 and Okuda stage I. The combination of octreotide LAR and TMX does not influence survival, tumour progression or quality of life in patients with advanced HCC.British Journal of Cancer (2007) 97, 582–588. doi:10.1038/sj.bjc.6603901 www.bjcancer.com Published online 7 August 2007 [ABSTRACT FROM AUTHOR]

Purpose: To report response rates (using mRECIST), overall survival (OS), progression-free survival and local tumour recurrence-free survival (LRFS) of balloon-occluded transarterial chemoembolisation (bTACE) for hepatocellular carcinoma (HCC)., Materials and Methods: Patients from five European centres treated with conventional or drug-eluting microsphere bTACE for HCC were included, and patients already lost to follow-up before 12 months were excluded. Possible factors contributing to LRFS and OS were evaluated with Cox proportional hazards models., Results: Seventy-three patients were enrolled. The mean number of nodules per patient was 2.07(± 1.68), and the average maximum diameter of the nodules was 37 ± 19.9 mm. The response of the target lesion at 6 months was complete response (CR) in 58.9%, partial response (PR) in 28.8%, stable disease (SD) in 6.8% and progressive disease (PD) in 5.5%. The median follow-up time was 31 months; at the last follow-up, target tumour response was CR in 49.3%, PR in 12.3%, SD in 5.5% and PD 32.9%. Overall response at the last follow-up was CR in 17.8%, PR in 9.6%, SD 2.7% and PD in 69.9% (for new lesions in 37% of patients). Median OS was not reached; mean overall survival was 50.0 months, while median LRFS was 31.0 months. At uni- and multivariable analysis, only tumour maximum diameter was related to LRFS (hazard ratio [HR] = 1.021; 95% CI 1.004-1.038, P = 0.015)., Conclusions: bTACE demonstrated high efficacy for HCC, with a complete response in 58.9% of patients, a median local recurrence-free survival of 31.0 months and a mean overall survival of 50.0 months., (© 2024. The Author(s).)

Purpose: Holmium-166 has emerged as a promising option for selective internal radiotherapy (SIRT) for hepatic malignancies, but data on routine clinical use are lacking. The purpose of this study was to describe the safety and effectiveness of Holmium-166 SIRT in real-world practice through retrospective analysis of a multicenter registry., Methods: Retrospective analysis was conducted on Holmium-166 SIRT procedures performed between July 15, 2019, and July 15, 2021, across seven European centers. Treatment planning, treatment realization and post-treatment follow-up were conducted according to routine local practice. Safety and effectiveness data were extracted from the patients' health records. Primary endpoint analysis was assessed for the entire study population with separate analysis for subgroups with hepatocellular carcinoma, metastatic colorectal cancer and intrahepatic cholangiocarcinoma., Results: A total of 167 SIRT procedures in 146 patients (mean age 66 ± 11 years, 68% male) were retrospectively evaluated. Most common tumor entities were hepatocellular carcinoma (n=55), metastatic colorectal cancer (n=35), intrahepatic cholangiocarcinoma (n=19) and metastatic neuroendocrine tumors (n=10). Nine adverse events grade ≥ 3 according to Common Terminology Criteria for Adverse Events were recorded, including one fatal case of radioembolization-induced liver disease. Response rates and median overall survival for the above mentioned subgroups were comparable to results from previous Holmium-166 trials as well as to results from Yttrium-90 registries., Conclusion: This study confirms that the safety and effectiveness of Holmium-166 SIRT derived from prospective trials also applies in routine clinical practice, reinforcing its potential as a viable treatment option for primary and secondary liver cancer., Competing Interests: Author GV is a consultant for Terumo/Quirem, speaker/advisory board member for Roche, Eisai and Astra-Zeneca. Author ML is a consultant for Terumo, Boston Scientific and Novartis and received research support from Terumo, Boston Scientific and Novartis. The department of Radiology and Nuclear Medicine of the UMC Utrecht receives royalties from Terumo. Author RD was employed by Terumo Europe. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The reviewer MS declared a past collaboration with the author ML to the handling editor. The authors declare that this study received funding from Terumo Europe N.V. Terumo Europe financially supported the study including publication fee. Furthermore, Terumo Europe provided support for data collection and statistical analysis. The authors interpreted the data and drafted and edited the manuscript. The first and the last author take full responsibility for the manuscript., (Copyright © 2024 Schulze-Zachau, Verset, De Bondt, De Keukeleire, Gühne, Heuschkel, Hoffmann, Bozzi, Sciuto, Lam, Deportós Moreno, Debrus and Zech.)

Background: Developments in transarterial radioembolization led to the conception of new microspheres loaded with holmium-166 ( 166 Ho). However, due to the complexity of the scatter components in 166 Ho single photon emission computed tomography (SPECT), questions about image quality and dosimetry are emerging. The aims of this work are to investigate the scatter components and correction methods to propose a suitable solution, and to evaluate the impact on image quality and dosimetry including Monte-Carlo (MC) simulations, phantom, and patient data., Methods: Dual energy window (DEW) and triple energy window (TEW) methods were investigated for scatter correction purposes and compared using Contrast Recovery Coefficients (CRC) and Contrast to Noise Ratios (CNR). First, MC simulations were carried out to assess all the scatter components in the energy windows used, also to confirm the choice of the parameter needed for the DEW method. Then, MC simulations of acquisitions of a Jaszczak phantom were conducted with conditions mimicking an ideal scatter correction. These simulated projections can be reconstructed and compared with real acquisitions corrected by both methods and then reconstructed. Finally, both methods were applied on patient data and their impact on personalized dosimetry was evaluated., Results: MC simulations confirmed the use of k = 1 for the DEW method. These simulations also confirmed the complexity of scatter components in the main energy window used with a high energy gamma rays component of about half of the total counts detected, together with a negligible X rays component and a negligible presence of fluorescence. CRC and CNR analyses, realized on simulated scatter-free projections of the phantom and on scatter corrected acquisitions of the same phantom, suggested an increased efficiency of the TEW method, even at the price of higher level of noise. Finally, these methods, applied on patient data, showed significant differences in terms of non-tumoral liver absorbed dose, non-tumoral liver fraction under 50 Gy, tumor absorbed dose, and tumor fraction above 150 Gy., Conclusions: This study demonstrated the impact of scatter correction on personalized dosimetry on patient data. The use of a TEW method is proposed for scatter correction in 166 Ho SPECT imaging., (© 2024. The Author(s).)

Background: The aim of the COSMIC-312 trial was to evaluate cabozantinib plus atezolizumab versus sorafenib in patients with previously untreated advanced hepatocellular carcinoma. In the initial analysis, cabozantinib plus atezolizumab significantly prolonged progression-free survival versus sorafenib. Here, we report the pre-planned final overall survival analysis and updated safety and efficacy results following longer follow-up., Methods: COSMIC-312 was an open-label, randomised, phase 3 study done across 178 centres in 32 countries. Patients aged 18 years or older with previously untreated advanced hepatocellular carcinoma were eligible. Patients must have had measurable disease per Response Evaluation Criteria in Solid Tumours version 1.1 (RECIST 1.1), and adequate marrow and organ function, including Child-Pugh class A liver function; those with fibrolamellar carcinoma, sarcomatoid hepatocellular carcinoma, or combined hepatocellular cholangiocarcinoma were ineligible. Patients were randomly assigned (2:1:1) using a web-based interactive response system to a combination of oral cabozantinib 40 mg once daily plus intravenous atezolizumab 1200 mg every 3 weeks, oral sorafenib 400 mg twice daily, or oral single-agent cabozantinib 60 mg once daily. Randomisation was stratified by disease aetiology, geographical region, and presence of extrahepatic disease or macrovascular invasion. Dual primary endpoints were for cabozantinib plus atezolizumab versus sorafenib: progression-free survival per RECIST 1.1, as assessed by a blinded independent radiology committee, in the first 372 randomly assigned patients (previously reported) and overall survival in all patients randomly assigned to cabozantinib plus atezolizumab or sorafenib. The secondary endpoint was progression-free survival in all patients randomly assigned to cabozantinib versus sorafenib. Outcomes in all randomly assigned patients, including final overall survival, are presented. Safety was assessed in all randomly assigned patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, NCT03755791., Findings: Between Dec 7, 2018, and Aug 27, 2020, 432 patients were randomly assigned to combination treatment, 217 to sorafenib, and 188 to single-agent cabozantinib, and included in all efficacy analyses. 704 (84%) patients were male and 133 (16%) were female. 824 of these patients received at least one dose of study treatment and were included in the safety population. Median follow-up was 22·1 months (IQR 19·3-24·8). Median overall survival was 16·5 months (96% CI 14·5-18·7) for the combination treatment group and 15·5 months (12·2-20·0) for the sorafenib group (hazard ratio [HR] 0·98 [0·78-1·24]; stratified log-rank p=0·87). Median progression-free survival was 6·9 months (99% CI 5·7-8·2) for the combination treatment group, 4·3 months (2·9-6·1) for the sorafenib group, and 5·8 months (99% CI 5·4-8·2) for the single-agent cabozantinib group (HR 0·74 [0·56-0·97] for combination treatment vs sorafenib; HR 0·78 [99% CI 0·56-1·09], p=0·05, for single-agent cabozantinib vs sorafenib). Grade 3 or 4 adverse events occurred in 281 (66%) of 429 patients in the combination treatment group, 100 (48%) of 207 patients in the sorafenib group, and 108 (57%) of 188 patients in the single-agent cabozantinib group; the most common were hypertension (37 [9%] vs 17 [8%] vs 23 [12%]), palmar-plantar erythrodysaesthesia (36 [8%] vs 18 [9%] vs 16 [9%]), aspartate aminotransferase increased (42 [10%] vs eight [4%] vs 17 [9%]), and alanine aminotransferase increased (40 [9%] vs six [3%] vs 13 [7%]). Serious adverse events occurred in 223 (52%) patients in the combination treatment group, 84 (41%) patients in the sorafenib group, and 87 (46%) patients in the single agent cabozantinib group. Treatment-related deaths occurred in six (1%) patients in the combination treatment group (encephalopathy, hepatic failure, drug-induced liver injury, oesophageal varices haemorrhage, multiple organ dysfunction syndrome, and tumour lysis syndrome), one (<1%) in the sorafenib group (general physical health deterioration), and four (2%) in the single-agent cabozantinib group (asthenia, gastrointestinal haemorrhage, sepsis, and gastric perforation)., Interpretation: First-line cabozantinib plus atezolizumab did not improve overall survival versus sorafenib in patients with advanced hepatocellular carcinoma. The progression-free survival benefit of the combination versus sorafenib was maintained, with no new safety signals., Funding: Exelixis and Ipsen., Competing Interests: Declaration of interests TY reports a consulting or advisory role with Bristol Myers Squibb, MSD, AstraZeneca, Eisai, and Ipsen; research funding from Bristol Myers Squibb, MSD, Exelixis, Eli Lilly, AstraZeneca, Roche, and Taiho; travel, accommodations, or expenses from Roche and Bayer; stock and other ownership interests in Moderna; and other financial or non-financial interests with Taiho and Ipsen. AK reports honoraria from Exelixis, Bristol Myers Squibb, Merck, Roche, and Eisai; a consulting or advisory role with Exelixis, Bristol Myers Squibb, Merck, Roche, and Eisai; research funding from Exelixis, Roche, Merck, Bristol Myers Squibb, AdaptImmune, and Tvardi; and travel, accommodations, or expenses from Exelixis, Bristol Myers Squibb, Merck, Roche, and Eisai. A-LC reports honoraria from Merck Sharp Dohme, Bristol Myers Squibb, Bayer Healthcare, AstraZeneca, Genentech/Roche, Ipsen Innovation, BeiGene, and Exelixis; a consulting or advisory role with Merck Sharp Dohme, Bristol Myers Squibb, Bayer Healthcare, AstraZeneca, Genentech/Roche, Ipsen Innovation, BeiGene, and Exelixis; and participation on a data safety monitoring board or advisory board for Abbisko Therapeutics Co. AXZ reports employment and leadership with I-Mab Biopharma; a consulting or advisory role with Lilly, Sanofi, Merck, Exelixis, Roche, Eisai, and Bayer; and stock and other ownership interests in I-Mab Biopharma. SLC reports honoraria from MSD, AstraZeneca, Eisai, Roche, and Bristol Myers Squibb; a consulting or advisory role with MSD, AstraZeneca, Eisai, Roche, and Bayer; and travel, accommodations, or expenses from Ipsen and Novartis. VB reports honoraria from AstraZeneca, Roche, Novartis, Eisai, Bristol Myers Squibb, and Pfizer; and participation on a data safety monitoring board or advisory board with AstraZeneca, Roche, Novartis, Eisai, Bristol Myers Squibb, and Pfizer. GV reports travel, accommodations, and expenses from Roche, Bayer, Terumo, and Ipsen; and participation on a data safety monitoring board or advisory board with Roche, Eisai, and AstraZeneca. EG reports participation on a data safety monitoring board or advisory board with Gilead, Janssen, and Aligos. IB reports honoraria from Roche, Servier, Ipsen, Eisai, and AstraZeneca; travel, accommodations, and expenses with Ipsen and Roche; and participation on a data safety monitoring board or advisory board with AstraZeneca. PM reports a consulting or advisory role with Roche, AstraZeneca, MSD, Bayer, and Ipsen; research funding from Ipsen; travel, accommodations, and expenses from Ipsen, Roche, MSD, and AstraZeneca; and participation on a data safety monitoring board or advisory board with Roche, MSD, Bayer, Ipsen, and AstraZeneca. FB reports employment and stock or other ownership interests with Ipsen. SM reports employment with Exelixis; and stock and other ownership interests in Exelixis, Amgen, and Fibrogen. ZW reports employment and stock and other ownership interests with Exelixis. DC reports employment and stock and other ownership interests with Exelixis. RKK reports a consulting or advisory role with Agios (paid to institution), AstraZeneca (paid to institution), Exelixis (paid to institution), Ipsen (paid to institution), Merck (paid to institution), Kinnate, Regeneron, Tyra Biosciences, and Compass Therapeutics; research funding from Agios, AstraZeneca, Bayer, Bristol Myers Squibb, Eli Lilly, EMD Serono, Genentech/Roche, Loxo Oncology, Merck, Novartis, Partner Therapeutics, QED, Relay Therapeutics, Surface Oncology, and Taiho, all paid to institution; travel, accommodations, and expenses from AstraZeneca and Merck; and participation on a data safety monitoring board or advisory board with Genentech/Roche, Merck, and Relay Therapeutics. LR reports honoraria from AstraZeneca, Bayer, Bristol Myers Squibb, Eisai, Incyte, Ipsen, Merck Serono, Roche, and Servier; a consulting or advisory role or participation on a data safety monitoring board with AstraZeneca, Basilea, Bayer, Bristol Myers Squibb, Eisai, Exelixis, Genenta, Hengrui, Incyte, Ipsen, IQVIA, Jazz Pharmaceuticals, MSD, Nerviano Medical Sciences, Roche, Servier, Taiho Oncology, and Zymeworks; research funding from Agios, AstraZeneca, BeiGene, Eisai, Exelixis, Fibrogen, Incyte, Ipsen, Lilly, MSD, Nerviano Medical Sciences, Roche, and Zymeworks, all paid to institution; a leadership or fiduciary role with the International Liver Cancer Association and the European Organisation for Research and Treatment of Cancer; and travel, accommodations, expenses from AstraZeneca. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: Recent data demonstrated that personalized dosimetry-based selective internal radiotherapy (SIRT) is associated with better outcome for unresectable hepatocellular carcinoma (HCC)., Aim: We aim to evaluate the contribution of personalized predictive dosimetry (performed with Simplicity 90 ® software) in our population of HCC patients by comparing them to our historical cohort whose activity was determined by standard dosimetry., Methods: This is a retrospective, single-center study conducted between February 2016 and December 2020 that included patients with HCC who received SIRT after simulation based on either standard dosimetry (group A) or, as of December 2017, on personalized dosimetry (group B). Primary endpoints were best overall response (BOR) and objective response rate (ORR) evaluated by mRECIST at 3 months. Safety and toxicity profiles were evaluated at 1- and 3-months post-treatment. For group A we compared the activity to be administered determined a posteriori using Simplicit 90 Y® and the activity actually administered determined by the standard approach., Results: Between February 2016 and December 2020, 66 patients received 69 simulations leading to 40 treatments. The median follow-up time was equal for both groups, 21 months (range 3-55) in group A and 21 months (range 4-39) in group B. The per patient analysis revealed a significant benefit of personalized predictive dosimetry in terms of better overall response at 3 months (80% vs. 33.3%, p = 0.007) and at 6 months (77.8% vs. 22.2%, p = 0.06). This trend was found in the analysis by nodule with a response rate according to mRECIST of 87.5% for personalized dosimetry versus 68.4% for standard dosimetry at 3 months, p = 0.24. Only one grade 3 biological toxicity (hyperbilirubinemia) was noted in group A. The comparison between the administered activity and the recommended activity recalculated a posteriori using Simplicit 90 Y® showed that the vast majority of patients who progressed (83.33%) received less activity than that recommended by the personalized approach or an inadequate distribution of the administered activity., Conclusions: Our study aligns to recent literature and confirms that the use of personalized dosimetry allows a better selection of HCC patients who can benefit from SIRT, and consequently, improves the effectiveness of this treatment., (© 2023. The Author(s).)

Purpose: To evaluate survival, efficacy and safety of transarterial chemoembolization (TACE) in the treatment of patients with hepatocellular carcinoma (HCC), through a pooled analysis of patients with BCLC 0, A and B HCC stages, treated with polyethylene glycol drug eluting microspheres (PEG-DEM) TACE., Materials and Methods: Patients from 3 retrospective and 2 prospective registries were included. Overall survival (OS), progression-free survival (PFS), tumour response and safety were evaluated. Multivariate Cox regression analysis was performed to evaluate predictors of OS., Results: A total of 580 patients (72.1% males, mean age 66.9 ± 10.3 years) were included. 43.5% had BCLC A, and 41.0% BCLC B disease stage, and 85.8% were Child-Pugh class A. Complete and partial response (mRECIST or RECIST1.1) were achieved in 60.14% and 27.11% of patients, with overall response and disease control rates of 87.30% and 94.60%, respectively. Median OS was 50.8 months for the total population, and 61.2 and 38.1 months for BCLC 0 + A and BCLC B patients, respectively. Median PFS for the total population, BCLC 0 + A and BCLC B groups was 15.6, 21.6 and 12.7 months, respectively., Conclusions: This multicentric pooled analysis confirmed efficacy and safety of PEG-DEM TACE, with a median OS of 50.8 months., (© 2023. The Author(s).)

Background: Selective internal radiotherapy based on transarterial radioembolization (TARE) with yttrium-90 ( 90 Y) microspheres is an established treatment for primary or metastatic liver disease., Purpose: The objective of this work is to optimize the dosimetry of patients treated with 90 Y TARE, using positron emission tomography (PET) images., Methods: The NEMA 2012 PET phantom was filled with nearly 3.9 GBq of 90 Y activity and acquired at days 0, 3, 5, 7, and 9 on a classic time-of-flight PET/computed tomography (CT) scanner (Philips TF64) and on a silicon photomultiplier (SiPM)-based PET/CT scanner (Philips Vereos). Acquisitions were carried on following the guidelines proposed in a previously published multicentric trial and images were reconstructed by varying and combining the available parameters. Comparisons were performed to identify the best set(s) of parameters leading to the most accurate 90 Y-PET image(s), in terms of activity distribution. Then, for both scanners, the best images were analyzed with Simplicit 90 Y, a personalized dosimetry software using multicompartmental Medical Internal Radiation Dose model. The comparison between measured and true doses allowed to identify the image granting the most consistent dose estimations and, therefore, to designate the set of parameters to be applied on patients' data for the reconstruction of optimized clinical images. Posttreatment dosimetry of four patients was then realized with Simplicit 90 Y using optimized imaging datasets., Results: Based on activity distribution comparisons and dose estimations over phantom and patients data, the SiPM-based PET/CT system appeared more suitable than the photomultiplier tube-based TF64 for 90 Y-PET imaging. With the SiPM-based PET/CT system, reconstructed images with a 2-mm voxel size combined with the application of the point spread function correction led to the most accurate results for quantitative 90 Y measures., Conclusions: For the SiPM-based PET/CT scanner, an optimized set of reconstruction parameters has been identified and applied on patients' data in order to generate the most accurate image to be used for an improved personalized 90 Y-PET dosimetry, ensuring a reliable evaluation of the delivered doses., (© 2022 American Association of Physicists in Medicine.)

Background: Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related death worldwide. The landscape of the systemic treatment for advanced HCC is changing quickly, and recently, the standard of care became either atezolizumab plus bevacizumab or tremelimumab plus durvalumab in the single tremelimumab regular interval durvalumab regimen. Nivolumab monotherapy has proven to be effective sometimes for advanced HCC and could be a valuable treatment option for patients outside current treatment indications and reimbursement criteria for the standard of care. This is a particular population of interest., Aim: To evaluate the real-world effectiveness of nivolumab monotherapy in patients with advanced HCC who are not eligible for other treatment., Methods: We conducted a retrospective, multicentric study including 29 patients with advanced HCC from 3 Belgian tertiary hospitals. All patients had had prior chemotherapy or were intolerant or ineligible for treatments. All study subjects received nivolumab 3 mg/kg in monotherapy, administered once every two weeks intravenously. Treatment continued until disease progression, severe adverse events or death. Data were retrieved from patients' medical records. The outcome parameters such as radiological response according to response evaluation criteria in solid tumors (RECIST) criteria, the biological response through the evolution of the alpha-fetoprotein (AFP) level, and clinical response considering both the Child-Pugh (CP) score and the World Health Organization (WHO) performance status (PS) were reported. A safety profile was also reported. Statistical analysis was performed using the SPSS Statistics 27 statistical software package., Results: The radiological overall response rate (defined as complete or partial response according to the immune RECIST and modified RECIST criteria) to nivolumab monotherapy was 24.1%. The biological overall response rate (defined as a decrease of ≥ 25% in AFP blood level) was 20.7%. Radiological and biological responses were significantly associated both with each other ( P < 0.001) and with overall survival ( P < 0.005 for radiological response and P < 0.001 for biological response). Overall survival was 14.5 mo (+/- 2.1), and progression-free survival was 10.9 mo (+/- 2.3). After 4 mo of treatment, 78.3% of patients remained clinically stable or even showed improvement in WHO PS. Grade 3 adverse events occurred in 17.2% of patients, none had grade 4 adverse events, and no patients ceased nivolumab due to adverse events., Conclusion: Nivolumab monotherapy is a good treatment choice in frail patients with HCC who are ineligible for the standard of care or other validated systemic treatments., Competing Interests: Conflict-of-interest statement: There are no competing interests to declare for all authors., (©The Author(s) 2022. Published by Baishideng Publishing Group Inc. All rights reserved.)

Background: Cabozantinib has shown clinical activity in combination with checkpoint inhibitors in solid tumours. The COSMIC-312 trial assessed cabozantinib plus atezolizumab versus sorafenib as first-line systemic treatment for advanced hepatocellular carcinoma., Methods: COSMIC-312 is an open-label, randomised, phase 3 trial that enrolled patients aged 18 years or older with advanced hepatocellular carcinoma not amenable to curative or locoregional therapy and previously untreated with systemic anticancer therapy at 178 centres in 32 countries. Patients with fibrolamellar carcinoma, sarcomatoid hepatocellular carcinoma, or combined hepatocellular cholangiocarcinoma were not eligible. Tumours involving major blood vessels, including the main portal vein, were permitted. Patients were required to have measurable disease per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1), Barcelona Clinic Liver Cancer stage B or C disease, an Eastern Cooperative Oncology Group performance status of 0 or 1, adequate organ and marrow function, and Child-Pugh class A. Previous resection, tumour ablation, radiotherapy, or arterial chemotherapy was allowed if more than 28 days before randomisation. Patients were randomly assigned (2:1:1) via a web-based interactive response system to cabozantinib 40 mg orally once daily plus atezolizumab 1200 mg intravenously every 3 weeks, sorafenib 400 mg orally twice daily, or single-agent cabozantinib 60 mg orally once daily. Randomisation was stratified by disease aetiology, geographical region, and presence of extrahepatic disease or macrovascular invasion. Dual primary endpoints were progression-free survival per RECIST 1.1 as assessed by a blinded independent radiology committee in the first 372 patients randomly assigned to the combination treatment of cabozantinib plus atezolizumab or sorafenib (progression-free survival intention-to-treat [ITT] population), and overall survival in all patients randomly assigned to cabozantinib plus atezolizumab or sorafenib (ITT population). Final progression-free survival and concurrent interim overall survival analyses are presented. This trial is registered with ClinicalTrials.gov, NCT03755791., Findings: Analyses at data cut-off (March 8, 2021) included the first 837 patients randomly assigned between Dec 7, 2018, and Aug 27, 2020, to combination treatment of cabozantinib plus atezolizumab (n=432), sorafenib (n=217), or single-agent cabozantinib (n=188). Median follow-up was 15·8 months (IQR 14·5-17·2) in the progression-free survival ITT population and 13·3 months (10·5-16·0) in the ITT population. Median progression-free survival was 6·8 months (99% CI 5·6-8·3) in the combination treatment group versus 4·2 months (2·8-7·0) in the sorafenib group (hazard ratio [HR] 0·63, 99% CI 0·44-0·91, p=0·0012). Median overall survival (interim analysis) was 15·4 months (96% CI 13·7-17·7) in the combination treatment group versus 15·5 months (12·1-not estimable) in the sorafenib group (HR 0·90, 96% CI 0·69-1·18; p=0·44). The most common grade 3 or 4 adverse events were alanine aminotransferase increase (38 [9%] of 429 patients in the combination treatment group vs six [3%] of 207 in the sorafenib group vs 12 [6%] of 188 in the single-agent cabozantinib group), hypertension (37 [9%] vs 17 [8%] vs 23 [12%]), aspartate aminotransferase increase (37 [9%] vs eight [4%] vs 18 [10%]), and palmar-plantar erythrodysaesthesia (35 [8%] vs 17 [8%] vs 16 [9%]); serious treatment-related adverse events occurred in 78 (18%) patients in the combination treatment group, 16 (8%) patients in the sorafenib group, and 24 (13%) in the single-agent cabozantinib group. Treatment-related grade 5 events occurred in six (1%) patients in the combination treatment group (encephalopathy, hepatic failure, drug-induced liver injury, oesophageal varices haemorrhage, multiple organ dysfunction syndrome, and tumour lysis syndrome), one (<1%) patient in the sorafenib group (general physical health deterioration), and one (<1%) patient in the single-agent cabozantinib group (gastrointestinal haemorrhage)., Interpretation: Cabozantinib plus atezolizumab might be a treatment option for select patients with advanced hepatocellular carcinoma, but additional studies are needed., Funding: Exelixis and Ipsen., Competing Interests: Declaration of interests RKK reports consulting or advisory roles for Agios (to institution), AstraZeneca (to institution), Exact Sciences, Ipsen (to institution), and Kinnate; research funding (to institution) from Agios, AstraZeneca, Bayer, Bristol-Myers Squibb, Eli Lilly, EMD Serono, Exelixis, Genentech/Roche, Ipsen, LOXO Oncology, Merck Sharp & Dohme, QED, Partner Therapeutics, Relay Therapeutics, and Surface Oncology; and honoraria from Genentech/Roche. LR reports honoraria from AbbVie, Amgen, Bayer, Eisai, Gilead, Incyte, Ipsen, Lilly, Merck Serono, Roche, and Sanofi; consulting or advisory roles for Amgen, ArQule, AstraZeneca, Basilea, Bayer, Bristol-Myers Squibb, Celgene, Eisai, Exelixis, Genenta, Hengrui, Incyte, Ipsen, IQVIA, Lilly, MSD, Nerviano Medical Sciences, Roche, Sanofi, Servier, Taiho Oncology, and Zymeworks; research funding (to institution) from Agios, ARMO BioSciences, AstraZeneca, BeiGene, Eisai, Exelixis, Fibrogen, Incyte, Ipsen, Lilly, MSD, Nerviano Medical Sciences, Roche, and Zymeworks; and travel, accommodations, and expenses from Ipsen. A-LC reports consulting or advisory roles for AstraZeneca, Bayer, BeiGene, Bristol-Myers Squibb, Eisai, Exelixis, F Hoffmann-La Roche, Genentech/Roche, Ipsen Innovation, MSD, and Ono Pharmaceutical; speakers bureau for Amgen Taiwan, Bayer Yakuhin, Eisai, Novartis, and Ono Pharmaceutical; and travel, accommodations, and expenses from Bayer Yakuhin, Chugai Pharmaceutical, Eisai, and IQVIA. AK reports consulting or advisory roles from Roche/Genentech; and research funding (to institution) from Roche/Genentech. AXZ reports employment by I-Mab Biopharma and personal fees from Bayer, Eisai, Exelixis, Lilly, Merck, Roche, and Sanofi. SLC reports honoraria from AstraZeneca, Eisai, and MSD; consulting or advisory roles for AstraZeneca, Eisai, and MSD Oncology; and research funding from Eisai and Ipsen. VB reports honoraria from AstraZeneca, Bristol-Myers Squibb, Eisai, MSD Oncology, Roche, and Takeda; consulting or advisory roles for Bayer, Bristol-Myers Squibb, Eisai, MSD Oncology, Roche, and Takeda; and travel, accommodations, and expenses from Bayer, Bristol-Myers Squibb, Ipsen, Roche, and Takeda. GV reports consulting or advisory roles for Bayer, Eisai, Roche, and Terumo; honoraria from Roche and Terumo; research funding from Exelixis; and travel and accommodations from Bristol-Myers Squibb. IB reports honoraria from Bayer, Eisai, Roche, and Servier; and travel and accommodations from Ipsen. PM reports consulting or advisory roles for AstraZeneca, Bayer, Eisai, Genosciences, Ipsen, MSD, and Roche. FB reports employment, stock, and other ownership interests with Ipsen. KB and SH report employment (former), stock, and other ownership interests with Exelixis. JF reports employment, stock, and other ownership interests with Exelixis. All other authors declare no competing interests., (Copyright © 2022 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Backgrounds and Aims: Even if no systemic treatment is currently validated for unresectable hepatocellular-cholangiocarcinoma (cHCC-CCA), tyrosine kinase inhibitors (TKIs) and platinum-based chemotherapy are frequently used in clinical practice. Our study aims to describe the effectiveness of first-line systemic treatments in patients with cHCC-CCA., Patients and Methods: Patients with histological diagnosis of unresectable or metastatic cHCC-CCA confirmed by a centralized review (WHO classification 2019) and who received systemic treatment from 2009 to 2020 were included retrospectively in 11 centers. The outcomes of patients with cHCC-CCA were compared with patients with hepatocellular carcinoma (HCC) treated by sorafenib ( n = 117) and with intrahepatic cholangiocarcinoma (iCCA, n = 94) treated mainly by platinum-based chemotherapy using a frailty Cox model. The efficacy of TKIs and platinum-based chemotherapies in patients with cHCC-CCA was assessed using a doubly robust estimator., Results: A total of 83 patients with cHCC-CCA were included and were predominantly male (72%) with underlying cirrhosis (55%). 67% of patients had extrahepatic metastases and 31% macrovascular tumor invasion. cHCC-CCAs were more often developed on cirrhosis (55.4%) than iCCA (26.6%) but less frequently than HCC (80.2%) ( p < 0.001). Both HCC (36.8% and cHCC-CCA (66.2%) had less frequent extrahepatic metastases than iCCA (81%) ( p < 0.001). Unadjusted overall survival (OS) was better in iCCA (13 months) compared to cHCC-CCA (12 months) and HCC (11 months) ( p = 0.130). In multivariable analysis, after adjustment by a Cox frailty model, patients with cHCC-CCA had the same survival as HCC and iCCA (HR = 0.67, 95% CI: 0.37-1.22, p = 0.189 and HR = 0.66, 95% CI: 0.43-1.02, p = 0.064, respectively). ALBI score (HR = 2.15; 95% CI: 1.23-3.76; p = 0.009), ascites (HR = 3.45, 95% CI: 1.31-9.03, p = 0.013), and tobacco use (HR = 2.29, 95% CI: 1.08-4.87, p = 0.032) were independently associated with OS in patients with cHCC-CCA. Among patients with cHCC-CCA, 25 patients treated with TKI were compared with 54 patients who received platinum-based chemotherapies. Patients treated with TKI had a median OS of 8.3 months compared to 11.9 months for patients treated with platinum-based chemotherapy ( p = 0.86). After a robust doubly adjustment on tumor number and size, vascular invasion, ALBI, MELD, and cirrhosis, the type of treatment did not impact OS (HR = 0.92, 95% CI: 0.27-3.15, p = 0.88) or progression-free survival (HR = 1.24, 95% CI: 0.44-3.49, p = 0.67)., Conclusions: First-line systemic treatments with TKIs or platinum-based chemotherapies have similar efficacy in patients with unresectable/metastatic cHCC-CCA. The ALBI score predicts OS., Competing Interests: E.G. received travel and congress fees from Bayer, Gilead, and Ipsen; M.B. received consulting fees from Bayer, BMS, Ipsen, Roche, Eisai, Sirtex, Servier, MSD, and AstraZeneca; M.R. received honoraria from Servier, GE Healthcare, Ipsen, Canon-Toshiba, Alexion Pharmaceuticals, Guerbet, and Sirtex; A.Z. received consulting and advisory board fees from Amgen, Lilly, Merck, Roche, Sanofi, Servier, Baxter, MSD, Pierre Fabre, Havas Life, Alira Health, and Zymeworks; D.T. received consulting fees from Amgen, Merck, Novartis, BMS, MSD, AstraZeneca, Sanofi, Roche, Bayer, Servier, and Ipsen; J.E. received consulting fees from MSD, Eisai, BMS, AstraZeneca, Bayer, Roche, Ipsen, Basilea, Merck Serono, Incyte, and Servier and also received travel fees from Amgen and research funding (institutional) from BMS, Beigene; J.-F.B. received consulting fees from Bayer, BMS, Ipsen, Eisai, MSD, Roche, and AstraZeneca; J.-C.N. received research grants from Ipsen and Bayer; and E.T. received research support from Gilead and speaker fees from Abbvie. The other authors have no conflicts of interest to declare., (Copyright © 2022 by The Author(s). Published by S. Karger AG, Basel.)

Purpose: KEYNOTE-224 cohort 1 demonstrated that pembrolizumab was efficacious and tolerable in patients with advanced hepatocellular carcinoma (HCC) previously treated with sorafenib. We report results from KEYNOTE-224 (NCT02702414) cohort 2, which enrolled patients with advanced HCC and no prior systemic therapy., Patients and Methods: KEYNOTE-224 was an open-label, multicountry phase II trial. Eligible patients in cohort 2 had advanced HCC not amenable or refractory to locoregional therapy and not previously treated with systemic therapy. Patients received pembrolizumab 200 mg intravenously every 3 weeks for ≤2 years. Primary endpoint was objective response rate (ORR) by central imaging review per RECIST v1.1. Secondary endpoints included duration of response (DOR), disease control rate (DCR), time to progression (TTP), progression-free survival (PFS), overall survival (OS), and safety/tolerability., Results: Between September 4, 2018, and February 20, 2019, 51 patients were allocated in cohort 2. The median time from the first dose to data cutoff (January 19, 2021) was 27 months (range, 23-29). ORR was 16% [95% confidence interval (CI), 7-29] and was similar across key subgroups. Median DOR was 16 months (range, 3-24+), and DCR was 57%. The median PFS was 4 months (95% CI, 2-8), and median TTP was 4 months (95% CI, 3-9). Median OS was 17 months (95% CI, 8-23). Grade ≥3 treatment-related adverse events occurred in 16% of patients., Conclusions: In patients with advanced HCC with no prior systemic therapy, pembrolizumab provided durable antitumor activity, promising OS, and had a safety profile consistent with previous observations. These findings support further evaluation of pembrolizumab-based regimens for HCC., (©2022 The Authors; Published by the American Association for Cancer Research.)

Objective: Pembrolizumab, a PD-1 inhibitor, demonstrated anti-tumour activity and tolerability in patients treated with sorafenib and with advanced hepatocellular carcinoma in KEYNOTE-224. Longer-term efficacy and safety after ∼2.5 years of additional follow-up are reported., Patients and Methods: Adults with confirmed hepatocellular carcinoma who experienced progression after or intolerance to sorafenib treatment received pembrolizumab 200 mg every 3 weeks for ≤35 cycles or until confirmed progression, unacceptable toxicity, withdrawal of consent or investigator decision. The primary end-point was objective response rate assessed by blinded independent central review per Response Evaluation Criteria in Solid Tumours v1.1. The secondary end-points included duration of response, disease control rate, time to progression, progression-free survival, overall survival and adverse events., Results: Efficacy and safety were assessed in 104 patients. The median time from first dose to data cutoff was 45.1 months (range, 41.3-49.3). Objective response rate was 18.3% (95% CI: 11.4-27.1), and median duration of response was 21.0 months (range, 3.1 to 39.5+). Disease control rate was 61.5%, and median time to progression was 4.8 months (95% CI: 3.9-7.0). Median progression-free survival was 4.9 months (95% CI: 3.5-6.7) and median overall survival was 13.2 months (95% CI: 9.7-15.3). Of 104 patients, 76 (73.1%) patients reported treatment-related adverse events; most were low grade in severity (grade 3-4, n = 26 [25.0%]; grade 5, n = 1 [1.0%]). Immune-mediated hepatitis occurred in 3 patients (all grade 3). No viral-induced hepatitis flares occurred., Conclusions: After ∼2.5 years of additional follow-up, pembrolizumab continued to provide durable anti-tumour activity and no new safety concerns were identified., Gov Identifier: NCT02702414., Competing Interests: Conflict of interest statement The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: M. Kudo has received a grant and fees from Eisai, and Bristol Myers Squibb; has received fees from Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, and Eli Lilly; has served a consultant for Bayer, Eisai, Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, Roche, Bristol Myers Squibb, and Ono; and has received a grant from Otsuka, Taiho, EA Pharma, Takeda, Gilead, AbbVie, and Sumitomo Dainippon Pharma; R.S. Finn has received fees and a grant to his institution from Merck, Bayer, Eli Lilly, Bristol Myers Squibb, Eisai, Pfizer, Roche/Genentech; and has received fees from AstraZeneca and CStone; J. Edeline has received personal fees from Bayer, Bristol Myers Squibb, AstraZeneca, Eisai, Ipsen, Boston Scientific, and Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA; and has received grants from Bristol Myers Squibb, BeiGene, and Boston Scientific; S. Cattan has nothing to disclose; S. Ogasawara has received a grant and fees from Bayer, Eisai, Eli Lilly; and has received fees from Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, AstraZeneca, and Chugai; D. Palmer has received a grant and fees from Bristol Myers Squibb, NuCana Inc, and Sirtex; has received a grant from AstraZeneca; and has received fees from Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, Roche, and Eisai; C. Verslype has received a grant from Baye and Ipsen and has served as a consultant for Bayer, Ipsen, and Roche; V. Zagonel has served in an advisory capacity or as a consultant for Bristol Myers Squibb and Merck; has served as a speaker for Bayer, Roche, Bristol Myers Squibb, Astellas Pharma, SERVIER, AstraZeneca, Eli Lilly; and has received travel, accommodations, and expenses from Bayer, Roche, and SERVIER; L. Fartoux has no conflicts of interest to report. A. Vogel has received fees for serving in an advisory capacity/consultant, has received speaking fees, has received fees for expert testimony, and has received honoraria from AstraZeneca, Bayer, Bristol Myers Squibb, BTG, Eli Lilly, Incyte Corporation, Ipsen, Janssen, Merck, Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, Novartis, Pierre Fabre, Roche, Sanofi, and Servier; D. Sarker has received fees from Eisai, Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, AstraZeneca, Bayer, and Surface Oncology; has received fees and non-financial support from Ipsen; has received non-financial support from MiNA Therapeutics; and has received a grant from Roche; G. Verset has received a grant from Terumo; has served as a consultant for Terumo and BTG; has served in an advisory capacity for Bayer, Eisai, and Roche; and has received travel expenses for attending congresses from Bayer, Bristol Myers Squibb, and Ipsen; S.L. Chan has participated as an advisor for AstraZeneca; J. Knox has received a grant for an investigator-initiated study from Merck; and has received fees for consulting from Merck, Ipsen, and Roche; B. Daniele has received fees from Ipsen, Eisai, Eli Lilly, AstraZeneca, Sanofi, Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, Bayer, Roche, and Amgen; and has received non-financial support from Ipsen, Bristol Myers Squibb; T. Yau has received fees for serving in an advisory capacity or as a consultant and has received honoraria from Bristol Myers Squibb, Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, Exelixis, Ipsen, Eisai, AstraZeneca, Bayer, Novartis, EMD Serono, AbbVie, Pfizer, Eli Lilly, Sirtex, SillaJen, Taiho, OrigiMed, New Beta Innovation, Sirtex, and H3 Biomedicine; E.B. Gurary and A. B. Siegel are employees of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA; A. Wang is an employee of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA and has stock in Merck & Co., Inc., Kenilworth, NJ, USA; A-L Cheng has received fees for consulting from AstraZeneca, Bristol Myers Squibb, Eisai, Merck Serono, Novartis, Ono Pharmaceutical, Exelixis, Nucleix, Ipsen Innovation, Bayer Healthcare, Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, Roche/Genentech, BeiGene, CSR Pharma Group, F Hoffmann-La Roche, and IQVIA; has received travel support from Roche/Genentech, IQVIA, and Bayer Yakuhin; and has received speaker fees from Eisai, Novartis, Ono Pharmaceutical, Bayer Yakuhin, and Amgen Taiwan; A.X. Zhu has received fees for consulting from Merck, Eli Lilly, Bayer, Sanofi, Eisai, Exelixis, and Roche., (Copyright © 2022 Masatoshi Kudo, Richard S. Finn, Julien Edeline, Stéphane Cattan, Sadahisa Ogasawara, Daniel H. Palmer, Chris Verslype, Vittorina Zagonel, Laetitia Fartoux, Arndt Vogel, Debashis Sarker, Gontran Verset, Stephen L. Chan, Jennifer Knox, Bruno Daniele, Thomas Yau, Ellen B. Gurary, Abby B. Siegel, Anran Wang, Ann-Lii Cheng, Andrew X. Zhu, KEYNOTE-224 Investigators. Published by Elsevier Ltd.. All rights reserved.)

The most common metastatic sites of pancreatic cancer are the liver, lymph nodes, peritoneum and lung. Here we report two cases of BRCA mutated pancreatic cancer that developed unusual metastasis while treatment with maintenance Olaparib and leading to rapid death. We hereby review the literature and address the possibility of a different nature and tumour biology of BRCA mutated cancer treated with PARP inhibitors., Competing Interests: Conflict of interest statement The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Conventional transarterial embolization (cTACE) has been proven to be effective for intermediate stage hepatocellular carcinoma (HCC), with a recent systematic review showing an overall survival (OS) of 19.4 months. Nevertheless, due to the rapid development of the systemic therapeutic landscape, the place of TACE is becoming questionable. Is there still a niche for TACE in the era of immunotherapy and combination treatments such as atezolizumab-bevacizumab, which has shown an OS of 19.2 months with excellent tolerance? The development of drug-eluting microspheres (DEMs) has led to the standardization of the technique, and along with adequate selection, it showed an OS of 48 months in a retrospective study. In order to increase treatment selectivity, new catheters have also been added to the TACE arsenal as well as the use of cone-beam CT (CBCT), which provides three-dimensional volumetric images and guidance during procedures. Moreover, the TACE indications have also widened. It may serve as a "bridging therapy" for liver transplantation candidates while they are on the waiting list, and it represents a valuable downstaging tool to transplantation criteria. The aim of this review is to explore the current data on the advancements of TACE and its future place amongst the growing panel of treatments.

Introduction: The aim of this multicenter comparison of balloon-occluded transarterial chemoembolization (B-TACE) versus conventional TACE (cTACE) in treating hepatocellular carcinoma (HCC) was to assess in which size range the 2 techniques offered higher complete response (CR) and objective response (OR) rates in a single session, and to evaluate the possibility of using B-TACE to reduce the need for re-treatment., Methods: 325 patients were retrospectively evaluated: 91 patients in the B-TACE group (22 with cTACE [B-cTACE] and 69 with drug-eluting microsphere TACE [B-DEM-TACE]) and 234 in the cTACE group. The results were compared according to tumor size: (A) <30 mm, (B) 30-50 mm, and (C) >50 mm; OR and CR rates after the first session and the number of TACE re-interventions within a 6-month period were also evaluated using propensity score matching (PSM)., Results: The best target ORs were very high (93.2%) and similar between the 2 treatments both before (94.4% for cTACE and 90.1% for B-TACE) and after PSM (94.5% for cTACE and 90.1%; p = 0.405), with slightly better results for the cTACE cohort probably due to better cTACE effectiveness in smaller lesions. In lesions <30 mm, cTACE obtained a slightly higher CR rate than B-TACE (61.9 vs. 56.3%, p = 0.680), whereas in intermediate-sized HCCs (30-50 mm), B-TACE showed a significant superiority in achieving a CR (72.3 vs. 54.1%, respectively; p = 0.047). In larger lesions (>50 mm), cTACE and B-TACE performed equally, with a poor CR rate (22.6 vs. 23.1%, respectively; p = 1.000). These results were additionally confirmed using PSM. The patients treated with B-TACE had a significantly lower re-treatment rate than the cTACE cohort (12.1 vs. 26.9%, respectively; p = 0.005). B-cTACE and B-DEM-TACE demonstrated similar ORs, with a slightly better CR rate for B-cTACE (68.2 vs. 56.5%, respectively; p = 0.456)., Conclusion: In HCCs of 30-50 mm, B-TACE should be preferred to cTACE, whereas in smaller nodules (<30 mm), cTACE can suffice in achieving a good CR rate. The statistically significant lower re-treatment rate of the B-TACE cohort after a single procedure reduced the risk of complications due to multiple TACE, which could worsen the patient prognosis., Competing Interests: The authors have no conflicts of interest to declare., (Copyright © 2021 by S. Karger AG, Basel.)

Purpose: The aim of this retrospective multicentric study was to compare the tumour response rates of Balloon-occluded Transarterial Chemoembolisation (B-TACE) to non-B-TACE using propensity score matching (PSM) in patients with hepatocellular carcinoma and to investigate the clinical benefit, such as lower rates of TACE re-intervention achieved using B-TACE., Material and Methods: The B-TACE procedures (n = 96 patients) were compared with a control group of non-B-TACE treatments (n = 434 pts), performed with conventional (cTACE) or drug-eluting microspheres TACE (DEM-TACE). Data were collected from six European centres from 2015 to 2019. Objective responses (OR) and complete response (CR) rates after the first session and the number of TACE re-interventions were evaluated using PSM (91 patients per arm)., Results: The best target OR after PSM were similar for both B-TACE and non-B-TACE (90.1% and 86.8%, p = 0.644); however, CR at 1-6 months was significantly higher for B-TACE (59.3% vs. 41.8%, p = 0.026). Patients treated with B-TACE had a significantly lower retreatment rate during the first 6 months (9.9%% vs. 22.0%, p = 0.041). Post-embolisation syndrome (PES) rates were 8.8% in non-B-TACE and 41.8% in B-TACE (p < 0.001), with no significant differences between groups regarding major adverse events., Conclusion: B-TACE is safe and effective, achieving higher CR rates than non-B-TACE. Patients undergoing B-TACE had a significantly lower retreatment rate within the first 6 months but higher PES rates., Level of Evidence Iii: Level 3, retrospective study.

Background and Aim: Transarterial chemoembolization with drug-eluting microspheres (DEM-TACE) is recommended for patients with BCLC stage B hepatocellular carcinoma (HCC) and stage 0-A unsuitable for curative treatments. We assessed efficacy and safety along with hepatobiliary toxicities (HBT) of DEM-TACE using a novel microsphere, LifePearl TM , loaded with anthracyclines., Materials and Methods: 97 patients diagnosed with HCC were prospectively enrolled and treated using LifePearl TM loaded with doxorubicin (77%) or idarubicin (23%). Safety and tolerability were assessed using CTCAE, HBT by CT/MRI scans, and tumor response by applying modified Response Evaluation Criteria in Solid Tumors (mRECIST). Follow-up was after 2 years., Results: Adverse events (AE) were reported in 73.2% of patients, majority being Grade 1-2. Grade ≥ 3 AE reported in 13.4% of patients were mainly related to postembolization syndrome. HBT were observed after 15.5% (29/187) of the DEM-TACEs. Objective response and disease control rates were 81% and 99%, respectively, as the best responses. Survival rates at one and two years were 81% and 66%, respectively, while the median overall survival (OS) was not reached. Median progression free survival was 13.7 months (95% CI: 11.3; 15.6) and median time to TACE untreatable progression was 16.7 months (95% CI: 12.7; not estimable (n.e.))., Conclusions: DEM-TACE using LifePearl TM provides a high tumor response rate in HCC patients. HBT rates within or below previously reported results for cTACE and DEM-TACE indicate a good safety profile for LifePearl TM . The trial was registered in ClinicalTrials.gov National Library of Medicine (ID: NCT03053596).

Aim: Evaluation of safety and efficacy of selective balloon-occluded transarterial chemoembolization using polyethylene glycol embolizing microspheres in patients with hepatocellular carcinoma., Materials & Methods: Twenty-four consecutive patients were included in this monocentric prospective trial. Adverse events were evaluated at 24 h and 1 month. Imaging response according to modified response evaluation criteria in solid tumors was assessed at 1, 3 and 6 months., Results: The median time of follow-up was of 22.8 months (interquartile range (IQR) 17.38-26.22). Clinical grade 1/2 toxicities (0% >grade 2) were reported in 25.7% of patients, with abdominal pain being the most frequent complication (17.1%). No 30-days mortalities or liver decompensation were observed. The 1-month follow-up MRI showed an overall response rate of 74.3%., Conclusion: Balloon-occluded transarterial chemoembolization was shown to be safe and effective., Competing Interests: Financial & competing interests disclosure A-M Bucalau, M Pezzullo, S Picchia and J-L Van Laethem have no conflicts to declare. I Tancredi is a consultant for Terumo Europe NV and BTG International. R Leveque is a consultant for BTG International. G Verset is a consultant for Terumo Europe NV and BTG International. This is an investigator-initiated study supported by a grant from Terumo Europe NV. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript., (© 2020 Ana-Maria Bucalau.)

Background: Immunotherapy represents a promising option for treatment of hepatocellular carcinoma (HCC) in cirrhotic patients but its efficacy is currently inconsistent and unpredictable. Locoregional therapies inducing immunogenic cell death, such as transarterial chemoembolization (TACE) or selective internal radiation therapy (SIRT), have the potential to act synergistically with immunotherapy. For the development of new approaches combining locoregional treatments with immunotherapy, a better understanding of the respective effects of TACE and SIRT on recruitment and activation of immune cells in HCC is needed. To address this question, we compared intra-tumor immune infiltrates in resected HCC after preoperative treatment with TACE or SIRT., Methods: Data fromr patients undergoing partial hepatectomy for HCC, without preoperative treatment (SURG, n = 32), after preoperative TACE (TACE, n = 16), or preoperative SIRT (n = 12) were analyzed. Clinicopathological factors, tumor-infiltrating lymphocytes (TILs), CD4 + and CD8 + T cells, and granzyme B (GZB) expression in resected HCC, and postoperative overall and progression-free survival were compared between the three groups., Results: Clinicopathological and surgical characteristics were similar in the three groups. A significant increase in TILs, CD4 + and CD8 + T cells, and GZB expression was observed in resected HCC in SIRT as compared to TACE and SURG groups. No difference in immune infiltrates was observed between TACE and SURG patients. Within the SIRT group, the dose of irradiation affected the type of immune infiltrate. A significantly higher ratio of CD3 + cells was observed in the peri-tumoral area in patients receiving < 100 Gy, whereas a higher ratio of intra-tumoral CD4 + cells was observed in patients receiving > 100 Gy. Postoperative outcomes were similar in all groups. Irrespective of the preoperative treatment, the type and extent of immune infiltrates did not influence postoperative survival., Conclusions: SIRT significantly promotes recruitment/activation of intra-tumor effector-type immune cells compared to TACE or no preoperative treatment. These results suggest that SIRT is a better candidate than TACE to be combined with immunotherapy for treatment of HCC. Evaluation of the optimal doses for SIRT for producing an immunogenic effect and the type of immunotherapy to be used require further evaluation in prospective studies.

DNA demethylating agents may increase the immunogenicity of malignant tumours and increase the efficacy of subsequent treatment with immune check point inhibitors. We investigated the safety of administrating the demethylating agent decitabine by hepatic arterial infusionin patients with unresectable liver meta stases from solid tumours in a dose escalation phase I clinical trial. A total of nine eligible patients were enrolled and initiated study treatment at three different dose levels (two patients at 10, four at 15 and six at a dose level of 20mg decitabine/m2/day) (per protocol there was no intent to escalate the dose above the median tolerated intravenous dose level). Decitabine was administered as a 1-hour hepatic arterial infusion on five consecutive days every 4 weeks. Intrapatient dose escalation was applied in five patients. Grades 1 and 2 haematological toxicity was the most frequent treatment-related adverse event. None of the patients experienced treatment-limiting adverse events. Expression analysis of 30 cancer test is antigens (CTA) in pretreatment and post-treatment biopsies from patients indicated an increased expression of 21 CTAs after treatment. There were no objective tumour responses on study treatment or during post study exposure to immune checkpoint therapy in four patients with uveal melanoma liver metastases. We conclude that the investigate d hepatic arterial administration regimen for decitabine can be safely applied, and a dose level of 20 mg/m2/day on five consecutive days every 4 weeks can be considered for further investigation in combinatorial immunotherapy regimens., Trial Registration Number: NCT02316028., Competing Interests: Competing interests: None declared.

Background: Immune checkpoint blockade therapy has shown promising results in patients with advanced hepatocellular carcinoma. We aimed to assess the efficacy and safety of pembrolizumab in this patient population., Methods: KEYNOTE-224 is a non-randomised, multicentre, open-label, phase 2 trial that is set in 47 medical centres and hospitals across ten countries. Eligible patients had pathologically confirmed hepatocellular carcinoma; had previously been treated with sorafenib and were either intolerant to this treatment or showed radiographic progression of their disease after treatment; an Eastern Cooperative Oncology Group performance status of 0-1; adequate organ function, and were Child-Pugh class A. Participants received 200 mg pembrolizumab intravenously every 3 weeks for about 2 years or until disease progression, unacceptable toxicity, patient withdrawal, or investigator decision. The primary endpoint was objective response, defined as the proportion of patients with complete or partial response in all patients who received at least one dose of pembrolizumab, which was radiologically confirmed by use of the Response Evaluation Criteria in Solid Tumors version 1.1 by central review. Safety was also assessed in all treated patients. This trial is ongoing but closed to enrolment and is registered with ClinicalTrials.gov number NCT02702414., Findings: Between June 7, 2016, and Feb 9, 2017, we screened 169 patients with advanced hepatocellular carcinoma, of whom 104 eligible patients were enrolled and treated. As of data cutoff on Feb 13, 2018, 17 (16%) patients were still receiving pembrolizumab. We recorded an objective response in 18 (17%; 95% CI 11-26) of 104 patients. The best overall responses were one (1%) complete and 17 (16%) partial responses; meanwhile, 46 (44%) patients had stable disease, 34 (33%) had progressive disease, and six (6%) patients who did not have a post-baseline assessment on the cutoff date were considered not to be assessable. Treatment-related adverse events occurred in 76 (73%) of 104 patients, which were serious in 16 (15%) patients. Grade 3 treatment-related events were reported in 25 (24%) of the 104 patients; the most common were increased aspartate aminotransferase concentration in seven (7%) patients, increased alanine aminotransferase concentration in four (4%) patients, and fatigue in four (4%) patients. One (1%) grade 4 treatment-related event of hyperbilirubinaemia occurred. One death associated with ulcerative oesophagitis was attributed to treatment. Immune-mediated hepatitis occurred in three (3%) patients, but there were no reported cases of viral flares., Interpretation: Pembrolizumab was effective and tolerable in patients with advanced hepatocellular carcinoma who had previously been treated with sorafenib. These results indicate that pembrolizumab might be a treatment option for these patients. This drug is undergoing further assessment in two phase 3, randomised trials as a second-line treatment in patients with hepatocellular carcinoma., Funding: Merck & Co, Inc., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background: Doxorubicin Transdrug (DT), a nanoformulation of doxorubicin, was demonstrated to overcome the chemoresistance of hepatocellular carcinoma (HCC) in preclinical models. Its efficacy and safety were thus investigated in phase I and randomised phase II trials in unresectable HCC., Patients and Methods: Phase I was a single dose of DT through the hepatic intra-arterial (HIA) route, dose-escalating 3+3 trial, evaluating five-dose levels from 10 to 40 mg/m 2 with maximal tolerated dose (MTD) as primary endpoint. The multicentre phase II trial randomly assigned (2:1 ratio) patients to receive either 30 mg/m 2 of DT through HIA route every 4 weeks for up to three courses or best standard of care (BSC). Progression-free survival (PFS) rate at 3 months was the primary endpoint. Overall survival (OS) and disease control rate (DCR) were secondary endpoints., Results: In phase I, haematological and respiratory limited toxicities were reported at 35 and 40 mg/m 2 , giving MTD at 30 mg/m 2 . Partial response rate was 10%, and stable disease 70%. Phase II was discontinued due to three severe acute respiratory distress events in the DT group while 17 patients had received 30 mg/m 2 DT and 11 BSC. At 3 months, PFS was 64% (95% CI 31 to 89) vs 75% (95% CI 35 to 97), and DCR 35% vs 27% in DT and BSC, respectively (p=NS). Median OS was 32.6 months (95% CI 8.2 to 34.1) in DT group and 15 months (95% CI 8.0 to 18.8) in BSC group (p < 0.05)., Conclusion: DT increased OS in unresectable HCC but induced severe respiratory distress. Efficacy data deserve further investigation using a safer dosing and schedule regimen., Trial Registration Number: EUDRACT 2006-004088-77; Results., Competing Interests: Competing interests: PM: participant to boards and consultancy for Onxeo and Bayer; participant to boards for BMS. JPZ: honorary from Abbvie and consultancy for Gilead, BMS and Janssen. MB: consultancy for Bayer Pharma and Bristol-Myers Squibb; advisory board for Bayer Pharma and Bristol-Myers Squibb; received honoraria from Bayer Pharma and Sirtex. JT: honorary from Roche, Merck, Amgen, Celgene, Baxalta, Sanofi, Lilly and Sirtex. BV is an employee of Onxeo. PA is a shareholder of Onxeo and a patent owner.

Pancreatic ductal adenocarcinoma carries a dismal prognosis. Both chemotherapy and targeted therapies have been disappointing when administered to unselected populations. Recently, progress has been made in our understanding of the genomic landscape of this cancer which displays remarkable heterogeneity suggesting a reorientation of management and research strategies based on molecular characterization and adapted personalized therapy. Resectable disease offers new opportunities for translational research through functional imaging response evaluation and tumor tissue acquisition before and after neoadjuvant therapy. There is urgent need for clinical trials based on molecular profiling in pancreatic ductal adenocarcinoma. In this review we discuss opportunities and limitations of these new strategies, underlining the importance of tissue acquisition and integration of molecular biomarkers in future molecularly driven clinical trials.

Aim: To describe a poorly known endoscopic entity associated with portal hypertension, characterized by polypoid lesions either in the stomach or small intestine of patients with cirrhosis., Methods: Between 2003 and 2012, patients with cirrhosis and portal hypertension underwent endoscopic workup of portal hypertension in our endoscopy unit. The clinical expression, endoscopic features of these lesions, and their pathological characteristics are described., Results: A total of 1538 patients were included, among which 14 (0.9%) presented polypoid lesions; these patients had evidence of portal hypertension and had dilated capillaries in the lamina propria. Four patients presented with severe anaemia or melaena and required treatment. Propranolol was administered to three patients, and one patient needed a transjugular intrahepatic portosystemic shunt in order to control bleeding. For asymptomatic patients in whom polypoid lesions were resected, no recurrence of lesions was observed during follow-up gastroscopy (median 36 months, range 7-85 months)., Conclusion: Portal hypertension-associated gastric or small intestine polypoid lesions may be associated with a significant risk of bleeding and are responsive to adequate treatment of portal hypertension.

Microsatellite instability (MSI) phenotype occurs in approximately 15 to 24% of colorectal cancer (CRC) patients and may be sporadic or hereditary. It reflects a mutator phenotype in the tumor due to a lack of mismatch repair system. MSI is indeed one of the characteristics of CRCs occurring in Lynch syndrome and some sporadic cases. CRCs with MSI have a better prognosis than CRCs with microsatellite stability (MSS). This is explained partly by a more important anti-tumor immune response and by apoptosis of tumor cells in which mutations accumulate. However, in some retrospective studies, microsatellite instability in stage II CRCs was associated with no benefit to or even a deleterious effect of 5-FU alone based adjuvant therapy. Nevertheless, results obtained in stage III CRCs with FOLFOX type adjuvant chemotherapy remain favorable in retrospective studies.

The management of gastro-entero-pancreatic neuroendocrine tumours is evolving thanks to new TNM-classification, diagnostic and staging procedures and new therapeutic options. Targeting new pathways, mostly angiogenesis, development of novel agents is under way and opens new perspectives in controlling the evolution of these tumours and possibly changing their management. In parallel, new functional imaging techniques and biomolecular markers will be developed to provide adequate tools for the assessment of tumor response according to therapeutic intervention on angiogenesis, proliferation and apoptosis. This paper reviews the potential role of new investigational targeted agents which will likely become the backbone of future therapy of neuroendocrine tumors.

Background & Aims: Endotherapy for patients with painful chronic pancreatitis (CP) gives early and midterm clinical results comparable with those of conventional surgery. The authors evaluated long-term clinical outcome after endoscopic pancreatic ductal drainage, focusing on pain and pancreatic endocrine/exocrine functions., Methods: Of 110 patients with painful CP endoscopically treated between October 1987 and December 1989, 56 long-surviving patients were followed-up for 14.4 years (SD, .6 y); 40 patients died and 14 patients were lost to follow-up evaluation. Technical results included decreased ductal dilation and stone clearance. Clinical results included the rate of hospitalizations for pain before and after endotherapy, the need for surgery, the course of endocrine/exocrine insufficiencies, and late mortality., Results: Complete or partial technical success initially was obtained in 48 of 56 long-surviving patients. Long-term clinical success (< or =5 hospitalizations for pain during follow-up evaluation, without surgery) was obtained for 37 of 56 patients. At a mean follow-up time of 14.4 years, 44 patients had avoided surgery and the annual rate of hospitalizations for pain decreased significantly (before endotherapy: 0.98 [+/-1.36] vs 0.40 [+/-0.51] for the 3 years thereafter vs 0.14 [+/-0.22] for the last 11 years of follow-up evaluation; P < .001). Short duration of disease before initial therapy and absence of smoking at the last follow-up evaluation were associated with long-term clinical success., Conclusions: Endotherapy provides long-term benefits for about two thirds of patients with painful CP. Good clinical outcome was associated with cessation or absence of smoking, whereas alcohol abuse increased the risks for diabetes mellitus, steatorrhea, and mortality.