Rony Avritscher

New strategies combining yttrium 90 ( ⁹⁰ Y) radioembolization and immune checkpoint inhibitor therapy for treatment of advanced-stage hepatocellular carcinoma show promising safety and improved tumor response rates, with ⁹⁰ Y radioembolization modulating the tumor immune microenvironment and enhancing responsiveness to immunotherapy.

Introduction Hepatocellular carcinoma (HCC) is the most common primary liver cancer and the fifth most common cancer worldwide. For patients with unresectable, localized, intermediate-stage HCC, the standard treatment is transarterial chemoembolization (TACE). Methods Given the recent advances in systemic treatments for HCC with immunotherapy and targeted therapies, several studies have explored the potential benefits of combining TACE with systemic therapy, owing to the possible synergistic effects. This review analyzes recent clinical studies of patients with unresectable HCC who received TACE in combination with different classes of systemic therapies. Conclusion Collectively, these studies suggest that combining TACE with systemic therapy may enhance treatment response and improve survival outcomes.

Supplementary Table S1. Representativeness of Study Participants.

Supplementary File S1. Patient Eligibility.

Mucosal melanoma, a rare subtype of melanoma affecting mucosal surfaces, presents significant challenges in diagnosis and treatment, particularly due to its low programmed death-ligand 1 (PD-L1) expression and reduced response to immune checkpoint inhibitors (ICIs). This case report describes a 58-year-old woman with metastatic nasal mucosal melanoma initially resistant to neoadjuvant ipilimumab and nivolumab. After undergoing hepatic transcatheter arterial embolization, she experienced an unexpected abscopal effect, where distant metastases showed near-complete resolution despite prior lack of response to immunotherapy. The patient’s disease initially progressed despite two cycles of ICI treatment, and further immunotherapy with nivolumab and relatimab did not improve her condition. Subsequently, after bland embolization of a dominant hepatic mass, the patient received re-challenged combination immunotherapy with ipilimumab and nivolumab, leading to significant regression in metastatic sites including the liver, lungs, lymph nodes, and bones. This response contrasts with prior reports and highlights a potential mechanism by which embolization therapies may alter the immune microenvironment and enhance the efficacy of immunotherapy. The abscopal effect observed following local hepatic embolization may be attributed to tumor-induced immune activation, which is further amplified by ICI treatment. This case underscores the potential for integrating local embolization with immunotherapy to overcome resistance in metastatic melanoma, particularly in mucosal subtypes. Further research is necessary to elucidate the immune mechanisms underlying these responses and to optimize treatment strategies for melanoma patients.

Objective This study evaluated the prognostic value of synthetic tumor extracellular volume fraction (ECV) and its association with somatic gene alternations in patients with colorectal liver metastases (CRLM) receiving neoadjuvant chemotherapy. Methods This retrospective single-center study included patients undergoing curative hepatectomy after neoadjuvant chemotherapy for CRLM (2013–2020). Contrast-enhanced computed tomography (CT) studies obtained after neoadjuvant chemotherapy were used to calculate synthetic ECV and synthetic hematocrit by linear regression analysis. Patients were grouped according to synthetic ECV cutoff point based on the Youden index. Multivariate analyses were performed with Cox regression models to analyze the prognostic factors of overall survival (OS) and recurrence-free survival (RFS). Results A total of 209 patients (median age 56 years, 119 men) were enrolled. Synthetic ECV correlated well with conventional ECV (r = 0.996, p < 0.0001) with minimal bias, according to the Bland–Altman analysis (bias = 0.007). The optimal synthetic ECV cutoff point was determined to be 21%, with 115 patients having high ECV and 94 low ECV. Multivariable analysis for predicting high ECV demonstrated significant associations with synchronous CRLM, anti-VEGF agent-containing regimen, and RAS-BRAF mutation (p = 0.022, < 0.001, and = 0.003, respectively). OS and RFS were significantly higher in the high ECV group compared to the low ECV group (p = 0.019 and p = 0.015, respectively). High ECV was independently associated with improved OS (HR 0.55, 95% CI 0.34–0.91) and RFS (HR 0.71, 95% CI 0.52–0.97). Conclusions Synthetic ECV can help predict OS and RFS in patients undergoing curative-intent CRLM resection after neoadjuvant chemotherapy and could be a useful imaging biomarker to stratify risk. Key Points Question There is a need for a biomarker predictive of treatment response after neoadjuvant chemotherapy, prior to curative-intent colorectal liver metastases. Findings Synthetic extracellular volume fraction can help predict overall and recurrence-free survival and is associated with somatic gene alterations. Clinical relevance Prognostic markers of response to neoadjuvant chemotherapy in curative-intent colorectal liver metastases include extracellular volume fraction. Synthetic extracellular volume fraction obviates the need for hematocrit; a simplification that is expected to streamline routine clinical practice. Graphical Abstract

CPRs to TTI-101 monotherapy in patients with ovarian and gastric cancers. A, The patient with ovarian cancer (76-year-old female) achieved a 61% decrease in the sum of target tumor diameter with a TTF of 8 months. The patient with gastric cancer (73-year-old male) experienced a 38% reduction in the sum of target tumor size with a TTF of 7 months. PET/CT scans demonstrate sample target tumor regression from baseline to on-treatment. B, cPRs in patients with HCC treated with TTI-101 monotherapy. Patient A (56-year-old male) achieved a 42% reduction in the sum of target tumor size as BOR with an 11-month TTF, patient B (61-year-old male) experienced a 66% reduction with a TTF of 14 months, and patient C (40-year-old female) showed a 45% reduction with a TTF of 4 months. These responses illustrate the potential efficacy of TTI-101 in heavily pretreated patients with HCC.

Best response to TTI-101 treatment per RECIST v1.1.

Summary of TRAEs reported in >10% of patients treated with TTI-101 monotherapy.

Study design and tumor response to TTI-101 monotherapy. A, Study design outlining the dose-escalation and dose-expansion phases. The dose-escalation phase involved advanced solid tumors across four DLs (DL1–DL4), with dose expansion at the RP2D for HCC and other solid tumors. Different TTI-101 formulations (F1, F2, and F3) were used to optimize delivery and tolerability. B, Spider plots depicting individual tumor responses to TTI-101 treatment over time. Each line represents a patient’s sum of target tumor response, with changes in tumor size from baseline measured at various time points. The plot illustrates the variability in response across patients and DLs. C, Waterfall plot showing the best response by RECIST criteria for patients treated with TTI-101 monotherapy. Bars represent the maximum reduction in the sum of target tumor size for each patient, categorized as a PR, SD, or progressive disease. Tumor types are indicated, highlighting the distribution of responses across HCC and other solid tumors.