Immune checkpoint inhibitor-based combination therapy has demonstrated high objective response rates in patients with hepatocellular carcinoma (HCC) and may improve clinical outcomes as neoadjuvant or perioperative therapy. This study evaluated the efficacy and safety of nivolumab plus ipilimumab in patients with potentially resectable HCC and explored predictive biomarkers of treatment response. Eligible patients received nivolumab (3 mg/kg) plus ipilimumab (1 mg/kg) every 3 weeks. Tumor response was assessed after two and four treatment cycles. Patients then proceeded to curative surgery or alternative treatments according to clinical guidelines. Serial tumor and peripheral blood samples were collected for genomic and transcriptomic analyses and immune cell profiling. Among the 43 enrolled patients (men/women: 37/6; viral/non-viral: 41/2; Barcelona Clinic Liver Cancer stage A/B/C: 4/13/26; median tumor size: 8.7 cm), 24 underwent surgery, and eight achieved a major pathological response (>90% tumor necrosis). The estimated 4-year progression-free survival and overall survival rates were 44% (95% CI 28-59%) and 60% (95% CI 42-74%), respectively. Increased interferon-γ and tertiary lymphoid structure (TLS) signatures in resected tumors were associated with objective response. In a mouse liver cancer model, B-cell depletion abolished the efficacy of anti-programmed death-1 plus anti-cytotoxic T lymphocyte-associated protein 4 therapy, supporting the mechanistic role of TLS. Peripheral blood T-cell activation and exhaustion at baseline and post-immunotherapy, assessed using spectral flow cytometry and deep learning algorithms, correlated with response and survival. Neoadjuvant nivolumab plus ipilimumab followed by surgery is feasible and may improve long-term survival in patients with potentially resectable HCC. Immunotherapy-induced TLS formation is associated with enhanced antitumor immunity. Immune checkpoint inhibitor-based systemic therapy is now an integral component of the multidisciplinary management of patients with hepatocellular carcinoma. Findings from this single-arm clinical trial indicate that: i) neoadjuvant nivolumab plus ipilimumab followed by surgery is feasible and may improve long-term survival in patients with potentially resectable hepatocellular carcinoma; ii) immunotherapy-induced tertiary lymphoid structure formation is associated with enhanced antitumor immunity; iii) monitoring T-cell exhaustion in peripheral blood may aid in the prediction of response to immunotherapy. NCT03510871.

Introduction: The tumor microenvironments of different organs often differ and thus may affect the immunotherapy response. Objective: This study elucidated that the efficacy of programmed cell death protein-1 (PD-1) inhibitors varies across different metastatic sites among individuals with advanced hepatocellular carcinoma (HCC). Methods: We retrospectively analyzed treatment outcomes in advanced HCC patients receiving PD-1 inhibitors with or without a combination of tyrosine kinase inhibitors (TKIs). Both the overall response rate (ORR) and organ-specific response rate (OSRR) were assessed using Response Evaluation Criteria in Solid Tumors 1.1 criteria. A survival analysis and its predictors were determined using a multivariate analysis. Results: We analyzed 42 advanced HCC patients (median age: 58.0 years; 78.6% males). Thirty (71.4%) patients were sorafenib-experienced and 27 (64.3%) were administered a combination of TKIs. The ORR was 14.3% and the disease control rate was 33.3%. The median overall survival (OS) and progression-free survival (PFS) were 12.0 and 2.9 months, respectively. The OSRRs were 14.7, 23.8, 28.6, and 50.0% for the liver, lungs, lymph nodes, and vascular response, respectively. The multivariate analysis indicated that the vascular response was significantly associated with PFS. ECOG performance status was a significant independent predictor of OS. Conclusions: PD-1 inhibitors improved OS and PFS in advanced HCC patients. Their efficacies varied among the metastatic locations regardless of the combination of TKIs; in particular, a higher response in vascular metastases was correlated with a longer PFS. PD-1 inhibitors may deliver a synergistic benefit in patients undergoing traditional therapy and progression in other organs in vascular responders.

Advancement in systemic therapy, particularly immune checkpoint inhibitor (ICI)-based combination regimens, has transformed the treatment landscape for patients with advanced hepatocellular carcinoma (HCC). The advancement in systemic therapy also provides new opportunities of reducing recurrence after curative therapy through adjuvant therapy or improving resectability through neoadjuvant therapy. Improved recurrence-free survival by adjuvant or neoadjuvant ICI-based therapy has been reported in other cancer types. In this article, developments of systemic therapy in adjuvant and neoadjuvant settings for HCC were reviewed. The design of adjuvant and neoadjuvant therapy using ICI-based regimens and potential challenges of trial conduct and result analysis was discussed. Results from these trials may extend the therapeutic benefit of ICI-based systemic therapy beyond the advanced-stage disease and lead to a new era of multidisciplinary management for HCC.

Purpose: Tumor-associated macrophages (TAMs) originate from monocytes and differentiate into mature macrophages. The interaction between cancer cells and TAMs promotes tumor growth and suppresses immunosurveillance. However, this phenomenon has seldom been observed in ampullary cancer. Patients and Methods: TAMs in ampullary cancer were investigated using immunohistochemical (IHC) staining of cancer tissues. Bioinformatic analysis of data from the Gene Expression Omnibus (GEO) database revealed transforming growth factor-beta (TGF-β) signaling in ampullary cancer. The complementary DNA microarray of cancer was compared with adjacent normal duodenum and enzyme-linked immunosorbent assay of serum was used to verify TGF-β signaling in patients. The THP-1 cell line was activated in vitro to imitate M2 TAMs. ClueGo and CluePedia software were operated to simulate TGF-β-related networks in ampullary cancer. Results: The IHC study revealed that the majority of TAMs inside ampullary cancer were cluster of differentiation (CD)163⁺ cells and that the expression of mature CD68⁺ macrophages was correlated with advanced cancer stage. Bioinformatics analysis revealed that TGF-β and its downstream signaling were significantly upregulated. To verify our bioinformatics-derived predictions, we performed several experiments and demonstrated that increased TGF-β expression was detected in the cDNA microarray. Higher serum levels of TGF-β were correlated with fewer CD68⁺ and more inducible nitric oxide synthase macrophages in ampullary cancer. Treatment with TGF-β induced modulation of THP-1-derived macrophages. Conclusion: The present study demonstrates that TGF-β modulates macrophage activity in ampullary cancer. Targeting TGF-β could be an approach to activating immunosurveillance.

The aim of the study was to use a previously proposed mask region–based convolutional neural network (Mask R-CNN) for automatic abnormal liver density detection and segmentation based on hepatocellular carcinoma (HCC) computed tomography (CT) datasets from a radiological perspective. Training and testing datasets were acquired retrospectively from two hospitals of Taiwan. The training dataset contained 10,130 images of liver tumor densities of 11,258 regions of interest (ROIs). The positive testing dataset contained 1,833 images of liver tumor densities with 1,874 ROIs, and negative testing data comprised 20,283 images without abnormal densities in liver parenchyma. The Mask R-CNN was used to generate a medical model, and areas under the curve, true positive rates, false positive rates, and Dice coefficients were evaluated. For abnormal liver CT density detection, in each image, we identified the mean area under the curve, true positive rate, and false positive rate, which were 0.9490, 91.99%, and 13.68%, respectively. For segmentation ability, the highest mean Dice coefficient obtained was 0.8041. This study trained a Mask R-CNN on various HCC images to construct a medical model that serves as an auxiliary tool for alerting radiologists to abnormal CT density in liver scans; this model can simultaneously detect liver lesions and perform automatic instance segmentation.

Solid organ transplant recipients have an increased risk of tuberculosis (TB). Due to the use of immunosuppressants, the incidence of TB among solid organ transplant recipients has been consistently reported to be higher than that among the general population. TB frequently develops within the first year after transplantation when a high level of immunosuppression is maintained. Extrapulmonary TB and disseminated TB account for a substantial proportion of TB among solid organ transplant recipients. Treatment of TB among recipients is complicated by the drug-drug interactions between anti-TB drugs and immunosuppressants. TB is associated with an increased risk of graft rejection, graft failure and mortality. Detection and management of latent TB infection among solid organ transplant candidates and recipients have been recommended. However, strategy to mitigate the risk of TB among solid organ transplant recipients has not yet been established in Taiwan. To address the challenges of TB among solid organ transplant recipients, a working group of the Transplantation Society of Taiwan was established. The working group searched literatures on TB among solid organ transplant recipients as well as guidelines and recommendations, and proposed interventions to strengthen TB prevention and care among solid organ transplant recipients.