田口 昌延

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is frequently associated with diabetes mellitus (DM), and their prognosis remains particularly poor. Metformin, a widely used antidiabetic agent, has demonstrated anti-tumor effects through multiple mechanisms and has been associated with improved outcomes in various malignancies. In this study, we investigated retrospectively survival outcomes and intra-tumoral infiltration patterns of various immune cells in diabetic patients who underwent curative resection of PDAC, comparing those who received metformin with those who did not. METHODS: A total of 65 diabetic patients who underwent curative resection for invasive PDAC were retrospectively analyzed. Among them, 17 patients received metformin, while 48 did not. Recurrence-free survival (RFS) and overall survival (OS) were compared between the two groups. Following propensity score matching, tumor-infiltrating CD3(+) and CD8(+) T cells were assessed by immunohistochemistry (IHC), and their densities were compared between metformin users and non-users. RESULTS: Patients in the metformin group showed significantly prolonged RFS [hazard ratio (HR) =0.42, P=0.03] and OS (HR =0.421, P=0.03) compared to those in the non-metformin group. Multivariate analysis identified metformin use as an independent prognostic factor for both RFS (HR =0.40, P=0.02) and OS (HR =0.21, P=0.02). The survival benefit of metformin was particularly evident in patients who underwent upfront surgery, whereas not significant in those who received neoadjuvant therapy. Immunohistochemical analysis revealed a significantly higher density of CD8(+) T cells (650.7 vs. 269.9/mm2, P<0.001) with an increased CD8/CD3 ratio in resected tumors from metformin-treated patients compared to non-users (58.9% vs. 44.8%, P<0.001). This trend was kept in patients who underwent upfront surgery, while less pronounced in patients treated with neoadjuvant therapy. CONCLUSIONS: Metformin may enhance the infiltration of cytotoxic CD8(+) T cells into the tumor microenvironment and improve the prognosis of diabetic patients with PDAC, particularly in those undergoing upfront surgical resection.

INTRODUCTION: Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality worldwide. While curative resection offers the best chance for long-term survival, the high postoperative recurrence rate suggests a persistent need for effective perioperative therapies. We investigated a multimodal approach, combining sequential lenvatinib with transarterial chemoembolization (TACE), as a presurgical treatment (PST) for resectable HCC. METHODS: This retrospective study included 19 patients with technically resectable HCC who underwent the PST protocol followed by surgery between March 2022 and September 2024. The protocol involved four phases: Pre-TACE lenvatinib administration (Pre-LEN), TACE, Post-TACE lenvatinib administration, and surgery. We assessed the feasibility, safety, and pathological response of the protocol. Liver function was evaluated using the albumin-bilirubin (ALBI) score, modified ALBI (mALBI) grade, and tumor response was assessed using the Response Evaluation Criteria in Cancer of the Liver (RECICL). RESULTS: The PST protocol demonstrated high efficacy and safety. The median tumor reduction rate was 22.9%, and the median pathological tumor necrosis rate was 95%. The preoperative overall RECICL response was a complete response in 84.2% of patients. With a median follow-up of 22 months, the 2-year recurrence-free survival rate was 84.6%, and the overall survival rate was 100%. A significant association was found between mALBI grade and the decision to proceed with surgery at two time points: Pre-LEN (p = 0.023) and before surgery (p = 0.006). CONCLUSION: Presurgical sequential lenvatinib-TACE therapy is a feasible and safe strategy for resectable HCC. This protocol achieved a high pathological response and favorable survival outcomes, suggesting that it may mitigate the risk of early recurrence. Our findings highlight the importance of mALBI grade monitoring for patient selection and provide a rationale for larger, prospective studies.