Diabetes mellitus impacts on expression of DNA mismatch repair protein PMS2 and tumor microenvironment in pancreatic ductal adenocarcinoma

ABSTRACT Aims/Introduction The mismatch repair (MMR) protein recognizes DNA replication errors and plays an important role in tumorigenesis, including pancreatic ductal adenocarcinoma (PDAC). Although PMS2, a MMR protein, is degraded under oxidative stress, the effects of diabetes are still unclear. Herein, we focused on whether diabetes affected MMR protein expression in PDAC. Materials and Methods Tissues from 61 surgically resected PDAC subjects were clinicopathologically analyzed. Immunohistochemical analysis was performed for MMR protein expression, oxidative stress, and immune cell infiltration. The change of MMR protein expression was assessed in PDAC cell lines under stimulation with 25 mM glucose and 500 μM palmitic acid. Survival curves were analyzed by the Kaplan–Meier method with the log‐rank test. Results Diabetes complicated with dyslipidemia significantly decreased the expression of PMS2 in PDAC tissues with an inverse correlation with the degree of oxidative stress. Palmitic acid combined with high glucose induced degradation of PMS2 protein, enhancing oxidative stress in vitro. CD8+ T‐cell infiltration was associated with a short duration of type 2 diabetes (≤4 years) and a low expression of PMS2 in PDAC tissues, while CD163+ tumor‐associated macrophage infiltration was increased with a long duration of diabetes (>4 years). A short duration of diabetes exhibited a better prognosis than nondiabetic subjects with PDAC (P < 0.05), while a long duration of diabetes had a worse prognosis (P < 0.05). Conclusions The different phases of diabetes have a major impact on PDAC by altering PMS2 expression and the tumor immune microenvironment, which can be targeted by an immune checkpoint inhibitor

Hepatocellular Carcinoma Rupture after Introducing Lenvatinib : An Autopsy Case Report

Hepatocellular carcinoma (HCC) hemorrhaging/rupture is a rare adverse effect of lenvatinib, and only limited pathological examinations have been reported. This report presents the case of a 69-year-old man who suffered from cardiac arrest and died 7 days after starting lenvatinib treatment for HCC, with an autopsy subsequently performed. Crack and coagulated blood were observed in the largest tumor. Pathologically, the hemorrhaging area was scattered in nearly all of the HCC lesions, regardless of tumor differentiation. This pathological feature is unusual in normal HCC. Thus, it is believed to have been the effect of lenvatinib

Dual epigenetic changes in diabetes mellitus‐associated pancreatic ductal adenocarcinoma correlate with downregulation of E‐cadherin and worsened prognosis

Abstract Diabetes mellitus (DM) is a risk factor for pancreatic ductal adenocarcinoma (PDAC) that promotes the promoter methylation of CDH1. It is still unclear whether DM can exert other epigenetic effects, such as altering microRNA (miR) expression, in PDAC. The expression of miR‐100‐5p is known to be changed in DM patients and can suppress the expression of E‐cadherin. In this study, the correlation between DM status and dual epigenetic changes was evaluated in PDAC specimens from patients who underwent radical surgical resection. A total of 132 consecutive patients with PDAC were clinicopathologically evaluated. E‐cadherin and nuclear β‐catenin expression was measured using immunohistochemistry. DNA and miRs were extracted from the main tumor site on formalin‐fixed paraffin‐embedded tissue sections. TaqMan miR assays were applied to assess miR‐100‐5p expression. Bisulfite modification was conducted on the extracted DNA, which was then subjected to methylation‐specific polymerase chain reaction. Immunohistochemistry revealed that decreased E‐cadherin expression and increased nuclear β‐catenin expression were significantly associated with DM and poor tumor cell differentiation. The presence of long‐duration DM (≥3 years)  was a significant factor contributing to CDH1 promoter methylation (p < 0.01), while miR‐100‐5p expression was proportionally correlated with the preoperative HbA1c level (R = 0.34, p < 0.01), but not the duration of DM. The subjects with high miR‐100‐5p expression and CDH1 promoter methylation showed the highest level of vessel invasion and prevalence of tumor size ≥30 mm. PDAC subjects with dual epigenetic changes showed poorer overall survival (OS) than those with a single epigenetic change. miR‐100‐5p expression ≥4.13 and CDH1 promoter methylation independently predicted poor OS and disease‐free survival (DFS) in the multivariate analysis. OS and DFS worsened in DM subjects with both HbA1c ≥ 6.5% and DM duration ≥3 years. Thus, DM is associated with two modes of epigenetic change by independent mechanisms and worsens prognosis