西村 渉

BACKGROUND: Perihilar cholangiocarcinoma with large hepatic resection is associated with high risk for morbidity and mortality. To improve outcomes, assessment of remnant liver function is crucial. METHODS: A total of 70 patients with perihilar cholangiocarcinoma were examined retrospectively. Liver function was evaluated <1 month preoperatively by hepatic clearance of remnant liver using 99mTc-galactosyl serum albumin (GAS) scintigraphy and computed tomography, and clinicopathological data and outcomes were analyzed in comparison GSA scintigraphy with liver function test based on computed tomography volumetry. RESULTS: There was no postoperative 90-day mortality, with 10 patients of posthepatectomy liver failure (PHLF) Grade A, 10 of Grade B, and 1 of Grade C. Area under the curve of receiver operating curve showed better prediction power for PHLF compared to remnant liver volume/body surface area or future liver remnant/body weight, especially in patients with incomplete change of liver function. In univariable analysis, <150 ml/min ml/min cutoff of hepatic clearance of remnant liver and >1750 ml intra-operative blood loss were significant risk factors for PHLF. In multivariable analysis, <150 ml/min cutoff was a significant risk factor for PHLF. The area under the curve of hepatic clearance of remnant liver indicated better predictivity in patients with incomplete change of liver function compared with complete change of liver function. CONCLUSIONS: The hepatic clearance of remnant liver may have predictive power in patients with incomplete changes in liver function compared to computed tomography-based methods. Preoperative measurement of hepatic clearance of remnant liver may assist in risk stratification for surgical management.

BACKGROUND: This study aimed to elucidate the clinical impact of osteopenia on the recurrence of colon cancer liver metastases. METHODS: Patients with colon cancer liver metastases (N = 186) undergoing hepatectomy at Jichi Medical University Hospital between March 2006 and March 2020 were examined retrospectively. Computed tomography (CT) scans on the 11th vertebra within 3 months of surgery assessed bone mineral density (BMD). Age-adjusted BMD determined osteopenia presence. Kaplan-Meier method with a log-rank test estimated survival. Factors associated with survival were assessed using Cox's proportional hazards model after adjustment for confounders. RESULTS: Patients with osteopenia had shorter overall (p = 0.0001; 5-year overall survival, 51.8% vs 81.8%) and recurrence-free survival (p = 0.0008, 5-year recurrence-free survival: 26.3% vs 51.5%) than BMD-normal patients. In multivariable analysis, the risk factor for overall survival was osteopenia (Hazard ratio (HR) 3.79, 95% confidence interval (CI) 2.09-6.87, p = 0.001). Risk factors for recurrence were chemotherapy (HR 1.92, 95%CI 1.12-3.30, p = 0.002), tumor number (HR 1.51, 95%CI 1.02-2.27, p = 0.04), and osteopenia (HR 2.18, 95%CI 1.46-3.24 p = 0.001). Patients with osteopenia are more likely to develop lung metastases, and BMD-value reduction associated with KRAS mutation. CONCLUSION: Osteopenia may have prognostic significance in patients with liver metastases colorectal cancer.

BACKGROUND: The aim of this study was to elucidate the association of pancreatic fluid cytology with intrapancreatic recurrence of intraductal papillary mucinous neoplasms (IPMNs). MATERIALS AND METHODS: A total of 68 patients with IPMN who underwent pancreatectomy and obtained cytologic analysis of pancreatic fluid at Jichi Medical University Hospital were included in this study. Computed tomography scan and magnetic resonance cholangiopancreatography were performed preoperatively. Endoscopic retrograde cholangiopancreatography was used to obtain pancreatic fluid. The association of recurrence with variables was determined by logistic regression multivariate analysis. RESULTS: Class V cytology was found in 7/68 patients preoperatively. Metachronous intrapancreatic recurrences occurred in 6/68 patients, including one branched type, main pancreatic duct type in two and mixed pancreatic duct type in three. Four of seven patients with class V cytology developed intra-pancreatic recurrences as a new lesion. Class V cytology was significantly associated with intrapancreatic recurrence, compared to those with class IV or lower cytology. In univariate analysis, patients with pathological findings with high-grade dysplasia or adenocarcinoma (P = 0.0392, odds ratio (OR) 10.2, 95 % confidence interval (CI) 1.12-93.6) and class V pancreatic fluid cytology (P = 0.0005, OR 38.7, 95 % CI 4.94-302) were significant risk factors. In multivariate analysis, class V pancreatic fluid cytology was significantly associated with developing intrapancreatic recurrence (P = 0.0149, OR 22.7, 95 % CI 1.83-279). CONCLUSION: Preoperative class V pancreatic fluid cytology is associated with intra-pancreatic recurrence after resection of IPMN.

Insulin-dependent diabetes in patients with Wolfram syndrome (WS; OMIM 222300) has been linked to endoplasmic reticulum (ER) stress caused by WFS1 gene mutations. However, the pathological process of ER stress-associated β cell failure remains to be fully elucidated. Our results indicate loss of β cell lineage and subsequent dedifferentiation as the mechanisms underlying functional and mass deficits in WS. An immunohistochemical analysis of human pancreatic sections from deceased individuals with WS revealed a near-complete loss of β cells and subsequent decrease in α cells, suggesting loss of endocrine function. Wfs1-deficient mice displayed dysfunction, gradual loss, and dedifferentiation of β cells, leading to permanent hyperglycemia. Impairment of the β cell lineage was observed after weaning, leading to the mixed phenotype of insulin- and glucagon-producing cells in a subset of the lineage-traced β cells. Islets of Wfs1-deficient mice increased the number of dedifferentiated cells that maintained general endocrine features but were no longer reactive with antisera against pancreatic hormones. Mechanistically, Wfs1-null islets had a lower adenosine triphosphate content and impaired oxidative glycolysis, although mitochondrial oxidative function was maintained. The functional and metabolic alterations of WS β cells were recovered by deletion of thioredoxin-interacting protein (Txnip), an ER stress-induced protein up-regulated in Wfs1 deficiency. Txnip deletion preserved functional β cells and prevented diabetes progression in Wfs1-deficient mice. Together, this study deciphered pathological mechanisms of β cell dedifferentiation in β cell failure and has implications for Txnip inhibition in WS therapy.

A lack of social relationships is increasingly recognized as a type 2 diabetes (T2D) risk. To investigate the underlying mechanism, we used male KK mice, an inbred strain with spontaneous diabetes. Given the association between living alone and T2D risk in humans, we divided the non-diabetic mice into singly housed (KK-SH) and group-housed control mice. Around the onset of diabetes in KK-SH mice, we compared H3K27ac ChIP-Seq with RNA-Seq using pancreatic islets derived from each experimental group, revealing a positive correlation between single-housing-induced changes in H3K27ac and gene expression levels. In particular, single-housing-induced H3K27ac decreases revealed a significant association with islet cell functions and GWAS loci for T2D and related diseases, with significant enrichment of binding motifs for transcription factors representative of human diabetes. Although these H3K27ac regions were preferentially localized to a polymorphic genomic background, SNVs and indels did not cause sequence disruption of enriched transcription factor motifs in most of these elements. These results suggest alternative roles of genetic variants in environment-dependent epigenomic changes and provide insights into the complex mode of disease inheritance.