Koichi Suyama

Involvement of autophagy in trypsinogen activation within the pancreatic acinar cells

Autophagy is mostly a nonselective bulk degradation system within cells. Recent reports indicate that autophagy can act both as a protector and killer of the cell depending on the stage of the disease or the surrounding cellular environment (for review see Cuervo, A.M. 2004. Trends Cell Biol. 14:70–77). We found that cytoplasmic vacuoles induced in pancreatic acinar cells by experimental pancreatitis were autophagic in origin, as demonstrated by microtubule-associated protein 1 light chain 3 expression and electron microscopy experiments. To analyze the role of macroautophagy in acute pancreatitis, we produced conditional knockout mice lacking the autophagy-related 5 gene in acinar cells. Acute pancreatitis was not observed, except for very mild edema in a restricted area, in conditional knockout mice. Unexpectedly, trypsinogen activation was greatly reduced in the absence of autophagy. These results suggest that autophagy exerts devastating effects in pancreatic acinar cells by activation of trypsinogen to trypsin in the early stage of acute pancreatitis through delivering trypsinogen to the lysosome.

C/EBP homologous protein is crucial for the acceleration of experimental pancreatitis.

C/EBP homologous protein (CHOP) is one of the main mediating factors in the ER stress pathway. To elucidate the role of the ER stress-CHOP pathway in experimental pancreatitis, wild-type (Chop(+/+)) and Chop deficient (Chop(-/-)) mice were administered cerulein, a cholecystokinin analogue, or both cerulein and lipopolysaccharide (LPS). In cerulein-induced acute pancreatitis, ER stress, serum amylase elevation and histological interstitial edema were induced. However, there was no remarkable activation downstream of the CHOP pathway regardless of the presence or absence of CHOP. Whereas, in the cerulein and LPS model, inflammation-associated caspases (caspase-11, caspase-1) and IL-1beta, but not apoptosis-associated caspases, were activated. In Chop(-/-) mice, the expression levels of these mediators returned to basal levels resulting in a milder pancreatitis and decreased serum amylase level. These results indicated that the ER stress-CHOP pathway has a pivotal role in the acceleration of pancreatitis through the induction of inflammation-associated caspases and IL-1beta.

Relationship of strain-dependent susceptibility to experimentally induced acute pancreatitis with regulation of Prss1 and Spink3 expression

To analyze susceptibility to acute pancreatitis, five mouse strains including Japanese Fancy Mouse 1 (JF1), C57BL/6J, BALB/c, CBA/J, and C3H/HeJ were treated with either a cholecystokinin analog, cerulein, or a choline-deficient, ethionine-supplemented (CDE) diet. The severity of acute pancreatitis induced by cerulein was highest in C3H/HeJ and CBA/J, moderate in BALB/c, and mildest in C57BL/6J and JF1. Basal protein expression levels of the serine protease inhibitor, Kazal type 3 (Spink3) were higher in JF1 and C57BL/6J mice than those of the other three strains under normal feeding conditions. After treatment with cerulein, expression level of Spink3 increased remarkably in JF1 and mildly in C57BL/6J, BALB/c, CBA/J, and C3H/HeJ strains. Increased proteinase, serine, 1 (Prss1) protein expression accompanied by increased trypsin activity with cerulein treatment was observed in susceptible strains such as CBA/J and C3H/HeJ. Similar results were obtained with a CDE diet. In the 3 kb Spink3 promoter region, 92 or 8 nucleotide changes were found in JF1 or C3H vs C57BL/6J, respectively, whereas in the Prss1 promoter region 39 or 46 nucleotide changes were found in JF1 or C3H vs C57BL/6J, respectively. These results suggest that regulation of Prss1 and Spink3 expression is involved in the susceptibility to experimentally induced pancreatitis. The JF1 strain, which is derived from the Japanese wild mouse, will be useful to examine new mechanisms that may not be found in other laboratory mouse strains.

Significance of endothelial molecular markers in the evaluation of the severity of acute pancreatitis

PurposeIn acute pancreatitis, neutrophil elastase is secreted which damages the endothelial cells. This study was designed to demonstrate that the plasma levels of soluble E-selectin (sES) and soluble thrombomodulin (sTM) serve as endothelial molecular markers; the former is used as an endothelial activation marker, while the latter, as an endothelial injury marker.MethodsA total of 27 acute pancreatitis patients were enrolled. The plasma sES and sTM levels were assessed for 10 days after admission.ResultsThe plasma sES levels of all the patients in different disease stages were elevated at the time of admission day (day 1). The plasma sTM levels correlated with the severity and prognosis of acute pancreatitis. The required cutoff to predict a fatal outcome was set as 32 Teijin Units (TU)/ml (sensitivity, 80%; specificity, 91%). On day 1, the mortality rate of patients with the sTM levels of ≥32 TU/ml (67%, 4/6) was significantly higher than of those with the sTM levels of <32 TU/ml (5%, 1/21).ConclusionThese results indicated that (1) the activation of the vascular endothelial cells and the resultant increase in the plasma sES levels might be evoked in all disease stages, and (2) an elevation of the plasma sTM level, which indicates the presence of vascular endothelial injury, might therefore result in a poor prognosis.

Recent Advances in Targeting the EGFR Signaling Pathway for the Treatment of Metastatic Colorectal Cancer

Outcomes for metastatic colorectal cancer (mCRC) patients have been improved by treatment with anti-epidermal growth factor receptor (anti-EGFR) antibodies, particularly when combined with predictive biomarkers to select patients lacking RAS mutations. New technologies such as liquid biopsy and next-generation sequencing have revealed that potential mechanisms of resistance to anti-EGFR therapies act through acquired mutations of KRAS and the EGFR ectodomain. Mutations in cross-talking molecular effectors that participate in downstream EGFR signaling are also negative predictors for anti-EGFR therapy. In the current review, we describe recent advances in anti-EGFR therapy and discuss new treatment strategies to target downstream RAS-MAPK signaling in mCRC.

Recanalization of Obstructed Choledochojejunostomy Using the Magnet Compression Anastomosis Technique

Recanalization of Obstructed Choledochojejunostomy Using the Magnet Compression Anastomosis Technique

Chemotherapy for Patients with Renal Dysfunction

Significant progress has been made in systemic chemotherapies for advanced cancer patients. Historically, the main anticancer drugs were cytotoxic agents, but recently, other agents such as molecularly-targeted therapies and immune checkpoint inhibitors have been introduced into clinical practice, and these agents have begun to achieve mainstream usage. The rapid development of novel anticancer drugs has forced clinicians to consider the effects of these chemotherapy agents in high-risk patients with liver or renal dysfunction, those undergoing dialysis and the elderly. Currently, there are no clear guidelines describing the best practices for anticancer drug administration in patients with renal dysfunction. However, the theory that renal dysfunction affects the ability of patients to cope with anticancer therapies is understandable compared with liver dysfunction or other risk factors. That is why there has always been an indication for dose adjustments for patients with renal dysfunction. In this review, recommended dose adjustments in cases of renal dysfunction are discussed based on the latest information on anticancer drugs.

Prognostic value of Programmed death-ligand 1 expression in patients with stage III colorectal cancer

The programmed death‐1/programmed death‐ligand 1 (PD‐L1) pathway is a negative feedback pathway that suppresses the activity of T cells. Previous studies reported that high PD‐L1 expression on tumor cells (TC) was associated with poor survival in patients with colorectal cancer; however, the prognostic evaluation of these studies was limited because they included patients at various disease stages. The purpose of the present study was to evaluate the relationship between PD‐L1 status in the immune microenvironment and the clinicopathological features of stage III colorectal cancer. Two hundred and thirty‐five patients were included in the analysis. PD‐L1 expression on TC and tumor‐infiltrating mononuclear cells (TIMC) was evaluated by immunohistochemistry. The median follow‐up of thisi study was 52.9 months. A total of 8.1% of stage III colorectal cancer showed high PD‐L1 expression on TC and 15.3% showed high PD‐L1 expression on TIMC. Patients with high PD‐L1 expression on TC had significantly shorter disease‐free survival (DFS) than patients with low expression (hazard ratio [HR] 2.36; 95% confidence interval [CI], 1.21–4.62; P = 0.012). In addition, patients with high PD‐L1 expression on TIMC were associated with longer DFS than patients with low expression (HR 0.40; 95% CI, 0.16–0.98; P = 0.046). These findings suggest that PD‐L1 expression status may be a new predictor of recurrence for stage III colorectal cancer patients and highlight the necessity of evaluating PD‐L1 expression on TC and TIMC separately in the tumor microenvironment.

Neuroendocrine tumor of the rectum.

The authors report a case of a neuroendocrine tumor of the rectum. A 57-year-old man was revealed to have a large tumor of the rectum with invasion to the urinary bladder and seminal capsule. After resection, the tumor was revealed to be composed of neuroendocrine cells. Adjuvant chemotherapy using cisplatin and camptothecin-11 was completed, and the patient was without recurrence 6 months after surgery.

Clinical features of lenvatinib treatment in elderly patients with advanced thyroid cancer

Until recently, there had not been an effective systemic chemotherapy for advanced differentiated thyroid carcinoma (DTC); lenvatinib, a multi-tyrosine kinase inhibitor, has been proven effective for DTC, but has also been revealed to have adverse side effects including hypertension, hand-foot syndrome (HFS) and diarrhea. There have been few clinical studies focused on the characteristics, safety concerns or precautions for lenvatinib treatment in elderly patients. The present study administered lenvatinib to 18 patients with DTC in Kumamoto University Hospital (Kumamoto, Japan), with 9 patients in both the younger group (<75 years old) and elderly group (≥75 years old). The median maximum systolic blood pressure (sBP) was significantly different between the two groups (158 mmHg in the younger group vs. 173 mmHg in the elderly group; P=0.042). There were no significant differences in median maximum diastolic blood pressure (94 vs. 95 mmHg; P=1.00), median degree of sBP elevation (43 vs. 55 mmHg; P=0.199) or median days until hypertension diagnosis (2.11 vs. 2.33 days; P=0.436). There were also no significant differences in other toxicities (HFS, proteinuria or diarrhea). In conclusion, lenvatinib should be introduced carefully to elderly patients with DTC, as they tend to present with hypertension during treatment. However, there were no differences in other toxicities between the younger and elderly groups; lenvatinib was fully tolerated in patients with DTC >75 years old.