Jun-Gi Kim

Autophagy deficiency in beta cells leads to compromised unfolded protein response and progression from obesity to diabetes in mice

Aims/hypothesisThe unfolded protein response (UPR) in endoplasmic reticulum (ER) and autophagy are known to be related. We investigated the role of autophagy in UPR of pancreatic beta cells and the susceptibility of autophagy-deficient beta cells to the ER stress that is implicated in the development of diabetes.MethodsRat insulin promoter (RIP)-Cre+;autophagy-related 7 (Atg7)F/W mice were bred with ob/w mice to derive RIP-Cre+;Atg7F/F-ob/ob mice and to induce ER stress in vivo. GFP-LC3+-ob/ob mice were generated to examine in vivo autophagic activity. Real-time RT-PCR was performed to study the expression of the genes of the UPR machinery. Proteolysis was assessed by determining release of incorporated radioactive leucine.ResultsProduction of UPR machinery was reduced in autophagy-deficient beta cells, which was associated with diminished production of p85α and p85β regulatory subunits of phosphoinositide 3-kinase. Because of compromised UPR machinery, autophagy-deficient beta cells were susceptible to ER stressors in vitro. When mice with beta cell-specific autophagy deficiency, which have mild hyperglycaemia, were bred with ob/ob mice to induce ER stress in vivo, severe diabetes developed, which was accompanied by an increase in beta cell death and accumulation of reactive oxygen species. The increased demand for UPR present in obesity was unmet in autophagy-deficient beta cells. Autophagy level and autophagic activity were enhanced by lipid, while proteolysis was reduced.Conclusions/interpretationThese results suggest that autophagy is important for intact UPR machinery and appropriate UPR in response to lipid injury that increases demand for UPR. Autophagy deficiency in pancreatic beta cells may contribute to the progression from obesity to diabetes.

Multidimensional analysis of the learning curve for laparoscopic rectal cancer surgery.

BACKGROUND The need for an initial learning experience in laparoscopic colorectal cancer surgery has been well established. However, the inherent differences in the complexity and results of laparoscopic rectal cancer surgery, as compared to colon surgery, warrant a study to analyze the learning curve exclusively for rectal cancer resections. MATERIALS AND METHODS four hundred thirty-one patients operated on between April 1994 and March 2006 were analyzed retrospectively for changes in surgical outcomes according to case sequence. A multidimensional analysis was done, based on the following parameters: conversion to laparotomy, intraoperative complications, postoperative complications, reoperations, operative time, and transfusion volumes. Multiple statistical methods were used for evaluation of the learning curve, which included the cumulative sum (CUSUM) method, risk-adjusted CUSUM, moving average method, and analysis of variance (ANOVA). RESULTS The risk factors for conversion were prior abdominal surgery (hazard ratio, 2.52; 95% CI, 1.04-6.10; P = 0.04) and tumor size > or =3.5 cm (hazard ratio, 5.05; 95% CI, 1.95-13.08; P = 0.001). Risk-adjusted CUSUM analysis showed that case 61 was the peak change point for conversion. Postoperative complications occurred in 56 patients (13.0%), and the rate was associated significantly with case sequence (P < 0.001). The turning point in the CUSUM model occurred at case 79, and the complication rates decreased thereafter. Operative time and intraoperative transfusion volumes stabilized over cases 61-75 and declined thereafter. CONCLUSIONS Multidimensional analysis considering various surgical outcomes is necessary to evaluate the learning curve for laparoscopic rectal cancer surgery. The effective surgical learning curve was approximately 60-80 procedures in this series.

The survival rate and prognostic factors in 26 perforated colorectal cancer patients

PurposeThe treatment for perforated colorectal cancer is not easy and the prognosis for this disease is not so predictable. There are some controversies about performing radical operations because colorectal cancer perforation was considered as an advanced stage disease due to the possibility of tumor cell dissemination through the perforation site.MethodsWe selected and enrolled 26 patients with perforated colorectal cancers among the 1,227 patients who underwent operation for colorectal cancer. These cases were retrospectively analyzed by using their medical records and clinicopathological data.ResultsTwenty-eight cases (2.3%) with perforated colorectal cancers were studied and the overall operative mortality rate was 11%. The overall 5-year survival rate was 57.8% when excluding the operative mortality. The overall 5-year cancer-free survival rate was 52.8%. There were significant differences in the survival rate and the cancer-free survival rate between the stages (p=0.008 and p<0.001, respectively). A univariate analysis of the prognostic factors revealed that the number of the metastatic lymph nodes (p=0.018) and the perforation proximal to the cancer (p=0.005) were significantly correlated to worse survival, and the higher number of the metastatic lymph nodes was correlated to a poorer cancer-free survival rate (p<0.001).ConclusionFor the perforated colorectal cancers, the stage, the perforation proximal to the cancer, and the number of the metastatic lymph nodes were correlated, with the survival and the cancer-free survival as factors of a poor prognosis. The surgical approach selected for perforated colorectal cancer should be in line with the principles of an appropriate cancer operation because the clinical pathway of perforated colorectal cancer is similar to that of uncomplicated colorectal cancer.

Single incision vs conventional laparoscopic anterior resection for sigmoid colon cancer: a case-matched study

BACKGROUND The purpose of the study was to evaluate the safety and effects of single-incision laparoscopic anterior resection (SILAR) for sigmoid colon cancer by comparing it with conventional laparoscopic anterior resection (CLAR). METHODS Twenty-four patients who underwent SILAR between April 2010 and July 2011 were case matched 1:2 with patients who underwent CLAR, with respect to age, sex, body mass index, tumor location, and history of abdominal surgery. RESULTS Two patients in the SILAR group and 1 patient in the CLAR group experienced anastomotic leakage. The operative time was longer in the SILAR group than in the CLAR group (251 ± 50 vs 237 ± 49 minutes; P = .253). The number of harvested lymph nodes (19.6 ± 10.7 vs 20.8 ± 7.7; P = .630) was not different. The postoperative hospital stay was shorter in the SILAR group (7.1 ± 3.4 days) than in the CLAR group (8.1 ± 3.5 days) (P = .234). CONCLUSIONS On the basis of the early outcomes, we conclude that SILAR is feasible and safe. Moreover, the adequate lymph node harvest and free margins support the use of this procedure.

Preoperative chemoradiotherapy (CRT) followed by laparoscopic surgery for rectal cancer: predictors of the tumor response and the long-term oncologic outcomes.

PURPOSE We have evaluated the predictors of a tumor response to chemoradiotherapy (CRT) and the long-term oncologic outcomes of preoperative CRT and laparoscopic surgery for patients who suffer from rectal cancer. METHODS AND MATERIALS The study involved 274 patients with locally advanced rectal cancer and who had been treated with preoperative CRT and curative laparoscopic total mesorectal excision between January 2003 and January 2009. We assessed the long-term oncologic outcomes, in terms of recurrence and survival, of the treated patients. RESULTS Forty-two (15.3%) of the 274 patients had complete pathologic responses (pCR). The pre-CRT carcinoembryonic antigen level was the only significant predictor of a pCR on the multivariate analysis (p = 0.01). The overall survival at 5 years was 73.1%, with a mean survival period of 59.7 months (95% CI, 57.1-62.3). The disease-free survival at 5 years was 67.3% with a mean survival period of 54.7 months (95% CI, 51.7-57.8). The pCR group had a higher rate of overall survival at 5 years than did the non-pCR group, and the difference was significant (86.0% vs. 71.2%; hazard ratio = 0.87; 95% CI, 0.78-0.96; p = 0.03). The cumulative incidences of local and distant recurrences at 5 years were 5.8% and 28.3%, respectively. A total of 84.5% (234 of 274) of the patients had their anal sphincters preserved. Grade 3 or 4 acute and long-term toxic effects occurred in 22.2% and 8.4% of the patients, respectively. CONCLUSION Preoperative CRT and laparoscopic surgery seems safe and feasible with favorable long-term outcomes and a high rate of sphincter preservation for the patients with low-lying tumors of the rectum.

Tumor budding as a risk factor of lymph node metastasis in submucosal invasive T1 colorectal carcinoma: a retrospective study

BackgroundThis study was designed to identify risk factors for lymph node metastasis of early stage colorectal cancer, which was confirmed to a carcinoma that invaded the submucosa after radical resection.MethodsIn total, 55 patients revealing submucosal invasive colorectal carcinoma on pathology who underwent curative radical resection at the Department of Surgery, St. Vincent’s Hospital, The Catholic University of Korea from January 2007 to September 2010 were evaluated retrospectively. Tumor size, depth of submucosal invasion, histologic grade, lymphovascular invasion, tumor budding, and microacinar structure were reviewed by a single pathologist. Student t-test for continuous variables and Chi-square test for categorical variables were used for comparing the clinicopathological features between two groups (whether lymph node involvement existed or not). Continuous variables are expressed as the mean ± standard error while statistical significance is accepted at P < 0.05.ResultsThe mean age of 55 patients (34 males and 21 females) was 61.2 ± 9.6 years (range, 43–83). Histologically, eight (14.5%) patients had metastatic lymph node. In the univariate analysis, tumor budding (P = 0.047) was the only factor that was significantly associated with lymph node metastasis. Also, the tumor budding had a sensitivity of 83.3%, a specificity of 60.5%, and a negative predictive value of 0.958 for lymph node metastasis in submucosal invasive T1 colorectal cancer.ConclusionsThe tumor budding seems to have a high sensitivity (83.3%), acceptable specificity (60.5%), and a high negative predictive value (0.958). A close examination of pathologic finding including tumor budding should be performed in order to manage early CRC properly.

The nutritional risk is a independent factor for postoperative morbidity in surgery for colorectal cancer

Purpose The authors evaluate the prevalence of malnutrition and its effect on the postoperative morbidity of patients after surgery for colorectal cancer. Methods Three hundred fifty-two patients were enrolled prospectively. Nutritional risk screening 2002 (NRS 2002) score was calculated through interview with patient on admission. Clinical characteristics, tumor status and surgical procedure were recorded. Results The prevalence of patients at nutritional risk was 28.1 per cent according to the NRS 2002. The rate of postoperative complication was 27%. There was a significant difference in postoperative complication rates between patients at nutritional risk and those not at risk (37.4% vs. 22.9%, P = 0.006). Nutritional risk was identified as an independent predictor of postoperative complications (odds ratio, 3.05; P = 0.045). Nutritional risk increased the rate of anastomotic leakage (P = 0.027) and wound infection (P = 0.01). Conclusion NRS may be a prognostic factor for postoperative complication after surgery for colorectal cancer. A large scaled prospective study is needed to confirm whether supplementing nutritional deficits reduces postoperative complication rates.

The diagnostic criteria for right colonic diverticulitis: prospective evaluation of 100 patients

Background and aimsIn this study, we evaluate prospective diagnostic criteria and propose a clinical scoring system for the evaluation of patients suspected to have right colonic diverticulitis (RCD) prospectively.Patients and methodsOne hundred adult patients, who were clinically suspected to have appendicitis or RCD, and in whom we were not able to preoperatively rule out appendicitis, were examined prospectively. Patients were scored upon clinical presentation based on major diagnostic criteria included (1) no migration pain to the right lower quadrant; (2) a leukocyte count <10,000/mm3; (3) lateralized abdominal pain, and (4) a history of right colonic diverticulum (two points each). Minor diagnostic criteria (one point each) included (1) a history of right lower quadrant abdominal pain; (2) no symptoms of nausea or vomiting; (3) symptoms of constipation or diarrhea, and (4) abdominal pain for at least seven days. For patients in whom the diagnostic score exceeded two points, a contrast enhanced computed tomography (CT) scan of the abdomen was performed.ResultsThirteen patients had a final diagnosis of RCD. These diagnostic criteria demonstrated a sensitivity of 85%, a specificity of 68%, a positive predictive value of 28%, a negative predictive value of 97%, and a diagnostic accuracy of 70%. Among the 38 patients examined with CT, diagnoses for acute diverticulitis included nine true positives, 26 true negatives, two false positives, and one false negative.ConclusionPerforming CT scans after application of these diagnostic criteria gave a superior preoperative diagnostic rate for patients with RCD.

Preoperative Short-Course Concurrent Chemoradiation Therapy Followed by Delayed Surgery for Locally Advanced Rectal Cancer: A Phase 2 Multicenter Study (KROG 10-01)

PURPOSE A prospective phase 2 multicenter trial was performed to investigate the efficacy and safety of preoperative short-course concurrent chemoradiation therapy (CRT) followed by delayed surgery for patients with locally advanced rectal cancer. METHODS AND MATERIALS Seventy-three patients with cT3-4 rectal cancer were enrolled. Radiation therapy of 25 Gy in 5 fractions was delivered over 5 consecutive days using helical tomotherapy. Concurrent chemotherapy was administered on the same 5 days with intravenous bolus injection of 5-fluorouracil (400 mg/m(2)/day) and leucovorin (20 mg/m(2)/day). After 4 to 8 weeks, total mesorectal excision was performed. The primary endpoint was the pathologic downstaging (ypStage 0-I) rate, and secondary endpoints included tumor regression grade, tumor volume reduction rate, and toxicity. RESULTS Seventy-one patients completed the planned preoperative CRT and surgery. Downstaging occurred in 20 (28.2%) patients, including 1 (1.4%) with a pathologic complete response. Favorable tumor regression (grade 4-3) was observed in 4 (5.6%) patients, and the mean tumor volume reduction rate was 62.5 ± 21.3%. Severe (grade ≥3) treatment toxicities were reported in 27 (38%) patients from CRT until 3 months after surgery. CONCLUSIONS Preoperative short-course concurrent CRT followed by delayed surgery for patients with locally advanced rectal cancer demonstrated poor pathologic responses compared with conventional long-course CRT, and it yielded considerable toxicities despite the use of an advanced radiation therapy technique.

miRNA-30a-5p-mediated silencing of Beta2/NeuroD expression is an important initial event of glucotoxicity-induced beta cell dysfunction in rodent models

Aims/hypothesisThe loss of beta cell function is a critical factor in the development of type 2 diabetes. Glucotoxicity plays a major role in the progressive deterioration of beta cell function and development of type 2 diabetes mellitus. Here we demonstrate that microRNA (miR)-30a-5p is a key player in early-stage glucotoxicity-induced beta cell dysfunction.MethodsWe performed northern blots, RT-PCR and western blots in glucotoxicity-exposed primary rat islets and INS-1 cells. We also measured glucose-stimulated insulin secretion and insulin content. In vivo approaches were used to evaluate the role of miR-30a-5p in beta cell dysfunction.ResultsmiR-30a-5p expression was increased in beta cells after exposure to glucotoxic conditions, and exogenous miR-30a-5p overexpression also induced beta cell dysfunction in vitro. miR-30a-5p directly suppressed expression of Beta2/NeuroD (also known as Neurod1) by binding to a specific binding site in its 3′-untranslated region. After restoration of Beta2/NeuroD expression by knockdown miR-30a-5p or transfection of the Beta2/NeuroD gene, beta cell dysfunction, including decreased insulin content, gene expression and glucose-stimulated insulin secretion, recovered. Glucose tolerance and beta cell dysfunction improved on direct injection of Ad-si30a-5p into the pancreas of diabetic mice.Conclusions/interpretationOur data demonstrate that miR-30a-5p-mediated direct suppression of Beta2/NeuroD gene expression is an important initiation step of glucotoxicity-induced beta cell dysfunction.