Efficacy and safety of a novel topical agent for gallstone dissolution: 2-methoxy-6-methylpyridine.

BACKGROUND: Although methyl-tertiary butyl ether (MTBE) is the only clinical topical agent for gallstone dissolution, its use is limited by its side effects mostly arising from a relatively low boiling point (55 °C). In this study, we developed the gallstone-dissolving compound containing an aromatic moiety, named 2-methoxy-6-methylpyridine (MMP) with higher boiling point (156 °C), and compared its effectiveness and toxicities with MTBE. METHODS: The dissolubility of MTBE and MMP in vitro was determined by placing human gallstones in glass containers with either solvent and, then, measuring their dry weights. Their dissolubility in vivo was determined by comparing the weights of solvent-treated gallstones and control (dimethyl sulfoxide)-treated gallstones, after directly injecting each solvent into the gallbladder in hamster models with cholesterol and pigmented gallstones. RESULTS: In the in vitro dissolution test, MMP demonstrated statistically higher dissolubility than did MTBE for cholesterol and pigmented gallstones (88.2% vs. 65.7%, 50.8% vs. 29.0%, respectively; P < 0.05). In the in vivo experiments, MMP exhibited 59.0% and 54.3% dissolubility for cholesterol and pigmented gallstones, respectively, which were significantly higher than those of MTBE (50.0% and 32.0%, respectively; P < 0.05). The immunohistochemical stains of gallbladder specimens obtained from the MMP-treated hamsters demonstrated that MMP did not significantly increase the expression of cleaved caspase 9 or significantly decrease the expression of proliferation cell nuclear antigen. CONCLUSIONS: This study demonstrated that MMP has better potential than does MTBE in dissolving gallstones, especially pigmented gallstones, while resulting in lesser toxicities.

Xanthogranulomatous cholecystitis: Is an initial laparoscopic approach feasible?

BACKGROUND: Xanthogranulomatous cholecystitis is an inflammatory disease with pathologically distinct characteristics such as accumulation of lipid-laden macrophages, fibrous tissue, and acute and chronic inflammatory cells. It often involves adjacent organs and mimics gallbladder cancer. The purpose of this study was to review the clinical findings of xanthogranulomatous cholecystitis and to determine the appropriate treatment plan. METHODS: We retrospectively analyzed clinical demographics, operation records, and postoperative results of 31 patients with a pathological diagnosis of xanthogranulomatous cholecystitis who underwent surgery between January 2010 and 2015 at two university hospitals. RESULTS: Xanthogranulomatous cholecystitis was found in 0.81% (31/3820) of cholecystectomy patients in our hospital over 5 years. The most frequently observed clinical symptom was abdominal pain (21 patients, 67.7%). Preoperative radiological studies showed cholelithiasis in 23 patients (74.2%), thickening of the gallbladder wall in 23 patients (74.2%), and suspicious cancer in 2 patients (6.5%), but there were no cases of gallbladder cancer accompanying xanthogranulomatous cholecystitis. Laparoscopic cholecystectomy was planned in all patients and was converted to open cholecystectomy in five patients. T-tube choledocholithotomy was needed in one patient due to common bile duct injury. Mean operation time was 149.2 min, and estimated blood loss was 270.1 mL. There were two patients with complications greater than Clavien-Dindo Classification grade III (CBD injury, pleural effusion). CONCLUSION: An initial laparoscopic approach is possible for xanthogranulomatous cholecystitis. However, it is troublesome and challenging, with significantly higher conversion and complication rates compared to standard laparoscopic cholecystectomy.

The utility of the preoperative neutrophil-to-lymphocyte ratio in predicting severe cholecystitis: a retrospective cohort study.

BACKGROUND: To evaluate whether the neutrophil-to-lymphocyte ratio (NLR), as a prognostic indicator, in patients can differentiate between simple and severe cholecystitis. METHODS: A database of 632 patients who underwent cholecystectomy due to cholecystitis during approximately a seven-year span in a single institution was evaluated. Severe cholecystitis was defined when the cholecystitis was complicated by secondary changes, including hemorrhage, gangrene, emphysema, and perforation. The NLR was calculated at admission as the absolute neutrophil count divided by the absolute lymphocyte count. We used receiver operating characteristic curve analysis to identify the optimal value for the NLR in relation to the severity of cholecystitis. Thereafter, the differences in clinical manifestations according to the NLR cut-off value were investigated. RESULTS: Our study population comprised 503 patients with simple cholecystitis (79.6%) and 129 patients with severe cholecystitis (20.4%). The NLR of 3.0 could predict severe cholecystitis with 70.5% sensitivity and 70.0% specificity. A higher NLR (≥3.0) was significantly associated with older age (p =0.001), male gender (p =0.001), admission via the emergency department (p <0.001), longer operation time (p <0.001), higher incidence of postoperative complications (p =0.056), and prolonged length of hospital stay (LOS) (p <0.001). Multivariate analysis found that patient age ≥50 years (odds ratio [OR]: 2.312, 95% confidence interval [CI]: 1.472-3.630, p <0.001), preoperative NLR ≥3.0 (OR: 1.876, 95% CI: 1.246-2.825, p =0.003), and admission via the emergency department (OR: 1.764, 95% CI: 1.170-2.660, p =0.007) were independent factors associated with prolonged LOS. CONCLUSIONS: NLR ≥3.0 was significantly associated with severe cholecystitis and prolonged LOS in patients undergoing cholecystectomy. Therefore, preoperative NLR in patients undergoing cholecystits due to cholecystitis seemed to be a useful surrogate marker for severe cholecystitis.

Feasibility of Iodine-131 6ß-Methyl-Iodo-19 Norcholesterol (NP-59) Scintigraphy to Complement Adrenal Venous Sampling in Management of Primary Aldosteronism: A Case Series.

PURPOSE: Primary aldosteronism (PA) is mainly comprised of aldosterone-producing adenoma and bilateral idiopathic adrenal hyperplasia. Current guidelines recommend adrenal venous sampling (AVS) as a gold standard method to classify the subtypes. However, because of technical challenges in AVS including invasiveness of AVS and a wide range of success rate for cannulation, it is not uncommon that appropriate decisions could not be made depending on AVS. The aim of this study is to elucidate the proper role of I­131­6ß­iodomethyl­norcholesterol (NP-59) scintigraphy in management of PA. PATIENTS AND METHODS: Between January 2009 and October 2018, patients with PA were retrospectively reviewed for the study. Five patients were included in the study who had NP-59 scintigraphy with non-conclusive AVS results or without AVS. We described the clinical outcome of patients in whom clinical decisions were made according to NP-59 scintigraphy results. RESULTS: Patients in the presenting cases were diagnosed for PA. AVS, the most reliable test to identify unilateral APA, were not applicable because of hypersensitivity to contrast dye (patient 1), and use of antiplatelet agents after acute cerebral infarction (patient 2). NP-59 scintigraphy was performed in patients 3 and 4 whose result of AVS and CT scan were inconsistent. In patient 5, who had bilateral adrenal adenomas (two in the left and one in the right adrenal gland), both unsuccessful catheterization and coexistence of cortisol overproduction made AVS results unreliable. CONCLUSION: Based on clinical outcomes of these case series, it is noticeable that NP-59 scintigraphy could play a substantial role in management of PA in selected cases.

Development and External Validation of Survival Prediction Model for Pancreatic Cancer Using Two Nationwide Databases: Surveillance, Epidemiology and End Results (SEER) and Korea Tumor Registry System-Biliary Pancreas (KOTUS-BP).

Background/Aims: Several prediction models for evaluating the prognosis of nonmetastatic resected pancreatic ductal adenocarcinoma (PDAC) have been developed, and their performances were reported to be superior to that of the 8th edition of the American Joint Committee on Cancer (AJCC) staging system. We developed a prediction model to evaluate the prognosis of resected PDAC and externally validated it with data from a nationwide Korean database. Methods: Data from the Surveillance, Epidemiology and End Results (SEER) database were utilized for model development, and data from the Korea Tumor Registry System-Biliary Pancreas (KOTUS-BP) database were used for external validation. Potential candidate variables for model development were age, sex, histologic differentiation, tumor location, adjuvant chemotherapy, and the AJCC 8th staging system T and N stages. For external validation, the concordance index (C-index) and time-dependent area under the receiver operating characteristic curve (AUC) were evaluated. Results: Between 2004 and 2016, data from 9,624 patients were utilized for model development, and data from 3,282 patients were used for external validation. In the multivariate Cox proportional hazard model, age, sex, tumor location, T and N stages, histologic differentiation, and adjuvant chemotherapy were independent prognostic factors for resected PDAC. After an exhaustive search and 10-fold cross validation, the best model was finally developed, which included all prognostic variables. The C-index, 1-year, 2-year, 3-year, and 5-year time-dependent AUCs were 0.628, 0.650, 0.665, 0.675, and 0.686, respectively. Conclusions: The survival prediction model for resected PDAC could provide quantitative survival probabilities with reliable performance. External validation studies with other nationwide databases are needed to evaluate the performance of this model.

Single-port transumbilical laparoscopic appendectomy: 43 consecutive cases.

BACKGROUND: In this modern era of minimally invasive surgery, cosmesis and early recovery are strongly emphasized. To reduce abdominal trauma and improve cosmesis, surgeons have adopted a single-port laparoscopic appendectomy for patients with acute appendicitis. METHODS: From August to December 2008, 43 cases of appendectomy were managed using the single-port transumbilical laparoscopic technique. A multichannel single port was created using a surgical glove (no. 6), three trocars, one-three-way catheter, and a wound retractor (Alexis). An umbilical incision (1.5-2.0 cm) was made transumbilically or infraumbilically. The intraabdominal procedures were almost identical to those for conventional laparoscopic appendectomy. The methods for mesenteric dissection and appendiceal stump ligation were identical. Despite slight discomforts with retraction and visualization, the procedure was nevertheless possible. A resected appendix was put into a finger of the single-port glove. RESULTS: The 43 study cases included 23 men and 20 women with a mean age of 31 years (range, 9-65 years) and a mean body mass index (BMI) of 22.3 kg/m(2) (range 15-29.7 kg/m(2)). The mean operative time was 61.3 min (range 24-120 min). Drainage was used in two cases with perforated appendicitis. Bowel movement returned at a mean of 1.2 days, and oral feeding was resumed on postoperative day 1.2. The pathology showed negative inflammation in 4 cases (9.3%), suppurative appendicitis in 29 cases (67.4%), gangrenous appendicitis in 8 cases (18.6%), and perforated appendicitis in 2 cases. Only one patient required readmission due to pericecal inflammation and pain, and another patient needed a percutaneous drainage of fluid collection. Three minor umbilical wound complications were controlled conservatively. CONCLUSIONS: Single-port appendectomy may require a longer operative time than laparoscopic appendectomy, but it is a feasible technique with good cosmetic results. It could be one of the alternative methods for treating acute appendicitis.

Current Status of Bariatric and Metabolic Surgery in Daejeon and Chungcheong Province: Early Experiences after Public Medical Insurance Coverage in 2019.

Purpose: This study aimed to investigate the current status of bariatric and metabolic surgery in Daejeon and Chungcheong province and to describe the early experiences after public medical insurance coverage in 2019. Materials and Methods: Between January 2019 and August 2019, 64 cases of bariatric and metabolic surgery were performed in patients with morbid obesity or uncontrolled type 2 diabetes. We prospectively collected and analyzed data regarding the patients' demographics and comorbidities, surgical results, and early complications. The patient information before and after the insurance coverage was also compared. Results: The number of surgeries in 9 years has been caught up only in the last 8 months after insurance coverage (58 vs. 64 patients). The mean body mass index was 37.7±5.8 kg/m2 (range, 22.7-52.1 kg/m2). The most frequently performed surgery was sleeve gastrectomy (53 cases, 82.8%), followed by Roux-en-Y gastric bypass (9 cases, 14.1%), and adjustable gastric banding (2 cases, 3.1%). Postoperative complications occurred in 6 patients (9.4%), and there was no mortality. The mean operation time (225.3±85.4 vs. 156.1±61.8 min, P<0.001) and postoperative stay (5.9±4.5 vs. 4.3±2.0 days, P=0.013) after the insurance coverage were significantly shorter than those before the insurance coverage. Conclusion: We could assess the patients who had bariatric and metabolic surgery in Daejeon and Chungcheong province after public medical insurance coverage in 2019.

Metabolic and Bariatric Surgery Accreditation Program and National Health Insurance System in Korea.

Since the first laparoscopic bariatric surgery in Korea introduced in January 2003, the number of metabolic and bariatric surgery has been steadily increasing. According to the report from National Health Insurance big data analysis, the prevalence of morbid and super obesity has greatly increased and metabolic and bariatric surgery also increased in the last 10 years. As the incidence of morbid obesity is more frequent in people of poor socioeconomic status, the need for a reimbursement by the government seemed to be necessary. Finally, the national health insurance system decided to financially cover metabolic and bariatric surgery from January 2019. In order to improve the safety and qualify of metabolic and bariatric surgery, the Korean Society for Bariatric and Metabolic Surgery (KSMBS) introduced surgeon's and institution's accreditation system. The authors intend to introduce comprehensive overview of accreditation system of bariatric surgery and discuss the contents of national health insurance for metabolic and bariatric surgery.

Appropriate Hospital Discharge Timing after Laparoscopic Cholecystectomy: Comparison of Postoperative Day 1 vs. Day 2 Discharge Protocol.

Purpose: The critical pathway (CP) was introduced as a means to provide quality healthcare service in many fields of surgery. CP may increase the patient's satisfaction rate and lowering hospital stay and medical cost also. We aimed to compare the two kinds of CP applied in laparoscopic cholecystectomy patients by different hospital stay length. Methods: From March 2016 to October 2016, 71 patients were enrolled in this analysis among 241 patients who underwent elective laparoscopic cholecystectomy. Patients were divided into two groups, 38 patients in the 1-day CP group and 33 patients in the 2-day CP group. In a retrospective review, surgical outcomes and related hospital costs were analyzed. Results: Preoperative characteristics were not different between two CP groups. In analysis of operative outcome, 2-day CP group showed longer operative time than 1-day CP (73.4 vs 54.1 min, p<0.001); otherwise, there was no significant difference in frequency of postop complications (6.1% vs 2.6%, p=0.474), numerical rating scale (NRS) pain score (1.82 vs 2.16, p=0.052), and count of analgesics injection (0.12 vs 0.16, p=0.754). Total admission cost and actual patient's expenditures were higher in 2-day CP group, but there was no statistically significant difference (347.04 vs 306.69×104 won, p=0.106; 147.85 vs 125.58×104 won, p=0.276). Conclusion: The length of hospital stay was shortened in 1-day CP group than in 2-day CP group, while there was no difference in other parameters. Therefore, it is feasible and safe practical policy the use 1-day CP in selected patients who undergo cholecystectomy according to our results.

Recurrence of common bile duct stones following laparoscopic common bile duct exploration: a multicenter study.

BACKGROUND: Recurrence of common bile duct stone (CBDS) is not common after laparoscopic common bile duct exploration (LCBDE). This study aimed to investigate the risk factors of recurrence of CBDS after LCBDE. METHODS: Patients who underwent LCBDE between January 2001 and December 2018 in four teaching hospitals of The Catholic University of Korea were included. The operation, fluoroscopy, and endoscopic retrograde cholangiopancreatography records were investigated retrospectively. The primary outcome of this study was the independent risk factors for recurrence of CBDS. RESULTS: A total of 230 patients were included in this study. Thirty-one patients had recurrence of CBDS. In univariate analysis, CBDS size (>9 mm) (P = 0.003), multiple stones (≥2) (P = 0.031), stone size (≥1.5 cm) (P = 0.041), CBD diameter (≥12 mm) (P = 0.005), CBD dilatation (≥10 mm) (P = 0.02), prior history of laparoscopic cholecystectomy (P = 0.002) were associated with recurrence. After multivariable logistic regression, CBDS size (>9 mm) (OR 4.67, 95% CI 1.35-16.18, P = 0.011), CBD dilatation (≥10 mm) (OR 5.66, 95% CI 1.47-21.82, P = 0.012), and prior history of laparoscopic cholecystectomy (AOR 3. 90, 95% CI 1.34-11.37, P = 0.013) were associated with recurrence. CONCLUSIONS: Stone size >9 mm, CBD diameter ≥10 mm, and prior history of laparoscopic cholecystectomy were risk factors for recurrence of CBDS after LCBDE.

Long-term effect of bariatric surgery versus conventional therapy in obese Korean patients: a multicenter retrospective cohort study.

PURPOSE: Long-term results following bariatric surgery compared to conventional treatments has never been reported in morbidly obese Korean patients. This study aimed to evaluate the long-term efficacy of bariatric surgery in morbidly obese Korean patients compared to conventional medical treatments. METHODS: In this multicenter retrospective cohort study, we reviewed 137 obese subjects between January 2008 and February 2011 with a body mass index (BMI) > 30 kg/m2 who had more than 5 years of follow-up clinical data after bariatric surgery (surgery group, n = 49) or conventional treatment (conventional treatment group, n = 88). Anthropometric data and the status of comorbidities were compared between the 2 groups. RESULTS: The median follow-up period was 72.1 months (range 19.3-109.7 months). At the last follow-up, the surgery group showed a greater amount of total weight loss than the conventional treatment group (24.9% vs. 2.8%, P < 0.001). The prevalence of diabetes and hypertension significantly decreased in the surgery group, while the conventional treatment group showed a marked increase in these comorbidities. In the surgery group, Roux-en-Y gastric bypass and sleeve gastrectomy achieved comparable long-term weight loss (26.5% vs. 22.4%, respectively; P = 0.087). CONCLUSION: In the long-term, bariatric surgery achieved and maintained significantly greater weight reduction, as well as a decrease in obesity-related comorbidities, than did conventional medical therapy in morbidly obese Korean patients.

Everolimus Plus Ku0063794 Regimen Promotes Anticancer Effects against Hepatocellular Carcinoma Cells through the Paradoxical Inhibition of Autophagy.

PURPOSE: Everolimus only inhibits mammalian target of rapamycin complex 1 (mTORC1), whereas Ku0063794 inhibits both mTORC1 and mTORC2. Although they have similar anticancer effects, their combination has a synergistic effect against hepatocellular carcinoma (HCC) cells. We aimed to determine the mechanism underlying the synergistic effects of everolimus and Ku0063794 associated with autophagy in HCC cells. MATERIALS AND METHODS: We compared the effects of everolimus and Ku0063794, individually or in combination, on both the in vitro and in vivo models of HCCs. RESULTS: HepG2 cells treated with both agents had significantly lower rates of cell proliferation and higher apoptosis than the individual monotherapies (p < 0.05). Autophagic studies consistently indicated that, unlike the monotherapies, the combination therapy significantly reduced autophagy (p < 0.05). Autophagic blockage directly promoted the pro-apoptotic effects of combination therapy, suggesting autophagy as the survival mechanism of HCC cells. Unlike the monotherapies, combination therapy showed the potential to inhibit sirtuin 1 (SIRT1), the positive regulator of autophagy. SIRT1 overexpression abrogated the autophagy-inhibiting and pro-apoptotic effects of combination therapy. In a nude mouse xenograft model, the shrinkage of tumors was more prominent in mice treated with combination therapy than in mice treated with the respective monotherapies (p < 0.05). The immunohistochemical and immunofluorescence stains of the tumor obtained from the xenograft model showed that combination therapy had the potential of reducing autophagy and promoting apoptosis. CONCLUSION: The combination of everolimus and Ku0063794 potentiates anticancer effects on HCCs through a decrease in autophagy, which is prompted by SIRT1 downregulation.

[Minimally invasive surgery for gastroesophageal reflux disease].

Gastroesophageal reflux disease (GERD) is a chronic disease deteriorating patient's quality of life. With the advent of proton pump inhibitors, treatment failures have decreased considerably. However, surgical therapy offers the potential for cure in more than 90% of patients with GERD. Specific indications for antireflux surgery are: incomplete response to medical therapy, frequent recurrences despite the medical treatment, laryngopharyngeal, and/or respiratory symptoms, and complications of GERD, such as esophageal stricture, erosive esophagitis, esophageal ulcer, and/or Barrett's esophagus. The introduction of laparoscopic surgery in early ninties had a profound impact on many surgical fields, including the treatment of GERD. In this review, laparoscopic Nissen fundoplication is described and controversial topics, such as total vs. partial fundoplication, and the natural history of Barrett's esophagus after antireflux surgery are addressed.

Long-term effects of duodenojejunal bypass on diabetes in Otsuka Long-Evans Tokushima Fatty rats.

BACKGROUND: Previous studies have shown that duodenojejunal bypass (DJB) resolves type 2 diabetes. However, this finding has been contradicted by several experimental and human trials and therefore needs to be clarified. METHODS: Otsuka Long-Evans Tokushima Fatty (OLETF) rats randomly underwent a sham operation or DJB. Thereafter, we measured daily body weight, serum levels of glucose and gut hormones such as glucagon-like peptide-1, insulin, and leptin. RESULTS: There was no significant difference in weight loss between rats in the DJB and sham-operated groups. There were also no differences in the area under the curve of glucose tolerance between the DJB and sham-operated groups (32466 ± 2261 mg/dL·min vs. 26319 ± 427 mg/dL·min; p = 0.35). Duodenojejunal bypass did not affect plasma concentrations of various gut hormones such as glucagon-like peptide-1, insulin, and leptin. CONCLUSIONS: We have shown that DJB alone does not improve glucose tolerance in obese, diabetic OLETF rats. Therefore, it may be that DJB alone is insufficient for diabetic control in obese diabetic rats. The addition of a restrictive component such as sleeve gastrectomy, or a new drug may be necessary for achieving diabetes reversal.

Risk assessment scales and predictors for simple versus severe cholecystitis in performing laparoscopic cholecystectomy.

BACKGROUND: Because acute cholecystitis has a different prognosis according to the degree of inflammation, early detection and prompt operation of severe cholecystitis are critical to the success of treatment. However, computed tomography (CT) has a low discriminative value for differentiating between simple and severe cholecystitis. Therefore, to enhance the diagnostic accuracy of CT scan, the imaging studies should be supplemented by preoperative clinical variables. METHODS: Patients undergoing laparoscopic cholecystectomy for simple and severe cholecystitis between 2007 and 2014 were compared. Severe cholecystitis included hemorrhagic, gangrenous, emphysematous, xanthogranulomatous, and perforated cholecystitis. Prediction models for severe cholecystitis were developed based on multivariate analyses of preoperative clinical and radiologic variables. RESULTS: Independent factors related with severe cholecystitis were age ≥65 years, male gender, body mass index (BMI) ≥25, serum leukocyte count ≥10,000/mm3, serum neutrophil fraction ≥80%, serum platelet count ≥20,000/mm3, serum alanine transaminase (ALT) level ≥40 IU/L, admission via the emergency department, and radiologic features of gallbladder wall thickening ≥4 mm, and presence of pericholecystic fluid collection (p < 0.05). A standard risk assessment scale (range: 0-77) for severe cholecystitis was developed based on the individual hazard rate of these variables. Patients scoring ≥28 on the risk assessment scale showed an 8.6 higher odds of severe cholecystitis than those scoring <28 (p < 0.01). CONCLUSION: Standard and quick-and-easy predictive models for severe cholecystitis have been developed based on preoperative radiological and clinical variables, which is expected to help improve surgical outcome of patients with cholecystitis.

HSP90 inhibitor 17-DMAG exerts anticancer effects against gastric cancer cells principally by altering oxidant-antioxidant balance.

Heat shock protein 90 (HSP90) stabilizes numerous oncoproteins and, therefore, its inhibition has emerged as a promising antineoplastic strategy for diverse malignancies. In this study, we determined the therapeutic effects and mechanisms of action of a specific HSP90 inhibitor, 17-dimethylamino-ethylamino-17-demethoxygeldanamycin (17-DMAG), in gastric cancer cell lines (AGS, SNU-1, and KATO-III), patient-derived tissues, and a mouse xenograft model. 17-DMAG exerted anticancer effects against gastric cancer cells, manifested by significantly decreased proliferation rates (P < 0.05) and increased expression of apoptotic markers. Flow cytometry using dichlorofluorescein (DCF) diacetate revealed that 17-DMAG dose-dependently increases reactive oxygen species (ROS) levels in gastric cancer cells. Inhibition of ROS by N-acetyl-L-cysteine (NAC) abrogated the proapoptotic effects of 17-DMAG, as demonstrated by the decreased expression of proapoptotic proteins. In addition, 17-DMAG dose- and time-dependently reduced the expression of antioxidants such as catalase and glutathione peroxidase (GPx). Moreover, 17-DMAG reduced the expression of nuclear respiratory factor (NRF)-1 and NRF-2, and prevented them from migrating from the cytoplasm to the nucleus dose-dependently. Finally, in a nude mouse xenograft model, the shrinkage of tumors was more prominent in mice treated with 17-DMAG than in control mice (P < 0.05). Taken altogether, our results suggest that 17-DMAG exerts potent antineoplastic activity against gastric cancer cells primarily by promoting ROS generation and suppressing antioxidant enzyme activities.

Potentiation of the anticancer effects of everolimus using a dual mTORC1/2 inhibitor in hepatocellular carcinoma cells.

There is lots of evidence to support the critical involvement of mTOR signaling in the carcinogenesis of hepatocellular carcinoma (HCC). However, it has not been determined how the roles of individual mTORC1 and mTORC2 inhibitors played in the HCC therapeutics. We thus compared the effects of everolimus, Ku0063794, and a combination of the two therapies on HCC cells, using various in vitro studies (HepG2, Hep3B, and Huh7 cells), ex vivo culturing of HCC tissues obtained from patients, and the in vivo mouse xenograft model of HCC cells. Our in vitro, ex vivo, and in vivo experiments consistently demonstrated that everolimus and Ku0063794 combination therapy was superior to individual monotherapies, as manifested by higher reduction of proliferation, migration, and invasion of HCC cells, and the higher inhibition of EMT process as well. Although individual monotherapies could not inhibit SIRT1 (positive regulator of EMT) expression, the combination therapy significantly inhibited SIRT1 expression. However, overexpression of SIRT1 mitigated the EMT-inhibiting effect of the combination therapy, suggesting that the combination therapy inhibits the EMT by way of suppressing SIRT1 expression. Therefore, when considering everolimus as an anti-HCC agent, the improved anticancer effects provided by combining it with an inhibitor of both mTORC1 and mTORC2 should be recognized.

Determination of optimized oxygen partial pressure to maximize the liver regenerative potential of the secretome obtained from adipose-derived stem cells.

BACKGROUND: A hypoxic-preconditioned secretome from stem cells reportedly promotes the functional and regenerative capacity of the liver more effectively than a control secretome. However, the optimum oxygen partial pressure (pO2) in the cell culture system that maximizes the therapeutic potential of the secretome has not yet been determined. METHODS: We first determined the cellular alterations in adipose tissue-derived stem cells (ASCs) cultured under different pO2 (21%, 10%, 5%, and 1%). Subsequently, partially hepatectomized mice were injected with the secretome of ASCs cultured under different pO2, and then sera and liver specimens were obtained for analyses. RESULTS: Of all AML12 cells cultured under different pO2, the AML12 cells cultured under 1% pO2 showed the highest mRNA expression of proliferation-associated markers (IL-6, HGF, and VEGF). In the cell proliferation assay, the AML12 cells cultured with the secretome of 1% pO2 showed the highest cell proliferation, followed by the cells cultured with the secretome of 21%, 10%, and 5% pO2, in that order. When injected into the partially hepatectomized mice, the 1% pO2 secretome most significantly increased the number of Ki67-positive cells, reduced serum levels of proinflammatory mediators (IL-6 and TNF-α), and reduced serum levels of liver transaminases. In addition, analysis of the liver specimens indicated that injection with the 1% pO2 secretome maximized the expression of the intermediate molecules of the PIP3/Akt and IL-6/STAT3 signaling pathways, all of which are known to promote liver regeneration. CONCLUSIONS: The data of this study suggest that the secretome of ASCs cultured under 1% pO2 has the highest liver reparative and regenerative potential of all the secretomes tested here.

Hypoxic Conditioned Medium From Human Adipose-Derived Stem Cells Promotes Mouse Liver Regeneration Through JAK/STAT3 Signaling.

UNLABELLED: Adipose-derived stem cells (ASCs) mainly exert their function by secreting materials that are collectively termed the secretome. Despite recent attention to the secretome as an alternative to stem cell therapy, the culture conditions for generating optimal secretome contents have not been determined. Therefore, we investigated the role of hypoxic-conditioned media (HCM) from ASCs. Normoxic-conditioned media (NCM) and HCM were obtained after culturing ASCs in 20% O2 or 1% O2 for 24 hours, respectively. Subsequently, partially hepatectomized mice were infused with saline, control medium, NCM, or HCM, and then sera and liver specimens were obtained for analyses. Hypoxia (1% O2) significantly increased mRNA expression of mediators from ASCs, including interleukin-6 (IL-6), tumor necrosis factor α (TNF-α), hepatocyte growth factor (HGF), and vascular endothelial growth factor (VEGF). HCM infusion significantly increased the number of Ki67-positive cells in the liver (p < .05). HCM infusion significantly increased phospho-signal transducer and activator of transcription 3 (STAT3) and decreased suppressor of cytokine signaling 3 (SOCS3) expression in the liver (p < .05). To determine the role of IL-6 in liver regeneration, we then performed IL-6 RNA interference study. Conditioned media (CM) obtained from ASCs, which were transfected with either siIL-6 or siControl, were administered to partially hepatectomized mice. The siIL-6 CM groups exhibited lower liver proliferation (Ki67-positive cells) and markers of regeneration (protein expression of proliferating cell nuclear antigen, p-STAT3, HGF, and VEGF and liver weights) than the siControl CM groups (p < .05). Taken together, hypoxic preconditioning of ASCs increased expression of mediators promoting anti-inflammatory and regenerative responses. The liver regenerative effects of HCM appear to be mediated by persistent and uninhibited expression of STAT3 in the liver, which results from decreased expression of SOCS3. SIGNIFICANCE: In this study, it was found that treatment with the medium from hypoxic-preconditioned adipose-derived stem cells (ASCs) increased the viability of hepatotoxic hepatocytes and enhance liver regeneration in partially hepatectomized mice. In addition, the researchers first revealed that the hepatoprotective effects of hypoxic-conditioned media are mediated by persistent and uninhibited expression of signal transducer and activator of transcription 3 in the liver, which result from a decreased expression of suppressor of cytokine signaling 3. Therefore, the hypoxic preconditioning of ASCs is expected to play a crucial role in regenerative medicine by optimizing the production of a highly effective secretome from ASCs.

Does Korea's current diagnosis-related group-based reimbursement system appropriately classify appendectomy patients?

PURPOSE: As several years have passed since the implementation of the Korean diagnosis-related group (DRG) payment system for appendicitis, its early outcomes should be assessed to determine if further improvements are warranted. METHODS: We retrospectively analyzed clinical data from Korean patients who underwent appendectomy, dividing the sample into 2 groups of those who received services before and after implementation of the DRG system. Based on the DRG code classification, patient data were collected including the amount of DRG reimbursement and the total in-patient costs. We subsequently performed univariate and multivariate analyses to identify independent factors contributing to higher total in-patient cost. RESULTS: Although implementation of the DRG system for appendicitis significantly reduced postoperative length of stay (2.8 ± 1.0 days vs. 3.4 ± 1.9 days, P < 0.001), it did not reduce total in-hospital cost. The independent factors related to total inhospital cost included patient age of 70 years or more (odds ratio [OR], 3.214; 95% confidence interval [CI], 1.769-5.840; P < 0.001) and operation time longer than 100 minutes (OR, 3.690; 95% CI, 2.007-6.599, P < 0.001). In addition, older patients (≥70 years) showed a nearly 10 times greater relative risk for having a comorbid condition (95% CI, 5.141-20.214; P < 0.001) and a 3.255 times greater relative risk for having higher total in-hospital cost (95% CI, 1.731-6.119, P < 0.001). CONCLUSION: It appears that older patients (>70 years) have greater comorbidities, which contribute to higher inpatient costs. Thus, our study suggests that patient age be considered as a DRG classification variable.