A polygenic risk score for breast cancer risk in a Taiwanese population.

BACKGROUND: Multiple common variants identified by genome-wide association studies showed limited evidence of the risk of breast cancer in Taiwan. In this study, we analyzed the breast cancer risk in relation to 13 individual single-nucleotide polymorphisms (SNPs) identified by a GWAS in an Asian population. METHODS: In total, 446 breast cancer patients and 514 healthy controls were recruited for this case-control study. In addition, we developed a polygenic risk score (PRS) including those variants significantly associated with breast cancer risk, and also evaluated the contribution of PRS and clinical risk factors to breast cancer using receiver operating characteristic curve (AUC). RESULTS: Logistic regression results showed that nine individual SNPs were significantly associated with breast cancer risk after multiple testing. Among all SNPs, six variants, namely FGFR2 (rs2981582), HCN1 (rs981782), MAP3K1 (rs889312), TOX3 (rs3803662), ZNF365 (rs10822013), and RAD51B (rs3784099), were selected to create PRS model. A dose-response association was observed between breast cancer risk and the PRS. Women in the highest quartile of PRS had a significantly increased risk compared to women in the lowest quartile (odds ratio 2.26; 95% confidence interval 1.51-3.38). The AUC for a model which contained the PRS in addition to clinical risk factors was 66.52%, whereas that for a model which with established risk factors only was 63.38%. CONCLUSIONS: Our data identified a genetic risk predictor of breast cancer in Taiwanese population and suggest that risk models including PRS and clinical risk factors are useful in discriminating women at high risk of breast cancer from those at low risk.

MSH2 rs2303425 Polymorphism is Associated with Early-Onset Breast Cancer in Taiwan.

BACKGROUND: Accumulated evidence indicates that the incidence of early-onset breast cancer has rapidly increased in Taiwan and other Asian compared to Western countries. The mismatch repair (MMR) pathway might be one of the crucial mechanisms of predisposition to early breast cancer. In this study, we explored whether MMR gene polymorphisms contribute to the risk of breast cancer in young women. METHODS: This was a 2-stage case-control study including 737 cases and 719 controls. After eight single nucleotide polymorphisms (SNPs) were genotyped in MMR pathway genes in the stage I study, a promising SNP, MSH2 rs2303425, was selected for validation in the stage II study. A luciferase reporter assay was used to evaluate the transcriptional activity of MSH2. RESULTS: Logistic regression analysis showed that individuals with the MSH2 rs2303425 C/C genotype had a significantly increased risk of breast cancer compared to those with the T/T genotype (adjusted odds ratio 2.0; 95 % confidence interval 1.1-3.8), particularly in early-onset breast cancer patients with the luminal A subtype. The luciferase assay in three cell lines indicated that the MSH2 rs2303425 T/C substitution decreased MSH2 expression, which is consistent with the finding of an association study. CONCLUSIONS: A common variant SNP in MSH2 may contribute to the susceptibility to early-onset breast cancer functionally, particularly for the luminal A subtype.

CHRNA9 polymorphisms and smoking exposure synergize to increase the risk of breast cancer in Taiwan.

Previous studies indicated that smoking exposure is associated with an increased risk of breast cancer, and α9-nicotine acetylcholine receptors (α9-nAChRs) are involved in breast tumorigenesis. However, no studies have explored the joint effect of α9-nAChRs (CHRNA9) genes and cigarette smoking exposure on breast cancer risk. A case-control study was conducted on 737 breast cancer patients and 719 age-matched healthy controls. Three single-nucleotide polymorphisms (SNPs) of CHRNA9 located in the promoter region were genotyped and compared between cases and controls to identify those SNPs associated with breast cancer susceptibility. A dual-luciferase reporter assay was used to analyze the promoter activities of these SNPs of the CHRNA9 gene. After a Bonferroni correction, the G allele of the CHRNA9 rs7329797 SNP was significantly associated with an increased risk of developing breast cancer compared with A/A genotype carriers (odds ratio, 1.8; 95% confidence interval, 1.2-2.6). A multiplicative interaction between passive smoking exposure and the CHRNA9 rs73229797 SNP on the risk of breast malignancy was observed. A functional assay further showed that rs73229797 was associated with increased promoter activity of the CHRNA9 gene. Our findings support a significant interaction effect existing between the CHRNA9 gene and smoking exposure on the risk of breast cancer development.

Benefit of Neoadjuvant Laparoscopic Hyperthermic Intraperitoneal Chemotherapy and Bidirectional Chemotherapy for Patients with Gastric Cancer with Peritoneal Carcinomatosis Considering Cytoreductive Surgery.

Comprehensive treatment comprising neoadjuvant laparoscopic HIPEC (L-HIPEC) and bidirectional intraperitoneal and systemic induction chemotherapy (BISIC) followed by cytoreductive surgery (CRS) for gastric cancer with peritoneal carcinomatosis (PC) has been developed. However, its benefits and patient selection criteria have not been thoroughly investigated. We retrospectively reviewed 113 patients, with 25 having received comprehensive treatment (L-HIPEC, BISIC, and then CRS-HIPEC; the BISIC group) and 88 having received direct CRS-HIPEC (the CRS group). The BISIC group showed greater tumor clearance in terms of post-CRS peritoneal cancer index ((PCI) 6 vs. 14, p = 0.002) compared to CRS group. The median survival was 20.0 months in the BISIC group and 8.6 months in the CRS group (p = 0.031). Multivariable analysis revealed that the factors associated with increased survival were the BISIC protocol, age, and post-CRS tumor clearance. BISIC significantly improved survival in cases of moderate severity (PCI 11-20) and severe cases (PCI 21-39) without increasing the morbidity rate. We recommend the use of this neoadjuvant strategy for patients with gastric cancer-associated PC and an initial PCI of >10 to provide superior survival outcomes.

Genetic alterations in peritoneal metastatic tumors predicted the outcomes for hyperthermic intraperitoneal chemotherapy.

Introduction: Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) are considered for patients with peritoneal metastasis (PM). However, patients selection that relies on conventional prognostic factors is not yet optimal. In this study, we performed whole exome sequencing (WES) to establish tumor molecular characteristics and expect to identify prognosis profiles for PM management. Methods: In this study, blood and tumor samples were collected from patients with PM before HIPEC. Tumor molecular signatures were determined using WES. Patient cohort was divided into responders and non-responders according to 12-month progression-free survival (PFS). Genomic characteristics between the two cohorts were compared to study potential targets. Results: In total, 15 patients with PM were enrolled in this study. Driver genes and enriched pathways were identified from WES results. AGAP5 mutation was found in all responders. This mutation was significantly associated with better OS (p = 0.00652). Conclusions: We identified prognostic markers that might be useful to facilitate decision-making before CRS/HIPEC.

Microsatellite instability is associated with a better prognosis for gastric cancer patients after curative surgery.

BACKGROUND: Microsatellite instability (MSI) is one of the leading mechanisms for the carcinogenesis of gastric cancer. Its prognostic value is controversial. METHODS: Between May 1988 and Oct 2003, a total of 214 gastric cancer patients undergoing curative surgery were enrolled, and their MSI statuses were classified as MSI-H (high) or MSI-L/S (low/stable). The clinicopathologic characteristics of MSI-H and MSI-L/S gastric cancers were compared. RESULTS: The MSI-H tumors accounted for 11.7 % (n = 25) of the 214 total gastric cancers. Although not statistically significant, the MSI-H gastric cancers were more frequently located in the lower third of the stomach (64 % vs. 49.2 %) and were more often the intestinal type (72 % vs. 61.4 %) compared to the MSI-L/S gastric cancers. The MSI-H gastric cancers had a significantly better 5-year overall survival (OS) rate (68 % vs. 47.6 %, p = 0.030) and a trend of a better 3-year disease-free survival rate (71.8 % vs. 55.2 %, p = 0.076) compared to the MSI-L/S gastric cancers. A multivariate analysis revealed that pathologic TNM stage and MSI status were the independent prognostic factors for OS after curative surgery. CONCLUSIONS: Compared to MSI-L/S tumors, MSI-H tumors are associated with a better OS rate for gastric cancer patients after R0 resection.

Combined splenectomy does not improve survival in radical total gastrectomy for advanced gastric cardia cancer.

BACKGROUND/AIMS: Splenectomy is the most common combined organ resection in the surgical management for gastric cardia cancer. The role of combined splenectomy is still controversial. METHODOLOGY: From January 1998 to December 2006, a total of 174 patients received radical total gastrectomy for advanced adenocarcinoma of cardia. Patients with previous gastric surgery or tumor invasion of pancreas or spleen were excluded. Among them, 115 patients were enrolled in this study. Patients were divided into group 1 (splenectomy, n=47) and group 2 (spleen preservation, n=68). Their clinicopathological characteristics were compared. RESULTS: Multivariate analysis showed that only tumor size and lymphovascular invasion were two independent indicators of survival. The surgically-related morbidity and mortality rates were similar between the two groups. Among the 3 patients with splenic hilar lymph nodes metastasis, all of them had large tumor size (=4cm), advanced stage (stage III and IV) and tumor center located at the posterior wall of stomach. The 5-year overall survival for advanced cancer was similar (57.1% vs. 60.2%, p=0.681). CONCLUSIONS: Splenectomy does not improve overall survival in the management of advanced gastric cardia cancer. Splenectomy has limited clinical benefits except for large advanced tumors located at the posterior wall of stomach.

Exendin-4 Attenuates Hepatic Steatosis by Promoting the Autophagy-Lysosomal Pathway.

Dysregulated hepatic steatosis may lead to chronic liver inflammation and nonalcoholic steatohepatitis (NASH). Recent studies have suggested that exendin-4, a glucagon-like peptide-1 agonist, may be a promising therapeutic for hepatic steatosis and NASH. However, the molecular mechanisms underlying the antihepatic steatosis actions of exendin-4 are not fully clear. Here, we demonstrate that autophagy is activated by either palmitic acid (PA) or oleic acid (OA) in HepG2 cells, and exendin-4 further enhances the autophagy-lysosomal pathway. We show that inhibition of autophagy by shLC3 attenuates exendin-4-mediated antisteatotic activity. Furthermore, expression of a key lysosomal marker, lysosome associated membrane protein 1 (LAMP1), is upregulated in OA + exendin-4-treated cells. The colocalization of LAMP1 and LC3 puncta further suggests that autophagic flux was enhanced by the cotreatment. Based on these findings, we conclude that autophagic flux might play an important role in the antisteatotic action of exendin-4.

Feasibility of Breast Cancer Metastasis Assessment of Ex Vivo Sentinel Lymph Nodes through a p-H&E Optical Coherence Microscopic Imaging System.

Frozen-sectioned hematoxylin-eosin (H&E) image evaluation is the current method for intraoperative breast cancer metastasis assessment through ex vivo sentinel lymph nodes (SLNs). After frozen sectioning, the sliced fatty region of the frozen-sectioned specimen is easily dropped because of different freezing points for fatty tissues and other tissues. Optical-sectioned H&E images provide a nondestructive method for obtaining the insight en face image near the attached surface of the dissected specimen, preventing the freezing problem of fatty tissue. Specimens from 29 patients at Wanfang Hospital were collected after excision and were analyzed at the pathology laboratory, and a fluorescence-in-built optical coherence microscopic imaging system (OCMIS) was then used to visualize the pseudo-H&E (p-H&E) images of the SLNs for intraoperative breast cancer metastasis assessment, and the specificity, sensitivity, and accuracy were 100%, 88.9%, and 98.8% (n = 83), respectively. Compared with gold-standard paraffin-sectioned H&E images, the specificity, sensitivity, and accuracy obtained with the frozen-sectioned H&E images (n = 85) of the specimens were the same as those obtained with the p-H&E images (n = 95). Thus, OCMIS is a useful noninvasive image-assisted tool for breast cancer metastasis assessment based on SLN images.

Factors associated with recurrence within 2 years after curative surgery for gastric adenocarcinoma.

BACKGROUND: Despite curative surgery for gastric cancer, many patients die of recurrent cancer. Few studies have investigated the time to recurrence after curative resection for gastric cancer. METHODS: Data were collected prospectively between December 1987 and December 2006. A total of 1,549 patients underwent curative resection of adenocarcinoma of the stomach at Taipei Veterans General Hospital. Among them, 419 patients had recurrence; they were divided into early recurrence (<2 years) and late recurrence (≥2 years). The clinicopathological characteristics, survival time after recurrence, and recurrence patterns were compared between the two groups. RESULTS: Multivariate analysis showed that stage III gastric cancer patients with early recurrence had larger tumors and more lymph node metastasis than patients with late recurrence, while no difference between early and late recurrence was observed in stage I and II patients. Early recurrence was associated with more distant metastasis than was late recurrence. Patients with advanced TNM stage tended to die within 2 years after recurrence. CONCLUSIONS: Gastric cancer patients with larger tumors and more lymph node metastasis tended to have early recurrence, especially stage III patients. Advanced TNM stage was associated with early cancer death after recurrence.

Comparison of the survival difference between AJCC 6th and 7th editions for gastric cancer patients.

BACKGROUND: The AJCC 7th edition changes the classification of T- and N-factors and the TNM stage of gastric cancer. We evaluated its prognostic impact. METHODS: From December 1987 to December 2006, a total of 1,380 patients underwent curative surgery for gastric cancer at the Department of Surgery, Taipei Veterans General Hospital, with a retrieved lymph node number ≥ 15. Survival was compared for disease classified according to the AJCC 6th and 7th editions. RESULTS: There is a significant difference in 5-year survival between T2 and T3 gastric cancer classified according to the AJCC 7th edition (75.2 vs. 54.9%, p < 0.001), as well as between N1 and N2 (71.4 vs. 44.1%, p < 0.001). Although patients with N3a had a better 5-year survival than did those with N3b (27.6 vs. 11.3%, p < 0.001), the N3 categories were combined and not applied in the TNM stage in the 7th edition. Multivariate analysis using Cox's proportional hazards model with a forward logistics regression stepwise procedure demonstrates that age, N category of 6th edition, and T and N categories of 7th edition are independent prognostic factors; however, T category of 6th edition is no longer significant. Furthermore, the discriminative power of survival difference between each TNM stage seems to be comparable between the 6th and 7th editions. CONCLUSIONS: The AJCC 7th edition provides a more stratified survival difference in staging of gastric cancer. Future division of N3a and N3b in the classification of the TNM stage is recommended.

Risk factors and management of anastomotic leakage after radical gastrectomy for gastric cancer.

BACKGROUND/AIMS: Radical gastrectomy remains the primary treatment for gastric cancer without distant metastasis. However, anastomotic leakage and extended lymph node dissection might cause additional morbidity and related mortality. METHODOLOGY: From January 1988 to December 2004, 2076 patients with gastric cancer underwent radical gastrectomy at Taipei Veterans General Hospital. The risk factors for anastomotic leakage, including clinicopathological factors, operative procedures, combined organ resection, operating time, blood loss, and associated disease, were analyzed. The various methods used to measure anastomotic leakage and the clinical courses of different sites of anastomotic leakage were compared. RESULTS: The overall complication rate was 18.7% and the incidence of anastomotic leakage was 2.7% (n=57). The anastomotic leakage-related mortality rate was 21.1% (n=12). Older age (> or =65 years), longer operating time, more blood loss, and co-morbidities were the precipitating factors. Adequate drainage was the treatment approach used for anastomotic leakage. The incidence of anastomotic leakage was reduced during the later period of the study (3.4% vs. 1.8%). CONCLUSION: Only in an institute with a well-established training program and high volume of gastric cancer patients can we improve the surgical skills and accumulate the experiences with management of anastomotic leakage that make radical gastrectomy safer.

Peritoneal recurrence in serosa-negative gastric adenocarcinoma after curative surgery.

BACKGROUND/AIMS: The rate of recurrence increases in proportion to the degree of tumor depth, even after curative resection for gastric adenocarcinoma. Serosal exposure is considered as an important risk factor of peritoneal recurrence. However, some patients with serosa-negative cancer were found to have peritoneal recurrence. There are few reports concerning risk factors of peritoneal recurrence in serosa-negative gastric adenocarcinoma. The aim of this study is to evaluate the incidence and risk factors of peritoneal recurrence in serosa-negative gastric adenocarcinoma after curative resection. METHODOLOGY: Total 1128 serosa-negative gastric cancer patients (574 pT1, 251 pT2, 303 pT3) diagnosed as gastric adenocarcinoma that underwent R0 resection from 1988 to 2005 were enrolled. RESULTS: Peritoneal recurrence was observed in 50 (4.4%) patients, including 3 pT1, 3 pT2 and 44 pT3 patients. The incidence of peritoneal recurrence increased significantly with tumor invading subserosa (pT3). Multivariate analysis showed that the independent risk factor of peritoneal recurrence was tumor depth. CONCLUSIONS: The incidence of peritoneal recurrence in serosa-negative cancer is low, and tumor depth is a significant risk factor. We should be aware of peritoneal recurrence during follow-up, especially for patients with subserosal tumor invasion.

Rapid staining and immediate interpretation of fine-needle aspiration cytology for palpable breast lesions: diagnostic accuracy, mammographic, ultrasonographic and histopathologic correlations.

OBJECTIVE: We investigated the role and turn around time of rapid staining and immediate interpretation of fine-needle aspiration cytology (FNAC) for women with palpable breast lesions. STUDY DESIGN: A total of 408 FNAC specimens from 400 patients with palpable breast lesions was analyzed for immediate interpretation and preliminary cytologic diagnosis. All cytological diagnoses were correlated with subsequent alcohol-fixed Papanicolaou-stained slides, mammographic, ultrasonographic and histopathological findings. RESULTS: Of the 408 specimens, 243 (59.6%) were interpreted as benign, 37 (9.0%) atypical, 22 (5.4%) suspicious, 68 (16.7%) malignant, and 38 (9.3%) unsatisfactory. 132 of 408 (32.4%) had subsequent surgical procedures; the sensitivity, specificity, positive predictive value, negative predictive value, and accuracy were 88.5, 100, 100, 81.9 and 92.4%, respectively. The average turn around time was 8.6 min. Mammographic results were available in 242 (59.3%) cases, with 112 (46.3%) undergoing surgical excision. In correlation with mammography and surgical pathology, the false-positive rate, false-negative rate, sensitivity, specificity and accuracy were 1.9, 10.5, 98.1, 89.5 and 95.8%, respectively. CONCLUSIONS: Rapid FNAC interpretation is a useful, effective diagnostic method for palpable breast lesions in our healthcare environment.

The Characteristics of 206 Long-Term Survivors with Peritoneal Metastases from Colorectal Cancer Treated with Curative Intent Surgery: A Multi-Center Cohort from PSOGI.

BACKGROUND: We conducted this study to review the patient characteristics associated with long-term survival in patients with peritoneal metastases from colorectal cancer who underwent cytoreductive surgery (CRS). METHODS: We retrospectively investigated patients with peritoneal metastases from CRC treated with curative intent surgery with or without hyperthermic intraperitoneal chemotherapy at 13 institutions worldwide between January 1985 and April 2015 and survived longer than five years after the first CRS for peritoneal metastases. Clinical and oncological features and therapeutic parameters were described and analyzed. RESULTS: Two hundred six long-term survivors were available for study. The median peritoneal cancer index (PCI) of this cohort was 4 (interquartile range (IQR), 2-7), and the median score of the small bowel regions of the PCI (SB-PCI) was 0 (IQR, 0-2). Complete cytoreduction (CC-0) was achieved in 180 (87.4%) patients. Recurrence was observed in 122 (59.2%) patients at a median of 1.8 (IQR, 1.2-2.6) years. CONCLUSIONS: While most long-term survivors showed low PCI/SB-PCI and CCR-0, some had characteristics considered associated with poor prognosis. Curative intent treatments may be considered in well-informed and fit patients showing negative factors affecting survival outcome.

Esophagogastric junction adenocarcinoma according to Siewert classification in Taiwan.

BACKGROUND: The incidence of adenocarcinoma of the esophagogastric junction (AEG) is rapidly increasing. We evaluated the clinicopathological difference and outcomes of Taiwanese patients with AEG according to the Siewert classification. METHODS: Data were prospectively collected between December 1987 and July 2007. Two hundred thirty-one patients underwent curative resection of AEG at Taipei Veterans General Hospital and were divided into different Siewert types. The clinicopathological characteristics, operative morbidity, survival, and initial recurrence pattern were compared between the different types. RESULTS: Fifty-one type II and 180 type III cancer patients were studied. Subtotal esophagectomy via a left thoracotomy (19.6% vs 2.8%), smaller tumor size (4.43 +/- 2.04 vs. 5.35 +/- 2.03 cm), and more combined organ resection (60% vs. 43.1%) were more common in type II than type III cancer. Multivariate analysis showed that three independent risk factors for death were gender, tumor size, and lymphovascular invasion. There were long-term survivors among the patients with lesser curvature site lymph node metastasis, whereas metastasis to the lymph nodes of the distal stomach and along the greater curvature site was associated with poor prognosis. The 5-year survival was similar between type II and type III cancer (59.6% vs. 63.5%, P = 0.947). CONCLUSIONS: Lymphovascular invasion, tumor size, and gender were determined to be three independent factors of survival after curative resection for AEG, and Siewert type was not associated with differences in survival.

Factors affecting recurrence in node-negative advanced gastric cancer.

BACKGROUND AND AIM: Prognostic factors of lymph node-negative gastric adenocarcinoma after curative resection have been discussed. Recurrent pattern of advanced lymph node-negative gastric cancer after curative resection has rarely been described. METHODS: Recurrent sites and correlated clinicopathological factors of 372 patients with lymph node-negative advanced gastric adenocarcinoma that underwent R0 resection from 1988 to 2005 were analyzed. RESULTS: Recurrence was noted in 51 (13.7%) patients. Recurrent rates according to site of recurrence were 26 peritoneal seeding (51.0%), 26 locoregional (51.0%), 17 hematogenous (33.3%), and 4 lymph node metastasis (7.8%). Clinicopathological factors to predict peritoneal seeding were serosal exposure, lymphovascular invasion, Lauren's diffuse type differentiation and scirrhous stromal reaction. Serosal exposure, tumor size, microscopic infiltrating growth type predicts locoregional recurrence. Tumor had only lymphovascular invasion predict hematogenous spreading. CONCLUSION: Node-negative advanced gastric cancer has more peritoneal seeding and locoregional recurrence. Aggressive cell behavior predicted the route of tumor cell spreading.

Mucin-producing gastric cancer: clinicopathological difference between signet ring cell carcinoma and mucinous carcinoma.

BACKGROUND/AIMS: Signet ring cell carcinoma and mucinous carcinoma are mucin-producing gastric cancers. Their clinicopathological difference was obscure. METHODOLOGY: From December 1987 to July 2005, a total of 1612 gastric cancer patients received curative surgery, 128 patients with signet ring cell carcinoma and 48 with mucinous carcinoma were enrolled in this study. Clinicopathological data were compared between the two groups. RESULTS: Early stage (stage I and II) patients with mucinous carcinoma were associated with more male predominant (p = 0.002), larger tumor size (p = 0.020), deeper cancer invasion (p < 0.001), and a worse 5-year overall survival (63.6% vs 88.2%, p = 0.012) than those with signet ring cell carcinoma. There was no significant difference between the two groups with advanced stage in 5-year overall survival. There is no significant difference in the initial recurrence pattern between the two groups. CONCLUSIONS: Patients with mucinous carcinoma had different biological behaviors with those with signet ring cell carcinoma, in particular early stage, hence had a worse survival.

Metformin reduces radiation-induced cardiac toxicity risk in patients having breast cancer.

To analyze the effects of metformin in reducing radiation-induced cardiac toxicity (RICT) risk during adjuvant radiotherapy (RT) after surgery for early-stage breast cancer women. We compare the consecutive occurrence of major heart events (heart failure and coronary artery disease) in women with early-stage breast cancer receiving adjuvant breast RT with metformin and in those receiving RT without metformin. A retrospective national cohort study was conducted using the Taiwan Cancer Registry of 2004-2014. This study included 6,993 women with early-stage breast cancer who received adjuvant breast RT. Metformin users were defined as patients prescribed metformin for >28 days during adjuvant breast RT. An inverse probability of treatment weighting (IPTW) Cox hazards model was used to estimate metformin effects on the occurrence of major heart events. Among women with breast cancer status post-surgery under adjuvant breast RT, 2,062 were prescribed metformin and 4,931 were not prescribed metformin. Cox proportional hazard regression analysis, with adjustment using IPTW, indicated that metformin use during adjuvant breast RT significantly reduces the risk of major heart events (adjusted hazard ratio [aHR], 0.789; 95% confidence interval [CI], 0.645-0.965; P = 0.021). In another negative control exposure, thiazolidinedione use during adjuvant breast RT did not statistically reduce consecutive RICT risk (aHR, 1.106; 95% CI, 0.768-1.594; P = 0.589). Our results suggest that metformin use during adjuvant breast RT was associated with reduced RICT risk in women with early-stage breast cancer.

Effects of duodenal-jejunal bypass surgery in ameliorating nonalcoholic steatohepatitis in diet-induced obese rats.

BACKGROUND: Duodenal-jejunal bypass (DJB) is an important component of many types of current bariatric surgery including Roux-en-Y gastric bypass, mini-gastric bypass, biliopancreatic diversion, duodenal switch, and DJB plus sleeve gastrectomy. Surgery is often observed to ameliorate nonalcoholic steatohepatitis (NASH), but without a clearly delineated mechanism. In this study, we investigated the effects of DJB in diet-induced obese rats with NASH. MATERIALS AND METHODS: Male Wistar rats were divided into four groups and fed the following diets over 6 months: A) normal chow (NC group, n=6); B) methionine-choline-deficient (MCD)-high-fat (HF) diet (HF group, n=6); C) MCD-HF diet for 3 months followed by DJB and MCD-HF diet for subsequent 3 months (DJB group, n=6); and D) MCD-HF diet for 3 months followed by treatment with pioglitazone (PGZ) with MCD-HF diet for subsequent 3 months (PGZ group, n=6). Body weight, glucose tolerance, the homeostatic model assessment-insulin resistance index, and lipid profiles were compared. Liver and visceral adipose tissue histology, inflammatory marker and hepatic stellate cell (HSC) activity, and hepatocyte autophagy were assessed. RESULTS: Compared with the HF group, the DJB group showed improved body weight, insulin sensitivity, lipid metabolism, and steatosis severity. The DJB group exhibited a significantly lower nonalcoholic fatty liver disease activity score than the HF and PGZ group (P<0.001 and P=0.003, respectively). Furthermore, DJB significantly reduced fat mass and adipocyte size. These effects were also observed in the PGZ group. Therefore, we speculated that the improvements induced by DJB are closely related to an alteration in insulin sensitivity. Moreover, DJB reduced HSC activity and TNF-α expression and enhanced hepatocyte autophagy. CONCLUSION: DJB improves NASH through several mechanisms, particularly by altering insulin sensitivity, inflammatory responses, HSC activity, and hepatocyte autophagy.