Efficacy and safety of one anastomosis gastric bypass versus Roux-en-Y gastric bypass for type 2 diabetes remission (ORDER): protocol of a multicentre, randomised controlled, open-label, superiority trial.

INTRODUCTION: Previous studies have demonstrated that one anastomosis gastric bypass (OAGB) is not inferior to Roux-en-Y gastric bypass (RYGB) in treating obesity. However, high level evidence comparing the efficacy and safety of both procedures in type 2 diabetes (T2D) treatment is still lacking, which is another main aim of bariatric surgery. The presented trial has been designed to aim at investigating the superiority of OAGB over the reference procedure RYGB in treating T2D as primary endpoint. And diabetes-related microvascular and macrovascular complications, cardiovascular comorbidities, weight loss, postoperative nutritional status, quality of life and overall complications will be followed up for 5 years as secondary endpoints. METHODS AND ANALYSIS: This prospective, multicentre, randomised superiority open-label trial will be conducted in patients of Asian descent. A total of 248 patients (BMI≥27.5 kg/m2) who are diagnosed with T2D will be randomly assigned (1:1) to OAGB or RYGB with blocks of four. The primary endpoint is the complete diabetes remission rate defined as HbA1c≤6.0% and fasting plasma glucose≤5.6 mmol/L without any antidiabetic medications at 1 year after surgery. All secondary endpoints will be measured at different follow-up visit points, which will start at least 3 months after enrolment, with a continuous annual follow-up for five postoperative years in order to provide solid evidence on the efficacy and safety of OAGB in patients with T2D. ETHICS AND DISSEMINATION: The study has been approved by the ethics committee of leading centre (Beijing Friendship Hospital, Capital Medical University, no. 2021-P2-037-03). The results generated from this work will be disseminated to academic audiences and the public via publications in international peer-reviewed journals and conferences. The data presented will be imported into a national data registry. Findings are expected to be available in 2025, which will facilitate clinical decision-making in the field. TRIAL REGISTRATION NUMBER: NCT05015283.

Five-year effectiveness of bariatric surgery on disease remission, weight loss, and changes of metabolic parameters in obese patients with type 2 diabetes: A population-based propensity score-matched cohort study.

AIMS: To compare disease remission rates, weight loss, and changes of metabolic parameters of patients after bariatric surgery with nonsurgical patients. METHODS: Based on the 2006-2017 Hospital Authority database, a population-based retrospective cohort of obese type 2 diabetes mellitus (T2DM) patients with and without bariatric surgery were identified. Surgical patients were matched with nonsurgical patients on 1-to-5 propensity score. Remission rates of diabetes, hypertension, and dyslipidaemia were reported annually up to 60 months. Changes in weight loss measurements (Body Mass Index [BMI], percentage of total weight loss [%TWL], percentage of excess weight loss [%EWL], and percentage of rebound in excess weight loss [%REWL]) and metabolic parameters (haemoglobin A1c [HbA1c ], systolic blood pressure [SBP], diastolic blood pressure [DBP], and low-density lipoprotein cholesterol [LDL-C]) were measured for both groups. RESULTS: Four hundred one surgical patients (310 restrictive surgeries; 91 bypass surgeries) and 1894 nonsurgical patients were included. Surgical patients had higher remission rates in diabetes and dyslipidaemia and better glycaemic control at 12 to 60 months (all Ps < .01). SBP and DBP were significantly lower for surgical group up to 12 months and similar between two groups after 12 months. Surgical patients had significantly lower BMI during follow-up period. %TWL and %EWL were higher in the surgery group (15.7% vs 3.7%; 48.8% vs 12.0%) at 60 months (P < .001); differences in %REWL between two groups were insignificant. The effectiveness of restrictive and bypass surgeries was similar at 60 months, although restrictive surgeries were slightly more effective in T2DM remission. CONCLUSIONS: Bariatric surgery was effective in weight loss, remission of diabetes, and dyslipidaemia in 5-year post-surgery.

Overexpression of microRNA-1288 in oesophageal squamous cell carcinoma.

PURPOSE: This study aims to examine the expression profiles miR-1288 in oesophageal squamous cell carcinoma (ESCC). The cellular implications and target interactions of ESCC cells following miR-1288 overexpression was also examined. METHODS: In total, 120 oesophageal tissues (90 primary ESCCs and 30 non-neoplastic tissues) were recruited for miR-1288 expression analysis using qRT-PCR. An exogenous miR-1288 mimic and its inhibitor were used to explore the in-vitro effects of miR-1288 on ESCC cells by performing cell proliferation, colony formation, cell invasion and migration assays. Localisation and modulatory changes of various miR-1288 regulated proteins such as FOXO1, p53, TAB3, BCL2 and kRAS was examined using immunofluorescence and western blot. RESULTS: Overexpression of miR-1288 was more often noted in ESCC tissues when compared to non-neoplastic oesophageal tissues. High expression was often noted in high grade carcinomas and with metastases. Patients with high levels of miR-1288 expression showed a slightly better survival compared to patients with low miR-1288 levels. Furthermore, overexpression of miR-1288 showed increased cell proliferation and colony formation, improved cell migration and enhanced cell invasion properties in ESCC cells. In addition, miR-1288 overexpression in ESCC cells showed repression of cytoplasmic tumour suppressor FOXO1 protein expression. Inversely, inhibition of miR-1288 expression exhibited remarkable upregulation of FOXO1 protein, while expressions of other tested proteins remain unchanged. CONCLUSIONS: Up regulation of miR-1288 expression in ESCC tissues and miR-1288 induced oncogenic features of ESCC cells in-vitro indicates the oncogenic roles of miR-1288 in ESCCs. Overexpression of miR-1288 play a key role in the pathogenesis of ESCCs and its modulation may have potential therapeutic value in patients with ESCC.

Corrigendum to "A Versatile Orthotopic Nude Mouse Model for Study of Esophageal Squamous Cell Carcinoma".

[This corrects the article DOI: 10.1155/2015/910715.].

Nuclear Localization of DNAJB6 Is Associated With Survival of Patients With Esophageal Cancer and Reduces AKT Signaling and Proliferation of Cancer Cells.

BACKGROUND & AIMS: The DnaJ (Hsp40) homolog, subfamily B, member 6 (DNAJB6) is part of a family of proteins that regulates chaperone activities. One of its isoforms, DNAJB6a, contains a nuclear localization signal and regulates ß-catenin signaling during breast cancer development. We investigated the role of DNAJB6 in the pathogenesis of esophageal squamous cell carcinoma (ESCC). METHODS: We performed immunohistochemical analyses of primary ESCC samples and lymph node metastases from a cohort of 160 patients who underwent esophagectomy with no preoperative chemoradiotherapy at Hong Kong Queen Mary Hospital. Data were collected on patient outcomes over a median time of 12.1 ± 2.9 months. Retrospective survival association analyses were performed. Wild-type and mutant forms of DNAJB6a were overexpressed in cancer cell lines (KYSE510, KYSE 30TSI, KYSE140, and KYSE70TS), which were analyzed in proliferation and immunoblot assays, or injected subcutaneously into nude mice. Levels of DNAJB6 were knocked down in ESCC cell lines (KYSE450 and T.Tn), immortalized normal esophageal epithelial cell lines (NE3 and NE083), and other cells with short hairpin RNAs, or by genome engineering. Bimolecular fluorescence complementation was used to study interactions between proteins in living cells. RESULTS: In primary ESCC samples, patients whose tumors had high nuclear levels of DNAJB6 had longer overall survival times (19.2 ± 1.8 months; 95% confidence interval [CI], 15.6-22.8 mo) than patients whose tumors had low nuclear levels of DNAJB6 (12.6 ± 1.4 mo; 95% CI, 9.8-15.4 mo; P = .004, log-rank test). Based on Cox regression analysis, patients whose tumors had high nuclear levels of DNAJB6 had a lower risk of death than patients with low levels (hazard ratio, 0.562; 95% CI, 0.379-0.834; P = .004). Based on log-rank analysis and Cox regression analysis, the combination of the nuclear level of DNAJB6 and the presence of lymph node metastases at diagnosis could be used to stratify patients into groups with good or bad outcomes (P < .0005 for both analyses). There was a negative association between the nuclear level of DNAJB6 and the presence of lymph node metastases (P = .022; Pearson χ(2) test). Cancer cell lines that overexpressed DNAJB6a formed tumors more slowly in nude mice than control cells or cells that expressed a mutant form of DNAJB6a that did not localize to the nucleus. DNAJB6 knockdown in cancer cell lines promoted their growth as xenograft tumors in mice. A motif of histidine, proline, and aspartic acid in the J domain of DNAJB6a was required for its tumor-suppressive effects and signaling via AKT1. Loss of DNAJB6a resulted in up-regulation of AKT signaling in cancer cell lines and immortalized esophageal epithelial cells. Expression of a constitutively active form of AKT1 restored proliferation to tumor cells that overexpressed DNAJB6a, and DNAJB6a formed a complex with AKT1 in living cells. The expression of DNAJB6a reduced the sensitivity of ESCC to AKT inhibitors; the expression level of DNAJB6a affected AKT signaling in multiple cancer cell lines. CONCLUSIONS: Nuclear localization of DNAJB6 is associated with longer survival times of patients with ESCC. DNAJB6a reduces AKT signaling, and DNAJB6 expression in cancer cells reduces their proliferation and growth of xenograft tumors in mice. DNAJB6a might be developed as a biomarker for progression of ESCC.

Factors that affect PERCIST-defined test-retest comparability: an exploration of feasibility in routine clinical practice.

PURPOSE: The aim of this study was to evaluate the factors affecting the comparability of F-FDG PET/CT scans using the PERSIST criteria for treatment response evaluation in a clinical PET/CT unit. PATIENTS AND METHODS: Patients diagnosed with esophageal cancer were assessed for treatment response by comparing 2 F-FDG PET/CT scans, at baseline (PET 1) and 1 month after the end of induction chemoradiation (PET 2). According to the PERCIST recommendations, patients with mean SUV normalized by the lean body mass within reference volume of interest that changed less than 0.3 unit and less than 20% were deemed as comparable. Absolute differences of body weight, blood glucose level, activity of F-FDG, and uptake time between the 2 scans were computed. Binary logistic regression was used to identify the predictive factors, and receiver operating characteristic curves were used for thresholds. P < 0.05 was considered statistically significant. RESULTS: Sixty-nine subjects were identified. The mean (SD) values at PET 0 and PET 2 were 5.9 (1.04) mmol/L and 6.2 (1.06) mmol/L (P = 0.013), 54.6 (10.0 kg) and 53.3 (10.3 kg) (P = 0.013), 7.7 (1.3 mCi) and 7.6 (1.5 mCi) (P = 0.349), as well as 74.2 (12.4) minutes and 73.0 (12.3) minutes (P = 0.539), for blood glucose level, body weight, injected activity, and uptake time, respectively. Seventeen (24.6%) failed to match the PERCIST-defined comparability criteria. Case-based discrepancies (mean [SD]) were 0.76 (0.62) mmol/L, 3.4 (2.9) kg, 0.8 (0.7) mCi, and 11.7 (9.8) minutes for blood glucose, body weight, injected activity, and uptake time, respectively, of which only uptake time significantly affected comparability (P = 0.046; odds ratio, 1.06; 95% confidence interval, 1.00-1.12), with a limit of 2.2-minute discrepancy identified as the requirement for 100% comparability. CONCLUSIONS: Uptake time had the strongest effect on PERCIST-defined comparability. Therefore, for response assessment scans, reference to initial scans for determination of optimal uptake time is recommended.

A versatile orthotopic nude mouse model for study of esophageal squamous cell carcinoma.

Increasing evidence indicates tumor-stromal interactions play a crucial role in cancer. An in vivo esophageal squamous cell carcinoma (ESCC) orthotopic animal model was developed with bioluminescence imaging established with a real-time monitoring platform for functional and signaling investigation of tumor-stromal interactions. The model was produced by injection of luciferase-labelled ESCC cells into the intraesophageal wall of nude mice. Histological examination indicates this orthotopic model is highly reproducible with 100% tumorigenesis among the four ESCC cell lines tested. This new model recapitulates many clinical and pathological properties of human ESCC, including esophageal luminal stricture by squamous cell carcinoma with nodular tumor growth, adventitia invasion, lymphovascular invasion, and perineural infiltration. It was tested using an AKT shRNA knockdown of ESCC cell lines and the in vivo tumor suppressive effects of AKT knockdown were observed. In conclusion, this ESCC orthotopic mouse model allows investigation of gene functions of cancer cells in a more natural tumor microenvironment and has advantages over previous established models. It provides a versatile platform with potential application for metastasis and therapeutic regimen testing.

Current management of cervical esophageal cancer.

BACKGROUND: Pharyngo-laryngo-esophagectomy (PLE) has been regarded as a standard treatment for cervical esophageal cancer, but the morbidity and mortality rates associated with PLE are substantial. Chemoradiation (CTRT) is widely used to treat esophageal cancer; however, its role in managing cervical esophageal cancer has not been fully elucidated. It was hypothesized that up-front CTRT could be an effective alternative treatment option to PLE. The purpose of this study was to compare the outcomes of patients with cervical esophageal cancer treated with these two methods. METHODS: Patients with cervical esophageal cancer from 1995 to 2008 were studied. Three main groups were identified: those treated with PLE, those managed with up-front concurrent chemoradiation, and those not suitable for either PLE or chemoradiation but to whom palliative treatment was offered. The demographics, management strategies, and outcomes of these patients were studied and analyzed. RESULTS: A total of 107 patients were studied: 87 (81.3%) were men, and the median age was 64 years (range 17-92 years). There were 62 patients who underwent PLE as the primary treatment, 21 had up-front chemoradiation, and the others had palliative treatment. In the PLE group, curative resection was achieved in 37 (59.7%) patients, 20 of whom had either adjuvant chemoradiation or radiotherapy. The hospital mortality rate was 7.1%. In the chemoradiation group, 10 (47.6%) had tumor down-staging, 6 of whom achieved a clinically complete response. Among the 11 patients with poor response, 5 required salvage PLE for palliation. Chemoradiation-associated morbidities included oral mucositis, bilateral vocal cord palsy, esophageal stricture, carotid artery blowout, and permanent hypothyroidism and hypoparathyroidism. The median survival durations of patients in the PLE and chemoradiation groups were 20 and 25 months respectively (P = 0.39). CONCLUSIONS: Up-front chemoradiation can be an alternative therapeutic strategy to PLE. However, this method is not without drawbacks. A significant proportion also requires salvage surgery. Both PLE and chemoradiation have significant curative as well as palliative role in the management of cervical esophageal cancer and treatment should be individualized.

Histological regression of squamous esophageal carcinoma assessed by percentage of residual viable cells after neoadjuvant chemoradiation is an important prognostic factor.

BACKGROUND: Whether the TNM staging system is applicable after neoadjuvant chemoradiation in esophageal cancer is controversial. The aim of this study was to evaluate the prognostic value of histopathological regression of the primary tumor in postchemoradiated patients. MATERIALS AND METHODS: The pretherapeutic and pathological ypTNM stages of patients who have had neoadjuvant chemoradiation followed by esophagectomy were analyzed. The percentage of residual viable cells of the primary tumor (ypV) and other clinicopathological factors were tested for their prognostic value. RESULTS: Of 175 recruited patients, 55 (31.4%) achieved pathological complete response. The median survival of these 55 patients was significantly longer than those with other disease stages (124.8 vs 21.1 months) (P < .001). Gender, ypT, ypN, ypTNM, and ypV stage were significant prognostic factors in univariate analysis. In patients without nodal metastases, the median survival in patients with residual viable cells in the primary tumor (ypV+) was 24.6 months, compared with that of 124.8 months in those with no viable cells (ypV0) (P = .043). In those who had nodal metastases, the median survival of patients with ypV0 and ypV+ were 21.2 months and 17.4 months respectively (P = .37). Cox regression analysis showed that male gender, high percentage of residual viable cells (ypV), and positive nodal status (ypN1) were independent predictors of poor prognosis. CONCLUSIONS: In patients who underwent neoadjuvant chemoradiation therapy, histopathological regression of the primary tumor indicated by percentage of residual viable cells is an important prognostic factor in addition to nodal status and gender.

Transvaginal cholecystectomy with endoscopic submucosal dissection instruments and single-channel endoscope: a survival study in porcine model.

BACKGROUND: Natural orifice transluminal endoscopic surgery has received much attention in recent years. Instead of using prototype devices, we explored the feasibility and practicability of using readily available off-the-shelf devices to perform Natural Orifice Transluminal Endoscopic Surgery in an animal model. METHODS: Twenty pigs underwent transvaginal cholecystectomy, 16 of which were used for surviving study after the procedure. A single-channel endoscope and standard instruments for endoscopic submucosal dissection (hook knife and Insulated Tip knife) were used for cholecystectomy. A single 5-mm laparoscopic port was inserted for gallbladder retraction. RESULTS: Completion of the procedure was achieved in all 20 pigs. In 16 pigs, which were used for surviving study after surgery, 15 survived. Death of 1 pig was due to leakage of urine from the colpotomy and urogenital sinus. Technical success was achieved in the access, dissection, and retrieval of specimen in all the animals. CONCLUSIONS: A hybrid approach with single-channel endoscope together with endoscopic submucosal dissection instruments for transvaginal cholecystectomy was shown to be safe and feasible in this pig model and this serves as a good training model before application of this technique in human. A distinct pattern of complications was identified and needed to be addressed.

Cervical nodal metastasis from intrathoracic esophageal squamous cell carcinoma is not necessarily an incurable disease.

BACKGROUND: It remains controversial if metastatic cervical lymph nodes in patients with intrathoracic esophageal cancer signify distant metastases and are therefore incurable or if they should be regarded as regional spread with a potential for cure. MATERIAL AND METHODS: Patients with intrathoracic esophageal squamous cell carcinoma managed from 1995 to 2007, in whom metastatic cervical lymph node spread was confirmed by fine needle aspiration cytology, were studied. Treatment strategies and outcome were reviewed. RESULTS: There were 109 patients, of whom 98 were men. Median age was 62 years (range, 34-88). Excluding those who underwent primarily palliative treatments, there were two main groups: 22 who had upfront chemoradiation therapy and subsequent esophagectomy +/- cervical lymphadenectomy and 46 who had chemoradiation only. Significant downstaging occurred in 29 of the 68 patients (42.6%), of whom eight (11.8%) had complete pathological/clinical response. There was no mortality after esophagectomy. Median survival of patients with chemoradiation plus esophagectomy was 34.8 months compared to those with no surgery at 9.9 months, (p < 0.001). Patients with stage IV disease at presentation by virtue of nodal disease survived longer than those with the same stage because of systemic organ metastases: 9.3 vs. 3 months, (p < 0.001). CONCLUSIONS: Prognosis of patients with metastatic cervical nodes was not uniformly dismal. Up to 20% had reasonable survival after chemoradiation and surgical resection. Stage IV disease should be revised to segregate those with nodal and systemic metastases.