Wolfram syndrome 1 gene regulates pathways maintaining beta-cell health and survival.

Wolfram Syndrome 1 (WFS1) protein is an endoplasmic reticulum (ER) factor whose deficiency results in juvenile-onset diabetes secondary to cellular dysfunction and apoptosis. The mechanisms guiding ß-cell outcomes secondary to WFS1 function, however, remain unclear. Here, we show that WFS1 preserves normal ß-cell physiology by promoting insulin biosynthesis and negatively regulating ER stress. Depletion of Wfs1 in vivo and in vitro causes functional defects in glucose-stimulated insulin secretion and insulin content, triggering Chop-mediated apoptotic pathways. Genetic proof of concept studies coupled with RNA-seq reveal that increasing WFS1 confers a functional and a survival advantage to ß-cells under ER stress by increasing insulin gene expression and downregulating the Chop-Trib3 axis, thereby activating Akt pathways. Remarkably, WFS1 and INS levels are reduced in type-2 diabetic (T2DM) islets, suggesting that WFS1 may contribute to T2DM ß-cell pathology. Taken together, this work reveals essential pathways regulated by WFS1 to control ß-cell survival and function primarily through preservation of ER homeostasis.

Prognostic significance of tumor budding in rectal cancer biopsies before neoadjuvant therapy.

Tumor budding is an increasingly important prognostic feature for pathologists to recognize. The aim of this study was to correlate intra-tumoral budding in pre-treatment rectal cancer biopsies with pathological response to neoadjuvant chemoradiotherapy and with long-term outcome. Data from a prospectively maintained database were acquired from patients with locally advanced rectal cancer who underwent neoadjuvant chemoradiotherapy. Pre-treatment rectal biopsies were retrospectively reviewed for evidence of intra-tumoral budding. Multivariate logistic regression was used to identify factors contributing to cancer-specific death, expressed as hazard ratios with 95% confidence intervals. Of the 185 patients with locally advanced rectal cancer, 89 patients met the eligibility criteria, of whom 18 (20%) exhibited budding in a pre-treatment tumor biopsy. Intra-tumoral budding predicted a poor pathological response to neoadjuvant chemoradiotherapy (higher ypT stage, P=0.032; lymph node involvement, P=0.018; lymphovascular invasion, P=0.004; and residual poorly differentiated tumors, P=0.005). No patient with intra-tumoral budding exhibited a tumor regression grade 1 or complete pathological response, providing a 100% specificity and positive predictive value for non-response to neoadjuvant chemoradiotherapy. Intra-tumoral budding was associated with a lower disease-free 5-year survival rate (33 vs 78%, P<0.001), cancer-specific 5-year survival rate (61 vs 87%, P=0.021) and predicted cancer-specific death (hazard ratio 3.51, 95% confidence interval 1.03-11.93, P=0.040). Intra-tumoral budding at diagnosis of rectal cancer identifies those who will poorly respond to neoadjuvant chemoradiotherapy and those with a poor prognosis.

A comparative study of short- and medium-term outcomes comparing emergent surgery and stenting as a bridge to surgery in patients with acute malignant colonic obstruction.

BACKGROUND: The use of self-expanding metal stents as a bridge to surgery in the setting of malignant colorectal obstruction has been advocated as an acceptable alternative to emergency surgery. However, concerns about the safety of stenting have been raised following recent randomized studies. OBJECTIVES: The aim of the current study was to compare outcomes. DESIGN: This was an observational, comparative study. SETTINGS: This study was conducted at a tertiary referral center and university teaching hospital. PATIENTS AND INTERVENTIONS: Patients with malignant colonic obstruction (n = 49) treated by either emergency surgery (n = 26) or with stent placement (n = 23) as a bridge to surgery were identified and followed. MAIN OUTCOME MEASURES: Short-term outcomes including stoma rates and postoperative morbidity and medium-term oncological outcomes were compared based on an "intention-to-treat" analysis. RESULTS: Patients in both groups were well matched on clinicopathological parameters. Technical and clinical successful stent deployment was achieved in 91% and 83%. This did not adversely impact cancer-specific and overall survival (log rank = nonsignificant). No difference was observed in stoma rates, primary anastomosis rates, perioperative mortality rates, or reoperation rates between the 2 groups. Significantly fewer patients underwent total colectomy in the stent group in comparison with the emergency surgery group (1/23 vs 6/26: p = 0.027). There was no difference in postoperative morbidity (59% vs 66%: p = 0.09). There was a significant reduction in readmission rates in the stent group (5/26 vs 0/23: p = 0.038). LIMITATIONS: The small sample size of this study could lead to type II error. In addition, the study was nonrandomized and demonstrated a limited length of follow-up. CONCLUSION: Despite a high rate of technical and clinical success in selected patients with colonic obstruction, stenting has no impact on stoma rates. Despite concerns about the rate of stent-associated perforation, stenting does not adversely impact disease progression or survival. Future comparative trials are essential to better define the role of stenting in this setting and to ensure that we are not using costly technology to create an elective operative situation without concomitant patient benefits.

Stage II colonic adenocarcinoma: a detailed study of pT4N0 with emphasis on peritoneal involvement and the role of tumour budding.

AIMS: Evaluation of peritoneal involvement in colonic cancer (CC) can be difficult. We studied pT4N0 cancers and their association with pathological prognostic markers, including tumour budding. METHOD AND RESULTS: Tumours were classified as (i) at the peritoneal surface or free in the peritoneal cavity (pT4a subgroup n = 44); (ii) directly invading adjacent organ (pT4b subgroup n = 8); or (iii) showing inflammatory involvement of the peritoneum (pT4I subgroup n = 25). A published pT3N0 cohort was used to compare Stage II subgroups. Standard pathological markers including tumour budding were assessed. Elastin staining was performed in the pT4I subgroup. Seventy-seven Stage II CCs met inclusion criteria. There was no significant difference in survival across subgroups. pT4b tumours were larger than pT4a tumours (P < 0.001). Over-represented features in pT4a versus pT4b tumours were tumour budding (P = 0.02) and infiltrative margin (P = 0.02). Tumour budding did not predict survival. Using multivariate analysis, neural invasion was the only parameter predictive of survival (hazard ratio = 2.8; 95% CI 1.2-6.4; P = 0.02). CONCLUSION: Stage II pT4I CCs have a similar outcome to T4a/b tumours. Elastin staining is useful in defining this group. Tumour budding may facilitate peritoneal invasion in pT4a tumours, but does not predict outcome in pT4N0 disease. Only neural invasion independently predicted poor outcome.

A prospective analysis of patient outcome following treatment of T3 rectal cancer with neo-adjuvant chemoradiotherapy and transanal excision.

BACKGROUND: Local excision is an alternative to anterior or abdomino-perineal resection in patients with early rectal cancer. In more advanced disease, neo-adjuvant therapy (CRXT) can result in significant disease regression such that local excision may be considered. The primary aim was to assess oncological outcome in patients with T3 rectal cancer treated with CRXT and local excision due to unsuitability for or aversion to anterior resection and stoma. The secondary aim was to examine oncological outcomes in patients treated in a similar way in the published literature. METHODS: Between July 2006 and July 2009, patients with rectal cancer staged T3, N0/N1, M0 who were deemed unfit for or who refused anterior resection were offered long-course CRXT. Patients were restaged 8 weeks following completion. If there was a good response (regression grade 2 or 3 clinically and radiologically), full thickness transanal excision was performed. All patients were followed regularly (monthly CT abdomen/pelvis and annual endoscopy) to assess for recurrence of disease. A literature search of PubMed was performed to identify all prospective data available of T3 rectal cancers managed with CRXT and local excision. RESULTS: Ten patients were treated over 3 years. Six patients had complete pathological response, while four patients had a partial response. The resection margins following local excision were clear in all. There was no local recurrence (median follow-up 24 months, range 9-42 months). CONCLUSION: Neo-adjuvant chemoradiotherapy and local excision is an option in patients unfit for or averse to major surgical resection if there is a good response to CRXT.

Treatment and outcomes of anorectal melanoma.

INTRODUCTION: anorectal melanoma is an uncommon disease constituting less than 3% of all melanomas. Due to its rarity, there are a lack of randomized control trials regarding appropriate management and current evidence is based mainly on retrospective studies. METHODS: in view of the controversial surgical treatment of anorectal melanoma, we review the most published literature in an attempt to elucidate its typical clinical features along with current thinking with respect to management approaches to this aggressive disease. Using the keywords "anorectal" and "malignant melanoma", a medline search of all articles in English was performed and the relevant articles procured. Additional references were retrieved by cross reference from key articles. RESULTS: anorectal melanoma affects the elderly with a slight preponderance for females. It commonly presents disguised as benign disease with local bleeding or suspicion for haemorrhoidal disease. There is no convincing evidence to indicate that radical resection of primary anorectal melanoma is associated with improvement in local control or survival, and local excision is an acceptable treatment option. CONCLUSION: optimum management depends on several factors and the therapeutic goals should be to lengthen survival and preserve quality-of-life. Given that wide local excision is a more limited intervention with comparable survival it should be considered as the initial treatment choice. Unfortunately prognosis for patients with this disease remains poor despite choice of treatment strategy with overall five year disease-free survival less than twenty percent in most studies.

Cardiac surgery in octogenarians and beyond.

Should we do it, is it worthwhile, and who should decide?