mTORC1 in the Paneth cell niche couples intestinal stem-cell function to calorie intake.

How adult tissue stem and niche cells respond to the nutritional state of an organism is not well understood. Here we find that Paneth cells, a key constituent of the mammalian intestinal stem-cell (ISC) niche, augment stem-cell function in response to calorie restriction. Calorie restriction acts by reducing mechanistic target of rapamycin complex 1 (mTORC1) signalling in Paneth cells, and the ISC-enhancing effects of calorie restriction can be mimicked by rapamycin. Calorie intake regulates mTORC1 in Paneth cells, but not ISCs, and forced activation of mTORC1 in Paneth cells during calorie restriction abolishes the ISC-augmenting effects of the niche. Finally, increased expression of bone stromal antigen 1 (Bst1) in Paneth cells­an ectoenzyme that produces the paracrine factor cyclic ADP ribose­mediates the effects of calorie restriction and rapamycin on ISC function. Our findings establish that mTORC1 non-cell-autonomously regulates stem-cell self-renewal, and highlight a significant role of the mammalian intestinal niche in coupling stem-cell function to organismal physiology.

Impact of perineal Crohn's disease on utilization of care in the absence of modifiable predictors of treatment failure.

INTRODUCTION: The burden of perineal Crohn's disease (PCD) remains poorly characterized, and many patients ultimately require fecal diversion or proctectomy. Our goal was to characterize the clinical course of patients presenting with perineal Crohn's disease, focusing on the cohort of patients ultimately requiring fecal diversion, and identify modifiable predictors for this unfortunate outcome. METHODS: We performed a retrospective review of 81 consecutive patients who underwent 172 operations to address complications of PCD. Diverted patients were compared to those who did not require diversion in regard to demographics, surgical procedure, postoperative infliximab, and presence of proctitis (chi square, t tests). Logistic regression was utilized to predict the need for fecal diversion. The number of visits needed to undergo care for this condition was quantified. RESULTS: Eight-one patients underwent a total of 172 surgical procedures and had a total of 2713 outpatient visits (range 1-118) to address symptoms of perineal Crohn's disease. Following first intervention, only 57.1 % healed at 3 months. These rates were highest in patients treated with fistulotomies and were not impacted by whether patients received postoperative infliximab (p = 0.703). Patients (23.5 %) underwent three or more surgical procedures to control their PCD and ultimately only 60 % healed without diversion, which was performed in 19 (23.5 %) patients. Patients undergoing more than three operations (OR = 10.9, p = 0.006) and women with rectovaginal fistula (OR = 3.88, p < 0.01) were at a high risk for diversion. Modifiable factors such as infliximab, smoking, proctitis, and surgery aimed at closing the internal anal opening did not alter outcome. CONCLUSIONS: In the patients with perineal Crohn's, complex fistulas healing rates appear to be independent of postoperative infliximab or procedures aimed at closing the internal anal opening. Those who do not heal require numerous specialist visits.

A prospective, randomized trial of esophageal submucosal tunnel closure with a stent versus no closure to secure a transesophageal natural orifice transluminal endoscopic surgery access site.

BACKGROUND: Secure esophagotomy closure methods are a critical element in the advancement of transesophageal natural orifice transluminal endoscopic surgery (NOTES) procedures. OBJECTIVE: To compare the clinical outcomes in swine receiving an esophageal stent or no stent after a submucosal tunnel NOTES access procedure. DESIGN: Prospective, randomized, controlled trial in 10 Yorkshire swine. SETTING: Academic center. INTERVENTION: An endoscopic mucosectomy device was used to create an esophageal mucosal defect. An endoscope was advanced through a submucosal tunnel into the mediastinum and thorax, and diagnostic mediastinoscopy and thoracoscopy were performed. Ten animals were randomized to no stenting (n = 5) or stenting (n = 5) with a prototype small-intestine submucosa-covered stent. MAIN OUTCOME MEASUREMENTS: Gross and histologic appearance of the mucosectomy and esophagotomy sites as well as clinical outcomes. RESULTS: There was a significant difference in the overall procedure time between the animals that received a stent (35.0 min, range 27-46.0 min) and those with no closure (19.0 min, range 17-32 min) (P value = .018). The unstented group achieved endoscopic and histologic evidence of complete re-epithelialization and healing (100%) at the mucosectomy site compared with the stented group (20%, P = .048). Stent migration into the stomach occurred in two swine. Both groups had complete closure of the submucosal tunnel and well-healed esophagotomy sites. LIMITATIONS: Animal study, small number of subjects. CONCLUSION: The placement of a covered esophageal stent significantly interferes with mucosectomy site healing.

Measurements of pelvic floor dyssynergia: which test result matters?

PURPOSE: Failure to expel a 60-mL balloon on manometry and abnormal relaxation of anal sphincter on electromyographic testing are frequently used to diagnose pelvic floor dyssynergia. However, the relationship between these 2 test results and their relationship to defecography is poorly characterized. We aimed to describe this relationship and create a predictive model for pelvic floor dyssynergia on defecography. METHODS: From March 2008 to April 2010 consecutive patients with symptoms suggestive of functional constipation were evaluated at our Pelvic Floor Disorders Center 125 and the results of their workups were collected prospectively. Sixty-three patients with pelvic floor dyssynergia on defecography were compared with 60 patients without dyssynergia in terms of manometry pressures, electromyographic text results, and balloon expulsion testing results (χ, t tests). RESULTS: Of 125 patients meeting Rome II symptom criteria for constipation, 123 patients underwent defecography and, of these, 63 (51.2%) had evidence of pelvic floor dyssynergia. Patients with and without dyssynergia had a slight difference in mean resting pressures (62.8 mmHg vs 49.5 mmHg, P = .02) and no discernable differences in rectal sensitivity and compliance: first sensation (56.5 vs 62.5, P = .34) and maximum tolerated volume (164.2 vs 191.2, P = .09). It appeared that abnormalities in electromyographic relaxation and balloon expulsion occurred in the same patients: 84.1% of patients with abnormal electromyographic results also did not expel the balloon. However, the presence of these abnormalities, in isolation or together, did not predict the presence of dyssynergia on defecography. CONCLUSION: Normal electromyographic results or the ability to expel a 60-mL balloon does not exclude the presence of pelvic floor dyssynergia on defecography. It is unclear which of these 3 tests should be used to guide the recommendation for (and to then measure response to) biofeedback.

Factors affecting lymph node yield from patients undergoing colectomy for cancer.

PURPOSE: Lymph node (LN) yield is a critical component of colon cancer staging and is often a surrogate for quality assessment in surgery. We investigated the impact of pathologists' training on LN harvest. METHODS: This is a retrospective review on 137 patients undergoing elective colectomy for adenocarcinoma at a single institution from 2008 to 2009. We studied surgeon-, patient- and pathologist-derived factors, and identified independent variables affecting LN yield using logistic regression. RESULTS: LN yield was similar between open and laparoscopic resections (21 versus 23, p = 0.54). Similarly, nodal counts were independent of tumor location (p = 0.08) and no difference was noted between colorectal and general surgeons (24 versus 21, p = 0.31). Strikingly, the number of LNs reported by PGY-1 pathology residents was significantly higher than those with two or more years of training (24 versus 19, p = 0.02). On logistic regression, only the reporting pathologists' year in training remained a significant predictor of the number of nodes reported (OR = 5.28, p = 0.0001). CONCLUSIONS: LN retrieval in patients with colon cancer is inversely related to the interpreting pathologists' level of training.

Short-term outcomes in obese patients after colectomy for adenocarcinoma at a bariatric center.

INTRODUCTION: Obesity (body mass index ≥30) is associated with worse outcomes after colon cancer surgery. Most research, however, has been performed outside bariatric centers of excellence. We sought to determine the relationship between obesity and outcomes after colon cancer resection when performed at a center with bariatric expertise. METHODS: We performed a retrospective review of 245 consecutive patients undergoing elective colectomy for adenocarcinoma at a single institution from 2008 to 2009. Body mass index, major and minor postoperative complications, tumor characteristics, lymph node yield, type of resection, and operating times were determined. RESULTS: Complication rates, operative times, and lymph node counts were all similar between the two weight groups. Obese patients had similar tumor characteristics at all stages when compared with nonobese patients. On multivariate analysis, obesity did not correlate with tumor size, tumor differentiation, or presence of lymphovascular or perineural invasion. CONCLUSION: We conclude that obese patients undergoing colon cancer resection at a bariatric center of excellence have similar tumor characteristics and equivalent short-term outcomes as do nonobese patients.

Superior prognostic importance of perineural invasion vs. lymph node involvement after curative resection of duodenal adenocarcinoma.

BACKGROUND: Unlike other gastrointestinal tumors, lymph node involvement has not consistently been a negative prognostic factor for survival in patients with duodenal adenocarcinoma. Our aim is to examine prognostic factors in patients who underwent a curative resection of their duodenal adenocarcinoma. METHODS: A retrospective review of 169 patients diagnosed with primary duodenal lesions between 1982 and 2010 was performed, of whom 103 were treated with curative intent. Clinico-pathologic factors were evaluated. RESULTS: A potentially curative resection was performed in 103 patients with a median age of 67 years (range, 22-91). Perineural and lympho-vascular invasion were identified in 30 (29.1%) and 39 patients (37.9%), respectively. Median follow-up was 26.5 months. The 5-year overall survival was 62% vs. 25% for patients with or without nodal metastases (p < 0.001) and 56% vs. 19% for patients with or without perineural invasion (p < 0.001), respectively. Lymph node ratio, type of resection, and size of tumor failed to stratify prognosis. By multivariate analysis, perineural invasion was the most powerful independent predictor of survival (HR, 2.520; CI, 1.361-4.664). CONCLUSIONS: Perineural invasion is a stronger predictor for recurrence and survival than tumor size, depth of infiltration, lymph node involvement, and type of resection in patients with duodenal adenocarcinoma.

Immediate versus tailored prophylaxis to prevent symptomatic recurrences after surgery for ileocecal Crohn's disease?

BACKGROUND: Studies have not established the optimal role for prophylaxis after surgery for Crohn's disease. Some suggest treatment should be initiated within the first month after surgery, whereas others advocate targeted treatment after endoscopic recurrence. In the present study, we compared the efficacy of these competing approaches. METHODS: One hundred and ninety-nine Crohn's disease patients who underwent ileocecectomy between September 1993 and April 2008 were retrospectively divided into 3 groups based on treatment timing: immediate, tailored, and none. Groups were compared for differences in demographics, pathology, and surgical technique (Chi-square, ANOVA). Rate of symptomatic recurrence (Chi-square), and time to symptomatic recurrence were analyzed (log rank, multivariate Cox proportional hazards). RESULTS: Sixty-nine (34.7%) received immediate prophylaxis, 32 (16.1%) received tailored prophylaxis, and 98 (49.3%) did not receive any prophylaxis. The groups were similar, though patients receiving immediate prophylaxis were younger and less likely to be lost to follow-up. At 5 years, 62 (31.2%) patients had endoscopic, 46 (23.1%) had symptomatic, and 22 (11%) had surgical recurrences. On simple univariate analysis, patients treated in a tailored fashion at time of endoscopic recurrence appeared more likely than patients treated with immediate prophylaxis to have symptomatic recurrence (43.7% vs 28.9%; P = .02), However, when censored for length of follow-up on multivariate analysis, the only enduring predictor of symptomatic recurrence was Charlson Comorbidity Index (P = .048). Timing of treatment, medicine used for immunoprophylaxis, age, history of prior resection, presence of active disease, and type of anastomosis were not predictive of symptomatic recurrence. CONCLUSION: Patients offered prophylaxis tailored to endoscopic recurrence have a similar time to symptomatic recurrence as those offered prophylaxis immediately. This suggests that a tailored treatment within a strict protocol of preemptive endoscopic surveillance may be reasonable.

Determining the need for radical surgery in patients with T1 rectal cancer.

HYPOTHESIS: In the era of modern preoperative staging of patients with rectal cancer, lymph node metastases can be reliably predicted by the histological features of the tumor and preoperative imaging. Local resection can then be safely offered to the patients who are at low risk of having malignant lymph nodes. DESIGN: We reviewed the records of 109 consecutive patients with preoperative imaging results suggestive of T1N0 or T2N0 disease who underwent total mesorectal excision. All patients underwent preoperative endorectal ultrasonography or magnetic resonance imaging and computed tomography, with or without positron emission tomography. Final pathologic investigation identified T3 disease in 27 patients. History, physical examination results, and radiologic and pathologic data were evaluated for predictors of positive nodes in the remaining 82 patients. SETTING: Tertiary care referral center. PATIENTS: Patients with preoperative imaging suggestive of T1N0 or T2N0 rectal cancer. MAIN OUTCOME MEASURES: To evaluate different clinical and pathologic tumor features as predictors of positive lymph nodes in T1 and T2 rectal cancers with negative radiographic nodes. BACKGROUND: Local resection of T1 and T2 rectal cancer results in lower morbidity compared with radical resection. However, recurrence rates after local resection are higher, likely owing to unresected nodal metastasis. Reports on predictors of lymph node metastasis remain inconsistent in the literature. Although local resection may be appropriate for some rectal cancers, selection criteria remain unclear. RESULTS: Despite indications of negative nodes on radiographic examination, 4 of 35 patients with T1 disease (11%) and 13 of 47 with T2 disease (28%) had positive nodes. On univariate analysis, the only significant predictor was depth of invasion: 24 of 65 patients with negative nodes (37%) vs 13 of 17 patients with positive nodes (76%) had tumors invading the lower third of the submucosa and beyond (P = .02). On logistic regression analysis accounting for depth of invasion (lower third of the submucosa and beyond), size, distance from anal verge, differentiation, and lymphovascular and small-vessel invasion, only depth of invasion remained a significant predictor. CONCLUSIONS: In all, 89% of patients with T1 disease (31 of 35) and 72% of those with T2 disease (34 of 47) underwent unnecessary radical resection. Endorectal ultrasonography or magnetic resonance imaging and computed tomography, with or without positron emission tomography, for preoperative staging could not identify these patients reliably. In addition, histologic markers of aggressive disease were not helpful. Thus, local resection for T2 rectal cancer is not justified. Local resection should be offered only to patients with superficial T1 tumors who will adhere to aggressive postoperative surveillance.

Metastatic tumors in the pancreas in the modern era.

BACKGROUND: Tumors metastasizing to the pancreas are rare, and published series are limited by few patients treated for extended periods of time. Renal cell cancer (RCC) is the most common primary tumor metastasizing to the pancreas. Our aim was to describe the clinicopathologic characteristics and patient outcomes in a modern series of patients who underwent metastasectomy, with an emphasis on RCC. STUDY DESIGN: Retrospective review of all pancreatic resections between January 1993 and October 2009. RESULTS: We identified 40 patients with a median age of 62 years; 55% were female. Patients most commonly presented with abdominal pain (47.5%). Operations performed included 10 pancreaticoduodenectomies, 1 middle, 23 distal, 3 total pancreatectomies, and 3 enucleations. Primary cancers were RCC (n = 20), ovarian (n = 6), sarcoma (n = 3), colon (n = 3), melanoma (n = 2), and others (n = 6). Median survival for all patients after metastasectomy was 4.4 years. Median survival after metastasectomy for RCC was 8.7 years, and the 5-year actuarial survival was 61%. For RCCs, pancreas was the first site of an extrarenal recurrence in 85% and was synchronous with the primary in 5% of patients. There was no survival difference if the time interval to metastasis was shorter than the median (8.7 years), if tumor nodules were multiple or bigger than the median (3 cm), or if the pancreas was not the first site of metastases. CONCLUSIONS: An aggressive approach to lesions metastatic to the pancreas is often warranted if the patient can be rendered free of disease. Although patients with RCC can experience long-term survival after metastasectomy, survival is less favorable for other primary tumors.