Sigmoid Colectomy for Acute Diverticulitis in Immunosuppressed vs Immunocompetent Patients: Outcomes From the ACS-NSQIP Database.

BACKGROUND: The management of acute diverticulitis in immunosuppressed patients is increasingly debated. The appropriate timing and type of operation remains controversial. OBJECTIVE: This study examines the impact of immunosuppression on mortality and morbidity following colectomies for diverticulitis in the emergency and elective settings. DESIGN SETTINGS: With the use of the American College of Surgeons National Surgical Quality Improvement Program database, the outcomes of immunosuppressed compared with immunocompetent patients who underwent colectomy for acute diverticulitis were compared. PATIENTS: The multi-institutional database was queried for patients who underwent colectomy for acute diverticulitis from 2005 to 2012. MAIN OUTCOMES MEASURES: The impact of immunosuppression on mortality, major morbidity, organ space infection, infectious complications, and wound dehiscence was assessed. RESULTS: Of 26,987 patients, 1332 were immunosuppressed and 25,655 were immunocompetent; 4271 patients had emergency (596 immunosuppressed and 3675 immunocompetent) and 22,716 patients had elective (736 immunosuppressed and 21,980 immunocompetent) colectomies for diverticulitis. In both groups, mortality and major morbidity were significantly higher in the emergency (immunosuppressed 16% and 45%, immunocompetent 4% and 28%) compared with the elective setting (immunosuppressed 2% and 25%, immunocompetent 0.4% and 12%), p < 0.001. On multivariate regression for the emergency setting, immunosuppression significantly increased mortality (OR, 1.79; 95% CI, 1.17-2.75) and did not significantly increase morbidity. On multivariate regression for the elective setting, mortality was similar in immunosuppressed and immunocompetent groups; however, major morbidity (OR, 1.46; 95% CI, 1.17-1.83) and wound dehiscence (OR, 2.69; 95% CI, 1.63-4.42) were significantly increased in immunosuppressed compared with immunocompetent patients. LIMITATIONS: The retrospective design and standardized outcomes are based on heterogeneous data. CONCLUSIONS: Emergency colectomy for diverticulitis is associated with higher mortality in immunosuppressed than in immunocompetent patients, whereas elective colectomy is associated with comparable mortality. In the elective setting, immunosuppressed compared with immunocompetent patients are at increased risk of major morbidity and wound dehiscence.

Prevention of perineal hernia after laparoscopic and robotic abdominoperineal resection: review with illustrative case series of internal hernia through pelvic mesh.

ABSTRACT: This review is intended to raise awareness of placing a pelvic mesh to prevent perineal hernias in cases of minimally invasive (MIS) abdominoperineal resections (APR) and, in doing so, causing internal hernias through the mesh. In this article, we review the published literature and present an illustrative series of 4 consecutive cases of early internal hernia through a pelvic mesh defect. These meshes were placed to prevent perineal hernias after laparoscopic or robotic APRs. The discussion centres on 3 key questions: Should one be placing a pelvic mesh following an APR? What are some of the technical details pertaining to the initial mesh placement? What are the management options related to internal hernias through such a mesh?

RESUME: L'objectif du présent examen est de sensibiliser les praticiens au risque associé à la pose d'un treillis pelvien visant à prévenir les hernies périnéales après une résection abdominopérinéale à effraction minimale, pratique qui peut entraîner une hernie interne. Nous nous penchons ici sur les articles publiés à ce sujet et présentons une série éloquente de 4 cas consécutifs de hernies internes précoces attribuables à un défaut du treillis. Les dispositifs avaient été mis en place pour prévenir une hernie périnéale après des résections laparoscopiques ou robotiques. La discussion porte sur 3 questions centrales : Devrait-on poser un treillis pelvien à la suite d'une résection abdominopérinéale? Quels sont les éléments techniques à surveiller lors de la pose initiale? Quelles sont les options de prise en charge des hernies internes causées par les treillis?

Dynamics of vitamin D in patients with mild or inactive inflammatory bowel disease and their families.

BACKGROUND: 25(OH) vitamin D levels may be low in patients with moderately or severely active inflammatory bowel diseases (IBD: Crohn's disease and Idiopathic Ulcerative Colitis) but this is less clear in patients with mild or inactive IBD. Furthermore there is limited information of any family influence on 25(OH) vitamin D levels in IBD. As a possible risk factor we hypothesize that vitamin D levels may also be low in families of IBD patients. OBJECTIVES: To evaluate 25[OH] vitamin D levels in patients with IBD in remission or with mild activity. A second objective is to evaluate whether there are relationships within IBD family units of 25[OH] vitamin D and what are the influences associated with these levels. METHODS: Participants underwent medical history, physical examination and a 114 item diet questionnaire. Serum 25[OH] vitamin D was measured, using a radioimmunoassay kit, (replete ≥ 75, insufficient 50-74, deficient < 25-50, or severely deficient < 25 nmol/L). Associations between 25[OH] vitamin D and twenty variables were evaluated using univariate regression. Multivariable analysis was also applied and intrafamilial dynamics were assessed. RESULTS: 55 patients and 48 controls with their respective families participated (N206). 25[OH] vitamin D levels between patients and controls were similar (71.2 ± 32.8 vs. 68.3 ±26.2 nmol/L). Vitamin D supplements significantly increased intake but correlation with serum 25[OH] vitamin D was significant only during non sunny months among patients. Within family units, patients' families had mean replete levels (82.3 ± 34.2 nmol/L) and a modest correlation emerged during sunny months between patients and family (r2 =0.209 p = 0.032). These relationships were less robust and non significant in controls and their families. CONCLUSIONS: In patients with mild or inactive IBD 25[OH] vitamin D levels are less than ideal but are similar to controls. Taken together collectively, the results of this study suggest that patient family dynamics may be different in IBD units from that in control family units. However contrary to the hypothesis, intra familial vitamin D dynamics do not pose additional risks for development of IBD.

Thromboembolism in inflammatory bowel disease: an insidious association requiring a high degree of vigilance.

Venous and arterial thromboembolism are both serious extraintestinal manifestations of inflammatory bowel disease (IBD). Acquired risk factors seem to play a more prominent role than congenital in promoting thrombotic events. Prevention of thromboembolism is thus mainly aimed at minimizing the acquired/reversible risk factors (e.g., inflammation, immobility, hospitalization, steroid therapy, central intravenous catheters, smoking, oral contraceptives, and deficiency of B vitamins and folate). The diagnosis of venous and arterial thromboembolism is extremely challenging and requires a high degree of vigilance. Deep vein thrombosis and pulmonary embolism may be clinically silent or manifest with only few specific symptoms. Thrombosis of the portal vein system may occur with nonspecific symptoms such as abdominal pain, nausea/vomiting, abdominal tenderness, ascites, and fever. The diagnosis of arterial thromboembolism may also be challenging, particularly when the splanchnic region is involved. Indeed, arterial thrombosis of the splanchnic region tends to be overlooked and misinterpreted as a clinical exacerbation of IBD. Early diagnosis plays a central role in optimizing the therapeutic intervention and reducing the risk of short-term and long-term thrombosis-associated complications. The decision regarding the duration of systemic anticoagulation must take into account the individual risk of intestinal bleeding.

High frequency of exon deletions and putative founder effects in French Canadian Lynch syndrome families.

Lynch syndrome is one of the most common autosomal dominantly inherited cancer syndromes. Mutations in MLH1, MSH2, MSH6, and PMS2 account for greater than 98% of reported mutations in Lynch syndrome families. It has been reported that large genomic deletions in MLH1 and MSH2 are a frequent cause of Lynch syndrome in certain populations. Using a multimodal approach, we have identified mutations in MLH1, MSH2, and MSH6 in French Canadian families fulfilling the Amsterdam criteria for Lynch syndrome and who displayed abnormal staining for at least one of the Lynch syndrome proteins. Mutations were identified in 28 of our 29 French Canadian probands (97%). A total of 18 distinct mutations (nine in MLH1, seven in MSH2, two in MSH6) were identified, of which six (33%) were genomic exon deletions. Another four (22%) resulted in exon deletions in cDNA alone. Three (17%) are novel mutations. Five of these 18 mutations were detected in more than one distinct family (four in MLH1, one in MSH2) and haplotype analysis suggests the possibility of founder effects. Fifteen of the 29 (52%) families carried one of these five putative founder mutations. These findings may simplify genetic testing for Lynch syndrome in French Canadians.

Intra-abdominal venous and arterial thromboembolism in inflammatory bowel disease.

Venous and arterial thromboembolism constitutes a significant cause of morbidity and mortality in patients with inflammatory bowel disease. The most common thrombotic manifestations are lower extremity deep vein thromboses with or without pulmonary embolism. Occasionally, thromboembolic events occur in the main abdominal vessels, such as the portal and superior mesenteric veins, vena cava and hepatic vein, aorta, splanchnic and iliac arteries, or in the limb arteries. The decision-making process for the treatment of these uncommon thromboembolic complications in inflammatory bowel disease may be very challenging for several reasons: 1) no standardized therapies are available; 2) the decision of starting anticoagulant therapy implies the potential risk of intestinal bleeding; 3) thromboembolic events may recur and be life-threatening if inadequately treated. The literature was searched by using MEDLINE, Embase, and the Cochrane library database. Studies published between 1970 and 2007 were reviewed. We discuss the medical and surgical therapeutic options that should be considered to optimize the outcome and reduce the risk of complications in abdominal thromboembolisms associated with inflammatory bowel disease.

Somatic mosaicism of androgen receptor CAG repeats in colorectal carcinoma epithelial cells from men.

BACKGROUND: The X-linked human androgen receptor gene (AR) contains an exonic polymorphic trinucleotide CAG. The length of this encoded CAG tract inversely affects AR transcriptional activity. Colorectal carcinoma is known to express the androgen receptor, but data on somatic CAG repeat lengths variations in malignant and normal epithelial cells are still sporadic. MATERIALS AND METHODS: Using laser capture microdissection (LCM), epithelial cells from colorectal carcinoma and normal-appearing mucosa were collected from the fresh tissue of eight consecutive male patients undergoing surgery (mean age, 70 y; range, 54-82). DNA isolated from each LCM sample underwent subsequent PCR and DNA sequencing to precisely determine AR CAG repeat lengths and the presence of microsatellite instability (MSI). RESULTS: Different AR CAG repeat lengths were observed in colorectal carcinoma (ranging from 0 to 36 CAG repeats), mainly in the form of multiple shorter repeat lengths. This genetic heterogeneity (somatic mosaicism) was also found in normal-appearing colorectal mucosa. Half of the carcinoma cases examined tended to have a higher number of AR CAG repeat lengths with a wider range of repeat size variation compared to normal mucosa. MSI carcinomas tended to have longer median AR CAG repeat lengths (n = 17) compared to microsatellite stable carcinomas (n = 14), although the difference was not significant (P = 0.31, Mann-Whitney test). CONCLUSIONS: Multiple unique somatic mutations of the AR CAG repeats occur in colorectal mucosa and in carcinoma, predominantly resulting in shorter alleles. Colorectal epithelial cells carrying AR alleles with shorter CAG repeat lengths may be more androgen-sensitive and therefore have a growth advantage.

Absence of prognostic value of nuclear shape factor analysis in colorectal carcinoma: relevance of interobserver and intraobserver variability.

PURPOSE: Several retrospective studies, including our previous investigation, have shown a prognostic value of nuclear shape factor in colorectal carcinomas. This prospective study was designed to assess the reliability of nuclear shape factor determined by nuclear morphometry and to confirm its prognostic value. METHODS: Ninety-eight patients who underwent colorectal carcinoma resection were prospectively enrolled. Measurement of nuclear shape factor was performed by using a computer-based image analysis system. Nuclear shape factor was defined as the degree of circularity of the nucleus (1.0 for a perfect circle and <1.0 for any other elliptical shape). The prognostic impact of nuclear shape factor on ten-year survival and the intraobserver and interobserver agreement were assessed. RESULTS: The nuclear shape factor mean values by American Joint Committee on Cancer stage were: 0.73 (0.07) in Stage I, 0.74 (0.06) in Stage II, and 0.75 (0.05) in Stage III carcinomas (P = 0.78, ANOVA). The intraobserver agreement was poor for observer A (r = 0.28) and practically nonexistent for observer B (r = -0.004, Pearson correlation). The intraclass coefficient for interobserver agreement was practically nonexistent. No significant association between nuclear shape factor and ten-year survival was found. CONCLUSIONS: Our prospective results, as opposed to our previous retrospective results, suggest that the reliability for nuclear shape factor morphometric analysis is very poor. We failed to confirm a prognostic value for nuclear shape factor in colorectal carcinoma.

Underexpression of mineralocorticoid receptor in colorectal carcinomas and association with VEGFR-2 overexpression.

BACKGROUND: The human mineralocorticoid receptor (MR) is a steroid receptor widely expressed in colorectal mucosa. A significant role for the MR in the reduction of vascular endothelial growth factor receptor-2 (VEGFR-2) mRNA levels has been demonstrated in vitro. To evaluate a potential contribution of MR to colorectal carcinoma progression, we analyzed the expression of MR in relation to VEGFR-2. METHODS: Fresh human colorectal cancer tissue and adjacent normal mucosa were harvested from 48 consecutive patients. MR and VEGFR-2 mRNA expression levels were determined by real-time reverse transcriptase-polymerase chain reaction and correlated with clinicopathological parameters. RESULTS: A decline of MR expression was observed in all carcinomas compared to normal mucosa. Expression of MR was a median of 11-fold lower in carcinoma compared to the normal mucosa, irrespective of the location, size, stage, and differentiation. MR was a median of 20-fold underexpressed in carcinomas with VEGFR-2 overexpression vs only 9-fold in carcinomas with VEGFR-2 underexpression (p = 0.035, Mann-Whitney test). CONCLUSIONS: These findings support the hypothesis that reduction of MR expression may be one of the early events involved in colorectal carcinoma progression. The inverse association between MR and VEGFR-2 expression in carcinoma suggests a potential tumor-suppressive function for MR.

Distinct patterns of germ-line deletions in MLH1 and MSH2: the implication of Alu repetitive element in the genetic etiology of Lynch syndrome (HNPCC).

A relatively high frequency of germ-line genomic rearrangements in MLH1 and MSH2 has been reported among Lynch Syndrome (HNPCC) patients from different ethnic populations. To investigate the underlying molecular mechanisms, we characterized the DNA breakpoints of 11 germ-line deletions, six for MLH1 and five for MSH2. Distinct deletion patterns were found for the two genes. The five cases of MSH2 deletions result exclusively from intragenic unequal recombination mediated by repetitive Alu sequences. In contrast, five out of the six MLH1 deletions are due to recombinations involving sequences of no significant homology (P=0.015). A detailed analysis of the DNA breakpoints in the two genes, previously characterized by other groups, validated the observation that Alu-mediated unequal recombination is the main type of deletion in MSH2 (n=34), but not in MLH1 (n=21) (P<0.0001). Plotting the distribution of known DNA breakpoints among the introns of the two genes showed that, the highest breakpoint density is co-localized with the highest Alu density. Our study suggests that Alu is a promoting factor for the genomic recombinations in both MLH1 and MSH2, and the local Alu density may be involved in shaping the deletion pattern.

The value of multi-modal gene screening in HNPCC in Quebec: three mutations in mismatch repair genes that would have not been correctly identified by genomic DNA sequencing alone.

Hereditary non-polyposis colorectal cancer (HNPCC) is a dominantly inherited cancer syndrome caused by a mutation in one of the mismatch repair genes, most frequently MLH1 or MSH2. The rate of mutation detection is influenced by many factors, including the diagnostic methods used. Large deletions, which occur frequently in MLH1 and MSH2, are not detected by exon-by-exon screening methods. Here, we describe three mutations in mismatch repair genes detected using a screening protocol that combines protein truncation test (PTT) analysis and multiplex ligation-dependent probe amplification (MLPA) with genomic and cDNA sequencing. Two of these mutations consist of large deletions in MLH1 that were detected by both MLPA and PTT but that would have been missed by genomic DNA sequencing. The third is a large deletion in MSH2 that could not be detected by PTT because of its location relative to the primers used to amplify the cDNA, or by sequencing. This mutation was detected by MLPA.

A real-time spike classification method based on dynamic time warping for extracellular enteric neural recording with large waveform variability.

BACKGROUND: Computationally efficient spike recognition methods are required for real-time analysis of extracellular neural recordings. The enteric nervous system (ENS) is important to human health but less well-understood with few appropriate spike recognition algorithms due to large waveform variability. NEW METHOD: Here we present a method based on dynamic time warping (DTW) with high tolerance to variability in time and magnitude. Adaptive temporal gridding for "fastDTW" in similarity calculation significantly reduces the computational cost. The automated threshold selection allows for real-time classification for extracellular recordings. RESULTS: Our method is first evaluated on synthesized data at different noise levels, improving both classification accuracy and computational complexity over the conventional cross-correlation based template-matching method (CCTM) and PCA+k-means clustering without time warping. Our method is then applied to analyze the mouse enteric neural recording with mechanical and chemical stimuli. Successful classification of biphasic and monophasic spikes is achieved even when the spike variability is larger than millisecond in width and millivolt in magnitude. COMPARISON WITH EXISTING METHOD(S): In comparison with conventional template matching and clustering methods, the fastDTW method is computationally efficient with high tolerance to waveform variability. CONCLUSIONS: We have developed an adaptive fastDTW algorithm for real-time spike classification of ENS recording with large waveform variability against colony motility, ambient changes and cellular heterogeneity.

Normalization of CEA Levels Post-Neoadjuvant Therapy is a Strong Predictor of Pathologic Complete Response in Rectal Cancer.

BACKGROUND: Recent attention has been focused on the relationship between carcinoembryonic antigen (CEA) and pathological complete response (pCR), without consensus regarding its predictive value. This study aims to examine the association between CEA and pCR. METHODS: We conducted a retrospective review of a prospectively maintained database of all patients who underwent primary rectal cancer resection after neo-adjuvant chemoradiotherapy (nCRT). Patients were divided into two groups, pCR or no-pCR, based on final pathology. CEA levels were measured at the initial visit with the surgeon/oncologist and post-completion of nCRT. RESULTS: One hundred and forty-one patients underwent primary rectal cancer resections after nCRT. Nineteen patients (13.5 %) achieved pCR, while 122 (86.5 %) had no-pCR. Pre-nCRT CEA levels were not significantly different between groups (2.75 vs 4.5 µg/L, p = 0.65). However, post-nCRT CEA levels were significantly lower in patients with pCR (1.7 vs 2.4 µg/L, p < 0.01). On multivariate logistic regression analyses, low post-nCRT CEA level was an independent predictor of pCR (OR 1.74, CI 1.06, 3.81) and normalization of CEA from an initially elevated level was a highly significant predictor of pCR (OR 64.8, CI 2.53, 18,371). CONCLUSION: Low post-nCRT CEA is an independent predictor of pCR, and normalization of CEA post-nCRT is a strong predictor of pCR.

Polymorphisms and HNPCC: PMS2-MLH1 protein interactions diminished by single nucleotide polymorphisms.

Hereditary nonpolyposis colorectal cancer (HNPCC) is one of the most common autosomal dominant inherited diseases. Mutations in the human mismatch repair (MMR) proteins MLH1, MSH2, MSH6, PMS1, and PMS2 have been found to co-segregate with HNPCC. The MLH1 and MSH2 proteins have been demonstrated to interact with PMS1, PMS2, and MSH6 proteins. A previous study reported that missense mutations in specific regions of MLH1 can lead to defects in protein-protein interactions with PMS2. Here we report that three missense alterations previously identified as single nucleotide polymorphisms (SNPs) in PMS2 (P511K, T597S, and M622I) cause defective protein-protein interactions with MLH1, even though the alterations are not in the previously reported interaction domain. These results suggest that an additional domain in PMS2 affects MLH1-PMS2 interaction. This study also demonstrates that SNPs can result in gene alterations that indeed have a functional effect on protein phenotype. Thus, these three SNPs may ultimately represent variants with an increased risk factor for tumorgenesis in HNPCC. This study is one of the first to use a functional assay to appraise the role of SNPs and suggests that traditional definitions of polymorphisms and mutations are in need of reconsideration.

Cancer prevention in inflammatory bowel disease and the chemoprophylactic potential of 5-aminosalicylic acid.

The risk of colorectal cancer is increased in ulcerative colitis and Crohn's colitis. Regular dysplasia surveillance colonoscopy in chronic colitis generally has been adopted as a strategy to prevent colorectal cancer or at least to diagnose it in an earlier stage. This has not been proven to reduce mortality, but it does provide the clinician and the patient with some confidence that they are participating in an active strategy to deal with the problem of colorectal cancer in chronic colitis. Disease extent and duration have long been held to be risk factors for colorectal cancer in chronic colitis, and recently some special risk groups have been identified which may require either more intensive surveillance or alternative approaches to cancer prevention. These include patients with primary sclerosing cholangitis, patients with first-degree relatives with sporadic colon cancer, and possibly, patients with backwash ileitis. There is an emerging interest in potential chemopreventative strategies in both sporadic and colitis-associated colorectal cancer. There also have been suggestive data that chronic maintenance 5-aminosalicylate use might reduce the risk of developing colorectal cancer. Recent data have suggested some potential preventative benefit of using ursodeoxycholic acid in patients with ulcerative colitis and primary sclerosing cholangitis. The scientific rationale for using these agents is sound but clinical data are lacking to fully support these approaches as chemoprevention in chronic colitis at present.

Surgical considerations in anal cancer.

SCC of the anus is rare; however, the surgeon is bound to encounter some of these patients during his or her career. It is important that the anatomic location and the histology be defined because the initial treatment may initially differ. Multimodality therapy is the treatment of choice in SCC of the anal canal, with surgery reserved for persistent or recurrent tumors. Multimodality therapy can be used selectively in SCC of the perianal skin, especially in large bulky tumors, followed by definitive surgery. Nevertheless, the initial treatment of perianal neoplasms is surgical therapy. In general, inguinal node metastases are treated with chemoradiation. In highly selected patients, groin dissections are performed, but this procedure is not routine.

Immediate postlaparotomy small bowel obstruction: a 16-year retrospective analysis.

Small bowel obstruction (SBO) is a particularly vexing problem in the postoperative period. The goal of this study was to compare the results of operative versus nonoperative treatment. A secondary goal was to explore risk factors for necessitating reoperation in the immediate postoperative period. We conducted a historical cohort retrospective chart review at a university-affiliated hospital. The medical records of patients treated between 1985 and 2000 at the Sir Mortimer B. Davis Jewish General Hospital (Montreal, Quebec, Canada) who developed SBO after undergoing a laparotomy during that admission were reviewed. Postoperative SBO was defined as cessation of flatus or bowel movements after their resumption following operation. To compare operative versus nonoperative management of early postoperative mechanical SBO we used the following outcome measures: Reoperation rate, time to return of function, length of stay, and mortality. Of 52 patients who developed SBO in the immediate postoperative period 37 were male, 25 had colorectal surgery, and nine had a gastrectomy as the initial operation on admission; five had inflammatory bowel disease, six had a previous SBO, 22 had virgin abdomens before the current operation, and 11 had adhesions noted at the initial operation. The median time to the development of obstructive symptoms was 8 days (range 1-33). The reoperation rate was 42 per cent overall (67% in women and 32% in men, P = 0.02). For operatively treated patients the median time between onset of symptoms and surgery was 5 days [range 1-23, interquartile range (IQR) = 5]. The median time to the return of bowel function was greater in the operatively treated patients compared with nonoperatively treated patients [11.5 days (range 4-37, IQR = 11) vs 6 days (range 1-28, IQR = 7), P < 0.0001] as was median length of stay from onset of obstruction [23 days (range 6-60, IQR = 14) vs 12 days (range 2-45, IQR = 16), P < 0.009]. Operatively treated patients also stayed longer after their obstruction was relieved although not significantly longer [8 days (range 1-35, IQR = 11) vs 4.5 days (range 0-40, IQR = 10), P = 0.15]. There were 11 complications in nine of 22 patients who underwent operative treatment of their SBO. Immediate postoperative SBO can be treated nonoperatively in stable patients resulting in significantly quicker return of bowel function and shorter lengths of hospital stay. Definitive risk factors for immediate SBO could not be identified.

Small bowel adenocarcinoma and Crohn's disease: any further ahead than 50 years ago?

This review of the literature on small bowel carcinoma associated with Crohn's disease specifically addresses the incidence, risk factors, and protective factors which have been identified. It also reviews the clinical presentation, the current modalities of diagnosis, the pathology, treatment, and surveillance. Finally, the prognosis and future direction are addressed. Our experience with small bowel adenocarcinoma in Crohn's disease is reported. Readers will be provided with a better understanding of this rare and often poorly recognized complication of Crohn's disease.