Is There a Role for Oral Antibiotic Preparation Alone Before Colorectal Surgery? ACS-NSQIP Analysis by Coarsened Exact Matching.

BACKGROUND: Recent studies demonstrated reduced postoperative complications using combined mechanical bowel and oral antibiotic preparation before elective colorectal surgery. OBJECTIVE: The aim of this study was to assess the impact of these 2 interventions on surgical site infections, anastomotic leak, ileus, major morbidity, and 30-day mortality in a large cohort of elective colectomies. DESIGN: This is a retrospective comparison of 30-day outcomes using the American College of Surgeons National Surgical Quality Improvement Program colectomy-targeted database with coarsened exact matching. SETTINGS: Interventions were performed in hospitals participating in the national surgical database. PATIENTS: Adult patients who underwent elective colectomy from 2012 to 2014 were included. INTERVENTIONS: Preoperative bowel preparations were evaluated. MAIN OUTCOME MEASURES: The primary outcomes measured were surgical site infections, anastomotic leak, postoperative ileus, major morbidity, and 30-day mortality. RESULTS: A total of 40,446 patients were analyzed: 13,219 (32.7%), 13,935 (34.5%), and 1572 (3.9%) in the no-preparation, mechanical bowel preparation alone, and oral antibiotic preparation alone groups, and 11,720 (29.0%) in the combined preparation group. After matching, 9800, 1461, and 8819 patients remained in the mechanical preparation, oral antibiotic preparation, and combined preparation groups for comparison with patients without preparation. On conditional logistic regression of matched patients, oral antibiotic preparation alone was protective of surgical site infection (OR, 0.63; 95% CI, 0.45-0.87), anastomotic leak (OR, 0.60; 95% CI, 0.34-0.97), ileus (OR, 0.79; 95% CI, 0.59-0.98), and major morbidity (OR, 0.73; 95% CI, 0.55-0.96), but not mortality (OR, 0.32; 95% CI, 0.08-1.18), whereas a regimen of combined oral antibiotics and mechanical bowel preparation was protective for all 5 major outcomes. When directly compared with oral antibiotic preparation alone, the combined regimen was not associated with any difference in any of the 5 postoperative outcomes. LIMITATIONS: This study was limited by its retrospective design with heterogeneous data. CONCLUSIONS: Oral antibiotic preparation alone significantly reduced surgical site infection, anastomotic leak, postoperative ileus, and major morbidity after elective colorectal surgery. A combined regimen of oral antibiotics and mechanical bowel preparation offered no superiority when compared with oral antibiotics alone for these outcomes. See Video Abstract at http://links.lww.com/DCR/A358.

Diverticular Abscess Managed With Long-term Definitive Nonoperative Intent Is Safe.

BACKGROUND: Initial nonoperative management of diverticular abscess has become the standard of care; however, the need for elective resection after this index episode is unclear. OBJECTIVE: The purpose of this study was to assess the long-term outcomes of expectant management after initial nonoperative treatment of diverticular abscess. DESIGN: This was a retrospective chart review with prospective telephone follow-up of patients. SETTINGS: The study was conducted at a large tertiary academic colorectal surgery practice in Canada. PATIENTS: Adult patients with CT-documented acute sigmoid diverticulitis complicated by abscess managed nonoperatively from 2000 to 2013 were included. INTERVENTIONS: Long-term definitive nonoperative management of diverticular abscess. MAIN OUTCOME MEASURES: The primary outcome was emergency sigmoidectomy or death from recurrent diverticulitis. Secondary outcomes were recurrent diverticulitis and elective sigmoidectomy for diverticulitis. RESULTS: Of 135 patients with acute diverticulitis complicated by abscess, a total of 73 patients were managed with nonoperative intent and long-term expectant management. The median follow-up was 62 (Q1 to Q3: 28-98) months. After resolution of the index episode, 22 patients [30.1% (95% CI, 19.6%-40.6%)] experienced a recurrent episode of diverticulitis at a median of 23 (range, 9-40) months. Two patients [2.7% (95% CI, -1.0% to 6.4%)] had a recurrent episode with peritonitis that required sigmoidectomy with stoma at 6 and 64 months. Both patients underwent reversal after 4 and 8 months. Seven [9.6% (95% CI, 2.8%-16.4%)] patients experienced a complicated recurrence and underwent an elective sigmoidectomy [median time to colectomy, 33 (range, 16-56) months]. Thirteen patients [17.8% (95% CI, 9.0%-26.6%)] experienced an uncomplicated recurrence, all of whom were managed with continued nonoperative intent [median follow-up, 81 (range, 34-115) months]. No mortality occurred. On multivariate logistic regression, female gender (p = 0.048) and a previous episode of uncomplicated diverticulitis before the index diverticular abscess (p = 0.020) were associated with a recurrent episode. LIMITATIONS: This study was limited by its retrospective design and modest sample size. CONCLUSIONS: After initial successful nonoperative management of diverticulitis with abscess, expectant management with nonoperative intent is a safe long-term option with low rates of surgery, especially in the emergency setting. See Video, Supplemental Digital Content 1, on the nonoperative management of diverticular abscess at http://links.lww.com/DCR/A234.

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.

Can we cut the incidence of necrotizing enterocolitis in half--today?

Necrotizing enterocolitis (NEC) is a common gastrointestinal emergency of neonates. Population studies estimate the incidence of NEC at between 0.3 and 2.4 per 1000 live births in the United States, with a predominance of cases among preterm neonates born at the earliest gestational ages. The disease burden of NEC includes an overall disease-specific mortality rate of 15-20%, with yet higher rates in those of earliest gestations. The NEC burden also includes an increase in hospital costs approximating $100,000/case, as well as severe late sequellae including parenteral nutrition-associated liver disease and short bowel syndrome. Differentiating NEC from other forms of acquired neonatal intestinal disease is critical to assessing the success of NEC prevention strategies. Promising new prevention strategies are now being tested; one such is prophylactic heparin-binding epidermal growth factor-like growth factor (HB-EGF) administration. However, two prevention strategies have already been shown in meta-analyses to reduce the incidence of NEC, but we speculate that these are not being fully utilized. They are; 1) implementing a written set of feeding guidelines (also called standardized feeding regimens) for newborn intensive care unit (NICU) patients, and 2) implementing programs to increase the availability of human milk for patients at risk of developing NEC.

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.

Improving communication of critical test results in a pediatric academic setting: key lessons in achieving and sustaining positive outcomes.

By applying the Institute for Healthcare Improvement's framework for strategic change (will, ideas and execution), The Hospital for Sick Children, in Toronto, Ontario, developed processes to improve patient safety through the effective communication of critical test results. In response to an adverse patient event, near misses and accreditation requirements, a task force with representatives from the laboratories and clinical services was established to ensure the timely and reliable communication of critical test results for biochemistry, hematology, coagulation, therapeutic drug monitoring and microbiology. The task force critically assessed processes and best practices, identified practical alternatives, tested changes, codified new processes in a hospital-wide policy and procedure and carried out post-implementation outcome audits. Lessons learned in sustaining improvements included the following: there is value in identifying strategies from a larger system perspective; there exist merits to working collaboratively as an inter-professional team (i.e., laboratory and clinical leaders); there is value in learning from failure; higher-cost but "higher-leverage" approaches can be pivotal; and regular monitoring and vigilance of policy compliance are required.

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.

Incidence Rates and Predictors of Colectomy for Ulcerative Colitis in the Era of Biologics: Results from a Provincial Database.

BACKGROUND: We evaluated long-term incidence and identified risk factors of colectomy in pre-biologics and biologics eras for treatment of ulcerative colitis. METHODS: After IRB approval, using data obtained from the Régie d'assurance maladie du Québec, we defined two cohorts: pre-biologics (1998-2004) and biologics (2005-2011) eras. Patients with inflammatory bowel disease or colectomy 1 year prior to first diagnosis of ulcerative colitis were excluded. Multivariate logistic regression model compared patient baseline characteristics. Kaplan-Meier curves displayed unadjusted time to event. Cox proportional hazards models were used to compare adjusted colectomy and mortality rates, respectively. RESULTS: In pre-biologics and biologics eras, 335/2829 and 314/3313 patients, respectively, underwent colectomy. Median follow-up (first and third quartiles) was similar (p = 0.206). Incidence rates for colectomy were 36.08/1000 and 29.99/1000 patient years. Unadjusted rate of colectomy was higher in pre-biologics era (p = 0.004). Predictors of colectomy included anemia (1.66; 1.38-2.01), gastrointestinal hospitalizations (1.24; 1.04-1.47), congestive heart failure (2.08; 1.27-3.40), and male gender (1.47; 1.26-1.72). Mortality was 8.06 and 3.18% in pre-biologics and biologics eras. After adjusting for potential confounders, age (1.08; 1.05-1.12) and urgent colectomy (5.65; 2.19-14.54) remained associated with increased mortality hazard. CONCLUSION: Incidence of colectomy decreased after introduction of biologics. Risk factors for colectomy were gastrointestinal hospitalizations, anemia, male gender, and congestive heart failure. Emergent surgery and age were predictors of mortality.

Retinal ganglion cell function in recovered optic neuritis: Faster is not better.

OBJECTIVE: To assess residual retinal ganglion cell (RGC) function in patients with recovered optic neuritis (ON) and multiple sclerosis (MS). METHODS: Age-matched controls (C, n = 32) and MS patients (n = 17) with history of ON in one eye but normal visual acuity and color vision were tested with steady-state Pattern Electroretinogram (PERG). Light Emitting Diodes (LED)-generated bar gratings, robust signal averaging and Fourier analysis were used to assess response amplitude and latency. RESULTS: PERG amplitude was similar for C, ON and fellow eyes (FE) (P = 0.4), but PERG latency was shortened in ON by 3.2 ms (P = 0.002) and in FE by 2.0 ms (P = 0.02) and was correlated (P < 0.01) with both Retinal Nerve Fiber Layer (RNFL) and Ganglion Cell Inner Plexiform Layer (GCIPL) thicknesses. PERG latency shortening could be simulated in control subjects (n = 8) by dioptrically blurring the edges of gratings (high spatial frequencies), which reduced activity of parvocellular RGCs with smaller/slower axons. The blurred PERG latency was shorter than baseline by 2.9 ms (P = 0.01). CONCLUSIONS: PERG latency is shortened in both eyes of MS patients with recovered unilateral ON, suggesting relative dysfunction of RGCs with slower axons and sparing of RGCs with faster axons. SIGNIFICANCE: Assessment of PERG latency in MS and ON may help identifying and monitoring RGC dysfunction. PERG latency shortening in FE suggests primary retinopathy in MS.

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.