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SWI/SNF chromatin remodeling complexes constitute a highly related family of multi-subunit complexes to modulate transcription, and SWI/SNF subunit genes are collectively mutated in 20% of all human cancers. Bcl11b is a SWI/SNF subunit and acts as a haploinsufficient tumor suppressor in leukemia/lymphomas. Here, we show expression of Bcl11b in intestinal crypt cells and promotion of intestinal tumorigenesis by Bcl11b attenuation in Apc (min/+) mice. Of importance, mutations or allelic loss of BCL11B was detected in one-third of human colon cancers. We also show that attenuated Bcl11b activity in the crypt base columnar (CBC) cells expressing the Lgr5 stem cell marker enhanced regeneration of intestinal epithelial cells after the radiation-induced injury. Interestingly, BCL11B introduction in human cell lines downregulated transcription of β-catenin target genes, whereas Bcl11b attenuation in Lgr5(+) CBCs increased expression of β-catenin targets including c-Myc and cyclin D1. Together, our results argue that Bcl11b impairment promotes tumor development in mouse and human intestine at least in part through deregulation of β-catenin pathway., (© The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Background: We retrospectively examined the optimal lymph node ratio (LNR) cutoff value and attempted to construct a new classification using the LNR in stage III colon cancer., Methods: The clinical and pathological data of 4,172 patients with histologically proven lymph node metastasis who underwent curative surgery for primary colon cancer at multiple institutions between 1995 and 2004 were derived from the multi-institutional database of the Japanese Society for Cancer of the Colon and Rectum (JSCCR). We determined independent prognostic factors and constructed a new classification using these factors. Finally, we compared the discriminatory ability between the new classification and the TNM seventh edition (TNM 7th) classification., Results: The optimal LNR cutoff value was 0.18. Multivariate analysis revealed that year of surgery, age, gender, histological type, TNM 7th T category, lymphatic invasion, venous invasion, TNM 7th N category, and LNR were found to be significant independent prognostic factors. We attempted to construct a new classification based on the combination of TNM 7th T category and LNR. As a result, the cancer-specific survivals were well stratified (P < .0001). According to the Akaike's information criteria value, the new classification was judged to be superior to the TNM 7th classification with respect to both a better fit and lower complexity., Conclusions: The optimal LNR cutoff value that was found using the Japanese multi-institutional database and the new classification using LNR are considered to be extremely significant. Therefore, these findings strongly support the application of LNR in the stage classification in stage III colon cancer.

Background & Aims: Categorization of colon cancers into distinct subtypes using a combination of pathway-based biomarkers could provide insight into stage-independent variability in outcomes., Methods: We used a polymerase chain reaction-based assay to detect mutations in BRAF (V600E) and in KRAS in 2720 stage III cancer samples, collected prospectively from patients participating in an adjuvant chemotherapy trial (NCCTG N0147). Tumors deficient or proficient in DNA mismatch repair (MMR) were identified based on detection of MLH1, MSH2, and MSH6 proteins and methylation of the MLH1 promoter. Findings were validated using tumor samples from a separate set of patients with stage III cancer (n = 783). Association with 5-year disease-free survival was evaluated using Cox proportional hazards models., Results: Tumors were categorized into 5 subtypes based on MMR status and detection of BRAF or KRAS mutations which were mutually exclusive. Three subtypes were MMR proficient: those with mutations in BRAF (6.9% of samples), mutations in KRAS (35%), or tumors lacking either BRAF or KRAS mutations (49%). Two subtypes were MMR deficient: the sporadic type (6.8%) with BRAF mutation and/or or hypermethylation of MLH1 and the familial type (2.6%), which lacked BRAF(V600E) or hypermethylation of MLH1. A higher percentage of MMR-proficient tumors with BRAF(V600E) were proximal (76%), high-grade (44%), N2 stage (59%), and detected in women (59%), compared with MMR-proficient tumors without BRAF(V600E) or KRAS mutations (33%, 19%, 41%, and 42%, respectively; all P < .0001). A significantly lower proportion of patients with MMR-proficient tumors with mutant BRAF (hazard ratio = 1.43; 95% confidence interval: 1.11-1.85; Padjusted = .0065) or mutant KRAS (hazard ratio = 1.48; 95% confidence interval: 1.27-1.74; Padjusted < .0001) survived disease-free for 5 years compared with patients whose MMR-proficient tumors lacked mutations in either gene. Disease-free survival rates of patients with MMR-deficient sporadic or familial subtypes was similar to those of patients with MMR-proficient tumors without BRAF or KRAS mutations. The observed differences in survival rates of patients with different tumor subtypes were validated in an independent cohort., Conclusions: We identified subtypes of stage III colon cancer, based on detection of mutations in BRAF (V600E) or KRAS, and MMR status that show differences in clinical and pathologic features and disease-free survival. Patients with MMR-proficient tumors and BRAF or KRAS mutations had statistically shorter survival times than patients whose tumors lacked these mutations. The tumor subtype found in nearly half of the study cohort (MMR-proficient without BRAF(V600E) or KRAS mutations) had similar outcomes to those of patients with MMR-deficient cancers., (Copyright © 2015 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Colon cancer remains a significant clinical problem worldwide and in the United States it is the third most common cancer diagnosed in men and women. It is generally accepted that most malignant neoplasms of the colon arise from precursor adenomatous polyps. This stepwise progression of normal epithelium to carcinoma, often with intervening dysplasia, occurs as a result of multiple sequential, genetic mutations-some are inherited while others are acquired. Malignant polyps are defined by the presence of cancer cells invading through the muscularis mucosa into the underlying submucosa (T1). They can appear benign endoscopically but the presence of malignant invasion histologically poses a difficult and often controversial clinical scenario. Emphasis should be initially focused on the endoscopic assessment of these lesions. Suitable polyps should be resected en-bloc, if possible, to facilitate thorough evaluation by pathology. In these cases, proper attention must be given to the risks of residual cancer in the bowel wall or in the surrounding lymph nodes. If resection is not feasible endoscopically, then these patients should be referred for surgical resection. This review will discuss the important prognostic features of malignant polyps that will most profoundly affect this risk profile. Additionally, we will discuss effective strategies for their overall management.

Purpose: Up to half of unique genetic variants in genomic evaluations of familial cancer risk will be rare variants of uncertain significance. Classification of rare variants will be an ongoing issue as genomic testing becomes more common., Methods: We modified standard power calculations to explore sample sizes necessary to classify and estimate relative disease risk for rare variant frequencies (0.001-0.00001) and varying relative risk (20-1.5), using population-based and family-based designs focusing on breast and colon cancer. We required 80% power and tolerated a 10% false-positive rate because variants tested will be in known genes with high pretest probability., Results: Using population-based strategies, hundreds to millions of cases are necessary to classify rare cancer variants. Larger samples are necessary for less frequent and less penetrant variants. Family-based strategies are robust to changes in variant frequency and require between 8 and 1,175 individuals, depending on risk., Conclusion: It is unlikely that most rare missense variants will be classifiable in the near future, and accurate relative risk estimates may never be available for very rare variants. This knowledge may alter strategies for communicating information about variants of uncertain significance to patients.

Introduction: The World Health Organization reviewed the classification for serrated colonic polyps in 2010. A new entity, sessile serrated adenoma, was included with two variants: with and without cytological dysplasia. This lesion's malignant potential has been recognized and according to the new classification, many polyps may be reclassified. The impact of this change is yet to be assessed., Objective: Analyze the proportion of lesions that were reclassified according to the new World Health Organization classification and the variables that influenced it., Material and Methods: Every patient with at least one sessile serrated adenoma diagnosed in a 5 year period was included. All polyps (regardless of type) resected during the study period were reviewed. Data concerning polyp's characteristics and patient variables were collected. Forty consecutive patients were included [13 female, mean age at 1st sessile serrated adenoma -59 yrs (34-80)]., Results: Were reviewed 247 polyps: hyperplastic--42%; conventional adenomas--29%; sessile serrated adenoma--24%; serrated adenomas--5%. Sixty-three polyps were reclassified: 43 hyperplastic, 12 serrated adenomas, 7 sessile serrated adenoma and 1 conventional adenoma with low grade dysplasia. Reclassification was significantly greater for hyperplastic polyps when compared with the other subtypes. Forty-three of one hundred and four (41%) hyperplastic polyps were reclassified all as sessile serrated adenoma. In these polyps the probability of reclassification was independent from polyp location but was greater if polyp size ≥ 5 mm., Discussion: This is a single center, rectrospective study. The fact that it was done in an Oncology Referral Institution with a Family Risk Clinic may have influenced the results. Nevertheless the impressive reclassification rate for Hyperplastic Polyps and the fact that they were reclassified mainly as Serrated Adenomas makes these results relevant to daily practice., Conclusion: Our results suggest that, according to the new World Health Organization classification for serrated colonic polyps, a considerable proportion of hyperplastic polyps will be reclassified. The serrated pathway of colorectal carcinogenesis has probably been underestimated and at-risk patients may have been under inappropriate surveillance.

Labeling a histopathology image as having cancerous regions or not is a critical task in cancer diagnosis; it is also clinically important to segment the cancer tissues and cluster them into various classes. Existing supervised approaches for image classification and segmentation require detailed manual annotations for the cancer pixels, which are time-consuming to obtain. In this paper, we propose a new learning method, multiple clustered instance learning (MCIL) (along the line of weakly supervised learning) for histopathology image segmentation. The proposed MCIL method simultaneously performs image-level classification (cancer vs. non-cancer image), medical image segmentation (cancer vs. non-cancer tissue), and patch-level clustering (different classes). We embed the clustering concept into the multiple instance learning (MIL) setting and derive a principled solution to performing the above three tasks in an integrated framework. In addition, we introduce contextual constraints as a prior for MCIL, which further reduces the ambiguity in MIL. Experimental results on histopathology colon cancer images and cytology images demonstrate the great advantage of MCIL over the competing methods., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Background: Colorectal cancer (CRC) was the fourth most commonly diagnosed cancer in Iran between 2000 and 2009, with adenocarcinoma (AC) as the most common histological type. Demographic, topographic and histological variables are important in the epidemiology and biology of cancer. The aim of this study was to investigate clinicopathological features of colon adenocarcinomas in Qazvin, Iran., Materials and Methods: With a retrospective design, patient records of two pathology wards from March 1997 to March 2013 were studied with regard to anatomical location and histological classification. A broader anatomical grouping was also used including distal vs proximal regions and right sided vs left sided tumors. Data were analyzed using T-test and chi-square test., Results: 118 (50.9%) male and 114 (49.1%) female patients were included in the study. Mean age was 57.3±14.7 years, with 29.2% under 50 years. There was no significant gender difference for age at diagnosis. The rectum (56%) and sigmoid colon (25%) were the most frequent anatomical locations. Proximal cases accounted for 18.6% in males and 8.8% in females (p=0.02). AC was more prevalent than other usual types in younger patients. The proportion of proximal cancer was 1.7% in first eight years of the study period vs 12.1% in the second one (p=0.005). A similar trend was also seen in right sided colon cancers (p=0.018)., Conclusions: Young people are also at risk for the cancer with poor prognosis. Screening programs and weight loss in obese individuals can reduce incidence and complications of CRC.

Recently we published two independent studies describing novel gene expression-based classifications of colorectal cancer (CRC). Notably, each study stratified CRC into a different number of subtypes: one reported 3 subtypes, whereas the second highlighted 5. Given that each ascribed clinical significance, distinctive biology, and therapeutic prognosis to the different subtypes, we sought to reconcile this apparent incongruity in subtype stratification of CRC, and to interrelate the results. To do so, we each evaluated the other's data sets and analytical methods and discovered that the subtypes and their classifiers are, in fact, clearly related to each other; indeed, the 5 subtype outcomes can be coalesced into the same three. In addition to presenting this clarification, we briefly discuss how both classification methods can be viewed within the broader literature on CRC subtypes, and potentially applied.

Background: Diagnostic problems in clinical trials are sometimes ordinal. For example, colon tumor staging was performed according to the TNM classification. However, clinical data are limited by markedly small sample sizes in some stage., Methods: We propose a distribution-free test for detecting ordered alternatives in a completely randomized design. The new statistic is based on summing all correctly (ascending) ordered samples., Results: The exact mean and variance of the null distribution are derived and it is shown that this distribution is asymptotically normal. Furthermore, we show using Monte Carlo simulation that the proposed test is a significant improvement over the Terpstra-Magel test. That is, power is decreased where the investigator falsely assumes an a priori ordering relationship., Conclusions: We conclude that these tests frequently detect an ordered trend when, in fact, one does not exist. However, the new test can reduce the error rate, at least not to the extent in which the Jonckheere-Terpstra test does.

Cancer involvement of the colonic serosa is designated pT4a by the American Joint Committee on Cancer Staging Manual, 7th edition. The manual defines criteria for pT4a as either tumor penetration of the serosa or comingling of cancer cells and mesothelial cells in histologic sections. Unfortunately, the pT4a grouping is inconsistently applied, because these guidelines are overly limited: fibroinflammatory changes near the serosa may be associated with peritoneal metastases even in the absence of overt peritoneal penetration. Thus, reliable ancillary techniques for detecting serosal penetration by the tumor and accurate criteria for stage assessment are needed. We evaluated the utility of cytologic preparations in determining tumor stage by comparing results of serosal scrape cytology with histologic stage assessment of 120 colon cancer resection specimens. We correlated our findings with the presence and type of inflammatory changes near the serosa to determine which, if any, are reliable indicators of peritoneal penetration. Cytologic smears from all pT1 and pT2 tumors were negative for carcinoma. However, 13 (19%) pT3 tumors showed cancer in cytologic smears, all of which were deeply invasive. In fact, 46% of pT3 cancers present ≤1 mm from a serosal tissue reaction were associated with cancer in cytologic preparations from the serosa, which was comparable to pT4a tumors (55%). We conclude that cytologic smears improve detection of peritoneal penetration among pT3 tumors compared with histology alone. Tumors close (≤1 mm) to a fibroinflammatory tissue reaction on the serosa are likely associated with peritoneal involvement by cancer. Peritumoral abscesses that communicate with the serosa and hemorrhage or fibrin on the serosa also predict cancer involvement of the peritoneum. The presence of these findings among deeply invasive cancers should prompt their classification as pT4a lesions.

Background: Probe-based confocal laser endomicroscopy may allow a strategy of "diagnose, resect, and discard" for small nonadvanced adenomas, but there are concerns about discarding polyps with advanced histology., Objective: The aim of this study was to evaluate the potential use of probe-based confocal laser endomicroscopy to aid in distinguishing low-grade from advanced colon adenomas., Design: Six observers, blinded to histopathology, scored 5 adenoma features and an overall diagnosis and confidence level for the diagnosis., Setting: This study was conducted at single, tertiary care referral center., Patients: Patients undergoing screening and surveillance colonoscopies and for whom an adenomatous polyp was removed were included., Interventions: A sample of 27 advanced adenomas and 120 nonadvanced adenomas were used in the study. An initial classification system was created with 10 advanced and 10 nonadvanced adenomas. The remaining 127 adenomas were scored by each observer in the validation portion of the study., Main Outcome Measures: The primary outcome measured was the accurate classification of advanced and nonadvanced adenomas., Results: Overall, across all 6 observers, the sensitivity in correctly classifying advanced adenomas was 43%, the negative predictive value was 89%, the specificity was 71%, and the positive predictive value was 19%. No single feature or combination of features as seen with probe-based confocal laser endomicroscopy consistently identified advanced adenomas., Limitations: Classification criteria were developed subjectively, and there was limited observer experience with probe-based confocal laser endomicroscopy use., Conclusions: Our initial attempt at creating classification criteria for probe-based confocal laser endomicroscopy did not consistently distinguish advanced from nonadvanced adenomas and, therefore, is not useful in applying a "diagnose, resect, and discard" strategy. However, further refinement of our probe-based confocal laser endomicroscopy classification scheme in future studies has potential to accurately detect advanced histology in colorectal polyps.

Non-linear feature extraction methods, neighborhood preserving embedding (NPE) and supervised NPE (SNPE), were employed to effectively represent the IR spectral features of stomach and colon biopsy tissues for classification, and improve the classification accuracy for diagnosis of malignancy. The motivation was to utilize the NPE and SNPE's capability of capturing non-linear spectral behaviors by simultaneously preserving local relationships in order that minute spectral differences among classes would be effectively recognized. NPE and SNPE derive an optimal embedding feature such that the local neighborhood structure can be preserved in reduced spaces (variables). The IR spectra collected from stomach and colon tissues were represented by several new variables through NPE and SNPE, and also by using the principal component analysis (PCA). Then, the feature-extracted variables were subsequently classified into normal, adenoma and cancer tissues by using both k-nearest neighbor (k-NN) and support vector machine (SVM), and the resulting accuracies were compared with each other. In both cases, the combination of SNPE-SVM provided the best classification performance, and the accuracy was substantially improved compared to when PCA-SVM was used. Overall results demonstrate that NPE and SNPE could be potential feature-representation strategies useful in biomedical diagnosis based on vibrational spectroscopy where effective recognition of minute spectral differences is critical.

Context: A significant portion of colorectal biopsies are performed for evaluation of polyps or polypoid lesions. Accurately identifying these lesions will promote better patient care., Objective: Review of the pathology of major colon polyps and polypoid lesions and highlight the most diagnostically useful features and their molecular biology., Data Source: Review of recent literature., Conclusions: Polypoid lesions of the colon can be thought of to be under 3 broad categories: syndromic, mesenchymal, and epithelial.

Colon cancer is a clinically diverse disease. This heterogeneity makes it difficult to determine which patients will benefit most from adjuvant therapy and impedes the development of new targeted agents. More insight into the biological diversity of colon cancers, especially in relation to clinical features, is therefore needed. We demonstrate, using an unsupervised classification strategy involving over 1,100 individuals with colon cancer, that three main molecularly distinct subtypes can be recognized. Two subtypes have been previously identified and are well characterized (chromosomal-instable and microsatellite-instable cancers). The third subtype is largely microsatellite stable and contains relatively more CpG island methylator phenotype-positive carcinomas but cannot be identified on the basis of characteristic mutations. We provide evidence that this subtype relates to sessile-serrated adenomas, which show highly similar gene expression profiles, including upregulation of genes involved in matrix remodeling and epithelial-mesenchymal transition. The identification of this subtype is crucial, as it has a very unfavorable prognosis and, moreover, is refractory to epidermal growth factor receptor-targeted therapy.

Background: With increasing interest in neuroendocrine tumors (NETs), three staging systems for NETs of the colon and rectum have been published. Their prognostic relevance has not been examined and compared in an independent clinical database., Methods: From the National Cancer Database (NCDB), 5457 patients diagnosed with colorectal neuroendocrine tumor (CRNETs) between 1998 and 2002 were staged according to the staging systems from (1) European Neuroendocrine Tumor Society (ENETS, 2006; n = 1537); (2) American Joint Committee on Cancer (AJCC, 2009; n = 1140); and (3) location-specific staging systems from the Surveillance Epidemiology and End Results (SEER, 2008; n = 942). Stage-stratified overall survival (OS) and Cox-specific concordance indices were calculated for each system. Independent prognostic factors were identified by multivariate analysis., Results: Five-year OS for stage I, II, III, and IV CRNETs as defined by the ENETS staging system were 90.8, 77.3, 53.1, and 14.8 %, respectively. For well-differentiated CRNETs, the 5-year OS for stage I, II, III, and IV as defined by the AJCC staging system were superior: 90.6, 83.9, 64.8, and 24.9 %, respectively. Both staging systems had a concordance index of 0.72. After specifying location in the colon versus rectum, all three systems demonstrated acceptable performance. Histologic grade was a significant independent predictor of OS not currently incorporated in the staging systems., Conclusions: The three staging systems showed comparable prognostic stratification of CRNETs, while the AJCC and ENETS systems are the most parsimonious. The current analysis supports the use of the AJCC for well-differentiated disease and ENETS systems for all CRNETs until there is further evidence for modification.

Background: Decision making for adjuvant chemotherapy in stage III colon cancer is based on the TNM system. It is well known that prognosis worsens with higher pN classification, and several recent studies propose superiority of the lymph node ratio (ln ratio) to the TNM system. Therefore, we compared the prognosis of ln ratio to TNM system in our stage III colon cancer patients., Methods: A total of 939 patients underwent radical surgery for colorectal cancer between January 2000 and December 2009. From this pool of patients, 142 colon cancer stage III patients were identified and taken for this analysis. Using martingale residuals, this cohort could be separated into a group with a low ln ratio and one with a high ln ratio. These groups were compared to pN1 and pN2 of the TNM system., Results: For ln ratio, the cutoff was calculated at 0.2. There was a good prognosis of disease-free and cancer-related survival for the N-category of the TNM system as well as for the lymph node ratio. There was no statistical difference between using the N-category of the TNM system and the ln ratio., Conclusions: There might not be a benefit in using the lymph node ratio rather than the N category of the TNM system as long as the number of subgroups is not increased. In our consideration, there is no need to change the N categorization of the TNM system to the ln ratio.

Background: The abundance of gene expression microarray data has led to the development of machine learning algorithms applicable for tackling disease diagnosis, disease prognosis, and treatment selection problems. However, these algorithms often produce classifiers with weaknesses in terms of accuracy, robustness, and interpretability. This paper introduces fuzzy support vector machine which is a learning algorithm based on combination of fuzzy classifiers and kernel machines for microarray classification., Results: Experimental results on public leukemia, prostate, and colon cancer datasets show that fuzzy support vector machine applied in combination with filter or wrapper feature selection methods develops a robust model with higher accuracy than the conventional microarray classification models such as support vector machine, artificial neural network, decision trees, k nearest neighbors, and diagonal linear discriminant analysis. Furthermore, the interpretable rule-base inferred from fuzzy support vector machine helps extracting biological knowledge from microarray data., Conclusions: Fuzzy support vector machine as a new classification model with high generalization power, robustness, and good interpretability seems to be a promising tool for gene expression microarray classification.

Anonymous or privacy preserving record linkage is the term for systems allowing the linkage of data from different sources while maintaining an individual's anonymity. This work displays the impact of variations in the process of generating weights in a probabilistic record linkage system on different datasets, the resulting set of weights of candidate pairs and consequently on the final classification process. Furthermore, the results give insight into general problems of current unsupervised classification methods.

Background: Colon cancer (CC) pathological staging fails to accurately predict recurrence, and to date, no gene expression signature has proven reliable for prognosis stratification in clinical practice, perhaps because CC is a heterogeneous disease. The aim of this study was to establish a comprehensive molecular classification of CC based on mRNA expression profile analyses., Methods and Findings: Fresh-frozen primary tumor samples from a large multicenter cohort of 750 patients with stage I to IV CC who underwent surgery between 1987 and 2007 in seven centers were characterized for common DNA alterations, including BRAF, KRAS, and TP53 mutations, CpG island methylator phenotype, mismatch repair status, and chromosomal instability status, and were screened with whole genome and transcriptome arrays. 566 samples fulfilled RNA quality requirements. Unsupervised consensus hierarchical clustering applied to gene expression data from a discovery subset of 443 CC samples identified six molecular subtypes. These subtypes were associated with distinct clinicopathological characteristics, molecular alterations, specific enrichments of supervised gene expression signatures (stem cell phenotype-like, normal-like, serrated CC phenotype-like), and deregulated signaling pathways. Based on their main biological characteristics, we distinguished a deficient mismatch repair subtype, a KRAS mutant subtype, a cancer stem cell subtype, and three chromosomal instability subtypes, including one associated with down-regulated immune pathways, one with up-regulation of the Wnt pathway, and one displaying a normal-like gene expression profile. The classification was validated in the remaining 123 samples plus an independent set of 1,058 CC samples, including eight public datasets. Furthermore, prognosis was analyzed in the subset of stage II-III CC samples. The subtypes C4 and C6, but not the subtypes C1, C2, C3, and C5, were independently associated with shorter relapse-free survival, even after adjusting for age, sex, stage, and the emerging prognostic classifier Oncotype DX Colon Cancer Assay recurrence score (hazard ratio 1.5, 95% CI 1.1-2.1, p = 0.0097). However, a limitation of this study is that information on tumor grade and number of nodes examined was not available., Conclusions: We describe the first, to our knowledge, robust transcriptome-based classification of CC that improves the current disease stratification based on clinicopathological variables and common DNA markers. The biological relevance of these subtypes is illustrated by significant differences in prognosis. This analysis provides possibilities for improving prognostic models and therapeutic strategies. In conclusion, we report a new classification of CC into six molecular subtypes that arise through distinct biological pathways.

For several years, the lack of consensus on definition, nomenclature, natural history, and biology of serrated polyps (SPs) of the colon has created considerable confusion among pathologists. According to the latest WHO classification, the family of SPs comprises hyperplastic polyps (HPs), sessile serrated adenomas/polyps (SSA/Ps), and traditional serrated adenomas (TSAs). The term SSA/P with dysplasia has replaced the category of mixed hyperplastic/adenomatous polyps (MPs). The present study aimed to evaluate the reproducibility of the diagnosis of SPs based on currently available diagnostic criteria and interactive consensus development. In an initial round, H&E slides of 70 cases of SPs were circulated among participating pathologists across Europe. This round was followed by a consensus discussion on diagnostic criteria. A second round was performed on the same 70 cases using the revised criteria and definitions according to the recent WHO classification. Data were evaluated for inter-observer agreement using Kappa statistics. In the initial round, for the total of 70 cases, a fair overall kappa value of 0.318 was reached, while in the second round overall kappa value improved to moderate (kappa = 0.557; p < 0.001). Overall kappa values for each diagnostic category also significantly improved in the final round, reaching 0.977 for HP, 0.912 for SSA/P, and 0.845 for TSA (p < 0.001). The diagnostic reproducibility of SPs improves when strictly defined, standardized diagnostic criteria adopted by consensus are applied.

Background: Sessile serrated adenomas (SSAs) and hyperplastic polyps (HP) are the two most common types of serrated colon polyps (SCPs). SSAs are suspected to be the precursor lesions for many colorectal cancers, and hence there is an emphasis on their detection and removal. On the other hand, recent guidelines such as those from the European Union consider HPs of limited clinical significance., Objective: Evaluate the reclassification rate of recently diagnosed HPs to SSAs and the predictors of such reclassification. DESIGN, SETTING, INTERVENTION, MAIN OUTCOME MEASUREMENTS: The provincial pathology database was searched for all colon polyps reported in the 6 pathology laboratories in the city of Winnipeg in 2009. All retrieved pathology slides for previously reported right-sided HPs and a 20% random sample of left-sided HPs were reassessed by two pathologists with a special interest in GI pathology. Polyp size, colon location, and age and sex of the study participants were evaluated as potential predictors of reclassification., Results: A total of 4096 pathology reports by 25 different pathologists were reviewed. Twenty percent of the polyps were reported as SCPs. Seventeen percent of right-sided previously reported HPs and 20% of those >5 mm were reclassified as SSAs. Size >5 mm (odds ratio [OR] 4.2; 95% confidence interval [CI], 1.5-11.4) and location in the right side of the colon (OR 4.7; 95% CI, 1.4-15.4) were independent predictors of reclassification., Limitations: Retrospective review., Conclusion: A significant proportion of recently reported right-sided HPs may be SSAs. Surveillance recommendations for SCPs should consider the size and location of SCPs and not just the reported type., (Copyright © 2012 American Society for Gastrointestinal Endoscopy. Published by Mosby, Inc. All rights reserved.)

Recently, microarrays that can simultaneously measure the expression levels of thousands of genes have become a valuable tool for classifying tumors. For such classification, where the sample size is usually much smaller than the number of genes, it is essential to construct properly sparse models for accurately predicting tumor types to avoid over-fitting. Bayesian shrinkage estimation is considered a suitable method for providing such sparse models, effectively shrinking estimates of the effects for many irrelevant genes to zero while maintaining those of a small number of relevant genes at significant magnitudes. However, Bayesian analysis usually requires time-consuming computational techniques such as computationally intensive MCMC iterations. This paper describes a computationally effective method of Bayesian shrinkage regression (BSR) incorporating multiple hierarchical structures for constructing a classification model for tumor types using microarray gene expression data. We use a variational approximation method which provides simple approximations of posterior distributions of parameters to reduce computational burden in the Bayesian estimation. This computationally efficient BSR procedure yields a properly sparse model for accurately and rapidly classifying tumor samples. The accuracy of tumor classification is shown to be at least equivalent to that of other methods such as support vector machine and partial least squares using simulated and actual gene expression data sets.

There is a growing amount of data supporting the concept that cancers originating from the proximal and distal colon are distinct clinicopathological entities. The incidence of MSI and BRAF mutation is strongly associated with right sided tumor location, whereas there are conflicting results for KRAS mutation rates. However, to date, no data exist whether and to what extent defined colonic subsites influence MSI status, KRAS and BRAF mutation rates. We selected primary colon cancer from 171 patients operated on at our institution between 2007 and 2010. BRAF, KRAS mutation rates and microsatellite instability were determined and correlated with clinicopathological features and tumor location. MSI-h cancers were significantly associated with poor histological grade but a lower rate of distant metastases. KRAS-mutated tumors were linked to lower T-stage and better differentiation. Colon carcinomas with BRAF mutation were significantly associated with distant metastatic spread and poor histological grade. Furthermore, we found that MSI-h status, KRAS and BRAF mutation rates varied remarkably among the colonic subsites irrespective of right- and left-sided origin, respectively. The results of the current study provide further evidence that a simple classification into right- and left-sided colon carcinoma does not represent the complexity of this tumor entity., (Copyright © 2012 Elsevier GmbH. All rights reserved.)

The incidence of malignant gastrointestinal cancers in Poland has been constantly growing, which has led to an intensification of the search for new markers of the early clinical stage of this disease. The oral cavity,as the first part of the gastrointestinal tract, has a very important role. The oral cavity presents symptoms of both typically stomatological and systemic diseases. Oral cancers, benign or malignant, may originate and grow in any of the tissues of the mouth, and within this small area they may be of varied clinical, histological and biological features. These can be lesions typically observed in the oral cavity, but also characteristic of cases where the symptoms occur both in the mouth and in other body parts. The aim of this study was to present a cytological picture of the oral mucosa in patients with gastric and colon cancer and to compare the cytological picture with that obtained from a group of patients with no cancer, using the Papanicolaou classification and the Bethesda system. The study was conducted in 126 patients treated surgically in the II General and Gastroenterological Surgery Clinic between 2006 and 2008. All patients were divided into two groups based on the type of lesions. In both of the studied groups, more than half of the patients did not present any abnormalities in the mucosa of the mouth, lips and cheeks in the physical examination. None of the patients had erosion, ulceration or lesions typical of leukoplakia or lichen planus. No malignant cells were detected in either of the studied groups, and there were no well-defined lesions found in the oral cavity that would distinguish the patients with gastrointestinal cancer.

Purpose: According to the American Joint Committee on Cancer (AJCC) 7th edition, T4 colon cancers have been sub-divided into T4a and T4b, resulting in a stage II sub-classification (T3N0, T4aN0, and T4bN0). This study was aimed: (a) to investigate the impact of the AJCC 7th edition stage II sub-classification on the overall survival (OS), disease-free survival (DFS) and disease-specific survival (DSS) of colon cancer patients who underwent surgical resection and (b) to compare the last three AJCC editions for identifying stage II patients with high-risk of progression., Methods: One hundred seventy-eight stage II colon cancers out of 682 colorectal cancer patients who underwent surgical resection were selected. T4N0 were sub-divided in accordance with the AJCC 7th edition. Mean follow-up was 41.9 months. Kaplan-Meier method was employed to estimate the survival curves., Results: OS analysis documented a significant difference between stage-sub-groups using the 6th edition; conversely, this difference was not seen if the 7th edition was applied (p = 0.03 and 0.12, respectively). Stage II DFS analysis reported a significant difference using both the AJCC 6th and 7th editions (p = 0.03 and 0.02, respectively). A significant difference was reported on stage II DSS analysis using the AJCC 6th edition (p = 0.03); however, when the 7th edition was applied, a substantial discrepancy between survival curves was noted with T3N0 and T4aN0 displaying similar outcomes (p = 0.006)., Conclusions: The AJCC 7th edition is a reliable classification that might implement the identification of those stage II colon cancer patients with high-risk of progression, recurrence, and cancer mortality.

Colorectal cancer is one of the most common cancers in the world. Histological staging is efficient, but combination with molecular markers may improve tumor classification. Gene expression profiles have been defined as prognosis predictors among stage II and III tumors, but their implementation in medical practice remains controversial. Stage II tumors have been recognized as a heterogeneous group, and high-risk morphologic features have been used to justify adjuvant chemotherapy. We propose here the investigation of clinical features and expression profiles from stage II and stage III colon carcinomas without DNA mismatch repair defects. Two series of 130 and 66 colon cancer samples were obtained. Expression profiles were established on oligonucleotide microarrays and processed in the R/Bioconductor environment. Hierarchical, then supervised, analyses were successively performed by applying a data-sampling approach. A molecular signature of seven genes was found to cluster stage III tumors with adjusted p values lower than 10(-10). A subgroup of stage II tumors aggregated this cluster in both series. No correlation was found with disease severity, but the function of the discriminating genes suggests that tumors have been classified according to their putative response to adjuvant targeted or classic therapies. Further pharmacogenetic studies might verify this observation.

Background: Currently, there is a surge of interest on the possible relationship between cancer and acid phosphatase locus 1 (ACP(1)), an enzyme involved in the modulation of growth factors and cellular metabolism. As far as the authors know, the possible relationship between ACP(1) genetic variability and cancer grading has not yet been considered. In this article, the authors have studied the relationship between ACP(1) genotype and grade in colon and endometrium cancers., Methods: Seventy-one patients with colon cancer and 71 patients with endometrium cancer were studied. ACP(1) genotype was determined by DNA analysis. Three-way contingency table analysis was carried out according to Sokal and Rohlf. Other statistical analyses were performed using SPSS programs., Results: There is a significant association between ACP(1) and cancer grade mainly due to ACP(1) genotypes carrying the *C allele that are much less represented in patients with low grade when compared with those with high grade. In both cancers, the concentration of S isoform is significantly lower in low grade than in high grade. The relationship between ACP(1) and grade is the same in the 2 cancers., Conclusions: Assuming the presence of diverse classes of cancer, the role of ACP(1) in the modulation of growth factors and cellular metabolism could have significant effects in less aggressive forms but not in more aggressive ones.

Background: Colon cancer patients with the same stage show diverse clinical behavior due to tumor heterogeneity. We aimed to discover distinct classes of tumors based on microarray expression patterns, to analyze whether the molecular classification correlated with the histopathological stages or other clinical parameters and to study differences in the survival., Methods: Hierarchical clustering was performed for class discovery in 88 colon tumors (stages I to IV). Pathways analysis and correlations between clinical parameters and our classification were analyzed. Tumor subtypes were validated using an external set of 78 patients. A 167 gene signature associated to the main subtype was generated using the 3-Nearest-Neighbor method. Coincidences with other prognostic predictors were assesed., Results: Hierarchical clustering identified four robust tumor subtypes with biologically and clinically distinct behavior. Stromal components (p < 0.001), nuclear β-catenin (p = 0.021), mucinous histology (p = 0.001), microsatellite-instability (p = 0.039) and BRAF mutations (p < 0.001) were associated to this classification but it was independent of Dukes stages (p = 0.646). Molecular subtypes were established from stage I. High-stroma-subtype showed increased levels of genes and altered pathways distinctive of tumour-associated-stroma and components of the extracellular matrix in contrast to Low-stroma-subtype. Mucinous-subtype was reflected by the increased expression of trefoil factors and mucins as well as by a higher proportion of MSI and BRAF mutations. Tumor subtypes were validated using an external set of 78 patients. A 167 gene signature associated to the Low-stroma-subtype distinguished low risk patients from high risk patients in the external cohort (Dukes B and C:HR = 8.56(2.53-29.01); Dukes B,C and D:HR = 1.87(1.07-3.25)). Eight different reported survival gene signatures segregated our tumors into two groups the Low-stroma-subtype and the other tumor subtypes., Conclusions: We have identified novel molecular subtypes in colon cancer with distinct biological and clinical behavior that are established from the initiation of the tumor. Tumor microenvironment is important for the classification and for the malignant power of the tumor. Differential gene sets and biological pathways characterize each tumor subtype reflecting underlying mechanisms of carcinogenesis that may be used for the selection of targeted therapeutic procedures. This classification may contribute to an improvement in the management of the patients with CRC and to a more comprehensive prognosis.

Appendicitis is a common diagnosis encountered by the acute care surgeon. Management of complicated appendicitis is controversial and often involves initial nonoperative therapy with interval appendectomy. This study reviews single-institutional experience with management of complicated appendicitis with interval appendectomy and addresses an unusually high occurrence of incidental appendiceal malignancies observed with a review of relevant literature. A retrospective review of all diagnoses of appendicitis was performed over 5 years at a tertiary care center. Patient demographics, time to surgery, operative technique, pathologic diagnosis, and clinical outcomes were examined. Three hundred fifteen patients were diagnosed with acute appendicitis. Of these, 24 (7.6%) were deemed complicated and did not undergo immediate appendectomy, and 18 ultimately underwent appendectomy at our institution and were included in analysis. There were no statistical demographic or symptomatic differences between the immediate and interval appendectomy patients. Ninety-nine per cent of the immediate appendectomy patients were treated laparoscopically; 78 per cent of the interval group underwent attempted laparoscopic treatment with 56 per cent completed without conversion to open (P < 0.01). Neoplasms were discovered in 1 per cent of the acute appendectomy group and 28 per cent of the interval appendectomy group (P < 0.0001). Two of the three neoplasms in the acute group were carcinoid, whereas three of the five neoplasms in the interval group were adenocarcinoma. Surgeons should consider appendiceal or colonic neoplasms in cases of complicated appendicitis when nonoperative management is considered. This is most important in patients older than 40 years, in those who forego interval appendectomy, or in those who could be lost to follow-up.

Background and Aims: Probe-based confocal laser endomicroscopy (pCLE; Cellvizio, Mauna Kea Technologies, Paris, France) enables in vivo histology during colonoscopy and may allow endoscopists to make real-time diagnoses. A collaboration of five experts proposed a new pCLE classification for colonic use. The aim of this study was to assess interobserver agreement and accuracy of the new pCLE classification in the colon., Patients and Methods: Eligible patients were prospectively investigated by pCLE. A subset of 13 pCLE video sequences was reviewed post hoc for the establishment of a new classification, which comprised three vessel categories and seven crypt categories. All five blinded observers then scored another set of 102 video sequences, using the new classification. Histopathology was used as a reference standard., Results: The interobserver agreements on vessel and crypt architecture were 'fair' with kappa values of 0.29 and 0.27, respectively. When the classification was reduced to neoplasia vs. non-neoplasia (i.e. vessel or crypt type 3), overall agreement became 'moderate' (κ = 0.56). Overall sensitivity and specificity for predicting neoplasia was 66 % and 83 %, respectively. When all observers agreed (69 % of videos), the corresponding figures became 80 % and 95 %., Conclusion: A new classification for pCLE in the colon had a 'moderate' interobserver agreement for differentiating neoplasia from non-neoplastic tissue in the colon. The overall accuracy (81 %) for predicting neoplasia was acceptable and became excellent (94 %) when all five observers agreed. Future research should focus on refinement and validation of the classification., (© Georg Thieme Verlag KG Stuttgart · New York.)

Purpose: Colorectal cancer studies typically include both colon and rectum tumors as a common entity, though this assumption is controversial and only minor differences have been reported at the molecular and epidemiologic level. We conducted a molecular study based on gene expression data of tumors from colon and rectum to assess the degree of similarity between these cancer sites at transcriptomic level., Experimental Design: A pooled analysis of 460 colon tumors and 100 rectum tumors from four data sets belonging to three independent studies was conducted. Microsatellite instable tumors were excluded as these are known to have a different expression profile and have a preferential proximal colon location. Expression differences were assessed with linear models, and significant genes were identified using adjustment for multiple comparisons., Results: Minor differences at a gene expression level were found between tumors arising in the proximal colon, distal colon, or rectum. Only several HOX genes were found to be associated with tumor location. More differences were found between proximal and distal colon than between distal colon and rectum., Conclusions: Microsatellite stable colorectal cancers do not show major transcriptomic differences for tumors arising in the colon or rectum. The small but consistent differences observed are largely driven by the HOX genes. These results may have important implications in the design and interpretation of studies in colorectal cancer., (©2011 AACR.)

Background: Metastasectomy is the standard treatment for patients with resectable liver metastasis from colon cancer. This study aimed to determine the impact of initial stage on overall survival (OS) after metastasectomy., Methods: A retrospective analysis of 2804 patients diagnosed with colon cancer between 1999 and 2008., Results: Of the cohort, 38.1% of the patients were stage IV or had recurrence after curative surgery, and 131 received liver metastasectomy. The 5-year survival rate for patients after liver metastasectomy was 42.1%. The 5-year survival rates after metastasectomy for initial stage I disease, stage II disease, stage III disease, and stage IV disease were 100%, 82.5%, 31.8%, and 36.9%, respectively (p = 0.014). When patients were grouped as initial stage I/II and stage III/IV, the 5-year survival rate after liver metastasectomy differed significantly (83.9% vs. 35.7%, p = 0.006). Patients with initial stage I/II disease after liver metastasectomy had a significantly better 5-year progression-free period compared to those with stage III/IV disease (60% vs. 28%, p = 0.021), which was due to the lower recurrence rate in the stage I/II group., Conclusion: Our results suggest that patients who receive liver metastasectomy for metastatic colon cancer should be grouped into two groups: those with initial stages I and II disease, and those with stages III and IV disease, since the progression-free survivals (PFS) and OS after metastasectomy in these two groups differ significantly., (Copyright © 2011. Published by Elsevier B.V.)

Background and Study Aims: Recent advances in endocytoscopy have enabled in vivo evaluation not on ly of structural atypia, but also of cellular atypia with observation of lumens and nuclei in the surface layer of the mucosa. The aim of this prospective pilot study was to evaluate the usefulness of our novel endocytoscopic classification in colorectal lesions., Patients and Methods: A total of 206 consecutive patients were enrolled in the study and underwent endocytoscopic examination. Endocytoscopic images were stored electronically and two endoscopists blinded to the findings at live examination assigned them diagnoses using the endocytoscopic (EC) classification. The endocytoscopic diagnosis was then compared to the final histopathological diagnosis., Results: In all, 196 patients with 213 specimens were available for analysis. All normal mucosae were classified as EC1a and all hyperplastic polyps as EC1b. Dysplasias were mainly classified as EC2, while massively invasive submucosal cancers (SMm) or worse, which have the possibility of metastasis, were mainly EC3b. Assuming that an EC1b classification was diagnostic of hyperplastic polyps, we were able to differentiate nonneoplastic from neoplastic lesions with a sensitivity of 100 % and a specificity of 100 % (P < 0.05). Assuming that an EC3b classification was diagnostic of SMm or worse, we were able to differentiate "SMm or worse" from other neoplastic lesions (dysplasias and slightly invasive submucosal cancers) with a sensitivity of 90.1 % and a specificity of 99.2 % (P < 0.05)., Conclusions: The endocytoscopic classification was particularly useful for differentiating between neoplastic and nonneoplastic lesions and between "SMm or worse" and other neoplastic lesions, which in the case of colorectal neoplasms would help to determine treatment., (© Georg Thieme Verlag KG Stuttgart · New York.)

The 5-year relapse-free survival rate (5Y-RFS) and 5-year overall survival rate (5Y-OS) were investigated in 766 patients with stage II/III colorectal cancer (CRC). The Stage II group included 283 patients with colon cancer (CC), 40 patients with rectosigmoid junction cancer (RSC), and 74 patients with rectal cancer (RC), while the Stage III group comprised 226 patients with CC, 52 patients with RSC, and 91 patients with RC. Stage III patients with RC were further divided into 68 patients with Ra cancer (Ra, rectum/above the peritoneal reflection) and 23 patients with Rb cancer (Rb, rectum/below the peritoneal reflection). Then the 5Y-RFS and 5Y-OS were calculated for each category or subcategory. The 5Y-RFS/5Y-OS was 80.3/80.6% for Stage II patients and 63.7% (p<0.001)/66.2% (p<0.001) for Stage III patients. In the Stage II group, the survival rates were 82.9/81.2% for CC, 77.6/74.8% for RSC, and 72.9/80.5% for RC, with no significant differences between each category. In the Stage III group, the survival rates were 69.3/72.8% for CC, 71.6/77.7% for RSC, and 46.5/46.2% for RC. There was no significant difference of survival for CC vs. RSC, but significant differences were noted for CC vs. RC (p<0.001/p<0.001) and RSC vs. RC (p=0.008/p=0.007). In the Stage III group, survival rates were 71.6/77.7% for RSC, 47.6/44.8% for Ra, and 45.7/51.3% for Rb, with significant differences for RSC vs. Ra (p=0.013/p=0.005) and RSC vs. Rb (p=0.026/p=0.180), but not for Ra vs. Rb. These results suggest that Stage II/III RS cancer should be classified as colon cancer and should not be considered an independent tumor type.

Gastroenterologists removing colorectal polyps expect standardized and well-structured pathological reports, providing them with all relevant data for the further clinical management of the patient. Over the last year, a task force of clinicians and pathologists has developed a checklist to improve and harmonize endoscopic and pathological reporting of colorectal polyps. This checklist concentrates more on concrete recommendations from evidence-based guidelines and established international classifications for daily practice rather than detailed molecular pathological pathways of carcinogenesis. These recommendations are based on the current S3 guidelines for colorectal cancer (the chapter entitled "Management of colorectal polyps"), the histomorphological consensus manuscript of the GI working group of the German Society for Pathology, as well as the current WHO classification for tumors of the digestive system.

For medical classification problems, it is often desirable to have a probability associated with each class. Probabilistic classifiers have received relatively little attention for small n large p classification problems despite of their importance in medical decision making. In this paper, we introduce 2 criteria for assessment of probabilistic classifiers: well-calibratedness and refinement and develop corresponding evaluation measures. We evaluated several published high-dimensional probabilistic classifiers and developed 2 extensions of the Bayesian compound covariate classifier. Based on simulation studies and analysis of gene expression microarray data, we found that proper probabilistic classification is more difficult than deterministic classification. It is important to ensure that a probabilistic classifier is well calibrated or at least not "anticonservative" using the methods developed here. We provide this evaluation for several probabilistic classifiers and also evaluate their refinement as a function of sample size under weak and strong signal conditions. We also present a cross-validation method for evaluating the calibration and refinement of any probabilistic classifier on any data set.

Objectives: To determine how patients complied with different components of guideline-recommended post-treatment surveillance in a large nationwide population-based cohort of patients with colon cancer., Study Design: Retrospective cohort study., Methods: We used the linked Surveillance, Epidemiology, and End Results-Medicare database to identify patients 66 years or older diagnosed as having stage I to stage III colon adenocarcinoma between January 2000 and June 2002 with a follow-up duration of at least 3.5 years. After tumor resection, patients who completed at least 2 office visits per year for 3 years, at least 2 carcinoembryonic antigen tests per year (in the first and second years of follow-up), and at least 1 colonoscopy within 3 years were defined as meeting the recommended post-treatment care., Results: We identified 7348 patients, with a median follow-up duration of 59 months. Adherence to post-treatment surveillance was 83.9% for office visits, 29.4% for carcinoembryonic antigen tests, and 74.3% for colonoscopy. Younger age at diagnosis, white race/ethnicity, married status, advanced tumor stage, fewer comorbidities, and chemotherapy use were significantly associated with guideline adherence., Conclusions: Adherence to colon cancer posttreatment surveillance was low, although proportions of patients complying with office visits and colonoscopy were reasonably high. Underlying reasons for noncompliance, which varied by type of service, may need further investigation.

Background: The clinicopathological characteristics of colorectal mucinous adenocarcinoma (MA) are still controversial. Most of the reports suggested that MA were associated with worse clinicopathological behavior and poorer prognosis than non-mucinous adenocarcinoma (NMA) while the others showed no difference., Objective: To compare clinicopathological characteristics and tumor recurrence of MA patients with those in NMA patients., Material and Method: During the period of 2000 to 2009 in Rajavithi Hospital, a total of 427 colorectal adenocarcinoma patient records consisting of 407 NMA and 20 MA were included in this study. Mean age, tumor location, TNM staging at diagnosis, T-stage, N-stage, preoperative CEA level and recurrent rate of MA patients were compared with those of NMA patients., Results: The distribution of MA patients for gender, mean age, tumor location, TNM stage and preoperative CEA level were similar to those of NMA patients (all p > 0.05). Only the tumor recurrence in MA was significantly more common than that in NMA (p = 0.020, OR = 3.28 (1.14-9.43)), whereas the TNM stage was not significantly different from NMA (p = 0.530). The metastatic site and pattern of metastasis also showed no statistical significance (p = 0.125)., Conclusion: The prognosis of MA is poorer than NMA. This may be associated with mucinous histological type itself.

In addition to histology, size and location, a morphologic description can be ascribed to polyps and adenomas. Traditionally, adenomas have been described as sessile and pedunculated, but it is now accepted that they can also present as flat or even depressed. Although first recognized in 1985, flat adenomas have become more common in Western published literature and in endoscopic reports. The Japanese Research Society Classification describes flat adenomas as lesions with a height that is less than one half of the diameter, while the Paris classification divides polyps into protruding and nonprotruding. The clinical significance of flat adenomas includes their potential malignancy, difficulty in detection and possible role in interval cancers. Serrated polyps represent a subset of polyps that have all the features that make flat lesions clinically important. Due to the relatively recent recognition of these lesions, as well as the technology required to detect them, the prevalence and malignant potential of these lesions in Western patients are still unknown. Finally, the best techniques and equipment for detecting flat polyps are also not established. In this article, we examine the issue of flat polyps and their significance in colorectal cancer screening with regard to prevalence, risk factors and methods for detecting flat polyps.

Background and Study Aim: The real-time identification and removal of adenomas is a cost-effective strategy to improve the prognosis of colorectal cancer. Confocal laser endomicroscopy (CLE) could provide real-time histological-level observation. We aimed to evaluate the efficacy of CLE diagnosis using a simple classification system that differentiates adenomas from non-neoplastic polyps with intravenous fluorescein staining alone., Patients and Methods: An endoscope integrated confocal laser microscopy system was used in this study. CLE images of 35 colonic polyps, including 15 hyperplastic polyps and 20 adenomas confirmed by histology, were first evaluated to develop criteria for diagnosis of neoplastic and non-neoplastic polyps. The diagnostic criteria included goblet cell depletion, villous architecture, and microvascular alterations. We then performed a prospective study of colonic polyps found during CLE and classified them according to the established criteria. A total of 115 patients with 115 colonic polyps were included. The real-time CLE diagnosis was compared with that from histology. The stored CLE images were evaluated later by a blinded observer., Results: The sensitivity, specificity, positive predictive value, and negative predictive value of real-time CLE in identifying colonic adenomas were 93.9 % (95 % confidence interval [CI] 85.4 - 97.6), 95.9 % (95 % CI 86.2 - 98.9), 96.9 % (95 % CI 89 - 99), and 92.2 % (95 % CI 81 - 97), respectively, compared with histological results. Interobserver agreement between real-time and post-CLE still-image evaluation was excellent (kappa = 0.929). Goblet cell depletion alone had a sensitivity of 84.9 % (95 % CI 73 - 92) and a specificity of 87.8 % (95 % CI 75 - 95), as well as excellent interobserver agreement (kappa = 0.824)., Conclusions: Endoscope integrated CLE with fluorescein staining may reliably assist in the real-time identification of colonic adenomas. Among three diagnostic categories, goblet cell depletion can be used to distinguish adenomas and hyperplastic polyps., (© Georg Thieme Verlag KG Stuttgart · New York.)

Clinicopathological characteristics and grading of poorly differentiated colon adenocarcinoma (Por) were discussed. A total of 1074 patients with colon cancer underwent surgical treatment at Kurume University Hospital in Fukuoka, between 1985 and 2005. Clinicopathological characteristics of 88 cases (8%) of Por and 986 cases (92%) of well differentiated tubular adenocarcinoma/moderately differentiated tubular adenocarcinoma (Tub1/Tub2) were studied. A multiple classification analysis showed that Por was more frequently observed in the right colon than Tub1/Tub2, and that the ratio of macroscopic types 3 and 4 was significantly higher in Por. Significant differences were also observed with regard to lymph vessel and perineural invasion. There were no significant differences between recurrence-free survivals of Por and Tub1/Tub2 after radical resection in Stages II and III. Recurrence of Por was significantly higher in peritonea and lymph nodes. These findings indicate that Por, which is generally considered to have a poor prognosis, has a similar recurrence rate to that of Tub1/Tub2 after the performance of radical surgery.

The classification of biological samples measured by DNA microarrays has been a major topic of interest in the last decade, and several approaches to this topic have been investigated. However, till now, classifying the high-dimensional data of microarrays still presents a challenge to researchers. In this chapter, we focus on evaluating the performance of the training algorithms of the single hidden layer feedforward neural networks (SLFNs) to classify DNA microarrays. The training algorithms consist of backpropagation (BP), extreme learning machine (ELM) and regularized least squares ELM (RLS-ELM), and an effective algorithm called neural-SVD has recently been proposed. We also compare the performance of the neural network approaches with popular classifiers such as support vector machine (SVM), principle component analysis (PCA) and fisher discriminant analysis (FDA).

Introduction: In cancer of the colon, the number of lymph nodes that should be analysed before a patient is classified as free of lymph node involvement has been widely discussed. A mathematical model is proposed which is based on the Bayes Theorem for calculating the probability of error (PE) similar to that normally used to evaluate a diagnostic test, but adapted to a quantitative variable, the lymph node count., Methods: The clinical histories of 480 patients routinely operated on in attempt to cure cancer of the colon were reviewed. Cases with any kind of metastasis were excluded. The proposed formula based on the Bayes Theorem was applied with the aim of calculating the PEs for the complete series and for different patient sub-groups (T2, T3, and T4 tumours)., Results: For the probabilities of error of classifying a patient as N negative, which varied between 5% and 1% (near or practically 0), the minimum number of negative lymph nodes required for analysis fluctuated between 7 and 17, respectively, for the complete series. This minimum figure was also variable for the different sub-groups (T2, T3, and T4 tumours) studied. These numbers mainly depended on the case characteristics of a specific study group as regards the prevalence of the N+ cases that they dealt with, and of its historically demonstrated ability to collect and identify positive lymph nodes in those patients that had them., Conclusion: From a mathematical point of view, the minimum number of lymph nodes that have to be analysed in cancer of the colon in order to classify a patient as N negative is not a constant. This depends on the error that is prepared to be assumed for that diagnosis, possibly depending on certain tumour traits, and also may be adapted to the cases of each study group., (Copyright © 2010 AEC. Published by Elsevier Espana. All rights reserved.)

The primary aim of this study was to analyze human colon cancer and normal adjacent tissue using (1)H HR MAS MR spectroscopy and chemometric analyses, evaluating possible biomarkers for colon cancer. The secondary aim was to investigate metabolic profiles of tissue samples (n = 63, 31 patients) with microsatellite instability (MSI-H) compared to microsatellite stable (MSS) colon tissue. Our hypothesis was that this method may provide an alternative to MSI genotyping. Cancer samples were clearly separated from normal adjacent mucosa by 100% accuracy. Several metabolites such as lactate, taurine, glycine, myo-inositol, scyllo-inositol, phosphocholine (PC), glycerophosphocholine (GPC), creatine, and glucose were identified as potential biomarkers for cancer detection. Adenomas (n = 4) were also separated from cancer and normal samples mainly based on higher GPC and PC levels. Interestingly, metabolic differences in normal colon mucosa between MSI-H and MSS patients were observed. MSI status was validated with 80% accuracy with a sensitivity and specificity of 79% and 82%, respectively, including both cancer and normal samples The metabolic differences between MSI-H and MSS may be very interesting in the early detection of cancer development and of high clinical importance in the work of improving diagnosis and characterization of colon cancer.