A Vulnerability of a Subset of Colon Cancers with Potential Clinical Utility.

BRAF(V600E) mutant colon cancers (CCs) have a characteristic gene expression signature that is also found in some tumors lacking this mutation. Collectively, they are referred to as "BRAF-like" tumors and represent some 20% of CCs. We used a shRNA-based genetic screen focused on genes upregulated in BRAF(V600E) CCs to identify vulnerabilities of this tumor subtype that might be exploited therapeutically. Here, we identify RANBP2 (also known as NUP358) as essential for survival of BRAF-like, but not for non-BRAF-like, CC cells. Suppression of RANBP2 results in mitotic defects only in BRAF-like CC cells, leading to cell death. Mechanistically, RANBP2 silencing reduces microtubule outgrowth from the kinetochores, thereby inducing spindle perturbations, providing an explanation for the observed mitotic defects. We find that BRAF-like CCs display far greater sensitivity to the microtubule poison vinorelbine both in vitro and in vivo, suggesting that vinorelbine is a potential tailored treatment for BRAF-like CCs.

Identification of unique rectal cancer-specific subtypes.

BACKGROUND: Existing colorectal cancer subtyping methods were generated without much consideration of potential differences in expression profiles between colon and rectal tissues. Moreover, locally advanced rectal cancers at resection often have received neoadjuvant chemoradiotherapy which likely has a significant impact on gene expression. METHODS: We collected mRNA expression profiles for rectal and colon cancer samples (n = 2121). We observed that (i) Consensus Molecular Subtyping (CMS) had a different prognosis in treatment-naïve rectal vs. colon cancers, and (ii) that neoadjuvant chemoradiotherapy exposure produced a strong shift in CMS subtypes in rectal cancers. We therefore clustered 182 untreated rectal cancers to find rectal cancer-specific subtypes (RSSs). RESULTS: We identified three robust subtypes. We observed that RSS1 had better, and RSS2 had worse disease-free survival. RSS1 showed high expression of MYC target genes and low activity of angiogenesis genes. RSS2 exhibited low regulatory T cell abundance, strong EMT and angiogenesis signalling, and high activation of TGF-ß, NF-κB, and TNF-α signalling. RSS3 was characterised by the deactivation of EGFR, MAPK and WNT pathways. CONCLUSIONS: We conclude that RSS subtyping allows for more accurate prognosis predictions in rectal cancers than CMS subtyping and provides new insight into targetable disease pathways within these subtypes.

Deep learning ensemble approach with explainable AI for lung and colon cancer classification using advanced hyperparameter tuning.

Lung and colon cancers are leading contributors to cancer-related fatalities globally, distinguished by unique histopathological traits discernible through medical imaging. Effective classification of these cancers is critical for accurate diagnosis and treatment. This study addresses critical challenges in the diagnostic imaging of lung and colon cancers, which are among the leading causes of cancer-related deaths worldwide. Recognizing the limitations of existing diagnostic methods, which often suffer from overfitting and poor generalizability, our research introduces a novel deep learning framework that synergistically combines the Xception and MobileNet architectures. This innovative ensemble model aims to enhance feature extraction, improve model robustness, and reduce overfitting.Our methodology involves training the hybrid model on a comprehensive dataset of histopathological images, followed by validation against a balanced test set. The results demonstrate an impressive classification accuracy of 99.44%, with perfect precision and recall in identifying certain cancerous and non-cancerous tissues, marking a significant improvement over traditional approach.The practical implications of these findings are profound. By integrating Gradient-weighted Class Activation Mapping (Grad-CAM), the model offers enhanced interpretability, allowing clinicians to visualize the diagnostic reasoning process. This transparency is vital for clinical acceptance and enables more personalized, accurate treatment planning. Our study not only pushes the boundaries of medical imaging technology but also sets the stage for future research aimed at expanding these techniques to other types of cancer diagnostics.

Human polyomaviruses genomes in clinical specimens of colon cancer patients.

Colon cancer is the third cause of cancer death in the developed countries. Some environmental factors are involved in its pathogenesis, including viral infections. The possible involvement of human polyomaviruses (HPyVs) in colon cancer pathogenesis has been previously reported, leading to inconsistent conclusions. Clinical specimens were collected from 125 colon cancer patients. Specifically, 110 tumor tissues, 55 negative surgical margins, and 39 peripheral blood samples were analyzed for the presence of six HPyVs: JC polyomavirus (JCPyV), BK polyomavirus (BKPyV), Merkel cell PyV (MCPyV), HPyV -6, -7, and -9 by means of DNA isolation and subsequent duplex Real Time quantitative polymerase chain reaction. HPyVs genome was detected in 33/204 samples (16.2%): the significant higher positivity was found in tumor tissues (26/110, 23.6%), followed by negative surgical margins (3/55, 5.5%, p < .05), and peripheral blood mononuclear cells (PBMCs) (4/39; 10.3%). HPyVs load was statistically higher only in the tumor tissues compared to negative surgical margins (p < .05). Specifically, MCPyV was detected in 19.1% (21/110) of tumor tissues, 3.6% (2/55) of negative surgical margins (p < .05), and 7.7% (3/39) of PBMCs; HPyV-6 in 2.7% (3/110) of tumor tissues, and 1.8% (1/55) of negative surgical margins; one tumor tissue (1/110, 0.9%) and one PBMCs sample (1/39, 2.6%) were positive for BKPyV; JCPyV was present in 0.9% (1/110) of tumor tissues. HPyV-7 and 9 were not detected in any sample. High prevalence and load of MCPyV genome in the tumor tissues might be indicative of a relevant rather than bystander role of the virus in the colon tumorigenesis.

Evaluation of a 55-gene classifier as a prognostic biomarker for adjuvant chemotherapy in stage III colon cancer patients.

BACKGROUND: Adjuvant chemotherapy reduces the risk of recurrence of stage III colon cancer (CC). However, more effective prognostic and predictive biomarkers are needed for better treatment stratification of affected patients. Here, we constructed a 55-gene classifier (55GC) and investigated its utility for classifying patients with stage III CC. METHODS: We retrospectively identified patients aged 20-79 years, with stage III CC, who received adjuvant chemotherapy with or without oxaliplatin, between the years 2009 and 2012. RESULTS: Among 938 eligible patients, 203 and 201 patients who received adjuvant chemotherapy with and without oxaliplatin, respectively, were selected by propensity score matching. Of these, 95 patients from each group were analyzed, and their 5-year relapse-free survival (RFS) rates with and without oxaliplatin were 73.7 and 77.1%, respectively. The hazard ratios for 5-year RFS following adjuvant chemotherapy (fluoropyrimidine), with and without oxaliplatin, were 1.241 (95% CI, 0.465-3.308; P = 0.67) and 0.791 (95% CI, 0.329-1.901; P = 0.60), respectively. Stratification using the 55GC revealed that 52 (27.3%), 78 (41.1%), and 60 (31.6%) patients had microsatellite instability (MSI)-like, chromosomal instability (CIN)-like, and stromal subtypes, respectively. The 5-year RFS rates were 84.3 and 72.0% in patients treated with and without oxaliplatin, respectively, for the MSI-like subtype (HR, 0.495; 95% CI, 0.145-1.692; P = 0.25). No differences in RFS rates were noted in the CIN-like or stromal subtypes. Stratification by cancer sidedness for each subtype showed improved RFS only in patients with left-sided primary cancer treated with oxaliplatin for the MSI-like subtype (P = 0.007). The 5-year RFS rates of the MSI-like subtype in left-sided cancer patients were 100 and 53.9% with and without oxaliplatin, respectively. CONCLUSIONS: Subclassification using 55GC and tumor sidedness revealed increased RFS in patients within the MSI-like subtype with stage III left-sided CC treated with fluoropyrimidine and oxaliplatin compared to those treated without oxaliplatin. However, the predictive power of 55GC subtyping alone did not reach statistical significance in this cohort, warranting larger prospective studies. TRIAL REGISTRATION: The study protocol was registered in the University Hospital Medical Education Network (UMIN) clinical trial registry (UMIN study ID: 000023879 ).

International validation of the consensus Immunoscore for the classification of colon cancer: a prognostic and accuracy study.

BACKGROUND: The estimation of risk of recurrence for patients with colon carcinoma must be improved. A robust immune score quantification is needed to introduce immune parameters into cancer classification. The aim of the study was to assess the prognostic value of total tumour-infiltrating T-cell counts and cytotoxic tumour-infiltrating T-cells counts with the consensus Immunoscore assay in patients with stage I-III colon cancer. METHODS: An international consortium of 14 centres in 13 countries, led by the Society for Immunotherapy of Cancer, assessed the Immunoscore assay in patients with TNM stage I-III colon cancer. Patients were randomly assigned to a training set, an internal validation set, or an external validation set. Paraffin sections of the colon tumour and invasive margin from each patient were processed by immunohistochemistry, and the densities of CD3+ and cytotoxic CD8+ T cells in the tumour and in the invasive margin were quantified by digital pathology. An Immunoscore for each patient was derived from the mean of four density percentiles. The primary endpoint was to evaluate the prognostic value of the Immunoscore for time to recurrence, defined as time from surgery to disease recurrence. Stratified multivariable Cox models were used to assess the associations between Immunoscore and outcomes, adjusting for potential confounders. Harrell's C-statistics was used to assess model performance. FINDINGS: Tissue samples from 3539 patients were processed, and samples from 2681 patients were included in the analyses after quality controls (700 patients in the training set, 636 patients in the internal validation set, and 1345 patients in the external validation set). The Immunoscore assay showed a high level of reproducibility between observers and centres (r=0·97 for colon tumour; r=0·97 for invasive margin; p<0·0001). In the training set, patients with a high Immunoscore had the lowest risk of recurrence at 5 years (14 [8%] patients with a high Immunoscore vs 65 (19%) patients with an intermediate Immunoscore vs 51 (32%) patients with a low Immunoscore; hazard ratio [HR] for high vs low Immunoscore 0·20, 95% CI 0·10-0·38; p<0·0001). The findings were confirmed in the two validation sets (n=1981). In the stratified Cox multivariable analysis, the Immunoscore association with time to recurrence was independent of patient age, sex, T stage, N stage, microsatellite instability, and existing prognostic factors (p<0·0001). Of 1434 patients with stage II cancer, the difference in risk of recurrence at 5 years was significant (HR for high vs low Immunoscore 0·33, 95% CI 0·21-0·52; p<0·0001), including in Cox multivariable analysis (p<0·0001). Immunoscore had the highest relative contribution to the risk of all clinical parameters, including the American Joint Committee on Cancer and Union for International Cancer Control TNM classification system. INTERPRETATION: The Immunoscore provides a reliable estimate of the risk of recurrence in patients with colon cancer. These results support the implementation of the consensus Immunoscore as a new component of a TNM-Immune classification of cancer. FUNDING: French National Institute of Health and Medical Research, the LabEx Immuno-oncology, the Transcan ERAnet Immunoscore European project, Association pour la Recherche contre le Cancer, CARPEM, AP-HP, Institut National du Cancer, Italian Association for Cancer Research, national grants and the Society for Immunotherapy of Cancer.

Colon Neuroendocrine Tumors: A New Lymph Node Staging Classification.

BACKGROUND: The American Joint Commission on Cancer, the European Neuroendocrine Tumor Society, and the North American Neuroendocrine Tumor Society all classify colon neuroendocrine tumor (NET) nodal metastasis as N0 or N1. This binary classification does not allow for further prognostication by the total number of positive lymph nodes. This study aimed to evaluate whether the total number of positive lymph nodes affects the overall survival for patients with colon NET. METHODS: The National Cancer Database was used to identify patients with colon NET. Nearest-neighborhood grouping was performed to classify patients by survival to create a new nodal staging system. The Surveillance, Epidemiology, and End Results database was used to validate the new nodal staging classification. RESULTS: Colon NETs were identified in 2472 patients. Distinct 5-year survival rates were estimated for the patients with N0 (no positive lymph nodes; 69.8%; 95% confidence interval [CI], 66.7-72.7%), N1a (1 positive lymph node; 63.9%; 95% CI, 59.6-68.0%), N1b (2-9 positive lymph nodes; 38.9%; 95% CI, 35.4-42.3%), and N2 (≥ 10 positive lymph nodes; 15.7%; 95% CI, 11.9-20.0%; p < 0.001) nodal classifications. The validation population showed distinct 5-year survival rates with the new nodal staging. In multivariable Cox regression, the new nodal stage was a significant independent predictor of overall survival. CONCLUSIONS: The number of positive locoregional lymph nodes in colon NETs is an independent prognostic factor. For patients with colon NETs, N0, N1a, N1b, and N2 classifications for nodal metastasis more accurately predict survival than current staging systems.

A multimodal (FACILE) classification for optical diagnosis of inflammatory bowel disease associated neoplasia.

BACKGROUND: Characterization of colonic lesions in inflammatory bowel disease (IBD) remains challenging. We developed an endoscopic classification of visual characteristics to identify colitis-associated neoplasia using multimodal advanced endoscopic imaging (Frankfurt Advanced Chromoendoscopic IBD LEsions [FACILE] classification). METHODS: The study was conducted in three phases: 1) development - an expert panel defined endoscopic signs and predictors of dysplasia in IBD and, using multivariable logistic regression created the FACILE classification; 2) validation - using 60 IBD lesions from an image library, two assessments of diagnostic accuracy for neoplasia were performed and interobserver agreement between experts using FACILE was determined; 3) reproducibility - the reproducibility of the FACILE classification was tested in gastroenterologists, trainees, and junior doctors after completion of a training module. RESULTS: The experts initially selected criteria such as morphology, color, surface, vessel architecture, signs of inflammation, and lesion border. Multivariable logistic regression confirmed that nonpolypoid lesion, irregular vessel architecture, irregular surface pattern, and signs of inflammation within the lesion were predictors of dysplasia. Area under the curve of this logistic model using a bootstrapped estimate was 0.76 (0.73 - 0.78). The training module resulted in improved accuracy and kappa agreement in all nonexperts, though in trainees and junior doctors the kappa agreement was still moderate and poor, respectively. CONCLUSION: We developed, validated, and demonstrated reproducibility of a new endoscopic classification (FACILE) for the diagnosis of dysplasia in IBD using all imaging modalities. Flat shape, irregular surface and vascular patterns, and signs of inflammation predicted dysplasia. The diagnostic performance of all nonexpert participants improved after a training module.

Computer-assisted assessment of colonic polyp histopathology using probe-based confocal laser endomicroscopy.

INTRODUCTION: Probe-based confocal laser endomicroscopy (pCLE) is a promising modality for classifying polyp histology in vivo, but decision making in real-time is hampered by high-magnification targeting and by the learning curve for image interpretation. The aim of this study is to test the feasibility of a system combining the use of a low-magnification, wider field-of-view pCLE probe and a computer-assisted diagnosis (CAD) algorithm that automatically classifies colonic polyps. METHODS: This feasibility study utilized images of polyps from 26 patients who underwent colonoscopy with pCLE. The pCLE images were reviewed offline by two expert and five junior endoscopists blinded to index histopathology. A subset of images was used to train classification software based on the consensus of two GI histopathologists. Images were processed to extract image features as inputs to a linear support vector machine classifier. We compared the CAD algorithm's prediction accuracy against the classification accuracy of the endoscopists. RESULTS: We utilized 96 neoplastic and 93 non-neoplastic confocal images from 27 neoplastic and 20 non-neoplastic polyps. The CAD algorithm had sensitivity of 95%, specificity of 94%, and accuracy of 94%. The expert endoscopists had sensitivities of 98% and 95%, specificities of 98% and 96%, and accuracies of 98% and 96%, while the junior endoscopists had, on average, a sensitivity of 60%, specificity of 85%, and accuracy of 73%. CONCLUSION: The CAD algorithm showed comparable performance to offline review by expert endoscopists and improved performance when compared to junior endoscopists and may be useful for assisting clinical decision making in real time.

Histotype influences emergency presentation and prognosis in colon cancer surgery.

AIM: To investigate whether differences in histotype in colon cancer correlate with clinical presentation and if they might influence oncological outcomes and survival. METHODS: Data regarding colon cancer patients operated both electively or in emergency between 2009 and 2014 were retrospectively collected from a prospectively maintained database and analyzed for the purpose of this study. Rectal cancer was excluded from this analysis. Statistical univariate and multivariate analyses were performed to investigate possible significant variables influencing clinical presentation, as well as oncological outcomes and survival. RESULTS: Data from 219 patients undergoing colorectal resection for cancer of the colon only were retrieved. One hundred seventy-four patients had an elective procedure and forty-five had an emergency colectomy. Emergency presentation was more likely to occur in mucinous (p < 0.05) and signet ring cell (p < 0.01) tumors. No definitive differences in 5-year overall (44.7% vs. 60.6%, p = 0.078) and disease-free (51.2% vs. 64.4%, p = 0.09) survival were found between the two groups as a whole, but the T3 emergency patients showed worse prognosis than the elective (p < 0.03). Lymph node invasion, laparoscopy, histology, and blood transfusions were independent variables found to influence survival. Distribution assessed for pTNM stage showed T3 cancers were more common in emergency (p < 0.01). CONCLUSIONS AND DISCUSSION: Mucinous and signet ring cell tumors are related to emergency presentation, pT3 stage, poorest outcomes, and survival. Disease-free survival in patients who had emergency surgery for T3 colon cancer seems related to the histotype.

The lymph node status as a prognostic factor in colon cancer: comparative population study of classifications using the logarithm of the ratio between metastatic and nonmetastatic nodes (LODDS) versus the pN-TNM classification and ganglion ratio systems.

BACKGROUND: pN stage in the TNM classification has been the "gold standard" for lymph node staging of colorectal carcinomas, but this system recommends collecting at least 12 lymph nodes for the staging to be reliable. However, new prognostic staging systems have been devised, such as the ganglion quotients or lymph node ratios and natural logarithms of the lymph node odds methods. The aim of this study was to establish and validate the predictive and prognostic ability of the lymph node ratios and natural logarithms of the lymph node odds staging systems and to compare them to the pN nodal classification of the TNM system in a population sample of patients with colon cancer. METHODS: A multicentric population study between January 2004 and December 2007. The inclusion criteria were that the patients were: diagnosed with colon cancer, undergoing surgery with curative intent, and had a complete anatomopathological report. We excluded patients with cancer of the rectum or caecal appendix with metastases at diagnosis. Survival analysis was performed using the Kaplan-Meier actuarial method and the Log-Rank test was implemented to estimate the differences between groups in terms of overall survival and disease-free survival. Multivariate survival analysis was performed using Cox regression. RESULTS: We analysed 548 patients. For the overall survival, the lymph node ratios and natural logarithms of the lymph node odds curves were easier to discriminate because their separation was clearer and more balanced. For disease-free survival, the discrimination between the pN0 and pN1 groups was poor, but this phenomenon was adequately corrected for the lymph node ratios and natural logarithms of the lymph node odds curves which could be sufficiently discriminated to be able to estimate the survival prognosis. CONCLUSIONS: Lymph node ratios and natural logarithms of the lymph node odds techniques can more precisely differentiate risk subgroups from within the pN groups. Of the three methods tested in this study, the natural logarithms of the lymph node odds was the most accurate for staging non-metastatic colon cancer. Thus helping to more precisely adjust and individualise the indication for adjuvant treatments in these patients.

[Clasificación molecular del carcinoma de colon y recto. Una revisión corta].

Traditionally, carcinoma classifications have been based on clinical or pathological features. However, with the development of molecular biology in recent decades, more tumors are increasingly being genetically studied and, in several of them, molecular classifications have been created (the most widely studied and used is that for breast cancer). Colon and rectum cancer are no exception. In this short review, the evolution of colon and rectum cancer molecular classification is explained and the consensus conclusions on the subject are addressed.

Tradicionalmente las clasificaciones de los carcinomas se han basado en características clínicas o patológicas. Sin embargo, en las últimas décadas, con el desarrollo de la biología molecular, cada vez más tumores se están estudiando genéticamente y en varios se han creado clasificaciones moleculares (la más estudiada y utilizada es la de cáncer de mama). El cáncer de colon y recto no es la excepción. En esta revisión corta se explica la evolución de la clasificación molecular del cáncer de colon y recto y se abordan los conclusiones consensuadas al respecto.

CDX2 prognostic value in stage II/III resected colon cancer is related to CMS classification.

BACKGROUND: Caudal-type homeobox transcription factor 2 (CDX2) is involved in colon cancer (CC) oncogenesis and has been proposed as a prognostic biomarker in patients with stage II or III CC. PATIENTS AND METHODS: We analyzed CDX2 expression in a series of 469 CC typed for the new international consensus molecular subtype (CMS) classification, and we confirmed results in a series of 90 CC. RESULTS: Here, we show that lack of CDX2 expression is only present in the mesenchymal subgroup (CMS4) and in MSI-immune tumors (CMS1) and not in CMS2 and CMS3 colon cancer. Although CDX2 expression was a globally independent prognostic factor, loss of CDX2 expression is not associated with a worse prognosis in the CMS1 group, but is highly prognostic in CMS4 patients for both relapse free and overall survival. Similarly, lack of CDX2 expression was a bad prognostic factor in MSS patients, but not in MSI. CONCLUSIONS: Our work suggests that combination of the consensual CMS classification and lack of CDX2 expression could be a useful marker to identify CMS4/CDX2-negative patients with a very poor prognosis.

The Severity of Symptoms Related to Irritable Bowel Syndrome is a Risk Factor for the Misclassification of Significant Organic Disease.

BACKGROUND AND AIMS: The diagnosis of irritable bowel syndrome (IBS) is based mainly on clinical evaluation. The reported incidence of misclassification of significant organic diseases in previously diagnosed IBS patients differs between studies. The aim of this study was to examine the incidence and risk factors for the misclassification of significant organic disease [colon cancer, inflammatory bowel disease (IBD), Celiac disease, and thyroid dysfunction] in a cohort of young patients with symptoms attributed to IBS. METHODS: In this population-based cohort study, we examined the incidence and risk factors for the diagnosis of a new significant organic diseases in a cohort of 2645 IBS patients. RESULTS: During follow-up, organic disease was diagnosed in 27 subjects (1.03%): IBD in 23, Celiac disease in 2, IBD and Celiac disease in 1, and hypothyroidism in1. The mean interval from the diagnosis of IBS to the diagnosis of an organic disorder was 13.08±8.51 months. Increased symptom severity was the only significant risk factor for the misclassification of an organic disease (hazard ratio, 2.26; 95% confidence interval, 1.01-5.05; P=0.047). The risk ratio for misclassification of organic diseases in moderate to severe IBS was increased by 2.575 (95% confidence interval, 1.10-6.51; P=0.027) as compared with mild IBS. CONCLUSIONS: The incidence of misclassification of major organic disease in IBS patients was low. Increased symptoms severity was the only significant risk factor for the misclassification of organic disorders. Further gastrointestinal evaluation should be considered in patients with moderate to severe symptoms attributed to IBS.

Molecular markers identify subtypes of stage III colon cancer associated with patient outcomes.

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.

The frequency of early colorectal cancer derived from sessile serrated adenoma/polyps among 1858 serrated polyps from a single institution.

BACKGROUND AND AIM: Sessile serrated adenoma/polyps (SSAPs) are suspected to have a high malignant potential, although few reports have evaluated the incidence of carcinomas derived from SSAPs using the new classification for serrated polyps (SPs). The aim of study was to compare the frequency of cancer coexisting with the various SP subtypes including mixed polyps (MIXs) and conventional adenomas (CADs). METHODS: A total of 18,667 CADs were identified between April 2005 and December 2011, and 1858 SPs (re-classified as SSAP, hyperplastic polyp (HP), traditional serrated adenoma (TSA), or MIX) were removed via snare polypectomy, endoscopic mucosal resection, or endoscopic sub-mucosal dissection. RESULTS: Among 1160 HP lesions, 1 (0.1%) coexisting sub-mucosal invasive carcinoma (T1) was detected. Among 430 SSAP lesions, 3 (0.7%) high-grade dysplasia (HGD/Tis) and 1 (0.2%) T1 were detected. All of the lesions were detected in the proximal colon, with a mean tumor diameter of 18 mm (SD 9 mm). Among 212 TSA lesions, 3 (1%) HGD/Tis were detected but no T1 cancer. Among 56 MIX lesions, 9 (16%) HGD/Tis and 1 (2%) T1 cancers were detected, and among 18,677 CAD lesions, 964 (5%) HGD/Tis and 166 (1%) T1 cancers were identified. CONCLUSIONS: Among the resected lesions that were detected during endoscopic examination, a smaller proportion (1%) of SSAPs harbored HGD or coexisting cancer, compared to CAD or MIX lesions. Therefore, more attention should be paid to accurately identifying lesions endoscopically for intentional resection and the surveillance of each SP subtype.

Factors associated with reclassification of hyperplastic polyps after pathological reassessment from screening and surveillance colonoscopies.

INTRODUCTION: A substantial interobserver variation in the differential diagnosis of hyperplastic polyps (HPs) and sessile or traditional serrated adenomas (SSAs/TSAs) has been described. METHODS: The aim of this study is to determine the magnitude of reclassification of HPs and associated factors after pathological reassessment of specimens from screening and surveillance colonoscopies, and to estimate its consequences for follow-up recommendations. RESULTS: Among 1694 screening and surveillance colonoscopies, a total of 536 polyps were initially diagnosed as HPs and remained unchanged in 88.5% (n = 474), whereas 7.6 (n = 41) and 1.1% (n = 6) were reclassified as SSA and TSA, respectively. Compared to definite HPs, SSAs were found more frequently in men than in women (82.9 vs. 61.2%, p < 0.05), and in individuals ≥65.0 years (51.2 vs. 31.6%, p = 0.05). Also, more SSAs were >5 mm in size (36.6 vs. 6.3%, p < 0.05) and were localized in the proximal colon (31.7 vs. 11.8%, p < 0.05). In a mixed model analysis, age ≥65.0 years (OR 4.13, 95% CI 1.22-14.2), snare polypectomy (OR 23.6, 95% CI 4.86-115), and coincident advanced adenomas (OR 7.56, 95% CI 1.31-43.5) were significantly (p < 0.05) associated with reclassification to SSAs. Only 0.53% of patients had received false recommendations for follow-up visits based on the incorrect HP diagnosis. A c.1799T>A, p.V600E BRAF mutation was detected in 21.9 % (n = 9) of reclassified SSAs. CONCLUSION: Considering these factors may be helpful in serrated lesions that are difficult to allocate. Incorrect recommendations regarding control colonoscopy intervals due to misdiagnosed HPs can explain only a small fraction of interval colorectal cancers.

Significance of the mucinous component in the histopathological classification of colon cancer.

PURPOSE: Mucinous carcinoma is often independently classified as a histological type of colon cancer, but there are currently no established diagnostic criteria. The relationship between the proportions of mucinous components to the oncological outcomes was examined to determine whether mucinous carcinoma should be classified as an independent histological type. METHODS: The study group comprised 1,038 patients with colon cancer. The relationships between the survival rates and recurrence patterns with the mucinous component area ratio (MC area ratio) and clinical variables were evaluated. RESULTS: Tumors were classified into three groups: Group 1 (MC area ratio, 0 %), Group 2 (1-49 %), and Group 3 (≥50 %). Of the 1038 tumors studied, 877 (84 %) were classified as Group 1, 123 (12 %) as Group 2, and 38 (4 %) as Group 3. The tumor size was significantly larger in Group 3, and an increased MC area ratio was significantly related to a higher proportion of right-sided tumors. Among patients with stage II or III disease, stage III disease, poorly differentiated adenocarcinoma, and no adjuvant chemotherapy were poor prognostic factors. There was no relationship between the MC area ratio and the survival or recurrence pattern. CONCLUSION: Mucinous carcinoma does not need to be classified as a separate histological type from ordinary differentiated adenocarcinoma.

Bcl11b SWI/SNF-complex subunit modulates intestinal adenoma and regeneration after γ-irradiation through Wnt/ß-catenin pathway.

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 ß-catenin target genes, whereas Bcl11b attenuation in Lgr5(+) CBCs increased expression of ß-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 ß-catenin pathway.

Proposal of new classification for stage III colon cancer based on the lymph node ratio: analysis of 4,172 patients from multi-institutional database in Japan.

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.