The endoscopic model for gastric carcinogenesis and Helicobacter pylori infection: A potential visual mind-map during gastroscopy examination.

Helicobacter pylori (Hp) is the main trigger of chronic gastric atrophy and the main leading cause of gastric cancer. Hp infects the normal gastric mucosa and can lead to chronic inflammation, glandular atrophy, intestinal metaplasia, dysplasia and finally adenocarcinoma. Chronic inflammation and gastric atrophy associated with Hp infection appear initially in the distal part of the stomach (the antrum) before progressing to the proximal part (the corpus-fundus). In recent years, endoscopic developments have allowed for the characterization of various gastric conditions including the normal mucosa (pyloric/fundic gland pattern and regular arrangement of collecting venules), Hp-related gastritis (Kyoto classification), glandular atrophy (Kimura-Takemoto classification), intestinal metaplasia (Endoscopic Grading of Gastric Intestinal Metaplasia), and dysplasia/adenocarcinoma (Vessel plus Surface classification). Despite being independent classifications, all these scales can be integrated into a single model: the endoscopic model for gastric carcinogenesis. This model would assist endoscopists in comprehending the process of gastric carcinogenesis and conducting a systematic examination during gastroscopy. Having this model in mind would enable endoscopists to promptly recognize the implications of Hp infection and the potential patient's risk of developing gastric cancer.

Real-life chromoendoscopy for neoplasia detection and characterisation in long-standing IBD.

OBJECTIVE: Outside clinical trials, the effectiveness of chromoendoscopy (CE) for long-standing IBD surveillance is controversial. We aimed to assess the effectiveness of CE for neoplasia detection and characterisation, in real-life. DESIGN: From June 2012 to 2014, patients with IBD were prospectively included in a multicentre cohort study. Each colonic segment was evaluated with white light followed by 0.4% indigo carmine CE. Specific lesions' features were recorded. Optical diagnosis was assessed. Dysplasia detection rate between expert and non-expert endoscopists and learning curve were ascertained. RESULTS: Ninety-four (15.7%) dysplastic (1 cancer, 5 high-grade dysplasia, 88 low-grade dysplasia) and 503 (84.3%) non-dysplastic lesions were detected in 350 patients (47% female; mean disease duration: 17 years). Colonoscopies were performed with standard definition (41.5%) or high definition (58.5%). Dysplasia miss rate with white light was 40/94 (57.4% incremental yield for CE). CE-incremental detection yield for dysplasia was comparable between standard definition and high definition (51.5% vs 52.3%, p=0.30). Dysplasia detection rate was comparable between expert and non-expert (18.5% vs 13.1%, p=0.20). No significant learning curve was observed (8.2% vs 14.2%, p=0.46). Sensitivity, specificity, and positive and negative predictive values for dysplasia optical diagnosis were 70%, 90%, 58% and 94%, respectively. Endoscopic characteristics predictive of dysplasia were: proximal location, loss of innominate lines, polypoid morphology and Kudo pit pattern III-V. CONCLUSIONS: CE presents a high diagnostic yield for neoplasia detection, irrespectively of the technology and experience available in any centre. In vivo, CE optical diagnosis is highly accurate for ruling out dysplasia, especially in expert hands. Lesion characteristics can aid the endoscopist for in situ therapeutic decisions. TRIAL REGISTRATION NUMBER: NCT02543762.

Lymph node pooling: a feasible and efficient method of lymph node molecular staging in colorectal carcinoma.

BACKGROUND: Pathologic lymph node staging is becoming a deficient method in the demanding molecular era. Nevertheless, the use of more sensitive molecular analysis for nodal staging is hampered by its high costs and extensive time requirements. Our aim is to take a step forward in colon cancer (CC) lymph node (LN) pathology diagnosis by proposing a feasible and efficient molecular method in routine practice using reverse transcription loop-mediated isothermal amplification (RT-LAMP). RESULTS: Molecular detection of tumor cytokeratin 19 (CK19) mRNA with RT-LAMP was performed in 3206 LNs from 188 CC patients using two methods: individual analysis of 1449 LNs from 102 patients (individual cohort), and pooled LN analysis of 1757 LNs from 86 patients (pooling cohort). A median of 13 LNs (IQR 10-18) per patient were harvested in the individual cohort, and 18 LNs (IQR 13-25) per patient in the pooling cohort (p ≤ 0.001). The median of molecular assays performed in the pooling cohort was 2 per patient (IQR 1-3), saving a median of 16 assays/patient. The number of molecular assays performed in the individual cohort was 13 (IQR 10-18), corresponding to the number of LNs to be analyzed. The sensitivity and specificity of the pooling method for LN involvement (assessed by hematoxylin and eosin) were 88.9% (95% CI 56.5-98.0) and 79.2% (95% CI 68.9-86.8), respectively; concordance, 80.2%; PPV, 33.3%; NPV, 98.4%. The individual method had 100% sensitivity (95% CI 72.2-100), 44.6% specificity (95% CI 34.8-54.7), 50% concordance, 16.4% PPV, and 100% NPV. The amount of tumor burden detected in all LNs of a case, or total tumor load (TTL) was similar in both cohorts (p = 0.228). CONCLUSIONS: LN pooling makes it possible to analyze a high number of LNs from surgical colectomies with few molecular tests per patient. This approach enables a feasible means to integrate LN molecular analysis from CC specimens into pathology diagnosis and provides a more accurate LN pathological staging with potential prognostic implications.

Transcriptional analysis of the intestinal mucosa of patients with ulcerative colitis in remission reveals lasting epithelial cell alterations.

OBJECTIVE: Ulcerative colitis (UC) is a chronic condition characterised by the relapsing inflammation despite previous endoscopic and histological healing. Our objective was to identify the molecular signature associated with UC remission. DESIGN: We performed whole-genome transcriptional analysis of colonic biopsies from patients with histologically active and inactive UC, and non-inflammatory bowel disease (non-IBD) controls. Real-time reverse transcriptase-PCR and immunostaining were used for validating selected genes in independent cohorts of patients. RESULTS: Microarray analysis (n=43) demonstrates that UC patients in remission present an intestinal transcriptional signature that significantly differs from that of non-IBD controls and active patients. Fifty-four selected genes were validated in an independent cohort of patients (n=30). Twenty-nine of these genes were significantly regulated in UC-in-remission subjects compared with non-IBD controls, including a large number of epithelial cell-expressed genes such as REG4, S100P, SERPINB5, SLC16A1, DEFB1, AQP3 and AQP8, which modulate epithelial cell growth, sensitivity to apoptosis and immune function. Expression of inflammation-related genes such as REG1A and IL8 returned to control levels during remission. REG4, S100P, SERPINB5 and REG1A protein expression was confirmed by immunohistochemistry (n=23). CONCLUSIONS: Analysis of the gene signature associated with remission allowed us to unravel pathways permanently deregulated in UC despite histological recovery. Given the strong link between the regulation of some of these genes and the growth and dissemination of gastrointestinal cancers, we believe their aberrant expression in UC may provide a mechanism for epithelial hyper-proliferation and, in the context of malignant transformation, for tumour growth.

Challenges and Therapeutic Opportunities in the dMMR/MSI-H Colorectal Cancer Landscape.

About 5 to 15% of all colorectal cancers harbor mismatch repair deficient/microsatellite instability-high status (dMMR/MSI-H) that associates with high tumor mutation burden and increased immunogenicity. As a result, and in contrast to other colorectal cancer phenotypes, a significant subset of dMMR/MSI-H cancer patients strongly benefit from immunotherapy. Yet, a large proportion of these tumors remain unresponsive to any immuno-modulating treatment. For this reason, current efforts are focused on the characterization of resistance mechanisms and the identification of predictive biomarkers to guide therapeutic decision-making. Here, we provide an overview on the new advances related to the diagnosis and definition of dMMR/MSI-H status and focus on the distinct clinical, functional, and molecular cues that associate with dMMR/MSI-H colorectal cancer. We review the development of novel predictive factors of response or resistance to immunotherapy and their potential application in the clinical setting. Finally, we discuss current and emerging strategies applied to the treatment of localized and metastatic dMMR/MSI-H colorectal tumors in the neoadjuvant and adjuvant setting.

Retroperitoneal inflammatory pseudotumor presenting as a pancreatic mass.

CONTEXT: The inflammatory pseudotumor is a rare chronic inflammatory disease not considered as a real tumor but with a similar locally aggressive behavior. Although usually located in the lungs it may be found in other organs. CASE REPORT: We present the clinical case of a 66-year-old woman diagnosed with inflammatory pseudotumor after undergoing an exploratory laparotomy due to a large non resectable abdominal mass. Preoperative abdominal CT revealed a large solid polylobulated mass involving the pancreas, duodenum, hepatic hilum and superior mesenteric artery. Percutaneous fine needle aspiration and tru-cut biopsies ruled out lymphoma but did not achieve a definitive diagnosis. CD68 antibody positivity of the surgical biopsy specimen confirmed the histiocytary origin. Ki67 antibody expression was 10%. The final diagnosis was inflammatory pseudotumor rather than malignant fibrohistiocytoma based on the features and the severity of the inflammatory component. Chemotherapy was ineffective and the patient died 25 months later because of local progression and infection of the tumoral necrotic tissue. CONCLUSION: Although inflammatory pseudotumor is not considered to be a real tumor, its aggressive local growth is similar to that of malignant soft tissue sarcomas. The only curative option is the complete surgical resection, albeit frequent recurrence.

Differentially Deregulated MicroRNAs as Novel Biomarkers for Neoplastic Progression in Ulcerative Colitis.

INTRODUCTION: Colorectal cancer (CRC) is a potentially life-threatening complication of long-standing ulcerative colitis (UC). MicroRNAs (miRNA) are epigenetic regulators that have been involved in the development of UC-associated CRC. However, their role as potential mucosal biomarkers of neoplastic progression has not been adequately studied. METHODS: In this study, we analyzed the expression of 96 preselected miRNAs in human formalin-fixed and paraffin-embedded tissue of 52 case biopsies (20 normal mucosa, 20 dysplasia, and 12 UC-associated CRCs) and 50 control biopsies (10 normal mucosa, 21 sporadic adenomas, and 19 sporadic CRCs) by using Custom TaqMan Array Cards. For validation of deregulated miRNAs, we performed individual quantitative real-time polymerase chain reaction in an independent cohort of 50 cases (13 normal mucosa, 25 dysplasia, and 12 UC-associated CRCs) and 46 controls (7 normal mucosa, 19 sporadic adenomas, and 20 sporadic CRCs). RESULTS: Sixty-four miRNAs were found to be differentially deregulated in the UC-associated CRC sequence. Eight of these miRNAs were chosen for further validation. We confirmed miR-31, -106a, and -135b to be significantly deregulated between normal mucosa and dysplasia, as well as across the UC-associated CRC sequence (all P < 0.01). Notably, these miRNAs also confirmed to have a significant differential expression compared with sporadic CRC (all P < 0.05). DISCUSSION: UC-associated and sporadic CRCs have distinct miRNA expression patterns, and some miRNAs indicate early neoplastic progression.

Narrow-band imaging as an alternative to chromoendoscopy for the detection of dysplasia in long-standing inflammatory bowel disease: a prospective, randomized, crossover study.

BACKGROUND: Narrow-band imaging (NBI) is a novel technique that may represent an alternative method to chromoendoscopy (CE) for the detection of colitis-associated intraepithelial neoplasia (IN) in patients with long-standing inflammatory bowel disease (IBD). OBJECTIVE: To compare NBI with CE for the detection of IN. DESIGN: Prospective, randomized, crossover study. SETTING: Academic hospital. PATIENTS: Patients with clinically inactive colonic IBD (≥8 years). INTERVENTION: Patients underwent both CE and NBI in randomized order. Targeted biopsy specimens from abnormal areas were obtained. Pathological examination was regarded as the reference standard. MAIN OUTCOME MEASUREMENTS: Number of false-positive and true-positive lesions in patients undergoing CE and NBI were compared as well as the proportion of patients with missed IN lesions. RESULTS: Eighty patients were screened, of whom 20 were excluded. Mean ± standard deviation withdrawal time for CE was significantly longer than that for NBI (26.87 ± 9.89 minutes vs 15.74 ± 5.62 minutes, P < .01). Thirteen patients had at least 1 IN lesion on 1 of the examinations. In the per-lesion analysis, NBI resulted in a significantly inferior false-positive biopsy rate (P = .001) and a similar true-positive rate. The percentage of missed IN lesions and patients was superior with NBI, albeit without reaching statistical significance. LIMITATIONS: Lesions were sampled immediately after detection, which precluded the possibility of paired analysis. CONCLUSIONS: NBI appears to be a less time-consuming and equally effective alternative to CE for the detection of IN. However, given the NBI lesion and patient miss rates, it cannot be recommended as the standard technique.

Pathologist Experience and Concordance in the Diagnosis of Dysplasia in Long-standing Inflammatory Bowel Disease.

Surveillance colonoscopies focused to detect dysplasia are recommended to prevent colorectal cancer in patients with long-standing colonic inflammatory bowel disease (IBD). To date, histologic diagnosis and gradation of IBD-related dysplasia has been challenged by a high variability among pathologists. We aimed to analyze the observer characteristics that are correlated with concordance deviations in this diagnosis. Eight pathologists evaluated a set of 125 endoscopic biopsy samples with a representative distribution of nondysplastic and dysplastic lesions from long-standing IBD patients. Two rounds of diagnosis were carried out during a period of 18 months. The κ test was applied to analyze concordance. Pathologists were grouped on the basis of their experience. A subanalysis was performed by eliminating the highly prevalent nondysplastic samples, as well as an analysis after observers' grouping. Overall interobserver agreement was good (κ=0.73), with an even higher pairwise value (κ=0.86) as well as the intraobserver agreement values (best κ=0.85). After eliminating the highly prevalent nondysplastic samples, the interobserver agreement was still moderate to good (best overall κ=0.50; best paired κ=0.72). Notable differences were seen between the pathologists with a high-volume and low-volume practice (best overall κ=0.61 and 0.41, respectively). The agreement in the diagnosis of dysplasia in IBD endoscopic biopsies may have been undervalued over time. This is the first study evaluating pathologists' diagnostic robustness in this field. The results suggest that examining a large volume of samples is the key factor to increase the consistency in the diagnosis and gradation of IBD-related dysplasia.

[Diabetic mastopathy in diabetes mellitus type 2]. / Mastopatía diabética en diabetes mellitus tipo 2.

Diabetic mastopathy is a little known entity and can easily be mistaken for breast carcinoma. This entity has mainly been described in patients with diabetes type 1 and, to a much lesser extent, in those with other endocrine disorders. We describe a case of diabetic mastopathy associated with diabetes mellitus type 2, which showed a rapid clinical course. Lack of awareness of this entity can lead to inappropriate management. Because there are no specific histological or clinical features for diabetic mastopathy, patients may receive an incorrect diagnosis or undergo unnecessary investigations. A high index of suspicion is required to reach a correct diagnosis and provide appropriate treatment. The results of diagnostic tests are non-specific and the key to diagnosis is core needle biopsy.

Rectal Aberrant Crypt Foci in Humans Are Not Surrogate Markers for Colorectal Cancer Risk.

INTRODUCTION: Over the past 20 years, aberrant crypt foci (ACF) have emerged as potential precursors and biomarkers for colorectal cancer (CRC). However, data regarding their molecular pathogenesis, as well as their endoscopic and histological identification, remain inconsistent. METHODS: A wide cohort of ACF from 100 control subjects and 100 case patients, including patients with adenoma and CRC, were characterized for endoscopic, morphologic, and molecular features. RESULTS: We observed that among all the endoscopic features evaluated, only the number of large ACF correlated with CRC risk (P = 0.003), whereas the histological classification, as assessed by 2 different pathologists, was inconsistent and did not differ between control and case patients. Moreover, only a few APC and BRAF mutations and no microsatellite instability were detected in our samples. KRAS mutations were detected in 16.3% of ACF samples, which also exhibited increased MGMT hypermethylation. However, none of those events were found to be predictive of CRC risk. DISCUSSION: Although ACF might be preneoplastic lesions of the colon, they are not suitable biomarkers for assessing CRC progression.

Xp11 translocation renal cell carcinoma in adults: expanded clinical, pathologic, and genetic spectrum.

The recently recognized Xp11 translocation renal cell carcinomas (RCCs), all of which bear gene fusions involving the TFE3 transcription factor gene, comprise at least one-third of pediatric RCC. Only rare adult cases have been reported, without detailed pathologic analysis. We identified and analyzed 28 Xp11 translocation RCC in patients over the age of 20 years. All cases were confirmed by TFE3 immunohistochemistry, a sensitive and specific marker of neoplasms with TFE3 gene fusions, which can be applied to archival material. Three cases were also confirmed genetically. Patients ranged from ages 22 to 78 years, with a strong female predominance (F:M=22:6). These cancers tended to present at advanced stage; 14 of 28 presented at stage 4, whereas lymph nodes were involved by metastatic carcinoma in 11 of 13 cases in which they were resected. Previously not described and distinctive clinical presentations included dense tumor calcifications such that the tumor mimicked renal lithiasis, and obstruction of the renal pelvis promoting extensive obscuring xanthogranulomatous pyelonephritis. Previously unreported morphologic variants included tumor giant cells, fascicles of spindle cells, and a biphasic appearance that simulated the RCC characterized by a t(6;11)(p21;q12) chromosome translocation. One case harbored a novel variant translocation, t(X;3)(p11;q23). Five of 6 patients with 1 or more years of follow-up developed hematogenous metastases, with 2 dying within 1 year of diagnosis. Xp11 translocation RCC can occur in adults, and may be aggressive cancers that require morphologic distinction from clear cell and papillary RCC. Although they may be uncommon on a percentage basis, given the vast predominance of RCC in adults compared with children, adult Xp11 translocation RCC may well outnumber their pediatric counterparts.

Biphasic Squamoid Alveolar Renal Cell Carcinoma: A Distinctive Subtype of Papillary Renal Cell Carcinoma?

Biphasic squamoid alveolar renal cell carcinoma (BSARCC) has been recently described as a distinct neoplasm. Twenty-one cases from 12 institutions were analyzed using routine histology, immunohistochemistry, array comparative genomic hybridization (aCGH) and fluorescence in situ hybridization. Tumors were removed from 11 male and 10 female patients, whose age ranged from 53 to 79 years. The size of tumors ranged from 1.5 to 16 cm. Follow-up information was available for 14 patients (range, 1 to 96 mo), and metastatic spread was found in 5 cases. All tumors comprised 2 cell populations arranged in organoid structures: small, low-grade neoplastic cells with scant cytoplasm usually lining the inside of alveolar structures, and larger squamoid cells with more prominent cytoplasm and larger vesicular nuclei arranged in compact nests. In 9/21 tumors there was a visible transition from such solid and alveolar areas into papillary components. Areas composed of large squamoid cells comprised 10% to 80% of total tumor volume. Emperipolesis was present in all (21/21) tumors. Immunohistochemically, all cases were positive for cytokeratin 7, EMA, vimentin, and cyclin D1. aCGH (confirmed by fluorescence in situ hybridization) in 5 analyzable cases revealed multiple numerical chromosomal changes including gains of chromosomes 7 and 17 in all cases. These changes were further disclosed in 6 additional cases, which were unsuitable for aCGH. We conclude that tumors show a morphologic spectrum ranging from RCC with papillary architecture and large squamoid cells to fully developed BSARCC. Emperipolesis in squamoid cells was a constant finding. All BSARCCs expressed CK7, EMA, vimentin, and cyclin D1. Antibody to cyclin D1 showed a unique and previously not recognized pattern of immunohistochemical staining. Multiple chromosomal aberrations were identified in all analyzable cases including gains of chromosomes 7 and 17, indicating that they are akin to papillary RCC. Some BSARCCs were clinically aggressive, but their prognosis could not be predicted from currently available data. Present microscopic, immunohistochemical, and molecular genetic data strongly support the view that BSARCC is a distinctive and peculiar morphologic variant of papillary RCC.

LINE-1 hypomethylation is neither present in rectal aberrant crypt foci nor associated with field defect in sporadic colorectal neoplasia.

BACKGROUND: Aberrant crypt foci (ACF) are considered the first identifiable preneoplastic lesion in colorectal cancer (CRC), and have been proposed as a potential biomarker for CRC risk. Global DNA hypomethylation is an early event in colorectal carcinogenesis, and long interspersed nuclear element-1 (LINE-1) methylation status is a well-known surrogate marker for genome-wide DNA methylation levels. Despite the gradual increase in DNA hypomethylation in the adenoma-carcinoma sequence, LINE-1 methylation in ACF has never been studied. Moreover, recent studies have reported a field defect for LINE-1 hypomethylation, suggesting that LINE-1 methylation status in normal mucosa could be used to stratify CRC risk and tailor preventive strategies. Thus, we assessed LINE-1 status by pyrosequencing in rectal ACF and paired normal colorectal mucosa from individuals with sporadic colon cancer (CC) (n = 35) or adenoma (n = 42), and from healthy controls (n = 70). FINDINGS: Compared with normal mucosa, LINE-1 in ACF were hypermethylated across all groups (P < 0.0001). Furthermore, LINE-1 methylation status in normal colorectal mucosa was independent of the presence of adenoma or CC (P = 0.1072), and did not differ depending on the distance to the adenoma or CC. Interestingly, when we compared the LINE-1 methylation status in normal mucosa from different segments of the colorectum, we found higher hypomethylation in the rectum compared with the descending colon (P < 0.0001). CONCLUSIONS: Overall, our results suggest that global hypomethylation is not present in rectal ACF and argues against the existence of LINE-1 methylation field defect in sporadic colon cancer.

Accuracy of advanced endoscopy and fecal calprotectin for prediction of relapse in ulcerative colitis: a prospective study.

BACKGROUND: The aim of this study was to determine the accuracy of advanced endoscopy for prediction of relapse in ulcerative colitis, in comparison with serum and fecal biomarkers. METHODS: Patients with ulcerative colitis with sustained clinical remission defined as absence of blood in stool for a minimum of 3 months and Mayo endoscopic subscore of 0 were included. High-resolution rectosigmoidoscopy was performed at baseline and at the end of study (week 52 or relapse), assessing mucosal pit pattern by chromoendoscopy and narrow band imaging as well as vascular pattern by narrow band imaging. Histology was evaluated at baseline and at the end of the study. Follow-up for 1 year or until relapse with clinical evaluations and serum and fecal biomarkers every 3 months was established. Relapse was defined as presence of blood in stool and a Mayo endoscopic subscore ≥1 with histologic confirmation. RESULTS: Seventeen out of 64 patients (27%) relapsed during the follow-up period. Baseline clinical characteristics in patients who relapsed and those who did not were similar. Neither pit or vascular pattern nor histology was significantly different between relapsers and nonrelapsers. Among serum biomarkers, high platelet count was significantly associated with higher relapse rates. Fecal calprotectin was predictor of relapse within 3- and 12-month period with high specificity but low sensitivity. CONCLUSIONS: Advanced endoscopy and histology do not predict relapse over 1-year period in patients with ulcerative colitis. Fecal calprotectin can predict relapse in 3- and 12-month period with low accuracy.

Co-expression of matrix metalloproteinase-7 (MMP-7) and phosphorylated insulin growth factor receptor I (pIGF-1R) correlates with poor prognosis in patients with wild-type KRAS treated with cetuximab or panitumumab: a GEMCAD study.

BACKGROUND: By transactivacion, phosphorylated insulin growth factor receptor I (IGF-1R) can activate epidermal growth factor receptor (EGFR). MMP-7, produced by colorectal cancer cells, also can activate IGF-1R by degrading IGFBP-3 and releasing IGF-I. METHODS: A cohort of patients (pts) with advanced colorectal cancer (CRC), under second- or third-line treatment with cetuximab or panitumumab, was tested using immunohistochemistry for expression of the activated form of IGF-1R (p-IGF-1R) and MMP-7. KRAS and BRAF mutation status was determined by sequencing and allelic discrimination analysis, respectively. Analyses were performed in primary CRC tumor samples or metastases, and the association of immunohistochemistry findings, mutational results, and treatment outcomes was investigated in both univariate and multivariate analyses. RESULTS: Expression of activated IGF-1R and MMP-7 was observed in 51 and 49% of pts, respectively. Co-expression of MMP-7 and pIGF-1R (double positivity, DP) was observed in 28 pts (25%). There was no association between KRAS or BRAF mutational status and DP (p=0.52). Pts with DP responded more poorly to first-line chemotherapy (p=0.005) and to anti-EGFR treatment (p=0.01) than non-DP pts. In wild type (WT) KRAS pts, those with DP have poorer PFS (2.7 months vs. 3.5m, p=0.036; HR 1.98, 95% CI 1.05-3.75) and OS (6.4 months vs. 8.6 m, p=0.010; HR 2.33, 95%CI 1.23-4.43) in the adjusted multivariate analysis. CONCLUSIONS: Our study suggests that concomitant expression of MMP-7 and activation of p-IGF-1R (DP) correlates with poor prognosis in WT KRAS pts treated with anti-EGFR.

Microsatellite instability of the colorectal carcinoma can be predicted in the conventional pathologic examination. A prospective multicentric study and the statistical analysis of 615 cases consolidate our previously proposed logistic regression model.

High microsatellite instability (MSI-H) allows the identification of a subset of colorectal carcinomas associated with good prognosis and a higher incidence of Lynch syndrome. The aim of this work was to assess the interobserver variability and optimize our MSI-H prediction model previously published based on phenotypic features.The validation series collected from five different hospitals included 265 primary colorectal carcinomas from the same number of patients. The eight clinicopathological parameters that integrate our original model were evaluated in the corresponding centers. Homogeneity assessment revealed significant differences between hospitals in the estimation of the growth pattern, presence of Crohn-like reaction, percentage of cribriform structures, and Ki-67 positivity. Despite this observation, our model was globally able to predict MSI-H with a negative predictive value of 97.0%. The optimization studies were carried out with 615 cases and resulted in a new prediction model RERtest8, which includes the presence of tumor infiltrating lymphocytes at the expense of the percentage of cribriform structures. This refined model achieves a negative predictive value of 97.9% that is maintained even when the immunohistochemical parameters are left out, RERtest6. The high negative predictive value achieved by our models allows the reduction of the cases to be tested for MSI to less than 10%. Furthermore, the easy evaluation of the parameters included in the model renders it a useful tool for the routine practice and can reinforce other published models and the current clinical protocols to detect the subset of colorectal cancer patients bearing hereditary nonpolyposis colorectal cancers risk and/or MSI-H phenotype.

Aberrant gene promoter methylation associated with sporadic multiple colorectal cancer.

BACKGROUND: Colorectal cancer (CRC) multiplicity has been mainly related to polyposis and non-polyposis hereditary syndromes. In sporadic CRC, aberrant gene promoter methylation has been shown to play a key role in carcinogenesis, although little is known about its involvement in multiplicity. To assess the effect of methylation in tumor multiplicity in sporadic CRC, hypermethylation of key tumor suppressor genes was evaluated in patients with both multiple and solitary tumors, as a proof-of-concept of an underlying epigenetic defect. METHODOLOGY/PRINCIPAL FINDINGS: We examined a total of 47 synchronous/metachronous primary CRC from 41 patients, and 41 gender, age (5-year intervals) and tumor location-paired patients with solitary tumors. Exclusion criteria were polyposis syndromes, Lynch syndrome and inflammatory bowel disease. DNA methylation at the promoter region of the MGMT, CDKN2A, SFRP1, TMEFF2, HS3ST2 (3OST2), RASSF1A and GATA4 genes was evaluated by quantitative methylation specific PCR in both tumor and corresponding normal appearing colorectal mucosa samples. Overall, patients with multiple lesions exhibited a higher degree of methylation in tumor samples than those with solitary tumors regarding all evaluated genes. After adjusting for age and gender, binomial logistic regression analysis identified methylation of MGMT2 (OR, 1.48; 95% CI, 1.10 to 1.97; p = 0.008) and RASSF1A (OR, 2.04; 95% CI, 1.01 to 4.13; p = 0.047) as variables independently associated with tumor multiplicity, being the risk related to methylation of any of these two genes 4.57 (95% CI, 1.53 to 13.61; p = 0.006). Moreover, in six patients in whom both tumors were available, we found a correlation in the methylation levels of MGMT2 (r = 0.64, p = 0.17), SFRP1 (r = 0.83, 0.06), HPP1 (r = 0.64, p = 0.17), 3OST2 (r = 0.83, p = 0.06) and GATA4 (r = 0.6, p = 0.24). Methylation in normal appearing colorectal mucosa from patients with multiple and solitary CRC showed no relevant difference in any evaluated gene. CONCLUSIONS: These results provide a proof-of-concept that gene promoter methylation is associated with tumor multiplicity. This underlying epigenetic defect may have noteworthy implications in the prevention of patients with sporadic CRC.