CONTEXT Lynch syndrome is the most common form of hereditary colorectal cancer (CRC) and is caused by germline mutations in DNA mismatch repair (MMR) genes. Identification of gene carriers currently ...relies on germline analysis in patients with MMR-deficient tumors, but criteria to select individuals in whom tumor MMR testing should be performed are unclear. OBJECTIVE To establish a highly sensitive and efficient strategy for the identification of MMR gene mutation carriers among CRC probands. DESIGN, SETTING, AND PATIENTS Pooled-data analysis of 4 large cohorts of newly diagnosed CRC probands recruited between 1994 and 2010 (n = 10 206) from the Colon Cancer Family Registry, the EPICOLON project, the Ohio State University, and the University of Helsinki examining personal, tumor-related, and family characteristics, as well as microsatellite instability, tumor MMR immunostaining, and germline MMR mutational status data. MAIN OUTCOME MEASURES Performance characteristics of selected strategies (Bethesda guidelines, Jerusalem recommendations, and those derived from a bivariate/multivariate analysis of variables associated with Lynch syndrome) were compared with tumor MMR testing of all CRC patients (universal screening). RESULTS Of 10 206 informative, unrelated CRC probands, 312 (3.1%) were MMR gene mutation carriers. In the population-based cohorts (n = 3671 probands), the universal screening approach (sensitivity, 100%; 95% CI, 99.3%-100%; specificity, 93.0%; 95% CI, 92.0%-93.7%; diagnostic yield, 2.2%; 95% CI, 1.7%-2.7%) was superior to the use of Bethesda guidelines (sensitivity, 87.8%; 95% CI, 78.9%-93.2%; specificity, 97.5%; 95% CI, 96.9%-98.0%; diagnostic yield, 2.0%; 95% CI, 1.5%-2.4%; P < .001), Jerusalem recommendations (sensitivity, 85.4%; 95% CI, 77.1%-93.6%; specificity, 96.7%; 95% CI, 96.0%-97.2%; diagnostic yield, 1.9%; 95% CI, 1.4%-2.3%; P < .001), and a selective strategy based on tumor MMR testing of cases with CRC diagnosed at age 70 years or younger and in older patients fulfilling the Bethesda guidelines (sensitivity, 95.1%; 95% CI, 89.8%-99.0%; specificity, 95.5%; 95% CI, 94.7%-96.1%; diagnostic yield, 2.1%; 95% CI, 1.6%-2.6%; P < .001). This selective strategy missed 4.9% of Lynch syndrome cases but resulted in 34.8% fewer cases requiring tumor MMR testing and 28.6% fewer cases undergoing germline mutational analysis than the universal approach. CONCLUSION Universal tumor MMR testing among CRC probands had a greater sensitivity for the identification of Lynch syndrome compared with multiple alternative strategies, although the increase in the diagnostic yield was modest.
In this issue of European Respiratory Journal, Viglino et al. 1 report that nonalcoholic fatty liver disease (NAFLD) is highly prevalent in chronic obstructive pulmonary disease (COPD) and might ...contribute to cardiometabolic comorbidities.
Background
Ampullary adenomas are rare and potentially malignant. Surgery was the standard treatment but endoscopic papillectomy (EP) is a possible alternative.
Aim
We retrospectively evaluated the ...principal clinical outcomes of EP in all patients referred to our unit also dividing sporadic ampullary adenoma (SAA) from familial adenomatous polyposis (FAP)–associated adenomas.
Methods
All consecutive patients who underwent endoscopic papillectomy because of ampullary adenoma were considered. The primary outcome was the technical success of EP. Secondary outcomes included the number of procedures, the adverse event rate, the recurrence rate, the concordance of histology pre- and post-EP, and the evaluation of factors related to technical success.
Results
Between January 2001 and December 2015, sixty-two patients were included (21 FAP and 41 SAA). Technical success was achieved in 75.8% and was different in the two groups (FAP 95.2%, SAA 65.8%,
p
0.025). Intraductal invasion was negatively associated with technical success (41.7% vs. 84.0%;
p
0.005). The intestinal subtype was predictive of success (79.7% vs. 0%;
p
0.012) as well as en bloc resection (90.3% vs. 61.3%;
p
0.016). Adverse events were reported in 14 patients (22.6%).
Conclusions
EP is an effective and safe procedure and is a viable alternative to surgery.
Trial Registration
ClinicalTrials.gov Identifier: NCT03494543
The most widely used system to define the histological grade of colorectal carcinoma (CRC) is based on the degree of gland formation. This system suffers from significant interobserver variability ...which may limit its prognostic value and consequently better standardized criteria for the assessment of histological grading of CRC are needed. The present study aims to evaluate and to compare, in a cohort of postsurgical pTNM stage I CRC, conventional histological grading, and a novel grading system based on the number of poorly differentiated clusters of neoplastic cells, in terms of interobserver reproducibility, prognostic significance on progression-free survival, and association with other clinicopathological characteristics. Grading with both systems was performed by two pathologists independently and blinded to the clinicopathological data. Interobserver agreement was higher when grade was assessed by counting poorly differentiated clusters than by assessing the relative proportion of the glandular component. Contrary to conventional grading, the novel system provided significant prognostic information in terms of progression-free survival and was significantly associated with budding, invasive growth, lymphatic invasion, and occult nodal metastases of CRC. In conclusion, our findings suggest that a tumor grading system based on the number of poorly differentiated clusters is more reproducible and provides better prognostic stratification of pTNM stage I CRC patients than conventional grading.
Colorectal mucosa is targeted by toxic agents, which can initiate or promote colon cancer. The mechanism of damage might be
a focal irritation with loss of normal epithelial cell barrier function. ...Genetic alterations in tumors may also affect host
inflammatory response. The aim of this study was to define the extent of inflammation in colorectal mucosa, along colorectal
carcinogenesis, and in microsatellite stable and unstable colorectal carcinomas. We collected 103 samples of normal colorectal
mucosa from 65 patients (35 with colorectal cancer or adenoma, 8 with inflammatory bowel diseases, and 22 controls with normal
colonoscopy). We also examined 24 aberrant crypt foci, 14 hyperplastic polyps, 16 adenomas, and 67 samples of colorectal carcinoma.
Immunohistochemistry was used to count myeloperoxidase (MPO)-positive cells (neutrophils and monocytes) in ×100 optical fields
under a light microscope. Patients with colorectal tumors had a higher mean number of MPO-positive cells in normal mucosa
than controls (mean ± SD, 2.7 ± 2.0 versus 1.4 ± 1.4; P = 0.017). MPO-positive cell number was tightly linked to dysplasia in aberrant crypt foci and adenomas, and it was higher
in carcinomas microsatellite unstable than those microsatellite stable (21.6 ± 15.5 versus 11.9 ± 8.0; P < 0.01). MPO immunohistochemistry is a simple and reliable technique for the quantification of inflammation in colorectal
mucosa., and it may be a potential marker of colorectal cancer risk. Microsatellite instability seems to influence host immune
responses to colorectal carcinoma. These observations strongly support a key role of inflammation in colorectal carcinogenesis.
(Cancer Epidemiol Biomarkers Prev 2008;17(9):2291–7)
Purpose: Many studies have evaluated the role of high levels of microsatellite instability (MSI) as a prognostic marker and predictor
of the response to chemotherapy in colorectal cancer (CRC); ...however, the results are not conclusive. The aim of this study
was to analyze the prognostic significance of high levels of MSI (MSI-H) in CRC patients in relation to fluorouracil-based
chemotherapy.
Experimental Design: In three different institutions, 1,263 patients with CRC were tested for the presence of MSI, and CRC-specific survival was
then analyzed in relation to MSI status, chemotherapy, and other clinical and pathologic variables.
Results: Two hundred and fifty-six tumors were MSI-H (20.3%): these were more frequently at a less advanced stage, right-sided, poorly
differentiated, with mucinous phenotype, and expansive growth pattern than microsatellite stable carcinomas. Univariate and
multivariate analyses of 5-year–specific survival revealed stage, tumor location, grade of differentiation, MSI, gender, and
age as significant prognostic factors. The prognostic advantage of MSI tumors was particularly evident in stages II and III
in which chemotherapy did not significantly affect the survival of MSI-H patients. Finally, we analyzed survival in MSI-H
patients in relation to the presence of mismatch repair gene mutations. MSI-H patients with hereditary non–polyposis colorectal
cancer showed a better prognosis as compared with sporadic MSI-H; however, in multivariate analysis, this difference disappeared.
Conclusions: The type of genomic instability could influence the prognosis of CRC, in particular in stages II and III. Fluorouracil-based
chemotherapy does not seem to improve survival among MSI-H patients. The survival benefit for patients with hereditary non–polyposis
colorectal cancer is mainly determined by younger age and less advanced stage as compared with sporadic MSI-H counterpart.
We describe a patient with constitutional mismatch repair-deficiency (CMMR-D) in whom the syndrome started at age 10 with the development of multiple adenomas in the large bowel. In the successive 25 ...years, four malignancies developed in different organs (rectum, ileum, duodenum, and lymphoid tissue). The patient had biallelic constitutional pathogenic variants in the PMS2 gene. We speculate that besides the PMS2 genotype, alterations of other genes might have contributed to the development of the complex phenotype. In the nuclear family, both parents carried different PMS2 germline mutations. They appeared in good clinical condition and did not develop polyps or cancer. The index case had a brother who died at age three of lymphoblastic leukemia, and a sister who was affected by sarcoidosis. Tumor tissue showed diffuse DNA microsatellite instability. A complete absence of immunoreactivity was observed for the PMS2 protein both in the tumors and normal tissues. Next-generation sequencing and multiple ligation-dependent probe amplification analyses revealed biallelic PMS2 germline pathogenic variants in the proband (genotype c.137G>T;(2174+1_2175-1)_(*160_?)del), and one of the two variants was present in both parents—c.137G>T in the father and c.(2174+1-2175-1)_(*160_?)del in the mother—as well as c.137G>T in the sister. Moreover, Class 3 variants of MSH2 (c.1787A>G), APC (c.1589T>C), and CHEK2 (c.331G>T) genes were also detected in the proband. In conclusion, the recognition of CMMR-D may sometimes be difficult; however, the possible role of constitutional alterations of other genes in the development of the full-blown phenotype should be investigated in more detail.
Despite its rarity, infliximab-related hepatitis constitutes a cutting edge and challenging problem. In December 2004, a drug warning was issued by the Food and Drug Administration to alert ...healthcare professionals to the risk of hepatotoxicity in course of infliximab therapy. Subsequently, several reports of probable infliximab hepatitis have been published and interest is growing in trying to elucidate the impact of these events on clinical practice. After discussing our case report, the main characteristics of infliximab-mediated liver injury are analyzed, coupled with a review of the medical literature. Infliximab seems to provoke both immunomediated and a direct liver injury, but how this latter happens remains unclear. Moreover, infliximab immunomediated liver dysfunction resembles that of autoimmune hepatitis type I, with elevation of antinuclear, anti-smooth muscle, anti-double-strand DNA antibodies, and a clear preference for female sex. Finally, a flow chart is proposed with the purpose to help clinicians in the management of patients who develop signs of liver dysfunction during treatment with infliximab.
Aberrant DNA methylation has been widely investigated in sporadic colorectal carcinomas (CRCs), and extensive work has been performed to characterize different methylation profiles of CRC. Less ...information is available about the role of epigenetics in hereditary CRC and about the possible clinical use of epigenetic biomarkers in CRC, regardless of the etiopathogenesis. Long interspersed nucleotide element 1 (LINE-1) hypomethylation and gene-specific hypermethylation of 38 promoters were analyzed in multicenter series of 220 CRCs including 71 Lynch (Lynch colorectal cancer with microsatellite instability (LS-MSI)), 23 CRCs of patients under 40 years in which the main inherited CRC syndromes had been excluded (early-onset colorectal cancer with microsatellite stability (EO-MSS)), and 126 sporadic CRCs, comprising 28 cases with microsatellite instability (S-MSI) and 98 that were microsatellite stable (S-MSS). All tumor methylation patterns were integrated with clinico-pathological and genetic characteristics, namely chromosomal instability (CIN), TP53 loss, BRAF, and KRAS mutations.
LS-MSI mainly showed absence of extensive DNA hypo- and hypermethylation. LINE-1 hypomethylation was observed in a subset of LS-MSI that were associated with the worse prognosis. Genetically, they commonly displayed G:A transition in the KRAS gene and absence of a CIN phenotype and of TP53 loss. S-MSI exhibited a specific epigenetic profile showing low rates of LINE-1 hypomethylation and extensive gene hypermethylation. S-MSI were mainly characterized by MLH1 methylation, BRAF mutation, and absence of a CIN phenotype and of TP53 loss. By contrast, S-MSS showed a high frequency of LINE-1 hypomethylation and of CIN, and they were associated with a worse prognosis. EO-MSS were a genetically and epigenetically heterogeneous group of CRCs. Like LS-MSI, some EO-MSS displayed low rates of DNA hypo- or hypermethylation and frequent G:A transitions in the KRAS gene, suggesting that a genetic syndrome might still be unrevealed in these patients. By contrast, some EO-MSS showed similar features to those observed in S-MSS, such as LINE-1 hypomethylation, CIN, and TP53 deletion. In all four classes, hypermethylation of ESR1, GATA5, and WT1 was very common.
Aberrant DNA methylation analysis allows the identification of different subsets of CRCs. This study confirms the potential utility of methylation tests for early detection of CRC and suggests that LINE-1 hypomethylation may be a useful prognostic marker in both sporadic and inherited CRCs.
Patients with colorectal cancers (CRC) and high microsatellite instability (MSI) have a better outcome than their chromosome-unstable counterpart. Given the heterogeneity of microsatellite-unstable ...CRCs, we wanted to see whether any MSI-associated molecular features are specifically associated with prognosis.
One hundred and nine MSI-high CRCs were typed for primary mismatch repair (MMR) defect and for secondary loss of MMR proteins. Frameshifts at seven target genes, mutations in the RAS pathway, and methylation at MLH1/CDKN2A promoters were also searched. The interplay of molecular findings with clinicopathologic features and patient survival was analyzed.
Of 84 MLH1-deficient CRCs, 31 (36.9%) had MSH3 and 11 (13.1%) had MSH6 loss (P < 0.001), biallelic frameshift mutations at mononucleotide repeats accounting for most (78%) MSH3 losses. As compared with MSH3-retaining cancers, MLH1-deficient tumors with MSH3 loss showed a higher number of mutated target genes (3.94 ± 1.56 vs. 2.79 ± 1.75; P = 0.001), absence of nodal involvement at pathology N0; OR, 0.11; 95% confidence interval (CI), 0.04-0.43, P < 0.001, and better disease-free survival (P = 0.06). No prognostic value was observed for KRAS status and for MLH1/CDKN2A promoter methylation. The association between MSH3 loss and N0 was confirmed in an independent cohort of 71 MLH1-deficient CRCs (OR, 0.23; 95% CI, 0.06-0.83, P = 0.02).
MLH1-deficient CRCs not expressing MSH3 have a more severe MSI, a lower rate of nodal involvement, and a better postsurgical outcome.
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