Full-spectrum (FUSE) versus standard forward-viewing colonoscopy in an organised colorectal cancer screening programme.

OBJECTIVE: Miss rate of polyps has been shown to be substantially lower with full-spectrum endoscopy (FUSE) compared with standard forward-viewing (SFV) colonoscopy in a tandem study at per polyp analysis. However, there is uncertainty on whether FUSE is also associated with a higher detection rate of colorectal neoplasia, especially advanced lesions, in per patient analysis. METHODS: Consecutive subjects undergoing colonoscopy following a positive faecal immunochemical test (FIT) by experienced endoscopists and performed in the context of a regional colorectal cancer population-screening programme were randomised between colonoscopy with either FUSE or SFV colonoscopy in seven Italian centres. Randomisation was stratified by gender, age group and screening history. Primary outcomes included detection rates of advanced adenomas (A-ADR), adenomas (ADR) and sessile-serrated polyps (SSPDR). RESULTS: Of 741 eligible subjects, 658 were randomised to either FUSE (n=328) or SFV (n=330) colonoscopy and included in the analysis. Overall, 293/658 and 143/658 subjects had at least one adenoma (ADR 44.5%) and advanced adenoma (A-ADR 21.7%), respectively, while SSP was the most advanced lesion in 18 cases (SSPDR 2.7%). ADR and A-ADR were 43.6% and 19.5% in the FUSE arm, and 45.5% and 23.9% in the SFV arm, with no difference for both ADR (OR for FUSE: 0.96, 95% CI 0.81 to 1.14) and A-ADR (OR for FUSE: 0.82, 95% CI 0.61 to 1.09). No difference in SSPDR or multiplicity was detected between the two arms. In the per polyp analysis, the mean number of adenomas and proximal adenomas per patient was 0.81±1.25 and 0.47±0.93 in the FUSE arm, and 0.85±1.33 and 0.48±0.96 in the SFV colonoscopy arm (p=NS for both comparisons). CONCLUSIONS: No statistically significant difference in ADR and A-ADR between FUSE and SFV colonoscopy was detected in a per patient analysis in FIT-positive patients. TRIAL REGISTRATION NUMBER: ISRCTN10357435.

Improved multiplex ligation-dependent probe amplification analysis identifies a deleterious PMS2 allele generated by recombination with crossover between PMS2 and PMS2CL.

Heterozygous PMS2 germline mutations are associated with Lynch syndrome. Up to one third of these mutations are genomic deletions. Their detection is complicated by a pseudogene (PMS2CL), which--owing to extensive interparalog sequence exchange--closely resembles PMS2 downstream of exon 12. A recently redesigned multiplex ligation-dependent probe amplification (MLPA) assay identifies PMS2 copy number alterations with improved reliability when used with reference DNAs containing equal numbers of PMS2- and PMS2CL-specific sequences. We selected eight such reference samples--all publicly available--and used them with this assay to study 13 patients with PMS2-defective colorectal tumors. Three presented deleterious alterations: an Alu-mediated exon deletion; a 125-kb deletion encompassing PMS2 and four additional genes (two with tumor-suppressing functions); and a novel deleterious hybrid PMS2 allele produced by recombination with crossover between PMS2 and PMS2CL, with the breakpoint in intron 10 (the most 5' breakpoint of its kind reported thus far). We discuss mechanisms that might generate this allele in different chromosomal configurations (and their diagnostic implications) and describe an allele-specific PCR assay that facilitates its detection. Our data indicate that the redesigned PMS2 MLPA assay is a valid first-line option. In our series, it identified roughly a quarter of all PMS2 mutations.

Exit strategies in inflammatory bowel disease: Looking beyond anti-tumor necrosis factors.

The long-term management of patients with inflammatory bowel disease (IBD) is still a matter of debate, and no clear guidelines have been issued. In clinical practice, gastroenterologists often have to deal with patients in prolonged remission after immunomodulatory or immunosuppressive therapies. When planning an exit strategy for drug withdrawal, the risk of disease relapse must be balanced against the risk of drug-related adverse events and healthcare costs. Furthermore, there is still a dearth of data on the withdrawal of novel biologics, such as the anti-α4ß7 integrin antibody (vedolizumab) and anti-IL12/23 antibody (ustekinumab), as well as the small molecule tofacitinib. Models for estimating the risk of disease relapse and the efficacy of retreatment should be evaluated according to the patient's age and IBD phenotype. These models should guide clinicians in programming a temporary drug withdrawal after discussing realistic outcomes with the patient. This would shift the paradigm from an exit strategy to a holiday strategy.

Appendiceal collision tumors: case reports, management and literature review.

Appendiceal tumors are incidentally detected in 0.5% cases of appendectomy for acute appendicitis and occur in approximately 1% of all appendectomies. Here, we report two cases of appendiceal collision tumors in two asymptomatic women. In both cases, imaging revealed right-lower-quadrant abdominal masses, which were laparoscopically resected. In both cases, histological examinations revealed an appendiceal collision tumor comprising a low-grade appendiceal mucinous neoplasm and well-differentiated neuroendocrine neoplasm (NEN). For complete oncological control, right hemicolectomy was performed in one patient for the aggressive behavior of NEN; however, histology revealed no metastasis. The other patient only underwent appendectomy. No further treatment was recommended. According to the latest guidelines, exact pathology needs to be defined. Proper management indicated by a multidisciplinary team is fundamental.

A comprehensive assessment of the impact of a colorectal cancer screening program in a northern Italian area.

BACKGROUND: The impact of a faecal immunochemical test-based colorectal cancer (CRC) screening program in terms of patient prognosis could be affected by lead-time bias, which artificially increases the survival of screen-detected patients due to the early diagnosis. AIMS: To provide a description of the impact of the CRC screening program in the Trentino Region (Italy), including the Cure Fraction (CF), a prognostic indicator not affected by lead-time bias. METHODS: The program started in 2008, inviting the resident population aged 50-69 years. In this retrospective cohort study, 1,697 CRC diagnosed between 2003 and 2014 in patients aged 50-69 years were classified as pre-screening (PS), screen-detected (SD), interval cancers (IC) and not-screen-detected (NSD). We compared groups by stage at diagnosis and CF. Trends in CRC mortality were reported. RESULTS: The proportion of stage I among SD cases was 51%, higher than PS (19%; OR 4.66, 95%CI 3.50-6.20), NSD (20.6%; OR 3.96, 95%CI 2.95-5.32) and IC (33.3%; OR 2.11, 95%CI 1.10-4.04). The CF of PS, NSD and SD cases was respectively 57% (95%CI 54-60%), 60% (95%CI 58-63%) and 93% (95%CI 89-96%). CRC mortality dropped from 40.7 to 25.6\100,000. CONCLUSION: The program significantly improved the prognosis of patients, decreasing CRC mortality and incidence of advanced CRCs.

Colonoscopic findings in first-degree relatives of patients with colorectal cancer: a population-based screening program.

BACKGROUND: A screening colonoscopy is recommended in first-degree relatives (FDRs) of colorectal cancer patients; few prospective, controlled studies have evaluated colorectal findings in a population-based screening program. OBJECTIVE: To evaluate the prevalence of colorectal neoplasia (adenomas and adenocarcinomas) in this increased-risk population, to compare it with that of average-risk individuals, and to identify features that might allow risk stratification for neoplasia among FDRs. DESIGN: Cross-sectional study. SETTING: Population-based screening program in Trentino, Italy. PATIENTS: FDRs of colorectal cancer patients between 45 and 75 years of age with no history of hereditary colorectal cancer syndromes or inflammatory bowel disease. CONTROLS: Average-risk individuals undergoing screening colonoscopy. INTERVENTION: Screening colonoscopy. RESULTS: Neoplasia was found in 33.4% of 1252 FDRs and in 30.3% of 765 controls; advanced neoplasia was found in 11.3% of FDRs and in 6.3% of controls. Odds ratios (ORs) from the multivariate logistic regression analysis adjusted for age, sex, cecal intubation rates, and colon cleansing showed an increased risk of advanced neoplasia (OR 2.41; 95% CI, 1.69-3.43; P < .0001) in FDRs. Age older than 56 years (OR 1.83; 95% CI, 1.15-2.99; P = .013) and male sex (OR 2.17; 95% CI, 1.39-3.10; P < .001) are independent predictors of advanced neoplasia. LIMITATIONS: Italian subjects living in the same geographic area; of 4301 FDRs, 2521 were excluded. CONCLUSIONS: The increased risk of advanced neoplasia supports the current recommendation for colonoscopic screening in this group; age and sex may assist in risk stratification of these individuals.

Lynch syndrome and Muir-Torre phenotype associated with a recurrent variant in the 3'UTR of the MSH6 gene.

A MSH6 3'UTR variant (c.*23_26dup) was found in 13 unrelated families consulted for Lynch/Muir-Torre Syndrome. This variant, which is very rare in the genomic databases, was absent in healthy controls and strongly segregated with the disease in the studied pedigrees. All tumors were defective for MSH2/MSH6/MSH3 proteins expression, but only MSH2 somatic pathogenic mutations were found in 5 of the 12 sequenced tumors. Moreover, we had no evidence of MSH6 transcript decrease in carriers, whereas MSH2 transcript was downregulated. Additional evaluations performed in representative carriers, including karyotype, arrayCGH and Linked-Reads whole genome sequencing, failed to evidence any MSH2 germline pathogenic variant. Posterior probability of pathogenicity for MSH6 c.*23_26dup was obtained from a multifactorial analysis incorporating segregation and phenotypic data and resulted >0.999, allowing to classify the variant as pathogenic (InSiGHT Class 5). Carriers shared a common haplotype involving MSH2/MSH6 loci, then a cryptic disease-associated variant, linked with MSH6 c.*23_26dup, cannot be completely excluded. Even if it is not clear whether the MSH6 variant is pathogenic per se or simply a marker of a disease-associated MSH2/MSH6 haplotype, all data collected on patients and pedigrees prompted us to manage the variant as pathogenic and to offer predictive testing within these families.

Filling the gap: A thorough investigation for the genetic diagnosis of unsolved polyposis patients with monoallelic MUTYH pathogenic variants.

BACKGROUNDS: MUTYH-associated polyposis (MAP) is an autosomal recessive disease caused by biallelic pathogenic variants (PV) of the MUTYH gene. The aim of this study was to investigate the genetic causes of unexplained polyposis patients with monoallelic MUTYH PV. The analysis focused on 26 patients with suspected MAP, belonging to 23 families. Ten probands carried also one or more additional MUTYH variants of unknown significance. METHODS: Based on variant type and on the collected clinical and molecular data, these variants were reinterpreted by applying the ACMG/AMP rules. Moreover, supplementary analyses were carried out to investigate the presence of other variants and copy number variations in the coding and promoter regions of MUTYH, as well as other polyposis genes (APC, NTHL1, POLE, POLD1, MSH3, RNF43, and MCM9). RESULTS: We reclassified 4 out of 10 MUTYH variants as pathogenic or likely pathogenic, thus supporting the diagnosis of MAP in only four cases. Two other patients belonging to the same family showed a previously undetected deletion of the APC gene promoter. No PVs were found in the other investigated genes. However, 6 out of the 18 remaining families are still interesting MAP candidates, due to the co-presence of a class 3 MUTYH variant that could be reinterpreted in the next future. CONCLUSION: Several efforts are necessary to fully elucidate the genetic etiology of suspected MAP patients, especially those with the most severe polyposis/tumor phenotype. Clinical data, tumor molecular profile, family history, and polyposis inheritance mode may guide variant interpretation and address supplementary studies.

Appropriateness and yield of surveillance colonoscopy in first-degree relatives of colorectal cancer patients: A 5-year follow-up population-based study.

BACKGROUND AND AIMS: There are few prospective data about the use of surveillance colonoscopy and the risk of recurrent neoplasia in first degree relatives (FDRs) of colorectal cancer (CRC) patients. We examined the use and yield of surveillance colonoscopy in a population-based screening program (Trentino, Italy) METHODS: 1252 FDRs have been included in this study. We calculated compliance (percentage of FDRs who underwent surveillance colonoscopy among those eligible), appropriateness of colonoscopy (appropriate if performed within 6 months of the guidelines recommended interval) and diagnostic yield for neoplasia. We compared these data with those of 765 individuals without a family history (FH) of CRC who underwent screening colonoscopy in the same period (controls). RESULTS: Compliance and appropriateness were higher in FDRs than in controls (93.0% vs. 48.0%; p < 0.001; 59.6% vs. 18.8%; p < 0.0001, respectively). Younger age, female sex, FH of CRC and both non-advanced adenomas (nAA) and advanced adenomas (AA) at screening colonoscopy were predictors of appropriate surveillance. The cumulative incidence of nAA and AA was similar in FDRs and controls (31.7% and 4.9% in FDRs, including three invasive cancers; 32.4% and 5.8% in controls, respectively). CONCLUSION: FH does not increase the risk of AA in a 5-year follow-up; appropriate surveillance practices in FDRs could be highly expected in an organized screening program.

The management of malignant polyps in colorectal cancer screening programmes: A retrospective Italian multi-centre study.

BACKGROUND: Although recognition of colorectal malignant polyps is increasing, treatment plans lack the evidence of randomised trials. AIM: To retrospectively evaluate presentation, management and outcomes of screen-detected colorectal malignant polyps, with special focus on the role of histological factors in therapeutic decision-making. METHODS: We retrospectively analysed data regarding malignant polyps detected during faecal immuno-chemical test-based screening programmes in five centres in North-Eastern Italy between April 2008 and April 2013. RESULTS: 306 malignant polyps in 306 patients were included; 72 patients underwent surgery directly (23.6%). Of 234 patients treated endoscopically, 133 subsequently underwent radicalisation surgery (56.8%) and in 17 there was evidence of residual disease (12.8%). Involved, unsafe (<1mm) or invaluable resection margins and sessile morphology represented the most frequent determinants of subsequent surgery. The mean number of nodes harvested during radicalisation surgery was 7.1±6.4 (range 0-29). Histological diagnosis was re-evaluated according to new guidelines in 125 cases (41%); in 18 this led to modification of the risk class (14.4%). CONCLUSIONS: Although the rate of surgical treatment following endoscopic resection is similar to other studies, residual disease at surgery was lower than most international series. Adhering to the new histological reporting system and respecting guidelines on node harvesting may favourably influence prognosis.

Familial colorectal cancer: a review.

Familial colorectal cancer constitutes a heterogeneous group of patients in whom the underlying molecular mechanism is still unknown. Predisposition to a such neoplasms in this setting seems to be due to common low-penetrance genetic components, but the role of genetic testing in clinical practice has to be determined. Although screening guidelines in this moderate-risk population are empiric, data obtained in epidemiologic, meta-analyses and cohort studies and, more recently, the increased risk of advanced adenomas in first degree relatives who underwent screening colonoscopy support the need to include these individuals in specific screening programs. However, data to determine what test to use, how often to use and which organizational strategy to implement are needed. At present, screening uptake in this population is less than optimal; offering the opportunity to access to screening and improving screening uptake is a first significant step.