Maria Liz Leoz

Bezafibrate normalizes alkaline phosphatase in primary biliary cirrhosis patients with incomplete response to ursodeoxycholic acid

Ursodeoxycholic acid (UDCA) is the standard treatment for primary biliary cirrhosis (PBC) but excellent response is not observed in all cases. Since potential favourable effects of fibrates have been reported in short series with inconclusive results, we have carried out a pilot study to analyse the effects of bezafibrate in patients with suboptimal response to UDCA.

Prevalence of somatic mutl homolog 1 promoter hypermethylation in Lynch syndrome colorectal cancer.

Colorectal cancers (CRCs) that have microsatellite instability (MSI) and mutL homolog 1 (MLH1) immunoloss are observed in 3 clinical scenarios: Lynch syndrome (LS), sporadic MSI CRC, and Lynch‐like syndrome (LLS). v‐Raf murine sarcoma viral oncogene homolog B1 (BRAF) mutational analysis is used to differentiate LS from sporadic MSI CRC. The role of MLH1 promoter methylation status for the differential diagnosis of these clinical forms is not well established. The objectives of this study were: 1) to analyze MLH1 promoter methylation in MLH1‐deficient CRCs by pyrosequencing, and 2) to assess its role in the differential diagnosis of MLH1‐deficient CRCs.

The genetic basis of familial adenomatous polyposis and its implications for clinical practice and risk management

Familial adenomatous polyposis (FAP) is an inherited disorder that represents the most common gastrointestinal polyposis syndrome. Germline mutations in the APC gene were initially identified as responsible for FAP, and later, several studies have also implicated the MUTYH gene as responsible for this disease, usually referred to as MUTYH-associated polyposis (MAP). FAP and MAP are characterized by the early onset of multiple adenomatous colorectal polyps, a high lifetime risk of colorectal cancer (CRC), and in some patients the development of extracolonic manifestations. The goal of colorectal management in these patients is to prevent CRC mortality through endoscopic and surgical approaches. Individuals with FAP and their relatives should receive appropriate genetic counseling and join surveillance programs when indicated. This review is focused on the description of the main clinical and genetic aspects of FAP associated with germline APC mutations and MAP.

Colorectal cancer risk factors in patients with serrated polyposis syndrome: a large multicentre study

Objective Serrated polyposis syndrome (SPS) is associated with an increased colorectal cancer (CRC) risk, although the magnitude of the risk remains uncertain. Whereas intensive endoscopic surveillance for CRC prevention is advised, predictors that identify patients who have high CRC risk remain unknown. We performed a multicentre nationwide study aimed at describing the CRC risk in patients with SPS and identifying clinicopathological predictors independently associated with CRC. Design From March 2013 through September 2014, patients with SPS were retrospectively recruited at 18 Spanish centres. Data were collected from medical, endoscopy and histopathology reports. Multivariate logistic regression was performed to identify CRC risk factors. Results In 296 patients with SPS with a median follow-up time of 45 months (IQR 26–79.7), a median of 26 (IQR 18.2–40.7) serrated polyps and 3 (IQR 1–6) adenomas per patient were detected. Forty-seven patients (15.8%) developed CRC at a mean age of 53.9±12.8, and 4 out of 47 (8.5%) tumours were detected during surveillance (cumulative CRC incidence 1.9%). Patients with >2 sessile serrated adenomas/polyps (SSA/Ps) proximal to splenic flexure and ≥1 proximal SSA/P with high-grade dysplasia were independent CRC risk factors (incremental OR=2, 95% CI 1.22 to 3.24, p=0.006). Patients with no risk factors showed a 55% decrease in CRC risk (OR=0.45, 95% CI 0.24 to 0.86, p=0.01). Conclusions Patients with SPS have an increased risk of CRC, although lower than previously published. Close colonoscopy surveillance in experienced centres show a low risk of developing CRC (1.9% in 5 years). Specific polyp features (SSA/P histology, proximal location and presence of high-grade dysplasia) should be used to guide clinical management.

Prospective Evaluation of Single-Operator Peroral Cholangioscopy in Liver Transplant Recipients Requiring an Evaluation of the Biliary Tract

In this descriptive study, we examined the role of single‐operator cholangioscopy (SOC) in the evaluation of biliary complications after liver transplantation (LT). We prospectively included adult recipients of deceased donor LT who were referred for endoscopic retrograde cholangiopancreatography between June 2009 and July 2011. All patients underwent SOC with biopsy of the biliary anastomosis. Sixteen patients were included: 12 with biliary anastomotic strictures (ASs), 2 with common bile duct stones, 1 with a bile leak, and 1 with sphincter of Oddi dysfunction. Patients with ASs displayed 1 of 2 patterns: (A) mild erythema (n = 9) or (B) edema, ulceration, and sloughing (n = 3). Those without ASs displayed a pale mucosa with mild edema at the anastomosis. Patients with ASs and pattern B required a longer period of stenting than patients with pattern A (457 versus 167 days, P = 0.01). In addition, patients with pattern A had a better response and better resolution of their strictures with endoscopic therapy than those with pattern B (88.9% versus 33.4%, P = 0.13). Histological examinations of ASs showed nonspecific intraepithelial inflammation in patients with patterns A and B. Biopsy samples from patients without ASs showed normal columnar epithelial bile duct cells. The total cholangioscopy time for all procedures was 26.8 ± 10.1 minutes. In conclusion, SOC in LT recipients is feasible and allows adequate visualization and tissue sampling of ASs and bile ducts. Two distinct visual patterns that are easily identified with SOC may help to predict the outcomes of endoscopic therapy in patients with biliary complications after LT. Liver Transpl 19:199‐206, 2013.

Reassessment colonoscopy to diagnose serrated polyposis syndrome in a colorectal cancer screening population

Background and study aims Serrated polyposis syndrome (SPS) is a high risk condition for colorectal cancer (CRC). Surveillance strategies for patients with serrated lesions remain controversial. We aimed to evaluate a diagnostic strategy to detect SPS consistently during reassessment colonoscopy in patients with proximal serrated lesions. Methods This was a retrospective study of all individuals from a fecal immunochemical test (FIT)-based CRC screening program (2010 - 2013) with one or more serrated lesions of ≥ 5 mm proximal to the sigmoid colon on baseline colonoscopy. We analyzed all individuals empirically scheduled for a reassessment colonoscopy aimed at diagnosing SPS within 1 year. Reassessment colonoscopy was performed with standard white-light or chromoendoscopy ± high definition endoscopy depending on availability. SPS diagnosis was based on the cumulative number of polyps in both the baseline and reassessment colonoscopies. Factors associated with SPS diagnosis were analyzed. Results From 3444 screening colonoscopies, 196 patients met the study entry criteria, of whom 11 patients (0.32 %) met the criteria for SPS on baseline colonoscopy. Reassessment colonoscopies were performed in 71 patients at 11.9 ± 1.7 months and detected 20 additional patients with SPS, a tripling of the rate of SPS up to 0.90 %. Independent factors associated with SPS diagnosis were: having five or more proximal serrated lesions (odds ratio [OR] 4.01 [95 % confidence interval 1.20 - 13.45]; P = 0.02) or two or more sessile serrated polyps ≥ 10 mm (OR 6.35 [1.40 - 28.81]; P = 0.02) on baseline colonoscopy and the use of chromoendoscopy ± high definition endoscopy during reassessment colonoscopy (OR 4.99 [1.11 - 22.36]; P = 0.04). Conclusions A 1-year reassessment colonoscopy using chromoendoscopy and high definition endoscopes substantially improves SPS detection in individuals from a FIT-based screening program with proximal serrated lesions. Five or more proximal serrated lesions or two or more sessile serrated polyps ≥ 10 mm could be thresholds for requiring a reassessment colonoscopy. Prospective studies are required to validate these results and adjust surveillance recommendations in patients with serrated lesions.

Pitfalls in the diagnosis of biallelic PMS2 mutations

Constitutional Mismatch Repair Deficiency (CMMR-D) syndrome is an inherited childhood cancer syndrome due to bi-allelic mutations in one of the four DNA mismatch repair genes involved in Lynch syndrome. The tumor spectrum of this syndrome includes hematological, brain and Lynch syndrome associated malignancies, with an increased risk of synchronous and metachronous cancers, and signs of Neurofibromatosis type-1 syndrome such as café-au-lait macules during the first three decades of life. Here, we report the first Argentinian patient with CMMR-D syndrome, focusing on her history of cancer and gastrointestinal manifestations, and the challenging molecular algorithm to finally reach her diagnosis.

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

BackgroundAberrant 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).FindingsCompared 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).ConclusionsOverall, 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.

Su1084 Clinicopathological Characterization of Serrated Polyposis Syndrome

Background. Post polypectomy surveillance colonoscopies are a huge burden on healthcare systems. Improved risk assessment could result in reduced colonoscopy use. Our aim was to identify patient, polyp and program factors associated with incidence of new neoplasia at first surveillance colonoscopy following an initial diagnosis of colorectal adenomaMethods. We reviewed colorectal cancer (CRC) surveillance outcome data contained in a colonoscopy recall database. Findings at first surveillance colonoscopy in people who had been diagnosed with advanced (high risk, HRA) adenoma ( ≥ 3 polyps, size ≥10mm, villous component, serration, high grade dysplasia) at diagnostic colonoscopy were compared to those with non-advanced (low risk, LRA) adenomas at diagnosis. Data included patient age and sex, polyp features and location, and interval between colonoscopies. Outcomes were compared using bivariate (Fishers exact) and multivariate (multinomial logistic regression) analyses. Results. Among 457 eligible patients, 266 (58%) were males, and mean age at diagnostic colonoscopy was 63 years. Mean time between diagnostic and surveillance colonoscopy were 43 and 31 months (median 40 and 35 months) for HRA and LRA respectively. There was a significant difference between groups for outcome at surveillance (Table, p=0.014). At the multivariate level, significant associations between outcome at surveillance and polyp features at diagnosis were limited. Controlling for age, gender and colonoscopy interval, those with LRA at diagnosis were more likely to have LRA at surveillance (RRR=1.91, p= 0.023, 95% CI 1.09-3.34). There was a non-significant trend towards increased risk for advanced neoplasia (HRA plus cancers) at surveillance in those originally diagnosed with HRA (RRR=1.31). Age and sex were significant predictors of adenoma incidence at surveillance. Relative risk ratios for HRA increased with each year of age for both males (RRR 1.04, p=0.007, 95% CI 1.01-1.07) and females (RRR 1.04, p=0.019, 95% CI 1.01-1.07), while the relative risk ratio for LRA increased significantly per year of age for males only (RRR 1.03, p=0.007, 95% CI 1.01-1.06). Conclusions: While features of polyps at diagnostic colonoscopies remain key predictors of findings at surveillance, age and sex are additional variables that predict worse outcome. Reduced risk of LRA at surveillance in patients previously diagnosed with HRA may reflect a more conscientious approach by proceduralists at diagnosis. Post polypectomy surveillance could focus more towards older patients. Table. Surveillance outcomes following a diagnosis of low or high risk adenoma.