Colonic Polyposis Research Articles

Cancer Risk Associated With PTEN Pathogenic Variants Identified Using Multigene Hereditary Cancer Panel Testing.

PTEN-associated clinical syndromes such as Cowden syndrome (CS) increase cancer risk and have historically been diagnosed based upon phenotypic criteria. Because not all patients clinically diagnosed with CS have PTEN pathogenic variants (PVs), and not all patients with PTEN PVs have been clinically diagnosed with CS, the cancer risk conferred by PTEN PVs calculated from cohorts of patients with clinical diagnoses of CS/CS-like phenotypes may be inaccurate. We assessed a consecutive cohort of 727,091 individuals tested clinically for hereditary cancer risk, with a multigene panel between September 2013 and February 2022. Multivariable logistic regression models accounting for personal and family cancer history, age, sex, and ancestry were used to quantify disease risks associated with PTEN PVs. PTEN PVs were detected in 0.027% (193/727,091) of the study population, and were associated with a high risk of female breast cancer (odds ratio [OR], 7.88; 95% CI, 5.57 to 11.16; P = 2.3 × 10-31), endometrial cancer (OR, 13.51; 95% CI, 8.77 to 20.83; P = 4.2 × 10-32), thyroid cancer (OR, 4.88; 95% CI, 2.64 to 9.01; P = 4.0 × 10-7), and colon polyposis (OR, 31.60; CI, 15.60 to 64.02; P = 9.0 × 10-22). We observed modest evidence suggesting that PTEN PVs may be associated with ovarian cancer risk (OR, 3.77; 95% CI, 1.71 to 8.32; P = 9.9 × 10-4). Among patients with similar personal/family history and ancestry, every 5-year increase in age of diagnosis decreased the likelihood of detecting a PTEN PV by roughly 60%. We demonstrate that PTEN PVs are associated with significantly increased risk for a range of cancers. Together with the observation that PTEN PV carriers had earlier disease onset relative to otherwise comparable noncarriers, our results may guide screening protocols, inform risk-management strategies, and warrant enhanced surveillance approaches that improve clinical outcomes for PTEN PV carriers, regardless of their clinical presentation.

Clinical features and long-term outcomes of patients with colonic oligopolyposis of unknown etiology.

Colonic adenomatous polyposis of unknown etiology (CPUE) is an adenomatous polyposis phenotype that resembles Familial Adenomatous Polyposis (FAP) even though no germline pathogenic variant is identified. We sought to better characterize the clinical features and outcomes in a cohort of CPUE patients. This is a retrospective case series of patients 18 years old or older with aden-omatous oligopolyposis (between 10-100 adenomas) and negative genetic testing, identified through the Hereditary Gastrointestinal Cancer Database at Massachusetts General Hospital, a tertiary academic referral center. A retrospective chart review was performed with a focus on demographics, alcohol and tobacco use, medication use, familial malignancy and polyp burden, genetic testing information, endoscopic surveillance data including the corresponding histopathology, colonic and extracolonic malignancies, mortality events, and their etiology. Spearman correlation and Pearson Chi-square test (or Fisher's exact test) were used for continuous and categorical variables respectively. CPUE patients were primarily male (69%) and presented for genetic counseling at 63.7 years. Only 2 patients (2.9%) reported a first-degree relative with polyposis. During an average surveillance period of 12.3 years, 0.5 colonoscopies per year were performed. Patients developed 2.3 new adenomas per year. 4 (5.7%) were diagnosed with colorectal cancer (CRC) at a mean age of 66 years, and 3 were diagnosed prior to the onset of oligopolyposis. 7 (10%) required colectomy due to advanced dysplasia or polyp burden. With respect to upper gastrointestinal manifestations, 1 patient had a gastric adenoma, but there were no cases of gastric or small bowel polyposis. During surveillance, 10 (14%) patients died at a mean age of 72, and none were due to CRC. CPUE is distinct from familial adenomatous polyposis (FAP) syndrome and the use of FAP surveillance guidelines may result in unnecessarily frequent upper and lower endoscopies.

Abstract IA018: Microbiome and intestinal barriers in colon cancer

Abstract Multiple factors (e.g., risk genes, environmental triggers, immunity, and microbiome) contribute to the pathogenesis of colorectal cancer (CRC). The intestinal dysbiosis and disruption of barrier function are common manifestations of CRC. Vitamin D/Vitamin D receptor (VDR) is known to protects against dysbiosis and tumorigenesis. Considering the multiple functional roles of VDR in the development of cancer, it is important to dissect the mechanisms by which host factors contribute to the intestinal barrier function in protecting cells from tumorigenesis. Here, we reported that in human tissue, reduced VDR in the colon of CRC patients is associated with the reduced intestinal barrier and enhanced bacterial translocation to tumors. VDR deficiency in the intestinal epithelial cells led to the reduced thickness of mucus layer and enhanced penetration of microbiota into the epithelial cells. VDR was a transcriptional factor regulating the genes of some tight junction (TJ) Claudins. The positively correlated status of VDR and Claudins (e.g., Claudin- 5 and10) contribute to the altered intestinal permeability in tumorigenesis. In the intestinal epithelial VDR conditionally knockout VDR∆IEC mice and myeloid VDR deletion mice, dysbiosis and inflammatory cytokines in the VDR deficient context further altered TJ proteins and manipulated the barrier functions in the development of colon cancer. Furthermore, we found that mice with colonic adenomatous polyposis coli (APC) mutation reduced thickness of mucus layer and enhanced penetration of microbiota into the epithelial cells, thus enhancing tumorigenesis in the colon. Studies on host factor regulation of microbiome and barriers could be potentially applied to risk assessment, early detection, and prevention of colon cancer. These studies will provide an additional avenue to restore microbiome and barrier functions for risk assessment and prevention of CRC and other cancers. Citation Format: Jun Sun, Jilei Zhang, Yinglin Xia, Yong-Guo Zhang. Microbiome and intestinal barriers in colon cancer [abstract]. In: Proceedings of the AACR Special Conference on Colorectal Cancer; 2022 Oct 1-4; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;82(23 Suppl_1):Abstract nr IA018.

Body Mass Index, sex, non-steroidal anti-inflammatory drug medications, smoking and alcohol are differentially associated with World Health Organisation criteria and colorectal cancer risk in people with Serrated Polyposis Syndrome: an Australian case-control study

ObjectiveThe unknown aetiology of Serrated Polyposis Syndrome (SPS) impedes risk prediction and prevention. We investigated risk factors for SPS, overall and stratified by World Health Organization (WHO)2010 clinical criteria and by colorectal cancer (CRC).MethodA retrospective case-control study involving a cross-sectional analysis from 350 unrelated individuals with SPS from the Genetics of Colonic Polyposis Study and 714 controls from the Australasian Colorectal Cancer Family Registry. Univariate and multivariate logistic regression modelling was used to determine the association between risk factors and SPS and risk factors associated with CRC in SPS.ResultsFemale biological sex (odds ratio (OR) = 4.54; 95%Confidence interval (CI) = 2.77–7.45), increasing body mass index (BMI) at age 20 years (OR = 1.09; 95%CI = 1.04–1.13), hormone replacement therapy (OR = 0.44; 95%CI = 0.20.98), and increasing weekly folate intake (OR = 0.82; 95%CI = 0.75–0.90) were associated with SPS by multivariate analysis. Increasing weekly calcium intake (OR = 0.79; 95%CI = 0.64–0.97) and smoking > 10 cigarettes daily (OR = 0.45; 95%CI = 0.23–0.86) were associated with WHO criterion I only. The consumption of 1-100 g of alcohol per week (OR = 0.39; 95%CI = 0.18–0.83) was associated with WHO criterion III only. Smoking 1–5 cigarettes daily (OR = 2.35; 95%CI = 1.09–5.05), weekly non-steroidal anti-inflammatory drug (NSAIDs) intake (OR = 0.88; 95%CI = 0.78–0.99), and increased height (OR = 1.09; 95% = 1.05–1.13), were associated with SPS fulfilling both WHO criteria I and III. Moreover, weekly NSAIDs intake (OR = 0.81; 95%CI = 0.67–0.98) was associated with a reduced likelihood of CRC in SPS.ConclusionWe identified novel risk and potential protective factors associated with SPS, some specific for certain WHO2010 criteria. Weekly use of NSAIDs may reduce the risk of CRC in people with SPS.

PMON132 Biochemical and Radiologic Discordance in the Post-operative Surveillance of a Filipino Patient With Acromegaly

Abstract Background Trans-sphenoidal surgery is the recommended initial therapy in patients with acromegaly. Early cure rate is 80-90% for microadenomas and <50% for macroadenomas. The goal is a serum IGF-1 that is normal for age and gender with GH <1mcg/L by immunoradiometric or chemiluminescent assays. Clinical Case A 71-year old male who consulted for diabetes management was eventually worked up for acromegaly He presented with coarsened facial features, hoarse voice, frontal bossing and enlarged hands and feet. Medical history includes hypertension, hepatosplenomegaly, colonic polyposis, obstructive sleep apnea and nasal septal deviation post-repair. Laboratory tests showed elevated IGF-1 (566.15, n: 91-282 ng/ml) and non suppressed GH after 75g OGTT (50.1, n<2.47 ng/mL). Pituitary hormonal profile showed normal prolactin (98.13, n: 86-324 mIU/L), TSH (1.63, n: 0.27-4.2 uIU/ml), FT4 (17.78, n: 12-22 pmol/L), ACTH (35, n: 7.2-63.3 pg/mL), Cortisol (387.4, n: 172-497 nmol/L), LH (4.56, n: 1.7-8.6 mIU/mL) and FSH (15.4, n: 1.5-12.4 mIU/mL). Contrast-enhanced pituitary MRI revealed a 1.5×2.0×1.9 cm pituitary macroadenoma with compression of the optic chiasm. Patient underwent trans-phenoidal surgery and excision of the tumor. Histopathology revealed a homogenous cells in sheets, acidophilic, densely granular and consistent with sommatotrophs, mammotrophs and sommatomammotrophs. Post-procedure GH was normal (2.731 ng/mL). Two months post-operatively, there was a significant decrease in both GH (1.84 ng/mL) and IGF-1 levels (258.59 ng/mL) while other pituitary hormones all within reference range. Contrast-enhanced pituitary MRI at 2 months showed interval surgical removal of the mass, with decompression of the optic chiasm. Clinically, there was softening of facial features and improvement in his voice. His cranial did not show pituitary mass. However, repeat GH after 75g OGTT (0.37 ng/mL, 2.3 ng/mL) and IGF-1 (361 ng/mL, 523,6 ng/mL) at 9 and 12 months post-surgery, respectively, were found above the reference range. Conclusion Discordance between anatomic and biochemical testing must be investigated thoroughly considering pulsatile hormone secretion, comorbidities and possible microscopic residual disease. Testing with the same assay is important to avoid inter-assay variability. Post-operative monitoring should be done at 12 weeks as it may take time for IGF-1 to normalize. If IGF-1 remains elevated, medical, surgical, radiotherapy, or combination may be considered especially in the presence of an identifiable focus. Presentation: Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.

ODP488 Incidental papillary thyroid cancer found after hemi-thyroidectomy in man with MUTYH-associated polyposis

Abstract MUTYH-associated polyposis (MAP) is an autosomal recessive syndrome caused by a mutation to the MUTYH gene, a base excision repair gene that repairs oxidative damage to DNA. Mutations to both allelic copies of this gene typically manifest as multiple colonic polyps, which develop by middle age. Individuals with MAP are also at higher risk for developing non-gastrointestinal (GI) cancers including those affecting the ovary, bladder, breast, endometrium, and possibly thyroid. A 66-year-old man with a history of MAP complicated by colonic polyposis requiring subtotal colectomy, an esophageal adenocarcinoma resected by esophagectomy, and a gastrointestinal stromal tumor also resected was referred to endocrinology clinic for an incidental thyroid nodule found on routine surveillance. The patient denied prior neck radiation but reported having a daughter and cousin with thyroid cancer. Ultrasound showed a left 3.3 by 2.8 by 1.6 cm thyroid nodule with multiple lobulations. Although a fine needle aspiration (FNA) of the nodule was benign, a repeat ultrasound several months later noted an increase in size to 3.5 by 3.5 by 2. 0 cm. Given the nodule's significant growth, the patient's history of MAP, and family history of thyroid cancer, the patient underwent a left hemi-thyroidectomy. Pathology revealed that the nodule was a follicular adenoma, however also identified two papillary microcarcinomas, measuring 1 and 2 mm. The patient was started on levothyroxine 50 mcg with a goal TSH below 0.5 mU/L and was monitored with ultrasounds which were unremarkable. In 2021, the national cancer institute estimated approximately 150,000 cases of colorectal cancer (CRC) with a 65% 5-year survival, compared to 44,000 cases of thyroid cancer with a 98% 5-year survival. Although the incidence of CRC in patients with MAP is high, approximately 43-63% by age 60, the risks of several associated non-GI malignancies are not as well defined. The national comprehensive cancer network (NCCN) and the American College of Gastroenterology (ACG) both published guidelines regarding appropriate screening for both GI and associated non-GI malignancies. In regards to thyroid cancer, both advise screening in patients with familiar adenomatous polyposis (FAP), another familial condition, due to the increased risk of papillary thyroid cancer (PTC) of approximately 1-2%. The evidence concerning MUTYH is not as strong, with the ACG recommending annual thyroid cancer screening, although the quality of evidence is low. Since a thyroid ultrasound is both low-cost and non-invasive and the overall survival of patients with PTC is high, we agree that patients with MAP be screened with thyroid ultrasounds. This case highlights the possibility that thyroid cancer is a manifestation of MAP, and a lower threshold to send for surgery may be warranted for those with other risk factors such as a family history or prior neck radiation. Presentation: No date and time listed

Long-term treatment of cancer-prone germline PTEN mutant micewith low-dose rapamycin extends lifespan and delays tumour development.

PTEN is one of the most commonly inactivated tumour suppressor genes in sporadic cancer. Germline heterozygous PTEN gene alterations also underlie PTEN hamartoma tumour syndrome (PHTS), a rare human cancer-predisposition condition. A key feature of systemic PTEN deregulation is the inability to adequately dampen PI3-kinase (PI3K)/mTORC1 signalling. PI3K/mTORC1 pathway inhibitors such as rapamycin are therefore expected to neutralise the impact of PTEN loss, rendering this a more druggable context compared with those of other tumour suppressor pathways such as loss of TP53. However, this has not been explored in cancer prevention in a model of germline cancer predisposition, such as PHTS. Clinical trials of short-term treatment with rapamycin have recently been initiated for PHTS, focusing on cognition and colon polyposis. Here, we administered a low dose of rapamycin from the age of 6 weeks onwards to mice with heterozygous germline Pten loss, a mouse model that recapitulates most characteristics of human PHTS. Rapamycin was well tolerated and led to a highly significant improvement of survival in both male and female mice. This was accompanied by a delay in, but not full blockade of, the development of a range of proliferative lesions, including gastro-intestinal and thyroid tumours and endometrial hyperplasia, with no impact on mammary and prostate tumours, and no effect on brain overgrowth. Our data indicate that rapamycin may have cancer prevention potential in human PHTS. This might also be the case for sporadic cancers in which genetic PI3K pathway activation is an early event in tumour development, such as endometrial cancer and some breast cancers. To the best of our knowledge, this is the first report of a long-term treatment of a germline cancer predisposition model with a PI3K/mTOR pathway inhibitor. © 2022 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Mono- and biallelic germline variants of DNA glycosylase genes in colon adenomatous polyposis families from two continents.

Recently, biallelic germline variants of the DNA glycosylase genes MUTYH and NTHL1 were linked to polyposis susceptibility. Significant fractions remain without a molecular explanation, warranting searches for underlying causes. We used exome sequencing to investigate clinically well-defined adenomatous polyposis cases and families from Finland (N=34), Chile (N=21), and Argentina (N=12), all with known susceptibility genes excluded. Nine index cases (13%) revealed germline variants with proven or possible pathogenicity in the DNA glycosylase genes, involving NEIL1 (mono- or biallelic) in 3 cases, MUTYH (monoallelic) in 3 cases, NTHL1 (biallelic) in 1 case, and OGG1 (monoallelic) in 2 cases. NTHL1 was affected with the well-established, pathogenic c.268C>T, p.(Gln90Ter) variant. A recurrent heterozygous NEIL1 c.506G>A, p.(Gly169Asp) variant was observed in two families. In a Finnish family, the variant occurred in trans with a truncating NEIL1 variant (c.821delT). In an Argentine family, the variant co-occurred with a genomic deletion of exons 2 - 11 of PMS2. Mutational signatures in tumor tissues complied with biological functions reported for NEIL1. Our results suggest that germline variants in DNA glycosylase genes may occur in a non-negligible proportion of unexplained colon polyposis cases and may predispose to tumor development.

S1538 Clinicopathologic Characterization and Genotype Correlation of Duodenal Polyposis Among Hispanics With Familial Adenomatous Polyposis

Introduction: Prognosis of individuals with familial adenomatous polyposis (FAP) has improved due to the implementation of specialized surveillance guidelines and prophylactic colectomy. Nonetheless, patients remain at increased risk for other neoplasia such as duodenal cancer. The Spigelman Classification for duodenal polyposis was designed to estimate a patient’s risk for duodenal cancer based on endoscopic and histopathologic findings. Prior studies have reported variation in colonic polyposis burden following a genotype-phenotype pattern according to APC gene mutation. The genotype-phenotype relationship in duodenal polyposis remains less clear. Methods: A total of 71 patients with FAP who had undergone at least one complete esophagogastroduodenoscopy (EGD). Age, sex, tobacco use, alcohol use, and BMI were among the sociodemographic factors evaluated. Study population was divided into mutations in the APC gene between codons 1000-1500 (Group 1) versus mutations before codon 1000 and after codon 1500 (Group 2). All participants were recruited as part of the UPR Medical Sciences Campus IRB approved prospective familiar cancer registry (PURIFICAR - http://purificar.rcm.upr.edu/). Results: Seventy-one patients with genetic diagnosis of FAP were evaluated. Duodenal adenomas were present in 42 (59%) patuents. 120 EGDs were evaluated for the study, with a mean of 1.7 EGDs per patient (Range = 1–4). Patients with duodenal adenomas on EGD were more likely to have APC mutations between codons 1000-1500 (65.7% vs 20%; P = 0.001). Differences in Spigelman stage between the 2 genotype groups were not statistically significant (P-value = 0.86). Furthermore, bivariate analysis of gender, age at last contact, BMI, tobacco use, and alcohol use were not independently associated with Spigelman stage. No cases of duodenal or ampullary cancer were observed after an overall follow-up of 304.6 patient-years. Conclusion: Our study provides the first phenotypic and genotypic characterization of duodenal polyposis among Hispanic patients with FAP. Duodenal polyposis was significantly associated with APC mutations within the 1000-1500 codon cluster. No other clinicodemographic or environmental associations were independently associated with presence of duodenal polyposis; no cases of duodenal cancer were observed in 304.6 patient-years of follow up. Our observations provide insightful information about the impact of APC genetic mutation location and endoscopic surveillance.

356P Biallelic MUTYH germline inactivation in patients with colon polyposis and subjects with sporadic colorectal cancer

MUTYH-associated polyposis (MAP) is a rare recessive condition typically characterized by the presence of 10-100 colorectal polyps and the elevated risk of colorectal cancer (CRC). CRCs arising in biallelic carriers of MUTYH mutation often contain KRAS G12C substitution and frequently arise without concomitant polyposis. This study included 74 consecutive patients with colon polyposis and 3486 consecutive patients with CRC referred to the N.N. Petrov Institute of Oncology (St. Petersburg, Russia) for molecular testing. Normal DNA obtained from subjects with polyposis was analyzed by NGS using custom panel for hereditary cancer genes. CRC patients were screened for recurrent MUTYH pathogenic alleles p.Y179C, p.R245H and p.G396D. The status of the remaining allele in MUTYH-heterozygous CRC cases was analyzed by Sanger sequencing. Biallelic MUTYH mutations were identified in 8/74 (11%) patients with polyposis. MAP was the second most common hereditary polyposis syndrome after familial adenomatous polyposis (47/74, 64%), with Peutz-Jeghers syndrome being in the third place (3/74, 5%). MUTYH biallelic alterations were detected in 9/3486 (0.3%) consecutive CRC patients. Somatic KRAS G12C substitution was observed in 223/3486 (6%) CRCs. Germ-line MUTYH inactivation was identified in 7/223 (3%) KRAS G12C-positive CRCs vs. 2/3253 (0.06%) patients without this mutation (p < 0.00001). Germ-line MUTYH biallelic mutations are significant contributors to the incidence of polyposis, while their impact in CRC morbidity is moderate. However, MUTYH gene analysis is highly feasible in CRC patients whose tumor harbors KRAS G12C substitution.

A case of early onset adenocarcinoma associated with colorectal polyposis with an unknown germline mutation

BackgroundTypically, in cases of adenomatous polyposis, colorectal cancer develops in the third or fourth decade of life. We report the case of a female patient with colorectal polyposis who developed adenocarcinoma at 8 years of age.Case presentationAn 8-year-old girl was admitted with a 4-year history of occasional bloody stools. Colonoscopy revealed colon polyposis and histopathological assessment confirmed a well-differentiated adenocarcinoma in the adenomatous polyps, so laparoscopy-assisted proctocolectomy was performed in the lithotomy position by a simultaneous abdominal and anal approach. To completely resect the rectal mucosa, excision was commenced just distal to the dentate line. After the mucosal resection up to the peritoneal reflection level, an inverted muscular cuff was cut circumferentially, and the terminal ileum was pulled through the muscular cuff and anastomosed to the anal canal. Histopathology revealed multiple adenomatous polyps and scattered well-differentiated tubular adenocarcinomas (tub1) in the adenomatous polyps and the non-polypoid mucosal lesions. Because complete resection was achieved, additional adjuvant chemotherapy was not administered. Polymerase chain reaction (PCR)-direct sequencing of the entire coding region and the exon–intron junctions, and real-time PCR of DNA extracted from blood cells, revealed no mutations of either APC or MUTYH. No deletions, duplications, translocations or inversions of APC, MUTYH and GREM1 genes were found using multiplex ligation-dependent probe amplification (MLPA) and G-banding analysis. Multi-gene panels sequencing for polyposis syndromes or hereditary colorectal cancers, and trio-whole exome sequencing was conducted. However, no candidate pathogenic variants of genes were detected in de novo dominant or autosomal recessive model. Somatic mutation of APC was not detected in 4 polyps by loss of heterozygosity analysis at a single nucleotide polymorphism in intron 14. The patient has remained disease-free for 5 years. Currently, the patient is on loperamide and passes stool 5 times/day without any soiling.ConclusionsThe genetic analysis suggests that she may have a germline mutation at unscreened region of these genes or in unidentified FAP gene. The patient will be carefully followed up for residual rectal carcinoma and for the development of other cancers.

Optical coherence tomography and angiography features of pigmented ocular fundus lesions in hereditary colonic polyposis syndrome.

Optical coherence tomography and angiography features of pigmented ocular fundus lesions in hereditary colonic polyposis syndrome.

Diagnostic accuracy of the CxPREVENTIVE Colon model for early detection of colorectal cancer.

e15518 Background: Despite different available methods for colorectal cancer (CRC) screening and their proven benefits, morbidity, and mortality of this malignancy are still high, partly due to technical limitations and low compliance with screening. The aim of the present study was to assess the diagnostic accuracy for early detection of CRC using a modeling algorithm based on multiple blood and urine biomarkers. Methods: In this retrospective cohort study, clinical and blood and urine markers-based algorithms with predefined cutoff values were applied to a generally healthy asymptomatic outpatient cohort of adults aged 50 years or older undergoing colonoscopy and histopathology for routine colorectal cancer screening. We used a modeling algorithm based on two different frameworks (Multiple Biomarkers Disease Activity Algorithm MBDAA [Bioprognos], and Artificial Intelligence Recursive Algorithm AIRA [Mintlot] both in Barcelona, Spain). Both algorithms compute information from a wide number of analytes, tumor markers (AFP, CA 19.9, CA 72.4, CA 125, CEA, Cyr61, NGAL, EGFR and 8-OHdG), and additional clinical data (age, weight, height, and BMI). MBDAA includes Barcelona Criteria (four criteria to correctly interpret the cause of the increase in tumor markers, benign or malignant, defined by the Spanish Society of Clinical Biochemistry and Molecular Pathology, Commission of Biological Markers of Cancer). To assess the association between the modelling algorithm and downstream diagnosis we used logistic regression to compute receiver operating characteristic curves (ROC). Exact binomial confidence limits were calculated to test accuracy, sensitivity, and specificity. Results: 221 people (median age 63 yr. [IQR 49-77]; 107 [49%] women and 114 [51%] men) who underwent colonoscopy at the Juan Ramón Jiménez Hospital (Huelva, Spain), were included in this analysis. Based on colonoscopy and histopathologic findings, CRC was diagnosed in 45 (20%) patients, colonic polyposis in 56 (25%), inflammatory bowel disease in 37 (17%), and absence of pathological findings (control group) was seen in 83 (38%). The diagnostic intervention for CRC yielded an area under the curve (AUC) of 1 among the entire specimen set, accuracy 1 (95% CI 0.996,1), Se 1 (0.988, 1) and Sp 1 (0.997, 1). Besides, the algorithm also performed very well in the identification of polyps with an accuracy 1 (95% CI, 0.967 to 1), Se of 1 (0.991, 1) and of Sp 1 (0.996, 1), as well in the diagnosis of inflammatory bowel disease with an accuracy of 1 (0.968 to 1), Se of 1 (0.986, 1) and Sp of 1 (0.997, 1). Conclusions: Using colonoscopy as a gold standard, our data suggest that an innovative newly designed non-invasive blood and urine-based biomarker algorithm CxPREVENTIVE Colon may provide a timely diagnosis of CRC with very high accuracy. Our findings warrant further investigation, and we are planning large-scale (n 10,000), fully powered study to inform clinical practice.

Gardner’s Syndrome and Myxoma: A Rare Clinical Case with Very Early Onset

Background: Gardner’s syndrome (GS) is an autosomal dominant inherited disease that predisposes individuals to a high risk of developing colonic polyposis, colorectal cancers, and multiple maxillofacial hard and soft tissue tumors. Odontogenic myxoma (OM) is classified as a benign locally invasive tumor of the jaws. It is estimated as the third most frequent odontogenic tumor, between 2% and 5% of cases. In the present study, we report and discuss a case of odontogenic myxoma in a 13-month-old patient diagnosed with GS. Case Presentation: A 13-month-old patient was referred to our department with a fast-growing tumor located in the left nasomaxillary region and a family history of GS. Computed tomography imaging of the face with contrast was performed, showing a well-defined, insufflating osteolytic lesion located in the left nasomaxillary region, extending up to the inferior orbital wall. The tumor was biopsied, and he was diagnosed with OM. Radical resection was performed and the anterior maxilla wall was reconstructed with PDS. Subsequently, germline mutation in APC gene was found in the patient. Follow up was carried out up to seven years after the intervention, an excellent cosmetic outcome and no signs of recurrence were observed in the area. Conclusion: Oral and maxillofacial surgeons must be aware of the different lesions which may be associated with systemic syndromes. OM may be first manifestation related to early diagnosis of GS and, lastly, colon cancer. OM could be an indication of referring to genetic counselling to determine the presence of the mutation in patients with or without familiar history.

Diagnosis and Management of Cancer Risk in the Gastrointestinal Hamartomatous Polyposis Syndromes: Recommendations From the US Multi-Society Task Force on Colorectal Cancer.

The gastrointestinal hamartomatous polyposis syndromes are rare, autosomal dominant disorders associated with an increased risk of benign and malignant intestinal and extraintestinal tumors. They include Peutz-Jeghers syndrome, juvenile polyposis syndrome, the PTEN hamartoma tumor syndrome (including Cowden's syndrome and Bannayan-Riley-Ruvalcaba syndrome), and hereditary mixed polyposis syndrome. Diagnoses are based on clinical criteria and, in some cases, confirmed by demonstrating the presence of a germline pathogenic variant. The best understood hamartomatous polyposis syndrome is Peutz-Jeghers syndrome, caused by germline pathogenic variants in the STK11 gene. The management is focused on prevention of bleeding and mechanical obstruction of the small bowel by polyps and surveillance of organs at increased risk for cancer. Juvenile polyposis syndrome is caused by a germline pathogenic variant in either the SMAD4 or BMPR1A genes, with differing clinical courses. Patients with SMAD4 pathogenic variants may have massive gastric polyposis, which can result in gastrointestinal bleeding and/or protein-losing gastropathy. Patients with SMAD4 mutations usually have the simultaneous occurrence of hereditary hemorrhagic telangiectasia (juvenile polyposis syndrome-hereditary hemorrhagic telangiectasia overlap syndrome) that can result in epistaxis, gastrointestinal bleeding from mucocutaneous telangiectasias, and arteriovenous malformations. Germline pathogenic variants in the PTEN gene cause overlapping clinical phenotypes (known as the PTEN hamartoma tumor syndromes), including Cowden's syndrome and related disorders that are associated with an increased risk of gastrointestinal and colonic polyposis, colon cancer, and other extraintestinal manifestations and cancers. Due to the relative rarity of the hamartomatous polyposis syndromes, recommendations for management are based on few studies. This US Multi-Society Task Force on Colorectal Cancer consensus statement summarizes the clinical features, assesses the current literature, and provides guidance for diagnosis, assessment, and management of patients with the hamartomatous polyposis syndromes, with a focus on endoscopic management.

Yield of upper gastrointestinal screening in colonic adenomatous polyposis of unknown etiology: a multicenter study.

Background and study aims The majority of patients with 10 or more cumulative colorectal adenomas have uninformative genetic testing and meet criteria for colonic adenomatous polyposis of unknown etiology (CPUE). The yield of upper gastrointestinal screening in patients with CPUE after multi-gene panel testing is unknown and our objective was to characterize this. Patient and methods A multicenter, retrospective analysis of screening upper endoscopies in adults with CPUE after multi-gene panel testing was performed. Those with a history of gastroduodenal neoplasia prior to CPUE diagnosis were excluded. Demographic and clinical variables were collected and compared. Results One hundred and twenty-eight patients with CPUE were included from five participating centers. Nine (7.0 %) had gastroduodenal neoplasia on initial screening upper endoscopy. Those with over 100 colorectal adenomas had a significantly higher rate of gastroduodenal neoplasia than those with 20–99 or 10–19 colorectal adenomas (44.4 % vs 4.1 % vs 4.4 %, P = 0.002). Similar results were seen when the analysis was restricted to only duodenal or ampullary adenomas. The only malignancy was a gastric cancer in a patient with 20 to 99 colorectal adenomas. When comparing patients with gastroduodenal neoplasia to those without, the only significantly different characteristic was the cumulative number of colorectal adenomas. Conclusions We found a 7 % rate of gastroduodenal neoplasia in patients with CPUE after multi-gene panel testing. Although patients with ≥ 100 colorectal adenomas had a significantly higher risk, over 4 % of patients with 10 to 99 colorectal adenomas had gastroduodenal neoplasia. Given this, we recommend a screening upper endoscopy at the time of a colonoscopy after CPUE diagnosis.

Gardner’s Syndrome, a variant of familial adenomatous polyposis: a case report

Introduction: Gardner’s syndrome is a rare, autosomal dominant disease associated with the mutation of the Adenomatous polyposis coli (APC) gene, characterized by colonic polyposis with a histopathology compatible with adenoma, associated with mesenchymal tumor, such as desmoid type, osteomas and dental alterations. Extraintestinal manifestations may be the first findings, being important knowledge and disclosure of the clinical condition, allowing early diagnosis, adequate management and family investigation. Case report: This case report aims to describe the clinical case of familial adenomatous polyposis with a variant compatible with Gardner’s Syndrome, in a patient with extra intestinal manifestations with desmoid tumor, supernumerary teeth and osteomas, ongoing at the Digestive System Unit of the Cassiano Antônio Moraes University Hospital, Federal University of Espirito Santo – Brazil, in addition to a literature review in the Pubmed databases to alert the health care community, especially doctors, about the phenotype presented in Gardner’s Syndrome, enabling early diagnosis.

95 Long-term dual antiplatelet therapy after myocardial infarction in clinical practice: impact of nuisance bleeding on medication adherence

Abstract Aims Long-term treatment with ticagrelor 60 mg and low-dose aspirin are indicated after acute coronary syndrome (ACS) for the secondary prevention of atherothrombotic events in high-risk patients with a history of myocardial infarction of at least 1 year. Long-term dual antiplatelet therapy (DAPT) had a well tolerability and safety profile, but the risk of TIMI major bleeding was significantly increased. However even nonsignificant bleeding may be important because have an effect on quality of life and therefore may lead to treatment discontinuation. To understand the experiences of patients with long-term DAPT with ticagrelor 60 mg and low-dose aspirin and nuisance bleeding, and their impact of nuisance bleeding on medication adherence. Methods and results We retrospectively reviewed aggregate data of 187 patients (155 M e 38 F) (mean age 63.8 ± 9 years) in follow-up after ACS with at least one high risk condition (multivessel disease, diabetes, GFR &amp;lt; 60 mL/min, history of prior myocardial infarction, age &amp;gt; 65 years) treated with ticagrelor 60 mg twice daily (after 90 mg twice daily for 12 months). The high risk groups were represented as follows: multivessel disease 105 pts (82%), diabetes 63 pts (33%), GFR&amp;lt; 60 mL/min 27 pts (14%), history of prior MI 33 pts (17%), and &amp;gt;65 year aged 85 pts (45%). The outpatient follow-up programme after hospitalization provides visits at day 30 after discharge and subsequently after 3 months, then continuing with 6-monthly checks. The intensity of bleeding was assessed according to the TIMI score.1 Any overt bleeding event that did not meet the criteria of major and minor was defined ‘minimal’. Treatment was withdrawn in seven patients: three cases showed atrial fibrillation and were placed on oral anticoagulant drugs, one developed intracranial bleeding. In three patients, a temporary withdrawal was due to surgery (one colon polyposis and two cases of bladder papilloma). Minimal bleedings (nasal, gingival, conjunctival, subcutaneous/dermal, rectal and urinary) were present in 31 patients, but were not a cause for discontinuation of therapy. However, 22 (70%) subjects had asked opinion on stop the therapy at the telephone consultation. We found that: (i) participants adhered to treatment when they believed long-term DAPT was important to health outcomes; (ii) those who experienced nuisance bleeding reported symptoms to be mild and manageable; (iii) participants’ and their family’s understanding of long-term DAPT risks and benefits, and their ability to manage symptoms, influenced medication adherence. Factors influencing long-term DAPT knowledge included access to medication counselling, engaging with information communicated during medication counselling, and access to timely, relevant and expert information and advice after discharge from hospital. Conclusions All adverse events judged to be ‘not serious’ in trials may have an effect on quality of life and therefore may lead to treatment discontinuation. The need to educate the patient in order to improve adherence should therefore be emphasized. The authors underline the importance of careful outpatient follow-up and constant counselling in order to check out compliance and possible adverse effect of long term DAPT risks treatment.

Rare germline variants in the AXIN2 gene in families with colonic polyposis and colorectal cancer.

Germline loss-of-function variants in AXIN2 are associated with oligodontia and ectodermal dysplasia. The association between colorectal cancer (CRC) and colonic polyposis is less clear despite this gene now being included in multi-gene panels for CRC. Study participants were people with genetically unexplained colonic polyposis recruited to the Genetics of Colonic Polyposis Study who had a rare germline AXIN2 gene variant identified from either clinical multi-gene panel testing (n=2) or from whole genome/exome sequencing (n=2). Variant segregation in relatives and characterisation of tumour tissue were performed where possible. Four different germline pathogenic variants in AXIN2 were identified in four families. Five of the seven carriers of the c.1049delC, p.Pro350Leufs*13 variant, two of the six carriers of the c.1994dupG, p.Asn666Glnfs*41 variant, all three carriers of c.1972delA, p.Ser658Alafs*31 variant and the single proband carrier of the c.2405G>C, p.Arg802Thr variant, which creates an alternate splice form resulting in a frameshift mutation (p.Glu763Ilefs*42), were affected by CRC and/or polyposis. Carriers had a mean age at diagnosis of CRC/polyposis of 52.5 ± 9.2 years. Colonic polyps were typically pan colonic with counts ranging from 5 to >100 (median 12.5) comprising predominantly adenomatous polyps but also serrated polyps. Two CRCs from carriers displayed evidence of a second hit via loss of heterozygosity. Oligodontia was observed in carriers from two families. Germline AXIN2 pathogenic variants from four families were associated with CRC and/or polyposis in multiple family members. These findings support the inclusion of AXIN2 in CRC and polyposis multigene panels for clinical testing.

Colonic ganglioneuromatous polyposis in a 6-year-old girl – A case report and review of literature

Ganglioneuroma of the gastrointestinal tract is a rare mesenchymal tumor of neural origin, especially in childhood. They are categorized into three different morphological subtypes, namely, polypoid ganglioneuroma, ganglioneuromatous polyposis (GP), and diffuse ganglioneuromatosis. Patients with ganglioneuromas have different presentations depending on the location, extent, and size of the lesion. We report here a case of colonic ganglioneuromatous polyposis, presenting as abdominal pain and chronic constipation in a 6‑year‑old girl. Although GP cases are reported in adult age group, cases in pediatric age group are rare. Only a few cases are reported in the literature of GP in the pediatric age group. Although rare, this disorder must be taken into consideration in the differential diagnosis in every patient with symptoms such as abdominal pain, constipation, and lower intestinal bleeding, to avoid a delayed diagnosis.