Development and Validation of a Colorectal Cancer Prediction Model: A Nationwide Cohort-Based Study.

BACKGROUND: Early diagnosis of colorectal cancer (CRC) is critical to increasing survival rates. Computerized risk prediction models hold great promise for identifying individuals at high risk for CRC. In order to utilize such models effectively in a population-wide screening setting, development and validation should be based on cohorts that are similar to the target population. AIM: Establish a risk prediction model for CRC diagnosis based on electronic health records (EHR) from subjects eligible for CRC screening. METHODS: A retrospective cohort study utilizing the EHR data of Clalit Health Services (CHS). The study includes CHS members aged 50-74 who were eligible for CRC screening from January 2013 to January 2019. The model was trained to predict receiving a CRC diagnosis within 2 years of the index date. Approximately 20,000 EHR demographic and clinical features were considered. RESULTS: The study includes 2935 subjects with CRC diagnosis, and 1,133,457 subjects without CRC diagnosis. Incidence values of CRC among subjects in the top 1% risk scores were higher than baseline (2.3% vs 0.3%; lift 8.38; P value < 0.001). Cumulative event probabilities increased with higher model scores. Model-based risk stratification among subjects with a positive FOBT, identified subjects with more than twice the risk for CRC compared to FOBT alone. CONCLUSIONS: We developed an individualized risk prediction model for CRC that can be utilized as a complementary decision support tool for healthcare providers to precisely identify subjects at high risk for CRC and refer them for confirmatory testing.

A POT1 Founder Variant Associated with Early Onset Recurrent Melanoma and Various Solid Malignancies.

POT1 (Protection of Telomeres 1) is a key component of the six-membered shelterin complex that plays a critical role in telomere protection and length regulation. Germline variants in the POT1 gene have been implicated in predisposition to cancer, primarily to melanoma and chronic lymphocytic leukemia (CLL). We report the identification of POT1 p.(I78T), previously ranked with conflicting interpretations of pathogenicity, as a founder pathogenic variant among Ashkenazi Jews (AJs) and describe its unique clinical landscape. A directed database search was conducted for individuals referred for genetic counselling from 2018 to 2023. Demographic, clinical, genetic, and pathological data were collected and analyzed. Eleven carriers, 25 to 67 years old, from ten apparently unrelated families were identified. Carriers had a total of 30 primary malignancies (range 1-6); nine carriers (82%) had recurrent melanoma between the ages of 25 and 63 years, three carriers (27%) had desmoid tumors, three (27%) had papillary thyroid cancer (PTC), and five women (63% of female carriers) had breast cancer between the ages of 44 and 67 years. Additional tumors included CLL; sarcomas; endocrine tumors; prostate, urinary, and colorectal cancers; and colonic polyps. A review of a local exome database yielded an allelic frequency of the variant of 0.06% among all ethnicities and of 0.25% in AJs. A shared haplotype was found in all carriers tested. POT1 p.(I78T) is a founder disease-causing variant associated with early-onset melanoma and additional various solid malignancies with a high tumor burden. We advocate testing for this variant in high-risk patients of AJ descent. The inclusion of POT1 in germline panels for various types of cancer is warranted.

Colorectal cancer screening at age 45 years in Israel: Cost-effectiveness and global implications.

BACKGROUND: Colorectal cancer (CRC) incidence at ages <50 years is increasing worldwide. Screening initiation was lowered to 45 years in the United States. The cost-effectiveness of initiating CRC screening at 45 years in Israel was assessed with the aim of informing national policy and addressing internationally relevant questions. METHODS: A validated CRC screening model was calibrated to Israeli data and examined annual fecal immunochemical testing (FIT) or colonoscopy every 10 years from 45 to 74 years (FIT45-74 or Colo45-74) versus from 50 to 74 years (FIT50-74 or Colo50-74). The addition of a fourth colonoscopy at 75 years was explored, subanalyses were performed by sex/ethnicity, and resource demands were estimated. RESULTS: FIT50-74 and Colo50-74 reduced CRC incidence by 57% and 70% and mortality by 70% and 77%, respectively, versus no screening, with greater absolute impact in Jews/Other versus Arabs but comparable relative impact. FIT45-74 further reduced CRC incidence and mortality by an absolute 3% and 2%, respectively. With Colo45-74 versus Colo50-74, CRC cases and deaths increased slightly as three colonoscopies per lifetime shifted to 5 years earlier but mean quality-adjusted life-years gained (QALYGs) per person increased. FIT45-74 and Colo45-74 cost 23,800-53,900 new Israeli shekels (NIS)/QALYG and 110,600-162,700 NIS/QALYG, with the lowest and highest values among Jewish/Other men and Arab women, respectively. A fourth lifetime colonoscopy cost 48,700 NIS/QALYG. Lowering FIT initiation to 45 years with modest participation required 19,300 additional colonoscopies in the first 3 years. CONCLUSIONS: Beginning CRC screening at 45 years in Israel is projected to yield modest clinical benefits at acceptable costs per QALYG. Despite different estimates by sex/ethnicity, a uniform national policy is favored. These findings can inform Israeli guidelines and serve as a case study internationally.

The benefit of pancreatic cancer surveillance in carriers of germline BRCA1/2 pathogenic variants.

BACKGROUND: Surveillance of high-risk individuals for pancreatic ductal adenocarcinoma (PDAC) is recommended. This study aimed to determine the prevalence and outcomes of PDAC and its precursor lesions in BRCA1/2 pathogenic variants (PVs) carriers undergoing pancreatic surveillance. METHODS: A retrospective multicenter cohort study of pancreatic surveillance outcomes in Israeli BRCA1/2 carriers preferably with a family history of PDAC. RESULTS: A total of 180 asymptomatic carriers participated in the screening programs, including 57 (31.7%) with BRCA1 PVs, 121 (67.2%) with BRCA2 PVs, and 12 (6.6%) with PVs in BRCA1/2 and other genes, for a median follow-up period of 4 years. Ninety-one individuals (50.5%) fulfilled the International Cancer of the Pancreas Screening (CAPS) criteria for surveillance whereas 116 (64.4%) fulfilled the American College of Gastroenterology (ACG) criteria. There were four cases of adenocarcinoma and four cases of grade 1-neuroendocrine tumor (G1-NET). All were BRCA2 carriers, and two had no family history of PDAC. Three cancer patients were at resectable stages (IA, IIA, IIB) whereas one had a stage IIIB tumor. Of the G1-NET cases, one had surgery and the others were only followed. Success rate for detection of confined pancreatic carcinoma was thus 1.6% (three of 180) in the whole cohort, 1.6% (two of 116) among individuals who fulfilled ACG criteria and 2.2% (two of 91) in those fulfilling CAPS criteria for surveillance. CONCLUSIONS: Despite the low detection rate of PDAC and its' high-risk neoplastic precursor lesions among BRCA1/2 carriers undergoing pancreatic surveillance, 75% of cancer cases were detected at a resectable stage.

Dysplasia detection rates under a surveillance program in a tertiary referral center for inflammatory bowel diseases: Real-world data.

BACKGROUND AND AIMS: Surveillance colonoscopies are crucial for high-risk patients with inflammatory bowel diseases (IBD) to detect colorectal carcinoma (CRC). However, there is no established quality metric for dysplasia detection rate (DDR) in IBD surveillance. This study assessed the DDR in a dedicated surveillance program at a tertiary referral center for IBD. METHODS: Consecutive patients with quiescent colitis were enrolled in a cross-sectional study evaluating DDR. High-definition colonoscopy with dye chromoendoscopy (DCE) was performed by a specialized operator. Advanced dysplasia (AD) was defined as low-grade dysplasia ≥ 10 mm, high-grade dysplasia, or colorectal cancer. Risk factors for dysplasia detection were analyzed. RESULTS: In total, 119 patients underwent 151 procedures, identifying 206 lesions, of which 40 dysplastic with seven AD . Per-lesion and per-procedure DDR were 19.4 % and 20.5 %, respectively. The per-procedure AD detection rate (ADDR) was 4.6 %. A Kudo pit pattern of II-V had a sensitivity of 92.5 % for dysplasia detection but a false positive rate of 64.8 % (p < 0.001). Age at diagnosis and at index colonoscopy and past or indefinite dysplasia were associated with per-procedure dysplasia detection. CONCLUSIONS: In a real-world setting, a dedicated surveillance program achieved a high DDR. We suggest that optimal DDR in high-risk IBD patients be defined and implemented as a standardized quality measure for surveillance programs.

Racial/ethnic and socioeconomic disparities in colorectal cancer screening in a large organization with universal insurance before and during the coronavirus disease 2019 pandemic.

OBJECTIVES: Israel is regarded as a country with a developed economy and a moderate income inequality index. In this population-based study, we aimed to measure the inequalities in colorectal cancer screening within Clalit Health, an organization with universal insurance, before and during the coronavirus disease 2019 pandemic. SETTING: Retrospective analysis within Clalit Health Services, Israel. METHODS: We evaluated the rate of being up to date with screening (having a colonoscopy within 10 years or a fecal occult blood test within 1 year) and the colonoscopy completion rate (having a colonoscopy within 6 months of a positive fecal occult blood test) among subjects aged 50-75 in 2019-2021. RESULTS: In 2019, out of 918,135 subjects, 61.3% were up to date with screening; high socioeconomic status: 65.9% (referent), medium-socioeconomic status: 60.1% (odds ratio 0.81, 95% confidence interval 0.80-0.82), low-socioeconomic status: 59.0% (odds ratio 0.75, 95% confidence interval 0.74-0.75); Jews: 61.9% (referent), Arabs: 59.7% (odds ratio 0.91, 95% confidence interval 0.90-0.92), Ultraorthodox-Jews: 51.7% (odds ratio 0.77, 95% confidence interval 0.75-0.78). Out of 21,308 with a positive fecal occult blood test, the colonoscopy completion rate was 51.8%; high-socioeconomic status: 59.8% (referent), medium-socioeconomic status: 54.1% (odds ratio 0.79, 95% confidence interval 0.73-0.86), low-socioeconomic status: 45.5% (odds ratio 0.60, 95% confidence interval 0.56-0.65); Jews: 54.7% (referent), Ultraorthodox-Jews: 51.4% (odds ratio 0.91, 95% confidence interval 0.90-0.92), Arabs: 44.7% (odds ratio 0.77, 95% confidence interval 0.75-0.78). In 2020-2021, there was a slight drop in the rate of being up to date with screening, while most of the discrepancies were kept or slightly increased with time. CONCLUSIONS: We report significant inequalities in colorectal cancer screening before and during the coronavirus disease 2019 pandemic in Israel, despite a declared policy of equality and universal insurance.

Multi-focal dysplasia is associated with high recurrence rates after successful ablation of dysplastic Barrett's esophagus.

BACKGROUND & AIMS: Barrett's esophagus (BE) might recur after complete eradication of intestinal metaplasia (CEIM). We investigated  factors associated with recurrence of BE after successful Radiofrequency ablation (RFA). METHODS: A longitudinal study of BE patients with dysplasia treated with RFA from 2014 to 2021 in two large referral centers. Recurrence was identified in histologic specimens. Factors associated with post-RFA recurrence were analyzed using Cox regression analysis. RESULTS: A total of 728 patients with BE were identified, 118 had underwent RFA, and 113 had sufficient follow up time. Mean age was 63.7 (±11.7) years, 73.5% were males, 59.3% had long segment of BE, and 30.1% had multifocal dysplasia. During 340.8 patient-years of follow-up, 15 patients (13.3%) had recurrence of BE, which represent an incidence rate of 4.41% per patient-year. Incidence rate of recurrence with dysplasia was 1.17% per patient-year. Multifocal dysplasia, number of RFA sessions, and endoscopic resection before RFA were associated with risk of recurrence in univariate analysis. However, in cox regression analysis only multifocal dysplasia (HR 10.99; 95% CI 2.83-22.62, p = 0.001) was associated with post-RFA recurrence. CONCLUSION: Total recurrence rates after CEIM are low, and multifocal dysplasia before the ablative therapy is significantly associated with BE recurrence after CEIM. Patients with multifocal dysplasia should be monitored rigorously after successful ablation.

The use of artificial intelligence to identify subjects with a positive FOBT predicted to be non-compliant with both colonoscopy and harbor cancer.

BACKGROUND: Subjects with a positive Fecal Occult Blood Test (FOBT) that are non-compliant with colonoscopy are at increased risk for colorectal cancer (CRC). Yet, in clinical practice, many remain non-compliant. AIMS: To evaluate whether machine learning models (ML) can identify subjects with a positive FOBT predicted to be both non-compliant with colonoscopy within six months and harbor CRC (defined as the "target population"). METHODS: We trained and validated ML models based on extensive administrative and laboratory data about subjects with a positive FOBT between 2011 and 2013 within Clalit Health that were followed for cancer diagnosis up to 2018. RESULTS: Out of 25,219 included subjects, 9,979(39.6%) were non-compliant with colonoscopy, and 202(0.8%) were both non-compliant and harbored cancer. Using ML, we reduced the number of subjects needed to engage from 25,219 to either 971 (3.85%) to identify 25.8%(52/202) of the target population, reducing the number needed to treat (NNT) from 124.8 to 19.4 or to 4,010(15,8%) to identify 55.0%(52/202) of the target population, NNT = 39.7. CONCLUSION: Machine learning technology may help healthcare organizations to identify subjects with a positive FOBT predicted to be both non-compliant with colonoscopy and harbor cancer from the first day of a positive FOBT with improved efficiency.

Mortality by age, gene and gender in carriers of pathogenic mismatch repair gene variants receiving surveillance for early cancer diagnosis and treatment: a report from the prospective Lynch syndrome database.

Background: The Prospective Lynch Syndrome Database (PLSD) collates information on carriers of pathogenic or likely pathogenic MMR variants (path_MMR) who are receiving medical follow-up, including colonoscopy surveillance, which aims to the achieve early diagnosis and treatment of cancers. Here we use the most recent PLSD cohort that is larger and has wider geographical representation than previous versions, allowing us to present mortality as an outcome, and median ages at cancer diagnoses for the first time. Methods: The PLSD is a prospective observational study without a control group that was designed in 2012 and updated up to October 2022. Data for 8500 carriers of path_MMR variants from 25 countries were included, providing 71,713 years of follow up. Cumulative cancer incidences at 65 years of age were combined with 10-year crude survival following cancer, to derive estimates of mortality up to 75 years of age by organ, gene, and gender. Findings: Gynaecological cancers were more frequent than colorectal cancers in path_MSH2, path_MSH6 and path_PMS2 carriers [cumulative incidence: 53.3%, 49.6% and 23.3% at 75 years, respectively]. Endometrial, colon and ovarian cancer had low mortality [8%, 13% and 15%, respectively] and prostate cancers were frequent in male path_MSH2 carriers [cumulative incidence: 39.7% at 75 years]. Pancreatic, brain, biliary tract and ureter and kidney and urinary bladder cancers were associated with high mortality [83%, 66%, 58%, 27%, and 29%, respectively]. Among path_MMR carriers undergoing colonoscopy surveillance, particularly path_MSH2 carriers, more deaths followed non-colorectal Lynch syndrome cancers than colorectal cancers. Interpretation: In path_MMR carriers undergoing colonoscopy surveillance, non-colorectal Lynch syndrome cancers were associated with more deaths than were colorectal cancers. Reducing deaths from non-colorectal cancers presents a key challenge in contemporary medical care in Lynch syndrome. Funding: We acknowledge funding from the Norwegian Cancer Society, contract 194751-2017.

A Highly Sensitive Flow Cytometric Approach to Detect Rare Antigen-Specific T Cells: Development and Comparison to Standard Monitoring Tools.

Personalized vaccines against patient-unique tumor-associated antigens represent a promising new approach for cancer immunotherapy. Vaccine efficacy is assessed by quantification of changes in the frequency and/or the activity of antigen-specific T cells. Enzyme-linked immunosorbent spot (ELISpot) and flow cytometry (FCM) are methodologies frequently used for assessing vaccine efficacy. We tested these methodologies and found that both ELISpot and standard FCM [monitoring CD3/CD4/CD8/IFNγ/Viability+CD14+CD19 (dump)] demonstrate background IFNγ secretion, which, in many cases, was higher than the antigen-specific signal measured by the respective methodology (frequently ranging around 0.05-0.2%). To detect such weak T-cell responses, we developed an FCM panel that included two early activation markers, 4-1BB (CD137) and CD40L (CD154), in addition to the above-cited markers. These two activation markers have a close to zero background expression and are rapidly upregulated following antigen-specific activation. They enabled the quantification of rare T cells responding to antigens within the assay well. Background IFNγ-positive CD4 T cell frequencies decreased to 0.019% ± 0.028% and CD8 T cells to 0.009% ± 0.013%, which are 19 and 13 times lower, respectively, than without the use of these markers. The presented methodology enables highly sensitive monitoring of T-cell responses to tumor-associated antigens in the very low, but clinically relevant, frequencies.

High prevalence of MUTYH associated polyposis among minority populations in Israel, due to rare founder pathogenic variants.

BACKGROUND: Autosomal recessive conditions are common in consanguineous populations. Since consanguinity is common in the Israeli Arab population, we evaluated the rate of MUTYH polyposis (MAP) among polyposis patients in this population and studied Pathogenic Variants (PVs) spectrum. METHODS: We reviewed health records of all Arab and Druze polyposis patients referred for counseling during 2013-2020 who fulfilled the Israeli Genetic Society criteria for MUTYH/APC testing, in a tertiary center in Northern Israel and four additional gastro-genetic clinics in Israel. RESULTS: The Northern cohort included 37 patients from 30 unrelated families; 8(26.6%) carried bi-allelic MUTYH PVs. The major variant p.Glu452del was detected in 6/8 Druze and Muslim families who shared the same haplotype. Other PVs detected in both cohorts included p.Tyr56Ter, p.His57Arg, c.849+3A>C, p.Ala357fs, and p.Tyr151Cys. Among bi-allelic carriers, 88% reported consanguinity, and 100% had positive family history for polyposis or colorectal cancer (CRC). Generally, the age of CRC was 10 years younger than reported in the general MAP population. CONCLUSIONS: MAP accounted for 27% of polyposis cases in the Arab population of Northern Israel. PVs spectrum is unique, with high frequency of the founder variant p.Glu452del. Our results may inform the genetic testing strategy in the Israeli Arab population.

Using an algorithm to assess the rate and trend over time of inappropriate proton pump inhibitors prescription upon hospital discharge.

BACKGROUND: There is an increasing interest in inappropriate proton pump inhibitors prescription (InPPIp), as defined by the National Institute for Clinical Excellence (NICE) guidelines. AIMS: To evaluate the rate, trend over time and factors associated with InPPIp upon discharge from internal medicine departments. METHODS: We evaluated patients discharged from internal medicine departments with a PPI prescription in 2014 and 2017 at an academic referral center according to a developed algorithm. RESULTS: A total of 3,982 patients were included (50.8% women, 74% ≥ 65 years). The rate of InPPIp was 44.3% (95% CI 42.8-45.9) for the entire cohort; 68.1% for subjects aged < 65 years and 36.0% for those aged ≥ 65 years (p<0.001); 43.2% in 2014 and 45.6% in 2017 (p = 0.130). In a decision-tree analysis, after the exclusion of 448 patients with gastrointestinal indications, 89.4% (1,580/1,766) of all InPPIp cases were of patients without dual antiplatelet treatment (DAPT) and 8.6% (151/1,766) were of patients younger than 65 years, who were taking aspirin. CONCLUSIONS: The rate of InPPIp is high, especially among patients not receiving DAPT and young patients taking aspirin. Time trend analysis showed no improvement over time. Our algorithm may serve as an automated quality measuring tool to reduce InPPIp.

Comorbidities and Risk Factors of Patients Diagnosed with CRC after Positive Fecal Test in Real Life.

(1) Background: Fecal occult blood test (FOBT) is the modality of choice in most countries for colorectal cancer (CRC) screening. We aimed to investigate the risk factors for CRC among patients with a positive FOBT in real life. (2) Methods: This was a retrospective study that included patients who tested positive for FOBT. Data regarding the comorbidities and laboratories were collected and compared between CRC and non-CRC groups. (3) Results: Positive FOBT was found among 45,500 (5.36%) subjects and CRC was found in 1502 (3.3%). CRC patients were older, age 62.7 ± 7.15 years compared with 59.33 ± 7.3 years (p < 0.001), and had significantly higher rates of hypertension (48.4% vs. 44.7%, p = 0.002), iron-deficiency anemia (20.6% vs. 16.4, p < 0.001), family history of CRC (7.3% vs. 5.1%, p < 0.001), and previous CRC (6.5% vs. 0.3%, p < 0.001). Lower levels of hemoglobin, iron, and ferritin were found in the CRC group. Age, family history of CRC, and previous CRC were found to be significant risk factors for diagnosis of CRC after positive FOBT with OR of 1.057, 1.4, and 15.9, respectively. (4) Conclusions: Iron-deficiency anemia, family history of CRC, previous colorectal cancer, and low hemoglobin, iron, and ferritin levels should direct physicians to give high priority to colonoscopy scheduling.

Characterization of blood-derived exosomal hTERT mRNA as a biomarker for colon cancer and Lynch syndrome.

Background: Human telomerase reverse transcriptase (hTERT)- mRNA was shown to be elevated in exosomes derived from the sera of a variety of hematological and solid cancer patients. We aimed to evaluate its role as a diagnostic marker in patients with newly diagnosed colon cancer and in hereditary syndromes with predisposition to colon cancer. Methods: hTERT -mRNA levels were determined in serum-derived exosomes from 88 patients with colon cancer, 71 Lynch-syndrome carriers with unknown active malignancies and 50 healthy controls. Data, including demographics, background diseases, clinical data regarding tumor characteristics and genetic data, were retrieved data from medical files. Results: Patients with colon cancer had both higher exosomal hTERT mRNA levels and a higher proportion of patients with positive exosomal hTERT mRNA than controls (29.5% vs. 4%, respectively, P values < 0.001). Within the cancer group, patients with a metastatic disease had higher levels of telomerase mRNA than non-metastatic disease patients, and these levels correlated with CEA levels. Likewise, Lynch syndrome carriers had a higher proportion of positive exosomal hTERT mRNA than controls (21.1% vs. 4%, respectively, P value 0.008) but only a trend towards higher exosomal hTERT mRNA levels. Higher telomerase mRNA levels were not correlated with the mutated gene. Conclusions: Exosomal serum hTERT -mRNA levels are associated with metastatic colon cancer and were also demonstrated in a subset of Lynch syndrome carriers. Its significance as a biomarker for developing malignancy should be elucidated.

Colorectal cancer incidences in Lynch syndrome: a comparison of results from the prospective lynch syndrome database and the international mismatch repair consortium.

OBJECTIVE: To compare colorectal cancer (CRC) incidences in carriers of pathogenic variants of the MMR genes in the PLSD and IMRC cohorts, of which only the former included mandatory colonoscopy surveillance for all participants. METHODS: CRC incidences were calculated in an intervention group comprising a cohort of confirmed carriers of pathogenic or likely pathogenic variants in mismatch repair genes (path_MMR) followed prospectively by the Prospective Lynch Syndrome Database (PLSD). All had colonoscopy surveillance, with polypectomy when polyps were identified. Comparison was made with a retrospective cohort reported by the International Mismatch Repair Consortium (IMRC). This comprised confirmed and inferred path_MMR carriers who were first- or second-degree relatives of Lynch syndrome probands. RESULTS: In the PLSD, 8,153 subjects had follow-up colonoscopy surveillance for a total of 67,604 years and 578 carriers had CRC diagnosed. Average cumulative incidences of CRC in path_MLH1 carriers at 70 years of age were 52% in males and 41% in females; for path_MSH2 50% and 39%; for path_MSH6 13% and 17% and for path_PMS2 11% and 8%. In contrast, in the IMRC cohort, corresponding cumulative incidences were 40% and 27%; 34% and 23%; 16% and 8% and 7% and 6%. Comparing just the European carriers in the two series gave similar findings. Numbers in the PLSD series did not allow comparisons of carriers from other continents separately. Cumulative incidences at 25 years were < 1% in all retrospective groups. CONCLUSIONS: Prospectively observed CRC incidences (PLSD) in path_MLH1 and path_MSH2 carriers undergoing colonoscopy surveillance and polypectomy were higher than in the retrospective (IMRC) series, and were not reduced in path_MSH6 carriers. These findings were the opposite to those expected. CRC point incidence before 50 years of age was reduced in path_PMS2 carriers subjected to colonoscopy, but not significantly so.

Adenomatous Polyposis Phenotype in BMPR1A and SMAD4 Variant Carriers.

INTRODUCTION: Variants in SMAD4 or BMPR1A cause juvenile polyposis syndrome, a rare autosomal dominant condition characterized by multiple gastrointestinal hamartomatous polyps. A phenotype of attenuated adenomatous polyposis without hamartomatous polyps is rare. METHODS: We describe a retrospective cohort of individuals with SMAD4 or BMPR1A heterozygous germline variants, having ≥10 cumulative colorectal adenomas and/or colorectal cancer without hamartomatous polyps. All individuals had multigene panel and duplication/deletion analysis to exclude other genetic syndromes. RESULTS: The study cohort included 8 individuals. The pathogenic potential of the variants was analyzed. Variants detected included 4 missense variants, 1 nonsense variant, 1 splice site variant, and 2 genomic deletions. Features of pathogenicity were present in most variants, and cosegregation of the variant with polyposis or colorectal cancer was obtained in 7 of the 8 families. Three of 8 individuals had colorectal cancer (age less than 50 years) in addition to the polyposis phenotype. Two individuals had extraintestinal neoplasms (pancreas and ampulla of Vater). DISCUSSION: The clinical phenotype of SMAD4 and BMPR1A variants may infrequently extend beyond the classical juvenile polyposis syndrome phenotype. Applying multigene panel analysis of hereditary cancer-related genes in individuals with unexplained polyposis can provide syndrome-based clinical surveillance for carriers and their family members.

Association of Celiac Serology Normalization With the Risk of Hypothyroidism: A Cohort Study.

INTRODUCTION: We evaluated whether persistent-positive celiac serology is associated with the risk of hypothyroidism. METHODS: We extracted a cohort of subjects aged 1-80 years with a positive IgA anti-tissue transglutaminase between January 1, 2008, and December 31, 2012, and a repeat anti-tissue transglutaminase test within 6-36 months from a large population-based electronic medical record database. Based on serology tests, we categorized the pediatric (age <21 years) and adult cohorts into normalized or persistent-positive serology groups. All subjects were followed up for incident diagnosis of hypothyroidism from the last serology date up to December 31, 2017. Hazard ratio (HR) along 95% confidence intervals (CIs) were prepared to evaluate the association of celiac serology group with a diagnosis of hypothyroidism, crude, and adjusted for age, sex, and diagnosis of type 1 diabetes mellitus. RESULTS: Among the pediatric cohort (n = 2,687), during a median follow-up of 64 months (interquartile range 48-80), 2.3% (16/681) of the persistent-positive serology group and 1.0% (20/2,006) of the normalized serology group developed hypothyroidism (HR 2.07 [95% CI 1.07-4.44], adjHR 1.77 [95% CI 0.91-3.46]). The rate among the pediatric cohort with an established diagnosis of celiac disease was 3.4% (10/486) vs 1.0% (5/481), HR 2.83 (0.96-8.32). In the adult cohort (n = 1,286), 4.5% (20/442) of the persistent-positive group and 3.9% (33/811) of the normalized serology group developed hypothyroidism (HR 1.13 [95% CI 0.65-1.97]). DISCUSSION: In this retrospective, age-stratified analysis, we report that persistent-positive serology may be associated with the risk of hypothyroidism among the pediatric population. Prospective cohorts are needed to validate our findings.

The risk of advanced neoplasia after polypectomy of one to two non-advanced adenomas less than 5 mm in size vs. normal colonoscopy.

BACKGROUND: Current guidelines are inconsistent regarding the follow-up of patients with 1-2 diminutive (1-5 mm) non-advanced adenomas (DNAAs). AIMS: To evaluate the risk of metachronous advanced neoplasia (AN), defined as cancer or advanced adenoma (AA), among patients with either normal colonoscopy or 1-2 DNAAs. METHODS: A retrospective cohort study. Cohort I included 2,347 subjects with normal colonoscopy and 483 subjects with polypectomy of 1-2 DNAAs followed by colonoscopy. Cohort II included 11,881 subjects with normal colonoscopy and 1,342 subjects with 1-2 DNAAs followed through the cancer registry. RESULTS: In cohort I, the rate of AN, cancer and AA among the polypectomy group vs. normal colonoscopy was 5.0% vs. 2.5%, Hazard Ratio (HR) 2.96 (95%CI [Confidence Interval]1.86-4.78) for AN; 0.6% vs. 0.3%, HR 3.32 (95%CI 0.85-13) for cancer; 4.3% vs. 2.2% HR 2.91 (95%CI 1.75-4.86) for AA. In cohort II, cancer occurred in 0.4% of the polypectomy group and 0.2% of the normal colonoscopy group, HR 2.27 (95% CI 0.56-9.19). CONCLUSION: Compared to subjects with normal colonoscopy, subjects with polypectomy of 1-2 DNAAs, are at increased risk for AA when followed by colonoscopy, while the risk for cancer is non-significantly increased. Our findings suggest that patients with 1-2 DNNAs should be followed more tightly than patients with normal colonoscopy.

Phenotypic diversity among juvenile polyposis syndrome patients from different ethnic background.

Juvenile polyposis syndrome (JPS), has diverse phenotypes. AIM: To assess mutation rate, clinical features and genotype-phenotype correlation among Israeli JPS kindreds from different ethnicities. METHODS: Patients' data were extracted retrospectively from 5 centers. RESULTS: Thirty five kindreds (49 patients) were included. Thirty one (89%) Jewish [10 (32%) Ashkenazi; 9 (29%) Sephardi; 11 (35%) non-Russia former Soviet-Union countries (NRFSU), one (3%) unknown]. 40/49 individuals from 27 families underwent genetic testing. Among them 34, from 21 families (85, 78%, respectively) had a pathogenic mutation: BMPR1A n = 15 (71%), SMAD4 n = 6 families (29%). While no SMAD4 mutation was described among Jewish families from NRFSU, 7 NRFSU families carried a founder mutation comprising a large genomic deletion of BMPR1A. GI involvement was reported in 42 patients (86%): colonic polyps (n = 40, 95%, > 50 polyps n = 14, 35%) and 12 underwent colonic resection. Fourteen patients (34%) had gastric or small bowel involvement (n = 5) and 4\14 underwent gastrectomy due to polyp burden. Families from NRFSU had more gastric involvement (66.7% vs. 22.2%- Sephardic and 20%- Ashkenazi Jews; p = 0.038), with more gastric polyps (p = 0.017). CONCLUSIONS: We demonstrated a high rate of mutation detection in the heterogeneous population of Israel. Patients from NRFSU with BMPR1A mutation had high rate of gastric involvement.

Risk of Cancer in Paediatric onset Inflammatory Bowel Diseases: A Nation-wide Study From the epi-IIRN.

BACKGROUND: Paediatric onset IBD [PIBD] is characterised by a more extensive phenotype than adult-onset IBD and a higher utilisation of immunosuppressive medications; both may be associated with malignancy. We aimed to assess the risk of cancer in a nationwide cohort of PIBD and to explore the risks associated with medical treatments. METHODS: PIBD patients [<18 years old] were included from the epi-IIRN cohort, covering 98% of the Israeli population from 2005, linked to the national cancer registry. We matched PIBD children to non-IBD children for calculating the cumulative incidence of cancer. RESULTS: In all, 3944 PIBD cases were included (2642 [67%] Crohn's disease, 1302 [33%] ulcerative colitis) translating into 23 635 person-years of follow-up, individually matched to 13 005 non-IBD children. By 30 years of age, 14 IBD patients [0.35%, 5.9/10 000 patient-years] were diagnosed with cancer and one [0.03%] with haemophagocytic-lymphohistiocytosis [HLH], compared with 14 [0.11%, 1.9/10 000 patient-years] cases of cancer {relative risk (RR) 2.5 (95% confidence interval [CI] 1.05-6.2); p = 0.04} and no HLH in the comparison-group. There were no cases of hepatosplenic T cell lymphoma, adenocarcinoma, or cholangiocarcinoma. Cancer risk was 15.6 cases/10 000 person-years in those treated with thiopurines alone (RR compared with IBD patients never exposed to either thiopurines or anti-tumuor necrosis factor [TNF] 1.8 [95% CI 0.6-6.1]; p = 0.2), 11.1/10 000 in those treated with anti-TNF alone (RR 1.3 [95% CI 0.3-6.6]; p = 0.5), and 23.1/10 000 treated with combination therapy of anti-TNF and thiopurines (RR 2.8 [95% CI 0.6-13.8]; p = 0.2). CONCLUSIONS: PIBD confers an increased risk for malignancy compared with non-IBD in children. However, the absolute risk is very low and no differences in risk with specific therapies were apparent in our data.