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.

Variable Features of Juvenile Polyposis Syndrome With Gastric Involvement Among Patients With a Large Genomic Deletion of BMPR1A.

OBJECTIVES: Loss-of-function mutations of BMPR1A cause juvenile polyposis syndrome (JPS), but large genomic deletions in BMPR1A are rare, reported in few families only, and data regarding the associated phenotype are limited. METHODS: We investigated clinical features and genomic data of 7 extended seemingly unrelated families with a genomic deletion of the entire coding region of BMPR1A. We defined mutation size, mutation prevalence, and tumor pathogenesis using whole-genome sequencing, targeted genotyping, and haplotype analysis. RESULTS: Patients with JPS from 7 families of Bukharin Jewish ancestry carried a deletion of 429 kb, encompassing the BMPR1A coding sequence and 8 downstream genes. Haplotype analysis and testing controls identified this as a common founder mutation occurring in 1/124 individuals of Bukharin origin. Tumor testing did not demonstrate loss of heterozygosity. Among carriers, JPS was almost fully penetrant, but clinical features varied widely, ranging from mild to very severe, including pan-enteric polyps, gastritis, and colorectal, esophageal, and testicular cancer, and carriers with phenotypes, which would not have raised suspicion of JPS. DISCUSSION: The phenotype in this large cohort was extremely variable, although all carriers shared the same variant and the same genetic background. New observations include a preponderance of adenomatous rather than juvenile polyps, possible association with testicular cancer, and unexpected upper gastrointestinal involvement.

Feasibility of Unbiased RNA Profiling of Colorectal Tumors: A Proof of Principle.

Despite recent advances in molecular profiling of colorectal cancer (CRC), as of yet this has not translated into an unbiased molecular liquid biopsy profile which can accurately screen for early CRC. In this study we depict the profile of early stage CRC as well as for advanced adenomas (AA) by combination of current molecular knowledge with microarray technology, using efficient circulating free plasma RNA purification from blood and RNA amplification technologies. We joined literature search with Affymetrix gene chip experimental procedure to draw the circulating free plasma RNA profile of colorectal cancer disease reflected in blood. The RNA panel was tested by two datasets comparing patients with CRC with healthy subjects and patients with AA to healthy subjects. For the CRC patient cohort (28 CRC cases vs. 41 healthy controls), the ROC analysis of the selected biomarker panel generated a sensitivity of 75% and a specificity of 93% for the detection of CRC using 8-gene classification model. For the AA patient cohort (28 subjects vs. 46 healthy controls), a sensitivity of 60% and a specificity of 87% were calculated using a 2-gene classification model. We have identified a panel of 8 plasma RNA markers as a preliminary panel for CRC detection and subset markers suitable for AA detection. Subjected to extensive clinical validation we suggest that this panel represents a feasible approach and a potential strategy for noninvasive early diagnosis, as a first-line screening test for asymptomatic, average-risk population before colonoscopy.

Role of autoimmune gastritis, Helicobacter pylori and celiac disease in refractory or unexplained iron deficiency anemia.

BACKGROUND AND OBJECTIVES: Conventional endoscopic and radiographic methods fail to identify a probable source of gastrointestinal blood loss in about one third of males and post-menopausal females and in most women of reproductive age with iron deficiency anemia (IDA). Such patients, as well as subjects refractory to oral iron treatment, are often referred for hematologic evaluation. DESIGN AND METHODS: Patient clinic, screened for non-bleeding gastrointestinal conditions including celiac disease (antiendomysial antibodies), autoimmune atrophic gastritis (hypergastrinemia with strongly positive antiparietal cell antibodies) and H. pylori infection (IgG antibodies confirmed by urease breath test). RESULTS: The mean age of all subjects was 39+/-18 years, and 119 of 150 were females. We identified 8 new cases of adult celiac disease (5%). Forty IDA patients (27%) had autoimmune atrophic gastritis of whom 22 had low serum vitamin B12 levels. H. pylori infection was the only finding in 29 patients (19%), but was a common co-existing finding in 77 (51%) of the entire group. Refractoriness to oral iron treatment was found in 100% of patients with celiac disease, 71% with autoimmune atrophic gastritis, 68% with H. pylori infection, but only 11% of subjects with no detected underlying abnormality. H. pylori eradication in previously refractory IDA patients in combination with continued oral iron therapy resulted in a significant increase in hemoglobin from 9.4+/-1.5 (mean +/- 1SD) before, to 13.5+/-1.2 g/ dL (p<0.001 by paired t test) within 3 to 6 months. INTERPRETATION AND CONCLUSIONS: The recognition that autoimmune atrophic gastritis and H. pylori infection may have a significant role in the development of unexplained or refractory IDA in a high proportion of patients should have a strong impact on our daily practice of diagnosing and managing IDA.

Helicobacter pylori DNA in dental plaques, gastroscopy, and dental devices.

The role of dental plaque in the transmission of Helicobacter pylori (Hp) is unclear due to variability in the detection rates and techniques used. We used nested PCR to estimate the incidence of Hp in dental plaques of 24 dental hygienists. We found an unexpectedly high incidence (50%) of Hp DNA in dental plaques using sterilized dental probes. Additional treatment of sonication and SDS wash prior to sterilization of dental probes reduced the incidence to 13%. We used the treated probes to assess Hp presence in plaque samples of 47 patients visiting the dental clinic for teeth cleaning. Hp DNA was detected in 24% of cases. Since these data may reflect instrument contamination, we tested dental probes, endoscopes, and endoscopy forceps and found that 12.5-37.5% of them were contaminated. Consequently, dental plaques may be a candidate reservoir for Hp, medical equipment may contribute to Hp transmission, and sample collection techniques can bias the true prevalence of Hp in a population.