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.

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.

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.

Volume of fluid consumption during preparation for colonoscopy is possibly the single most important determinant of bowel preparation adequacy.

BACKGROUND: The effectiveness and safety of colonoscopy are directly dependent on the quality of bowel preparation. Multiple risk factors for inadequate bowel preparation (IBP) have been identified; however, IBP is still reported in 20-30% of cases in most studies. We aimed to identify modifiable predictors of the adequacy of bowel preparation using sodium picosulfate, and to recommend easily modifiable parameters to increase the success rate of colonoscopies. METHODS: This was a single-center observational study of adult outpatients referred for an elective colonoscopy. Patients were interviewed prior to colonoscopy; volume of liquids consumed was calculated as number of 200-mL cups showed to the patient. Additional information, including medical history, diagnoses and regular medications, was procured from patients' medical records. Univariate and multivariate regression analyses were performed to identify factors significantly associated with IBP in a subgroup analysis of high-risk patients. RESULTS: The rate of IBP in 1172 subjects was 19.4%. This rate decreased as fluid consumption increased, with a further drop associated with shorter intervals from end of preparation to colonoscopy. Drinking < 1.4 L significantly increased the risk of IBP (odds ratio [OR] 3.62, 95% confidence interval [CI] 2.65-4.95), while drinking ≥2 L was associated with adequate preparation (OR 0.09, 95%CI 0-0.42). These associations were stronger in high-risk individuals. CONCLUSION: Greater fluid intake and short interval to colonoscopy are easily modifiable parameters that can substantially reduce the rate of IBP, especially among high-risk individuals.

Post-polypectomy surveillance colonoscopy: Comparison of the updated guidelines.

BACKGROUND: Recently, three updated guidelines for post-polypectomy colonoscopy surveillance (PPCS) have been published. These guidelines are based on a comprehensive summary of the literature, while some recommendations are similar, different surveillance intervals are recommended after detection of specific types of polyps. AIM: In this review, we aimed to compare and contrast these recommendations. METHODS: The updated guidelines for PPCS were reviewed and the recommendations were compared. RESULTS: For patients with 1-4 adenomas <10 mm with low-grade dysplasia, irrespective of villous components, or 1-4 serrated polyps <10 mm without dysplasia, the European Society of Gastrointestinal Endoscopy (ESGE) and British Society of Gastroenterology (BSG), the Association of Coloproctology of Great Britain and Ireland (ACPGBI) and Public Health England (PHE) (BSG/ACPGBI/PHE) guidelines do not recommend colonoscopic surveillance and instead recommend that the participate in routine CRC screening program (typically based on the fecal immunochemical test), while the USMSTF recommends surveillance colonoscopies 7-10 years after diagnosis of 1-2 tubular adenomas <10 mm and 3-5 years for 3-4 tubular adenomas of the same size. The USMSTF define adenomas with tubulovillous or villous histology as high-risk adenomas; thus, surveillance colonoscopy is recommended after 3 years. However, the ESGE and BSG do not consider such histology as a criterion for repeating colonoscopy at this short interval. For patients with 1-2 sessile serrated polyps (SSPs) <10 mm and those with 3-4 SSPs <10 mm, the USMSTF recommends surveillance colonosocopy after 5-10 and 3-5 years, respectively.

Intratumoral HLA-DR-/CD33+/CD11b+ Myeloid-Derived Suppressor Cells Predict Response to Neoadjuvant Chemoradiotherapy in Locally Advanced Rectal Cancer.

Capecitabine-based neoadjuvant chemoradiation therapy (nCRT) is currently the mainstay of treatment for locally advanced rectal cancer (LARC), prior to surgical tumor removal. While response to this treatment is partial, it carries significant risk of side effects. As of today, there is no accepted model to predict tumor response, and allow for patient stratification. The level of circulating Myeloid-derived suppressor cells (MDSCs), a subpopulation of early myeloid cells (EMCs), has been shown to correlate with prognosis and response to therapy in advanced colon cancer, but their role in LARC is not clear. We sought to study the effect of intratumoral and circulating levels of different EMCs subpopulations including MDSCs on response to nCRT. We analyzed tumor, normal mucosa, and peripheral blood samples from 25 LARC patients for their different EMCs subpopulation before and after nCRT, and correlated them with degree of pathologic response, as determined postoperatively. In addition, we compared LARC patient to 10 healthy donors and 6 metastatic patients. CD33+HLA-DR-CD16-CD11b+EMCs in the circulation of LARC patients were found to inhibit T-cell activation. Furthermore, elevated levels of CD33+HLA-DR- myeloid cells were found in the tumor relative to normal mucosa, but not in the circulation when compared to healthy subjects. Moreover, intratumoral, but not circulating levels of MDSCs correlated with clinical stage and response to therapy in patients treated with nCRT, with high levels of MDSCs significantly predicting poor response to nCRT. Importantly, therapy by itself, had significant differential effects on MDSC levels, leading to increased circulating MDSCs, concomitantly with decreasing intratumoral MDSCs. Our results suggest that high levels of intratumoral, but not circulating MDSCs may confer drug resistance due to immunomodulatory effects, and serve as a biomarker for patient stratification and decision-making prior to nCRT.

Homozygosity for CHEK2 p.Gly167Arg leads to a unique cancer syndrome with multiple complex chromosomal translocations in peripheral blood karyotype.

BACKGROUND: Chromosomal instability, as reflected by structural or copy-number changes, is a known cancer characteristic but are rarely observed in healthy tissue. Mutations in DNA repair genes disrupt the maintenance of DNA integrity and predispose to hereditary cancer syndromes. OBJECTIVE: To clinically characterise and genetically diagnose two reportedly unrelated patients with unique cancer syndromes, including multiorgan tumourogenesis (patient 1) and early-onset acute myeloid leukaemia (patient 2), both displaying unique peripheral blood karyotypes. METHODS: Genetic analysis in patient 1 included TruSight One panel and whole-exome sequencing, while patient 2 was diagnosed by FoundationOne Heme genomic analysis; Sanger sequencing was used for mutation confirmation in both patients. Karyotype analysis was performed on peripheral blood, bone marrow and other available tissues. RESULTS: Both patients were found homozygous for CHEK2 c.499G>A; p.Gly167Arg and exhibited multiple different chromosomal translocations in 30%-60% peripheral blood lymphocytes. This karyotype phenotype was not observed in other tested tissues or in an ovarian cancer patient with a different homozygous missense mutation in CHEK2 (c.1283C>T; p.Ser428Phe). CONCLUSIONS: The multiple chromosomal translocations in patient lymphocytes highlight the role of CHK2 in DNA repair. We suggest that homozygosity for p.Gly167Arg increases patients' susceptibility to non-accurate correction of DNA breaks and possibly explains their increased susceptibility to either multiple primary tumours during their lifetime or early-onset tumourigenesis.

Update on Screening for Urological Malignancies.

Urological malignancies are a major source of morbidity and mortality in men over 40. Screening for those malignancies has a potential benefit of reducing both. However, even after more than two decades of screening for prostate cancer, the implications of most resulting information are still a matter of debate. Controversy extends over several aspects of prostate cancer screening programs, including age of onset, defining populations at risk, most appropriate intervals, as well as the optimal methods to be used for screening. The medical community is still divided regarding the effectiveness of prostate cancer-related death prevention and its benefits-to-harms ratio, reflecting an inconsistency regarding screening recommendations. Similarly, benefits of screening for urothelial and kidney tumors are yet lacking high-level evidence, although recent evidence supports screening of populations at risk. Clearly, the current era of evolving molecular and genetic biomarkers harbors the potential to change screening practice. In this paper, we review current guidelines as well as giving an update on new developments which might influence screening strategies in common urological malignancies.

Development and validation of a predictive model for detection of colorectal cancer in primary care by analysis of complete blood counts: a binational retrospective study.

OBJECTIVE: The use of risk prediction models grows as electronic medical records become widely available. Here, we develop and validate a model to identify individuals at increased risk for colorectal cancer (CRC) by analyzing blood counts, age, and sex, then determine the model's value when used to supplement conventional screening. MATERIALS AND METHODS: Primary care data were collected from a cohort of 606 403 Israelis (of whom 3135 were diagnosed with CRC) and a case control UK dataset of 5061 CRC cases and 25 613 controls. The model was developed on 80% of the Israeli dataset and validated using the remaining Israeli and UK datasets. Performance was evaluated according to the area under the curve, specificity, and odds ratio at several working points. RESULTS: Using blood counts obtained 3-6 months before diagnosis, the area under the curve for detecting CRC was 0.82 ± 0.01 for the Israeli validation set. The specificity was 88 ± 2% in the Israeli validation set and 94 ± 1% in the UK dataset. Detecting 50% of CRC cases, the odds ratio was 26 ± 5 and 40 ± 6, respectively, for a false-positive rate of 0.5%. Specificity for 50% detection was 87 ± 2% a year before diagnosis and 85 ± 2% for localized cancers. When used in addition to the fecal occult blood test, our model enabled more than a 2-fold increase in CRC detection. DISCUSSION: Comparable results in 2 unrelated populations suggest that the model should generally apply to the detection of CRC in other groups. The model's performance is superior to current iron deficiency anemia management guidelines, and may help physicians to identify individuals requiring additional clinical evaluation. CONCLUSIONS: Our model may help to detect CRC earlier in clinical practice.

Constitutional Mismatch Repair Deficiency in Israel: High Proportion of Founder Mutations in MMR Genes and Consanguinity.

BACKGROUND: Heterozygous germline mutations in any of the mismatch repair (MMR) genes, MLH1, MSH2, MSH6, and PMS2, cause Lynch syndrome (LS), an autosomal dominant cancer predisposition syndrome conferring a high risk of colorectal, endometrial, and other cancers in adulthood. Offspring of couples where both spouses have LS have a 1:4 risk of inheriting biallelic MMR gene mutations. These cause constitutional MMR deficiency (CMMRD) syndrome, a severe recessively inherited cancer syndrome with a broad tumor spectrum including mainly hematological malignancies, brain tumors, and colon cancer in childhood and adolescence. Many CMMRD children also present with café au lait spots and axillary freckling mimicking neurofibromatosis type 1. PROCEDURE: We describe our experience in seven CMMRD families demonstrating the role and importance of founder mutations and consanguinity on its prevalence. Clinical presentations included brain tumors, colon cancer, lymphoma, and small bowel cancer. RESULTS: In children from two nonconsanguineous Ashkenazi Jewish (AJ) families, the common Ashkenazi founder mutations were detected; these were homozygous in one family and compound heterozygous in the other. In four consanguineous families of various ancestries, different homozygous mutations were identified. In a nonconsanguineous Caucasus/AJ family, lack of PMS2 was demonstrated in tumor and normal tissues; however, mutations were not identified. CONCLUSIONS: CMMRD is rare, but, especially in areas where founder mutations for LS and consanguinity are common, pediatricians should be aware of it since they are the first to encounter these children. Early diagnosis will enable tailored cancer surveillance in the entire family and a discussion regarding prenatal genetic diagnosis.

Gastric microbiota is altered in oesophagitis and Barrett's oesophagus and further modified by proton pump inhibitors.

Gastro-oesophageal reflux can cause inflammation, metaplasia, dysplasia and cancer of the oesophagus. Despite the increased use of proton pump inhibitors (PPIs) to treat reflux, the incidence of oesophageal adenocarcinoma has increased rapidly in Europe and in the United States in the last 25 years. The reasons for this increase remain unclear. In this study, we aimed to determine whether the microbiota of the gastric refluxate and oesophageal biopsies differs between patients with heartburn and normal-appearing oesophageal mucosa versus patients with abnormal oesophageal mucosa [oesophagitis or Barrett's oesophagus (BE)] and to elucidate the effect of PPIs on the bacterial communities using 16S rRNA gene pyrosequencing. Significant differences in the composition of gastric fluid bacteria were found between patients with heartburn and normal oesophageal tissue versus patients with oesophagitis or BE, but in the oesophagus-associated microbiota differences were relatively modest. Notably, increased levels of Enterobacteriaceae were observed in the gastric fluid of oesophagitis and BE patients. In addition, treatment with PPIs had dramatic effects on microbial communities both in the gastric fluids and the oesophageal tissue. In conclusion, gastric fluid microbiota is modified in patients with oesophagitis and BE compared with heartburn patients with normal biopsies. Furthermore, PPI treatment markedly alters gastric and oesophageal microbial populations. Determining whether the changes in bacterial composition caused by PPIs are beneficial or harmful will require further investigation.

False negative fecal occult blood test may be associated with increased mortality from colorectal cancer.

BACKGROUND: Fecal Occult Blood Test (FOBT) is an accepted screening test for colorectal cancer (CRC). It has been shown to decrease mortality by up to 30%. The outcome of screening failures has not been adequately studied. AIMS: The purpose of this study was to assess the outcome of patients who were diagnosed with CRC after a false negative FOBT. METHODS: We identified all consecutive CRCs from pathology reports between 2005 and 2010. Patients were divided according to their FOBT result. Those who became positive were compared to patients who remained negative. RESULTS: Altogether 401 CRCs were identified. Of those, 202 never performed a FOBT. At least one negative FOBT was performed by 133 individuals (67%). Of these, 76 remained negative (false negatives, FN) and 57 became positive (positive conversion, PC, controls). The prevalence of metastatic disease was threefold higher among the FNs as compared to the PC group (16 [22.2%] vs. 4 [7.5%], P=0.022). All-cause mortality was also significantly higher among FNs versus PCs (24 [31.6%] vs. 5 [8.8%], P=0.001); in Cox regression analysis of survival (covariates: FNs vs. PC, gender, age, medications and co-morbidities) FNs had increased mortality compared to the PC (HR 2.929, P=0.033, CI 95% 1.092-7.858). No statistically significant difference was found regarding all primary end points when comparing the FN and the "No test" group. CONCLUSION: These data disclose a particular risk of FOBT as a screening test. A subgroup of patients with "false" negative tests may have increased morbidity and mortality. Efforts should be made to recognize and characterize this high-risk group.

Effects of age and cholecystectomy on common bile duct diameter as measured by endoscopic ultrasonography.

BACKGROUND AND AIM: Increased common bile duct (CBD) diameter has been attributed to aging and previous cholecystectomy. These relationships are, however, controversial and based mainly on old studies and methodologies. Our objective is to evaluate the relationship between age, cholecystectomy, and other clinical factors and CBD diameter, as measured by endoscopic ultrasound (EUS). METHODS: We carried out a retrospective cohort study including patients who underwent EUS in our institution. Patients with an obstructing lesion of the bile ducts, previous sphincter manipulation, or insufficient data were excluded. CBD diameter was measured as a routine part of the examination, in the most distal extrapancreatic portion, between its two exterior margins. The patients were divided into five age groups. The mean CBD diameter in each group was calculated and compared with the other groups. Effects of cholecystectomy, gender, time from operation, and elevated liver enzymes were also evaluated. RESULTS: Six hundred forty-seven patients were included in the study (66% women). Twenty-three percent were postcholecystectomy. There was no difference between the first three groups regarding CBD diameter, but it was significantly wider in groups 4 and 5 (p < 0.001). In all age groups, the postcholecystectomy patients had significantly wider CBD than those with an intact gallbladder (in all groups, p < 0.01). CONCLUSIONS: This EUS study confirms that the CBD dilates significantly after the age of 70 years, but even in the most elderly patients, with an intact gallbladder, the normal CBD does not exceed 7.6 mm, thus a wider CBD warrants further investigation. The single additional factor contributing to dilatation of the CBD was cholecystectomy. A linear regression equation is proposed for the prediction of CBD diameter.

Chemoprevention of colorectal cancer: two steps forward, one step back?

Colorectal cancer (CRC) is a leading cause of cancer-related morbidity and mortality in the Western world. The poor survival rate has prompted the emphasis on prevention of this disease. Removal of adenomas at colonoscopy is highly effective and is the cornerstone of screening/surveillance strategies. However, screening efforts have had limited impact owing to low compliance with guidelines. Chemoprevention aims to prevent the development or recurrence of precancerous lesions and cancers with the use of compounds that block the carcinogenic process. A major advantage was the establishment and understanding of the multistage process of CRC carcinogenesis. Progress has been remarkable because of the availability of reliable animal models and clinical studies using colonic adenomas as a reliable and economic target for testing chemopreventive agents. Nonsteroidal anti-inflammatory drugs have drawn the most attention. Sulindac and celecoxib were shown to be effective in promoting polyp regression in high-risk individuals with familial adenomatous polyposis. In the more common sporadic setting, the Adenomatous Polyp PRevention On Vioxx (rofecoxib), Adenoma Prevention with Celecoxib and Prevention of Sporadic Adenomatous Polyps (celecoxib) trials have demonstrated a significant reduction in adenoma recurrence, but important concerns were raised regarding cardiovascular toxicity associated with selective cyclo-oxygenase-2 inhibitors. These landmark studies are very important, as they are a proof-of-concept that we can prevent CRC. More clinical studies are required to better select high-risk patients with safer regimens. Potential advantage versus risk for a given chemopreventive agent will have to be assessed on an individual basis. Currently, the only approved agent for chemoprevention is celecoxib in high-risk individuals with familial adenomatous polyposis.

Weight loss and improvement of obesity-related illness in 500 U.S. patients following laparoscopic adjustable gastric banding procedure.

BACKGROUND: Obesity and its related illness is a primary health concern today. METHODS: Five hundred morbidly obese patients (mean age 42 years; mean preoperative weight 123 kg) underwent laparoscopic adjustable gastric banding surgery in a private U.S. hospital setting within a comprehensive multidisciplinary bariatric program. Patients were followed up to 36 months. Comorbidity status was assessed for 163 patients who completed > or =18 months' follow-up by comparing medications (type and dosage) prescribed for each comorbid condition before surgery and at follow-up. RESULTS: At 36 months after surgery, mean body mass index (BMI) had decreased from 45.2 to 34.9 kg/m(2) and mean percent excess weight loss (%EWL) was 47%. Complications were as follows: gastric pouch dilatation (6.8%), slippage (2.8%), and stoma obstruction (0.6%). There was no mortality. Resolution or improvement of comorbidities were as follows: gastroesophageal reflux disease (GERD) (87%; usually immediately postsurgery), asthma (81.8%), diabetes (66%), dyslipidemia (65.5%), hypertension (48%), and sleep apnea (33%). CONCLUSIONS: Gastric banding provides good weight loss and significant reduction in comorbidities with few and minor complications.

Frequent CpG island methylation in sporadic and syndromic gastric fundic gland polyps.

We studied methylation of 2 tumor suppressor genes (p14, p16) and 4 MINT (methylated in tumor) clones (MINT1, MINT2, MINT25, MINT31) among 51 fundic gland polyps (FGPs) and 27 normal gastric body biopsy samples using bisulfite treatment of genomic DNA followed by methylation-specific polymerase chain reaction. Thirty-two FGPs were syndromic polyps from 14 patients with familial adenomatous polyposis (FAP); 19 were sporadic FGPs from 15 patients without FAP. Significantly higher mean methylation indices were found between FGPs and normal gastric mucosa (P = .012). FGPs arising in a background of proton pump inhibitor (PPI) effect had significantly higher mean methylation indices than those that did not (P = .023). Perhaps because sporadic FGPs were more likely to be associated with PPI effect than were FAP-associated FGPs, they also demonstrated higher mean methylation indices than syndromic polyps (P = .024). Among FAP-associated FGPs, there was no statistical difference in methylation indices between polyps that were dysplastic, indefinite for dysplasia, or nondysplastic (P = .87). Epigenetic alterations involving methylation of CpG islands might have a role in the development of some FGPs, particularly those with a PPI effect. They do not account for the presence or absence of a dysplastic phenotype in FGPs.