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.

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.

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.

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.

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.

Association Between Polyp Detection Rate and Post-Colonoscopy Cancer Among Patients Undergoing Diagnostic Colonoscopy.

Postcolonoscopy colorectal cancer (PCCRC) can arise from missed cancers, missed premalignant lesions, incomplete resection, and new cancers with an accelerated route to cancer.1.

Double heterozygotes of BRCA1/BRCA2 and mismatch repair gene pathogenic variants: case series and clinical implications.

BACKGROUND: Hereditary breast and ovarian cancer syndrome (HBOC) and Lynch syndrome (LS), the most common inherited cancer syndromes, are attributed to a single heterozygous pathogenic variant (PV) in BRCA1/2 or in a DNA MMR gene, respectively. Little is known about the phenotype in double heterozygotes who carry PVs in both genes. METHODS: Carriers of double-PVs in any DNA MMR gene and BRCA1/2 attending one of three tertiary oncogenetic clinics between 1/2005 and 1/2020 were identified by database search, and their relevant data were retrieved and analyzed. RESULTS: Eleven double carriers from four seemingly unrelated Ashkenazi Jewish families were evaluated. All carried an Ashkenazi Jewish founder BRCA PV, BRCA2 c.5946delT/c.6174delT (n = 10) or BRCA1 c.185delAG (n = 1). Four carried the MSH2 c.1906G > C founder PV, and 3, the MSH6 c.3984_3987dupGTCA founder PV; 3 patients had the MSH6 c.3956_3957dup PV. Eight double carriers (73%) had cancer: breast cancer (5 cases, 2 bilateral), melanoma (2 cases), urothelial cancer (2 cases), and colon, endometrial, prostate, cutaneous squamous cell cancer, glioblastoma, gastric stromal tumor, and lymphoma (1 case each). Six carriers had 1-2 tumors, one had 3 tumors, and one had 5 primary tumors. Age at diagnosis of the first tumor was 36-76 years. All carriers met NCCN BRCA1/2 testing criteria, and 3 met the revised Bethesda guidelines. CONCLUSIONS: This case series, supported by the literature, suggests that the phenotype of double MSH2/6 and BRCA1/2 carriers is not associated with early disease onset or a more severe phenotype. The findings have implications for improved genetic testing guidelines and treatment strategies.

Rifabutin triple therapy for first-line and rescue treatment of Helicobacter pylori infection: A systematic review and meta-analysis.

BACKGROUND AND AIM: Due to the increasing resistance of Helicobacter pylori, there is a need for novel antibiotic treatment protocols. We aimed to perform a systematic review and meta-analysis in order to determine the effectiveness and safety of rifabutin triple therapy for H. pylori infection. METHODS: We performed a systematic review of prospective clinical trials with a treatment arm consisting of proton pump inhibitor, amoxicillin, and rifabutin and a meta-analysis of randomized controlled trials (RCTs). RESULTS: Thirty-three prospective studies including 44 datasets were identified. Meta-analysis of four RCTs for rescue treatment found no difference between treatment groups (odds ratio [OR] 0.88, 95% confidence interval [CI] 0.437-1.791, I2  = 68.1%, P = 0.733). Only one RCT compared rifabutin therapy with control for first-line treatment of H. pylori infection (OR 3.78, 95% CI 2.44-5.87, P < 0.0001). Treatment was more likely to be successful in Asian versus non-Asian populations (81.0% vs 72.4%, P = 0.001) and when daily amoxicillin dose was ≥ 3000 mg or proton pump inhibitor dose was ≥ 80 mg or treatment duration was 14 days (80.6% vs 66.0%, P = 0.0001). The overall event rate for adverse effects was 24.8% (729/2937) (95% CI 0.23-0.26), and the pooled OR for adverse effects in the treatment versus control group was 0.93 (95% CI 0.50-1.75) (I2  = 79.76, P = 0.82). CONCLUSION: Evidence for the effectiveness of rifabutin for the first-line treatment of H. pylori infection in adults is limited, and studies comparing rifabutin with conventional first-line treatments are lacking.

Susceptibility-guided versus empirical treatment for Helicobacter pylori infection: A systematic review and meta-analysis.

BACKGROUND AND AIM: Empirical therapy for Helicobacter pylori infection is limited by increasing antibiotic resistance and suboptimal eradication rates. Studies of the relative effectiveness of susceptibility-guided therapy have produced conflicting results. We performed a systematic review and meta-analysis of randomized controlled trials (RCTs) to determine whether susceptibility-guided therapy is superior to empirical therapy for H. pylori infection. METHODS: We searched articles listed in PubMed, MEDLINE, EMBASE, and Web of Science through May 25, 2020, RCTs comparing susceptibility-guided versus empirical therapy for H. pylori infection. Outcomes, including effectiveness and safety, were analyzed in a meta-analysis. RESULTS: Our final analysis included 16 studies, comprising 2374 patients who received susceptibility-guided therapy and 2451 patients who received empirical treatment. In previously untreated subjects, susceptibility-guided therapy was slightly more effective than empirical therapy (intent to treat risk ratio [RR], 1.14; 95% confidence interval [CI], 1.07-1.21; P < 0.0001, I2  = 75%). Susceptibility-guided therapy was superior to first-line clarithromycin-based triple therapy only when clarithromycin resistance exceeded 20% (RR, 1.18; 95% CI, 1.07-1.30; P = 0.001, I2  = 81%). Susceptibility-guided therapy was not more effective than empirical quadruple therapy (RR, 1.02; 95% CI, 0.92-1.13; P = 0.759, I2  = 80%). Three RCTs were performed exclusively among previously treated subjects, and were highly heterogeneous. CONCLUSIONS: Our findings suggest that susceptibility-guided treatment may be slightly superior to empirical first line triple therapy. Susceptibility- guided treatment does not appear to be superior to empirical first-line quadruple therapy or empirical rescue therapy.

The Transition from Gastric Intestinal Metaplasia to Gastric Cancer Involves POPDC1 and POPDC3 Downregulation.

Intestinal metaplasia (IM) is an intermediate step in the progression from premalignant to malignant stages of gastric cancer (GC). The Popeye domain containing (POPDC) gene family encodes three transmembrane proteins, POPDC1, POPDC2, and POPDC3, initially described in muscles and later in epithelial and other cells, where they function in cell-cell interaction, and cell migration. POPDC1 and POPDC3 downregulation was described in several tumors, including colon and gastric cancers. We questioned whether IM-to-GC transition involves POPDC gene dysregulation. Gastric endoscopic biopsies of normal, IM, and GC patients were examined for expression levels of POPDC1-3 and several suggested IM biomarkers, using immunohistochemistry and qPCR. Immunostaining indicated lower POPDC1 and POPDC3 labeling in IM compared with normal tissues. Significantly lower POPDC1 and POPDC3 mRNA levels were measured in IM and GC biopsies and in GC-derived cell lines. The reduction in focal IM was smaller than in extensive IM that resembled GC tissues. POPDC1 and POPDC3 transcript levels were highly correlated with each other and inversely correlated with LGR5, OLFM4, CDX2, and several mucin transcripts. The association of POPDC1 and POPDC3 downregulation with IM-to-GC transition implicates a role in tumor suppression and highlights them as potential biomarkers for GC progression and prospective treatment targets.

Association between time to colonoscopy after a positive guaiac fecal test result and risk of colorectal cancer and advanced stage disease at diagnosis.

We evaluated time to colonoscopy after a positive guaiac-based fecal occult blood test (gFOBT) result and its association with the risk of overall colorectal cancer (CRC) and advanced-stage disease at diagnosis. We conducted a retrospective cohort study (2011-2013) within the Clalit Health Services, Israel. Participants were patients between 50 and 74 years old with a positive gFOBT result who had follow-up colonoscopies within 24 months. The exposure was time to colonoscopy, and the main outcome measure was a risk for overall and advanced CRC (defined as Stages III-IV). Odds ratios (ORs) and 95% confidence intervals (CIs) were adjusted for patient demographics and baseline risk factors. Of the 17,958 patients with positive gFOBT results (median age, 61 years [interquartile range, 56-67 years]; women, 52.2%), there were 685 cases of CRC and 156 cases of an advanced-stage disease diagnosed. The rate of cancer diagnosis at 0-3, 4-6, 7-9, 10-12 and 13-24 months was 3.9%, 2.5%, 3.5%, 4.2% and 7.3%, respectively (p < 0.001). Compared to colonoscopy follow-up within 0-3 months, risks for any CRC and advanced stage disease were higher for a follow-up of 12-24 months: OR, 1.97 (95% CI, 1.51-2.56) and 1.88 (95% CI, 1.43-2.46), respectively. For right-sided cancer (n = 194), an increased risk starts at 10 months, OR, 1.91 (95% CI 1.03-3.56). A result of 3-6 positive fields was significantly associated diagnosis of cancer (OR, 5.52; 95% CI, 4.71-6.46) and advanced stage disease (OR, 8.07; 95% CI, 5.74-11.36). Encouraging an early uptake of colonoscopy and targeting those with 10-24 months delay and a 3-6 positive fields is warranted.

Effect of Previous Nitroimidazole Treatment on Helicobacter pylori Eradication Success.

GOALS: The goal of this study was to examine the impact of prior treatment with a nitroimidazole antibiotic on the success of Helicobacter pylori treatment. BACKGROUND: Prior nitroimidazole exposure may increase the likelihood of nitroimidazole-resistant H. pylori. Current H. pylori treatment guidelines recommend that, in the absence of susceptibility testing, patients with prior nitroimidazole exposure should not be treated with a nitroimidazole antibiotic. Data to support this recommendation are lacking. STUDY: We searched the Clalit Health Services database to identify subjects 25 to 60 years old who underwent a first-ever C-urea breath test between 2010 and 2015. Patients who underwent a previous H. pylori stool antigen test or gastroscopy were excluded. Pharmacy dispensation data were retrieved. RESULTS: A total of 1386 subjects (34.8% male individuals, age 40.7±10.7 y) received a nitroimidazole-containing regimen including 282 (20.4%) with prior nitroimidazole exposure. Successful eradication was achieved in 58.9% and 73.8% of subjects with and without prior nitroimidazole exposure, respectively (odds ratio, 0.51; 95% confidence interval, 0.39-0.67; P<0.0001). Nitroimidazole exposure adversely impacted the success of triple therapy with nitroimidazole, proton pump inhibitor, and amoxicillin or clarithromycin (39.4% vs. 63.4% and 54.4% vs. 73.6%, P<0.01, respectively), but not quadruple therapy. Following multivariate analysis, nitroimidazole exposure was significantly associated with eradication failure (odds ratio, 1.89; 95% confidence interval, 1.43-2.50; P<0.0001). A greater time elapsed from nitroimidazole exposure, and a lower cumulative nitroimidazole dose were observed in subjects with successful eradication (P<0.0001 for both). CONCLUSION: Nitroimidazole exposure may adversely impact the success of nitroimidazole-based triple therapy, but not quadruple therapy. Clinicians should conduct a thorough patient drug history before administering empiric treatment for H. pylori infection.

Comparative Effect of Proton-Pump Inhibitors on the Success of Triple and Quadruple Therapy for Helicobacter pylori Infection.

INTRODUCTION: Suppression of gastric acid secretion with proton-pump inhibitors (PPI) is an integral part of the treatment of Helicobacter pylori infection. Esomeprazole has been shown to be superior to other PPIs when used in the context of triple therapy; however, comparative data for PPI efficacy in quadruple therapy are lacking. Current guidelines recommend H. pylori eradication with quadruple therapy in areas with high clarithromycin resistance. OBJECTIVE: To determine whether esomeprazole is more effective than other PPIs in the context of quadruple therapy for H. pylori eradication. METHODS: We retrospectively identified 25- to 60-year-old subjects with a positive 13C-urea breath test and no prior laboratory or endoscopic test for H. pylori infection. Pharmacy dispensation data were retrieved. RESULTS: A total of 7,896 subjects including 2,856 (36.2%) males, aged 40.4 ± 10.6 years, were identified. Of those, 78.1% received omeprazole, 20.1% received lansoprazole, 1.5% received esomeprazole, and 0.34% received pantoprazole together with antibiotics for H. pylori eradication. Esomeprazole was associated with a greater proportion of successful eradication (85.0 vs. 77.5%, esomeprazole vs. omeprazole, OR 1.64; 95% CI 0.99-2.72; p = 0.05). A nonsignificant trend favored esomeprazole over omeprazole among subjects receiving quadruple therapy (90.0 vs. 82.0%, respectively, OR 1.98; 95% CI 0.68-5.72; p = 0.16). Independent predictors of treatment success included older age and quadruple therapy. CONCLUSION: Esomeprazole is more beneficial than other PPIs for H. pylori eradication. Studies with larger subgroups are necessary to confirm our findings among subjects receiving quadruple therapy.

Impact of Previous Exposure to Macrolide Antibiotics on Helicobacter pylori Infection Treatment Outcomes.

OBJECTIVES: Helicobacter pylori (H. pylori) guidelines, including the recent ACG clinical guideline, recommend avoiding clarithromycin-based triple therapy (TT-C) among patients with past macrolide exposure. Data to support this recommendation are scarce, and the impact of macrolide exposure on quadruple therapies is unclear. We aimed to determine the impact of macrolide exposure on the efficacy of H. pylori treatment in our region. METHODS: We searched the Clalit Health Services database to identify subjects aged 25-60 years who underwent the first-ever C-urea breath test between 2010 and 2015. Patients who underwent a previous H. pylori stool antigen test or gastroscopy were excluded. Pharmacy dispensation data were retrieved. RESULTS: We identified 7,842 subjects (36.1% male individuals, age: 40.3 ± 10.5 years), including 3,062 (39.0%) with previous macrolide exposure. The efficacy of TT-C was 74.3% and 82.4% among subjects with and without macrolide exposure, respectively (odds ratio (OR), 0.62; 95% confidence interval (CI), 0.55-0.70; P < 0.0001). TT success was adversely affected by exposure to clarithromycin (55.5%; OR, 0.31; 95% CI, 0.24-0.39; P < 0.0001), roxythromycin (74.4%; OR, 0.65; 95% CI, 0.58-0.74; P < 0.0001), and erythromycin (73.9%; OR, 0.72; 95% CI, 0.57-0.89; P < 0.01) but not by exposure to azithromycin. A greater time elapsed because exposure to clarithromycin and roxythromycin was associated with higher eradication (OR, 1.007; 95% CI, 1.002-1.012; P < 0.01 and OR, 1.004; 95% CI, 1.002-1.006; P < 0.0001). A higher dose of clarithromycin and roxythromycin was associated with a lower likelihood of successful eradication (OR, 0.99988; 95% CI, 0.99982-0.99996; P < 0.01 and OR, 0.99981; 95% CI, 0.99971-0.99992; P < 0.001). The efficacies of sequential and concomitant therapies were 82.7% and 81.3%, respectively, and were not significantly affected by macrolide exposure. CONCLUSIONS: TT-C is adversely affected by previous exposure to macrolide antibiotics. Sequential, concomitant, and bismuth-based treatment may be preferred in this setting.

Optimization of 13 C-urea breath test threshold levels for the detection of Helicobacter pylori infection in a national referral laboratory.

BACKGROUND: Threshold values for 13 C-urea breath test (13C-UBT) positivity may be affected by various sociodemographic, host, bacterial, and laboratory factors. Manufacturer recommended cutoffs for 13C-UBT assays may not be applicable in all settings. Optimizing 13C-UBT cutoffs may have profound public health ramifications. We aimed to determine the optimal threshold for 13C-UBT positivity in our population. METHODS: Consecutive test samples collected at our central laboratory from patients undergoing a first-time 13C-UBT between 1 January 2010 and 31 December 2015 were included. The difference between values at 30 minutes and at baseline (T30-T0) was expressed as delta over baseline (DOB). Cluster analysis was performed on the 13C-UBT test results to determine the optimal cutoff point with minimal interclass variance. RESULTS: Two lakhs thirty four thousand eight hundred thirty one patients (87 291 (37.2%) male, age 39.9 ± 19.9) underwent a first-time 13C-UBT, including 124 701 (53.1%) negative and 110 130 (46.9%) positive tests, using the manufacturer-recommended cutoff of 3.5 DOB. Cluster analysis determined an optimized cutoff of 2.74 DOB, representing an additional 2180 (0.93%) positive subjects who had been previously categorized as negative according to the manufacturer-specified cutoff of 3.5 DOB. Mean positive and negative DOB values were 19.54 ± 14.95 and 0.66 ± 0.51, respectively. The cutoffs for male and female subjects were 2.23 and 3.05 DOB, respectively. Threshold values for <45-year-olds, 45-60-year-olds and >60-year-olds were 2.67, 2.55, and 2.93 DOB, respectively. Of the 2180 (0.93%) patients with DOB 2.73-3.49, 289 (13.3%) performed a subsequent 13C-UBT and 140 (48.4%) remained positive when tested at 20.3 ± 14.4 months. CONCLUSIONS: Major referral laboratories should optimize threshold values for 13C-UBT positivity for their geographical location. Different cutoff values should be applied for male and female subjects.

Risk factors associated with gastroenteropancreatic neuroendocrine tumors in a cohort of 2.3 million Israeli adolescents.

We investigated whether obesity and sociodemographic factors at adolescence are associated with incident gastroenteropancreatic neuroendocrine tumors (GEP-NET).Our cohort included 2.3 million Israeli adolescents examined at ages 16 to 19 years between 1967 and 2010. The baseline database included sex, country of birth, residential socioeconomic status (SES), body-mass index (BMI) and height. Participants were followed through linkage with the National Cancer Registry up to 2012. We identified 221 cases of GEP-NET (66 pancreatic, 52 gastric, 39 rectal, 27 appendiceal, 23 small bowel and 14 colonic). Immigration from the Former Soviet Union (FSU) was associated with the risk of small bowel and rectal NET's, [Hazard Ratio (HR) 4.79, 95% Confidence Interval (CI) 1.37-16.76 and 3.43, 95% CI 1.20-9.83, respectively].Height >75th percentile and BMI ≥ 85th percentile were associated with increased risk of gastric NET (HR 2.25 95% CI 1.14-4.42 and HR 2.38, 95% CI 1.19-4.75, respectively). Female sex was associated with appendiceal NET (HR 2.30, 95% CI 1.06-4.96) while male gender was associated with an increased risk for NET of the small bowel [HR 4.72 (95% CI 1.10-20.41)].In conclusion, our findings suggest different risk factor associations with the various GEP-NETS: immigrants from the FSU were at increased risk for small bowel and rectal NET; increased height and weight were associated with the risk of gastric NET and females were at increased risk for appendiceal NET. Further focus on the FSU population is indicated in addition to studies verifying the association of BMI and height with gastric NET.

Body mass index at adolescence and risk of noncardia gastric cancer in a cohort of 1.79 million men and women.

BACKGROUND: This study assessed adolescent predictors of noncardia gastric cancer (NCGC) with a focus on the body mass index (BMI) in late adolescence. METHODS: This study analyzed a cohort of 1,087,358 Israeli Jewish males and 707,212 Israeli Jewish females who underwent a compulsory physical examination between the ages of 16 and 19 years from 1967 to 2002. By linkage to the national cancer registry, participants were followed for NCGC through December 31, 2012. With a median follow-up of 23 years, 515 NCGC cases occurred (379 men and 136 women), and the median age was 47.0 years (interquartile range, 39.3-53.4 years). Multivariate-adjusted Cox regression was used to estimate hazard ratios (HRs) for NCGC according to the US Centers for Disease Control and Prevention BMI percentiles at the baseline (normal weight, 5th to <85th percentile; overweight, 85th to <95th percentile; and obesity, ≥95th percentile) as well as the country of birth, residential socioeconomic status (SES), and education. RESULTS: In comparison with normal weight, adolescent obesity, but not overweight, was associated in both men and women with the risk of subsequent NCGC (unadjusted HR, 1.95; 95% confidence interval [CI], 1.25-3.06; adjusted HR, 1.78; 95% CI, 1.12-2.83). Immigration from the former Soviet Union (FSU), a low education level, and a low residential SES were also associated with the risk for NCGC with adjusted HRs of 2.67 (95% CI, 1.86-3.83), 1.85 (95% CI, 1.53-2.25), and 1.48 (95% CI, 1.13-1.93), respectively. CONCLUSIONS: The findings suggest that adolescent obesity, but not overweight, is associated with an increased risk for NCGC. Immigration from the FSU, a low residential SES, and a low education level are also significantly associated with the risk for NCGC. Cancer 2018;124:356-63. © 2017 American Cancer Society.

Temporal Trends in Helicobacter pylori Eradication Success in a Test-and-Treat Population.

BACKGROUND/AIMS: Although the efficacy of first-line treatment for Helicobacter pylori infection should aim to be > 90%, it is unclear whether this target has been achieved in Israel. We aimed to determine the success rate of treatment for H. pylori and to describe temporal changes in our region. Methods: Adult patients who underwent a first-time -C13-urea breath test (C13-UBT) at Clalit Health Services between January 1, 2010 and December 31, 2015 were included. In order to isolate a naïve "test-and-treat" population who were unlikely to have undergone an initial endoscopy-based H. pylori test, we excluded patients ≥45 years and those with any previous C13-UBT. RESULTS: A total of 94,590 subjects (36.1% male, age 28.5 ± 6.0) who underwent at least one C13-UBT during the study period were included. C13-UBT was positive in 48,509 (51.3%) subjects. A confirmatory post-treatment C13-UBT was performed in 37.8, 44.1, 46.6, and 45.9% following 1st, 2nd, 3rd, and 4th-line treatment respectively. Eradication was successful in 65.4% following first-line treatment, and eradication success improved during the study period (59.2, 63.3, 65.7, 66.0, 69.0, and 73.1% in 2010, 2011, 2012, 2013, 2014, and 2015 respectively; OR 1.11; 95% CI 1.09-1.13; p < 0.0001). Eradication was successful in 44.7% following second-line treatment, although eradication success did not significantly improve during the study period (OR 1.05; 95% CI 0.99-1.10; p = 0.09). CONCLUSIONS: Despite the increasing success of first-line treatment for H. pylori infection over the study period, eradication rates remain suboptimal. Initiatives to implement the Toronto and Maastricht Consensus Reports should be advanced.

Risk of Neoplastic Progression Among Patients with an Irregular Z Line on Long-Term Follow-Up.

BACKGROUND: Barrett's esophagus (BE) is a known complication of gastroesophageal reflux disease. In a previous study, we described a high prevalence of intestinal metaplasia (IM) in patients with an irregular Z line. However, the clinical importance of this finding is unclear. GOALS: To evaluate the long-term development of BE and relevant complications in patients diagnosed with an irregular Z line, with or without IM, on routine esophago-gastro-duodenoscopy (EGD). METHODS: In our previously described cohort, 166 out of 2000 consecutive patients were diagnosed with an incidental irregular Z line. Of those with irregular Z line, 43% had IM. In this continuation study, patients' status was reassessed after a median follow-up of 70 months. Patients were divided into two groups: Patients with IM (IM-positive group) and without IM (IM-negative group). The incidence of long-term development of BE, dysplasia, and esophageal adenocarcinoma were compared between groups. RESULTS: At least one follow-up EGD was performed in 102 (61%) patients with an irregular Z line. Endoscopic evidence of BE was found in eight IM-positive patients (8/50 [16%]) and in one IM-negative patient (1/52 [1.9%]). Two (4%) IM-positive patients developed BE with low-grade dysplasia. None of the patients developed high-grade dysplasia, or esophageal adenocarcinoma. CONCLUSIONS: Patients with irregular Z line do not develop major BE complication in more than 5 years of follow-up.