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PURPOSE Cancer is the second leading cause of death globally. However, by implementing evidence-based prevention strategies, 30%-50% of cancers can be detected early with improved outcomes. At the integrated cancer prevention center (ICPC), we aimed to increase early detection by screening for multiple cancers during one visit. METHODS Self-referred asymptomatic individuals, age 20-80 years, were included prospectively. Clinical, laboratory, and epidemiological data were obtained by multiple specialists, and further testing was obtained based on symptoms, family history, individual risk factors, and abnormalities identified during the visit. Follow-up recommendations and diagnoses were given as appropriate. RESULTS Between January 1, 2006, and December 31, 2019, 8,618 men and 8,486 women, average age 47.11 ± 11.71 years, were screened. Of 259 cancers detected through the ICPC, 49 (19.8%) were stage 0, 113 (45.6%) stage I, 30 (12.1%) stage II, 25 (10.1%) stage III, and 31(12.5%) stage IV. Seventeen cancers were missed, six of which were within the scope of the ICPC. Compared with the Israeli registry, at the ICPC, less cancers were diagnosed at a metastatic stage for breast (none v 3.7%), lung (6.7% v 11.4%), colon (20.0% v 46.2%), prostate (5.6% v 10.5%), and cervical/uterine (none v 8.5%) cancers. When compared with the average stage of detection in the United States, detection was earlier for breast, lung, prostate, and female reproductive cancers. Patient satisfaction rate was 8.35 ± 1.85 (scale 1-10). CONCLUSION We present a proof of concept study for a one-stop-shop approach to cancer screening in a multidisciplinary outpatient clinic. We successfully detected cancers at an early stage, which has the potential to reduce morbidity and mortality as well as offer substantial cost savings. [Media: see text]

Video capsule endoscopy (VCE) is an effective, noninvasive modality for small bowel (SB) investigation. Its usage in the older adults is rising. However, data in octa-nonagenarians regarding diagnostic yield and motility are lacking. Our aim was to evaluate and compare safety and efficacy of VCE between age subgroups of older adult patients.This was a retrospective study of prospectively documented data. All consecutive VCEs of patients ≥65 years (01/2010-12/2017) were included. Patients unable to swallow the capsule or videos with significant recording technical malfunction were excluded. The cohort was divided into the younger group aged 65-79 years old and octa-nonagenarians aged ≥80 years old. Indications for referral, diagnostic yield and transit times were compared between groups.A total of 535 VCEs were performed in 499 older adult patients (51.2% males); 82.8% were 65-79 years old and 17.2% were ≥80 years old. The ≥80-year-old group had higher rates of clinically significant findings (52.7% vs. 40.0%, p = 0.025), active bleeding (12.5% vs. 6.5%, p = 0.053) and angioectasia (36.0% vs. 23.4%, p = 0.014). Crohn's disease was newly diagnosed in approximately 8% of the entire cohort and 12% of the ≥80 years old. Anemia was the most common indication in both groups, followed by overt bleeding in the ≥80-year-old group (25% vs. 9.9% in 65-79-year-old group, p 0.001) and Crohn's disease in the 65-79 years old (17.2% vs. 5.4% in ≥80 years old, p = 0.004). Groups were comparable in transit time and cecal documentation rates.In octa-nonagenarians, VCE is as safe as in younger older-adults with a higher diagnostic yield of significant and treatable conditions.

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. 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.

Purified cannabinoids have been shown to prevent proliferation and induce apoptosis in colorectal carcinoma cell lines. To assess the cytotoxic effect of cannabinoid extracts and purified cannabinoids on both colorectal polyps and normal colonic cells, as well as their synergistic interaction. Various blends were tested to identify the optimal synergistic effect. Methods: Biopsies from polyps and healthy colonic tissue were obtained from 22 patients undergoing colonic polypectomies. The toxicity of a variety of cannabinoid extracts and purified cannabinoids at different concentrations was evaluated. The synergistic effect of cannabinoids was calculated based on the cells’ survival. Isolated cannabinoids illustrated different toxic effects on the viability of cells derived from colorectal polyps. THC-d8 and THC-d9 were the most toxic and exhibited persistent toxicity in all the polyps tested. CBD was more toxic to polypoid cells in comparison to normal colonic cells at a concentration of 15 µM. The combinations of the cannabinoids CBDV, THCV, CBDVA, CBCA, and CBGA exhibited a synergistic inhibitory effect on the viability of cells derived from colon polyps of patients. Isolated cannabinoid compounds interacted synergistically against colonic polyps, and some also possessed a differential toxic effect on polyp and adjacent colonic tissue, suggesting possible future therapeutic value.

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

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.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.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).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.

Background Laparoscopic one anastomosis gastric bypass has become a prominent bariatric procedure. Yet, early and late complications, primarily leaks and strictures, are not uncommon. This study summarizes our experience with endoscopic treatment of laparoscopic one anastomosis gastric bypass complications. Methods This is a retrospective study of consecutive patients referred to our hospital from 2015 to 2017 with post laparoscopic one anastomosis gastric bypass complications. Therapy was tailored to each case, including fully covered self-expandable metal stents, fibrin glue, septotomy, internal drainage with pigtail stents, through-the-scope and pneumatic dilation. Success was defined as resuming oral nutrition without enteral or parenteral support or further surgical intervention. Results Nine patients presented with acute or early leaks: 5 (56%) had staple-line leaks, 3 (33%) had anastomotic leaks and 1 (11%) had both. All were treated with stents. Adjunctive endoscopic drainage was applied in 4 patients (44%). Overall 5 patients (56%) with acute/ early leaks recovered completely, including all 3 patients with anastomotic leak and the patient with both leaks but only 1/5 with staple line leak (20%). Complication rate in the leak group reached 22%. Eight patients presented with strictures, 7 at the anastomosis and one due to remnant stomach misalignment. All anastomotic strictures were dilated successfully. However, the patient with the pouch stricture required conversion to Roux-en-Y gastric bypass after 3 failed attempts of dilation. Conclusion Endoscopic treatments of laparoscopic one anastomosis gastric bypass complications are relatively effective and safe. Anastomosis-related complications are more amenable to endoscopic treatment compared to staple line leaks.

BACKGROUND AND AIMS: There is a need to evaluate the benefit-risk ratio of current therapies in inflammatory bowel disease (IBD) patients to provide the best quality of care. The primary objective of I-CARE (IBD Cancer and serious infections in Europe) was to assess prospectively safety concerns in IBD, with specific focus on the risk of cancer/lymphoma and serious infections in patients treated with anti-tumor necrosis factor and other biologic monotherapy as well as in combination with immunomodulators.METHODS: I-CARE was designed as a European prospective longitudinal observational multicenter cohort study to include patients with a diagnosis of Crohn's disease, ulcerative colitis, or IBD unclassified established at least 3 months prior to enrollment.RESULTS: A total of 10,206 patients were enrolled between March 2016 and April 2019, including 6169 (60.4%) patients with Crohn's disease, 3853 (37.8%) with ulcerative colitis, and 184 (1.8%) with a diagnosis of IBD unclassified. Thirty-two percent of patients were receiving azathioprine/thiopurines, 4.6% 6-mercaptopurine, and 3.2% methotrexate at study entry. At inclusion, 47.3% of patients were treated with an anti-tumor necrosis factor agent, 8.8% with vedolizumab, and 3.4% with ustekinumab. Roughly one-quarter of patients (26.8%) underwent prior IBD-related surgery. Sixty-six percent of patients had been previously treated with systemic steroids. Three percent of patients had a medical history of cancer prior to inclusion and 1.1% had a history of colonic, esophageal, or uterine cervix high-grade dysplasia.CONCLUSIONS: I-CARE is an ongoing investigator-initiated observational European prospective cohort study that will provide unique information on the long-term benefits and risks of biological therapies in IBD patients. (EudraCT, Number: 2014-004728-23; ClinicalTrials.gov, Number: NCT02377258).

Summary: Liver-resident macrophages Kupffer cells (KCs) and infiltrating Ly6Chi monocytes both contribute to liver tissue regeneration in various pathologies but also to disease progression upon disruption of orderly consecutive regeneration cascades. Little is known about molecular pathways that regulate their differentiation, maintenance, or inflammatory behavior during injury. Here, we show that copper metabolism MURR1 domain (COMMD)10-deficient KCs adopt liver-specific identity. Strikingly, COMMD10 deficiency in KCs and in other tissue-resident macrophages impedes their homeostatic survival, leading to their continuous replacement by Ly6Chi monocytes. While COMMD10 deficiency in KCs mildly worsens acetaminophen-induced liver injury (AILI), its deficiency in Ly6Chi monocytes results in exacerbated and sustained hepatic damage. Monocytes display unleashed inflammasome activation and a reduced type I interferon response and acquire “neutrophil-like” and lipid-associated macrophage differentiation fates. Collectively, COMMD10 appears indispensable for KC and other tissue-resident macrophage survival and is an important regulator of Ly6Chi monocyte fate decisions and reparative behavior in the diseased liver.

Several studies have demonstrated that curcumin can cause the regression of polyps in familial adenomatous polyposis (FAP), while others have shown negative results. Wholistic turmeric (WT) containing curcumin and additional bioactive compounds may contribute to this effect. We performed a double-blinded, randomized, controlled trial to assess the efficacy of WT in FAP patients. Ten FAP patients were randomly assigned to receive either WT or placebo for 6 months. Colonoscopies were performed at baseline and after 6 months. The polyp number and size, as well as the cumulative polyp burden, were assessed. No differences were noted between the groups in terms of changes from the baseline’s polyp number, size, or burden. However, stratifying the data according to the right vs. left colon indicated a decrease in the median polyp number (from 5.5 to 1.5, p = 0.06) and polyp burden (from 24.25 mm to 11.5 mm, p = 0.028) in the left colon of the patients in the WT group. The adjusted left polyp number and burden in the WT arm were lower by 5.39 (p = 0.034) and 14.68 mm (p = 0.059), respectively. Whether WT can be used to reduce the polyp burden of patients with predominantly left-sided polyps remains to be seen; thus, further larger prospective trials are required.

Background. Lynch syndrome is the most common genetic predisposition for hereditary cancer. Carriers of pathogenic changes in mismatch repair (MMR) genes have an increased risk of developing colorectal (CRC), endometrial, ovarian, urinary tract, prostate, and other cancers, depending on which gene is malfunctioning. In Lynch syndrome, differences in cancer incidence (penetrance) according to the gene involved have led to the stratification of cancer surveillance. By contrast, any differences in penetrance determined by the type of pathogenic variant remain unknown. Objective. To determine cumulative incidences of cancer in carriers of truncating and missense or aberrant splicing pathogenic variants of the MLH1 and MSH2 genes. Methods. Carriers of pathogenic variants of MLH1 (path_MLH1) and MSH2 (path_MSH2) genes filed in the Prospective Lynch Syndrome Database (PLSD) were categorized as truncating or missense/aberrant splicing according to the InSiGHT criteria for pathogenicity. Results. Among 5199 carriers, 1045 had missense or aberrant splicing variants, and 3930 had truncating variants. Prospective observation years for the two groups were 8205 and 34,141 years, respectively, after which there were no significant differences in incidences for cancer overall or for colorectal cancer or endometrial cancers separately. Conclusion. Truncating and missense or aberrant splicing pathogenic variants were associated with similar average cumulative incidences of cancer in carriers of path MLH1 and path_MSH2.

Introduction Hamartomatous polyposis syndromes (HPS) are rare autosomal-dominant inherited disorders associated with gastrointestinal (GI) tract and other cancers. HPS include Peutz-Jeghers syndrome (PJS), juvenile polyposis syndrome (JPS), and phosphatase and tensin homolog hamartomatous tumor syndromes (PHTS). Diagnosis, management, and outcome prediction of HPS pose a clinical challenge. To characterize genotype, phenotype, histology and outcomes of individuals with HPS. Methods A retrospective cohort study (2004-2017) of consecutive patients that were clinically diagnosed with HPS that visited a specialized GI oncology clinic. Demographic, clinicopathological, and genetic data were obtained from medical records. Results Fifty-two individuals from 34 families were included. Common clinical manifestations were GI bleeding (40% JPS, 23% PJS, and 25% PHTS) and bowel obstruction (46.15% PJS and 11.4% JPS). Twenty patients (38.4%) underwent surgery, 5 of whom required multiple procedures. Higher polyp burden was associated with the need for surgery (P = 0.007). Polyp histology varied widely with 69.2% of patients exhibiting histology different from the syndrome hallmark. GI cancer history was positive in 65%, 40%, and 50% of JPS, PJS, and PHTS families, respectively. Five (9.6%) patients developed cancers (one patient each had small bowel-1, colon-1, and thyroid-1, one patient had both small bowel adenocarcinoma and breast cancer, and one had both breast cancer and liposarcoma). Twenty (38.4%) patients tested positive for STK11, PTEN, SMAD4, BMPR1A, or AKT1 mutations: Sanger sequencing and multi-gene next generation sequencing panels detected mutations in 40.9% and 100% of tested cases, respectively. Discussion HPS patients present versatile phenotypes with overlapping clinical and histological characteristics. Polyp burden is associated with the need for surgery. Next-generation sequencing increases mutation detection.

Contains fulltext : 205162.pdf (Publisher’s version ) (Open Access) BACKGROUND AND AIMS: Colorectal cancer (CRC) is largely preventable with routine screening and surveillance colonoscopy; however, interval cancers arising from precancerous lesions missed by standard colonoscopy still occur. An increased adenoma detection rate (ADR) has been found to be inversely associated with interval cancers. The G-EYE device includes a reusable balloon integrated at the distal tip of a standard colonoscope, which flattens haustral folds, centralizes the colonoscope's optics, and reduces bowel slippage. The insufflated balloon also aims to enhance visualization of the colon during withdrawal, thereby increasing the ADR. METHODS: In this randomized, controlled, international, multicenter study (11 centers), patients (aged >/=50 years) referred to colonoscopy for screening, surveillance, or changes in bowel habits were randomized to undergo either balloon-assisted colonoscopy by using an insufflated balloon during withdrawal or standard high-definition colonoscopy. The primary endpoint was the ADR. RESULTS: One thousand patients were enrolled between May 2014 and September 2016 to undergo colonoscopy by experienced endoscopists; 803 were finally analyzed (standard colonoscopy n = 396; balloon-assisted colonoscopy n = 407). Baseline parameters were similar in both groups. Balloon-assisted colonoscopy provided a 48.0% ADR compared with 37.5% in the standard colonoscopy group (28% increase; P = .0027). Additionally, balloon-assisted colonoscopy provided for a significant increase in detection of advanced (P = .0033) flat adenomas (P < .0001) and sessile serrated adenomas/polyps (P = .0026). CONCLUSION: Balloon-assisted colonoscopy yielded a higher ADR and increased the detection of advanced, flat, and sessile serrated adenomas/polyps when compared with standard colonoscopy. Improved detection by the G-EYE device could impact the quality of CRC screening by reducing miss rates and consequently reducing interval cancer incidence. (Clinical trial registration number: NCT01917513.).

BACKGROUND Adenomatous polyposis syndromes (APS) patients with ileal pouch anal anastomosis (IPAA) suffer frequent symptoms with scarce signs of inflammation, distinct from ulcerative colitis patients. While the management of pouchitis in ulcerative colitis patients is well established, data regarding response to treatment modalities targeting pouch-related disorders in APS patient population is scarce. AIM To assess clinical, endoscopic and histologic response to various treatment modalities employed in the therapy of pouch related disorders. METHODS APS patients who underwent IPAA between 1987-2019 were followed every 6-12 mo and pouch-related symptoms were recorded at every visit. Lower endoscopy was performed annually, recording features of the pouch, cuff and terminal ileum. A dedicated gastrointestinal pathologist reviewed biopsies for signs and severity of inflammation. At current study, files were retrospectively reviewed for initiation and response to various treatment modalities between 2015-2019. Therapies included dietary modifications, probiotics, loperamide, antibiotics, bismuth subsalicylate, mebeverine hydrochloride, 5-aminosalicylic acid compounds and topical rectal steroids. Symptoms and endoscopic and histologic signs of inflammation before and after treatment were assessed. Pouchitis disease activity index (PDAI) and its subscores was calculated. Change of variables before and after therapy was assessed using Wilcoxon signed rank test for continuous variables and using McNemar's test for categorical variables. RESULTS Thirty-three APS patients after IPAA were identified. Before treatment, 16 patients (48.4%) suffered from abdominal pain and 3 (9.1%) from bloody stools. Mean number of daily bowel movement was 10.3. Only 4 patients (12.1%) had a PDAI ≥ 7. Mean baseline PDAI was 2.5 ± 2.3. Overall, intervention was associated with symptomatic relief, mainly decreasing abdominal pain (from 48.4% to 27.2% of patients, P = 0.016). Daily bowel movements decreased from a mean of 10.3 to 9.3 (P = 0.003). Mean overall and clinical PDAI scores decreased from 2.58 to 1.94 (P = 0.016) and from 1.3 to 0.87 (P = 0.004), respectively. Analyzing each treatment modality separately, we observed that dietary modifications decreased abdominal pain (from 41.9% of patients to 19.35%, P = 0.016), daily bowel movements (from 10.5 to 9.3, P = 0.003), overall PDAI (from 2.46 to 2.03, P = 0.04) and clinical PDAI (1.33 to 0.86, P = 0.004). Probiotics effectively decreased daily bowel movements (from 10.2 to 8.8, P = 0.007), overall and clinical PDAI (from 2.9 to 2.1 and from 1.38 to 0.8, P = 0.032 and 0.01, respectively). While other therapies had minimal or no effects. No significant changes in endoscopic or histologic scores were seen with any therapy. CONCLUSION APS patients benefit from dietary modifications and probiotics that improve their pouch-related symptoms but respond minimally to anti-inflammatory and antibiotic treatments. These results suggest a functional rather than inflammatory disorder.

Purpose: This study aimed to report the uptake of hysterectomy and/or bilateral salpingo-oophorectomy (BSO) to prevent gynaecological cancers (risk-reducing surgery [RRS]) in carriers of pathogenic MMR (path_MMR) variants.Methods: The Prospective Lynch Syndrome Database (PLSD) was used to investigate RRS by a cross-sectional study in 2292 female path_MMR carriers aged 30-69 years.Results: Overall, 144, 79, and 517 carriers underwent risk-reducing hysterectomy, BSO, or both combined, respectively. Two-thirds of procedures before 50 years of age were combined hysterectomy and BSO, and 81% of all procedures included BSO. Risk-reducing hysterectomy was performed before age 50 years in 28%, 25%, 15%, and 9%, and BSO in 26%, 25%, 14% and 13% of path_MLH1, path_MSH2, path_MSH6, and path_PMS2 carriers, respectively. Before 50 years of age, 107 of 188 (57%) BSO and 126 of 204 (62%) hysterectomies were performed in women without any prior cancer, and only 5% (20/392) were performed simultaneously with colorectal cancer (CRC) surgery.Conclusion: Uptake of RRS before 50 years of age was low, and RRS was rarely undertaken in association with surgical treatment of CRC. Uptake of RRS aligned poorly with gene-and age-associated risk estimates for endometrial or ovarian cancer that were published recently from PLSD and did not correspond well with current clinical guidelines. The reasons should be clarified. Decision-making on opting for or against RRS and its timing should be better aligned with predicted risk and mortality for endometrial and ovarian cancer in Lynch syn-drome to improve outcomes. (C) 2021 The Author(s). Published by Elsevier Ltd.

Purpose To determine impact of risk-reducing hysterectomy and bilateral salpingo-oophorectomy (BSO) on gynecological cancer incidence and death in heterozygotes of pathogenic MMR ( path_MMR ) variants. Methods The Prospective Lynch Syndrome Database was used to investigate the effects of gynecological risk-reducing surgery (RRS) at different ages. Results Risk-reducing hysterectomy at 25 years of age prevents endometrial cancer before 50 years in 15%, 18%, 13%, and 0% of path_MLH1 , path_MSH2 , path_MSH6 , and path_PMS2 heterozygotes and death in 2%, 2%, 1%, and 0%, respectively. Risk-reducing BSO at 25 years of age prevents ovarian cancer before 50 years in 6%, 11%, 2%, and 0% and death in 1%, 2%, 0%, and 0%, respectively. Risk-reducing hysterectomy at 40 years prevents endometrial cancer by 50 years in 13%, 16%, 11%, and 0% and death in 1%, 2%, 1%, and 0%, respectively. BSO at 40 years prevents ovarian cancer before 50 years in 4%, 8%, 0%, and 0%, and death in 1%, 1%, 0%, and 0%, respectively. Conclusion Little benefit is gained by performing RRS before 40 years of age and premenopausal BSO in path_MSH6 and path_PMS2 heterozygotes has no measurable benefit for mortality. These findings may aid decision making for women with LS who are considering RRS.

Liver resident macrophages Kupffer cells (KCs) and infiltrating Ly6C(hi) monocytes both contribute to liver tissue regeneration in various pathologies, but also to disease progression upon disruption of orderly consecutive regeneration cascades. Little is known about molecular pathways that regulate their differentiation, maintenance, or their inflammatory behavior during injury. Here we show that COMMD10-deficient KCs adopt liver-specific identity. Strikingly, COMMD10-deficiency in KCs and in other tissue resident macrophages impedes their homeostatic survival, leading to their continuous replacement by Ly6C(hi) monocytes. While COMMD10-deficiency in KCs mildly worsens acetaminophen-induced liver injury (AILI), its deficiency in Ly6C(hi) monocytes results in exacerbated and sustained hepatic damage. Monocytes display unleashed inflammasome activation and reduced type I interferon response and acquire ‘neutrophil-like’ and lipid associated macrophage differentiation fates. Collectively, COMMD10 appears indispensable for KC and other tissue resident macrophage survival and is an important regulator of Ly6C(hi) monocyte fate decisions and reparative behavior in the diseased liver.

INTRODUCTION: Total proctocolectomy with ileal pouch anal anastomosis (IPAA) is performed in patients with adenomatous polyposis syndromes (APSs). Data regarding pouch outcomes in APS are scarce. The purposes of this study were to determine the prevalence of pouch-related symptoms in patients with APS and to identify the contributing factors. METHODS: This is a prospective cohort study. Demographic, surgical, and clinical data were collected. Endoscopy was performed, and biopsies from the terminal ileum, pouch, and cuff were obtained in all patients and reviewed by a dedicated pathologist. RESULTS: Fifty-one patients with APS after IPAA were followed. Twenty patients (39.2%) had pouch-related symptoms. Single-stage IPAA had better outcomes than 2-stage IPAA: fewer daily bowel movements (42.9% vs 13.8% with ≤5 daily bowel movement, P = 0.02), more solid consistency (52.4% vs 6.9%, P < 0.001), and less abdominal pain (19% vs 48.3%, P = 0.034). Younger age at IPAA (

Lynch syndrome (LS) results from pathogenic variants in the mismatch repair (MMR) genes and is the most common hereditary cancer syndrome, affecting an estimated 1 in 300 individuals. Pathogenic variants in each of the MMR genes path_MLH1, path_MSH2, path_MSH6, and path_PMS2 result in different risks for cancers in organs including the colorectum, endometrium, ovaries, stomach, small bowel, bile duct, pancreas, and upper urinary tract. Accurate estimates of these risks are essential for planning appropriate approaches to the prevention or early diagnosis of cancers but the robustness of previous studies has been limited by factors including retrospective design,1,2 lack of validation in independent cohorts,3-5 and inconsistent classification of genetic variants. Unexpected findings from previous studies have included path_MLH1 and path_MSH2 carriers appearing to have a lifetime risk of colorectal cancer (CRC) of approximately 50%, despite surveillance colonoscopy,6-8 and that shorter intervals between colonoscopies do not seem to reduce the incidence of CRC in LS.9,10 These findings challenge the assumptions that CRC in LS usually develops from a noninfiltrative adenoma precursor and that CRC can be prevented by colonoscopic detection and removal of adenomas in the colon and rectum. Additionally, previous studies in the Prospective Lynch Syndrome Database (PLSD) have shown no increase in cancer risk in path_PMS2 carriers before 40 years of age and, although observation years were limited in older path_PMS2 carriers, LS-associated cancers other than endometrial and prostate were not observed.6-8 In this study we collected prospective data from a new large cohort of path_MMR carriers to validate previous findings from PLSD. We also updated information on the original cohort to ensure consistent classification of pathogenicity of MMR gene variants. We then combined both data sets, providing larger numbers that allowed us to derive more precise risk estimates for cancers in LS categorized by gene and gender.

Exclusion of the proximal gut from nutrient absorption entails significant metabolic benefits. The duodenal-jejunal bypass liner (DJBL) is the first endoscopic device that excludes the first part of the gut by covering it.To assess weight and glycemic control at the end of treatment and after 1 year of follow-up.Bariatric endoscopy service in a tertiary medical center.Diabetic patients were treated with DJBL and followed prospectively between 2013 and 2016. Data were collected during scheduled visits.Out of 51 patients treated, 39 completed at least 9 months with the device. Complications were recorded for the entire cohort. Percent of total weight loss was 15.05% ± 6.0% after 12 months of treatment (P.001 versus baseline). Twelve months postretrieval, percent of total weight loss decreased to 8.75% ± 5.07% (P.001 versus baseline). Patients with baseline body mass index ≥35 kg/mProximal bowel bypass by DJBL is an effective tool for weight reduction and glycemic control. Metabolic achievements are partially preserved at 1 year after device removal. Because DJBL entails a considerable rate of side effects, strategies to mitigate them are warranted.

Indoline carbamates, AN680 and AN917 decrease cytokines, TNF-α and IL-6 in peritoneal macrophages activated by lipopolysaccharide (LPS) and in mouse tissues after LPS injection. They prevent nuclear translocation of nuclear factor κB (NF-κB) and activator protein 1. Only AN917 inhibits cholinesterase (ChE) at relevant concentrations. ChE inhibitors decrease NF-κB by activating α7 nicotinic acetylcholine receptors (α7nAChR). The current study compared the effect of rivastigmine, a ChE inhibitor, AN680 and AN917 on ulcerative colitis induced in mice by ingestion of dextran sodium sulfate (4.5%) solution. Rivastigmine (1 mg/kg), AN680 (2.5–10 mg/kg) and AN917 (2–5 mg/kg) were injected subcutaneously once daily for 8 days. Disease severity was assessed by disease activity index (DAI), colonoscopy, colon length and body weight loss, colonic levels of TNF-α, IL-6, IL-1β and myeloid peroxidase (MPO) activity. AN680 (5 mg/kg) reduced DAI, colon shrinkage, weight loss, histopathological signs of colon damage, MPO activity, TNF-α, IL-1β and IL-6 levels without inhibiting ChE. AN917 (5 mg/kg) and rivastigmine (1 mg/kg) inhibited ChE in plasma and colon by 65%, reduced DAI, MPO activity and IL-6, but not TNF-α or IL-1β. AN917 did not prevent weight loss or colon shrinkage. Mecamylamine abolished the reduction of DAI, MPO activity and IL-6 by AN917 and rivastigmine, indicating they were mediated by α7nAChR. Conclusions: AN680 is very effective in preventing DSS-induced UC in mice and may therefore have potential therapeutic application in humans. Addition of ChE inhibition and indirect activation of α7nAChR lessens the efficacy of AN917 in this model.

Background: Laparoscopic one anastomosis gastric bypass has become a prominent bariatric procedure. Yet, early and late complications, primarily leaks and strictures, are not uncommon. This study summarizes our experience with endoscopic treatment of laparoscopic one anastomosis gastric bypass complications. Methods: This is a retrospective study of consecutive patients referred to our hospital from 2015 to 2017 with post laparoscopic one anastomosis gastric bypass complications. Therapy was tailored to each case, including fully covered self-expandable metal stents, fibrin glue, septotomy, internal drainage with pigtail stents, through-the-scope and pneumatic dilation. Success was defined as resuming oral nutrition without enteral or parenteral support or further surgical intervention. Results : Nine patients presented with acute or early leaks: 5 (56%) had staple-line leaks, 3 (33%) had anastomotic leaks and 1 (11%) had both. All were treated with stents. Adjunctive endoscopic drainage was applied in 4 patients (44%). Overall 5 patients (56%) with acute/ early leaks recovered completely, including all 3 patients with anastomotic leak and the patient with both leaks but only 1/5 with staple line leak (20%). Complication rate in the leak group reached 22%. Eight patients presented with strictures, 7 at the anastomosis and one due to remnant stomach misalignment. All anastomotic strictures were dilated successfully. However, the patient with the pouch stricture required conversion to Roux-en-Y gastric bypass after 3 failed attempts of dilatation. Conclusion: Endoscopic treatments of laparoscopic one anastomosis gastric bypass complications are relatively effective and safe. Anastomosis-related complications are more amenable to endoscopic treatment compared to staple line leaks.

Background: Laparoscopic one anastomosis gastric bypass has become a prominent bariatric procedure. Yet, early and late complications, primarily leaks and strictures, are not uncommon. This study summarizes our experience with endoscopic treatment of laparoscopic one anastomosis gastric bypass complications. Methods: This is a retrospective study of consecutive patients referred to our hospital from 2015 to 2017 with post laparoscopic one anastomosis gastric bypass complications. Therapy was tailored to each case, including fully covered self-expandable metal stents, fibrin glue, septotomy, internal drainage with pigtail stents, through-the-scope and pneumatic dilation. Success was defined as resuming oral nutrition without enteral or parenteral support or further surgical intervention. Results: Nine patients presented with acute or early leaks: 5 (55.6%) had staple-line leaks, 3 (33.3%) had anastomotic leaks and 1 (11.1%) had both. All were treated with stents. Adjunctive endoscopic drainage was applied in 4 patients (44.4%). Overall 5 patients (55.6%) with acute/ early leaks recovered completely, including all 3 patients with anastomotic leak and the patient with both leaks but only 1/5 with staple line leak (20%). Complication rate in the leak group reached 22.2%. Eight patients presented with strictures, 7 at the anastomosis and one due to remnant stomach misalignment. All anastomotic strictures were dilated successfully. However, the patient with the pouch stricture required conversion to Roux-en-Y gastric bypass after 3 failed attempts of dilatation. Conclusion: Endoscopic treatments of laparoscopic one anastomosis gastric bypass complications are relatively effective and safe. Anastomosis-related complications are more amenable to endoscopic treatment compared to staple line leaks.

Identification of early processes leading to complex tissue pathologies, such as inflammatory bowel diseases, poses a major scientific and clinical challenge that is imperative for improved diagnosis and treatment. Most studies of inflammation onset focus on cellular processes and signaling molecules, while overlooking the environment in which they take place, the continuously remodeled extracellular matrix. In this study, we used colitis models for investigating extracellular-matrix dynamics during disease onset, while treating the matrix as a complete and defined entity. Through the analysis of matrix structure, stiffness and composition, we unexpectedly revealed that even prior to the first clinical symptoms, the colon displays its own unique extracellular-matrix signature and found specific markers of clinical potential, which were also validated in human subjects. We also show that the emergence of this pre-symptomatic matrix is mediated by sub-clinical infiltration of neutrophils and monocytes bearing remodeling enzymes. Remarkably, whether the inflammation is chronic or acute, its matrix signature converges at pre-symptomatic states. We suggest that the existence of a pre-symptomatic extracellular-matrix is general and relevant to a wide range of diseases.

Background Recent epidemiological evidence shows that colorectal cancer (CRC) continues to occur in carriers of pathogenic mismatch repair (path_MMR) variants despite frequent colonoscopy surveillance in expert centres. This observation conflicts with the paradigm that removal of all visible polyps should prevent the vast majority of CRC in path_MMR carriers, provided the screening interval is sufficiently short and colonoscopic practice is optimal. Methods To inform the debate, we examined, in the Prospective Lynch Syndrome Database (PLSD), whether the time since last colonoscopy was associated with the pathological stage at which CRC was diagnosed during prospective surveillance. Path_MMR carriers were recruited for prospective surveillance by colonoscopy. Only variants scored by the InSiGHT Variant Interpretation Committee as class 4 and 5 (clinically actionable) were included. CRCs detected at the first planned colonoscopy, or within one year of this, were excluded as prevalent cancers. Results Stage at diagnosis and interval between last prospective surveillance colonoscopy and diagnosis were available for 209 patients with 218 CRCs, including 162 path_MLH1, 45 path_MSH2, 10 path_MSH6 and 1 path_PMS2 carriers. The numbers of cancers detected within 3.5 years since last colonoscopy were 36, 93, 56 and 33, respectively. Among these, 16.7, 19.4, 9.9 and 15.1% were stage III–IV, respectively (p = 0.34). The cancers detected more than 2.5 years after the last colonoscopy were not more advanced than those diagnosed earlier (p = 0.14). Conclusions The CRC stage and interval since last colonoscopy were not correlated, which is in conflict with the accelerated adenoma-carcinoma paradigm. We have previously reported that more frequent colonoscopy is not associated with lower incidence of CRC in path_MMR carriers as was expected. In contrast, point estimates showed a higher incidence with shorter intervals between examinations, a situation that may parallel to over-diagnosis in breast cancer screening. Our findings raise the possibility that some CRCs in path_MMR carriers may spontaneously disappear: the host immune response may not only remove CRC precursor lesions in path_MMR carriers, but may remove infiltrating cancers as well. If confirmed, our suggested interpretation will have a bearing on surveillance policy for path_MMR carriers.

e23544 Background: Abdominal desmoid tumors are locally aggressive, non-metastatic tumors that develop mainly in Familial adenomatous polyposis (FAP) patients, within the mesentery or abdominal wall. Understanding and implications of treatment regimens are evolving. We aimed to assess course, treatment and outcomes of FAP and non-FAP abdominal desmoids and their related genetic alterations. Methods: Retrospective cohort study. Demographics, tumor characteristics, oncological and surgical history, complications, genetic-testing and mortality data were retrieved from two tertiary referral centers. Results: Sixty-two patients were identified (46 FAP, 16 non-FAP) with a median follow up of 72.4 months. Thirty-eight patients (61.3%) underwent surgical procedures: twelve urgent and 26 elective. Out of 33 tumor resections, 39.4% recurred. Hormonal therapy, COX-inhibitors, chemotherapy, imatinib and sorafenib were used in 35(56.4%), 30(48.4%), 18(29.1%), 7(11.3%) and 8(12.9%) of patients, respectively, with 2 years progression-free survival of 67.8%, 57.7%, 38.4%, 28.5%, respectively. Only 1/9 patients treated with sorafenib had disease progression after a median follow up of 6.8 months. Forty-one patients (66.1%) suffered complications: bowel obstruction (30.6%), hyperalimentation (14.5%), ureteral obstruction (12.9%), perforation (11.3%), abscess formation (3.2%) and spinal cord compression (3.2%). Two patients died. Non-FAP patients presented with three renal-cell carcinomas and one germ-cell tumor and carried pathogenic mutations in CHEK2, BLM, ERCC5, MSH6 and PALB2. Conclusions: Abdominal desmoids are mostly FAP-related and are associated with severe outcomes. We report a group of non-FAP abdominal desmoids that includes patients with additional cancer-related gene alterations. This interesting group should undergo genetic consultation and be further explored.

e15591 Background: More than 1.8 million new cancer cases are expected to be diagnosed in 2020. Only in the U.S, about 606,520 Americans are expected to die this year, which translates to about 1,660 deaths per day. However, when found early, in the asymptomatic phase, cancer is often effectively treated or even cured. The few cancer screens available today, including mammograms and colonoscopies, each look for a single type of cancer. CD24 is hardly expressed in normal cells (but to B-lymphocytes, differentiating neuroblasts and neutrophils) but is overexpressed in numerous human cancers. Aim: To establish a universal cancer screening blood test. Methods: Blood samples were obtained from consecutive patients and healthy volunteers. 1x106 leukocytes were stained using anti-CD11b-PerCp-Cy5.5 and anti-CD24-FITC and analyzed by flow cytometry (CyFlow Cube 6, Sysmex, Germany). Percentage of positive cells was determined by subtracting the percentage of CD24 and CD11b-positive cells (dual stain) from CD24-positive cells (single stain). The cut off for cancer detection was 25. Healthy subjects underwent a thorough evaluation at the health promotion center and integrated cancer prevention center. All cancers were verified histologically. Results: CD24/CD11b expression in the healthy population was evaluated in 337 women and 408 men, ages 20-85. There were 222 cancer patients. After excluding thyroid and bladder cancers, the assay detected 146 out of 196 (75%) cancers at all stages and even in 31 out of colonic adenomas (table). The levels of CD24 drop back to near normal level following successful surgery/chemotherapy. The test score was not affected by age, gender, fasting and the time of the day that the blood sample is taken. In 55 cases the test was performed twice, with similar results, as well as when the test was performed in another flow cytometry, after 1d, 1w, 1m after freezing . Conclusions: 1. CD24 is a universal cancer screening. 2. It can detect pre malignant lesions like adenomas in the colon. 3. Preliminary results suggest that it can serve as a predictive marker. [Table: see text]

Summary Staphylococcus aureus is a major cause of infectious disease. Liver Kupffer cells (KCs) are responsible for sequestering and destroying S. aureus through the phagolysosomal pathway. Proteins belonging to the COMMD family emerge as key intracellular regulators of protein trafficking, but the role of COMMD10 in macrophage-mediated S. aureus eradication is unknown. Here we report that COMMD10 in macrophages was necessary for its timely elimination, as demonstrated with two different S. aureus subspecies. In vivo, COMMD10-deficient liver KCs exhibited impaired clearance of systemic S. aureus infection. S. aureus-infected COMMD10-deficient macrophages exhibited impaired activation of the transcription factor EB, resulting in reduced lysosomal biogenesis. Moreover, S. aureus-initiated phagolysosomal maturation and function were significantly attenuated in COMMD10-deficient macrophages. Finally, expression of COMMD/CCDC22/CCDC93 complex, linked to phagolysosomal maturation, was reduced by COMMD10 deficiency. Collectively, these results support an important role for COMMD10 in instructing macrophage phagolysosomal biogenesis and maturation during S. aureus infection., Graphical Abstract, Highlights • COMMD10 facilitates timely clearance of S. aureus by liver Kupffer cells • COMMD10 drives transcription program of lysosome biogenesis in infected macrophages • COMMD10 drives phagolysosomal maturation and acidification in infected macrophages, Biological Sciences; Immunology; Microbiology; Molecular Microbiology

Germline mutations in the DNA polymerase genes POLD1 and POLE confer high risk for multiple colorectal adenomas and colorectal cancer. However, prevalence and the clinical phenotype of mutation carriers are still not fully characterized.The purpose of this study was to assess the prevalence of germline mutations and to describe the genotype-phenotype correlation in POLD1 and POLE genes in Jewish subjects with multiple colorectal adenomas and/or early-onset mismatch repair proficient colorectal cancers.This study is a comparison of genetic and clinical data from affected and control groups.The study was conducted at a high-volume tertiary referral center.The study cohort included 132 subjects: 68 with multiple colorectal adenomas and 64 with early-onset mismatch repair proficient colorectal cancers. The control group included 5685 individuals having no colorectal cancer or colorectal adenomas.Study and control subjects were tested for POLD1 and POLE mutations and a clinical correlation was assessed.Eleven of the 132 study subjects (8.3%) carried either a POLD1 or a POLE mutation: 7 of 68 (10.3%) subjects with multiple colorectal adenomas and 4 of 64 (6.2%) subjects with early-onset mismatch repair proficient colorectal cancer. Three mutations were detected, showing statistical significance in frequency between study and control groups (p0.001). Eight of the 11 mutation carriers were Ashkenazi Jews carrying the same POLD1 mutation (V759I), implicating it as a possible low-to-moderate risk founder mutation. Phenotype of mutation carriers was notable for age under 50 at diagnosis, a propensity toward left-sided colorectal cancer, and extracolonic tumors (64%, 100%, and 27% of cases).The study cohort was limited by its relatively small size.Germline mutations in POLD1 and POLE were found to be relatively frequent in our Jewish cohorts. Further studies are needed to clarify the importance of POLD1 and POLE mutations and to define the most suitable surveillance program for Jewish and other POLD1 and POLE mutation carriers. See Video Abstract at http://links.lww.com/DCR/A658.

Immunotherapies targeting T lymphocytes are revolutionizing cancer therapy but only benefit a subset of patients, especially in colorectal cancer. Thus, additional insight into the tumor microenvironment (TME) is required. Eosinophils are bone marrow–derived cells that have been largely studied in the context of allergic diseases and parasite infections. Although tumor-associated eosinophilia has been described in various solid tumors including colorectal cancer, knowledge is still missing regarding eosinophil activities and even the basic question of whether the TME promotes eosinophil recruitment without additional manipulation (e.g., immunotherapy) is unclear. Herein, we report that eosinophils are recruited into developing tumors during induction of inflammation-induced colorectal cancer and in mice with the Apcmin/+ genotype, which develop spontaneous intestinal adenomas. Using adoptive transfer and cytokine neutralization experiments, we demonstrate that the TME supported prolonged eosinophil survival independent of IL5, an eosinophil survival cytokine. Tumor-infiltrating eosinophils consisted of degranulating eosinophils and were essential for tumor rejection independently of CD8+ T cells. Transcriptome and proteomic analysis revealed an IFNγ-linked signature for intratumoral eosinophils that was different from that of macrophages. Our data establish antitumorigenic roles for eosinophils in colorectal cancer. These findings may facilitate the development of pharmacologic treatments that could unleash antitumor responses by eosinophils, especially in colorectal cancer patients displaying eosinophilia.

Staphylococcus aureus (S. aureus) is a major cause of infectious disease. Macrophages, and especially liver Kupffer cells (KCs), are responsible for sequestering and destroying S. aureus bacteria through the phagolysosomal pathway. Proteins belonging to the COMMD family emerge as key intracellular regulators of protein trafficking, but the role of COMMD10 in macrophage-mediated eradication of S. aureus is unknown. Here we report that COMMD10-deficiency in macrophages did not affect S. aureus internalization, but was necessary for its timely elimination, as demonstrated with two different S. aureus subspecies. In vivo, COMMD10-deficient liver KCs exhibited impaired clearance of systemic S. aureus infection. S. aureus-infected COMMD10-deficient macrophages exhibited impaired activation of the transcription factor EB, resulting in reduced lysosomal biogenesis. Moreover, S. aureus-initiated phagolysosomal maturation and function was significantly attenuated in the COMMD10-deficient macrophages. Collectively, these results support an important role for COMMD10 in instructing macrophage phagolysosomal biogenesis and maturation during S. aureus infection.

Background Patients with familial adenomatous polyposis (FAP) may carry various adenomatous polyposis coli (APC) mutations. However, genotype-phenotype correlation for APC mutations is still debated and is yet to be evaluated with regard to pouch polyp formation. Objective To evaluate the association between APC mutation type and exon location and the outcome of pouch adenoma. Design setting and patients Forty-five FAP patients with defined pathogenic APC mutations, who underwent total proctocolectomy and ileal pouch anal anastomosis were classified by mutation type and location. Analysis was conducted for clinical and endoscopic parameters. Results Twenty patients had either indel/deletion mutations and 25 had nonsense/missense mutations. The indel/deletion group was associated with higher prevalence of preoperative hundreds of colonic adenomas (66.7% vs. 30%; P=0.030), lower rates of stapled versus sewn anastomosis (46.7% vs. 76%; P=0.060), of single stage surgery (13.3% vs. 44%; P=0.045) and with higher pouch adenoma formation rate (50% vs. 8%; P=0.002). Twenty-seven were carriers of exons 1 to 14 mutations and 18 were carriers of exon 15 mutations. Carriers of exon 15 mutations had higher prevalence of preoperative hundreds of colonic adenomas (55.6% vs. 22.2%; P=0.003) and a higher tendency for pouch and cuff adenoma formation rate. Adjusted odds ratio for pouch adenoma formation was 8.32 (1.42-48.80; P=0.019) for the indel/deletion group versus nonsense/missense, but no significant independent association was noted with mutation location. The mean number of pouch and cuff adenoma formation (per endoscopy) was higher among carriers of exon 15 mutations, but no significant independent association was noted the with mutation type. Conclusions Type and location of APC mutation are associated with colonic polyp burden, surgical outcome and likelihood of developing pouch adenomas. These findings may contribute to surgical and endoscopic surveillance decisions for FAP patients.

Many patients are reluctant to undergo optical colonoscopy for colorectal cancer screening. The Check-Cap colon imaging system is a non-invasive test that comprises an ingestible imaging capsule that emits and detects ultra-low-dose radiation. The capsule generates a 3D reconstruction of the colonic lumen for detection of polyps and cancer. Preliminary preclinical and clinical testing has demonstrated safety and feasibility. Mean radiation dose is estimated at 0.04 mSv. In conclusion, we describe a novel capsule-based, patient-friendly colorectal test that holds potential for non-invasive screening.

The X-ray imaging capsule overcomes the requirement for bowel preparation, a major deterrent for colorectal cancer (CRC) screening. This prospective multicentre study examined capsule safety and efficacy (compared with fecal immunochemical test (FIT)) for polyp detection confirmed by ensuing colonoscopy. In 45 analysed patients, capsule and FIT sensitivity for polyps was 44% and 37%, respectively. Capsule sensitivity increased to 78% when >50% of the colon surface area was imaged, with a linear correlation between imaged area and sensitivity. An updated scanning algorithm, retrospectively implemented on these study data, dramatically increased numbers of subjects with imaged area >50%, from 21 to 41/45 (46% to 91%). Capsule specificity for polyps approached 90%. Transit time was 52±32 hours. No device-related serious adverse events occurred. Average X-ray dose was 0.05 mSv. Many patients forego screening by colonoscopy due to the need for cathartic preparation,1 2 posing a major obstacle to implementation of current screening programmes.3 4 A test not requiring laxative preparation could increase adherence with screening.1 Moreover, inadequate preparation for colonoscopy impairs adenoma and cancer detection rates and often necessitates repeating of the procedure.5 A prep-less modality would not suffer from these limitations. In a previous proof-of-concept study, a prep-less screening capsule was shown to be safe, capable of 3D reconstruction of the colonic wall and lumen and identifying adenomatous polyps.6 In a prospective multicentre comparative study, we studied the safety and efficacy of a first version of the capsule for identifying colonic polypoid lesions and masses compared with FIT and colonoscopy. The system has …

The demand for bowel cleansing hampers participation in screening colonoscopy, while poor preparation impairs adenoma detection. A novel prepless X-ray imaging capsule for colon screening is presented; the capsule emits low dose X-rays, which are scattered by ingested contrast agent mixed with colon contents, and sensed by detectors in the capsule to generate high-resolution three-dimensional (3D) imagery of the colon without bowel cleansing. Following preliminary studies with implanted polyps in synthetic colon phantoms, bovine cadaver and live swine, and human experiments with dummy capsules (n=75), 49 patients swallowed the capsule with natural excretion in 48 after 73.2±45.4 h. Pedunculated and sessile polyps were clearly seen and validated by subsequent colonoscopy. Total radiation exposure was ultra low (0.03±0.007 mSv). Bowel preparation remains a major obstacle limiting complete uptake of colonoscopy for colon cancer screening.1 ,2 Therefore any test which does not require preparation would probably increase compliance.3 However, the accuracy to depict cancers as well as adenomas should not suffer substantially. A new X-ray capsule is shown in a series of proof-of-concept studies to be safe and effective in 3D reconstruction of the colonic wall and lumen including identifying adenomatous polyps. The capsule system includes a short-lived radio isotope within a collimator housing that emits three X-ray beams in all directions, by way of a rotating miniature electric motor as the capsule scans the length of the GI tract. A small volume of ingested radiopaque contrast agent increases the contrast of the colon's walls and differentiates them from stool content. Compton backscattered photons, attenuated by the contrast agent mixed with the colon contents, and X-ray fluorescence photons emitted from the contrast agent, are detected by sensors in …

NF-kappaB is a master regulator of inflammation and has been implicated in the pathogenesis of immune disorders and cancer. Its regulation involves a variety of steps, including the controlled degradation of inhibitory IkappaB proteins. In addition, the inactivation of DNA-bound NF-kappaB is essential for its regulation. This step requires a factor known as copper metabolism Murr1 domain-containing 1 (COMMD1), the prototype member of a conserved gene family. While COMMD proteins have been linked to the ubiquitination pathway, little else is known about other family members. Here we demonstrate that all COMMD proteins bind to CCDC22, a factor recently implicated in X-linked intellectual disability (XLID). We showed that an XLID-associated CCDC22 mutation decreased CCDC22 protein expression and impaired its binding to COMMD proteins. Moreover, some affected individuals displayed ectodermal dysplasia, a congenital condition that can result from developmental NF-kappaB blockade. Indeed, patient-derived cells demonstrated impaired NF-kappaB activation due to decreased IkappaB ubiquitination and degradation. In addition, we found that COMMD8 acted in conjunction with CCDC22 to direct the degradation of IkappaB proteins. Taken together, our results indicate that CCDC22 participates in NF-kappaB activation and that its deficiency leads to decreased IkappaB turnover in humans, highlighting an important regulatory component of this pathway.