PIGA Mutations and Glycosylphosphatidylinositol Anchor Dysregulation in Polyposis-Associated Duodenal Tumorigenesis.

The pathogenesis of duodenal tumors in the inherited tumor syndromes familial adenomatous polyposis (FAP) and MUTYH-associated polyposis (MAP) is poorly understood. This study aimed to identify genes that are significantly mutated in these tumors and to explore the effects of these mutations. Whole exome and whole transcriptome sequencing identified recurrent somatic coding variants of phosphatidylinositol N-acetylglucosaminyltransferase subunit A (PIGA) in 19/70 (27%) FAP and MAP duodenal adenomas, and further confirmed the established driver roles for APC and KRAS. PIGA catalyzes the first step in glycosylphosphatidylinositol (GPI) anchor biosynthesis. Flow cytometry of PIGA-mutant adenoma-derived and CRISPR-edited duodenal organoids confirmed loss of GPI anchors in duodenal epithelial cells and transcriptional profiling of duodenal adenomas revealed transcriptional signatures associated with loss of PIGA. IMPLICATIONS: PIGA somatic mutation in duodenal tumors from patients with FAP and MAP and loss of membrane GPI-anchors may present new opportunities for understanding and intervention in duodenal tumorigenesis.

GRANULOMATOUS DISEASE OF UNUSUAL SITES CAUSING HYPERCALCEMIA: TWO CASE REPORTS.

OBJECTIVE: Hypercalcemia with suppressed parathyroid hormone (PTH) levels is mostly due to granulomatous disease (GD) or neoplastic disease. In GD, autonomous activity of extra-renal 1α-hydroxylase enzyme is usually the underlying cause. We describe a pair of cases where hypercalcemia resulted from GD of unusual sites posing significant diagnostic challenges. METHODS: We describe 2 cases of PTH-independent hypercalcemia due to GD of the prostate gland and the stomach. RESULTS: Both cases presented with marked hypercalcemia and suppressed PTH levels. Case 1 is an elderly male who presented with marked symptomatic hypercalcemia on multiple occasions. Investigations revealed elevated levels of 1,25-dihydroxyvitamin D3 and prostate-specific antigen but normal PTH-related protein. Transrectal biopsy of the prostate gland confirmed the presence of chronic granulomatous prostatitis. The patient responded very well to steroids which entirely normalized his calcium level. Case 2 is a male who presented similarly with significant hypercalcemia but had upper gastrointestinal symptoms and anemia at onset. Endoscopy and biopsy established the presence of granulomatous gastritis likely due to Crohn disease which responded to steroids resulting in normalization of calcium levels within a short span of time. CONCLUSION: While the majority of PTH-independent hypercalcemia cases are due to GDs of lymph nodes or malignancy, our cases indicate that in uncertain cases, granulomatous processes involving unusual sites should be considered in the evaluation of hypercalcemia with suppressed PTH.

The impact of chromoendoscopy for surveillance of the duodenum in patients with MUTYH-associated polyposis and familial adenomatous polyposis.

BACKGROUND AND AIMS: Duodenal polyposis and cancer have become a key issue for patients with familial adenomatous polyposis (FAP) and MUTYH-associated polyposis (MAP). Almost all patients with FAP will develop duodenal adenomas, and 5% will develop cancer. The incidence of duodenal adenomas in MAP appears to be lower than in FAP, but the limited available data suggest a comparable increase in the relative risk and lifetime risk of duodenal cancer. Current surveillance recommendations, however, are the same for FAP and MAP, using the Spigelman score (incorporating polyp number, size, dysplasia, and histology) for risk stratification and determination of surveillance intervals. Previous studies have demonstrated a benefit of enhanced detection rates of adenomas by use of chromoendoscopy both in sporadic colorectal disease and in groups at high risk of colorectal cancer. We aimed to assess the effect of chromoendoscopy on duodenal adenoma detection, to determine the impact on Spigelman stage and to compare this in individuals with known pathogenic mutations in order to determine the difference in duodenal involvement between MAP and FAP. METHODS: A prospective study examined the impact of chromoendoscopy on the assessment of the duodenum in 51 consecutive patients with MAP and FAP in 2 academic centers in the United Kingdom (University Hospital Llandough, Cardiff, and St Mark's Hospital, London) from 2011 to 2014. RESULTS: Enhanced adenoma detection of 3 times the number of adenomas after chromoendoscopy was demonstrated in both MAP (P = .013) and FAP (P = .002), but did not affect adenoma size. In both conditions, there was a significant increase in Spigelman stage after chromoendoscopy compared with endoscopy without dye spray. Spigelman scores and overall adenoma detection was significantly lower in MAP compared with FAP. CONCLUSIONS: Chromoendoscopy improved the diagnostic yield of anomas in MAP and FAP 3-fold, and in both MAP and FAP this resulted in a clinically significant upstaging in Spigelman score. Further studies are required to determine the impact of improved adenoma detection on the management and outcome of duodenal polyposis.

Burden and Profile of Somatic Mutation in Duodenal Adenomas from Patients with Familial Adenomatous- and MUTYH-associated Polyposis.

Purpose: Duodenal polyposis and cancer are important causes of morbidity and mortality in familial adenomatous polyposis (FAP) and MUTYH-associated polyposis (MAP). This study aimed to comprehensively characterize somatic genetic changes in FAP and MAP duodenal adenomas to better understand duodenal tumorigenesis in these disorders.Experimental Design: Sixty-nine adenomas were biopsied during endoscopy in 16 FAP and 10 MAP patients with duodenal polyposis. Ten FAP and 10 MAP adenomas and matched blood DNA samples were exome sequenced, 42 further adenomas underwent targeted sequencing, and 47 were studied by array comparative genomic hybridization. Findings in FAP and MAP duodenal adenomas were compared with each other and to the reported mutational landscape in FAP and MAP colorectal adenomas.Results: MAP duodenal adenomas had significantly more protein-changing somatic mutations (P = 0.018), truncating mutations (P = 0.006), and copy number variants (P = 0.005) than FAP duodenal adenomas, even though MAP patients had lower Spigelman stage duodenal polyposis. Fifteen genes were significantly recurrently mutated. Targeted sequencing of APC, KRAS, PTCHD2, and PLCL1 identified further mutations in each of these genes in additional duodenal adenomas. In contrast to MAP and FAP colorectal adenomas, neither exome nor targeted sequencing identified WTX mutations (P = 0.0017).Conclusions: The mutational landscapes in FAP and MAP duodenal adenomas overlapped with, but had significant differences to those reported in colorectal adenomas. The significantly higher burden of somatic mutations in MAP than FAP duodenal adenomas despite lower Spigelman stage disease could increase cancer risk in the context of apparently less severe benign disease. Clin Cancer Res; 23(21); 6721-32. ©2017 AACR.

Inherited predisposition to colorectal cancer: towards a more complete picture.

Colorectal carcinoma (CRC) is the third most common cancer worldwide. Hereditary factors are important in 15%-35% of affected patients. This review provides an update on the genetic basis of inherited predisposition to CRC. Currently known genetic factors include a group of highly penetrant mutant genes associated with rare mendelian cancer syndromes and a group of common low-penetrance alleles that have been identified through genetic association studies. Additional mechanisms, which may underlie a predisposition to CRC, will be outlined, for example, variants in intermediate penetrance alleles. Recent findings, including mutations in POLE, POLD1 and NTHL1, will be highlighted, and we identify gaps in present knowledge and consider how these may be addressed through current and emerging genomic approaches. It is expected that identification of the missing heritable component of CRC will be resolved through evermore comprehensive cataloguing and phenotypic annotation of CRC-associated variants identified through sequencing approaches. This will have important clinical implications, particularly in areas such as risk stratification, public health and CRC prevention.

The molecular genetics of colorectal cancer.

Colorectal cancer is a common but heterogeneous disease, which arises through the accumulation of genetic mutations. Knowledge of the molecular basis of colorectal cancer has advanced at a rapid pace in recent years, reflecting progress made in the field of genomic medicine. Targeted therapies have come into mainstream use, and the exciting prospect of treatment regimens tailored to the mutation profile of individual tumours is beginning to emerge. In order to understand the development and application of the next generation of colorectal cancer treatments, it is important that gastroenterologists have a working knowledge of the pathological mechanisms that drive the disease. This review examines our current understanding of the molecular genetics of colorectal carcinogenesis.

The Welsh Institute for Minimal Access Therapy colonoscopy suitcase has construct and concurrent validity for colonoscopic polypectomy skills training: a prospective, cross-sectional study.

BACKGROUND: The Welsh Institute for Minimal Access Therapy (WIMAT) colonoscopy suitcase is an ex vivo porcine simulator for polypectomy training. OBJECTIVE: To establish whether this model has construct and concurrent validity. DESIGN: Prospective, cross-sectional study. SETTING: Endoscopic training center. PARTICIPANTS: Twenty novice (N), 20 intermediate (I), 20 advanced (Ad), and 20 expert (E) colonoscopists. INTERVENTION: A simulated polypectomy task aimed at removing 2 polyps; A (simple), B (complex). MAIN OUTCOME MEASUREMENTS: Two accredited colonoscopists, blinded to group allocation, scored performances according to Direct Observation of Polypectomy Skills (DOPyS) assessment parameters. Group performances were compared. Real-life DOPyS scores were correlated to simulator DOPyS results. RESULTS: Median overall DOPyS scores for novices were 1.00 (1.00-1.87) for A and 0.50 (0.00-1.00) for B (A vs B; P < .01). Intermediates scored 2.50 (2.00-2.88) for A and 2.00 (1.13-2.50) for B (A vs B; P = .03). The advanced group scored 3.00 (2.50-3.50) for A and 2.50 (2.00-3.00) for B (A vs B; P = .01). Experts scored 3.00 (3.00-3.88) for A and 3.00 (2.50-3.50) for B (A vs B; P = .47). Intergroup comparisons for A were, N vs I; P < .01, N vs Ad; P < .01, N vs E; P < .01, I vs Ad; P < .01, I vs E; P < .01, and Ad vs E; P = .46. Intergroup comparisons for B were, N vs I; P < .01, N vs Ad; P < .01, N vs E; P < .01, I vs Ad; P = .03, I vs E; P <.01, and Ad vs E; P = .06. There was no difference between real-life DOPyS scores and simulator scores (0.07). LIMITATIONS: The model does not have inbuilt assessment parameters. CONCLUSION: This simulator demonstrates construct and concurrent validity for colon polypectomy training.

Gastrointestinal polyposis syndromes for the general gastroenterologist.

The occurrence of colonic polyps is a common phenomenon; however, where there are numerous adenomas or other polyps, and/or the patient is at a relatively young age, an inheritable form of gastrointestinal polyposis should be considered. Patients can present via different referral routes, for example, at colonoscopy where multiple polyps are detected, following a personal diagnosis of colorectal cancer, or by family screening. This article outlines the important considerations in the diagnosis of a polyposis syndrome and key diagnostic features to consider. It will also describe the underlying genetic factors associated with the common polyposis syndromes, including classical familial adenomatous polyposis (FAP), attenuated FAP, MUTYH-associated adenomatous polyposis, Peutz-Jeghers syndrome, juvenile polyposis syndrome, Cowden syndrome and serrated polyposis, and the subsequent management of each condition.

Can endoscopists accurately self-assess performance during simulated colonoscopic polypectomy? A prospective, cross-sectional study.

BACKGROUND: The aim of this study was to establish if endoscopists can reliably self-assess their ability to perform simulated colonic polypectomy. METHODS: Novices, intermediates, advanced, and experts performed a video-recorded polypectomy task using the Welsh Institute for Minimal Access Therapy (WIMAT) colonoscopy suitcase simulator. This involved removal of a simple polyp (A) and a complex polyp (B). Participants self-assessed themselves using a Direct Observation of Polypectomy Skills (DOPyS) assessment form. Two blinded, independent, Joint Advisory Group on Gastrointestinal Endoscopy (JAG) accredited assessors graded each performance using the same DOPyS scoring. The Spearman coefficient was used to determine the correlation between self and assessors' scores. RESULTS: Eighty participants completed the task. There was a weak correlation between assessors' scores and self-assessment scores for all groups (novices: ρ = -.44, P = .85; intermediates: ρ = -.16, P = .51; advanced: ρ = .16, P = .50; and experts: ρ = .07, P = .76). There was a strong correlation between scores from assessor 1 and 2 for polyp A (ρ = .80, P ≤ .01) and polyp B (ρ = .80, P ≤ .01). CONCLUSIONS: The correlation between self-assessment and assessors' scores is weak. Novices and intermediates underestimate performance, whereas advanced and experts overestimate performance. Regular feedback may improve accuracy.

Incidence and presentation of reported coeliac disease in Cardiff and the Vale of Glamorgan: the next 10 years.

OBJECTIVE: To determine whether there is a continued increase in the incidence of coeliac disease (CD) in the population of Cardiff and the Vale of Glamorgan between 1996 and 2005 compared with previous data for 1981-1995, and to describe the presenting features during this time. DESIGN: Retrospective case-finding study using pathology, dietetic and clinical records held in hospitals and general practice within Cardiff and the Vale of Glamorgan. All local consultants including those at private hospitals were contacted. Incidence rates were calculated using the Welsh Assembly Government's mid-year estimates. RESULTS: In total, 347 newly diagnosed cases of CD (42 children, 305 adults) were detected. Compared with previous published data, incidence rates in adults per 100 000 have increased from 3.08 at the end of 1995 to 11.13 in 2005. In children, the disease incidence has trebled to 6.89 per 100 000. There have been some changes in presenting symptoms, with a marked preponderance of abdominal pain and bloating in women (P<0.05). There has been a 14-fold increase in the numbers of patients undergoing coeliac serology testing from 1996 to 2005, associated with an increased absolute number of new cases. However, the proportion of new cases diagnosed compared with numbers of serological tests performed decreased from 5.8 to 1.1%. CONCLUSION: The incidence of CD in children and adults has markedly increased. One of the most striking features of our data in adult CD is the increasing frequency of abdominal pain and bloating in the female cohort. Incorporation of antibody testing into clinical guidelines is likely to result in a wider spectrum of individuals with nonspecific gastrointestinal symptoms being investigated and diagnosed with CD in the future.

An opportune finding in suspected liver metastases.

Opportunistic mycobacterial infections are rare in immunocompetent patients. The authors describe a case of disseminated Mycobacterium avium complex disease in a previously healthy patient presenting with hepatosplenomegaly and non-specific symptoms which initially led to a diagnosis of metastatic carcinoma. After correct treatment she made a full recovery, with resolution of symptoms and the radiological findings.

Two for the price of one: a dual treatment benefit of long-acting octreotide in occult bleeding and diuretic intractable ascites.

Transfusion-dependent anaemia and portal hypertension are recognised complications of hereditary haemorrhagic telangiectasia (HHT). The anaemia is a result of chronic bleeding from gastrointestinal telangiectasias, which are usually multiple and located throughout the gastrointestinal tract. As a result, treatment with argon plasma coagulation via gastroscopy and or colonoscopy is often insufficient to prevent ongoing blood loss. Portal hypertension in HHT occurs as a result of blood shunting between the hepatic artery and the portal vein within the liver. The somatostatin analogue octreotide has been used as a treatment for bleeding angiodysplasia; however, its possible role as a treatment for diuretic intractable ascites secondary to portal hypertension has not been previously established. The authors report a case that apparently illustrates a dual benefit of long-acting octreotide in the management of both occult bleeding and refractory ascites in a patient with HHT.

Using email and text messaging to improve patient compliance with blood monitoring.

BACKGROUND: Patients with inflammatory bowel disease may need immunosuppressant therapy. This involves frequent blood tests to ensure results are within safe limits. AIM: To investigate whether the use of email and text messaging to remind patients to have blood tests might result in better compliance than using more conventional methods of communication. METHOD: Patients were divided into three groups by self-selection: one wanted email reminders; one wanted texts; while a control group received telephone calls and letters. Data on the delays was analysed. RESULTS: In all groups receiving email, text messages or traditional phone call reminders, delays were reduced. Patients in the email/text messaging groups overwhelmingly found these methods helpful and wished them to continue. DISCUSSION AND CONCLUSION: The use of email and text messaging helped to reduce delays in monitoring and patients who selected these methods found it helpful. We aim to continue this service.

Anaemia in older people with chronic heart failure: The potential cost.

Studies suggest benefits from correcting anaemia in heart failure using a combination of erythropoiesis-stimulating agents (ESAs) and intravenous iron. We set out to investigate the number of older patients who would require treatment of anaemia in a large teaching hospital in the United Kingdom and the cost implications. The prevalence of anaemia and chronic kidney disease (CKD) in patients 65 years and older with systolic dysfunction attending the local heart failure clinic was determined. The projected numbers of patients in our health district who would meet published kidney disease guidelines for treatment of anaemia was then estimated. The costs of treatment with combination ESAs and IV iron were calculated for these patients based on the treatment costs for renal anaemia in our local renal unit. Sensitivity analysis for different thresholds of haemoglobin and eGFR was performed. In our study of 86 heart failure patients, mean age 81 years, 34% have anaemia and 73% have stage III CKD with estimated glomerular filtration rate < 60 ml/min/1.73 cm2. At the haemoglobin threshold value of

Molecular approaches to the study of gene expression during human preimplantation development.

Understanding of gene expression during the early stages of human development has increased markedly in the last 2 years, as refined and highly sensitive procedures have been developed enabling construction of cDNA libraries from single preimplantation embryos and unfertilized oocytes. The genes identified so far include key regulatory genes such as imprinted genes, transcription factors and cell cycling genes, as well as repetitive sequences, brain transcripts and housekeeping genes. In addition, sequencing of random clones has revealed cDNAs matching known expressed sequence tags in the GenBank and dbEST databases, in addition to novel sequences not currently present in these databases. This article focuses on the various molecular biology techniques applicable to the study of gene expression during human preimplantation development.