Extracolonic Manifestations Research Articles

Abstract 5140: TALEN mediated mutation of apc and β-catenin in Xenopus tropicalis as powerful models for Wnt driven cancer and Familial Adenomatous Polyposis (FAP)

Abstract Hyperactivation of the Wnt pathway is a common hallmark of many cancers. Deregulation of the pathway is mostly due to mutations in the tumor suppressor gene Adenomatous Polyposis Coli (APC) or the transcriptional regulator of the Wnt pathway β-catenin (CTNNB1). Heterozygous germline mutations in the Mutation Cluster Region (MCR) of the APC gene cause Familial Adenomatous Polyposis (FAP), a condition characterized by multiple colorectal polyps, which over time become malignant. FAP patients also frequently suffer from extracolonic manifestations, such as Congenital Hypertrophy of the Retinal Pigment Epithelium (CHRPE), desmoid tumors and medulloblastoma. Despite many mouse models and the clear etiology of colorectal cancer and FAP, no drugs targeting the Wnt pathway have reached the clinic and there is a need for new genetic animal models. The recent TALEN (Transcription Activator Like Effector Nuclease) and CRISPR/Cas9 gene targeting technologies open the door for novel genetic cancer models. Xenopus tropicalis, an aquatic tetrapod with a true diploid genome, offers unique experimental opportunities to model human cancer. We have adopted the TALEN technology in Xenopus tropicalis to generate a model for Wnt deregulated cancer, by targeting either APC or β-catenin. Targeting of the apc gene in the MCR region induces phenotypes reminiscent of FAP in tadpoles and froglets, including hyperplasia of the intestinal epithelium, desmoid tumors, retinal hyperproliferation and medulloblastoma. These neoplasms show bi-allelic truncating mutations in the apc gene, associated with activation of the Wnt signalling pathway and increased cell proliferation. Secondly, we generated a more direct model for the hyperactivation of the Wnt pathway by developing TALENs against the Ser33 phosphorylation site of β-catenin. Small in frame deletions removing this phosphorylation site will result in a stabilized dominant active form of β-catenin, activating Wnt signalling at the transcriptional endpoint. Injection of this TALEN pair induces similar neoplasms as apc TALEN injection, including desmoid and brain tumors, indicating that these tumors are the consequence of activated Wnt signalling, rather than any of the other disrupted functions of APC. In addition we were able to achieve very efficient double bi-allelic mutation of apc and other genes in different tumors by co-injection of two TALEN pairs. This creates the opportunity to use our model for therapeutic target validation, simply by co-injection of TALENs (or CRISPR/Cas9) against potential targets together with the apc TALENs. We have developed the first genetic cancer models in Xenopus tropicalis by using apc or β-catenin TALENs. These models closely resemble human FAP and will be used for preclinical drug screening and to evaluate potential novel therapeutic targets by multiplexed gene targeting via TALEN and CRISPR/Cas9 technology. Citation Format: Tom Van Nieuwenhuysen, Thomas Naert, David Creytens, Frans Van Roy, Kris Vleminckx. TALEN mediated mutation of apc and β-catenin in Xenopus tropicalis as powerful models for Wnt driven cancer and Familial Adenomatous Polyposis (FAP). [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5140. doi:10.1158/1538-7445.AM2015-5140

The genetic basis of familial adenomatous polyposis and its implications for clinical practice and risk management.

Familial adenomatous polyposis (FAP) is an inherited disorder that represents the most common gastrointestinal polyposis syndrome. Germline mutations in the APC gene were initially identified as responsible for FAP, and later, several studies have also implicated the MUTYH gene as responsible for this disease, usually referred to as MUTYH-associated polyposis (MAP). FAP and MAP are characterized by the early onset of multiple adenomatous colorectal polyps, a high lifetime risk of colorectal cancer (CRC), and in some patients the development of extracolonic manifestations. The goal of colorectal management in these patients is to prevent CRC mortality through endoscopic and surgical approaches. Individuals with FAP and their relatives should receive appropriate genetic counseling and join surveillance programs when indicated. This review is focused on the description of the main clinical and genetic aspects of FAP associated with germline APC mutations and MAP.

Detection of APC mosaicism by next-generation sequencing in an FAP patient.

Familial adenomatous polyposis (FAP) of the colon is characterized by multiple polyps in the intestine and extra-colonic manifestations. Most FAP cases are caused by a germline mutation in the tumor-suppressor gene APC, but some cases of adenomatous polyposis result from germline mutations in MUTYH, POLD1 or POLE. Although sequence analysis of APC by the Sanger method is routinely performed for genetic testing, there remain cases whose mutations are not detected by the analysis. Next-generation sequencing has enabled us to analyze the comprehensive human genome, improving the chance of identifying disease causative variants. In this study, we conducted whole-genome sequencing of a sporadic FAP patient in which we did not find any pathogenic APC mutations by the conventional Sanger sequencing. Whole-genome sequencing and subsequent deep sequencing identified a mosaic mutation of c.3175G>T, p.E1059X in ~12% of his peripheral leukocytes. Additional deep sequencing of his buccal mucosa, hair follicles, non-cancerous mucosa of the stomach and colon disclosed that these tissues harbored the APC mutation at different frequencies. Our data implied that genetic analysis by next-generation sequencing is an effective strategy to identify genetic mosaicism in hereditary diseases.

Gardner's syndrome presenting as duodenal carcinoma in a young male

Gardners syndrome (GS) is a variant of familial adenomatous polyposis (FAP) and presents with both colonic and extra colonic manifestations. It is an autosomal dominant disorder and results from mutations in adenomatous polyposis coli (APC) gene. Patients with GS if not treated early will invariably develop colonic cancers at a much younger age than those with sporadic colonic carcinoma. These patients also develop other malignant tumours like duodenal cancers, gastric cancer, hepatoblastoma, papillary carcinoma of the thyroid and multifocal cholangiocarcinomas. With early diagnosis and treatment of colonic polyposis, adenocarcinoma of the duodenum has become the leading cause of death in FAP patients. The mean age at which duodenal carcinoma is diagnosed in FAP is 45-52 years. We report the rare occurrence of duodenal carcinoma as the presenting feature of Gardner’s syndrome in a young 25-year-old male with no obvious malignant changes in the colonic adenomas.

Fidaxomicin--the new drug for Clostridium difficile infection.

Clostridium difficile is one of the many aetiological agents of antibiotic associated diarrhoea and is implicated in 15-25 per cent of the cases. The organism is also involved in the exacearbation of inflammatory bowel disease and extracolonic manifestations. Due to increase in the incidence of C. difficile infection (CDI), emergence of hypervirulent strains, and increased frequency of recurrence, the clinical management of the disease has become important. The management of CDI is based on disease severity, and current antibiotic treatment options are limited to vancomycin or metronidazole in the developing countries. this review article briefly describes important aspects of CDI, and the new drug, fidaxomicin, for its treatment. Fidaxomicin is particularly active against C. difficile and acts by inhibition of RNA synthesis. Clinical trials done to compare the efficacy and safety of fidaxomicin with that of vancomycin in treating CDI concluded that fidaxomicin was non-inferior to vancomycin for treatment of CDI and that there was a significant reduction in recurrences. The bactericidal properties of fidaxomicin make it an ideal alternative for CDI treatment. However, fidaxomicin use should be considered taking into account the potential benefits of the drug, along with the medical requirements of the patient, the risks of treatment and the high cost of fidaxomicin compared to other treatment regimens.

Duodenal adenoma surveillance in patients with familial adenomatous polyposis.

Familial adenomatous polyposis (FAP) is a hereditary disorder caused by Adenomatous Polyposis Gene mutations that lead to the development of colorectal polyps with great malignant risk throughout life. Moreover, numerous extracolonic manifestations incorporate different clinical features to produce varied individual phenotypes. Among them, the occurrence of duodenal adenomatous polyps is considered an almost inevitable event, and their incidence rates increase as a patient's age advances. Although the majority of patients exhibit different grades of duodenal adenomatosis as they age, only a small proportion (1%-5%) of patients will ultimately develop duodenal carcinoma. Within this context, the aim of the present study was to review the data regarding the epidemiology, classification, genetic features, endoscopic features, carcinogenesis, surveillance and management of duodenal polyps in patients with FAP.

A Rare Case of Attenuated Familial Adenomatous Polyposis

Introduction: Attenuated familial adenomatous polyposis (AFAP) is a rare, less-aggressive subset of familial adenomatous polyposis (FAP). We report a rare case of AFAP presenting as symptomatic iron deficiency anemia. Case Report: A 61-year-old female with a history of iron deficiency anemia, on iron replacement therapy, with a base line hemoglobin of 8.5 g/dL presented with complaints of fatigue and a 26-pound weight gain over a 6-month period. The patient denied melena, hematochezia, hematemesis and change in stool caliber, color or shape. The patient reports a family history of unknown colon cancer in her father at age 76 years, mother at age 78 years, and sister at age 48 years. Physical exam findings are unremarkable. Labs: hemoglobin 5.8 g/dL, WBC 10.3 K/uL, Fe 21 ug/dL, Fe% Sat 5%, and TIBC 419 ug/dL. Colonoscopy was positive for sporadic polyps (2-3) in the rectum, sigmoid, and descending colon, innumerable polyps (estimated to be less than 100) in the cecum, transverse colon, and ascending colon, culminating into a 10-cm-long circumferential ulcerated mass beginning distal to the ileocecal valve. Biopsies were positive for invasive adenocarcinoma. The patient elected to undergo treatment with colectomy. Discussion: AFAP is a subset of FAP. FAP is a rare manifestation of colorectal adenomatous disease in which without treatment will lead to a lifetime cancer risk as high as 100%. FAP typically presents as hundreds to thousands of adenomas in the colon and rectum, usually before the age of 30 years, with progression to cancer before the patient is 40 years old. FAP is responsible for less than 1% of all gastrointestinal cancers. AFAP is less aggressive than FAP, in that the patient develops less than 100 colorectal polyps and is usually diagnosed in their 40s with progression to colorectal cancer in their 60s. Like FAP, AFAP patients have a lifetime cancer risk as high as 100%. Recent studies have demonstrated that AFAP is an autosomal dominant disease that may be caused by mutations in the adenomatous polyposis coli gene (APC) or the mutY homologue gene (MUTYH), but the exact mechanism of the disease in unknown. AFAP most commonly presents with vague abdominal complaints, constipation, lower abdominal pain, or anemia. AFAP is most commonly diagnosed by colonoscopy. Prophylactic colectomy is recommended for the prevention of progression to colorectal cancer, however, it has been reported that AFAP can have extracolonic manifestations, such as gastroduodenal lesions. Conclusion: AFAP is a rare, less-aggressive subtype of FAP, characterized by fewer polyps and with an older age of onset, diagnosis, and progression to colorectal cancer.

Early Detection of CHRPE and Subsequent Familial Adenomatous Polyposis Syndrome by Ultra-Wide Field Retinal Laser Scanning Technology

Introduction: Congenital hypertrophy of the retinal pigment epithelium (CHRPE) has been associated with familial adenomatous polyposis (FAP) and may be the first presenting feature of the disease process. This case presents the diagnosis of CHRPE by ultra-wide field retinal laser scanning technology. A 68-year-old male who was seen in the outpatient ophthalmologic care setting for post-op follow-up 1 month after photorefractive keratectomy (PRK) of OU in both eyes and correction of retinal detachment (RD) of the (OS) left eye. This patient has also previously tolerated phacoemulsification (PE) and intraocular lens placement (IOL), with open capsule for a cataract and Lasik surgery of OU without complication. Patient came in with complaints of his distance vision not being as clear as before the RD. Near is closer in the OS than before. Post-op follow up included ultra-wide field retinal laser scanning that reveal an OS peripheral CHRPE, and vitelliform dystrophy. We recommended IOL and referred the patient to oncology and gastrotroenterology, where he was diagnosed and treated as a new incident case of FAP. The most common and very first extracolonic manifestation is CHRPE, with reports of expression in 36-90% of FAP kindred, and with a specificity of 95% for being a carrier of the APC tumor suppressor gene deletion that leads to FAP. This tumor suppressor gene was identified at the long arm of chromosome 5 (5q21). Guidelines using older technology recommended that patients with more than 3 CHRPE in 1 eye or bilateral CHRPE, as well as patients with a positive family history and 1 unilateral CHRPE require further gastroenterological evaluation. In the future, the use of ultra-wide field retinal laser technology may detect CHRPE earlier than standard diagnostics, and subsequently lead to timely care for FAP.Figure 1

A Case Report of Gardner’s Syndrome: A Familial Adenomatous Polyposis Variant

Introduction: Gardner syndrome is a rare autosomal dominant clinical variant of familial adenomatous polyposis. It is characterized by the prominence of inherited colonic adenomatosis together with osteomas, epidermoid cysts, desmoid tumors, and dental abnormalities. Along with familial adenomatous polyposis, Gardner syndrome can be explained by the mutation of the APC gene on chromosome 5q21-q22. In addition, the specific mutation of the MYH gene on chromosome 1p34.3-p32.1 may determine the extra-colonic manifestations found in Gardner syndrome, as well as the number, time frame, and malignant potential of the disorder. Due to its rarity, the exact prevalence of Gardner syndrome is unknown, as its statistical prevalence cannot be separated from familial adenomatous polyposis when considering reported studies. Estimates for the prevalence of the combined syndromes vary from 1 in 6,850 to 1 in 31,250 individuals. In this case report, we will present a patient with a prior diagnosis of Gardner syndrome who was seen for screening EGD and colonoscopy, and was found to have enlarging bilateral formed painful breast masses. In addition, the patient was also found to have various lesions biopsied and removed in the past, but continues to have clinically detectable cranial lesions and soft tissue lesions. Right breast mass needle biopsy performed and pathology resulted with fibrous tissue proliferation consistent with desmoid and fibromatosis. EGD resulted in innumerable number of polyps within the cardia, fundus, and proximal aspect of the greater curvature, as well as several large polyps in the second portion of the duodenum. Colonoscopy resulted in innumerable number of polyps throughout the colon from the rectum to the cecum. Polyps were biopsied during both exams, and pathology returned with an inflammatory, hyperplastic polyp in the stomach and tubular adenomas in the duodenum, cecum, and colon. Patients with Gardner syndrome and any familial adenomatous polyposis encompassing disease will require regular screening for numerous neoplastic transformations, as presented in this case. A prophylactic colectomy recommendation is unavoidable, and should be made early within the disease course in order to decrease patient’s risk of colorectal cancer formation. After surgical prophylaxis has been conducted, patients will continue to require lower gastrointestinal surveillance at anastomosis site, based on which surgical operation was performed, as well as lifetime upper gastrointestinal screening at varying intervals based on the Spigelman classification. Strict follow-up and surveillance guidelines remain a vital component to the treatment of these patients in order to reduce their lifetime morbidity and mortality.

APC rearrangements in familial adenomatous polyposis: heterogeneity of deletion lengths and breakpoint sequences underlies similar phenotypes.

Familial adenomatous polyposis (FAP) is a dominantly inherited syndrome leading to the development of multiple intestinal polyps and colorectal cancer. FAP is associated with germline defects of APC tumor suppressor gene; although truncating mutations account for the majority of cases, large APC deletions represent a common disease-causing defect. While a number of intragenic deletions have been well-characterized, sequencing data of breakpoints involved in large APC rearrangements are extremely scanty. We characterized six deletions identified by multiplex ligation-dependent probe amplification (three intragenic and three larger deletions encompassing the APC locus): in each case, we precisely mapped the breakpoints by array-comparative genomic hybridization and/or long-range PCR followed by sequencing. All rearrangements were novel and no rearrangements proved to be recurrent or clustered. The three intragenic deletions involved exons 4, 9 and 14, respectively; larger deletions (30,444, 265,471 and 921,295bp in length) involved APC as well as adjacent genes. Nine out of 12 breakpoints fell within repetitive elements (5 Alu, 2 LINE, 1 Tigger and 1 MIR), while the remaining 3 fell within unique sequences. In five out of six patients, non-allelic homologous recombination or non-homologous end joining appear as the most likely mechanisms behind APC rearrangements. Although a certain variability of clinical features was detectable both between and within families with deletions, all deletion carriers were classifiable as FAP patients showing colonic and extracolonic manifestations that belong to the spectrum of the syndrome. Therefore, different sized deletions, variable breakpoint localizations and haploinsufficiency for other genes besides APC, resulted in the same FAP clinical phenotype.

Molecular analysis of the APC gene in Sicilian patients with familial adenomatous polyposis (F.A.P.)

Familial adenomatous polyposis (FAP) is an autosomal dominant inherited syndrome, caused by germline mutations in the adenomatous polyposis coli (APC) suppressor gene. Patients with colorectal polyps are more likely to develop a malignant condition with poor prognosis. Typical FAP is characterized by hundreds to thousands of colorectal adenomatous polyps and by several extra-colonic manifestations; an attenuated form of polyposis (AFAP), presenting less than 100 adenomas and later onset, has been reported.In this study we have examined five Sicilian families affected by FAP syndrome, in order to provide predictive genetic testing for the affected families, as well as to contribute to mutation catalog enrichment.We have detected different APC mutations in these five pedigrees, confirming the remarkable heterogeneity of the mutational spectrum in FAP.

Colorectal Carcinomas, a Consideration on MUTYH-Associated Polyposis

: Colorectal cancer (CRC) is the second most prevalent cancer worldwide, and in 35% of cases it is an inherited form. The most common inherited forms of CRC include; Lynch syndrome, familial adenomatous polyposis (FAP), attenuated FAP, and MUTYH-associated polyposis (MAP). Although they are inherited, they have different phenotypic effects with regards to the number of polyposis, age of onset and the pattern of inheritance. Some of these CRCs are associated with other extracolonic manifestation symptoms. MUTYH-associated polyposis (MAP) was first described in 2002. MUTYH is a component of a base excision repair system that protects the genomic information from oxidative damage. When the MUTYH gene product is impaired by bi-allelic germline mutation, it leads to the mutation of cancer-related genes, such as the APC and/or the KRAS genes, via G to T transversion. MAP is a hereditary colorectal cancer syndrome inherited in an autosomal-recessive fashion. The proposed mechanism of individual CRC is distinguished in this review paper.

Promoter-specific alterations of APC are a rare cause for mutation-negative familial adenomatous polyposis.

n familial adenomatous polyposis (FAP), 20% of classical and 70% of attenuated/atypical (AFAP) cases remain mutation-negative after routine testing; yet, allelic expression imbalance may suggest an APC alteration. Our aim was to determine the proportion of families attributable to genetic or epigenetic changes in the APC promoter region. We studied 51 unrelated families/cases (26 with classical FAP and 25 with AFAP) with no point mutations in the exons and exon/intron borders and no rearrangements by multiplex ligation-dependent probe amplification (MLPA, P043-B1). Promoter-specific events of APC were addressed by targeted resequencing, MLPA (P043-C1), methylation-specific MLPA, and Sanger sequencing of promoter regions. A novel 132-kb deletion encompassing the APC promoter 1B and upstream sequence occurred in a classical FAP family with allele-specific APC expression. No promoter-specific point mutations or hypermethylation were present in any family. In conclusion, promoter-specific alterations are a rare cause for mutation-negative FAP (1/51, 2%). The frequency and clinical correlations of promoter 1B deletions are poorly defined. This investigation provides frequencies of 1/26 (4%) for classical FAP, 0/25 (0%) for AFAP, and 1/7 (14%) for families with allele-specific expression of APC. Clinically, promoter 1B deletions may associate with classical FAP without extracolonic manifestations.

Inducible loss of one Apc allele in Lrig1-expressing progenitor cells results in multiple distal colonic tumors with features of familial adenomatous polyposis.

Individuals with familial adenomatous polyposis (FAP) harbor a germline mutation in adenomatous polyposis coli (APC). The major clinical manifestation is development of multiple colonic tumors at a young age due to stochastic loss of the remaining APC allele. Extracolonic features, including periampullary tumors, gastric abnormalities, and congenital hypertrophy of the retinal pigment epithelium, may occur. The objective of this study was to develop a mouse model that simulates these features of FAP. We combined our Lrig1-CreERT2/+ mice with Apcfl/+ mice, eliminated one copy of Apc in leucine-rich repeats and immunoglobulin-like domains protein 1 (Lrig1)-positive (Lrig1(+)) progenitor cells with tamoxifen injection, and monitored tumor formation in the colon by colonoscopy and PET. Initial loss of one Apc allele in Lrig1(+) cells results in a predictable pattern of preneoplastic changes, culminating in multiple distal colonic tumors within 50 days of induction, as well as the extracolonic manifestations of FAP mentioned above. We show that tumor formation can be monitored by noninvasive PET imaging. This inducible stem cell-driven model recapitulates features of FAP and offers a tractable platform on which therapeutic interventions can be monitored over time by colonoscopy and noninvasive imaging.

Duodenal adenomatosis in Japanese patients with familial adenomatous polyposis.

Duodenal adenomatosis is the most frequent extracolonic manifestation of familial adenomatous polyposis (FAP), and duodenal cancer has been assumed to be the second most significant cause of death in patients with the disease. To stratify the risk of duodenal cancer, Spigelman's classification was proposed for the staging of duodenal adenomatosis. According to Western guidelines, patients with stage IV of the classification are candidates for prophylactic duodenectomy. Since our institutional experience disclosed only 2% of duodenal or ampullary cancers among 130 patients with FAP, and because most duodenal adenomatosis remains unchanged under endoscopic surveillance, it seems likely that aggressive endoscopic or surgical removal is unnecessary for most FAP patients with duodenal adenomatosis. In the present article, we demonstrate our data and present our strategy for duodenal adenomatosis of FAP.

Familial adenomatous polyposis: natural history and care of the patient

Familial adenomatous polyposis (FAP) is a rare, autosomal dominantly inherited condition. It is characterised by the development of hundreds to thousands of colorectal adenomas, which usually develop during adolescence (Bussey, 1975). The diagnosis of FAP is based clinically upon the identification of the colorectal adenomas, and may be confirmed by genetic testing. In many cases, a family history will reveal an autosomal dominant inheritance pattern. This article will review the natural history of FAP and discuss the care of this patient group. It will include the recommended screening and surgical options for the lower gastrointestinal tract and discuss suggestions for screening the upper gastrointestinal tract. The associated extra-colonic manifestations of FAP will be explained and the importance of a multidisciplinary approach for the care of these patients will be highlighted.

Surgical treatment of familial adenomatous polyposis: dilemmas and current recommendations.

Familial adenomatous polyposis (FAP) is an autosomal dominant inherited syndrome characterized by multiple adenomatous polyps (predisposing to colorectal cancer development) and numerous extracolonic manifestations. The underlying genetic burden generates variable clinical features that may influence operative management. As a precancerous hereditary condition, the rationale of performing a prophylactic surgery is a mainstay of FAP management. The purpose of the present paper is to bring up many controversial aspects regarding surgical treatment for FAP, and to discuss the results and perspectives of the operative choices and approaches. Preferably, the decision-making process should not be limited to the conventional confrontation of pros and cons of ileorectal anastomosis or restorative proctocolectomy. A wide discussion with the patient may evaluate issues such as age, genotype, family history, sphincter function, the presence or risk of desmoid disease, potential complications of each procedure and chances of postoperative surveillance. Therefore, the definition of the best moment and the choice of appropriate procedure constitute an individual decision that must take into consideration patient's preferences and full information about the complex nature of the disease. All these facts reinforce the idea that FAP patients should be managed by experienced surgeons working in specialized centers to achieve the best immediate and long-term results.

Familial risk-colorectal cancer: ESMO Clinical Practice Guidelines

J. Balmana1, F. Balaguer2, A. Cervantes3 & D. Arnold4, on behalf of the ESMO Guidelines Working Group* Department of Medical Oncology, Hospital Vall d’Hebron, Vall d’Hebron Institute of Oncology (VHIO), Universitat Autonoma de Barcelona, Barcelona; Department of Gastroenterology, Hospital Clinic, CIBERehd, IDIBAPS, University of Barcelona, Barcelona; Department of Hematology and Medical Oncology, INCLIVA, University of Valencia, Valencia, Spain; Department of Medical Oncology, Tumor Biology Clinic, Albert Ludwigs University, Freiburg, Germany;

Necrotizing Pancreatitis in a Patient with Gardnerʼs Variant Familial Adenomatous Polyposis

Purpose: To evaluate the etiology of necrotizing pancreatitis in a patient with Gardner's variant familial adenomatous polyposis (FAP). Review of patient records and literature review with OVID and PubMED. Patient was a 62-year-old male with Gardner's syndrome status-post colectomy and subsequent secondary proctectomy with ileostomy secondary to anastomatic tumor. Patient had high-grade dysplasia of papilla on prior EGD and was undergoing scheduled EGD as part of surveillance. After the endoscopy, the patient was discharged but within 10 minutes of discharge complained of severe pain and a stat CT showed no perforation but some stranding of pancreas. He was hemodynamically stable but labs were significant for WBC 21.04 (16.4 neutrophils, 0.13 bands), amylase 2,312, and lipase 4,477. Other labs were normal. Patient was admitted with pancreatitis and resuscitated aggressively. He was started on empiric antibiotic therapy and re-imaging revealed necrotizing pancreatitis. He continued to deteriorate with development of ARDS and sepsis. Patient was taken for ex-lap 29 days after the EGD with removal of 1.8 L of necrotic fluid. He succumbed to the complications and died 31 days after EGD. Review of literature revealed one other case of iatrogenic necrotizing pancreatitis in a patient with FAP.1 In a case similar to this, patient developed necrotizing pancreatitis after surveillance EGD. Even though the exact incidence of pancreatitis after biopsy is unknown, there appears to be an increased risk of pancreatitis in patients with FAP, even without endoscopic intervention. Classically, this has been attributed to development of obstructive ampullary adenomas (though the incidence of this is also rare). One retrospective review studied eight patients with Gardner's variant FAP who developed pancreatitis.2 Five of eight patients had obstructing focal or diffuse adenomatous disease involving the ampulla and the others had no identifiable cause. Finally, one case series suggests that patients with FAP are at increased risk of pancreatitis regardless of obstruction of ampulla.3 This series reviewed seven patients with FAP who experienced one or more episodes of pancreatitis. None of these patients had obstruction of the ampulla. Two of the seven patients developed pancreatitis after endoscopic treatment of ampullary adenoma, while the etiology of pancreatitis in the other five could not be determined. This suggests that pancreatitis may be a extra-colonic manifestation of FAP through an unknown mechanism. However, despite the risks of iatrogenic pancreatitis (with biopsy or with ampullary lesion) the risk of malignancy supports continued surveillance both ethically and clinically. This is the second case FAP in the literature to have fatal outcome after biopsy of papilla.

CLOSTRIDIUM DIFFICILE ENTERITIS COMPLICATING UNDIAGNOSED COELIAC DISEASE, A NEW CLINICAL PROBLEM?

IntroductionClostridium difficile (CD) represents the leading cause of health care associated infective diarrhea in the UK. Normally manifesting as infectious colitis, small bowel involvement known as CD enteritis is a...