Haemolytic uraemic syndrome - a rare case report of bloody diarrhoea in adults.

BACKGROUND: Haemolytic uraemic syndrome is a rarely seen in adults often leading to critical illness. This case highlights how difficult it can be to establish a diagnosis and treat when a patient presents with bloody diarrhoea. CASE PRESENTATION: A 17-year-old Iraqi man presented to the emergency department with abdominal pain and bloody diarrhoea. He was initially treated as acute appendicitis, undergoing an appendectomy but following a recurrence in his symptoms a colonoscopy was performed. A diagnosis of shiga toxin-producing Escherichia coli leading to HUS was suspected following histology obtained at colonoscopy and this was confirmed on antibody testing. Despite intravenous fluids and supportive therapy the patient's symptoms and condition deteriorated. He developed seizures and acute renal failure requiring intubation and plasma exchange in the intensive care setting. He eventually required treatment with ecluzimab therapy; a monoclonal antibody and subsequently made a full recovery. CONCLUSIONS: Haemolytic uraemic syndrome is a triad of progressive renal failure, thrombocytopenia and haemolytic anaemia which is a condition rarely seen in adults. It is usually associated with an E. coli infection and supportive therapy remains the mainstay of treatment.

Distribution of the c-MYC gene product in colorectal neoplasia.

AIMS: Recent attempts to study MYC distribution in human samples have been confounded by a lack of agreement in immunohistochemical staining between antibodies targeting the N-terminus and those targeting the C-terminus of the MYC protein. The aim of this study was to use a novel in-situ hybridization (ISH) approach to detect MYC mRNA in clinically relevant samples, and thereby determine the reliability of MYC-targeting antibodies. METHODS AND RESULTS: We performed immunohistochemistry on human formalin-fixed paraffin embedded normal colon (n = 15), hyperplastic polyp (n = 4) and neoplastic colon samples (n = 55), using the N-terminally directed antibody Y69, and the C-terminally directed antibody 9E10. The MYC protein distributions were then compared with the location of MYC mRNA, determined by ISH. We found that the localization of MYC mRNA correlated well with the protein distribution determined with the N-terminally directed antibody Y69, and was also associated with expression of the proliferation marker Ki67. The protein distribution determined with the C-terminally directed antibody 9E10 was not always associated with MYC mRNA, Y69, or Ki67, and indeed often showed a reciprocal pattern of expression, with staining being strongest in non-proliferating cells. CONCLUSIONS: The observed discrepancy between the staining patterns suggests that the significance of 9E10 in immunohistochemical staining is currently uncertain, and therefore should be interpreted with caution.

Pneumocystis pneumonia complicating immunosuppressive therapy in Crohns disease: A preventable problem?

We report the case of a 76-year-old man who presented with moderate active Crohn's colitis that was refractory to high-dose corticosteroids, mesalazine and 6-mercaptopurine. He subsequently received a trial of infliximab with poor response and was diagnosed with cytomegalovirus (CMV) colitis, improving on antiviral therapy. Three weeks into treatment he developed acute respiratory distress with hypoxaemia and diffuse pulmonary interstitial infiltrates. This was confirmed as Pneumocystis jirovecii on bronchoalveolar lavage. He responded well to treatment with trimethoprim-sulfamethoxazole (TMP-SMX) and was subsequently discharged home. Despite the favourable outcome, our case raises the question of whether chemoprophylaxis against opportunistic infections in immunosuppressed patients with inflammatory bowel disease (IBD) is appropriate. There are currently no recommendations on providing chemoprophylaxis against CMV colitis and so we focus on pneumocystis pneumonia (PCP) where wide debate surrounds the use of prophylactic TMP-SMX in HIV-negative patients. Contrasting approaches to chemoprophylaxis against PCP in IBD likely relates to a lack of clear parameters for defining risk of PCP among patient groups. This must be addressed in order to develop universal guidelines that take into account patient-dependent risk factors. Awareness of the severity of PCP among HIV-negative individuals and the current consensus on PCP prophylaxis in IBD must be raised in order to minimise the risk of PCP and drive research in this controversial area.

Glucagon receptor gene mutations with hyperglucagonemia but without the glucagonoma syndrome.

Pancreatic neoplasms producing exclusively glucagon associated with glucagon cell hyperplasia of the islets and not related to hereditary endocrine syndromes have been recently described. They represent a novel entity within the panel of non-syndromic disorders associated with hyperglucagonemia. This case report describes a 36-year-old female with a 10 years history of non-specific abdominal pain. No underlying cause was evident despite extensive diagnostic work-up. More recently she was diagnosed with gall bladder stones. Abdominal ultrasound, computerised tomography and magnetic resonance imaging revealed no pathologic findings apart from cholelithiasis. Endoscopic ultrasound revealed a 5.5 mm pancreatic lesion. Fine needle aspiration showed cells focally expressing chromogranin, suggestive but not diagnostic of a low grade neuroendocrine tumor. OctreoScan(®) was negative. Serum glucagon was elevated to 66 pmol/L (normal: 0-50 pmol/L). Other gut hormones, chromogranin A and chromogranin B were normal. Cholecystectomy and enucleation of the pancreatic lesion were undertaken. Postoperatively, abdominal symptoms resolved and serum glucagon dropped to 7 pmol/L. Although H and E staining confirmed normal pancreatic tissue, immunohistochemistry was initially thought to be suggestive of alpha cell hyperplasia. A count of glucagon positive cells from 5 islets, compared to 5 islets from 5 normal pancreata indicated that islet size and glucagon cell ratios were increased, however still within the wide range of normal physiological findings. Glucagon receptor gene (GCGR) sequencing revealed a heterozygous deletion, K349_G359del and 4 missense mutations. This case may potentially represent a progenitor stage of glucagon cell adenomatosis with hyperglucagonemia in the absence of glucagonoma syndrome. The identification of novel GCGR mutations suggests that these may represent the underlying cause of this condition.

Divergent effects of liraglutide, exendin-4, and sitagliptin on beta-cell mass and indicators of pancreatitis in a mouse model of hyperglycaemia.

AIMS: Glucagon-like peptide-1 (GLP-1) receptor agonists and dipeptidyl peptidase-4 (DPP4) inhibitors improve glucose tolerance by still incompletely understood mechanisms. Each class of antihyperglycemic drugs has also been proposed to increase pancreatitis risk. Here, we compare systematically the effects of two widely-used GLP-1 analogues, liraglutide and exendin-4, and the DPP4 inhibitor, sitagliptin, in the mouse. METHODS: C57BL6 mice were maintained for 131 days on a normal diet (ND) or a diet comprising 60% fat (HFD) before measurements of fasting blood glucose and insulin, and intraperitoneal glucose tolerance. Beta- and alpha- cell volume, and Reg3b immunoreactivity, were measured by immunohistochemical analysis of pancreatic slices. RESULTS: Whereas liraglutide (200 µg/kg) and exendin-4 (10 µg/kg) treatment reduced body weight and/or improved glucose tolerance, sitagliptin (10 mg/kg) was without effect on either parameter. Liraglutide caused a sharp reduction in beta-cell mass in both ND and HFD mice, whereas exendin-4 exerted no effect. By contrast, sitagliptin unmasked an action of high fat diet to increase beta-cell mass. Reg3B positive area was augmented by all three agents in normal chow-fed mice, whilst sitagliptin and exendin-4, but not liraglutide, affected this parameter in HFD animals. Correspondingly sitagliptin, but not the GLP-1 analogues, increased circulating amylase levels in ND and HFD mice. CONCLUSIONS: Liraglutide improves glucose tolerance in the mouse whilst exerting relatively modest effects on pancreatitis risk. Conversely, exendin-4 and sitagliptin, at doses which exert, respectively, minor or no effects on metabolic parameters, lead to signs of pancreatitis.

Growth arrest-specific transcript 5 associated snoRNA levels are related to p53 expression and DNA damage in colorectal cancer.

BACKGROUND: The growth arrest-specific transcript 5 gene (GAS5) encodes a long noncoding RNA (lncRNA) and hosts a number of small nucleolar RNAs (snoRNAs) that have recently been implicated in multiple cellular processes and cancer. Here, we investigate the relationship between DNA damage, p53, and the GAS5 snoRNAs to gain further insight into the potential role of this locus in cell survival and oncogenesis both in vivo and in vitro. METHODS: We used quantitative techniques to analyse the effect of DNA damage on GAS5 snoRNA expression and to assess the relationship between p53 and the GAS5 snoRNAs in cancer cell lines and in normal, pre-malignant, and malignant human colorectal tissue and used biological techniques to suggest potential roles for these snoRNAs in the DNA damage response. RESULTS: GAS5-derived snoRNA expression was induced by DNA damage in a p53-dependent manner in colorectal cancer cell lines and their levels were not affected by DICER. Furthermore, p53 levels strongly correlated with GAS5-derived snoRNA expression in colorectal tissue. CONCLUSIONS: In aggregate, these data suggest that the GAS5-derived snoRNAs are under control of p53 and that they have an important role in mediating the p53 response to DNA damage, which may not relate to their function in the ribosome. We suggest that these snoRNAs are not processed by DICER to form smaller snoRNA-derived RNAs with microRNA (miRNA)-like functions, but their precise role requires further evaluation. Furthermore, since GAS5 host snoRNAs are often used as endogenous controls in qPCR quantifications we show that their use as housekeeping genes in DNA damage experiments can lead to inaccurate results.

Poorly-differentiated signet-ring cell carcinoma of the ampulla of Vater: report of a rare malignancy.

CONTEXT: Signet-ring cell carcinoma (SRCC) of the ampulla of Vater is a very rare clinical entity, which is infrequently reported in medical literature. CASE REPORT: A 78-year-old woman was admitted with jaundice, pruritus and postprandial vomiting. Abdominal ultrasound and computed tomography scanning demonstrated gross dilatation of the common bile and pancreatic ducts with gallbladder calculi. Endoscopic retrograde cholangiopancreatography suggested a duodenal tumour at the ampulla. The patient underwent Whipple's procedure with cholecystectomy. Immunohistopathological examination confirmed poorly-differentiated SRCC of the ampulla of Vater. The tumour had infiltrated the duodenal muscularis propria and pancreatic parenchyma, but local lymph nodes were clear (T3N0M0). The patient was disease-free at 6-month follow-up. CONCLUSIONS: We here report a case of poorly-differentiated SRCC of the Ampulla of Vater. The majority of patients with such tumours undergo pancreaticoduodenectomy, which affords good outcomes in early disease. However, owing to the rarity of cases, the exact prognosis of ampullary SRCC remains as yet undetermined.

Reactive lymphoid hyperplasia of the pancreas: a clinical conundrum.

CONTEXT: Localized reactive lymphoid hyperplasia is a rare condition characterized by the presence of lymphoid follicles. CASE REPORT: We describe a case of a 60-year-old woman who presented with right upper quadrant pain and was found to have a reactive nodular hyperplasia of the pancreas involving the uncinate process, body and tail of the gland. Due to the multifocal distribution of these hypoechoic vascular lesions, a total pancreatectomy was performed since malignancy could not be safely excluded. CONCLUSION: There have been a handful of cases reporting reactive lymphoid hyperplasia affecting the pancreas; however, it is uncommon to perform such a radical pancreatic resection for this benign condition.

Tumor infiltration in the medial resection margin predicts survival after pancreaticoduodenectomy for pancreatic ductal adenocarcinoma.

BACKGROUND: Microscopic tumor involvement (R1) in different surgical resection margins after pancreaticoduodenectomy (PD) for pancreatic ductal adenocarcinoma (PDAC) has been debated. METHODS: Clinico-pathological data for 258 patients who underwent PD between 2001 and 2010 were retrieved from a prospective database. The rates of R1 resection in the circumferential resection margin (pancreatic transection, medial, posterior, and anterior surfaces) and their prognostic influence on survival were assessed. RESULTS: For PDAC, the R1 rate was 57.1% (48/84) for any margin, 31.0% (26/84) for anterior surface, 42.9% (36/84) for posterior surface, 29.8% (25/84) for medial margin, and 7.1% (3/84) for pancreatic transection margin. Overall and disease-free survival for R1 resections were significantly worse than those for R0 resection (17.2 vs. 28.7 months, P = 0.007 and 12.3 vs. 21.0 months, P = 0.019, respectively). For individual margins, only medial positivity had a significant impact on survival (13.8 vs. 28.0 months, P < 0.001), as opposed to involvement in the anterior (19.7 vs. 23.3 months, P = 0.187) or posterior margin (17.5 vs. 24.2 months, P = 0.104). Multivariate analysis demonstrated R0 medial margin was an independent prognostic factor (P = 0.002, HR = 0.381; 95% CI 0.207-0.701). CONCLUSION: The medial surgical resection margin is the most important after PD for PDAC, and an R1 resection here predicts poor survival.

MicroRNAs targeting oncogenes are down-regulated in pancreatic malignant transformation from benign tumors.

BACKGROUND: MicroRNA (miRNA) expression profiles have been described in pancreatic ductal adenocarcinoma (PDAC), but these have not been compared with pre-malignant pancreatic tumors. We wished to compare the miRNA expression signatures in pancreatic benign cystic tumors (BCT) of low and high malignant potential with PDAC, in order to identify miRNAs deregulated during PDAC development. The mechanistic consequences of miRNA dysregulation were further evaluated. METHODS: Tissue samples were obtained at a tertiary pancreatic unit from individuals with BCT and PDAC. MiRNA profiling was performed using a custom microarray and results were validated using RT-qPCR prior to evaluation of miRNA targets. RESULTS: Widespread miRNA down-regulation was observed in PDAC compared to low malignant potential BCT. We show that amongst those miRNAs down-regulated, miR-16, miR-126 and let-7d regulate known PDAC oncogenes (targeting BCL2, CRK and KRAS respectively). Notably, miR-126 also directly targets the KRAS transcript at a "seedless" binding site within its 3'UTR. In clinical specimens, miR-126 was strongly down-regulated in PDAC tissues, with an associated elevation in KRAS and CRK proteins. Furthermore, miR-21, a known oncogenic miRNA in pancreatic and other cancers, was not elevated in PDAC compared to serous microcystic adenoma (SMCA), but in both groups it was up-regulated compared to normal pancreas, implicating early up-regulation during malignant change. CONCLUSIONS: Expression profiling revealed 21 miRNAs down-regulated in PDAC compared to SMCA, the most benign lesion that rarely progresses to invasive carcinoma. It appears that miR-21 up-regulation is an early event in the transformation from normal pancreatic tissue. MiRNA expression has the potential to distinguish PDAC from normal pancreas and BCT. Mechanistically the down-regulation of miR-16, miR-126 and let-7d promotes PDAC transformation by post-transcriptional up-regulation of crucial PDAC oncogenes. We show that miR-126 is able to directly target KRAS; re-expression has the potential as a therapeutic strategy against PDAC and other KRAS-driven cancers.

Gastrointestinal stromal tumours treated before and after the advent of c-kit immunostaining.

BACKGROUND: Recently developed immunohistochemical markers have revolutionised the classification of gastrointestinal stromal tumours (GISTs) whilst tyrosine kinase inhibitors (imatinib) have had a significant impact on the treatment of advanced tumours. We review the clinicopathological features of previously resected mesenchymal tumours of the gastrointestinal tract in our institution to 1) reclassify the histological diagnosis of those stained prior to c-kit availability; 2) perform survival analysis to identify prognostic factors, and 3) to consider the implications for patients. METHODS: Clinicopathological records of patients with a diagnosis of mesenchymal tumours treated between May 1992 and April 2007 were reviewed. RESULTS: 82 patients were reviewed. 26 (32%) were reclassified as GISTs following c-kit immunostaining and a further 14 patients were treated for GIST up to April 2007 (Total: 40 patients; 21 males and 19 females, mean age 67, range 30-92 years). 36 (90%) underwent complete resection. 5-year survival of patients with GIST alone was 80%. Females had a better median survival (M: F 43 months: 73 months). CONCLUSIONS: The availability of c-kit staining allowed 32% of previously diagnosed mesenchymal tumours to be reclassified as GISTs. This may have implications for the follow-up of patients diagnosed prior to the availability of this method.

Differential expression of p53 and p504s in hyperplastic polyp, sessile serrated adenoma and traditional serrated adenoma.

AIMS: Known collectively as serrated polyps, hyperplastic polyps (HP), sessile serrated adenomas (SSA/SSP) and traditional serrated adenoma (TSA) may represent a spectrum of increasing malignant potential with characteristic immunological markers. There is increasing evidence that HP, SSA/SSP and TSA are biologically different and are likely to represent a spectrum along the serrated polyp pathway. Although there is general consensus about the diagnostic features of serrated polyps, the morphological differences between the categories are often subtle. This study compares the expression of p53 and P504S among serrated polyps. Sixty seven randomly selected biopsies (n = 59) and resection specimens (n = 8) histologically diagnosed for SSA/SSP, TSA and HP (19, 30 and 18 specimens, respectively) were obtained. METHODS AND RESULTS: There was a significant difference in p53 (P < 0.001) and P504S (P < 0.001) immunopositivity and distribution among the serrated polyps. In particular, there is diffuse expression p53 and P504S in TSA compared to HP and SSA/SSP where p53 and P504S expression was more frequently confined to the lower 1/3 of the crypts. In addition, percentage of cells expressing p53 and p504S expression was higher in TSA than those of HP and SSA/SSP. CONCLUSION: Immunostains, p53 and P504S, may be useful adjuncts to morphological diagnosis of serrated polyps.

En bloc resection of the pancreatic head and second part of duodenum for a duodenal gastrointestinal stromal tumor: a multi-media report.

Duodenal gastrointestinal stromal tumors are rare tumors. When these tumors arise from the second part of the duodenum they can easily be misdiagnosed as a pancreatic head cancer. A case of a 37-year-old female presenting with a one-year history of right upper quadrant pain is described here, who was subsequently found to have a mass in the head of the pancreas. Computed tomography scans showed a 2 cm hypervascular lesion lying between the head of pancreas and the second part of the duodenum, suggestive of a neuroendocrine tumor, and confirmed by endoscopic ultrasound scan. She underwent a pancreatic head resection with duodenal segmentectomy. Histopathological and immunohistochemical analysis revealed the tumor to be peri-ampullary duodenal gastrointestinal stromal tumor not invading the pancreas. Duodenal gastrointestinal stromal tumor can have a wide spectrum of clinical presentation. The accurate diagnosis of duodenal gastrointestinal stromal tumor is essential for determining the appropriate surgical intervention. In our case, a conservative surgical approach was utilised therefore avoiding a formal pancreaticoduodenectomy.

Wide-field fluorescence lifetime imaging of cancer.

Optical imaging of tissue autofluorescence has the potential to provide rapid label-free screening and detection of surface tumors for clinical applications, including when combined with endoscopy. Quantitative imaging of intensity-based contrast is notoriously difficult and spectrally resolved imaging does not always provide sufficient contrast. We demonstrate that fluorescence lifetime imaging (FLIM) applied to intrinsic tissue autofluorescence can directly contrast a range of surface tissue tumors, including in gastrointestinal tissues, using compact, clinically deployable instrumentation achieving wide-field fluorescence lifetime images of unprecedented clarity. Statistically significant contrast is observed between cancerous and healthy colon tissue for FLIM with excitation at 355 nm. To illustrate the clinical potential, wide-field fluorescence lifetime images of unstained ex vivo tissue have been acquired at near video rate, which is an important step towards real-time FLIM for diagnostic and interoperative imaging, including for screening and image-guided biopsy applications.

The McKittrick-Wheelock syndrome: a case of acute renal failure due to neoplastic cholera.

The McKittrick-Wheelock syndrome is characterized by severe electrolyte and fluid depletion as a result of rectal tumor hypersecretion. Typically, a metabolic acidosis ensues. We report the case of a 58-year-old man who presented with a mixed metabolic acidosis and alkalosis. He was hyponatremic, hypokalemic, and hypochloremic, with acute renal failure on blood testing. Following fluid resuscitation, a predominant alkalemia was observed. The patient was found to be passing 1.5 L of mucous per rectum per day, containing high concentrations of sodium and potassium, similar to that observed in cholera stool. A large rectal villous adenoma was discovered on sigmoidoscopy, and definitive management was achieved by removal of the tumor. This case provides a demonstration of the ranging metabolic disturbance associated with secretory diarrhea. Other endogenous and infective causes are discussed, and mechanisms compared with the case described.