Paul Crotty

The management of insulinoma

Insulinomas are rare tumours. Their clinical presentation, localization techniques and operative management were reviewed.

Gastric Mucosal Mast Cells Are Increased in Helicobacter pylori-Negative Functional Dyspepsia

BACKGROUND & AIMS Mast cells might be involved in pathogenesis of functional dyspepsia because they can release a wide range of potent mediators, capable of altering gastric nerve and muscle function. This study aimed to determine whether mast cell numbers were increased in the gastric mucosa of patients with functional dyspepsia compared to control subjects. METHODS Biopsy samples were taken from the antrum and corpus of 111 patients: 20 asymptomatic control subjects, 62 patients with Rome criteria functional dyspepsia (33 Helicobacter pylori positive, 29 H. pylori negative), and 29 inflammatory control subjects (H. pylori positive). Mast cells were detected immunohistochemically by using a mouse monoclonal antibody specific for tryptase. Quantification was performed with light microscopy, and results were expressed as mast cells/mm(2) +/- standard error of mean. RESULTS Mast cells were significantly increased in H. pylori negative functional dyspepsia samples compared to normal control samples in the antrum (230.1 +/- 11.3 vs. 94.8 +/- 8.4, P < 0.001) and corpus (264.1 +/- 27.1 vs. 123.9 +/- 11.5, P = 0.001). Mast cells were also significantly increased in the antrum of patients with H. pylori positive functional dyspepsia compared to asymptomatic control subjects (166.5 +/- 17.0 vs. 94.8 +/- 8.4, P < 0.03). However, there was no significant difference between mast cell numbers in patients with H. pylori positive functional dyspepsia compared to inflammatory control subjects. CONCLUSIONS Mast cells are increased in functional dyspepsia, independently of inflammation. This might contribute to the pathogenesis of functional dyspepsia by altering signaling in the brain-gut axis.

NUT Midline Carcinoma in a Young Woman

Case Report A 22-year-old Latvian woman presented to the accident and emergency department with a 3-week history of nonproductive cough and right-sided pleuritic chest pain. Her medical, surgical, and family histories were unremarkable. Socially, she smoked approximately 20 cigarettes per day and drank alcohol infrequently. Examination of her chest was significant for right basal crepitations, reduced breath sound on auscultation, and stoney dullness on percussion, clinically consistent with a right-sided pleural effusion. Laboratory investigations were significant for elevated WBC of 14.5 10mm/L (normal range [NR], 4.0 to 11.0 10mm/L) consisting predominantly of neutrophils (11.3 10mm/L; NR, 2.0 to 7.5 10mm/L), raised C-reactive protein (155 mg/L; NR, 0 to 5 mg/L), and lactate dehydrogenase (LDH; 762 u/L; NR, 100 to 350 u/L). Chest radiograph demonstrated a right-sided pleural effusion and widening of the mediastinum, suggestive of a hilar mass (Fig 1). Computed tomography (CT) of the thorax confirmed a large 13 11 cm right anterior upper mediastinal mass with extension into the right lower lobe and a pleural effusion (Figs 2A, cross-sectional CT of thorax at diagnosis; 2B, coronal view of right anterior medistinal mass at diagnosis). The differential diagnosis was extensive, but because the clinical picture was suggestive of lymphoma, a positron emission tomography/CT scan was performed. There were multiple focal abnormal areas of fluorodeoxyglucose accumulation in the visualized axial and appendicular skeleton, suggestive of bone marrow involvement. Pleurocentesis confirmed an exudate but demonstrated nonmalignant cytology. Endoscopic ultrasound–guided core biopsy of the mediastinal mass revealed a neoplastic process consisting of small to moderately sized neoplastic cells with focal areas of necrosis. Immunohistochemistry staining ruled out lymphoma. The tumor demonstrated a high proliferative index with focal cytokeratin staining of uncertain significance. The differential diagnosis now included Ewing’s sarcoma, synovial sarcoma, or another rare variant of poorly differentiated carcinoma. Because more tissue was required, bone marrow samples were obtained. Hematoxylin and eosin (HE) staining showed hypercellular marrow with approximately 50% replacement by malignant cells of intermediate size with high nuclear to cytoplasmic ratio (Fig 3A, low-power HE staining of bone marrow biopsy demonstrating replacement of marrow space by tumor cells on left). A majority of the cells were dyshesive, with some focal cohesive growth pattern and no clear pattern of differentiation (Fig 3B, high-power HE staining of bone marrow biopsy demonstrating medium to large tumor cells with dyshesive growth pattern). Immunohistochemistry showed focal positivity for pan-cytokeratin AE1/AE3, CK7, and CK19; diffuse expression of EMA and CD99; and scanty vimentin positivity, with no evidence of melanocytic, germ cell, or mesothelial differentiation (Fig 3C, immunohistochemical staining for AE1/3). Molecular testing for the transcripts associated with synovial sarcoma was negative. Given the patient’s age and presence of disseminated disease in the context of a mediastinal mass, a diagnosis of NUT carcinoma was considered. Sections sent for immunohistochemical staining at the Brigham and Women’s Hospital (Boston, MA) were positive for expression of nuclear protein in testis (NUT), confirming this diagnosis (Fig 3D). At confirmation of diagnosis, the patient had worsening chest pain and elevated LDH of 13,525 U/L. Intensive chemotherapy (doxorubicin 60 mg/m day 1 and ifosfamide 1,750 mg/m continuous infusion days 1 to 3, every 3 weeks) was urgently administered. Within 10 days of chemotherapy administration, the patient had clinically improved, and LDH had fallen to 2,000 U/L. She was discharged from the hospital and received two additional treatment cycles without complications. Despite this initial improvement, she was readmitted to the hospital before her fourth treatment cycle with worsening chest pain and dyspnea. CT scan confirmed marked disease progression, with compromise of the superior vena cava and obliteration of the right main bronchus (Figs 4A, crosssectional CT of thorax at 3 months postdiagnosis; 4B, coronal view of CT of thorax at 3 months postdiagnosis). She deteriorated rapidly over 3 days and died.

BRAF T1799A Mutation Occurring in a Case of Malignant Struma Ovarii

Struma ovarii is an extremely rare tumor that occasionally undergoes malignant transformation. Because struma ovarii is composed of thyroid tissue, it is conceivable that the pathogenetic events involved in thyroid follicular transformation may take place also in struma ovarii. The authors describe a case of a classical variant of papillary thyroid carcinoma arising in a struma ovarii of a 22-year-old female. The tumor was heterozygous for BRAF T1799A mutation. No ret/ PTC-1 or ret/PTC-3 rearrangements were detected. This finding would suggest that malignant struma ovarii is similar histologically and genetically to primary papillary thyroid carcinoma.

Increased spontaneous apoptosis, but not survivin expression, is associated with histomorphologic response to neoadjuvant chemoradiation in rectal cancer

PurposeSurvivin has been shown to be an important mediator of cellular radioresistance in vitro. This study aims to compare survivin expression and apoptosis to histomorphologic responses to neoadjuvant radiochemotherapy (RCT) in rectal cancer.Materials and methodsThirty-six pre-treatment biopsies were studied. Survivin mRNA and protein expression plus TUNEL staining for apoptosis was performed. Response to treatment was assessed using a 5-point tumour regression grade.ResultsSurvivin expression was not found to be predictive of response to RCT (p = NS). In contrast, spontaneous apoptosis was significantly (p = 0.0051) associated with subsequent response to RCT. However, no association between survivin expression and levels of apoptosis could be identified.ConclusionsThis in vivo study failed to support in vitro studies showing an association between survivin and response to chemotherapy and radiation therapy. These results caution against the translation of the in vitro properties of survivin into a clinical setting.

Invasive markers identified by gene expression profiling in pancreatic cancer

BACKGROUND Molecular profiling has proven utility as a diagnostic and predictive tool in clinical oncology. However, a clinically relevant gene expression profile in pancreatic cancer remains elusive. METHODS Primary and metastatic pancreatic cancer cell lines (BxPC-3 and AsPC-1), were stimulated with phorbol-12-myristate 13-acetate (PMA), a known inducer of cell invasion. Affymetrix gene expression microarray analysis was performed, comparing gene expression to unstimulated controls. Differential expression was identified using ArrayAssist, and confirmed using quantitative real-time PCR. Bioinformatic analysis was performed using Pathway Studio and GOstat. The derived gene expression was further validated in fresh frozen pancreatic tumour samples. The ability of the derived 3 gene expression markersto differentiate between pancreatic adenocarcinoma (PDAC) and other neoplasms, and its association with clinicopathological variables was examined. RESULTS PMA-induced significant changes in cell line gene expression, from which distinctive 3 potential invasive markers were derived. Expression of these genes, uPA, MMP-1 and IL1-R1 was confirmed in human pancreatic tumours, and was found to differentiate PDAC from other pancreatic neoplasms. The expression of IL1-R1 in PDAC is a novel finding. We found that the expression of MMP-1 was associated with high-grade PDAC (p = 0.035, Wilcoxon rank sum). CONCLUSION We have identified three potential invasive markers, uPA, MMP-1 and IL1-R1, whose gene expression may differentiate PDAC from other pancreatic neoplasms, and potentially reflect a more invasive phenotype.

The Irish helicobacter pylori Working Group consensus for the diagnosis and treatment of h. pylori infection in adult patients in Ireland

Background Irish eradication rates for Helicobacter pylori are decreasing and there is an increase in the prevalence of antibiotic-resistant bacteria. These trends call into question current management strategies. Objective To establish an Irish Helicobacter pylori Working Group (IHPWG) to assess, revise and tailor current available recommendations. Methods Experts in the areas of gastroenterology and microbiology were invited to join the IHPWG. Questions of relevance to diagnosis, first-line and rescue therapy were developed using the PICO system. A literature search was performed. The ‘Grading of Recommendations Assessment, Development and Evaluation’ approach was then used to rate the quality of available evidence and grade the resulting recommendations. Results Key resultant IHPWG statements (S), the strength of recommendation and quality of evidence include S8: standard triple therapy for 7 days’ duration can no longer be recommended (strong and moderate). S9: 14 days of clarithromycin-based triple therapy with a high-dose proton pump inhibitor (PPI) is recommended as first-line therapy. Bismuth quadruple therapy for 14 days is an alternative if available (strong and moderate). S12: second-line therapy depends on the first-line treatment and should not be the same treatment. The options are (a) 14 days of levofloxacin-based therapy with high-dose PPI, (b) 14 days of clarithromycin-based triple therapy with high-dose PPI or (c) bismuth quadruple therapy for 14 days (strong and moderate). S13: culture and antimicrobial susceptibility testing should be performed following two treatment failures (weak and low/very low). Conclusion These recommendations are intended to provide the most relevant current best-practice guidelines for the management of H. pylori infection in adults in Ireland.

Isolated active ileitis: is it a mild subtype of Crohn's disease?

Background:Ileal intubation is being increasingly performed at colonoscopy and has in turn lead to an increasingly recognized subgroup of patients—those with mild terminal ileal inflammation, an entity that we have coined isolated active ileitis (IAI). The aims of this study were to define the natural history of IAI and determine if IAI shares a similar genetic and serologic profile with Crohn’s disease (CD). Methods:Patients with IAI were identified from our institutions histopathology and endoscopy databases. Cases attended for repeat colonoscopy and blood were analyzed for the expression of antineutrophil cytoplasmic antibody, anti-OmpC, anti-Saccharomyces cerevisiae antigen (ASCA) IgA, ASCA IgG, and anti-CBir antibodies and NOD2 genotyping. Age and sex-matched healthy controls, CD, and UC cases were also recruited. Results:Sixty-three patients with IAI were recruited. There was no significant difference in the prevalence of antibodies between IAI cases and healthy controls for antineutrophil cytoplasmic antibody, OmpC, ASCA IgA, or ASCA IgG. The presence of all 5 antibodies was significantly higher in the CD group than the IAI group, P < 0.05. There were 28.6% of CD cases that carried one or more NOD2 variants, compared to 26.2% of the IAI cohort and 6.1% of healthy controls. Forty-three cases underwent follow-up ileocolonoscopy. Six of 43 cases (14%) had definite CD. Conclusions:A majority of IAI cases developed persistent symptoms and terminal ileal abnormalities; however, only 14% developed classical, histological, or radiological features of CD. Although patients with IAI have a low level of seropositivity, similar to healthy controls, they do share an excess of NOD2 mutations with CD cases.

Small cell cervical cancer: an unusual finding at cholecystectomy.

BackgroundSmall cell carcinoma of the cervix is a rare cancer, comprising less than 3% of all cervical neoplasms. It uniformly has a poor prognosis, and has a high mortality even with early stage disease. It can metastasise rapidly and metastatic sites include lung, liver, brain, bone, pancreas and lymph nodes.CaseHere, we report the case of a 60-year-old woman with no symptoms of cervical pathology who developed post-renal failure following a laparoscopic cholecystectomy. The cause was bilateral ureteric obstruction from metastatic small cell cervical cancer and metastases were subsequently found on her gallbladder specimen.ConclusionThis is an unusual presentation of small cell cervical cancer and demonstrates the aggressive nature of this disease.

Assessment of the clinical significance of intestinal spirochaetosis.

Background: Spirochaetes are well known causative agents of diarrhoea in veterinary medicine. However, there is no agreement as to whether or not they have any clinical significance in humans. Aims: To assess the symptoms associated with intestinal spirochaetosis, their response to treatment and the natural history of untreated cases. Methods: A retrospective review of all cases of intestinal spirochaetosis identified within an eight year period in a single university teaching hospital was performed. A chart review and follow up telephone interview was performed to assess the indications for colonoscopy that led to the diagnosis, treatment received, and duration and nature of symptoms. Results: 18 cases were identified. The indications for colonoscopy were diarrhoea in 50% and rectal bleeding in 16.7%; also investigation of constipation, anaemia and abdominal pain, and in two cases reassessment of chronic proctitis. Two subjects were treated with metronidazole and two were treated with aminosalicylates. 69% had complete resolution of symptoms at follow-up, 15% had persistent symptoms and 15% had intermittent symptoms. Of the two patients treated with metronidazole, one had resolution of symptoms and one has persistent abdominal pain. Conclusion: Symptoms do not appear to parallel spirochaete persistence or eradication and therefore it seems appropriate to adopt a wait and see approach to treatment of patients in whom spirochaetes are identified, giving a trial of antimicrobial treatment only in those who have severe or persistent symptoms. Careful consideration of both host and pathogen should be undertaken.