Impact of controlled attenuation parameter on detecting fibrosis using liver stiffness measurement.

BACKGROUND: Liver fibrosis is often accompanied by steatosis, particularly in patients with non-alcoholic fatty liver disease (NAFLD), and its non-invasive characterisation is of utmost importance. Vibration-controlled transient elastography is the non-invasive method of choice; however, recent research suggests that steatosis may influence its diagnostic performance. Controlled Attenuation Parameter (CAP) added to transient elastography enables simultaneous assessment of steatosis and fibrosis. AIM: To determine how to use CAP in interpreting liver stiffness measurements. METHODS: This is a secondary analysis of data from an individual patient data meta-analysis on CAP. The main exclusion criteria for the current analysis were unknown aetiology, unreliable elastography measurement and data already used for the same research question. Aetiology-specific liver stiffness measurement cut-offs were determined and used to estimate positive and negative predictive values (PPV/NPV) with logistic regression as functions of CAP. RESULTS: Two thousand and fifty eight patients fulfilled the inclusion criteria (37% women, 18% NAFLD/NASH, 42% HBV, 40% HCV, 51% significant fibrosis ≥ F2). Youden optimised cut-offs were only sufficient for ruling out cirrhosis (NPV of 98%). With sensitivity and specificity-optimised cut-offs, NPV for ruling out significant fibrosis was moderate (70%) and could be improved slightly through consideration of CAP. PPV for significant fibrosis and cirrhosis were 68% and 55% respectively, despite specificity-optimised cut-offs for cirrhosis. CONCLUSIONS: Liver stiffness measurement values below aetiology-specific cut-offs are very useful for ruling out cirrhosis, and to a lesser extent for ruling out significant fibrosis. In the case of the latter, Controlled Attenuation Parameter can improve interpretation slightly. Even if cut-offs are very high, liver stiffness measurements are not very reliable for ruling in fibrosis or cirrhosis.

Synchronization dynamics on the picosecond time scale in coupled Josephson junction neurons.

Conventional digital computation is rapidly approaching physical limits for speed and energy dissipation. Here we fabricate and test a simple neuromorphic circuit that models neuronal somas, axons, and synapses with superconducting Josephson junctions. The circuit models two mutually coupled excitatory neurons. In some regions of parameter space the neurons are desynchronized. In others, the Josephson neurons synchronize in one of two states, in-phase or antiphase. An experimental alteration of the delay and strength of the connecting synapses can toggle the system back and forth in a phase-flip bifurcation. Firing synchronization states are calculated >70 000 times faster than conventional digital approaches. With their speed and low energy dissipation (10^{-17}J/spike), this set of proof-of-concept experiments establishes Josephson junction neurons as a viable approach for improvements in neuronal computation as well as applications in neuromorphic computing.

Prognosis and management of adult wild type gastrointestinal stromal tumours (GISTs): A pooled analysis and review of literature.

A pooled review was performed to determine survival in adult WT GIST (Wild Type GastroIntestinal Stromal Tumours) and compare the same with pediatric WT GISTs. Electronic databases were searched using the terms "Wild type" AND "GIST". Eighty-two adult patients from 14 studies were included in the pooled analysis. Cumulative survival was greater than 50% in both age groups, hence medial survival could not be computed. Mean survival in adults was 15.7 years ± 0.78 and in children was 18.8 years ± 1.3 (p = 0.241). Median disease free survival in adults was 10 years while 5-year overall survival was 88%. There was no statistically significant difference in the survival between the two groups (p = 0.241). Overall survival in adults with WT GISTs is favourable compared to other adult GIST subtypes likely reflects a common molecular pathway similar to pediatric GIST.

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.

A changing trend in the management of patients with newly diagnosed Crohn's disease.

BACKGROUND: Epidemiologic shift with rising incidence of Crohn's disease (CD) has been reported in recent studies. AIMS: To determine disease behaviour and therapeutic interventions undertaken in newly diagnosed patients with CD. METHODS: Patients diagnosed with CD between January 2006 and June 2008 were included. Disease type, location, degree of involvement and type of therapeutic interventions were recorded. RESULTS: A total of 78 patients were included. Colonic, ileo-colonic, terminal ileal and isolated small bowel disease were present in 37, 27, 9 and 5 patients, respectively. Disease phenotype was inflammatory, stenosing and fistulising in 42, 30 and 6 patients, respectively. Surgery was required in 22 patients, including right hemicolectomy (n = 8), subtotal colectomy (n = 4), segmental colonic resection (n = 2), segmental small bowel resection (n = 2), appendectomy (n = 2) and perianal surgery (n = 4). Fourteen patients underwent surgery at the time of diagnosis. Laparoscopic surgery was performed in 14 patients. CONCLUSIONS: A significant proportion of newly diagnosed patients with CD underwent surgical intervention on their first admission to hospital. This may signify a changing trend in the management approach.

Malignant priapism: a case report.

BACKGROUND: Metastatic involvement of the penis is most commonly from a primary malignant genitourinary tumour. It is a rare phenomenon usually reflecting disseminated malignancy associated with a poor prognosis. Metastasis to the penis mimicking priapism is extremely rare, particularly in the absence of disseminated disease. MATERIALS AND METHODS: We describe a case of painful priapism caused by a high-grade urothelial malignancy without disseminated disease. CONCLUSION: Life expectancy is estimated at less than 1 year in these patients. Our patient remains in clinical and radiologic remission over 36 months from his original radical surgery.

Hepatic lymphangioma: a rare cause of abdominal pain in a 30-year-old female.

BACKGROUND: Lymphangiomas are rare tumours usually found in the paediatric population in extra abdominal sites. AIM: To report on a patient with a hepatic lymphangioma. RESULT: A 30-year-old woman presented with a 4-year history of right upper quadrant pain. Ultrasound and CT imaging demonstrated a cystic mass adjacent to the gallbladder. Histology of the resected specimen conferred a diagnosis of hepatic lymphangioma. CONCLUSION: We present a case of hepatic lymphangioma together with a review of diagnostic and therapeutic strategies currently available.

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.

Silver nitrate cauterisation, does concentration matter?

Epistaxis from the anterior septum is frequently treated with a topical application of silver nitrate. There are two concentrations commercially available and in use by otolaryngologists, these are 75% and 95% silver nitrate. The purpose of the present study was to investigate the histological effect of the two different silver nitrate concentrations on mucosal tissue at a fixed contact time of 5 s. Twelve children undergoing routine tonsillectomy were included in this study. Prominent blood vessels on the mucosal surface of the tonsils were identified and a single vessel on each tonsil was selected for application of either 75% or 95% concentration of silver nitrate for 5 s. Depth of penetration across the tonsil tissue was measured following application of the two different silver nitrate concentrations. This study demonstrated a significant difference in depth of tissue penetration with the 95% averaging a twofold increase in penetration depth. It is likely that the increased depth of penetration with 95% silver nitrate may increase the risk of complication of nasal cautery such as septal perforation, particularly in patients undergoing repeated or bilateral nasal cautery.

Non-seminomatous testicular metastasis mimicking acute appendicitis.

This is the first report in the literature of a non-seminomatous metastasis from an occult testicular primary that presented as an acute appendicitis. The report highlights the necessity of testicular re-imaging in cases of occult malignancy and reviews the association of chromosome 12 with embryonal germ cell tumours.

The management of insulinoma.

BACKGROUND: Insulinomas are rare tumours. Their clinical presentation, localization techniques and operative management were reviewed. METHODS: An electronic search of the Medline, Embase and Cochrane databases was undertaken for articles published between January 1966 and June 2005 on the history, presentation, clinical evaluation, use of imaging techniques for tumour localization and operative management of insulinoma. RESULTS AND CONCLUSION: Most insulinomas are intrapancreatic, benign and solitary. Biochemical diagnosis is obtained during a supervised 72-h fast. Non-invasive preoperative imaging techniques to localize lesions continue to evolve. Intraoperative ultrasonography can be combined with other preoperative imaging modalities to improve tumour detection. Surgical resection is the treatment of choice. In the absence of preoperative localization and intraoperative detection of an insulinoma, blind pancreatic resection is not recommended.

Morphologically distinct patterns of apoptosis correlate with size and high-grade dysplasia in colonic adenomas.

AIMS: To examine the relationship of morphological patterns of apoptosis in colonic adenomas to standard pathological variables. METHODS AND RESULTS: Apoptosis patterns were evaluated in 184 consecutive colonic adenomas and 14 adenocarcinomas, using haematoxylin and eosin sections. Apoptosis identification was selectively validated by electron microscopy. There were three patterns of apoptosis: (i) confluent basal apoptosis; (ii) crypt lumen apoptosis, both assessed semiquantitatively; and (iii) scattered apoptosis (not quantified). Adenoma site, size, type, mitoses, and grade of dysplasia were also assessed. MIB-1 immunostaining was performed in 20 cases. In 142 adenomas (77%) confluent basal apoptosis (n = 124) and/or crypt lumen apoptosis (n = 69) were identified; 42 (23%) had scattered apoptosis only. Significant correlations were: (i) extensive confluent basal apoptosis with small adenomas < or =5 mm (P < 0.0001); (ii) crypt lumen apoptosis with large adenomas >5 mm (P < 0.0001) and (iii) with high-grade dysplasia (P < 0.0003); and (iv) coexistence of both patterns (n = 51) with large adenomas >5 mm (P < 0.0001). Neither apoptosis pattern correlated with other variables. Adenocarcinomas had minimal confluent basal apoptosis (5/14), conspicuous crypt lumen apoptosis (14/14), intraglandular coagulative necrosis, and scattered apoptotic tumour cells. CONCLUSIONS: Confluent basal apoptosis is maximal early in colonic tumorigenesis. The 'switch' to a predominant crypt lumen apoptosis pattern suggests that a different apoptosis induction mechanism might be associated with the transition to adenocarcinoma.

Carditis: all Helicobacter pylori or is there a role for gastro-oesophageal reflux?

BACKGROUND: Recent epidemiological studies have reported a threefold increase in the incidence of adenocarcinoma of the lower oesophagus and gastro-oesophageal junction (cardia). There are conflicting reports available implicating both gastro-oesophageal reflux disease and Helicobacter pylori infection in the aetiology of carditis and cardia intestinal metaplasia, despite strong evidence to show that these two conditions are, if anything, inversely related. We aimed to determine the prevalence of carditis and cardia intestinal metaplasia in dyspeptic subjects and also their association with H. pylori infection and gastro-oesophageal reflux disease. METHOD: Histological samples from the gastric cardia were obtained from dyspeptic subjects. H. pylori status was assessed based on histological, microbiological and rapid urease testing. Gastro-oesophageal disease was diagnosed on the basis of histological evidence and/or erosive oesophagitis. Patient demographics were recorded. Cardia intestinal metaplasia (CIM), when present, was subgrouped as complete or incomplete. RESULTS: Overall, 276 subjects were enrolled; 163 (59%) had carditis and 36 (13%) CIM. H. pylori infection and gastro-oesophageal reflux disease occurred in 64 (23%) and 150 (54%), respectively. H. pylori infection was strongly associated with carditis and CIM (P<0.001 and P<0.01). Older age and male gender were also associated with inflammation and intestinal metaplasia of the cardia. Gastro-oesophageal reflux was not associated with either entity. CONCLUSION: Carditis and CIM occur frequently. Both conditions are strongly associated with H. pylori infection, older age and male gender. There was no association with gastro-oesophageal reflux disease.

Morphologic, immunophenotypic, and molecular evaluation of bone marrow involvement in non-Hodgkin's lymphoma.

The diagnosis of marrow involvement in non-Hodgkin's lymphoma (NHL) relies on morphology with support from immunophenotyping by flow cytometry (FCM). We assessed the relative sensitivity of morphology, FCM, and consensus primer polymerase chain reaction (PCR) of antigen receptor genes in the detection of marrow involvement. In 78 of 100 (78%) cases, there was concordance between FCM and PCR. FCM detected more cases of clonality in B-cell neoplasia. There were 40 cases with objective evidence of involvement by B-cell neoplasia. In this group, FCM had a sensitivity of 97.5% (39 of 40); PCR had a sensitivity of 67.5% (27 of 40). In contrast, PCR had a sensitivity of 71.4%, and FCM a sensitivity of 28.6%, in T-cell neoplasia. In all 12 cases with involvement detected by biopsy, there was objective evidence of clonality. However, clonality was detected in four of seven patients with chronic lymphocytic leukemia and in five of eight patients with T-cell neoplasia in the absence of morphologically detectable disease. Clonality was identified in only one of seven patients with B-cell lymphoma in which the biopsy was interpreted as "suspicious but not diagnostic of involvement." We conclude that morphology remains of central importance in the evaluation of marrow involvement in NHL. We show that FCM and PCR identify involvement in the absence of morphologically apparent disease. In B-cell neoplasms, FCM remains the method of choice for the detection of clonality. PCR for T-cell receptor gene rearrangements may be an important adjunct to the diagnosis of marrow involvement in patients with T-cell neoplasms.

Mycosis fungoides palmaris et plantaris or acral pagetoid reticulosis?

There has been ongoing debate about the nature of Woringer-Kolopp disease (unilesional pagetoid reticulosis). Despite the histologic resemblance to mycosis fungoides, these lesions are typically solitary and indolent. Recently, cutaneous plaques of epidermotropic lymphocytes restricted to acral sites resembling Woringer-Kolopp disease were reported to show T-cell clonality, leading to the designation mycosis fungoides palmaris et plantaris. We describe a similar case of recurrent plaques on palms and soles of a 45-year-old man that persisted for >14 years without other cutaneous or systemic disease. Histologically, the lesions were comprised of epidermotropic atypical lymphocytes with sparse dermal infiltrates. Immunohistochemically, the majority of intraepidermal lymphocytes labeled as CD8-positive suppressor/cytotoxic T cells and expressed alphaE beta7 (CD103), an integrin associated with epitheliotropism. Polymerase chain reaction studies revealed similar clonal gene rearrangements of T-cell receptors beta and gamma in tissue from both palm and sole. In view of these findings, the diagnosis of mycosis fungoides palmaris et plantaris may be appropriate. To date, however, the lesions have remained localized and continue to resolve spontaneously. As such, the behavior is similar to what has been described as pagetoid reticulosis. Long-term follow-up will be necessary to determine the biologic potential of this disease.