Karen Byth

Endoscopic mucosal resection outcomes and prediction of submucosal cancer from advanced colonic mucosal neoplasia.

BACKGROUND & AIMS Large sessile colonic polyps usually are managed surgically, with significant morbidity and potential mortality. There have been few prospective, intention-to-treat, multicenter studies of endoscopic mucosal resection (EMR). We investigated whether endoscopic criteria can predict invasive disease and direct the optimal treatment strategy. METHODS The Australian Colonic Endoscopic (ACE) resection study group conducted a prospective, multicenter, observational study of all patients referred for EMR of sessile colorectal polyps that were 20 mm or greater in size (n=479, mean age, 68.5 y; mean lesion size, 35.6 mm). We analyzed data on lesion characteristics and procedural, clinical, and histologic outcomes. Multiple logistic regression analysis identified independent predictors of EMR efficacy and recurrence of adenoma, based on findings from follow-up colonoscopy examinations. RESULTS Risk factors for submucosal invasion were as follows: Paris classification 0-IIa+c morphology, nongranular surface, and Kudo pit pattern type V. The most commonly observed lesion (0-IIa granular) had a low rate of submucosal invasion (1.4%). EMR was effective at completely removing the polyp in a single session in 89.2% of patients; risk factors for lack of efficacy included a prior attempt at EMR (odds ratio [OR], 3.8; 95% confidence interval, 1.77-7.94; P=.001) and ileocecal valve involvement (OR, 3.4; 95% confidence interval, 1.20-9.52; P=.021). Independent predictors of recurrence after effective EMR were lesion size greater than 40 mm (OR, 4.37; 95% confidence interval, 2.43-7.88; P<.001) and use of argon plasma coagulation (OR, 3.51; 95% confidence interval, 1.69-7.27; P=.0017). There were no deaths from EMR; 83.7% of patients avoided surgery. CONCLUSIONS Large sessile colonic polyps can be managed safely and effectively by endoscopy. Endoscopic assessment identifies lesions at increased risk of containing submucosal cancer. The first EMR is an important determinant of patient outcome-a previous attempt is a significant risk factor for lack of efficacy.

Epidemiology and Host- and Variety-Dependent Characteristics of Infection Due to Cryptococcus neoformans in Australia and New Zealand

A prospective population-based study was conducted in Australia and New Zealand during 1994-1997 to elucidate the epidemiology of cryptococcosis due to Cryptococcus neoformans var. neoformans (CNVN) and C. neoformans var. gattii (CNVG) and to relate clinical manifestations to host immune status and cryptococcal variety. The mean annual incidence per 10(6) population was 6.6 in Australia and 2.2 in New Zealand. Of 312 episodes, CNVN caused 265 (85%; 98% of the episodes in immunocompromised hosts) and CNVG caused 47 (15%; 44% of the episodes in immunocompetent hosts). The incidence of AIDS-associated cases in Australia declined annually (P<.001). Aborigines in rural or semirural locations (P<.001) and immunocompetent males (P<.001) were at increased risk of CNVG infection. Cryptococcomas in lung or brain were more common in immunocompetent hosts (P< or =.03) in whom there was an association only between lung cryptococcomas and CNVG. An AIDS-associated genetic profile of CNVN serotype A was confirmed by random amplification of polymorphic DNA analysis. Resistance to antifungal drugs was uncommon. The epidemiology of CNVN infection has changed substantially. Clinical manifestations of disease are influenced more strongly by host immune status than by cryptococcal variety.

Dermoscopic Evaluation of Amelanotic and Hypomelanotic Melanoma

OBJECTIVE To determine the predictive dermoscopic features of amelanotic and hypomelanotic melanoma. DESIGN A total of 105 melanomas (median Breslow thickness, 0.76 mm), 170 benign melanocytic lesions, and 222 nonmelanocytic lesions lacking significant pigment (amelanotic, partially pigmented, and light colored) were imaged using glass-plate dermoscopy devices and scored for 99 dermoscopic features. Diagnostic models were derived from and tested on independent randomly selected lesions. SETTING Predominantly hospital-based clinics from 5 continents. MAIN OUTCOME MEASURES Sensitivity, specificity, and odds ratios for individual features and models for the diagnosis of melanoma and malignancy. RESULTS The most significant negative predictors of melanoma were having multiple (>3) milialike cysts (odds ratio, 0.09; 95% confidence interval, 0.01-0.64), comma vessels with a regular distribution (0.10; 0.01-0.70), comma vessels as the predominant vessel type (0.16; 0.05-0.52), symmetrical pigmentation pattern (0.18; 0.09-0.39), irregular blue-gray globules (0.20; 0.05-0.87), and multiple blue-gray globules (0.28; 0.10-0.81). The most significant positive predictors were having a blue-white veil (odds ratio,13; 95% confidence interval, 3.9-40.0), scarlike depigmentation (4.4; 2.4-8.0), multiple blue-gray dots (3.5; 1.9-6.4), irregularly shaped depigmentation (3.3; 2.0-5.3), irregular brown dots/globules (3.2; 1.8-5.6), 5 to 6 colors (3.2; 1.6-6.3), and predominant central vessels (3.1; 1.6-6.0). A simple model distinguishing melanomas from all nonmelanomas had a sensitivity of 70% and a specificity of 56% in the test set. A model distinguishing all malignant lesions from benign lesions had a sensitivity of 96% and a specificity of 37%. Conclusion Although the diagnostic accuracy of dermoscopy for melanoma lacking significant pigment is inferior to that of more pigmented lesions, features distinguishing the former from benign lesions can be visualized on dermoscopic evaluation.

Long-term adenoma recurrence following wide-field endoscopic mucosal resection (WF-EMR) for advanced colonic mucosal neoplasia is infrequent: results and risk factors in 1000 cases from the Australian Colonic EMR (ACE) study

Objective Wide-field endoscopic mucosal resection (WF-EMR) is an alternative to surgery for treatment of advanced colonic mucosal neoplasia up to 120 mm in size, but has been criticised for its potentially high recurrence rates. We aimed to quantify recurrence at 4 months (early) and 16 months (late) following successful WF-EMR and identify its risk factors and clinical significance. Design Ongoing multicentre, prospective, intention-to-treat analysis of sessile or laterally spreading colonic lesions ≥20 mm in size referred for WF-EMR to seven academic endoscopy units. Surveillance colonoscopy (SC) was performed 4 months (SC1) and 16 months (SC2) after WF-EMR, with photographic documentation and biopsy of the scar. Results 1134 consecutive patients were enrolled when 1000 successful EMRs were achieved, of whom 799 have undergone SC1. 670 were normal. Early recurrent/residual adenoma was present in 128 (16.0%, 95% CI 13.6% to 18.7%). One case was unknown. The recurrent/residual adenoma was diminutive in 71.7% of cases. On multivariable analysis, risk factors were lesion size >40 mm, use of argon plasma coagulation and intraprocedural bleeding. Of 670 with normal SC1, 426 have undergone SC2, with late recurrence present in 17 cases (4.0%, 95% CI 2.4% to 6.2%). Overall, recurrent/residual adenoma was successfully treated endoscopically in 135 of 145 cases (93.1%, 95% CI 88.1% to 96.4%). If the initial EMR was deemed successful and did not contain submucosal invasion requiring surgery, 98.1% (95% CI 96.6% to 99.0%) were adenoma-free and had avoided surgery at 16 months following EMR. Conclusions Following colonic WF-EMR, early recurrent/residual adenoma occurs in 16%, and is usually unifocal and diminutive. Risk factors were identified. Late recurrence occurs in 4%. Overall, recurrence was managed endoscopically in 93% of cases. Recurrence is not a significant clinical problem following WF-EMR, as with strict colonoscopic surveillance, it can be managed endoscopically with high success rates. Trial registration number: NCT01368289.

Genotype-specific mechanisms for hepatic steatosis in chronic hepatitis C infection

Abstract Background: Hepatic steatosis is common in hepatitis C, but the relative importance of host and viral factors is controversial. In the present prospective study, we examined metabolic factors associated with non‐alcoholic fatty liver and viral genotype as predictors of steatosis and fibrosis in chronic hepatitis C infection.

What is the best predictor of spontaneous ventricular tachycardia and sudden death after myocardial infarction

BackgroundDeath during the first year after myocardial infarction is most commonly due to spontaneous ventricular tachycardia (VT) or fibrillation (VF). The purpose of this study was to compare, in a single cohort of patients, the values of inducible VT, delayed ventricular activation, low left ventricular ejection fraction, high-grade ventricular ectopy, and ST segment displacement on exercise in predicting electrical events (witnessed instantaneous death and spontaneous VT or VF) during the first year after myocardial infarction. Methods and ResultsThree hundred sixty one patients aged less than 71 years underwent electrophysiological study, signal-averaged electrocardiogram, gated blood-pool scan, 24 hour ambulatory electrocardiographic monitoring, and exercise testing 1-2 weeks after myocardial infarction and were then followed up for at least 1 year. There were 34 deaths (eight witnessed instantaneous, 26 other), and nine patients survived one or more episodes of spontaneous VF or VT. Patients with inducible VT were 15.2 times more likely to suffer electrical events than patients without inducible VT. No proportional-hazards model excluding inducible VT was as good a predictor of electrical events as was inducible VT alone. ConclusionsInducible VT at electrophysiological study was the single best predictor of spontaneous VT and sudden death after myocardial infarction. (Circulation 1991;83:756–763)

Herpes Simplex Virus Type 1 Capsid Protein Vp26 Interacts With Dynein Light Chains Rp3 And Tctex1 And Plays A Role In Retrograde Cellular Transport.

Cytoplasmic dynein is the major molecular motor involved in minus-end-directed cellular transport along microtubules. There is increasing evidence that the retrograde transport of herpes simplex virus type 1 along sensory axons is mediated by cytoplasmic dynein, but the viral and cellular proteins involved are not known. Here we report that the herpes simplex virus outer capsid protein VP26 interacts with dynein light chains RP3 and Tctex1 and is sufficient to mediate retrograde transport of viral capsids in a cellular model. A library of herpes simplex virus capsid and tegument structural genes was constructed and tested for interactions with dynein subunits in a yeast two-hybrid system. A strong interaction was detected between VP26 and the homologous 14-kDa dynein light chains RP3 and Tctex1. In vitro pull-down assays confirmed binding of VP26 to RP3, Tctex1, and intact cytoplasmic dynein complexes. Recombinant herpes simplex virus capsids were constructed either with or without VP26. In pull-down assays VP26+ capsids bound to RP3; VP26-capsids did not. To investigate intracellular transport, the recombinant viral capsids were microinjected into living cells and incubated at 37 °C. After 1 h VP26+ capsids were observed to co-localize with RP3, Tctex1, and microtubules. After 2 or 4 h VP26+ capsids had moved closer to the cell nucleus, whereas VP26-capsids remained in a random distribution. We propose that VP26 mediates binding of incoming herpes simplex virus capsids to cytoplasmic dynein during cellular infection, through interactions with dynein light chains.

Impact of endoscopic intervention in 100 patients with suspected postcholecystectomy bile leak.

BACKGROUND Bile leak is a recognized complication of cholecystectomy. Endoscopic intervention is widely accepted as a treatment for this complication, but the optimal form is not well defined. METHODS An ERCP database was reviewed retrospectively to identify all cases of bile leak related to cholecystectomy. Patient records and endoscopy reports were reviewed, and structured telephone interviews were conducted to collect data. RESULTS A total of 100 patients (61 women, 39 men; mean age, 53 [17] years) with suspected postcholecystectomy bile leak were referred for ERCP. Cholecystectomy was commenced laparoscopically in 83 patients (with an open conversion rate of 30%). The most common symptoms were pain (n = 62) and fever (n = 37). Cholangiography was obtained in 96 patients. A leak was identified in 80/96 patients, the most common site being the cystic-duct stump (48), followed by ducts of Luschka (15), the T-tube site (7), and other sites (10). Treatment included stent insertion alone (40), sphincterotomy alone (18), combination stent/sphincterotomy (31), none (6), and other (1). Three patients with major bile-duct injuries were excluded from the analysis. Endoscopic therapy was unsuccessful in 7 patients (6 in the sphincterotomy alone group; p = 0.001). Four patients underwent surgery subsequent to ERCP to control the leak. All 4 were in the sphincterotomy alone group ( p = 0.001). Post-ERCP pancreatitis developed in 4 patients (3 mild, 1 moderate). CONCLUSIONS The optimal endoscopic intervention for postcholecystectomy bile leak should include temporary insertion of a biliary stent.

Pre-translational regulation of cytochrome P450 genes is responsible for disease-specific changes of individual P450 enzymes among patients with cirrhosis

We have recently reported that disease-specific differential alterations in the hepatic expression of xenobiotic-metabolizing cytochrome P450 (CYP P450) enzymes occur in patients with advanced liver disease. In order to determine whether the observed changes in CYP proteins are modulated at pre- or post-translational levels, we have now examined the hepatic levels of mRNA for CYPs 1A2, 2C9, 2E1 and 3A4 by solution hybridization in the same livers of 20 controls (surgical waste from histologically normal livers), 32 cases of hepatocellular and 18 of cholestatic severe chronic liver disease. CYP1A2 mRNA and CYP1A immunoreactive protein were both reduced in livers with hepatocellular and cholestatic types of cirrhosis. In contrast, CYP3A4 mRNA and protein were reduced only in livers from patients with hepatocellular diseases. For 1A2 and 3A4 there were significant correlations between mRNA species and the respective protein contents (rS1A2 = 0.74, rS3A4 = 0.64, P < 0.0001). CYP2C9 mRNA was reduced in patients with both cholestatic and hepatocellular types of liver disease, but 2C protein was reduced only in patients with cholestatic dysfunction. The correlation between CYP2C9 mRNA and protein, was also significant (rs = 0.36, P < 0.005) but mRNA levels accounted for only 13% of the variability in protein rankings. This is probably a consequence of other CYP2C proteins apart from 2C9 being detected by the anti-2C antibody. CYP2E1 mRNA and protein were reduced in patients with cholestatic liver disease, but in hepatocellular disease the expression of only CYP2E1 mRNA was decreased. CYP2E1 mRNA was significantly correlated with CYP2E1 protein but accounted for only 18% of the variability in protein rankings (rs = 0.43, P < 0.0005). Taken collectively these data indicate that the disease-specific alterations of xenobiotic-metabolizing CYP enzymes among patients with cirrhosis is due, at least in part, to pre-translational mechanisms. The lack of a strong correlation between CYP2E1 mRNA and protein suggests that this gene, like its rat orthologue, may be subject to pre-translational as well as translational and/or post-translational regulation.

Huntington's disease: clinical correlates of disability and progression.

Objective: To define the phenotypic variation in a large population of patients with Huntington disease (HD) and to identity clinical features that predict disability and the rate of disease progression. Methods: The authors analyzed data on 1,026 patients, followed for a median of 2.7 years, using a mixed effects model. The factors studied included the age at onset, the major clinical feature at onset, the severity of motor and cognitive impairment, and the level of disability. Results: The mean age at onset was 41.5 (range 8 to 83) years, and patients were enrolled at all stages of disease. Younger onset was associated with more dystonia, less chorea, and a faster rate of motor, cognitive, and functional progression. The rate of progression was not related to the major clinical feature at onset or the sex of the affected parent. Disability correlated with the motor score (excluding chorea and dystonia) and the symbol-digit modalities test. Weight loss correlated with severe chorea. Conclusions: The rate of progression of HD was significantly more rapid with a younger age at onset. Therefore, CAG repeat length may be an important determinant of not only the age at onset, but also the rate of disease progression. Chorea was associated with weight loss, but chorea and dystonia were not major determinants of disability.