Inaug.-Diss.--Zürich. / Vita. Bibliography: p. [25]-27.

Inaug.-Diss.--Heidelberg.

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Alpha-methyacyl-CoA racemase (AMACR) is a critical peroxisomal and mitochondrial enzyme, encodes a key enzyme in the catabolism of long-chain fatty acid thus is indispensable in the £]-oxidation of fatty acid to generate biological energy. AMACR stands in many organs with only very low expression level and its overexpression is exclusively in neoplastic conditions. Recently, AMACR overexpresison has been discerned to relevant to tumor progression of prostate, gastric, and colon cancers, and its overexpression has now been introduced in pathological differential diagnosis of prostate carcinoma from non-malignant mimickers. By using 89 gallbladder carcinoma (GBCA) samples for AMACR immunostaining we found AMACR overexpression is frequently discerned in GBCA. It not only significantly correlates with numerous adverse clinicopathologic factors but also manifests a significant independent predictor of worse outcome in GBCA patients. In multivariate comparison, higher tumor stage represented the strongest prognosticator (p = 0.0101), followed by old patient age (p = 0.0378). Moreover, AMACR overexpression also identified patients at around 2-fold higher risk of disease-specific death (p = 0.0452). By Western blot analyses, we found AMACR expression in the metastatic cells, RCB1129, was apparently more abundant than that in its primary lesion RCB1130. By XTT analyses, the viability of both RCB1129 and RCB1130 cells were significantly decreased by AMACR inhibitor. The RCB1129 cell line, with more abundant AMACR protein expression, was more resistant to AMACR inhibitor treatment than RCB1130 cell line at various drug concentrations. Our data suggest AMACR is a prognostic marker that can serve as a promising therapeutic target in gallbladder cancer.

No description available.

Background: Biliary sludge is associated with gallbladder (GB) dysmotility and mucus hypersecretion suggesting that these factors could lead to GB mucoceles. If biliary sludge does progress to GB mucoceles, treatments to reduce the production and progression of sludge are warranted. Objectives: The aim of this study was to determine the natural history of biliary sludge in dogs. Animals: Healthy, client-owned dogs (n=74) screened for biliary sludge; 42 affected dogs identified Methods: Prospective, observational design. Serial ultrasound examinations and biochemistries were evaluated over 1 year. The following were determined: percentage of the GB filled with sludge (mild (0.01%-24.4%), moderate (24.5%-49.4%), moderate to severe (49.5%-74.4%), severe (74.5%-100%)), gravity dependency of sludge, GB dimensions, and biochemical indices (ALT, GGT, ALP, total bilirubin, albumin, total calcium, triglycerides, and cholesterol). Mixed model ANOVA, Friedman chi-square, Mantel-Haenzsel chi-square tests, and Kruskal-Wallis test were performed to detect significant changes in these parameters. Significance at P <0.05. Results: After 1 year of follow-up, the percentage of the GB filled by sludge was mild (34%), moderate (47%), moderate to severe (13%), severe (3%), or absent (3%) with no significant difference in the median degree of biliary sludge within 1 year (P=0.36). There was no significant change in the gravity dependency of sludge over 1 year. Dogs had resolved (2%), decreased (19%), static (40%), increased (29%), or recurrent (10%) sludge at the conclusion of the study. Biochemical indices or GB volume were not significantly different over time or among groups. Conclusion: Biliary sludge is prevalent, affected dogs remain asymptomatic, and it rarely resolves in healthy dogs over a period of 1 year. Some dogs developed non-gravity dependent sludge within 1 year, which may indicate changes in consistency. / Master of Science

Background: The pathogenesis of gallbladder mucocele is unknown in the dog. It has been proposed that hyperlipidemia could impair gallbladder motility and contribute to gallbladder mucocele formation. Objectives: The objective of this study was to compare gallbladder motility in dogs with hyperlipidemia to healthy, control dogs using ultrasonography. We hypothesized that hyperlipidemic dogs have decreased gallbladder motility, defined by increased fasting gallbladder volume (GBV) and decreased gallbladder ejection fractions at 60 (EF60) and 120 minutes (EF120) compared to controls. Animals: 26 hyperlipidemic dogs, 28 healthy control dogs Methods: Twenty-six hyperlipidemic and 28 healthy, age-matched control dogs were prospectively enrolled. Hyperlipidemia was defined as hypercholesterolemia (>332 mg/dL) and/or hypertriglyceridemia (>143 mg/dL). Dogs with both primary and secondary causes of hyperlipidemia were included. All dogs were fasted for at least 12 hours prior to collection of plasma biochemistry and pre-prandial ultrasound. Ultrasound was performed on dogs in the fasted state as well as at 60 and 120 minutes after being fed 10g/kg of a high fat diet (Hill's a/d diet; Hill's Pet Nutrition, Topeka, Kansas, USA). GBVs and EFs were calculated using the following formulas: GBV = (0.52 x L x W x H)/kg and EF = ((GBV0- GBV60,120)/GBV0) x 100, respectively. GBV0, GBV60, GBV120, EF60 and EF120 were compared between dogs with hyperlipidemia and controls using the Wilcoxon rank sum test. Statistical significance was set to p<0.05. Results: Hypercholesterolemia and hypertriglyceridemia were present in 15/26 (58%) and 21/26 (81%) hyperlipidemic dogs, respectively and 10/26 (38%) had elevations in both parameters. The median age in both groups was 10 years. Median (range) cholesterol concentration was 346 mg/dL (181-1372 mg/dL) and 238 mg/dL (153-324) in hyperlipidemic and control dogs, respectively. Median triglyceride concentration was 330 mg/dL (52-2213) and 65.5 mg/dL (32-142) in hyperlipidemic and control dogs, respectively. Eleven (42%) hyperlipidemic dogs were considered severely hyperlipidemic based on the triglyceride and/or cholesterol concentrations above 500 mg/dL. There were significant differences in GBV0 and GBV60 between hyperlipidemic and control dogs. Dogs with severe hyperlipidemia had significantly larger GBVs at all time points. Dogs with hypercholesterolemia also had significantly greater GBVs at all times compared to dogs without hypercholesterolemia. Median EF60 and EF120 were not significantly different between hyperlipidemic and control dogs nor severely hyperlipidemic and mildly hyperlipidemic dogs. Conclusions: Hyperlipidemic dogs have significantly greater fasting and postprandial GBVs but similar ejection fractions when compared to control dogs. Gallbladder emptying is unaltered in hyperlipidemic dogs, but gallbladder volume is higher in hyperlipidemic dogs after feeding. This distention could contribute to bile retention of bile and potentially gallbladder disease. / Master of Science / The gallbladder (GB) is a reservoir for bile. The GB contracts to deliver bile to the intestines after a meal to help with digestion of nutrients and fats, and to rid the body of harmful waste. When the GB becomes diseased, abnormal bile flow can become toxic to the liver and endanger the patient's health. One of the most common GB diseases in dogs is GB mucocele (buildup of mucus in the GB). The cause of GB mucocele formation is not well understood. One proposed cause is decreased contractions of the GB related to increased cholesterol and/or elevated triglycerides (hyperlipidemia). Our study investigated whether hyperlipidemia leads to poor gallbladder contraction, possibly explaining GB mucocele formation. We used ultrasound scans before and after eating to compare gallbladder motility in dogs with hyperlipidemia to healthy, control dogs. We hypothesized that hyperlipidemic dogs would have decreased gallbladder motility compared to controls. Twenty-six dogs with elevated cholesterol and/or elevated triglycerides and 28 healthy, age-matched control dogs were enrolled. Ultrasound was performed on dogs in the fasted state as well as 60 and 120 minutes after being fed. There were significant differences in findings between affected dogs and control dogs. Dogs with very high blood lipid levels had significantly larger gall bladder volumes (GBVs). Dogs with high cholesterol also had significantly greater GBVs at all times compared to normal dogs. This finding indicates that excessive bile may be retained in the gall bladders of dogs with hyperlipidemia, possibly affecting the function of the organ. Our study also looked at difference between the two groups in measures of ejection fraction, which can gage how efficiently the gall bladder releases bile. No differences were noted between the healthy group and the affected group. Conclusions and Outcomes: Hyperlipidemic dogs have significantly greater GBVs than control dogs both before and after eating, but similar ejection fractions. This study provides a clearer understanding of the mechanisms of gall bladder disfunction in dogs.

A Dissertation submitted to the Faculty of Health Sciences, University of the Witwatersrand, in fulfilment of the requirements for the Degree of Masters of Medicine in the branch of General Surgery, Johannesburg 2018 / Gallbladder cancer (GBCa) has a dismal prognosis, with poor short-term and long-term outcomes, even following surgery and all current adjuvant therapies. Routine submission of all postcholecystectomy gallbladder specimens (GBS) for histopathology to detect cancer is standard practice at all University of the Witwatersrand (Wits) hospitals, as at many institutions globally. The cost-ineffectiveness associated with the results adding no value to overall patient care is debated. The low reported rate of GBCa – between 0.27% and 3.6% of all GBS –prompted advocacy for selective GBS submission based on demographic, clinical, and macroscopic features as indications for evaluation, considered logical from a practical and cost-effective perspective, especially in resource-constrained healthcare systems. Retrospective analysis of histopathology reports of 1194 adult GBS was performed. The histopathology findings of GBS submitted to the National Health Laboratory Service (NHLS) between January 1, 2010 and December 31, 2012 from three Wits hospitals were entered into spreadsheets, categorised into malignant, premalignant, and benign, and analysed, allowing determination of the profile of gallbladder disease. The frequency of GBCa determined, multivariate analysis of demographic and diagnostic subtypes was used to identify associations or risk factors for GBCa. The mean age of adult patients was 46.62 years (standard deviation, 17.81; range, 34-87); 925 (77.5%) female and 269 (22.5%) male. Benign diseases were documented in 1159 (97.1%) adult GBS with acute and chronic cholecystitis, in 705 (59.04%) and 401 (33.58%) specimens, respectively, representing 92.6% of total GBS. Forty-five (4.43%) and 33 (2.7%) specimens were ‘normal’ and benign tumours, respectively. GBCa and premalignant diseases composed 20 (1.67%) and 8 (0.7%) specimens, respectively with incidental GBCa found in 7 (0.59%) of 20 GBCa cases. Surgeon’s macroscopic appearance assessments were inadequately documented, so the value of this practice could not be determined. A small number (48) of GBS were obtained from paediatric patients <18 years of age where-in acute cholecystitis was most commonly diagnosed, no malignancies but one case of cytological atypia detected. The GBS disease profile and incidence of GBCa in this study were consistent with reports from international literature. No single demographic or clinical factor was identified to guide the surgeon in being more selective in submitting GBS. However, with only 7 cases of incidental GBCa in 1194 adult specimens, the routine submission of all GBS specimens to rule out malignancy cannot be justified and is not cost-effective. / XL2018