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.

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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

This document only includes an excerpt of the corresponding thesis or dissertation. To request a digital scan of the full text, please contact the Ruth Lilly Medical Library's Interlibrary Loan Department (rlmlill@iu.edu).

This document only includes an excerpt of the corresponding thesis or dissertation. To request a digital scan of the full text, please contact the Ruth Lilly Medical Library's Interlibrary Loan Department (rlmlill@iu.edu).