Inhibition of Lipid Oxidation Increases Glucose Metabolism and Enhances 2-Deoxy-2-[(18)F]Fluoro-D-Glucose Uptake in Prostate Cancer Mouse Xenografts.

PURPOSE: Prostate cancer (PCa) is the second most common cause of cancer-related death among men in the United States. Due to the lipid-driven metabolic phenotype of PCa, imaging with 2-deoxy-2-[(18)F]fluoro-D-glucose ([(18)F]FDG) is suboptimal, since tumors tend to have low avidity for glucose. PROCEDURES: We have used the fat oxidation inhibitor etomoxir (2-[6-(4-chlorophenoxy)-hexyl]oxirane-2-carboxylate) that targets carnitine-palmitoyl-transferase-1 (CPT-1) to increase glucose uptake in PCa cell lines. Small hairpin RNA specific for CPT1A was used to confirm the glycolytic switch induced by etomoxir in vitro. Systemic etomoxir treatment was used to enhance [(18)F]FDG-positron emission tomography ([(18)F]FDG-PET) imaging in PCa xenograft mouse models in 24 h. RESULTS: PCa cells significantly oxidize more of circulating fatty acids than benign cells via CPT-1 enzyme, and blocking this lipid oxidation resulted in activation of the Warburg effect and enhanced [(18)F]FDG signal in PCa mouse models. CONCLUSIONS: Inhibition of lipid oxidation plays a major role in elevating glucose metabolism of PCa cells, with potential for imaging enhancement that could also be extended to other cancers.

Molecular profiling of ETS gene rearrangements in patients with prostate cancer registered in REDEEM clinical trial.

OBJECTIVE: Androgen-induced E26 transformation-specific (ETS) gene fusion-positive tumors have been associated with aggressive prostate cancer. The aim is to evaluate the ETS gene rearrangement status on initial biopsy of patients registered in the Reduction by Dutasteride of Clinical Progression Events in Expectant Management trial study and determine if gene fusion status was associated with disease progression. MATERIALS AND METHODS: Initial biopsy material from 146 men registered in Reduction by Dutasteride of Clinical Progression Events in Expectant Management trial study treated with dutasteride (73/146, 50%) and as placebo (73/146, 50%) were reviewed, and ERG and SPINK1 immunohistochemistry was performed. ERG- and SPINK1-negative cancer samples were evaluated for ETV1, ETV4, and ETV5 rearrangements by fluorescence in situ hybridization. Frequency of ETS gene aberrations in both groups was correlated with cancer progression including prostate-specific antigen progression, Gleason progression, and progression-free survival by logistic analysis, pairwise differences, and chunk likelihood ratio tests for the genotype groups. RESULTS AND CONCLUSIONS: Of the 146 patients, 99 (67.8%) (placebo, 51; dutasteride, 48) samples displayed the following Gleason patterns: 3+3 = 6 in 80 (54.8%) (placebo, 39; dutasteride, 41), 3+4 = 7 in 18 (12.3%) (placebo, 11; dutasteride, 7), and 4+4 = 8 in 1(0.68%) (placebo, 1). The remaining 47 samples showed atypical glands in 5 (3.4%) (placebo, 2; dutasteride, 3), HGPIN in 9 (6.1%) (placebo, 5; dutasteride, 4), and benign in 33 (22.6%) (placebo, 15; dutasteride, 18). Immunohistochemistry findings were positive for ERG and SPINK1 in 56 (56%) (placebo, 31; dutasteride, 25) and 9 (6.1%) (placebo, 5; dutasteride, 4) cases, respectively. ETV1 and ETV4 rearrangements were noted in 2 cases (1.4%) (placebo, 1; dutasteride, 1) and 1 (0.7%) (placebo, 1) case, respectively. No significant differences in the incidence of prostate cancer molecular aberrations between the groups were observed. There was no evidence that ETS fusion status was associated with disease progression.

Renal epithelioid angiomyolipoma with a negative premelanosome marker immunoprofile: a case report and review of the literature.

INTRODUCTION: The rare variant of renal epithelioid/pleomorphic angiomyolipoma has been reported in approximately 120 cases. One of the most important characteristics to differentiate these tumors from other renal cell neoplasms is their typical reactivity to premelanosome antigens. If such a tumor does not stain for HMB-45 or Melan-A, a specific diagnosis of epithelioid pleomorphic angiomyolipoma cannot be made with certainty. CASE PRESENTATION: We present here what is, to the best of our knowledge, the first case of epithelioid/pleomorphic angiomyolipoma of the kidney in a 50-year-old Caucasian man with no history of tuberous sclerosis, and with a tumor marker profile negative for several premelanosome antigens. The tumor was composed of sheets of pleomorphic, round to polygonal epithelioid cells with prominent eosinophilic cytoplasm, large nuclei, many multinucleated, and very prominent nucleoli. There were prominent vessels and rare interspersed smooth muscle fibers, but adipocytes were not identified. A tumor marker profile showed tumor cell reactivity for CD68, calponin and focally for CD10. Intervening smooth muscle was reactive with smooth muscle actin. The tumor lacked reactivity for melanin-associated antigens HMB-45 and Melan-A, and for CD31, pan-cytokeratin (AE1/3) and desmin. Electron microscopic examination of tumor cells confirmed the presence of premelanosome-like granules. CONCLUSIONS: Based on the characteristic microscopic appearance of this tumor, and its overall tumor marker profile, we concluded this was a renal epithelioid/pleomorphic angiomyolipoma with a negative premelanosome antigen phenotype.

The value of second-opinion pathology diagnoses on prostate biopsies from patients referred for management of prostate cancer.

Gleason score (GS) (sum of primary plus secondary grades) is used to predict patients' clinical outcome and to customize treatment strategies for prostate cancer (PC). However, due in part to pathologist misreading, there is significant discrepancy of GS between needle-core biopsies (NCB) and radical prostatectomy specimens. We assessed the requirement for re-evaluating NCB diagnosed by outside pathologists in patients referred to our institution for management of PC. In 100 patients, we reviewed both their original "outside" and second-opinion ("in-house") diagnoses of the same NCB specimens, and compared them with the diagnoses of the whole-mount radical prostatectomy (WMRP) specimens (gold standard for analysis). We found that both outside and in-house biopsy GS vary significantly from the WMRP diagnoses, with GS undergrading substantially predominating above overgrading. Statistical analysis demonstrated that the main diagnostic discrepancy was in the differentiation between primary and secondary Gleason grades (mainly 3 and 4) and that outside NCB GS was significantly less accurate with respect to the WMRP specimens than the in-house NCB GS. In addition, in a different cohort of 65 NCB cases, we found that in 5 out of 11 patients, outside pathologists failed to report the presence of extraprostatic extension, an important feature for diagnosis of a higher pathology stage (pT3a). Since histopathological evaluation is a critical factor for appropriate treatment selection, we recommend that a re-evaluation by in-house urologic pathologists should be performed in all outside NCB specimens before patients are admitted for treatment in any given institution.