Reduced Expression of Fumarate Hydratase in Clear Cell Renal Cancer Mediates HIF-2α Accumulation and Promotes Migration and Invasion

Germline mutations of FH, the gene that encodes for the tricarboxylic acid TCA (TCA) cycle enzyme fumarate hydratase, are associated with an inherited form of cancer referred to as Hereditary Leiomyomatosis and Renal Cell Cancer (HLRCC). Individuals with HLRCC are predisposed to the development of highly malignant and lethal renal cell carcinoma (RCC). The mechanisms of tumorigenesis proposed have largely focused on the biochemical consequences of loss of FH enzymatic activity. While loss of the tumor suppressor gene von Hippel Lindau (VHL) is thought to be an initiating event for the majority of RCCs, a role for FH in sporadic renal cancer has not been explored. Here we report that FH mRNA and protein expression are reduced in clear cell renal cancer, the most common histologic variant of kidney cancer. Moreover, we demonstrate that reduced FH leads to the accumulation of hypoxia inducible factor- 2α (HIF-2α), a transcription factor known to promote renal carcinogenesis. Finally, we demonstrate that overexpression of FH in renal cancer cells inhibits cellular migration and invasion. These data provide novel insights into the tumor suppressor functions of FH in sporadic kidney cancer

PSA levels of 4.0 - 10 ng/ml and negative digital rectal examination: antibiotic therapy versus immediate prostate biopsy

Purpose: The management of mildly elevated (4.0-10.0 ng/ml) prostate specific antigen (PSA) is uncertain. Immediate prostate biopsy, antibiotic treatment, or short term monitoring PSA level for 1-3 months is still in controversy. Material and Methods: We conducted a retrospective chart review of patients in a large community practice (2003 - 2007) who had PSA levels between 4.0-10 ng/mL without any further evidence of infection. Data was gathered regarding patient's age, whether standard antibiotic therapy (10-14 days of ofloxacin or ciprofloxacin) had been administered before the second PSA measurement, results of a second PSA test performed at 1- to 2-month intervals, whether a prostate biopsy was performed and its result. Results: One-hundred and thirty-five men met the study inclusion criteria with 65 (48.1%) having received antibiotics (group 1); the PSA levels decreased in 39 (60%) of which, sixteen underwent a biopsy which demonstrated prostate cancer in 4 (25%). Twenty-six (40%) patients of group 1 exhibited no decrease in PSA levels; seventeen of them underwent a biopsy that demonstrated cancer in 2 (12%). The other 70 (51.9%) patients were not treated with antibiotics (group 2); the PSA levels decreased in 42 (60%) of which, thirteen underwent a biopsy which demonstrated prostate cancer in 4 (31%). In the other 28 (40%) patients of group 2 there was no demonstrated decrease in PSA, nineteen of these subjects underwent a biopsy that demonstrated cancer in 8 (42%). Conclusions: There appears to be no advantage for administration of antibacterial therapy with initial PSA levels between 4-10 ng/mL without overt evidence of inflammation

The impact of PLCO control arm contamination on perceived PSA screening efficacy

PURPOSE: To quantify the extent to which a clinically significant prostate cancer mortality reduction due screening could have been masked by control arm screening (contamination) in the Prostate, Lung, Colorectal, and Ovarian (PLCO) trial. METHODS: We used three independently developed models of prostate cancer natural history to conduct a virtual PLCO trial. Simulated participants underwent pre-trial screening based on population patterns. The intervention arm followed observed compliance during the trial then resumed population screening. A contaminated control arm followed observed contamination during the trial then resumed population screening, while an uncontaminated control arm discontinued screening upon entry. We assumed a clinically significant screening benefit, applied population treatments and survival patterns, and calculated mortality rate ratios relative to the contaminated and uncontaminated control arms. RESULTS: The virtual trial reproduced observed incidence, including stage and grade distributions, and control arm mortality after 10 years of complete follow-up. Under the assumed screening benefit, the three models found that contamination increased the mortality rate ratio from 0.68–0.77 to 0.86–0.91, increased the chance of excess mortality in the intervention arm from 0–4% to 15–28%, and decreased the power of the trial to detect a mortality difference from 40–70% to 9–25%. CONCLUSIONS: Our computer simulation models indicate that contamination substantially limited the ability of the PLCO to identify a clinically significant screening benefit. While the trial shows annual screening doesn’t reduce mortality relative to population screening, contamination prevents concluding whether screening reduces mortality relative to no screening

Obesity and prostate cancer-specific mortality after radical prostatectomy: results from the Shared Equal Access Regional Cancer Hospital (SEARCH) database

BACKGROUND: At the population level, obesity is associated with prostate cancer (PC) mortality. However, few studies analyzed the associations between obesity and long-term PC-specific outcomes after initial treatment. METHODS: We conducted a retrospective analysis of 4268 radical prostatectomy patients within the Shared Equal Access Regional Cancer Hospital (SEARCH) database. Cox models accounting for known risk factors were used to examine the associations between body mass index (BMI) and PC-specific mortality (PCSM; primary outcome). Secondary outcomes included biochemical recurrence (BCR) and castration-resistant PC (CRPC). BMI was used as a continuous and categorical variable (normal <25 kg/m(2), overweight 25–29.9 kg/m(2) and obese ⩾30 kg/m(2)). Median follow-up among all men who were alive at last follow-up was 6.8 years (interquartile range=3.5–11.0). During this time, 1384 men developed BCR, 117 developed CRPC and 84 died from PC. Hazard ratios were analyzed using competing-risks regression analysis accounting for non-PC death as a competing risk. RESULTS: On crude analysis, higher BMI was not associated with risk of PCSM (P=0.112), BCR (0.259) and CRPC (P=0.277). However, when BMI was categorized, overweight (hazard ratio (HR) 1.99, P=0.034) and obesity (HR 1.97, P=0.048) were significantly associated with PCSM. Obesity and overweight were not associated with BCR or CRPC (all P⩾0.189). On multivariable analysis adjusting for both clinical and pathological features, results were little changed in that obesity (HR=2.05, P=0.039) and overweight (HR=1.88, P=0.061) were associated with higher risk of PCSM, but not with BCR or CRPC (all P⩾0.114) with the exception that the association for overweight was no longer statistical significant. CONCLUSIONS: Overweight and obesity were associated with increased risk of PCSM after radical prostatectomy. If validated in larger studies with longer follow-up, obesity may be established as a potentially modifiable risk factor for PCSM