Biochemical and Epigenetic Insights into L-2-Hydroxyglutarate, a Potential Therapeutic Target in Renal Cancer.

PURPOSE: Elevation of L-2-hydroxylgutarate (L-2-HG) in renal cell carcinoma (RCC) is due in part to reduced expression of L-2-HG dehydrogenase (L2HGDH). However, the contribution of L-2-HG to renal carcinogenesis and insight into the biochemistry and targets of this small molecule remains to be elucidated. EXPERIMENTAL DESIGN: Genetic and pharmacologic approaches to modulate L-2-HG levels were assessed for effects on in vitro and in vivo phenotypes. Metabolomics was used to dissect the biochemical mechanisms that promote L-2-HG accumulation in RCC cells. Transcriptomic analysis was utilized to identify relevant targets of L-2-HG. Finally, bioinformatic and metabolomic analyses were used to assess the L-2-HG/L2HGDH axis as a function of patient outcome and cancer progression. RESULTS: L2HGDH suppresses both in vitro cell migration and in vivo tumor growth and these effects are mediated by L2HGDH's catalytic activity. Biochemical studies indicate that glutamine is the predominant carbon source for L-2-HG via the activity of malate dehydrogenase 2 (MDH2). Inhibition of the glutamine-MDH2 axis suppresses in vitro phenotypes in an L-2-HG-dependent manner. Moreover, in vivo growth of RCC cells with basal elevation of L-2-HG is suppressed by glutaminase inhibition. Transcriptomic and functional analyses demonstrate that the histone demethylase KDM6A is a target of L-2-HG in RCC. Finally, increased L-2-HG levels, L2HGDH copy loss, and lower L2HGDH expression are associated with tumor progression and/or worsened prognosis in patients with RCC. CONCLUSIONS: Collectively, our studies provide biochemical and mechanistic insight into the biology of this small molecule and provide new opportunities for treating L-2-HG-driven kidney cancers.

Medical testosterone: an iatrogenic cause of male infertility and a growing problem.

OBJECTIVE: To determine (1) the frequency of testosterone (T) use in 2 academic male infertility practices, (2) the effect on semen parameters, and (3) the potential for reversibility. METHODS: We performed a retrospective review. Inclusion criteria were supplemental T usage at the time of initial visit, T cessation, and semen analyses before and after T cessation. RESULTS: From January 2005 to March 2011, 110 of 1540 patients evaluated for infertility (7.1%) were on supplemental T. Thirty-nine patients met the inclusion criteria. Twenty-two of 39 patients (56%) were started on medical recovery by medical treatment. Median sperm concentration increased from 0 to 6.3 million/mL (P <.0001) after T cessation, with median follow-up of 4.5 months. Eight men (21%) remained azoospermic, and 3 men had sperm concentrations of ≤ 0.1 million/mL. Fifteen of 22 men given medical treatment and 16 of 17 men given no treatment had sperm return to the semen, respectively (P = .1061). Final sperm concentration did not differ between those who received medical treatment and those who did not. CONCLUSION: Exogenous T treatment causes infertility and is common among reproductive-aged men. These effects are transient for some, but not all men had return of sperm to the semen during the study interval, suggesting a possible underlying primary testicular dysfunction or ongoing hypothalamic-pituitary-testicular axis suppression. Education about exogenous T's negative reproductive effects is necessary to avoid this preventable form of infertility. Men with low T levels should have sufficient evaluation to evaluate for underlying pathology before starting T.

Effect of African-American Race on Tumor Recurrence After Radical Cystectomy for Urothelial Carcinoma of the Bladder.

BACKGROUND: African-American race appears to be associated with higher stages of urothelial carcinoma of the bladder (UCB) at presentation and poorer survival. However, the independent effect of African-American race on objective tumor recurrence after radical cystectomy (RC) after controlling for clinical and pathologic variables is unknown. PATIENTS AND METHODS: The data from consecutive patients with UCB who underwent RC with curative intent at a single institution (University of Alabama, Birmingham) from 2001 to 2012 with or without perioperative chemotherapy or chemoradiation were reviewed. The patient demographics, risk factors, clinical course, pathologic characteristics, and long-term outcomes were collected. Descriptive statistics were performed. Cox regression analysis was performed for key clinical, demographic, and pathologic variables, including race, stratified as African American versus white. RESULTS: A total of 215 patients, 163 men (76%) and 52 women (24%), with a mean age at RC of 65.6 years, were identified and reviewed. A total of 186 patients (87%) were white and 28 (13%) were African American. The median follow-up period after RC was 17.6 months. On conventional multivariate analysis, African-American race nearly attained statistical significance (hazard ratio [HR], 2.48; 95% confidence interval [CI], 0.98-6.29; P = .055). In a stepwise regression model, race was significantly associated with tumor recurrence (HR, 3.11; 95% CI, 1.2-7.4; P < .011). CONCLUSION: African-American race appears to be independently associated with a greater risk of tumor recurrence after RC for UCB. The effect of host genetics on tumor biology needs to be characterized at the genomic level to develop precision medicine.

The impact of temporary artery occlusion during intracranial aneurysm surgery on long-term clinical outcome: Part II. The patient who undergoes elective clipping.

BACKGROUND: Temporary artery occlusion (TAO) during intracranial aneurysm surgery is a key element in facilitating aneurysm dissection and clipping. Despite its significance, knowledge of its effects on long-term clinical outcome in patients undergoing elective clipping for unruptured aneurysms is limited. This study evaluated the safety of this technique in this patient population by 1 surgeon. METHODS: Patients managed for an intracranial aneurysm were followed from 2000-2009. This study included a cohort of patients found to have unruptured intracranial aneurysms who underwent TAO during their elective clipping procedure. Potential risk factors to affect outcome were considered. Effects of TAO on long-term clinical outcome were evaluated using the Glasgow Outcome Scale (GOS) obtained retrospectively by analyzing medical records at the last follow-up visit or discharge. Analyses included descriptive statistics, binary logistic regression, and ordinal logistic regression. RESULTS: Inclusion criteria were met by 246 patients (75.2% female, age 54 years±10.9) with electively clipped, unruptured aneurysms. Mean follow-up was 53 months±67.5. Mean temporary artery clipping time was 16.1 minutes±14.7. Of patients, 86% had a good outcome and made a complete recovery at last follow-up (GOS 5); 9% of patients were moderately disabled (GOS 4); 5% of patients were severely disabled (GOS 3), were in a vegetative state (GOS 2), or had died (GOS 1). TAO time had no effects on overall long-term clinical outcomes (P=0.59). Although patients with posterior circulation aneurysms had a worse outcome compared with patients with anterior circulation aneurysms (P=0.008), age (P=0.176) and aneurysm size (P=0.497) were not significantly associated with clinical outcome. CONCLUSIONS: This study did not demonstrate any relationship between limited duration of TAO and clinical outcome. Posterior circulation aneurysms are associated with worse long-term clinical outcomes in patients with electively clipped, unruptured aneurysms.

The impact of temporary artery occlusion during intracranial aneurysm surgery on long-term clinical outcome: part I. Patients with subarachnoid hemorrhage.

BACKGROUND: Temporary artery occlusion (TAO) during intracranial aneurysm surgery is an integral element in facilitating aneurysm dissection and clipping. Despite its significance, knowledge of effects of TAO on long-term clinical outcome is limited. The purpose of this study was to evaluate the impact of TAO in patients with subarachnoid hemorrhage (SAH) at one institution. METHODS: Patients managed for an intracranial aneurysm were followed from January 2000 to July 2009. This study included a cohort of patients with a diagnosis of SAH who underwent TAO during aneurysm surgery. Risk factors known to affect outcome were considered. Effects of TAO time on long-term clinical outcome were evaluated using the Glasgow Outcome Scale (GOS) at last follow-up visit or hospital discharge. Analyses included descriptive statistics and binary logistic and ordinal logistic regression. RESULTS: Inclusion criteria were met by 382 patients (74.3% female, age 52 years ± 13.5) with aneurysmal SAH. Mean follow-up was 39 months ± 57.3. Mean TAO time was 19.4 minutes ± 15.7. Of patients, 66% had a good outcome and made a complete recovery at last follow-up (GOS 5); 13% of patients were moderately disabled (GOS 4); and 27% of patients were severely disabled (GOS 3), were in a vegetative state (GOS 2), or had died (GOS 1). Overall, TAO time had no effect on overall long-term clinical outcome (P = 0.76). Higher Hunt and Hess grades (P < 0.001), Fisher computed tomography grades (P < 0.001), age (P < 0.001), larger size of aneurysm (P < 0.008), aneurysms of the posterior circulation (P = 0.044), and presence of clinical vasospasm (P < 0.001) were significantly associated with worse outcomes. On logistic regression analysis, the association between location of aneurysm (anterior vs. posterior circulation) and outcome disappeared. CONCLUSIONS: Limited duration of TAO during aneurysm surgery did not affect long-term clinical outcome and appears to be safe in patients with aneurysmal SAH. Established SAH risk factors including Hunt and Hess grades, Fisher computed tomography grades, and presence of clinical vasospasm clearly correlated with long-term clinical outcomes.

Effect of elective inguinal hernia repair on urinary symptom burden in men.

BACKGROUND: Our study sought to examine the prevalence of urinary symptoms in men undergoing hernia repair and whether there is an association between symptoms and short-term outcomes. METHODS: This is a prospective cohort study of male veterans consenting to inguinal hernia repair. The American Urological Association Symptom Score (AUASS) was administered preoperatively at 48 hours and again at 30 days after surgery. RESULTS: Median preoperative AUASS was 6 (interquartile range [IQR]: 3 to 12); at 48 hours, the median score increased significantly to 10 (IQR: 4 to 16, P < .01) and at 30 days, the median score dropped below baseline to 3 (IQR: 1 to 8, P < .0001). Multivariable linear regression modeling revealed that the use of an intraoperative urinary catheter was significantly associated with an increase in AUASS from preop to both 48 hours and 30 days. CONCLUSION: Elective repair of an inguinal hernia is associated with reduction in urinary symptom burden at 30 days, whereas the use of an intraoperative foley catheter is associated with no improvement at 30 days.