Understanding the Impact of Belzutifan on Treatment Strategies for Patients with VHL.

Belzutifan was recently approved for the management of Von Hippel-Lindau disease (VHL). Given the morbidity of recurrent treatment, systemic therapy to reduce or eliminate the need for surgery has been long-awaited. Herein, we sought to gain insight about future utilization by surveying VHL kidney cancer experts in the United States. A survey developed by members of the VHL Alliance (VHLA) Clinical Advisory Council was distributed to kidney cancer providers at VHLA and National Comprehensive Cancer Network (NCCN) centers. Surveys were administered on a secure web-based platform. A total of 60 respondents from 29 institutions participated. Urologists (50%) and medical oncologists (43%) represented the majority of participants. The majority (98%) of respondents anticipated that belzutifan's approval would significantly change the current treatment landscape. Most reported that therapy should be continuous (76%). There was a difference in willingness to prescribe belzutifan by specialty (38% of urologists vs 91% of medical oncologists (P = 0.02)). In individuals with renal tumors <3 cm, 36% would still recommend surveillance, while 36% would initiate belzutifan to prevent growth. In those with multifocal renal lesions and growth of a solitary tumor on belzutifan, 50% would proceed with only treatment of that site. In conclusion, VHL kidney cancer specialists anticipate a paradigm shift with the approval of belzutifan. Provider roles may change with movement away from surgical management. Opinions on treatment indications, such as when to initiate therapy and how to best salvage, vary widely and therefore collaborative efforts among experts may assist in the development of new clinical guidelines.

Persistent Discordance in Grade, Stage, and NCCN Risk Stratification in Men Undergoing Targeted Biopsy and Radical Prostatectomy.

OBJECTIVE: To elucidate the accuracy of MRI and MRI-ultrasound fusion guided targeted biopsy (TBx) on risk stratification in men who underwent subsequent radical prostatectomy (RP). MATERIALS AND METHODS: A single-center, retrospective study was performed in men at risk for prostate cancer who (n = 140) underwent TBx and RP between November 2012 and August 2018. Comparisons were made between patients clinically staged by preoperative MRI and TBx Gleason grade group (GGG) and stage after RP. Multivariable regression was performed to identify factors associated with MRI and TBx compared to RP grading, staging, and consistency with National Comprehensive Cancer Network (NCCN) risk stratification. RESULTS: There was an increase in NCCN risk stratification in 47 men (33.6%) and a decrease in 17 men (12.1%) compared to the resected prostate. GGG upgrading and downgrading occurred in 35 (25.0%) and 31 men (22.1%), respectively. Upstaging occurred in 41 men (29.3%). In adjusted analysis for age, BMI, PSA Density (PSAD), median maximal diameter of the regions of interest, and PIRADS, men with PIRADS 4 were less likely to be upgraded (OR 0.26, 95% CI 0.08-0.81, P = .020) than PIRADS 3. PSAD ≥ 0.15 ng/mL/cc was associated with upstaging (OR 3.92, 95% CI 1.60-9.62, P = .003). CONCLUSION: Accurate risk stratification is critical for disease management, mandated by the increasing use of active surveillance, partial gland ablation, and androgen deprivation therapy with radiation therapy for men with unfavorable intermediate and high-risk prostate cancer. This study confirms the need for advances in imaging and biomarker to increase the accuracy of pretreatment staging.

Off-Target Effect of Sildenafil on Postsurgical Erectile Dysfunction: Alternate Pathways and Localized Delivery System.

INTRODUCTION: There is no consensus on the best oral phosphodiesterase type 5 inhibitor (PDE5I) for patients undergoing penile rehabilitation after surgical nerve injury. AIM: To determine the mechanism of PDE5I on cultured neuronal cells and the effectiveness of local drug delivery using nanospheres (NSPs) to sites of nerve injury in a rat model of bilateral cavernous nerve injury (BCNI). METHODS: The effects of sildenafil, tadalafil, and vardenafil on cyclic adenosine monophosphate, cyclic guanosine monophosphate, and cell survival after exposure to hypoxia and H2O2 were measured in PC12, SH-SY5Y, and NTERA-2 (NT2) cell cultures. The effects of phosphodiesterase type 4 inhibitor (PDE4I) and PDE5I on neuronal cell survival were evaluated. Male rats underwent BCNI and were untreated (BCNI), immediately treated with application of empty NSPs (BCNI + NSP), NSPs containing sildenafil (Sild + NSP), or NSPs containing rolipram (Rol + NSP). MAIN OUTCOME MEASURES: Viability of neuronal cells was measured. Intracavernous pressure changes after cavernous nerve electrostimulation and expression of neurofilament, nitric oxide synthase, and actin in mid-shaft of penis were analyzed 14 days after injury. RESULTS: Sildenafil and rolipram significantly decreased cell death after exposure to H2O2 and hypoxia in PC12, SH-SY5Y, and NT2 cells. PC12 cells did not express PDE5 and knockdown of PDE4 significantly increased cell viability in PC12, SH-SY5Y, and NT2 cells exposed to hypoxia. The ratio of intracavernous pressure to mean arterial pressure and expression of penile neurofilament, nitric oxide synthase, and actin were significantly higher in the Sild + NSP and Rol + NSP groups than in the BCNI and BCNI + NSP groups. Limitations included analysis in only two PDE families using only a single dose. CONCLUSION: Sildenafil showed the most profound neuroprotective effect compared with tadalafil and vardenafil. Sildenafil- or rolipram-loaded NSP delivery to the site of nerve injury prevented erectile dysfunction and led to increased neurofilament, nitric oxide synthase, smooth muscle content in rat penile tissue after BCNI.

Thyroid Dysfunction and Male Reproductive Physiology.

Normal thyroid physiology is paramount for the proper development and important for the maintenance of male reproduction. Both short- and long-term deviations in thyroid hormone levels have been shown to alter male reproductive function on a micro- and macroscopic level. Thyrotoxicosis and hypothyroidism are associated with changes in spermatogenesis, semen quality, levels of sexual hormones, and erectile function. However, the degree to which thyroid dysfunction is clinically responsible for male infertility has not been clearly elucidated.

Prostate-specific antigen density toward a better cutoff to identify better candidates for active surveillance.

OBJECTIVE: To investigate the impact of prostate-specific antigen density (PSAD) on existing prostate cancer (PCa) active surveillance (AS) protocols. METHODS: Prospectively maintained database on men with PCa who underwent radical prostatectomy was reviewed retrospectively. Demographic data and pathologic characteristics of patients who fulfilled the AS inclusion criteria under the National Comprehensive Cancer Network (NCCN), Prostate Cancer Research International Active Surveillance (PRIAS), and University of California, San Francisco (UCSF) guidelines were examined. RESULTS: Of 930 patients, 231, 280, and 325 fulfilled the NCCN, PRIAS, and UCSF AS criteria, respectively. The frequencies of advanced disease on surgical pathology (upstaging and/or upgrading) were 31.6% (NCCN), 35.4% (PRIAS), and 34.2% (UCSF) of the study cohorts. PSAD was significantly higher in patients with advanced disease compared with that in patients with nonadvanced disease in all 3 AS schemas. Modifying the PRIAS and UCSF criteria using the NCCN's lower PSAD cutoff of 0.15 ng/mL(2) decreased the rates of the advanced disease significantly to 33.5% and 31.4%, respectively. Using the receiver operating characteristic curve analysis, the optimal PSAD cutoff level for the prediction of advanced disease was 0.085 ng/mL(2) (sensitivity/specificity of 76.7%/50.6% in NCCN and 75.6%/49.7% in PRIAS). CONCLUSION: Among patients with low-risk PCa who underwent radical prostatectomy, PSAD is a predictor of advanced disease at the time of surgery. Adopting a lower PSAD threshold of 0.085 ng/mL(2) decreased the risk of the advanced disease to 17.5%-21.7%. Therefore, PSAD should be part of all AS guidelines.

(N-3) long-chain polyunsaturated fatty acids prolong survival following myocardial infarction in rats.

Many clinical studies report that (n-3) PUFAs decrease the incidence of sudden death in patients with coronary artery disease after myocardial infarction (MI). However, the mechanisms for the beneficial effects of (n-3) PUFAs are unknown. The objectives of the present study were to confirm the findings from clinical trials using an animal model of MI in which dietary intake could be closely controlled and to utilize the model to investigate molecular mechanisms for the beneficial effects of (n-3) PUFAs. Male rats were subjected to coronary ligation to induce MI and were randomly assigned to diets high in (n-6) (58% of lipid) or (n-3) (28% of lipid) PUFAs for 6 mo. A diet high in (n-3) PUFAs was associated with an improvement in 6-mo survival (89.2% vs. 64.9%, P = 0.013) compared with rats consuming a diet high in (n-6) PUFAs (n = 37/group). In a separate study (n = 5 rats/diet group), the (n-3) PUFA diet decreased the (n-6):(n-3) PUFA ratio in plasma (0.6 +/- 0.1 vs. 7.9 +/- 1.8, P < 0.05) and cardiac tissue (0.9 +/- 0.1 vs. 11.8 +/- 1.6, P < 0.05) of rats fed for 4 wk. The increased survival in the (n-3) diet group was associated with decreased cardiac activities of protein kinase A and calcium calmodulin-dependent kinase II by 33-38% (P < 0.05) and a 28% decrease (P < 0.05) in phosphorylation (activation) of the ryanodine receptor calcium release channel. Based upon our results, we speculate that decreased activities of protein kinases induced by diets high in (n-3) PUFAs are associated with a decrease in sudden death after MI in rats.