Research Spotlight

Jacob, A., J. Shook and T. E. Hutson (2020). “Tivozanib, a highly potent and selective inhibitor of VEGF receptor tyrosine kinases, for the treatment of metastatic renal cell carcinoma.” Future Oncol 2020 Jul 21. [Epub ahead of print.].

Full text of this article.

The VHL mutation-HIF upregulation-VEGF transcription sequence is the principal pathway in the development of renal cell carcinoma. Tyrosine kinase inhibitors target the VEGF receptors to inhibit further growth of renal cell carcinoma tumors. Tivozanib, originally named AV-951 and KRN-951, is a novel, orally bioavailable VEGF tyrosine kinase inhibitor that is selective for VEGF receptors 1, 2 and 3. Further, only picomolar concentrations of tivozanib are required to target these VEGF receptors and prevent phosphorylation; this potency prevents the debilitating side effects that occur with treatments whose mechanisms of action involve broad-spectrum tyrosine kinase inhibition. This review summarizes the growing body of evidence supporting tivozanib’s efficacy and safety in the treatment of advanced renal cell carcinoma.

Ismaeel, A., E. Papoutsi, D. Miserlis, R. Lavado, G. Haynatzki, G. P. Casale, W. T. Bohannon, R. S. Smith, J. L. Eidson, R. Brumberg, A. Hayson, J. S. Kirk, C. Castro, I. Sawicki, C. Konstantinou, L. P. Brewster, Pipinos, II and P. Koutakis (2020). “The Nitric Oxide System in Peripheral Artery Disease: Connection with Oxidative Stress and Biopterins.” Antioxidants (Basel) 9(7).

Full text of this article.

Peripheral artery disease (PAD) pathophysiology extends beyond hemodynamics to include other operating mechanisms, including endothelial dysfunction. Oxidative stress may be linked to endothelial dysfunction by reducing nitric oxide (NO) bioavailability. We aimed to investigate whether the NO system and its regulators are altered in the setting of PAD and to assess the relationship between NO bioavailability and oxidative stress. Sera from 35 patients with intermittent claudication (IC), 26 patients with critical limb ischemia (CLI), and 35 non-PAD controls were analyzed to determine levels of tetrahydrobiopterin (BH4), dihydrobiopterin (BH2), nitrate/nitrite (nitric oxides, or NOx), arginine, citrulline, asymmetric dimethylarginine (ADMA), symmetric dimethylarginine (SDMA), and the oxidative stress markers 8-Oxo-2′-deoxyguanosine (8-OHdG), 4-hydroxynonenal (4-HNE), advanced glycation end products (AGEs), and protein carbonyls. NOx was significantly lower in IC and CLI patients compared to controls in association with elevated oxidative stress, with the greatest NOx reductions observed in CLI. Compared with controls, IC and CLI patients had reduced BH4, elevated BH2, and a reduced BH4/BH2 ratio. SDMA, the arginine/SDMA ratio, and the arginine/ADMA ratio were significantly higher in CLI patients. The NO system and its regulators are significantly compromised in PAD. This dysregulation appears to be driven by increased oxidative stress and worsens as the disease progresses from claudication to CLI.

Idris, A., J. L. Christensen, Z. Wang, K. M. Al-Azizi, T. J. George and M. Szerlip (2020). “Echocardiography-Guided Novel Transcatheter Approach for Frozen Cusp of Mitral Bioprosthesis.” JACC Cardiovasc Interv 13(13): e123-e126.

Full text of this article.

This is the first reported 3-dimensional TEE-guided transcatheter approach for a frozen cusp of mitral bioprosthesis. Heart team collaboration is key for successful novel transcatheter approaches for complex patients who are at high surgical risk. Three-dimensional TEE plays an essential role in the accurate diagnosis and guidance of structural heart disease procedures. Alternative options and thinking outside the box can be an approach for patients at high surgical risk who have no other options. [No abstract; excerpt from article].

High, R. A., J. M. Danford, Z. Shi, C. Karmonik, T. J. Kuehl, E. T. Bird and R. Khavari (2020). “Protocol for a multicenter randomized, double blind, controlled pilot trial of higher neural function in overactive bladder patients after anticholinergic, beta-3 adrenergic agonist, or placebo.” Contemp Clin Trials Commun 19: 100621.

Full text of this article.

INTRODUCTION: Overactive bladder (OAB) syndrome has a negative impact on quality of life and prevalence increases with advanced age. Anticholinergics (AC) and beta-3 adrenergic agonists (β3a) are commonly prescribed medications for treatment of OAB. AC medication has been associated with dementia in population studies and with cortical atrophy in imaging studies. Higher neural effects of both classes of OAB medications have not been evaluated with functional neuroimaging. Longitudinal clinical assessments of cognition after OAB therapy with AC has produced conflicting results. β3a medication is has not been associated with dementia in clinical studies; however, higher neural effects are unknown.Our multicenter, double blind, randomized, placebo-controlled trial uses functional magnetic resonance imaging (fMRI) and cognitive testing to evaluate the effects of AC and β3a on brain functional connectivity in females with non-neurogenic OAB. METHODS AND ANALYSIS: and analysis: Female patients with OAB symptoms ages 50-90 years old without baseline cognitive impairment, moderate to severe depression or anxiety, neurologic disorders, or significant incomplete bladder emptying are invited to participate. Subjects are randomized to one of three interventions for 29 ± 1 day: AC (Solifenacin succinate, Teva), β3a (Mirabegron, Myrbetriq, Astellas), or placebo. Functional neuroimaging data at baseline and post-intervention will be analyzed accordingly. Clinical cognitive assessments will be compared from baseline to post-intervention. ETHICS: All qualifying patients are properly consented before enrolling in this study that has been approved by the Institutional Review Board of participating institutions.

High, R., K. Thai, H. Virani, T. Kuehl and J. Danford (2020). “Prevalence of Pelvic Floor Disorders in Female CrossFit Athletes.” Female Pelvic Med Reconstr Surg 26(8): 498-502.

Full text of this article.

OBJECTIVES: This study aimed to estimate the prevalence of pelvic floor disorders by symptoms in female CrossFit athletes in the United States and characterize subjects reporting pelvic organ prolapse symptoms, urinary incontinence, and fecal incontinence. METHODS: A 27-question anonymous questionnaire was distributed to owners of CrossFit-affiliated gyms. Select questions from validated questionnaires were used to define symptoms. Positive responses with “moderate, or quite a bit” bother defined the presence of urinary incontinence (with stress or urgency). A response of “yes” to “having a bulge or something falling out” defined the presence of pelvic organ prolapse. A response of “yes” to “lose stool beyond your control” questions defined the presence of fecal incontinence. RESULTS: Three hundred fourteen respondents had mean age of 36 ± 10 years and a mean body mass index of 25.2 ± 4 kg/m. Forty-four percent reported ≥1 vaginal delivery. For each workout, respondents reported lifting mean weights of 91 to 217 lb, and 90% reported participation in ≥3 CrossFit workouts per week. Pelvic floor disorder symptoms reported included the following: pelvic organ prolapse, 3.2% (10/314); urinary incontinence, 26.1% (82/314); and fecal incontinence, 6% (19/314). Higher age, parity, and number of vaginal deliveries were associated with urinary incontinence. Higher parity and number of vaginal deliveries were associated with prolapse. Fecal incontinence was not associated with age, body mass index, or obstetric history. CONCLUSION: The prevalence of pelvic floor symptoms in female CrossFit athletes from the general population is likely similar to the general population; however, the prevalence of bothersome urinary incontinence is higher than the general population in women younger than 40 years.