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Video: Co-administration of TRPV4 and TRPV1 antagonists

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Co-administration of transient receptor potential vanilloid 4 (TRPV4) and TRPV1 antagonists potentiate the effect of each drug in a rat model of cystitis

Ana Charrua†‡§, Célia D. Cruz‡§, Dick Jansen¶ , Boy Rozenberg¶ , John Heesakkers¶ and Francisco Cruz*†§

*Department of Urology, S. João Hospital, †Department of Renal, Urologic and Infectious Disease, ‡Department of Experimental Biology, Faculty of Medicine of the University of Porto, §IBMC – Instituto de Biologia Molecular e Celular da Universidade do Porto, Porto, Portugal, and ¶Department of Urology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands

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OBJECTIVE

To investigate transient receptor potential vanilloid 4 (TRPV4) expression in bladder afferents and study the effect of TRPV4 and TRPV1 antagonists, alone and in combination, in bladder hyperactivity and pain induced by cystitis.

MATERIALS AND METHODS

TRPV4 expression in bladder afferents was analysed by immunohistochemistry in L6 dorsal root ganglia (DRG), labelled by fluorogold injected in the urinary bladder. TRPV4 and TRPV1 co-expression was also investigated in L6 DRG neurones of control rats and in rats with lipopolysaccharide (LPS)-induced cystitis. The effect of TRPV4 antagonist RN1734 and TRPV1 antagonist SB366791 on bladder hyperactivity and pain induced by cystitis was assessed by cystometry and visceral pain behaviour tests, respectively.

RESULTS

TRPV4 is expressed in sensory neurones that innervate the urinary bladder. TRPV4-positive bladder afferents represent a different population than the TRPV1-expressing bladder afferents, as their co-localisation was minimal in control and inflamed rats. While low doses of RN1734 and SB366791 (176.7 ng/kg and 143.9 ng/kg, respectively) had no effect on bladder activity, the co-administration of the two totally reversed bladder hyperactivity induced by LPS. In these same doses, the antagonists partially reversed bladder pain behaviour induced by cystitis.

CONCLUSIONS

TRPV4 and TRPV1 are present in different bladder afferent populations. The synergistic activity of antagonists for these receptors in very low doses may offer the opportunity to treat lower urinary tract symptoms while minimising the potential side-effects of each drug.

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Video: Hypogonadism and testosterone-enhancing therapy on alkaline phosphatase and BMD

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The effect of hypogonadism and testosterone-enhancing therapy on alkaline phosphatase and bone mineral density

Ali A. Dabaja, Campbell F. Bryson, Peter N. Schlegel and Darius A. Paduch

 

Department of Urology, Weill Cornell Medical College, New York, NY, USA

 

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OBJECTIVE

To evaluate the relationship of testosterone-enhancing therapy on alkaline phosphatase (AP) in relation to bone mineral density (BMD) in hypogonadal men.

PATIENTS AND METHODS

Retrospective review of 140 men with testosterone levels of <350 ng/dL undergoing testosterone-enhancing therapy and followed for 2 years. Follicle-stimulating hormone, luteinising hormone, free testosterone, total testosterone, sex hormone binding globulin, calcium, AP, vitamin D, parathyroid hormone, and dual-energy X-ray absorptiometry (DEXA) scans were analysed. A subgroup of 36 men with one DEXA scan before and one DEXA 2 years after initiating treatment was performed.

RESULTS

Analysis of the relationship between testosterone and AP at initiation of therapy using stiff linear splines suggested that bone turnover occurs at total testosterone levels of <250 ng/dL. In men with testosterone levels of <250 ng/dL, there was a negative correlation between testosterone and AP (R2 = −0.347, P < 0.001), and no correlation when testosterone levels were between 250 and 350 ng/dL. In the subgroup analysis, the mean (sd) testosterone level was 264 (103) ng/dL initially and 701 (245), 539 (292), and 338 (189) ng/dL at 6, 12, and 24 months, respectively. AP decreased from a mean (sd) of 87 (38) U/L to 57 (12) U/L (P = 0.015), 60 (17) U/L (P < 0.001), and 55 (10) U/L (P = 0.03) at 6, 12, and 24 months, respectively. The BMD increased by a mean (sd) of 20 (39)% (P = 0.003) on DEXA.

CONCLUSION

In hypogonadal men, the decrease in AP is associated with an increase in BMD on DEXA testing. This result suggests the use of AP as a marker of response to therapy.

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Video: Does TT status modify a man’s risk of cancer?

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Testosterone Therapy and Cancer Risk

Michael L. Eisenberg*†, Shufeng Li*‡, Paul Betts§, Danielle Herder, Dolores J. Lamb¶ and Larry I. Lipshultz

 

Departments of *Urology, †Obstetrics/Gynecology and ‡Dermatology, Stanford University School of Medicine, Stanford, CA, §Cancer Epidemiology and Surveillance Branch, Texas Cancer Registry, Texas Department of State Health Services, Austin, TX, and Scott Department of Urology, Baylor College of Medicine, Houston, TX, USA

 

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OBJECTIVE

To determine if testosterone therapy (TT) status modifies a man’s risk of cancer.

PATIENTS AND METHODS

The Urology clinic hormone database was queried for all men with a serum testosterone level and charts examined to determine TT status. Patient records were linked to the Texas Cancer Registry to determine the incidence of cancer. Men accrued time at risk from the date of initiating TT or the first office visit for men not on TT. Standardised incidence rates and time to event analysis were performed.

RESULTS

In all, 247 men were on TT and 211 did not use testosterone. In all, 47 men developed cancer, 27 (12.8%) were not on TT and 20 (8.1%) on TT. There was no significant difference in the risk of cancer incidence based on TT (hazard ratio [HR] 1.0, 95% confidence interval [CI] 0.57–1.9; P = 1.8). There was no difference in prostate cancer risk based on TT status (HR 1.2, 95% CI 0.54–2.50).

CONCLUSION

There was no change in cancer risk overall, or prostate cancer risk specifically, for men aged >40 years using long-term TT.

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Video: Indications for Intervention During Active Surveillance of Prostate Cancer: A Comparison of the Johns Hopkins and PRIAS Protocols

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Indications for Intervention During Active Surveillance of Prostate Cancer: A Comparison of the Johns Hopkins and PRIAS Protocols

Max Kates, Jeffrey J. Tosoian, Bruce J. Trock, Zhaoyong Feng, H. Ballentine Carter and Alan W. Partin
James Buchanan Brady Urological Institute, Johns Hopkins Medical Institutions, Baltimore, MD, USA
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OBJECTIVE

To analyse how patients enrolled in our biopsy based surveillance programme would fare under the Prostate Cancer Research International Active Surveillance (PRIAS) protocol, which uses PSA kinetics.

PATIENTS AND METHODS

Since 1995, 1125 men with very-low-risk prostate cancer have enrolled in the AS programme at the Johns Hopkins Hospital (JHH), which is based on monitoring with annual biopsy. The PRIAS protocol uses a combination of periodic biopsies (in years 1, 4, and 7) and prostate-specific antigen doubling time (PSADT) to trigger intervention. Patients enrolled in the JHH AS programme were retrospectively reviewed to evaluate how the use of the PRIAS protocol would alter the timing and use of curative intervention.

RESULTS

Over a median of 2.1 years of follow up, 38% of men in the JHH AS programme had biopsy reclassification. Of those, 62% were detected at biopsy intervals corresponding to the PRIAS criteria, while 16% were detected between scheduled PRIAS biopsies, resulting in a median delay in detection of 1.9 years. Of the 202 men with >5 years of follow-up, 11% in the JHH programme were found to have biopsy reclassification after it would have been identified in the PRIAS protocol, resulting in a median delay of 4.7 years to reclassification. In all, 12% of patients who would have undergone immediate intervention under PRIAS due to abnormal PSA kinetics would never have undergone reclassification on the JHH protocol and thus would not have undergone definitive intervention.

CONCLUSIONS

There are clear differences between PSA kinetics-based AS programmes and biopsy based programmes. Further studies should address whether and how the differences in timing of intervention impact subsequent disease progression and prostate cancer mortality.

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Video: Holmium Laser Enucleation and Photoselective Vaporization of the Prostate for Patients with Benign Prostatic Hyperplasia and Chronic Urinary

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Holmium Laser Enucleation and Photoselective Vaporization of the Prostate for Patients with Benign Prostatic Hyperplasia and Chronic Urinary Retention

Christopher D. Jaeger, Christopher R. Mitchell, Lance A. Mynderse and Amy E. Krambeck

Department of Urology, Mayo Clinic School of Medicine, Rochester, MN, USA

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OBJECTIVES

To evaluate short-term outcomes of holmium laser enucleation of the prostate (HoLEP) and photoselective vaporisation of the prostate (PVP) in patients with benign prostatic hyperplasia (BPH) and chronic urinary retention (CUR).

PATIENTS AND METHODS

A retrospective chart review was performed of all patients with CUR who underwent HoLEP or PVP at our institution over a 3-year period. CUR was defined as a persistent post-void residual urine volume (PVR) of >300 mL or refractory urinary retention requiring catheterisation.

RESULTS

We identified 72 patients with CUR who underwent HoLEP and 31 who underwent PVP. Preoperative parameters including median catheterisation duration (3 vs 5 months, P = 0.71), American Urological Association Symptom Index score (AUASI; 18 vs 21, P = 0.24), and PVR (555 vs 473 mL, P = 0.096) were similar between the HoLEP and PVP groups. The HoLEP group had a larger prostate volume (88.5 vs 49 mL, P < 0.001) and higher PSA concentration (4.5 vs 2.4 ng/mL, P = 0.001). At median 6-month follow-up, 71 (99%) HoLEP patients and 23 (74%) PVP patients were catheter-free (P < 0.001). Of the voiding patients, postoperative AUASI (3 vs 4, P = 0.06), maximum urinary flow rate (23 vs 18 mL/s, P = 0.28) and PVR (56.5 vs 54 mL, P = 1.0) were improved in both groups.

CONCLUSIONS

Both HoLEP and PVP are effective at improving urinary parameters in men with CUR. Despite larger prostate volumes, HoLEP had a 99% successful deobstruction rate, thus rendering patients catheter-free.

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Video: Enzalutamide in European and North American men participating in the AFFIRM trial

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Enzalutamide in European and North American men participating in the AFFIRM trial

Axel S. Merseburger, Howard I. Scher†, Joaquim Bellmunt‡, Kurt Miller§, Peter F.A. Mulders¶, Arnulf Stenzl**, Cora N. Sternberg††, Karim Fizazi‡‡, Mohammad Hirmand§§, Billy Franks¶¶, Gabriel P. Haas¶¶, Johann de Bono*** and Ronald de Wit†††

Medizinische Hochschule Hannover, Hannover, §Charité – Universitätsmedizin Berlin, Berlin, **Universitätsklinikum Tübingen, Tübingen, Germany; †Memorial Sloan-Kettering Cancer Center, New York, NY, ‡Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, §§Medivation, Inc., San Francisco, CA, ¶¶Astellas Scientific and Medical Affairs, Inc., Northbrook, IL, USA; ¶Radboud University Nijmegen Medical Centre, Nijmegen, †††Erasmus University Medical Center, Rotterdam, The Netherlands; ††San Camillo – Forlanini Hospitals, Rome, Italy; ‡‡Institut Gustave Roussy, University of Paris Sud, Villejuif, France; ***Institute of Cancer Research and Royal Marsden NHS Foundation Trust, Sutton, UK

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OBJECTIVE

To explore any differences in efficacy and safety outcomes between European (EU) (n = 684) and North American (NA) (n = 395) patients in the AFFIRM trial (NCT00974311).

PATIENTS AND METHODS

Phase III, double-blind, placebo-controlled, multinational AFFIRM trial in men with metastatic castration-resistant prostate cancer (mCRPC) after docetaxel. Participants were randomly assigned in a 2:1 ratio to receive oral enzalutamide 160 mg/day or placebo. The primary end point was overall survival (OS) in a post hoc analysis.

RESULTS

Enzalutamide significantly improved OS compared with placebo in both EU and NA patients. The median OS in EU patients was longer than NA patients in both treatment groups. However, the relative treatment effect, expressed as hazard ratio and 95% confidence interval, was similar in both regions: 0.64 (0.50, 0.82) for EU and 0.63 (0.47, 0.83) for NA. Significant improvements in other end points further confirmed the benefit of enzalutamide over placebo in patients from both regions. The tolerability profile of enzalutamide was comparable between EU and NA patients, with fatigue and nausea the most common adverse events. Four EU patients (4/461 enzalutamide-treated, 0.87%) and one NA patient (1/263 enzalutamide-treated, 0.38%) had seizures. The difference in median OS was related in part to the timing of development of mCRPC and baseline demographics on study entry.

CONCLUSION

This post hoc exploratory analysis of the AFFIRM trial showed a consistent OS benefit for enzalutamide in men with mCRPC who had previously progressed on docetaxel in both NA- and EU-treated patients, although the median OS was higher in EU relative to NA patients. Efficacy benefits were consistent across end points, with a comparable safety profile in both regions.

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Video: Separating the wheat from the chaff – Cognitive skills assessment during RA surgery

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Cognitive skills assessment during robot-assisted surgery: separating the wheat from the chaff

Khurshid A. Guru, Ehsan T. Esfahani†, Syed J. Raza, Rohit Bhat†, Katy Wang‡,
Yana Hammond, Gregory Wilding‡, James O. Peabody§ and Ashirwad J. Chowriappa

Department of Urology, Roswell Park Cancer Institute, Buffalo, NY; †Brain Computer Interface Laboratory, Department of Mechanical & Aerospace Engineering, University at Buffalo, Buffalo, NY; ‡Department of Biostatistics, Roswell Park Cancer Institute, Buffalo, NY; and §Henry Ford Health System, Detroit, MI, USA

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OBJECTIVE

To investigate the utility of cognitive assessment during robot-assisted surgery (RAS) to define skills in terms of cognitive engagement, mental workload, and mental state; while objectively differentiating between novice and expert surgeons.

SUBJECTS AND METHODS

In all, 10 surgeons with varying operative experience were assigned to beginner (BG), combined competent and proficient (CPG), and expert (EG) groups based on the Dreyfus model. The participants performed tasks for basic, intermediate and advanced skills on the da Vinci Surgical System™. Participant performance was assessed using both tool-based and cognitive metrics.

RESULTS

Tool-based metrics showed significant differences between the BG vs CPG and the BG vs EG, in basic skills. While performing intermediate skills, there were significant differences only on the instrument-to-instrument collisions between the BG vs CPG (2.0 vs 0.2, P = 0.028), and the BG vs EG (2.0 vs 0.1, P = 0.018). There were no significant differences between the CPG and EG for both basic and intermediate skills. However, using cognitive metrics, there were significant differences between all groups for the basic and intermediate skills. In advanced skills, there were no significant differences between the CPG and the EG except time (1116 vs 599.6 s), using tool-based metrics. However, cognitive metrics revealed significant differences between both groups.

CONCLUSION

Cognitive assessment of surgeons may aid in defining levels of expertise performing complex surgical tasks once competence is achieved. Cognitive assessment may be used as an adjunct to the traditional methods for skill assessment during RAS.

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Video: Robot Assisted Retroperitoneal Lymph Node Dissection

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Robot-assisted retroperitoneal lymph node dissection: technique and initial case series of 18 patients

Scott M. Cheney, Paul E. Andrews, Bradley C. Leibovich* and Erik P. Castle

Mayo Clinic Arizona Department of Urology, Phoenix, AZ, and *Mayo Clinic Rochester Department of Urology, Rochester, MN, USA

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Abstract

OBJECTIVE

To evaluate outcomes of the first 18 patients treated with robot-assisted retroperitoneal lymph node dissection (RA-RPLND) for non-seminomatous germ cell tumours (NSGCT) and paratesticular rhabdomyosarcoma (RMS) at our institution.

PATIENTS AND METHODS

Between March 2008 and May 2013, 17 patients underwent RA-RPLND for NSGCT and one for paratesticular RMS. Data were collected retrospectively on patient demographics, preoperative tumour characteristics, and perioperative outcomes including open conversion rate, lymph node (LN) yield, rate of positive LNs, operative time, estimated blood loss (EBL), and length of stay (LOS). Perioperative outcomes were compared between patients receiving primary RA-RPLND vs post-chemotherapy RA-RPLND. Medium-term outcomes of tumour recurrence rate and maintenance of antegrade ejaculation were recorded.

RESULTS

RA-RPLND was completed robotically in 15 of 18 (83%) patients. LNs were positive in eight of 18 patients (44%). The mean LN yield was 22 LNs. For cases completed robotically, the mean operative time was 329 min, EBL was 103 mL, and LOS was 2.4 days. At a mean (range) follow-up of 22 (1–58) months, there were no retroperitoneal recurrences and two of 17 (12%) patients with NSGCT had pulmonary recurrences. Antegrade ejaculation was maintained in 91% of patients with a nerve-sparing approach. Patients receiving primary RA-RPLND had shorter operative times compared with those post-chemotherapy (311 vs 369 min, P = 0.03). There was no significant difference in LN yield (22 vs 18 LNs, P = 0.34), EBL (100 vs 313 mL, P = 0.13), or LOS (2.75 vs 2.2 days, P = 0.36).

CONCLUSION

This initial selected case series of RA-RPLND shows that the procedure is safe, reproducible, and feasible for stage I–IIB NSGCT and RMS in the hands of experienced robotic surgeons. Larger studies are needed to confirm the diagnostic and therapeutic utility of this technique.

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Video: Progression and treatment of incident lower urinary tract symptoms (LUTS) among men in the California Men’s Health Study

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Progression and treatment of incident lower urinary tract symptoms (LUTS) among men in the California Men’s Health Study

Lauren P. Wallner, Jeff M. Slezak*, Ronald K. Loo†, Virginia P. Quinn*, Stephen K. Van Den Eeden‡ and Steven J. Jacobsen*

Department of Medicine and Comprehensive Cancer Center, University of Michigan, Ann Arbor, MI, *Department of Research and Evaluation, Kaiser Permanente Southern California, †Department of Urology, Southern California Permanente Medical Group, Pasadena, CA, and ‡Division of Research, Kaiser Permanente Northern California, Oakland, CA, USA

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OBJECTIVES

To characterise the progression and treatment of lower urinary tract symptoms (LUTS) among men aged 45–69 years in the California Men’s Health Study.

PATIENTS AND METHODS

A total of 39 222 men, aged 45–69 years, enrolled in the Southern California Kaiser Permanente Health Plan were surveyed in 2002–2003 and again in 2006–2007. Those men who completed both surveys who did not have a diagnosis of benign prostatic hyperplasia (BPH) and were not on medication for LUTS at baseline were included in the study (N = 19 505). Among the men with no or mild symptoms at baseline, the incidence of moderate/severe LUTS (American Urological Association Symptom Index [AUASI] score ≥8) and odds of progression to severe LUTS (AUASI score ≥20) was estimated during 4 years of follow-up.

RESULTS

Of the 9640 men who reported no/mild LUTS at baseline, 3993 (41%) reported moderate/severe symptoms at follow-up and experienced a 4-point change in AUASI score on average. Of these men, 351 (8.8%) had received a pharmacological treatment, eight (0.2%) had undergone a minimally invasive or surgical procedure and 3634 (91.0%) had no treatment recorded. Men who progressed to severe symptoms (AUASI score ≥20; n = 165) were more likely to be on medication for BPH (odds ratio [OR] 8.09, 95% confidence interval [CI] 5.77–11.35), have a BPH diagnosis (OR 4.74, 95% CI 3.40–6.61) or have seen a urologist (OR 2.49, 95% CI 1.81–3.43) when compared with men who did not progress to severe symptoms (AUASI score <20).

CONCLUSION

These data show that the majority of men who experienced progression did not have pharmacological or surgical therapy for their symptoms and, therefore, may prove to be good candidates for a self-management plan.

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Video: Bimanual Examination Of The Retrieved Specimen And Regional Hypothermia During Robot-Assisted Radical Prostatectomy: A Novel Technique For Reducing Positive Surgical Margin And Achieving Pelvic Cooling

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Bimanual examination of the retrieved specimen and regional hypothermia during robot-assisted radical prostatectomy: a novel technique for reducing positive surgical margin and achieving pelvic cooling

Wooju Jeong, Akshay Sood, Khurshid R. Ghani, Dan Pucheril, Jesse D. Sammon, Nilesh S. Gupta*, Mani Menon and James O. Peabody

Vattikuti Urology Institute and *Department of Pathology, Henry Ford Health System, Detroit, MI, USA

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OBJECTIVE

To describe a novel method of achieving pelvic hypothermia during robot-assisted radical prostatectomy (RARP) and a modification of technique allowing immediate organ retrieval for intraoperative examination and targeted frozen-section biopsies.

PATIENTS AND METHODS

Intracorporeal cooling and extraction (ICE) consists of a modification of the standard RARP technique with the use of the GelPOINT™ (Applied Medical, Rancho Santa Margarita, CA, USA), a hand access platform, which allows for delivery of ice-slush and rapid specimen extraction without compromising pneumoperitoneum.

RESULTS

The ICE technique reproducibly achieves a temperature of 15 °C in the pelvic cavity with no obvious body temperature change. Adopting this technique during RARP, there was an absolute risk reduction by 26.6% in positive surgical margin rate in patients with pT3a disease when compared with similar patients undergoing conventional RARP (P = 0.04).

CONCLUSIONS

The ICE technique eliminates the potential handicap of decreased tactile sensation for oncological margins, especially in the high-risk patients. This technique allows the surgeon to immediately examine the surgical specimen after resection, and with the aid of frozen-section pathology determine if further resection is required. A prospective trial is underway in our centre to evaluate the effects of this novel technique on postoperative outcomes.

 

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