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Video: TRP channel modulators as pharmacological treatments for LUTS – myth or reality?

Transient receptor potential channel modulators as pharmacological treatments for lower urinary tract symptoms (LUTS): myth or reality?

Yves Deruyver*‡¶, Thomas Voets†¶, Dirk De Ridder*‡¶and Wouter Everaerts*§¶

 

*Laboratory of Experimental Urology, Department of Development and Regeneration,† Laboratory for Ion Channel Research, Department of Molecular Cell Biology, KU Leuven, University Hospitals Leuven, TRP Research Platform Leuven (TRPLe), Leuven, Belgium, and §Royal Melbourne Hospital, Melbourne, Australia

 

Transient receptor potential (TRP) channels belong to the most intensely pursued drug targets of the last decade. These ion channels are considered promising targets for the treatment of pain, hypersensitivity disorders and lower urinary tract symptoms (LUTS). The aim of the present review is to discuss to what extent TRP channels have adhered to their promise as new pharmacological targets in the lower urinary tract (LUT) and to outline the challenges that lie ahead.

  • TRP vanilloid 1 (TRPV1) agonists have proven their efficacy in the treatment of neurogenic detrusor overactivity (DO), albeit at the expense of prolonged adverse effects as pelvic ‘burning’ pain, sensory urgency and haematuria.
  • TRPV1 antagonists have been very successful in preclinical studies to treat pain and DO. However, clinical trials with the first generation TRPV1 antagonists were terminated early due to hyperthermia, a serious, on-target, side-effect.
  • TRP vanilloid 4 (TRPV4), TRP ankyrin 1 (TRPA1) and TRP melastatin 8 (TRPM8) have important sensory functions in the LUT. Antagonists of these channels have shown their potential in pre-clinical studies of LUT dysfunction and are awaiting clinical validation.

Video: Percutaneous targeting using 3D navigation that integrates position-tracking technology with a tablet display

Three-dimensional navigation system integrating position-tracking technology with a movable tablet display for percutaneous targeting

Arnaud Marien, Andre Castro de Luis Abreu, Mihir Desai, Raed A. AzharSameer Chopra, Sunao Shoji, Toru Matsugasumi, Masahiko Nakamoto, Inderbir S. Gill and Osamu Ukimura

 

USC Institute of Urology, Center for Focal Therapy of Prostate and Kidney Cancer, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA

 

OBJECTIVES

To assess the feasibility of a novel percutaneous navigation system (Translucent Medical, Inc., Santa Cruz, CA, USA) that integrates position-tracking technology with a movable tablet display.

MATERIALS AND METHODS

A total of 18 fiducial markers, which served as the target centres for the virtual tumours (target fiducials), were implanted in the prostate and kidney of a fresh cadaver, and preoperative computed tomography (CT) was performed to allow three-dimensional model reconstruction of the surgical regions, which were registered on the body intra-operatively. The position of the movable tablet’s display could be selected to obtain the best recognition of the interior anatomy. The system was used to navigate the puncture needle (with position-tracking sensor attached) using a colour-coded, predictive puncture-line. When the operator punctured the target fiducial, another fiducial, serving as the centre of the ablative treatment (treatment fiducial), was placed. Postoperative CT was performed to assess the digitized distance (representing the real distance) between the target and treatment fiducials to evaluate the accuracy of the procedure.

RESULTS

The movable tablet display, with position-tracking sensor attached, enabled the surgeon to visualize the three-dimensional anatomy of the internal organs with the help of an overlaid puncture line for the puncture needle, which also had a position-tracking sensor attached. The mean (virtual) distance from the needle tip to the target (calculated using the computer workstation), was 2.5 mm. In an analysis of each digitalized axial component, the errors were significantly greater along the z-axis (P < 0.01), suggesting that the errors were caused by organ shift or deformation.

CONCLUSION

This virtual navigation system, integrating a position-tracking sensor with a movable tablet display, is a promising advancement for facilitating percutaneous interventions. The movable display over the patient shows a preoperative three-dimensional image that is aligned to the patient. Moving the display moves the image, creating the feeling of looking through a window into the patient, resulting in instant perception and a direct, intuitive connection between the physician and the anatomy.

Video: Is a 12-core biopsy still necessary in addition to a targeted biopsy?

In patients with a previous negative prostate biopsy and a suspicious lesion on magnetic resonance imaging, is a 12-core biopsy still necessary in addition to a targeted biopsy?

Simpa S. Salami*, Eran Ben-Levi, Oksana Yaskiv, Laura Ryniker*, Baris Turkbey§, Louis R. Kavoussi*, Robert Villani† and Ardeshir R. Rastinehad*

 

*The Arthur Smith Institute for Urology, Department of Diagnostic and Interventional Radiology, and Department of Pathology, Hofstra North Shore-LIJ School of Medicine, New Hyde Park, NY, and § Molecular Imaging Program, National Institutes of Health, Bethesda, MD, USA

 

OBJECTIVES

To evaluate the performance of multiparametric magnetic resonance imaging (mpMRI) in predicting prostate cancer on repeat biopsy; and to compare the cancer detection rates (CDRs) of MRI/transrectal ultrasonography (TRUS) fusion-guided biopsy with standard 12-core biopsy in men with at least one previous negative biopsy.

PATIENTS AND METHODS

We prospectively enrolled men with elevated or rising PSA levels and/or abnormal digital rectal examination into our MRI/TRUS fusion-guided prostate biopsy trial. Participants underwent a 3 T mpMRI with an endorectal coil. Three radiologists graded all suspicious lesions on a 5-point Likert scale. MRI/TRUS fusion-guided biopsies of suspicious prostate lesions and standard TRUS-guided 12-core biopsies were performed. Analysis of 140 eligible men with at least one previous negative biopsy was performed. We calculated CDRs and estimated area under the receiver operating characteristic curves (AUCs) of mpMRI in predicting any cancer and clinically significant prostate cancer.

RESULTS

The overall CDR was 65.0% (91/140). Higher level of suspicion on mpMRI was significantly associated with prostate cancer detection (P < 0.001) with an AUC of 0.744 compared with 0.653 and 0.680 for PSA level and PSA density, respectively. The CDRs of MRI/TRUS fusion-guided and standard 12-core biopsy were 52.1% (73/140) and 48.6% (68/140), respectively (P = 0.435). However, fusion biopsy was more likely to detect clinically significant prostate cancer when compared with the 12-core biopsy (47.9% vs 30.7%; P < 0.001). Of the cancers missed by 12-core biopsy, 20.9% (19/91) were clinically significant. Most cancers missed by 12-core biopsy (69.6%) were located in the anterior fibromuscular stroma and transition zone. Using a fusion-biopsy-only approach in men with an MRI suspicion score of ≥4 would have missed only 3.5% of clinically significant prostate cancers.

CONCLUSIONS

Using mpMRI and subsequent MRI/TRUS fusion-guided biopsy platform may improve detection of clinically significant prostate cancer in men with previous negative biopsies. Addition of a 12-core biopsy may be needed to avoid missing some clinically significant prostate cancers.

Video: 1,138 consecutive laparoscopic radical prostatectomies – Minimum five-year follow-up

Minimum five-year follow-up of 1,138 consecutive laparoscopic radical prostatectomies

Ricardo Soares, Antonina Di Benedetto, Zach Dovey, Simon Bott*, Roy G. McGregor† and Christopher G. Eden

 

Department of Urology, Royal Surrey County Hospital, Guildford, *Department of Urology, Frimley Park Hospital, Frimley, Surrey, UK, and Cornwall Regional Hospital, Montego Bay, Jamaica

 

OBJECTIVES

To investigate the long-term outcomes of laparoscopic radical prostatectomy (LRP).

PATIENTS AND METHODS

In all, 1138 patients underwent LRP during a 163-month period from 2000 to 2008, of which 51.5%, 30.3% and 18.2% were categorised into D’Amico risk groups of low-, intermediate- and high-risk, respectively. All intermediate- and high-risk patients were staged by preoperative magnetic resonance imaging or computed tomography and isotope bone scanning, and had a pelvic lymph node dissection (PLND), which was extended after April 2008. The median (range) patient age was 62 (40–78) years; body mass index was 26 (19–44) kg/m2; prostate-specific antigen level was 7.0 (1–50) ng/mL and Gleason score was 6 (6–10). Neurovascular bundle was preservation carried out in 55.3% (bilateral 45.5%; unilateral 9.8%) of patients.

RESULTS

The median (range) gland weight was 52 (14–214) g. The median (range) operating time was 177 (78–600) min and PLND was performed in 299 patients (26.3%), of which 54 (18.0%) were extended. The median (range) blood loss was 200 (10–1300) mL, postoperative hospital stay was 3 (2–14) nights and catheterisation time was 14 (1–35) days. The complication rate was 5.2%. The median (range) LN count was 12 (4–26), LN positivity was 0.8% and the median (range) LN involvement was 2 (1–2). There was margin positivity in 13.9% of patients and up-grading in 29.3% and down-grading in 5.3%. While 11.4% of patients had up-staging from T1/2 to T3 and 37.1% had down-staging from T3 to T2. One case (0.09%) was converted to open surgery and six patients were transfused (0.5%). At a mean (range) follow-up of 88.6 (60–120) months, 85.4% of patients were free of biochemical recurrence, 93.8% were continent and 76.6% of previously potent non-diabetic men aged <70 years were potent after bilateral nerve preservation.

CONCLUSIONS

The long-term results obtainable from LRP match or exceed those previously published in large contemporary open and robot-assisted surgical series.

Video: Co-administration of TRPV4 and TRPV1 antagonists

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

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.

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

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

 

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.

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

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

 

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.

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

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
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.

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

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

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.

 

Video: Robot-assisted laparoscopic vs open radical cystectomy – health-related QoL from a prospective randomised clinical trial

Health-related quality of life from a prospective randomised clinical trial of robot-assisted laparoscopic vs open radical cystectomy

Jamie C. Messer, Sanoj Punnen*, John Fitzgerald, Robert Svatek and Dipen J. Parekh

Department of Urology, University of Texas Health Sciences Center at San Antonio, San Antonio, TX and *Department of Urology, Miller School of Medicine, University of Miami, Miami, FL, USA

Objective

To compare health-related quality-of-life (HRQoL) outcomes for robot-assisted laparoscopic radical cystectomy (RARC) with those of traditional open radical cystectomy (ORC) in a prospective randomised fashion.

Patients and Methods

This was a prospective randomised clinical trial evaluating the HRQoL for ORC vs RARC in consecutive patients from July 2009 to June 2011. We administered the Functional Assessment of Cancer Therapy–Vanderbilt Cystectomy Index questionnaire, validated to assess HRQoL, preoperatively and then at 3, 6, 9 and 12 months postoperatively. Scores for each domain and total scores were compared in terms of deviation from preoperative values for both the RARC and the ORC cohorts. Multivariate linear regression was used to assess the association between the type of radical cystectomy and HRQoL.

Results

At the time of the study, 47 patients had met the inclusion criteria, with 40 patients being randomised for analysis. The cohorts consisted of 20 patients undergoing ORC and 20 undergoing RARC, who were balanced with respect to baseline demographic and clinical features. Univariate analysis showed a return to baseline scores at 3 months postoperatively in all measured domains with no statistically significant difference among the various domains between the RARC and the ORC cohorts. Multivariate analysis showed no difference in HRQoL between the two approaches in any of the various domains, with the exception of a slightly higher physical well-being score in the RARC group at 6 months.

Conclusions

There were no significant differences in the HRQoL outcomes between ORC and RARC, with a return of quality of life scores to baseline scores 3 months after radical cystectomy in both cohorts.

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