Annals of Urology Vol II Issue 1

Vascular Endothelial Growth Factor Receptor (VEGFR) Tyrosine Kinase Inhibitor (TKI) Resistance in Metastatic Renal Cell Carcinoma (mRCC): Possible Mechanisms and Clinical Approaches

Michael R Harrison¹ and Daniel J George^2,3

Affiliations: ¹Division of Hematology/Oncology, Department of Medicine, University of Wisconsin Carbone Cancer Center, Madison, WI, USA; ²Division of Medical Oncology, Department of Medicine, Duke Cancer Institute, Durham, NC, USA and ³Division of Urology, Department of Surgery, Duke Cancer Institute, Durham, NC, USA

Correspondence: Daniel J. George, Division of Medical Oncology, Department of Medicine, Duke University Medical Center, DUMC 102002, Durham, NC 27710, USA. Tel: +1 919 668 8650; Fax: +1 919 668 7117; e-mail: daniel.george@duke.edu

ABSTRACT

INTRODUCTION

The approvals of sorafenib, sunitinib, and pazopanib have led to increased options for patients with mRCC. Unfortunately, some patients treated with these vascular endothelial growth factor receptor (VEGFR) TKI progress rapidly, while the majority of remaining patients will develop evidence of disease progression within 2 years.

OBJECTIVES

We gathered preclinical and clinical evidence regarding potential mechanisms of VEGFR TKI resistance and clinical approaches to counter it.

METHODS

We searched the published medical literature, searching the National Library of Medicine (PubMed) as well as abstracts from annual meetings of the American Society of Clinical Oncology (ASCO) and American Association for Cancer Research (AACR).

RESULTS

No clear evidence-based mechanism of VEGFR TKI resistance has been defined to date; therefore, we summarize the existing hypothesis-generating preclinical, biomarker, and clinical data. Potential mechanisms of resistance to VEGFR TKI include variations in the inherent genetic alterations associated with RCC, independent of VHL. In addition, response to hypoxia induced by VEGFR TKI may drive alternative growth factor mediated angiogenesis. Molecular imaging evidence of early angiogenesis and proliferation rebound following VEGFR TKI exposure suggests progression is still driven by a proangiogenic phenotype.

CONCLUSION

By necessity, clinicians must currently make treatment decisions on the basis of limited data regarding the biology of VEGFR TKI resistance. RCC is a heterogeneous disease from the onset. Understanding the specific genetic profiles of sensitive and resistant subtypes of RCC may aid in both first-line and subsequent treatment selection. In addition, better understanding of tumor response and resistance may lead to novel combination strategies in the future.

Noninvasive Techniques in Urodynamics: An Update

Françoise A. Valentini^1,2, Pierre P. Nelson¹ and Gilberte Robain^1,2

Affiliations: ¹ER6-Université Pierre et Marie Curie, Service de Reeducation Neurologique and ²Service de Rééducation Neurologique, Hôpital Rothschild, Paris, France

Correspondence: Françoise A. Valentini, Service de Rééducation Neurologique, Hôpital Rothschild, 5, rue Santerre, 75012 – Paris, France. Tel: 33 1 40 19 36 18; Fax: 33 1 40 19 36 56; e-mail: francoise.valentini@rth.aphp.fr; favalentini@gmail.com

ABSTRACT

PURPOSE

From the beginning of urodynamics, clinicians were aware that the method was invasive, expensive, time consuming, and had some morbidity. A consequence was the suggestion of many noninvasive methods to evaluate lower urinary tract dysfunctions. Our purpose was to list these methods with special interest for the methods that eliminated the drawbacks of urodynamics and for new methods.

MATERIALS

A PubMed search of published literature on noninvasive methods in urodynamics until October 2010 was performed.

RESULTS

Except for the first historical attempts (voiding distance, drop spectrophotometer), methods were broadly classified by their incidence on the flow. Many techniques required a complex and expensive equipment (Doppler ultrasound, functional brain imaging) and some caused adverse events (cuff, condom). Controversies existed when different measurement techniques were used (bladder ultrasound). Some techniques needed further studies (near infrared). The simplest methods (PCR, D index) fulfilled the outgoings.

CONCLUSION

Noninvasive urodynamics is a large challenge and is not solved. Some methods, which can be applied to man and woman, are promising: ultrasound to assess lower urinary tract dysfunction when a standardization will be obtained, and brain imaging to give a better understanding of the pathophysiology of micturition.

The Role of Docetaxel and Other Chemotherapy Regimes in Castration-Resistant Prostate Cancer

BE Ayres¹, SRJ Bott², A Bahl³, MJA Perry¹, and RA Persad⁴

Affiliations: ¹Department of Urology, St. George’s Hospital, London, UK; ²Department of Urology, Frimley Park Hospital, Surrey, UK; ³Department of Oncology, Bristol Haematology and Oncology Centre, Bristol, UK and ⁴Department of Urology, Bristol Royal Infirmary, Bristol, UK

Correspondence: Benjamin Ayres, Department of Urology, St George’s Hospital, Blackshaw Road, London, SW17 0QT, UK. Tel: +44 20 86 721255; e-mail: beayres@hotmail.com

ABSTRACT

Prostate cancer is the most common male cancer in Europe and the United States. The majority of men diagnosed with this disease will have a good prognosis. Despite this a large number of men have advanced prostate cancer, with significant morbidity and poor survival, especially once it becomes castration-resistant. In the last decade, chemotherapy, in particular docetaxel, has played a greater role in the management of men with castration-resistant prostate cancer resulting in improved symptom-control, quality of life, and survival. Advances have also been made with second-line salvage therapies following disease progression on docetaxel.

Beyond Taxanes: Novel Therapeutic Strategies for Castration-Resistant Prostate Cancer

Yasser Rehman¹ and Jonathan E Rosenberg²

Affiliations: ¹Division of Hospital Medicine, UMass Memorial Healthcare, Worcester, MA and ²Lank Center for Genitourinary Oncology, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA, USA

Correspondence: Yasser Rehman, UMass Memorial Healthcare, Division of Hospital Medicine, 119 Belmont Street, Worcester MA 01605, USA. Tel: +646 402 2900; e-mail: Yasser_rehman@dfci.harvard.edu

ABSTRACT

BACKGROUND

Prostate cancer is one of the leading causes of cancer mortality among men. The initial success in treating advanced prostate cancer with androgen deprivation is short lived. Historically, there have been few treatment options for castrate-resistant prostate cancer (CRPC). The recent approvals of new treatments for CRPC appear promising.

MATERIALS AND METHODS

A comprehensive review of recently published prospective phase II/III trials of therapeutic options for CRPC was done. Studies that led to FDA approval and high impact phase II studies were selected for inclusion in this review.

RESULTS

The approvals of docetaxel, cabazitaxel, and sipuleucel-T by the FDA for treatment of CRPC have demonstrated survival benefit in advanced CRPC. A number of clinical trials are underway looking at the efficacy of newer androgen pathway inhibitors such as Abiraterone and MDV 3100. Preliminary results suggest that these agents are promising for the treatment of CRPC.

CONCLUSION

The treatment of CRPC has shifted from pure palliation of symptoms to life prolonging therapy. Although the newer agents have improved CRPC survival, there is a continued need to develop better and more effective treatments.

Urodynamics: State of Art Review of Literature and Recent Controversies

Eric Chung¹ and Albert Tiu²

Affiliations: ¹Department of Urology, Princess Alexandra Hospital, Queensland, Australia and ²Department of Urology, Wagga Wagga Base Hospital, NSW, Australia

Correspondence: Dr Eric Chung, Department of Urology, Princess Alexandra Hospital, Ipswich Road, Woollongabba, Queensland 4102, Australia. Tel: +61-31766946; Fax: +61-31762560; e-mail: ericchg@hotmail.com

ABSTRACT

INTRODUCTION

There is ongoing debate about the diagnostic utility of urodynamic studies (UDS) in the management of women with urinary incontinence given the conflicting statements by various governing bodies. Most patients with urinary incontinence will respond well to conservative measures and/or minimally invasive anti-incontinence surgery without the need for routine urodynamic testing. Furthermore several controversies continue to exist on the utility of UDS in the preoperative investigation value, degree of detrusor- or bladder neck-related voiding dysfunction, application of leak point pressures and urethral pressure profile, and the need for UDS in healthy, treatment-naive woman with no history of prior incontinence or prolapsed surgery.

OBJECTIVES

To highlight the arguments surrounding the current controversies and explore the value of UDS based on published literature.

MATERIALS AND METHODS

The Pubmed and Medline database were searched for recent articles published over the last 5 years. Only peer-reviewed articles published in English were evaluated and specific emphasis on major international guidelines, statements from major urinary and continence organizations, and published studies from randomized controlled multicenter trials were placed. The search terms were urodynamics, recent controversies, preoperative and surgical outcome, valsalva leak point pressure, and cost-effectiveness.

RESULTS

Many issues pertaining to UDS remain unresolved but UDS should be considered in women with prior stress-incontinent and/or pelvic surgery or radiation, concomitant large pelvic organ prolapse, or who have history of neurological conditions.

CONCLUSION

Further research is needed to determine the role of UDS in preoperative patient counseling and surgical success.

The Relevance of Continued Medical Castration for Patients With Castration-Resistant Prostate Cancer

Cora N. Sternberg¹ and Karim Fizazi²

Affiliations: ¹San Camillo and Forlanini Hospitals, IT-00512 Rome, Italy and ²Institut Gustav Roussy, University of Paris Sud, Villejuif, 94805 France

Correspondence: Cora N Sternberg, Department of Medical Oncology, San Camillo and Forlanini Hospitals, Nuovi Padiglioni, 4th Floor, Circonvallazione Gianicolense 87, IT-00152 Rome, Italy. Tel: 39 06 5870 4356; Fax: 39 06 663 0771; e-mail: cstern@mclink.it

ABSTRACT

Prostate cancer is an androgen-responsive disease with the treatment of advanced prostate cancer involving hormonal therapy. Gonadotropin-releasing hormone (GnRH) analogues are currently the mainstay of treatment, used either as monotherapy or combined with antiandrogens. The GnRH analogues suppress testosterone levels and thus slow proliferation of the tumor cells that depend on testosterone for growth. Androgen deprivation results in the downregulation of androgen receptor (AR) transcriptional activity in the tumor, but the response is transient and tumors eventually progress as castration-resistant prostate cancer (CRPC). Although serum testosterone levels decline dramatically with androgen deprivation, it is clear that CRPC growth remains largely dependent on AR activity. Secondary hormonal therapies, often employed in CRPC patients to further reduce AR-driven transcription, either further deplete androgen synthesis or directly and competitively antagonise the AR. Two new agents, the androgen synthesis inhibitor abiraterone and the AR antagonist MDV3100 have provided the strongest evidence to date that CRPC remains a hormonally driven disease. Although other therapeutic approaches have also been investigated, the continued hormonal dependency of prostate cancer postprogression has ensured that maintenance of the castrate state via continued use of GnRH analogues remains an essential aim in the treatment of CRPC patients who progress on primary hormonal therapy.

Neuroendocrine Dedifferentiation in Progressive Prostate Cancer: New Therapeutic Approaches

E Barrascout¹, B Beuselinck^1,2, J Gachet¹, A Morel¹, J Medioni^1,3, F Scotte¹, E Fabre¹ and S Oudard^1,2,3

Affiliations: ¹Medical Oncology Department, Assistance Publique—Hopitaux de Paris, Georges Pompidou European Hospital, Paris, France; ²Inserm U674 Paris, France and ³Paris Descartes University, Paris 5, France

Correspondence: S Oudard, Medical Oncology Department, Assistance Publique—Hopitaux de Paris, Georges Pompidou European Hospital, Paris, France. email: stephane.oudard@egp.aphp.fr

ABSTRACT

The prognosis for metastatic castrate-resistant prostate cancer (CRPC) is currently limited, with a median survival without treatment of about 12 months. Current management of the disease at this castrate-resistant stage is based on the use of taxanes, which have demonstrated efficacy in terms of overall survival. Other compounds such as epothilones, satraplatin, and navelbine anti-Rank ligands, tyrosine kinase inhibitors, monoclonal antibodies and antiangiogenic agents have been evaluated with variable results.

One of the mechanisms in the transition of the disease to a castrate-resistant stage is the acquisition of a neuroendocrine phenotype of prostate cells. Neuroendocrine biomarkers, particularly neuron-specific enolase and chromogranin A, are evidence of this transformation. New treatment approaches directed at neuroendocrine cells are under development. Somatostatin and its analogs combined with dexamethasone have shown a significant clinical benefit in the treatment of CRPC compared with standard chemotherapy. Other regimens based on treatment of neuroendocrine tumors at other sites have been evaluated (ie, cisplatin, carboplatin, etoposide). However, current results are not encouraging despite an acceptable safety profile.

Surgical Management of Metastases to the Adrenal Gland

Jennifer Yates and Ravi Munver

Affiliation: Department of Urology, Hackensack University Medical Center, Hackensack, NJ, USA

Correspondence: Ravi Munver, Department of Urology, Hackensack University Medical Center, 360 Essex Street, Suite 403, Hackensack, NJ 07601, USA. Tel: 201-336-8090; Fax: 201-336-8221; e-mail: rmunver@humed.com

ABSTRACT

The adrenal gland can be the site of metastatic disease in the setting of a number of primary malignancies. Differentiating a metastatic lesion from a primary adrenal lesion is important and may require the use of radiologic imaging, an endocrinologic evaluation, and adrenal biopsy. Adrenal biopsy may be especially useful in those patients with a known primary malignancy in order to determine whether the patient is a candidate for metastatectomy or systemic therapy. Patients with isolated adrenal metastases may have superior outcomes from adrenalectomy as compared to chemotherapy. In the past, open adrenalectomy was the standard of care for patients with an isolated adrenal metastasis, but recently laparoscopic adrenalectomy has been utilized with favorable outcomes. Appropriate patient selection for the surgical approach is critical to determine the best treatment for the individual patient.

Laparoscopic, Robotic, and Laparoendoscopic Single-Site (LESS) Surgery: Applications in Female Urology and Urogynecology

Michael S Ingber¹ and Courtenay K Moore²

Affiliations: ¹Department of Urology and Urogynecology, Saint Clare’s Hospital, Denville, NJ, USA and ²Glickman Urological and Kidney Institute, Cleveland Clinic, Cleveland, OH, USA

Correspondence: Michael Ingber, Morris Urology Associates, 16 Pocono Rd, Suite 205, Denville, NJ 07834, USA. Tel: +1 (973) 627-0060; Fax: +1 (973) 627-6821; email: ingbermd@aol.com

ABSTRACT

Traditional pelvic reconstructive and incontinence surgery required large abdominal incisions and carried significant morbidity for the patient. The introduction of laparoscopy and robotic-assisted laparoscopic surgery provided patients the option to have the same long-term outcomes with much smaller incisions and a significantly shorter recovery. Surgical technology has further evolved, and we are now offering patients laparoendoscopic single-site (LESS) surgery, which can be performed through a single incision, often through a natural orifice such as the umbilicus. This manuscript reviews the available literature on these minimally invasive techniques and how they have been applied in the field of female urology and urogynecology.

Castration-Resistant Prostate Cancer: Current Status and Future Directions

Saadettin Eskicorapci, Ali Ersin Zumrutbas, Tahir Turan and Omer Levent Tuncay

Affiliation: Department of Urology, Pamukkale University Medical School, Denizli, Turkey

Correspondence: Saadettin Eskicorapci, Department of Urology, Pamukkale University Medical School, Denizli, Turkey. Tel: +90 258 444 0 728; Fax: 0090 2582134922; e-mail: drsye@yahoo.com

ABSTRACT

Over the past decade, the treatment alternatives of castration-resistant prostate cancer (CRPC) have developed significantly, especially with the revelation of the docetaxel-based chemotherapy regimes. However, despite several attempts, the median survival for men with metastatic CRPC remains as 1–2 years. The purpose of this article is to discuss the current status and recent developments in the field of CRPC, focusing particularly on the new agents that are most encouraging. Nonetheless, there are serious improvements being made in the development of more effective antiandrogens and cytochrome P17 inhibitors (abiraterone, MDV3100), novel chemotherapy regimens, targeted therapies, and immunotherapies (sipuleucel-T). For the most part, new therapeutic agents are being combined with chemotherapy, similar to the approach taken in other tumors. However, the development of new approaches to the treatment of castration resistant prostate cancer presents many challenges that will demand collaboration and consensus building with respect to biomarkers for patient selection, clinical endpoints, and trial designs.

Surgical Options in the Management of Ureteropelvic Junction Obstruction

Joseph E Jamal and Thomas W Jarrett

Affiliation: Department of Urology, George Washington University Hospital, Washington, District of Columbia, USA

Correspondence: Joseph E Jamal, Department of Urology, Medical Faculty Associates—George Washington University Hospital, 2150 Pennsylvania Ave, NW, Washington, DC 20037, USA. Tel: +1 202 741 3100; Fax: +1 202 741 3113; e-mail: jjamal@mfa.gwu.edu

ABSTRACT

A variety of surgical management options to treat ureteropelvic junction obstruction (UPJO) exist. Most of these techniques have been well established, are highly efficacious, and have low morbidity. Historically, open pyeloplasty (OP) has been the treatment of choice with success rates exceeding 90%. Advancements in instrumentation have allowed more minimally invasive treatment options in the management of UPJO. There is a wide spectrum of minimally invasive options, each with specific indications, advantages, and compromises. Despite a variety of minimally invasive techniques, the least invasive generally has slightly decreased efficacy than other options but the benefits of decreased pain and shorter convalescence. Other minimally invasive techniques have comparable efficacy to, but significantly less morbidity and shorter convalescence than OP. Although OP is still largely considered the criterion standard for UPJO in infants, laparoscopic pyeloplasty (LP), with or without robotic assistance, is currently the treatment of choice in older children and in most adults. This review will briefly touch upon the pathogenesis and diagnostic workup; however, the focus will be on surgical options in the management of UPJO. Current treatment options reviewed in this article include antegrade and retrograde endopyelotomy, endopyeloplasty, LP, robotic-assisted pyeloplasty, and conventional and robotic laparoendoscopic single-site surgery.

Urodynamic Evaluation of Experimental Rat Models of Urinary Bladder Overactivity: A Systematic Review of the Literature

Kajetan Juszczak^1,2, Marek Wyczółkowski² and Piotr J. Thor¹

Affiliations: ¹Department of Pathophysiology, Jagiellonian University, Medical College, Cracow, Poland and ²Department of Urology, Rydygier Memorial Hospital, Cracow, Poland

Correspondence: Kajetan Juszczak MD, PhD, Department of Pathophysiology, Medical College, Jagiellonian University, Czysta 18 Street, 31-121 Cracow, Poland. Tel: +48126333947; Fax: + 48126329056; e-mail: kajus13@poczta.onet.pl

ABSTRACT

BACKGROUND

Many in vivo experimental models of overactive bladder (OAB) have been frequently used as tools to explore the pathophysiology and therapeutical options for the treatment of OAB. However, there is no standard recommendation according to the OAB model.

PURPOSE

Our aim was to perform a systematic revision of the literature to identify articles devoted to the experimental models of OAB. The following review is focused on the backgrounds, methodology, and outcomes of the described models.

EVIDENCE ACQUISITION

This review is based on a systemic literature research. The MedLine, Embase, and Web of Science databases were browsed in order to identify original and review articles, as well as editorials relating to “overactive bladder,” “urodynamic evaluation,” “cystometry,” “experimental model,” “methodology,” and “rat” in urinary bladder dysfunction. The controlled vocabulary of the Medical Subject Headings (MeSH) database was used to ensure sensitivity of the searches.

EVIDENCE SYNTHESIS AND CONCLUSIONS

Different OAB models in conscious and anesthetized rats were described. However, a wide range of differences in experimental protocols concerning urodynamic evaluation of bladder motor activity was observed. Also, in the majority of papers the way of calibration of intravesical pressure measurement systems is not mentioned. All these factors could exert influence on bladder motor activity recordings and, consequently, could lead to differences in cystometrogram traces and cystometric parameters values even though the same experimental protocol was used. Therefore, the standardization of cystometric protocol seems to be pivotal for correct bladder motor activity assessment. Based on our experience and the previously described studies we suggest some steps that should always be taken to minimize the artifacts occurrence during cystometry.

Controversies in Pelvic Organ Prolapse: Mesh Interposition in Prolapse Repair

Alex Gomelsky¹ and Roger R Dmochowski²

Affiliations: ¹Department of Clinical Urology, Louisiana State University Health sciences Center–Shreveport, Louisiana, USA and ²Department of Urologic Surgery, Vanderbilt University Medical Center, Nashville, Tennessee, USA

Correspondence: Roger R. Dmochowski, Department of Urologic Surgery, Vanderbilt University Medical Center, A-1302, Medical Center North, Nashville, Tennessee 37232, USA. Tel: +1 615 343 5602; Fax: +1 615 322 8990; e-mail: roger.dmochowski@Vanderbilt.edu

ABSTRACT

INTRODUCTION

As the durability of standard prolapse repairs may be in question, synthetic meshes have become a popular adjunct for providing additional support. However, several questions remain unanswered regarding their implementation.

OBJECTIVES

(1) To summarize the available literature regarding the transvaginal placement of synthetic mesh for prolapse repair, with a focus on the outcomes and complications of commercial prolapse kits; (2) draw comparisons with standard prolapse repairs; and (3) address common questions regarding vaginal mesh placement.

METHODS

A MEDLINE search was performed for available English language literature relating to transvaginal synthetic mesh placement. GOOGLE translator was used for pertinent non-English language articles.

RESULTS

Short-term anatomic recurrence rates after mesh-augmented anterior repair are lower than standard repairs. Currently, there is no data to support mesh placement in the posterior compartment. Kit repairs are associated with unique complications relating to trocar passage and mesh placement (eg, extrusion and erosion). Dyspareunia may be multifactorial and may occur after standard and mesh repairs. Currently, a causal relationship between mesh placement and dyspareunia is not clear.

CONCLUSIONS

The decision to place mesh transvaginally should be tailored to each patient, as both the rates of short-term anatomic success and complications may both be higher than those associated with standard prolapse repairs. Long-term, prospective, randomized controlled trials are vital to progress our knowledge of mesh-augmented prolapse repair.