Daniele D'Agostino

Efficacy of an assisted low-intensity programme of perioperative pelvic floor muscle training in improving the recovery of continence after radical prostatectomy: a randomized controlled trial

Study Type – Therapy (RCT)

Paclitaxel-Hyaluronic Acid for Intravesical Therapy of Bacillus Calmette-Guerin Refractory Carcinoma In Situ of the Bladder: Results of a Phase I Study

PURPOSE Carcinoma in situ represents high grade anaplasia of the bladder mucosa. Intravesical immunotherapy with bacillus Calmette-Guérin is the gold standard treatment for patients with carcinoma in situ. Patients with carcinoma in situ refractory to bacillus Calmette-Guérin are candidates for major surgery such as radical cystectomy. We identified the maximum tolerated dose and the recommended dose, and evaluated the safety profile of paclitaxel-hyaluronic acid bioconjugate given by intravesical instillation to patients with carcinoma in situ refractory to bacillus Calmette-Guérin. MATERIALS AND METHODS A total of 16 patients with carcinoma in situ refractory to bacillus Calmette-Guérin were enrolled in a phase I, open label, single institution study. A minimum of 3 eligible patients were included per dose level. Paclitaxel-hyaluronic acid solution (ONCOFID-P-B™) was administered for 6 consecutive weeks. The primary objective was to identify the maximum tolerated dose and the recommended dose. As secondary objectives the safety profile of ONCOFID-P-B, the pharmacokinetic profile after each instillation and the tumor response were also evaluated. RESULTS No dose limiting toxicity occurred at any drug level evaluated. The plasma levels of the study drug were always below the lower limit of quantification at all tested doses after each instillation. A total of 11 adverse events were reported by 7 patients and 9 (60%) showed complete treatment response. CONCLUSIONS Intravesical instillation of ONCOFID-P-B for carcinoma in situ refractory to bacillus Calmette-Guérin showed minimal toxicity and no systemic absorption in the first human intravesical clinical trial to our knowledge. Finally, satisfactory response rates were observed.

Value of Current Chemotherapy and Surgery in Advanced and Metastatic Bladder Cancer

The aim of the present paper was to review findings from the most relevant studies and to evaluate the value of current chemotherapy and surgery in advanced unresectable and metastatic bladder cancer. Studies were identified by searching the MEDLINE® and PubMed® databases up to 2011 using both medical subject heading (Mesh) and a free text strategy with the name of the known individual chemotherapeutic drug and the following key words: ‘muscle-invasive bladder cancer’, ‘chemotherapeutics agents’, and ‘surgery in advanced bladder cancer’. At the end of our literature research we selected 141 articles complying with the aim of the review. The results showed that it has been many years since the MVAC (methotrexate, vinblastine, adriamycin, cisplatin) regimen was first developed. The use of cisplatin-based combination chemotherapy is associated with significant toxicity and produces long-term survival in only approximately 15–20% of patients. Gemcitabine + cisplatin represents the gold standard in the treatment of metastatic bladder cancer. In conclusion, the optimal approach in the management of advanced urothelial cancer continues to evolve. Further progress relies on the expansion of research into tumor biology and an understanding of the underlying molecular ‘fingerprints’ that can be used to enhance diagnostic and therapeutic strategies. Cisplatin-based therapy has had the best track record thus far.

Discovery history and clinical development of mirabegron for the treatment of overactive bladder and urinary incontinence

Introduction: Overactive bladder (OAB) and urinary incontinence, although not life-threatening, are very bothersome chronic health conditions. The limitations of current pharmacological treatment urge the need for novel drugs with alternative mechanisms of action. Huge efforts in this area of research led to the synthesis of several selective and potent β3-adrenoceptor agonists that gained relevance through research during the late 80s and 90s. Mirabegron was the first compound of this new class of drugs that showed preclinical efficacy in several models of storage bladder dysfunction, together with a favorable human pharmacological profile. Having passed the proof-of-concept stage, an extensive clinical development and pharmacology program was performed during the last 10 years, involving > 10,000 individuals, before mirabegron was granted marketing approval. Areas covered: In this case history, the authors review the milestones in mirabegrons discovery based on a systematic literature review. Expert opinion: Thanks to its tolerability and safety/efficacy balance, mirabegron has potential to fill a need for new treatment options for OAB, and paves the way for further development of a completely new class of drugs aimed to treat this condition. However, the exact role of mirabegron in clinical practice has yet to be defined. Further studies are needed in order to clarify, together with post-launch information, critical safety issues and cost-effectiveness in head-to-head comparison with current standard treatments.

Imaging of Renal Cell Carcinoma: State of the Art and Recent Advances

Background and Aim: Renal cell carcinoma (RCC) is the 13th most common cancer worldwide and accounts for 4% of all adult malignancies. Herein the state of the art and recent advances in cross-sectional radiological imaging applied to RCC are reviewed, including ultrasonography, computed tomography, magnetic resonance imaging, and positron emission tomography. Methods: Literature search of peer-reviewed papers published by October 2010. Results: In front of more conventional and widespread imaging tools, such as ultrasonography and computed tomography, an array of newer and attractive radiological modalities are under investigation and show promise to improve our ability to noninvasively detect renal tumors and its recurrences, accurately assess the extent of the disease, and reliably evaluate treatment response, particularly in the era of antiangiogenetic therapy. Conclusions: Recent major advances in radiological imaging techniques have considerably improved our ability to diagnose, stage and follow-up RCC. Further studies are needed to evaluate the potential of most recent and still investigational imaging tools.

Imaging in Bladder Cancer: Present Role and Future Perspectives

Advances in imaging have an increasingly significant role in the diagnosis, staging and restaging of patients with bladder cancer. This paper reviews the current use of imaging in bladder neoplasms, comparing the different radiologic investigations, and discusses the potential applications of novel imaging techniques in the management of patients with bladder cancer.

Bladder tumor markers: a review of the literature

Bladder cancer is among the top eight most frequent cancers. Its natural history is related to a combination of factors that impact on its aggressiveness. Cystoscopy and urine cytology are the currently used techniques for the diagnosis and surveillance of non-invasive bladder tumors. The sensitivity of urine cytology for diagnosis is not high, particularly in low-grade tumors. The combination of voided urine cytology and new diagnostic urine tests would be ideal for the diagnosis and follow-up of bladder cancer. However, in order to have some clinical utility, new diagnostic and/or prognostic markers should achieve better predictive capacity that the currently used diagnostic tools. None of the markers evaluated over the last years showed remarkable sensitivity or specificity for the identification of any of the diverse types of bladder cancer in clinical practice. The limitations of the known prognostic markers have led to the research of new molecular markers for early detection of bladder cancer. This research focused in particular on the discovery of biomarkers capable of reducing the need for periodic cystoscopies or, ideally, offering a non-invasive examination instead. In this review, we will examine various new markers of bladder cancer and their value in the diagnosis and follow-up of non-muscleinvasive bladder cancer. When compared with urine cytology, which showed the highest specificity, most of these markers demonstrated an increased sensitivity.

Thermochemotherapy for non-muscle-invasive bladder cancer: is there a chance to avoid early cystectomy?.

Objectives: Non-muscle-invasive bladder cancer is characterized by a high recurrence rate after primary transurethral resection. In case of bacillus Calmette-Guérin-refractory neoplasms, cystectomy is the gold standard. In this study the effects of thermochemotherapy with mitomycin C were evaluated in high-risk bladder cancer nonresponders to previous therapy. Patients and Methods: Between January 2006 and December 2009, 30 patients were enrolled with recurrent stage carcinoma in situ, Ta and T1, grade G1 to G3 non-muscle-invasive bladder cancer refractory to chemotherapy or immunotherapy and so becoming suitable for radical cystectomy. All patients underwent endovesical thermochemotherapy: 16 patients underwent a prophylactic scheme and 14 patients underwent an ablative scheme. Results: All the patients completed the study. The mean follow-up for all the patients enrolled was 14 months. Thirteen of 30 patients (43.30%) were disease free and 17 patients (56.70%) had recurrence. In the prophylactic group, 7 of 16 patients (43.75%) were disease free and 9 patients (46.25%) had tumor recurrence; no progression was observed. In the ablative group, 3 patients (17, 64%) had progression to muscle-invasive disease. Side effects were generally mild. Conclusions: Thermochemotherapy could be considered an additional tool in patients refractory to intravesical therapies before considering early cystectomy.

OnabotulinumtoxinA injection therapy in men with LUTS due to primary bladder‐neck dysfunction: Objective and patient‐reported outcomes

To determine efficacy and safety of OnabotulinumtoxinA (BoNT‐A) injection therapy in medically refractory patients with lower urinary tract symptoms (LUTS) due to primary bladder‐neck dysfunction (PBND).

High-intensity focused ultrasound in prostate cancer: Today's outcomes and tomorrow's perspectives

Abstract High-intensity focused ultrasound (HIFU) is a minimally invasive therapy applied for prostate cancer that capitalizes on the coagulation necrosis that occurs at temperatures greater than 60°C. Owing to a lack of long-term follow-up data the procedure is still considered experimental treatment. As primary therapy, HIFU is indicated in patients aged ≥70 years with clinical organ-confined disease, although it has also been used, with encouraging results, as first line salvage therapy after definitive treatment, and in locally advanced (T3–4) and non-metastatic hormone-resistant prostate cancer. Morbidity associated with this treatment method appears to be low and includes urinary retention (1–9%), urethral stricture (4–14%), incontinence (1–15%), erectile dysfunction (13–53%) and rectourethral fistulae (0–3%). The risk of complications increases with repeated treatments. A few studies have recently been published on HIFU as focal therapy. HIFU technology can be enhanced using means such as ultrasound microbubble contrast agents for assessment of therapy efficacy, magnetic resonance imaging to guide the enhancement of heat rate, and localized drug and gene delivery.