Pathology and genetics of tumours of the urinary system and male genital organs

EAU Guidelines on Non-Muscle-invasive Urothelial Carcinoma of the Bladder: Update 2016.

https://uroweb.org/wp-content/uploads/Babjuk-M-et-al.-Eur-Urol-2013-644639.-EAU-Guidelines-on-non-muscle-invasive-urothelial-carcinoma-of-the-bladder-updqte-2013.pdf

EAU Guidelines on Non–Muscle-invasive Urothelial Carcinoma of the Bladder: Update 2013

Metastatic spread of cancer continues to be the greatest barrier to cancer cure. Understanding the molecular mechanisms of metastasis is crucial for the design and effective use of novel therapeutic strategies to combat metastases. One class of molecules that has been repeatedly implicated in metastasis is the matrix metalloproteinases (MMPs). In this review, we re-examine the evidence that MMPs are associated with metastasis and that they make a functional contribution to the process. Initially, it was believed that the major role of MMPs in metastasis was to facilitate the breakdown of physical barriers to metastasis, thus promoting invasion and entry into and out of blood or lymphatic vessels (intravasation, extravasation). However, recent evidence suggests that MMPs may have a more complex role in metastasis and that they may make important contributions at other steps in the metastatic process. Studies using intravital videomicroscopy, as well as experiments in which levels of MMPs or their inhibitors (tissue inhibitors of metalloproteinases [TIMPs]) are manipulated genetically or pharmacologically, suggest that MMPs are key regulators of growth of tumors, at both primary and metastatic sites. On the basis of this evidence, a new view of the functional role of MMPs in metastasis is presented, which suggests that MMPs are important in creating and maintaining an environment that supports the initiation and maintenance of growth of primary and metastatic tumors. Further clarification of the mechanisms by which MMPs regulate growth of primary and metastatic tumors will be important in the development of novel therapeutic strategies against metastases.

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Changing Views of the Role of Matrix Metalloproteinases in Metastasis

2458 Despite dramatic improvements in treatment over the past 40 years, acute lymphoblastic leukemia (ALL) remains one of the most common causes of death from disease in childhood. Glucocorticoids are among the most effective agents used in the treatment of lymphoid malignancies, and patient response to treatment is an important determinant of long-term outcome in childhood ALL. In spite of its clinical significance, the molecular basis of glucocorticoid resistance is still poorly understood. The aim of this study was to develop an experimental model system to define clinically relevant mechanisms of glucocorticoid resistance in childhood ALL. An in vivo model of childhood ALL has been developed in our laboratory, using patient biopsies established as xenografts in immune-deficient nonobese diabetic severe-combined immunodeficient (NOD/SCID) mice. This model is highly representative of the human disease (Lock et al., Blood, 99: 4100-4108, 2002). The in vivo responses of these xenografts to the glucocorticoid dexamethasone (DEX) correlated significantly with patient outcome (p 1 μM) in xenografts from six patients, five of whom died of their disease. In contrast, four DEX-sensitive xenografts (IC50 values 2-fold in sensitive xenografts within 8 hours of treatment. In contrast, Bim induction was dramatically attenuated in DEX-resistant xenografts. These results have identified a clinically significant and novel mechanism of glucocorticoid resistance in childhood ALL, which occurs downstream of receptor-ligand interactions, but upstream of the signalling pathway resulting in Bim induction and apoptosis.

Novel mechanisms of glucocorticoid resistance in childhood acute lymphoblastic leukemia.

684 Efficacy of mirabegron in patients with and without prior antimuscarinic therapy for overactive bladder (OAB): Post-hoc analysis of a prospective, randomised European-Australian phase III trial

Context Mirabegron, the selective β3-adrenoceptor agonist, heralds the latest development for the treatment of overactive bladder (OAB). Objective To present the evidence available on the efficacy and tolerability of mirabegron and to discuss this treatment's potential in our setting. Evidence acquisition We reviewed 11 studies conducted with mirabegron in patients with OAB (2 phase ii , 9 phase iii ), all studies were compared to placebo with 6 studies also including tolterodine as an additional arm. Greater emphasis shall be given to the main phase iii trials performed in Europe, the USA and Australia evaluating efficacy and safety after 12 weeks ( NCT00662909 , NCT00689104 , NCT00912964 ) and safety after 12 months ( NCT00688688 ). The combined analyses of these 12-week studies are also available, with emphasis on global efficacy (FAS), efficacy with regard to incontinence (FAS i ) and safety (SAF). More than 50% of patients had previously discontinued anticholinergics medication for OAB, thus allowing us to obtain data on the effectiveness of mirabegron in patients already treated with anticholinergics. Evidence synthesis Mirabegron is an efficacious drug which presents a statistically significant reduction in the number of incontinence episodes and in urinary frequency as of 4 weeks, with a higher percentage of dry patients and a higher percentage of patients with reduction ≥50% in the number of incontinence episodes than placebo. The efficacy of mirabegron 50 and 100 mg in the reduction of incontinence episodes occurs in de novo patients and who have received antimuscarinics, with adjusted mean difference and improvement in urinary frequency greater in treated patients. Its tolerability is very similar to placebo particularly for the adverse effects of the antimuscarinics (dry mouth, constipation and blurred vision). A minimal, non-clinically significant change is observed in systolic and diastolic blood pressure and pulse. Its efficacy is long-term. Mirabegron at the doses of 50 and 100 mg presents an improvement versus placebo in patient satisfaction, health-related quality of life (HRQoL), symptom bother and patient's perception of bladder condition (PPBC). In the 12-week phase III European study tolterodine deliverred a lesser degree of improvement than mirabegron versus placebo in patient satisfaction, HRQoL, symptom bother and PPBC. Conclusions Mirabegron is the first of a new class of compounds with a novel mechanism of action that is different to the antimuscarinics. It presents significant and clinically important efficacy in the treatment of the symptoms of OAB. It has advantages with regard to the results described by the patient in treatment satisfaction. Studies on its combined use with anticholinergics are ongoing.

Evidence available on the use of the selective β3-adrenoceptor agonist mirabegron for the treatment of overactive bladder.

Introduction Urethroplasty with oral mucosa grafting is the most popular technique for treating nontraumatic bulbar urethral strictures; however, cases involving the membranous portion are usually treated using progressive perineal anastomotic urethroplasty. We assessed the feasibility of performing dorsal (or ventral) graft urethroplasty on bulbar urethral strictures with mainly membranous involvement using a modified Barbagli technique. Materials and methods This was a prospective study of 14 patients with bulbomembranous urethral strictures who underwent dilation urethroplasty with oral mucosa graft between 2005 and 2013, performed using a modified technique Barbagli, with proximal anchoring of the graft and securing of the graft to the tunica cavernosa in 12 cases (85.7%) and ventrally in 2 (14.3%). The minimum follow-up time was 1 year. We evaluated the subjective (patient satisfaction) and objective (maximum flow [Qmax] and postvoid residual volume [PVRV], preoperative and postoperative) results and complications. Failure was defined as the need for any postoperative instrumentation. Results A total of 14 patients (median age, 64 ± 13 years) underwent surgery. The main antecedent of note was transurethral resection of the prostate in 9 cases (64.3%). The median length of the stenosis was 45 ± 26.5 mm. Prior to surgery, 50% of the patients had been subjected to dilatations and 4% to endoscopic urethrotomy. The mean surgical time and hospital stay were 177 ± 76 min and 1.5 ± 1 day, respectively. The preoperative Qmax and PVRV values were 4.5 ± 4.45 ml/s and 212.5 ± 130 cc, respectively. The postoperative values were 15.15 ± 7.2 ml/s and 6 ± 21.5 cc, respectively (p  Conclusion The repair of long bulbar urethral strictures with membranous involvement using urethroplasty with free oral mucosa grafts represents a viable alternative for patients with nontraumatic etiology and little fibrosis. The dilation of the urethral lumen achieves good results with minimum failure rates and little probability of complications. For many of these patients, the length of the stricture is too long to perform the tension-free anastomosis technique.

Treatment for long bulbar urethral strictures with membranous involvement using urethroplasty with oral mucosa graft.

Context Beta-lactamases are bacterial enzymes that protect microorganisms from the lethal effects of β-lactam antibiotics. The production of beta-lactamases is the most important mechanism of resistance to these antibiotics, especially in Gram-negative bacteria. Objective Review the magnitude of the problem of extended-spectrum beta-lactamases (ESBLs) in the urological setting and present the fundamental action guidelines on the issue, the main risk factors and the prevention strategies. Acquisition of evidence A structured search strategy for patient, problem, intervention, comparison and result was conducted in the PubMed-Medline database to identify the most relevant studies related to the management of patients with urinary tract infection by ESBL-producing microorganisms. We also present a caseload analysis of our center on this issue. Summary of the evidence ESBLs are found in Enterobacteria, mainly Klebsiella sp. and Escherichia coli and are characterized by their hydrolytic ability compared with beta-lactam antibiotics, which entails resistance to penicillin, cephalosporin and aztreonam. They are also associated with resistance to other antibiotics. There is a high risk of infection and colonization by ESBL producers in patients with prolonged hospital stays or who required invasive devices. The prior use of antibiotics and stays in residential care are also risk factors. Prevention programs should focus on preventing nosocomial infection. It is essential that a restrictive policy on the use of antibiotics be implemented. The therapy of choice for severe infections is focused on carbapenems, although their indiscriminate use should be avoided. In uncomplicated lower urinary tract infections, fosfomycin and nitrofurantoin are the best treatment alternatives. Conclusion ESBL-producing strains constitute a true global health problem. Prevention strategies should focus on nosocomial infection. We should not forget, however, that the appearance of these pathogens in community-acquired infections is increasingly frequent. Therapeutic decisions should be based on an understanding of the local distribution of microorganisms and their resistance patterns.

Extended-spectrum beta-lactamases in urinary tract infections caused by Enterobacteria: Understanding and guidelines for action

Objetives To analyze the surgical and oncologic outcome of prospective experience with laparoscopic partial nephrectomy. We describe the surgical technique and mid-term oncological results achieved. Material and methods 60 patients were operated with this technique between June 2005 and June 2009. The mean age of patients was 58.9 [38–77] years, being 40 (66.7%) males and 20 (33.3%) women. The average BMI was 26.8 [18–40]. Laterality was 28 (46.7%) right tumors and 32 (53.3%) left, being located in the upper pole in 14 (23.3%) patients, in the middle third in 13 (21.7%), in the lower pole in 22 (36.7%), and hiliar region in 11 (18.3%). In 23 cases (38.3%) tumors were located in the anterior valve, in 24 (40%) in the posterior valve, in 10 (16.7%) at the outer edge and 3 (5%) at the inner edge. The average size tumor on CT was 3.3 [1–6.4] cm and in the surgical specimen 3.1 [1.2–7] cm. Results The mean operative time was 107.17 [50–185] min, with a warm ischemia time of 33 [0–70] min. In 56 cases (93.3%) there was a single artery and in 4 (6.7%) cases there were 2 arteries. The artery was clamped alone in 15 patients (25%), artery and vein in 44 (73.3%) and no clamping was performed in 1 (1.7%). We repaired the urinary tract in 32 patients (53.3%), leaving ureteral catheter in all patients. 20% of patients (12) required transfusion. Intraoperative complications occurred in 5 patients (8.7%). These were: 1 splenic injury requiring splenectomy (1.7%), 1 tear in the vena cava, sutured laparoscopically (1.7%) and 3 cases of bleeding due to bulldog malfunction (5%). Postoperative complications occurred in 11 patients (18.7%) and these were: 1 wall hematoma that required reoperation (1.7%), 1 urinary fistula ending in renal atrophy and subsequent nephrectomy (1.7%), 3 intracavitary hematomas which resolved conservatively (5%), 1 arteriovenous fistula that needed embolization (1.7%), 1 urinoma that was resolved with percutaneous drainage (1.7%) and 3 cases of postoperative fever (5%). Margins were positive in 1 patient (1.7%). In 49 cases (81.7%) histology was renal cell carcinoma, in 8 (13.3%) oncocytoma, in 2 (3.3%) angiomyolipoma and 1 (1.7%) metastasis. The average stay was 5 [3–29] days. Median follow up was 31 [12–61] months. There was a local recurrence at 16 months (hiliar primary tumor 2.5 cm) and an ipsilateral adrenal metastasis at 34 months (primary tumor 5.6 cm in left lower pole). Conclusions In this series of laparoscopic partial nephrectomy low rate of complications, good oncologic results and low recurrence rate in the short term are shown. More patients and further monitoring is required to strengthen the functional and oncological outcomes of this surgical technique.

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Javier C. Angulo

Papers

684 Efficacy of mirabegron in patients with and without prior antimuscarinic therapy for overactive bladder (OAB): Post-hoc analysis of a prospective, randomised European-Australian phase III trial

Evidence available on the use of the selective β3-adrenoceptor agonist mirabegron for the treatment of overactive bladder.

Treatment for long bulbar urethral strictures with membranous involvement using urethroplasty with oral mucosa graft.

Extended-spectrum beta-lactamases in urinary tract infections caused by Enterobacteria: Understanding and guidelines for action

Laparoscopic partial nephrectomy