The clinical use of statistical permutation test methodology: a tool for identifying predictive variables of outcome.

OBJECTIVES: To identify the predictive variables affecting the outcome after radical surgery for bladder cancer by a newer statistical methodology, i.e. nonparametric combination (NPC). METHODS: A multicenter study enrolled 1,312 patients who had undergone radical cystectomy for bladder cancer in 11 Italian oncological centers from January 1982 to December 2002. A statistical analysis of their medical history and diagnostic, pathological and postoperative variables was performed using a NPC test. The patients were included in a comprehensive database with medical history and clinical and pathological data. Five-year survival was used as the dependent variable, and p values were corrected for multiplicity using a closed testing procedure. The newer nonparametric approach was used to evaluate the prognostic importance of the variables. All of the analyses were performed using routines developed in MATLAB© and the significance level was set at α = 0.05. RESULTS: A significant prognostic predictive value (p < 0.01) for tumor clinical staging, hydronephrosis, tumor pathological staging, grading, presence of concomitant carcinoma in situ, regional lymph node involvement, corpora cavernosa invasion, microvascular invasion, lymphatic invasion and prostatic stroma involvement was found. CONCLUSIONS: The NPC test could handle any type of variable (categorical and quantitative) and take into account the multivariate relation among variables. This newer methodology offers a significant contribution in biomedical studies with several endpoints and is recommended in presence of non-normal data and missing values, as well as solving high-dimensional data and problems relating to small sample sizes.

Etiology, presentation and management of urinary tract infections in multiple sclerosis patients: A review of the current literature.

Urinary tract infections (UTIs) present a formidable challenge in the care of individuals affected by multiple sclerosis (MS). Lower urinary tract dysfunction is a prevalent issue among MS patients, predisposing them to an elevated risk of UTIs. When left untreated, UTIs can further exacerbate the already compromised quality of life in individuals with MS. The diagnosis and management of UTIs in MS patients necessitate a careful clinical evaluation. The objective of this review is to delineate preventive strategies and current and developing therapeutic approaches for preventing and treating UTIs associated with urinary dysfunction, catheterization, and upper urinary tract infections in patients with MS. Effectively addressing UTIs and urinary tract dysfunction in individuals with multiple sclerosis calls for a comprehensive, interdisciplinary approach.

Size of bladder cancers: correlation among different types of measurement.

OBJECTIVE: It was the aim of this study to evaluate the accuracy of the measurement of tumor size comparing the objective size with that measured by preoperative cystoscopy, by preoperative ultrasound (US) and with the diameter described by the operator before the transurethral resection. PATIENTS AND METHODS: This study included 100 patients with bladder papillary endoscopic features of single or multiple neoplasms who were candidates for transurethral resection. The sizes of the same neoplasms measured during preoperative cystoscopy, preoperative US and described by the operator before the transurethral resection were evaluated. A statistical analysis of the errors of measurement was performed if compared with an objective measurement done with an ureteral catheter. RESULTS: The statistical analysis of the data shows that there are no substantial differences between the objective and subjective measurement, and therefore, the measurements reported by individual operators are reliable. On the contrary, the diameters given by preoperative cystoscopy and US differ significantly from the objective measurement. CONCLUSIONS: This study shows that the most reliable measurement is the subjective measurement made directly by the urologist in the operating room.

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.

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.

Paclitaxel-hyaluronic acid for intravesical therapy of bacillus Calmette-Guérin 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.

Mitomycin C for the treatment of bladder cancer.

Bladder cancer is a heterogeneous disease: approximately 75% of its forms are non muscle invasive neoplasms. Standard treatment for non muscle invasive bladder cancer (NMIBC) consists of complete transurethral resection (TURB) of all visible lesions. Recurrence rates following TURB and intravesical chemoprophylaxis seem to decrease to 25-50% in 2 years of follow-up. The aim of the present paper is to review findings from the most relevant studies and evaluate the potentials of mitomycin C (MMC) in the treatment of non muscle invasive bladder cancer. Studies were identified by searching MEDLINE(R) and Pubmed(R) databases up to 2010 using both medical subject heading (Mesh) and a free text strategy with the name of known individual chemotherapeutic drug and the following key words: "non muscle-invasive bladder cancer", "intravesical therapy", "Mitomycin C", "Device Therapy". At the end of our research in literature we selected 66 articles. From literature is clear that in case of low or intermediate risk superficial bladder cancer, MMC is one of the most used agents with limited side effects. In fact MMC has a high molecular weight and is relatively hydrophobic, resulting in less sistemic absorption. Regimens are based on weekly instillations but despite many studies there is not universal consensus on timing and duration of therapy. MMC early istillation seems effective in preventing tumour recurrence in low risk non muscle invasive neoplasms. MMC maintenance chemotherapy continue to be considered effective in reducing tumour recurrence rate in low and intermediate risk tumours. It is known in literature that the lack of response to intravesical chemotherapy in patients with non muscle invasive bladder cancer is due to two factors: lack of sensitivity of the neoplasm to intravesical chemotherapy and inadequate drug delivery to the tumour. In order to resolve these limitations in the last years MMC, in many centers, is used with device assisted therapies or with new administration scheme.

Methodology of superficial bladder cancer trials: objective evaluation of treatment - the need for standardization.

The formulation of proper evaluation criteria after superficial bladder cancer therapy poses several methodological problems that are often peculiar to the disease. The Achilles' heel of many trials is possibly found in the criteria used in the evaluation of the trial's outcome. As a consequence, total agreement regarding the criteria for response and the evaluation of response is needed. The adoption of standard response criteria should be given high priority. Uniform criteria of response should be chosen because they meet standards of reliability and statistical validity. Thus, the criteria must be reproducible and correlate with some measures of patient benefit such as quantity and quality of survival. A proposal for standardization in superficial bladder cancer clinical trials is presented based upon the current knowledge of methodology used for conducting clinical trials and upon the experience coming from clinical research groups.

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.

Systematic review and meta-analysis of non RCT's on health related quality of life after radical cystectomy using validated questionnaires: Better results with orthotopic neobladder versus ileal conduit.

PURPOSE: The current literature on the impact of different urinary diversions on patients' health related quality of life (HR-QoL) showed a marginally better quality of life scores of orthotopic neobladder (ONB) compared to ileal conduit (IC). The aim of this study was to update the review of all relevant published studies on the comparison between ONB and IC. MATERIALS AND METHODS: Studies were identified by searching multiple literature databases, including MEDLINE, CINAHL, the Cochrane Library, PubMed Data were synthesized using meta-analytic methods conformed to the PRISMA statement. RESULTS: The current meta-analysis was based on 18 papers that reported a HR-QoL comparison between IC and ONB using at least a validate questionnaire. Pooled effect sizes of combined QoL outcomes for IC versus ONB showed a slight, but not significant, better QoL in patients with ONB (Hedges' g = 0.150; p = 0.066). Patients with ileal ONB showed a significant better QoL than those with IC (Hedges' g = 0.278; p = 0.000); in case series with more than 65% males, ONB group showed a slight significant better QoL than IC (Hedges' g = 0.190; p = 0.024). Pooled effects sizes of all EORTC-QLQ-C30 aspects showed a significant better QoL in patients with ONB (Hedges' g = 0.400; p = 0.0000). CONCLUSIONS: This meta-analysis of not-randomized comparative studies on the impact of different types of urinary diversions on HR-QoL showed demonstrated a significant advantage of ileal ONB compared to IC in terms of HR-QoL.

Refluxes in orthotopic neobladders: can the ileocecal sphincter be considered an adequate antireflux mechanism?

OBJECTIVES: To evaluate the usefulness of the ileocecal sphincter in preventing ureteral refluxes in ileocecal orthotopic neobladder, thus avoiding the use of antireflux technique for ureteroileal anastomosis. METHODS: From 1980 to 1992, 95 patients underwent orthotopic bladder substitution. In 30 our detubularized ileal reservoir was used and in 65 first only an integral ileocecal segment was used and subsequently multiple transverse teniamyotomies on the cecal portion to increase the capacity and reduce the pressure. The upper urinary tract was indirectly protected in the ileal reservoir technique by leaving an integral 8 to 10 cm long afferent segment folded behind the reservoir and in the ileocecal technique by the ileocecal sphincter, thus keeping the anastomosis between ureters and ileum simple and direct. RESULTS: The mean follow-up of the 65 patients with ileocecourethrostomy is 37 +/- 33 months (range, 2 to 141 months); in 13.8% of the patients (9/65) monolateral refluxes appeared, but without any evident clinical consequences. The appearance of monolateral stenosis on the ureterointestinal anastomosis requiring treatment occurred in 4 patients (6%): 3 underwent an endoscopic treatment and 1 a surgical one. Modifications of renal function with respect to the preoperative status were not verified in any of the patients. CONCLUSIONS: The ileocecal sphincter is an effective antireflux mechanism for an orthotopic neobladder in which multiple transverse teniamyotomies (5 to 7) increase the capacity of the neobladder itself, reduce its internal pressure, and confer a nearly spherical configuration. Moreover, a correct anastomosis between the cecum and membranous urethra decisively reduces the resistance to emptying of the neobladder, thus avoiding too strong pressures against the ileocecal sphincter. The integrity of the circular muscular layer maintains a healthy tonic wall: this fact, combined with the low peripheral resistances, ensures good emptying and a stable capacity. The procedure is easy to perform and not time-consuming; these considerations lead us to consider the ileocecal unit an excellent structure for bladder substitution.

Vitamin B12 and folic acid plasma levels after ileocecal and ileal neobladder reconstruction.

OBJECTIVES: To compare the plasma levels of vitamin B12 and folic acid following resection of ileocecal or ileal segments used for orthotopic bladder substitution. METHODS: Hemoglobin, hematocrit, and plasma levels of vitamin B12 and folic acid were measured in 34 patients with ileocecourethrostomy (ICUS) and in 16 patients with ileal reservoir (IR), with a mean follow-up of 59.8 +/- 41.9 months. The results were compared with regard to both the type of operation and the length of time since surgery. RESULTS: The level of folic acid was normal in all patients. The mean level of vitamin B12 in the ICUS group was 413.67 +/- 160.45 ng/mL compared to 257.63 +/- 121.36 for the IR group. This difference was statistically significant. In the IR group, 18.75% of the patients had a level of vitamin B12 below normal. CONCLUSIONS: There is a tendency for vitamin B12 levels to fall in patients in whom the ileum is used. Resection of the ileocecal segment including the junction does not alter the level of vitamin B12.

Adenocarcinoma of the urachus: radical or conservative surgery? A report of a case and a review of the literature.

AIMS: To identify the most appropriate surgical strategy for carcinoma of the urachus. METHODS: Analysis of a case of adenocarcinoma of the urachus and an examination of the current literature were carried out. CONCLUSIONS: Partial cystectomy is considered the most appropriate surgical strategy but the need for close follow-up is underlined.

125I seeds implantation plus pelvic lymphadenectomy in the management of localized prostate cancer.

In this study the authors present their experience of treatment of intraglandular prostate cancer with 125I seed implantation. At ten years, the overall survival for T1 and T2 stages is 71% and 57% respectively; and for G1, G2 and G3 grades the survival rate is 84%, 54% and 44% respectively; NED ten-year survival is 53% and 52% for T1 and T2 stages, 84%, 40% and 33% for G1, G2, and G3 grades respectively. The statistical evaluation seems to confirm that iodine brachytherapy is suitable for well differentiated and small volume tumors. Local recurrences, complications and side effects are also reported and compared to corresponding data collected following external radiotherapy and radical prostatectomy; the survival results are similar, but the incidence of complications is lower following implantation and in particular regarding continence and potency. In conclusion, the authors believe that iodine seed implantation could offer patients, who are often young and asymptomatic, satisfactory chances of survival and a very high quality of life.

[Diagnostic difficulties in renal leiomyosarcoma. Case report and review of the literature]. / Difficoltà diagnostiche nel leiomiosarcoma renale. Case report e review della letteratura.

The authors report a case of renal leiomyosarcoma and a review of the literature, underlining the difficulties of making a correct differential diagnosis with the benign neoplasms of the kidney and in performing correct surgical therapy.

[DRG charge and real cost of a radical prostatectomy: preliminary considerations before a study of cost reduction]. / Tariffa DRG e costo reale di una prostatectomia radicale: considerazioni preliminari a uno studio per il contenimento della spesa.

Aim of the work was to evaluate the real cost of a radical prostactemy in comparison with the DRG's tariff rates. This work has been conduct before a next study whose objective is the reduction of the costs. The unitary estimated cost of the radical prostatectomies performed from 1997 to April 1998 in the Urological Division of the Università Cattolica S. Cuore has been extrapolated from the entire clinical activity of the same period. The real cost of an uncomplicated radical prostatectomy was also detected. The estimated cost was Lit. 8,225,872 in comparison to the DRG's tariff rate of Lit. 8,842,000; instead the real cost was Lit. 9,085,407. Forty-seven percent of this sum was for routine care in the Division, while 30% for operating room, 5% for pharmacy, 4% for laboratory and 14% for other items. In our institution an operation of high specialization like radical prostatectomy already performed without any complication is little remunerative. Routine care was the major cost: we think its improvement is the first step in order to contain the expense. In this way we can expect secondarily also a reduction in the days of stay.

Three consecutive cases of adenomatoid tumour of the epididymis: histological considerations and therapeutical implications. Review of the literature.

Adenomatoid tumour is an uncommon neoplasm of the male genital tract. The Authors report their recent observation of three consecutive cases of adenomatoi tumour of the epididymis. In all cases the diagnosis was difficult and done only by an accurate histological examination. The treatment was conservative, consisting in the removal of the neoplasm. After a follow up of at least two years the patients do not show any sign of relapses confirming the validity of the surgical therapeutical approach performed. Because of the unfrequent observation of these forms and the difficulty in the diagnosis, the Authors stress the necessity of the surgical exploration with an accurate microscopic examination of the specimens. Moreover a review of the literature from a histological and therapeutical point of view was done and reported.

[Serum ferritin determination: is it useful in the early diagnosis of renal carcinoma?]. / Dosaggio della ferritina sierica: un aiuto nella diagnosi precoce del carcinoma renale?

The aim of the study was to evaluate the usefulness of ferritin as an early marker in the diagnosis of renal cell carcinoma (RCC). The Authors dosed the pre-operative concentration of ferritin in the sera of 22 patients (16 males and 6 females) affected by stage I-II, according to Robson's classification, RCC. Plasma concentrations of ferritin were matched for the presence of tumor and for the tumor volume. The results did not evidence any relationship between plasma concentration of ferritin and the presence of renal cancer. In the same way a linear correlation did not show any significant relationship between serum concentration of ferritin and tumor diameter. Ferritin does not seem to be a usefull marker in the early diagnosis of renal cell carcinoma.

Economic and organizational aspects in the management of prostate cancer.

In the last decade a rapid increase in the incidence of prostate cancer was observed. The reasons for this increase are associated to the progressive population aging, especially in the developed countries as well as to the growing number of identified cases with the widespread use of prostate specific antigen. A number of aspects of the disease are still to be considered in depth: the natural history of the disease in patients with early diagnosis, the potential costs of screening programs in financial, social and psychologic terms, the effectiveness and especially cost-effectiveness of different treatments and follow-up for local and advanced forms. Because of the long natural history of prostate cancer and the effectiveness of hormonal treatments used as salvage after failure of primary therapy, the differences in survival among the various therapeutic options, from radical prostatectomy to radiotherapy, or simple clinical control in selected cases are probably minor. This is the reason why future clinical studies should necessarily be based on multidimensional evaluations, taking into account the clinical outcome as well as the quality of life and costs of the different treatment modalities examined.

[Androgen-deprivation therapy in prostate cancer: clinical evidence and future perspectives]. / La deprivazione androgenica nel carcinoma prostatico: evidenze cliniche e prospettive future.

Androgens are involved in the development and progression of prostate cancer even if the mechanism is not well-recognized. For this reason androgen-deprivation therapy remains a milestone for the treatment of patients with advanced and metastatic disease and, in the last years, in conjunction with radiotherapy and surgery in locally advanced tumors. Alternative options, such as intermittent deprivation suppression, seem to be promising in terms of clinical benefits and toxicity profile. However, current therapies present side effects, such as testosterone surge with consequent clinical flare-up, metabolic syndrome and hormone-resistance, which develops after a variable number of years. Novel therapies such as LH-RH antagonists and prolonged depot LH-RH analogues have been developed in order to avoid clinical flare-up and testosterone microsurges. Novel androgen synthesis inhibitors, such as abiraterone acetate and MDV3100, have been recently discovered and tested as promising hormonal second-line agents in patients with castration-resistant prostate cancer. Finally, long-term side effects from androgen deprivation, such as osteoporosis, sarcopenic obesity and cardiovascular morbidity should be carefully monitored and properly treated.