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.

Enhanced urinary gelatinase activities (matrix metalloproteinases 2 and 9) are associated with early-stage bladder carcinoma: a comparison with clinically used tumor markers.

Matrix metalloproteinases (MMPs) are involved in tumor growth and metastasis, promoting the migration and invasion of cells. In this study, the amount of MMP-2 and MMP-9 activity was measured in urine from superficial bladder carcinoma patients (pTa, pT1) to evaluate their possible diagnostic value. The active and total amount of MMP-2 and MMP-9, respectively, in urine from tumor patients were compared with the levels in urine from age- and gender-matched healthy volunteers. Both MMP-2 and MMP-9 activity levels were significantly enhanced in urine from patients with high invasive cancers (pT2, PT3), whereas in urine from healthy controls no or very low MMP activities were found. More importantly, a substantial number of urine samples from patients with superficial tumors contained elevated MMP-2 and MMP-9 activities, suggesting that enhanced urinary MMP activity levels, indeed, might be indicative for early-stage bladder cancer. Overall, urinary MMP-2 and MMP-9 activity levels were significantly correlated to each other, with some individual exceptions. A comparison between urinary MMP-9 activity and a recently proposed urinary marker for bladder cancer, NMP-22, showed slightly lower numbers of patients with elevated levels for MMP-9. But because MMP-9 and NMP-22 levels were not correlated, enhanced urinary MMP activity might be useful as a marker for superficial bladder carcinoma like, or especially in combination with, other markers.

White blood cell DNA adducts, smoking, and NAT2 and GSTM1 genotypes in bladder cancer: a case-control study.

We conducted a case-control study on 114 bladder cancer patients and 46 hospital controls. DNA adducts were measured in WBCs by 32P postlabeling and showed no association with smoking habits and the glutathione-S-transferase M1 genotype. A strong association between adduct levels and the N-acetyltransferase (NAT2) genotype was found (P = 0.0002). The NAT2 genotype was associated in a nonstatistically significant way to the case-control status (odds ratio, 1.6; 95% confidence interval, 0.8-3.2). In a logistic regression model, the log of DNA adduct levels was associated in a highly significant way to the risk of bladder cancer (regression coefficient, 0.75; P = 0.0006), independently of smoking habits. Using the median of DNA adducts (RAL, 0.3) as a cutoff point, the odds ratio for the risk of bladder cancer was 4.1 (age-adjusted; 95% confidence interval, 1.9-9.0). Our study suggests that sources other than tobacco smoke contribute to the formation of aromatic DNA adducts in WBCs. The role of WBC-DNA adducts in predicting bladder cancer is still to be clarified.

Carcinogen-DNA adducts in bladder biopsies and urothelial cells: a risk assessment exercise.

We have determined the levels of DNA adducts (using 32P-postlabelling) in the biopsies of 20 bladder cancer patients and in the exfoliated bladder cells of 36 healthy volunteers. The aims of the study were (a) to estimate the concentration of DNA adducts in cancer cases and controls according to the level of smoking; and (b) to investigate whether bladder cancer cases had higher levels of adducts in bladder cells than healthy controls had. A dose-response relationship between smoking levels and adduct levels was present among both cancer cases and controls. Cancer cases and the controls had similar adduct levels for the same level of smoking. According to a risk assessment exercise, adduct levels among heavy smokers were roughly comparable with those found in mice and dogs treated with bladder carcinogens, at doses which induce a 50% lifetime risk of bladder cancer.

Progression from superficial to invasive carcinoma of the bladder: genetic evidence of either clonal heterogeneous events.

Until now, no definitive molecular evidence proving or disproving a true progression from superficial to invasive bladder tumors has been reported. A total of 36 lesions from 6 patients affected by invasive bladder cancer after multiple superficial recurrences were analyzed for loss of heterozygosity on 8 loci of chromosome 9 and 2 loci of chromosome 17. In addition, the clonal composition of the tumors from two female patients was examined using the human androgen receptor assay. Our data suggest that papillary bladder lesions can and sometimes do make a true progression into invasive life-threatening tumors; however, this progression is not an invariable sequence because it was definitely proven in 2 but not confirmed in 3 of the cases we examined.

Bladder tumor antigen assay as compared to voided urine cytology in the diagnosis of bladder cancer.

BACKGROUND: The study was aimed at comparing the diagnostic accuracy of the quantitative bladder tumor antigen (BTA) TRAK immunoassay with exfoliative urine cytology in the detection of primary and recurrent bladder cancer. METHODS: The analysis was carried out on 194 high risk patients undergoing a diagnostic cystoscopy, 279 patients with previous history of transitional cell carcinoma awaiting a follow-up cystoscopy, and 45 healthy controls. Urine cytology was performed by a skilled cytopathologist on three consecutive samples. RESULTS: BTA TRAK values resulted significantly higher in tumor positive cases than in absence of bladder tumor for both groups of patients. Non neoplastic urothelial diseases as well as the absence of mucosal abnormalities were associated with a marked increase in BTA TRAK levels with respect to the control group. Overall sensitivity and specificity was 63 and 63% for BTA TRAK (cut-off 34 U/ml), and 68.3 and 73.4% for urine cytology, respectively. The diagnostic advantage of urine cytology was maintained when patients were stratified by tumor grade. CONCLUSIONS: The clinical performance of the BTA TRAK in the detection of primary or recurrent bladder cancer is acceptable and reproducible as shown by similar results with previous reports, although urine cytology performed on three samples showed the highest sensitivity and specificity.

Serum prostate-specific antigen determination in prostatic carcinoma.

Prostate-specific antigen (PSA) is a tissue-specific glycoprotein identified by Wang in 1979. It is synthesized in the prostate independently of prostatic acid phosphatase (PAP). A total of 199 subjects were divided into four groups: controls aged less than 50 years, controls aged more than 50 years, patients with benign prostatic hyperplasia (BPH) and patients with prostatic carcinoma. PSA cut-off value was set at 10 ng/ml (mean for the BPH group plus 2 SD). With this cut-off value PSA could not be used as an early predictor of prostatic carcinoma. The association of PSA and PAP in prostatic cancer increases the number of patients with positive biological markers.

Prostatic duct carcinoma with combined prostatic duct adenocarcinoma and urothelial carcinoma features: report of a case.

We report a unique case of prostatic duct carcinoma (PDC) featuring both prostatic duct adenocarcinoma (PDA) and high-grade urothelial carcinoma (HG-UC). An 84-year-old man presenting with hematuria showed at ultrasonography and cystoscopy a papillary neoplasia located near to the verumontanum. Histopathologic examination of specimens from transurethral resection revealed a tumor originating from large prostatic ducts showing 2 different components: PDA with endometrioid features (main pattern) and HG-UC (minor part). Immunohistochemically, the areas of PDA were positive for prostatic acid phosphatase (PAP), prostatic specific antigen (PSA), and androgen receptors (AR), while negative for estrogen (ER) and progesterone receptors (PGR). Prognostic factors evaluation pointed out a low proliferation index (10%) and focal expression of p53 (6%); c-erb-B2 was not overexpressed. The HG-UC areas were negative for all previous markers, while positive for thromobomodulin. The proliferation index was high (60%), and p53 was diffusely expressed (55%). The incidence and significance of PDC with combined features is discussed with reference to literature data.

[A case of retroperitoneal leiomyosarcoma]. / Su un caso di leiomiosarcoma retroperitoneale.

The Authors present a case of retroperitoneal leiomyosarcoma, diagnosed because of the early symptomatic hydronephrosis due to the compression of the tumour on the lumbar ureter. Some general clinical aspects of retroperitoneal sarcomas are discussed too. In the case presented adjuvant therapy was not advised, because of the small volume of the tumour and the possibility of its complete excision.

[Communication between urologist and pathologist. Proposal for the standardization of histological tests requests for neoplasms]. / La comunicazione tra urologo e patologo. Proposta di standardizzazione delle richieste di esami istologici per neoplasie.

The aim of this work is to propose a new clinical data system which should accompany the histological sample for the histologic diagnosis made by the pathologist. Six different schedules on the most important urological tumours are presented: prostate (needle biopsies and surgical approach), bladder (endoscopic procedure and open surgery), kidney and ureter, testis. In each schedule the urologist provides, in a scheme, the clinical report needed for the pathologist's final diagnosis. A clear explanation of the clinical data and a faster method of filling in the form are the qualifying elements of these schedules.

[Comparison of fluoroquinolones (norfloxacin, enoxacin, ofloxacin) in the therapy of lower urinary tract infections]. / Fluorochinoloni a confronto (norfloxacina, enoxacina, ofloxacina) nella terapia delle infezioni delle basse vie urinarie.

The present study was carried out to assess comparatively the effectiveness and tolerance of norfloxacin, enoxacin and ofloxacin in the treatment and prophylaxis of infections of the low urinary tract in non-hospitalised patients. Thirty patients presenting positive uroculture on clinical evidence of ongoing infection were treated. Doses were 400 mg b.i.d. for norfloxacin, and 300 mg b.i.d. for ofloxacin and enoxacin; duration of treatment was 7 days in treatment. The pathogen was eradicated in 94% of cases at the control carried out after 5 days from the end of treatment; in the follow-up at 20 days, recurrences or reinfections were observed in 30% of the cases, almost all of them consisting of complicated infections. Slight side-effects were observed in 8 patients. No significant differences in effectiveness or tolerance were reported between the 3 quinolones under study which are therefore considered reliable overall for urological treatment. The absence of greater side-effects is related to the restriction of indications and the brevity of the therapeutic cycles.

[Perirenal immunoblastic lymphoma. Description of a case]. / Linfoma immunoblastico perirenale. Descrizione di un caso.

The primary perirenal localization of non-Hodgkin lymphomas is rare and normal methods of image diagnosis do not enable a reliable preoperative diagnosis. In the majority of cases renal function is not affected and this pathology is often presented as an occasional finding. The pathologies included in the differential diagnosis are renal neoplasias, abscess and inflammatory processes in a perirenal site. Echotomography shows the lesion as an hypoanechoic zone surrounding the kidney. Computed tomography show it as isodense with the renal parenchyma. Histological tests together with immunohistochemical tests identified a malignant large B cell immunoblastic-type lymphoma in the case described here, with plasmoblastic-plasmocytic differentiation and high malignancy according to the Working Formulation. The pathogenesis of this rare localisation is controversial. We maintain that lymphomatous proliferation may be triggered off by lymphatic follicles present in the perirenal space. The concomitant presence of other clinical signs, such as splenomegalia and adenopathies, may contribute to the diagnosis. On the contrary, monolateral involvement in the absence of other signs, as in this case, raises considerable problems of differential diagnosis. Perirenal lymphoma must therefore always be borne in mind in the diagnosis of renal or perirenal masses.

[Blood and urine determinations of tissue polypeptide antigen in patients with bladder carcinoma]. / Determinazione sierica ed urinaria del Tissue Polypeptide Antigen (TPA) nei pazienti affetti da carcinoma vescicale.

The Tissue Polypeptide Antigen (TPA) is an oncofetal antigen widely used in the diagnosis and follow-up of several urothelial cancers. Its urinary and serum detection is performed by means of RIA technique. We determined urinary and serum TPA in 30 patients with bladder cancer who underwent a transurethral resection. Ten out of 30 patients were correctly diagnosed by serum TPA, 22 by urinary TPA. The ANOVA test showed a statistically significant correlation between grade and urinary TPA between stage and serum TPA. Urinary TPA showed a good sensibility in low grade and moreover in Ta stage carcinoma. Serum TPA increased its performance with higher grade carcinoma and in presence of a muscle infiltration, but it never reached a sufficient sensibility to be considered a bladder cancer marker. In conclusion the simultaneous determination of urinary and serum TPA does not give more information than the urinary determination alone.

[Measurement of skeletal alkaline phosphatase in prostatic carcinoma. Preliminary report]. / Il dosaggio della fosfatasi alcalina scheletrica nel carcinoma prostatico. Rapporto preliminare.

Bone metastases frequently occur in prostate carcinoma. Total body radionuclide scan with diphosphonate methylene labelled with 99Tc is commonly used to diagnose such metastases. However this technique is aspecific and frequently unreliable. In recent years several biological markers dealing with bone metabolism were studied. Serum determination of skeletal alkaline phosphatase (ALP) and moreover of its bone isoenzyme (BAP) could be considered a reliable index of osteoblastic activity. In this preliminary report we analyzed a group of 43 patients affected by prostate carcinoma with or without bone metastases. The American Urological Association (AUA) staging system was adopted. Sixteen patients were D2, bone metastases had been suspected by means of radionuclide bone scan and confirmed by Computerized Tomography and/or aimed X-rays. Tandem R-Ostase by Hybritech was used to measure BAP, normal value is set to 20 micrograms/L. All D2 tumours had pathological BAP values (mean value 87.50 micrograms/l); 1/3 stage A, 5/13 stage B, 5/9 stage C and 0/2 stage D1 patients had pathological findings. One of this patients, stage C, revealed a bone metastase at a later bone scan.

[Renal multifocal carcinoma with adrenal gland metastasis in a patient previously treated with radical nephrectomy: what kind of therapy. Review of the literature]. / Carcinoma renale multifocale con metastasi surrenaliche multiple in paziente già sottoposto a nefrectomia radicale dell'adelfo: quale terapia? Revisione della letteratura.

A case of multiple adrenal metastases due to renal cells carcinoma, associated with a multifocal simultaneous renal cells carcinoma has been observed in a female patient previously submitted to radical contralateral nephrectomy for the same disease. In particular, stress is laid on computerized tomography scan diagnosis and surgical procedure.

[Leiomyosarcoma of the spermatic cord. Case report and revision of the literature]. / Leiomiosarcoma del funicolo spermatico. Presentazione di un caso clinico e revisione della letteratura.

A 76 year old man presented with an asymptomatic, very big left scrotal mass that was found to be a leiomyosarcoma of the spermatic cord. It was treated by radical orchiectomy with ligation of the spermatic cord at the internal inguinal ring. Convalescence was uneventful. 6 months postoperatively there was no evidence of local recurrence of the neoplasm or distant metastasis.

[Immunohistochemical determination of antigen 19-9 (CA 19-9) in transitional carcinoma of the bladder]. / Determinazione immunoistochimica dell'antigene 19-9 (CA 19-9) nel carcinoma transizionale della vescica.

Carbohydrate Antigen 19-9 (CA 19-9) histological expression in transitional cell bladder carcinoma (TCBC) was studied by means of immunohistochemistry and its findings compared with those of Tissue Polypeptidic Antigen (TPA) and Carcino Embryonic Antigen (CEA). Twenty-one TCBC of various grade and stage were analyzed by using Avidin-Biotin complex method for CA 19-9 and TPA Peroxidase-Antiperoxidase method for CEA. Grade 3 and pT1, pT2/pT3 carcinomas showed a constant staining for CA 19-9 antigen, grade 2 showed a 50% positive immunoreaction while all grade 1 cases were negative. TPA showed an inverse correlation with well differentiated carcinomas which were better and more extensively stained than anaplastic ones. CEA expression was not correlated either with grade or stage. CA 19-9 could be considered as a dedifferentiation marker in TCBC.

[The Sarig test. A simple method to evaluate the inhibitory effect on urinary crystallization of calcium oxalate]. / Il test di Sarig. Un semplice metodo per valutare l'inibizione della cristallizzazione urinaria dell'ossalato di calcio.

In this study, the Authors evaluate a simple test proposed by Sarig for the discrimination of kidney stone-formers, based on the overall urine inhibitory effect. A solution of the tested urine is added with sodium-oxalate and the kinetics of calcium-oxalate precipitation is indirectly followed with ionometric selective measurement of the progressive reduction of free calcium ions. A Discriminating Index may be therefore calculated; higher values are obtained in lithiasic patients in comparison with normal controls.

[Renal agenesis and homolateral seminal vesicle cyst. Case report]. / Agenesia renale e cisti della vescicola seminale omolaterale. Caso clinico.

The authors present a case of renal agenesis and seminal vesicle cyst in a young man, diagnosed because of several micturion disorders partially cleared up with antibiotic therapy. We discuss about the diagnosis technique which includes Ultrasound Scanner, Computed Tomography, Magnetic Resonance and pelvic arteriography. Then we describe the surgical approach and finally we discuss about embryogenesis.

[Surgical treatment of benign prostatic hypertrophy and Kelami syndrome]. / Trattamento chirurgico dell'ipertrofia prostatica benigna e sindrome di Kelami.

The authors analyze a group of 116 consecutive patients treated with transvesical prostatic adenomectomy or transurethral prostatic resection for benign prostatic hypertrophy (BPH) isolated five of them with a Kelami syndrome. These patients, aged between 53 and 70 years old, had a relevant ventral penile deflection with severe sexual impairment postoperatively. Among them only one asked for a corrective surgical procedure. Aetiology, preventive measures and therapeutic choices are discussed. Authors pointed out that this syndrome is actually underestimated considering the high number of transurethral or open surgery procedures for BPH.