Ivan Matteo Tavolini

Pharmacokinetic study of intravesical gemcitabine in carcinoma in situ of the bladder refractory to Bacillus Calmette-Guérin therapy

Introduction: Gemcitabine, a chemotherapeutic agent, has been shown to be active against transitional cell cancer of the bladder. The aim of the study was to determine the pharmacokinetic profile of gemcitabine, administered intravesically in patients with carcinoma in situ(CIS). Material and Methods: Nine patients with CIS refractory to intravesical bacillus Calmette-Guérin (BCG) therapy were enrolled. Gemcitabine was given in 50 ml 0.9% NaCl by catheterization and held in the bladder for 1 h, once weekly for 6 consecutive weeks. The pharmacokinetics for gemcitabine metabolites were performed in plasma and serum. Dose levels were: 1,000, 1,250, and 1,500 mg. Clinical evaluation was repeated 4 weeks after therapy and thereafter every 6 months. Results: Grade-1 neutropenia was observed only in 1 patient. Grade-1 urinary frequency and hematuria were observed in 1 and 3 patients, respectively. No grade 2–4 toxicity or clinically relevant myelosuppression were observed. Gemcitabine was detectable in serum, but with an irrelevant pharmacological effect, in only 1 patient treated with 1,500 mg of gemcitabine. With regard to activity, after 6 instillations of this drug, 4 complete responses were observed. Conclusion: Intravesical gemcitabine is well tolerated and safe. No systemic absorption with a clinical or pharmacological effect was detected and only slightly irritative bladder symptoms were observed. These results warrant further investigation in phase-II trials.

Lessons from 52 Patients with Leydig Cell Tumor of the Testis: The GUONE (North-Eastern Uro-Oncological Group, Italy) Experience

Introduction: The goal of the study was to define treatment rules for the uncommon, rarely (10%) malignant and chemorefractory Leydig cell tumors (LCT) of the testis. Methods: The main clinical data of patients treated in centers affiliated to the GUONE (North-Eastern Uro-Oncological Group, Italy) were reviewed. We considered 52 patients (54 tumors, 2 bilateral) whose ages ranged from 13 to 70 years (mean 36). Of the treatments performed, 52 were orchiectomies and 2 were enucleations (unfavorable pathology in only 2 tumors). There were 5 lymphadenectomies (retroperitoneal lymph node dissections): 2 for suspected stage II disease and 1 each for unfavorable pathology, bilateral disease and associated Sertoli tumor (pathology: pN0 in all cases). The length of follow-up ranged from 15 to 249 months (mean 81). Results: There was no relapse in 51 patients and 1 died as a result of metastatic disease (orchiectomy at the age of 70; unremarkable pathology). Conclusions: Malignant LCT seems to be, in our experience, less frequent than previously reported. Age and pathology are useful prognostic factors, but their predictive value should never be considered absolute. Enucleation seems justified in young patients with favorable pathology. In clinical stage I LCT, retroperitoneal lymph node dissection should be offered to older patients and/or to patients with unfavorable pathology. A prolonged follow-up is mandatory.

Cellular and molecular gateways to urolithiasis: a new insight.

Urolithiasis is a relevant clinical problem in everyday practice with a subsequent burden for the health system. Urolithiasis is classically explained as the derangement in the process of biomineralization involving the equilibrium between promoters and inhibitors of crystallization: a deficit of one or several inhibitors or an excess of one or several promoters plays a pivotal role in the stone formation. The revolutionary introduction of the molecular biology in medicine has given a new insight in urolithiasis too. Genetic factors have also been postulated to play an important role. A review of the current knowledge on urolithiasis based upon a molecular and genetic approach is reported.

UNMANAGEABLE FEVER AND GRANULOMATOUS RENAL MASS AFTER INTRACAVITARY UPPER URINARY TRACT BACILLUS CALMETTE-GUERIN THERAPY

Intracavitary bacillus Calmette-Guerin (BCG) therapy is considered an effective option for the treatment of noninvasive transitional cell carcinomas of the upper urinary tract. Few treatment related side effects have been reported to date. We report a case of a clinically symptomatic granulomatous renal mass after percutaneous BCG therapy for upper urinary tract transitional cell carcinoma in situ. A 51-year-old white man was successfully treated with 2, 6-week courses of intravesical BCG therapy for carcinoma in situ of the bladder 2 years previously. During followup visits endoscopic evaluation of the right upper urinary tract was performed because of a suspicious filling defect on excretory urography. No tumors were seen but repeated positive urine cytologies. Therefore, an 8Fr percutaneous nephrostomy tube was placed and by-weekly instillation of 81 mg. Connaught BCG in 250 ml. sterile saline was infused under gravity in 4 hours. Nephrostography was performed before every instillation to evaluate the proper position of the tube and absence of ureteral obstruction. No side effects were observed during the first 4 instillations.

Intracavitary therapy of noninvasive transitional cell carcinomas of the upper urinary tract. A review of the literature.

Noninvasive (stages Ta, T1, Tis) transitional cell carcinomas of the upper urinary tract are suitable for a conservative therapeutic approach. Intracavitary therapy (alone or as adjuvant treatment) has recently been proposed and successfully used by some authors. Even though bacillus Calmette-Guérin is the most frequent agent employed, chemotherapeutic drugs, such as mitomycin C and thiotepa, have also been successfully used. The current information available in the literature is therefore reviewed. According to the data available, intracavitary therapy is a worthwhile conservative therapeutic option for noninvasive upper urinary tract urotheliomas with acceptable side effects. For this reason it may be included in the routine urological armamentarium.

The novel hormone INSL3 is expressed in human testicular Leydig cell tumors: A clinical and immunohistochemical study

Insulin-like 3 (INSL3) is a novel peptidic hormone member of the relaxin-insulin-like family of peptide factors. It is almost exclusively produced by Leydig cells within the testis and participates to the complex mechanisms leading to physiological testicular descent during embryonic development. We performed a retrospective study evaluating clinical and histopathological characteristics of 13 patients surgically treated for testicular tumor and diagnosed to be affected by Leydig cell tumor (LCT). Furthermore, it was possible to retrieve the archived paraffin embedded tumor together with neighboring healthy testicular tissue of all subjects affected by LCT (12 benign and 1 malignant form), that were analyzed for INSL-3 expression. Immunohistochemical analysis of the tumor sections of the 13 patients affected by LCT demonstrated constitutive expression of INSL3 protein in all LCT, irrespective of the histological pattern of each LCT and with no significant differences of staining intensity between all tumors. In particular, no gross differences were evident between the staining for INSL3 in the 12 benign LCTs and the only one showing malignant clinical behavior. The present study shows that LCTs, a very rare form of testicular tumor with no proven specific serum and histological markers, express a novel member of the relaxin-insulin-like family of peptide factors previously identified as a secretory product of Leydig cells and named INSL3. Thus, there could be the possibility to evaluate the expression and secretion of this novel hormone as a marker of this rare testicular tumor.

Late Recurrence of Clinical Stage I Seminoma of the Testis after 12 Years despite Adjuvant Infradiaphragmatic Irradiation

A patient treated with prophylactic infradiaphragmatic radiation therapy for clinical stage I left testicular pure seminoma developed a large mass of the chest wall 12 years after primary treatment. An incisional biopsy confirmed pure seminoma. After chemotherapy, surgical removal of the residual mass and second-line chemoradiation therapy for persistent seminoma, the patient had a vertebral relapse. He died of progression 24 months after the first relapse despite further therapy.

Predictive medicine in non-malignant urological disorders

The potential of disease prediction in non-malignant disorders should not be undervalued. Such disorders present several characteristics which make them suitable for disease prediction: they can be wide-spread, strongly affect the patients’ quality of life, lead to a heavy burden on social health expenses and have a protracted clinical course. Moreover, people who present a high risk for non-malignant disease can be successfully introduced to long-term preventive measures such as lifestyle modifications, dietary changes and improvement in hygienic conditions. There is a growing demand for developing predictive medical strategies in urology. While urological cancers are the main focus of interest, we analyse the potentialities and challenges of predictive medicine in non-malignant urological disorders, with particular attention to benign prostate hyperplasia and urolithiasis.

The Hereditary Renal Cancer Syndromes

Although the majority of renal cell carcinomas (RCC) are sporadic, hereditary types of kidney cancer such as Von Hippel-Lindau (VHL) disease and hereditary papillary renal carcinoma syndromes are thought to account for approximately 4% of kidney cancers. A germline mutation seems to predispose to the development of specific histologic types of RCC. Hereditary kidney cancers are bilateral multifocal kidney tumors that, in some instances, occur at a younger age than do sporadic renal cancers. A better knowledge of the genetic basis of renal carcinogenesis has been useful in identifying genetic causes of renal tumorigenesis, such as inactivation of the VHL tumor suppressor gene in clear cell carcinoma. Moreover, the genes responsible for hereditary renal cancer syndromes seems to play a role in the development of sporadic counterparts. Knowledge of genetic cancer syndromes may allow clinicians to screen and counsel family members, identify those patients at risk for multiple cancer development, and give the chance to intervene therapeutically when cancers are still treatable by identifying localized tumors through early screening. This article reviews the current status and recent advances in the field of familial kidney cancer syndromes.