JAK3/STAT5/6 pathway alterations are associated with immune deviation in CD8 T cells in renal cell carcinoma patients.

To investigate the molecular mechanisms underlying altered T cell response in renal cell carcinoma (RCC) patients, we compared autologous and allogeneic CD8(+) T cell responses against RCC line from RCC patients and their HLA-matched donors, using mixed lymphocyte/tumor cell cultures (MLTCs). In addition, we analyzed the expression of molecules associated with cell cycle regulation. Autologous MLTC responder CD8(+) T cells showed cytotoxic activity against RCC cell lines; however the analysis of the distribution of CD8(+) T-cell subsets revealed that allogenic counterparts mediate superior antitumor efficacy. In RCC patients, a decreased proliferative response to tumor, associated with defects in JAK3/STAT5/6 expression that led to increased p27KIP1 expression and alterations in the cell cycle, was observed. These data define a molecular pathway involved in cell cycle regulation that is associated with the dysfunction of tumor-specific CD8(+) effector cells. If validated, this may define a therapeutic target in the setting of patients with RCC.

Penile prostheses.

Penile prosthesis implantation is recognized as a valid option to obtain an artificial erection satisfactory for sexual intercourse in those patients in which a pharmacological approach is contraindicated or ineffective. Penile prostheses are subbject to continuous development and they are achieving ever better mechanical reliability and safety. The devices are divided into two general types: semirigid (malleable and mechanical) and inflatables. The AMS® (American Medical Systems) and Coloplast Ltd® produce the majority of inflatable and semirigid devices.Malleable and mechanical prostheses have the disadvantage that the penis is always erect although it can be orientated in different ways, while the advantages are ease of use and the need for a simpler surgical procedure compared with inflatable prostheses. Three-component prostheses are more sophisticated than semirigid devices. The advantages of these devices are that the prosthesis feels softer than semirigid or two-piece devices when deflated, with a better cosmetic result, and it ensures a more natural erection than others kinds of prosthesis. The disadvantages are the possibility of malfunction and the need for a more complicated surgical technique. Implantation of a penile prosthesis can be performed in a short surgical time under locoregional anaesthesia, and for this reason hospitalization is usually brief and the patient can be discharged 2 days after the operation if complications are not evident. Patient and partner satisfaction reflect the quality and the effectiveness of this treatment. Even though the results are positive in the vast majority of patients, the possibility of several complications makes penile prosthesis implantation a delicate kind of surgery. Complications can happen when the operation is carried out, in the peri-operative and in the postoperative period, and include infections, erosions of the prosthesis and mechanical failure in case of inflatable prosthesis. Penile prostheses available on the market have improved the success of this kind of surgery, thanks to the introduction of new materials and designs.

Altered p53 and pRb expression is predictive of response to BCG treatment in T1G3 bladder cancer.

BACKGROUND: The aim of this study was to determine the prognostic value of p53 and retinoblastoma protein (pRb) expression in patients with stage T1 grade 3 (T1G3) bladder cancer (BC) treated by transurethral resection of bladder tumour (TURBT) and intravesical instillations of bacillus Calmette-Guerin (BCG). MATERIALS AND METHODS: p53 and pRb expression were independently recorded within a homogeneous series of 27 patients. Fisher exact test and the log-rank test were carried out, along with Kaplan-Meier survival analysis. RESULTS: Sixteen tumours showed altered p53 expression, while 14 showed altered pRb expression. Overall, 7 tumours showed normal expression of both markers, 10 altered expression of one of the two markers, and 10 altered expression of both markers. Only altered pRb expression was an independent predictor of both recurrence (p=0.037) and progression (p=0.018); altered expression of both markers was a strong predictor (p=0.001) of progression. CONCLUSION: This is the first study demonstrating that altered p53 and pRb expression are predictive of T1G3 BC response to BCG treatment. These findings provide grounds for inclusion and prospective validation of these markers in the decision-making process for treating BC.

Current insights in renal cell cancer pathology.

In recent years molecular biologists and pathologists have described new entities of renal cell cancer (RCC) with a totally different morphology and biology among the histotypes of renal carcinoma, but always referring to the same renal cancer disease. The evidence of a distinct biological behavior and long-term prognosis among these makes the correct pathological diagnosis of renal cancer critically important for the clinician. Advances in understanding of the pathogenesis, behavior, and importance of prognostic factors for RCC have paved the way for a revision of its classification and staging. We reviewed the role of histological classification, microscopic tumor necrosis, microscopic venous invasion, lymph node involvement and, particularly, pathological stage. In our series of patients who underwent renal surgery for neoplasm, a retrospective study established the predictive role of tumor size on recurrence rate, compared with other known prognostic factors, and we conclude that histological grade, pathological stage and tumor size remain relevant prognosticators in early stage RCC patients. In order to optimize the management of patients with RCC it is necessary to develop an interdisciplinary approach (surgeon, radiologist, pathologist, oncologist) and find new prognostic parameters at molecular and cellular levels. Many efforts are ongoing to integrate molecular data (from tissue microarrays) and clinical data (traditional prognosticators) into a molecular integrated staging system. In the postgenomic era, new tumor-associated antigens and molecules can be identified at the protein level using proteomics, providing a major opportunity for screening and finding novel targets that are the basis of new emerging therapies for RCC.

What does the urologist expect from the pathologist (and what can the pathologists give) in reporting on adult kidney tumour specimens?

OBJECTIVE: To identify the parameters required by the urologist to determine the prognosis and the treatment of renal cancer in adults, and to establish the potential therapeutic targets of the new treatments that started to show clinical efficacy. METHODS: A literature search of the last 10 yr was done, paying specific attention to TNM 2002 (UICC staging) and Fuhrman's grading. Also, the main genetic characteristics of the different subtypes (according to the WHO 2004 classification) with potential therapeutic implications have been compiled. RESULTS: After the review of the literature, the opinion of the joint meeting including urologists and pathologists is that some aspects of the TNM 2002 classification must be refined. Criteria for nuclear grading should be different for the subtypes of renal cell carcinoma, and the WHO 2004 histological classification is clinically useful. CONCLUSIONS: In the workshop held in Palermo, common opinion was achieved on a number of points. The TNM 2002 classification is useful, but some adjustments should be made, particularly as referred to the tumour size cut-off, assessment of the invasion of the renal sinus fat tissue, and invasion of the ipsilateral adrenal gland. The Fuhrman's grading system is useful in clear cell renal cell carcinoma (RCC), and probably also in papillary RCC, but a redefinition for chromophobe RCC is needed. Finally, the determination of certain markers, such as VEGF and HIF, could constitute good target markers for the new therapies, but they remain under investigation.

Prospective randomized trial comparing high lumbotomic with laparotomic access in renal cell carcinoma surgery.

OBJECTIVE: We compared laparotomic with lumbotomic access in renal cell carcinoma (RCC) surgery by means of a prospective randomized trial, in order to evaluate differences in surgical time, blood loss, number of lymph nodes removed, duration of postoperative ileus and hospitalization, perioperative complications and progression-free and cancer-specific survival rates. MATERIAL AND METHODS: Between November 1991 and November 1996, 94 patients with RCC were recruited and randomly assigned to undergo surgery by lumbotomic (n = 50) or laparotomic (n = 44) access. All patients underwent radical nephrectomy and lymph node dissection. RESULTS: The mean surgical time was 59.1 min (range 20-140 min) and 84.4 min (range 40-180 min) for lumbotomic and laparotomic access, respectively (p < 0.01). Blood loss was 502 ml (range 200-1800 ml) for lumbotomic and 648 ml (range 200-2000 ml) for laparotomic access (p < 0.005). Mean hospital stay was 6.8 days (range 3-13 days) for lumbotomic and 8.2 days (range 5-15 days) for laparotomic access (p < 0.001). The perioperative complication rates were 6.1% and 13.6% for lumbotomic and laparotomic access, respectively. After a mean follow-up period of 7.5 years, cancer-specific and progression-free survival rates were 88% and 75%, respectively for lumbotomic and 88% and 72.7%, respectively for laparotomic access (p = NS). Multivariate analysis of risk factors showed that pathological stage was the best prognostic indicator of tumor progression, while other variables (age, tumor grade, surgical access, tumor size and incidental diagnosis of tumor) were not predictive of the prognosis of patients with RCC. CONCLUSIONS: During radical nephrectomy, control of the renal vessels is easier and faster with high lumbotomic access. The suggested risk of tumor cell spread due to manipulation of the kidney before vessel ligature was not confirmed in our study. Because of the shorter surgical time, lower blood loss, lower perioperative and late complication rates and shorter hospital stay involved, lumbotomic access should be preferred to laparotomic access in radical nephrectomy for RCC.

Low-calcium diet in hypercalciuric enuretic children restores AQP2 excretion and improves clinical symptoms.

In this study, we analyzed the effect of a therapeutic intervention in 46 enuretic children, 26 (57%) of whom were hypercalciuric. All the patients (n = 46) were treated with DDAVP for 3-6 mo. The hypercalciuric patients (n = 26) received a low-calcium diet (approximately 500 mg/day) for the same period. After the therapy, the bed-wetting episodes stopped in 80% of the 46 patients tested. In those patients having low-AVP levels before the therapy, circulating AVP concentration returned to normal (>4 pg/ml), and the hypercalciuria was resolved in the hypercalciuric patients (calcium/creatinine ratio <0.2). Urinary aquaporin-2 (AQP2) levels were semiquantified by densitometric scanning and reported as a ratio between the intensity of the signal in the day vs. the night urine samples (day/night AQP2 ratio). In the hypercalciuric patients, the day/night AQP2 ratio returned to values close to those found in the healthy children (from 1.19 +/- 0.20 before to 0.69 +/- 0.10 after the treatment, n = 26, P = 0.03). In contrast, in the normocalciuric children we saw no significant modulation of AQP2 excretion (from 1.07 +/- 0.14 before to 0.99 +/- 0.14 after the treatment, n = 20). This study clearly demonstrates that urinary calcium levels modulate AQP2 excretion and is likely to be useful for treatment of children with enuresis.

Urinary aquaporin 2 and calciuria correlate with the severity of enuresis in children.

This study examined the hypothesis that nocturnal enuresis might be paralleled by aquaporin 2 (AQP2) urinary excretion. Eighty children who experienced nocturnal enuresis were studied and compared with 9 healthy children. The 24-h urine samples were divided into two portions: night collections and day collections. Creatinine equivalents of urine samples from each patient were analyzed by Western blotting. AQP2 levels were semiquantified by densitometric scanning and reported as a ratio between the intensity of the signal in the day urine sample versus the night urine sample (D/N AQP2 ratio). The D/N AQP2 ratio was 0.59 +/- 0.11 (n = 9) in healthy children and increased to 1.27 +/- 0.24 (n = 10) in a subpopulation of enuretic children who had low nocturnal vasopressin levels. In enuretic children who displayed hypercalciuria and had normal vasopressin levels, the D/N AQP2 ratio was 1.05 +/- 0.27 (n = 8). These data indicate that reduced secretion of vasopressin and absorptive hypercalciuria are independently associated with an approximately twofold increase in the urinary D/N AQP2 ratio. When low nocturnal vasopressin levels were associated with hypercalciuria, a nearly threefold increase in the D/N AQP2 ratio was observed (1. 67 +/- 0.41, n = 11). In addition, in all enuretic patients tested, the urinary D/N AQP2 ratio correlates perfectly with the severity of the disorder (nocturnal polyuria). The findings reported in this article indicate that urinary AQP2 correlates with the severity of enuresis in children.