Jean-Jacques Patard

Various protein kinases are known to be activated in cancer cells and drive tumor growth and progression. In metastatic renal cell carcinoma tyrosine-kinase inhibitors (TKIs) have achieved significant progression-free and overall survival improvements. For bladder and prostate cancers TKIs may also be considered as a promising treatment option. Our aim was to report the most relevant published articles to support the interest of the use of TKIs in the treatment of bladder and prostate cancer. PubMed database and bibliographies of retrieved articles were reviewed. The key words used were tyrosine-kinase inhibitor, protein-kinase inhibitor, hormone refractory prostate cancer, muscle invasive bladder cancer. The most relevant publications from basic science and clinical randomized controlled studies were summarized and analyzed. Regarding bladder cancer, TKI treatment is one of the most studied therapeutic strategies in the field of targeted therapy. Indeed, it has been suggested that targeting TK alone and/or in association with cytotoxic chemotherapy may represent a promising option for treating locally advanced and/or metastatic bladder cancer. Concerning hormone refractory prostate cancer (HRPC), collected data are still confusing. Basic science studies found an interesting expression of EGF and VEGF receptors on cancer cells supporting the idea that TKIs could be efficient in HRPC. Nonetheless most of published clinical phase II studies found a weak effect on symptoms and quality of life without any decrease in PSA levels or overall survival. TKIs have not yet achieved in bladder and prostate cancers similar efficacy to what has been obtained in metastatic renal cell carcinoma. Further studies are needed to establish the place of such an approach in non renal tumors.

Introduction: Dendritic cells (DCs) are antigen-presenting cells that are currently employed in cancer clinical trials. However, it is not clear whether their ability to induce tumour-specific immune responses when they are isolated from cancer patients is reduced relative to their ability in vivo. We determined the phenotype and functional activity of DCs from cancer patients and investigated the effect of putrescine, a polyamine molecule that is released in large amounts by cancer cells and has been implicated in metastatic invasion, on DCs. Methods: The IL-4/GM-CSF (granulocyte–macrophage colony-stimulating factor) procedure for culturing blood monocyte-derived DCs was applied to cells from healthy donors and patients (17 with breast, 7 with colorectal and 10 with renal cell carcinoma). The same peroxide-treated tumour cells (M74 cell line) were used for DC pulsing. We investigated the effects of stimulation of autologous lymphocytes by DCs pulsed with treated tumour cells (DC-Tu), and cytolytic activity of T cells was determined in the same target cells. Results: Certain differences were observed between donors and breast cancer patients. The yield of DCs was dramatically weaker, and expression of MHC class II was lower and the percentage of HLA-DR^-Lin^- cells higher in patients. Whatever combination of maturating agents was used, expression of markers of mature DCs was significantly lower in patients. Also, DCs from patients exhibited reduced ability to stimulate cytotoxic T lymphocytes. After DC-Tu stimulation, specific cytolytic activity was enhanced by up to 40% when DCs were from donors but only up to 10% when they were from patients. IFN-γ production was repeatedly found to be enhanced in donors but not in patients. By adding putrescine to DCs from donors, it was possible to enhance the HLA-DR^-Lin^- cell percentage and to reduce the final cytolytic activity of lymphocytes after DC-Tu stimulation, mimicking defective DC function. These putrescine-induced deficiencies were reversed by treating DCs with all-trans retinoic acid. Conclusion: These data are consistent with blockade of antigen-presenting cells at an early stage of differentiation in patients with breast cancer. Putrescine released in the microenvironmement of DCs could be involved in this blockade. Use of all-trans retinoic acid treatment to reverse this blockade and favour ex vivo expansion of antigen-specific T lymphocytes is of real interest.

We validate the prognostic value of a symptom based classification (S classification) in a multi-institutional study. A total of 2,242 patients from 5 European centers were included in this study. Based on symptoms at diagnosis, patients were stratified into 3 groups of S1-asymptomatic tumors, S2-tumors with local symptoms and S3-tumors with systemic symptoms. Variables such as age, gender, tumor size, TNM stage, Fuhrman grade, Eastern Cooperative Oncology Group (ECOG) performance status, perinephric fat, renal vein and adrenal invasion were also considered for prognostic value. The end point of the study was cancer specific survival. Survival assessment was made with univariate and multivariate analyses using the Kaplan-Meier method and Cox regression analysis. Of the patients 1,018 (45.4%) were classified as S1, 865 (38.6%) S2 and 339 (16.0%) S3. The S classification correlated to tumor stage, grade and ECOG (p <0.001). On univariate analysis ECOG performance status, S classification, tumor size, TNM stage, Fuhrman grade, and adrenal, perinephric fat or vein invasion were significant prognostic factors (p <0.001). The S classification provided a significant prognostic stratification in the aggregate as well at each of the 5 centers. On multivariate analysis the S classification, TNM stage, Fuhrman grade, and perinephric fat and renal vein invasion remained independent prognostic factors (p <0.001). This study confirms that it is possible to graduate symptoms for a prognostic purpose. The proposed symptom score should be evaluated for its integration in prognostic algorithms.

The objective of this study was to determine the clinical and histological factors influencing survival of patients with renal cancer and caval thrombus. The clinical and pathological data of 46 patients operated for renal cancer with caval thrombus were reviewed. The following prognostic factors were studied: tumour stage and grade, tumour diameter, invasion of the perirenal fat or adrenal gland, presence of lymph node involvement or distant metastases, level of the thrombus, invasion of the wall of the vena cava, partial or complete nature of the resection. Survival was determined by the Kaplan-Meier method and multivariate analysis was performed with the Cox test. The study population comprised 30 males and 16 females with a mean age of 64.4 years. The mean tumour diameter was 10.6 cm. Twelve thrombi were perirenal (26.1%), 15 were infrahepatic (32.6%), 12 were retrohepatic (26.1%), and 7 were supradiaphragmatic (15.2%). Forty four tumours were stage T3 and 2 were stage T4. Fifteen tumours were N1-2 or M1 (32.6%). The median disease-specific survival was 22 months and the 5-year survival rate was 25%. On univariate analysis, complete resection, lymph node invasion and metastases and adrenal gland invasion had an impact on survival. On multivariate analysis, only the presence of metastases had an independent prognostic value. This study confirms the prognostic value of certain factors (lymph node invasion and metastases, complete tumour resection) and raises the question of the prognostic significance of adrenal gland invasion. On the basis of these data, the authors recommend that surgery should only be performed in patients with a good general status, without metastases and in whom complete resection of the tumour mass appears to be possible.

To analyse recent advances in intravesical instillation therapy for superficial bladder cancer. Although intravesical bacillus Calmette-Guérin has been used for many years in the treatment of superficial bladder cancer, its mechanism of action remains unclear, its poor tolerance remains a problem, the prediction of its efficacy has still to be validated, and its long-term effects on progression and survival are controversial. The exact timing and place of intravesical chemotherapy needs to be better defined, as well as the place of some new molecules. Finally, new approaches need to be explored for overcoming the limitations of the usual intravesical agents. No dramatic advances have been made in understanding the mechanisms of action of bacillus Calmette-Guérin during the past year. However, a careful dissection of this complex immunological pathway continues and immunological criteria are promising for predicting the response to bacillus Calmette-Guérin. Evidence has been accumulating to suggest that a dose reduction during the initial treatment remains effective and reduces side-effects. In addition, bacillus Calmette-Guérin maintenance therapy is useful for high-risk patients. However, long-term tolerance remains an important issue, and the optimal protocol has not yet been defined. On the other hand, it has been proved that intravesical chemotherapy, when administered early after transurethral resection, is effective in preventing frequent recurrences, whereas maintenance chemotherapy is ineffective. Finally, new approaches, including instillations of activated immune cells or targeted gene therapy, are being explored.

Neuroendocrine bladder tumours (NET) constitute a group of various tumours with a common neuroendocrine phenotype. This is a very well defined entity (morphological, immunohistochemical, and ultrastructural). The great majority of bladder NETs reported in the literature are high-grade small cell carcinomas, but large cell carcinoma are probably underestimated due to the lack of systematic investigation. This paper reviews these rare, poorly known tumours, which require specific management. All bladder NETs are described. The frequency and diagnostic and therapeutic strategy of neuroendocrine bladder tumours are described.