Integrated staging systems for conventional renal cell carcinoma: a comparison of two prognostic models.

OBJECTIVE: The objective of the current study was to compare, in a single center experience, the discriminating accuracy of two prognostic models to predict the outcome of patients surgically treated for conventional renal cell carcinoma (RCC). PATIENTS AND METHODS: We retrospectively evaluated the clinical and pathological data of 100 patients surgically treated for RCC between 1998-2008 at our institution. For each patient, prognostic scores were calculated according to two models: the University of California Los Angeles integrated staging system (UISS) and the Stage, Size, Grade, and Necrosis (SSIGN) developed at the Mayo Clinic. The prognostic predictive ability of models was evaluated using receiver operating characteristic (ROC) curves. RESULTS: The median follow-up was 62 months (range 12-120). All clinical and pathological features that compound the algorithms were significantly associated with death from RCC in univariate and multivariate setting. The 5-year cancer-specific survival (CSS) according to the SSIGN score were 95% in the '0-2' category, 88% in '3-4', 60% in '5-6', 37% in '7-9' and 0% in the '> or = 10' group (long-rank p value < 0.001); according to the UISS the 5 yr CSS probabilities in non-metastatic patients were 100% in low, 80% in intermediate and 54% in high-risk groups; in metastatic patients, the respectively CSS were 40% in low and 25% in high-risk groups (long-rank p value < 0.001). The area under the ROC curve was 0.815 for the SSIGN score and 0.843 for the UISS (p = 0.632). CONCLUSION: In our series the SSIGN and UISS discriminated well, without relevant differences. Currently both algorithms represent usefuls clinical tools that allow risk assessment after surgical treatment of RCC. We encourage the uro-oncologist to begin to routinely rely on them in real-life practice.

Hormonal therapy promotes hormone-resistant phenotype by increasing DNMT activity and expression in prostate cancer models.

We hypothesized that hormonal therapy favors the development of the hormone-resistant phenotype through epigenetic mechanisms. Human prostate cancer tissues and in vitro and in vivo models were used to verify this hypothesis. We demonstrated that tumor cells continuously treated with bicalutamide (BCLT) or cultured in androgen-depleted medium progressively acquire higher DNA methyltransferase (DNMT) activity and expression than cells cultured in standard condition. Increased DNMT expression and activity also paralleled the up-regulation of truncated AR isoforms, which favors the development of the hormone-resistant phenotype. After androgen stimulation with 10(-12) m dihydrotestosterone, DNMT activity was significantly reduced in comparison with hormonal therapy. Consistent with these observations, the silencing of DNMT3a and DNMT3b significantly decreased the DNMT activity levels. These findings were also directly correlated with phosphatase and tensin homolog down-regulation and activation of ERK and phosphatidylinositol 3-kinases/AKT8 virus oncogene cellular homolog pathways. The use of a pan-DNMT inhibitor (5-Azacitidine) greatly reduced the development of the hormone-resistant phenotype induced by long-term BCLT treatment, and this finding correlated with low DNMT activity. The regulation of DNMT activity was, in some measure, dependent on the androgen receptor, as small interfering RNA treatment targeting the androgen receptor greatly decreased the modulation of DNMT activity under androgenic and antiandrogenic stimulation. These observations were correlated in vivo in patients, as demonstrated by immunohistochemistry. Patients treated by BCLT before surgery had higher DNMT3a and DNMT3b expression than patients who had not undergone this treatment. Our findings provide evidence of a relationship between the castration-resistant phenotype and DNMT expression and activity in human prostate cancer.

Sarcoma of prostate: case report and review of the literature.

OBJECTIVES: Prostate sarcomas are rare entity, the most common is leiomyosarcoma which account for 0.1% of all prostate malignancies. The presenting symptoms are mainly obstructive urinary symptoms. Surgery with chemo- or radiotherapy are the mainstay treatment options. The overall survival rate remains poor regardless of initial tumour size, grade or histological subtype. Immunohistochemistry reveals tumour cells diffusely positive for vimentin, smooth muscle actin, focally positive for progesterone receptor, whilst keratins are usually negative. MATERIALS AND METHODS: We describe a case of a patient affected by sarcoma of prostate. Furthermore, we reviewed the cases of prostate sarcomas available in literature to clarify the best therapeutic options to be applied. RESULTS: In the case described leiomyosarcoma diagnosed by an ultrasound guided biopsy was characterized by fascicles of spindle-shaped cells with a variable degree of nuclear atypia. The immunohistochemistry showed positive staining for smooth muscle actin, vimentin and focally for the S-100 protein. The patient was treated with radical retropubic prostatectomy and radiotherapy of the local recurrence, and chemotherapy at metastases onset. CONCLUSIONS: Prostate sarcomas are highly aggressive, with limited therapeutic options. An early diagnosis and complete surgical excision with negative margins offer patients the long-term disease free survival.

Effects of dutasteride on prostate carcinoma primary cultures: a comparative study with finasteride and MK386.

PURPOSE: The profound decrease in serum dihydrotestosterone observed with the dual 5alpha-reductase inhibitor dutasteride makes it an attractive agent for prostate cancer therapy. To our knowledge we compared for the first time the antitumor effect of dutasteride with that of the specific 5alpha-reductase-1 inhibitor MK386 and the specific 5alpha-reductase-2 inhibitor finasteride in human prostate primary cultures. MATERIALS AND METHODS: Biochemical markers of the cellular response to 5alpha-reductase inhibitors were evaluated in primary cultures of prostate epithelial cancer cells from 54 patients with prostate carcinoma. RESULTS: In our cohort of 54 patients prostate cancer cell growth decreased with dutasteride in 42 (about 78%), whereas in 21 (39%) it decreased with finasteride or MK386 alone. We observed a relationship between the levels of 5alpha-reductase enzymes in cell culture extracts and those revealed by immunohistochemistry in sections of samples from which we established primary cultures. Finasteride effects depended on 5alpha-reductase-2 levels and they were higher when the 5alpha-reductase-1:2 ratio was low. However, dutasteride effects were related to 5alpha-reductase-1 and 2 levels, and were not influenced by the 5alpha-reductase-1:2 ratio. Conversely the effects of MK386 were related to 5alpha-reductase-1 levels and they were higher when the 5alpha-reductase-1:2 ratio was high. CONCLUSIONS: Our data may provide a rationale for the use of a dual 5alpha-reductase inhibitor rather than a mono specific inhibitor for the prevention or treatment of early prostate cancer. This finding appears to confirm some preliminary clinical results and it could be due to the simultaneous presence of each 5alpha-reductase isoenzyme in prostate tumor cells.

Bicalutamide increases phospho-Akt levels through Her2 in patients with prostate cancer.

Bicalutamide monotherapy is emerging as an alternative in the treatment of locally advanced prostate cancer. However, a significant number of these patients will recur and be in need of second-line therapies. The knowledge of molecular arrangements after pharmacological therapy seems to be a new primary prerequisite to predict the efficacy or the failure of a secondary therapy. Based on these considerations, we have conducted this study in order to analyze the expressions of phosphatase and tensin homolog deleted on chromosome 10 (PTEN), Akt, epidermal growth factor receptor (EGFR), phospho-EGFR (p-EGFR), human EGFR2 (Her2), and phospho-Her2 (p-Her2) after bicalutamide treatment. For this purpose, we evaluated retrospectively 69 prostate cancer tissues derived from patients who received radical prostatectomy as the only treatment, and 81 from patients who received bicalutamide for 120 days before surgery. In addition, we analyzed at different time points the effects of castration performed on athymic mice bearing the LuCaP 35 xenograft line at different times. We observed that bicalutamide treatment increased significantly the levels of p-Akt, EGFR, and Her2 with a concomitant reduction in PTEN. This effect was time dependent and required of sufficient time to be evident as indicated by data obtained with the LuCaP 35 tumors. A logistic multiple regression analysis revealed that a switch of p-Akt control from a PTEN/EGFR- to Her2-after bicalutamide treatment was possible. Since Akt and Her2 can be associated with reduced drug sensitivity, our report suggests that the evaluation of molecular arrangements after bicalutamide treatment could be useful to identify subsets of patients who will be molecular permissive for new adjuvant anti-target therapies.

In vitro and in vivo effects of bicalutamide on the expression of TrkA and P75 neurotrophin receptors in prostate carcinoma.

RATIONALE: Neurotrophine tyrosine kinase receptors (NTR) are expressed in prostate carcinoma (PCa), and their distribution seems to be related to disease malignancy. MATERIAL AND METHODS: In this article we analyzed the expression of NTRK1 (TrkA), NTRK2 (TrkB), NTRK3 (TrkC), and p75NTR in a 102 patient cohort with clinically localized tumors, which had been surgically treated with radical prostatectomy (RP). Among these, 61 patients received RP as sole treatment, and 41 patients received neoadjuvant hormone therapy (NHT) for 120 days with bicalutamide 150 mg/day. In addition, we analyzed the NTR expression in vitro in the androgen receptor positive, androgen-sensitive cell strains derived from CWR22R. RESULTS AND CONCLUSIONS: We demonstrated that: (i) TrkA and TrkC levels were significantly upmodulated, whereas (ii) p75NTR seemed to be reduced, and (iii) TrkB expression seemed to be not affected by NHT. TrkA were constitutively activated when its levels were very high. In vitro studies showed that the dehydrotestosterone (DHT) was able to maintain low TrkA and TrkC protein levels. Conversely, DHT was able to maintain p75NTR at high levels. Bicalutamide treatment induced TrkA and TrkC and reduced p75NTR expression. Antiproliferative effects of CEP701 were dependent to TrkA levels. A therapeutical effect of CEP701 was seen in all culture conditions, and bicalutamide seemed to sensitize prostate cancer cells to the effects of a pan TrkA inhibitor CEP701, suggesting that a sequential therapy between these drugs could further increase the efficacy of Trk inhibition.