A Randomised Phase II Trial Comparing Docetaxel Plus Prednisone with Docetaxel Plus Prednisone Plus Low-Dose Cyclophosphamide in Castration-Resistant Prostate Cancer.

BACKGROUND: Docetaxel plus prednisone is a standard treatment for castration-resistant prostate cancer. Cyclophosphamide may be an effective combination partner. METHODS: This randomised, multicentre, phase II trial compared the combination therapy of docetaxel plus prednisone plus cyclophosphamide with the standard therapy of docetaxel plus prednisone. RESULTS: Thirty-three patients received six 3-week treatment cycles (in total 171 cycles). During treatment, an adequate decline in prostate-specific antigen was seen in both groups (p = 0.068) without between-group differences (p = 0.683). No relevant differences between within-group changes were observed for blood pressure, weight, pain score, laboratory variables or quality of life. There were no serious side effects apart from leucopenia requiring treatment (docetaxel + prednisone + cyclophosphamide arm) and no drug-related withdrawals; all three fatalities were considered to be cancer related. CONCLUSIONS: The oncological effectiveness and tolerability of docetaxel plus prednisone were supported; an additional effect of cyclophosphamide was not detected. However, the small number of patients and short observation period restrict the generalisability of the results.

Inducer-stimulated Fas targets activated endothelium for destruction by anti-angiogenic thrombospondin-1 and pigment epithelium-derived factor.

Natural inhibitors of angiogenesis are able to block pathological neovascularization without harming the preexisting vasculature. Here we show that two such inhibitors, thrombospondin-1 and pigment epithelium-derived factor, derive specificity for remodeling vessels from their dependence on Fas/Fas ligand (FasL)-mediated apoptosis to block angiogenesis. Both inhibitors upregulated FasL on endothelial cells. Expression of the essential partner of FasL, Fas/CD95 receptor, was low on quiescent endothelial cells and vessels but greatly enhanced by inducers of angiogenesis, thereby specifically sensitizing the stimulated cells to apoptosis by inhibitor-generated FasL. The anti-angiogenic activity of thrombospondin-1 and pigment epithelium-derived factor both in vitro and in vivo was dependent on this dual induction of Fas and FasL and the resulting apoptosis. This example of cooperation between pro- and anti-angiogenic factors in the inhibition of angiogenesis provides one explanation for the ability of inhibitors to select remodeling capillaries for destruction.

Synthesis and localization of trefoil factor family (TFF) peptides in the human urinary tract and TFF2 excretion into the urine.

Trefoil factor family (TFF) peptides promote regeneration and repair processes of mucous epithelia. They also probably play a key role in the remarkable regenerative capacity of the urinary tract epithelia. We have localized TFF1, TFF2, and TFF3 expression systematically in surgical specimens from the urinary tract by reverse transcription with the polymerase chain reaction, Western blot analysis, and immunohistochemistry. Urine samples from patients suffering from nephrolithiasis have been investigated and compared with those of healthy controls. TFF synthesis is detectable along the entire urinary tract epithelia. TFF3 synthesis is the most pronounced followed by TFF1, whereas TFF2 synthesis is occasionally detectable but only in trace amounts. In contrast, TFF2 is the predominant TFF peptide excreted into the urine, and significantly increased urinary TFF2 levels (together with occasionally raised TFF3 levels) have been observed in patients suffering from nephrolithiasis. Thus, we consider that TFF3 plays a major part in regeneration and restitution processes in urinary tract epithelia. TFF2 and probably also TFF3 are candidate biomarkers for nephrolithiasis and possibly other inflammatory conditions of the urinary tract.

Management and outcome of bilateral testicular germ cell tumors: a 25-year single center experience.

OBJECTIVES: To analyze risk factors, management, histology, and outcome of bilateral testicular germ cell tumors (TGCT) based on a 25-year single center experience. METHODS: Out of 612 patients treated for TGCT between 1982 and 2007, 17 (3%) were found to have bilateral disease. Data of these patients were reviewed and analyzed. RESULTS: Eleven patients (65%) were identified with metachronous and 6 (35%) with synchronous bilateral TGCT. One patient had a cryptorchism in childhood. Patients with metachronous bilateral disease presented at lower stages than those with synchronous bilateral disease (stage I: 82% vs 33%, P = 0.02). In metachronous bilateral TGCT, the interval between the tumors ranged from 4 months to 25 years with a median of 47 months. The risk of developing a TGCT in the contralateral testicle was 26-fold higher than the a-priori risk for a healthy individual to develop TGCT. Overall, 74% of the bilateral tumors were seminomas and >50% of the patients had similar histology on both sides. After a median follow up of 121 months for patients with synchronous and 95 months for patients with metachronous bilateral TGCT, all patients were alive with no evidence of disease. CONCLUSIONS: Most bilateral TGCT develop metachronously and are seminomas. Although patients with synchronous bilateral disease present at higher stages, both synchronous and metachronous bilateral TGCT carry a similar, excellent prognosis. Patients with unilateral TGCT require careful long-term monitoring of the remaining testicle due to a 26-fold increased risk of contralateral disease and a potentially long risk interval of up to 25 years.

Adjuvant cisplatin plus methotrexate versus methotrexate, vinblastine, epirubicin, and cisplatin in locally advanced bladder cancer: results of a randomized, multicenter, phase III trial (AUO-AB 05/95).

PURPOSE: Radical cystectomy as standard treatment of muscle-invasive urothelial carcinoma of the urinary bladder cures less than 50% of patients with locally advanced bladder cancer. We compared two adjuvant combination chemotherapies in patients with stage pT3a-4a and/or pathologic node-positive transitional-cell carcinoma of the bladder after radical cystectomy. PATIENTS AND METHODS: A total of 327 patients were randomly assigned to either adjuvant systemic chemotherapy with three cycles of cisplatin 70 mg/qm(2) on day 1 and methotrexate 40 mg/qm(2) on days 8 and 15 of a 21-day cycle (CM) or three cycles of methotrexate 30 mg/qm(2) on days 1, 15, and 22, vinblastine 3 mg/qm(2) on days 2, 15, and 22, epirubicin 45 mg/qm(2) on day 2, and cisplatin 70 mg/qm(2) on day 2 of a 28-day cycle (M-VEC). RESULTS: The hazard ratio for progression-free survival as the primary end point was 1.13 (90% CI, 0.86 to 1.48) for 163 CM patients compared with 164 M-VEC patients whose right-hand limit remained below the upper bound compatible with the noninferiority hypothesis (alpha = .0403). The 5-year progression-free, tumor-specific, and overall survival rates (point estimates +/- SE) for CM versus M-VEC were 46.3% +/- 4.6% v 48.8% +/- 4.5%, 52.0% +/- 4.6% v 52.3% +/- 4.8%, and 46.1% +/- 4.3% v 45.1% +/- 4.6%, respectively. WHO grade 3 and 4 leukopenia occurred in 7.0% of patients treated with CM and 22.2% of patients treated with M-VEC (P < .0001). CONCLUSION: CM cannot be considered inferior to M-VEC with regard to progression-free survival of patients with locally advanced bladder cancer after radical cystectomy. Moreover, patients receiving adjuvant CM combination therapy experienced significantly less grade 3 and 4 leukopenia than patients treated with M-VEC.

Evaluation of peri-operative peripheral and renal venous levels of pro- and anti-angiogenic factors and their relevance in patients with renal cell carcinoma.

OBJECTIVE: To evaluate peri-operative peripheral and renal venous plasma levels of vascular endothelial growth factor (VEGF), platelet-derived growth factor type BB (PDGF-BB), transforming growth factor (TGF)-beta1, endostatin, and thrombospondin-1 (TSP-1) in relation to pathological variables and prognosis, as pro- and anti-angiogenic factors are important for tumour growth and treatment of patients with renal cell carcinoma (RCC). PATIENTS AND METHODS: The study included 74 consecutive patients with sporadic RCC who had tumour nephrectomy. Peripheral venous blood was drawn 1 day before, immediately and 1, 3 and 5 days after surgery. Renal venous blood was collected in a subgroup of 33 patients during surgery. The variables were analysed using quantitative enzyme-linked immunoassay kits, and associated with pathological variables and disease-specific survival. RESULTS: Soon after surgery, peripheral venous VEGF, PDGF-BB and TGF-beta1 levels were decreased, whereas endostatin levels were significantly increased. Renal venous VEGF, PDGF-BB and TGF-beta1 levels were higher than in the general venous blood pool. Renal venous VEGF levels were correlated with tumour diameter and associated with grade and vascular invasion. After a mean follow-up of 30 months, higher peripheral preoperative, early peripheral postoperative and renal venous VEGF levels were associated with a poorer prognosis. However, in a multivariate analysis only Tumour-Node-Metastasis stage and Eastern Cooperative Oncology Group performance status were independent prognosticators of disease-specific survival. CONCLUSIONS: Circulating pro- and anti-angiogenic factors change early after nephrectomy. VEGF, PDGF-BB and TGF-beta1 are higher in the renal vein than in the general venous blood pool. Higher renal venous and peripheral levels of VEGF might be associated with a poorer prognosis.

Characterization of prognostic factors and efficacy in a phase-II study with docetaxel and estramustine for advanced hormone refractory prostate cancer.

BACKGROUND: Docetaxel based chemotherapy not only reduces pain and improves quality of life in advanced hormone refractory prostate cancer (HRPC), but it also improves survival. We investigated the combination of docetaxel and estramustine in patients with HRPC regarding efficacy and prognostic parameters. PATIENTS AND METHODS: We conducted a phase-II trial, administering docetaxel (70 mg/m(2) i.v., day 2, every 3 weeks) and estramustine (280 mg 3 times daily p.o., 1 day prior to docetaxel, on 5 consecutive days) to patients with HRPC. Patients were monitored for PSA (prostate-specific antigen) response and toxicity. RESULTS: 62 patients were treated. The median age was 67.5 years, the median PSA was 177.9 ng/ml. The median number of cycles was 6. The median time to progression (TTP) and median survival time were 14 (+/-2) and 24 (+/-5) months, respectively. A = 50% decrease in PSA levels from baseline occurred in 38 (61.3%) patients of whom 25 (40.3%) had a = 75% PSA decrease. The main grade 3-4 hematologic toxicities were neutropenia 34% and anemia 18%. CONCLUSIONS: The combination of docetaxel and estramustine exerts substantial activity in HRPC suggesting an overall survival benefit with manageable toxicity. This trial also demonstrated a survival advantage for patients with early chemotherapeutic intervention. We identified PSA relapse, baseline PSA and hemoglobin as valuable prognostic factors in this setting.

p53 and microvessel density in primary resection specimens of superficial bladder cancer.

PURPOSE: p53 Regulates angiogenesis in fibrosarcoma and correlative studies suggest a similar role for muscle invasive bladder cancer. We evaluated the associations of p53 status and microvessel density with pathological features and clinical outcomes in a large population of patients with superficial bladder cancer. In addition, we assessed the correlation of p53 status with microvessel density, which would suggest the regulation of angiogenesis by p53. MATERIALS AND METHODS: We stained 84 primary bladder resection specimens, including 55 stage pTa, 29 stage pT1, 27 grade 1, 35 grade 2 and 22 grade 3 samples, for p53, CD31 and CD34. The relationships of p53 or microvessel density and tumor stage-grade or clinical recurrence-progression were analyzed by analysis of variance and pairwise comparison analysis for least significant difference, and Pearson correlation coefficients. Only patients with no previous biopsy were included in analysis to preclude interference by granulation tissue related neovascularization. The 4 samples with significant inflammation were also excluded from study. RESULTS: At a mean followup of 33 months (range 1 to 93) 34 of 84 patients (40.4%) experienced 1 or more tumor recurrences and 10 (11.9%) had stage and/or grade progression. Statistically significant associations were observed of p53 immunostaining and microvessel density with tumor stage and grade (p <0.05). However, the association of p53 status with microvessel density was weak and not statistically significant. Similar results were observed for the CD31 and CD34 based estimates of microvessel density. Neither p53 status nor microvessel density correlated with recurrence or progression. CONCLUSIONS: Our study confirms the strong association of p53 and microvessel density with the well established prognostic factors of grade and stage in superficial bladder cancer, supporting other evidence of an important role for p53 and angiogenesis in the tumor biology of this disease. However, our data argue against a primary role of p53 in the regulation of angiogenesis in superficial bladder cancer. This study, which to our knowledge is the first to focus on primary resection specimens, suggests that other genetic or environmental factors may contribute to the regulation of angiogenesis in superficial bladder cancer.

Inhibition of tumor growth by systemic treatment with thrombospondin-1 peptide mimetics.

Many normal human cells produce thrombospondin-1 (TSP-1), a potent antiangiogenic protein that promotes vascular quiescence. In various organ systems, including the brain, breast and bladder and in fibroblasts, TSP-1 secretion is reduced during tumorigenesis, thereby allowing induction of the vigorous neovascularization required for tumor growth and metastasis. Full-length and short TSP-1-derived peptides inhibit angiogenesis by inducing endothelial cell apoptosis and thus disrupting the vasculature of the growing tumor. CD36 expressed on the surface of endothelial cells functions as the primary antiangiogenic receptor for TSP-1. A D-isoleucyl enantiomer of a TSP-1 heptapeptide specifically inhibits the proliferation and migration of capillary endothelial cells. DI-TSP, an approximately 1 kDa capped version of this peptide, is also antiangiogenic in vitro, with a specific activity approaching that of the 450 kDa parental molecule. Here, we show that DI-TSP delivered systemically dose-dependently inhibits the growth of murine melanoma metastases in syngeneic animals and that its more soluble isomer, DI-TSPa, similarly blocks the progression of primary human bladder tumors in an orthotopic model in immune-deficient mice. Like intact TSP-1, these peptide mimetics had no effect on cancer cells growing in vitro but markedly suppressed the growth of endothelial cells by inducing receptor-dependent apoptosis. Antibodies raised against CD36 blocked the ability of peptides to induce apoptosis in endothelial cells but had no effect on tumor necrosis factor-alpha-induced apoptosis. In vivo, the peptide mimetics were associated with a significantly reduced microvessel density and increased apoptotic indices in both the endothelial and tumor cell compartments. Such short peptides targeted to a specific antiangiogenic receptor, potent and easy to synthesize, show great promise as lead compounds in clinical antiangiogenic strategies.