Therapeutic vaccination with an interleukin-2-interferon-gamma-secreting allogeneic tumor vaccine in patients with progressive castration-resistant prostate cancer: a phase I/II trial.

Immunotherapy with whole cell cancer vaccines has been tested in various tumor types. This study investigated the safety profile and antitumor activity of an allogeneic prostate carcinoma cell line, LNCaP, expressing recombinant human interleukin-2 and human interferon-gamma. Thirty HLA-A*0201-matched patients with progressive, castration-resistant prostate cancer received four intradermal injections on days 1, 15, 29, and 92, and then every 90 days, as long as no tumor progression occurred. Three patients received a dose level of 7.5 million cells, and 27 patients received 15 million cells per injection. The primary study criteria were safety and the difference in prostate-specific antigen doubling time (PSA-DT), determined in the pretreatment phase (before the start of vaccination) and in the trial treatment phase (during vaccination). No dose-limiting or autoimmune toxicity was seen. During vaccination there was a significant prolongation of the PSA-DT compared with the prevaccination period (prolongation from 63 to 114 days; p < 0.01; intention to treat). In addition, results showed a period of PSA stabilization of at least 12 weeks, together with stable bone scans in 12 of 30 patients, and 3 patients sustained a >50% decrease in PSA versus baseline. The median overall survival time from first vaccination was 32 months (mean value, 34 months). Immune monitoring revealed T cell stimulation in the majority of patients. This vaccine strategy was found to be safe and well tolerated and was accompanied by prolongation of PSA-DT. The results of this trial warrant clinical development of this vaccine.

Value of 11C-choline PET and contrast-enhanced CT for staging of bladder cancer: correlation with histopathologic findings.

UNLABELLED: Lymph node involvement is a major prognostic factor in bladder cancer, but the accuracy of conventional imaging modalities for the prediction of regional and distant metastatic diseases is limited. This study was performed to compare the diagnostic accuracies of contrast-enhanced CT and PET with (11)C-choline for the staging of urothelial bladder cancer. METHODS: Twenty-seven patients (median age, 69.1 y) who had urothelial bladder cancer and who were referred for radical cystectomy and pelvic lymph node dissection (PLND) on the basis of a histologic evaluation after transurethral resection of bladder cancer (TURB) were studied. PET scanning, using 2 multiring whole-body tomographs, was performed 5 min after intravenous injection of approximately 370-500 MBq of (11)C-choline. In addition, conventional bone scintigraphy and contrast-enhanced CT were performed. After imaging, cystectomy and PLND were performed in all patients. Pathologic (11)C-choline uptake that could not be explained by intestinal activity was noted as a positive result. Node positivity was determined by size on CT: nodes measuring more than 1 cm in the long axis were described as being positive for tumor. Histopathologic findings were used as a reference. RESULTS: The presence of residual bladder cancer (pTa-pT4) was correctly detected in 21 of 25 histologically tumor-positive patients (84%) by CT and in 24 of 25 patients (96%) by (11)C-choline PET. Lymph node involvement was correctly detected in 4 of 8 patients (50%) by CT and in 5 of 8 patients (62%) by (11)C-choline PET. The median size of the 3 nodes with false-negative PET results was 9 mm (range, 6-21 mm), and the median size of the metastatic lesions within the lymph nodes was 3 mm (range, 1-15 mm). CT resulted in 6 (22%) false-positive lymph nodes, whereas none was demonstrated by (11)C-choline PET; these data indicated a significantly higher accuracy of PET than of CT (P < 0.01). Both modalities missed a small peritoneal metastasis verified by histologic evaluation. No positive results were obtained from bone scintigraphy. CONCLUSION: These preliminary data suggest that (11)C-choline PET is comparable to CT for detecting residual bladder cancer after TURB but appears to be superior to CT for the evaluation of potential additional lymph node metastases. (11)C-choline PET should be further evaluated for staging in patients who have bladder cancer and who are scheduled for radical cystectomy.

Influence of blood transfusions during radical retropubic prostatectomy on disease outcome.

OBJECTIVES: Blood transfusion in patients with malignant neoplasms may alter the disease outcome because of a theoretical immunomodulatory effect. This effect may reduce prostate-specific antigen (PSA)-free and disease-specific survival in patients with prostate cancer after radical prostatectomy. However, the results in published studies have been contradictory, and this effect has not yet been determined. METHODS: We evaluated 1412 patients after radical prostatectomy from 1984 to 2003 in a retrospective analysis, with a special focus on the rate and type of blood transfusions, specifically heterologous versus autologous blood. Univariate analysis and Cox regression analysis were performed to evaluate the impact of blood transfusions on disease outcome. RESULTS: The overall transfusion rate was 56.7%. The rate dropped from 88.9% in 1988 to 9.1% in 2002. PSA recurrence (greater than 0.5 ng/mL) was noted in 11.0% in patients without and in 26.0% with blood transfusions, which was not statistically significant on Kaplan-Meier analysis. Again, no difference was noted when patients were stratified according to the type (autologous versus heterologous) or the amount (2 U or less versus more than 2 U) of blood transfusion. Evaluating overall survival, again no differences were found. The established Cox regression model also proved that blood transfusions had no impact on disease outcome. CONCLUSIONS: Our retrospective analysis did not detect any effect of blood transfusions in patients with prostate cancer after radical prostatectomy. If a negative adverse effect occurs, this effect must be minimal. However, the infectious risk and the costs of blood transfusions should be reason enough to reduce blood loss and the transfusion rate further in patients with prostate cancer.

Optimization of prostatic biopsy: a prospective randomized trial comparing the sextant biopsy with a 10-core biopsy. Impact of prostatic region of sampling.

OBJECTIVE: New prostatic biopsy protocols suggest to increase the core numbers to enhance detection. Additional cores are usually sampled from the lateral part of the p-zone. We direct the sextant biopsy to the most lateral part of the p-zone, therefore we investigated if there is a gain by adding 4 median biopsy cores. MATERIAL AND METHODS: The prospective randomized trial (n = 200) compared our modified sextant biopsy to a 10-core strategy with 2 additional median cores on both sides. Directed biopsies to suspicious areas were allowed in both groups. Morbidity was assessed by a self-administered questionnaire. RESULTS: PC detection was 32% for 6 cores and 40% for 10 cores. Four patients were detected only by median biopsies. Using the binomial distribution table the gain of 4% is statistically significant. There was no statistical difference in morbidity, but a trend towards a higher rate of side effects in the 10-core group. CONCLUSIONS: The gain in prostate cancer detection rate by additional median biopsies is low, but statistically significant. There is no difference in morbidity and patient acceptance is high, therefore we favor the 10-core biopsy in our patients.

In vitro cytotoxic effects of imatinib in combination with anticancer drugs in human prostate cancer cell lines.

BACKGROUND: The platelet-derived growth factor receptor (PDFG-r), a tyrosine kinase, is expressed in 88% of primary prostate cancer and in 80% of the metastases. The tyrosine kinase inhibitor imatinib blocks the PDGF signaling pathway by inhibiting PDGF-r autophosphorylation. We examined the cytotoxic effects of imatinib in combination with other anticancer agents in the human prostate cancer cell lines LNCaP, PC-3, and DU 145. METHODS: The cells were exposed to imatinib and to the other drugs simultaneously for 5 days. Cell growth inhibition was determined by XTT assay. The cytotoxic effects in combinations were evaluated at the inhibitory concentration of 50% level by the isobologram. RESULTS: Imatinib produced additive effects with estramustine phosphate (EMP) and 4-hydroperoxy-cyclophosphamide in all three cell lines. In combination with etoposide imatinib produced additive effects in two of three cell lines. Imatinib with docetaxel produced antagonistic effects in PC-3 and additive to antagonistic effects in LNCaP and DU 145 cells. CONCLUSIONS: The simultaneous exposure of imatinib and EMP would be effective against hormone sensitive and hormone insensitive cell lines and this combination should be evaluated in clinical trials. In contrast, the simultaneous exposure of imatinib and docetaxel would have little therapeutic efficacy. Although there are gaps between in vitro studies and clinical trials, the present findings provide useful information for the establishment of clinical protocols involving imatinib in hormone-refractory prostate cancer.

Residual benign prostatic glands at the urethrovesical anastomosis after radical retropubic prostatectomy: prediction and impact on disease outcome.

OBJECTIVE: Biochemical failure after radical prostatectomy (RP) for localized prostate cancer (PC) is the first evidence of disease recurrence. If residual benign prostatic glands are left behind on RP a theoretical PSA production from benign glands or residual neoplastic tissue could explain PSA failure. This study investigates the prediction and impact on disease outcome of residual benign glands at the urethrovesical anastomosis. MATERIAL AND METHODS: 802 patients who underwent RP were retrospectively evaluated with special focus on residual benign glands (B+) at the urethrovesical anastomosis. B-status was defined from a biopsy of the urethral stump at 9, 12 and 3 o'clock position. RESULTS: From 802 patients 73.6% were classified as B+, 26.4% B0. 92.0% of B+ patients demonstrated only isolated glands (B1), 8.0% showed abundant glands (B2). There was no difference in disease outcome for B0 and B+ patients. Patients with early PC who are candidates for nerve sparing procedures are more likely for B+ status. CONCLUSIONS: Benign prostatic glands at the apical margin of the RP specimen are a common finding, but neither isolated nor abundant glands have an impact on disease outcome. We think that a precise apical dissection to improve continence rates is possible, although these patients are at risk for residual benign tissue at the apex.

Transcutaneous IL-2 uptake mediated by Transfersomes depends on concentration and fractionated application.

INTRODUCTION: Transfersomes (TF) are new, ultradeformable carriers with characteristics that enable them to penetrate the skin spontaneously. TFs are able to transport noninvasively both low- and high-molecular-weight molecules into the body. MATERIALS AND METHODS: TFs contain phosphatidylcholine and sodium cholate. Recombinant human interleukin-2 (Proleukin, Chiron) was added to the TFs and incubated for 24 h at 4 degrees C. The immunotransfersomes (ITF) were isolated from free interleukin-2 (IL-2) by filtration (Centrisart, Sartorius). Twenty-five thousand, 50,000 and 150,000 IU pure IL-2 and ITFs, which had been incubated with the same concentrations of IL-2, were applied subcutaneously (s.c.) (n = 8) and epicutaneously (e.c.) (n = 8) to mice. The IL-2 serum concentrations in the mice were then measured by ELISA after 2, 4, 6, 8, 10 and 24 h. Fractionation of the transdermal IL-2 application was also examined as a means of improving uptake. RESULTS: In concentrations of 25,000 and 50,000 IU IL-2, the subcutaneous application of ITFs resulted in a longer lasting IL-2 serum concentration than did the subcutaneous application of pure IL-2. While at 25,000 IU, the epicutaneous application of ITFs resulted in serum concentrations comparable to those resulting from s.c. application, at 50,000 and 150,000 IU, only 50% and 22.6% of the maximum serum concentration resulting from the s.c. application of pure IL-2 was obtained. Fractionating the transdermal IL-2 application improved uptake. CONCLUSION: We were able to show that biologically active IL-2 can be bonded to TFs up to 75%. It is possible to transport IL-2 through the skin using TFs. Both the concentration-dependent saturation of the TFs with IL-2 and fractionation of the application resulted in differing degrees of transcutaneous IL-2 uptake.

Morbidity of prostatic biopsy for different biopsy strategies: is there a relation to core number and sampling region?

OBJECTIVES: The standard sextant prostatic biopsy is a safe procedure associated with low morbidity. Newer biopsy protocols suggest an increase in core numbers or sampling in distinct areas. In this respect we investigated the morbidity of different biopsy regimens. METHODS: Morbidity was assessed using self-administered questionnaires 1 week and 1 month after biopsy in a prospective randomized trial of 405 men with three different biopsy protocols. We compared a sextant biopsy regimen to a 10-core biopsy strategy, as well as patients with a re-biopsy including t-zone sampling. We investigated pain during and after biopsy, gross hematuria, rectal bleeding, hematospermia, fever and chills. RESULTS: There is a trend towards a more painful biopsy and higher rate of side effects if the number of core samples is increased, this difference did not reach statistical significance. There was no increase in severity of side effects. Regarding the rate and severity of side effects of biopsy strategies to different areas of the prostate we could not find a difference. About 95% of patients would accept a repeat biopsy based on their experience on first biopsy. CONCLUSIONS: Morbidity of transrectal prostatic biopsy is low and increasing the number of cores correlates with a minor and statistically not significant increase in the rate of side effects. Transrectal sextant prostatic biopsy and extensive biopsy protocols are generally well tolerated and widely accepted from patients.