Efficacy of Testosterone Suppression with Sustained-Release Triptorelin in Advanced Prostate Cancer.

INTRODUCTION: Androgen deprivation therapy (ADT) is a mainstay of treatment against advanced prostate cancer (PC). As a treatment goal, suppression of plasma testosterone levels to <50 ng/dl has been established over decades. Evidence is growing though that suppression to even lower levels may add further clinical benefit. Therefore, we undertook a pooled retrospective analysis on the efficacy of 1-, 3-, and 6-month sustained-release (SR) formulations of the gonadotropin-releasing hormone (GnRH) agonist triptorelin to suppress serum testosterone concentrations beyond current standards. METHODS: Data of 920 male patients with PC enrolled in 9 prospective studies using testosterone serum concentrations as primary endpoint were pooled. Patients aged 42-96 years had to be eligible for ADT and to be either naïve to hormonal treatment or have undergone appropriate washout prior to enrolment. Patients were treated with triptorelin SR formulations for 2-12 months. Primary endpoints of this analysis were serum testosterone concentrations under treatment and success rates overall and per formulation, based on a testosterone target threshold of 20 ng/dl. RESULTS: After 1, 3, 6, 9, and 12 months of treatment, 79%, 92%, 93%, 90%, and 91% of patients reached testosterone levels <20 ng/dl, respectively. For the 1-, 3-, and 6-month formulations success rates ranged from 80-92%, from 83-93%, and from 65-97% with median (interquartile range) serum testosterone values of 2.9 (2.9-6.5), 5.0 (2.9-8.7), and 8.7 (5.8-14.1) ng/dl at study end, respectively. CONCLUSION: In the large majority of patients, triptorelin SR formulations suppressed serum testosterone concentrations to even <20 ng/dl. Testosterone should be routinely monitored in PC patients on ADT although further studies on the clinical benefit of very low testosterone levels and the target concentrations are still warranted.

Evaluation of Lymphorrhea and Incidence of Lymphoceles: 4DryField® PH in Radical Retropubic Prostatectomy.

Purpose. To investigate impact of polysaccharide hemostat 4DryField PH (4DF) applied on lymph node dissection area after radical retropubic prostatectomy (RRP) on lymphorrhea and lymphocele (LC) formation. Methods. 104 consecutive patients underwent RRP, 51 without 4DF treatment (CT-group) and 53 with 4DF treatment (4DF-group). Groups were comparable (age, risk profile, and lymph node numbers). Postoperative drain loss (PDL) and development of early and late LC were analyzed (mean follow-up at 7 months: 100%). Results. PDL was 452.5 ± 634.2 mL without and 308.5 ± 214 mL with 4DF treatment. PDL > 1000 mL only occurred in CT-group (5/51). Overall, 45 LC (26 in CT- versus 19 in the 4DF-group) were diagnosed. At day 8, LC were equally distributed between groups. Incidence of late LC, however, was twice in controls (16/51) versus 4DF-patients (8/53). Symptomatic LC (4 in untreated patients, 2 in 4DF-patients) were treated with percutaneous drainage (duration: 45 days in untreated patients versus 12 days in 4DF-patients). Conclusion. Application of 4DF on lymph node dissection areas lessened total drain loss and significantly lowered high volume drain loss. Furthermore, 4DF reduced frequency of late lymphoceles and lymphoceles requiring treatment by half, as well as duration of percutaneous drainage by more than two-thirds.

The Significance of Accurate Determination of Gleason Score for Therapeutic Options and Prognosis of Prostate Cancer.

The Gleason score (GS) to date remains one of the most reliable prognostic predictors in prostate cancer (PCa). However, the majority of studies supporting its prognostic relevance were performed prior to its modification by the International Society of Urological Pathology (ISUP) in 2005. Furthermore, the combination of Gleason grading and nuclear/nucleolar subgrading (Helpap score) has been shown to essentially improve grading concordance between biopsy and radical prostatectomy (RP) specimens. This prompted us to investigate the modified GS and combigrading (Gleason/Helpap score) in association with clinicopathological features, biochemical recurrence (BCR), and survival. Core needle biopsies and corresponding RP specimens from 580 patients diagnosed with PCa between 2005 and 2010 were evaluated. According to the modified GS, the comparison between biopsy and RP samples resulted in an upgrading from GS 6 to GS 7a and GS 7b in 65% and 19%, respectively. Combigrading further resulted in an upgrading from low grade (GS 6/2a) to intermediate grade PCa (GS 6/2b) in 11.1% and from intermediate grade (GS 6/2b) to high grade PCa (GS 7b/2b) in 22.6%. Overall, well-differentiated PCa (GS 6/2a) was detected in 2.8% of RP specimens, while intermediate grade (GS 6/2b and GS 7a/2b) and high grade cancers (≥ GS 7b) accounted for 39.5% and 57.4% of cases, respectively. At a mean follow-up of 3.9 years, BCR was observed in 17.6% of patients with intermediate (9.8%) or high grade PCa (30.2%), while PSA relapse did not occur in GS 6/2a PCa. In conclusion, adding nuclear/nucleolar subgrading to the modified GS allowed for a more accurate distinction between low and intermediate grade PCa, therefore offering a valuable tool for the identification of patients eligible for active surveillance (AS).

The Value of Prognostic Grouping of Prostatic Carcinomas for Urologists and Pathologists.

OBJECTIVES: To improve the prognostic stratification for different therapeutic options of prostatic carcinomas (PCa) with low and intermediate grade by combining Gleason grading with cytological findings and prognostic grade grouping. METHODS: We analyzed PCa after radical prostatectomy using the combined grading of Gleason and Helpap, which allows an exact differentiation particularly of low and intermediate grade tumors. Additionally, we attached time-interval and percentage value of recurrences of prostate-specific antigen (PSA) as well as death on disease (DoD) to the prognostic grade grouping. RESULTS: Carcinomas of group I/V are very low-grade tumors with very good prognosis without biochemical recurrence and DoD predestining for active surveillance (AS). The group II/V with low progress of PSA without DoD allows the options of an active treatment or AS and shows a prognostic separation of the intermediate group III/V. Within the high-grade groups, a differentiation is necessary between GS 7b (4 + 3), 8, and 9-10 regarding TNM staging and rate of DoD. Prognosis of GS 7b (4 + 3) group III/V is more favourable without DoD in contrast to group IV and V/V with cases of DoD. CONCLUSION: Morphologically prognostic classification by using combined grading may improve the prognostic stratification of patients with PCa.

Effects of Marine Phospholipids Extract on the Lipid Levels of Metastatic and Nonmetastatic Prostate Cancer Patients.

High intake of omega-3 fatty acids (n-3 FAs) from fish has shown to reduce metastatic progression of prostate cancer. This clinical trial investigated the influence of high n-3 FA intake (marine phospholipids, MPL) on the FA composition of blood lipids, lysophosphatidylcholine (LPC), and on lipoproteins in prostate cancer patients and elderly men without prostate cancer. MPL supplementation resulted in a significant increase of n-3 FAs (eicosapentaenoic and docosahexaenoic acid) in blood lipids, while arachidonic acid (n-6 FA) decreased significantly. Low density lipoprotein (LDL) and high density lipoprotein (HDL) increased significantly, but the LDL increase was observed only in subjects with an inactive tumour. Similarly, LPC plasma concentration increased significantly only in patients without tumour. The missing increase of LDL and LPC after MPL supplementation in patients with actively growing (metastasizing) prostate cancer suggests that tumour cells have an elevated demand for LDL and LPC. Due to the MPL-induced increase of n-3 FAs in these blood lipids, it can be assumed that especially actively growing and metastasizing prostate cancer cells are provided with elevated amounts of these antimetastatic n-3 FAs. A hypothetic model explaining the lower incidence of metastatic progression in prostate cancer patients with high fish consumption is presented.

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.

A perfused renal human organ culture model: impact of monocyte attack.

BACKGROUND: Key processes of atherosclerosis and restenosis are triggered and/or modified by the contact of human monocytes (MCs) with the inner layers of the arterial vessel wall. This is the first report on monocyte attack in a perfused renal human organ culture model (perfused renal HOC-model). MATERIAL/METHODS: Parts of the renal arteries were extracted during routine nephrectomies. A closed loop system was established by fixing the segments between two hard plastic tubes and connecting the distal endings of the hard plastic tubes with soft plastic tubes. 5x10(5) human MCs were added to the culture medium for a period of 24 h. Immunohistological staining was carried out before adding the MCs and after 2, 24, 48, and 72 hours. RESULTS: Perfusion of the model with culture medium was performed with a steady flow of 1.6 mL/min. One, two, and three days after adding the intravascular MCs, almost no extravascular MCs were detected. Although the number of MCs was merely slightly increased on the endothelium, in the plaque-intima, and in the media, a large number of MCs was detected in the adventitia. During the three-day period of steady flow perfusion, no stimulation of smooth muscle cell proliferation in the artery wall was detected. CONCLUSION: Steady perfusion of the renal HOC-model is an important step in the attempt to adapt human ex vivo models to the various roles of inflammation in the pathophysiology of atherosclerosis and restenosis.

[Diagnostic work-up of the prostate carcinoma]. / Prostatadiagnostik von der rektalen Untersuchung bis zum Tumor-staging. Nichts ubersehen, Fehlalarm vermeiden.

The most important investigation in the diagnostic work-up of prostate carcinoma is the determination of the prostate-specific antigen (PSA) in the serum. The rate of increase in PSA (PSA velocity) may provide valuable additional information. The highest detection rate is achieved using the combination of digital rectal examination (DRE) and PSA determination. Transrectal ultrasound is of importance in particular in the context of biopsy-taking. Nomograms permit an estimation of the local tumor spread and lymph node status. The currently accepted most sensitive method for the detection of bone metastases is scintigraphy. The value of PET in the primary diagnostic work-up has yet to be established.

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.

Human cytomegalovirus infection in human renal arteries in vitro.

Studies with animal cytomegaloviruses, epidemiological data from humans as well as in vitro studies suggest the involvement of the human cytomegalovirus (HCMV) in the development of atherosclerosis. Cell culture systems are insufficient for examination of the entire pathogenetic process and a satisfactory animal model for HCMV is not available. An organ culture model was established for HCMV infection of human renal arteries in vitro. After infection with three representative HCMV strains, infectious virus was recovered from supernatants until 144 days post-infection with a peak around day 30 due to a long-lasting productive HCMV infection in still vital cells. Differences in cell tropism and kinetics of infection were identified between the HCMV strains. Specifically, differences in infecting endothelial cells and virus penetration into the lamina media were observed. In infected artery segments, but also in some non-infected arteries from seropositive donors, HCMV DNA could be localized by in situ PCR. Nevertheless, HCMV early antigen was detected by immunohistochemistry exclusively in artery segments infected in vitro. The new organ culture model will permit the study of functional and molecular consequences of HCMV infection in a more physiological micro-environment.

Effect of endothelin-A receptor blockade with atrasentan on tumor progression in men with hormone-refractory prostate cancer: a randomized, phase II, placebo-controlled trial.

PURPOSE: To evaluate the efficacy and safety of atrasentan (ABT-627), an endothelin-A receptor antagonist, in the treatment of asymptomatic, hormone-refractory prostatic adenocarcinoma. PATIENTS AND METHODS: A double-blind, randomized, placebo-controlled clinical trial of hormone-refractory prostate cancer (HRPCa) patients was conducted in the United States and Europe. Two hundred eighty-eight asymptomatic patients with HRPCa and evidence of metastatic disease were randomly assigned to one of three study groups receiving a once-daily oral dose of placebo, 2.5 mg atrasentan, or 10 mg atrasentan, respectively. Primary end point was time to progression; secondary end points included time to prostate-specific antigen (PSA) progression, bone scan changes, and changes in bone and tumor markers. RESULTS: The three treatment groups were similar in all baseline characteristics. Median time to progression in intent-to-treat (ITT) patients (n = 288) was longer in the 10-mg atrasentan group compared with the placebo group: 183 v 137 days, respectively; (P =.13). Median time to progression in evaluable patients (n = 244) was significantly prolonged, from 129 days (placebo group) to 196 days (10-mg atrasentan group; P =.021). For both ITT and evaluable populations in the 10-mg atrasentan group, median time to PSA progression was twice that of the placebo group (155 v 71 days; P =.002). Patients who received placebo continued to have significant increases from baseline in serum (lactate dehydrogenase [LDH]), a marker of disease burden; elevations in LDH were uniformly attenuated by atrasentan in the ITT population. Headache, peripheral edema, and rhinitis were primary side effects, typically of mild to moderate severity. Quality of life was not adversely affected by atrasentan. CONCLUSION: Atrasentan is an oral, targeted therapy with favorable tolerability and the potential to delay progression of HRPCa.

Suppression of prostate cancer induced bone remodeling by the endothelin receptor A antagonist atrasentan.

PURPOSE: We examined the effects of atrasentan (endothelin-A receptor antagonist) on bone deposition and resorption markers and on bone scan index. MATERIALS AND METHODS: This double-blind, randomized, placebo controlled clinical trial of hormone refractory prostate cancer patients was done at 74 medical centers in the United States and Europe. A total of 288 asymptomatic patients with hormone refractory prostate adenocarcinoma and evidence of metastatic disease were randomized to 1 of 3 treatment groups, namely 2.5 mg. atrasentan, 10 mg. atrasentan or placebo administered orally daily until disease progression. The main outcomes measures were changes in bone deposition markers (total alkaline phosphatase and bone alkaline phosphatase) and bone resorption (N-telopeptides, C-telopeptides and deoxypyridinoline), and in the bone scan index. RESULTS: At baseline markers of bone deposition and resorption were elevated 1.4 to 2.7-fold above respective upper limits of normal. Subjects receiving placebo experienced a 58% elevation in mean total alkaline phosphatase and a 99% elevation in mean bone alkaline phosphatase (p < 0.001), whereas subjects receiving 10 mg. atrasentan maintained stable mean total alkaline phosphatase and bone alkaline phosphatase values compared with baseline. N-telopeptides, C-telopeptides and deoxypyridinoline elevation from baseline were consistently less in patients receiving 10 mg. atrasentan compared with placebo. Similar trends were observed in subjects who received 2.5 mg. atrasentan. Changes in clinical bone scan studies paralleled bone marker changes. CONCLUSIONS: Atrasentan suppressed markers of biochemical and clinical prostate cancer progression in bone and demonstrates clinical activity for hormone refractory prostate cancer.