[en] The results of a dummy run involving nine centers participating in a study comparing radiotherapy alone with radiotherapy plus hormone therapy in patients with high metastatic risk prostatic cancer (EORTC protocol 22863) show that, in all centers but one, patients are treated in the same way. However, they have also indicated that protocol compliance could be improved by a better assessment of the target volume, by taking into account of the use of protective shields and of variations in radiological density, by determining beam position on a large number of slices, and by the use of CT scan images for treatment planning

[en] Purpose/Objective: The purpose of this study is to investigate the potential use of TGFβ1 as a tumor marker to aid in the selection of optimal therapy in patients with prostate cancer and to correlate plasma TGFβ1 levels with prostate specific antigen (PSA). Materials and Methods: 14 consecutive newly diagnosed patients with stage I and II carcinoma of the prostate treated with radiation (RT) alone were enrolled. Plasma samples for TGFβ1 were obtained before RT (pre RT), during the last week of RT (end RT) and at first follow up (6 weeks) after RT (post RT). TGFβ1 was extracted from plasma using an acid-ethanol method. An enzyme linked immunosorbent assay was used to quantify the plasma TGFβ1 levels. The statistical significance was estimated using t-tests. Results: The pre-RT plasma TGFβ1 level (mean±SEM) in prostate cancer patients was 13.7±2.7 ng/ml vs. 4.4±0.2 ng/ml in normal controls (p<0.01). Elevated pre RT TGFβ levels (>7.5 ng/ml) were present in (10(14)) patients. The pre RT PSA was 8.1±0.74 ng/ml, with (13(14)) patients having PSA's >4.0 ng/ml. 11 patients for whom complete PSA and TGFβ data were available were divided into 2 groups by post RT PSA levels. Group A had a post RT PSA>4 ng/ml (6.4 ±0.8 ng/ml, n=5) and group B had a post RT PSA≤4 ng/ml (1.7±0.4 ng/ml, n=6) (left figure). The mean pre RT PSA level in group A was significantly higher than group B (10.0±1.1 vs. 6.4±0.8 ng/ml, p=0.046). While the mean pre RT TGFβ1 level was not significantly different between groups A and B (17.0±6.9 ng/ml vs 12.0±2.0 ng/ml, p=0.38), there was a significant difference in the mean post RT TGFβ1 level (A=20.0±4.1 ng/ml vs B=4.7±1.4 ng/ml, P=0.004). The mean plasma TGFβ1 level in group A did not change significantly at end RT or post RT, however, the mean TGFβ1 level in group B decreased significantly at both end RT (6.0±1.0 ng/ml, p=0.02) and post RT (4.7±1.4 ng/ml, p=0.01). Both the end RT and post RT TGFβ1 levels are tightly correlated with post RT PSA level (right figure). Conclusions: The plasma TGFβ1 level measured during the last week of RT might help identify patients with moderately elevated pre-RT PSA's who will have a good outcome with RT alone. The utility of TGFβ1 as an adjunct to PSA to select patients for RT alone vs RT plus androgen deprivation therapy is currently being studied

[en] Purpose: Androgen deprivation therapy (ADT) is frequently given to men with localized prostate cancer. This study was designed to determine what proportion of men require subsequent ADT if their localized prostate cancer is first treated by radiation. Methods and Materials: A retrospective review of the outcome of 768 men with T1-4NxM0 prostate cancer treated with external beam radiation at a single institution from 1988 to 1995. The median follow-up for the entire group was 5.8 years. The end points analyzed were biochemical failure (3 successive rises in prostate-specific antigen) and ADT (either medical or surgical castration). Results: A total of 322 biochemical failure events occurred among the 768 treated patients, and 187 began ADT during the period of observation. Fifty-four percent of men starting ADT did so without rebiopsy or radiographic evidence of persistent disease. The overall freedom from biochemical failure rate at 10 years was 43.3% and the 10-year freedom from ADT rate was 56.3%. The corresponding values for the most favorable subgroup (T1-2a, Gleason sum 6, prostate-specific antigen ≤10 ng/mL) were 61.8% and 72.8%. Conclusions: Curative therapy is often given to men with prostate cancer and a life expectancy of <10 years, even when a survival gain is not expected. One new measure of its value, if any, may be its efficacy in preventing a subsequent, potentially more morbid, therapy such as ADT. The results of this study showed that most men with early-stage prostate cancer do avoid ADT in the 10 years after radiation therapy. This rate is less than that seen in the few contemporary watchful-waiting series

[en] Epidermal growth factor receptor (EGFR) overexpression has been understood as the major reason for uncontrolled tumor growth in various types of cancers, including head and neck cancer and colorectal cancer. The anti-EGFR monoclonal antibody, cetuximab, specifically binds to the EGFR with high affinity, blocking growth-factor binding, receptor activation and subsequent signal-transduction events leading to cell proliferation. Cetuximab labeled with suitable diagnostic and therapeutic radionuclides has demonstrated clinical significance as molecular imaging and radioimmunotherapy agents. However, in view of improved pharmacokinetics, antigen-binding fragments (Fab) of cetuximab hold much greater promise in development of new-generation of radioimmunotheranostic agent for personalized cancer management. In this study, cetuximab-Fab was generated by enzymatic papain digestion over a period of 16 h maintaining cetuximab/papain ratio ~ 1:40. The reaction mixture was purified from the Fc fragments of cetuximab by passing through Protein-A column. The concentration of cetuximab-Fab in the solution was determined from UV absorbance at 280 nm using UV-Visible spectrophotometer. The purity of cetuximab-Fab generated was established by sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) and matrix-assisted laser desorption/ionization (MALDI) mass spectrometry. The cetuximab-Fab was conjugated with p-SCN-Bn-NOTA and the bioconjugate was separated from the unreacted chelator by size-exclusion chromatography using PD-10 column. The bioconjugate was subsequently labeled with no-carrier-added (NCA) ⁶⁴Cu (T½ = 12.7 h) produced via ⁶⁴Zn (n, p) ⁶⁴Cu reaction in APSARA-U reactor. The radiolabeled agent was purified from the uncomplexed ⁶⁴Cu²⁺ ions by passing through PD-10 column. The radiolabeling yield was 78 ± 3 % and it could be obtained with > 98 % purity after the purification process. ⁶⁴Cu-NOTA-cetuximab-Fab was administered in Swiss mice bearing fibrosarcoma tumor, wherein, it showed rapid tumor uptake (13.1 ± 0.6 %ID/g at 4 h post-injection) with good tumor-to-background contrast and clearance through both renal as well as hepatobiliary routes. Blocking studies carried out with pre-injection of excess cetuximab demonstrated the specificity of the radioimmuoconjugate towards EGFR expression. Overall, this study amply demonstrates the pivotal role of separation science in development of new radiopharmaceuticals for improved cancer care and therefore holds significant promise in the burgeoning nuclear medicine industry

[en] We undertook a retrospective review of patients presenting with apparently localised prostatic carcinoma to a single practitioner for consideration of radiation therapy to clarify the characteristics of those patients who might benefit from the use of neo-adjuvant androgen deprivation. Of 133 patients referred between January 1989 and June 1994, 85 were considered suitable for radical therapy, of whom 31 were treated with hormone therapy prior to radiotherapy, frequently on the basis of an elevated PSA. Increasing PSA levels (p = 0.0016) and Gleason grade (p = 0.026) were independent variables for relapse. It was possible to define three prognostic groups of patients, on the basis of initial PSA and Gleason grade. Those of intermediate risk (PSA < 10 μg/1, Gleason score 8-10; PSA 10-25 μg/l, Gleason 5-7 or 8-10; PSA > 25 μg/l, Gleason score 2-4) had a superior duration of disease-free survival if given initial hormone therapy. This group of patients is potentially the most likely to benefit from such an approach and should be enrolled in prospective randomised studies of neoadjuvant androgen deprivation

[en] Purpose: This study identifies two early prostate cancer populations within the T1/T2AB, Gleason 2-7, pretreatment prostate specific antigen (PSA) 4-15 ng/ml grouping. By demonstrating different outcomes we may be able to more appropriately select a subgroup for whom adjuvant therapy trials or altered treatment techniques are indicated. Materials and Methods: One hundred forty-six patients with T1/T2AB, Gleason score 2-7, PSA 4-15 ng/ml prostate cancer were treated with external beam radiotherapy alone from November 1987 to October 1993. The median pretreatment PSA was 8.6 and the mean 8.7. Minimum follow-up was 2 years with a median of 38 months (mean 42 months, range 24-87). The median age was 70 years (range 58-83) and the median central axis dose delivered was 7240 cGy (mean 7273, range 6541-7895 cGy). Eleven patients received conventional radiotherapy while 135 were treated using conformal techniques. As there is evidence that a low PSA nadir is an early marker for long term biochemical control, time to post treatment PSA < 1 ng/ml was actuarially analyzed by Gleason score, pretreatment PSA, radiation dose, stage, and the presence of perineural invasion. Pretreatment PSA was the only patient characteristic predictive of achieving a PSA level <1.0 ng/ml. Biochemical relapse free (bNED) control (non rising PSA) was then compared for patients above and below the approximate median pretreatment PSA level of 8 ng/ml. bNED control rates and the time to PSA <1.0 ng/ml were estimated using Kaplan-Meier methodology, and differences in bNED control and PSA <1.0 ng/ml according to PSA level were evaluated using the log-rank test. Results: Results from actuarial analysis revealed that pretreatment PSA was the only significant variable predictive of a PSA <1.0 ng/ml. Ninety-eight percent of patients with pretreatment PSA <8 achieved a PSA level <1.0 ng/ml within 3 years compared to 78% for patients with a PSA >8 ng/ml (p = 0.0003). bNED control for the two groups separated at a pretreatment PSA of 8 ng/ml confirms a favorable outcome, 88% bNED control at 5 years for <8 ng/ml and 74% for a pretreatment PSA ≥8 ng/ml (p = 0.007 for overall curve comparison). Conclusion: For early prostate cancer patients (T1/T2AB, Gleason 2-7, pretreatment PSA 4-15) there is a significant break in bNED control following external beam radiation at a pretreatment PSA level of 8 ng/ml. Patients with pretreatment PSA <8 have a very favorable bNED response with radiation alone while those with a pretreatment PSA 8-15 have a significant decrease in bNED response. The 27% failure rate at 5 years in the PSA 8-15 ng/ml patients may justify altered treatment techniques or clinical trials of adjuvant androgen deprivation in this group

No abstract available

[en] Highlights: • PEDF expression is detected in epididymal tract of male rats. • PEDF expression was not detected in rat testes. • PEDF expression was decreased by using flutamide. • PEDF expression was recovered after flutamide cessation. Pigment epithelium derived factor (PEDF) expression has been described in many organs as showing neurotrophic, anti-angiogenic, anti-apoptotic, anti-inflammatory, anti-oxidant and pro-cell survival properties. However, references to its activity in the male reproductive system are scarce. We aimed to characterize the expression of PEDF in the male reproductive tract of Wistar rats by using RT-PCR, western blot and immunostaining and also evaluate the effect of flutamide in PEDF expression. We found that PEDF is expressed in the epididymis, prostate and seminal vesicles in Wistar rats, but notably not in the testes. Under the effect of flutamide PEDF expression decreased, recovering by suppressing the antiandrogen. The epididymis is an essential organ in sperm maturation-storages. The role of PEDF in this physiological process has not been fully elucidated yet, but considering that in other systems PEDF has anti-apoptotic, anti-oxidants and pro-cell survival properties, its expression along the epididymis could play a role in the protection of spermatozoa while they are stored.

[en] Purpose: To compare, by a secondary analysis, the therapeutic benefits of androgen suppression in protocol prostate cancer patients with relapse after radiotherapy (RT) for locally advanced disease who, in the Phase III trial beginning in 1987, were assigned to receive or not receive a short course of neoadjuvant maximal androgen suppression before definitive RT. Methods and Materials: Between 1987 and 1991, 456 patients were entered in the Radiation Therapy Oncology Group trail 86-10 and randomized to receive (Arm I) or not to receive (Arm II) neoadjuvant hormonal therapy (HT), which was 4 months of goserelin (3.6 mg every 4 weeks) and flutamide (250 mg t.i.d.) before and during RT for bulky T2-T4 tumors. The overall and disease-specific survival after both randomization and salvage HT for patients with relapse was evaluated, as well as the duration of response in those patients undergoing salvage HT. The outcomes in patients who had received neoadjuvant HT vs. those who had not were compared. The median follow-up after randomization for all alive patients was 9.0 years and was 5.5 years for alive patients after beginning salvage HT. Results: Fewer patients received salvage HT on Arm I than on Arm II (45% vs. 63%, p<0.001). The outcomes by randomized treatment arm (I vs. II) from the time of beginning salvage HT were similar. At 5 years after salvage HT, the overall survival rates were 41% and 41% and the disease-specific survival rates were 50% and 50%. At 8 years after randomization, the overall survival rates were 47% and 44% and the disease-specific survival rates were 55% and 56%. Conclusion: Although a 4-month course of neoadjuvant and concurrent maximum androgen suppression and RT (compared with RT alone) significantly increases the freedom from relapse rate and freedom from receiving salvage HT, it does not compromise the long-term beneficial effect of subsequent salvage HT, if needed for relapse. These findings with long follow-up in patients treated for locally advanced disease diagnosed 9-14 years previously should help allay concerns of the possible development of 'resistance' to androgen suppression when 4-month courses of neoadjuvant HT are used before primary treatment

[en] Recruitment of cofactors in the interaction of the androgen receptor (AR) and AR ligands plays a critical role in determining androgenic/antiandrogenic effects of the AR ligand on signaling, but the functions of key cofactors, including nuclear receptor coactivator (NCOA), remain poorly understood in prostate cancer cells treated with AR ligands. We examined prostate cancer cell lines LNCaP and VCaP expressing mutated and wild-type ARs, respectively, to clarify the significance of NCOAs in the effect of antiandrogens. Hydroxyflutamide showed antagonistic activity against VCaP and an agonistic effect on LNCaP. Bicalutamide served as an antagonist for both. We analyzed mRNA transcription and protein expression of NCOAs in these cells pretreated with dihydrotestosterone and thereafter treated with the mentioned antiandrogens. Transcriptional silencing of candidate NCOAs and AR was performed using small interfering RNA (siRNA). Cell proliferation was evaluated with MTT assay. LNCaP treated with bicalutamide showed an about four-fold increase in the expression of NCOA2 mRNA compared to those pretreated with dihydrotestosterone alone (P <0.01). In VCaP pretreated with dihydrotestosterone, transcriptions of NCOA2 and NCOA7 were slightly increased with bicalutamide (1.96- and 2.42-fold, respectively) and hydroxyflutamide (1.33-fold in both). With Western blotting, the expression of NCOA2 protein also increased in LNCaP cells treated with bicalutamide compared with that in control cells pretreated with dihydrotestosterone alone. Following silencing with siRNA for NCOA2, PSA levels in media with LNCaP receiving bicalutamide were elevated compared with those in non-silencing controls (101.6 ± 4.2 vs. 87.8 ± 1.4 ng/mL, respectively, P =0.0495). In LNCaP cells treated with dihydrotestosterone and bicalutamide, NCOA2-silencing was associated with a higher proliferation activity compared with non-silencing control and AR-silencing. NCOA2, which has been thought to be recruited as a coactivator, possibly plays a corepressive role in AR of prostate cancer cells when treated with antiandrogens, suggesting its potential as a therapeutic target. The online version of this article (doi:10.1186/s12885-016-2378-y) contains supplementary material, which is available to authorized users