G-protein beta3 subunit gene (GNB3) variant in causation of essential hypertension

OBJECTIVES: To evaluate the response of testicular androgen ablation in patients with advanced prostate cancer with a biochemical recurrence after finasteride or combined finasteride and flutamide therapy. METHODS: Eighteen hormone na?ve men with advanced prostate cancer (10 with detectable prostate-specific antigen [PSA] levels after radical prostatectomy, 4 with rising PSA levels after definitive radiation therapy, and 4 with Stage D2 disease) were treated with finasteride (5 mg/day) alone or in combination with flutamide (250 mg three times a day). All men experienced an initial reduction in serum PSA, but later had treatment failure with two consecutive rising PSA measurements. All men were then treated with testicular androgen ablation (bilateral orchiectomy in 15 and luteinizing hormone-releasing hormone analogue in 3). RESULTS: Overall, serum PSA declined by more than 80% in 15 (83%) of 18 and to undetectable levels in 14 (78%) of 18. With a median+/-semi-interquartile range follow-up of 22+/-14.5 months from the initiation of hormone therapy, 12 (67%) of 18 currently have undetectable PSA levels. Two men having rising serum PSA levels above 100 ng/mL and 1 man has died from complications of metastatic prostate cancer. CONCLUSIONS: Testicular androgen ablation effectively lowers serum PSA levels in most men with advanced prostate cancer who have experienced a biochemical recurrence despite initial response and subsequent relapse on finasteride or combined finasteride and flutamide therapy.     

Pathologic seminal vesicle invasion after radical prostatectomy for patients with prostate carcinoma: effect of early adjuvant radiation therapy on biochemical control

BACKGROUND: The authors evaluated the effect of postoperative radiation therapy on freedom from biochemical failure (bNED) in men with prostate carcinoma who had pathologic seminal vesicle invasion after radical prostatectomy and negative pelvic lymph node dissection (pT3cN0). METHODS: Between 1989 and 1995, 375 men underwent radical prostatectomy at Thomas Jefferson University Hospital. Fifty-three men (13%) had pT3cN0 prostate carcinoma and were the subject of this analysis. Men in whom prostate specific antigen (PSA) could not be detected were deemed free of biochemical failure. RESULTS: Of the 53 men with pT3cN0 prostate carcinoma, 18 had an elevated PSA immediately after surgery and received salvage radiation therapy (RT). The 3-year bNED rate for this group was only 38%. At 3 months, PSA could not be detected in the other 35 men. Fifteen of those 35 men underwent early adjuvant RT, and the other 20 were observed for biochemical failure. The 3-year bNED rate for the 15 patients treated with immediate adjuvant RT was 86%, compared with 48% for the 20 men who were observed (P = 0.01). CONCLUSIONS: These data suggest that early adjuvant RT for men with pT3cN0 prostate carcinoma and no detectable PSA postoperatively reduces the likelihood of future biochemical failure. Men with pT3cN0 prostate carcinoma and a persistently elevated postoperative PSA level are less likely to benefit from RT and should be considered for systemic therapy.     

Comparison of percent free prostate specific antigen and prostate specific antigen density as methods to enhance prostate specific antigen specificity in early prostate cancer detection in men with normal rectal examination and prostate specific antigen between 4.1 and 10 ng./ml

PURPOSE: We analyzed the behavior of prostate specific antigen (PSA) density and percent free PSA to enhance the specificity of PSA in the early diagnosis of prostate cancer in men with normal digital rectal examination and PSA serum level between 4.1 and 10 ng./ml. MATERIALS AND METHODS: PSA serum level, PSA density and percent free PSA were analyzed in 74 men with normal digital rectal examination and PSA serum level between 4.1 and 10 ng./ml. All men underwent systematic prostate biopsy, and the diagnosis was benign prostate hyperplasia in 52 and prostate cancer in 22. Furthermore, we determined the decrease in unnecessary biopsies and the cancer detection rate using 0.10 versus 0.15 as cut points for PSA density, and 20 versus 25 as cut points for percent free PSA. RESULTS: In patients with benign prostatic hyperplasia and prostate cancer, respectively, the median PSA level was 6.7 and 7.0 ng./ml. (p > 0.05), median prostate volume was 50 and 37 cc (p < 0.04), median PSA density was 0.14 and 0.19 (p < 0.007) and median percent free PSA was 18.9 and 10.1 (p < 0.005). Using PSA density cut points of 0.15 and 0.10, the decrease in negative biopsies was 53.8 and 36.5% with a sensitivity of 86.4 and 90.9%, respectively. However, using percent free PSA cut points of 20 and 25, the decrease in negative biopsies was 36.5 and 26.9% with a sensitivity of 77.3 and 95.5%, respectively. CONCLUSIONS: Although both methods could minimize unnecessary biopsies in men with normal digital rectal examination and PSA serum level between 4.1 and 10 ng./ml., the percent free PSA was more cost-effective since transrectal ultrasound was not required. In this small series of symptomatic patients a percent free PSA cut point of 25 could detect at least 95% of prostate cancers and decrease 26.9% of negative biopsies.     

Finasteride and flutamide as potency-sparing androgen-ablative therapy for advanced adenocarcinoma of the prostate

OBJECTIVES: Androgen ablation with luteinizing hormone-releasing hormone (LHRH) agonists, orchiectomy, or oral estrogens has significant untoward sexual side effects. We evaluated a combination of finasteride and flutamide as potency-sparing androgen ablative therapy (AAT) for advanced adenocarcinoma of the prostate. In addition, we evaluated whether finasteride provided additional intraprostatic androgen blockade to flutamide. METHODS: Twenty men with advanced prostate cancer were given flutamide, 250 mg orally three times daily. Serum prostate-specific antigen (PSA) values were measured weekly. At a nadir PSA value, finasteride, 5 mg orally every day, was added. PSA values were then measured weekly until a second nadir PSA value was achieved. Sexual function was evaluated at baseline, at the second nadir PSA value, and every 3 months thereafter. Testosterone, dihydrotestosterone (DHT), and dehydroepiandrostenedione (DHEA) levels were measured at baseline and at the first and second nadir PSA values. RESULTS: The median follow-up period was 16.9 months. Therapy failed in 1 patient with Stage D2 disease at 12 months, but an additional response to subsequent LHRH agonist therapy was observed. One patient developed National Cancer Institute grade 3 diarrhea and was withdrawn from the study. Seven of 20 men developed mild gynecomastia, and 3 of 20 developed mild transient liver function test elevations. Mean PSA levels were 94.6 +/- 38.2 ng/mL at baseline and 7.8 +/- 2.7 and 4.7 +/- 2.2 ng/mL at the first and second PSA nadir values, respectively (P = 0.034). Mean percent decline in PSA value from baseline was 87.0 +/- 3.1% with flutamide alone and 94.0 +/- 1.9% with both flutamide and finasteride (P = 0.001). Eleven of 20 men were potent at baseline. At the second nadir PSA value, 9 (82%) of 11 were potent, whereas 2 (18%) of 11 were impotent. With longer follow-up (median 16.4 months), 6 (55%) of 11 men were potent, 2 (18%) of 11 were partially potent, and 3 (27%) of 11 were impotent. With flutamide alone, testosterone rose a mean of 77 +/- 14.7% of baseline (P = 0.0001), DHEA fell a mean of 32.4 +/- 4.6% (P = 0.0001), and DHT was unchanged. With the addition of finasteride, testosterone rose another 14 +/- 6% (P = 0.06, not significant), DHEA was unchanged, and DHT fell a mean of 34.8 +/- 4.7% (P = 0.0009). CONCLUSIONS: Finasteride and flutamide were safe and well tolerated as AAT for advanced prostate cancer. Finasteride provided additional intraprostatic androgen blockade to flutamide, as measured by additional PSA suppression. Sexual potency was preserved initially in most patients, although there was a reduction in potency and libido in some patients on longer follow-up. Further evaluation of this therapy is needed.     

Ten-year disease free survival after transperineal sonography-guided iodine-125 brachytherapy with or without 45-gray external beam irradiation in the treatment of patients with clinically localized, low to high Gleason grade prostate carcinoma

BACKGROUND: The authors report observed 10-year brachytherapy results in the treatment of 152 consecutive patients with clinically organ-confined prostate carcinoma. METHODS: One hundred and fifty-two consecutive patients with T1-T3, low to high Gleason grade, prostate carcinoma were treated between January 1987 and June 1988 at Northwest Hospital in Seattle, Washington. Their median age was 70 years (range, 53-92 years). Of these 152 patients, 98 (64%) received an iodine-125 implant alone (Group 1), and the remaining 54 patients (36%), who were judged to have a higher risk of extraprostatic extension, also were treated with 45 gray (Gy) of external beam irradiation to the pelvis (Group 2). No patient underwent lymph node sampling, and none received androgen ablation therapy. Multivariate regression and the Mann-Whitney rank sum test were used for statistical analysis. Preoperative patient data with associated success or failure outcomes at 10 years after treatment were used for training and validating a back-propagation neural network prediction program. RESULTS: The average preoperative prostate specific antigen (PSA) value, clinical stage, and Gleason grade were 11.0 ng/mL, T2, and 5, respectively. The median posttreatment follow-up was 119 months (range, 3-134 months). Overall survival 10 years after treatment was 65%. At last follow-up only 3 of the 152 patients (2%) had died of prostate carcinoma. Ninety-seven patients (64%) remained clinically and biochemically free of disease at 10 years of follow-up and had an average PSA value of 0.18 ng/mL (range, 0.01-0.5 ng/mL). In these patients a period of 42 months was required to reach the average PSA (0.5 ng/mL). The median to last PSA follow-up was 95 months (range, 3-134 months). Postoperative needle biopsies were negative in 56% of patients, positive in 15% of patients, and not available in 29% of patients. Only 6% of patients developed bone metastasis. At 10 years there was no statistically significant difference in treatment outcome between patients who received iodine-125 alone, and those who received iodine-125 with 45-Gy external beam irradiation (P = 0.08). Nevertheless, in these two groups preoperative PSA, stage, and Gleason grade were significantly different (P < 0.01). In the artificial neural network analysis, pretreatment serum PSA was the most accurate predictor of disease-free survival. CONCLUSIONS: Percutaneous prostate brachytherapy is a valid and efficient option for treating patients with clinically organ-confined, low to high Gleason grade, prostate carcinoma. Observed 10-year follow-up documents serum PSA levels superior to those reported in several published external beam irradiation series, and comparable to those published in a number of published radical prostatectomy series.     

Hepatocyte growth factor activator: a possible regulator of morphogenesis during fetal development of the rat gastrointestinal tract

PURPOSE: Cryosurgical ablation of the prostate is a novel therapeutic modality that induces cell lysis in the prostate by direct application of low temperatures. We have been conducting an ongoing prospective pilot study of the use of cryosurgical prostate ablation in treating patients with nonmetastatic prostate adenocarcinoma since January 1993. Results in 145 consecutive patients with mean 36 months and minimum 12 months of followup are presented. MATERIALS AND METHODS: Accrual was open to patients with clinical stages T1a to T3c prostate adenocarcinoma. Pelvic lymph node dissections were recommended but not required for patients with prostate specific antigen (PSA) greater than 15 ng./ml. before study entry. PSA changes, random prostate biopsy findings and morbidities after cryosurgical prostate ablation were recorded for each patient. RESULTS: Overall actuarial rates at 42 months for maintaining PSA less than 0.3 and less than 1.0 were 59% and 66%, respectively. The overall actuarial progression-free rate at 60 months was 56%. Among 160 biopsies performed 16% showed some evidence of residual carcinoma. Overall crude rates of maintaining either a negative biopsy or PSA less than 0.3 at 6 and 24 months after cryosurgical prostate ablation were 87% and 73%, respectively. Significantly higher morbidities were seen in previously radiated patients undergoing cryosurgical prostate ablation compared to those with no prior radiation. Among nonradiated patients 85% experienced no significant morbidity after cryosurgical prostate ablation. CONCLUSIONS: Although preliminary, short-term outcomes after cryosurgical prostate ablation appear to be comparable to identical outcomes reported for external beam radiotherapy. Based on these results cryosurgical prostate ablation appears to be an effective therapeutic alternative for treating patients with localized prostate adenocarcinoma.     

Genetic alterations in the development of mammary and prostate cancer in the C3(1)/Tag transgenic mouse model

PURPOSE: Finasteride therapy for benign prostatic hyperplasia (BPH) results in a marked lowering of serum prostate specific antigen (PSA) levels. However, little is known about the effect of finasteride on unbound or free serum levels of PSA. Such information would be important since percent free PSA may substantially improve the cancer specificity of PSA testing. Thus, we prospectively studied the effect of finasteride therapy on total and free serum PSA levels. MATERIALS AND METHODS: In a randomized, placebo controlled, double-blind trial 40 men with histologically confirmed BPH (age range 52 to 78 years) were treated with either 5 mg. finasteride daily (26 patients) for 9 months or placebo (14) for 6 months. Prostate volume was assessed by transrectal ultrasound. Serum levels of free and total PSA were measured from archived serum samples stored at -70C at baseline and for as long as 9 months of treatment. RESULTS: In the finasteride group mean total PSA levels declined from 3.0 ng./ml. at baseline to 1.5 ng./ml. after 6 months of treatment (50% decrease, p <0.01). In the placebo group, with similar baseline levels, no significant change was observed. PSA density declined significantly in finasteride treated men (p <0.01) but not in men receiving placebo. The mean percent free PSA (13 to 17% at baseline) was not altered significantly by finasteride or placebo. CONCLUSIONS: Total PSA serum levels decreased by an average of 50% during finasteride therapy but percent free PSA did not change significantly. This information is potentially useful in the interpretation of PSA data used for early detection of prostate cancer in men receiving finasteride. However, further studies are required to demonstrate the use of percent free PSA to detect the development of cancer.     

Prostate-specific antigen and its complexes with alpha 1-antichymotrypsin in the plasma of patients with prostatic disease

OBJECTIVE: To improve the specificity and sensitivity of the prostate-specific-antigen (PSA) assay for the distinction between prostate cancer and benign prostate hyperplasia (BPH). METHODS: Two sensitive immunoassays, one that measures free PSA and PSA complexed to alpha 1-antichymotrypsin (alpha 1-ACT) with the same efficiency (PSAag assay) and another that specifically measures the complex between PSA and alpha 1-ACT, have been designed to measure the PSA forms in the plasma of 84 patients with prostate disease and in the seminal plasma from 60 healthy individuals. RESULTS: The proportion of plasma PSA in complex with alpha 1-ACT was significantly higher in the 34 patients with prostate cancer (89 +/- 12%, mean +/- SD; median, 91%) than in the 50 patients with BPH (71 +/- 12%; 73%) and did not correlate with the total amount of PSA. Normal seminal plasma (n = 60) had 2.1 +/- 0.6 mg/ml PSA, 175 +/- 62 microns/ml alpha 1-ACT and 9.6 +/- 3.4 micrograms/ml PSA: alpha 1-ACT complex. CONCLUSION: These results confirm that PSA: alpha 1-ACT may be a good marker for a differential diagnosis of carcinoma of the prostate and BPH.     

Antiandrogen suppression syndrome in patients with hormone-resistant cancer of the prostate

OBJECTIVE: To analyze the evolution of serum prostate specific antigen (PSA) levels and the clinical response following the suppression of the antiandrogen in patients with metastatic prostate cancer who undergo complete androgen blockade in a hormone refractory status. MATERIAL AND METHODS: 19 patients were evaluated. Following flutamide suppression, their PSA serum levels were measured monthly and the subjective clinical response assessed. Additionally, the objective clinical response was also assessed at three months. RESULTS: In 11 patients (57.9%), PSA serum concentration continued to increase and no clinical response was seen in any of them. In the 8 remaining cases (42.1%) there was a decrease in PSA serum levels ranging between 2.1 and 84.5%; this decrease was greater than 50% in 5 patients (26.3%). Mean duration of the biochemical response was 4.5 months (2-11). Subjective clinical responses were reported in 5 patients (26.2%), while an objective clinical response was seen in 2 (10.5%) cases who had PSA reductions greater than 50% and were maintained for periods of over 6 months. CONCLUSIONS: Antiandrogen suppression in patients with hormone refractory prostate cancer with complete hormone blockade, can result in considerable albeit short biochemical and clinical responses. For this reason, this should be considered as the first therapeutical approach, whereas in responder patients any other second line treatment could be delayed until a new PSA increase or symptomatic worsening is detected.     

Antitumor activity of suramin in hormone-refractory prostate cancer controlling for hydrocortisone treatment and flutamide withdrawal as potentially confounding variables

BACKGROUND: A prospective Phase II clinical trial was conducted to assess the clinical activity of a pharmacokinetically guided suramin regimen in patients who had documented progression of metastatic prostate cancer after hydrocortisone plus antecedent or simultaneous withdrawal of flutamide. METHODS: Fifty-four patients whose disease had progressed after castration and flutamide administration were enrolled on this trial. The study was divided into two parts. Initially, 52 patients received hydrocortisone (30 mg/day) and for those patients receiving flutamide, at study entry (34 patients) flutamide was simultaneously discontinued. Forty-three patients whose disease progressed on hydrocortisone received suramin for 6-8 weeks. Six patients who progressed on hydrocortisone became ineligible for suramin due to clinical deterioration, four patients are still responding to hydrocortisone at more than 1 year, and one patient elected to postpone initiation of suramin. Suramin was given as intermittent infusions at fixed doses on days 1-5 and thereafter dosing was guided by adaptive control with feedback to maintain plasma suramin concentrations between 300-175 micrograms/ml. Antitumor activity was assessed by prostate specific antigen (PSA) decline and soft-tissue disease response. RESULTS: Ten patients (19%; 95% CI, 9.6%-32.5%) responded to hydrocortisone therapy with either a 50% or greater PSA decline for at least 4 weeks (9 patients) and/or a partial response of measurable soft-tissue disease (2 patients). Five of these patients (10%) demonstrated a 80% or greater PSA decline. All responders to hydrocortisone had simultaneous flutamide withdrawal, and had been receiving flutamide as part of initial combined androgen blockade. Seven of 37 evaluable patients (19%; 95% CI, 8.0%-35.2%) responded to suramin with a 50% or greater decline in PSA for 4 weeks or longer. One patient (3%) had a 80% or greater decline in PSA. There were no soft-tissue disease responses to suramin. The median time to progression was 1.9 months for hydrocortisone therapy and 2.6 months for suramin therapy. The median survival for all patients was 14.6 months. CONCLUSION: Suramin has antitumor activity in metastatic prostate carcinoma independent of the therapeutic effect of hydrocortisone administration or flutamide withdrawal. The role of prior flutamide withdrawal and hydrocortisone replacement should be taken into account in future studies of suramin.     

Prognostic implications of prostate-specific antigen in patients with locally advanced prostate cancer treated with high energy neutron beam therapy: preliminary results

Serial serum prostate-specific antigen (PSA) levels were analyzed retrospectively for prognostic implications in 70 patients with locoregional (Stages B2, C, and D1) prostate cancer who were managed with high energy neutron beam therapy. Three groups of patients were identified. Group I included 30 patients whose serum PSA level decreased to the reference range (0-4 ng/mL) following neutron therapy and remained so subsequently: 28 (93%) remained disease-free and 2 (7%) have failed distantly. All 30 patients (100%) had no evidence of locally progressive disease. This group was categorized as having a good prognosis. The mean time for serum PSA value to decline to reference range was six months; calculated mean time to achieve a stable base-line PSA was 53 +/- 37 days. Follow-up period ranged from twelve to fifty-six months (median: 21 months). Group II consisted of 13 patients in whom there was an initial decrease in serum PSA to reference range followed by a subsequent increase: 6 of 13 (46%) have no overt clinical progression of disease; 7 (54%) have either persistent locoregional or distant metastatic disease. Follow-up period was from twelve to seventy-two months (median: 39 months). Calculated mean time to achieve stable baseline PSA for serum PSA in this group was 61 +/- 21 days. Group III patients had a persistently elevated or rising serum PSA concentration. Of 27 patients in this group, only 9 (33%) have no evidence of disease progression, while 18 patients (67%) have failed already, either locoregionally or distantly. Follow-up period ranged from twelve to sixty-nine months (median: 21 months). Mean time to achieve stable baseline of serum PSA in this cohort of patients with a poor prognosis was 108 +/- 76 days. We conclude that PSA has a predictable prognostic value in patients with locally advanced prostate cancer managed with high energy neutron beam therapy. Rapid normalization of PSA after therapy indicates a good prognosis. Persistent elevation signifies either presence of persistent locoregional disease or development of distant metastases. Subsequent elevation of the serum PSA concentration after definitive therapy signals progression of prostate cancer.     

A worse prognosis for men with testicular atrophy at therapeutic orchiectomy for prostate carcinoma

BACKGROUND: The significance of testicular atrophy at the time of therapeutic orchiectomy for prostate carcinoma has not been examined even though pretreatment hypogonadism has been associated with poor prognosis during chemical androgen ablation for these tumors. METHODS: Survival after therapeutic orchiectomy was determined for 78 men with prostate carcinoma and related to the histologic severity of testicular atrophy. Included in analysis were the presence or absence of prior radiation therapy, tumor grade and stage at diagnosis, host age, obesity, and smoking habits. RESULTS: Among 35 men who underwent therapeutic orchiectomy for progressive disease after primary radiation therapy to the prostate bed, the 25 men with testicular atrophy had worse 5-year, tumor specific, postorchiectomy survival than the 10 men without testicular atrophy (30% vs. 89%) (P=0.02). These 25 men had tumors of more advanced stage and greater undifferentiation at the time of diagnosis an average of 45 months before orchiectomy, but neither characteristic was related to postorchiectomy survival. Among 25 men with Stage D2 disease (American Urologic Association staging system) with orchiectomy as the primary treatment, the 7 men with testicular atrophy more often had undifferentiated tumors and had lower 2-year tumor specific survival than the 18 men without atrophy (43% vs. 72% ) (P > 0.10). CONCLUSIONS: Testicular atrophy at the time of therapeutic orchiectomy for prostate carcinoma is associated with poor postorchiectomy prognosis in men with prior prostate bed radiation therapy and perhaps in men without prior radiation. The association may reflect a high frequency of inherently more aggressive tumors (often relatively nonandrogen-dependent) among those tumors that are progressing in hypogonadal men.     

Prostate specific antigen in the expressed prostatic fluid of men with benign prostatic hyperplasia and prostate carcinoma

PURPOSE: We tested the hypothesis that the histochemically demonstrated prostate specific antigen (PSA) content of prostate carcinoma cells does not necessarily reflect PSA production and secretion by evaluating expressed prostatic fluid. MATERIALS AND METHODS: Expressed prostatic fluid and serum from 152 men with clinical benign prostatic hypertrophy (BPH), 132 with histologically proved BPH and 46 with prostate carcinoma were analyzed with the Hybritech PSA assay. RESULTS: Expressed prostatic fluid PSA levels from carcinoma patients (median 1.70 mg./ml., mean 2.25) were significantly higher than in the histologically proved BPH group (median 1.28 mg./ml., mean 1.42, p < 0.05). CONCLUSIONS: PSA concentration is increased in the expressed prostatic fluid of prostates of men with carcinoma compared to those with histological BPH. This finding may be a functional manifestation of a field change or paracrine effects within the prostate.     

Optimization of arbitrarily primed polymerase chain reaction (AP-PCR)-based DNA fingerprinting of Mycobacterium tuberculosis and its clinical application

OBJECTIVE: External irradiation is an accepted curative treatment modality for patients with localized prostatic tumor. The 15-year results in patients treated by radical irradiation alone are presented. The determinant prognostic factors for local tumor control and disease free survival are analyzed. METHODS: 135 patients with a histologically confirmed localized carcinoma of the prostate were treated at our department from May 1972 to January 1998. Fifty patients received Co-60 therapy; the linear accelerator and high energy photons were utilized in the remaining 80 patients. By tumor stage, 53 patients were B1, 49 B2 and 33 C. The mean follow-up was 61 months (range 1-180). Most patients were exposed to localized fields of irradiation; dose ranged from 50-74 Gy, fractionated at a dose of 180-200 cGy/day. RESULTS: Overall local tumor control was 77% at 5 years and 73% at 15 years, with a disease free survival of 63% and 45% at 5 and 15 years, respectively. Local tumor control at 13 years was 71% for stage B1, 82% for B2 and 70% for C. The disease free survival at 13 years for stages B1, B2 and C were 46%, 49% and 36%, respectively. The BD and MD tumors had a 15-year disease free survival of 48% vs 32% for the PD tumors (p = 0.005). Patients with PSA < or = 20 ng/ml before treatment showed a disease free survival of 87% vs 48% for those with PSA > 20 ng/ml ((p = 0.011). Multivariate analysis showed dose to be a determinant prognostic factor for local tumor control (0.0432); dose and histological grade were determinants for disease free survival (p = 0.029 and 0.033). CONCLUSIONS: This retrospective study found dose to be a determinant prognostic factor for local tumor control and both dose and histological grade were determinants for disease free survival. Radiotherapy is a therapeutic option for these patients. The results can be enhanced if the dose delivered to the prostate can be increased while maintaining the complication rate within the same ranges.     

Comparison of the efficacy and bioequivalence of two oral formulations of tiludronate in the treatment of Paget''s disease of bone

BACKGROUND: There has been a resurgence of interest in cryosurgical ablation of the prostate for the treatment of carcinoma. This is due to recent advances in cryosurgical technology, which have resulted in relatively lower morbidity. The objective of this study was to evaluate the effectiveness of ultrasound-guided cryosurgical ablation of prostate carcinoma. METHODS: Eighty-three patients who had biopsy-proven prostate carcinoma underwent cryosurgical ablation of their entire prostate gland. The initial group of 12 patients had their procedures performed under ultrasound guidance only. The other 71 patients had cryosurgery performed with temperature monitoring in combination with ultrasound guidance. Twelve patients who had positive biopsies underwent a second cryosurgical procedure. All patients had prostate specific antigen (PSA) levels measured at 3, 6, 12, 18, 24, and 30 months after cryosurgery. Ultrasound-guided sextant biopsies were performed at 3-6, 12-18, and 24 months. RESULTS: The median PSA dropped by 95%, from a preoperative value of 4.3 ng/mL to 0.2 ng/mL 30 months after cryosurgery. The authors experienced a high failure rate (positive biopsies) of 83% for the initial group of 12 patients who did not have temperature monitoring during the cryosurgical procedure. This was in contrast to a success rate of 90% (negative biopsies) for the next 71 patients, who did have temperature monitoring (P < 0.05, chi-square test). Twelve patients underwent a second cryosurgery, and the success rate for this group was 91% (11 of 12 patients). The combined success rate for both the first cryosurgery and the second was 94% (62 of 77 patients). Complications included urethral sloughing, urinary incontinence, impotence, bladder neck contracture, and bladder contracture. The majority of patients recovered rapidly from their cryosurgical procedures and were able to resume normal activities 3-4 weeks afterward. CONCLUSIONS: These preliminary results demonstrate that cryosurgical ablation of the prostate is a viable treatment option for prostate carcinoma. In the authors' experience, ultrasound alone may not be adequate for monitoring the entire cryosurgical procedure. The authors found that temperature monitoring shortened their learning curve, enabled them to freeze prostate tissue more aggressively, and may have contributed to their overall success.     

Contemporary hormonal management of advanced prostate cancer

The traditional definition of "advanced" prostate cancer includes only patients with widespread osteoblastic or soft-tissue metastases (clinical or pathologic stage T any N any M1; or stage D2). Current evidence indicates that this definition should be broadened. Because many patients with T3 disease or local lymph node metastases progress to distant metastases, the concept of advanced prostate cancer should also include stages C and D1 (T3, T4, and any T N1). Furthermore, based on pretreatment prostate-specific antigen (PSA) levels, many men treated for clinically localized disease will progress rapidly and, depending on their age and general health, should be included in the advanced-disease category. Also, using prognostic marker modeling with PSA, tumor grade, and other factors, recurrences can be predicted even earlier in many cases. This may be particularly significant in light of recent clinical data indicating that early androgen ablation therapy delays disease progression and improves survival in patients with advanced (M0 or M1) disease. The luteinizing hormone-releasing hormone (LHRH) agonists have become the preferred method of androgen ablation in patients with advanced prostate cancer. Use of an LHRH agonist, alone or combined with an antiandrogen, is more acceptable to many patients than orchiectomy and lacks the potential cardiotoxicity associated with estrogens. Combined hormonal therapy remains controversial but may provide a modest survival benefit, especially in men with minimal metastatic disease. Intermittent hormonal therapy has great appeal, particularly because of the potentially deleterious effects of long-term hormonal therapy; however, its efficacy has yet to be proven.     

Histological presence of viable prostatic glands on routine biopsy following cryosurgical ablation of the prostate

PURPOSE: Cryosurgical ablation of the prostate has recently received much attention as a therapeutic alternative for the treatment of localized prostatic adenocarcinoma. Biopsies after treatment reveal a variety of dysplastic changes as well as unaltered prostatic glandular epithelial elements. Prostate specific antigen (PSA) remains undetectable in the majority of men. However, in some PSA increases without demonstrable local recurrence. MATERIALS AND METHODS: A total of 383 patients underwent 447 procedures between June 1990 and January 1994. Of 358 biopsies performed at our institution, 317 (2,075 cores) were available for review. Each core was examined for unaltered prostatic glandular epithelial elements and then scored for the percentage of epithelial glandular involvement according to a scale of: 0-no, 0.5-less than 10%, 1-10 to 25%, 2-25 to 50%, 3-50 to 75% and 4-76 to 100% unaltered prostatic glandular epithelial elements. RESULTS: Of 317 biopsies 158 (49.8%) contained no unaltered prostatic glandular epithelial elements, while 185 (58.3%) and 206 (65%) had 1 core containing 10% and 10 to 25%, respectively, of such elements. Of 262 cases (82.6%) with a mean of 10% unaltered prostatic glandular epithelial elements per core 22 (8.4%) were positive for residual carcinoma. Among 55 cases with more normal epithelium per core 24 (43.6%) were positive for residual carcinoma. Patients with a positive biopsy had a median PSA of 2.02 ng./ml. (average gland/core score 0.54). Median PSA for men with negative biopsies was 0.2 ng./ml. (gland/core score 0.124). CONCLUSIONS: Cryosurgical ablation of the prostate has the ability to ablate prostatic tissue completely, thus rendering it free of glandular elements as determined by biopsy. Increasing PSA can indicate residual glandular elements. Increases in unaltered prostatic glandular epithelial elements with time are not paralleled by increased rates of local disease recurrence. undetectable serum PSA has a low risk of residual unaltered prostatic glandular epithelial elements and localized carcinoma. Results as measured by unaltered prostatic glandular epithelial elements and PSA improve with the surgical experience.     

The presence of atopy does not determine the type of cellular infiltrate in nasal polyps

Prostate cancer screening with DRE, TRUS, and PSA testing was offered to 2,400 randomly selected men 55-70 years old. Among 1,782 examined, 65 (3.6%) men with prostate cancer were diagnosed. The PSA results were correlated to the diagnosis, the men's age, and the prostate volume. Least square regression analysis was used to calculate the 95% upper confidence intervals for PSA in each year of age in men without prostate cancer. The PPV was calculated for: (i) PSA > 4 ng/ml, (ii) PSAD > 0.15, (iii) PSAD > 0.20 and (iv) age-adjusted PSA reference values. A significant correlation was found between PSA and prostate volume, between PSA and age, and between the prostate volume and age. The calculated annual growth of the prostate was 1.6% and the annual increase in PSA was 2.4%. The age-adjusted upper PSA reference values for the three age categories studied (55-59, 60-64 and 65-70 years) were 5.2, 5.8, and 6.7 ng/ml, respectively. The PPVs for PSA > 4 ng/ml, PSAD > 0.15, PSAD > 0.20, and the age-adjusted PSA reference values were 17%, 14%, 22%, and 27%, respectively. Age-adjusted PSA or PSAD may increase the PPV compared to PSA > 4 ng/ml. The detection rate is, however, inadequate. A PSA cut-off at 4 ng/ml could therefore be maintained in men 55-70 years old. The median PSA values and median prostate volumes calculated for men with benign findings may serve as a reference in future studies.     

Treatment of metastatic prostate cancer: certainty and doubts

HIGH MORTALITY: Despite progress in early diagnosis, mainly due to prostate specific antigen (PSA) assay, metastasic cancer of the prostate remains an important health problem; more than 40,000 men died from prostate cancer in 1996 in the USA. More than 50 years after the hormone sensitivity of prostate cancer, antiandrogen therapy remains the cornerstone of treatment protocols. Although this is only a palliative therapy, it does delay disease progression for several years before the tumor inevitably escapes from hormone control. STAGE D1 DISEASE: In patients with microscopic nodal metastases (stage D1) it is classical to propose early or delayed hormone therapy which gives a 5-year survival rate in the 77-85% range. Certain teams also associate radical treatment (radical prostatectomy or pelvic prostate radiotherapy) with the hormone therapy, basically with the aim of better local control despite the lack of proven gain in survival rate. STAGE D2 DISEASE: Medical or surgical castration is the gold standard when the disease reaches stage D2. Specific treatments for urinary, neurological or bone complications may also be associated. Median survival is approximately 3 years. ASYMPTOMATIC PATIENTS: There remains a certain controversy about the best time to initiate treatment. Some advocate treatment immediately upon diagnosis while others propose delaying treatment until the onset of symptoms. There is a trend towards early treatment, but the beneficial effect in terms of survival and quality of life has not been proven. STAGE D3 DISEASE: When the tumor escapes hormone control (stage D3) mean survival is less than one year. Castration should be maintained and antiandrogens, which may have been given initially in combination with castration to achieve total androgen blockade, should be withdrawn (antiandrogen withdrawal syndrome) before assessing the need for second intention hormonal or other treatment. Such second intention regimens usually have a temporary and symptomatic effect. Their indication depends on side effects which may have a deleterious effect on quality of life. Symptomatic treatment plays a predominant role at this stage, combining analgesics, external or metabolic radiotherapy for bone pain, transurethral excision and/or urinary tract derivations for neurological or urological complications, and psychological care which requires the combined efforts of the radiotherapist, oncologist, urologist, and general practitioner.     

Ratio of free-to-total prostate specific antigen in serum cannot distinguish patients with prostate cancer from those with chronic inflammation of the prostate

PURPOSE: We demonstrate the effect of chronic inflammation of the prostate on the ratio of free-to-total prostate specific antigen (PSA) in serum calculated as a percentage of free PSA and, therefore, that percentage of free PSA is an unspecific means to distinguish among prostate cancer, chronic prostatitis and benign prostatic hyperplasia (BPH). MATERIALS AND METHODS: Total, free and percentage of free PSA was measured in 66 men with prostate cancer, 119 with BPH and 17 with asymptomatic chronic prostatitis. In all patients the diagnosis was histopathologically confirmed by microscopic examination of prostatic specimens after sextant biopsy, transurethral prostatic resection or prostatectomy. RESULTS: The median values of total, free and percentage of free PSA were 4.11 microg./l., 0.75 microg./l. and 20.4% in patients with BPH, 10.0 microg./l., 0.84 microg./l. and 8.5% in those with prostate cancer, and 7.60 microg./l., 1.23 microg./l. and 10.6% in those with chronic prostatitis. Patients with prostate cancer and chronic prostatitis had a significantly lower percentage of free PSA than those with BPH. Receiver operating characteristics curve analysis showed that percentage of free PSA as a discriminator between prostate cancer and BPH was not suitable for differentiating between prostate cancer and chronic prostatitis. CONCLUSIONS: Chronic prostatitis is not characterized by elevated total PSA concentrations alone but also by a decreased percentage of free PSA, a tendency similar to that in prostate cancer. This unspecific change in percentage of free PSA must be considered to interpret the percentage of free PSA correctly.