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The expression of fatty acid synthase (FAS), a key lipogenic enzyme and potential target for antineoplastic therapy, was analyzed in 87 frozen needle biopsies of prostate cancer using a highly sensitive immunohistochemical detection technique (Envision). In comparison to normal or benign, hyperplastic glandular structures, which were all negative for FAS staining, immunohistochemical signal was evident in 24/25 low grade prostatic epithelial neoplasia (PIN) lesions, in 26/26 high grade PIN lesions and in 82/87 invasive carcinomas. Staining intensity tended to increase from low grade to high grade PIN to invasive carcinoma. Cancers with a high FAS expression had an overall high proliferative index. No correlation was found between FAS expression and lipid accumulation. These findings indicate that increased FAS expression is one of the earliest and most common events in the development of prostate cancer, suggesting that FAS may be used as a general prostate cancer marker and that antineoplastic therapy based on FAS inhibition may be an option for chemoprevention or curative treatment for nearly all prostate cancers., (Copyright 2001 Wiley-Liss, Inc.)

A clinical cT3 prostate cancer can mean so many different tumors, that no single approach can actually be proposed. Radical prostatectomy has become standard treatment for T1/T2 tumors, but the surgical treatment for the clinical T3 prostate cancer has always been and remains controversial, although some urologists felt that radical prostatectomy remained a treatment option for T3 prostatic cancer when poor prognosis patients were excluded. The clinical staging of locally confined or locally advanced prostate cancer is not reliable. More than 70% of the clinically T2-tumors are pT3. On the others hand clinically T3-tumors are sometimes overestimated and about 20% of the clinical T3 cancers were shown to be pT2.--At the Department of Urology, University Hospital Gasthuisberg, Katholieke Universiteit Leuven, Belgium--158 patients had radical prostatectomy for clinical stage T3N0M0 prostate cancer. 110 patients were surgically treated only. 30 patients had adjuvant hormone-therapy and were considered to be progressive at 1 month because PSA follow-up is unreliable. 18 other patients were irradiated postoperatively. PSA-free survival rate exceeds 70% at 24 months and the 5 years estimated PSA-free survival is more than 60%. Summarizing radical prostatectomy appears to be a justified treatment modality in pT3-prostate cancer, if PSA is < 10 ng/ml.

Three designs of transurethral applicators have been analysed to find the one that is best able to selectively heat the desired volume of prostate. A helix-loaded-dipole-antenna (HLDA) inserted into a Foley type catheter was found to be the most promising design. A change in the heat deposition pattern of the antenna depending on prostate size is possible by moving the position of the antenna within a Foley catheter. A number of prototypes of HLDA were manufactured and tested to optimize their design. These tests were performed in solid and liquid phantoms and in laboratory animals. Intra-operative measurements of intra-prostatic temperature distribution were also performed. A comparison of the HLDA with other commercially available transurethral applicators and the published data showed that the present design has a higher linear homogeneity coefficient and a better heat deposition in the prostate.

Objectives: The treatment of patients presenting with an isolated PSA recurrence after radical prostatectomy (RP) remains controversial. The present study aims at assessing the results of salvage radiotherapy (RT), to define prognostic factors and to identify subgroups of patients most suitable for RT with curative intent., Materials and Methods: A retrospective study was performed of 53 patients, diagnosed with a rising PSA after RP, and treated with RT to the prostate bed, between July 1992 and July 1998., Results: On univariate analysis, significant determinants to obtain and maintain a nondetectable PSA (< 0.02 ng/ml) were Gleason grade (< or = III vs. < or = IV), pre-RT PSA, considered as categorical or continuous variable, and pathological stage, pT (2 vs. 3). Pre-RP PSA (< or = 10 vs. >10), time interval between surgery and moment of rising PSA and pathological section margin status were not significant. On multivariate analysis, only Gleason grade and pre-RT PSA remained significant. For the patient group with a Gleason grade < or = III the PSA-free survival at 3 years was 75% (+/- 11%) compared to 27% (+/- 9%) for the patients with a Gleason grade > or = IV (p = 0.002). Pre-RT PSA significantly influenced PSA-free survival in the first group, but not in the latter., Conclusion: From the group of RP patients with rising PSA following a postsurgery PSA-free period, subgroups can be defined with a distinctly different probability of obtaining and maintaining nondetectable PSA levels after salvage RT.

A substantial subset of breast, colorectal, ovarian, endometrial and prostatic cancers displays markedly elevated expression of immunohistochemically detectable fatty acid synthase, a feature that has been associated with poor prognosis and that may be exploited in anti-neoplastic therapy. Here, using an RNA array hybridisation technique complemented by in situ hybridisation, we report that in prostate cancer fatty acid synthase expression is up-regulated at the mRNA level together with other enzymes of the same metabolic pathway. Contrary to the observations that in many cell systems (including androgen-stimulated LNCaP prostate cancer cells) fatty acid and cholesterol metabolism are co-ordinately regulated so as to supply balanced amounts of lipids for membrane biosynthesis, storage or secretion, no changes in the expression of genes involved in cholesterol synthesis were found. These findings point to selective activation of the fatty acid synthesis pathway and suggest a shift in the balance of lipogenic gene expression in a subgroup of prostate cancers., (Copyright 2000 Wiley-Liss, Inc.)

Objective: Radical prostatectomy is commonly believed not to achieve the eradication of locally advanced disease. This retrospective study aimed to elucidate the role of radical prostatectomy in this condition., Methods: A retrospective study of 158 patients surgically treated for clinical stage T3N0M0 prostate cancer was undertaken. Thirty patients had postoperative hormonal treatment, rendering prostate-specific antigen (PSA) follow-up unreliable, and were considered to be progressive at 1 month. Eighteen other patients received postoperative radiotherapy. One hundred and ten patients had radical prostatectomy only. PSA-relapse-free survival was analyzed. The mean follow-up time was 30 months., Results: Seventy-nine percent of the resected specimens were pathologically T3 (pT3), and about 25% were pT3c. Thirteen percent were pT2 and 8% were pT4. Ninety-five specimens (60%) had positive surgical margins. There was poor accordance between the biopsy Gleason score and that of the specimen. A multivariate analysis showed that seminal vesicle and nodal invasion, margin status and a PSA level above 10 ng/ml were independent prognostic factors. In 47 cT3a patients with PSA <10 ng/ml, the PSA-free survival rate exceeded 70% at 24 months and the 5-year estimated PSA-free survival rate was more than 60%., Conclusions: Radical prostatectomy has a place in the treatment of clinical stage T3 prostate cancer patients with a PSA value lower than 10 ng/ml. There is a need to definitively rule out nodal or seminal vesicle invasion in order to select those patients that can benefit from surgery.

Background: Almost all patients that undergo hormonal manipulation for metastatic prostate cancer will ultimately progress because of hormone resistance. Therefore we assessed the effect of early addition of intravenous Mitomycin C to orchiectomy in patients with newly diagnosed metastatic prostate cancer., Patients and Methods: 178 patients with histologically proven and previously untreated metastatic prostate cancer were included in a prospective, randomized multicenter trial. Randomization was done centrally between orchiectomy alone and orchiectomy with Mitomycin C. 148 patients were evaluable., Results: At the final analysis 139 patients have deceased. The remaining 9 patients are still alive, but all present progression. There was no statistically significant difference in the real time to progression, or in the estimated cancer related and overall survival between both groups. Mean time to progression was 29 months in group 1 (orchiectomy alone), and 26 months in group 2 (orchiectomy and Mitomycin C) (p = 0.64). Mean time to cancer related death was 32 months and mean overall survival was 31 months in both groups., Conclusions: Mitomycin C has no beneficial effect when used in conjunction to orchiectomy in patients with newly diagnosed metastatic prostate cancer.

Objectives: To compare the efficacy, tolerability, and quality of life benefits of bicalutamide (Casodex) 150-mg/day monotherapy and castration in previously untreated nonmetastatic (M0) advanced prostate cancer., Methods: A total of 480 patients with Stage T3/T4 nonmetastatic disease randomly received oral bicalutamide 150 mg/day or castration (either bilateral orchiectomy or goserelin acetate [Zoladex] 3.6 mg every 28 days) in a 2:1 ratio in two open multicenter studies (studies 306 and 307). The design of these studies was similar to allow a pooled analysis., Results: In the combined survival analysis, at median follow-up of 202 and 205 weeks in studies 306 and 307, respectively, with 31% of the cases resulting in death, bicalutamide 150-mg monotherapy was statistically equivalent to castration; the risk of death from any cause was 7% less with bicalutamide than with castration (hazard ratio [HR] = 0.93). Data on time to treatment failure and objective progression could not be pooled, as results for these end points differed between the trials. In study 306, bicalutamide 150-mg monotherapy increased time to objective progression (HR = 0.58; P = 0.033) and treatment failure (HR = 0.66; P = 0.074), whereas in study 307, time to progression (HR = 1.35; P = 0.0471) and treatment failure (HR = 1.24; P = 0.097) favored castration. Bicalutamide therapy showed significant advantages over castration for both sexual interest (P = 0.029) and physical capacity (P = 0.046). Bicalutamide 150-mg monotherapy was well tolerated., Conclusions: Bicalutamide 150-mg monotherapy provides a similar survival outcome to castration in previously untreated patients with nonmetastatic advanced prostate cancer and confers statistically significant benefits over castration with respect to sexual interest and physical capacity.

Objectives: To evaluate the efficacy and tolerability of 'Casodex' monotherapy (150 mg daily) for metastatic and locally advanced prostate cancer., Methods: A total of 1,453 patients with either confirmed metastatic disease (M1), or T3/T4 non-metastatic disease with elevated prostate-specific antigen (M0) were recruited into one of two identical, multicentre, randomised studies to compare 'Casodex' 150 mg/day with castration. The protocols allowed for combined analysis., Results: At a median follow-up period of approximately 100 weeks for both studies, 'Casodex' 150 mg was found to be less effective than castration in patients with metastatic disease (M1) at entry (hazard ratio of 1.30 for time to death) with a difference in median survival of 6 weeks. In symptomatic M1 patients, 'Casodex' was associated with a statistically significant improvement in subjective response (70%) compared with castration (58%). Analysis of a validated quality-of-life questionnaire proved an advantage for 'Casodex' in sexual interest and physical capacity. 'Casodex' had a substantially lower incidence of hot flushes compared to castration (6-13% compared with 39-44%) and the most commonly reported adverse events were those expected for a potent antiandrogen. However, in patients with M0 disease at entry, the data are still immature with only 13% of M0 patients having died. An initial analysis of this immature data has suggested that the results in these patients may be different to those obtained in patients with M1 disease. A further survival analysis in patients with M0 disease is therefore planned when the data are more mature., Conclusions: 'Casodex' 150 mg is less effective than castration in patients with M1 disease. However, 'Casodex' has shown a benefit in terms of quality of life and subjective response when compared to castration and has an acceptable tolerability profile. Thus 'Casodex' 150 mg monotherapy is an option for patients with M1 prostate cancer for whom surgical or medical castration is not indicated or is not acceptable.

Purpose: Adenocarcinoma of the prostate is the most common human cancer of internal organs. Radical surgery is regarded by many to be the treatment of choice for capsule confined disease. Since accurate preoperative assessment of tumor stage is difficult to define, many patients are subsequently found to have pathological stage C (T3) disease. These patients should be considered for adjuvant radiotherapy., Methods and Materials: A group of 201 PS C (T3) unselected patients, treated with radical prostatectomy and limited pelvic lymphadenectomy, received postoperative irradiation to the prostate bed. This radiotherapy was given between 42-90 days after surgery and consisted of a median dose of 48 Gy. Patient survival, disease free survival, time to clinical and chemical relapse and the incidence of local and systemic relapse were analyzed. The influence of multiple parameters on the treatment outcome including patient age, treatment period, clinical stage, pathological stage, Gleason's score, prostate specific antigen (PSA), radiotherapy techniques and radiation dose were examined using univariate and multivariate analysis. Follow-up ranged from 3 to 15 years, with a median of 5 years., Results: The overall 5- and 10-year actuarial survival was 92% and 83% (median > 10 years), respectively and the 5- and 10-year disease-free survival (clinical and PSA) was 67% and 53% (median > 10 years), respectively. A total of 61 (30%) patients had a recurrence, including 23 (11%) patients who had clinical and 38 (19%) who had PSA recurrence. Of the 23 patients with clinical recurrence, 10 (5%) had local recurrence, including two patients who had local and systemic recurrence. Pathological stage and Gleason's score were independently predictive of recurrence (each with p < 0.001 after controlling for the other). Patients in the worst prognostic category with pathological stage C3 and Gleason's score 8-10 were predicted to be at 7.2 times the risk of recurrence, compared to stage C1 or C2 and Gleason's score 2-7 patients. Preoperative PSA level (> 25 ng/ml) was also an important independent factor predicting tumor recurrence, p = 0.05. All other investigated parameters were not significant in predicting tumor recurrence. This treatment program was very well tolerated by the study patients, with seven (3.5%) recorded with major and 18 (9%) with minor surgical complications, while 65% of patients had minor and clinically insignificant radiation complications., Conclusion: Surgery followed by moderate dose radiotherapy in patients with PS C (T3) prostatic carcinoma was well tolerated and resulted in excellent overall and disease free survival, with a low incidence of local recurrence. New treatment strategies need to be developed for patients with C3 tumors and those with high (8-10) Gleason's score and those with high (> 25 ng/ml) PSA level at diagnosis.

Adenocarcinoma of the prostate (CaP) in the Western world has become the most common noncutaneous human tumor. CaP is also the second most important cause of cancer deaths among the male population in the United States. Major progress was made in the past decade in better understanding this disease process, as well as in improved diagnostic accuracy. This improved diagnostic accuracy was due to wide application of prostate-specific antigen (PSA), use of transrectal ultrasound (TRUS), and greater awareness among clinicians of CaP. The use of PSA in clinical practice has resulted in a sharp increase in the number of patients diagnosed with capsule-confined tumors. The optimal treatment for capsule-confined CaP is in the process of being defined. Radical prostatectomy in the United States is currently the most commonly applied treatment for younger patients. Excellent treatment results with a 10-year actuarial survival > 80% are readily obtainable in properly selected patients. Nerve-sparing procedures helped reduce the high incidence of impotence that occurs in patients after radical retropubic prostatectomy. Radiotherapy remains the other curative treatment method in the management of CaP patients, with long-term survival rates similar to those reported in surgical series. Due to the problem of frequent preoperative tumor understaging, a routine use of postoperative irradiation to the prostatic fossa produces an excellent (> 95%) incidence of local tumor control. Management of patients with metastatic disease has undergone a considerable evolution with the development of modern hormonal management and treatment with strontium-89 to control intractable bone pain. Newer treatment methods such as hyperthermia are currently being investigated. Major efforts are directed toward the reduction of short- and long-term treatment toxicity associated with surgery, radiotherapy, and hormonal management, thus improving patient quality of life.

As long as advanced prostate cancer remains androgen-dependent, it can be treated by castration in combination with anti-androgens. When despite maximal androgen blockade (MAB), progression occurs, the anti-androgen withdrawal can result in partial remission. Otherwise corticosteroids can be used in low doses in order to suppress the androgens originating from the adrenal gland: total androgen suppression (TAS). The minimal side effects and the low cost price of this treatment are important advantages, given the fact that only few efficient cytostatic agents are actually available for hormone-escaped prostate cancer. About 30% of the patients with advanced prostate cancer that became androgen independent will show a secondary remission under low doses hydrocortisone or prednisone.

Disseminated carcinoma of the prostate (CaP) is a common manifestation of this disease. Metastatic CaP in the United States is seen in about 45,000 patients each year at diagnosis. At least the same number of patients who have had prior definitive treatment with surgery or radiotherapy develop evidence of metastatic disease. Hormonal management is the most important and well established treatment for patients with prostatic metastases. Orchiectomy remains the most efficient and most cost effective therapy in a rapid ablation of testicular androgens. Due to a well known psychological reaction to castration which is seen in many patients, diethylstilbestrol (DES) is a good alternative and cost effective therapy. The mode of action of DES is to suppress LH production and to slowly, indirectly, decrease serum testosterone level. In recent years, total androgen blockade (TAB) has become a widely accepted treatment option. This treatment has been shown in several clinical trials to be effective and well tolerated by the patients. A major problem with a routine use of TAB is a relatively high cost of this therapy. In a European prospective randomized trial, goserelin acetate-flutamide combination significantly increased time to progression when compared with orchiectomy alone. Patients with localized and symptomatic metastases are best treated with radiotherapy. Those with multiple sites of involvement are best treated with strontium-89 which results in a good palliation in a majority of patients. Nearly all hormonally treated patients, with metastatic CaP, eventually show tumor progression. Presently available chemotherapy is of a low effectiveness and should not be used for these patients outside of controlled clinical trials. Current research is directed to identify effective therapy for hormone refractory patients. Immunotherapy and gene therapy may be useful future therapeutic options.

Purpose: We analyzed 100 consecutive radical prostatectomy specimens to evaluate the extent and clinical relevance of the stage T1c cancers discovered., Materials and Methods: All cases were diagnosed by systematic prostatic puncture biopsies because of abnormal prostate specific antigen (PSA) or PSA density. Surgical specimens were examined with the whole organ multiple step-section technique (4 mm.) to identify primary tumor location (peripheral or transition zone cancer), tumor volume, tumor volume divided by prostate volume (percent tumor volume), Gleason score, pathological T stage and positive surgical margins. Tumors smaller than 0.5 cm.3 and without unfavorable pathology (Gleason score 7 or more, or positive surgical margins) were considered insignificant., Results: Median patient age, PSA, tumor volume and Gleason score were 64 years, 8.8 micrograms./l., 1.6 cm.3 and 6, respectively. Of the specimens 46 (46%) had transition zone cancer that was clinically undetectable due to anterior location, while peripheral zone cancers were small, diffuse, anterolateral or in large glands with low percent tumor volume. Transition zone cancer showed greater PSA, PSA density, tumor volume and percent tumor volume than peripheral zone cancer (p = 0.08, 0.03, 0.0002 and 0.0004, respectively), yet with similar Gleason score (p = 0.4). Of the tumors 34 (34%) were locally advanced (stage pT3 and/or positive surgical margins, mostly anterior in 16 transition zone cancers, and apical or posterolateral in 18 peripheral zone cancers), whereas 22 were insignificant (6 transition and 16 peripheral zone cancers). Prostatic puncture biopsies with a core cancer length of less than 3 mm. could have predicted 18 of 19 insignificant tumors but underestimated 13 (33%) and 6 (17%) significant transition and peripheral zone cancers., Conclusions: The majority of our stage T1c tumors were significant with a distinguished high incidence of transition zone cancer. Therefore, they were large but occult. Transition zone cancer behaved differently than peripheral zone cancer, and warranted considerations during treatment of stage T1c prostate carcinoma.

Purpose: We investigated whether impalpable, invisible (stage T1c) but significant prostate cancer can be detected better by determining the free-to-total prostate specific antigen (PSA) ratio of equivocal PSA serum levels., Materials and Methods: The specificity of free-to-total PSA ratio using research monoclonal enzyme immunoassays was compared to that of PSA greater than 4.0 ng./ml. in 117 consecutive patients with PSA 3 to 15 ng./ml. (Hybritech Tandem-R assay) due to untreated benign prostatic hypertrophy or prostate cancer. Of the patients 77% underwent adenectomy or radical prostatectomy with thorough pathological evaluation of surgical specimens., Results: Benign prostatic hypertrophy had a greater median free-to-total PSA ratio than stages T1c and T2 or greater prostate cancer (0.16 versus 0.09 and 0.11 ng./ml., p = 0.0001 and p = 0.0268, respectively). In stage T1c prostate cancer, areas under receiver operating characteristic curves were 0.58 and 0.84 for PSA and free-to-toal PSA ratio, and free-to-total PSA ratio correlated with prostate volume (r = 0.49, p = 0.005) and Gleason score (r = -0.37, p = 0.036). Pathologically, 84% of stage T1c cancers were significant and comparable to stage T2 or greater cancers., Conclusions: Free-to-total PSA ratio enhances the efficacy of PSA measurement by improving specificity for detecting impalpable, invisible but significant stage T1c prostate cancer.

Purpose: We explored the immunohistochemical expression of prostate specific antigen (PSA) in pancreas and salivary glands., Materials and Methods: We investigated 62 specimens from male and female subjects, representing normal cases and several pathological conditions of pancreas and salivary glands. Two commercially available monoclonal antisera for PSA and 1 for prostatic acid phosphatase were used., Results: A consistently positive reaction for PSA and prostatic acid phosphatase, independent of patient sex, was noted in ductal cells of normal pancreas and normal salivary glands, as well as pleomorphic adenoma, adenocarcinoma and all oncocytic epithelial cells of Warthin's tumor. Reaction was absent in normal stromal and acinar cells, and squamous carcinoma., Conclusions: PSA is detectable in normal and cancer tissues far from the prostate. Therefore, we may not entirely rely on specificity of PSA alone to diagnose metastatic prostate cancer.

A structural change of chromosome 1 in q12 may be a new, possibly consistent, chromosome change in adenocarcinoma of the prostate.

Hypoechoic lesions in the peripheral zone of the prostate gland are one of the commonest abnormalities at transrectal ultrasonography (TRUS). 90% of all carcinomas originating in the peripheral zone present as a hypoechoic lesion. Hypoechogenicity though is not specific, as many benign lesions are also hypoechoic. In this retrospective study, based on TRUS alone 57% of the hypoechoic lesions showed carcinoma in the biopsy core (43% of the biopsy cores were benign). The number of positive biopsies increased up to 75% when the hypoechoic lesion was palpable at digital rectal examination. 5.2% of the hypoechoic cancers would have been missed when non-palpable lesions would not have had a biopsy. When the hypoechoic lesion was associated with increased serum concentration of prostate specific antigen (PSA > 4 ng/ml) 74% of the biopsies were positive. 20% to 25% of all hypoechoic cancers would not have had a biopsy. The positive predictive value was 85% when the hypoechoic lesion was palpable at digital rectal examination and the PSA-concentration was > 4 ng/ml (and 90% when volume-adjusted PSA-parameter would have been applied).

Background: In recent years, the routine use of prostate-specific antigen (PSA) to detect cancer of the prostate (CaP) early has renewed the controversy regarding radiotherapy versus radical prostatectomy as the superior definitive treatment. Radiotherapy alone has been reported to result in a high incidence of local recurrence, whereas on the other hand surgical treatment has resulted in a high incidence of microscopic residual tumor. The purpose of this study was to review our treatment results with radical prostatectomy followed by planned courses of postoperative irradiation in patients with pathologic Stage (PS) C disease., Methods: From 1972 to 1989, 95 patients with CaP with PS C tumors were treated with radical prostatectomy and bilateral pelvic lymphadenectomy. Pathologic stage distribution was: C1 in 26 (27%), C2 in 37 (39%), and C3 in 32 (34%) patients. The median follow-up was 6 years. All 95 study patients received postoperative pelvic irradiation as the only adjuvant treatment. Radiotherapy treated volume included the prostatic fossa and its immediate vicinity. The RT dose ranged from 33 Gy to 61.8 Gy (median, 45 Gy)., Results: The overall 5- and 10-year actuarial survival rates were 94% and 73%, respectively, with the 5 and 10 year disease specific survival of 98% and 91%, respectively. Clinical and/or prostate specific antigen recurrence was 31% at 5 years and 44% at 10 years. Prostate specific antigen elevation without clinical evidence of recurrent disease was recorded in 26 (27%) patients. Seminal vesicle involvement (C3) and high Gleason's score (8-10) were the most important factors predicting recurrence. Of the 95 patients treated, 2 had pelvic recurrence alone and 1 had local and distant metastatic disease. Radiotherapy was well tolerated with no clinically important morbidity., Conclusion: Based on this experience, moderate dose adjuvant radiotherapy after radical prostatectomy in patients with PS C CaP is recommended.

Purpose: We investigated the effect of neoadjuvant treatment before radical prostatectomy for clinically localized prostate cancer., Materials and Methods: A total of 130 patients with stages T2b and T3 prostate cancer was randomized in a multicenter study: 62 underwent immediate radical prostatectomy and 65 received 560 mg. estramustine phosphate daily for 6 weeks preoperatively., Results: For clinical stage T2b tumors the neoadjuvant treatment resulted in a significant decrease in positive surgical margins compared to the nonpretreated group. This difference was not found for clinical stage T3 tumors. The impact on progression and survival still must be analyzed., Conclusions: Neoadjuvant treatment can be beneficial for clinical stage T2 prostate cancer. Optimal treatment for stage T3 tumors remains controversial.

We examined retrospectively 107 step-sectioned radical prostatectomy specimens. The index tumor in each specimen was designated a transition zone carcinoma (TZCa) or a peripheral zone carcinoma (PZCa) based on its location. All tumor sections were immunohistochemically stained with chromogranin A (ChrA). A semiquantitative ChrA score (0 to 3) was assessed. ChrA-positive neuroendocrine cells were found in 83% of the index tumors. The ChrA score was significantly related to the Gleason score, the volume of the tumor, and the pathologic stage. Twenty-two percent of the index tumors were designated TZCas; 75% of these demonstrated neuroendocrine differentiation versus 85% of the PZCas. A high ChrA score of > or = 2 was found in 46% of PZCas and in only 33% of TZCas. Capsular transgression, seminal vesicle involvement, positive surgical margins, and lymph node metastasis were seen in the TZCa group in 33%, 17%, 29%, and 4%, respectively versus 58%, 20%, 48%, and 6% in the PZCa group. These findings were associated with a higher mean tumor volume in the TZCa group compared with the PZCa group. The average Gleason score of 4.5 in the TZCa group was significantly (P < 0.0001) lower than the Gleason score 6.2 in the PZCa group. Multicentricity was found in 62% of TZCas and in 49% of PZCas. Eighty-seven percent of the second tumors in the prostates with a primary TZCa were located in the peripheral zone. We conclude that the frequently occurring neuroendocrine cells population enlarges with tumor progression, especially in PZCas.(ABSTRACT TRUNCATED AT 250 WORDS)

The interim results of a randomized trial comparing orchidectomy alone versus orchidectomy and mitomycin C in 178 newly diagnosed metastatic prostate cancer patients are presented. Of 148 evaluable patients 75 were treated with orchidectomy alone and 73 received adjuvant intravenous mitomycin C. Mean time to progression was 15 months in the orchidectomy group versus 14 months in the mitomycin C group. Interim analysis did not demonstrate a favorable effect of the combination with this chemotherapeutic agent compared to orchidectomy alone (P = .45).

Background: Estramustine phosphate (EMP) and flutamide (FL) were used as reversible preoperative hormonal drugs in the surgical treatment of patients with localized prostate cancer., Methods: The authors descriptive and quantitatively examined the morphologic and immunohistochemical changes in 40 of 200 step-sectioned radical prostatectomies, obtained after treatment with EMP (25 patients) and with FL (15 patients). Of these, 28 pretreatment needlecore biopsies were available., Results: Every specimen contained adenocarcinoma. Understaging was found in 50% of the cases and a higher Gleason score in 70%. Benign glands underwent atrophy and squamous metaplasia. Treated tumors showed cytoplasmic vacuolization, nuclear pyknosis, fibrosis and lymphocytic infiltrates. The EMP group had an 84% (P < 0.05) higher mean total regression score than the FL group. Estramustine phosphate induced a 56% (P < 0.05) and a 34% decrease in tumoral prostate specific antigen and prostate specific acid phosphatase intensity scores, respectively, versus 29% and 32% after FL. The mean proliferating cell nuclear antigen (PCNA) labeling index and the mean mitotic index of the EMP group were 52% (P < 0.05) and 70% (P < 0.05) lower than those measured in the FL group. Each FL-treated tumor and 92% of EMP-treated tumors expressed chromogranin A (ChrA); ChrA labeling correlated significantly with PCNA labeling. Seventy-six percent of EMP-treated specimens revealed venous thrombosis., Conclusions: Estramustine phosphate induces important morphologic and immunohistochemical changes in prostate cancer with an apparent decrease of secretory and proliferative activity when compared with FL-treated tumors. These changes represent pitfalls in the diagnosis and grading of treated carcinomas. Nearly every treated adenocarcinoma of the prostate has neuroendocrine differentiation, showing increasing ChrA labeling with higher tumor stage. A significant correlation between tumor proliferation and neuroendocrine differentiation was noticed in this small cohort of patients. There was a high incidence of periprostatic venous thrombosis after EMP treatment.

The sensitivity and accuracy rate of computerized tomography (CT) in lymph node staging of localized prostatic carcinoma is commonly considered to be low. Fine needle aspiration cytology of pathological lymph nodes seen on radiological staging can enhance this low accuracy rate. We prospectively investigated the accuracy of CT and fine needle aspiration cytology in lymph node evaluation of 285 patients with clinically locally confined prostatic carcinoma. The sensitivity, specificity and accuracy rates of this combined method were 77.8%, 100% and 96.5%, respectively. False-negative staging results were found in only 10 patients with minimal nodal disease. Although in contrast with previous reports, combined CT and fine needle aspiration cytology in our hands seems to be a highly efficient staging method for lymph node involvement. This method could be considered as an alternative to surgical lymphadenectomy in the preoperative evaluation of the nodal status of patients with localized prostatic carcinoma who are scheduled for radical prostatectomy or curative radiotherapy.

127 patients with a clinical stage T2b and T3 prostate cancer were randomized in order to undergo either a radical prostatectomy alone or a radical prostatectomy after hormonal treatment (560 mg of estramustine phosphate daily for 6 weeks) in a prospective multi-center study. The clinical or radiological evaluation of an eventual downstaging being extremely difficult, the authors compared in the 2 groups the influence on the surgical act and the number of positive surgical margins at pathological examination of the resected specimen. There was no significant difference between the 2 groups concerning the surgery (duration of the procedure, blood transfusion, degree of difficulty). For clinical T2 prostate tumors the number of positive surgical margins was significantly lower in the group that had preoperative hormonal treatment. In the group with clinical T3 prostate cancer this difference was not found. The influence of positive margins on the later development of local or systemic recurrence and on survival still has to be awaited. At this moment one could conclude that only patients with a T2 prostate cancer benefit of a preoperative hormonal treatment.

We present an unusual variant of prostatic adenocarcinoma with obvious mucinous and neuroendocrine features, arising in the transition zone. The neuroendocrine component is largely represented by Paneth-like cells (PLCs). These cells correspond to previously described eosinophilic cells and are amphicrine. We could demonstrate immunohistochemically the presence of calcitonin in some of these PLCs. The prognostic significance of these special characteristics is not well known, but it is most likely that this type of prostate cancer will not respond well to hormonal therapy.

Purpose: To ascertain the reliability of computed tomography (CT) and CT-guided fine-needle aspiration biopsy (FNAB) in staging of lymph nodes in patients with locally confined prostatic carcinoma., Materials and Methods: A total of 285 patients were studied prospectively. FNAB was performed in 43 patients (15%) with lymph nodes suspect for metastasis on CT scans. FNAB findings were correlated with either the findings of the pathologic examination performed after lymph node dissection (LND) or the status of the lymph node at follow-up with CT after hormone therapy., Results: The sensitivity, specificity, and accuracy of CT-guided FNAB were 77.8%, 100%, and 96.5%. If CT only had been performed, these results would have been 77.8%, 96.7%, and 93.7%. CT staging was false-negative in only 10 patients, who had microscopic metastatic deposits in a solitary lymph node., Conclusion: Combined CT and FNAB is highly efficient for assessment of lymph node metastasis. Therefore, it could be considered an alternative to surgical or laparoscopic lymphadenectomy in patients scheduled for radical prostatectomy or curative radiation therapy.

Purpose: To describe a benign nodular lesion in the peripheral zone (PZ) of the prostate gland., Materials and Methods: In 1,087 patients, the features of 722 focal lesions in the PZ or central zone of the prostate on transrectal ultrasound (TRUS) scans were retrospectively compared with histologic findings in biopsy samples., Results: In 18 patients (5.5% of the 328 patients with benign lesions), benign hyperplasia was found in a focal, nodular lesion obviously located within the PZ. On TRUS scans, the nodules were well circumscribed, ovoid or round, and slightly hypoechoic (n = 11) or isoechoic (n = 7). The isoechoic lesions were surrounded by an anechoic halo. One nodule was an incidental sonographic finding; the 17 others were felt as firm (n = 11) or soft (n = 6) at digital rectal examination. The ratio of serum prostate-specific antigen (PSA) level to prostatic volume was low (< 0.1), except in one patient (0.24)., Conclusion: Some sonographic features and the normal PSA values might suggest a benign nodule in the PZ, but TRUS-guided biopsies and histologic correlation are necessary to confirm the diagnosis.

Benign prostatic hyperplasia (BPH) is a very common condition affecting over 800,000 American males each year. A standard, effective, and well-proven therapy is prostatectomy. This surgical procedure is used to treat, in the United States, approximately 400,000 BPH patients annually. Major treatment benefit is expected in 70% to 80% of patients. Complications are seen in 20% of the surgically treated patients. Due to the advanced age of BPH patients and the presence of other serious coexisting medical problems, surgical therapy may be difficult to utilize. These patients, who present a high risk for surgery, are in need of alternative treatments. Alternative therapy in BPH patients with clinically important symptoms and signs of urinary outflow obstruction include treatment with pharmacological agents, balloon dilatation, laser beam therapy, transurethral thermal therapy, transrectal microwave hyperthermia, and transurethral microwave hyperthermia. These alternative treatment modalities are currently under intensive study. These new treatment modalities ultimately must be compared with the standard treatment, which is prostatectomy. Due to the unpredictable natural history of BPH, it is desirable that each Phase III study should contain a no-treatment observation-only arm. Adenocarcinoma of the prostate (CaP) has become a tumor, which first in frequency, and second in importance in cancer mortality statistics of American males. Local tumor control rates and long-term survivals, with radical prostatectomy or radiation therapy, have been excellent. There was, however, recent concern regarding a high incidence of microscopic local tumor recurrence following a definitive course of irradiation. Deep regional or intracavitary hyperthermia (HT) with phase steering may be of value as an adjuvant treatment to radiotherapy. This HT may increase the incidence of local tumor control obtained with radiotherapy. Phase I-II clinical studies are currently underway.

The preliminary results of a randomized trial comparing orchiectomy versus orchiectomy and mitomycin C in 119 newly diagnosed metastatic prostate cancer patients are presented. Of 109 evaluable patients 57 were treated with orchiectomy alone and 52 received adjuvant intravenous mitomycin C. Mean interval to progression was 13 months in the orchiectomy group versus 11 months in the mitomycin C group. Preliminary analysis did not demonstrate a favorable effect of the combination with this chemotherapeutic agent compared to orchiectomy alone (p = 0.3).

A retrospective analysis of 70 patients, undergoing a radical prostatectomy in 1989 and 1990 is reported. The value of computed tomography (CT) scanning in preoperative lymph node staging should be reconsidered. Evaluation of the resection margins is of utmost importance as is the distinction between capsular invasion, penetration and transgression. The etiology of local failure and its treatment are discussed.

Sixty-eight patients who underwent radical prostatectomy without or after neo-adjuvant hormonotherapy for B2 or C stage prostate cancer were evaluated as concerned to the ease of the surgical procedure. Although it is difficult to assess this parameter, we experienced more difficulties and blood loss was higher in patients who had preoperative hormonal deprivation. Ongoing randomized trials could demonstrate an oncological benefit of neo-adjuvant hormonotherapy before radical prostatectomy. This eventual benefit will have to be balanced against an increased surgical difficulty.

With estramustine phosphate the clinician has the possibility to ensure complete hormonal as well as cytotoxic control of advanced prostate cancer with a single drug. EMP is considered as a first choice for treatment of hormone refractory prostate cancer. It is at least as effective as conventional chemotherapy, yet less aggressive with regard to its toxicity profile. EMP is particularly useful in patients with limited bone marrow reserve, e.g. in case of prior or associated radiotherapy. As to the use of EMP in primary treatment, more information is required before we can define with certainty subgroups of patients who would benefit more from an early course of EMP than from other hormonal therapy. The existing data point in the direction of poorly differentiated tumors, patients with bone pain and poor prognosis. EMP treatment is associated with an increased risk of cardiovascular morbidity. This should be avoided as much as possible by proper selection of patients or by prophylaxis. Gastro-intestinal side effects, such as nausea, diarrhea and anorexia are dose-dependent. These adverse events tend to interfere with compliance at dosages over 560 mg/day. Dosage modifications or an anti-emetic may help. The intravenous administration of EMP offers the possibility for high loading doses at a substantially reduced risk for cardiovascular and gastrointestinal side effects.

A retrospective study of 70 patients who underwent a radical prostatectomy in 1989 and 1990 was done. The significance of CT-scan in preoperative lymph node assessment should be reconsidered. The correct examination of the resection margins is very important: the pathologist should clearly distinguish between capsular invasion and capsular penetration or transgression. The etiology of local failure and its treatment are discussed.

Total serum testosterone, serum testosterone binding globulin and free androgen index were determined before and during treatment in 14 patients with previously untreated disseminated prostatic cancer. Six patients received estramustine phosphate and six other patients underwent orchiectomy. Two further patients received estramustine phosphate because of tumor progression one and two years after orchiectomy. The result of the study indicates that estramustine phosphate is significantly more effective than orchiectomy in eliciting low levels of free androgens. This complete androgen ablation is produced by a depression of total testosterone and a concomitant increase of total serum testosterone binding globulin which yields a free androgen index an average 4.6 times lower in estramustine phosphate treated patients than in patients who underwent orchiectomy.

To investigate the feasibility and antitumoral effect of ketoconazole in the treatment of disseminated prostatic cancer, 22 patients with stage D2 disease were treated with 400 mg. ketoconazole orally every 8 hours. Of the 17 patients evaluable for antitumoral effect an initial tumor response of 88 per cent was observed (1 complete and 8 partial responses, and 6 with stable disease) with a mean duration of 15.8 months (range 5 to more than 30 months). Treatment-related side effects were encountered in 21 patients and consisted of asthenia, gastrointestinal complaints, skin reactions and cardiovascular complications. They were judged to be mild in 8 patients, moderate in 5 and severe in 8. Treatment had to be discontinued because of side effects in 7 patients (32 per cent). During treatment with ketoconazole serum testosterone levels decreased rapidly and attained nearly castrate levels at the end of week 3. However, after 1 month a steady increase was noted and the testosterone levels reached low normal ranges after 5 months. No hormonal or biochemical indications of adrenocortical insufficiency were noted. High dose ketoconazole is effective in the treatment of disseminated prostatic cancer. Its use is limited by the side effects and the inability to maintain castrate levels of testosterone.