A conditional replication-competent adenoviral vector, Ad-OC-E1a, to cotarget prostate cancer and bone stroma in an experimental model of androgen-independent prostate cancer bone metastasis.

Prostate cancer has a high propensity to metastasize to bone, which often resists hormone, radiation, and chemotherapies. Because of the reciprocal nature of the prostate cancer and bone stroma interaction, we designed a cotargeting strategy using a conditional replication-competent adenovirus to target the growth of tumor cells and their associated osteoblasts. The recombinant Ad-OC-E1a was constructed using a noncollagenous bone matrix protein osteocalcin (OC) promoter to drive the viral early E1a gene with restricted replication in cells that express OC transcriptional activity. Unlike Ad-PSE-E1a, Ad-OC-E1a was highly efficient in inhibiting the growth of PSA-producing (LNCaP, C4-2, and ARCaP) and nonproducing (PC-3 and DU145) human prostate cancer cell lines. This virus was also found to effectively inhibit the growth of human osteoblasts and human prostate stromal cells in vitro. Athymic mice bearing s.c. androgen receptor-negative and PSA-negative PC-3 xenografts responded to a single intratumoral administration of 2 x 10(9) plaque-forming unit(s) of Ad-OC-E1a. In SCID/bg mice, intraosseous growth of androgen receptor-positive and PSA-producing C4-2 xenografts responded markedly to i.v. administrations of a single dose of Ad-OC-E1a. One hundred percent of the treated mice responded to this systemic Ad-OC-E1a therapy with a decline of serum PSA to an undetectable level, and 80% of the mice with PSA rebound responded to the second dose of systemic Ad-OC-E1a. Forty percent of the mice were found to be cured by systemic Ad-OC-E1a without subsequent PSA rebound or tumor cells found in the skeleton. This cotargeting strategy shows a broader spectrum and appears to be more effective than systemic Ad-PSE-E1a in preclinical models of human prostate cancer skeletal metastasis.

Radioactive implant migration in patients treated for localized prostate cancer with interstitial brachytherapy.

PURPOSE: In several of the initial patients undergoing brachytherapy at our institution radioactive implants were visible in the thorax on chest radiography. The clinical ramifications of this unanticipated finding were unclear. Thus, we investigated the incidence of brachytherapy seed migration to the chest and whether these seeds were associated with any clinical significance. MATERIALS AND METHODS: We retrospectively reviewed the records of all patients who underwent ultrasound or computerized tomography guided brachytherapy of 103palladium seeds from March 1997 to March 1999. This list of patients on brachytherapy was then matched against the radiology computer system to determine those who had undergone chest X-ray after brachytherapy. When the radiology report was unclear regarding brachytherapy seeds, chest x-rays were reviewed by one of us (R. O.) to determine the presence and position of the seeds. RESULTS: Post-brachytherapy chest x-rays were available in 110 of the 183 patients. In 78 cases no brachytherapy seeds were identified. Radioactive implants were identified on chest radiography in 32 patients (29%), including 1 to 5 seeds in 20, 8, 1, 2 and 1, respectively. No patients complained of any change in pulmonary symptoms after brachytherapy. CONCLUSIONS: Radioactive implants migrated after brachytherapy for localized prostate cancer in 29% of the patients who underwent post-procedure radiography. There did not appear to be a pattern to the seed distribution. However, while the incidence was not negligible, no patient appeared to have any acute pulmonary symptoms. Therefore, while the migration of radioactive implants to the chest is a real phenomenon, it appears to have no adverse clinical consequences in the early post-procedure period.

Prostatourethral-rectal fistula after prostate brachytherapy.

BACKGROUND: Brachytherapy (BT) has seen increased utilization as a potentially curative treatment for patients with localized initial or recurrent prostate carcinoma. This modality can be delivered by palladium 103 (Pd(103)) or iodine 125 (I(125)) implant with or without external beam radiotherapy (EBRT). Prostatourethral-rectal fistula (PRF) is a serious complication of this approach, and its incidence, clinical presentation, and risk factors for occurrence have not been documented thoroughly. Thus, the authors sought to determine these factors in a large series of patients who were treated at two institutions. METHODS: Seven hundred sixty-five patients received outpatient BT using a computed tomography (CT)-guided or transrectal ultrasound (TRUS)-guided technique between July 1994 and June 1999 using either Pd(103) or I(125) implants. Of the 754 patients with follow-up, 640 patients received BT monotherapy, 69 patients received BT monotherapy as a boost after EBRT, and 45 patients received BT as salvage therapy after locally recurrent prostate carcinoma that was treated initially with BT (20 patients), EBRT (20 patients), surgery plus EBRT (3 patients), surgery and high dose rate radiotherapy (HDR) (1 patient), or EBRT plus HDR (1 patient). CT dosimetry of the TRUS-guided implants was carried out in all patients 1-7 days postprocedure. Patient follow-up and clinical status were compiled in a data base. RESULTS: Seven PRFs developed in 754 patients (1%) between 9 months and 12 months after treatment. One PRF (0.2%) occurred in patients who were treated with BT monotherapy. PRFs occurred in patients who were treated with combination therapy (2 of 69 patients; 2.9%) and in patients who underwent salvage BT (4 of 45 patients; 8.8%) patients. All six patients who developed fistulas in the context of combination BT/EBRT or salvage BT had biopsy of an anterior rectal lesion overlying the prostate noted on physical examination during routine follow-up. Gastrointestinal endoscopic evaluation alone was not associated with any PRF. Five of the seven PRFs resolved with either surgical repair (3 patients) or conservative management (2 patients). CONCLUSIONS: There is a low incidence of PRF formation after BT monotherapy. Because all patients who developed PRF did so subsequent to prior rectal biopsies, the authors currently are discouraging such practices strongly if the rectal lesion is consistent with radiation-induced effects.

High- and low-risk prostate cancer treated with 3D CT-guided brachytherapy: 1-to 5-year follow-up.

PURPOSE: To provide a preliminary report of 301 patients treated for prostate carcinoma with three-dimensional CT-guided transischiorectal stereotactic brachytherapy using either iodine-125 or palladium-103 seeds as monotherapy. PATIENTS AND METHODS: Patients with clinical stage T1, T(2ab), or T(3ab) disease with prostate volumes 23 to 180 cm3 and serum prostate specific antigen (PSA) concentrations of 0.9 to 143 ng/mL had seeds placed 10 mm apart under CT guidance. No androgen blockade was used postoperatively, but 47% of the patients had hormonal therapy preoperatively. RESULTS: At 12 to 63 months (median 26 months) of follow-up, PSA concentrations had decreased to <2 ng/mL in 90% of the patients and to <1 ng/mL in 83%. Four patients underwent transurethral resection or incision at least 12 months after implantation; none became incontinent. Three patients had rectal ulceration that lasted for several months. CONCLUSIONS: Computed tomography-guided transischiorectal brachytherapy allows accurate placement of radionuclide seeds in prostate glands of all sizes. The early results, as judged by serum PSA, are encouraging.

Osteocalcin-directed gene therapy for prostate-cancer bone metastasis.

Osteocalcin (OC) is a major noncollagenous bone protein whose expression is limited almost exclusively to osteotropic tumors and mature calcified tissue (differentiated osteoblasts). The function of OC, a highly conserved gamma-carboxyglutamic acid-containing protein, relies in part on its ability to bind hydroxyapatite and act as a chemoattractant for bone-resorbing cells. Serum osteocalcin levels are used clinically as an index of active bone turnover. Research in our laboratory has revealed that OC is expressed in several solid tumors, including osteosarcoma and ovarian, lung, brain, and prostate cancers. Evidence arising from reverse-transcription polymerase chain reaction (RT-PCR; detection of OC mRNA), immunohistochemical staining (detection of OC protein), and transient transfection and reporter assay (detection of OC mRNA transcription) reveals that OC expression is up-regulated in numerous solid tumors, with its expression being further elevated in androgen-independent prostate cancers. A recombinant, replication-defective adenovirus, Ad-OC-TK (OC promoter-driven herpes-simplex-virus thymidine kinase) was constructed and, when combined with the appropriate prodrug, either ganciclovir (GCV) or acyclovir (ACV), was found to be effective at destroying prostate-cancer cell lines in vitro and prostate tumor xenografts in vivo in both subcutaneous and bone sites. Additionally, via use of the OC promoter the supporting bone stromal cells are cotargeted when the prostate cancer interdigitates with bone stroma at the metastatic skeletal sites. Thus, maximal tissue-specific cell toxicity is achieved by the interruption of cellular communication between the prostate cancer and the bone stroma. We describe herein the preclinical foundation as well as the design and implementation of an ongoing phase I clinical trial at the University of Virginia that targets androgen-independent metastatic prostate cancer using the Ad-OC-TK vector.

Determination of optimal freezing parameters of human prostate cancer in a nude mouse model.

BACKGROUND: We sought to determine whether more than one freeze/thaw cycle is required and what minimum temperature reliably kills prostate cancer in vivo. METHODS: Two human prostate cancer cell lines (LNCaP and PC3) were implanted subcutaneously in male nude BALB/c mice. Tumors were frozen with contemporary cryosurgery equipment and monitored for temperature, size, and serum prostate-specific antigen (PSA) measurements. The tumors were subjected to one or two freeze/thaw cycles through a wide range of temperatures from 0 - -80 degrees C. RESULTS: These experiments show that a single freeze/thaw to a temperature < -40 degrees C is adequate to kill most tumor cells in this mouse model of prostate cancer. CONCLUSIONS: Freezing prostate cancer to < -40 degrees C and ensuring that the entire tumor is frozen is more important than additional freeze/thaw cycles in this experimental model.

Preirradiation PSA predicts biochemical disease-free survival in patients treated with postprostatectomy external beam irradiation.

PURPOSE: To assess the clinical outcome and prostate-specific antigen (PSA) response and to determine prognostic factors for biochemical disease-free survival in patients treated with external beam radiotherapy following radical prostatectomy without hormonal therapy. METHODS AND MATERIALS: Forty-eight patients were treated after prostatectomy with radiotherapy between March, 1988 and December, 1993. Seven patients had undetectable PSA (<0.2) and the remainder had detectable PSA at the time of irradiation (overall: median 2.7, range 0-24.9). Nine patients had biopsy proven local recurrence, palpable local disease, or positive preirradiation imaging. No patients received hormonal therapy prior to irradiation. Median follow-up was 55 months. A median dose of 60 Gy (range 58-66) was given to the prostate bed. Survival was analyzed using the life-table method. Actuarial biochemical disease-free survival was the primary endpoint studied. RESULTS: In patients with detectable PSA, 51% had levels return to undetectable after irradiation. The actuarial 5-year freedom from biochemical failure for all patients was 24%. A significant difference in biochemical disease-free survival was seen for patients irradiated with preirradiation PSA that was undetectable (p < 0.001), or preirradiation PSA that was < or =2.7 (p = 0.002), vs. preirradiation PSA that was >2.7. Five-year actuarial biochemical disease-free survival values were 71, 48, and 0%, respectively, for the three groups. Biochemical disease-free survival was not affected by preoperative PSA level, clinical stage, Gleason's score, pathologic stage, surgical margins, presence of undetectable PSA after surgery, surgery to radiation interval, total dose, or presence of clinically suspicious local disease. Based on digital rectal exam, there were no local failures. CONCLUSION: Biochemical disease-free survival after postprostatectomy radiation is predicted by the PSA at the time of irradiation. Clinical local control is excellent, but distant failure remains a significant problem in this population. The addition of concomitant systemic therapy should be investigated in patients with PSA >2.7.

Combined analysis of two multicenter studies of finasteride 5 mg in the treatment of symptomatic benign prostatic hyperplasia.

The purpose of this paper is to examine effects of finasteride 5 mg across different age groups in an ethnically diverse population of men with symptomatic benign prostatic hyperplasia (BPH) seen in community urology and primary care practices. Data were combined from two previous placebo-controlled randomised trials of finasteride that evaluated changes in urinary symptoms, blinded global assessments of urologic status, adverse experiences, and effects on dihydrotestosterone (DHT) and prostate-specific antigen (PSA) in over 4500 men. Finasteride showed a favourable efficacy and tolerability profile in this large ethnically diverse population and was similarly effective in middle-aged and older men with BPH and prostate gland enlargement.

Radical prostatectomy with preservation of urinary continence.

PURPOSE: In an effort to improve postoperative urinary continence after radical retropubic prostatectomy, a new operation to preserve the bladder neck and a significant portion of the prostatic urethra has been developed. MATERIALS AND METHODS: The prostatic urethra is dissected in continuity with the bladder away from the lumen of the prostate, which allows for a true urethra-to-urethra anastomosis. RESULTS: A total of 24 patients who underwent the new continence sparing radical retropubic prostatectomy was compared retrospectively to 80 who previously underwent a nerve sparing procedure. Total continence was noted immediately in 11 patients, within 9 days in 15 and within 7 weeks in 21 of 24 who underwent the new operation, compared to 1, 5 and 33, respectively, of 80 who underwent the standard operation. Microscopic positive margins were noted in 2 of 24 patients with the new continence sparing operation. Early results of cancer control were good. CONCLUSIONS: Early followup of this new technique of radical retropubic prostatectomy suggest that preservation of the continence mechanism at the level of the bladder neck and prostatic urethra results in significantly improved postoperative urinary continence without adversely affecting cancer control.

Tentative direct antimicrobial susceptibility testing in urine.

PURPOSE: Tentative direct disk susceptibilities in bacteriuria compared to standard techniques were reevaluated. MATERIALS AND METHODS: A sterile cotton swab was saturated with urine and uniformly streaked over the surface of a Mueller-Hinton agar plate. Susceptibility disks were added within 5 minutes and the zone of inhibition around the antibiotic disk was read after 16 to 18 hours of incubation. RESULTS: The tentative direct susceptibilities showed an accuracy of 98.2% compared to standard techniques in 2,906 positive pure cultures. The false-positive rate was 0.53% and the false-negative rate was 0.14%. CONCLUSIONS: Results of tentative direct antibiotic susceptibility in bacteriuria are comparable to those of standard techniques and are obtained 24 hours sooner.

Efficacy, tolerability, and effect on health-related quality of life of finasteride versus placebo in men with symptomatic benign prostatic hyperplasia: a community based study. CUSP Investigators. Community based study of Proscar.

This study sought to assess the efficacy, tolerability, and effect of finasteride on health-related quality of life (HRQL) in a diverse population of men with moderate-to-severe symptomatic benign prostatic hyperplasia (BPH). This double-blind study evaluated finasteride and placebo for 12 months in 2342 men with BPH (16.2% black, 14.5% Hispanic, 69.3% Caucasian/other) in a community-based setting. At 3-month intervals, urinary symptoms were measured by use of the American Urologic Association symptom index. HRQL was assessed by use of the BPH impact index (BII), which evaluated degree of bother, worry, physical discomfort, and restriction in activities as a result of urinary symptoms. Additional questions regarding activities of living were administered, and global assessments of change in urologic status were performed by both patients and investigators. Compared with placebo, patients treated with finasteride had a statistically significant decrease in symptom scores when first measured at month 3. Symptom scores continued to improve in finasteride-treated patients throughout the study; at month 12, the mean decrease in symptom scores in the finasteride-treated patients was -4.8 compared with -3.4 for placebo patients ( P = 0.0001). Statistically significant differences in favor of finasteride also were noted at month 12 on the BII (P = 0.0465), and finasteride-treated patients experienced less interference with activities of living (P = 0.0518). Patient and investigator global assessments of urologic status showed that significantly more patients in the finasteride group considered themselves improved and were considered improved by investigators at month 12 (P = 0.000). Finasteride was generally well tolerated. The incidence of drug-related sexual adverse experiences was significantly higher in the finasteride group (P = 0.000), but led to withdrawal in only 1.5% of patients. The demonstrated efficacy and tolerability of finasteride in reducing symptoms and improving quality of life confirm observations of previous trials and make finasteride a highly desirable treatment option for many men with symptomatic BPH.

Doxazosin for the treatment of benign prostatic hyperplasia in patients with mild to moderate essential hypertension: a double-blind, placebo-controlled, dose-response multicenter study.

A total of 248 hypertensive patients 45 years old or older with benign prostatic hyperplasia (BPH) was included in this 16-week, multicenter, double-blind, placebo-controlled, parallel-group dose-response study. Doxazosin, a selective alpha 1-adrenoceptor antagonist, produced a significant increase in maximum urinary flow rate (2.3 to 3.6 ml. per second) at doses of 4 mg., 8 mg. and 12 mg., and in average flow rate (8 mg. and 12 mg.) compared with placebo. The increase in maximum flow rate was significant with doxazosin versus placebo within 1 week of initiating double-blind therapy. Doxazosin compared to placebo significantly decreased patient-assessed total, obstructive and irritative BPH symptoms. Blood pressure was significantly lower with all doxazosin doses compared with placebo. Adverse events, primarily mild to moderate in severity, were reported in 48% of patients on doxazosin and 35% on placebo. Our results strongly support the use of doxazosin as a nonoperative therapeutic alternative in the management of uncomplicated BPH. Doxazosin would also be particularly useful in the management of patients who have BPH and hypertension.

Bladder outlet obstruction after multiple periurethral polytetrafluoroethylene injections.

Periurethral polytetrafluoroethylene (Teflon) injections have been reported to be successful for the treatment of urinary incontinence after transurethral resection or radical prostatectomy. However, the use of polytetrafluoroethylene is controversial due to reports of distant migration and granulomatous reaction after periurethral injection. We report on a patient with a history of periurethral polytetrafluoroethylene injection for postoperative stress incontinence in whom bladder outlet obstruction developed and who underwent repeat transurethral resection 9 years later. Pathological examination revealed that the material responsible for the obstruction was almost totally composed of a foreign body giant cell response to the polytetrafluoroethylene implant ("teflonoma").