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Purpose: The overall purpose of this study was to determine the potential usefulness of 1,19-di-(ethylamino)-5,10,15-triazononadecane (BE-4-4-4-4) in the treatment of prostate cancer using in vitro and in vivo models. More specifically the objectives were: (1) to determine the in vitro and in vivo sensitivity of human and rat prostate cancer cells to two polyamine analogues N1,N11-di(ethyl)norspermine (DENSPM) and BE-4-4-4-4; (2) to determine whether the mechanism of cell kill occurred through an apoptotic pathway; and (3) to determine the toxicity associated with therapeutic doses of BE-4-4-4-4 using an animal model.Methods: In order to determine the ability of these drugs to cause in vitro cytotoxicity, colony-forming assays were performed utilizing the well-characterized Dunning rat prostate cancer cell lines AT3.1, AT6.1 and AT6.3, and the androgen-insensitive human prostate cancer cell lines DU145, DuPro-1 and TSU-Pr1. Apoptotic cell death was determined using DNA laddering and DAPI staining of nuclei. The antitumor activity of BE-4-4-4-4 was evaluated by treatment of DuPro- and PC-3 xenograft tumors in nude mice.Results: BE-4-4-4-4 was shown to be approximately 4 to 86 times more cytotoxic in clonogenic assays than DENSPM in both rat and human prostate carcinoma cell lines. Cells treated with cytotoxic doses of DENSPM or BE-4-4-4-4 showed no signs of apoptosis using either DNA laddering or DAPI staining of nuclei. There was a significant inhibition of DuPro-1 tumors for animals treated with BE-4-4-4-4 compared with control animals. Equitoxic doses of BE-4-4-4-4 resulted in greater tumor inhibition than DENSPM, although the difference was not significant. After treatment with therapeutic doses of BE-4-4-4-4, histopathologic evaluation indicated minimal to mild necrosis and inflammation in the kidneys on days 15 and 22 following treatment. On day 35, there was no necrosis or regeneration present in the kidney, indicating that the toxicity was transient and that regeneration of epithelial cells was complete with apparent return to normalcy.Conclusions: These initial studies demonstrate that BE-4-4-4-4 is cytotoxic against rat and human prostate cancer cells in culture and effective against DuPro-1 xenografts in nude mice. Polyamine analogues, such as DENSPM or BE-4-4-4-4, should be considered for clinical use in the treatment of prostate adenocarcinomas. [ABSTRACT FROM AUTHOR]

Objectives: To assess the effectiveness and tolerability of transdermal estrogen in men with hot flushes after hormonal therapy for prostate cancer., Methods: Twelve men with moderate to severe hot flushes were randomized to receive either low-dose (0.05 mg) or high-dose (0.10 mg) estrogen patches applied twice weekly for 4 weeks. After a 4-week washout period in which no treatment was given, each patient received the alternative dose for 4 weeks. Treatment response was assessed by daily logs and questionnaires completed every 4 weeks that included a visual analog assessment. Serum luteinizing hormone, follicle-stimulating hormone, testosterone, and estradiol levels were also measured every 4 weeks during the study., Results: There was a significant reduction in the overall severity of the hot flushes seen in patients with both the low and high-dose estrogen patch. A significant reduction in the daily frequency of the hot flushes was seen with the high-dose patch only. Overall, 10 (83%) of 12 men reported either mild, moderate, or major improvement in symptoms with either the low or high-dose patch. Mild, painless breast swelling or nipple tenderness was noted in 2 (17%) and 5 (42%) of 12 men treated with the low and high-dose estrogen patch, respectively. FSH levels decreased significantly with both the low and high-dose patch. Estradiol levels increased from 12.1 to 16.4 pg/mL and 26.9 pg/mL with the low and high-dose patch, respectively. There was no significant change in serum testosterone or luteinizing hormone levels., Conclusions: Transdermal estrogen appears to be a promising, well-tolerated therapy for men with hot flushes after endocrine treatment for prostate cancer. Further study in larger groups of patients is necessary to assess the relative effectiveness and morbidity of this treatment.

Purpose: The initial and secondary management of pelvic fracture associated with disruption of the membranous urethra is the subject of a wide literature containing varied and controversial viewpoints. We have noted the presence of heterotopic bone formation surrounding the area of urethral injury in patients undergoing delayed repair. We investigated the etiology, incidence and risk factors associated with such an injury, as well as potential means of prophylaxis., Materials and Methods: We reviewed the current literature on heterotopic bone formation with similar traumatic injury. While instances of severe urethral disruption of this type are fortunately rare in children we describe prepubertal boys with such an injury complicated by heterotopic ossification., Results: The incidence of heterotopic ossification reported in children and adolescents is 3 to 15%, which is less than 15 to 80% reported in adults. Risk factors associated with traumatic heterotopic ossification include prolonged operating time, hematoma formation, degree of bony debris, devitalized muscle and concomitant infection. Prophylaxis with single low dose radiation or nonsteroidal anti-inflammatory drugs has been shown to be effective in the prevention of heterotopic ossification and may be beneficial in this patient population., Conclusions: Heterotopic bone formation associated with severe traumatic injury in the presence of devitalized tissue resulting in the pathological formation of new bone is rare. This complication is only associated with the most severe pelvic fractures. Prophylaxis in these most severe cases with low dose radiation or nonsteroidal anti-inflammatory drugs can prevent the formation of heterotopic bone.

Purpose: We report a straightforward surgical technique for the correction and anatomical alignment of the skin in patients with various degrees of buried penis., Materials and Methods: A combined series of 74 patients 7 months to 10 years old who were treated for buried penis at 2 institutions during a 7-year period. Patients presented with various symptoms, including balanitis, urinary tract infection, painful voiding, ballooning of the foreskin and urinary retention. In 29 patients (38%) trapped penis was due to previous circumcision. In our estimation the major anatomical defect in buried penis is an insufficient attachment of the dartos fascia and penile skin to Buck's fascia. Our technique involves making a circumferential incision of the inner preputial skin layer proximal to the corona, unfurling it from the shaft skin and leaving a coronal collar of approximately 1 cm. The annular band that usually constricts the corpora on retraction of the penile skin is incised, and the remaining proximal penile skin and dartos fascia are dissected off Buck's fascia proximally to the base of the penis. The penile dermis is sutured to the lateral aspect of the tunica albuginea at the penopubic junction and mid shaft of the penis. This technique restores normal anatomical relationships with excellent cosmetic results and negligible complications., Results: At a median 5-year followup cosmesis was excellent in all cases. Two patients with micropenis who required revision responded to endocrine therapy., Conclusions: Excellent cosmetic results were obtained in all cases using this surgical technique.

There is a critical need for markers that can be used to predict accurately the malignant potential of histological prostate cancers (J. T. Isaacs. Am. J. Pathol., 150: 1511-1521, 1997). Metastasis-suppressor genes are attractive candidates for marker development because, by definition, their loss should be associated with the acquisition of metastatic ability. In an effort to identify such genes, a single copy of human chromosome 12, tagged with the neomycin resistance gene, was introduced into highly metastatic Dunning AT6.1 prostate cancer cells by microcell-mediated chromosomal transfer. Thirty-two AT6.1-12 clonal cell lines were established and the region(s) of chromosome 12 retained was determined by sequence tagged site-based PCR analysis. Representative AT6.1-12 clones containing overlapping regions of chromosome 12 were characterized cytogenetically and were shown to have a normal complement of parental AT6.1 rat chromosomes. Fluorescence in situ hybridization, performed on representative AT6.1-12 hybrids, demonstrated a single human chromosome 12-specific signal. The metastatic ability of six representative clones was tested in immunodeficient mice. All of the AT6.1-12 clones showed the same in vivo growth rates as the control AT6.1-neo cells. Clonal cell lines that contained a conserved approximately 70-cM portion of chromosome 12 (e.g., AT6.1-12-8, -8-1, and -8-3), showed a >30-fold suppression in the number of macroscopic surface lung metastases. Mice that received injections of these cells developed a mean number 4 lung metastases whereas mice that received injections of other AT6.1-12 hybrids (lacking the approximately 70-cM region) or AT6.1-neo control cells, developed a mean number of 140 metastases. Interestingly, histological examination of the lungs of the mice that received injections of AT6.1-12-8 cells showed essentially no microscopic metastases. These findings suggest that a gene(s) encoded by the approximately 70-cM portion of human chromosome 12 suppresses an early step in the metastatic cascade.

Objectives: To assess the effects of saw palmetto on voiding symptoms and urodynamic parameters in men with lower urinary tract symptoms (LUTS) presumed secondary to benign prostatic hyperplasia (BPH)., Methods: Fifty men with previously untreated LUTS and a minimum International Prostate Symptom Score (IPSS) of 10 or greater were treated with a commercially available form of saw palmetto (160 mg twice per day) for 6 months. The initial evaluation included measurement of peak urinary flow rate, postvoid residual urine volume, pressure-flow study, and serum prostate-specific antigen (PSA) level. Patients completed an IPSS, serum PSA was determined, and flow rate was measured every 2 months during the course of the study. A urodynamic evaluation was repeated at the completion of the 6-month trial., Results: The mean IPSS (+/-SD) improved from 19.5+/-5.5 to 12.5+/-7.0 (P <0.001) among the 46 men who completed the study. Significant improvement in the symptom score was noted after treatment with saw palmetto for 2 months. An improvement in symptom score of 50% or greater after treatment with saw palmetto for 2, 4, and 6 months was noted in 21% (10 of 48), 30% (14 of 47), and 46% (21 of 46) of patients, respectively. There was no significant change in peak urinary flow rate, postvoid residual urine volume, or detrusor pressure at peak flow among patients completing the study. No significant change in mean serum PSA level was noted., Conclusions: Saw palmetto is a well-tolerated agent that may significantly improve lower urinary tract symptoms in men with BPH. However, we were unable to demonstrate any significant improvement in objective measures of bladder outlet obstruction. Placebo-controlled trials of saw palmetto are needed to evaluate the true effectiveness of this compound.