Long-term results of treatment for prostate carcinoma by staging pelvic lymph node dissection and definitive irradiation using low-dose rate temporary iridium-192 interstitial implant and external beam radiotherapy.

BACKGROUND: The objective of this study was to evaluate long-term treatment outcome of definitive irradiation by using temporary interstitial implant and limited dose of external beam radiotherapy in treatment of localized prostate carcinoma. METHODS: In total, 536 patients with biopsy-proven adenocarcinoma of the prostate, classification T1-T3, underwent staging pelvic lymph node dissection and brachytherapy delivering an average tumor dose of 30 grays (Gy), supplemented by external beam radiation therapy for an additional dose of 36 Gy delivered over 4 weeks. One hundred of 536 (18%) patients had pathologic D1 disease. A total of 181 patients had undergone transurethral prostatectomy before the treatment. Repeat prostate biopsy was performed on 132 patients 18 or more months after treatment. None of the patients received neoadjuvant or adjuvant hormone therapy. RESULTS: Cumulative disease free survival (DFS) including biochemical DFS at 10 and 15 years for classification T1B,C was 78% and 72%; for T2A, 78% and 78%; for T2B,C, 68% and 66%; and for T3A-C, 45% and 45%, respectively. Cause specific survival for the entire group at 10 and 15 years was 89% and 87%, respectively. Severe complications occurred only in the early developmental phase of the study. CONCLUSIONS: In univariate analysis, the clinical stage, histologic grade, pretreatment PSA level, lymph node status, and results of repeat posttreatment biopsy were all independently significant prognostic factors. However, the authors' study indicates that in multivariate analysis, only two factors emerged with statistical significance-the status of pelvic lymph nodes and the results of posttreatment biopsy. This signifies the importance of local tumor control to achieve ultimate cure and the importance of assessment of pelvic lymph nodes before definitive local therapy other than radical prostatectomy, especially in the high-risk group.

Relative susceptibilities of mitochondrial and nuclear DNA to damage induced by hydrogen peroxide in two mouse germ cell lines.

The objective of this study was to determine the relative susceptibilities to the damaging effects of hydrogen peroxide of DNA in the mitochondrial and nuclear compartments of two murine germ cell lines. We used a quantitative polymerase chain reaction assay (QPCR) to measure gene- and mitochondrial-specific DNA damage and examined for the presence of alkali-labile sites using alkaline gel electrophoresis. No DNA damage was observed in a nuclear gene (beta-globin) in response to hydrogen peroxide treatment. In addition, no increase in alkali-labile sites was observed. However, mitochondrial DNA suffered extensive damage which increased in a dose-dependent manner. These results demonstrate that the nuclear DNA in these germ cell lines is relatively resistant to peroxide-mediated DNA damage, and that mitochondrial DNA is a sensitive biomarker for oxidative stress in these cells.

Diminished decondensation and DNA synthesis in activated sperm from rats treated with cyclophosphamide.

Standard andrology tests do not predict fertility or assess the genetic quality of spermatozoa. To address these problems, we have analyzed sperm nuclear activation in vitro using cytoplasmic extracts of Xenopus laevis frog eggs. The objective of this study was to determine if rat sperm chemically damaged in vivo by cyclophosphamide treatment would respond abnormally in an in vitro rat sperm activation assay (RSAA). Male Sprague-Dawley rats were treated for 6 weeks with cyclophosphamide (CP) to induce DNA damage in post-meiotic germ cells. After the treatment period, cauda epididymal sperm were isolated, and incubated in cytoplasmic extracts of X. laevis frog eggs to induce chromatin decondensation and DNA synthesis in vitro. Sperm from treated rats displayed significant decreases in both decondensation and DNA synthesis when compared to sperm from control rats, consistent with the presence of CP-induced DNA crosslinks. No differences in body, testes, or epididymal weights were observed between control and treated rats, nor was sperm count diminished in the treatment group. These results demonstrate that the RSAA can be used to detect damaged sperm chromatin in the absence of detrimental effects on sperm count, and testis and epididymal weights.

Altered nuclear activation parameters of rat sperm treated in vitro with chromatin-damaging agents.

Standard semen measures do not assess the genetic integrity of sperm. A human sperm activation assay (HSAA) has proven very useful for assessing sperm quality and predicting pregnancy outcome. The HSAA involves incubating permeabilized sperm in cytoplasmic extracts of Xenopus laevis frog eggs. The extracts activate sperm nuclei, which undergo chromatin decondensation, DNA synthesis, and chromatin recondensation, mimicking events that occur after fertilization in vivo. However, no animal model sperm activation assay has been reported. We hypothesize that sperm activation assays will be useful for studying molecular mechanisms of sperm DNA repair by egg cytoplasm and for screening sperm for damaged DNA. Thus, the objectives of this study were to develop an in vitro rat sperm activation assay (RSAA) using cytoplasmic extracts of X. laevis frog eggs and to determine how chemically damaging the sperm chromatin would affect two sperm activation parameters, chromatin decondensation and DNA synthesis. We incubated demembranated rat sperm in a cytoplasmic extract of X. laevis frog eggs supplemented with tritiated thymidine triphosphate ([3H]TTP). The activated sperm nuclei underwent chromatin decondensation and DNA synthesis. Decondensation kinetics were examined using image analysis to measure the size of the sperm nuclei as they decondensed. DNA synthesis kinetics were examined using autoradiography of incorporated [3H]TTP. To investigate how chemical damage affects nuclear activation, we treated rat sperm in vitro with ethylene glycolbis(sulfosuccinimidyl-succinate; SEGS), a reversible crosslinking agent, or hydroxylamine (HA), a DNA base modifier. Treatment with SEGS blocked decondensation in a dose-dependent manner. In contrast, treatment with HA enhanced decondensation, induced gross chromatin abnormalities, and increased [3H]TTP incorporation into activated sperm nuclei, responses consistent with an attempt by the egg cytoplasm to repair DNA damage. These results suggest that the RSAA may be useful for detecting damaged sperm chromatin as a result of toxicant exposure.

The use of an in vitro sperm activation assay to detect chemically induced damage of human sperm nuclei.

A human sperm activation assay (HSAA) has recently been developed to assess sperm quality and functionality. The HSAA involves incubating lysolecithin-permeabilized sperm in Xenopus laevis ova cytoplasmic extract. Factors in the extract activate sperm nuclei; the activation involves sperm chromatin decondensation, DNA synthesis, and chromatin recondensation. We report that human sperm chemically damaged in vitro by treatment with a reversible crosslinker, ethylene glycolbis(sulfosuccinimidylsuccinate; SEGS), display abnormal chromatin decondensation when analyzed in the HSAA. Less than 20% of SEGS-treated sperm fully decondensed, vs. 97% of control sperm. Chemical reversal of the crosslinks by treatment with 5 microM hydroxylamine restored full decondensation in 76% of treated sperm. These results demonstrate that chemically damaged sperm respond abnormally in the HSAA, and that chemical damage to sperm nuclei can be detected using the HSAA. Thus, there is potential for the HSAA to be used to detect chemical alterations of sperm nuclei from men exposed to environmental toxicants.

Depth of penetration of the neodymium: yttrium-aluminum-garnet laser in the human prostate and clinical results of high-dose laser energy in 50 patients.

We evaluated the treatment of the human prostate with the Nd:YAG laser using a Cytocare Prolase II fiber. We utilized this first in 12 patients prior to radical prostatectomy and then appropriately serially sectioned the prostate to measure the depth of penetration. The studies clearly revealed that 60 W of power and 60 s of pulse duration gave the most consistent depth of penetration in the human prostate model. This depth of penetration averaged 2 cm in the glands that were removed. At the same time there was absolutely no evidence of damage to the neurovascular bundle or to the capsule of the prostate using the above-mentioned dosimetry regime. This study was then transferred to our initial experience in treating 50 patients with benign prostatic hypertrophy and obstructive voiding symptoms. The first 25 patients were also treated with so-called spot radiation of the prostate, whereas the second 25 patients were treated by total photoirradiation of all visible endoscopic tissue. The results reveal that both groups of patients had a fairly highly satisfactory result as measured objectively with American Urological Association (AUA) symptom scores and uroflow studies. In the latter group (photoirradiation of all visible endoscopic tissue) a significantly higher dose of laser energy was utilized and a smaller failure rate was noted on a long-term basis in patients who subsequently came to transurethral resection of the prostate (TURP) because of failure of the laser procedure.(ABSTRACT TRUNCATED AT 250 WORDS)

Depth of penetration of the neodymium:yttrium-aluminum-garnet laser in the human prostate at various dosimetry.

OBJECTIVE: To determine depth of thermal penetration by the neodymium:yttrium-aluminum-garnet (Nd:YAG) laser at various dosimetry in the human prostate and to compare results of two techniques of laser application, single spot versus whole tissue photoirradiation. METHODS: Twelve men with Stage T2 (B) cancer of the prostate consented to laser prostatectomy immediately prior to a planned radical prostatectomy. In the first 3 patients (group I) the prostate was treated with the Nd:YAG laser in one spot area of each lobe. The next 9 patients underwent photoirradiation of all endoscopically visible tissues on one side of the prostate at different dosimetries: 60 W at sixty seconds (group II), 50 W at sixty seconds (group III), and 40 W at ninety seconds (group IV). Depth of laser penetration was measured from both histologic and gross evaluations of removed specimens within twenty-four hours. RESULTS: Thermal necrosis in group I showed an inconsistent depth of penetration even with the same amount of laser energy. Groups II, III, and IV all demonstrated clearly demarcated areas of thermal necrosis. Group II showed the greatest depth of laser effect among all groups, with a mean depth of 1.75 cm. No laser effect is detected near the true capsule of the prostate on any specimen. CONCLUSIONS: High dosage laser energy application at 60 W and sixty seconds of pulse duration with the whole tissue treatment provide the greatest depth of penetration in the human prostate while maintaining safety for the capsular area.

Extensive neodymium-YAG photoirradiation of the prostate in men with obstructive prostatism.

OBJECTIVE: To determine if high-dosage, extensive photoirradiation of the prostate could be used safely in men with large prostate glands and obstruction, coupled with acceptable clinical results. METHODS: Treatment of 25 men consecutively with eight quadrant photoirradiation of the prostate. Treatment of the next 25 men with high-dosage energy up to 109,000 joules. Simultaneous transrectal needle biopsy of the prostate performed on all 50 men after treatment. Patients evaluated with four- to sixteen-month follow-up. RESULTS: Success rate of 86 percent on all patients with mean American Urological Association (AUA) symptom score decreasing by nineteen points and mean peak uroflow rate increasing by 7.9 cc. Needle biopsy after high-dosage laser therapy shows no laser effect on the peripheral zone. CONCLUSIONS: High-dosage laser energy can be used safely, and allows us to treat large prostates with excellent clinical results and minimal complications.

Cost analysis of neodymium-YAG laser versus transurethral resection treatment of superficial bladder carcinoma.

We have analyzed a group of patients treated by various urologists with both neodymium-YAG laser photoirradiation and transurethral resection in the treatment of superficial bladder carcinoma. The average hospitalization for the group of patients treated by the laser was significantly shorter than the group of patients treated by transurethral resection of the bladder tumor. The complications were similar. The cost savings to patients treated by laser photoirradiation appears to be significantly greater in laser groups of patients as opposed to conventional transurethral resection techniques.

Modification of Le Bag ileocolonic pouch with improved results. Review of 17 cases.

The use of detubularized terminal ileum and cecum to construct a highly compliant, low-pressure, continent ileocolonic pouch was first described by Light and Engelman and was termed the "Le Bag." Results were excellent in terms of continence and preservation of renal function; however, nocturnal incontinence persisted in a substantial number of patients. We have modified the original procedure in 17 patients by performing a urethral-cecal anastomosis instead of using a tail of nondetubularized ileum. In addition, in those patients in whom a urethral anastomosis is contraindicated, we have modified the nipple as the continence-providing mechanism. Overall daytime and nighttime continence rate is 94 percent. Of the 13 patients with urethral-cecal anastomoses, only 1 patient requires intermittent catheterization. The remainder are voiding by Valsalva maneuver and with minimal residual urine. Based on our experience with the Le Bag ileocolonic pouch, we believe it is an excellent choice for total bladder replacement or continent diversion--the advantages being the relative ease of construction, minimal long-term complications, and near total urinary continence.

The use of continent diversion in the management of rhabdomyosarcoma of the prostate in childhood.

Three children with rhabdomyosarcoma of the prostate treated with combination chemotherapy and radiation therapy underwent radical extirpation with continent diversion to the urethra. This urological procedure is technically feasible even in the small child (2 years old) and offers chance for cure. Radical cystectomy with continent diversion need not be considered as mutilating surgery.

Followup prostate biopsy in patients with carcinoma of the prostate treated by 192iridium template irradiation plus supplemental external beam radiation.

We reviewed our experience with 81 patients who had undergone followup needle biopsies of the prostate between 12 and 27 months after 192iridium template radiotherapy combined with external beam radiation therapy. When broken down by stage 82% of the patients with stage A2, 92% with B1, 95% with B2 and 55% with C disease demonstrated a negative biopsy and adequate local control of the cancer. We believe that in elderly patients, poor risk patients with early stage disease and stage C lesions this low morbidity, low mortality therapy offers a viable option to other modalities of treatment.