Bladder wall penetration of intravesical mitomycin C in dogs.

We examined the kinetics of penetration of mitomycin C (MMC) in the dog bladder wall after intravesical instillation of 20 mg/40 ml, a dose used in patients. Bladder tissues were harvested and concentration-depth profiles were established by analysis of thin tissue slices cut parallel to the urothelial surface of the bladder. Tissue concentrations after a dwell time of 5-7 min were similar to those after 30-120 min. In tissues harvested 60 and 75 min after removal of the dose, MMC was not detected in 5 of 6 samples and was less than 1 micrograms/g at the mucosa in the remaining sample, suggesting a rapid "washout" of the drug. The rapid equilibrium between the drug in urine and bladder tissue indicates that the duration of exposure of the bladder wall tissue was approximately equal to the dwell time of intravesical therapy. Tissue concentrations declined log-linearly with respect to the depth of penetration. The concentration immediately underneath the urothelium (C0) showed considerable intra- and interanimal variability. Bladder distention appeared to increase C0 by several fold. C0 ranged from 2 to 275 micrograms/g wet tissue weight, with a median value of 24 micrograms/g, or 11 micrograms/g when two animals with distended bladders were excluded. MMC concentrations in 3 different sites of the same bladder varied up to 5-fold. Within the capillary-perfused mucosa and muscularis (between 50 and 2000 microns from the urothelial surface), concentrations decreased by 50% for each 500-microns distance. The median concentration at 2000 microns was 1 microgram/g (n = 24). At 2000-3000 microns, tissue concentrations in most (18 of 24) specimens either declined to an asymptotic value or were lower than the detection limit of 0.1 microgram/g. Concentrations in the bladder contents were 200-500 micrograms/ml, the average tissue concentration from 50 to 3000 microns was 10 micrograms/g, and plasma concentrations were less than 0.1 microgram/ml. This supports the therapeutic advantage of intravesical therapy of high local drug concentrations while minimizing systemic exposure. A comparison of the urine concentration and C0 indicated a 30-fold decline in concentration across the urothelium. This suggests the importance of the urothelium as a barrier to MMC absorption. A separate study in our laboratories showed that 16 micrograms/ml of MMC was needed to produce a 90% inhibition of the labeling index of explants of human bladder cancers located in the urothelium (Ta tumor, TNM classification), 25 micrograms/ml in the lamina propria (T1 tumors), and 43 micrograms/ml in the muscle layer (T2 tumors).(ABSTRACT TRUNCATED AT 400 WORDS)

Pharmacokinetics of intravesical mitomycin C in superficial bladder cancer patients.

Intravesical mitomycin C (MMC) therapy is used to treat superficial bladder cancer. This study was to establish the intra- and intersubject variabilities in the systemic (plasma) and target site (bladder) exposure to the drug and to identify the factors which contribute to these variabilities. The pharmacokinetics of MMC were studied in 10 patients. Treatment consisted of transurethral tumor resection followed by six weekly intravesical treatments with MMC (20 mg in 40 ml of water). The dosing solution was maintained in the bladder for 2 h. Pharmacokinetic studies were performed at the time of the first, fourth, and sixth or first, second, and fourth treatments with MMC for a total of 28 treatments. Concentration-time profiles of the plasma and bladder contents (i.e., urine), urine volumes, and urine pH were determined during and for up to 4 h after intravesical administration. Maximal plasma MMC concentrations averaged 43 ng/ml (range, 2.1-180.5 ng/ml) in treatment 1. In comparison, the MMC plasma concentration for myelosuppression reported in the literature is 400 ng/ml. Maximal plasma concentrations in treatments 2, 4, and 6 were at least 4-fold lower than those in treatment 1 and in most cases were below the detection limit of 0.5 ng/ml. This indicates that the absorption of MMC during the later treatments was less than in the first treatment given shortly after surgery. Urinary MMC concentrations during instillation declined from 519.4 +/- 34.8 micrograms/ml (mean +/- SD) in the dosing solution to 64.6 +/- 39.4 micrograms/ml 2 h after instillation. Thus, the superficial bladder tissue was exposed to drug concentrations 300- to greater than 34,000-fold higher than the plasma-perfused systemic tissues. Intravesical exposure to MMC, as determined by the area under the urine concentration-time curve, showed large intra- and intersubject variabilities (range, 2,185-40,411 micrograms-min/ml). Pharmacokinetic analysis showed that the bladder exposure to MMC inversely correlated with the residual urine volume at the time of drug administration (P less than 0.001), the urine production rate (P = 0.05), and the rate of drug removal by degradation and absorption during therapy (P less than 0.01). At the end of the 2-h treatment, recovery of MMC from the bladder instillate ranged from 1 to 100% and correlated with the urine pH at the time of removal (P less than 0.001). At pH between 5 and 5.5, less than 30% of the dose was recovered.(ABSTRACT TRUNCATED AT 400 WORDS)

Transurethral incision of prostate.

Transurethral incision of the prostate was performed in 100 males with prostates that measured under 30 g via rectal examination or transrectal ultrasound. Urodynamic measurements including uroflow rate, post-void residual, as well as physical examination have been evaluated in these patients. Eighty-five percent of these patients have been successfully treated with outpatient transurethral incision of the prostate.

Cystectomy and urinary diversion: a safe procedure for elderly patients.

Cystectomy and urinary diversion have been done on 28 patients more than age seventy with a zero perioperative mortality. Nine female patients with an average age of 77.6 years and 19 male patients with an average age of 74.4 years with 3 patients being greater than age eighty, are the subject of this review. Complication rate, blood loss, and hospital stay were not significantly different from patients having cystectomy and urinary diversion who were seventy years of age or less. Twenty-seven of the 28 patients had muscle-invading tumors; 12 patients are alive with a median survival of greater than thirty months. Five of 10 patients who did not receive radiation therapy are alive; 7 of 18 patients who received some form of radiation therapy are alive. Six patients had been treated initially with 7,000 rad for definitive therapy of bladder carcinomas. In carefully selected patients, when appropriate attention is paid to general patient status, cardiovascular system, pulmonary function, and fluid and electrolyte status, cystectomy and diversion can be completed with an acceptable rate of morbidity.

Effect of long-acting LHRH analog (Zoladex) on prostate cancer: evaluated by transrectal ultrasonography.

Transrectal ultrasonography has proved valuable in assessing the effect of primary treatment modalities for prostate carcinoma. This study shows patients who had a significant reduction in primary tumor volume had a significantly better prognosis and had less local symptoms than did the group of patients that did not have a significant reduction (less than 50%) in primary volume secondary to therapy. Patients were treated with either castration or Zoladex and all had Stage D2 cancer of the prostate.

Paraganglioma of urethra.

Paraganglioma of the urethra is a rare tumor; only 4 cases have been reported previously. We report a fifth case of urethral paraganglioma and review the literature.

Childhood embryonal carcinoma of testes.

Aggressive combined therapy for pediatric embryonal carcinoma of the testis appears to be warranted. The use of cycled chemotherapy has a place in treatment of this disease even in patients with a negative lymphadenectomy.

Transrectal ultrasonography. Early experience with use as prostate cancer detection tool.

Two hundred forty asymptomatic males, aged fifty-five to seventy years, underwent transrectal ultrasound of the prostate as part of a screening examination in conjunction with The National Prostate Cancer Detection Project (NPCDP). Nineteen prostate adenocarcinomas were detected, eight of which were nonpalpable. Fifteen of these patients had pathologic Stage B, 2 had microscopic Stage C (seminal vesicle involvement), and 2 had Stage D2 (bone) disease. While the activity and treatment of the eight nonpalpable lesions remain in question, the diagnosis certainly was made only with this type of examination. The use of transrectal ultrasound as a screening tool must continue to be prospectively evaluated in a multicenter trial.

Radical prostatectomy 1972-1987 single institutional experience: comparison of standard radical prostatectomy and nerve-sparing technique.

During the period of time from 1972 to 1987 a total of 104 radical prostatectomies were performed at the Ohio State University. From 1972 to 1985, standard radical retropubic prostatectomy was done in 60 patients and from 1986 to June 30, 1987, radical retropubic nerve-sparing prostatectomy was carried out in 44 patients. Transrectal ultrasound evaluation was available only for three quarters of the patients in the latter group. In the early part of the series, standard prostatectomy revealed 51 percent of the patients to have organ-confined disease and in the latter series 75 percent had organ-confined disease. In the earlier study only a retrospective analysis of the pathology reports was available, and in the latter study prospective evaluation was available with regard to pre- and postoperative staging, erectile function, blood loss and replacement, PSA data, and clinical and pathologic staging. It appears the radical nerve-sparing prostatectomy has several advantages including decreased blood loss, increased reservation of erectile function in 70 percent of the patients who were potent preoperatively, and a more accurate assessment of clinical stage prior to surgery through the use of transrectal ultrasonography.

Pyelosinus extravasation and urinoma associated with malignancy. Computed tomography demonstration.

We report 3 cases of abdominal malignancy with urinary tract obstruction and pyelosinus extravasation. Urinomas were present in 2 cases. The computed tomographic findings are emphasized, including the distribution of the extravasated urine reflecting the partitioning in the perirenal space. The cases presented within an eighteen-month period suggest pyelosinus extravasation and urinoma formation may not be uncommon in malignant disease affecting the retroperitoneum and pelvis.

Virilizing adrenal cortical carcinoma with hypertrophy of spermatic tubules in childhood.

A review of adrenal cortical carcinoma in childhood is presented, including endocrinologic aspects. Electron microscopic features are presented, as well as the finding of hypertrophied spermatic tubules. The importance of serial steroidal determinations is stressed as a "tumor marker" that may help in early detection of recurrent disease and possibly increased long-term survival.

Bilateral ureteropelvic junction avulsion after blunt abdominal trauma.

Ureteral pelvic junction avulsion can occur after deceleration injury. A case of this type of injury is presented herein, as well as a review of the literature.

Diagnosis of hyperparathyroidism.

Hyperparathyroidism is an important cause of calculous disease. A simple reliable protocol for evaluation of patients has been developed. In 20 patients with hyperparathyroidism this protocol has produced no false positive studies. Normocalcemic hyperparathyroidism can be diagnosed by this convenient method, and this protocol can be carried out in any hospital as part of an out- or inpatient workup.

Localized staging of prostate carcinoma: comparison of transrectal ultrasound and magnetic resonance imaging.

To evaluate the usefulness of two new imaging modalities in the clinical staging of prostate cancer the following study was done. Twelve patients with biopsy-proved carcinoma of the prostate were evaluated preoperatively with magnetic resonance imaging (MRI) of the pelvis and transrectal ultrasound of the prostate. The main parameters evaluated were the ability of these two modalities to accurately predict capsular penetration and seminal vesicle involvement in these 12 patients: 10 went on to pelvic lymph node dissections, and 8 had radical retropubic prostatectomies. Thus the preoperative studies could be compared to the pathologic results. Based on our results we believe transrectal ultrasonography is more accurate in the assessment of seminal vesicle involvement and comparable to MRI in determining capsular penetration. Because of the lower cost of ultrasound we believe it to be both an economical and accurate way to preoperatively stage prostate carcinoma.

Testicular torsion and its effects on contralateral testicle.

Twenty-six male adult Noble (Nb) rats underwent unilateral left testicular torsion of 720 degrees. The testicles of the 6 control animals were immediately detorsed. The experimental animals were divided into 4 groups according to the surgical approach (abdominal vs. scrotal) and location where the torsed testicle was placed (abdomen vs. scrotum). After six hours all torsed testicles in the experimental groups were detorsed. One month later all animals were sacrificed, and the contralateral testicles were examined for spermatogenesis and mean seminiferous tubular diameter. All groups displayed decreased spermatogenesis with smaller mean seminiferous tubular diameter as compared with the control group.

Relative value of prostate-specific antigen and prostatic acid phosphatase in diagnosis and management of adenocarcinoma of prostate. Ohio State University experience.

Serum concentrations of prostate-specific antigen (PSA), prostate-specific acid phosphatase (PAP), and transrectal prostatic ultrasound were utilized in the evaluation of 193 men with various urologic disorders. Of the 193 patients, 48 had prostate cancer, and the other 145 included 5 with genitourinary neoplasms, 69 with benign prostatic hypertrophy, and 71 with other non-neoplastic genitourinary disease. PSA levels were elevated in 35 patients with prostate cancer and in 25 of the 145 without prostate cancer. PAP levels were elevated in 15 with prostate cancer and in 2 of the 145 without prostate cancer. The data indicate that PSA is a more sensitive but less specific tumor marker than PAP in the detection of prostate cancer. PSA appears to be more sensitive than PAP in monitoring the response to treatment. The use of PSA and PAP jointly to detect and to monitor prostate cancer did not appear to enhance the clinical utility over that of PSA alone.

ESWL treatment of urinary calculi.

A total of 711 patients with symptomatic upper and lower urinary tract calculi underwent extracorporeal shock-wave lithotripsy (ESWL) at the Ohio Kidney Stone Center during the first six months. At follow-up 84 percent of the first 180 patients are stone-free. Retreatment was required for 2.8 percent of the patients with residual stone material. Thirty-seven percent of the treatments required cystoscopy with ureteral stent placement for manipulation of stones or delineation of distal ureteral anatomy to facilitate ESWL. Complications were minimal at less than 3 percent.

Radical prostatectomy: OSU and affiliated hospitals' experience 1985-1989.

A total of 528 patients have been treated with radical prostatectomy and node dissection during the last five years. Correlation of clinical and pathologic staging will be presented. Over 85 percent of these patients had Gleason scores of 6 or less. Patients who had nerve-sparing surgery had a potency rate of over 60 percent post surgery.

Treatment of an Nb-Pr-A.I.-3 (autonomous) tumor with combination chemotherapy.

The rat prostatic adenocarcinoma Nb-Pr-A.I.-3, an androgen-insensitive tumor, was evaluated with the following treatments: cyclophosphamide, cis-platinum, adriamycin, and the following combination therapies: cyclophosphamide and cis-platinum; adriamycin and cis-platinum; adriamycin, cis-platinum, and cyclophosphamide. Successful therapeutic combinations included cyclophosphamide alone (P Less Than 0.001) and the triple-drug combination (P Less Than 0.001). Significance was based on the final tumor volume at the termination of the experiment. Cyclophosphamide treatment alone was the only therapeutic regimen that resulted in complete tumor regression (16%) (2/12). Cyclophosphamide therapy also resulted in the lowest number of animals with metastasis (25%). On the basis of this study, the authors rate this animal model as a suitable one for trials of various chemotherapeutic combinations as well as for determining combination or single agents useful in preducing tumor regression and a decreased number of metastasis.

Immunobiology and therapeutic manipulation of heterotransplanted Nb rat prostatic adenocarcinoma. Chemotherapy of autonomous tumor, 102 Pr, heterotransplanted into congenitally athymic (nude) mice and syngeneic Nb rats.

Nb rat prostatic adenocarcinomas, previously induced by the administration of testosterone and estrogen, have been serially studied as heterotransplants into congenitally athymic (nude) mice and into groups of Nb rats. This animal system has been used to evaluate the chemotherapeutic efficacy of 5-fluorouracil and Ftorafur. The use of both species was to determine if there would be any significant difference in relative tumor growth in nude mice which lack functional T cells as opposed to intact Nb rats. The autonomous tumor, 102 Pr, is the subject of the thesis presented herein. One donor Nb rat bearing 102 Pr prostatic adenocarcinoma served as the donor for this experiment. The nude mice and Nb rats received the transplant on the same date and were subjected to the chemotherapies outlined above and were treated after there was sufficient increase in tumor volume from the 2 mm3 wedge to assure growth and neovascularity (greater than 60 mm3). Statistically significant data was presented revealing 5-fluorouracil to be efficacious in the treatment of these tumors. Also presented is data revealing differences in growth versus time in the respective recipient animal hosts. It is suggested herein that this combination animal model system could be used for screening potential cytotoxic chemotherapeutic agents.