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.

Chromosome aberrations of human small cell lung cancer induced by a new 111In-bleomycin complex.

A new 111Indium labeled bleomycin complex (111In-BLMC) was prepared and found to be effective for tumor imaging and therapy both in mouse glioma and human small cell lung cancer (SCLC) cells. Chromosome aberrations were studied in human SCLC cells to explore its mechanisms of killing cancer cells. SCLC cells (N417) were exposed to 111In-BLMC, BLM, or 111InCl3 (for control) for 1 hour, treated with colcemid, and chromosomal changes were analyzed. A dramatic increase in chromatic gaps, breaks, chromosome breaks, double minutes, rings, triradii, quadriradii, and chromosome stickiness were observed in the cells treated by 111In-BLMC compared to BLM or 111InCl3. These results indicated that 111In-BLMC has therapeutic potential for combination chemo-radiotherapy of cancer (e.g., by Auger electrons and local energy deposition).

Penile cancer. Clinical presentation, diagnosis, and staging.

A high index of suspicion for penile cancer and a low threshold for biopsy of all penile lesions that do not respond to a short trial of conservative therapy are the primary requirements for early diagnosis and treatment of patients with penile cancer. Survival is related to stage; however, there is a considerable difference between clinical and pathologic stage. This discrepancy is attributable to the difficulty in determining corpora cavernosal invasion and inguinal lymph node metastases because of concomitant inflammatory changes and inaccuracies in diagnostic imaging modalities. Aggressive clinical staging may identify otherwise occult tumor and improve locoregional control and survival.

Prostate-specific antigen, digital rectal examination, and transrectal ultrasound in predicting the probability of cancer.

Over a 4 1/2 year period, 1,940 asymptomatic men were entered in a prostate cancer detection program consisting of digital rectal examination (DRE), prostate-specific antigen (PSA), and transrectal prostate ultrasound (TRUS). Four hundred and sixteen biopsies were performed resulting in the diagnosis of 79 cancers; 82% had clinically organ confined tumors. A recommendation for biopsy was made in 260 (62%) based on the TRUS alone, 55 (13%) by DRE alone, 92 (22%) when the DRE and TRUS were both abnormal, and in 9 (2.2%) cases when only PSA levels were elevated. The DRE, PSA, and TRUS were abnormal in 1,261 (65%), 989 (51%), and 1,552 (80%) of the patients with cancer, respectively. Prostate cancer detection increased as the serum PSA level increased above 4 ng/ml. The positive predictive value of both DRE and TRUS were significantly influenced by an elevated PSA, (P = .042 and P less than .00005, respectively). The results of this study support the idea that, although the prostate cancer detection rate is influenced by these three modalities and the detection rate of localized disease can be improved by early detection programs, its effect on mortality rates remains undefined at this time.

The relationship of prostate-specific antigen to digital rectal examination and transrectal ultrasonography. Findings of the American Cancer Society National Prostate Cancer Detection Project.

The participating institutions of the American Cancer Society National Prostate Cancer Detection Project did 520 biopsies on 2425 men over a 3.5-year period. A total of 88 cancers were confirmed pathologically, 93% of which clinically were organ confined. In 324 men (62.3%), a recommendation for biopsy was made based solely on the results of transrectal ultrasonography (TRUS); in 69 patients (13.3%), solely on the digital rectal examination (DRE); in 116 patients (22.3%), on abnormal DRE and TRUS examinations; and in 11 patients (2.1%), in whom DRE and TRUS were normal, on elevated prostate-specific antigen (PSA) levels. The TRUS was abnormal in 80.6% of men found to have cancer, and the PSA level and DRE were abnormal for 67% and 50% of cancers, respectively. The influence of PSA level on cancer detection increased as the serum level increased above 4 ng/ml. The positive predictive values of both the DRE and TRUS were influenced significantly by the presence of an elevated PSA level (P = 0.044 and P less than 0.001, respectively). The results of this ongoing multicenter study support the following statements: (1) the prostate cancer detection rate is influenced by this diagnostic triad and (2) the detection rate of organ-confined disease can be improved substantially by early detection programs.

Prostate-specific antigen levels in 1695 men without evidence of prostate cancer. Findings of the American Cancer Society National Prostate Cancer Detection Project.

The American Cancer Society National Prostate Cancer Detection Project is a prospective, multidisciplinary, and multicenter trial to assess the potential for early detection of prostate cancer by transrectal ultrasonography (TRUS), digital rectal examination (DRE), and serum prostate-specific antigen assay (PSA). By November 1990, 2805 men between the ages of 55 and 70 years with no known signs or symptoms of prostate cancer were enrolled in the study, which is planned to run for 5 years. Annual TRUS, DRE, and PSA tests were done on these subjects, and biopsies were recommended for suspicious lesions when detected. To study the performance of PSA testing in presumed normal subjects, all men were eliminated who had (1) prostate cancer detected on their initial examinations and proven by biopsy or (2) cancer detected during the year or subsequent examinations. Additionally, all men with TRUS or DRE findings that were interpreted as suspicious for cancer but who are being followed and have not yet had biopsies done were removed from this series. This left a unique, extensively screened group of 1695 men who were free of prostate cancer, as far as could be determined. Analyses of the PSA levels in this large population in the appropriate age range for increasing risk of prostate cancer revealed several important findings. First, there was a direct relationship between serum PSA levels and estimated prostate volume for both the currently available monoclonal and polyclonal PSA assays. Individuals with benign prostatic hyperplasia and larger gland volume have a higher normal limit of PSA than men with normal gland volume. Second, analyses showed no relationship between age and PSA levels or between symptoms of prostatism and PSA levels independent of gland enlargement. It was concluded that volume-adjusted upper limits of normal PSA can be determined for different levels of specificity desired. This information may be applicable to the use of PSA in men not already suspected of having prostate cancer and may increase its effectiveness as a tool for early detection.

Changes in PSA and early diagnosis of cancer of the prostate.

During the last four years approximately 400 men were evaluated in the early detection program for prostate cancer at The Ohio State University. Of these 400 men, 25 were found to have cancer. Eleven of the 25 had normal PSAs at the time cancer was diagnosed. The rise with a Hybritech assay, PSA of 1.2 ng/ml per year, one to two and subsequent years of greater than 1.2 ng/ml in this study indicates a higher likelihood of having a diagnosis of prostate cancer. Of the 25 patients who have been evaluated, only 4 patients had a subsequent drop of PSA from year one to two when the value dropped less than 0.6 ng/ml. Prostate intraepithelial neoplasia grade III has also been associated in these patients.

Enhancement of bacillus Calmette-Guerin attachment to the urothelium by removal of the rabbit bladder mucin layer.

It has been established that the urothelial mucin layer functions as a bacterial anti-adherence factor. Intravesical Bacillus Calmette-Guerin is used to treat patients with superficial bladder cancer. The proposed mechanism of action of Bacillus Calmette-Guerin is adherence to the urothelium with induction of an immunologic and/or inflammatory response. The current study was designed to determine if rabbit bladder mucin removal results in increased Bacillus Calmette-Guerin urothelial adherence. PAS and colloidal iron stains were used to demonstrate that intravesical instillation of 50% acetone renders rabbit bladder urothelium mucin deficient. The urothelium remains mucin deficient at two hours, but by 24 hours the mucin layer has been regenerated. Two hours following intravesical 3H-labeled Escherichia coli administration, bacterial adherence was 29-fold greater in mucin deficient than mucin intact rabbits (p = 0.05). By 12 hours, the difference in adherence was not significant. Two hours following intravesical administration of 3H-labeled Bacillus Calmette Guerin, mucosal adherence was 21-fold greater in mucin deficient compared to mucin intact rabbits (p = 0.002). After mucin removal, Bacillus Calmette Guerin urothelial adherence was significantly increased. The significant increase in Bacillus Calmette Guerin adherence after mucin removal may be clinically exploitable.

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.

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.

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)

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.

DNA ploidy and prostate-specific antigen as prognostic factors in clinically resectable prostate cancer.

Prostate-specific antigen (PSA) and DNA ploidy as measured by flow cytometry were compared with conventional prognostic indicators in 112 patients who underwent radical prostatectomy for clinically resectable prostate cancer. The variables examined included age, race, prostatic acid phosphatase (PAP), Gleason score of the radical prostatectomy specimen, and pathologic stage. No significant relationships were found between DNA ploidy and age, mean PAP value, and absolute PAP value. Of the 112 patients, 65 (58.0%) had disease limited to the prostate (pathologic Stages A and B); 47 (42.0%) had extraprostatic disease (pathologic Stages C and D1). The stage was related to the Gleason score (P less than 0.0001) where extraprostatic disease was associated with a Gleason score of 6 to 10. Nineteen (17.0%) patients had aneuploid tumors, and 93 (83.0%) had diploid tumors. DNA ploidy significantly correlated with pathologic stage (P = 0.04); aneuploidy was identified more frequently in patients with Stages C and D1 tumors. Aneuploid tumors occurred more frequently than diploid tumors in patients with a Gleason score of 6 to 10 (P = 0.034). Mean PSA values were higher in patients with aneuploid tumors (P = 0.078), extraprostatic neoplasms (P = 0.00001), and cancers with a Gleason score of 6 to 10 (P = 0.0004). Furthermore, PSA values greater than 10.0 ng/ml were associated with extraprostatic disease and a Gleason score of 6 to 10 (P less than 0.05 and P less than 0.001, respectively). Significant racial differences were found with respect to DNA ploidy, mean DNA indices, and mean PSA values. The 18 black patients had more DNA aneuploid tumors (P = 0.043), a higher mean DNA index (P = 0.017), and a higher mean PSA value (P = 0.043) than the 94 white patients. Both PSA and DNA ploidy analysis by flow cytometry appear to be valuable indicators in the evaluation of patients with prostatic carcinoma.

Prostate cancer.

Prostate cancer is the most common malignancy in men and the second leading cause of cancer deaths. Although the mortality rate for prostate cancer has remained unchanged for 50 years, new advances have changed classic concepts in the diagnosis and management of patients with this disease. Our understanding of the anatomy and natural history of patients with prostate cancer has been enhanced. The ability to diagnose early stage prostate tumors has been improved by the introduction of prostate-specific antigen and transrectal ultrasound. Clinical staging of patients with prostate cancer has been refined, which has decreased adverse effects of inappropriate treatment. Modifications in the technique of radical prostatectomy have minimized the morbidity associated with this procedure, making it a more attractive therapeutic option. DNA ploidy analysis holds promise as a predictor of response to hormonal therapy. New agents are available to reduce adverse effects of hormonal therapy. In addition, traditional ideas about the timing of hormonal therapy and the use of total androgen blockade are being challenged. These changes may presage an improved quality of life and improve survival for patients with prostate cancer.

Multifocal, synchronous inverted papillomas involving the ureter.

Inverted papillomas involving the upper urinary tract remain a rarely diagnosed phenomenon. A case of bilateral ureteral inverted papillomas is presented. The treatment and diagnosis of this lesion remain a challenge.

A method to study drug concentration-depth profiles in tissues: mitomycin C in dog bladder wall.

Determination of the depth of penetration of locally applied drug therapy and evaluation of possible mechanisms of drug transport require knowledge of drug concentration-versus-tissues depth profiles. A method to determine the drug concentration-depth profile is needed. We have devised such a method and used it to determine the penetration of mitomycin C (MMC) in the dog bladder wall after intravesical drug instillation. This method is based on sectioning of frozen tissue into 40-microns segments, followed by drug extraction and high-pressure liquid chromatography analysis. Tissue concentrations could be detected with a sensitivity of 1 ng/sample, or 20 ng/g for tissue samples of approximately 2 x 2 cm. This sensitivity was sufficient to describe the penetration of MMC in the bladder wall of dogs, using an identical instillation technique, dwell time, and MMC concentration as in human patients. Tissue concentrations were expressed relative to tissue weight or tissue protein contents. For MMC, standardization to tissue weight yielded a better mathematical fit of the concentration-versus-depth profiles than standardization to protein content. The time interval between tissue harvesting and freezing was critical. The MMC concentration at the urothelial side of dog bladders was 2- to 10-fold higher in samples processed immediately after harvesting, compared to samples processed after 1 hr or longer. This significant decrease was not due to drug metabolism in situ. In separate in vitro experiments, we found that the degradation of MMC in 8% tissue homogenate was relatively slow, with only a 30% decline in concentration over 24 hr.(ABSTRACT TRUNCATED AT 250 WORDS)

The use of the Nb rat in combination chemotherapeutic experiments for prostate cancer.

The Nb rat adenocarcinoma model has been used to evaluate combination chemotherapy. The Nb rat is a model system in which one can measure tumor regression, tumor metastasis and response to treatment. Combination treatment decreased metastasis and increased the incidence of regression in this triple chemo treatment program of 5-FU, Adriamycin and Cisplatinum.

Cultured human bladder tumors for pharmacodynamic studies.

Human bladder tumor fragments were cultured on collagen gel. In this system, the three dimensional architecture, cell-to-stroma and cell-to-cell interactions, and tumor heterogeneity were maintained. Cell viability and labeling index (LI) were determined by exposure to 3H-thymidine and autoradiography. Of the samples from 20 patients with transitional cell carcinoma, 14 (70%) were successfully cultured and had a mean LI of 32%. In addition, one specimen from a patient with squamous cell carcinoma was cultured and had a LI of 61%. Cultured samples were tested for chemosensitivity using a two hour exposure of mitomycin C in concentrations ranging from one to 50 micrograms./ml. A dose-dependent relationship was demonstrated; LI decreased as mitomycin C concentrations increased. The methodology described provides an alternative to suspension or monolayer techniques of culturing human bladder tumors for pharmacological studies.

Colon carcinoma associated with ureterosigmoidostomy.

A patient developing a colonic adenoma 38 years following ureterosigmoidostomy is presented. The mechanisms of neoplastic transformation associated with ureterosigmoidostomy is now better understood. This knowledge is being applied to develop modifications both of the surgical technique and the management of patients with this form of urinary diversion, and is a subject of discussion.