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.

Familial pheochromocytoma, hypercalcemia, and von Hippel-Lindau disease. A ten year study of a large family.

Long-term epidemiological and laboratory studies were carried out in a kindred with familial pheochromocytoma associated with von Hippel-Lindau disease. Thirteen members were affected by the syndrome and the trait appears to be transmitted in an autosomal dominant fashion. Of 13 patients, 7 had pheochromocytoma alone. Of the remaining six patients, one had pheochromocytoma combined with von Hippel-Lindau disease, four had pheochromocytoma with retinal disease only, and a single patient had a retinal lesion without pheochromocytoma. In four patients, pheochromocytoma antedated the development of retinal lesions. Ten members also had mild hypercalcemia without accompanying elevations of PTH in the 4 patients in whom this was determined. In all, hypercalcemia was corrected with removal of tumors, and no patient had a return of hypercalcemia in the absence of recurrent increases in urinary catecholamines. The clinical presentations in 12 patients varied markedly, as did their urinary excretion rates of norepinephrine, epinephrine and their metabolites. However, an analysis of the data revealed significant correlations not previously described between the urinary excretion of free catecholamines (norepinephrine plus epinephrine), blood pressure, the free catecholamine content of the tumor and the age of the patient. Urinary excretion of free norepinephrine plus epinephrine appear to be decreased with advancing age (p less than 0.001). Both systolic and diastolic blood pressures and the age of the patient were inversely correlated (p less than 0.01). A significant inverse relationship between the tumor content of free catecholamines and the age of the patients was, although to a lesser degree, also present (p less than 0.05). As a whole, the size of the tumors and their norepinephrine content were not correlated. We present a concept that, in familial pheochromocytoma, the metabolism of catecholamines is altered by the process of aging, and that this change modifies the clinical presentations of the disease.

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.

Renal liposarcoma.

A liposarcoma arose in the kidney of a 52-year-old man. After 13 years, it recurred, was resected, and recurred again. The second recurrence was inoperable.

Home urine cultures by the dip-strip method: results in 289 cultures.

Bacteriuria screening on 289 children was performed by their parents by means of a self-administered dip-strip culture which was inoculated, incubated, and interpreted in the home. Simultaneous pour-plate quantitative cultures and laboratory-tested dip-strip cultures were done on the same urine specimen which had been tested at home. The dip-strip culture was reliable (89%) in detecting significant bacteriuria with home administration and interpretation. Only 1.6% false-positive results occurred in the home testing. The dip-strip home cultures are an effective way for screening or follow-up of patients with bacteriuria.

An autosomal dominant syndrome of radial hypoplasia, triphalangeal thumbs, hypospadias, and maxillary diastema.

We describe a family in which eight persons (three males, five females) in three generations had a syndrome of bilateral and strikingly symmetrical triphalangeal thumbs and radial hypoplasia. The affected males also had a first-degree hypospadias and all affected family members had an anterior maxillary diastema. The syndrome was inherited in an autosomal dominant fashion.

Pharmacokinetics of iodamide in normal subjects and in patients with renal impairment.

The pharmacokinetic characteristics of iodamide, a contrast agent for excretion urography, were studied in seven normal subjects and in 15 patients with various degrees of renal impairment. Two different formulations were administered, namely, a 65% solution (iodamide 300) by slow intravenous injection and a 24% solution by slow intravenous (drip) infusion. Both preparations of iodamide exhibited characteristics of an open two-compartment model. In both normal subjects and patients, the contrast agent was excreted almost exlusively in urine. In normal subjects, the pharmacokinetic parameters of both formulations were similar, with a distribution half-life (1/2alpha) of about 3 minutes and a disposition half-life (t1/2beta) of about 69 minutes. An average of 84 per cent of the dose was excreted in urine within 4 hours after administration of iodamide with net renal tubular secretion of about 38 per cent. The binding of iodamide to plasma proteins was negligible, and the extent of biotransformation of iodamide was minimal. In patients with renal impairment, the disposition half-life (t1/2beta) of iodamide ranged from 4.1 to 16.4 hours. Other changes in pharmacokinetic parameters were also seen in patients with renal impairment.

Evaluation of Uricult dip slide in two hospital populations.

The Uricult dip slide was compared to traditional methods of bacterial isolation and quantitation in two different hospital wards. In a chronic care ward for patients with spinal cord injuries, the correlation of the dip slide and pour plate results was 96 per cent; there were very few specimens which had colony counts between 10(4) and 10(5) per ml. In a busy emergency room, the correlation between the dip slide and quantitative loop techniques was 75 per cent. In this population 18 per cent of the dip slide and 2l per cent of the calibrated loop cultures yielded colony counts between 10(4) and 10(5) per ml., and most of these cultures contained a mixture of bacteria. The results show that the Uricult dip slide performs well under ideal conditions. The dip slide can alleviate, but not eliminate, the problem of mixed bacterial growth at 10(4) to 10(5) colones per ml. The usefulness of the slide must be assessed in relation to the patient population and clinical situation in which it is to be employed.

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.

The role of the urologist in urinary tract infection.

The urologist's role in urinary tract infections will vary according to the situation. Urologists do give primary care, consult, define anatomic abnormalities, surgically correct abnormalities, and do basic research in the field of urinary tract infections. Urologists are essential in diagnosing and managing cases with infections behind obstructions and working out the differential diagnoses of chronic prostatitis.

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.

A new surgical technique for phalloplasty in patients with exstrophy of the bladder.

Posterior pelvic osteotomy has not been a satisfactory operation to provide penile length in the repair of defects associated with bladder exstrophy. The authors are proposing a new technique based on the movement of the halves of the symphysis and pubic rami (en bloc with the attached corpora cavernosa) to the midline. This is accomplished by osteotomies of the superior and inferior rami and bone grafting of the resulting defects in the superior rami only. The hip joints are not disturbed, risk of complications appears to be reduced, and increased effective penile length is obtained. Cadaver dissections confirmed the practicality of this operation and a successful case is reported. The anatomy and physiology of penile function that is important to surgeons is reviewed.

The bladder flap for urethral reconstruction in total phalloplasty.

At the University of Virginia Hospital we have developed a new technique of urethroplasty utilizing a full-thickness flap of bladder wall. Tubing and transfer of the flap may be completed in two stages. The bladder flap is approximately 28 X 4 cm in size. Strictures have not occurred with this technique, but special care is needed in placing the tube to avoid kinking of the new urethra at the angle where the penile urethra passes anterior to the pubic bone. In conjunction with modern methods of phalloplasty, a two-stage reconstruction of the entire phallus, including a functioning urethra, can be performed by combining the bladder wall flap with a modern (axial vessel) abdominal or groin skin flap. This will allow a patient to have satisfactory intercourse and permit orthostatic micturition with a minimum number of operative procedures.