Jay Y. Gillenwater

Report of the United States Cooperative Study of Extracorporeal Shock Wave Lithotripsy

Extracorporeal shock wave lithotripsy effectively fragments urinary calculi in the upper urinary tract and upper ureter. These fragments pass completely by 3 months in 77.4 per cent of the patients with single stones. Risk of obstruction, increased postoperative pain, need for additional urological operations and retained fragments are low for stones less than 1 cm. in size. As the number of stones treated or single stone size increases above 1 cm. the risk for these factors increases. Adjunctive urological surgical management is required in 9 per cent of the patients preoperatively and 8 per cent postoperatively. Only 0.6 per cent of the patients require some type of open operation to resolve the stone problems after extracorporeal shock wave lithotripsy. Hemorrhage, obstruction by fragments, severe pain and urinary infection all constitute known complications and require careful urological management of all patients. Hospitalization averages 2 days after treatment and patients usually return to work within a few days after they are discharged from the hospital.

Extracorporeal Shock Wave Lithotripsy in the Prone Position: Treatment of Stones in the Distal Ureter or Anomalous Kidney

A total of 15 patients underwent ESWL using the Dornier HM3 lithotriptor with the patient in the prone position. The stones were in the distal ureter over the sacroiliac joint in 10 patients, 8 of whom had undergone unsuccessful ureteroscopic manipulation. Two patients had horseshoe kidneys with stones that were too anterior to permit accurate targeting with the patient in the standard supine position. One patient had a solitary stone in a pelvic kidney and 1 had an obstructing ureteropelvic junction stone in a crossed ectopic kidney. The final patient had a reconstructed lower urinary tract with a stone at 1 of the ureterointestinal anastomoses. Excellent pulverization was achieved in all patients after only 1 prone ESWL treatment. One patient required temporary percutaneous nephrostomy after ESWL and 1 may require retrograde manipulation of fragments at the ureterovesical junction. No patient had melena, and other than temporary ileus in 1 patient who had concurrent supine ESWL of renal calculi, no gastrointestinal complications were seen. All but 1 patient were free of stones 1 month after prone ESWL. Prone ESWL prevents blockage of shock wave energy by the bony pelvis, because the shock waves enter anteriorly and exit posteriorly. ESWL with the patient in the prone position is a safe and effective treatment of calculi in the distal ureter or anomalous kidney.

Phase I Dose Escalation Clinical Trial of Adenovirus Vector Carrying Osteocalcin Promoter-Driven Herpes Simplex Virus Thymidine Kinase in Localized and Metastatic Hormone-Refractory Prostate Cancer

Osteocalcin (OC), a major noncollagenous bone matrix protein, is expressed prevalently in prostate cancer epithelial cells, adjacent fibromuscular stromal cells, and osteoblasts in locally recurrent prostate cancer and prostate cancer bone metastasis [Matsubara, S., Wada, Y., Gardner, T.A., Egawa, M., Park, M.S., Hsieh, C.L., Zhau, H.E., Kao, C., Kamidono, S., Gillenwater, J.Y., and Chung, L.W. (2001). Cancer Res. 61, 6012-6019]. We constructed an adenovirus vector carrying osteocalcin promoter-driven herpes simplex virus thymidine kinase (Ad-OC-hsv-TK) to cotarget prostate cancer cells and their surrounding stromal cells. A phase I dose escalation clinical trial of the intralesional administration of Ad-OC-hsv-TK followed by oral valacyclovir was conducted at the University of Virginia (Charlottesville, VA) in 11 men with localized recurrent and metastatic hormone-refractory prostate cancer (2 local recurrent, 5 osseous metastasis, and 4 lymph node metastasis) in order to determine the usefulness of this vector for the palliation of androgen-independent prostate cancer metastasis. This is the first clinical trial in which therapeutic adenoviruses are injected directly into prostate cancer lymph node and bone metastasis. Results show that (1). all patients tolerated this therapy with no serious adverse events; (2). local cell death was observed in treated lesions in seven patients (63.6%) as assessed by TUNEL assay, and histomorphological change (mediation of fibrosis) was detected in all posttreated specimens; (3). one patient showed stabilization of the treated lesion for 317 days with no alternative therapy. Of the two patients who complained of tumor-associated symptoms before the treatment, one patient with bone pain had resolution of pain, although significant remission of treated lesions was not observed by image examination; (4). CD8-positive T cells were predominant compared with CD4-positive T cells, B cells (L26 positive), and natural killer cells (CD56 positive) in posttreated tissue specimens; (5). levels of HSV TK gene transduction correlated well with coxsackie-adenovirus receptor expression but less well with the titers of adenovirus injected; and (6). intrinsic OC expression and the efficiency of HSV TK gene transduction affected the levels of HSV TK protein expression in clinical specimens. Our data suggest that this form of gene therapy requires further development for the treatment of androgen-independent prostate cancer metastasis although histopathological and immunohistochemical evidence of apoptosis was observed in the specimens treated. Further studies including the development of viral delivery will enhance the efficacy of Ad-OC-hsv-TK.

Osteocalcin-directed gene therapy for prostate-cancer bone metastasis

Abstract Osteocalcin (OC) is a major noncollagenous bone protein whose expression is limited almost exclusively to osteotropic tumors and mature calcified tissue (differentiated osteoblasts). The function of OC, a highly conserved gamma-carboxyglutamic acid-containing protein, relies in part on its ability to bind hydroxyapatite and act as a chemoattractant for bone-resorbing cells. Serum osteocalcin levels are used clinically as an index of active bone turnover. Research in our laboratory has revealed that OC is expressed in several solid tumors, including osteosarcoma and ovarian, lung, brain, and prostate cancers. Evidence arising from reverse-transcription polymerase chain reaction (RT-PCR; detection of OC mRNA), immunohistochemical staining (detection of OC protein), and transient transfection and reporter assay (detection of OC mRNA transcription) reveals that OC expression is up-regulated in numerous solid tumors, with its expression being further elevated in androgen-independent prostate cancers. A recombinant, replication-defective adenovirus, Ad-OC-TK (OC promoter-driven herpes-simplex-virus thymidine kinase) was constructed and, when combined with the appropriate prodrug, either ganciclovir (GCV) or acyclovir (ACV), was found to be effective at destroying prostate-cancer cell lines in vitro and prostate tumor xenografts in vivo in both subcutaneous and bone sites. Additionally, via use of the OC promoter the supporting bone stromal cells are cotargeted when the prostate cancer interdigitates with bone stroma at the metastatic skeletal sites. Thus, maximal tissue-specific cell toxicity is achieved by the interruption of cellular communication between the prostate cancer and the bone stroma. We describe herein the preclinical foundation as well as the design and implementation of an ongoing phase I clinical trial at the University of Virginia that targets androgen-independent metastatic prostate cancer using the Ad-OC-TK vector.

The effect of ursodiol on the efficacy and safety of extracorporeal shock-wave lithotripsy of gallstones: The dornier national biliary lithotripsy study

BACKGROUND In the treatment of gallstones with extracorporeal shock-wave lithotripsy, the bile acid ursodiol is administered to dissolve the gallstone fragments. We designed our study to determine the value of administering this agent. METHODS At 10 centers, 600 symptomatic patients with three or fewer radiolucent gallstones 5 to 30 mm in diameter, as visualized by oral cholecystography, were randomly assigned to receive ursodiol or placebo for six months, starting one week before lithotripsy. RESULTS The stones were fragmented in 97 percent of all patients, and the fragments were less than or equal to 5 mm in diameter in 46.8 percent. On the basis of an intention-to-treat analysis of all 600 patients, 21 percent receiving ursodiol and 9 percent receiving placebo (P less than 0.0001) had gallbladders that were free of stones after six months. Among those with completely radiolucent solitary stones less than 20 mm in diameter, 35 percent of the patients receiving ursodiol and 18 percent of those receiving placebo (P less than 0.001) were free of stones after six months. Biliary pain, usually mild, occurred in 73 percent of all patients but in only 13 percent of those who were free of stones after three and six months (P less than 0.01). There were few adverse events. Only diarrhea occurred with a significantly different frequency in the two groups: 32.6 percent were affected in the ursodiol group, as compared with 24.7 percent in the placebo group (P less than 0.04). Severe biliary pain occurred in 1.5 percent of all patients, acute cholecystitis in 1.0 percent, and acute pancreatitis in 1.5 percent; endoscopic sphincterotomy was performed in 0.5 percent, and cholecystectomy in 2.5 percent. CONCLUSIONS Extracorporeal shock-wave lithotripsy with ursodiol was more effective than lithotripsy alone for the treatment of symptomatic gallstones, and equally safe. Treatment was more effective for solitary than multiple stones, radiolucent than slightly calcified stones, and smaller than larger stones.

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, Gleasons 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.

Radical Prostatectony with Preservation of Urinary Continence

PURPOSE In an effort to improve postoperative urinary continence after radical retropubic prostatectomy, a new operation to preserve the bladder neck and a significant portion of the prostatic urethra has been developed. MATERIALS AND METHODS The prostatic urethra is dissected in continuity with the bladder away from the lumen of the prostate, which allows for a true urethra-to-urethra anastomosis. RESULTS A total of 24 patients who underwent the new continence sparing radical retropubic prostatectomy was compared retrospectively to 80 who previously underwent a nerve sparing procedure. Total continence was noted immediately in 11 patients, within 9 days in 15 and within 7 weeks in 21 of 24 who underwent the new operation, compared to 1, 5 and 33, respectively, of 80 who underwent the standard operation. Microscopic positive margins were noted in 2 of 24 patients with the new continence sparing operation. Early results of cancer control were good. CONCLUSIONS Early followup of this new technique of radical retropubic prostatectomy suggest that preservation of the continence mechanism at the level of the bladder neck and prostatic urethra results in significantly improved postoperative urinary continence without adversely affecting cancer control.

Radioactive implant migration in patients treated for localized prostate cancer with interstitial brachytherapy.

PURPOSE In several of the initial patients undergoing brachytherapy at our institution radioactive implants were visible in the thorax on chest radiography. The clinical ramifications of this unanticipated finding were unclear. Thus, we investigated the incidence of brachytherapy seed migration to the chest and whether these seeds were associated with any clinical significance. MATERIALS AND METHODS We retrospectively reviewed the records of all patients who underwent ultrasound or computerized tomography guided brachytherapy of 103palladium seeds from March 1997 to March 1999. This list of patients on brachytherapy was then matched against the radiology computer system to determine those who had undergone chest X-ray after brachytherapy. When the radiology report was unclear regarding brachytherapy seeds, chest x-rays were reviewed by one of us (R. O.) to determine the presence and position of the seeds. RESULTS Post-brachytherapy chest x-rays were available in 110 of the 183 patients. In 78 cases no brachytherapy seeds were identified. Radioactive implants were identified on chest radiography in 32 patients (29%), including 1 to 5 seeds in 20, 8, 1, 2 and 1, respectively. No patients complained of any change in pulmonary symptoms after brachytherapy. CONCLUSIONS Radioactive implants migrated after brachytherapy for localized prostate cancer in 29% of the patients who underwent post-procedure radiography. There did not appear to be a pattern to the seed distribution. However, while the incidence was not negligible, no patient appeared to have any acute pulmonary symptoms. Therefore, while the migration of radioactive implants to the chest is a real phenomenon, it appears to have no adverse clinical consequences in the early post-procedure period.

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

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.

Complications following ureteroscopy

We report 4 cases of ureteral injury and stricture formation following ureteroscopic stone manipulation. Possible etiologies of stricture formation and our methods of managing them are discussed. The complications of ureteroscopy have been reported only rarely and the ureteroscopist should be aware that the procedure is not always benign.