Prostate-specific antigen response and systemic T cell activation after in situ gene therapy in prostate cancer patients failing radiotherapy.

In an extended phase I/II study we evaluated 36 prostate cancer patients with local recurrence after radiotherapy who received single or repeated cycles of replication-deficient adenoviral vector (ADV)-mediated herpes simplex virus-thymidine kinase (HSV-tk) plus ganciclovir (GCV) in situ gene therapy with respect to serum PSA levels, alterations in immune cells, and numbers of apoptotic cells in needle biopsies. An initial cycle of HSV-tk plus GCV gene therapy caused a significant prolongation of the mean serum PSA-doubling time (PSADT) from 15.9 to 42.5 months (p = 0.0271) and in 28 of the injected patients (77.8%) there was a mean PSA reduction (PSAR) of 28%. It took a mean of 8.5 months for the PSA to return to the initial PSA (TR-PSA) value. A repeated cycle of gene therapy failed to significantly extend PSADT but did result in significant increases in PSAR (29.4%) and TR-PSA (10.5 months). Moderately increased serum adenovirus antibody titers were generally observed 2 weeks after initial vector injection. Also at this time there was a statistically significant increase in the mean percent of CD8(+) T cells positive for the HLA-DR marker of activation in peripheral blood (p = 0.0088). Studies using prostate biopsies obtained at the same time point demonstrated that vector DNA was detectable by PCR in most samples yet all patients remained positive for prostate cancer in at least one biopsy core. Further analysis demonstrated a correlation between the level of CD8(+) cells and the number of apoptotic cells in biopsies containing cancer cells (p = 0.042). We conclude that repeated cycles of in situ HSV-tk plus GCV gene therapy can be administered to prostate cancer patients who failed radiotherapy and have a localized recurrence. Biological responses to this experimental therapy including increases in PSADT, PSAR, and TR-PSA, and activated CD8(+) T cells present in the peripheral blood, were demonstrated. Interestingly, the density of CD8(+) cells in posttreatment biopsies correlated with the number of apoptotic cells.

The prognostic value of DNA ploidy in small renal cell carcinoma.

The objective was to study the prognostic value of Deoxyribonucleic Acid (DNA) ploidy status in small renal cell carcinomas (RCC). The nuclear DNA content of renal cell carcinoma tissues from patients who underwent radical or partial nephrectomy has been analyzed by flow cytometry. The results of the DNA ploidy have been correlated to the size of tumors and disease progression. Of the 50 patients with RCC studied, 8 (16%) progressed. Tumors with non-diploid DNA patterns were found in 24 (48%) of the 50 patients and in 4 of the 8 patients who progressed. Overall the median tumor size in our series was 50 mm. A tumor diameter of 50 mm or less was measured in 26 patients (group I) and above 50 mm in 24 (group II). Non-diploid DNA patterns were found in 11 (42.3%) and 13 (54.2%) patients in groups I and II, respectively. This difference between the groups was not significant. Only one patient in group I (3.8%) developed metastatic disease and died 72 months after the operation. In group II, 7 patients (29.2%) presented tumor progression and 5 died of metastatic disease. The survival probability in group I was 95% at 5 and 8 years (95% CI 70% to 99%) and for group II 94% at 5 years (95% CI 67%-99%) and 67% at 8 years (95% CI 39%-83%). DNA ploidy is an inaccurate predictor of tumor behavior in patients with RCC, even in small tumors. Tumor size is a more significant predictor of outcome.

Nephrovesical subcutaneous stent: an alternative to permanent nephrostomy.

PURPOSE: We studied whether a subcutaneous ureteral bypass may be an alternative to a permanent nephrostomy tube in patients with ureteral obstruction caused by pelvic malignancy. MATERIALS AND METHODS: Using local anesthesia we inserted an especially designed nephrovesical stent into subcutaneous tissue. The stent consists of 2 J stents that are joined by a connector after insertion into the renal pelvis and bladder. RESULTS: In 8 patients 10 subcutaneous stents were inserted instead of a permanent nephrostomy tube. Nephrostomy was required because of obstructed ureters caused by metastatic prostate or invasive bladder cancer. Attempted Double-J stent insertion into the obstructed ureter had previously failed. The bypass has functioned well in all cases during 6 weeks to 18 months of followup (mean 5.5 months). CONCLUSIONS: The high complication rate of a permanent nephrostomy tube and frequent rehospitalization render the subcutaneous stent an important alternative to nephrostomy. The subcutaneous stent eliminates external devices for urine drainage and improves patient quality of life.

The role of sildenafil in the treatment of erectile dysfunction in patients with pelvic fracture urethral disruption.

PURPOSE: Erectile dysfunction (ED) is a common sequel of pelvic fracture urethral disruption (PFUD). After repair of the urethral injury ED may be the most devastating long-term effect for the patient. Some patients with ED may regain normal erectile function. We prospectively studied the response to sildenafil and the erectile function of patients with ED due to PFUD. MATERIALS AND METHODS: The erectile function of patients referred to us with PFUD for urethroplasty were prospectively evaluated before surgery. Patients underwent nocturnal penile tumescence testing and, if results were abnormal, penile duplex ultrasonography with intracavernous injection and arteriography were performed to diagnose the etiology of ED. Patients were questioned about erectile function every 3 months after surgery and if they complained of ED they were offered 100 mg sildenafil. Patients were followed for at least 18 months after surgery. RESULTS: A total of 29 consecutive patients were evaluated and 22 (76%) of them had ED before surgery. Sufficient followup was available for 15 of the patients. Overall 47% of these patients responded favorably to sildenafil. Of the patients 60% with neurogenic ED and 20% of those with arterial ED responded to this treatment. In 33% of the patients ED resolved within the followup period. All patients with spontaneous resolution of ED previously responded to sildenafil (71% of sildenafil responders). CONCLUSIONS: In patients with ED due to PFUD, those with neurogenic ED are more likely to respond to sildenafil than those with arterial damage. Favorable response to sildenafil may predict spontaneous resumption of normal erectile function over time.