Intraprostatic distribution and long-term follow-up after AdV-tk immunotherapy as neoadjuvant to surgery in patients with prostate cancer.

A phase I-II study to evaluate gene-mediated cytotoxic immunotherapy in newly diagnosed prostate cancer before radical prostatectomy was conducted in Monterrey, Mexico. First, to investigate delivery of adenovirus to the prostate, fluorescently labeled vector was injected into fresh prostatectomy specimens and distribution was visually analyzed. The optimal volume and site instillation was then used for transrectal ultrasound guided intraprostatic injection in 10 patients with adenocarcinoma scheduled for radical prostatectomy. Each received two apical and two basal 0.5 ml injections of AdV-tk for a total of 1 × 10(11) vp followed by 14 days of prodrug. Nine patients continued to tumor resection: six high risk, one intermediate and two low risk. In vivo vector distribution was analyzed from the resected tissue of four patients. Patients were monitored for tumor progression and acute and long-term safety. For vector delivery, two apical and two basal injections of 0.5 ml led to optimal organ-wide distribution ex vivo and in vivo. Cytotoxicity was evidenced by transient rise in PSA and tumor histology. There were no significant adverse events deemed related to the treatment and no late toxicities after median follow-up of 11.3 years. All six high-risk patients had positive surgical margins and one had seminal vesicle involvement. Despite slow PSA rise post surgery in three of these patients, none developed metastases. The intermediate- and low-risk patients had complete resections and none have progressed. In conclusion, in vivo transrectal ultrasound guided instillation of an adenoviral vector into four sites in the prostate was practical as an outpatient procedure, well tolerated and led to distribution throughout the intraprostatic tumor mass. AdV-tk demonstrated no significant acute or late toxicities. Trends in PSA and disease progression conveyed the possibility of a sustained immune response against residual disease.

In vivo surgical resection plus adjuvant gene therapy in the treatment of mammary and prostate cancer.

Adenoviral-mediated gene therapy delivery, combining the herpes simplex virus thymidine kinase gene (Ad-tk) with gancyclovir, has been evaluated as a treatment modality for numerous tumors in the laboratory and in the clinics. As a single modality, gene therapy has shown some promising local and systemic results but no curative success. Surgery is the standard of care for many solid tumors. However, minor residual tumor following surgical resection can lead to local recurrence, and surgery is neither efficient nor plausible for metastatic disease. In this study, two tumor models were used to evaluate the effects of Ad-tk gene therapy as an adjuvant to surgery. Subcutaneous mammary- and prostate-derived tumors were produced in syngeneic mice. To evaluate systemic effects, tumor cells were injected intravenously, with subsequent formation of lung nodules. The subcutaneous tumors were surgically resected and the tumor bed was bathed with saline or Ad-tk. The animals were evaluated for toxicity, local tumor recurrence, survival, and lung nodule formation. No evidence of additional toxicity was observed. In the less aggressive mammary model, the time to recurrence was increased from 11.7 (+/-1.0) days to 22.7 (+/-5.5) days. In the prostate model, recurrence went from a mean of 17.3 (+/-5.6) to 22.6 (+/-6.8) days. Survival was also improved from a mean of 19.7 (+/-1.1) to 32.3 (+/-4.8) and 26.1 (+/-5.0) to 34.1 (+/-6.1) days in the mammary and prostate models, respectively. Evidence of systemic benefits from the use of adjuvant Ad-tk therapy was demonstrated by a significant reduction in lung nodules from a mean of 17 to 3.5. These results suggest that Ad-tk gene therapy may be a useful adjuvant for patients undergoing surgery for treatment of cancer.

Does slow-release 5-fluorouracil and triamcinolone reduce subglottic stenosis?

The surgical management of subglottic stenosis may be complicated by reformation of strictures. A slow-release combination of 5-fluorouracil, which has an antiproliferative effect on fibroblasts, and the corticosteroid triamcinolone acetonide has been used experimentally to control scar production in ophthalmic operations. This study was performed to determine if this material also can be used to reduce formation of subglottic stenosis. Subglottic stenosis was induced in rabbits by means of injury to the subglottic mucosa and submucosa. A suspension of the compound at a concentration of 2.5 mg/ml or 12.5 mg/ml was injected into the adjacent soft tissues. A control group of rabbits received the same volume of the suspension fluid but no compound. Two rabbits from each group were killed 1, 2, and 12 weeks postoperatively. No stenosis was seen at 1 or 2 weeks, but at 12 weeks the rate of formation of subglottic stenosis was decreased to a mean of 15.20% in the experimental groups compared with 47.37% in the control group. There were no indications of local or systemic toxicity. The promising results from this preliminary study suggest that use of this compound may reduce restenosis among patients treated surgically for subglottic stenosis. Further studies are being conducted.