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Biomedical subjects

M Shalev

Publications and source records attributed to M Shalev.

At least 37 records · Page 2Linked to original sources
PubMed2000

Fenretinide therapy in prostate cancer: effects on tissue and serum retinoid concentration.

PURPOSE: To examine the feasibility of using fenretinide (4-HPR) for the prevention and treatment of prostate cancer. MATERIALS AND METHODS: We measured the impact of 4-HPR therapy on retinoid concentrations in vivo, in a mouse model of prostate cancer and clinically, in patients with prostate cancer who were given oral 4-HPR (200 mg/d) or placebo for 4 weeks before undergoing a radical prostatectomy. RESULTS: Prostate tumors in mice treated with 4-HPR contained high levels of 4-HPR and of all-trans-retinoic acid (RA) and reduced levels of retinol (ROH). Patients given 4-HPR were found to have significantly higher concentrations of 4-HPR in the cancerous prostate as compared with the serum levels (463 nmol/L v 326 nmol/L; P =.049), but they were only 1/10 the levels found in mice and were far below the concentrations reported in human breast tissue. Serum and tissue ROH levels were reduced to less than half the concentrations found in untreated controls. RA concentrations in human serum and in cancerous prostates were not significantly affected by 4-HPR treatment, in contrast with the findings in mice. CONCLUSION: The standard oral dose of 4-HPR proposed for breast cancer (200 mg/d) achieved only modest drug levels in the prostate and is unlikely to be effective for prostate cancer prevention or treatment. Higher doses need to be explored.

Aged↗
PubMed2000

Suicide gene therapy for prostate cancer using a replication-deficient adenovirus containing the herpesvirus thymidine kinase gene.

Current therapies for localized prostate cancer include radical prostatectomy, local radiation therapy, and cryoablation and are associated with a high rate of cure and acceptable morbidity. However, for men who have failed primary curative attempts or have metastatic disease, no effective therapy associated with acceptable morbidity exists. "Suicide" gene therapy delivered alone or in combination with other forms of treatment could potentially provide simultaneous efficacy against localized and systemic disease via the generation of cytotoxic activity and/or systemic immunity to the cancer. In this article we discuss our preclinical and clinical experience with a herpes-simplex-virus thymidine kinase/ganciclovir gene-therapy protocol for prostate cancer.

Adenoviridae↗
PubMed2000

The indwelling ureteric stent: a 'friendly' procedure with unfriendly high morbidity.

OBJECTIVE: To review the morbidity and complications of ureteric stent insertion and to evaluate specifically the effect of an indwelling ureteric stent on the changes in hydronephrosis after stenting. PATIENTS AND METHODS: In a prospective study, 110 renal units with a stent in place were evaluated in 90 patients. Of the 110 stents, 52 were left in place for 3 months, 23 for 6, 11 for 9, 19 for 12 and five (forgotten stents) for 13-30 months. The patients were followed using plain abdominal X-ray at 1 and 30 days after stenting. They were further followed using ultrasonography and plain films every 3 months until the scheduled date for stent removal or the appearance of complications. RESULTS: Thirty-four patients had fever and bacteriuria after stent insertion. Of the 110 stents, 11 (10%) fragmented and nine (8%) migrated. Seventeen patients complained of flank pain on voiding. In 21 renal units (19%) there was no change in the severity of hydronephrosis, whereas in six (5.5%) hydronephrosis developed or worsened after stenting. CONCLUSION: Although ureteric stenting is undoubtedly an important procedure to relieve ureteric obstruction, the indications for stent insertion should be considered carefully in every patient. The close follow-up of stented patients is valuable for the early detection of morbidity or complications and in such cases the stent should be removed or exchanged as soon as possible.

Catheters, Indwelling↗
PubMed2000

Cytopathic effect of in situ gene therapy in prostate cancer.

This is a morphologic study of in situ gene therapy effects in patients with prostate cancer using the Herpes Simplex VirusThymidine Kinase gene (HSV-tk) followed by ganciclovir. Prostatectomy specimens from the first 4 patients showed the following morphologic changes: (1) various degrees of necrosis were seen in cancer foci; (2) cytopathic changes were seen across the whole spectrum of Gleason grades; (3) the normal prostate was rarely affected by necrosis, but contained an intense mononuclear infiltrate; (4) loss of nuclear detail was a common finding. Volumetric studies showed that only portions of the tumor show morphologic effects as well as an inverse relationship between percentage of affected tumor and prostate and tumor size. An inflammatory response was observed, with predominance of CD20-positive cells in normal prostate tissue, CD8 (cytotoxic T cells) in the tumor, and macrophages in all areas of the treated prostates. We believe that these changes represent the cytopathic effect of our in situ gene therapy on prostate cancer, and that they trigger a local immune response.

Aged↗
PubMed2000

Late complications of ureteral stents.

OBJECTIVE: To review morbidity and late complications of ureteral stent insertion and to specifically evaluate hydronephrosis as a radiologic finding of obstruction in the presence of an indwelling ureteral stent. METHODS: In this prospective study, we evaluated 110 stented kidneys in a group of 90 patients. Of 110 stents, 52 were left in place for 3 months, 23 for 6 months, 11 for 9 months, and 24 for up to 12 months. With the stent in place, patients were followed by plain abdominal X-ray 1 and 30 days after stenting. Further follow-up was performed through ultrasound and plain film every 3 months until scheduled date for stent removal or the appearance of complications. RESULTS: In 11 of 110 cases (10%) there was stent fragmentation and in 9 (8.2%) stent migration. In 10 cases (9.1%), there was no change in the severity of the hydronephrosis, but because of flank pain or urinary tract infection with fever, the stents had to be removed. In 6 cases (5.4%) hydronephrosis developed or worsened after stenting. Of the 110 ureteral stents, 32.7% had to be removed because of late complications. CONCLUSIONS: Although ureteral stenting is undoubtedly an important procedure for the release of ureteral obstruction, the indications for stent insertion should be carefully considered in each patient. Late complications of ureteral stents are frequent and appear in one third of the patients. Close follow-up of stented patients is valuable in early detection of morbidity or complications, and in such cases the stent should be removed or exchanged as soon as possible.

Catheters, Indwelling↗
PubMed2000

Differential expression of nuclear retinoid receptors in normal and malignant prostates.

PURPOSE: To determine (1) whether nuclear retinoic acid receptors (RARs) and retinoid X receptors (RXRs) are differentially expressed in normal and in cancerous human prostate tissues and (2) whether oral fenretinide therapy impacts the expression of these receptors in prostate cancer. PATIENTS AND METHODS: In situ hybridization with antisense riboprobes was used to probe for RAR and RXR transcripts in prostate tissues in a two-phased study: (1) expression of retinoid receptors in eight normal prostates was compared with their expression in 10 randomly picked radical prostatectomy specimens (group A); (2) expression of retinoid receptors was determined in 22 radical prostatectomy specimens from participants in a clinical study (group B). Twelve patients received oral fenretinide 200 mg/d, and 10 received placebo pills for 28 days before surgery. RESULTS: RARalpha, RARgamma, RXRalpha, and RXRgamma mRNAs were detected in most normal and cancerous prostates. In group A, RARbeta mRNA was expressed in only four of 10 malignant prostates but was present in seven of eight benign prostates (P =.05). RXRbeta mRNA was expressed in four of eight benign prostates and in zero of 10 malignant prostates (P =.023). In group B prostates, RARbeta and RXRbeta mRNAs were markedly reduced in all cancers and in the adjacent, nonmalignant tissue. There were no differences between receptor expression in the fenretinide-treated group and the placebo group. CONCLUSION: RARbeta and RXRbeta mRNAs are selectively lost in both prostate cancer and adjacent morphologically normal prostatic tissue, supporting the concept of a field of carcinogenesis. One month of oral fenretinide (200 mg/d) did not influence the expression of retinoid receptors in prostate cancer.

Aged↗
PubMed2000

Suicide gene therapy toxicity after multiple and repeat injections in patients with localized prostate cancer.

PURPOSE: We assess risks, toxicity and side effects of multiple and repeat in situ suicide gene therapy in patients with localized prostate cancer. MATERIALS AND METHODS: The study population comprised patients with localized prostate cancer receiving multiple and/or repeat intraprostatic injections of a replication deficient adenovirus containing the herpes simplex virus thymidine kinase (HSV-tk) gene. Intravenous ganciclovir or oral valaciclovir was given for 14 days after injection. Patients were recruited from 4 different clinical protocols in studies of toxicity and efficacy of suicide gene therapy, and closely monitored for toxicity and side effects during and after treatment. Toxicity was graded according to the Cancer Therapy Evaluation Program common toxicity criteria published by the National Cancer Institute. RESULTS: A total of 52 patients were treated under these clinical protocols with a total of 76 gene therapy cycles. Toxic events were recorded in 16 of 29 patients (55.2%) who were given multiple viral injections into the prostate, 7 of 20 (35%) who received 2 cycles of "suicide" gene therapy and 3 of 4 (75%) who received a third course of gene therapy. All toxic events after multiple or repeat injections were mild (grades 1 to 2) and resolved completely once the therapy course was terminated. No additive toxicity was noted in patients receiving repeat gene therapy cycles. Mean followup was 12.8 months (range 3 to 34). Preliminary results for 28 patients in 2 clinical protocols indicated a mean decrease of 44% in PSA in 43%. CONCLUSIONS: Direct injection into the prostate of a replication defective adenovirus containing the HSV-tk gene followed by intravenous ganciclovir is safe even in repeat cycles.

Acyclovir↗
PubMed2000

Effect of 13-cis-retinoic acid on serum prostate-specific antigen levels in patients with recurrent prostate cancer after radical prostatectomy.

The objective of this study was to determine whether there is any beneficial effect of oral 13-cis-retinoic acid (isotretinoin) on prostate cancer, using serum prostate-specific antigen (PSA) levels as a surrogate end point in patients with a rising serum PSA after radical prostatectomy. In the first phase, the effect of the drug on the serum PSA level was tested in 14 control patients with normal prostates. Our goal was to exclude any effect of isotretinoin on PSA secretion and metabolism and thus to validate any observed effect on PSA as indicative of anticancer activity. In the second phase, patients with rising PSA levels after radical prostatectomy and no evidence of metastatic disease were treated with oral isotretinoin at a daily dose of 1.0 mg/kg. Serum PSA levels were checked monthly for the first 4 months after initiation of treatment and every 3 months thereafter. No significant changes in serum PSA levels after 3 months of isotretinoin treatment were recorded in the control group (P = 1.000). Three of 11 postprostatectomy patients (27%) had a PSA reduction of 28%, 15%, and 6.6% after initiation of treatment that lasted for a period of 2-3 months. In two of these three patients, the PSA levels subsequently rose exponentially. Another patient displayed a stabilization of the serum PSA curve for 3 months after an initial sharp rise. No grade 3 or 4 toxicity was recorded in this group of patients. Isotretinoin had a modest, transient effect on the serum PSA level in 4 of 11 (36%) patients with a rising serum PSA after radical prostatectomy. We conclude that this drug is unlikely to be of major therapeutic benefit in prostate cancer patients when used as a single agent. However, its modest effect argues for the exploration of other, more potent retinoids for prostate cancer therapy.

Adult↗
PubMed1999

Multiformic modulation of endotoxin effects by linomide.

Linomide is a potent immunomodulator that either enhances or suppresses certain immunological processes. Of particular interest is this compound's capacity to inhibit a variety of organ-specific autoimmune diseases. Here, we report on the effects of linomide on several immunological reactions elicited by endotoxin (LPS), both in vivo and in vitro. In rats and mice linomide inhibited the elicitation of endotoxin-induced uveitis (EIU), an acute inflammatory eye disease that develops within 24 h following footpad injection of LPS. Linomide also inhibited the production of TNF-alpha and IL-6 by LPS-stimulated rat and mouse macrophage monolayers. On the other hand, treatment with linomide significantly increased the levels of IL-1beta (mice and less in rats), IL-6 (rats), and TNF-alpha (mice) in serum samples collected 2 h following injection with LPS. The increased production of proinflammatory cytokines in linomide-treated mice was also indicated by the enhanced lethal effect of LPS in these mice. The finding of elevated levels of these cytokines in animals with suppressed EIU is also in line with previous observations of an inverse relationship between EIU severity and levels of TNF-alpha. Data recorded here underscore the unique capacity of linomide to both enhance and suppress the immune system.

Adjuvants, Immunologic↗
PubMed1999

Early postureteroscopy vesicoureteral reflux--a temporary and infrequent complication: prospective study.

BACKGROUND: Early complications after ureteroscopy include discomfort, renal colic, urinary infection, and hematuria. Vesicoureteral reflux has been reported as a late complication. The presence of early vesicoureteral reflux after ureteroscopy has not been investigated. METHODS: Forty patients were randomly selected for a study in which early vesicoureteral reflux after ureteroscopy was searched for through retrograde cystography. RESULTS: In four patients (10%), vesicoureteral reflux was found. Follow-up cystograms 2 weeks after ureteroscopy were normal in all four. CONCLUSION: These results suggest that early vesicoureteral reflux after ureteroscopy is rare and that if it appears, it is of low grade and temporary.

Female↗