Effective long-term androgen suppression in men with prostate cancer using a hydrogel implant with the GnRH agonist histrelin.

OBJECTIVES: To evaluate the effectiveness of a hydrogel implant containing the gonadotropin-releasing hormone (GnRH) agonist histrelin in suppressing testosterone production in men with prostate cancer and to determine the effective dose (one, two, or four implants). METHODS: Forty-two men with prostate cancer and indications for androgen ablation were treated with one, two, or four implants. In two of the clinics, comprising 27 subjects, the treatment period was 12 months, with replacement with the same number of implants at 12-month intervals. In a third clinic, which treated 15 subjects, the implants were left in place for up to 30 months. The total experience was 605 treatment months. RESULTS: The histrelin levels were detected in serum proportional to the number of implants placed. The response, however, was similar among all three dose levels, with testosterone and luteinizing hormone essentially completely suppressed. Serum testosterone levels decreased from 21.9 +/- 17.6 nmol/L to 0.93 +/- 1.57 nmol/L within 1 month and were maintained at 0.55 +/- 0.24 nmol/L at 6 months and 0.60 +/- 0.28 nmol/L after 12 months of treatment. Of the 38 assessable patients, 35 (92%) had castrate levels of testosterone within 4 weeks of the initial implant placement. All patients followed for up for 12 months after placement of the initial set of implants maintained suppression of testosterone production while the implant was in place. CONCLUSIONS: The histrelin hydrogel implant provided adequate and reliable delivery of the potent GnRH agonist histrelin during at least 1 year using a single implant in men with prostate cancer. No apparent advantages were found in using more than one implant, and the question of the possible effectiveness of even lower doses remains open. This treatment modality appears to be both safe and effective.

Clinical outcome of microsurgical subinguinal varicocelectomy in infertile men.

The present study assesses the clinical outcome of microsurgical subinguinal varicocelectomy in infertile men, especially with regard to sperm count, motility and fertility. Between June 1990 and October 1998, 272 patients had subinguinal microsurgical varicocelectomy operations for clinical varicoceles, and their long-term results were assessed. In nearly all the patients there was a significant improvement in sperm count and sperm motility after 3 and 6 months. Very few complications arose from this procedure. We concluded that microsurgical subinguinal varicocelectomy is an effective treatment for clinical varicoceles in infertile men. The significant improvement in the quality of spermatozoa, the low complication rates and the remarkably high pregnancy rates make this a valuable alternative to in vitro reproduction techniques.

Endocrine profiles after radiotherapy in stage I seminoma: impact of two different radiation treatment modalities.

BACKGROUND AND PURPOSE: In patients with stage I seminoma treated with elective lymph node irradiation, testicular scatter doses are often thought to be responsible for later disturbances in fertility. We studied the influence of radiation field extensions and testicular doses on hormonal function. MATERIALS AND METHODS: FSH (follicle stimulating hormone) and LH (luteinizing hormone) were evaluated before radiotherapy (RT) and by serial analyses after treatment for 4 years. Twenty-three patients were irradiated by hockey stick fields with a mean dose of 31.9 Gy (+/-4.7 SD) and a mean scatter dose of 54 8 cGy (+/-16.6 SD). Twenty-one patients received limited RT to the paraaortic nodes with 28.1 Gy (+/-2.4 SD). The mean testicular dose was only 25 cGy (+/-7.8 SD). All patients had normal pre-treatment hormonal values. RESULTS: Six months after the end of RT, mean FSH values were significantly elevated in the hockey stick group (P = 0.032), returning to normal after 3 years. The increase in LH was also significant, but stayed within normal ranges. Limited RT resulted in a minimal, dose-dependent increase of FSH; no changes in LH were noted. CONCLUSIONS: In patients with a normal hormonal status after semicastration, FSH is a reliable monitor for transient radiation-induced effects. To avoid treatment-related disturbances in spermatogenesis, scatter doses should be reduced to less than 20 cGy.

Tissue polypeptide-specific antigen in renal cell carcinoma.

OBJECTIVES: The usefulness of serum tissue polypeptide-specific antigen (TPS), a cytokeratin 18-associated marker, in renal cell carcinoma (RCC) was assessed in vitro and in vivo. METHODS: Indirect immunoperoxidase staining for TPS expression was performed on frozen sections of normal renal tissue and RCC specimens. By using a monoclonal TPS immunoradiometric assay, serum TPS concentrations were analyzed in 82 healthy controls, in 20 patients with locoregional RCC before and after surgery and in 18 patients with advanced disease following surgery receiving immunotherapy with interferon-gamma. RESULTS: Using immunohistochemistry, TPS was found to be expressed by both normal and cancerous renal epithelial cells. The mean TPS concentrations in 82 healthy controls was 56 +/- 49 U/1 with a 95% percentile of 78.5 U/1. Out of 20 patients with locoregional RCC, 8 presented with elevated values (mean 168 +/- 82 U/1) above the cut-off level (78.5 U/1, sensitivity 40%) which dropped to normal within 2 weeks after surgery. During a follow-up period of 1 year, none of the patients presented with tumor recurrence and TPS concentrations remained low (mean 52 +/- 36 U/1). In 18 patients receiving interferon-gamma therapy, serum TPS concentrations were monitored over a period of 12 months. In 5/18 patients, baseline levels were within the normal range (mean 37 +/- 21 U/1); interestingly, these at the same time were the only responders to immunotherapy (n = 2) or at least showed stable disease (n = 3). Response to therapy was reflected by low serum TPS levels (mean 28 +/- 23 U/1) over the entire observation period. Thirteen patients suffered progressive disease during therapy, all of them exhibiting significantly elevated (p < 0.005) pretherapeutic TPS concentrations (mean 186 +/- 124 U/1) that remained equally elevated throughout therapy (mean 192 +/- 102 U/1), reflecting tumor progression. CONCLUSIONS: TPS might have some clinical value as prognostic marker in RCC, possibly by reflecting the proliferative tendency of the tumor.

Circulating immune markers in advanced renal cell carcinoma during immunotherapy with interferon gamma.

Circulating immune markers sICAM-1, sELAM-1, sMHC-I, beta 2-MG, sCD4 and sCD8 were evaluated prior to and during immunotherapy with biologically active doses of interferon gamma (IFN-gamma) in 16 patients with advanced renal cell carcinoma (RCC) over a period of 12 months. Compared to 20 healthy controls, significantly (P < 0.01) elevated baseline levels of circulating adhesion molecules sICAM-1 (mean 1166 vs 230 ng/ml) and sELAM-1 (70 vs 17 ng/ml) were found in all patients. Compared to responders (n = 2) or patients with stable disease (n = 2), progressive disease during therapy (n = 12) was associated with significantly (P < 0.05) higher mean concentrations of sICAM-1 (1574 vs 962 ng/ml) and sELAM-1 (86 vs 46 ng/ml). Pretherapeutic and intratherapeutic levels of sMHC-I among the RCC patients were significantly (P < 0.05) lower than among the controls (0.41 vs 0.8 ng/ml). sCD4 levels clearly showed the same tendency (24 vs 33 U/l). sCD8 baseline levels, by contrast, were significantly (P < 0.05) elevated (564 vs 336 U/l), reflecting either activation of the NK-cell subset or increased synthesis of CD8+ T-suppressor cells. Again, significantly (P < 0.05) higher intratherapeutic sCD8 concentrations were observable with progressive disease than with response to therapy or stable disease (721 vs 355 U/l). Interestingly, although the biologically active dose of IFN-gamma was defined by an increase in beta 2-MG release of at least 30% within 48 h after injection, none of the other markers showed any significant alteration following IFN-gamma administration, suggesting that IFN-gamma in vivo does not produce changes in circulating markers of activation that might be expected on the basis of its effects in vitro. The finding of significantly elevated concentrations of sICAM-1, sELAM-1 and sCD8 in the presence of low sCD4 and sMHC-I levels might be of clinical significance for indicating ongoing tumor progression.

Major histocompatibility complex class I and class II expression in renal cell carcinoma and modulation by interferon gamma.

PURPOSE: To determine the expression of MHC class I and II in human renal cancer. MATERIALS AND METHODS: We analyzed tissue sections from 22 primary and 28 metastatic renal cell carcinomas (RCC), as well as 31 established RCC cell lines. Tissue specimens from normal kidney and cell cultures of normal kidney epithelium were also studied. In addition, MHC antigen expression on RCC cell lines was assessed both before and after incubation with human recombinant interferon gamma (IFN-gamma). Antigen expression was determined by mixed hemadsorption, indirect immunofluorescence, fluorescence activated cell sorting (FACS) or immunoperoxidase staining using the monoclonal antibodies (mAbs) W6/32 (anti-MHC class I), mAbs NAMB-1 and BBM.1 (anti-beta-2 microglobulin), and mAbs L243 and 13-17 (anti-MHC class II) antibodies. Soluble beta-2 microglobulin in conditioned medium was measured by ELISA. RESULTS: Normal renal epithelial cells, both in vivo and in vitro, showed low level expression of class I antigens. Immunohistochemical staining for MHC class II was limited to some proximal tubular cells, while cultured renal tubular cells were uniformly class II negative. The tumor cell populations in all 22 primary and in 26 of 28 (93%) metastatic RC specimens consisted predominantly of class I positive cells. Half of the samples from primary and metastatic tumors were class II negative. Incubation of RCC cell lines with IFN-gamma enhanced the expression of MHC class I, beta-2 microglobulin and class II. The upregulation of MHC expression was time and dose dependent and associated with increased release of soluble beta-2 microglobulin. CONCLUSIONS: (i) Like normal kidney, virtually all primary human renal cell carcinomas express MHC class I antigens and retain this phenotype even during tumor progression and metastasis; (ii) class II expression on normal and RCC cells appears more limited but occurs frequently in both primary and metastatic lesions; and (iii) in most continuous RCC cell lines expression of MHC class I and II can effectively be stimulated by IFN-gamma. Since expression of MHC molecules might determine the immunogenicity of human RCC, its constitutive expression and augmentation could play an important role for the immunotherapy and prognosis of human renal cancer.