Rolf-Hermann Ringert

Regression of human metastatic renal cell carcinoma after vaccination with tumor cell-dendritic cell hybrids

Reports of spontaneous regressions of metastases and the demonstration of tumor-reactive cytotoxic T lymphocytes indicate the importance of the hosts immune system in controlling the devastating course of metastatic renal cell carcinoma. Recent research indicates that immunization with hybrids of tumor and antigen presenting cells results in protective immunity and rejection of established tumors in various rodent models. Here, we present a hybrid cell vaccination study of 17 patients. Using electrofusion techniques, we generated hybrids of autologous tumor and allogeneic dendritic cells that presented antigens expressed by the tumor in concert with the co-stimulating capabilities of dendritic cells. After vaccination, and with a mean follow-up time of 13 months, four patients completely rejected all metastatic tumor lesions, one presented a ‘mixed response’, and two had a tumor mass reduction of greater 50%. We also demonstrate induction of HLA-A2-restricted cytotoxic T cells reactive with the Muc1 tumor-associated antigen and recruitment of CD8+ lymphocytes into tumor challenge sites. Our data indicate that hybrid cell vaccination is a safe and effective therapy for renal cell carcinoma and may provide a broadly applicable strategy for other malignancies with unknown antigens.

EXPRESSION OF METALLOPROTEINASE 2 AND 9 AND THEIR INHIBITORS IN RENAL CELL CARCINOMA

Degradation of the extracellular matrix is necessary for invasion and metastasis by cancer cells. Two gelatinolytic matrix metalloproteinase enzymes, MMP-2 and MMP-9, are supposed to be key enzymes in this process. The purpose of this study was to correlate the presence of MMP-2, MMP-9 and their inhibitors with the tissue inhibitors of metalloproteinases TIMP-1 and TIMP-2 RNA using reverse transcriptase PCR technique with tumor stage in 17 samples of renal cell carcinoma. The ratio of tissues expressing MMP-2 and MMP-9 to those expressing TIMP-1 and TIMP-2 was defined to be 1 in normal kidney tissue. This MMP:TIMP ratio was significantly increased to 2.43 (standard deviation, SD = 0.8) in locally confined renal cell carcinoma and to 4.86 (SD = 1.1) in advanced carcinoma (p <0.01). In primary tumor cell lines the ratio of MMP:TIMP expression was 3.44 (SD = 0.6). These data suggest that the balance of MMP-2 and MMP-9 to TIMP-1 and TIMP-2 expression is an essential factor in the aggressiveness of renal cell carcinoma.

Matrix Metalloproteinases and Their Inhibitors

Matrix metalloproteinases (MMPs) are a group of 16 enzymes that are capable of degrading extracellular matrix components. Their catalytic function is dependent on a zinc ion in the active center. MMPs are separated in three groups: gelatinases (type IV-collagenases), stromelysins, and interstitial collagenases. Their physiological and pathological significance is to modulate the extracellular matrix-e. g., in embryogenesis, in the ovarian cycles, or in inflammatory diseases such as rheumatoid arthritis or fibrosis of the liver or kidney (1,2).

Vascular endothelial growth factor expression, angiogenesis, and necrosis in renal cell carcinomas

Rapidly growing tumors often develop necrosis. In the present study the expression of vascular endothelial growth factor (VEGF) was investigated and compared to microvessel density and necrosis of renal cell carcinomas. In the tumor-host interface the microvessel density was significantly increased compared to central tumor areas. Tumor necrosis was associated with a decrease of microvessel density and an increase of the VEGF protein expression within the perinecrotic rim. VEGF protein was focally upregulated in vital tumor tissue. An increase of the apoptotic rate of endothelia and vital tumor tissue in tumors with necrosis could not be detected. VEGF(121,165) mRNA was decreased in proliferatively active carcinomas compared to less proliferative tumors. Multicellular renal cell cancer spheroids as a model of chronic hypoxia developed central apoptosis but no necrosis. VEGF was upregulated in the spheroid. Tumor microvessels expressed matrix metalloproteinase -2 and -9 and an incomplete pericyte covering in comparison to tumor-free tissue indicating immature active angiogenesis. We conclude that highly proliferative renal cell carcinomas outgrow their vascular supply and develop chronic hypoxia inducing a decrease of proliferation and an increase of VEGF expression. However, chronic hypoxia does not cause significant necrosis or apoptosis. Tumor necrosis is more likely induced by acute hypoxia due to immature microvessels. Furthermore, VEGF expression associated with concomitant tumor necrosis may help identify renal cell carcinomas susceptible to antiangiogenic therapy.

Evaluation of seminal plasma parameters in patients with chronic prostatitis or leukocytospermia

Summary. Though detailed cytological and microbiological diagnostic procedures are routinely carried out in male genital tract infection, the correct diagnosis and localization of inflammation or infection is often difficult. In this prospective study, the relevance of the seminal plasma markers PMN elastase, complement C3, CRP, fructose, PSP 94, PSA, and α‐glucosidase was investigated in 13 patients with chronic prostatitis, 31 patients with significant leukocytospermia, and 58 patients with non‐inflammatory diseases (controls). Statistically relevant results were obtained for PMN elastase when comparing chronic prostatitis with controls, leukocytospermia with controls (P<0.001) and chronic prostatitis with leukocytospermia (P<0.05); for complement C3 chronic prostatitis and leukocytospermia vs. controls (P<0.05) and for fructose/ejaculate leukocytospermia vs. controls (P<0.05). No statistically relevant differences were found for C‐reactive protein, α‐glucosidase, PSA and prostatic secretory protein (PSP 94). To delimit genital tract inflammation from non‐inflammatory patients, cutpoint levels for PMN elastase of 230 ng ml−1 and for C3c of 0.01 g l−1 were suggested. PMN elastase was shown to possess the strongest discriminating power. The assessment of a cutpoint for fructose to indicate seminal vesicle dysfunction is not possible as the significance level is weak (P<0.05).

Treatment of Iatrogenic Postoperative Ureteral Strictures with Acucise Endoureterotomy

OBJECTIVES To determine factors influencing the outcome of Acucise endoureterotomy in patients with iatrogenic postoperative ureteral strictures after different open surgical procedures. MATERIAL AND METHODS Acucise endoureterotomy was performed in 18 patients with ureteral strictures after pyeloplasty (n = 5), renal transplantation (n = 5), ureteroenteric anastomosis (n = 3), calicoureterostomy (n = 1), ureterocystoneostomy (n = 1), hysterectomy (n = 1), ureterorenoscopy (n = 1) and transurethral resection of the ureteral orifice (n = 1). Success was determined as relief of clinical symptoms, improvement of renal function or improvement of radiographic findings. RESULTS The overall success rate was 61% (mean follow-up: 21.5 months). Six out of 18 patients showed relevant side effects. Neither the localization of the stricture nor the duration of postoperative ureteral stenting but the length of the stricture had influence on the postoperative outcome. Decreased renal function to less than 25% of the total function was always associated with failure of the treatment. The time period between the ureteral injury and the appearance of the ureteral stricture had influence on the outcome of the treatment. CONCLUSIONS Acucise endoureterotomy is effective in the treatment of postoperative ureteral strictures, but only in selected cases. The selection criteria are the time period from the primary operation to the appearance of the stricture (>6 months), the length of the stricture (<1.5 cm) and the renal function (>25% of the total function). In other cases, open surgical treatment of the ureteral stricture may provide better results.

Polyploidization and Losses of Chromosomes 1, 2, 6, 10,13, and 17 in Three Cases of Chromophobe Renal Cell Carcinomas

Clonal chromosome aberrations identified after short-term culture are presented for three cases of chromophobe renal cell carcinomas (RCC). All tumors revealed abnormal karyotypes with a varying proportion of polyploid tumor cells. Common numerical abnormalities were combined losses of chromosomes 1, 2, 6, 10, 13, and 17. Clonal karyotypic evolution was demonstrated in one case in which several related clones could be identified. An additional balanced translocation t(3;14)(p24;q22) observed in this case proved to be of constitutional nature by cytogenetic analysis of normal kidney cells and peripheral blood lymphocytes. These cytogenetic findings provide further evidence that chromophobe renal cell carcinomas are characterized by a highly specific combination of chromosomal losses most commonly including chromosomes 1, 2, 6, 10, 13, and 17.

Metastasis from renal cell carcinoma to the cervix uteri.

We report on a patient with clear cell adenocarcinoma of the left kidney and a solitary metastasis to the cervix uteri. Metastases from renal cell carcinoma to the female genitalia are uncommon and metastatic involvement of the uterus is very rare. To our knowledge, no more then five cases have been published. A review of the literature is given.

Wallstents in Patients with Detrusor-Sphincter Dyssynergia

PURPOSE For patients with spinal cord injuries who are unable to perform clean intermittent self-catheterization, sphincterotomy is performed most commonly to avoid high bladder pressure. This procedure causes additional trauma and does not always lead to a satisfactory result. Therefore, we sought an alternative therapy. MATERIALS AND METHODS We introduce our initial experience with the UroLume Wallstent* in the treatment of 51 patients with spinal cord injuries and detrusor-sphincter dyssynergia (observation time 12 to 36 months). Prior sphincterotomy was unsuccessful in all patients. RESULTS All observed urodynamic, radiological and clinical findings improved, and the results are encouraging. CONCLUSIONS Implantation of this device seems to be appropriate in select paraplegic patients.

Phytoestrogens from Belamcanda chinensis regulate the expression of steroid receptors and related cofactors in LNCaP prostate cancer cells

To investigate the changes in expression underlying the marked reduction of tumour growth in vivo, by analysing the effect of Belamcanda chinensis extract (BCE) on LNCaP cells in vitro, as phytoestrogens are chemopreventive in prostate cancer, and in previous studies we examined the effects of the isoflavone tectorigenin isolated from B. chinensis on LNCaP prostate cancer cells, and a BCE consisting of 13 phytoestrogenic compounds on tumour‐bearing nude mice.