Decreased expression of the pro-apoptotic protein Par-4 in renal cell carcinoma.
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Par-4 is a widely expressed leucine zipper protein that confers sensitization to apoptosis induced by exogenous insults. Because the expression of genes that promote apoptosis may be down-regulated during tumorigenesis, we sought to examine the expression of Par-4 in human tumors. We present here evidence that Par-4 protein levels were severely decreased in human renal cell carcinoma specimens relative to normal tubular cells. Replenishment of Par-4 protein levels in renal cell carcinoma cell lines conferred sensitivity to apoptosis. Because apoptosis may serve as a defense mechanism against malignant transformation or progression, decreased expression of Par-4 may contribute to the pathophysiology of renal cell carcinoma. (+info)
Profound variation in dihydropyrimidine dehydrogenase activity in human blood cells: major implications for the detection of partly deficient patients.
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Dihydropyrimidine dehydrogenase (DPD) is responsible for the breakdown of the widely used antineoplastic agent 5-fluorouracil (5FU), thereby limiting the efficacy of the therapy. To identify patients suffering from a complete or partial DPD deficiency, the activity of DPD is usually determined in peripheral blood mononuclear cells (PBM cells). In this study, we demonstrated that the highest activity of DPD was found in monocytes followed by that of lymphocytes, granulocytes and platelets, whereas no significant activity of DPD could be detected in erythrocytes. The activity of DPD in PBM cells proved to be intermediate compared with the DPD activity observed in monocytes and lymphocytes. The mean percentage of monocytes in the PBM cells obtained from cancer patients proved to be significantly higher than that observed in PBM cells obtained from healthy volunteers. Moreover, a profound positive correlation was observed between the DPD activity of PBM cells and the percentage of monocytes, thus introducing a large inter- and intrapatient variability in the activity of DPD and hindering the detection of patients with a partial DPD deficiency. (+info)
Presentation of renal tumor antigens by human dendritic cells activates tumor-infiltrating lymphocytes against autologous tumor: implications for live kidney cancer vaccines.
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The clinical impact of dendritic cells (DCs) in the treatment of human cancer depends on their unique role as the most potent antigen-presenting cells that are capable of priming an antitumor T-cell response. Here, we demonstrate that functional DCs can be generated from peripheral blood of patients with metastatic renal cell carcinoma (RCC) by culture of monocytes/macrophages (CD14+) in autologous serum containing medium (RPMI) in the presence of granulocyte macrophage colony-stimulating factor and interleukin (IL) 4. For testing the capability of RCC-antigen uptake and processing, we loaded these DCs with autologous tumor lysate (TuLy) using liposomes, after which cytometric analysis of the DCs revealed a markedly increased expression of HLA class I antigen and a persistent high expression of class II. The immunogenicity of DC-TuLy was further tested in cultures of renal tumor infiltrating lymphocytes (TILs) cultured in low-dose IL-2 (20 Biologic Response Modifier Program units/ml). A synergistic effect of DC-TuLy and IL-2 in stimulating a T cell-dependent immune response was demonstrated by: (a) the increase of growth expansion of TILs (9.4-14.3-fold; day 21); (b) the up-regulation of the CD3+ CD56- TcR+ (both CD4+ and CD8+) cell population; (c) the augmentation of T cell-restricted autologous tumor lysis; and (d) the enhancement of IFN-gamma, tumor necrosis factor-alpha, granulocyte macrophage colony-stimulating factor, and IL-6 mRNA expression by TILs. Taken together, these data implicate that DC-TuLy can activate immunosuppressed TIL via an induction of enhanced antitumor CTL responses associated with production of Thl cells. This indicates a potential role of DC-TuLy vaccines for induction of active immunity in patients with advanced RCC. (+info)
Sarcomatoid renal cell carcinoma: biologic behavior, prognosis, and response to combined surgical resection and immunotherapy.
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PURPOSE: Sarcomatoid variants of renal cell carcinoma (RCC) are aggressive tumors that respond poorly to immunotherapy. We report the outcomes of 31 patients with sarcomatoid RCC treated with a combination of surgical resection and immunotherapy. PATIENTS AND METHODS: Patients were identified from the database of the University of California Los Angeles Kidney Cancer Program. We retrospectively reviewed the cases of 31 consecutive patients in whom sarcomatoid RCC was diagnosed between 1990 and 1997. Clinical stage, sites of metastasis, pathologic stage, and type of immunotherapy were abstracted from the medical records. The primary end point analyzed was overall survival, and a multivariate analysis was performed to distinguish any factors conferring an improved survivorship. RESULTS: Twenty-six percent of patients were male and 74% were female, and the median age was 59 years (range, 34 to 73 years). Length of follow-up ranged from 2 to 77 months (mean, 21.4 months). Twenty-eight patients (84%) had known metastases at the time of radical nephrectomy (67% had lung metastases and 40% had bone, 21% had liver, 33% had lymphatic, and 15% had brain metastases). Twenty-five patients (81%) received immunotherapy, including low-dose interleukin (IL)-2-based therapy (five patients), tumor-infiltrating lymphocyte-based therapy plus IL-2 (nine patients), high-dose IL-2-based therapy (nine patients), dendritic cell vaccine-based therapy (one patient), and interferon alpha-based therapy alone (one patient). Two patients (6%) achieved complete responses (median duration, 46+ months) and five patients (15%) achieved partial responses (median duration, 36 months). One- and 2-year overall survival rates were 48% and 37%, respectively. Using a multivariate analysis, age, sex, and percentage of sarcomatoid tumor (< or >50%) did not significantly correlate with survival. Improved survival was found in patients receiving high-dose IL-2 therapy compared with patients treated with surgery alone or any other form of immunotherapy (P = .025). Adjusting for age, sex, and percentage of sarcomatoid tumor, the relative risk of death was 10.4 times higher in patients not receiving high-dose IL-2 therapy. Final pathologic T stage did not correlate significantly with outcome, but node-positive patients had a higher death rate per year of follow-up than did the rest of the population (1.26 v 0.76, Cox regression analysis). CONCLUSION: Surgical resection and high-dose IL-2-based immunotherapy may play a role in the treatment of sarcomatoid RCCs in select patients. (+info)
Autoimmunity resulting from cytokine treatment predicts long-term survival in patients with metastatic renal cell cancer.
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PURPOSE: In patients undergoing cytokine therapy, systemically applied interleukin-2 (IL-2) and/or interferon-alpha (IFN-alpha) have been reported to induce thyroid dysfunction as well as thyroid autoantibodies. We analyzed the correlation of thyroid autoimmunity with HLA phenotype, various other autoimmune parameters, and patient survival. PATIENTS AND METHODS: For this purpose, antithyroglobulin autoantibodies, antimicrosomal thyroid autoantibodies, thyroglobulin receptor autoantibodies, thyroid dysfunction, and multiple clinical parameters were determined in 329 unselected patients with metastatic renal cell cancer before and after systemic IL-2 and IFN-alpha2 therapy. For statistical analysis, we used both univariate and multivariate Cox proportional hazards models and the two-tailed Fisher's exact test. RESULTS: Antithyroglobulin autoantibodies and antimicrosomal thyroid autoantibodies were detected in 60 patients (18%); positive autoantibody titers of various other autoimmune parameters were statistically unrelated. The presence of thyroid autoantibodies was correlated with prolonged survival (P<.0001). There was a statistically significant difference in frequencies of HLA-Cw7 expression between thyroid autoantibody-positive and -negative patients (P< or =.05), and the Cw7 expression was associated with prolonged overall survival (P = .009). CONCLUSION: The evaluation of thyroid autoantibodies during cytokine therapy could be a useful prognostic marker for patients with renal cell carcinoma who benefit from cytokine treatment. IL-2- and IFN-alpha2-induced tumor control and prolonged survival may require breaking of immunologic tolerance against self-antigens. (+info)
Hypertension, antihypertensive medication use, and risk of renal cell carcinoma.
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To investigate whether diuretic medication use increases risk of renal cell carcinoma (RCC), the authors conducted a case-control study of health maintenance organization members in western Washington State. Cases (n = 238) diagnosed between January 1980 and June 1995 were compared with controls (n = 616) selected from health maintenance organization membership files. The computerized health maintenance organization pharmacy database provided information on medications prescribed after March 1977. Additional exposure information was collected from medical records. For women, use of diuretics was associated with increased risk of RCC (odds ratio (OR) = 1.8, 95% confidence interval (CI) 1.0-3.1), but the association was not independent of a diagnosis of hypertension (adjusted for hypertension, OR = 1.1, 95% CI 0.5-2.1). Similarly, nondiuretic antihypertensive use was associated with increased risk, but only when unadjusted for hypertension. For men, neither diuretic nor nondiuretic antihypertensive use was associated with risk of RCC. A diagnosis of hypertension was clearly associated with RCC risk for women (OR = 2.5, 95% CI 1.2-5.1), but not men (OR = 1.3, 95% CI 0.7-2.5). High systolic and diastolic blood pressures were associated with increased risk in both sexes. These results do not support the hypothesis that use of diuretic medication increases RCC risk; they are more consistent with an association between RCC and high blood pressure. (+info)
Increased renal retention of 99mTc-methylene diphosphonate after nephron-sparing surgery.
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Nephron-sparing surgery has become established as an effective treatment for localized renal cell carcinoma when preservation of renal function is necessary. The surgery usually requires temporary renal artery occlusion and may induce ischemic renal damage. In this study, we retrospectively evaluated renal activity on bone scintigraphy after nephron-sparing surgery. METHODS: Eleven patients who underwent nephron-sparing surgery for renal cell carcinoma and had a normal contralateral kidney were studied. A total of 12 bone scintigraphy images with 99mTc-labeled methylene diphosphonate were obtained within 1 y after surgery in these patients to assess skeletal metastasis. Activity in the spared renal parenchyma was compared visually with that in the contralateral normal kidney. RESULTS: The tumor was successfully resected in every patient, and no clinically significant complications occurred. Activity in the spared renal parenchyma was elevated in six of seven examinations performed within 21 d after surgery. In three examinations, the increase in renal activity was heterogeneous, being relatively prominent near the surgical margin. Increased renal activity was not observed on five examinations performed 3 mo or more after surgery. CONCLUSION: Renal retention of bone-seeking agents is elevated in the early period after nephron-sparing surgery, probably as a result of ischemic insult during the surgical procedure. Bone scintigraphy may aid in evaluating the presence and degree of ischemic damage of the spared renal parenchyma. (+info)
Renal carcinogenesis, hepatic hemangiomatosis, and embryonic lethality caused by a germ-line Tsc2 mutation in mice.
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Germ-line mutations of the human TSC2 tumor suppressor gene cause tuberous sclerosis (TSC), a disease characterized by the development of hamartomas in various organs. In the Eker rat, however, a germ-line Tsc2 mutation gives rise to renal cell carcinomas with a complete penetrance. The molecular mechanism for this phenotypic difference between man and rat is currently unknown, and the physiological function of the TSC2/Tsc2 product (tuberin) is not fully understood. To investigate these unsolved problems, we have generated a Tsc2 mutant mouse. Tsc2 heterozygous mutant (Tsc2+/-) mice developed renal carcinomas with a complete penetrance, as seen in the Eker rat, but not the angiomyolipomas characteristic of human TSC, confirming the existence of a species-specific mechanism of tumorigenesis caused by tuberin deficiency. Unexpectedly, approximately 80% of Tsc2+/- mice also developed hepatic hemangiomas that are not observed in either TSC or the Eker rat. Tsc2 homozygous (Tsc2-/-) mutants died around embryonic day 10.5, indicating an essential function for tuberin in mouse embryonic development. Some Tsc2-/- embryos exhibited an unclosed neural tube and/or thickened myocardium. The latter is associated with increased cell density that may be a reflection of loss of a growth-suppressive function of tuberin. The mouse strain described here should provide a valuable experimental model to analyze the function of tuberin and its association with tumorigenesis. (+info)