Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027627 (metastases)
 103,950 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

This study reports on biological response modification induced by prolonged continuous subcutaneous (s.c.) infusion of recombinant interferon-gamma (rIFN-gamma) with particular attention to changes of soluble CD14. This glycoprotein with an unknown function is derived from myeloid cells carrying membrane CD14, which is the receptor for lipopolysaccharide (LPS)-LPS-binding protein (LBP) complexes. Fifteen metastatic cancer patients received weekly escalating doses of rIFN-gamma starting at either 50 or 100 micrograms/24 h and increasing up to 400 micrograms/24 h for a median duration of 6 weeks. The maximum tolerated dose was higher (200 micrograms/24 h) with the lower (50 micrograms/24 h) starting dose. Biological activity of rIFN-gamma was evaluated by weekly measurements of CD14, neopterin, and beta 2-microglobulin concentrations in serum as well as monocyte HLA class I and II antigen expression and tumor cytotoxicity. Serum IFN-gamma concentrations increased 20-fold within 4 weeks of therapy. The levels were correlated to the mean dose (r = 0.95, p less than 0.05). Among the biological markers, two patterns were observed. First, serum CD14 concentration and expression of monocyte HLA class II antigens increased significantly during the first week, and marker expression correlated with serum IFN-gamma levels (p less than 0.05); CD14 and HLA class II antigens thereafter returned to pretreatment levels within 4 weeks of therapy despite persistently elevated serum IFN-gamma concentrations. Second, serum neopterin and beta 2-microglobulin concentrations as well as monocyte HLA class I expression also increased significantly within the first week, but remained elevated thereafter without any further dose relationship.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Prolonged interferon-gamma application by subcutaneous infusion in cancer patients: differential response of serum CD14, neopterin, and monocyte HLA class I and II antigens. 137 54

Therapeutic approaches to metastatic renal cell carcinoma (RCC) often focus on the application of immune modulators; the success rates, however, are not satisfactory. Up to the time of this study, no diagnostic tool has been available to select those patients who might profit from immunotherapy. Starting from this point, we have been assessing the immune status of patients suffering from RCC, intending to find markers that would characterize the more favorable prognosis. Our interest is focused not only on the metastatic but also on the nonmetastatic disease, i.e., the disease with the better prognosis. In the present study, we have assessed both the postoperative long-term course of several immune parameters of the peripheral blood and the reactivity of the immune system to immunostimulation with keyhole limpet hemocyanin (KLH) in patients with nonmetastatic RCC. In a prospectively randomized study, the verum group (n = 8) got 1 mg KLH per month up to 1 year while the control group (n = 9) got no immunostimulator after tumor nephrectomy. Both patient groups had stable or even increasing cell counts of lymphocyte subpopulations (T, B, natural killer, T4, T8 cells), and the humoral immunoactivation markers neopterin, beta 2-microglobulin and tumor necrosis factor increased considerably after tumor nephrectomy. An effect of KLH is evident 4-8 months postoperatively: here, the neopterin values in the KLH group are more than twice as high as in the control group. Thus, while patients with metastatic disease had turned out to be immunosuppressed (previous study), in patients with nonmetastatic RCC, both the long-term course indicating postoperative immunostimulation and the reactivity to KLH give evidence of immunocompetence.
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PMID:Postoperative long-term course of peripheral blood immune parameters and immunomodulating effects of keyhole limpet hemocyanin in patients with nonmetastatic renal cell carcinoma. 145 54

An astoundingly high frequency of micrometastatic cells have been found in bone marrow aspirates of patients with colon carcinomas (G. Schlimok et al., J. Clin. Oncol., 8:831-837, 1990), although these tumors very rarely metastasize to the skeleton. This observation has raised questions about the malignant potential of such cells. In a first attempt to characterize this potential, we have assessed the expression of major histocompatibility complex (MHC) class I antigens on bone marrow micrometastases, inasmuch as down-regulation of these molecules is a potential mechanism to escape from MHC class I-restricted lysis by cytotoxic T-cells. The two groups of cancer patients compared were those with tumors known to rarely (stomach and colon cancer) or frequently (breast cancer) manifest skeleton metastases. Bone marrow aspirates taken from these patients were probed for individual disseminated tumor cells using the immunoalkaline phosphatase technique with monoclonal antibody CK2 to the epithelial differentiation antigen cytokeratin 18 (CK-18), as described previously (G. Schlimok et al., Proc. Natl. Acad. Sci. USA, 84:8672-8676, 1987). Specimens containing CK18-positive cells were colabeled with monoclonal antibody W6/32 directed to a framework (or nonpolymorphic) antigenic determinant of MHC class I heavy chains associated with beta 2-microglobulin. W6/32-positive CK-18-positive cells could be detected in 25 of 54 patients (46.3%) with significantly higher incidences in 26 breast cancer patients (61.9%) as compared to 28 patients with carcinomas of the stomach and colon (27.3 and 29.4%). Independent from the origin of the primary carcinoma, the incidence of W6/32-negative CK18-positive cells was positively correlated to both the differentiation grade of the primary tumor (P less than 0.05) and appeared to be linked to the occurrence of regional lymph node metastases (statistically not significant) determined by conventional histological examination. The present results demonstrate for the first time that down-regulation of MHC expression on individual micrometastatic cells correlates to the differential pattern of metastasis obtained by comparing breast and gastrointestinal carcinomas. This finding together with the suggestive link to clinical risk factors supports the significance of reduced MHC class I expression for the survival of residual metastatic cells which is a major determinant of prognosis for patients with solid tumors.
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PMID:Frequent down-regulation of major histocompatibility class I antigen expression on individual micrometastatic carcinoma cells. 187 15

Increased concentrations of beta 2-microglobulin in cerebrospinal fluid have been used to detect central nervous system involvement with metastatic cancer and with neurological complications of AIDS. However, no adequate reference interval study has been reported for beta 2-microglobulin in cerebrospinal fluid. We established a reference interval with both the Abbott IMx microparticle enzyme-linked immunoassay (EIA) (0.6-2.0 mg/L) and the Pharmacia beta 2-micro EIA 96 method (0.8-2.2 mg/L) for beta 2-microglobulin in cerebrospinal fluid. The two methods correlate well, with the latter method giving slightly higher values. beta 2-Microglobulin increases with age in adults by about 0.1 mg/L every 7.5 years, with no significant difference between genders.
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PMID:Establishment of a reference interval for beta 2-microglobulin in cerebrospinal fluid with use of two commercial assays. 198 88

To assess biological response, therapeutic activity, and side effects, a randomized, double-blind trial of two doses of interferon-beta ser (IFN-beta ser), differing by 20-fold 4.5 and 90 x 10(6) units), was undertaken in 64 patients with metastatic renal carcinoma. Patients were treated intravenously with injections daily for 10 days with an 11-day rest before treatment was reinitiated. The trial confirmed the relatively good toleration of IFN-beta ser; in the first cycle only 4/63 patients had anorexia of moderate or greater severity. Median weight change over the duration on study was -1.5 kg; in the first cycle only 7% of patients had performance status decline greater than 1 level. Statistically significant changes (p less than 0.05) occurred in granulocytes, lymphocytes, calcium, cholesterol, alkaline phosphatase, and aspartate transferase (AST); however, except for AST, overall clinical differences in the two doses were not great. Of 60 patients evaluated, 1 developed neutralizing antibody. When assessed 24 h after IFN-beta ser at 4.5 x 10(6) units, significant (p less than 0.05) augmentation had occurred in beta 2-microglobulin, HLA-DR, and HLA-DQ expression on monocytes, 2',5'-oligoadenylate (2-5A) synthetase in peripheral mononuclear cells, and natural killer (NK) and K cells functional activity. Although the 90 x 10(6) unit dose also resulted in stimulation of these responses, little additional augmentation of biological response occurred at the higher dose. Except for a decline in monocyte HLA-DR expression, biological responses remained increased at both doses over the 10-day period of treatment. However, no objective regressions of metastatic disease occurred. In view of objective responses in metastatic renal carcinoma in other trials with IFN-beta ser, consideration should be given to alternative schedules.
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PMID:Biological and clinical effects of interferon-beta ser at two doses. 208 72

At present, no sufficient therapy for metastatic renal cell carcinoma is available. Several immunotherapeutical protocols have been studied, success rates, however, were inconsistent. The purpose of this study was to assess the pretherapeutic immunological status of 13 patients with metastatic and 16 patients with nonmetastatic renal cell carcinoma and of 15 healthy volunteers. Determined were differential blood counts, lymphocyte subpopulations, beta 2-microglobulin, tumor necrosis factor (TNF), neopterin, immunoglobulin, fibronectin and ferritin. Additionally, these parameters were recorded for monitoring an immunotherapeutical approach with the xenogeneic biological response modifier Keyhole limpet hemocyanine (KLH) in 10 patients with metastatic and in 5 patients with nonmetastatic disease. The pretherapeutic immunological status of patients with metastatic disease was characterized by significantly reduced T4-, T8- and B-cell counts. Significantly increased were granulocyte counts, beta 2-microglobulin, neopterin and TNF. In patients who did not suffer from metastases, only beta 2-microglobulin and neopterin were increased significantly. During immunotherapy, in patients with metastases, there was a decline of lymphocyte subsets and of the T4/T8-ratio, which correlated with progress of the disease. Humoral immune parameters showed no changes compared to pretherapeutic values. In patients who did not suffer from metastases, cellular immune parameters showed stable values during immunotherapy; neopterin, beta 2-microglobulin and TNF increased considerably. These findings indicate immunosuppression in patients with metastatic renal cell carcinoma, increasing with progression of the disease and possibly impairing the immunostimulating effects of biological response modifiers during immunotherapy. In conclusion, the clinical response of metastatic renal cell carcinoma to immunotherapy might be improved if the immunostimulant is combined with agents suitable to overcome immunosuppression, i.e. low doses of cyclophosphamide or inhibitors of prostaglandin synthesis. In addition, assessment of immune parameters for monitoring the actual immune status of a patient and the immunological effects of therapy was found to be a necessary part of immunotherapy.
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PMID:Immune status and immune therapy of renal cell carcinoma. 221 64

We describe here the chromosomal distribution of sister chromatid exchanges (SCEs) in four human tumor cell lines (two melanomas and two astrocytomas), and have mapped the sister chromatid recombination (SCR) sites. A higher incidence of SCR sites than expected on the basis of chromosome length occurred in chromosomes 2, 4, 5 and 15 in both the RPMI 5966 and MEL57 melanoma cell lines, and in chromosomes 1, 5, 13 and 15 of the IJKt and GUVW astrocytoma cell lines. A majority of the recombination sites occurred close to chromosomal fragile sites. A third of these occurred at the same bands as fragile sites. The recombination sites involved the N-ras and the epidermal growth factor gene in the melanomas. In the astrocytomas, the N-ras, Rb and c-mos genes appeared to be involved in the recombination events. The beta 2-microglobulin gene was involved in both astrocytomas and one melanoma. The erbB2 was involved in SCR only in the RPMI melanoma.
Clin Exp Metastasis
PMID:Genetic recombination in human melanoma and astrocytoma cell lines involves oncogenes and growth factor genes. 229 15

Twenty-eight evaluable patients with metastatic cancer refractory to standard therapy received escalating doses of muramyl tripeptide phosphatidylethanolamine (MTP-PE) (.05 to 12 mg/m2) in phosphatidylserine (PC):phosphatidylcholine (PS) liposomes (lipid:MTP-PE) ratio 250:1). Liposomal MTP-PE (L-MTP-PE) was infused over 1 hour twice weekly; doses were escalated within individual patients every 3 weeks as tolerated for a total treatment duration of 9 weeks. Routine clinical laboratory parameters, acute phase reactants and various immunologic tests were monitored at various time points during treatment. Toxicity was moderate (less than or equal to grade II) in 24 patients with chief side effects being chills (80% of patients), fever (70%), malaise (60%), and nausea (55%). In four patients L-MTP-PE treatment was deescalated due to severe malaise and recurrent fever higher than 38.8 degrees C. The maximum-tolerated dose (MTD) was 6 mg/m2. Significant (P less than .05) increases in WBC count, absolute granulocyte count, ceruloplasmin, beta 2-microglobulin, c-reactive protein, monocyte tumoricidal activity, and serum IL-1 beta were found. Significant decreases in serum cholesterol were also observed. Clearance of intravenously (iv)-infused technetium-99 (99mTc)-labeled liposomes containing MTP-PE in four patients was biphasic; gamma camera scans revealed uptake of radiolabel in liver, spleen, lung, nasopharynx, thyroid gland, and tumor (two patients). No objective tumor regression was seen. In view of its definite immunobiologic activity and lack of major toxicity, additional phase II and adjuvant trials of L-MTP-PE are warranted.
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PMID:Phase I trial of liposomal muramyl tripeptide phosphatidylethanolamine in cancer patients. 247 21

HLA class I and II expression was studied on 244 (177 primary and 67 metastatic) solid human tumours of different origin. Alkaline immunophosphatase (APAAP) and immunoperoxidase were used on cryostatic sections to stain MHC antigens. Monomorphic MoAbs were used against class I heavy chain, beta 2-microglobulin, DR, DQ and DP molecules. Class I expression was homogeneous on colon, melanoma and epidermoidal primitive tumours. Loss of HLA class I antigens was more frequent on basal cell carcinomas and sarcomas and was related to tumour differentiation on larynx carcinoma. Class I expression was heterogeneous on breast, larynx and stomach primitive neoplasias. Class I negative tumours were more frequent on metastatic than on primitive melanomas. Divergence of class I between primary tumours and autologous metastases was observed on melanomas, larynx and colorectal carcinomas. Class II expression was heterogeneous on all tumours and in a large number of cases was associated with high intensity of leukocytic infiltrate. HLA-DR expression was higher than HLA-DP and HLA-DQ (DR greater than DP greater than DQ) and was related to tumour progression. Four human tumour cell lines were modulated with recombinant interferon-gamma for HLA class I and II antigens. Different HLA profiles were obtained: increased class I and II expression, increased class II or a low response. Finally, class I genes from 22 tumours were compared with autologous normal cells by Southern blot analysis: 12 tumours were class I positive and 10 negative. No clear differences in RFLP were observed that could be associated with class I rearrangement. The results are discussed in relation to the role that histocompatibility antigens may play in tumour progression and invasiveness.
Clin Exp Metastasis
PMID:Phenotypic expression of histocompatibility antigens in human primary tumours and metastases. 249 52

A series of 38 primary laryngeal and hypopharyngeal tumours, 15 lymph-node metastases and normal tissue were evaluated in frozen sections for the expression of MHC class I and II antigens, using monomorphic monoclonal antibodies (MAbs) to HLA-ABC, beta 2-microglobulin, DR, DP, DQ, HLA-B and polymorphic HLA-ABC antigens. Normal distant mucosa of larynx reacted to anti-class I antibodies but not to anti-class II. In 9 primary tumours (23.7%) HLA class I antigens were not observed. The remaining 29 showed a strong reaction to not observed. The remaining 29 showed a strong reaction to anti-HLA-ABC (heavy chain) and anti-beta 2-microglobulin, although in 3 cases out of 29 no staining was observed with anti-HLA-B locus-specific MAbs. These selective losses were confirmed using the corresponding anti-HLA polymorphic MAbs. For HLA class II molecules, only DR was observed in 3 of 38 cases. Defective HLA class I expression statistically correlates with high scores according to Jakobsson's criteria for histopathological tumour grading. Loss of HLA-ABC antigens was most frequent among the cases with poor differentiation (6/8 cases). On the contrary, class II antigen expression was correlated with a well differentiated pattern and a more favourable prognosis (p less than 0.001). We have found differences in HLA class I expression when comparing primary tumours and autologous metastases (3/9 cases). Immunoprecipitation and SDS-PAGE of class I antigens, Northern and Southern blot analyses of MHC class I genes were performed. We have not detected class I gene rearrangement using HLA coding and locus-specific non-coding probes. However, we have found a class I transcription defect that corresponds with a class-I-negative phenotype.
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PMID:Histocompatibility antigens in primary and metastatic squamous cell carcinoma of the larynx. 264 39


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