Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

In a phase I/II dose escalation study performed at our institution, a total of 14 advanced metastatic cancer patients received between 4 and 16 weeks of subcutaneous recombinant interleukin-2. Doses were escalated at weekly intervals, starting at 1.8 million IU/m2/day up to a maximum dose of 14.4 million U/m2 daily. When comparing patients with (n = 4) and without (n = 7) prior chemotherapy on day 0 (i.e., before rIL-2), both patient groups exhibited Tac IL-2 receptor (CD25) positive peripheral blood lymphocytes at equal levels of positivity (8%). In contrast, 4-week systemic treatment with subcutaneous rIL-2 at escalating dose levels revealed a significant difference in the up-regulation by interleukin-2 of CD25 cell surface receptor. Thus, after 4 consecutive weeks of treatment, patients without previous chemotherapy showed a mean CD25 positivity of peripheral blood lymphocytes at 38%, as compared with 22% in patients who did receive prior chemotherapy (p less than 0.05). These data suggest that chemotherapy pretreatment may have a significant effect on biological response to rIL-2 in vivo.
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PMID:Diminished expression of interleukin-2 receptors in vivo after prior chemotherapy in advanced cancer patients receiving recombinant interleukin-2. 191 Jun 21

Twenty-four patients with advanced stomach cancer were treated with OK-432 combined adoptive immunotherapy [AIT] as prophylaxis or therapy against peritoneal metastases. Lymphocytes isolated mainly from regional lymph nodes were cultured for 9-13 days with T cell growth factor and sonicated tumor extract. OK-432 administration and cell transfer were performed via a catheter inserted into the abdominal cavity at surgery. The proliferation rate of regional lymph node lymphocytes was higher than that of peripheral blood lymphocytes (p less than 0.01). Cultured regional lymph node lymphocytes expressed CD25 and CD4+45R- more frequently than those of peripheral blood lymphocytes. On the other hand, cytotoxic activity of regional lymph node lymphocytes were slightly lower than that of peripheral blood lymphocytes. These results suggest that regional lymph node lymphocytes could be used in AIT because of their different function from that of peripheral blood lymphocytes. Survival of the patients with peritoneal metastasis at primary laparotomy was higher than that of the historical control group (4-9 months after surgery). These results show that OK-432 combined adoptive immunotherapy appears to be a new therapeutic approach to peritoneal metastases from stomach cancer.
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PMID:[Adoptive immunotherapy against peritoneal metastases from stomach cancer--application of regional lymph node lymphocytes]. 235 54

Phenotypic characterization of peripheral blood lymphocytes was performed in patients with advanced metastatic cancer receiving low-dose recombinant interleukin-2 (rIL-2) and recombinant interferon-alpha (rIFN-alpha) as subcutaneous home therapy. A total of 31 patients with progressive metastatic renal cell carcinoma, malignant melanoma, colorectal cancer, B-cell lymphoma, and Hodgkin's disease, were evaluated. Patients were treated with a combination of low-dose subcutaneous rIL-2 and rIFN-alpha, consisting of a 2-day rIL-2 pulse at 9.0 million IU/m2 twice daily, followed by 6 weeks of combined low-dose rIL-2 at 1.8 million IU/m2 twice daily, 5 days per week, and rIFN-alpha at 5.0 million U/m2 3 times per week. This treatment regimen resulted in an overall significant (p < 0.002) increase in peripheral blood lymphocyte subsets expressing CD3, CD8, CD16, CD25, and CD56. Expansion of peripheral blood natural killer (NK) cells was correlated to treatment response. Thus, treatment-related increase in CD56-positive lymphocytes was 1.8-fold higher in complete or partial responders when compared to progressive disease patients (p = 0.0). Increase in NK cells upon low-dose rIL-2 and rIFN-alpha was associated with a significant expansion (p = 0.0) of peripheral blood eosinophils (r = 0.71). Patient pretreatment using rIL-2, rIL-2 and rIFN-alpha, or chemotherapy abrogated the treatment-induced induction of NK cells and IL-2 receptor- (CD25) positive T lymphocytes, respectively. Peripheral blood NK cells were significantly decreased (p < 0.05) in patients developing neutralizing antibodies specific to rIL-2.
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PMID:Low-dose interleukin-2 in combination with interferon-alpha effectively modulates biological response in vivo. 768 66

Treatment of metastatic melanoma patients with an autologous vaccine modified by the hapten, dinitrophenyl (DNP), produces a striking immunological effect: the induction of clinically evident inflammatory responses in metastatic tumors. Histological examination shows these tumors to be infiltrated with T lymphocytes. We studied the expression of activation markers on those cells and compared them with matched peripheral blood lymphocytes (PBL) and with lymphocytes extracted from metastases before treatment with DNP-conjugated vaccine. The median fraction of cells that were T cells in post-vaccine tumors was 41%, as compared with 9% in pre-treatment tumors, and those T cells were predominantly CD8+ (mean CD8/CD4 ratio = 5.0). A high proportion of both pre- and post-treatment infiltrating T cells expressed HLA-DR (mean +/- SE = 48% +/- 4%), CD69 (56% +/- 7%), and ganglioside GD3 (68% +/- 5%). This distinguished them from matched PBL in which expression of those markers was significantly lower (HLA-DR = 10% +/- 2%; CD69 = 2% +/- 0.4%; GD3 = 49% +/- 4%). These changes were not accompanied by increased cell-surface expression of interleukin-2 (IL-2) receptors, either CD25 or p75, which were expressed by 1%-2% and 12% of tumor-infiltrating lymphocytes (TIL), respectively. The pattern of activation marker expression that we identified appears to be characteristic of tissue T cells with the memory phenotype. The low expression of IL-2 receptors could indicate functional impairment of TIL in situ, perhaps because of inhibitory molecules produced by melanoma cells.
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PMID:Activation markers on T cells infiltrating melanoma metastases after therapy with dinitrophenyl-conjugated vaccine. 792 43

Swainsonine, an alpha-mannosidase inhibitor which blocks Golgi oligosaccharide processing, represents a new class of compounds that inhibit both rate of tumor growth, and metastasis, in murine experimental tumor models. In this first phase I study, the quantitative and qualitative toxicities of swainsonine have been studied in patients given a continuous i.v. infusion over 5 days, repeated at 28-day intervals. Dose levels were escalated in increments of 100 micrograms/kg/day from 50-550 micrograms/kg/day. Nineteen patients with both solid tumor and hematological malignancies were given a total of 31 courses. Hepatotoxicity, particularly in patients with liver metastases, was the dose-limiting toxicity. The maximum tolerated dose (MTD) and the recommended starting dose (MTD -1 level) were 550 and 450 micrograms/kg/day, respectively. Common side effects included edema, mild liver dysfunction, a rise in serum amylase, and decreased serum retinol. Acute respiratory distress syndrome possibly precipitated by swainsonine resulted in a treatment-related death in a patient with significant pretreatment hepatic dysfunction. One patient with head and neck cancer showed > 50% shrinkage of tumor mass for 6 weeks after treatment. Two patients with lymphangitis carcinomatosis on chest X-ray noted improvement in cough and shortness of breath during the infusion of swainsonine and for 1 week thereafter. Clearance and serum half-life for swainsonine were determined to be approximately 2 ml/h/kg, and 0.5 day, respectively. Golgi oligosaccharide processing, a putative anticancer target for swainsonine was inhibited in peripheral blood lymphocytes as evidenced by a marked decrease in leukoagglutinin binding after 5 days of treatment. Oligomannosides in patient urine increased 5-to 10-fold over the 5 days of treatment, indicating that tissue lysosomal alpha-mannosidases were also blocked by swainsonine. Urine oligomannoside accumulation reached steady state at 3 days, approximately 1 day after serum drug levels reached steady state. The fraction of HLA-DR-positive cells in peripheral blood lymphocytes increased following 5 days of swainsonine treatment, an effect similar to that observed for peripheral blood lymphocytes from normal subjects cultured with swainsonine. No significant changes in CD3, CD4, CD8, CD16, and CD25 were observed. Swainsonine produces minimal toxicity when administered i.v. to cancer patients at dosages that inhibit both Golgi alpha-mannosidase II and lysosomal alpha-mannosidases. Detection of hepatic metastases or liver enzyme abnormalities prior to treatment predict for more significant toxicity.
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PMID:A phase I study of swainsonine in patients with advanced malignancies. 813 47

We evaluated adoptive immunotherapy using LAK cells combined with systemic administration of interleukin-2 (IL-2) in 11 patients with metastatic renal cell carcinoma. The LAK cells were generated by incubation in serum-free medium (AIM-V) supplemented with IL-2 (1,000 U/ml) for 4 days and were generally administered twice weekly (4 times/cycle). Daily administration of IL-2 (50 x 10(5) U) was started 3 days prior to the first LAK infusion and continued throughout the cycle. Each course of therapy comprised 1-6 cycles, with the total dose of LAK cells and IL-2 varying from 3.3-52.6 x 10(9) cells and 140-900 x 10(5) U, respectively. Clinical response was evaluated in terms of metastasis to specific organs (lung only: eight cases, lung and brain: one, lung and lymph nodes: one, lung and bone and pleuropericardium: one). The outcome was complete response in one patient, partial response in one, no change in six and disease progression in three. The response rate was 18.8%. This therapy was most effective against pulmonary metastases. Adverse reactions to LAK cell infusion included fever, headache, and chills. Eosinophilia and weight gain due to IL-2 administration were also observed. However, all of these symptoms were transient and no serious side effects occurred. In these patients, the proportion of natural killer (NK) cells (CD16) and cells with IL-2 receptor (CD25) among PBL was increased markedly in the early phase of therapy, and activated T cell (CD3+DR+) and suppressor T cells (CD8+11+) increased significantly at a later phase. It was suggested that the clinical response would be expected in case of increasing of CD16 cells or CD25 cells and augmentation of NK or LAK activity. Our results indicate that this regimen of adoptive immunotherapy shows some promise for the treatment of advanced renal cell carcinoma.
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PMID:[Study of adoptive immunotherapy for metastatic renal cell carcinoma with lymphokine-activated killer (LAK) cells and interleukin-2. II. Clinical evaluation]. 832 Aug 88

Tumor regression induced by IL-2 in a fraction of patients with metastatic renal-cell carcinoma (MRCC) could not be predicted by immunological monitoring. In addition, the general mechanisms leading to tumor regression or even the distinct cell subsets (e.g., T vs. NK cells) involved are poorly identified. To evaluate the influence of IL-2 administration on circulating T-cell subpopulations, TCR V alpha and V beta gene segment usage was analysed by PCR in 7 MRCC patients using a panel of V gene segment subfamily-specific oligonucleotide primers (V alpha I-w29/V beta I-w24). Three samples were examined in each patient: (i) peripheral blood cells (PBMCs) before therapy (day I); (ii) PBMC 2 days after the interruption of IL-2, at day 36 (i.e., at the lymphocytic rebound), (iii) the CD25-enriched cell fraction at day 36. Virtually all V alpha and V beta subfamily specificities were found in pre- as well as in post-treatment PBMCs and CD25+ cell fractions. These results support the view that circulating T-cell subpopulations are highly polyclonal after IL-2 therapy without any major alteration in the TCR V alpha and V beta repertoire. In addition, the results of quantificative densitometric analysis of V alpha and V beta amplified products suggest that a unique V beta 18-expressing T-cell subpopulation may be expanded in the CD25+ cell fraction after IL-2 therapy. Further characterization of these T cells may contribute to a better understanding of in vivo effects of IL-2 on renal-cell carcinoma metastases.
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PMID:Influence of interleukin-2 administration on the expression of T-cell receptor V gene segments in patients with renal-cell carcinoma. 832 4

To examine the intra-individual heterogeneity of the local inflammatory infiltrate in metastases of untreated melanoma patients we analysed 42 skin and subcutaneous metastases from 11 patients. Metastases were excised on the same date (10 patients) or consecutively (six patients), and processed in a two-step immunoperoxidase technique using monoclonal antibodies directed against T-cells (CD3, CD25) and two macrophage subpopulations (RM 3/1, 27E10). The number of positively stained T-cells and macrophages were counted for each lesion in representative high power fields. The mean values were calculated. We observed limited heterogeneity among T-cells (CD3+) and activated T-cells (CD25+) in simultaneously excised metastases. Contrary to this, markedly heterogeneous CD3+ infiltrates were found in metastases taken on different dates, even if there was a time difference of only 1 day between excisions, suggesting spontaneous variations. However, activated T-cells in follow-up biopsies showed only limited heterogeneity. In spite of inter-individual variations, metastases taken simultaneously, as well as consecutively, showed little intra-individual heterogeneity with respect to macrophages. Our findings should be taken into account for comparative studies of the infiltrate in metastatic melanoma during immunotherapy.
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PMID:Heterogeneity of the T-cell and macrophage infiltrate in cutaneous and subcutaneous metastases of melanoma patients. 840 Aug 57

Peripheral blood mononuclear cells (PBMC) were taken by leukapheresis from a patient with melanoma skin metastases and stimulated in vitro using 1000 IU recombinant interleukin 2 (IL-2)/ml to generate lymphokine-activated killer cells (LAK cells). Two-colour immunofluorescence analysis demonstrated an IL-2-induced up-regulation of CD25 on natural killer cells (CD56+) as well as on T lymphocytes (CD3+). After radiolabelling with indium-111, the cells were reinfused. Gamma-camera imaging revealed an enrichment at the tumour sites. Immunostaining of tumour tissue taken before and after scintigraphy demonstrated CD25+ T lymphocytes (CD2+, CD3+), but no natural killer cells (CD16+, CD56+) infiltrating the metastases. LAK cell enrichment at melanoma metastases in vivo did not involve natural killer cells, but was characterized by increased numbers of activated T lymphocytes in this patient.
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PMID:T cells migrate to tumour sites after extracorporeal interleukin 2 stimulation and reinfusion in a patient with metastatic melanoma. 849 52

The purpose of this study was to investigate the relationship between changes in density and distribution of dendritic cells, both in epidermis and in peritumoral infiltrate, and lymphocyte subset variations in malignant melanomas (MM) of patients belonging to different risk groups. The collective immunoreactive expression of six markers (S100 protein, CD1-a, HLA-DR, CD4, CD8 and CD25) was analyzed in 13 cutaneous malignant melanomas. Changes were observed in density and distribution of Langerhans cells (LC) (S100+, CD1-a+) in the epidermis overlying the tumor, as well as in peritumoral and intratumoral locations, independently of the tumor-invasion level. A decrease was recorded in LC (S100+, CD1-a+) in the epidermis overlying six tumors, whereas most of the MM studied showed an increase of LC (S100+, CD1-a+) in peritumoral infiltrate. The expression of HLA-DR in tumor cells was controversial; it was observed in three moderate-risk MM, but it was negative in high-risk tumors. The percentage of CD4+ cells was in most cases greater than that of CD8+ in the peritumoral infiltrate, irrespective of the degree of histopathological malignancy. The concomitant expression of the lymphocytic activation marker CD25 (receptor for interleukin 2) in lymphocytic infiltrate was variable. Peritumoral infiltrate in three high risk MM contained few CD25+ cells, and a concomitant decrease was recorded in LC. This preliminary report shows that alterations in the density and distribution of LC may be responsible for determining the degree or T lymphocyte activation, and this may be critical for the development of effective tumor-directed immunity. Further studies are required to demonstrate these hypothetical interrelations.
Invasion Metastasis 1995
PMID:Immunophenotype analysis of dendritic cells and lymphocytes associated with cutaneous malignant melanomas. 862 Dec 68


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