Availability of immune globulin intravenous for treatment of immune deficient patients--United States, 1997-1998.
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Immune globulin intravenous (IGIV) is a lifesaving treatment for patients with primary immunodeficiency. Since November 1997, a shortage of IGIV has existed in the United States. In 1998, the Food and Drug Administration (FDA) required pharmaceutical companies to increase the frequency of reporting on IGIV distribution from biannually to monthly; in addition, FDA facilitated IGIV distribution and informed clinicians about the ongoing shortage. To assess the impact of the IGIV shortage on patient care, in 1998 the Immune Deficiency Foundation (IDF) surveyed physicians caring for immunodeficient patients about whether they have had difficulty obtaining IGIV, measures they have taken because of the shortage, and the effect of the shortage on their patients. This report summarizes data reported to FDA and data obtained from the IDF survey and provides recommendations for IGIV use during the shortage. (+info)
Treatment of multiple myeloma.
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BACKGROUND AND OBJECTIVE: Multiple myeloma (MM) accounts for about 10% of all hematologic malignancies. The standard treatment with intermittent courses of melphalan and prednisone (MP) was introduced more than 30 years ago and, since then there has been little improvement in event-free and overall survival (EFS & OS). The aim of this article is to review: 1) the role of initial chemotherapy (ChT), maintenance treatment with alpha-interferon and salvage ChT, 2) the results of high-dose therapy (HDT) followed by allogeneic or autologous stem cell transplantation (allo-SCT and auto-SCT), and 3) the most important supportive measures. EVIDENCE AND INFORMATION SOURCES: The authors of this review have been actively working and contributing with original investigations on the treatment of MM during the last 15 years. In addition, the most relevant articles and recent abstracts published in journals covered by the Science Citation Index and Medline are also reviewed. STATE OF THE ART AND PERSPECTIVES: The importance of avoiding ChT in asymptomatic patients (smoldering MM) is emphasized. The criteria and patterns of response are reviewed. MP is still the standard initial ChT with a response rate of 50-60% and an OS of 2-3 years. Combination ChT usually increases the response rate but does not significantly influence survival when compared with MP. Exposure to melphalan should be avoided in patients in whom HDT followed by auto-SCT is planned, in order to not preclude the stem cell collection. The median response duration to initial ChT is 18 months. Interferon maintenance usually prolongs response duration but in most studies does not significantly influence survival (a large meta-analysis by the Myeloma Trialists' Collaborative Group in Oxford is being finished). In alkylating-resistant patients, the best rescue regimens are VBAD or VAD. In patients already resistant to VBAD or VAD and in those in whom these treatments are not feasible we recommend a conservative approach with alternate day prednisone and pulse cyclophosphamide. While HDT followed by autotransplantation is not recommended for patients with resistant relapse, patients with primary refractory disease seem to benefit from early myeloablative therapy. Although results from large randomized trials are still pending in order to establish whether early HDT intensification followed by auto-SCT is superior to continuing standard ChT in responding patients, the favorable experience with autotransplantation of the French Myeloma Intergroup supports this approach. However, although the complete response rate is higher with intensive therapy, the median duration of response is relatively short (median, 16 to 36 months), with no survival plateau. There are several ongoing trials comparing conventional ChT with HDT/autoSCT in order to identify the patients who are likely to benefit from one or another approach. With allo-SCT there is a transplant-related mortality ranging from 30 to 50% and also a high relapse rate in patients achieving CR. However, 10 to 20% of patients undergoing allo-SCT are long-term survivors (> 5 years) with no evidence of disease and, consequently, probably cured. The use of allogeneic peripheral blood stem cells (PBSC) in order to speed the engraftment and also the use of partially T-cell depleted PBSC which can decrease the incidence of graft-versus-host disease are promising approaches. In the setting of allo-SCT, donor lymphocyte infusion is an encouraging strategy in order to treat or prevent relapses. Finally, important supportive measures such as the treatment of anemia with erythropoietin, the management of renal failure and the use of bisphosphonates are reviewed. (+info)
Host modulation as a therapeutic strategy in the treatment of periodontal disease.
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Specific microorganisms initiate the immunoinflammatory processes that destroy tissue in periodontitis. Recent work has demonstrated, in addition to bacterial control, that modulation of the host immunoinflammatory response is also capable of controlling periodontitis. Matrix metalloproteinases (MMPs) destroy collagen and other matrix components, and the osteoclastic bone remodeling determines the periodontal bone response to a bacterial challenge. Other components of the biology, including cytokines and prostanoids, regulate MMPs and bone remodeling and are also involved in regulating the production of defensive elements, such as antibody. Agents directed at blocking MMPs or osteoclastic activity are effective in reducing periodontitis. Agents that inhibit prostaglandin E2 and selective blockage of specific cytokines have also been effective. Improved knowledge of bacterium-host interactions and of the processes leading to tissue destruction will help to identify targets for host modulation to reduce periodontitis in selected situations. (+info)
Airways inflammation among workers in a paper industry.
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Exposure to organic dusts may cause airways inflammation in a large proportion of exposed persons. Most studies have relied on questionnaires and spirometry for diagnosis. To assess the possibility of determining the presence of inflammation using clinical diagnostic procedures, a study was undertaken among workers in a paper industry. Participants were 83 workers and 44 controls. Airborne endotoxin and (1-->3)-beta-D-glucan levels at the worksites were determined. The effects of this exposure were evaluated using a questionnaire, spirometry and measurements of airway responsiveness (methacholine) and levels of eosinophil cationic protein (ECP), myeloperoxidase (MPO), and C-reactive protein (CRP) in serum. The workers had a decreased baseline forced expiratory volume in one second (FEV1) and an increased airway responsiveness compared with controls. The concentrations of ECP and MPO were elevated compared with controls. There was a relation between exposure to endotoxin and (1-->3)-beta-D-glucan and airway responsiveness as well as ECP levels, when controlling for age, sex, smoking habits, atopy and asthma. The results suggest an increased prevalence of subjective respiratory symptoms, and an increased airway responsiveness among exposed workers. There was also a relationship between the serum concentration of eosinophil cationic protein and airway responsiveness. Taken together, the results suggest the presence of airways inflammation in the workers. (+info)
Interleukin-10-induced CD8 cell proliferation.
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Interleukin (IL)-10, a product of T helper 2 (Th2) lymphocytes, has been shown to be an important regulator of lymphoid and myeloid cells, inhibiting mitogen, peptide and alloantigen-induced T-cell proliferation and IL-2 production. The microenvironment at the time of cell activation, notably the presence or absence of cytokines such as IL-10, interferon-gamma (IFN-gamma) and IL-2, is believed to determine the lineage and magnitude of cell-mediated responses. In this study, we show that recombinant human IL-10 (rhIL-10) exerts a dose-dependent inhibitory effect on human peripheral blood mononuclear cells stimulated in vitro, when these cells have not previously been exposed to rhIL-10. Furthermore, incubation of these cells with high doses of rhIL-10, either before or at the time of activation, results in inhibition which is followed several days later by the emergence of a population of CD8 positive cells. This rhIL-10-responsive CD8, positive cell population still emerges even when the cells are washed following incubation with rhIL-10 prior to cell activation. Using purified CD8 populations this was shown to be a direct action of rhIL-10 on CD8 cells and not via CD4 positive cells and monocytes. This finding was only observed when cells were activated with a cross-linking anti-CD3 antibody and not when activated with phorbol-12-mystrate-13-acetate (PMA) and calcium ionophore (CaIon), suggesting that the effect is mediated through cell-surface receptors. Analysis of CD8 positive clones reveal production of Tc2 patterns of cytokines and reduced cell cytotoxicity to allogeneic, natural killer and lymphokine activated cell targets. (+info)
Autologous transplantation in multiple myeloma: a GITMO retrospective analysis on 290 patients. Gruppo Italiano Trapianti di Midollo Osseo.
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BACKGROUND AND OBJECTIVE: Autologous transplantation is a better treatment for multiple myeloma (MM) than chemotherapy, but uncertainty remains about patient selection, optimal timing of autograft, conditioning regimen, need for a second autograft, and role of maintenance. To provide partial answers to these questions we assessed the results of autologous transplantation in a large cohort of patients whose data were reported to the GITMO registry. DESIGN AND METHODS: We retrospectively analyzed data from 290 patients with MM (M = 150; F = 140; median age 52 years, range 19-70; stage I = 34, stage II = 75, stage III = 167) reported to the GITMO. At the time of autograft, 20% were in CR, 66% in PR, while the remaining had non-responsive or progressive disease. Median time between diagnosis and transplant was 16 months (1-90). Seventy-two patients (26%) had been planned to receive a double autograft, but this was actually done in only 35 (12%). The conditioning was chemotherapy in 90%. Peripheral blood was the only source of stem cells in 94%, and purging was applied in 10% of cases. For statistical analysis of data, differences between patient subsets were analyzed using the chi-square test, while the Kaplan-Meier method was used to estimate event-free survival (EFS) and survival (OS) probabilities. The Cox model was used for multivariate analysis. RESULTS: Following the autograft, 116 patients (40%) were in CR, 144 (50%) in PR, 24 (8%) did not respond or progressed and 6 (2%) died before response evaluation. Transplant-related mortality occurred in 3%. At a median follow-up of 23 months, 223 (77%) patients are alive, 71 (24%) of them in CR, and 67 (23%) patients have died at a median time of 20 months (0-70). OS and EFS at 6 years are 47% and 28%, respectively, but the EFS curve shows no plateau. In multivariate analysis, age, beta2-microglobulin level and status at transplant emerged as significant prognostic factors for both OS and EFS, while time from diagnosis to transplant showed borderline significance. INTERPRETATION AND CONCLUSIONS: Based on the prognostic factors identified in multivariate analysis, we were able to assess the weight of a single prognostic factor or their combinations on transplant outcome. We also calculated the probability of OS and EFS by the number of factors at the time of autograft. Autologous transplantation is a safe and effective procedure, not only in sensitive patients, but also in resistant cases, provided they are <55 years of age and have low beta2-microglobulin. It should be applied early after the diagnosis of multiple myeloma, following the delivery of brief primary chemotherapy. (+info)
Beta-glucan, a "specific" biologic response modifier that uses antibodies to target tumors for cytotoxic recognition by leukocyte complement receptor type 3 (CD11b/CD18).
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beta-Glucans were identified 36 years ago as a biologic response modifier that stimulated tumor rejection. In vitro studies have shown that beta-glucans bind to a lectin domain within complement receptor type 3 (CR3; known also as Mac-1, CD11b/CD18, or alphaMbeta2-integrin, that functions as an adhesion molecule and a receptor for factor I-cleaved C3b, i.e., iC3b) resulting in the priming of this iC3b receptor for cytotoxicity of iC3b-opsonized target cells. This investigation explored mechanisms of tumor therapy with soluble beta-glucan in mice. Normal mouse sera were shown to contain low levels of Abs reactive with syngeneic or allogeneic tumor lines that activated complement, depositing C3 onto tumors. Implanted tumors became coated with IgM, IgG, and C3, and the absent C3 deposition on tumors in SCID mice was reconstituted with IgM or IgG isolated from normal sera. Therapy of mice with glucan- or mannan-rich soluble polysaccharides exhibiting high affinity for CR3 caused a 57-90% reduction in tumor weight. In young mice with lower levels of tumor-reactive Abs, the effectiveness of beta-glucan was enhanced by administration of a tumor-specific mAb, and in SCID mice, an absent response to beta-glucan was reconstituted with normal IgM or IgG. The requirement for C3 on tumors and CR3 on leukocytes was highlighted by therapy failures in C3- or CR3-deficient mice. Thus, the tumoricidal function of CR3-binding polysaccharides such as beta-glucan in vivo is defined by natural and elicited Abs that direct iC3b deposition onto neoplastic cells, making them targets for circulating leukocytes bearing polysaccharide-primed CR3. Therapy fails when tumors lack iC3b, but can be restored by tumor-specific Abs that deposit iC3b onto the tumors. (+info)
Sequential biochemical modulation of fluorouracil with folinic acid, N-phosphonacetyl-L-aspartic acid, and interferon alfa-2a in advanced colorectal cancer.
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PURPOSE: Several agents have been evaluated for their effect as biochemical modulators of fluorouracil (5-FU) in the treatment of metastatic colorectal carcinoma. In this study, we used folinic acid (FA), N-phosphonacetyl-L-aspartic acid (PALA), and recombinant interferon alfa-2a (IFNalpha-2a) in a sequential order to assess the efficacy of this approach in patients with metastatic colorectal carcinoma. PATIENTS AND METHODS: Forty-four patients with metastatic colorectal carcinoma were enrolled onto the study. The treatment course consisted of three cycles: (cycle 1) FA 20 mg/m(2) followed by 5-FU 425 mg/m(2) on days 1 to 5; (cycle 2) PALA 250 mg/m(2) on days 29, 36, 43, and 50 and 5-FU 2,600 mg/m(2) as a 24-hour infusion on days 30, 37, 44, and 51; and (cycle 3) IFNalpha-2a 9 million units (MU) three times a week for 5 weeks beginning on day 57, with a continuous infusion of 5-FU 750 mg/m(2) on days 57 to 61, and then weekly bolus of 5-FU 750 mg/m(2)/wk on days 71, 78, and 85. Response was determined after cycle 3. RESULTS: All patients had a Zubrod performance status >/= 2, measurable disease, and had received no prior chemotherapy for their metastatic disease. A total of 212 cycles were given. Thirty-six patients were assessable for response. No complete responses were seen. Seven patients had a partial response, eight had stable disease, and 15 had progressive disease. The median duration of response was 25 weeks, and the median survival was 53 weeks. Grade 3 and 4 toxic effects included granulocytopenia, stomatitis, diarrhea, rash, nausea, and fatigue. CONCLUSION: This trial provided no evidence that sequential biochemical modulation of 5-FU in patients with metastatic colorectal carcinoma had any therapeutic advantage over conventional treatment regimens of 5-FU plus FA. (+info)