Biomedical subjects

E Katsanis

Publications and source records attributed to E Katsanis.

At least 37 records · Page 2Linked to original sources

PubMed1996

IL-15 administration following syngeneic bone marrow transplantation prolongs survival of lymphoma bearing mice.

The toxicity and antitumor efficacy of simian IL-15 was compared with human IL-2 in the context of syngeneic BMT. Groups of mice receiving or not receiving anti-CD3 activated splenocytes, termed "T-activated killer" (T-AK) cells, were treated between days 7 and 12 with escalating doses of IL-2 or IL-15 given twice daily. Recipients of IL-2+T-AK or IL-15+T-AK had significantly higher survival rates than saline+T-AK. Tissues from IL-2+T-AK, but not IL-15+Y-AK, treated mice revealed the presence of perivascular infiltrates in the lung and liver consisting of CD8+ T cells and Mac-1+ cells. Our findings demonstrate that IL-15 can be used effectively to stimulate antitumor responses post-BMT and may be associated with less toxicity than IL-2.

Bone Marrow Transplantation↗

PubMed1996

Interleukin-2 secretion by transduced and unselected BDL-2 lymphoma results in increased survival in mice with previously established disseminated disease.

The transfer and expression of cytokine genes into malignant cells to provide a more effective tumor response has shown promise. The majority of murine models in which tumor vaccination strategies have been tested have utilized selected and expanded clones of tumor cells, which is impractical clinically. In a model of murine B lineage lymphoma (BDL-2), we compared the effectiveness of tumor vaccines composed of a) a BDL-2 clone established by G-418 resistance following transduction with the LIL2SN retrovirus and screened for maximal IL-2 secretion, b) a syngeneic fibroblast line transduced with LIL2SN and screened for G-418 resistance and IL-2 expression, which was co-injected with the parental line, and c) a heterogeneous (unselected) population of BDL-2 cells transduced with the MFG/IL2 virus, reported to provide enhanced expression of cytokine genes and minimize the need for selection. Testing of splenocytes derived from vaccinated animals reveals that injections of BDL-2 expressing IL-2 results in an increased capacity of splenocytes to kill BDL-2 in vitro, compared to vaccination of BDL-2 alone or in combination with IL-2 secreting fibroblasts. We show that a vaccine composed of MFG/IL2 transduced, unselected BDL-2 cells is equivalent or superior to a clone derived from LIL2SN transduction in prolonging survival of animals with previously established tumor. These studies provide evidence that transduction of tumor with MFG based vectors without in vitro selection leads to expression of high levels of IL-2 and can impact the survival of animals with disseminated tumor.

Animals↗

PubMed1996

Effective immunization against neuroblastoma using double-transduced tumor cells secreting GM-CSF and interferon-gamma.

Murine neuroblastoma, neuro-2a, was transduced with the retroviral vector MFG-granulocyte-macrophage colony-stimulating factor (GM-CSF), to examine immune stimulation conferred by localized GM-CSF production. Expression of murine GM-CSF by neuro-2a (N-2a/GM) significantly reduced its tumorigenicity. Moreover, immunization of mice with irradiated N-2a/GM cells resulted in a significant protective effect against live tumor challenge 14 days later. Approximately 41% of mice immunized with irradiated N-2a/GM versus 0% of those vaccinated with irradiated parental tumor survived. Surviving mice were rechallenged after 50 days with wild-type neuro-2a or with the Sa1 syngeneic sarcoma to discern whether the generated immunity was durable and tumor specific. All mice survived wild-type neuro-2a challenge, whereas none survived inoculation with Sa1. Because both CD4+ and CD8+ T cells were necessary during priming to this MHC class Ilo, II-tumor, these data indicate that major histocompatibility complex (MHC) class I+, II+ antigen-presenting cells (APCs) were required for the T-cell antitumor response. Co-expression of GM-CSF and IFN-gamma, both of which have immunostimulatory activities on antigen-presenting cells, abrogated the tumorigenic potential of this tumor and increased immunogenicity over N-2a/IFN but not N-2a/GM. Vaccination of mice with preexisting retroperitoneal tumors with irradiated N-2a/GM and irradiated N-2a/IFN/GM improved survival. There was a trend for nonirradiated transduced cells to be more immunogenic than their irradiated counterparts. Immunohistochemistry of tissues from the vaccination site revealed a pronounced macrophage infiltration associated with nonirradiated N-2a/GM and N-2a/IFN/GM. These data suggest that vaccination involving nonirradiated neuroblastoma cells transduced with genes that stimulate APCs may be a useful approach in stimulating antitumor T-cell responses.

Animals↗

PubMed1995

B7-1 expression decreases tumorigenicity and induces partial systemic immunity to murine neuroblastoma deficient in major histocompatibility complex and costimulatory molecules.

Neuroblastoma may escape an immune attack by virtue of its low expression of surface accessory molecules essential in the antitumor response. Murine neuroblastoma, neuro-2a, was transduced with the retroviral vector LB7-1SN to examine the influence of B7-1 expression on the immune response directed against a low major histocompatibility class (MHC) I and class II negative, B7-2, and ICAM-1 negative tumor. Using a retroperitoneal model for implantation of neuroblastoma in its natural site, we demonstrated that expression of B7-1 by neuro-2a reduces its tumorigenicity. Coinjection of B7-1-positive and -negative cells improved survival compared with mice receiving B7-1-negative cells alone. This was dependent on the ratio of B7-1+ to B7-1- neuro-2a cells injected. CD8+ and not CD4+ T-cell depletion significantly increased tumor-induced mortality in syngeneic A/J mice, indicating that B7-1 decreases tumorigenicity primarily by direct constimulation of CD8+ T cells. Rejection of N-2a/B7-1 tumors or preimmunization with irradiated N-2a/B7-1 cells die not increase protection to challenge with unmodified neuro-2a cells over mice vaccinated with N-2a/neo. Furthermore, cytotoxic T lymphocyte (CTL) precursor frequencies were not significantly higher after in vivo priming and in vitro stimulation with irradiated N-2a/B7-1 compared with N-2a/neo, indicating that B7-1 costimulation by the tumor, in the absence of adequate antigen presentation by MHC molecules, may limit the generation of effective CTLs.

Animals↗

PubMed1994

Interleukin-1 alpha administered after autologous transplantation: a phase I/II clinical trial.

Interleukin-1 alpha (IL-1 alpha) can act as both a hematopoietic growth factor and a stimulant of cellular and humoral immune responses. To promote acceleration of hematologic recovery and induce immune antitumor activity, we initiated a phase I/II dose escalation trial of 6-hour daily infusions of recombinant human IL-1 alpha after autologous transplantation. Forty patients with Hodgkin's disease (n = 9) and non-Hodgkin's lymphoma (n = 31) transplanted with unmobilized autologous peripheral blood stem cells or bone marrow stem cells received daily 6-hour infusions of IL-1 alpha (day 0 to day +13) at daily doses between 0.1 to 10 micrograms/m2/d; 7 patients received only 7 planned days of IL-1 alpha (day 0 through 6). Most patients received all 14 days of therapy, although 5 patients discontinued treatment early (after 1 to 6 doses) because of fever and severe chills. Toxicity included IL-1 alpha-related fever (occurring on a median of 9 of 14 treatment days), fatigue, and severe chills. Hypotension was dose-limiting and led to discontinuation of IL-1 alpha in both patients receiving 10 micrograms/m2/d. IL-1 alpha-treated patients receiving 3.0 micrograms/m2/d (the maximum tolerated dose) achieved neutrophil recovery (absolute neutrophil count greater than 500/microL) significantly earlier (median, 12 days; range, 11 to 27) than untreated control patients or those receiving IL-1 alpha at 0.1 to 1.0 micrograms/m2/d (median, 27; range, 9 to 63; P < .0001). In addition, the IL-1 alpha patients' bone marrows at day +14 were significantly enriched with committed myeloid progenitor cells. Strong trends to earlier freedom from red blood cell (P = .06) and platelet (P = .09) transfusions were also noted after IL-1 alpha treatment. This earlier hematopoietic engraftment after 3.0 micrograms/m2/d IL-1 alpha allowed earlier hospital discharge (median, 25 v 37 days for control or low-dose IL-1 alpha patients [P < .0001]) and a concomitant reduction (by $38,000) in median hospital charges (P = .01). The clinical toxicities of IL-1 alpha infusion are substantial, though not life-threatening. The accelerated hematopoiesis and immune response activation observed in this trial suggest the value of its further investigation in controlled trials and perhaps in combination with other hemopoietins after transplantation.

Adolescent↗

PubMed1994

Transfection of the mouse ICAM-1 gene into murine neuroblastoma enhances susceptibility to lysis, reduces in vivo tumorigenicity and decreases ICAM-2-dependent killing.

We determined the expression of intercellular adhesion molecules (ICAM) on neuro-2a cells in order to evaluate whether they were involved in cytolysis of murine neuroblastoma. Fluorescence-activated cell sorting analysis revealed that the control neomycin-resistance-gene-transduced line (neuro-2a/LN) had poor expression of ICAM-1 (mean channel fluorescence, MCF = 3.7). An ICAM-1-positive transfectant of neuro-2a (neuro-2a/ICAM-1+) (MCF = 64.3) was generated to evaluate directly the role of this adhesion molecule in cytolysis. Neuro-2a/ICAM-1+ was more sensitive to LAK killing (69.7% at an effector-to-target ratio of 100:1) compared to neuro-2a/LN (48.6%) (P < 0.001). Blocking of neuro-2a/LN and neuro-2a/ICAM-1+ lysis with anti-ICAM-1 monoclonal antibodies (mAbs) did not account for all the LFA-1-dependent killing. These data indicate that even in neuro-2a/ICAM-1+ cells, other LFA-1 ligands participated in the effector-target interaction. Therefore, we examined these cell lines for ICAM-2 expression. Both neuro-2a/LN and neuro-2a/ICAM-1+ lines expressed ICAM-2 (MCF = 16.4 and 16.5). ICAM-2 accounted for the majority of the LFA-1-dependent killing in the ICAM-1-negative target, neuro-2a/LN, while ICAM-1 played a primary role in the cytolysis of the ICAM-1+ transfectant. Inhibition of lysis in the presence of anti-ICAM-1 and ICAM-2 mAbs was comparable to that seen with the addition of anti-LFA-1 mAb, indicating that other LFA-1 ligands were not involved in this system. ICAM-1 expression was associated with decreased in vivo tumorigenicity, mice inoculated with neuro-2a/ICAM-1+ cells had a significantly longer survival compared to those receiving neuro-2a/LN cells (median survival time 35.5 versus 24.5 days) (P < 0.001). It is important to note that ICAM-1 transfection of murine neuroblastoma did not alter its metastatic potential. We conclude that transfection of mouse neuroblastoma with ICAM-1 increases its sensitivity to in vitro lysis and reduces its in vivo tumorigenicity. In ICAM-1-negative murine neuroblastoma cells, ICAM-2 plays a primary role in cell-mediated lysis.

Animals↗

PubMed1994

Infusions of interleukin-1 alpha after autologous transplantation for Hodgkin's disease and non-Hodgkin's lymphoma induce effector cells with antilymphoma cytolytic activity.

We evaluated the cytolytic function, phenotypic characteristics, and cytokine levels of 22 patients with non-Hodgkin's lymphoma and 7 with Hodgkin's disease receiving interleukin-1 alpha (IL-1 alpha) following autologous bone marrow or peripheral blood stem cell transplantation. IL-1 alpha was given i.v. over 6 hr, between day 0 and day +13 posttransplant. On day +14, cells from patients receiving high-dose IL-1 alpha (3.0 micrograms/m2/day) had significantly enhanced killing of natural killer (NK)-sensitive and -resistant lymphoma targets compared to those treated with low-dose IL-1 alpha (0.1, 0.3, or 1.0 microgram/m2/day). The differences in cytolytic function between the two groups persisted but were not as striking on day +28. Patients receiving higher-dose IL-1 alpha had a significantly increased proportion of CD3+ T cells on days +14 and +28, while the proportion of CD16+ and CD56+ NK cells was decreased compared to those of patients treated with the lower dose. There were no detectable levels of IL-2, interferon-gamma, or tumor necrosis factor-alpha in the plasma of patients receiving IL-1 alpha posttransplant. However, higher-dose IL-1 alpha therapy was associated with significant increases in serum IL-6 levels in comparison to those in patients receiving low-dose IL-1 alpha. IL-1 alpha may increase cytolytic function post-bone marrow transplantation; it remains to be determined, however, whether this would have an impact on decreasing relapse rates of patients undergoing transplantation for lymphoma.

Antigens, CD↗

PubMed1994

Retroperitoneal inoculation of murine neuroblastoma results in a reliable model for evaluation of the antitumor immune response.

To more closely mimic the natural site of human neuroblastoma and the original spontaneous arising paraspinal murine tumor, the authors developed a new model system in which murine neuroblastoma cells (neuro-2a) are implanted directly into the retroperitoneal space. This method of administration resulted in an aggressive and reproducible neuroblastoma model, with death occurring at a median of 20.3 days after tumor implantation using 1 x 10(6) neuro-2a cells, compared with the intraperitoneal (median, 31 days) and subcutaneous routes (median, 35.1 days) (P < .001). Adoptive transfer of single cell suspensions from livers, spleens, and bone marrows of mice with retroperitoneal tumors into healthy hosts resulted in tumor growth, confirming the presence of metastatic foci in these organs. The retroperitoneal murine neuroblastoma model was used to assess the importance of natural killer (NK) and T cells in regulating the growth of neuro-2a in vivo. T cells played an equally protective role as NK cells; depletion of either T or NK populations significantly decreased survival as compared with undepleted mice. Elimination of both NK and T cells further accelerated mortality of neuro-2a-bearing mice as compared to those depleted of either T or NK populations. The retroperitoneal murine model is a highly relevant in vivo system for preclinical studies of new therapeutic approaches for neuroblastoma.

Animals↗

PubMed1994

Interleukin-2 gene transfer into murine neuroblastoma decreases tumorigenicity and enhances systemic immunity causing regression of preestablished retroperitoneal tumors.

Murine neuroblastoma, neuro-2a, was transduced with the retroviral vector LIL-2SN in order to examine the influence of localized interleukin (IL)-2 production on the immune response against a low major histocompatibility complex (MHC) class I, class II-negative, and intercellular adhesion molecule (ICAM)-1-negative tumor. Two neomycin-resistant (neo R) clones, N-2a/IL-2/L (2.5 +/- 0.4 U/ml/10(6) cells/24 h) and N-2a/IL-2/H (44.6 +/- 8.8 U/ml), were studied as representative low and high IL-2 producers, respectively. Using a recently developed retroperitoneal (r.p.) model for implantation of neuroblastoma in its natural site, we demonstrated that production of IL-2 by neuro-2a reduces its tumorigenicity in a dose-dependent fashion. T-cell, but not natural killer (NK) cell, depletion significantly increased tumor induced mortality in syngeneic A/J mice. Mice genetically devoid of T-cells (C.B-17 scid/scid) also experienced a significant increase in mortality rates. This indicates that the antitumor effect of locally secreted IL-2 is mediated primarily through activation of T-cells. Immunization of mice with irradiated N-2a/IL-2/H cells resulted in protection when challenged at a later date with unmodified neuro-2a cells. Depletion of CD8+, but not CD4+, T-cells prior to vaccination abrogated the protective effect, indicating that the priming phase of the immune response is CD8+ T-cell dependent. Mice with established r.p. tumors were vaccinated with N-2a/IL-2/H, which significantly prolonged their survival compared to unimmunized controls and to mice immunized with non-IL-2-producing neuro-2a cells. Because of the similarities of this model with the human tumor, our studies indicate that IL-2-transduced neuroblastoma cells may be effective in generating systemic immunity leading to eradication of minimal residual disease.

Animals↗

PubMed1994

Short-term ex vivo activation of splenocytes with anti-CD3 plus IL-2 and infusion post-BMT into mice results in in vivo expansion of effector cells with potent anti-lymphoma activity.

We investigated the proliferation and therapeutic utility of anti-CD3 activated splenocytes infused into mice following BMT. Using congenic mouse strains we demonstrated that splenocytes activated briefly ex vivo with anti-CD3 plus IL-2 (T-activated killer cells or T-AK) and infused intravenously following BMT had a greater expansion in blood, spleen and BM compared with splenocytes stimulated with IL-2 alone. T-AK cells recovered from blood, spleen and BM consisted predominantly of CD8+ T cells. A single infusion of T-AK cells given on day +1 post-syngeneic BMT and sustained in vivo with liposomal encapsulated IL-2, significantly increased survival of mice with BDL-2 lymphoma when compared with mice receiving saline and those treated with IL-2 liposomes alone. The anti-tumor effect of T-AK cells was significantly enhanced when IL-2 was given by continuous infusion compared with bolus injections. Depletion studies confirmed that the CD8+ T-AK cells were mainly responsible for the anti-tumor effect against BDL-2 lymphoma. Our findings demonstrate that brief ex vivo activation of splenocytes with anti-CD3 plus IL-2 results in in vivo proliferation of effector cells with potent anti-tumor activity following BMT.

Animals↗

PubMed1992

Depot characteristics and biodistribution of interleukin-2 liposomes: importance of route of administration.

Due to rapid clearance of interleukin-2 (IL-2), it has had limited effective use as an in vivo immunostimulant. Current experimental and clinical protocols generally must utilize large doses, multiple injections, or continuous infusions of IL-2 in order to achieve significant immunostimulation, often at the expense of systemic toxicity. Therefore, the pharmacodynamics of IL-2 liposomes were investigated. IL-2 liposome incorporation efficiency was 80.4% (SD 5.5); vesicle diameter was 1.65 microns (SD 0.09) as determined by fluorescence-activated cell sorting (FACS). Both formulation (free cytokine vs. IL-2 liposomes) and route of administration were important variables in determination of the biodistribution and pharmacokinetic characteristics of IL-2. When free [125I]IL-2 was given i.v. to mice, only 6.5% was in the blood and 3% in liver and spleen 2 h after injection; on the other hand, at 2 h greater than 70% of i.v. [125I]IL-2 liposomes were detected in the blood, liver, spleen, and lungs. Mean i.v. elimination t1/2 from the blood of rats given 20 x 10(6) U/kg free cytokine or IL-2 liposomes was 41 versus 102 min, respectively, as measured by bioassay and 59 and 119 min as measured by enzyme immunoassay (EIA). After i.v. administration, the estimated Vd of IL-2 liposomes was 13-fold smaller than the free cytokine. Intrathoracic (i.tx.), i.p., and s.c. administration of [125I]IL-2 to mice also demonstrated significant depot effects when IL-2 was incorporated into liposomes. These data suggest IL-2 liposomes may provide in vivo immunostimulation superior to the free cytokine due to biodistribution and depot characteristics.

Animals↗

PubMed1991

Proliferation and cytolytic function of anti-CD3 + interleukin-2 stimulated peripheral blood mononuclear cells following bone marrow transplantation.

We evaluated the proliferation, cytolytic function, and phenotypic characteristics of anti-CD3 plus interleukin-2 (IL-2) stimulated peripheral blood mononuclear cells (PBMCs) from 44 patients with leukemia or non-Hodgkin's lymphoma (NHL) treated with multiagent chemotherapy or following bone marrow transplantation (BMT). BMT patients had decreased cell growth with only a 1.35 +/- 0.25 (autologous BMT for acute lymphoblastic leukemia [ALL]), 1.24 +/- 0.25 (autologous BMT for NHL), and 0.8 +/- 0.1 (allogeneic BMT for leukemia) mean fold increase by day 5 of culture compared with controls (4.0 +/- 0.4), P less than .001. Anti-CD3 + IL-2 activated cells from patients with ALL and NHL who had received autologous BMT and cells from patients with leukemia who underwent allogeneic BMT were more effective in lysing the natural killer (NK) sensitive target, K562, and the NK-resistant target, Daudi, compared with controls. In contrast, cytolysis of K562 and Daudi by cultured PBMCs from patients with ALL and NHL receiving multi-agent chemotherapy was similar to that of controls. Cultures from BMT recipients had a significant increase in CD16+ (autologous ALL 5.7 +/- 1.5%, P less than .01; autologous NHL 12.4 +/- 3.5%, P less than .001; allogeneic 14.3 +/- 2.9%, P less than .001) and CD56+ cells (autologous ALL 27.6 +/- 12.0%, P less than .01; autologous NHL 39.3 +/- 9.5%, P less than .001; allogeneic 42.7 +/- 7.4%, P less than .001) compared with controls (CD16+ 2.5 +/- 0.4%; CD56+ 6.9 +/- 0.9%). Stimulation of PBMCs with anti-CD3 + IL-2 is effective in generating cells with high cytolytic function post-BMT.

Adolescent↗

PubMed1991

Antitumor effects of interleukin 2 liposomes and anti-CD3-stimulated T-cells against murine MCA-38 hepatic metastasis.

The stimulation of murine splenocytes with the monoclonal antibody anti-CD3 and interleukin 2 (IL-2) results in the propagation of large numbers of cells (T-activated killer; T-AK) which demonstrate high therapeutic efficacy when infused with IL-2 into mice bearing pulmonary metastases. Interleukin 2 infusions are required to maintain the function of the adoptively transferred cells. Recent data demonstrate that the therapeutic efficacy can be enhanced by encapsulating IL-2 in liposomes. The present work tested the combination of T-AK cells with IL-2 liposomes in an immunotherapy model utilizing the MCA-38 murine colon adenocarcinoma. Expansion of murine splenocytes was achieved with anti-CD3 monoclonal antibody plus IL-2 and was consistently greater than 50-fold during a 9-day culture period. Cytolytic activity of the murine T-AK cells was mediated primarily by Lyt-2+ cells. In vivo results demonstrate synergistic therapeutic efficacy of the combination of IL-2 liposomes and T-AK cells. Evaluation of the in vivo distribution of these T-AK cells utilizing congenic mice demonstrates that Lyt-2+ cells from these in vitro cultures infiltrate hepatic metastases in vivo. The activation of lymphocytes with anti-CD3 monoclonal antibody and IL-2 appears to be a reproducible and convenient method of producing cells capable of producing antitumor effects in models of adoptive immunotherapy.

Animals↗

PubMed1991

Importance in timing of cyclophosphamide on the enhancement of interleukin-2-induced cytolysis.

We investigated the in vivo effects of cyclophosphamide (CY) on interleukin-2(IL-2)-induced cytolytic function and spleen cell immunophenotype. Pretreatment of A/J mice with CY (25 mg/kg or 75 mg/kg) i.p. on days -10 and -15 followed by IL-2 (50,000 U i.p. on days 0 to +3) resulted in increased lysis of YAC-1 target cells compared to the group receiving IL-2 without previous CY therapy. In contrast, when CY was given on day -5, the cytotoxicity against YAC-1 was not enhanced. Phenotypic analysis of splenocytes obtained from mice treated with CY on day -10 or -15 revealed a relative decrease in L3T4- and Lyt2-positive T cells. In vivo depletion of natural killer (NK) cells by anti-asialoGM1, prior to IL-2 therapy, abrogated the enhancing effect of CY on cytolysis while in vivo elimination of T cells by anti-L3T4 and anti-Lyt2 monoclonal antibodies did not, indicating that in the absence of T cell antigenic challenge, the increased cytolytic function after CY administration is probably mediated through NK cells. These findings provide evidence that CY may be used more effectively in IL-2-based immunotherapy protocols, if consideration is given to timing of CY and IL-2 administration.

Animals↗

PubMed1990

Increased local antitumor effects of interleukin 2 liposomes in mice with MCA-106 sarcoma pulmonary metastases.

The effects of liposome formulations of interleukin 2 (IL-2) and local route were studied in C57BL/6 mice with MCA-106 sarcoma pulmonary metastases. IL-2 liposomes made by hydration of powdered dimyristoyl-phosphatidylcholine with aqueous recombinant IL-2 had 95% of the IL-2 associated with the lipid fraction. When mice with pulmonary micrometastases were treated once daily with free cytokine on days 5, 6, and 7 after tumor inoculation, the intrathoracic route was superior to the i.p. or s.c. routes. When IL-2 liposomes were administered by the local intrathoracic route, significantly better antitumor effects (P less than 0.01) were seen compared to empty liposomes or free IL-2 as determined by (a) increased survival and (b) reduced numbers of pulmonary metastases. Minimal toxicity was observed. Results indicate that local route and incorporation of IL-2 in liposomes may enhance therapeutic efficacy and facilitate more practical daily dosing regimens.

Animals↗

PubMed1990

Thyroid dysfunction following bone marrow transplantation: long-term follow-up of 80 pediatric patients.

Thyroid function was evaluated in children surviving disease-free for 2 years or more following bone marrow transplantation (BMT) for severe aplastic anemia (27 patients), acute non-lymphoblastic leukemia (28 patients), and acute lymphoblastic leukemia (25 patients). Pre-BMT conditioning consisted of high dose chemotherapy and total lymphoid irradiation with 750 cGy for patients with severe aplastic anemia, and for patients with leukemia, high dose chemotherapy and single dose total body irradiation with 750-850 cGy (33 patients) or fractionated total body irradiation with 1320 cGy (20 patients). Compensated hypothyroidism (elevated thyroid stimulating hormone (TSH) with a normal thyroxine index) occurred in 20/80 patients with a median time of onset of 12.3 months post-BMT (range 4-30). No patients developed primary hypothyroidism (elevated thyroid stimulating hormone with low thyroxine index). In seven patients, compensated hypothyroidism was transient with TSH returning to normal at a median of 60 months post-BMT (range 11-75). Six patients with compensated hypothyroidism received thyroid hormone replacement therapy. Time to development of compensated hypothyroidism was associated (p = 0.03) with underlying disease and radiation (11 of 27 patients with severe aplastic anemia + total lymphoid irradiation versus nine of 53 patients with leukemia + total body irradiation). In aplastic anemia patients, but not patients with leukemia, the incidence of thyroid hypofunction 5 years post-transplant was significantly higher (p less than 0.001) in those receiving methotrexate alone (82%) as prophylaxis for graft-versus-host disease compared with those receiving a regimen of methotrexate, antithymocyte globulin and prednisone (16%).

Adolescent↗

PubMed1989

Influenza in children with cancer.

We prospectively followed a group of unimmunized, immunosuppressed children with cancer to determine their relative risk of influenza and the severity of infection compared with those of siblings or matched community controls. The incidence of influenza infection was higher in children with cancer (23/73, 32%) than in control subjects (10/70, 14%, p = 0.02). A preseason hemagglutination inhibition titer greater than or equal to 1:32, generally used as a marker of successful immunization in vaccine trials, was protective for all children in the control groups, but did not prevent influenza infection in 24% of the patients with cancer. Infection rates of patients and community controls with titers greater than or equal to 1:32 differed significantly (p = 0.006). No significant differences were noted in duration of reported symptoms between groups, and clinical complications occurred too infrequently to analyze. However, 2 (11%) of 18 of the cancer patients with positive culture results were hospitalized during the illness and one patient developed a nosocomial infection. None of the control children was hospitalized. These findings suggest the need for further study of the immunologic response of immunosuppressed children to influenza infection and a clinical efficacy trial of the influenza vaccine in these patients.

Adolescent↗

PubMed1989

Treatment of acquired severe aplastic anemia.

The management of patients with acquired severe aplastic anemia has been directed at intensive supportive care and restoration of normal marrow function. Bone marrow transplantation remains the treatment of choice with approximately 70% long-term survivors, after related histocompatible transplants. More intensive conditioning regimens, using cyclophosphamide with some form of radiation, have decreased the incidence of graft rejection to less than 5%. Immunosuppression with antilymphocyte (ALG) or antithymocyte (ATG) globulin may induce complete or partial hematologic recovery in 35-70% of patients, with 1- and 2-year survival rates in the range of 50-70% and 45-55%, respectively. The role of high-dose corticosteroids, cyclosporine A, and colony-stimulating factors in the management of patients with acquired severe aplastic anemia is less clear and requires further investigation. Finally, androgens, either alone or in combination with other agents, do not seem to have a place in the treatment of severe bone marrow aplasia.

Anemia, Aplastic↗