Search PubMed⌕ Search

Biomedical subjects

K K Matthay

Publications and source records attributed to K K Matthay.

At least 91 records · Page 5Linked to original sources
PubMed1992

Neuroblastoma: dose-related sensitivity of MIBG scanning in detection.

Iodine-131 metaiodobenzylguanidine (MIBG) has shown effectiveness as a systemic radiotherapeutic agent in neuroblastoma. The authors postulated a likely dose-related relationship of MIBG sensitivity when it was administered for neuroblastoma detection. They studied this relationship in neuroblastoma patients who underwent scanning after receiving diagnostic and therapeutic doses of MIBG in temporal proximity. Seven patients with stage IV disease received a total of 14 therapeutic administrations of I-131 MIBG (150-350 mCi [5,550-12,950 MBq]/m2 per treatment). Posttherapy scans were obtained at 3 and at 5-7 days. Diagnostic MIBG scans had been obtained no more than 4 weeks before the start of therapy. Use of diagnostic MIBG scanning led to underestimation of the tumor burden by 50% compared with use of posttherapy scanning. This difference may be an important consideration in selecting therapeutic strategies for individual patients. It further suggests that use of much larger diagnostic doses of MIBG is a rational strategy in histologically confirmed cases of advanced disease.

3-Iodobenzylguanidine↗
PubMed1990

Total body irradiation and bone marrow transplantation for immunodeficiency disorders in young children.

Congenital immunodeficiency disorders such as severe combined immunodeficiency disease (SCID), Wiskott-Aldrich syndrome, and Chediak-Hegashi syndrome are almost uniformly fatal with most children dying before age one. Allogeneic bone marrow transplant (BMT) is the treatment of choice. Few of these children have matched donors. We use bone marrow processing techniques that allow us to utilize marrow from the parents. Children who lack HLA-identical donors are offered haploidentical, T-cell depleted parental BMTs. Some of these children do not have an immune deficiency severe enough to allow durable engraftment of processed mismatched bone marrow. Successful engraftment may necessitate the use of immunosuppression. Total body irradiation (TBI) is part of our intensive conditioning regimen for children with Wiskott-Aldrich and Chediak-Hegashi syndrome and most children with SCID who have undergone an unsuccessful prior mismatched, T-cell depleted BMT, or who have a high likelihood of donor marrow rejection based on pre-transplant immune function testing. TBI is considered extremely toxic therapy in infancy, with little information available on the acute and chronic effects. The 10 children presented in this report are among the youngest to have received TBI. Five patients were 2 to 6 months of age when they received TBI. The conditioning regimen for all patients was; antithymocyte globulin (25 mg/kg/day, x 3 days), cyclophosphamide (60 mg/kg/day, x 2 days), and TBI. 7.0 Gy TBI was given as a single dose AP-PA at approximately 15 cGy/min. Half value blocks shielded the brain, eyes and lungs. Six of 10 children were alive from 7 to 72 months post transplant.(ABSTRACT TRUNCATED AT 250 WORDS)

Bone Marrow Transplantation↗
PubMed1989

Comparison of anti-Tac and anti-transferrin receptor-conjugated liposomes for specific drug delivery to adult T-cell leukemia.

Adult T-cell leukemia (ATL) is a rapidly progressive and usually fatal malignancy of mature T cells characterized by the expression of large numbers of interleukin-2 (IL-2) receptors on the cell surface. Anti-Tac, a monoclonal antibody directed against the IL-2 receptor, was conjugated to liposomes and compared with anti-transferrin receptor (anti-TFR) conjugates for specific binding, internalization, and intracellular drug delivery to ATL cells. Two independent assays were used: a fluorimetric assay with liposome encapsulated 1-hydroxypyrene-3,6,8-trisulfonic acid, a pH-sensitive fluorescent dye, and a growth inhibition assay using methotrexate-gamma-aspartate, a liposome-dependent cytotoxic drug. MT-1 and HUT-102 cell lines derived from patients with ATL were compared with Molt-4, a leukemia cell line that does not express IL-2 receptors in an uninduced state. Fluorimetric studies showed specific binding and internalization of anti-Tac-conjugated liposomes by HUT-102 and MT-1 but not by the Tac-negative cell line Molt-4, demonstrating the lack of nonspecific or Fc receptor-mediated uptake. Anti-TFR-conjugated liposomes were effectively bound and internalized by all three cell lines and consistently showed the highest degree of cellular liposome uptake. Drug-containing liposomes conjugated to anti-Tac were more than tenfold more effective in causing growth inhibition of ATL cells than the nonspecific control conjugates. Anti-Tac conjugates caused minimal growth inhibition of Molt-4 cells over the concentration range effective against the ATL cells. Anti-TFR-coupled liposomes gave better growth inhibition of HUT-102 and MT-1 cells (40- to 60-fold) than anti-Tac conjugates. Both anti-Tac-directed and anti-TFR-directed liposomes are effective for intracellular drug delivery to ATL cells and may represent a useful method of treatment in this disease.

Antibodies, Monoclonal↗
PubMed1989

Role of ligand in antibody-directed endocytosis of liposomes by human T-leukemia cells.

The rate of uptake and intracellular processing of ligand-directed drug carriers may depend heavily on the endocytic pathway of the target antigen. We examined the role of the target antigen and type of antibody-liposome linkage in determining endocytosis of liposomes by three human T-cell leukemias, Jurkat, CEM, and Molt-4. Liposome-cell binding and internalization over time were studied using two independent assays for intracellular delivery of liposome contents: a new fluorescence assay using a pH-sensitive fluorescent dye; and a growth inhibition assay for delivery of cytotoxic drug, methotrexate-gamma-aspartate. Liposomes targeted against the transferrin receptor showed greater surface binding, internalization, and growth inhibition than liposomes targeted against the T-cell surface antigens, CD2, CD3, or CD5. Furthermore, liposomes made by conjugating the targeting antibody directly to the liposome surface were more efficiently internalized and retained than were liposomes linked to antibody-coated cells via Protein A. Selection of the type of antibody-liposome conjugate as well as the appropriate surface receptor to facilitate endocytosis is essential in antibody-directed drug treatment of cancer.

Antibodies, Monoclonal↗
PubMed1989

Excellent outcome of stage II neuroblastoma is independent of residual disease and radiation therapy.

The optimal management for patients with stage II neuroblastoma has not yet been established. In order to determine the impact of adding chemotherapy and/or radiation therapy to surgery, we reviewed by questionnaire 156 patients with stage II neuroblastoma treated by 28 Childrens Cancer Study Group (CCSG) institutions from 1978 to 1985. Survival and progression-free survival (PFS) were analyzed by life-table methods with respect to age at diagnosis, site and size of primary tumor, spinal cord involvement, extent of initial resection, and treatment in addition to surgery. The overall 5-year survival was 96%; the PFS was 90%, similar to previous CCSG studies. Age at diagnosis had a small impact on PFS, with 92% PFS for patients less than 2 years of age at diagnosis, and 84% for those greater than 2 (P = .10). The only site with an adverse outcome was the head and neck (n = 11), with a PFS of 68% compared with 93% for the remaining sites (P = .02). Size of primary and intraspinal extension of primary did not affect PFS. The extent of resection and subsequent treatment with radiation therapy and/or chemotherapy did not affect the PFS. The outcome for 75 patients treated with surgery alone (6-year PFS, 89%) was not significantly different from that of 66 patients receiving radiation therapy (6-year PFS, 94%). There was no significant difference between 40 patients with gross or microscopic residual disease treated with surgery alone (PFS, 92%) and 59 patients with residual disease who also received radiation (PFS, 90%). Five of seven patients who progressed after surgery alone have been salvaged with further therapy and are now free of disease. One survives with disease, so that the 6-year survival is 98% for those treated initially with surgery alone, compared with 95% for those receiving radiation therapy and/or chemotherapy. These data suggest that surgery alone, even if complete resection is not achieved, is sufficient initial therapy for stage II neuroblastoma. The data also identify another stage of neuroblastoma, in addition to stage IV-S, for which almost all patients have a favorable prognosis because their tumor may be biologically limited in growth.

Abdominal Neoplasms↗
PubMed1989

Hematologic disorders affecting the lungs.

Pulmonary involvement by hematologic disorders can occur through any number of mechanisms involving abnormalities of the fluid phase of hemostasis, quantitative or qualitative defects in the cellular components, and direct and indirect involvement of the malignancies derived from the hematopoietic system. Consideration of possible mechanisms through which the blood can alter pulmonary physiology and result in recognizable disorders, such as pulmonary hemorrhage, thromboembolism, fibrosis, or obstruction, can lead to more rapid and appropriate diagnosis. Further work aimed at diagnosis and management of hematologic disorders, prior to the development of pulmonary manifestations, will enable us to prevent the long-term sequelae. Intervention aimed at relieving the acute pulmonary symptoms followed by long-term management of the hematologic disease can result in significantly improved prognosis and quality of life for our patients who have manifested pulmonary symptoms secondary to a hematologic disease.

Anemia, Sickle Cell↗
PubMed1988

Complete pathologic maturation and regression of stage IVS neuroblastoma without treatment.

Spontaneous maturation of Stage IVS neuroblastoma has been postulated as a mechanism for its favorable prognosis, but this has rarely been documented pathologically. We report on a patient with congenital Stage IVS neuroblastoma who had extensive subcutaneous and bone-marrow involvement. Serial photographs, biopsies, and vanillomandelic acid determinations documented the tumor's initial progression which was followed by spontaneous maturation and involution of the patient's disease over a 6-year period. No cytotoxic therapy was administered. Favorable biologic prognostic factors were documented, including tumor DNA and protein analyses for N-myc amplification or overexpression and analysis for serum neuron-specific enolase and ferritin. Implications for management and therapy of Stage IVS neuroblastoma are discussed with reference to this case and the recent literature.

Biomarkers, Tumor↗
PubMed1988

Childhood acute lymphoblastic leukemia.

Acute lymphoblastic leukemia accounts for 80% of leukemia in children. The exact cause is unknown, but some genetic, immunologic, viral, and environmental factors have been implicated. Symptoms at the time of diagnosis frequently include fever, bleeding, fatigue, and irritability. Initial white blood cell count and patient age at diagnosis are the most reliable indicators of prognosis. Acute lymphoblastic leukemia is a heterogenous disease. Lymphoblast morphology, immunologic markers, enzyme abnormalities, cytogenetic findings, and staining characteristics in conjunction with clinical characteristics allow classification into risk groups. Appropriate therapy for each risk group is based on these parameters. Combination chemotherapy administered alone or with additional chemotherapy or radiotherapy to sanctuary sites is the principal modality for treatment of ALL. Optimal therapy for relapse has not yet been determined, but for patients with appropriate donors, allogeneic bone marrow transplant is promising. Common complications of chemotherapy include tumor lysis syndrome, myelosuppression, and other problems such as gastrointestinal toxicity, neurotoxicity and cardiac toxicity. Significant late effects of chemotherapy include neurological impairment ranging from learning problems to leukoencephalopathy and a possible increased risk of second malignancy. Complete remission is achieved in 95% of children with acute lymphoblastic leukemia, and more than 55% will continue to be in complete remission at five years. Optimal CNS prophylaxis, effective treatment of relapse, and adjustment of therapy to minimize acute and late adverse effects are a continuing challenge. With improved understanding of biologic factors, and development of more specific therapy for each subgroup, children with acute lymphoblastic leukemia should enjoy a better long term outcome.

Adolescent↗
PubMed1987

Antibody-directed targeting of liposomes to human cell lines: role of binding and internalization on growth inhibition.

Small unilamellar liposomes containing methotrexate or methotrexate-gamma-aspartate were conjugated to Staphylococcus aureus protein A and were thus able to bind cell-specific immunoglobulins for targeting to malignant human B- and T-cell lines. We were able to demonstrate enhanced protein A liposome uptake and growth inhibition by targeting with an anti-major histocompatibility complex class II antibody recognizing two different B-cell lines. The enhanced growth inhibition was specific for the targeting antibody and amounted to a 2- to 3-fold lowering of the concentration of drug required to inhibit cell growth by 50% as compared to nontargeted liposomes or liposomes targeted with an antibody not recognizing a cell surface antigen. A strong association between enhanced growth inhibition and liposome internalization as assessed by fluorescent-activated cell sorter analysis of carboxyfluorescein containing protein A liposomes was seen. By contrast, specific enhancement of growth inhibition was not seen with several anti-idiotype antibodies or antibodies to T-cell differentiation antigens. Liposome internalization did not occur with these antibodies. Failure of growth inhibition and PA liposome internalization could not be explained by differences in cell binding of the antibody PA liposomes or the degree of protein A binding of the targeting antibody. Although the ability of the targeting antibody to bind to the cell and to protein A are important, these factors alone are not sufficient to guarantee internalization and growth inhibition. Variations in rates of internalization of various cell surface antigen-antibody complexes may account for different protein A liposome mediated cytotoxicities.

Animals↗
PubMed1986

Bone marrow in children with acute lymphocytic leukemia: MR relaxation times.

Magnetic resonance imaging of the lumbar spine was performed in 17 children with acute lymphocytic leukemia (ALL): eight with newly diagnosed ALL, four with ALL in relapse, and five with ALL in remission. Eleven age-matched children were also imaged as controls. The T1 and T2 relaxation times of the bone marrow in the lumbar spine were calculated for all the children. The T1 relaxation times of the bone marrow were as follows (mean +/- standard deviation): newly diagnosed ALL, 968 msec +/- 68; ALL in relapse, 765 msec +/- 19; ALL in remission, 404 msec +/- 135; and age-matched controls, 441 msec +/- 82. T1 relaxation time was statistically significant in differentiating children with newly diagnosed ALL from normal children and from children with ALL in remission. In addition, T1 may be useful in differentiating children with ALL in relapse from children with ALL in remission and from healthy children. T2 was not significantly different among the four groups.

Adolescent↗
PubMed1986

Antibody-directed liposomes: comparison of various ligands for association, endocytosis, and drug delivery.

We have developed and compared the cytotoxicity of methotrexate-gamma-aspartate encapsulated in several liposome formulations which bind mouse monoclonal antibody in order to define conditions for screening cell lines and antibodies for liposomal efficacy. Liposomes conjugated to Staphylococcus aureus Protein A were more potent than liposomes conjugated to either rabbit or affinity-purified goat anti-mouse immunoglobulin (Ig) when incubated with AKR/J SL2 cells sensitized with specific antibody. The antibody-directed Protein A liposomes were also 10-fold more potent than liposomes conjugated directly to specific antibody against the AKR/J SL2. We examined the effect of antibody specificity, concentration, and isotype on liposome-mediated drug delivery to AKR/J SL2 cells. The growth-inhibitory effect of the drug in the antibody-directed Protein A liposomes varied with the target antigen on the cell. The potency of the liposomes with a given antibody was proportional to their relative binding and endocytosis by the cells, and to the reactivity of the particular antibody with the cell as demonstrated by indirect immunofluorescence. The Protein A liposomes maintained maximal potency down to antibody concentrations as low as 1 microgram/ml with the anti-Thy 1.1-sensitized AKR/J SL2 cells, thus demonstrating the possible use of these liposomes for hybridoma screening. Use of isotype-switched variants of the anti-Thy 1.1 antibody with the AKR/J SL2 cells showed the superior efficacy of the IgG2a, IgG2b, and IgG3 isotypes to the IgG1 with the Protein A liposomes. The large differential potency of the free drug and the drug encapsulated in antibody-directed Protein A liposomes was maintained even at short incubation times, thus providing a system which may be useful for eradication of tumor cells from bone marrow in vitro.

1,2-Dipalmitoylphosphatidylcholine↗
PubMed1984

Prenatal diagnosis of chronic granulomatous disease.

A luminol enhanced chemiluminescence micromethod has been adapted for use in prenatal diagnosis of chronic granulomatous disease (CGD). After validation of the assay in normal adults, newborns, fetuses, CGD carriers, and CGD patients, the fetuses of two pregnant CGD carriers were tested after fetoscopic aspiration of fetal blood. Normal neutrophil chemiluminescence and nitroblue tetrazolium slide tests were followed by delivery of two healthy infants whose normality was confirmed. Amniocytes proved useless for the prenatal diagnosis of CGD. They were found to have negligible nitroblue tetrazolium reduction, oxygen metabolism, and oxygen dependence.

Adult↗