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Biomedical subjects

K K Matthay

Publications and source records attributed to K K Matthay.

105 records · Page 6Linked to original sources
PubMed1984

Specific enhancement of drug delivery to AKR lymphoma by antibody-targeted small unilamellar vesicles.

Antibody targeting of drug-containing liposomes to specific cell populations provides the opportunity to improve cancer chemotherapy. We report here the efficacy of targeted liposomes containing methotrexate-gamma-aspartate against two murine T-lymphomas, AKR/J SL2 and R1.1. Both large and small unilamellar vesicles conjugated to anti-Thy-1.1 antibody associated with AKR lymphoma cells in 10-fold greater amounts than nonconjugated liposomes or liposomes conjugated to a nonspecific antibody. Cell association was inhibited by two different anti-Thy-1.1 monoclonal antibodies, but not by nonspecific antibody. Vesicle size is the critical factor determining drug delivery of targeted liposomes to both AKR and R1.1 T-lymphoma cells. Although targeted large unilamellar vesicles (mean diameter, 0.45 micron) specifically bind to lymphoma cells, they probably are not internalized, because they fail to enhance the efficacy of the drug for growth inhibition of either AKR or R1.1 cells. In contrast, drug encapsulated in targeted small unilamellar vesicles (mean diameter, 0.053 micron) is up to 22 times more effective than free drug against AKR cells, and is 40 times more effective against R1.1 cells. We have also demonstrated the efficacy of small compared to large unilamellar vesicles using two different target antigens, Thy-1.1 for AKR cells and H-2Kk for R1.1 cells. These experiments establish a system which can be used to test the antitumor efficacy of targeted liposomes against AKR/J SL2 lymphoma implanted in AKR/Cu mice.

Animals↗
PubMed1983

Increased serum opsonic activity and antibody concentration in patients with sickle cell disease after pneumococcal polysaccharide immunization.

Opsonic defects have been reported in unimmunized patients with sickle cell disease. We found significant increases (P less than 0.001) in serum opsonic activity, measured by a radiolabeled bacterial uptake assay, and in type 7 pneumococcal polysaccharide antibody concentration in 17 such patients 2 years of age or older after pneumococcal polysaccharide immunization. All 17 patients and six healthy controls achieved a type 7 antibody concentration of more than 300 ng antibody nitrogen per milliliter, believed to be the protective level of antibody in vivo. Six patients with sickle cell disease less than 2 years of age did not have a significant increase in type 7 antibody concentration after immunization. Only three of these six patients achieved a postimmunization type 7 antibody concentration exceeding 300 ng Ab N/ml. Overall, 16 of 23 patients with sickle cell disease (70%) had a twofold or greater increase in type 7 antibody concentration, and 13 of these (81%) had a corresponding increase in opsonic activity (P less than 0.001). Thus most patients who responded to pneumococcal polysaccharide immunization had a concurrent increase in opsonic activity in vitro.

Adolescent↗
PubMed1981

Evaluation of the opsonic requirements for phagocytosis of Streptococcus pneumoniae serotypes VII, XIV, and XIX by chemiluminescence assay.

A luminol-enhanced chemiluminescence assay was used to investigate opsonic requirements for phagocytosis of STreptococcus pneumoniae serotypes VII, XIV, and XIX. After opsonization with whole immune sera (with antibody and total complement pathway), heat-inactivated immune sera (with antibody alone), or magnesium dichloride-ethylene glycol tetraacetic acid-chelated immune sera (with antibody and alternative complement pathway), live S. pneumoniae cells were incubated at 37 degrees C with normal polymorphonuclear leukocytes while serial chemiluminescence measurements were recorded. The amount of chemiluminescence observed correlated closely with evidence of phagocytosis as observed by microscopy. Complement was required for efficient opsonization, since all three serotypes showed a slower rise and less integral chemiluminescence after opsonization with heat-inactivated serum as compared with whole serum. The alternative pathway provided opsonic activity equal to that of the total complement pathway for type XIX, but only intermediate activity for types VII and XIV. Type-specific antibody was also required for effective opsonization of all three serotypes since chemiluminescence was markedly reduced when bacteria were opsonized with antibody-depleted serum (serum absorbed with type-specific S. pneumoniae cells at 4 degrees C). Thus, chemiluminescence proved to be an effective means of defining the requirement for both antibody and complement in the opsonization and phagocytosis of S. pneumoniae.

Adult↗
PubMed1979

Modification of hemoglobin H disease by sickle trait.

The rarity of hemoglobin (Hb) H disease in combination with sickle trait may be due in part to the absence of actual Hb H in individuals who, nonetheless, have inherited the deletion of three alpha-globin genes. We describe here a boy with persistent microcytic, hypochromic anemia despite adequate iron stores, who exhibited splenomegaly with a normal reticulocyte count and only rare inclusions in circulating erythrocytes. Starch gel electrophoresis and isoelectric focusing at age 5 yr showed 21% Hb S, persistent Hb Bart's, but no Hb H. Recticulocyte alpha/non-alpha globin chain synthesis ratio was 0.58 at age 5. The mother (Asian) had laboratory evidence of alpha-thalassemia trait and the father (Black) had sickle trait. The nature of alpha-thalassemia in this patient was investigated both by liquid hybridization and by the Southern method of gene mapping, in which DNA is digested with restriction endonucleases and the DNA fragments that contained the alpha-globin structural gene identified by hybridization with complementary DNA. The patient had only one alpha-globin structural gene, located in a DNA fragment shorter than that found in normal or alpha-thalassemia trait individuals, but similar to that present in other patients with Hb H disease. Morphologic studies of bone marrow by light and electron microscopy revealed erythroid hyperplasia with inclusions in polychromatic and orthochromatic erythroblasts, suggesting early precipitation of an unstable hemoglobin. The lack of demonstrable Hb H may be the result of both diminished amounts of beta(A) available for Hb H formation (since one beta-globin gene is beta(S)) and the greater affinity of alpha-chains for beta(A) than beta(S)-globin chains leading to the formation of relatively more Hb A than Hb S. The presence of a beta(S) gene may thus modify the usual clinical expression of Hb H disease.

Anemia, Sickle Cell↗
PubMedDate not supplied

Congenital leukemia: successful treatment of a newborn with t(5;11)(q31;q23).

A male neonate presented with a high white cell count, an 11q23 translocation, and M5b leukemia. He was treated at 3 days of age with intensive combination chemotherapy after progressing despite exchange transfusions. The patient achieved complete remission at 28 days of age. Therapy was completed at the age of 6 months. At the time of this report, the patient is 17 months old and remains in remission. Twenty-nine patients with congenital acute myeloid leukemia were also reviewed. Twenty of these patients received varying therapies. Ten of the treated patients achieved complete remission; two died of toxicity; and eight died of progressive disease. Two patients had a translocation affecting 11q23. Congenital leukemia is a rare and usually fatal condition in patients without Down syndrome. The patient reported here shows that survival may be achieved with very intensive chemotherapy plus supportive care, despite extremely high white blood cell counts and unfavorable translocation.

Adult↗
PubMedDate not supplied

Metastatic sites in stage IV and IVS neuroblastoma correlate with age, tumor biology, and survival.

PURPOSE: The goal of this study was to determine the incidence of metastatic sites in neuroblastoma and the extent to which metastatic sites correlate with age, tumor biology, and survival. PATIENTS AND METHODS: All 648 patients with stage IV and IVS neuroblastoma registered on Children's Cancer Group protocols 3881 and 3891 were analyzed. Metastatic site data were provided by treating institutions and reviewed in patients with central nervous system (CNS), intracranial, lung, or "other" metastases. RESULTS: The incidence of metastatic sites at diagnosis was 70.5% in bone marrow, 55.7% in bone, 30.9% in lymph nodes, 29.6% in liver, 18.2% in intracranial and orbital sites, 3.3% in lung, and 0.6% in CNS. Event-free survival (EFS) was decreased in patients with bone, bone marrow, CNS, intracranial/ orbital, lung, and pleural metastases, and improved in those with liver and skin metastases. In infants, MYCN amplification and unfavorable Shimada histopathology correlated with increased frequencies of bone and intracranial or orbital metastases. In older patients, MYCN amplification correlated with increased frequencies of intracranial or orbital, liver, and lung metastases. Multivariate analysis revealed that metastatic site is not an independent prognostic factor. CONCLUSIONS: Metastatic pattern in neuroblastoma differs with age and correlates with tumor biological features and EFS. These correlations could reflect changes in host or tumor biological features with age resulting in differences in metastatic capacity or tumor affinity for specific sites.

Adolescent↗
PubMedDate not supplied

Antineuronal antibodies in patients with neuroblastoma and paraneoplastic opsoclonus-myoclonus.

PURPOSE: To identify serologic markers in children with paraneoplastic opsoclonus-myoclonus (POM). MATERIALS AND METHODS: We examined the sera of 64 children with neuroblastoma (16 with POM and 48 age-matched and stage-matched controls) by immunohistochemistry of rat brain and human cerebellum, and by Western blot analysis of protein extracts from human Purkinje cells, cortical neurons, neuroblastoma cell lines, and HuD. RESULTS: Using immunohistochemistry, IgG reactivity against neurons was identified in 13 of 16 POM sera (81%), and 12 of 48 non-POM sera (25%; P<0.001). IgM antineural antibodies were present in 3 of 16 POM sera (19%) and 11 of 48 (23%) non-POM sera. Except for anti-Hu antibodies detected in 10 sera (4 with POM), no other specific reactivities were identified by Western blot analysis of neuronal or of neuroblastoma protein extracts. CONCLUSIONS: We conclude that: 1) patients with neuroblastoma and POM are more likely to harbor antineuronal antibodies than patients without POM; 2) no specific serologic marker of POM was identified, but the frequent presence of antineuronal antibodies suggests that POM is immune-mediated; and 3) anti-Hu antibodies are present in some sera from patients with neuroblastoma, irrespective of the presence of POM.

Adult↗
PubMedDate not supplied

Neuroblastoma: a clinical challenge and biologic puzzle.

Neuroblastoma is the third most common malignancy in childhood and accounts for at least 15 percent of cancer-related deaths in children. The varied clinical behavior of this disease, ranging from spontaneous regression in some to progression while under aggressive therapy in others, has been associated with various biologic differences, providing insight into pathophysiology and possibilities for more specific treatments. This article reviews the epidemiology, pathophysiology, clinical evaluation, and treatment of neuroblastoma.

Adolescent↗
PubMedDate not supplied

Efficacy and safety of [131I]metaiodobenzylguanidine therapy for patients with refractory neuroblastoma.

Metaiodobenzylguanidine (MIBG) is a guanethidine derivative that is selectively concentrated in sympathetic nervous tissue. MIBG labeled with 123I or 131I has proven to be a specific and sensitive tool for detection of primary and metastatic pheochromocytoma and neuroblastoma. Eleven patients, with refractory stage IV neuroblastoma were treated with a total of 23 courses of 131I-MIBG, 100-400 mCi/m2/course. Total activity administered per course ranged from 90-550 mCi; maximum cumulative radioactivity per patient was 1356 mCi. The 131I-MIBG was given as a 2 hour infusion. Total body dose was calculated from whole body activity measurements, ranging from 73-250 cGy. The main toxicity was thrombocytopenia, with platelet nadirs to less than 25,000/microL in 5/23 courses (5 patients), all occurring in patients with greater than 25% replacement by tumor in the bone marrow. Neutropenia to a nadir of less than 500/microL was seen in only 2 patients, both with greater than 50% bone marrow replacement after 2 and 4 courses of 131I-MIBG, respectively. Tumor doses were calculated in patients with an evaluable measurable lesion, and ranged from 312-6329 cGy per course. Two of the eleven patients had partial responses, with one long-term survivor with stage IV neuroblastoma with no evidence of active disease now 4 years off treatment. Two other patients survive with stable disease after 3 treatments, at 3+ and 5+ months. Seven patients died with progressive disease. This study shows that treatment with 131I-MIBG is safe and can be effective in refractory neuroblastoma, particularly in patients who do not have extensive bone and bone marrow involvement.

3-Iodobenzylguanidine↗