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Biomedical subjects

J Blatt

Publications and source records attributed to J Blatt.

At least 55 records · Page 3Linked to original sources
PubMed1992

Lack of significant activity of 2'-deoxycoformycin alone or in combination with adenine arabinoside in relapsed childhood acute lymphoblastic leukemia. A randomized phase II trial from the Childrens Cancer Study Group.

Forty-nine children with recurrent acute lymphoblastic leukemia (ALL) were entered into a randomized Phase II trial evaluating 2'-deoxycoformycin (dCF) alone or in combination with adenine arabinoside (ara-A). 2'-Deoxycoformycin is an inhibitor of adenosine deaminase (ADA), an enzyme found in relatively high amounts in malignant lymphoid cells. Ara-A inhibits DNA polymerase and DNA synthesis. Because its efficacy in vivo as an anticancer agent is limited by its rapid inactivation by ADA, ara-A was combined with dCF to produce cytoreductive levels of ara-A. Twenty-four patients were assigned to receive dCF alone and 25 to receive the combination. No patient responded to dCF alone, and one patient developed a complete remission after treatment with the combination. The toxicity of dCF alone was minimal, except for one patient who became obtunded on day 5 following the first cycle of therapy. In contrast, five patients developed severe toxicity with the combination, including renal failure (three patients), hepatic failure (three patients), and neurologic toxicity (two patients). These results indicate that, at the doses and schedule used in this study, the combination of dCF and ara-A has significant toxicity and minimal activity against recurrent ALL in children.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1992

Continued remission in children with neuroblastoma despite elevations of urinary catecholamine metabolites.

Our experience at the Children's Hospital of Pittsburgh with a patient with neuroblastoma suggested that renewed elevations of urinary catecholamine metabolites may not necessarily be an indication of progressive disease. To test this possibility, we reviewed the courses of children with neuroblastoma who achieved a clinical status of "no evidence of disease" (NED), and in whom homovanillic acid (HVA) and/or vanillylmandelic acid (VMA) levels were subsequently noted to exceed normal limits initially in the presence of normal restaging studies. Five patients were identified. Of these, one had stage I, one had stage II, two had stage III, and one had stage IV disease at diagnosis. Elevations of their HVA and/or VMA levels following achievement of NED status ranged from 1 1/2 to 4 times maximal normal levels for age, and abnormalities persisted for 17 to 47 months. Only one patient relapsed, while the other four remain disease-free 8-12 years following diagnosis. These results confirm that in patients with neuroblastoma, mild elevations of HVA and/or VMA may be compatible with continuous remission.

Child, Preschool↗
PubMed1992

Stimulation of growth of neuroblastoma cells by ferritin in vitro.

Among children with advanced neuroblastoma, serum concentrations of the iron storage protein ferritin correlate inversely with prognosis. To determine whether ferritin stimulates tumor cell growth, the effects of graded concentrations on cell number were studied for each of three neuroblastoma cell lines (CHP-126, CHP-100, IMR-32) plated in serum-free tissue culture medium. Ferritin extracted from human liver, spleen, or CHP-126 cells (150 ng/ml, final concentration) but not from human heart (150-300 ng/ml) resulted in 1.4-fold +/- 0.2-fold increases in cell numbers over 72 hours as measured spectrophotometrically after reduction of a tetrazolium dye. Higher concentrations of isoferritins (up to 1000 ng/ml) did not further increase cell number, but stimulation was abrogated by rabbit immunoglobulin G antiferritin. Although specific receptors for iodine 125-labeled ferritin could not be demonstrated on the two cell lines tested, deoxyribonucleic acid (DNA) synthesis, measured by incorporation of 3H-thymidine, also increased after addition of ferritin, by approximately 25%. We conclude that ferritin has mitogenic activity for human neuroblastoma cells in vitro which may explain the clinical correlation between levels of that protein and prognosis. Possible implications for therapy are discussed.

Cell Division↗
PubMed1991

Intellectual function in long-term survivors of childhood acute lymphoblastic leukemia: protective effect of pre-irradiation methotrexate? A Childrens Cancer Study Group study.

Having demonstrated in a laboratory model that the neurotoxicity of CNS irradiation can be ameliorated with pre-irradiation methotrexate, we retrospectively compared two methods of CNS prophylaxis in childhood acute lymphoblastic leukemia which differed only in the timing of intrathecal methotrexate and radiotherapy. The results of standard IQ tests conducted 2-11 years after 24 Gy of cranial radiotherapy were obtained in 72 patients, of whom 27 had pre-irradiation methotrexate and 45 did not (control group). The two groups were otherwise comparable. In girls, the full-, performance-, and verbal-scale IQ scores were consistently higher in the pre-irradiation methotrexate group than in the corresponding control group (P less than 0.025). Among girls less than 5 years of age when irradiated, the mean IQ scores were 25-29 points higher after pre-irradiation methotrexate than after the control treatment (P less than 0.0007). These results suggest that pre-irradiation methotrexate may help prevent CNS radiotoxicity in children, and that the benefit is dependent on patient age and gender.

Asparaginase↗
PubMed1991

Failure to alter the course of acute myelogenous leukemia in the rat with subcutaneous deferoxamine.

Deferoxamine (DFO) is an iron chelator that is known to inhibit acute non-lymphocytic leukemia cells in vitro. To explore the possibility that this drug has cytotoxic activity in vivo, rats were inoculated with a small lethal dose (10(2] of tumor cells from the transplantable BN acute myelogenous leukemia model. Animals were then treated with one of several regimens of bolus subcutaneous DFO: 10 mg/day x 5; 20 mg/day x 5; 10 mg/day x approximately 5 weeks; or no DFO. There were no consistently significant differences in survival between any of the DFO and untreated groups. Because the short plasma half-life of DFO was thought to be a potential reason for this lack of protection, a high molecular weight polymeric conjugate of DFO that is known to provide sustained intravascular drug levels was also studied. However, hydroxyethyl starch conjugated with DFO in amounts equivalent to 100 mg free drug (intraperitoneally for 5 days) also failed to have major impact on survival. These findings suggest that it may not be possible to achieve levels of this chelating agent in vivo that are cytotoxic for this disease.

Animals↗
PubMed1990

Cancer chemotherapy after solid organ transplantation.

To assess how well chemotherapy is tolerated after solid organ transplantation, we reviewed our experience at the Children's Hospital of Pittsburgh with five patients aged 1 to 12 years. Four patients had a liver transplant, indications for which were hepatoblastoma in two patients, hepatic failure secondary to Wilms' tumor chemoradiotherapy in one patient, and familial intrahepatic cholestasis in one patient. A fifth patient received a cardiac transplant for unresectable angiosarcoma of the right atrium. After transplant, chemotherapy was given for the treatment of the primary malignancy in four of the patients. The patient with familial intrahepatic cholestasis received chemotherapy for secondary lymphoproliferative disease that had not responded to the cessation of immunosuppression. All patients other than this patient were on immunosuppression with prednisone (0.5 to 2 mg/kg daily) and cyclosporine (to maintain serum levels at 800 to 1000 ng/ml radioimmunoassay) throughout the duration of chemotherapy. Courses of chemotherapy included one or more of the following agents: Adriamycin (Adr, 20 mg/m2 daily, three patients), Cyclophosphamide (Ctx, 1 gm/m2, one patient), cisplatin (CDDP, 90 mg/m2, one patient), Vincristine (Vcr, greater than 0.75 to 1.5 mg/m2, three patients), Actinomycin D (Act-D, 7.5 micrograms/kg, one patient), Ifosfamide (I, 1800 mg/m2, one patient) and Etoposide (VP-16, 100 mg/m2, one patient). All patients received greater than or equal to 3 courses (range, 3 to 9; mean, 5) of chemotherapy every 3 to 4 weeks. Dose reductions were made because of neutropenia in three patients but none were greater than 50%. Severe rejection was seen in one patient who had, however, manifested evidence of rejection prior to his first postoperative course of chemotherapy. No nephro or cardiac toxicity was seen. This preliminary experience suggests that chemotherapy is well tolerated after solid organ transplantation.

Adolescent↗
PubMed1990

Excessive chemotherapy-related granulocytopenia in a child with non-Hodgkin's lymphoma and a congenital abnormality of purine salvage.

A girl with non-Hodgkin's lymphoma and immunodeficiency based on absence of the purine salvage pathway enzyme purine nucleoside phosphorylase experienced profound neutropenia while receiving combination chemotherapy with cyclophosphamide, vincristine, methotrexate, and prednisone (COMP). Neutropenia was most severe following courses that included either systemic or intrathecal methotrexate, even in the face of major dose reductions. Delays in the development of neutropenia-during periods of leucovorin administration also implicate methotrexate as the primary responsible agent. This case suggests that certain immunodeficiency states predispose patients to extensive chemotherapy-induced myelosuppression and supports the concept that purine salvage is a clinically important mechanism for modulating methotrexate toxicity.

Agranulocytosis↗
PubMed1990

A retrospective review of undifferentiated malignancy in childhood.

We reviewed the experience of children with "undifferentiated" cancer at The Children's Hospital of Pittsburgh (CHP) from 1971 through 1987. Of 2,095 patients 0-18 years old with diagnoses during that time of any cancer, the initial CHP pathology report rendered a diagnosis in 22 children (1.1%) of "undifferentiated malignancy" or "malignant tumor" (15 cases), "undifferentiated carcinoma" (two cases) or "anaplastic tumor or carcinoma" not otherwise specified (five cases). A review of pathologic findings using current methods and immunostaining led to the assignment of a specific diagnosis in 15 of the 20 cases so studied. Thus, the incidence of undifferentiated cancer by current criteria was reduced to no more than 0.23%. Two of the five tumors for which an alternative diagnosis could not be established were described as "rhabdoid," but because it is not clear that these tumors fit into a single category they were still considered to be undifferentiated. Clinical features and management of the 22 cases including the five persistently diagnosed as undifferentiated malignancy were heterogeneous. In the face of reassigned diagnoses, a number of patients would likely have received different chemotherapy as well as radiation. Nonetheless, seven patients with malignancy show no evidence of disease (NED), including several whose therapy, given the current best diagnosis, would not be considered to have been optimal. We recommend that for patients undergoing biopsy of a tumor, sufficient material be obtained for extensive pathologic evaluation. In this way, the diagnosis of undifferentiated malignancy in children can be almost eliminated.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1990

Synthesis of ferritin by neuroblastoma.

Ferritin is an iron-containing protein which is a normal component of serum. The levels of ferritin are increased in the sera of some children with neuroblastoma, and this increase appears to be a potent indicator of prognosis. To determine whether synthesis of ferritin by the tumor cells contributes to these increased serum levels, we examined incorporation of radiolabeled leucine by CHP 126, a neuroblastoma derived cell line, into ferritin. Using sequential immunoprecipitation and gel electrophoresis of sonicates from cells maintained in medium containing iron in amounts standard for tissue culture, incorporation of label into ferritin was 0.04% of that into total protein synthesized over the same time period. Addition of up to 40 micrograms of iron as ferric ammonium citrate increased ferritin synthesis to a maximum of 0.16% without altering synthesis of total protein. The pattern of iron-induced enhancement in the neuroblastoma cells was similar to that which was seen using Chang liver cells, a cell line well known to be capable of ferritin synthesis. These results confirm that neuroblastoma cells can synthesize ferritin and that synthesis is regulated by exogenous iron.

Child↗
PubMed1989

Enhancement of in vitro activity against neuroblastoma by doxorubicin and deferoxamine.

A colorimetric assay was used to compare the in vitro effects on neuroblastoma cell viability of 3.75-60 microM deferoxamine or 0.125-2 microM doxorubicin alone with those of the two drugs in combination. For each of two human neuroblastoma cell lines (CHP 100 and CHP 126), exposure to each drug individually produced dose-related cytotoxic effects within 3 days. When these cells were simultaneously exposed to both drugs, even at concentrations achievable in vivo, cell death was greater than what could be accounted for by either drug alone. Cytotoxicity was further potentiated to a variable extent when the cells were sequentially exposed to deferoxamine and doxorubicin at 24-hour intervals. Thus, this combination of drugs warrants further study.

Cell Line↗
PubMed1989

Comparison of activity of deferoxamine with that of oral iron chelators against human neuroblastoma cell lines.

The iron chelator, deferoxamine, has demonstrated cytotoxicity against neuroblastoma cells. In this study we examined the in vitro antineuroblastoma activity of several potentially less expensive oral chelating agents. On a mole for mole basis, 1-hydroxypyridine-2-thionine (omadine) had 100 times the cytotoxicity of deferoxamine. 1,2-Dimethyl-3-hydroxypyrid-4-one also caused demonstrable cell death but at considerably higher molar concentrations than those required for deferoxamine. 2,3-Dihydroxybenzoic acid had no effect on neuroblastoma cell viability over a range of concentrations. In contrast to the effect of both deferoxamine and 1,2-Dimethyl-3-hydroxypyrid-4-one, those due to omadine were permanent within 24 hours of incubation, were not significantly altered by the presence of ionic iron, and correlated with an increase in the percentage of cells in the S-G2-M phases of the cell cycle. On the basis of these in vitro studies, we believe that the use of omadine in particular and iron chelators in general, by themselves or as cell cycle-recruiting agents together with standard cell cycle specific drugs, is an approach to the treatment of cancer worth further investigation.

Administration, Oral↗
PubMed1989

Thrombocytosis as a presenting feature of acute lymphoblastic leukemia in childhood.

To determine the incidence of thrombocytosis at presentation in acute lymphoblastic leukemia (ALL), medical records of all children diagnosed at the Children's Hospital of Pittsburgh from 1980 to 1987 were reviewed. Out of 217 such patients, 7 (3.2%) had platelet counts greater than 400,000/mm3. All of the seven were boys compared with a male:female ration of 1.4:1 in the entire ALL population. Other than sex, no characteristics were clearly associated with thrombocytosis, including white blood cell count, hemoglobin, lymphoblast morphology, and immunologic or chromosomal markers. Apart from ALL, no inflammatory or infectious process which might have caused a thrombocytosis, was detected in any of these patients. The period of induction therapy was notable for the preservation of platelet counts greater than 20,000/mm3 in all patients. However, of the seven children with thrombocytosis, two had major induction complications: one, a cavernous sinus thrombosis; and the other, gastrointestinal bleeding with duodenal perforation. We conclude that thrombocytosis at diagnosis can be seen in children, particularly boys, with ALL. Based on small numbers, this group of patients may be at risk for major events during induction therapy. Large numbers, longer follow-up, and platelet function studies on similar patients will be of interest.

Biopsy↗
PubMed1989

Interleukin-2 induction of lymphokine-activated killer (LAK) activity in the peripheral blood and bone marrow of acute leukemia patients: II. Feasibility of LAK generation in children with active disease and in remission.

Activation and expansion in culture with rIL-2 of peripheral blood (PB) and/or bone marrow (BM) specimens derived from children with ALL and ANLL, with active disease (AP) and in remission were studied (RP). Baseline NK cytolytic activity from AP was found to be depressed, whereas RP-derived cells had normal NK activity, as assayed against K562 targets. Culture in rIL-2 significantly enhanced the NK activity of both AP- and RP-derived cells and generated LAK activity, as assayed by 4-hour 51Cr release, against NK-resistant Raji cell line and against fresh, allogeneic, and autologous tumor cells. Lytic activity against fresh, cryopreserved leukemia blasts was of lower than that found against cell lines. In three patients higher lytic activity against autologous than against allogeneic blasts was demonstrated. Expansion in culture with rIL-2 varied from twofold to 120-fold. rIL-2 activation and expansion was better in RP than in AP. The predominant phenotype of activated cells, as determined by flow cytometry, was [mean % (SD)]: CD3- = 54 (12), CD8+ = 55 (17), and NKH1+ = 26 (7). The consistently high level of CD8+ cells was accompanied by very low levels of CD4+ cells: mean = 11% (14). Double-marker analysis showed mean of 33% (10) for CD3+/NKH1+ cells and mean = 32 (11) for CD8+/NKH1+ cells, implying that these populations were overlapping. Kinetics of expression of cell surface markers during 2 to 3 weeks in culture showed that CD8+ and NKH1+ enrichment occurred during the first week and lasted for up to 4 weeks, whereas CD4+ expression decreased after the second week. A significant decrease in the expression of IL-2 receptors (CD25) was observed from the second week of culture. This study shows the feasibility of in vitro generation of killer cells from PB and BM of pediatric leukemia patients.

Antigens, CD↗
PubMed1988

Flow cytometric DNA analysis of neuroblastoma and ganglioneuroma. A 10-year retrospective study.

Retrospective quantitative DNA analysis was done on 147 samples from 89 patients with neuroblastoma and ganglioneuroma using flow cytometry. In the neuroblastoma patients, nuclear DNA content was found to be a stable tumor marker irrespective of site (primary versus metastatic) and despite changes with time in tumor progression, maturation, or therapy. The occurrence of DNA aneuploidy, which was detected in 60% of the neuroblastoma patients, paralleled other favorable indicators and was highly associated with survival (P less than 0.001). Of clinical stage, age, primary site, sex, and DNA content, only stage and DNA content correlated with survival. Those patients with favorable stage and DNA aneuploidy had higher survival rates. Further, favorable stage and the presence of DNA aneuploidy were independent prognostic indicators. Abnormal DNA content was also detected in samples from ganglioneuromas in which significant numbers of ganglion cell nuclei were recovered. These results indicate a striking difference between neuroblastoma and adult tumors in which DNA aneuploidy is generally a poor prognostic sign and provide a molecular link between ganglioneuromas and their malignant counterparts.

Adolescent↗
PubMed1988

Rhabdomyosarcoma in Roberts syndrome.

A 23-month-old child diagnosed as having Roberts syndrome, born to consanguineous parents, developed a sarcoma botryoides. Cytogenetic evaluation of peripheral blood lymphocytes and tumor cells showed premature centromere separation, which is characteristic of Roberts syndrome.

Abnormalities, Multiple↗
PubMed1988

Pulsatile growth hormone secretion in children with acute lymphoblastic leukemia after 1800 cGy cranial radiation.

The relationship between intensity of central nervous system preventive therapy and the development of hypothalamic pituitary dysfunction is unclear in patients with acute lymphoblastic leukemia. In a previous report, we demonstrated uniform decreases in spontaneous secretion of growth hormone following 2400 cGy whole brain radiation. In this study, we measured basal growth hormone levels every 20 minutes over 24 hr in five survivors of childhood acute lymphoblastic leukemia treated with 1800 cGy cranial radiation. Four of the patients had been off therapy 2 9/12-4 3/12 years. Growth hormone secretion in these patients, as indicated by mean growth hormone concentration, pulse amplitude and frequency, was clearly greater than that seen following 2400 cGy and appeared to be normal compared with sex- and Tanner stage-matched literature controls. However, serial growth measurements showed significant decreases in height percentiles in two of these children. The fifth patient, who had already approached her adult height at the time of diagnosis, had been off therapy only 1 year and had a mean growth hormone level intermediate between those of normal controls and previously reported children treated with 2400 cGy. These data suggest (a) that the effect of radiation therapy on spontaneous pulsatile growth hormone secretion may be dose related, and (b) that short stature in a given patient may not be indicative of subnormal basal growth hormone levels. Further longitudinal investigation may clarify whether early transient changes in GH secretion occur that may normalize over time.

Adolescent↗
PubMed1988

Mechanism of antineuroblastoma activity of deferoxamine in vitro.

Deferoxamine previously has been shown to have potent activity in vitro against human neuroblastoma cells, activity that results from its ability to chelate iron. To further understand the mechanism of deferoxamine-induced cytotoxicity, we looked at its effects on cell cycling and on DNA, RNA, and protein synthesis by CHP 126, a cell line that is derived from tumor tissue of a patient with a neuroblastoma and that is known to be drug sensitive. After 24 hours of exposure to 60 mumol/L deferoxamine, there was a 35% increase in the percent of cells in the nonproliferating and prereplicative phases of the cell cycle and a corresponding decrease in the percent of cells in the DNA synthesis, postreplicative, and mitotic phases of the cell cycle, results that are consistent with a block of cell cycle progression at the early DNA synthesis phase. The inhibitory effects of deferoxamine on DNA synthesis were confirmed by demonstration of a 60% decrease in thymidine incorporation into DNA in short-term cultures of CHP 126. Effects on RNA and protein synthesis were minimal. Equivalent effects on growth were seen by using several chelators that interact with different iron pools, suggesting that both intracellular and extracellular iron are required for growth of neuroblastoma cells.

2,2'-Dipyridyl↗