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Biomedical subjects

J Mirro

Publications and source records attributed to J Mirro.

At least 55 records · Page 3Linked to original sources
PubMed1991

Improved outcome in childhood acute lymphoblastic leukaemia with reinforced early treatment and rotational combination chemotherapy.

To improve outcome in childhood acute lymphoblastic leukaemia (ALL), a stratified, randomised study of extended intensified chemotherapy was done. 358 evaluable patients received remission reinforcement therapy (teniposide, cytarabine, high-dose methotrexate) added to a four-drug induction regimen. Those achieving complete remission were randomised on the basis of risk group assignment to conventional continuation treatment or to four pairs of drugs rotated weekly or every 6 weeks. All patients received intrathecal chemotherapy; higher-risk patients also received 1800 cGy cranial irradiation after 1 year of remission. Complete remission was induced in 96% of the patients. At median follow-up of 40 (range 19-73) months, 4-year event-free survival (SE) was 73 (4)% overall, 81 (6)% in the lower-risk group (n = 110), and 69 (5)% in the higher-risk group (n = 248). Outcome within risk groups was not significantly affected by the speed of rotation of drug pairs during continuation treatment. Various high-risk subgroups had apparently improved responses to this treatment. This intensified chemotherapy may cure 69-77% of children with ALL.

Actuarial Analysis↗
PubMed1991

Midazolam premedication for pediatric bone marrow aspiration and lumbar puncture.

The ability of midazolam, a benzodiazepine, to reduce the distress associated with lumbar puncture and bone marrow aspiration was examined in 23 children with acute lymphocytic leukemia. Patients were randomized to receive 0.2 mg/kg midazolam HCl or placebo intravenously 3-5 min before the procedures, under double-blind conditions. Based on prior experiences, children in both groups anticipated severe pain from these procedures. Postprocedure pain ratings by patients were markedly reduced in the midazolam but not the placebo group. Both physicians and parents judged the midazolam group as significantly less distressed than controls during and after the procedures. Trained observers recorded significantly fewer pain- and anxiety-related behaviors in the midazolam group immediately before and after, but not during the procedures. The amnestic effects of midazolam, confirmed in a visual recall/recognition test, appear to account for the decreased pain ratings since the behavioral manifestations were similar in the two groups. There were no adverse drug reactions or significant changes in vital signs. Midazolam warrants further investigation as a premedication for painful diagnostic and treatment procedures in children with cancer.

Adolescent↗
PubMed1991

Pharmacokinetics of continuous-infusion amsacrine and teniposide for the treatment of relapsed childhood acute nonlymphocytic leukemia.

The systemic disposition of both amsacrine and teniposide was determined in children receiving treatment for resistant acute nonlymphocytic leukemia. As part of a phase I-II study, amsacrine and teniposide were given as continuous 72-h i.v. infusions at doses of 75-150 and 150-250 mg m-2 day-1, respectively. Plasma samples obtained during steady state were analyzed for drug concentrations by high-performance liquid chromatography assays specific for each compound. Clearance and systemic exposure values for both amsacrine and teniposide were calculated for 14 patients, and data were available for teniposide alone in an additional 14 subjects. Interpatient variability in clearance was substantial for each drug, producing overlapping systemic exposure across dose levels. No evidence of dose-dependent drug clearance was evident. Clearance values for teniposide given in combination with amsacrine were similar to previous values obtained when teniposide was given in an identical manner but as a single agent. In all, 80% of patients experienced some degree of mucositis after chemotherapy administration. Severe mucositis (Pediatric Oncology Group grades 3-4) occurred in 18% of cases, all of whom showed teniposide steady-state plasma concentrations above the median population value (11.9 micrograms/ml; P less than 0.0001). A comparison of the results of the present study on teniposide combined with amsacrine with those previously obtained for single-agent teniposide suggest that amsacrine produced little additive gastrointestinal toxicity. The evaluation of anti-cancer drug pharmacokinetics in individual patients during combination chemotherapy regimens helps to determine the relative importance of each agent when toxicity patterns are similar.

Adolescent↗
PubMed1991

A phase I clinical trial of 2-chlorodeoxyadenosine in pediatric patients with acute leukemia.

To evaluate its toxicity and clinical efficacy in children with relapsed or refractory leukemia, we performed a phase I trial of 2-chloro-2'-deoxy-adenosine (2-chlorodeoxyadenosine; 2-CDA) given as a continuous 5-day infusion at doses of 3 to 10.7 mg/m2/d. In this study of 31 children with acute leukemia, the only dose-limiting toxicity was myelosuppression. At the highest dose level, three of seven patients developed fatal systemic bacterial or fungal infections. At dose levels above 6.2 mg/m2/d, significant oncolytic responses occurred in all patients. In addition, there was a significant correlation between both the responsiveness by cell type and dose of 2-CDA, such that more oncolytic responses were noted in acute myeloid leukemia (AML) patients than acute lymphoblastic leukemia (ALL) patients (P = .02). Although this was a phase I trial in heavily pretreated patients with refractory disease, two AML patients treated at 5.2 and 10.7 mg/m2/d, respectively, had complete hematologic responses, and one patient treated at 10.7 mg/m2/d had a partial response. In addition, there was a dose-response relationship in all patients with improved cytoreduction of peripheral blast cells at higher doses of 2-CDA. In vitro evaluation of 2-CDA uptake and anabolism by leukemic blast cells from 22 patients demonstrated that 2-chloro-2'-deoxyadenosine (Cld-AMP) and 2-chloro-2'-deoxyadenosine 5'-striphosphate (CldATP) reached concentrations close to steady-state levels within 1 hour. Intracellular nucleotide disappearance rates were high with half-lives of 1.29 and 2.47 hours for CldAMP and CldATP, respectively. This suggests that continuous infusion is necessary to maintain the desired plasma concentration. The results of this study confirm the antileukemic activity of 2-CDA and the lack of prohibitive nonhematologic toxicity. Phase II trials in patients with AML and ALL are warranted.

2-Chloroadenosine↗
PubMed1991

Serum CD4, CD8, and interleukin-2 receptor levels in childhood acute myeloid leukemia.

Leukemic cell expression and serum levels of CD4, CD8, and interleukin-2 receptor (IL-2R) were determined at diagnosis for children or adolescents with acute myeloid leukemia (AML). Cellular expression of CD4 was detected in 18 of 62 cases, CD8 in none of 60 cases, and IL-2R in one of 33 cases tested. Myeloblasts of the M4 and M5 subtypes expressed CD4 significantly more frequently than other FAB subtypes (p = 0.0001). Serum levels of the three soluble factors (tested for 91 patients) were positively correlated with each other. Increased serum CD4 levels were significantly associated with cellular CD4 expression, high leukocyte count, M5 leukemia, spleen enlargement, and age less than 1 year. High serum CD8 levels correlated significantly with splenomegaly, extramedullary disease, absence of Auer rods, and high leukocyte count. Cases with high serum IL-2R levels were less likely to have Auer rods and more likely to have splenomegaly and M5 leukemia; serum levels greater than 750 U/ml were associated with a higher probability of treatment failure (p = 0.05), even after adjustment for other potential prognostic factors. Further studies of serum CD4, CD8, and IL-2R levels may help to clarify the immunoregulatory role of T-cells in patients with AML.

Antigens, Differentiation, T-Lymphocyte↗
PubMed1991

Expression of a novel surface antigen MKW in childhood acute leukemia has prognostic significance.

A monoclonal antibody (MoAB) has been developed which reacts with a previously unidentified hematopoietic cell surface protein called MKW. This MoAB (anti-MKW) does not cluster with antibodies in any of the known cluster groups of differentiation. Blast cell expression of MKW was studied in 196 consecutively diagnosed children with acute lymphoblastic leukemia (ALL), 69 children with previously untreated acute myeloblastic leukemia (AML) and four children with secondary AML. MKW expression, clinical, laboratory and cytogenetic features at diagnosis, and treatment response and duration were examined for significant correlations. MKW was expressed on blasts from 12.8% of children with ALL and 24.6% of children with de novo AML. The expression of MKW appears to be more common in patients with secondary AML (three of four) than de novo AML (17 of 69). In patients with AML, the expression of MKW was correlated with an elevated initial leukocyte count (p = 0.0005) and poorer disease-free survival (p = 0.04). In patients with ALL, the expression of MKW was associated with a lower hemoglobin level (p less than 0.05) and a lower complete remission rate (p = 0.02). At a median follow-up of 4.6 years ALL patients with greater than or equal to 50% MKW+ blasts had a poorer event-free survival (EFS) than both MKW+ patients with 25-49% positive blasts (p = 0.03) and MKW+ patients (p = 0.0001). The disease-free survival was also poorer for ALL patients with greater than or equal to 50% MKW+ blasts (p = 0.02). In Cox regression analysis, the expression of MKW had an independent prognostic significance in children with ALL. As MKW is a unique cell surface antigen and its expression has prognostic significance in acute leukemias in children, further study in a larger series of patients is warranted.

Adolescent↗
PubMed1991

The t(10;11)(p14;q21) translocation in three children with acute myeloblastic leukemia.

A total of 161 cases of pediatric de novo acute myeloblastic leukemia (AML) have been reviewed, for which complete karyotyping was available and three cases (2%) were identified with t(10;11)(p14;q21). Two of the three children were infants with monoblastic (FAB M5) leukemia and the third was an adolescent with undifferentiated myeloid (FAB M1) leukemia. Both infants presented with increased levels of lactate dehydrogenase. None of these cases had increased eosinophils. One of the infants is in remission 18+ months after diagnosis and intensive chemotherapy; the two other children attained brief initial remissions but succumbed to their disease within 11 months of diagnosis. The prognosis of such children appears to be similar to that of cases of AML lacking this translocation.

Adolescent↗
PubMed1990

14q32 translocations are associated with mixed-lineage expression in childhood acute leukemia.

The frequency and characteristics of childhood acute leukemia with a 14q32 translocation [other than the t(8;14)(q24;q32)] were determined in 335 cases of newly diagnosed acute lymphoblastic leukemia (ALL) and 105 cases of acute nonlymphoblastic leukemia (ANLL). Ten children, representing 2.3% of the entire cohort, had this abnormality (1.5% of ALL patients and 4.8% of ANLL patients). By French-American-British (FAB) criteria, 4 cases were classified as L1, 1 as L2, 2 as M1, 1 as M2, and 2 as M5. Remarkably, mixed-lineage expression was found in 6 of these 10 cases, but in only 21 of the other 430 cases without a 14q32 translocation (P less than .001). Leukemic cells from 5 of these 6 cases (4 ANLL, and 1 ALL) coexpressed CD13, a myeloid-associated antigen, and CD2, a T-cell-associated antigen; blasts from the sixth case (ALL) coexpressed CD13 and CD19, a B-lineage-associated antigen. Thus, in addition to the well-described 11q23 translocations and t(9;22), 14q32 translocations also appear to be associated with mixed lineage antigen expression. Break-points of the reciprocal chromosomes from chromosome 14 were identified in five of these cases: 1q23, 6q23-q25, 7p15, 8q11, and 12q13. Of the four mixed-lineage cases that were tested, none showed rearrangement of the immunoglobulin heavy chain (IgH) gene. This suggests that the 14q32 breakpoint does not involve the IgH gene and that an unidentified important gene may reside on 14q32.

Adolescent↗
PubMed1990

N-ras gene point mutations in childhood acute lymphocytic leukemia correlate with a poor prognosis.

Ras genes can be altered by point mutations at critical portions of their coding regions to acquire transforming ability in vitro. These point mutations have been detected in a variety of human malignancies. However, their relevance for the clinical and biologic behavior of the subgroups of patients exhibiting these mutations in unclear. We analyzed 100 patients with childhood acute lymphocytic leukemias (ALLs) for point mutations of exons 1 and 2 of all three ras genes (H-ras, K-ras, and N-ras) by polymerase chain reaction and a combination of oligonucleotide hybridization and direct DNA sequencing. A 6% incidence of N-ras gene mutations was detected, all of which occurred at different nucleotides of codons 12 or 13 of N-ras. When correlating presence of ras mutations with the clinical and biologic features and the clinical outcome of these cases, a significantly higher risk for hematologic relapse (P = .01) and a trend toward a lower rate of complete remission (P = .07) was noted. The two groups did not differ in any of the known high-risk factors of ALL. These results suggest that presence of an N-ras mutation in children with ALL may be an independent predictor for worse clinical outcome and therefore may have therapeutic implications; further studies to confirm these findings are required because of the small number of patients with N-ras mutations.

Antigens, CD↗
PubMed1990

Myeloid-associated antigen expression lacks prognostic value in childhood acute lymphoblastic leukemia treated with intensive multiagent chemotherapy.

Frequency and clinical significance of myeloid-associated antigen expression in blast cells were assessed in 372 consecutive children with acute lymphoblastic leukemia (ALL). A comprehensive panel of myeloid monoclonal antibodies representing seven cluster groups showed myeloid-associated antigen expression in 61 cases (16.4%), 18 of which expressed two or more antigens. The antigens expressed comprised CD11b (8.9% of the total series), CD13 (6.5%), CD33 (3.2%), CD36 (1.9%), CD15 (1.6%), CD14 (1.3%), and CDw12 (1.1%). No significant associations were found between myeloid-associated antigen expression and the presence of known adverse prognostic features (eg, higher leukocyte count, nonwhite race, older age). Myeloid-associated antigen expression had no effect on remission induction or event-free survival for the 267 children who had been treated with the same combination of chemotherapeutic agents (P = .34). Thus, blast cell expression of myeloid-associated antigens in childhood ALL appears to lack prognostic value in the context of contemporary intensive chemotherapy.

Antibodies, Monoclonal↗
PubMed1990

A comparison of placement techniques and complications of externalized catheters and implantable port use in children with cancer.

The complications associated with the placement and use of Hickman catheters (n = 120), Broviac catheters (n = 146), and implantable ports (n = 93) in children with cancer were analyzed. Percutaneously placed central venous access devices (CVADs) tended to fail less often (P = .86) and to develop infections less often (P = .056) than surgically placed CVADs. The difference in complications with percutaneous versus surgically placed CVADs requires confirmation in a randomized trial to assure they are not a result of differences in patient characteristics. When all catheter failures (removal due to infection, obstruction, or dislodgement) were considered, ports had a significantly longer failure-free duration of use than externalized Hickman and Broviac catheters (P = .0009). Ports also remained infection-free longer than externalized catheters (P = .0014). The greatest risk of infection occurs in the first 100 days of use, particularly for ports. This study demonstrates that for long-term use (greater than 100 days) ports are superior to externalized catheters in children with cancer.

Bacterial Infections↗
PubMed1990

Prognostic importance of cytogenetic subgroups in de novo pediatric acute nonlymphocytic leukemia.

Reports of close associations between recurring chromosomal abnormalities and the clinical behavior of acute nonlymphocytic leukemia (ANLL) have stimulated efforts to define this disease in cytogenetic terms. Here we report on the leukemic cell karyotypes of 155 children with ANLL who were treated from 1980 to 1987 in consecutive programs of chemotherapy at this institution. Of 121 cases with adequate banding, 20% were normal, 30% had miscellaneous clonal abnormalities, and 50% were classified into known cytogenetic subgroups: inv(16)/del(16q) (n = 15), t(8; 21) (n = 14), t(15;17) (n = 9), t(9;11) (n = 9), t(11;V)/del(11q) (n = 7) and -7/del(7q) (n = 6). The inv(16)/del(16q) cases showed a nearly equal distribution of myelocytic and monocytic French-American-British (FAB) subtypes; only four of these patients presented with M4Eo morphology. Despite a 100% remission induction rate, patients with inv(16)/del(16q)-positive ANLL fared no better overall than the entire group; only 40% of this subgroup were event-free survivors at 2 years from diagnosis (P = .23). Patients with inv(16)/del(16q) frequently had CNS involvement at diagnosis (eight of 15) or initially relapsed in this site (three of eight). Event-free survival (EFS) was clearly superior for young patients with FAB M5 leukemia and the t(9;11) (P = .041). These patients were clinically indistinguishable from others with the FAB disease subtype, yet their responses to etoposide-containing therapies were noteworthy. By contrast, children with structural abnormalities involving 11q23, other than t(9;11), were infants (median age, 6 months) with FAB M4 or M5 leukemia, hyperleukocytosis, and frequent coagulation abnormalities. Patients with such changes [t(11;V) or del(11q)] relapsed early during postremission therapy: none remained disease-free more than 16 months from diagnosis. Because of resistant leukemia, patients with monosomy 7/del(7q) had a poor remission induction rate (17%; P = .0015); patients with the t(15;17) were also poor responders to induction therapy (44%; P = 0.02) because of hemorrhagic deaths. These results identify several cytogenetic subtypes of pediatric ANLL that may represent unique disease processes for which more effective early cytoreduction [-7/del(7q), t(11;V)], better supportive care measures [t(15;17)], or more effective CNS prophylaxis [inv(16)/del(16q)] would be warranted.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1990

Allogeneic bone marrow transplantation in a program of intensive sequential chemotherapy for children and young adults with acute nonlymphocytic leukemia in first remission.

Eighty-seven consecutive children and young adults with acute nonlymphocytic leukemia (ANLL) were treated uniformly with induction chemotherapy based on daunorubicin and cytarabine (ara-C), with the addition of etoposide (VP-16) and azacytidine (5-Az) for refractory patients. Of the 65 patients who entered complete remission, 42 were eligible for assessment of response to intensive chemotherapy consisting of four pairs of drugs administered in sequential fashion. Nineteen others with available histocompatibility locus antigen (HLA)-compatible donors were assigned to receive allogeneic bone marrow transplants within 16 weeks from their dates of complete remission. Durations of continuous complete remission (CCR) in the two groups were not significantly different at a median follow-up time of 6 years (P = .30 by log-rank analysis). Kaplan-Meier estimates of CCR probabilities (+/- SE) at 6 years were 43% +/- 13% (transplantation) and 31% +/- 7% (sequential chemotherapy). Postremission failures in the sequential chemotherapy group resulted from bone marrow relapse in 23 of 29 patients (79%), whereas in the transplantation group, failures were equally divided between marrow relapse and transplantation-related complications of graft-versus-host disease (GVHD) or infection due to the immunosuppressive effects of ablative chemotherapy. Comparison of hematologic remission curves indicated a significant advantage for marrow transplantation in terms of systemic leukemia control (P = .06). Thus, in programs of intensive chemotherapy of the type described here, allogeneic marrow transplantation should be seriously considered as alternative therapy for patients in first remission who have an HLA-matched sibling donor, provided that effective methods for control of transplant-related complications are available.

Adolescent↗
PubMed1990

Alterations in immunoglobulin or T cell receptor gene rearrangement at relapse: involvement of 11q23 and changes in immunophenotype.

We studied the organization of immunoglobulin (Ig) genes and the beta-chain gene of the T cell receptor (TCR) along with the clinical features, immunophenotypes, and karyotypes of 14 children with acute leukemia at diagnosis and relapse. The median time to relapse was 23 months. Eleven children had identical gene rearrangement patterns at diagnosis and relapse. All three patients whose blast cells showed variations in gene rearrangement patterns between diagnosis and relapase also demonstrated a change in the immunophenotype: one from cALLA+ to cALLA- B precursor cell ALL; one from T-ALL to AML; and one showed a marked increase in myeloid characteristics at relapse. Blast cells from these three patients at relapse showed the presence of chromosomal translocations involving 11q23; for two patients, this involved replacement of the original karyotype. We conclude that while most relapses are the result of reemergence of the original clone, new clones that differ in immunophenotype, karyotype, and gene rearrangement are occasionally present at relapse. Relapses may also occur in which the original clone has undergone major changes in gene expression and arrangement of the Ig heavy chain genes in the absence of karyotypic replacement.

Acute Disease↗
PubMed1990

Radiation-induced binding of DNA from irradiated mammalian cells to hydroxyapatite columns.

In experiments designed to measure radiation-induced DNA damage using the DNA unwinding-hydroxyapatite chromatography technique, we observed that under some experimental conditions a significant proportion of the test DNA became tightly bound to the hydroxyapatite (HA) and could not be released even with a high concentration of phosphate buffer. Approximately 5-10% of DNA from unirradiated cells binds to the HA. With increasing radiation doses in air, the fraction of bound DNA increases, reaching about 30% at about 35 Gy. The binding exhibits many of the characteristics of a radiation-induced cell lesion: the proportion of DNA retained by the HA is less when cells are irradiated under hypoxic conditions or in the presence of the thiol radioprotector dithiothreitol; and the binding decreases when an incubation period is allowed between irradiation and harvest of the cells for assay. Studies to determine the nature of the lesion responsible for the binding demonstrated that lesion production requires a component found in cells since no binding was observed with irradiated isolated DNA or nuclear matrix; the binding is not a result of the production of DNA-protein crosslinks; and the bound DNA is single-stranded, based on its sensitivity to nuclease S1. Because of the dose dependence of the binding of DNA to HA, the slopes of the dose-response curves for DNA damage determined with this assay depend on the method used to calculate the fraction of double-stranded DNA. Our demonstration that the bound DNA is single-stranded guides the choice of the method for data analysis.

Animals↗
PubMed1990

Mixed-lineage leukemia and asynchronous antigen expression.

Considerable confusion exists regarding the definition of acute mixed-lineage leukemia. We have proposed a list of strict criteria, limiting the term acute mixed-lineage leukemia to those patients whose blast cells co-express lymphoid and myeloid characteristics. This system includes cytochemical, immunologic, molecular, and cytogenetic characteristics that are strongly associated with either lymphoid or myeloid lineages. As more information becomes available, the criteria for mixed-lineage leukemia will undoubtedly change. Identification of patients with mixed-lineage leukemia and metachronous leukemia (lineage switch) is important for determining the prognostic implications of these findings. Care must be taken in identifying cases of metachronous leukemia because of the increased incidence of second malignancies following aggressive therapy. Evidence of a recurrence of the original clone must be obtained before metachronous leukemia can be diagnosed. As with mixed-lineage and metachronous leukemias, the potential clinical and prognostic implications of lymphoid leukemias with antigenic asynchrony should be identified. The asynchronous antigen expression in leukemic lymphoblasts may provide a means for detecting minimal residual disease. Detection of minimal residual leukemia is possible because these blasts differ from the predominant population of normal lymphoid cells in their expression of cell surface markers. Study of the mechanisms that lead to these unusual leukemias may result in better understanding of the processes that underlie both normal hematopoietic differentiation and leukemogenesis. An understanding of these leukemias may also permit identification of cases that are destined to fail current therapies so that more intensive or selective therapy can be instituted for such children. Curing the 30% of children with ALL that relapse despite our best efforts should be one of the top priorities for pediatric oncologists.

Antigens, Neoplasm↗
PubMed1990

Mechanism for 193-nm laser radiation-induced effects on mammalian cells.

The cellular sites for damage in mammalian cells caused by 193-nm radiation from an argon fluoride excimer laser were investigated. The ability of Chinese hamster ovary cells to reduce a tetrazolium dye (MTT) was decreased to 37% of unirradiated control by 2.5 x 10(3) J/m2 of 193-nm radiation when measured either 4 or 24 h after irradiation. In contrast, inhibition of MTT reduction by 254-nm radiation which primarily causes DNA damage was not measurable using this assay at 4 h after exposure; at 24 h 45 J/m2 inhibited MTT reduction to 37% of control. An increase in plasma membrane permeability, detected by 51Cr release, was observed within 15 min of exposure to 193-nm radiation, whereas exposure to 254-nm radiation did not cause this immediate release of 51Cr. In control experiments, the mitochondrial poison, carbonyl cyanide m-chlorophenyl hydrazone, did not cause 51Cr release in the dark, indicating that the 193-nm radiation-induced increase in plasma membrane permeability was not subsequent to loss of mitochondrial function. [3H]-Arachidonic acid was released from C3H10T1/2 cells using low 193-nm fluences, whereas release of [3H]arachidonic acid using UVB (290-32 nm) radiation required cytotoxic fluences. DNA does not appear to be a major site of 193 nm-induced cellular damage because alkali-labile sites were not detected in cells exposed on ice to up to 2 x 10(4) J/m2 of 193-nm radiation. These results indicate that 193-nm radiation produces primary damage on the level of the plasma membrane.

Animals↗