Biomedical subjects

P Steinherz

Publications and source records attributed to P Steinherz.

At least 19 recordsLinked to original sources

PubMed1996

Growth pattern and clinical correlation of subcutaneously inoculated human primary acute leukemias in severe combined immunodeficiency mice.

We examined the ability of patient-derived human leukemic blasts to generate leukemic growth and dissemination in severe combined immunodeficiency (SCID) mice by subcutaneous inoculation without conditioning treatment or administration of growth-promoting cytokines. Additionally, we correlated the growth pattern with the clinical outcome of patients from whom the leukemic cells were derived. The leukemias displayed three distinct growth patterns, ie, either aggressive, indolent, or no tumor growth. Leukemic cells from 6 of 13 patients with acute myeloid leukemia (AML), 4 of 7 T-cell acute lymphoblastic leukemia (T-ALL), and 11 of 16 patients with B-lineage ALL grew as subcutaneous tumors, with a significant number subsequently disseminating into distant organs in SCID mice. Patients whose leukemic blasts displayed an aggressive growth and dissemination pattern in SCID mice had a relatively poor clinical outcome, whereas patients with AML and T- or B-lineage ALL whose leukemic blasts grew indolently or whose cells failed to induce growth had a more favorable clinical course. Our study has shown that the subcutaneous inoculation of patient-derived human leukemic cells in SCID mice can engraft and grow as subcutaneous tumors with subsequent dissemination to distant organs in a manner analogous to their pattern of growth in humans. Additionally, these data suggest a clinical correlation to the growth and dissemination of some leukemic subtypes that may represent not only an additional prognosticator for patient outcome, but also a vehicle for the study of the biologic behavior of human leukemias and the development of novel therapeutic strategies.

Acute Disease↗

PubMed1996

Craniospinal irradiation for acute lymphoblastic leukemia with central nervous system disease at diagnosis: a report from the Children's Cancer Group.

PURPOSE: This study attempted to determine if central nervous system (CNS) disease at diagnosis is a poor prognostic factor in children with acute lymphoblastic leukemia (ALL) and whether 6 Gy of spinal irradiation is an adequate dose for these patients. METHODS AND MATERIALS: Previously the Children's Cancer Group (CCG) treated patients with ALL and CNS disease at diagnosis with cranio (24 Gy)-spinal (12 Gy) irradiation, as well as systemic and intrathecal chemotherapy. In a series of CCG trials completed in 1989 the spinal dose was empirically reduced to 6 Gy for patients receiving systemic chemotherapy with an intensive consolidation phase to limit hematopoietic toxicity. The spinal dose was left at 12 Gy for patients treated with a less intensive consolidation phase. RESULTS: With a median follow-up for surviving patients of 74 months, the 5-year event-free survival for 53 patients with CNS disease at diagnosis was 69 +/- 13% (+/- 2 standard deviations), similar to the value obtained for 3364 patients without CNS disease, 67 +/- 2%. Corresponding values for 5-year survival were 77 +/- 12% and 80 +/- 1%, and for freedom from isolated first CNS relapse, were 90 +/- 9% and 94 +/- 1%. Event-free survival, survival, and freedom from isolated first CNS relapse in the 6-Gy group were as good as in the 12-Gy group. CONCLUSION: CNS disease at diagnosis is not a poor prognostic factor for children with ALL who are treated with intensive systemic chemotherapy, craniospinal irradiation, and intrathecal chemotherapy. Six Gy is an adequate dose of spinal irradiation for these patients.

Central Nervous System Neoplasms↗

PubMed1995

Amplification of the dihydrofolate reductase gene is a mechanism of acquired resistance to methotrexate in patients with acute lymphoblastic leukemia and is correlated with p53 gene mutations.

Although dihydrofolate reductase (DHFR) gene amplification is a common mechanism of resistance to methotrexate (MTX) in tumor cell lines, with the exception of a few case reports, the incidence of this phenomenon as a mechanism of MTX resistance in the clinic has not been reported. We studied 38 untreated patients and 29 patients in relapse with acute lymphoblastic leukemia (ALL) for gene amplification and p53 gene mutations. Three patients were studied both at diagnosis and at each of two relapses after treatment with MTX. Nine of 29 relapsed patients (31%) had low-level DHFR gene amplification (two to four gene copies) associated with increased levels of DHFR mRNA and enzyme activity. Of significance was a correlation of gene amplification with p53 mutations in seven of nine relapsed patients (P < .001). Low-level DHFR gene amplification may be an important cause of MTX resistance in ALL and strengthens the concept that mutations in the p53 gene may lead to gene amplification as a consequence of defective cell cycle control.

Adolescent↗

PubMed1995

Predictors of depressive symptomatology among parents of newly diagnosed children with cancer.

Examined predictors of depressive symptoms among 59 parents providing primary care to children newly diagnosed with cancer. Parents were studied for a 3-month period. The parent providing primary care to the child during medical treatment completed measures of depressive symptoms, endorsement of family routines, family functioning, amount of assistance from the spouse in providing care to the child, child behavior problems, as well as measures of the severity of the child's treatment regimen. A strong relationship was found between child behavior problems and parent depressive symptomatology. Although disease-related factors such as the child's functional impairment played a role in the parent's depressive symptoms, results revealed that the child's behavior problems were most strongly associated with parent depressive symptoms and that family cohesiveness also had a contributory role in the maintenance of parent depressive symptoms.

Adolescent↗

PubMed1993

Decreased polyglutamylation of methotrexate in acute lymphoblastic leukemia blasts in adults compared to children with this disease.

We compared blast cells from adult and pediatric patients with untreated acute lymphoblastic leukemia (ALL) (as separated groups of T-lineage cell and B-lineage cell ALL) to determine if methotrexate (MTX) polyglutamate formation in adult patients might be a contributing cause to the known difference in clinical outcome, since MTX is a key drug in chemotherapy regimens. Adult B-lineage cell ALL blasts and blasts from the patients with T-lineage cell ALL accumulated lower amounts of total MTX and polyglutamates, especially long-chain MTX polyglutamates (glu3-6) than pediatric B-lineage cell ALL blasts. In view of the importance of polyglutamylation of MTX as a determinant of cytotoxicity of this drug, decreased formation of MTX polyglutamates is likely a contributing cause to the lower cure rate in adult ALL and T-lineage cell ALL as compared to childhood B-lineage cell ALL.

Adult↗

PubMed1992

Defective transport as a mechanism of acquired resistance to methotrexate in patients with acute lymphocytic leukemia.

Although the mechanisms of resistance to methotrexate (MTX) are known in experimental tumors made resistant to this drug, little information is available regarding acquired resistance to MTX in patients. A competitive displacement assay using the fluorescent lysine analogue of MTX, N-(4-amino-4-deoxy-N10-methylpteroyl)-N epsilon-(4'-fluorescein-thiocarbamyl)-L-lysine (PT430), was developed as a sensitive method of detection of transport resistance to MTX in cell lines, as well as in blast cells from patients with leukemia. Rapid uptake of PT430 at high concentrations (20 mumol/L) in leukemic blasts resulted in achievement of steady-state levels within 2 hours. Subsequent incubation with the folate antagonists, MTX and trimetrexate (TMTX), which differ in the mode of carrier transport, produced characteristic patterns of PT430 displacement. Flow cytometric analysis of the mean fluorescence intensity in the human CCRF-CEM T-cell lymphoblastic leukemia cell line and its MTX-resistant subline clearly identified the presence of transport deficiency in the resistant subline. Analysis of blasts from 17 patients with leukemia, nine with no prior chemotherapy and eight previously treated with chemotherapy, found evidence of MTX transport resistance in two of the four patients who were treated with MTX and considered to be clinically resistant to the drug. The finding that blast cells of some patients with leukemia considered clinically resistant to MTX is due to decreased MTX transport has important implications for clinical use of this drug and for new drug development.

Adolescent↗

PubMed1992

Monosomy 7 myeloproliferative disease in children with neurofibromatosis, type 1: epidemiology and molecular analysis.

Loss of constitutional heterozygosity is a common molecular feature of cancers in which inactivation of one or more tumor suppressor genes is thought to contribute to tumorigenesis. Recent evidence suggests that the gene responsible for neurofibromatosis, type 1 (NF-1), belongs to this class of heritable cancer genes. Children with NF-1 show an increased incidence of myeloid leukemia, including juvenile chronic myelogenous leukemia (JCML) and, perhaps, the myeloproliferative syndrome (MPS) associated with bone marrow monosomy 7 (Mo 7). We have investigated five children with Mo 7: three with NF-1 and two others with suggestive evidence of NF-1. Southern blotting experiments performed in four patients showed no loss of heterozygosity in bone marrow specimens using probes linked to the NF-1 locus on the long arm of chromosome 17. Both of our patients with familial NF-1 inherited the disease from their mothers, as did 14 of 19 other cases of myeloid leukemia in children with familial NF-1. Seventeen of these 21 children were boys. Myeloid leukemia developed in 12 boys and four girls who inherited NF-1 from their mothers, and in five boys who inherited the disease from their fathers. Father-to-daughter transmission was not observed. Taken together, the presence of chromosome 7 deletions in the leukemias of children with NF-1, a pattern of inheritance favoring maternal transmission of NF-1, and the marked predilection for boys to develop JCML and Mo 7 suggest a multistep mechanism of oncogenesis in which epigenetic factors might play a role. Further investigation is required to determine if the NF-1 genes in the leukemic bone marrows of these patients have acquired point mutations or small deletions.

Blotting, Southern↗

PubMed1992

Phase I/II trial and pharmacokinetics of intrathecal diaziquone in refractory meningeal malignancies.

PURPOSE: Because there is a compelling need to develop new agents for intrathecal use, we investigated the safety, efficacy, and CSF pharmacokinetics of diaziquone (AZQ) following intrathecal administration in patients with refractory meningeal malignancies. PATIENTS AND METHODS: Thirty-nine patients received 45 courses of intrathecal AZQ. Two schedules were studied; twice-weekly administration of a 1- or 2-mg dose and "concentration times time" (C x T) administration of 0.5 mg every 6 hours for three doses, administered once weekly. RESULTS: Dose-limiting toxicity consisting of headache, nausea, or vomiting occurred in only three patients and only at the 2-mg, twice weekly dose. The schedules of 1 mg twice-weekly and 0.5 mg every 6 hours for three doses were well tolerated. Thirty-seven courses were assessable for response. The overall response rate was 62%. Complete responses (CRs) occurred in 14 of 37 courses (38%) and partial responses (PRs) occurred in nine of 37 courses (24%). Among patients with meningeal leukemia, CRs were observed in 11 of 26 courses (42%) and PRs in nine of 26 courses (35%). There was no difference in response rate related to dose or schedule. The pharmacokinetic behavior of intrathecally administered AZQ was characterized by biexponential disappearance from ventricular CSF, with mean half-lives of 18.2 and 78.6 minutes. The mean clearance rate was 0.37 mL/min. CONCLUSION: Intrathecal AZQ is safe, well tolerated, and highly active against refractory meningeal malignancies.

Adolescent↗

PubMed1991

Basis for natural resistance to methotrexate in human acute non-lymphocytic leukemia.

The basis of intrinsic resistance of blasts from patients with acute non-lymphocytic leukemia (ANLL) to methotrexate was studied. MTX polyglutamate formation was measured in blast cells from 19 patients with ANLL and in 7 pediatric patients with acute lymphocytic leukemia (ALL), after in vitro incubation for 24 h with 3H-methotrexate. There was no significant differences seen in the total amount of MTX plus polyglutamates measured between ANLL and ALL blasts, indicating that transport defects do not account for intrinsic MTX resistance in ANLL. However, there were significant differences between the amounts of long chain MTX polyglutamates found in ANLL cells as compared to ALL cells. Most, but not all, ANLL blasts were unable to form long chain polyglutamates. In as much as the level of MTX polyglutamates found in blast cells after MTX administration allows for retention of this drug, this property may explain, at least in part, the refractoriness of most patients with ANLL to methotrexate.

Adolescent↗

PubMed1991

Delayed cardiac toxicity from anthracycline therapy.

Survivors of childhood cancer who received anthracycline treatment have a high incidence of abnormal cardiac function. Cardiac decompensation and death can appear many years after completion of chemotherapy. These survivors require periodic evaluation of cardiac function and rhythm.

Arrhythmias, Cardiac↗

PubMed1990

Delayed central nervous system (CNS) radiation in childhood CNS acute lymphoblastic leukemia. Results of a pilot trial.

With the introduction of effective prophylactic central nervous system (CNS) therapy in childhood acute lymphoblastic leukemia (ALL), the incidence of CNS relapse has been significantly reduced. Nonetheless, there is a continuing need for effective CNS therapy for the 5% to 10% of children who escape prophylaxis and in whom active CNS disease develops. In July 1985, a pilot study was initiated whereby the consolidative CNS treatment, given in the form of craniospinal axis radiation, was delayed and administered after delivery of a prolonged course of intensive systemic and CNS chemotherapy. Ten leukemic patients with CNS relapse were treated according to this pilot study. One patient did not respond to pre-CNS consolidative therapy and died at 2 months with progressive disease. The remaining nine patients have completed the craniospinal axis radiation. Five patients are off all therapy and remain in remission at a median time of 38 months (range, 31 to 46 months). Two patients are near completion of therapy and are disease-free at 22 and 24 months. Testicular relapse occurred in two patients at 14 and 29 months. CNS chemotherapy, as used in this trial, appears to have allowed for a delay in the administration of the consolidative craniospinal radiation without negatively affecting the CNS remission rate or duration. In turn, this delay has allowed for the uncompromised delivery of intensive multiagent systemic chemotherapy, as well as the separation of those patients destined to early systemic relapse from those who will achieve a sustained complete remission. In both cases, a reduction in the need for multiple courses of potentially toxic CNS therapy as a result of CNS reseeding after radiation is anticipated.

Adolescent↗

PubMed1990

A study of multidrug resistance and cell kinetics in a child with near-haploid acute lymphoblastic leukemia.

Marked hypodiploidy is found in a small group of patients with acute lymphoblastic leukemia (ALL) and is associated with very poor prognosis. Cells from a patient with near-haploid ALL (karyotype: 27 XY, DNA index = 0.5) were investigated by multiparameter flow cytometry at relapse and at multiple time-points during reinduction chemotherapy. The cell cycle of these near-haploid leukemic blasts and their chromatin structure was studied by acridine orange (AO) DNA/RNA flow cytometric assays. Most leukemic cells were in "G0", and no recruitment of the bone marrow cells into the G1 phase of the cell cycle was found during reinduction therapy with high dose cytosine arabinoside. After two cycles of chemotherapy, the patient achieved clinical remission, but persistent haploid cells were identified by flow cytometry and he relapsed after 8 weeks and died after 16.7 weeks. The leukemic blasts expressed very high levels of a 180 kd p-glycoprotein associated with multidrug resistance and daunomycin efflux could be blocked by verapamil. Expression of gp 180 and the verapamil effect on intracellular daunomycin concentration indicate multidrug resistance. We conclude that cell kinetic quiescence and multidrug resistance may both be factors responsible for the poor prognosis of this patient with near-haploid ALL. Further studies of this patient group should determine if these mechanisms are indeed responsible for the poor prognosis associated with near-haploid leukemia.

Cell Cycle↗

PubMed1989

Reduced incidence of the somnolence syndrome in leukemic children with steroid coverage during prophylactic cranial radiation therapy. Results of a pilot study.

Chemotherapeutic regimens for childhood acute lymphoblastic leukemia (ALL) include a remission induction period with high, daily doses of prednisone among other agents. A period of central nervous system (CNS) prophylaxis follows, during which steroids are often tapered entirely before cranial radiation (CRT) is completed or even initiated. The somnolence syndrome (SS) has been described 4 to 6 weeks after completion of CRT in up to 60% of the children with doses as low as 1800 cGy. A pilot study of continuous steroid coverage during CRT in childhood ALL was conducted. From July 1984 to July 1986, 38 children entered on Children's Cancer Study Group ALL protocols received CRT of 1800 cGy (180 cGy x 10). All patients received oral prednisone throughout the entire course of CRT at daily doses varying from 3.0 to 60.0 mg/m2. The overall incidence of the SS was 13% (five patients). The development of the syndrome was steroid dose-dependent: greater than or equal to 15 mg/m2/d (one of 32 patients), 3% incidence; less than 15 mg/m2 (four of six patients), 67% incidence. The presence of headache during CRT was also steroid dose-related: greater than or equal to 15 mg/m2, one of 32 patients; less than 15 mg/m2, six of six patients. Of the seven patients with headache during CRT, five developed the SS. The two patients (both of the less than 15 mg/m2 group) who did not develop the SS were the only cases treated with increased steroid doses at the onset of headache symptoms. Steroid coverage at a dose of greater than or equal to 15 mg/m2 during CRT appears to significantly reduce the incidence of acute radiation reactions and the SS. A prospective randomized study is planned to confirm these initial findings.

Adolescent↗

PubMed1989

Reinduction therapy for advanced or refractory acute lymphoblastic leukemia of childhood.

Thirty-four children after multiple relapse or with refractory acute lymphoblastic leukemia were treated with two novel combinations of high-dose cytosine arabinoside, methotrexate, asparaginase, vincristine, and prednisone. The first combination was given to 19 patients. Oncolytic response and marrow hypoplasia was achieved in all. There were four early infectious deaths. Thirteen of the remaining 15 (87%) in whom the response to therapy could be evaluated achieved complete remission. Two achieved good partial remissions. The median duration of complete remission and survival on study was 8 and 10 months, respectively. The four proven and three suspected fungal infections seen in the initial 19 patients was the major toxicity observed. The therapy was modified in the last 15 patients to retain efficacy while reducing the period of neutropenia from a median of 28 to 22 days. No deep-seated fungal infections were seen in these patients. Twelve (80%) achieved a complete remission. Three had an oncolytic response without achieving remission. Eighty-three percent of the 30 evaluable patients, or 74% of all patients entered on study, achieved remission. It is anticipated that the therapy described here will not only achieve another remission in the majority of patients with advanced ALL but that the patients will be able to proceed to alternate therapies with potentially more durable benefit.

Adolescent↗

PubMed1988

Sequelae of thrombotic or hemorrhagic complications following L-asparaginase therapy for childhood lymphoblastic leukemia.

Thirty-four cases of childhood lymphoblastic leukemia that were complicated by CNS and peripheral thrombosis or hemorrhage associated with L-asparaginase (L-asp) therapy were reviewed to determine the effect of the events on the subsequent clinical status. There was no predilection for any site in the CNS cases; all but one of the peripheral events occurred in the lower extremities. The median time for 28 CNS and eight peripheral events from the beginning of L-asp therapy was 17 and 16 days, respectively. One patient died as a result of the CNS event. Twenty-six patients were surviving with a median follow-up of 27 months at the close of the study. Of the patients with peripheral thromboses, only the patient with a dorsal pedal artery occlusion had a significant problem (autoamputation of a toe). Although eight patients received L-asp subsequently without recurrence of the complication, two had transient neurological deterioration associated with the repeat administration of L-asp. Twenty-two patients received CNS prophylaxis consisting of intrathecal methotrexate, CNS radiation, or both, following the CNS event without deterioration. In general, clinical status was not compromised after thrombotic or hemorrhagic events. Although most patients had gross recovery of their neurological impairment, detailed neurological and neuropsychological testing is needed to elucidate possible defects.

Adolescent↗

PubMed1987

Phase I and clinical pharmacological study of 4-demethoxydaunorubicin (idarubicin) in children with advanced cancer.

We conducted a phase I and pharmacokinetic study of i.v. idarubicin, a new anthracycline analogue, in 42 evaluable children 1-19 years old. Twenty-seven had leukemia and 15 had various solid tumors. The drug was administered in escalating doses of 10 to 40 mg/m2/course in 3 equal fractions over 3 consecutive days at 14- to 21-day intervals. Myelosuppression and mucositis were the limiting toxicities for short-term administration. Nausea, vomiting, and elevation of liver enzymes and bilirubin were the other toxicities encountered. Peak toxicity occurred 2 weeks after drug administration with median recovery by day 24. All but 4 patients with solid tumors had prior anthracyclines. Mild cardiac function changes without clinical symptoms were observed in 17 of 35 patients measured by serial cardiac evaluations. In addition, there were 4 patients with congestive heart failure. On postmortem examination, 4 patients had changes consistent with anthracycline cardiomyopathy at a prior median total anthracycline dose of 175 mg/m2. The maximum tolerated dose for patients with solid tumors was 15 mg/m2 course in 3 divided doses. Patients with leukemia tolerated 30 mg/m2/course. Six of 15 evaluable patients with acute lymphoblastic leukemia who received greater than or equal to 30 mg/m2 idarubicin achieved a remission (M1 marrow status). The plasma clearance of idarubicin fits a 3-compartment model with a harmonic mean half-life of 2.4 min, 0.6 h, and 11.3 h for alpha, beta, and gamma phases, respectively. Idarubicinol was the only metabolite detected in the plasma and it accumulated during the 3 days of therapy. Idarubicin is similar to daunorubicin in pharmacology and toxicity. While the cardiotoxic dose still must be delineated, the complete remission achieved in multiple relapsed patients with acute lymphoblastic leukemia indicate promising activity in at least that disease.

Adolescent↗

PubMed1987

Phase I trial of homoharringtonine in children with refractory leukemia.

Continuous infusion of homoharringtonine was administered to 17 children with refractory leukemia. Ten children with acute lymphoblastic leukemia received a total of 18 courses and seven children with acute nonlymphoblastic leukemia had a total of 13 courses. Doses were escalated from 1.65 to 8.5 mg/m2 for 5-10 consecutive days. Side effects included mild nausea and vomiting and transient changes in liver enzymes. Mucositis and diarrhea were more frequently seen at higher dose levels. Grade 3 hypotension and pain were seen at doses of 7 mg/m2 for 10 days. This is considered to be the maximum tolerated dose in this limited phase I trial. None of these previously heavily treated patients achieved a marrow remission.

Adolescent↗

PubMed1985

Therapy of CNS leukemia with intraventricular chemotherapy and low-dose neuraxis radiotherapy.

Successful treatment of CNS leukemic relapse has been frustrated by frequent local recurrence and eventual marrow relapse. We describe the treatment of meningeal leukemia in 39 children with intrathecal remission induction followed by the placement of an Ommaya reservoir to facilitate the administration and distribution of chemotherapeutic agents into the CSF. Six hundred or 900 rad of craniospinal radiation and maintenance intraventricular and intrathecal chemotherapy was then administered. Systemic reinduction therapy was added in the later cases. Sixteen children (41%) experienced no further events, with 17+ months to 13+ years (median, 25 months) follow-up . Eleven patients (28%) had CNS recurrence, nine (23%) bone marrow (BM) relapse, and two (5%) testicular relapse as the next adverse event. The course of patients with first isolated CNS relapse differed from that of the others. Eleven (69%) of 16 patients treated for first isolated CNS relapse are alive and 9 are event free, while only 35% of patients whose CNS relapse occurred simultaneously or after recurrent disease at other sites are alive (P = .04). Seven of 23 in the later group are event free. The difference is due to the increased incidence of BM relapse in the later group (30% v 6%; P = .04). For patients with first isolated CNS relapse, the life-table median CNS remission duration is 42 months. The projected CNS relapse-free survival and event-free survival 8 to 10 years after CNS relapse are 40% and 32%, respectively. Headache, nausea, and emesis of short duration were frequent during therapy. In three patients, the reservoir had to be removed for infection. No patient suffered neurologic deficit related to the reservoir. The therapy described can reduce the CNS relapse rate with manageable toxicity. Systemic relapse is still a major problem after multiple CNS relapse and in those in whom the CNS relapse follows or is simultaneous with relapse at other sites.

Adolescent↗