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Biomedical subjects

M E Horowitz

Publications and source records attributed to M E Horowitz.

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

Development of chemotherapy treatment for pediatric brain tumors.

Until relatively recently the standard treatment for the child diagnosed with a brain tumor was surgical resection followed by radiation therapy. If initial treatment failed patients were rarely referred for chemotherapy. This, in large part, was owing to the therapeutic nihilism that resulted from the disappointing experience with chemotherapy in the treatment of adults with glioblastoma multiforme. Following encouraging reports of clinical responses to chemotherapy in children with recurrent medulloblastoma, however, the value of adjuvant chemotherapy has become more accepted.

Antineoplastic Agents↗
PubMed1990

Preirradiation cisplatin and etoposide in the treatment of high-risk medulloblastoma and other malignant embryonal tumors of the central nervous system: a phase II study.

Medulloblastoma, pineoblastoma, and cerebral neuroblastoma are malignant embryonal tumors of the CNS that may demonstrate similar histologic features, a propensity for neuraxis dissemination and sensitivity to radiation therapy and, in certain cases, chemotherapy. To evaluate the activity of preirradiation chemotherapy in such tumors, 11 newly diagnosed children with measurable residual disease and characteristics indicative of poor prognosis were treated postoperatively with cisplatin (CDDP) and etoposide (VP-16). Responses graded on the basis of radiographic findings in areas of either macroscopic residual tumor or metastatic disease included two complete responses (CRs), eight partial responses (PRs), and one stable disease (SD). Acute and subacute toxicity consisted of high-frequency hearing loss in four patients, reversible signs and symptoms of increased intracranial pressure in two patients, and transient neutropenia. Seven of eight patients with high-risk medulloblastoma and two of two with pineoblastoma remain free of tumor progression following neuraxis irradiation at 8 to 48 months postdiagnosis (median, 18 months). CDDP and VP-16 is a highly active drug combination when given before irradiation in children with high-risk medulloblastoma and other malignant embryonal tumors of the CNS, producing objective responses in at least one site of measurable disease in 10 of 11 newly diagnosed patients, including all of five with gross neuraxis dissemination.

Adolescent↗
PubMed1990

Pediatric AIDS: a perspective for the oncologist.

By the mid 1990s the number of newly diagnosed children with HIV infections in the US may rival the 6,500 children diagnosed with cancer each year. But recent developments in therapy for the child with AIDS offer some hope. A pediatric trial at the NCI used a continuous infusion of azidothymidine in order to achieve the desired blood and cerebrospinal fluid levels. Objective and subjective evidence of response to therapy was noted in all patients who presented with neurodevelopmental deficit. Increases in appetite and weight gain and reductions in lymphadenopathy and hepatosplenomegaly, and increases in CD4 count similar to those observed in adults were apparent. Promising preliminary results have also been seen in trials of dideoxycytidine, dideoxyinosine, and recombinant CD4.

Acquired Immunodeficiency Syndrome↗
PubMed1989

Modulation by verapamil of vincristine pharmacokinetics and toxicity in mice bearing human tumor xenografts.

The effect of the calcium channel blocker verapamil (VRP) on the accumulation and retention of vincristine (VCR) has been examined in mice bearing xenografts of human rhabdomyosarcomas. The tumors were Rh18, moderately sensitive to VCR, and its subline, Rh18/VCR3, selected in vivo for primary resistance to VCR. Administration of VRP by i.p. bolus at dose levels above 75 mg/kg was limited by acute lethality. At this dose, the maximal concentration in plasma was 24 microM, with rapid elimination such that plasma concentrations reported to modulate resistance in vitro (approximately 5-10 microM) were maintained for less than 60 min. To sustain a 10 microM plasma concentration, mice were infused with VRP at 6.25 mg/kg/hr (150 mg/kg/day) for up to 7 days using osmotic pumps implanted in the peritoneal cavity. Steady-state plasma levels were greater than or equal to 10 microM for at least 96 hr, and this schedule demonstrated minimal toxicity. Administration of VCR 20 hr after the start of VRP infusion produced significant lethality, requiring an 8-fold reduction in the VCR dose. Pharmacokinetic studies showed that VRP markedly increased the uptake and retention of VCR in small intestine, liver and kidney of mice. In small intestine, 8-fold greater levels of VCR were determined 24 hr after VCR administration, and this was associated with in increase in T1/2 for elimination from 350 to 913 min. HPLC analysis of extracts from small intestine showed that greater than 90% of the radiolabel eluted with VCR or 4-desacetyl-VCR. Modulation of VCR retention was also related to the dose of VCR administered. The VRP-sensitive efflux pathway appeared more effective in certain tissues only at higher concentrations of VCR. In contrast, VRP did not alter significantly the uptake and retention of VCR in either the parent or VCR-resistant human xenografts. The data demonstrated that, in the mouse, VRP modulates the uptake and retention of VCR in several tissues, and this may indicate that drug efflux mediated by a VRP-sensitive mechanism (e.g. GP-170, associated with the multiple drug resistance phenotype) has a protective function against xenobiotics in these tissues.

Animals↗
PubMed1989

Phase I study of 4'-deoxydoxorubicin (esorubicin) in children with malignant solid tumors.

4'-Deoxydoxorubicin was given to 15 patients with drug-resistant pediatric malignant solid tumors with the objectives of determining the maximum tolerated dosage and dose-limiting toxicity. Maximum tolerated dosage was 36 mg/m2 given IV once every 3 weeks. Dose limiting toxicity was myelosuppression, which was severe and prolonged. Therapeutic benefits were not observed for these patients.

Adolescent↗
PubMed1989

Ifosfamide in pediatric malignant solid tumors.

Ifosfamide/mesna was given to 97 patients who had malignant solid tumors diagnosed before they were 21 years of age. Patients received 1.6 g/m2 ifosfamide daily x 5, given i.v. over 15 min, followed by 400 mg/m2 i.v. mesna at 15 min and 4 and 6 h after ifosfamide. Responses were noted in patients with osteosarcoma, Ewing's sarcoma, rhabdomyosarcoma and other soft-tissue sarcomas, rhabdoid tumor, neuroblastoma, Wilms' tumor, primitive neuroectodermal tumor, retinoblastoma, germ-cell tumors, and B-cell lymphoma. Toxicity included mild to moderate nausea and vomiting, transient, reversible myelosuppression, transient elevations of serum blood urea nitrogen (BUN) and creatinine and liver enzymes, infections, and self-limiting neurotoxicity characterized by changes in mental status, motor dysfunction, cranial nerve palsy, cerebellar dysfunction, and seizures. Neurotoxic symptoms were generally seen in patients who had previously received cisplatin. Ifosfamide is an important alkylating agent that should be combined with other agents in phase II and III trials. Alternate dose schedules should also be investigated.

Adolescent↗
PubMed1989

Intensive combined modality therapy of small round cell and undifferentiated sarcomas in children and young adults: local control and patterns of failure.

Seventy-five patients (ages 4-35 years) with the following small round cell tumors and undifferentiated sarcoma were treated at the National Cancer Institute: Ewing's sarcoma (n = 32), peripheral neuroepithelioma (n = 14), rhabdomyosarcoma (n = 24), undifferentiated sarcoma (n = 5). Most patients had poor prognostic features including 36 (48%) with metastatic disease, and 42 (56%) with central (truncal) tumors (22 in the pelvis). Treatment included 5 cycles of intensive induction chemotherapy with vincristine, cyclophosphamide and adriamycin, plus aggressive local radiation therapy using simulation and computerized treatment planning for all patients. Thereafter, complete clinical responses were consolidated with intensive chemotherapy, total body irradiation and autologous bone marrow transplantation. There were three local only failures, 10 local plus distant failures, 36 distant only failures, 3 treatment-related deaths, and one intercurrent death. Overall actuarial survival and event-free survival at 4 years are 49 and 29%, respectively. Actuarial freedom from local progression was seen in 74% of patients at 4 years, quite remarkable considering the bulk and location of most of these tumors. Without aggressive surgery, many of these high risk patients had satisfactory outcomes, but better systemic treatments are still needed.

Adolescent↗
PubMed1989

Purpura fulminans. A case for heparin therapy.

A 6.5-year-old boy developed purpura fulminans. He had no evidence of congenital protein C deficiency. He responded readily to heparin therapy with resolution of his coagulopathy. The coagulopathy resumed rapidly after heparin therapy was interrupted to allow for surgical procedures. Despite correction of his coagulopathy with heparin, surgical amputation of his leg was necessary because of inadequate perfusion.

Amputation, Surgical↗
PubMed1989

Neurodevelopmental status of infants and young children treated for brain tumors with preirradiation chemotherapy.

In an effort to reduce the severity of late neurotoxicities associated with cranial irradiation, 14 infants and young children with malignant brain tumors were given preirradiation chemotherapy for 2 to 22 months (median, 8 months). Prospective neurodevelopmental evaluations were routinely conducted and now extend from 35 to 60 months (median, 41 months) postdiagnosis, and 10 to 52 months (median, 31 months) postirradiation in the 12 surviving children. At the initiation of chemotherapy, less than one fourth of the patients displayed normal performance status or mental functioning on age-corrected tests; the majority remained stable or declined while receiving chemotherapy. Declining mental development and adaptive behavior were noted in six patients following radiation therapy with only two patients now functioning in the normal range for age. The analysis suggests that neurodevelopmental progress is a function of multiple factors, including neurologic and sensorimotor deficits associated with the tumor, surgical intervention, and chemotherapy that antedated radiation therapy. This implies that delaying irradiation will not necessarily improve the patients' functional status. Whether the interval of postponement of irradiation evidenced in this sample will translate into an ultimately better quality of life remains unknown. Given the probable interaction of multiple risk factors, well-controlled prospective clinical trials are needed to definitively analyze this issue.

Auditory Perception↗
PubMed1989

Clinical studies of ifosfamide/mesna at St Jude Children's Research Hospital, 1983-1988.

A phase-II study of ifosfamide with mesna, given intravenously daily for five days by bolus injection, has demonstrated the activity of ifosfamide against a spectrum of childhood malignant solid tumors. Ifosfamide presently is being investigated in alternative phase-I schedules, daily times three or every other day times three with the aim of delivering comparable amounts of ifosfamide without increasing toxicity--specifically, neurotoxicity. Additionally, response following ifosfamide treatment is being evaluated for previously untreated children with osteosarcoma and rhabdomyosarcoma after 6 weeks of treatment, and for previously untreated patients with Ewing's sarcoma after 9 weeks of treatment with ifosfamide/VP-16 (etoposide) given in combination.

Adolescent↗
PubMed1989

Ewing's sarcoma: current status of diagnosis and treatment.

Ewing's sarcoma, second only to osteosarcoma as the most common malignant bone tumor of children and adolescents, can be cured in more than half of all cases. Combination chemotherapy and local irradiation is the most effective multimodality approach, with chemotherapy being initiated as soon as possible after diagnosis and work-up. The first Intergroup Ewing's Sarcoma Study, completed in 1978, demonstrated that adjuvant therapy with vincristine, dactinomycin was superior to VAC alone or VAC with pulmonary irradiation. The most recent treatment advance is the identification of a high level of activity of ifosfamide and etoposide in patients with recurrent disease. This combination will soon be tested in a collaborative group Phase III trial.

Adolescent↗
PubMed1988

Brain tumors in the very young child. Postoperative chemotherapy in combined-modality treatment.

Twelve consecutively diagnosed children with brain tumors, ages 7 to 27 months, were treated by a combined-modality approach featuring aggressive surgical resection followed by chemotherapy and delayed irradiation. Patients received multiple clinical neurologic examinations and psychological evaluations, as well as diagnostic imaging studies, to monitor the efficacy of chemotherapy and toxic effects of therapy. Six of the eight children with residual tumor evident postoperatively on computed tomography scans had objective responses to chemotherapy. The efficacy of chemotherapy was further demonstrated by the lack of disease progression for 7 months or longer in eight children, seven of whom remain free of tumor 19 to 57 months (median, 28 months) from the date of diagnosis. The neurologic status of ten patients improved during treatment. Developmental progress was normal in two, low average in three, and frankly deficient in four of ten children formally evaluated. These results indicate that postoperative chemotherapy, added to a regimen of surgical resection and delayed irradiation, prolong survival with only minimal short term neurotoxicity in the majority of very young children with malignant brain tumors.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1988

Phase II testing of melphalan in children with newly diagnosed rhabdomyosarcoma: a model for anticancer drug development.

We describe events that led to successful testing of melphalan, one of the nitrogen mustard compounds, in children with newly diagnosed, poor-risk rhabdomyosarcoma (RMS). Preclinical studies with xenografts of human RMS, growing in the flanks of immune-deprived mice, had indicated superior oncolytic activity by melphalan compared with other agents commonly used to treat this tumor. However, in a conventional phase II trial, melphalan failed to produce partial responses in 12 of 13 heavily pretreated patients with recurrent tumors. Subsequent comparison of the drug's pharmacokinetics in mice and patients indicated that its poor clinical performance was not the result of interspecies differences in drug disposition. Therefore, we elected to retest melphalan in untreated patients, before they were enrolled in a phase III study. Of 13 children who received the drug for 6 weeks, ten had partial responses, confirming the significant antitumor activity seen in the xenograft system. These findings illustrate the inherent limitations of phase II drug trials in previously treated patients and suggest a useful paradigm for the development of antineoplastic drugs.

Adolescent↗
PubMed1988

Feasibility and efficacy of preirradiation chemotherapy for pediatric brain tumors.

Preirradiation chemotherapy is a potentially important component of combined treatment for brain tumors; however, concerns over its side effects and antitumor activity have impeded its evaluation in clinical trials. To determine the feasibility of administering such therapy to children, we assessed the responses of 38 brain tumor patients (median age, 2 years) to 12 weeks of combination chemotherapy given after surgical resection but before irradiation. Transient myelosuppression was noted in all patients, but was not associated with infections or complications of surgical wounds. The ability of the patients to perform activities of daily life, as rated with the Karnofsky performance scale, was either improved (n = 14) or unchanged (n = 18) at the end of the evaluation period. In the remainder of the group, functional deterioration was clearly related to causes other than drug treatment. Prior chemotherapy did not compromise the delivery of radiation except for a brief interruption of spinal irradiation in 3 patients. Objective responses to chemotherapy, defined as a greater than 50% decrease in tumor masses, occurred in 16 of the 31 patients who had subtotal resections; only 6 patients in the entire group showed disease progression during the 12 weeks of drug administration. We conclude that chemotherapy of the type used in this study is well tolerated and produces beneficial effects in children with brain tumors.

Adolescent↗