Biomedical subjects

M E Horowitz

Publications and source records attributed to M E Horowitz.

At least 37 records · Page 2Linked to original sources

PubMed1994

Immunohistochemical detection of P-glycoprotein in Ewing's sarcoma and peripheral primitive neuroectodermal tumors before and after chemotherapy.

The authors evaluated P-glycoprotein expression in a total of 35 cases of Ewing's sarcoma and peripheral primitive neuroectodermal tumors (PNET). Fifteen cases had matched tumors before and after treatment. The 20 unmatched tumors included 14 pretreatment PNETs and Ewing's sarcomas and 6 posttreatment Ewing's sarcomas. Two antibodies, C219 and JSB-1, were used. Immunoreactivity was almost exclusively membranous. Variability in the number of positive cells and in staining intensity was noted within individual tumors. Among the 15 matched tumors, 7 were positive for P-glycoprotein before treatment; 6 of these remained positive after treatment. Four of the 8 that were negative for P-glycoprotein before treatment became positive after treatment. Of the unmatched tumors, 9 of 14 pretreatment and 3 of 6 posttreatment tumors were positive. When relapse-free survival time, based on the presence or absence of P-glycoprotein positivity in pretreatment tumor samples, was evaluated in this group, no significant difference was found (P2 = .92); however, the numbers are too small to draw definitive conclusions. The high incidence of positive primary tumors suggests that P-glycoprotein expression is probably intrinsic in Ewing's sarcoma and PNET and not necessarily induced by therapy.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed1994

Desmoplastic infantile gangliogliomas: an approach to therapy.

Desmoplastic infantile gangliogliomas are massive cystic tumors, typically occurring in the cerebral hemispheres of infants. They are remarkable pathologically for a prominent desmoplasia and, in some cases, for a cellular mitotically active component that can be readily interpreted as a malignant neoplasm. Four children less than 1 year of age were diagnosed with desmoplastic infantile gangliogliomas in the Pediatric Oncology Group infant brain tumor study (Protocol number 8633). All had been diagnosed by their respective institutions as having malignant tumors, i.e., Grade III astrocytoma, malignant meningioma, leptomeningeal fibrosarcoma, and gliosarcoma. All had increased intracranial pressure, and two had seizures. The tumors were extremely large, with one measuring 12 x 9 x 9 cm. None had evidence of metastatic disease. One patient had a gross total resection, and the other three had debulking procedures. All four children were treated with chemotherapy (cyclophosphamide, vincristine, cisplatinum, etoposide) for periods ranging from 12 to 24 months. Of those with postoperative measurable disease, one child had a complete response, one a partial response, and one had stable disease at the conclusion of chemotherapy. No child received radiation therapy. All children are alive with progression-free survivals after diagnosis of more than 36, 42, 48, and 60 months, respectively. Although desmoplastic infantile gangliomas are rare, recognition of this tumor type is essential because, despite their massive size and pathologically malignant appearance, they may have a relatively benign clinical course. If total surgical resection can be achieved, further therapy may not be indicated. In those patients in whom residual disease is present, chemotherapy appears to be an effective form of therapy.(ABSTRACT TRUNCATED AT 250 WORDS)

Antineoplastic Combined Chemotherapy Protocols↗

PubMed1993

Long-term survival after central nervous system relapse in a patient with osteosarcoma.

BACKGROUND: Since the advent of multiagent adjuvant chemotherapy, survival among patients with localized osteosarcoma has improved to 60% or more. Pulmonary relapse, the most common cause of treatment failure, is associated with less than 25% long-term survival; central nervous system (CNS) metastasis, when it occurs, often presents as a catastrophic clinical event in preterminal patients. METHODS: The authors report a patient with osteosarcoma who had an isolated pulmonary relapse and a subsequent isolated CNS relapse. Complete surgical resection was accomplished on both occasions and followed in the initial instance by adjuvant chemotherapy and in the latter instance by adjuvant whole-brain irradiation. RESULTS: An isolated CNS metastasis was resected and adjuvant whole brain irradiation was administered; the patient is alive and relapse free more than 5 years later. CONCLUSIONS: Patients with osteosarcoma in whom isolated, resectable metastases develop can derive benefit from gross total resection followed by adjuvant chemotherapy or radiation therapy for microscopic residual disease.

Brain Neoplasms↗

PubMed1993

A phase II evaluation of thiotepa in pediatric central nervous system malignancies.

BACKGROUND: Both thiotepa and its active metabolite, tepa, efficiently cross the blood-brain barrier. After intravenous administration, the cerebrospinal fluid concentrations achieved are nearly identical to those in plasma. This provides a strong rationale for testing this agent against brain tumors. METHODS: Sixty pediatric patients with recurrent primary brain tumors were treated on a multiinstitutional Phase II study of intravenous thiotepa at a dose of 65 mg/m2 administered every 3 weeks. This dose is the result of a prior pediatric Phase I trial and is significantly higher than those previously recommended. RESULTS: Three of 13 assessable patients with medulloblastoma had partial responses lasting 22, 25, and 54 weeks. Although no objective responses were observed in 16 assessable patients with malignant gliomas and 14 with brain stem gliomas, 5 of 16 and 4 of 14 patients in these respective strata had prolonged periods of stable disease (SD) lasting from 12 to more than 33 weeks. Nine assessable patients with ependymoma had no objective response, but two had SD, both for more than 33 weeks. Myelosuppression was the principle toxic effect encountered and appeared to be more severe in patients who had received prior craniospinal radiation therapy or nitrosourea therapy. CONCLUSIONS: By conventional Phase II criteria, thiotepa appears to have activity in medulloblastoma. Based on several patients with prolonged SD, it also may possess some limited activity in brain stem and malignant gliomas. The steep in vitro dose-response curve of thiotepa and the long durations of response or SD observed with the dose reported here suggest that moderate-dose to high-dose thiotepa with cytokine support or autologous bone marrow rescue may be associated with an improved response rate to this agent.

Adolescent↗

PubMed1993

Postoperative chemotherapy and delayed radiation in children less than three years of age with malignant brain tumors.

BACKGROUND: Among patients with malignant brain tumors, infants and very young children have the worst prognosis and the most severe treatment-related neurotoxic effects. Therefore, in 1986, the Pediatric Oncology Group began a study in which postoperative chemotherapy was given in order to permit a delay in the delivery of radiation to the developing brain. METHODS: Children under 36 months of age with biopsy-proved malignant brain tumors were treated postoperatively with two 28-day cycles of cyclophosphamide plus vincristine, followed by one 28-day cycle of cisplatin plus etoposide. This sequence was repeated until the disease progressed or for two years in 132 children 24 months of age at diagnosis and for one year in 66 children 24 to 36 months of age at diagnosis. After this, the patients received radiation therapy. The response to the first two cycles of chemotherapy was measured in 102 patients with residual postoperative disease. RESULTS: The first two cycles of cyclophosphamide and vincristine produced complete or partial responses in 39 percent of the 102 patients who could be evaluated. The response rates were highest among patients with medulloblastomas, malignant gliomas, or ependymomas. Patients with brain-stem gliomas or embryonal tumors (primitive neuroectodermal tumors) had little or no response. The progression-free survival rate was 41 percent at one year for children who were 24 to 36 months old at diagnosis and 39 percent at two years for those under 24 months of age at diagnosis. Multivariate analysis identified embryonal tumors as a significant adverse prognostic feature (relative risk, 2.2; 95 percent confidence interval, 1.4 to 3.4) and complete resection as a favorable feature (relative risk, 0.33; 95 percent confidence interval, 0.20 to 0.54). Complete responses to chemotherapy were associated with a progression-free survival rate approaching that achieved with gross total resection. A comparison of cognitive evaluations obtained at base line and after one year of chemotherapy revealed no evidence of deterioration in cognitive function. CONCLUSIONS: Chemotherapy appears to be an effective primary postoperative treatment for many malignant brain tumors in young children. Disease control for one or two years in a large minority of patients permitted a delay in the delivery of radiation and, on the basis of preliminary results, a reduction in neurotoxicity. For patients who had undergone total surgical resection or who had a complete response to chemotherapy, the results are sufficiently encouraging to suggest that radiation therapy may not be needed in this subgroup of children after at least one year of chemotherapy.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed1993

Malignant schwannoma with melanocytic and neuroepithelial differentiation in an infant with congenital giant melanocytic nevus: a complex neurocristopathy.

We describe an infant girl, born with a pigmented giant nevus, who developed a malignant schwannoma in the retroperitoneum at 16 months of age. At birth the nevus covered over 50% of her body and histologically was a compound nevus with extension into the deep dermis surrounding dermal appendages. The malignant schwannoma was biphasic with areas composed of spindle and round cells. Ultrastructurally, the majority of the tumor cells exhibited a Schwann cell phenotype, but neuroepithelial and melanocytic cells were identified as well. We believe that this constellation of findings represents a form of neurocristopathy. Neurocristopathy, as defined by Bolande (Hum Pathol 5:409-429, 1974), is a disease that results from aberrations in the migration, growth, or cytodifferentiation of neural crest tissues. These diseases may be simple (a singular pathologic process, usually localized) or complex (multiple neuroectodermal lesions). We report this case because the occurrence of retroperitoneal malignant schwannoma arising in a 16-month-old infant born with a pigmented giant nevus is unique, and may represent a previously undescribed form of a complex neurocristopathy.

Female↗

PubMed1993

Total-body irradiation and autologous bone marrow transplant in the treatment of high-risk Ewing's sarcoma and rhabdomyosarcoma.

PURPOSE: In an effort to improve outcome in patients with metastatic or high-risk localized Ewing's sarcoma family of tumors (ESF) and rhabdomyosarcoma (RMS), we explored the role of consolidation therapy with total-body irradiation (TBI) plus autologous bone marrow transplantation (ABMT). PATIENTS AND METHODS: Ninety-one patients were entered onto one of three consecutive protocols from 1981 to 1986. Induction therapy consisted of four or five cycles of vincristine, doxorubicin, and cyclophosphamide (VAdriaC); in the earlier series, patients received one or two cycles with dactinomycin instead of doxorubicin. Irradiation of the primary site was used for local control. Patients who attained a complete response (CR) to induction therapy were eligible for consolidation with 8 Gy TBI plus VAdriaC and ABMT. RESULTS: Nineteen patients were ineligible for consolidation after failing to achieve or maintain a CR following induction therapy; all 19 are dead of disease. Seven eligible patients elected to forgo consolidation; three of seven are long-term event-free survivors. Sixty-five patients received consolidation therapy; 20 of 65 are long-term event-free survivors. A local control rate of 83% was achieved using radiation therapy as the primary modality of local control. Patients with metastatic disease at diagnosis fared substantially worse than did patients with localized tumors (6-year event-free survival [EFS] rate, 14% v 38%; two-sided P [P2] = .008). CONCLUSIONS: Consolidation of patients with metastatic or high-risk localized pediatric sarcomas with 8 Gy TBI plus ABMT has failed to improve the outcome of this group of patients. Metastatic disease at diagnosis continues to confer the poorest prognosis. New therapeutic strategies are needed to consolidate more effectively the remissions that can be achieved in the majority of these patients.

Adolescent↗

PubMed1993

A novel germline p53 splicing mutation in a pediatric patient with a second malignant neoplasm.

A novel germline p53 splicing mutation was identified in a pediatric patient with two metachronous primary cancers that are constituent tumors of the Li-Fraumeni syndrome. Genomic DNA from the second tumor showed the same mutation and loss of heterozygosity at the p53 locus. The mutant mRNA and protein were present in the tumor tissue. In contrast, in the normal tissues bearing the germline mutation in the heterozygous state, predominantly normal mRNA was expressed and the mutant p53 protein was not detectable. The functional silence and relative lack of mutant p53 mRNA expression in the normal tissues of this patient may be caused by decreased stability or decreased production. If this proves a more general pattern of expression of mutant p53 in individuals with germline mutations, these findings may explain the paucity of tumors in individuals affected with the Li-Fraumeni syndrome.

Adult↗

PubMed1992

Expression of the cholecystokinin gene in pediatric tumors.

We have examined a wide range of cultured human tumor cell lines and found that a specific subset of tumors expresses the cholecystokinin (CCK) gene. All neuroepitheliomas (eight) and Ewing sarcoma (eight) cell lines that were tested express CCK RNA. In addition, two of six rhabdomyosarcoma cell lines also express the CCK gene, suggesting that rhabdomyosarcomas are probably heterogenous and that a subset may be similar to Ewing sarcoma and neuroepithelioma. Very few of the positive tumors express completely processed immunoreactive CCK. However, we have used a radioimmunoassay that detects the CCK precursor to demonstrate synthesis of CCK precursor-like peptides by all of the Ewing sarcoma and neuroepithelioma lines that were tested and by the rhabdomyosarcoma cell line that expresses CCK mRNA. These data demonstrate a consistent association of CCK gene expression with a specific group of human neoplasms. The data also add credence to the theory that Ewing sarcoma and neuroepithelioma are derived from the same transformed cell type. Finally, our results suggest that CCK gene expression may serve as a marker to distinguish these tumors, which are considered to be small-round-cell tumors of childhood, from other pediatric tumors.

Cholecystokinin↗

PubMed1992

Neuraxis dissemination in pediatric brain tumors. Response to preirradiation chemotherapy.

Of 29 consecutive children treated for malignant primary tumors of the central nervous system (CNS) at this institution, postoperative examination showed radiographic or cytologic evidence of neuraxis dissemination in 10 (34%). Given the historically poor results in disseminated CNS tumors treated with surgery and radiation therapy alone, these ten patients were treated prospectively with an investigational Phase II protocol consisting of preirradiation cisplatin (90 mg/m2 on day 1) and etoposide (150 mg/m2 on days 3 and 4). The diagnoses included medulloblastoma (n = 4), malignant glioma (n = 3), cerebral primitive neuroectodermal tumor (n = 1), pineoblastoma (n = 1), and mixed glioma of the brainstem (n = 1). Postoperative neuraxis scanning with computed tomography, magnetic resonance imaging, or spinal myelography showed measurable intracranial or spinal metastases in all children. The cerebrospinal fluid (CSF) cytologic examination was positive for tumor cells in five. The best responses, based on serial imaging of neuraxis metastases, included two complete responses, four partial responses, and three stable disease states. One patient had progressive disease at the primary site despite stable disease in the spine; progressive neuraxis disease was documented in only one patient during chemotherapy. Clearance of tumor cells from the CSF was documented in three patients. The adverse effects of chemotherapy, consisting of transient myelosuppression and mild ototoxicity, were minimal. Reversible neurologic deterioration occurred in two patients; one patient became acutely quadriplegic after a prolonged convulsive seizure without radiographic evidence of tumor progression.

Adolescent↗

PubMed1992

Cytogenetic studies in subgroups of rhabdomyosarcoma.

Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma of childhood and accounts for 10% of all solid tumors in children. There are three different histologic forms of this tumor: embryonal (RMS-E), alveolar (RMS-A), and primitive (RMS-P). Among these, the embryonal form has responded well to chemotherapy. Identification of the correct subtype is important for both the management and treatment of this malignancy. However, the histopathologic classification of RMS is sometimes difficult and distinguishing between the embryonic and primitive forms can present a diagnostic dilemma. Chromosomal abnormalities have been observed in all subtypes. We present the cytogenetic findings in six cases of RMS or related sarcoma. All four cases with RMS-A had both numerical and structural abnormalities in the tumor and involved bone marrow specimens. Three patients had a common marker, t(2;13)(q37;q14), and one patient had a variant marker involving 13q14, t(1;13) (p36;q14), and double minutes (dmin). The single embryonal RMS patient had modal chromosome numbers in the hypertriploid range and extensive structural abnormalities; the t(2;13) was not present, but translocation of 13q to both 1q and 2p was observed, der(1)t(1;13)(q21;q14) and der(2)t(2;13)(p25;q14). The patient with primitive type RMS had a hypodiploid line with several markers, including a complex translocation involving chromosomes 5 and 13 with a breakpoint at 13q14, and t(11;12)(q24;q12), a chromosome marker heretofore found only in Ewing's sarcoma and related tumors. This patient had atypical RMS with mixed neural and myogenic elements. The significance of these chromosomal markers and their importance in the characterization of childhood tumors are discussed, along with a review of the literature.

Adolescent↗

PubMed1992

Pulmonary metastases: MR imaging with surgical correlation--a prospective study.

The sensitivity of magnetic resonance (MR) imaging for detection of pulmonary metastases in 11 patients scheduled for thoracotomy and curative resection of metastases was evaluated with a prospective, controlled study. MR imaging performed at 0.5 T was compared with chest radiography, computed tomography (CT), and thoracotomy in 12 cases. (One patient had two separate occurrences of pulmonary metastases.) All images were interpreted in blinded fashion. When all MR sequences were interpreted together, MR imaging enabled correct identification of all patients with pulmonary nodules (100%). CT enabled detection of at least one nodule in all 12 cases (100%) by design; the sensitivity of chest radiography was only 64%. For individual nodules, MR imaging was at least as sensitive as CT (P2 less than .25 [two-sided value]) and significantly more sensitive than chest radiography (P2 less than .01). Among all MR sequences, short inversion time inversion-recovery sequences had the highest sensitivity for detection of individual nodules (82%).

Adult↗

PubMed1992

Phase I and pharmacokinetic evaluation of all-trans-retinoic acid in pediatric patients with cancer.

PURPOSE: Recent reports of the dramatic antitumor effect of all-trans-retinoic acid (RA) in patients with acute promyelocytic leukemia (APL) have renewed interest in the oncologic indications for retinoids. Furthermore, a variety of pediatric tumors are responsive to RA in vitro, which provides additional rationale for a phase I evaluation of RA in children with cancer that is refractory to standard therapy. PATIENTS AND METHODS: A phase I trial of RA administered orally twice daily for 28-day treatment courses was performed. Cohorts of at least three pediatric cancer patients were entered at successive RA dose levels (from 45 to 80 mg/m2/d) until dose-limiting toxicity (DLT) was consistently observed. RESULTS: The maximum-tolerated dose (MTD) of RA was 60 mg/m2/d. Three of eight patients at the 80-mg/m2/d dose level developed reversible pseudotumor cerebri that necessitated discontinuation of the agent. Both patients with APL achieved complete remission (CR), whereas no patients with solid tumors had objective responses. Pharmacokinetic studies demonstrated a relatively short terminal half-life for RA (45 minutes), with diminution in plasma levels after chronic dosing. CONCLUSIONS: The MTD and recommended phase II dose for RA in children is 60 mg/m2/d given twice daily. Reversible CNS toxicity related to RA-induced pseudotumor cerebri is dose-limiting. Two children with APL achieved a CR to RA, which supports the inclusion of pediatric patients in clinical trials that evaluate the use of RA for patients with APL.

Administration, Oral↗

PubMed1991

Influence of doxorubicin dose intensity on response and outcome for patients with osteogenic sarcoma and Ewing's sarcoma.

The goal of this study was to use dose-intensity analyses of published Ewing's sarcoma and osteogenic sarcoma trials to determine which agents were most closely associated with a favorable response. The percentage of patients with more than 90% tumor necrosis following neoadjuvant chemotherapy was the end point for analysis of osteogenic sarcoma trials, and disease-free survival and percentage of patients with distant-only relapse were the end points for analysis of Ewing's sarcoma trials. The data were analyzed using logistic regression analysis to circumvent the distortion of univariate analysis resulting from the correlation between doxorubicin dose intensity and the dose intensity of other agents. Our analysis suggests that doxorubicin dose intensity is an important determinant of favorable outcome for both Ewing's sarcoma and osteogenic sarcoma and that the dose intensities of other agents do not contribute as significantly to outcome as does doxorubicin dose intensity. Increasing dactinomycin dose intensity was associated with a poorer outcome in treatment of osteogenic sarcoma and Ewing's sarcoma, most likely resulting from regimens with a higher dactinomycin dose intensity having a lower doxorubicin dose intensity. While our analysis of osteogenic sarcoma trials is consistent with significant activity for cisplatin and high-dose methotrexate (and likely ifosfamide), a rank ordering of the efficacy of these agents when given with doxorubicin in multiagent regimens is not possible. Our analysis illustrates the importance of analyzing the contributions of individual agents to combination chemotherapy regimens. In the design of future clinical trials for osteogenic sarcoma and Ewing's sarcoma, careful attention should be given to optimizing doxorubicin dose intensity in regimens to be tested.

Dose-Response Relationship, Drug↗

PubMed1991

Long-term follow-up of Ewing's sarcoma of bone treated with combined modality therapy.

Between 1968 and 1980, 107 consecutive patients with Ewing's sarcoma of bone were entered on three sequential combined modality treatment protocols (S2, S3, S4) at the National Cancer Institute (NCI). Protocol treatment involved 4 cycles of two drug [cyclophosphamide (CTX) and vincristine (VCR)] or three drug [CTX and VCR with either actinomycin-D (ACT-D) or doxorubicin (ADR)] regimens and local irradiation (50 Gy) to the involved bone. Eighty patients presented with localized disease and 27 patients had metastatic disease at presentation, including 11 patients with multiple metastatic sites. With a median potential follow-up of greater than 15 yrs (range 8-20 yrs), 28 pts (27%) remain alive. Disease-free (DFS) and overall survival (OS) decreased most rapidly during the initial 5 yrs of follow-up with 5-yr DFS of 29% and 5-yr OS of 39%. Only two patients with metastases at presentation are long term (greater than 5 yr) survivors. For localized disease patients, the 2, 5, 10, and 15 yr DFS and OS are 52%, 37%, 35%, and 33% DFS and 68%, 51%, 39%, and 34% OS, respectively. Eleven patients relapsed locally as the first site of failure. Using the Cox proportional hazards model, four significant variables for both DFS and OS were recognized, including metastatic disease at presentation, age greater than 25 yrs, high LDH in localized disease patients, and central primary tumor in localized disease patients in decreasing order of significance. We conclude that a majority of these patients with Ewing's sarcoma of bone relapsed within 5 yrs of presentation although late relapse (5-15 yrs) did occur. Local failure occurred in 20% of patients using these combined modality treatments but had no impact on overall survival.

Adolescent↗

PubMed1991

Ewing's sarcoma. Radiotherapy versus surgery for local control.

Significant strides in the treatment of Ewing's sarcoma, the second most common bone tumor of childhood, have resulted in cure for approximately 50% of patients. Successful therapy requires systemic chemotherapy for the eradication of microscopic or overt metastatic disease and surgery or irradiation therapy for control of the primary lesion. The article debates the controversy over the extent to which surgical resection should play a role in the local management of this disease.

Bone Neoplasms↗

PubMed1991

The child with recurrent solid tumor.

A significant percentage of relapse occurs in children with solid tumors despite advances in treatment. This article discusses reasons for failure of primary therapy, evaluation of the relapsed patient, treatment of the relapsed patient, as well as questionable cancer therapies and therapy cessation.

Algorithms↗

PubMed1991

Changing pattern of pulmonary metastases with adjuvant chemotherapy in patients with osteosarcoma: results from the multiinstitutional osteosarcoma study.

The multiinstitutional osteosarcoma study (MIOS), a randomized trial of adjuvant therapy for osteosarcoma with a concurrent control group, registered 113 patients from June 1982 to August 1984. Preliminary analysis of the study indicated a significant event-free survival advantage favoring immediate adjuvant chemotherapy, (P less than .001). For patients treated with surgery alone or with surgery and adjuvant chemotherapy, the lungs were involved in more than 80% of the relapses. Patients relapsing after surgery alone tended to relapse earlier (P less than .01), had more pulmonary nodules (P less than .01), and had more frequent bilateral pulmonary involvement (P less than .01) than those treated with immediate postsurgical adjuvant chemotherapy. However, patients relapsing after treatment with surgery alone experienced a significantly longer interval to further disease progression (P less than .01) and improved survival after relapse (P = .01) when compared with patients who relapsed after treatment with immediate adjuvant chemotherapy. The only factor predictive of survival after relapse was if the patient could be made surgically disease-free after initial relapse (P = .03).

Antineoplastic Agents↗