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Biomedical subjects

H S Friedman

Publications and source records attributed to H S Friedman.

At least 91 records · Page 5Linked to original sources
PubMed1997

PTEN gene mutations are seen in high-grade but not in low-grade gliomas.

The PTEN gene, located on 10q23, has recently been implicated as a candidate tumor suppressor gene in brain, breast and prostate tumors. In the present study, 123 brain tumors, including various grades and histological types of gliomas occurring in children and adults, were analyzed for PTEN mutations by SSCP assay and sequencing. Mutations in the PTEN gene were found in 13 of 42 adult glioblastomas and 3 of 13 adult anaplastic astrocytomas, whereas none of the 21 low-grade adult gliomas or the 22 childhood gliomas of all grades showed mutations. The single medulloblastoma with a mutation was a recurrent tumor that also possessed a p53 mutation. High-grade adult gliomas with PTEN mutations included cases that also contained gene amplification or p53 gene mutations, as well as cases that did not contain either of these abnormalities. There was no obvious relationship between presence of PTEN mutation and survival; however, there was a tendency for PTEN mutations to occur in older age group patients. This analysis suggest that PTEN gene mutations are restricted to high-grade adult gliomas and that this abnormality is independent of the presence or absence of gene amplification or p53 gene mutation in these tumors.

Adult↗
PubMed1997

Methylator resistance mediated by mismatch repair deficiency in a glioblastoma multiforme xenograft.

A methylator-resistant human glioblastoma multiforme xenograft, D-245 MG (PR), in athymic nude mice was established by serially treating the parent xenograft D-245 MG with procarbazine. D-245 MG xenografts were sensitive to procarbazine, temozolomide, N-methyl-N-nitrosourea, 1,3-bis(2-chloroethyl)-1-nitrosourea, 9-aminocamptothecin, topotecan, CPT-11, cyclophosphamide, and busulfan. D-245 MG (PR) xenografts were resistant to procarbazine, temozolomide, N-methyl-N-nitrosourea, and busulfan, but they were sensitive to the other agents. Both D-245 MG and D-245 MG (PR) xenografts displayed no O6-alkylguanine-DNA alkyltransferase activity, and their levels of glutathione and glutathione-S-transferase were similar. D-245 MG xenografts expressed the human mismatch repair proteins hMSH2 and hMLH1, whereas D-245 MG (PR) expressed hMLH1 but not hMSH2.

Animals↗
PubMed1997

Modulation of melphalan resistance in glioma cells with a peripheral benzodiazepine receptor ligand-melphalan conjugate.

Peripheral benzodiazepine receptors (PBRs) are located on the outer membrane of mitochondria, and their density is increased in brain tumors. Thus, they may serve as a unique intracellular and selective target for antineoplastic agents. A PBR ligand-melphalan conjugate (PBR-MEL) was synthesized and evaluated for cytotoxicity and affinity for PBRs. PBR-MEL (9) (i.e., 670 amu) was synthesized by coupling of two key intermediates: 4-[bis(2-chloroethyl)-amino]-L-phenylalanine ethyl ester trifluoroacetate (6) and 1-(3'-carboxylpropyl)-7-chloro-1,3- dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one (8). On the basis of receptor-binding displacement assays in rat brain and glioma cells, 9 had appreciable binding affinity and displaced a prototypical PBR ligand, Ro 5-4864, with IC50 values between 289 and 390 nM. 9 displayed differential cytotoxicity to a variety of rat and human brain tumor cell lines. In some of the cell lines tested including rat and human melphalan-resistant cell lines, 9 demonstrated appreciable cytotoxicity with IC50 values in the micromolar range, lower than that of melphalan alone. The enhanced activity of 9 may reflect increased membrane permeability, increased intracellular retention, or modulation of melphalan's mechanisms of resistance. The combined data support additional studies to determine how 9 may modulate melphalan resistance, its mechanisms of action, and if target selectivity can be achieved in in vivo glioma models.

Animals↗
PubMed1997

False positive images in the follow-up of patients with brain tumors.

In recent years, major advances in the diagnosis and treatment of patients with brain tumors have been seen. Today, evaluation of the central nervous system almost always includes magnetic resonance imaging (MRI). The appearance of a new lesion on the MRI scan of a patient previously treated for a central nervous system (CNS) tumor raises concern for recurrent disease with the need for selection of new, potentially toxic therapy. However, the sensitivity of MRI may allow demonstration of new lesions which are not due to tumor. We now report three patients with medulloblastoma who demonstrated new enhancing lesions on MRI following treatment of their tumors with surgery (3 patients), chemotherapy (2 patients), and radiotherapy (2 patients). Two patients underwent resection of the lesion revealing gliosis. One patient had serial imaging that showed disappearance of the lesions. This suggests that not all new enhancing lesions in previously treated brain tumor patients represent tumor. Histologic proof of a suspicious lesion should be demonstrated prior to initiation of new therapy.

Brain Neoplasms↗
PubMed1997

L-amino acid oxidase (LOX) modulation of melphalan activity against intracranial glioma.

These studies evaluated the efficacy of sequential pretreatment with L-amino acid oxidase (LOX) and LOX antiserum in the modulation of melphalan activity against intracranial glioma in athymic nude mice. LOX produced statistically significant (P < 0.01) depletion of the large neutral amino acids isoleucine, leucine, methionine, phenylalanine, tyrosine, and valine in murine plasma at doses of 100 and 200 micrograms administered intravenously. Polyclonal anti-LOX antibody was successfully produced in mice, rabbits, and goats subsequent to immunization with LOX. Staphylococcal protein A-purified rabbit anti-LOX serum inhibited approximately 50% of LOX activity in vitro relative to control samples. This antiserum was used in vivo to inactivate LOX after it had depleted the large neutral amino acids, thereby preventing LOX-mediated catabolism of melphalan. Inoculation of three mice with rabbit anti-LOX serum after the treatment with LOX (100 micrograms) reduced LOX activity by 100%, 89%, and 100% at 6 h compared with reductions of 80%, 59%, and 52% over the same period in animals receiving LOX alone. In three separate studies using groups of eight to ten mice bearing intracranial human glioma xenografts, pretreatment with LOX followed by anti-LOX serum increased the antitumor activity of melphalan as compared with treatments with melphalan plus LOX, melphalan plus anti-LOX serum, or melphalan alone.

Amino Acid Oxidoreductases↗
PubMed1997

Therapeutic efficacy of the topoisomerase I inhibitor 7-ethyl-10-(4-[1-piperidino]-1-piperidino)-carbonyloxy-camptothecin against pediatric and adult central nervous system tumor xenografts.

Therapy of patients with malignant central nervous system tumors is frequently unsuccessful, reflecting limitations of current surgical, radiotherapeutic, and pharmacotherapeutic treatments. The camptothecin derivative irinotecan (CPT-11) has been shown to possess antitumor activity in phase II trials for patients with carcinoma of the lung, cervix, ovary, colon, or rectum and for patients with non-Hodgkin's lymphoma. The current study was designed to test the efficacy of the drug against a panel of human tumor xenografts derived from adult and pediatric central nervous system malignancies. Tumors included childhood high-grade gliomas (D-212 MG, D-456 MG), adult high-grade gliomas (D-54 MG, D-245 MG), medulloblastomas (D341 Med, D487 Med), ependymomas (D528 EP, D612 EP), and a rhabdomyosarcoma (TE-671), as well as sublines with demonstrated resistance to busulfan (D-456 MG (BR)), cyclophosphamide (TE-671 CR), procarbazine (D-245 MG (PR)) or melphalan (TE-671 MR), growing subcutaneously and intracranially in athymic nude mice. In replicate experiments, CPT-11 was given at a dosage of 40 mg/kg per dose via intraperitoneal injection in 10% dimethylsulfoxide on days 1-5 and 8-12, which is the dosage lethal to 10% of treated animals. CPT-11 produced statistically significant (P < 0.001) growth delays in all subcutaneous xenografts tested, including those resistant to busulfan, cyclophosphamide, procarbazine, and melphalan, with growth delays ranging from 21.3 days in D487 Med to 90+ days in several tumor lines. Further, tumor regression was evident in every treated animal bearing a subcutaneous tumor, with some xenografts yielding complete tumor regression. Statistically significant (P < 0.001) increases in survival were demonstrated in the two intracranial xenografts-D341 EP (73.0% increase) and D-456 MG (114.2% increase)-treated with CPT-11. These studies demonstrate that, of over 40 drugs evaluated in this laboratory, CPT-11 is the most active against central nervous system xenografts and should be advanced to clinical trial as soon as possible.

Adult↗
PubMed1997

Intraarterial O6-benzylguanine enables the specific therapy of nitrosourea-resistant intracranial human glioma xenografts in athymic rats with 1,3-bis(2-chloroethyl)-1-nitrosourea.

The prognosis for patients with malignant gliomas continues to be dismal. The high degree of resistance of gliomas to nitrosourea-based chemotherapy is one major factor in poor treatment outcome. The identification of O6-alkylguanine-DNA alkyltransferase (AGAT) as a major determinant of nitrosourea resistance has resulted in the development of several agents to inactivate this repair protein and counteract tumor cell resistance. However, a major problem in preclinical trials has been the marked nitrosourea dose limitations imposed by the prior administration of AGAT-depleting agents. We investigated the AGAT depletion and selective enhancement of BCNU activity of intraarterial (i.a.) O6-benzylguanine (O6BG) in the human malignant glioma xenograft D-456 MG growing intracranially (i.e.) in athymic rats. Whereas i.a. O6BG at 2.5 mg/kg produced 100% inhibition of D-456 MG AGAT i.e. activity 8 h after administration, intraperitoneal (i.p.) O6BG at this dose produced only 40% inhibition, requiring dose escalation to 10 mg/kg to produce 100% AGAT depletion. Prior administration of i.p. O6BG (10 mg/kg) and i.a. O6BG (2.5 mg/kg) limited maximum tolerated intravenous (i.v.) BCNU doses (37.5 mg/kg when given alone) to 6.25 and 25 mg/kg, respectively. Higher doses of BCNU alone or in combination with O6BG produced histopathologic evidence of cerebral and hepatic toxicity. Therapy experiments revealed a significantly improved median survival for rats treated with O6BG i.a. (2.5 mg/kg) plus BCNU i.v. (25 mg/kg, days 61 and 59 in duplicate experiments) compared with saline (day 21. P = 0.001). O6BG i.a. or i.p. (days 22 and 23, P = 0.001), BCNU i.v. (37.5 mg/kg, day 29, P = 0.001), and O6BG i.p. (10 mg/kg), plus BCNU i.v. (6.25 mg/kg, day 37, P < 0.001). Therefore, O6BG i.a., by virtue of rapid AGAT depletion and selective uptake into i.c. tumors, offers significant potential for regional chemomodulation of AGAT-mediated nitrosourea resistance in malignant human gliomas with concomitant reduction of systemic toxicity.

Alkyl and Aryl Transferases↗
PubMed1997

Characterization of the mechanisms of busulfan resistance in a human glioblastoma multiforme xenograft.

Busulfan is an alkylating agent commonly used in the treatment of chronic myelogenous leukemia and in combination with cyclophosphamide in preparation for allogeneic bone marrow transplantation. Serial treatment of a childhood high-grade glioma xenograft (D-456 MG) with busulfan resulted in a busulfan-resistant xenograft, D-456 MG(BR). Cross-resistance to 1,3-bis(2-chloroethyl)-1-nitrosourea was seen but not resistance to cyclophosphamide or CPT-11. Cytoplasmic levels of glutathione in D-456 MG(BR) were approximately one-half those found in D-456 MG. This depletion could not be explained by levels of glutathione-S-transferase, or by amplification, rearrangement, or increased levels of transcript of gamma-glutamylcysteine synthetase. Furthermore, depletion of glutathione in D-456 MG did not alter busulfan activity. Quantitation of busulfan levels in D-456 MG and D-456 MG(BR) xenografts following treatment of mice at the dose lethal to 10% of the animals demonstrated that significantly lower levels of drug were achieved in D-456 MG(BR). These studies suggest that alterations in drug transport or metabolism of busulfan may play a role in the resistance of D-456 MG(BR) to this alkylator.

Animals↗
PubMed1997

Chromosomal characteristics of childhood brain tumors.

In the present cytogenetic analysis of 116 pediatric brain tumors, chromosomal abnormalities were demonstrated in 44 cases, 48 cases revealed only 46,XX or 46,XY cells, and 24 cases were nonproductive. In contrast to studies of adult brain tumors in which isolated loss of one X or the Y chromosome is often encountered, 45,X,-X and 45,X-Y stemlines or sidelines were not observed in this series of childhood tumors. Among the 17 medulloblastomas with cytogenetic abnormalities, chromosome 1 was most frequently affected by structural deviations; the most prevalent specific alteration (7 of 17 tumors) was loss of 17p, through i(17)(q10) or unbalanced translocation. The majority of low grade astrocytomas had normal stemlines, although one pilocytic astrocytoma and one cerebellar astrocytoma had frequent telomeric associations and a second pilocytic astrocytoma had a clone with trisomy 11. Thirteen of 19 high-grade and recurrent astrocytic tumors had abnormal stemlines that were approximately equally divided among cases with chromosomal counts in the near-diploid, hyperdiploid, and near-triploid-tetraploid ranges. Although no consistent abnormalities were observed, subsets of cases had structural abnormalities of chromosome 3, 7q, 9q, or 17p. The cases of childhood brain tumors described here demonstrate that 45,X,-X, and 45,X,-Y stemlines or sidelines are rare in these tumors and confirm frequent loss of 17p in medulloblastomas. High-grade astrocytic tumors in children frequently have abnormal stemlines, often in the hyperdiploid and polyploid ranges, and they differ from high-grade gliomas in the adult by lacking consistent numerical and structural deviations.

Adolescent↗
PubMed1997

Parental divorce: effects on individual behavior and longevity.

Using an archival prospective design, the authors studied associations among parental divorce occurring during participants' childhood, adult psychosocial mediators, and mortality over the life span of a subgroup of participants (N = 1,261) in the Terman Life Cycle Study (1921-1991). Children from divorced families grew up to show a higher risk of premature mortality across the life span. The higher mortality risk for men was explained, in part, when 3 mediating factors were controlled: Men who had experienced parental divorce were more likely to have their own marriages end in divorce, obtained less education, and engaged in fewer service activities. Women who had experienced parental divorce smoked more and were more likely themselves to divorce, both of which predicted higher mortality risk. The findings extend previous work on the negative sequelae of parental divorce to long-term effects on personality and longevity.

Adolescent↗
PubMed1997

High-dose chemotherapy with autologous stem-cell rescue in patients with recurrent and high-risk pediatric brain tumors.

PURPOSE: We treated 49 patients with recurrent or poor-prognosis CNS malignancies with high-dose chemotherapy regimens followed by autologous marrow rescue with or without peripheral-blood stem-cell augmentation to determine the toxicity of and event-free survival after these regimens. PATIENTS AND METHODS: Nineteen patients had medulloblastomas, 12 had glial tumors, seven had pineoblastomas, five had ependymomas, three had primitive neuroectodermal tumors, two had germ cell tumors, and one had fibrosarcoma. Thirty-seven received chemotherapy with cyclophosphamide 1.5 g/m2 daily x 4 and melphalan 25 to 60 mg/m2 daily x 3. Nine received busulfan 37.5 mg/m2 every 6 hours x 16 and melphalan 180 mg/m2 (n = 7) or 140 mg/m2 (n = 2). Three received carboplatin 700 mg/m2/d on days -7, -5, and -3 and etoposide 500 mg/m2/d on days -6, -4, and -2. All patients received standard supportive care. RESULTS: Eighteen of 49 patients survive event-free 22+ to 55+ months (median, 33+) after transplantation, including nine of 16 treated before recurrence and nine of 33 treated after recurrence. There was one transplant-related death from pulmonary aspergillosis. Of five patients assessable for disease response, one had a partial remission (2 months), one has had stable disease (55+ months), and three showed progression 2, 5, and 8 months after transplantation. CONCLUSION: The toxicity of these regimens was tolerable. Certain patients with high-risk CNS malignancies may benefit from such a treatment approach. Subsequent trials should attempt to determine which patients are most likely to benefit from high-dose chemotherapy with autologous stem-cell rescue.

Adolescent↗
PubMed1997

Malignant supratentorial glial-neuronal neoplasms: report of two cases and review of the literature.

OBJECTIVE: Malignant neoplasms exhibiting mixed populations of neuronal and glial cells occurring in the cerebral hemispheres of young adults and children are well recognized, but rare. A confusing array of diagnostic terms has arisen. We describe two patients with such tumors and review the literature concerning these interesting cases. PATIENTS: A 21-year-old man and a 5-year-old girl presented with large, cystic, intracerebral lesions on magnetic resonance images, which proved to be composite neoplasms exhibiting malignant neurons and astrocytes. RESULTS: The 21-year-old man had a frontal lobe mass with enhancing and nonenhancing regions, which corresponded to cerebral neuroblastoma and anaplastic astrocytoma, respectively. The presence of occasional microtubules and rare primitive presynaptic processes, accompanied by antisynaptophysin immunoreactivity, established the neuronal nature of the cells in the enhancing region. The nonenhancing region was composed of a moderately cellular neoplasm of fibrillar astrocytes that were mitotically active. The 5-year-old girl presented with a left parietal lobe neoplasm, which histologically was composed of lobular proliferations of neuroblasts and glia. The neuroblastic populations exhibited evidence of maturation with small anaplastic cells, spindle-shaped cells, and large dysmorphic ganglion cells. The glial tumor showed both well-differentiated fibrillary astrocytes with microcysts and anaplastic populations with central necrosis and pseudopalisading. CONCLUSIONS: Present classification systems devised to describe mixed neuronal and glial tumors do not adequately encompass the diversity of morphologies presented by these two cases. We conclude that the terms cerebral neuroblastoma-anaplastic astrocytoma for case 1 and cerebral ganglioneuroblastoma-glioblastoma for case 2 are preferred because they convey useful clinical information by reflecting concepts already encompassed by the World Health Organization's classification system of tumors of the central nervous system.

Adult↗
PubMed1996

Zones of atrial vulnerability. Relationships to basic cycle length.

BACKGROUND: Bradycardia is commonly found in individuals at risk for paroxysmal atrial fibrillation (AF). However, a clear relationship between lengthening of basic cyclic length (BCL) and AF has not been demonstrated. METHODS AND RESULTS: In 20 open-chest dogs, atrial refractoriness, AF vulnerability, and atrial activation times (ACTs) were determined in sinus rhythm and at BCLs of 400, 300, and 200 ms, and the findings at the same coupling intervals and stimulus strengths were compared. As BCL increased, AFV zone lengthened, and its outer limit occurred later in diastole. The outer limit of the AF vulnerability zone for a BCL was its relative refractory period; the inner limit, however, was not its effective refractory period. A border zone, defined by the inner limit of the AF vulnerability zone and the effective refractory period for a BCL, decreased as BCL lengthened, offsetting the increase in the AF vulnerability zone. The border zone was characterized by paradoxical stimulus current strength propagation relations and features suggesting supernormal conduction. ACT also increased with BCL lengthening. When AF induced by rapid atrial burst pacing was contrasted with AF induced by an extrastimulus, it tended to have a more disorganized pattern and lasted longer. CONCLUSIONS: Lengthening of BCL increases the AF vulnerability zone, extending its outer limit later in diastole and comprising an increasing component of the total duration of the relative refractory period. Very short BCLs create conditions that also favor AF vulnerability.

Animals↗
PubMed1996

Is there a correlation between duration of presenting symptoms and stage of medulloblastoma at the time of diagnosis?

BACKGROUND: Does a "delay in diagnosis" lead to a child being diagnosed with advanced stage as opposed to early stage medulloblastoma? Correlation between the duration of a patient's presenting symptoms and stage at diagnosis was examined. METHODS: The population consisted of 72 consecutive patients with histologically proven medulloblastoma diagnosed between July 1, 1983 and July 31, 1995. A standard history and physical examination format was used to record the nature and duration of presenting symptoms. Patients were staged by use of the operative findings, pre- and postoperative cranial computed tomography (CT) scans and, later in the series, cranial magnetic resonance imaging (MRI) studies and, for determination of the M stage, myelography, spinal MRI, and postoperative cerebrospinal fluid cytology. RESULTS: There were 40 males (56%) and 32 females (44%) with a mean age of 11.8 years. The most common presenting symptoms were vomiting (67%), headache (60%), ataxia (40%), and nausea (39%). By the Chang-Harisiadis (CH) system, 39 patients (54%) were found to have high stage medulloblastoma (T3b-4M0 or any TM1-4), 27 (38%) had low stage disease (T1-3aM0), and in 6 (8%) the stage could not be fully determined. By the Langston modification of the Change-Harisiadis system (LCH) 38 patients (54%) had high stage, 24 (32%) had low stage, and in 10 (14%) the stage could not be fully determined. Fifty of the 66 patients for whom the duration of symptoms was known (76%) had < or = 3 months of symptoms prior to stage. High CH stage patients had a mean duration of symptoms of 7.4 +/- 6.9 weeks versus 19.5 +/- 22.5 weeks for low stage patients. (P < 0.001). High LCH stage patients had a mean duration of symptoms of 7 +/- 6.6 weeks versus 15.4 +/- 16.4 weeks for low stage patients (P < 0.01). Patients ultimately found to have MO disease were diagnosed more slowly (16.1 +/- 20 weeks) than those with M1 (7.3 +/- 5.3 weeks), M2 (6 +/- 5.3 weeks), or M3 disease (6.8 +/- 5.9 weeks) M0 vs. M1-3, P < 0.02). No patients had M4 disease. Using an alternative definition of high versus low stage (T4M0 or any TM1-4 vs. T1-3bM0) currently under consideration by pediatric oncologists, the duration of symptoms remained significantly longer for low stage disease in the CH system (high vs. low, 7.2 +/- 5.8 weeks vs. 17.5 +/- 19.1 weeks, P < 0.01) but not in the LH system (high vs. low, 10.6 +/- 16.1 weeks vs. 13.9 +/- 15.9 weeks, P not significant). CONCLUSIONS: A short duration of symptoms is associated with the diagnosis of more advanced medulloblastoma. This finding has significant potential implications for the identification of prognostic groups in medulloblastoma as well as medical-legal claims of "delay in diagnosis" and capitated health care issues.

Cerebellar Neoplasms↗