Thrombolytic therapy for acute myocardial infarction: GUSTO criticized.
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Aged↗
Biomedical subjects
H S Friedman
Publications and source records attributed to H S Friedman.
Do non-scientists really live longer?
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Aged↗
Management of pineal non-germinoma germ cell tumor with residual teratoma and normal alpha-fetoprotein.
A 16-year-old white male presented with multiple abnormal extraocular movements secondary to an enhancing pineal tumor. Subtotal resection of the lesion revealed a mixed malignant germ cell tumor. The preoperative serum alpha-fetoprotein (AFP) was markedly elevated at 155 IU/L. The patient subsequently received radiotherapy and adjuvant chemotherapy consisting of cisplatin rotating monthly with vincristine and cyclophosphamide, with dramatic tumor regression and return of AFP to normal. Eighteen months later the persistence of a substantial tumor mass despite a normal AFP raised concern for residual active tumor. Histological examination of the resected lesion revealed benign teratoma and fibrous tissue. Repeat management of mixed malignant germ cell tumors, which demonstrate a persistent mass following an initial response to treatment.
Adolescent↗
Arteriovenous malformation mimicking recurrent medulloblastoma.
Magnetic resonance imaging (MRI) is becoming the method of choice for evaluation of central nervous system tumors. However, the sensitivity of this modality raises concern that new lesions in patients previously diagnosed with a brain tumor may not necessarily represent recurrent disease. We report a patient previously treated with surgery, radiotherapy, and chemotherapy for a medulloblastoma who developed a new lesion in the floor of the fourth ventricle. Histologic review following excision revealed an arteriovenous malformation.
Brain Neoplasms↗
Cerebral atrophy in an infant following treatment with ifosfamide.
Ifosfamide, a nitrogen mustard derived alkylating agent commonly used in the treatment of solid tumors, has been associated with neurotoxicity in 5-33% of treated patients. Encephalopathy most often occurs during or shortly following drug administration, with increased drowsiness or irritability, confusion, hallucinations, visual blurring, extrapyramidal dysfunction, cranial nerve abnormalities, incontinence, generalized muscle twitching, seizures, and coma reported in infants, children, and older adults. While most reported neurologic abnormalities associated with ifosfamide have been reversible, encephalopathy resulting in death has occurred. We now report an infant who developed ifosfamide-induced encephalopathy, loss of developmental milestones, progressive brain atrophy, and cessation of cranial growth. This is the first case of cerebral atrophy and loss of developmental milestones that has been reported in a pediatric patient treated with ifosfamide. Given the efficacy of this anti-neoplastic agent and its increasing use in pediatrics, further investigation is indicated, especially in infants where brain growth is ongoing.
Atrophy↗
Activity of 9-dimethylaminomethyl-10-hydroxycamptothecin against pediatric and adult central nervous system tumor xenografts.
The activity of dimethylaminomethyl-10-hydroxycamptothecin (topotecan) was evaluated against a panel of xenografts derived from ependymomas (D528 EP, D612 EP), childhood high-grade gliomas (D-456 MG, D-212 MG), adult high-grade gliomas (D-245 MG, D-54 MG), and medulloblastomas (D425 Med) growing s.c. and i.c. (intracranially) in athymic nude mice. Topotecan was given at a dose of 1.9 mg/kg by i.p. injection in 0.9% saline using a volume of 90 ml/m2 on days 1-5 and 8-12, which represents the dose lethal to 10% of treated animals. Topotecan was active in the therapy of all s.c. xenografts tested, with growth delays ranging from 6.3 days in D-54 MG to 55.7 days in D528 EP. Topotecan produced statistically significant tumor regressions in D425 Med, D-456 MG, D-245 MG, D528 EP, and D612 EP. No tumor regression was seen in any control animal. Statistically significant increases in median survival were seen in the two i.c. xenografts--D-456 MG (28.6% increase) and D-54 MG (39% increase)--treated with topotecan. These studies suggest that topotecan may be an important new addition to the therapy of central nervous system tumors.
Adult↗
Biodistribution of O6-benzylguanine and its effectiveness against human brain tumor xenografts when given in polyethylene glycol or cremophor-EL.
O6-Benzylguanine effectively inactivates the DNA-repair protein O6-alkylguanine-DNA alkyltransferase in tumor cells and has been shown to increase the cytotoxicity of chloroethylnitrosoureas. This study was undertaken to ascertain the optimal vehicle for further toxicological evaluation and eventual clinical trials of O6-benzylguanine. The solubility, metabolism, bioavailability and effectiveness of O6-benzylguanine as an adjuvant therapy with BCNU were compared using two vehicles, cremophor-EL and PEG 400. Nude mice bearing s.c. D456 MG glioblastoma xenografts were injected i.p. with 10-30 mg/kg O6-benzylguanine dissolved in either 40% PEG 400/saline or 10% cremophor-EL/saline. The number of tumor regressions noted after treatment with 10 mg/kg O6-benzylguanine followed by 12.7 mg/kg BCNU were 8/9 for the drug dissolved in PEG and 1/10 for the drug given in cremophor-EL. Using the same treatment regimen but increasing the dose of O6-benzylguanine to 30 mg/kg led to a growth delay of 45.2 and 11.5 days for the drug dissolved in PEG 400 and cremophor-EL, respectively, although the number of regressions observed were the same for both treatments. 8-[3H]-O6-Benzylguanine was more rapidly distributed to the tumor when it was delivered in PEG vehicle than when it was given in cremophor-EL. In contrast, there was a 3-fold greater amount of O6-benzylguanine in the small intestine of mice at 1 h after i.p. injection of the drug in cremophor-EL as compared with PEG 400. The rate and extent of metabolism in the liver was the same, whether the parent drug was given in PEG 400 or in cremophor-EL. These studies demonstrate that O6-benzylguanine is a more effective enhancer of the antitumor activity of BCNU when it is given in PEG 400 than when it is delivered in cremophor-EL, which may be due to a more rapid distribution of the drug to the tumor.
Adjuvants, Pharmaceutic↗
Busulfan therapy of central nervous system xenografts in athymic mice.
We evaluated the antitumor activity of busulfan against a panel of tumor cell lines and xenografts in athymic nude mice derived from childhood high-grade glioma, adult high-grade glioma, ependymoma, and medulloblastoma. Busulfan displayed similar activity against a panel of four medulloblastoma cell lines (D283 Med, Daoy, D341 Med, and D425 Med) and four corresponding sublines with laboratory-generated or clinically acquired resistance to 4-hydroperoxycyclophosphamide [D283 Med (4-HCR), Daoy (4-HCR), D341 Med (4-HCR), and D458 Med] and cross-resistance to melphalan. This is consistent with a nearly total lack of cross-resistance of busulfan to 4-hydroperoxycyclophosphamide. Busulfan was active in the therapy of all but one of the subcutaneous xenografts tested, with growth delays ranging from 14.3 days in D612 EP to 58.4 days in D528 EP. Busulfan produced statistically significant increases in the median survival of mice bearing intracranial D456 MG (66%-90%), D612 EP (18%-33%), and D528 EP (89%) xenografts. These studies suggest that busulfan may be active against medulloblastomas, high-grade gliomas, and ependymomas as well as against cyclophosphamide-resistant neoplasms.
Animals↗
Hyperfractionated irradiation and concurrent cisplatin in brain stem tumors: a Pediatric Oncology Group pilot study (9139).
A phase I Pediatric Oncology Group Study was performed combining 7,020 cGy hyperfractionated irradiation (117 cGy twice daily separated by 6 h) with increasing concurrent doses of cisplatin given with the intent of radiosensitization as treatment for children with newly diagnosed brain stem tumors. Cisplatin was infused over 120 h on weeks 1, 3, and 5 during a 6-week radiotherapy course. The following cisplatin dose levels were studied: (1) 50 mg/m2/120 h, (2) 75 mg/m2/120 h and (3) 100 mg/m2/120 h. Sixteen of 17 children completed therapy. One child expired after 2 days of treatment secondary to massive intratumoral hemorrhage. At cisplatin dose level 3 (100 mg/m2/120 h), grade 2-4 myelosuppression was encountered in 3 of 5 evaluable patients. Otherwise, no other excessive toxicities, including renal and ototoxicity, were noted.
Adolescent↗
Symptoms of patients with silent ischemia as detected by thallium stress testing.
This study was undertaken to determine whether patients with silent ischemia (SI) (a positive thallium stress test without chest pain) have nonchest-pain symptoms that might serve as "anginal equivalents." Two hundred ninety-four individuals on completing a stress test were requested to score ten symptoms on a questionnaire (0 absent; 3 severe). Forty-three with a positive test had pains (chest, back, arm, and/or jaw) (no SI), whereas 93 with a positive test did not (SI). Patients with SI and patients without SI did not differ as to age, gender, or clinical features (including presence of diabetes or a history of myocardial infarction), but patients with SI were less likely to report a history of effort-related chest pains. Patients with SI exercised longer and had a higher peak heart rate. Patients were comparable with respect to myocardial ischemia (ST segment depression, double product, thallium lung uptake, and positive thallium scintigrams) and severity of coronary disease. Patients with SI complained less of weakness (p < 0.02) and tended to have lower overall symptom scores (4.2 +/- 0.3 vs 5.4 +/- 0.6), but breathlessness was comparable for both groups. On multivariate analysis, no nonanginal symptom was associated with SI. Only absence of a history of chest pain with activity and longer exercise time were related to SI. Patients with SI have similar clinical features as those with angina but tend to be less symptomatic with myocardial ischemia even for symptoms other than chest pain.
Exercise Test↗
Is breast-feeding in infancy associated with adult longevity?
OBJECTIVES: The purpose of the study was to determine whether breast-feeding is associated with increased longevity or cause-specific survival. METHODS: Teachers throughout California identified intellectually gifted children as part of a prospective study begun in the 1920s by Lewis Terman. Information on breast-feeding was available on 1170 subjects, who have been followed for more than 65 years. RESULTS: Survival analysis (Cox proportional hazards model) indicated that breast-feeding was associated with increased longevity, even after adjustment for age at baseline, birthweight, infant health, and childhood socioeconomic status, but only among men, and the association was not significant (P = .15). Neither cardiovascular disease nor cancer survival was significantly associated with duration of breast-feeding for either sex. Survival from deaths due to injuries was positively associated with breast-feeding after adjustment (P = .03) and demonstrated a clear gradient with duration, but only among men. CONCLUSIONS: Overall, the present study does not provide strong evidence that breast-feeding is associated with adult longevity. The reduced risk of death from injury may reflect chance, in that the association was significant only for men, or it may reflect psychosocial correlates of breast-feeding practices.
Aged↗
Final results of a study of escalating doses of hyperfractionated radiotherapy in brain stem tumors in children: a Pediatric Oncology Group study.
PURPOSE: In September 1984, the Pediatric Oncology Group began accrual to a Phase I/II study designed to assess the efficacy and toxicity of sequentially escalated doses of hyperfractionated (twice daily) radiotherapy in children with poor-prognosis brain stem tumors. Pediatric Oncology Group Study #8495 closed in June 1990 with a total of 136 patients on study. We report here the outcome of patients treated at the third and final dose level (75.6 Gy), and compare the results to those obtained at the 66 and 70.2 Gy dose levels. METHODS AND MATERIALS: Patients eligible for study were those between 3 and 21 years of age with previously untreated tumors arising in the midbrain, pons or medulla. Histological confirmation of diagnosis was not mandatory provided that the clinical and radiological findings were typical for brain stem glioma. Treatment consisted of radiotherapy delivered to local fields. At the third dose level, fraction sizes of 1.26 Gy were given twice daily, with a minimum interfraction interval of 6 hr to a dose of 75.6 Gy in 60 fractions over 6 weeks. Between 5/89 and 6/90, 41 patients were accrued to the study. Two were excluded from analysis leaving 39 evaluable patients, 21 male and 19 female, whose ages ranged from 3 to 15 years (median 7.5 years). RESULTS: Following treatment, neurological improvement was reported in 30/39 (77%) of the patients. On central review of imaging studies in 29 patients, one patient was found to have had a complete response to radiotherapy, five a partial (> 50% response), and only three had non-responding or progressive disease. The median time to disease progression was 7 months; median survival time was 10 months; survival at 1 year was 39.9% (SE 8.3%) and at 2 years, 7% (SE 4.8%). The pattern of failure was local in all patients; in addition six had evidence of leptomeningeal seeding. Morbidity of treatment included an enhanced skin reaction (21%), otitis media and/or externa (26%), and steroid use > 3 months (62%). Intralesional necrosis was a frequent finding (45%) on imaging studies performed at a median time of 6 weeks post treatment. CONCLUSION: The results of treatment in terms of progression-free survival and overall survival are not significantly different (at p = .55 and p = .46, respectively) from those obtained at the two previous dose levels. There is no evidence that higher doses of hyperfractionated radiotherapy given as in this study improve the outlook of patients with poor-risk brain stem gliomas.
Adolescent↗
Treatment of acute myocardial infarction.
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Angioplasty, Balloon, Coronary↗
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↗
Chemotherapy for pilocytic astrocytomas.
BACKGROUND: Although pilocytic astrocytomas (PA) generally are considered benign, a subset of patients with PA have disease progression despite standard treatment with surgery and radiation therapy. The authors report their experience with chemotherapy in this patient group. METHODS: The authors treated 11 patients (4 males and 7 females; median age at diagnosis, 8 years) with pathologically confirmed PA with chemotherapy. In eight patients, tumor progression or recurrence despite prior surgery and radiation therapy led to chemotherapy treatment. In three children younger than 5 years, chemotherapy was given in lieu of radiation therapy immediately after diagnosis (in one patient) or at the time of disease progression after surgery (in two patients). The authors used ten different chemotherapy regimens to treat the 11 patients. RESULTS: Chemotherapy produced clinical and radiographic improvement (R/R) in four (36%) patients, clinical stabilization and radiographic improvement (SD/R) in 1 (9%), clinical and radiographic stabilization (SD/SD) in 3 (27%), and was associated with clinical and radiographic progression (PD/PD) in 3 (27%). Three of the five patients with radiographic improvement had a greater than 75% reduction of maximal cross-sectional tumor area. Hematologic toxicity resulted in dose reductions in 43 of 110 (39%) total courses of chemotherapy. There were three hospitals admissions for fever and neutropenia and one chemotherapy-related death. CONCLUSIONS: The authors conclude that chemotherapy may benefit those with progressive inoperable PA. Chemotherapy may delay the need for radiation therapy in young patients with unresectable PA requiring treatment. PA may be a chemosensitive primary brain tumor.
Adolescent↗
Intraarterial therapy of human glioma xenografts in athymic rats using 4-hydroperoxycyclophosphamide.
The addition of chemotherapy, notably using nitrosoureas, in the treatment of patients with glioblastoma multiforme has resulted in only modest improvements in long-term patient survival over the use of surgical intervention and irradiation alone. Intraarterial (i.a.) chemotherapy offers the potential benefit of increasing tumor drug delivery because of first-pass drug uptake, while minimizing systemic drug levels and toxicity. We have now investigated the i.a. therapy of intracerebral human glioma xenografts in athymic rats with 4-hydroperoxycyclophosphamide (4-HC), a preactivated derivative of cyclophosphamide. Athymic male rats were given intracerebral injections of the human glioma line D-54 MG. On Day 5 after injection, the rats were randomized (n = 8-10) by body weight (mean weight, approximately 300 g). In one set of experiments, each group received either i.v. saline, i.a. saline, 6 mg i.a. 4-HC, 6 mg i.v. 4-HC (6 mg), or 12 mg i.v. 4-HC. Intraarterial 4-HC produced significant increases in median survival (Day 24) compared with i.a. saline controls (140% increase), equivalent doses given i.v. (71% increase), and twice the equivalent dose given i.v. (50% increase) (by Wilcoxon rank sum analysis, P < 0.05 is statistically significant). The i.a. maximum tolerated dose was subsequently determined to be approximately 12.5 mg in non-tumor-bearing rats. Further experiments demonstrated a dose-response increase in survival for i.a. dosages of 6, 9, and 12.5 mg with significant improvement when compared with saline controls and 12.5 mg i.v. Pharmacokinetic experiments also demonstrated a significant first-pass uptake advantage for i.a. (versus i.v.) administered 4-HC. The short plasma half-life and marked antiglioma activity of 4-HC, without the need for hepatic activation, suggest a therapeutic application of this drug in the i.a. treatment of brain tumors.
Animals↗
Lactotetraose series ganglioside 3',6'-isoLD1 in tumors of central nervous and other systems in vitro and in vivo.
Two monoclonal antibodies, DMAb-21 and DMAb-22, directed against the lactotetraose series ganglioside-associated epitope IV3NeuAc,III6-NeuAcLcOse4Cer (3',6'-isoLD1), were found to define the minimum binding epitope NeuAc(or NeuGc)alpha 2-3Gal beta 1-3(NeuAc or NeuGc)alpha 2-6GlcNAc. The distribution of 3',6'-isoLD1 in cultured cell lines and derived xenografts of primary tumors of the human central nervous system and of embryonal or neuroectodermal tumor derivation was determined. Only 4 of 26 cell lines, 3 teratomas and 1 pancreatic adenocarcinoma, expressed detectable 3',6'-isoLD1 when cultured in vitro; none of 14 tested glioma lines, including 2 that expressed the monosialo-precursor IV3NeuAcLcOse4Cer in vitro, expressed detectable levels. Expression of 3',6'-isoLD1 was more frequent when neoplastic cells were grown in xenograft form in athymic mice; 4 of 10 glioma and 2 of 2 teratoma xenograft ganglioside extracts were positive for 3',6'-isoLD1. The absence of 3',6'-isoLD1 in cultured tumor cells of the central nervous system and its proportional increased presence in tumor cells of the same origin grown in vivo further supports previous studies suggesting that ganglioside expression may be modified by environmental forces. The expression of lacto series gangliosides both in vitro and in vivo by teratoma and pancreatic adenocarcinoma cells, as opposed to only in vivo expression by glioma cells, suggests that tissue-specific forces may also exist. Immunohistochemical localization of 3',6'-isoLD1 in frozen sections of primary central nervous system neoplasms including those of glial and nonglial origin was performed; 20 of 30 (67%) of glial tumors were positive. Among nonglial tumors, 21 of 34 (62%) of epithelial cancers were reactive with anti-3',6'-isoLD1 monoclonal antibodies; notably negative were carcinomas of the ovary and lung carcinomas of all subtypes. Lymphomas and infiltrative lymphocytes were uniformly negative. The restriction of 3',6'-isoLD1 expression within the human central nervous system to periods of fetal-neonatal astroglial proliferation, to intense reactive astrocytosis, and to primary neoplasms, and the production of specific monoclonal antibodies to this epitope provide a specific complex for immunolocalization and, eventually, immunotherapy.
Animals↗
Comparison of serial PET and MRI scans in a pediatric patient with a brainstem glioma.
Profound clinical deficits may be associated with insults to the brainstem, making management of patients with brainstem gliomas very complex. Small changes in the radiographic appearance of a brainstem tumor may be associated with significant clinical deterioration. Furthermore, both magnetic resonance imaging and computed tomography are frequently unable to differentiate between therapy-related tissue reactions and progressive tumor. Two clinical scenarios particularly difficult to resolve include: (1) transient radiographic and clinical deterioration following hyperfractionated radiotherapy, and (2) clinical deterioration in a patient who has failed initial therapy, but has stable radiographic findings following a second therapy. We report a child with a pontine glioma whose tumor progression was demonstrated more convincingly with a 18F-deoxyglucose positron emission scan than with magnetic resonance imaging. PET scans may be helpful in confirming that tumor progression is responsible for clinical deterioration in a patient whose MRI scans remain stable.
Brain Neoplasms↗