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Biomedical subjects

J C Allen

Publications and source records attributed to J C Allen.

At least 163 records · Page 9Linked to original sources
PubMed1987

PCNU and recurrent childhood brain tumors.

PCNU, the latest nitrosourea analogue to be subjected to clinical trials, held promise as a superior chemotherapy agent for brain tumors because of more favorable biochemical and cytotoxic characteristics in laboratory studies. Thirty-nine children with a variety of recurrent primary CNS tumors, all of whom had evaluable disease, participated in a phase II PCNU trial. Their mean age was 9.7 (3-20) years. PCNU was administered as a 2 hour intravenous infusion in one of 2 dose schedules at 6-7 week intervals; 100-125 mg/m2 for minimally treated patients and 70-90 mg/m2 for heavily treated patients. Response was assessed after 2 courses of chemotherapy after attempting to taper the steroid dose. The overall objective response rate was 18% (7/39) for a mean of 5.9 months (2+ -12). Only partial responses were observed. Disease-specific responses rates were: brainstem glioma--18% (3/17); cerebral glioma--27% (3/12); ependymoma--1/1; and primitive neuroectodermal tumors--(0/9) including 5 medulloblastomas, 2 pineoblastomas and 3 cerebral primitive neuroectodermal tumors. Toxicity was primarily hematologic and clinically significant thrombocytopenia (less than 50,000 mm3) was encountered in 30/38 (79%) patient trials. Modest activity of PCNU in recurrent childhood gliomas is confirmed. Our response rates, using objective CT criteria, are somewhat lower than those reported for BCNU and CCNU. Because of comparable hematologic toxicity and efficacy, intravenous PCNU does not appear to offer a clinical advantage to existing nitrosoureas for children with recurrent brain tumors using a 2 hour intravenous infusion schedule.

Adolescent↗
PubMed1987

Primary intracranial rhabdomyosarcoma: case report and review of the literature.

Invasion of the meninges is a relatively common complication of head and neck rhabdomyosarcoma (RMS), while RMS arising primarily within the brain or meninges is rare. We report the case of an 11-year old child with a primary "primitive" frontal lobe tumor, subsequent leptomeningeal spread and fatal intratumoral hemorrhage; the diagnosis of RMS was discovered only at postmortem examination. The literature contains a total of 34 reported cases of primary intracranial RMS. This tumor has been observed to arise in a variety of central nervous system (CNS) locations in patients of all ages, but most commonly within the posterior fossa of children. Leptomeningeal dissemination and spontaneous intratumoral hemorrhage are important clinical features. Postoperative chemotherapy and craniospinal radiation may improve the anticipated poor prognosis of patients treated with surgery and radiation alone. The diagnosis of RMS may be missed unless electron microscopic and specific immunohistochemical studies are applied to "undifferentiated" or "primitive" CNS tumors.

Brain Neoplasms↗
PubMed1987

A competitive immunosorbent assay for detection of Pseudomonas pseudomallei exotoxin.

The development of monoclonal antibody and enzyme-linked immunosorbent assay (ELISA) techniques has made possible the detection of specific antigens at extremely low concentrations. Diagnosis of recalcitrant diseases such as melioidosis depends upon either early isolation and identification of the causative organism or the identification of a specific marker antigen, Pseudomonas pseudomallei exotoxin, in serum; the latter is better because it allows more rapid and simple diagnosis. A method of detecting exotoxin concentrations of greater than 16 ng/ml by an ELISA based on a monoclonal antitoxin is here described; it is significantly more sensitive than the mouse lethality test (lower threshold 30 micrograms/ml) currently in use and an in-vitro cytotoxicity test (lower threshold 10 micrograms/ml) that we have developed and describe here.

Animals↗
PubMed1987

Management of primary intracranial germ cell tumors of childhood.

Primary CNS germ cell tumors present several biologic and therapeutic concerns. Their predilection to midline locations (pineal and suprasellar) has discouraged until recently attempts at biopsy, much less radical surgical resection. Their heterogeneity (germinomas, embryonal carcinoma, endodermal sinus tumor, choriocarcinoma and malignant teratoma) has made uniform treatment planning unrealistic. Their rarity (less than 50 cases per year in USA) precludes a large institutional experience. More recently, with the use of microsurgical techniques, major resections are possible and accurate pretreatment histologic diagnosis can be established. Following surgery, patients should be staged with cerebrospinal fluid (CSF) cytology, serum and CSF tumor markers (alpha-fetoprotein and human beta-chorionic gonadotrophin) and myelography. The majority of patients will present with disseminated disease and require craniospinal radiotherapy. Chemotherapy should eventually prove to be an effective adjuvant treatment modality, not only for the highly radiosensitive germinoma with a good prognosis (5-year survival greater than 60%) following radiotherapy alone, but also for the radioinsensitive nongerminoma germ cell variants where longterm survival is unusual. Chemotherapy agents such as cyclophosphamide, cisplatin, vinblastine, VP-16 and bleomycin appear to be useful for patients with newly diagnosed and recurrent disease.

Adolescent↗
PubMed1987

Carboplatin and recurrent childhood brain tumors.

Carboplatin, a cisplatin analogue, was administered as an intravenous (IV) one-hour infusion in a 4-consecutive weekly dose schedule to 44 patients with recurrent childhood brain tumors. Twenty-four patients were registered on our phase I, and 20 on our phase II studies. The maximum tolerable dose derived from our phase I study was 210 mg/m2/wk in patients with solid tumors, and the recommended dose for subsequent pediatric phase II studies was 175 mg/m2/wk. This dose was administered to 14 patients in the phase I and all 20 patients in the phase II study. Nine of 36 (25%) evaluable patients in the combined studies experienced objective responses for a median duration of 10+ months. Seven of nine responders had received prior cisplatin. Disease-specific response rates were as follows: medulloblastoma, six of 14 (43%) with three complete (CR) and three partial responses (PR); pineoblastoma, one of one (PR); germinoma, one of two (CR); and brainstem glioma, one of eight (13%) (PR). Carboplatin had mild emetic effects but no significant auditory or renal toxicity. Thrombocytopenia (less than 49,000) was encountered in nine of 28 (32%) evaluable trials at a dose of 175 mg/m2/wk. Because of its low potential for auditory, renal, and emetic toxicity, ease of administration, and high disease-specific activity, carboplatin deserves further study in multiagent phase II and III trials, especially in chemotherapy-sensitive diseases such as medulloblastoma.

Adolescent↗
PubMed1987

Neoadjuvant chemotherapy for newly diagnosed germ-cell tumors of the central nervous system.

A neoadjuvant (preradiotherapy) chemotherapy regimen consisting of either cyclophosphamide alone (60 to 80 mg/kg) or a modified multidrug regimen (vinblastine, bleomycin, cyclophosphamide, and cisplatin) was administered to 15 newly diagnosed patients with histologically confirmed, fully staged, primary germ-cell tumors (GCT's) of the central nervous system (CNS). There were 11 patients with germinomas and four with non-germinoma malignant GCT's. There were six females and nine males, whose median age was 13 years (range 4 months to 24 years). Seven germinoma patients (64%) had disseminated disease. For the germinoma patients, the subsequent radiotherapy dose was modified based on the response to the neoadjuvant chemotherapy, and craniospinal radiotherapy was given only to those with disseminated CNS disease at diagnosis. Ten of the 11 germinoma patients had complete disappearance of all evaluable disease after two courses of chemotherapy (cyclophosphamide in eight and multidrug in three) and one had a partial response. The planned dose of radiotherapy to the primary tumor was reduced from 5500 to 3000 rads, and the craniospinal dose was lowered from 3600 to 2000 rads. Ten patients remain in continuous disease-free remission 20+ to 89+ months after diagnosis (median follow-up period 47 months). All four patients with non-germinoma GCT's received the multidrug regimen, and two fo three patients with evaluable disease had a partial response. High-dose regional and craniospinal radiotherapy was administered thereafter, but only two patients remain in their first remission. Previously untreated germinoma is a highly chemosensitive disease and the neoadjuvant treatment strategy permits the identification of active chemotherapy regimens in newly diagnosed patients. Patients who have complete responses to neoadjuvant chemotherapy tolerate a significant radiotherapy dose reduction without compromising long-term survival, thereby allowing a reduction of some of the late effects of therapeutic radiation. Germinomas tend to disseminate early in the course of the disease and a pre-therapy staging evaluation permits individualized radiotherapy treatment planning.

Adolescent↗
PubMed1987

Growth hormone response to GRF 1-44 in children following cranial irradiation for central nervous system tumors.

The growth hormone (GH) responses to (A) GRF 1-44, 1 microgram/kg i.v., (B) L-dopa and either arginine, insulin, or glucagon, and (C) exercise were evaluated in 10 children (3 girls, 7 boys; ages 10 years to 15 years, 8 months), 2-10.75 years following cranial irradiation for medulloblastoma (8 patients), pineoblastoma (1 patient), and a fourth ventricular ependymoma (1 patient). Nine of the 10 children had abnormal growth rates. All children were euthyroid at the time of the study. The mean 0-60-min peak GH response to GRF (10.06 +/- 2.6 ng/ml) in the patients was less than the mean peak GH response (29 +/- 2.3 ng/ml) in the control children (n = 7). In 6 patients (5 with poor growth rates), a decreased GH response was noted to GRF and all other tests. Of the remaining patients, all with poor growth rates, two patients demonstrated an adequate response to GRF and pharmacologic testing; one patient had a normal GH response to GRF with a low GH response to pharmacologic testing; and one patient had a low response to GRF, despite a normal response to both exercise and pharmacologic testing. The decrease in mean peak GH response to GRF in the patient population confirms that radiation to the hypothalamic-pituitary region produces abnormalities in growth hormone release. Furthermore, in these patients, discordant GH responses to GRF and pharmacologic or physiologic tests can be observed. The abnormality in growth hormone release may result from a hypothalamic dysfunction in GRF release and/or damage to GH secretory pituicytes.

Adolescent↗
PubMed1986

Acute high-dose methotrexate neurotoxicity in the rat.

Intravenous high-dose methotrexate chemotherapy may produce acute, subacute, or chronic neurotoxicity in patients with cancer. Acute encephalopathies following high-dose methotrexate treatment are recognized with increasing frequency. This study describes a model of acute high-dose methotrexate neurotoxicity in the rat characterized by a profound dose-dependent depression of cerebral glucose metabolism in association with behavioral and electroencephalographic abnormalities. Alterations in the amino acid profile, similar to those described in cancer patients after high-dose methotrexate treatment, were observed in the absence of biochemical evidence of systemic organ toxicity. This model facilitates the study of the biochemical mechanisms of antifolate neurotoxicity in humans and permits the evaluation of potential therapeutic interventions.

Amino Acids↗
PubMed1986

Long-term endocrine sequelae after treatment of medulloblastoma: prospective study of growth and thyroid function.

Endocrine evaluations were performed prospectively in 22 patients with medulloblastoma (ages 2 1/2 to 23 1/2 years at diagnosis), after craniospinal radiation with or without adjuvant chemotherapy. The mean craniospinal hypothalamic-pituitary). and thyroid radiation doses were 3600 and 2400 rads, respectively. Fourteen (73%) of 19 patients who had not yet completed their growth experienced a decrease in growth velocity. However, only three of 10 of these children, who underwent growth hormone stimulation tests, had evidence of deficient growth hormone responses, suggesting that growth hormone secretory or regulatory dysfunction, rather than absolute growth hormone deficiency, is present in the majority of these children. Elevated thyroid-stimulating hormone levels were noted in 15 of 22 patients; one patient had hypothalamic hypothyroidism. Thus, the late effects of therapy for medulloblastoma include frequent endocrine morbidity involving hypothalamic-pituitary and thyroid dysfunction.

Adolescent↗
PubMed1986

Na+-K+-ATPase in vascular smooth muscle.

Na+-K+-ATPase has been isolated and characterized from canine aortic tissue. The ouabain-sensitive enzyme activity was 24 mumol X mg protein-1 X h-1, and the remaining Mg2+-ATPase activity was 54 mumol X mg protein-1 X h-1. The ratio of Na+-K+-ATPase to ouabain-sensitive K+-phosphatase was 13 to 1, similar to other more homogeneous preparations from other tissues. The dissociation characteristics of the enzyme-glycoside complex of this aortic preparation were the same as for cardiac preparations in that it was stabilized by K+. These data suggest that the nature of both the ATP hydrolytic site of Na+-K+-ATPase and the ouabain binding site are the same in preparations from vascular smooth muscle as in preparations from other tissues.

Alkaline Phosphatase↗
PubMed1986

Comparison of ouabain-sensitive 86Rb uptake of canine renal and femoral arteries.

We have previously reported that various manifestations of the Na+ pump, such as ouabain binding, Na+-K+-ATPase, and 86Rb uptake, were similar in canine renal and femoral arteries [R.D. Bukoski, C.L. Seidel, and J.C. Allen. Am. J. Physiol. 245 (Heart Circ. Physiol. 14): H604-H609, 1983.]. In this report we compare ouabain-sensitive 86Rb uptake in renal and femoral arteries under two selected conditions of intracellular Na+:low Na+ and Na+ loaded. When intracellular Na+ was low, the renal artery dissociation constant for Rb+ was 1.13 mM compared with the Na+-loaded condition of 2.49 mM. The femoral artery dissociation constant remained the same at both Na+ levels. The maximal rate of 86Rb uptake (Vmax) of the renal artery was the same at both Na+ levels, but the femoral artery Vmax was 23.6 and 11.11 nmol X mg-1 X 20 min-1 in Na+-loaded and low-Na+ vessels, respectively. The reason for the difference in Na+ pump regulation in these two vessels is not clear, but these results suggest that there are heterogeneous mechanisms for controlling ionic movements in vascular smooth muscle.

Animals↗
PubMed1986

Na+-H+ exchange is present in sarcolemmal vesicles from dog superior mesenteric artery.

The Na+ concentration inside vascular smooth muscle cells is an important regulator of vascular smooth muscle function, but the mechanisms that mediate Na+ influx are not known. We studied Na+ transport in a newly described vesicle preparation preferentially enriched in sarcolemma and obtained by Mg2+ aggregation and differential centrifugation of homogenized dog superior mesenteric artery. In the presence of an outwardly directed proton gradient (pHout = 7.5, pHin = 5.0), 1 mM 22Na+ uptake was stimulated over twofold relative to the absence of a pH gradient (pHin = 7.5 or 5.0). pH gradient-stimulated Na+ uptake was inhibited by 1 mM amiloride. 22Na efflux was stimulated by an inwardly directed proton gradient (pHin = 7.5, pHout = 5.7 vs. 7.5). The rate of proton efflux from acid-loaded vesicles was measured by acridine orange fluorescence and was stimulated by 100 mM Naout but not by Nain = Naout = 100 mM. H+ gradient-stimulated Na+ transport and Na+ gradient-stimulated H+ transport were not due to electrical coupling between the two cations. The pH gradient-stimulated component of Na+ transport in the final vesicles, an intermediate fraction, and microsomes were proportional to the respective enzyme marker activities for sarcolemma but not for sarcoplasmic reticulum or mitochondrial membranes. We conclude that Mg2+ aggregation and differential centrifugation of homogenized vascular smooth muscle yield a vesicle preparation preferentially enriched in sarcolemma. Furthermore, the sarcolemma of vascular smooth muscle contains an amiloride-sensitive Na+-H+ proton countertransport system.

Animals↗
PubMed1986

Transient cerebral dysfunction secondary to high-dose methotrexate.

A transient acute neurologic syndrome occurred in 22 patients receiving high-dose methotrexate (HDMTX) (8 to 9 g/m2) for a variety of malignancies. The neurologic signs were similar in all cases. The syndrome occurred an average of six days after the second or third weekly treatment. Common findings included behavioral abnormalities, focal sensorimotor signs, and abnormal reflexes. Signs often alternated from one side to the other. Evaluations including computed tomography (CT) scan, lumbar puncture, hemogram, and blood chemistry were normal. The EEG revealed some slowing in all cases. The cause of this syndrome is unknown. It is transient and usually does not recur. Its appearance does not preclude further treatment with HDMTX.

Adolescent↗
PubMed1985

Tumor staging for pineal region tumors of childhood.

The central midline location of the pineal gland, its intricate contact with cerebrospinal fluid pathways, and the generally large size of tumors in this area before they produce symptoms raise problems in the use of TNM classification. Biopsy was performed on 30 consecutive pineal region tumors seen in children detected over an 8-year period. The pathologic features did not conform to previous autopsy data. Germinomas comprised only 7% of tumors, whereas 23% were malignant germ cell tumors. Neither computerized tomography, magnetic resonance imaging scan, nor markers were shown to be diagnostic of pathologic type. It was concluded that the significant factors affecting outcome are tumor cell type and presence or absence or mitoses. Surgical biopsy is recommended for all pineal region tumors in children. At the current time, the data base is insufficient to devise a staging classification specific for pineal region tumors and the TNM system appears largely inappropriate. Thus, it is reasonable to develop a data base for tumors of this region that then may lead to a specific staging system.

Brain Neoplasms↗
PubMed1985

The design and conduct of clinical trials in childhood brain tumors.

The orderly conduct of clinical research trials in pediatric oncology has laid the foundation for modern curative therapy in several childhood malignancies. Such types of large clinical trials are relatively new to pediatric neuro-oncology. New treatments such as single and combination chemotherapy agents are studied in a Phase II trial in children with specific recurrent primary brain tumors. Computerized tomography (CT) and magnetic resonance imaging (MRI) scans and myelography allow the accurate determination of objective responses. The relative lack of promising Phase II trials has hampered the design of new Phase III studies for a variety of primary childhood brain tumors. The results of several Phase II trials may be incorporated into a prospective randomized Phase III study in which the endpoint is disease-free survival rather than response rate. Because of the rarity of specific types of primary childhood brain tumors, randomized Phase III trials are conducted more easily by cooperative cancer study groups. This article suggests some guidelines for the conduct of these Phase II and III trials in children with primary brain tumors so that accurate data may be accrued in an efficient manner.

Antineoplastic Agents↗
PubMed1985

Development of the trochlear nucleus in quail and comparative study of the trochlear nucleus, nerve, and innervation of the superior oblique muscle in quail, chick, and duck.

The present study was undertaken to examine the development of the trochlear nucleus in quail and to compare the mature trochlear nucleus, nerve, and their sole target of innervation, the superior oblique muscle, in quail, chick, and duck. Study of the trochlear nucleus in quail from embryonic day 5 through hatching shows a maximum of 1,248 neurons on embryonic day 10 followed by spontaneous degeneration of 40% of the neurons between days 10 and 16. Previous studies have shown that although the initial and final number of neurons is different in chick and duck, the magnitude of trochlear cell loss in both species is about 40%. This study shows the average number of neurons in the nucleus of quail, chick, and duck, 2 weeks post-hatching, to be 658, 743 and 1,459, respectively. Fiber counts in the trochlear nerve from electron micrograph montages at the same period indicated a ratio of about 1:1 between neurons and axons. While a majority of the fibers in these nerves are myelinated, an average of 3-6% of the fibers are unmyelinated. The nucleus in the quail not only contains the smallest number of neurons but it also innervates the smallest muscle in terms of total number of muscle cells and endplates. However, the opposite relationship does not hold true. The nucleus in duck contains the largest number of neurons, yet the largest number of muscle cells and endplates were found in the chick. The ratios between the neurons and muscle cells as well as between neurons and endplates are about the same in quail and duck. These ratios are much higher in the chick, reflecting the relatively small neuron pool destined for a relatively large target. In spite of variations in the number of neurons, muscle fibers, and endplates the average number of endplates per muscle fiber is relatively constant among the three species.

Animals↗