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Biomedical subjects

A I Freeman

Publications and source records attributed to A I Freeman.

At least 55 records · Page 3Linked to original sources
PubMed1982

Pharmacokinetics of methotrexate following intravenous and intraventricular administration in acute lymphocytic leukemia and non-Hodgkin's lymphoma.

A pharmacokinetic study of methotrexate (MTX) administered by the intravenous (IV) and intraventricular (via an Ommaya reservoir) route was performed in 16 children, 13 with acute lymphocytic leukemia (ALL) and three with non-Hodgkin's lymphoma. Five children with ALL were treated "prophylactically" for presumed subclinical central nervous system (CNS) leukemia. The remaining 11 patients were treated for overt meningeal involvement. MTX was administered intravenously at a dose of either 500 mg/m2 or 1500 mg/m2 with one third by rapid intravenous infusion and two thirds intravenously over 24 hours with leucovorin rescue. Intraventricular MTX was given in some treatment courses at a dose of 12 mg/m2. At either 500 mg/m2 or 1500 mg/m2, when given only IV, MTX results in a 100 fold higher concentration in plasma compared to cerebrospinal fluid (CSF). The plasma levels are three times higher with the 1500 mg/m2 dose compared to the 500 mg/m2 dose. After intraventricular administration of MTX, patients with overt CNS leukemia retained MTX in the CSF significantly longer than patients treated prophylactically. This may be due to abnormal transport of MTX out of the CSF in patients with meningeal disease.

Adolescent↗
PubMed1982

The use of subcutaneous cerebrospinal fluid reservoirs for the prevention and treatment of meningeal relapse of acute lymphoblastic leukemia.

Subcutaneous cerebrospinal fluid reservoirs (Ommaya) were placed in 27 children and adolescents with acute lymphoblastic leukemia. Eleven of the reservoirs were used for administration of preventive central nervous system therapy and the remaining 16 reservoirs were used in the management of overt meningeal leukemia. Seven of the 11 patients treated prophylactically had recurrence of leukemia. The first site of recurrence was the central nervous system in three (42%) cases. Four of the 16 patients with reservoirs placed for the treatment of overt meningeal leukemia have not had recurrent disease. Of the 12 patients who relapsed, the site of first recurrence was the central nervous system in five cases. The incidence of major complications was 26%.

Adolescent↗
PubMed1981

Severe hypertension in a child with ganglioneuroblastoma.

A 26-month-old boy with Stage III abdominal ganglioneuroblastoma had tachycardia and hypertension. The hypertension increased following the institution of chemotherapy and necessitated the use of both alpha and beta adrenergic blocking agents to control the effects of the marked catecholamine production. After excision of the residual tumor, the blood pressure and urinary catecholamine excretion returned to normal. Histologic examination of this tissue under light microscopy revealed some sections of ganglioneuroblastoma as well as large areas of ganglioneuroma. Examination by electron microscopy demonstrated a moderate number of dense core neurosecretory-type granules in the cell bodies of the ganglion-like cells and an abundance of the same type of granules in the bundles of the interwoven cytoplasmic neural processes. To data, 32 months after diagnosis and 20 months off chemotherapy, the patient remains free of tumor and is in excellent general health. We postulate that the large number of secretory granules in this tumor permitted storage and release of markedly increased quantities of norepinephrine and resulted in a clinical profile similar to that associated with pheochromocytoma.

Abdominal Neoplasms↗
PubMed1981

Adjuvant adriamycin and cis-diamminedichloroplatinum (cis-platinum) in primary osteosarcoma.

Twelve consecutive patients with osteosarcoma who were without evidence of metastases were treated with Adriamycin and cis-platinum in an adjuvant fashion. The primary lesion was in the distal femur in five patients, proximal tibia in three, and one each in the proximal femur, proximal humerus, sacrum, and a previously irradiated orbit. Surgery consisted of amputation in eight, limb-salvage procedures in two, and regional resections in the patients with orbital and sacral lesions. Postoperatively, Adriamycin at 30 mg/m2/d, for three days alternated every three weeks with cis-platinum, 100 mg/m2, once daily or 60 mg/m2/d, for two days i.v. drip forced i.v. fluid diuresis. Adriamycin was given to a total dose of 540 mg/m2. Ten of 12 patients remain continually disease-free with a median time on study of 23+ months (range 12+-41+ months). Local recurrences, without evidence of metastatic disease, occurred in the patient with the orbital lesion and the patient who underwent the regional resection for the lesion of the proximal humerus at 20 and 17 months from diagnosis, respectively. Nine patients are off all chemotherapy from 6+ to 33+ months (median 22+ months). Administration of cis-platinum was limited to eight courses because of renal and ototoxicity. Despite appreciable toxicity, this chemotherapeutic regimen appears to be a highly effective adjuvant in the management of primary nonmetastatic osteosarcoma.

Adolescent↗
PubMed1981

Gonadal function in pediatric patients following treatment for Hodgkin disease.

Gonadal function was assessed by determination of the serum levels of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) in 24 children and adolescents 6-98 months after completion of treatment for Hodgkin disease that included pelvic irradiation and/or combination chemotherapy. Four of the five women and six of the nine men who received pelvic irradiation had elevations of serum FSH. Nine of these patients with an elevated FSH received combination chemotherapy in addition to pelvic irradiation. Five of seven males who received combination chemotherapy but no pelvic irradiation and were postpubertal at the time of evaluation had an elevated FSH level. Three of these five were prepubertal at the time of treatment. These results suggest that gonadal dysfunction occurred frequently among children and adolescents following treatment that included combination chemotherapy for Hodgkin disease.

Adolescent↗
PubMed1981

Efficacy of amikacin and ticarcillin as empiric therapy in febrile neutropenic children with cancer.

Amikacin (600 mg/M2/day IV) and ticarcillin (12 gm/m2/day IV) were administered to 38 children with cancer, neutropenia (less than 1,000 PMN/mm3), and fever (greater than or equal to 38 degrees C) during 46 febrile episodes. Sixty-one percent of the children were severely neutropenic (less than 200 PMN/mm3). Febrile episodes consisted of 15 documented (E coli 5, K pneumoniae and P aeruginosa 1, P. Aeruginosa 1, S marcescens 1, S aureus 4, S epidermidis 1, S viridans 1, adenovirus 1), 13 clinically apparent, nine possible, and nine doubtful infections. Efficacy of amikacin and ticarcillin was not determined in persons with gram-positive, viral, and doubtful infections. Amikacin and ticarcillin were administered from 3 to 13 days (mean 7.3 days). Peak serum concentrations of amikacin on days two and five of treatment ranged between 13 and 35 microgram/ml; trough levels remained below 2 microgram/ml in 92% of the samples. Eighty-six percent of evaluable febrile episodes improved and 14% were unchanged. Among eight infections due to gram-negative enteric bacilli, six were cured (75%), and two (25%) improved temporarily. The excellent results observed in this study may be attributed, in part, to the predictably high serum concentrations of amikacin which exceeded the MICs of seven of eight gram-negative pathogens. Renal toxicity was not observed. Two children (9.5%) developed mild, transient, unilateral hearing losses. These data suggest that the combination of amikacin and ticarcillin is an effective and safe empiric regimen in febrile children with cancer.

Adolescent↗
PubMed1981

The treatment of primary childhood acute lymphocytic leukemia with intermediate dose methotrexate.

Fifty-four consecutive children with acute lymphocytic leukemia (ALL) were treated from August 1974 until December of 1976 at Rosewell Park Memorial Institute (RPMI) according to a protocol which substituted cranial irradiation with systemic intermediate dose methotrexate (IDM) 500 mg/m2 each 3 weeks for a total of 3 courses immediately following induction. Of 54 patients, 52 went into remission (96%). There were 35 standard risk and 17 increased risk patients according to age and presenting white blood count (WBC). As of September 1979 9 of the 35 standard risk patients had relapsed: (five central nervous system (CNS), three systemic, and one testicular. The overall disease control is comparable to other published methods of therapy involving cranial irradiation but has the added advantage of not exposing these children to the long range side effects currently being observed in children who had previously been treated with prophylactic cranial irradiation.

Adolescent↗
PubMed1981

Interferon production and lymphocyte transformation in lymphocytes of leukemic patients.

The high incidence of viral infections in patients with lymphocytic leukemia is well documented, but the role played by interferon in the pathogenesis of such infections is not known. In this study, we investigated the possibility that gamma (gamma) interferon production, induced by phytohemagglutinin (PHA) might be impaired in leukocytes from patients with acute lymphocytic leukemia (ALL). We also compared this response with alpha (alpha) interferon production, and with PHA-stimulated lymphocyte transformation. We have shown that the gamma interferon response of leukocytes from patients, both in relapse and in remission, was markedly lower than in leukocytes from normal donors. However, the alpha interferon response in leukocytes from the patients was normal. In contrast the defective gamma interferon response to PHA stimulation of cells from patients in remission, lymphocyte transformation by PHA was normal. Lymphocytes from patients in relapse has a delayed response. Our findings suggest (1) that the defective gamma interferon response which occurs in cells from patients with ALL, both in relapse and remission, contributes to increased susceptibility to viral infections, (2) that alpha interferon may not be the optimal type of interferon for treatment of certain viral infections, and (3) that different triggering mechanisms, or different receptors, exist for PHA-induced gamma interferon production and for lymphocyte transformation in cells of patients with ALL.

Adolescent↗
PubMed1981

Prevention of varicella zoster (VZ) with poly(I) . poly(C) given during the incubation period.

Poly I . Poly C (Poly I:C) was administered to six children with cancer who were exposed to varicella zoster (VZ) and who were under active treatment to determine if this agent could prevent the development of overt varicella zoster (chickenpox). Poly I:C was administered as a single injection during the incubation period, but beyond 72 hours, since zoster immunoglobulin (ZIG) is a proven effective agent in the first 72 hours. None of these patients had a prior history of VZ and neither ZIG nor any other known antiviral agent was administered to these patients. None of the children developed chickenpox. This appears significant but awaits confirmation in a larger control study.

Antibodies, Viral↗
PubMed1981

Effect of leukemia and methotrexate on digestive enzymes in the jejunum of mice.

A leukemic mouse model was employed to elucidate the separate effect of leukemia and cytotoxic drugs on the jejunal mucosa and its associated digestive enzymes. The mitotic activity, depth of the crypt and villus-crypt quotient were not significantly changed in leukemic mice in comparison to normal mice. The mitotic activity and the depth of the crypt 48 h after 20 mg methotrexate (MTX)/kg were significantly reduced (p less than 0.01) in leukemic mice. Sucrase (p less than 0.001) and maltase (p less than 0.025) activities in the jejunum from leukemic mice were significantly elevated in comparison with non-leukemic controls. In both non-leukemic and leukemic mice, the dose-response curves for MTX administration revealed a significant decrease and a nadir in sucrase (p less than 0.001) and maltase (p less than 0.0025) activities at the dosage of 20 mg/kg. Thus, in the mouse model, leukemia per se does not contribute to significant diminution in small intestinal function. In the small intestine, MTX appears to be responsible for a decrease in the mitotic activity of crypt cells, depth of the crypt and diminished sucrase and maltase activities.

Alkaline Phosphatase↗
PubMed1981

Primitive neuroectodermal tumors of childhood. An approach to therapy.

Primitive neuroectodermal tumors are found in the cerebrum of children and young adults. The are clinically highly malignant and have rapid course from diagnosis to death. Their microscopic pathology reveals 90% to 95% nondifferentiation, frequent mitoses, and small dark cells with no observable cytoplasm. This paper discusses the treatment of three children with this tumor with a combination of surgery irradiation, and combination chemotherapy. The results of this approach are compared with previous reports in the literature. The average survival in this series is 24 months versus approximately 8 months reported in the literature.

Adolescent↗
PubMed1980

Bone sarcoma as a second malignant neoplasm in children: influence of radiation and genetic predisposition for the Late Effects Study Group.

Osteosarcoma or chondrosarcoma developed as a second malignant neoplasm (SMN) in 40 of 188 individuals with SMN whose first neoplasm occurred in childhood. A genetic susceptibility to cancer was found in 23; the SMN developed in an irradiated field in 32; both factors wer present in 16; neither in one. When a genetic predisposition was present, radiation shortened the interval to SMN. The intervals between tumors and the age at which the bone sarcomas developed in relation to genetic disease and therapy were analyzed by a two-mutation hypothesis. Studies of SMN in childhood permit us to make observation about the role of genetic factors and environmental mutagens in cancer etiology.

Adolescent↗
PubMed1980

Comparison of three methods of central-nervous-system prophylaxis in childhood acute lymphoblastic leukaemia.

A retrospective comparison was made of three methods of central-nervous-system prophylaxis in childhood acute lymphoblastic leukaemia; (1) intrathecal methotrexate only; (2) intermediate-dose methotrexate infusion and intrathecal methotrexate and, (3) 2400 rads cranial irradiation and intrathecal methotrexate. The incidence of primary meningeal relapse was statistically significantly lower in both standard-risk patients (age grear than 24 months and less than or equal to 120 months white-cell count less than 20,000) and increased-risk patients (age less than or equal to 24 months or greater than 120 months and/or white-cell count greater than 20,000) whose central-nervous-system prophylaxis included cranial irradiation. The disease-free and overall survival of irradiated increased-risk patients was significantly better than that of unirradiated increased-risk patients. The disease-free survival of standard-risk patients who received intermediate-dose methotrexate was statistically superior to that of the remaining standard-risk patients. There were no significant differences in overall survival between the three groups of standard-risk patients.

Adolescent↗
PubMed1980

Computed tomography brain scans in children with acute lymphocytic leukemia receiving methotrexate alone as central nervous system prophylaxis.

Central nervous system (CNS) "prophylaxis" is critical in the treatment of acute lymphocytic leukemia (ALL). The standard method employed combines cranial radiation (CRT) and intrathecal methotrexate (IT MTX). Recently, a 52% incidence of abnormal computed tomography (CT) brain scans was found in asymptomatic children with ALL whose CNS prophylaxis consisted of CRT and either IT MTX or intrathecal cytosine arabinoside (IT Ara-C). In the present study, CT brain scans were studied in 43 asymptomatic children with ALL in continuous complete remission. The CNS prophylaxis consisted of IT MTX alone in 10 patients and IT MTX combined with intermediate-dose intravenous MTX in 33 patients. No patient had received CRT. The patients' ages at the time of diagnosis ranged from 22 months to 17 years, 7 months. The time interval from completion of CNS prophylaxis to CT scanning ranged from ten to 59 months. Only one CT scan was clearly abnormal; it showed mildly dilated ventricles and visualization of the cortical sulci. The CT scans of 7 additional patients were classified as abnormal because of borderline dilatation of the lateral ventricles (3 patients) and/or visualization of the cortical sulci (7 patients). No patient demonstrated areas of decreased cerebral attenuation coefficient or intracerebral calcification--findings previously ascribed to the use of methotrexate. Clinical leukoencephalopathy has not been observed in any of our patients. This would suggest that MTX alone in the absence of CNS leukemia or CRT is highly unlikely to produce structural CNS abnormalities detectable by CT.

Adolescent↗
PubMed1980

Heterotransplantation and clonal growth of human Ph'-chromosome-positive leukemia-cell (NALM-1) and B-cell leukemia-cell (BALM-2) lines.

Human hematopoietic cell lines, NALM-1, derived from Ph'-chromosome-positive chronic myelocytic leukemia (CML) in blastic crisis, and BALM-2, derived from B-cell acute lymphoblastic leukemia (ALL), were tested for their heterotransplantability and clonability. Two previously established cell lines, a Burkitt's lymphoma cell line, B35M, and a B-lymphoblastoid cell line, B411-4, derived from a hematologically normal person, were used for comparison. Ten million cells were needed in order for the BALM-2 cell line to grow with 74% success in the immunosuppressed mice, but 1000 million cells were needed in order for the NALM-1 cell line to grow with 74% success in those mice. As in the case of the BALM-2 line, 10 million cells of the B35M cell line were needed for 100% success in heterotransplantation, whereas 30 million cells of the B411-4 cell line resulted in 20% success of heterotransplantation. In a semisolid agarose (0.15%) medium, the cloning efficiencies of BALM-2, B35M, and B411-4 were 1.52--2.08, 26.31--38.46, and 0.09--0.12, respectively. With as many as 25,000 cells per well plated, NALM-1 did not produce any colonies in the semisolid agarose medium. Unlike most previous findings, those of the present study suggest that the heterotransplantability and clonability of cultured cells may not be invariably reliable characteristics of all proven human leukemia-lymphoma cell lines. The behavior of these leukemia cell lines representing their respective original leukemia clones is interpreted as reflecting the heterogeneity inherent in the biologic characteristics seen in human leukemias.

Animals↗
PubMed1980

Cystadenocarcinoma of the ovary in a 4-year-old: benign transformation during therapy.

Ovarian tumors comprise only 1% of all tumors in females below the age of 17 years. Of these, the epithelial tumors are the least common, being particularly rare before puberty and then increasing in frequency with advancing age after puberty. The youngest girl previously reported in the literature with an epithelial ovarian tumor was a 9-year-old child with an ovarian papillary cystadenocarcinoma. This is the only case thus far reported of a malignant ovarian epithelial tumor occurring before puberty. Only histologically benign appearing glands were detected in the resected tumor masses, on a second-look laparotomy following the use of multiagent chemotherapy.

Antineoplastic Agents↗
PubMed1980

Multimodality therapy for medulloblastoma.

Eight patients with recurrent medulloblastoma were treated with a chemotherapy regimen consisting of vincristine, BCNU, dexamethasone and intrathecal and intermediate dose intravenous methotrexate (500 mg/m2). Five also received local low dose radiotherapy (RT). All 8 patients responded to treatment; 6 completely and 2 partially. These latter 2 were in their second and third recurrences. Three remain in remission. The median duration of response was 18.8 months, and median time from start of chemotherapy to death was 32 months using the Kaplan-Meier technique. In addition, 9 other patients with newly diagnosed medulloblastoma were treated with craniospinal radiation and the same adjuvant chemotherapy as above. The first 5 patients also received intraventricular methotrexate and/or intravenous BCNU during radiotherapy. The toxicity in the 5 patients was very severe. There were three toxic deaths, one death from cancer; one patient survives disease-free, but he is demented. With the discontinuance of intraventricular methotrexate and the postponement of myelo-suppressive chemotherapy until after the completion of radiotherapy, the regimen has been well tolerated. All 4 patients treated this way remain alive, well, and disease-free at intervals up to 36 months. We conclude that recurrent medulloblastomas are sensitive to multiagent chemotherapy and that prolonged remissions may occur. With primary adjuvant chemotherapy, extreme caution with myelo-suppressive drugs must be exercised during the period of craniospinal radiotherapy. We also do not recommend the use of intraventricular methotrexate. When these two criteria were followed, the preliminary results with adjuvant chemotherapy appear encouraging.

Adolescent↗