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Biomedical subjects

A I Freeman

Publications and source records attributed to A I Freeman.

At least 37 records · Page 2Linked to original sources
PubMed1987

Acute megakaryoblastic leukemia associated with mosaic Down's syndrome.

There have been several reports of the association between Down's Syndrome and acute megakaryoblastic (M7) leukemia (AMKL). The diagnosis of this rare form of leukemia has been better delineated by the use of the platelet peroxidase reaction and the antifactor VIII antibody immunoperoxidase test. In the past, the prognosis of patients with a combination of Down's Syndrome and AMKL has been extremely poor, with a median survival of 6.9 months for 11 reported cases in the literature. The present report reviews the previously reported cases and describes a unique patient with mosaic Down's syndrome and AMKL with favorable response to therapy.

Amsacrine↗
PubMed1987

Toxicity of high dose Ara-C in children and adolescents.

The toxicity of high dose cytosine arabinoside (Ara-C) in 23 leukemic children aged 1.5 years to 16 years 11 months was evaluated. The group included 11 children with acute lymphoblastic leukemia (ALL), nine with acute nonlymphoblastic leukemia (ANLL), two with chronic myelocytic leukemia (CML) in blastic crisis, and one with Burkitt's lymphoma. Toxicity consisted of bone marrow suppression in all patients, with a mean nadir time of 11 days for platelets and granulocytes. All patients experienced nausea and vomiting; 12 of 23 had drug induced fever; seven of 23 conjunctivitis; five of 23 mucositis; four of 23 diarrhea, and one of 23 elevated transaminase with hyperbilirubinemia. Adverse reactions were mild and reversible in all patients. No serious neurologic toxicity was seen. The toxicity observed in four patients with prior cranial irradiation was not any different from nonirradiated patients. The only life-threatening effect was neutropenia, the consequences of which were generally well controlled with antibiotic therapy. While this agent was effective in induction of remission in AML patients resistant to standard doses of Ara-C, it had no significant effect in a very small number of patients with relapsed ALL and CML in blast crisis. Side effects of high dose Ara-C though relatively substantial are manageable enough to warrant wider scale efficacy trials of this agent in childhood leukemias and solid tumors.

Adolescent↗
PubMed1987

Malignant histiocytosis. Complete remission in two pediatric patients.

The experience with the treatment of malignant histiocytosis has been disappointing. Despite modest treatment success with a combination of cyclophosphamide, Adriamycin (doxorubicin), vincristine and prednisone, the overall prognosis remains poor. There are only a few reports of prolonged complete remissions in pediatric patients. The following report describes two children who have had long-term remission with an aggressive combination chemotherapy program that included intrathecal prophylaxis. The chemotherapeutic regimen described merits further evaluation in a larger number of patients.

Adolescent↗
PubMed1986

Intermediate dose methotrexate in childhood acute lymphoblastic leukemia resulting in decreased incidence of testicular relapse.

Six hundred thirty-four children with acute lymphoblastic leukemia (ALL) were randomized to receive sanctuary therapy consisting of either cranial irradiation (CRT) plus intrathecal (IT) methotrexate (MTX) or three courses of intermediate-dose methotrexate (IDM) plus intrathecal methotrexate. Two hundred sixty-six male patients achieved a complete response and were evaluable for the effects of prophylactic therapy on the duration of remission. There was one isolated testicular relapse (0.8%) in the IDM group compared with 14 (10%) in the CRT group. The incidence of testicular relapse was significantly lower in the patients treated with IDM (P less than 0.001). High plasma levels of MTX achieved during the 24-hour infusions may result in increased penetration of MTX into the interstitium of the testes, thus allowing for the eradication of sequestered leukemic cells and preventing the emergence of drug resistance resulting from exposure to sublethal concentration of MTX.

Actuarial Analysis↗
PubMed1986

Targeted drug delivery.

Cancer chemotherapy drugs are neither specific, i.e., they do not act exclusively on the metabolic pathways of cancer cells, nor are they targeted solely toward cancer cells. However, recent research has begun to address, in part, the latter issue. Improved delivery of chemotherapeutic agents to tumor tissue in man appears to be an achievable goal in the next decade. Improved drug delivery includes developing predictive models that allow for laboratory assessment of the best treatment for a patient's cancer without exposing the patient to an empirical trial or to the possible morbidity from exposure to a less useful drug, or to the loss of time in the fight against cancer because of ineffectual therapy. Monoclonal antibodies directed against tumor-associated antigens have the potential to achieve major advances in targeted drug delivery. Monoclonal antibodies may have direct antitumor effects, or they can be used as "homing devices" when attached to a payload and can guide diagnostic or therapeutic agents to the targeted tissues. Carrier systems of all types have become available; these include liposomes and polymeric compounds which can carry drugs, radionuclides, toxins, or other materials in a protected environment. These carriers can also be bound to monoclonal antibodies for possible targeted delivery. Pharmacological sanctuaries have been recognized as a problem in cancer treatment. The best known of these is the central nervous system (CNS). Techniques to temporarily disrupt the blood-brain barrier are now appearing. Mechanisms to administer therapy directly into the CNS are also being reassessed. Implantable pumps and reservoirs have been used to treat selected organs or for regional perfusions. Other treatments that are regional in scope include administration directly into a cavity or into a tumor. Computerized implantable devices should play a major role in cancer therapy in the future, in pain control as well as antibiotic and hormone administration. In recent years, mathematical models have been developed that can more accurately predict drug distribution and metabolism in various tissues of the body. Such models point the way to more logical designs of chemotherapeutic administration. The expanded use of autologous bone marrow transplantation, along with improving techniques of "purging" the marrow of tumor cells before reinfusion can be anticipated. Pro-drugs are substances that must be biotransformed in vivo to exert their pharmacologic effect.(ABSTRACT TRUNCATED AT 400 WORDS)

Antibodies, Monoclonal↗
PubMed1986

Hypothalamic-pituitary function of children with acute lymphocytic leukemia after three forms of central nervous system prophylaxis. A retrospective study.

The hypothalamic-pituitary function of 93 children, who had received central nervous system (CNS) prophylaxis as part of their therapy for acute lymphocytic leukemia (ALL), and who remained in continuous complete remission, was evaluated retrospectively. Treatment regimens included--Group I: 31 subjects, intrathecal methotrexate (IT MTX); Group II: 31 subjects, IT MTX plus 2400 rad cranial irradiation; and Group III: 31 subjects, IT MTX and intravenous intermediate-dose methotrexate. Serum thyroid-stimulating hormone (TSH) and T4 levels were normal. All participants had normal adrenocorticotropic hormone (ACTH) secretion as assessed by plasma cortisol responses to insulin hypoglycemia. Urinary follicle-stimulating hormone (FSH) and luteinizing hormone (LH) excretion of pubertal and postpubertal patients (N = 37) was appropriate, except for one subject from Group I who had an abnormally high output of gonadotropins, and one from Group II who had abnormally low levels. Growth hormone (GH) responses were subnormal after sequential arginine-insulin stimulation as follows--Group 1: 3 of 31 patients; Group II: 6 of 25 patients; and Group III: 2 of 29 patients. Nevertheless, all children had normal linear growth. It was concluded that the three forms of CNS prophylaxis evaluated had no long-term adverse effect on TSH and ACTH secretion. FSH-LH production appears to be normal, but final judgment must await follow-up studies because 60% of the patients were prepuberteral or still receiving chemotherapy. Eleven patients had subnormal GH responses after pharmacologic stimulation of the pituitary, but long-term linear growth was unaffected.

Adolescent↗
PubMed1986

Human T-cell leukemia-associated cell surface glycoprotein GP37: studies with three monoclonal antibodies and a rabbit antiserum.

Three monoclonal antibodies (mAbs), termed SN2, SN2a and SN2b, were used in the present work to study a human T-cell leukemia-associated cell surface glycoprotein, GP37. Strong specificity of mAbs SN2, SN2a and SN2b for T leukemia cells was demonstrated by radioimmunoassay and fluorescence-activated cell sorter (FACS) analysis. GP37 was not detected on normal human peripheral blood lymphocytes, purified normal T-cells, normal thymocytes nor normal bone marrow cells. Furthermore, GP37 was barely detectable on phytohemagglutinin (PHA)- and Concanavalin A (Con A)-activated T-cells. The results indicate clinical utility of these mAbs. Competitive binding experiments show that the epitopes recognized by SN2 and SN2a are sufficiently close to each other to allow complete reciprocal inhibition of binding whereas the epitopes recognized by SN2 and SN2b are less close to allow only partial reciprocal binding inhibition. The biochemical nature of antigenic determinants defined by these mAbs was studied by treating T leukemia cells with trypsin, chymotrypsin, thermolysin, neuraminidase and mixed glycosidases. The results suggest that the antigenic determinants defined by these mAbs all consist of the protein moiety of the glycoprotein GP37. No significant antigenic modulation was observed when T leukemia cells were reacted with SN2. In a sequential immunoprecipitation experiment, a 125I-labeled leukemia antigen preparation was first treated with a rabbit anti-T leukemia antiserum. The latter had been prepared by immunizing a rabbit with a partially purified human T leukemia antigen preparation and showed a good specificity for T leukemia cells. Subsequent treatment of the labeled antigen preparation with SN2 showed that SN2 antigen had been precleared. Thus, both mouse mAb SN2 and the rabbit anti-T leukemia antiserum react with the same GP37 molecule.

Animals↗
PubMed1986

Adjuvant adriamycin and cisplatin in newly diagnosed, nonmetastatic osteosarcoma of the extremity.

Twenty-two patients with newly diagnosed nonmetastatic osteosarcoma of the extremity were treated with an adjuvant chemotherapeutic regimen consisting of Adriamycin (Adria Laboratories, Columbus, Ohio) and cisplatin. Fourteen of the 22 patients remain continuously disease free for 65+ to 113+ months, with a median time on study of 70+ months. The 72-month disease-free survival estimate is 64%. Pulmonary metastases occurred in six patients, an isolated stump recurrence was seen in one patient, and one patient had a local recurrence following a limb-salvage procedure. For those patients in whom pulmonary metastases developed, the onset was late in three of six, and the number of metastases was three or fewer in all patients. Two patients with pulmonary metastases and one with a stump recurrence have apparently been salvaged, thus resulting in a 77% 72-month survival. Toxicity observed in patients treated with this regimen was in keeping with previous reports. This chemotherapeutic regimen is effective in the adjuvant therapy of nonmetastatic osteosarcoma of the extremity. It should be incorporated into other adjuvant protocols in an effort to continue to improve the outcome in patients with osteosarcoma.

Adolescent↗
PubMed1985

Computerized tomography scan findings in children with acute lymphocytic leukemia treated with three different methods of central nervous system prophylaxis.

Computerized tomography (CT) scans of the head were done on 93 children with acute lymphocytic leukemia in continuous complete remission who had been randomly assigned to three different methods. of central nervous system (CNS) prophylaxis. Twenty-nine children had received six doses of intrathecal methotrexate, 30 had received six doses of intrathecal methotrexate plus 2400 rad of cranial irradiation, and 34 had received six doses of intrathecal methotrexate plus three courses of intermediate-dose intravenous methotrexate. The overall incidence of abnormal scans was 35%, of which 91% were felt to represent minimal abnormalities. CT scan abnormalities were noted in 30% of the children receiving intrathecal methotrexate only, in 40% of those receiving intrathecal methotrexate plus cranial irradiation, and in 35% of those receiving intrathecal methotrexate plus intermediate dose methotrexate. These differences were not statistically significant. None of the three methods of CNS prophylaxis resulted in significant CT scan abnormalities. However, the few moderately or markedly abnormal scans evaluated were restricted to patients who received intrathecal methotrexate plus cranial irradiation. The clinical significance of CT scan abnormalities in leukemic children receiving these treatments remains unclear.

Brain Neoplasms↗
PubMed1985

Persistence of Inoue-Melnick virus and antibody in cerebrospinal fluid.

Serial cerebrospinal fluid samples were obtained from 14 multiple sclerosis patients over a period of several months and were tested under code for Inoue-Melnick virus. In five of the positive patients, virus was present in 28 of 32 specimens collected over a period of 2 to 5 months. Four patients, from whom a total of 34 specimens were taken, yielded only a single isolate each. Five patients contributed 28 specimens, all of which were negative. In six patients (three virus positive and three virus negative), neutralizing antibody was detected in serum and in cerebrospinal fluid.

Adult↗
PubMed1985

High-dose cyclophosphamide and intermediate-dose methotrexate for the treatment of far-advanced Burkitt's lymphoma.

Ten consecutive patients were entered on a pilot study--for the treatment of children with far-advanced Burkitt's lymphoma--which was conducted at the Roswell Park Memorial Institute (R.P.M.I.) and the University of Rochester Medical Center (U. of R.). With the use of high-dose cyclophosphamide (HDC), intermediate-dose methotrexate (IDM), vincristine (VCR), prednisone (PRED), and intrathecal (IT) chemotherapy, nine of these 10 children achieved a complete remission (CR), and six of these nine children have remained in CR for more than 3 years and are likely cured of their disease. This regimen had significant, but generally manageable, toxicity. A single patient with ataxia-telangiectasia died during induction therapy of pneumonia and a gastrointestinal hemorrhage. A single patient with severe hemorrhagic cystitis required the substitution of cytosine arabinoside for cyclophosphamide (Cytoxan) in the regimen. One of five children presenting with bone marrow involvement survives. Such involvement appears to place patients at greater risk for developing meningeal disease. Attempts at more aggressive methods of central nervous system (CNS) prophylaxis should be employed in this group of patients.

Adolescent↗
PubMed1983

Comparison of intermediate-dose methotrexate with cranial irradiation for the post-induction treatment of acute lymphocytic leukemia in children.

We compared two regimens with respect to their ability to prolong disease-free survival in 506 children and adolescents with acute lymphocytic leukemia. All responders to induction therapy were randomized to treatment with 2400 rad of cranial irradiation plus intrathecal methotrexate or to treatment with intermediate-dose methotrexate plus intrathecal methotrexate, as prophylaxis for involvement of the central nervous system and other "sanctuary" areas. Patients were then treated with a standard maintenance regimen. Complete responders were stratified into either standard-risk or increased-risk groups on the basis of age and white-cell count at presentation. Among patients with standard risk, hematologic relapses occurred in 9 of 117 given methotrexate and 24 of 120 given irradiation (P less than 0.01). The rate of central-nervous-system relapse was higher in the methotrexate group (23 of 117) than in the irradiation group (8 of 120) (P = 0.01). Among patients with increased risk, radiation offered greater protection to the central nervous system than methotrexate (P = 0.03); there was no difference in the rate of hematologic relapse. In both risk strata the frequency of testicular relapse was significantly lower in the methotrexate group (1 patient) than the radiation group (10 patients) (P = 0.01). Methotrexate offered better protection against systemic relapse in standard-risk patients and better protection against testicular relapse overall, but it offered less protection against relapses in the central nervous system than cranial irradiation.

Adolescent↗
PubMed1983

The use of different induction and maintenance chemotherapy regimens for the treatment of advanced yolk sac tumors.

Four children with yolk sac tumor were treated with an aggressive combination chemotherapy program. Three children had presacral primary tumors, one having pulmonary metastases, and one had a testicular primary tumor with pulmonary metastases. Three children were treated when they had measurable disease, and one had no measurable disease. The chemotherapy program consisted of a 6-wk induction period with vincristine (VCR), cis-diamminedichloroplatinum (DDP), and bleomycin. Maintenance therapy consisted of VCR, actinomycin D, and cyclophosphamide (cytoxan) every 3-4 wk as tolerated. Treatment was discontinued after 12 mo of complete remission. All three patients with evaluable disease had a partial response (PR) to induction therapy. Two underwent surgical exploration following induction therapy, one a laparotomy and the other a thoracotomy, and were found to have only scar tissue at the sites of presumed residual disease. The third child with measurable disease progressed to a clinical complete response (CR) during maintenance therapy. Two patients have had no evidence of disease (NED) for 42+ and 41+ mo since starting therapy (28+ and 27+ mo since completing treatment). Two patients are NED 11+ and 7+ mo since starting therapy and remain on treatment. We have encountered no significant renal or pulmonary toxicity, and there have been only two hospitalizations during maintenance therapy for fever and neutropenia. These preliminary results employing different induction and maintenance chemotherapy programs and planned second-look surgical intervention appear encouraging.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1983

A prospective analysis of the frequency, course, and possible prognostic significance of the joint manifestations of childhood leukemia.

During a 2-year prospective study of 28 leukemic children (24, acute lymphocytic leukemia [ALL]; 4, non-ALL) unselected for musculoskeletal symptoms, objective joint findings were present in 14 cases (p = 0.001 vs normal controls). These findings varied in severity, were most frequently present in the knee (12 of 14 children), and were found most frequently only at disease onset (7 of 14). The group with joint abnormalities had a higher frequency of functionally significant joint complaints prior to diagnosis of leukemia (p = less than 0.01) and radiographic abnormalities of periarticular bone of the knees and ankles (p = less than 0.10). Four of the 5 children with ALL who died had joint findings, a trend whose significance is uncertain because of unequal followup periods.

Child↗
PubMed1982

The use of intermediate dose methotrexate in increased risk childhood acute lymphoblastic leukemia. A comparison of three versus six courses.

Between January 1974 and November 1978, 41 consecutive increased risk (age less than 24 months or less than 120 months, or leukocyte count greater than 30,000/mm3) patients with acute lymphoblastic leukemia (ALL) were entered on two consecutive treatment protocols which employed intermediate dose methotrexate (IDM). IDM was employed for central nervous system prophylaxis and systemic intensification. It was anticipated that the avoidance of prophylactic cranial irradiation would result in a lower incidence of longterm central nervous system sequelae. Twenty-two children and adolescents were entered on the first study (IDM X 3) which employed three courses of IDM (500 mg/m2) and six doses of intrathecal (IT) methotrexate (MTX). Nineteen children and adolescents were entered on the second study (IDM X 6) which employed six courses of IDM (3-500 mg/m2 and 3-1500 mg/m2), six doses of IT MTX and three additional doses of triple IT chemotherapy (MTX, cytosine arabinoside, and hydrocortisone or dexamethasone). The cumulative percentage of patients who remained in continuous complete remission was 30% for IDM X 3 and 57% for IDM X 6. This difference was statistically significant (P = 0.046; and BM + CNS, I-using IDM X 6. The cumulative incidence of primary CNS relapse was 36.4% for IDM X 3 and 29.9% for IDM X 6. This difference was not statistically significant (P = 0.44). The use of more intensive therapy with IDM and triple IT chemotherapy did improve the duration of continuous, complete remission but did not decrease the incidence of primary CNS relapse in increased risk patients.

Adolescent↗