Clinical cancer: 33. Clinical applications and research advances in marrow transplantation.
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Bone Marrow Transplantation↗
Biomedical subjects
J T Casper
Publications and source records attributed to J T Casper.
Cytosine arabinoside/cyclophosphamide pulses during continuation therapy for childhood acute lymphoblastic leukemia. Potential selective effect in T-cell leukemia.
One hundred seventy-seven children with acute lymphoblastic leukemia (ALL) were admitted to a study designed to determine whether pulses of cytosine arabinoside (ara-C) and cyclophosphamide (cyclo) would improve disease-free survival (DFS). All patients received vincristine, prednisone, and asparaginase for remission induction, CNS prophylaxis with cranial irradiation and intrathecal methotrexate, and continuation therapy with 6-mercaptopurine plus methotrexate. Forty-seven of 101 patients with non-T ALL and 18 of 26 patients with T-cell ALL received ara-C/cyclo pulses every eight weeks during continuation therapy. The age, sex, and initial white cell count distributions were similar in both treatment groups. Patients with non-T-cell ALL had similar DFS with or without ara-C/cyclo pulses (36% versus 48%; P = 0.32). Ara-C/cyclo pulses significantly improved DFS in children with T-cell ALL (36% versus 0%; P = 0.015). Toxicities of the ara-C/cyclo pulses included reversible pancytopenia, drug induced fever, fever associated with neutropenia, and death in one patient from systemic candidiasis while neutropenic. This is the first clinical evidence to indicate that the combination of ara-C/cyclo used during continuation therapy is selectively beneficial in T-cell ALL.
Antineoplastic Combined Chemotherapy Protocols↗
Consistent N-myc copy number in simultaneous or consecutive neuroblastoma samples from sixty individual patients.
Amplification of the N-myc oncogene is detected in about 30% of untreated neuroblastomas. Amplification is associated with advanced stages of disease and rapid tumor progression. However, it was not known if the N-myc copy number was homogeneous in tumor tissue of an individual patient, or if it changed with time in vivo. Therefore, we have made 66 observations on multiple simultaneous or consecutive tumor samples from 60 patients with neuroblastoma. (a) Simultaneous samples were obtained from different areas of 31 tumor masses from 30 patients: a similar N-myc copy number (1-2, 3-10, or greater than 10) was found in all samples from each patient. (b) Simultaneous samples were obtained from different anatomical sites in ten patients. No difference in N-myc copy number was seen. (c) Finally, 25 patients had two or more tumor samples obtained over time. Thirteen patients had a single copy of N-myc in all samples, and 12 had consistent levels of amplification in all samples. Two of the latter cases had single copy of N-myc in a second-look surgery sample, but no tumor was evident histologically. This study demonstrates that the N-myc copy number in human neuroblastomas is usually consistent within a tumor, not only at different tumor sites, but also at different times in vivo. Overall, these findings suggest that N-myc amplification is an intrinsic biological property of a subset of neuroblastomas, and if amplification is going to occur, it is generally present at the time of diagnosis.
Child↗
Expression of GD3 ganglioside in childhood T-cell lymphoblastic malignancies.
Lymphoblasts from seven children with T-cell lymphoblastic malignancies and three children with non-T, non-B acute lymphoblastic leukemia (ALL) were analyzed for ganglioside content. Nonmalignant T-cells from thymus served as controls. Both ganglioside and glycoprotein sialic acid were increased approximately 3-3.5-fold in T-cell disease compared to thymic tissue when expressed on a per cell basis, but not on a per milligram protein basis. Thin-layer chromatography of the isolated ganglioside fraction from T-cell lymphoblasts revealed two major resorcinol-positive bands. One ganglioside comigrated with II3-alpha-N-acetylneuraminosyllactosylceramide (GM3), the major ganglioside in normal lymphoid tissue, and the other ganglioside comigrated with authentic II3-alpha-N-acetylneuraminosyl-alpha 2----8-N-acetylneuraminosyllactosylceramide (GD3) in three different solvent systems. Neuraminidase treatment of the latter ganglioside yielded GM3 and lactosyl ceramide, hydrolysis products of GD3. Scanning densitometry revealed that whereas thymus cells contained 97% GM3 and 3% GD3, T-cell lymphoblasts contained from 22 to 86% GD3 and a corresponding decrease in GM3. The shift to increased GD3 was observed in the blasts from all seven T-cell patients, but not in the blasts from the non-T, non-B patients studied. Only trace quantities of GD3 were detected from two continuous T-ALL cell lines, HSB2 and RPMI 8402. The results demonstrate a consistently significant increase in ganglioside GD3 in uncultured, patient-derived T-cell ALL lymphoblasts when compared to non-T-cell ALL and normal lymphoid tissue. Therefore, GD3 may represent a tumor-associated antigen for the T-cell subclass of childhood lymphoblastic malignancy.
Adolescent↗
Cyclic neutropenia in identical twins.
Cyclic neutropenia developed in identical twin girls. The onset of neutropenia in these children occurred three years apart. Neutrophil cycling diminished, and symptoms decreased in the initially affected twin during a five-year follow-up. Some cases of cyclic neutropenia may be genetically determined; however, the onset and clinical manifestations may be modified by other internal and external factors. There may also be a prodromal period during which neutrophils cycle, but the patient is neither neutropenic nor symptomatic.
Adolescent↗
HTLV-III serology in hemophilia: relationship with immunologic abnormalities.
We investigated the relationship of the presence of antibodies to HTLV-III and immunologic abnormalities in patients with hemophilia. Serum antibodies to HTLV-III were analyzed by ELISA assay, immunoprecipitation of labeled cell extracts, and immunoprecipitation of purified HTLV-III p24. Thirty-four (61%) of the total group (n = 56) had antibody to HTLV-III; 34 (76%) of 45 patients given commercial factor VIII preparations were seropositive, compared with none of 11 patients treated exclusively with cryoprecipitate obtained from volunteer blood donors. Of patients who were seropositive for HTLV-III antibody, 94% had abnormal T4/T8 ratios, and 33% of those whose serum was antibody negative had abnormal T4/T8 ratios; five patients, each antibody positive, have lymphadenopathy syndrome. Sequential studies in a subset of patients indicate that there is a changing pattern of antibody production to HTLV-III antigens after seroconversion.
Acquired Immunodeficiency Syndrome↗
Cerebral toxoplasmosis in an immunocompromised host. A precise and rapid diagnosis by electron microscopy.
In immunocompromised patients with cerebral toxoplasmosis, the tachyzoite forms rather than cystic and bradyzoite forms of the protozoon are commonly seen. These tachyzoites are minute, scattered among cellular debris, sometimes lodged inside macrophages and neutrophils, and difficult to visualize by light microscopy, even with special stains. Immunodiagnostic tests may be falsely negative due to inability of the host to produce appropriate antibodies. Isolation of the organism is dangerous because Toxoplasma gondii is highly infective. In this situation, transmission electron microscopy (EM) may be a diagnostic tool of choice. It demonstrates the fine definitive features of the protozoon and can be expedited to give results in five hours. Further evaluation of EM for diagnosing possible toxoplasmosis in immunocompromised patients is indicated.
Adolescent↗
Isolated bilateral T-cell renal lymphoblastic lymphoma.
A 3-year-old girl presented with bilateral renal masses. The histologic diagnosis was lymphoblastic lymphoma. Cell surface markers showed a cytotoxic/suppressor T cell phenotype. The patient was treated with APO therapy. She has remained continuously disease-free for 30 months and has been off all therapy for 6 months. This rare case supports the value of precise classification (by histologic and immunologic methods) as a guide to appropriate tumor therapy.
Antineoplastic Combined Chemotherapy Protocols↗
Effectiveness of a six-drug regimen (APO) without local irradiation for treatment of mediastinal lymphoblastic lymphoma in children.
Fourteen children with mediastinal lymphoblastic lymphoma (MLL) were treated with the six-drug APO protocol. This regimen includes aggressive intermittent chemotherapy and prophylactic central nervous system therapy. Mediastinal irradiation was given only for emergency relief of mediastinal compression (two children) or for incomplete resolution of mediastinal widening with chemotherapy (one child). All 14 patients achieved complete remission; only 1 has relapsed. Toxicities were not severe. APO is effective therapy for children with MLL. APO should receive further trials in children and adults with T-cell lymphoblastic lymphomas.
Adolescent↗
Persistence and progression of immunologic abnormalities in haemophilia.
Immunologic parameters in 51 patients with haemophilia treated with cryoprecipitate from volunteer donors or with commercial lyophilized concentrate were studied on 2-7 occasions. Concentrate users had significantly decreased mean T4 (helper)/T8 (suppressor) lymphocyte ratios when the initial (1.5 +/- .43) and most recent (1.25 +/- .60) values were compared (p less than .001), whereas in cryoprecipitate users mean values remained normal. Of the 22 concentrate users with initially normal T4/T8 ratios, 10 became abnormal during the study, an incidence of 45%. Fifteen of 28 (54%) patients with abnormal T4/T8 ratios had elevated circulating immune complexes (CIC), whereas all 16 patients with normal T4/T8 ratios had normal levels of CIC. Six patients have persistent lymphadenopathy.
Antigens, Surface↗
Inherited absence of OKT4 lymphocyte antigen in a chronically transfused patient with homozygous sickle cell disease.
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Adolescent↗
Contribution of electron microscopy of cell cultures to the classification of three round cell sarcomas in children.
We have studied three round cell sarcomas from pediatric patients in tissue culture to compare the electron microscopic morphology of cells in culture to cells from original biopsy specimens. None of the original tumors displayed distinctive features by light microscopy that would allow classification of a specific tumor type, and electron microscopy was not helpful in identifying specific morphologic features that would allow further classification of tumor types. However, electron microscopy of cells in culture from the three neoplasms revealed distinctive morphologic features that did allow further classification of all three tumors. Cells from an inguinal lymph node, which were cultured in soft agar tumor colony-forming assay, revealed Z-bands and actin and myosin filaments indicative of a rhabdomyosarcomatous nature for the tumor. Cells from 5-day, 10-day, and 4-month cultures of a bone marrow metastasis of a second tumor revealed features of skeletal muscle in the young cultures and neuroblasts in the older culture, suggesting a primitive neuroectodermal neoplasm. Cultured cells from the third tumor, a neoplasm of the calf in an infant, displayed large lakes of glycogen, typical of cells of Ewing's sarcoma, which were not present in the cells examined from the original lesion. Ultrastructural studies of cells in culture have the potential to add morphologic data that may be useful to further define and classify a neoplasm, as illustrated in the 3 cases reported here.
Bone Marrow↗
Terminal transferase surveillance of remission bone marrows in childhood acute lymphoblastic leukemia: improved sensitivity with countercurrent centrifugal elutriation.
In an attempt to better define hematologic remission and relapse in children with TdT positive acute lymphoblastic leukemia (ALL), 101 bone marrow (BM) aspirates were obtained from 74 pediatric patients. The mononuclear cell population of these specimens was isolated using countercurrent centrifugal elutriation (CCE) and characterized by an immunofluorescent terminal deoxynucleotidyl transferase (IF-TdT) assay. Twenty-two children with non-leukemic disorders had a median of 8% (range 0-34%) TdT positive mononuclear bone marrow cells. This was similar to values obtained for 25 children with ALL off therapy and in remission (median 10%, range 1-22%) and 16 children with ALL on continuous anti-leukemic therapy and in remission (median 7%, range 1-26%). Twenty-three BM samples were obtained from 11 children in early or high risk to relapse because of increased immature cells on a routine marrow examination or previous relapse(s). Samples from the early and high risk to relapse groups contained a median of 56% (range 25-80%) and 39% (range 25-72%) TdT positive cells. In contrast, the median percent marrow lymphoblasts identified using standard morphologic criteria for these 2 groups was 12.5% (range 9-23%) and 3% (range 0-5%), respectively. All high risk patients relapsed in their BM 1-4 1/2 months after these TdT determinations. Longitudinal studies in 4 patients at increased risk to relapse consistently demonstrated elevated percentages of TdT positive cells while morphologic surveillance was inadequate in establishing a clinical diagnosis of leukemic relapse. CCE in combination with an IF-TdT assay may enhance detection of recurrent and/or residual leukemia in BM samples from children with TdT positive ALL.
Bone Marrow↗
Editors have ethical responsibilities, too.
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Ethics↗
Treatment of meningeal relapse in childhood acute lymphoblastic leukemia. I. Results of craniospinal irradiation.
Fourteen children were treated for isolated meningeal relapse occurring seven to 44 months (median, 14 months) after prophylactic cranial irradiation (2,400 rad/12 fractions) and intrathecal methotrexate (IT MTX, 12 mg/m2 for four doses during cranial irradiation). Eight had "high-risk" acute lymphocytic leukemia with age less than 2 years, white blood cell counts greater than 20,000, or T cell markers. Treatment for central nervous system leukemia included IT MTX (12 mg/m2 twice weekly until clearance of spinal fluid cytology) followed by craniospinal irradiation (CSI, 3,000 rad/20 fractions to the cranium and 1,800 rad/12 fractions to the spine). No maintenance IT MTX was given. Systemic chemotherapy was continued or reinstituted for a minimum of one year after CSI. No instance of second meningeal relapse has occurred. Five patients remain in secondary complete remission 66+, 54+, 36+, 26+, and 24+ months after meningeal relapse. Disease-free survival was limited by marrow relapse in eight patients (2-20 months after CSI) and testicular relapse in one. No acute toxicities were noted with CSI. Myelosuppression occurred in seven patients. Infections within two months of CSI were noted in five. No neurologic sequelae are apparent. Serial neuropsychometric studies in 10 patients revealed a significant decline in mean values on Global IQ scales. Long-term survival with acceptable toxicity is possible following aggressive, prompt treatment of meningeal relapse occurring after prophylactic cranial irradiation. Hematologic relapse remains the major obstacle to long-term disease-free survival.
Acute Disease↗
T-lymphocyte subpopulations in patients with classic hemophilia treated with cryoprecipitate and lyophilized concentrates.
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Adolescent↗
Distinguishing characteristics of a new neuroblastoma cell line.
The characteristics of a new neuroblastoma cell line (MC-NB-1) established from the bone marrow of a 2-year-old male are described. Morphologically, the cells appear as flattened and epithelial-like or as small and spherical. Electron microscopy demonstrated microtubules and dense core secretory granules. The doubling time was approximately 35 hr. Isoenzyme patterns and catecholamine secretion indicated a human line of neuronal origin. The soft agar tumor colony forming system demonstrated drug resistance in vitro comparable to in vivo nonresponsiveness. The stemline karyotype of MC-NB-1 is 44,Y,del(1) (p22:), -4, -7, +del(7)(q22:), -16, +t(7;16)(16pter leads to 16q24::7q22 leads to 7q32), -17. Additionally, double-minute bodies were observed. However, no evidence of homogeneous staining regions (HSRs) were detected.
Carboxylesterase↗
Evaluation of cerebrospinal fluid mononuclear cells obtained from children with acute lymphocytic leukemia: advantages of combining cytomorphology and terminal deoxynucleotidyl transferase.
Sixty cerebrospinal fluid (CSF) samples were obtained from 28 children with terminal deoxynucleotidyl transferase (TdT) positive acute lymphocytic leukemia (ALL). Cell morphology was evaluated using Wright's stained cytocentrifugation prepared slides. The presence of nuclear TdT was detected by an immunofluorescent (IF) assay. Evaluation of CSF mononuclear cells using these two methods simultaneously allowed us to differentiate between leukemic and nonleukemic pleocytosis. Agreement between cytomorphology and TdT in identifying CNS lymphoblasts was found in 55 of 60 samples. Seventy-two per cent of the TdT-positive samples were obtained from children with CSF cell counts less than 10 WBC/mm3. We recommend that these two methods be used in conjunction when evaluating CSF mononuclear cells from children with TdT positive ALL.
Child↗