Intensive sequential chemotherapy for children with acute myelogenous leukemia.
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Adolescent↗
Biomedical subjects
M P Link
Publications and source records attributed to M P Link.
Stage I-II pediatric Hodgkin's disease: long-term follow-up demonstrates equivalent survival rates following different management schemes.
The results of treatment of 171 children with stage I-II Hodgkin's disease from two institutions with differing approaches to management have been analyzed. At the Stanford University Medical Center/Children's Hospital at Stanford (SUMC/CHaS), pathologic staging followed by extended-field radiation alone or involved-field radiation plus combination chemotherapy have been cardinal to the management policy. At St Bartholomew's Hospital/The Hospital for Sick Children at Great Ormond Street (Barts/GOS), clinical staging only has been used over the last 10 years, and involved/regional-field radiotherapy used as the treatment of choice rather than extended-field radiotherapy. Some children at each institution received combined modality therapy as primary management. Relapse among children with stage I disease was a more frequent occurrence in the Barts/GOS series than in the SUMC/CHaS group. However, the survival rates from the two centers are identical, 91% at 10 years. The following scientific-philosophic question is asked: Should one maximally stage and treat all children to increase the likelihood of a high freedom from relapse (FFR; cure) rate, or is it acceptable to minimize the initial staging and treatment, realizing that a proportion of patients will fail and require salvage/rescue therapy? With the awareness of morbidity from pathologic staging and aggressive treatment, and the favorable survival data reported from specialized centers using differing approaches, treatment strategies should be directed toward the long-term goal of cure of disease with maximal quality of life. A multidisciplinary management philosophy undertaken at a center with extensive experience in pediatric Hodgkin's disease is important to achieving this goal.
Actuarial Analysis↗
Absence of Ig V region gene somatic hypermutation in advanced Burkitt's lymphoma.
Somatic hypermutation of rearranged Ig V region gene plays a major role in generating antibody diversity. Recently, V mutation has been established as a major mechanism of tumor escape from anti-Id immunotherapy. We cloned and sequenced the expressed Ig H and L chain V regions from a case of B acute lymphoblastic leukemia in order to evaluate B cell stages associated with V region mutation, and to determine which tumors would be better suited to Id directed immunotherapy. A consensus VH and V lambda sequence representing tumor at diagnosis was obtained by conventional cDNA cloning in lambda gt10 from a heterohybridoma. Primers which flanked both V regions were used in a modified polymerase chain reaction to generate multiple independent sequences from tumor cells harvested at relapse. In order to exclude mutations due to infidelity of the amplification procedure, single cDNA templates of known sequence were also amplified. The polymerase chain reaction proved to be an effective procedure to obtain multiple clones, but replication in M13 was associated with a low rate of base misincorporation. The results indicate that there is no evidence for biologically significant ongoing mutation in this t(8;14) B cell tumor when comparing sequences at diagnosis and relapse. Thus, V somatic mutation may be restricted to a discrete B cell stage whose malignant counterpart is follicular lymphoma.
Adolescent↗
Diffuse small noncleaved cell lymphoma in children, Burkitt's versus non-Burkitt's types. Results from the Pediatric Oncology Group and St. Jude Children's Research Hospital.
The clinical relevance of a morphologic distinction between Burkitt's (B) and non-Burkitt's (NB) types of small non-cleaved cell (SNC) non-Hodgkin's lymphoma (NHL) has been controversial. Numerous attempts to discern an important clinical difference between the subtypes have failed to provide a convincing reason to maintain this distinction for other than descriptive purposes. Because of conflicting reports in the literature, the authors have analyzed 183 cases of SNC NHL in children from the Pediatric Oncology Group and 129 from St. Jude Children's Research Hospital (Memphis, TN). The results from both series, which consist of approximately the same proportions of B and NB subtypes, (i.e., approximately 54%-58% B, 36% NB, and 6%-10% not otherwise specified) show no significant differences in age at presentation, extent of disease, primary site of involvement, or survival. The authors conclude that the morphologic distinction between B and NB types of SNC NHL in children lacks demonstrable clinical importance.
Burkitt Lymphoma↗
Cytotoxic T lymphocytes specific for self tumor immunoglobulin express T cell receptor delta chain.
CTL are thought to play a role in the elimination of transformed cells in vivo. The effectiveness of such CTL is in part dependent on recognition of tumor specific antigens. Among the best characterized tumor-specific antigens are the unique or idiotypic determinants on the Ig of B cell lymphomas. Here we describe the generation and properties of human CTL specific for the idiotype on autologous B cell tumors. These cells are CD3+,CD4-,CD8- and express the delta chain of the TCR. Such cells may prove useful in tumor-specific adoptive therapy.
Adolescent↗
Poor-risk non-lymphoblastic lymphoma of childhood: results of an intensive pilot study.
Children with "poor-risk" nonlymphoblastic lymphoma, especially those with marrow or nervous system (CNS) involvement at presentation, have fared poorly even on aggressive chemotherapy regimens. We report here the results of a pilot study of 30 children treated with a highly intensive chemotherapy regimen. This regimen includes an intensive Induction Phase consisting of three cycles of CHOP therapy (cyclophosphamide, doxorubicin, vincristine, and corticosteroids) as well as intensive intrathecal therapy with each cycle. This is followed by a CNS Consolidation Phase consisting of a single cycle of CHOP therapy with five intrathecal doses of "triple" chemotherapy (methotrexate, cytosine arabinoside, and hydrocortisone). Thereafter, a Maintenance Phase consists of alternating cycles of 1) cytosine arabinoside and 6-thioguanine, 2) oral methotrexate and VP-16, and 3) CHOP, for a duration that varied from 36 to 72 wk. Neither debulking surgery nor radiation therapy were recommended. There were 20 patients with Stage III disease (St. Jude's Staging System) and an additional ten patients with bone marrow and/or CNS involvement. The latter group included six patients with B-cell leukemia, three of whom also had CNS disease at presentation. Two additional patients had CNS disease without marrow involvement. Twenty-nine of 30 patients achieved a complete response. Six patients died with recurrent or progressive disease. Twenty-three patients are alive without any adverse events between 21 and 65 mo after diagnosis, with the median time of survival not yet reached (at least 32 mo). All seven adverse events occurred within 7 mo of diagnosis. Event-free survival for all patients is 77%, for Stage III patients is 80%, and for patients with marrow and/or CNS involvement is 70%. This pilot study offers encouragement for improvement in the prognosis of children with "poor-risk" nonlymphoblastic lymphoma and merits evaluation in a Phase III randomized trial in the multicenter cooperative group setting.
Adolescent↗
Aggressive management of second primary tumors in survivors of hereditary retinoblastoma.
Survivors of hereditary retinoblastoma are at increased risk for the development of second primary tumors, most commonly osteosarcoma. Recent molecular genetic data demonstrate that a pleiotrophic effect of the retinoblastoma gene may be responsible for the development of these sarcomas. This report describes the incidence of second nonocular malignancies among 53 infants seen at Stanford University Medical Center who have been followed a median of 11.7 years. Of these, 42 initially had bilateral disease and eleven had unilateral disease. Of 53 infants, 50 received irradiation either as part of the initial therapy or as treatment for recurrent disease. The actuarial survival for the entire group is 67% at 30 year follow-up with a median survival of 79% at 11.7 years. Eight patients developed eleven second primary tumors. All occurred in the group having hereditary retinoblastoma. Eight were within the previously irradiated field and three were at distant sites. The second tumors included seven osteosarcomas, one angiosarcoma, one rhabdomyosarcoma, one malignant fibrous histiocytoma, and one unclassifiable round blue cell tumor. The actuarial incidence of the development of a second primary malignancy was 6% at 10 years, 19% at 20 years, and 38% at 30 years. The latent period from treatment of retinoblastoma to the diagnosis of malignancy ranged from 5.2 years to 36.2 years (median 16 years). An aggressive approach with combined modality therapy including radical resection, re-irradiation and/or chemotherapy was used to treat these second primary tumors in five of eight patients. In four of the five, there was no evidence of disease at 22-72 months following treatment. In the three patients who did not receive aggressive combined treatment, there were no survivors. These data confirm the previously reported risk of developing a second primary tumor among survivors with hereditary retinoblastoma. Careful long-term follow-up for this genetically susceptible group is essential for early detection and implementation of curative therapy.
Bone Neoplasms↗
Pediatric Hodgkin's disease: pulmonary, cardiac, and thyroid function following combined modality therapy.
Since pediatric Hodgkin's disease is a curable malignancy, it is essential to limit treatment sequelae. This study examines post-treatment pulmonary, cardiac, and thyroid function in 34 children, ages 5 to 17 (23 male and 11 female) with Hodgkin's disease. All received combined modality therapy of 6 cycles of alternating ABVD/MOPP chemotherapy and low dose (1500-2500 cGy) involved field radiotherapy. Mean follow-up period is 27.5 months with actuarial freedom from relapse of 94% and survival of 92%. Twenty asymptomatic patients underwent pulmonary function testing following chemotherapy and supradiaphragmatic radiotherapy. Eleven patients had post-treatment carbon monoxide diffusing capacity (DLCO) performed. Six of 11 children (55%) had abnormal values (mean 66%, range 58-80) showing either a reduced DLCO compared to pretreatment or an low absolute value. Eight of the twenty patients (40%) tested post-treatment for FEV1, FVC, TLC and flow volume loop had abnormal results. Six showed restrictive abnormalities and two had obstructive dysfunction. Fourteen patients underwent cardiac nuclear gated angiogram after completion of chemotherapy. Two asymptomatic patients (14%) had abnormal scans showing either a low resting ejection fraction or a decreased response to exercise. Thyroid function was evaluated post-treatment in twenty-one patients by TSH, T4, free T4 or sensitive TSH analysis. Four (21%) had an elevated TSH with a normal T4 after treatment. Although post-treatment thyroid and cardiac effects were minimal, post-treatment pulmonary dysfunction in asymptomatic patients was substantial with more than 50% of tested children demonstrating an abnormal DLCO and 40% showing restrictive or obstructive pulmonary parameters. These abnormalities were observed following a maximum bleomycin dose of 60 units/m2. Bleomycin and pulmonary radiotherapy have adverse effects on diffusing capacity and the long-term pulmonary sequlae of combined ABVD chemotherapy and radiotherapy are unknown. Our analysis suggests that even in asymptomatic children, pulmonary abnormalities are frequent.
Adolescent↗
Cerebellar atrophy caused by high-dose cytosine arabinoside: CT and MR findings.
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Atrophy↗
Clinical investigations of children with Hodgkin's disease at Stanford University Medical Center. A preliminary overview using low-dose irradiation and alternating ABVD/MOPP chemotherapy.
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Adolescent↗
Treatment of osteosarcoma.
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Antineoplastic Agents↗
Philadelphia chromosome-positive acute lymphoblastic leukemia cell lines without classical breakpoint cluster region rearrangement.
The Philadelphia (Ph) chromosome translocation which is classically observed in chronic myeloid leukemia (CML) is sporadically found in acute lymphoblastic leukemia (ALL). In CML the translocation breakpoint on chromosome 22 is within the breakpoint cluster region, while in childhood ALL, no detectable change in breakpoint cluster region is routinely observed. In order to investigate the nature of this difference, we have established and characterized two cell lines from a child with Ph positive ALL. The cell lines have retained the cytochemical staining pattern, enzyme activity, monoclonal antibody profile, and immunoglobulin gene rearrangements of the child's malignant cells. The cell lines had the same Ph translocation t(9;22) (q34;q11) as the child's malignant cells along with additional chromosome changes. Southern blot analysis showed that the Ph translocation did not involve the 5.8-kilobase breakpoint cluster region segment characteristically seen in CML. The cell lines reported here will be a valuable resource in ascertaining the biological significance of the Ph translocation seen in ALL.
Adenosine Deaminase↗
Clinical and biologic characterization of T-cell neoplasias with rearrangements of chromosome 7 band q34.
In T cell malignancy, rearrangements of chromosome 14 have been observed with a break in the band that contains the alpha chain gene for the T cell receptor (TCR). Because the beta chain TCR gene is in chromosome band 7q34, we searched for and report finding specific rearrangements of 7q34 exclusively in T cell malignancies. The rearrangements were reciprocal translocations between 7q34 and other points: 1p34, 9q32, 9q34, 15q22, and 19p13. The malignancies containing a 7q34 translocation were either T cell acute lymphoblastic leukemias or T cell lymphoblastic lymphomas that had similarities in clinical, enzyme, immunologic, and cellular characteristics. Hybridization using a probe to the beta-TCR gene disclosed unique rearrangements consistent with clonality in every case. A common pattern with chromosome breakpoints involving TCR genes may be emerging in T cell neoplasia.
Adenosine Deaminase↗
Idiotype as a tumor-specific marker in childhood B cell acute lymphoblastic leukemia.
Immunoglobulin (Ig) or idiotype (Id) is a tumor-specific target in those B cell malignancies that express this molecule on their surface. We explored the biology of B cell acute lymphoblastic leukemia (B cell ALL) using Id as a tumor marker. In this report we describe the development of anti-Id monoclonal antibodies (MAB) for two children with B cell ALL. These reagents were used retrospectively to study tumor kinetics and to detect residual disease after chemotherapy. In both cases serum Id values were strikingly high at diagnosis (1.2 mg/mL and 10.8 mg/mL), suggesting that the tumor cells were relatively mature B cells capable of significant antibody production. In both patients the serum Id levels fell with the institution of therapy and confirmed that the patients were in remission. Increasing serum Id predicted relapse four months before conventional methods in patient 1, and Id proved to be a more sensitive measure of tumor burden than Southern blot analysis of rearranged Ig genes in bone marrow samples. Surprisingly, low levels of Id were redetected in the second patient just before completing therapy and have persisted for over a year despite the absence of clinical evidence of recurrent disease. Thus, serum Id levels reflect tumor burden during initial therapy but may not necessarily predict tumor progression after a complete clinical remission.
Adolescent↗
Absence of cell surface LFA-1 as a mechanism of escape from immunosurveillance.
During studies of T-cell recognition of autologous tumour cells, a number of tumour cell lines derived from patients with lymphoma proved to be poor stimulators of both autologous and allogeneic T-cell responses. Analysis of the tumour cell surface molecules indicated that expression of the lymphocyte-function-associated antigen, LFA-1, was lacking, whereas normal leucocytes from these patients expressed normal levels of LFA-1. Examination of other lymphoid tumours revealed that most high grade lymphomas, but not most low or intermediate grade lymphomas, do not express the LFA-1 molecule. Furthermore, in an initial survey, the tumours from 5 of 7 patients with non-relapsing large cell lymphomas expressed LFA-1 whereas only 3 of 18 patients with relapsing lymphomas had tumours that did so. These findings suggest that tumour cells lacking surface LFA-1 cannot initiate an effective immune response in vivo. This lack of immunogenicity might contribute to escape from immunosurveillance.
Antigens, Surface↗
Establishment and characterization of a common acute lymphoblastic leukemia cell line with a deletion of chromosome 3 band q26.
This paper describes the establishment and characterization of a new cell line (SUP-B7) which was established from a child with "common" acute lymphoblastic leukemia. The SUP-B7 cells (and the patient's tumor) have been characterized by cytochemical staining, monoclonal antibodies, enzyme analyses, gene rearrangement studies, and karyotype analysis. The SUP-B7 cells are periodic acid-Schiff positive, common acute lymphoblastic leukemia antigen positive, and terminal deoxynucleotidyl transferase positive, and they lack the Epstein-Barr virus genome. In addition, the SUP-B7 cells lack cytoplasmic and surface immunoglobulins, and the immunoglobulin gene rearrangement studies showed rearranged heavy chain genes with germ line light chain genes. Concordance between the cell line and the patient's tumor was established by the immunoglobulin gene rearrangement studies. Using Southern blot analysis of the DNA from the patient's tumor and the SUP-B7 cells, there was comigration of the bands representing the rearranged immunoglobulin heavy chain gene. In addition, the SUP-B7 cells possess a single chromosome abnormality: del(3)(q26q28), with the chromosome breakpoint at or near the transferrin receptor gene. Since the SUP-B7 cell line is concordant with the patient's malignancy and since these cells possess a single chromosomal abnormality, the SUP-B7 cell line may be a useful tool in determining the biological significance of the chromosome deletion: del(3)(q26q28).
Antigens↗
Quantitation and estimation of lymphocyte subsets in tissue sections. Comparison with flow cytometry.
A quantitation method for lymphocyte subsets in immunoperoxidase-stained frozen tissue sections was compared with flow cytometry in 23 cases of non-Hodgkin's lymphoma. Close correlations were obtained, demonstrating the accuracy of the technic. Weak intensity of fluorescence and fragility of the tumor cells during the fluorescence-activated cell sorter (FACS) analyses were the most likely explanations for a number of the discrepancies observed. The tissue quantitation method was precise, particularly at low values, where it was better than the FACS. A simpler and faster estimation method employing categories within 10 percentage units was also tested in this study; this method correlated as well with the FACS as the quantitation method and gave the best interobserver correlations.
Antigens, Differentiation, T-Lymphocyte↗
Combined modality treatment with low-dose radiation and MOPP chemotherapy for children with Hodgkin's disease.
High doses of radiation administered to children with Hodgkin's disease may be associated with long-term alterations in soft tissue and bone growth. In an attempt to minimize this complication, we initiated a protocol using low doses of radiation in conjunction with six cycles of MOPP (nitrogen mustard, vincristine, procarbazine, prednisone) chemotherapy in newly diagnosed, pathologically staged children with Hodgkin's disease. Of 55 children treated in this fashion, the actuarial survival and freedom from relapse rates are 89% and 90%, respectively, with median follow-up of 7 1/2 years and maximum follow-up of 15 1/2 years. The local control rate is 97%. The previously encountered growth alteration did not occur when lower doses of radiation were used. However, three children developed acute leukemia. This study demonstrates that the vast majority of children with Hodgkin's disease can be cured with combined modality therapy. This experience provides long-term follow-up and thus serves as the basis for new ongoing protocols using low-dose involved field radiation with new drug combinations.
Adolescent↗