Detection and partial characterization of human thymus-leukemia antigens.

Two monkey antisera against human thymocytes after absorption with human erythrocytes and peripheral blood leukocytes were shown to detect human thymus-leukemia (HTL)-like antigens. These sera were cytotoxic for thymocytes (> 90% lysis at a 1:10 dilution) but were nonreactive with enriched peripheral blood T- and B-lymphocytes or with cells from myeloid or B-cell lymphoid leukemias. Most (16/17) sheep erythrocyte rosette-forming acute lymphoblastic leukemia (ALL) cells reacted with these sera. Cells from patients with T-cell chronic lymphocytic leukemia, lymphoblastic lymphoma (LBL), and thymoma were also positive. Three of 4 T-cell lymphoblastoid lines derived from ALL patients reacted with these sera. Absorption of the sera with MOLT-4F cells, thymocytes, or LBL cells removed the reactivity against all types of cells tested. However, sera absorbed with the T-cell line HSB remained cytotoxic for thymocytes, MOLT-4F, and most (6/9) T-cell cancers tested. The peripheral blood cell-absorbed sera precipitated a molecule with an apparent molecular weight of 48,000 from lactoperoxidase-labeled thymocytes but not from similarly labeled peripheral blood lymphocytes. The ability of the sera to precipitate this antigen was decreased by absorption with thymocytes, MOLT-4, or LBL cells but not by absorption with HSB, SB, or non-T, non-B ALL cells. Sequential precipitation studies suggested that the HTL antigen was not associated with beta 2 microglobulin.

Environmental factors in the etiology of rhabdomyosarcoma in childhood.

In a case-control study of childhood rhabdomyosarcoma (RMS), families of 33 cases and 99 controls were interviewed. A relative risk (RR) of 3.9 was found associated with fathers' (but not mothers') cigarette smoking (P = 0.003). Cases had had fewer immunizations than controls, particularly smallpox vaccination (RR = 0.2; P = 0.001), and conversely had more preventable infections. An RR of 3.2 (P = 0.03) was found associated with exposure to chemicals and and RR of 3.7 (P = 0.004) was found associated with diets that included organ meats. Mothers of cases were more likely to be over age 30 years at subject's birth, to have used antibiotics preceding or during pregnancy, and to have had an overdue and/or assisted delivery. Other findings suggest that low socioeconomic status is associated with an increased risk of RMS. These aggregate findings imply that environmental factors may play an important role in the etiology of childhood RMS.

Wilms' tumor and paternal occupation.

A case-control study was conducted to examine the relationship between Wilms' tumor and paternal occupational exposures. The case group consisted of 200 children diagnosed as having Wilms' tumor who were registered at selected National Wilms' Tumor Study institutions during the period June 1, 1984, to May 31, 1986. Disease-free controls were matched to each case using a random digit dialing procedure. The parents of cases and controls completed a self-administered questionnaire. There was no consistent pattern of increased risk for paternal occupational exposure to hydrocarbons or lead found in this study. However, certain paternal occupations were found to have an elevated odds ratio (OR) of Wilms' tumor, including vehicle mechanics, auto body repairmen, and welders. Offspring of fathers who were auto mechanics had a 4- to 7-fold increased risk of Wilms' tumor for all 3 time periods. The largest increased odds ratio for auto mechanics was in the preconception period [OR = 7.58; 95% confidence interval (CI) = 0.90-63.9]. Welders had a 4- to 8-fold increased odds ratio, with the strongest association during pregnancy (OR = 8.22; CI = 0.95-71.3). Although chance cannot be excluded as a possible explanation, association of Wilms' tumor with these occupations has been reported in previous studies. Further study is needed to provide data on the specific occupational exposures involved.

S-adenosylhomocysteine catabolism and basis for acquired resistance during treatment of T-cell acute lymphoblastic leukemia with 2'-deoxycoformycin alone and in combination with 9-beta-D-arabinofuranosyladenine.

A patient with refractory T-cell acute lymphoblastic leukemia was treated with eight courses of the adenosine deaminase inhibitor, 2'-deoxycoformycin (dCF), over a 5-month period. After developing resistance to dCF, he responded to treatment with the combination of dCF and 9-beta-D-arabinofuranosyladenine (ara-A). We monitored the levels in plasma and urine of adenosine, 2'-deoxyadenosine, and ara-A as well as the accumulation of their nucleotide derivatives in erythrocytes and circulating lymphoblasts. We also monitored the activities of adenosine deaminase and S-adenosylhomocysteine (AdoHcy) hydrolase and the concentrations of AdoHcy and S-adenosylmethionine in lymphoblasts. Production of 2'-deoxyadenosine was related to both the duration of dCF infusion and the magnitude of cytolysis that occurred during treatment: much more 2'-deoxyadenosine was produced by dCF infusion when disease was active than by the same infusion given during remission. Resistance to dCF was associated with a decrease of greater than 90% in the amount of deoxyadenosine 5'-triphosphate accumulated by circulating lymphoblasts. Infusion of dCF resulted in increases of up to 20-fold in the concentration of AdoHcy in circulating lymphoblasts, causing a decrease in the S-adenosylmethionine:AdoHcy ratio (the "methylation index") from a pretreatment value of greater than 40:1 to less than 4:1. This ratio decreased to 2.5:1 during combined treatment with dCF and ara-A, which caused nearly complete inactivation of lymphoblast AdoHcy hydrolase. Decline in the methylation index was accompanied by inhibition of the methylation of newly synthesized lymphoblast RNA. Impaired ability to catabolize AdoHcy may have contributed to the cytolytic responses to dCF and ara-A, as well as to hepatic and central nervous system toxicity associated with their combined use.

Clinicopathologic aspects of E rosette negative T cell acute lymphocytic leukemia: a Pediatric Oncology Group study.

The Pediatric Oncology Group has studied 1,367 patients with non-B cell acute lymphocytic leukemia (ALL) of whom 186 (14%) had blasts that reacted with previously well-characterized heteroantisera, recognizing a T-lymphocyte specific surface membrane antigen (PT+). In 87 of these T cell cases, the leukemic cells failed to form at least 20% of sheep erythrocytic rosettes at 4 degrees C. Comparison of clinicopathologic features among PT-, E-PT+, and E+ groups of patients revealed significant differences among them. E-PT+ patients were older than PT- patients, had higher white blood cell counts (WBCs) and were more likely to have a mediastinal mass, and thus contained a higher proportion of poor-risk patients. However, the E-PT+ patients were also significantly different from the more traditionally-defined E+ patients in that they had lower WBCs and hemoglobin levels, and less frequent lymphadenopathy or mediastinal mass. In many respects, then, E-PT+ patients were intermediate in character between PT- and E+ patients. Our findings support the notion that further subclassification of ALL using antibodies recognizing lineage-specific surface determinants will permit recognition of groups of patients with distinct clinicopathologic features that may differ in prognosis or response to therapy. Such classification also focuses future biological studies on the pathogenesis of leukemias to immunologically well-defined subgroups of lymphoid neoplasms.

Treatment of children with progressive or recurrent brain tumors with carboplatin or iproplatin: a Pediatric Oncology Group randomized phase II study.

PURPOSE: The Pediatric Oncology Group (POG) conducted a randomized phase II study to evaluate the activity of carboplatin and iproplatin in children with progressive or recurrent brain tumors. PATIENTS AND METHODS: The study was designed to evaluate the activity of these agents and to compare the toxicities associated with their use. Treatment consisted of carboplatin 560 mg/m2 at 4-week intervals or iproplatin 270 mg/m2 at 3-week intervals. RESULTS: The major toxicity observed was myelosuppression, particularly thrombocytopenia, for both agents. Ototoxicity (grade 1 or 2) was seen in 2.5% of patients treated with carboplatin and 1.3% of patients treated with iproplatin. The majority of patients with low-grade astrocytic neoplasms treated with carboplatin (nine of 12 patients) or iproplatin (eight of 12 patients) demonstrated tumor response or prolonged stable disease that persisted off-therapy. The duration of stable disease produced by carboplatin was particularly striking, ranging from 2 months to 68 + months (median, 40 + months). Neither drug demonstrated appreciable activity in the treatment of medulloblastoma (two of 26 responses to carboplatin, one of 14 responses to iproplatin), ependymoma (two of 17 responses to carboplatin, none of seven responses to iproplatin), high-grade glioma (two of 19 responses to carboplatin, one of 14 responses to iproplatin), or brain-stem tumors (one of 23 responses to carboplatin, none of 14 responses to iproplatin). CONCLUSION: Carboplatin is active against low-grade gliomas. Further evaluation of the role of carboplatin in the preirradiation treatment of children with low-grade gliomas of the optic pathway is currently underway in a clinical trial.

Different patterns of relapse associated with three intensive treatment regimens for pediatric E-rosette positive T-cell leukemia: a Pediatric Oncology Group study.

One hundred and ninety-three children with T-cell acute lymphocytic leukemia (T-ALL) whose leukemia cells were E-rosette positive were treated on a Pediatric Oncology Group study (1979-1986) designed specifically for patients with T-ALL. The results of modified LSA2L2 therapy with or without intensified intrathecal chemotherapy and cranial irradiation (radiotherapy) were compared with those obtained using a simpler multi-agent protocol which included radiotherapy (T-cell 2). The complete remission (approximately 90%) and 3-year event-free survival rates (approximately 40%) were similar in the three treatment groups. However, the pattern of extramedullary relapse varied according to specific treatment regimen. Patients who received LSA2L2 therapy with less intensive intrathecal chemotherapy and no radiotherapy had a central nervous system (CNS) relapse rate (i.e. isolated CNS +/- other site) of over 20%, compared to only 10% for patients receiving the same systemic chemotherapy with intensified intrathecal therapy and radiotherapy, and less than 5% for those receiving T-cell 2 therapy. In contrast, males receiving T-cell 2 therapy had a testicular relapse rate of greater than 20% compared to less than 10% for patients receiving either regimen (i.e. +/- intensified intrathecal chemotherapy and radiotherapy) of modified LSA2L2 therapy. We conclude that, in the context of these therapies, central nervous system irradiation plus intensive triple (hydrocortisone, methotrexate, cytarabine) intrathecal chemotherapy is more effective than CNS preventative therapy comprised of intrathecal low-dose methotrexate only, and that the more complex multi-agent chemotherapy used in the modified LSA2L2 regimens appeared to be more effective in prevention of testicular leukemia, indicating that the effectiveness of sanctuary site treatment was therapy-specific.

Immunologic chimerism as evidence of bone marrow graft acceptance in an identical twin with acute lymphocytic leukemia.

Bone marrow from a well child was infused into her identical twin who had acute lymphocytic leukemia. In an attempt to provide an immunologic tag for use in twin transplantation, the donor twin was immunized to Keyhole limpet hemocyanin (KLH) and yellow fever virus prior to the marrow infusion. Subsequent immunological chimerism in the recipient twin gave evidence for graft acceptance.

Treatment of patients with recurrent primary brain tumors with AZQ.

We have evaluated the efficacy of intravenous 2,5-diaziridinyl-3,6-biscarboethoxyamino-1,4-benzoquinone (diaziquone or AZQ, NSC-182986) in the treatment of recurrent primary anaplastic brain tumors. Three of 16 evaluable patients (18.8%) showed clinical and radiographic improvement that permitted discontinuation of corticosteroids, 4 patients (25%) showed either clinical or radiographic improvement and were considered partial responders, and 9 patients (56.2%) showed no effects after two courses of AZQ. The treatment was well tolerated, and hematologic toxicity was mild. Pharmacokinetic studies indicated rapid decay of the parent compound from plasma using two different infusion schedules. These results compare favorably with those obtained using the nitrosoureas or procarbazine as single agents.

Criteria for termination of phase II chemotherapy for patients with progressive or recurrent brain tumor.

We report six patients with progressive primary tumors of the brain who had prolonged periods with stable contrast-enhancing CT lesions following initial responses to chemotherapy. Chemotherapy was discontinued after 21 to 36 months, despite the persistence of apparent disease in each patient. PET using (F-18) fluorodeoxyglucose was performed in three patients, revealing hypometabolic lesions. All six patients are alive and well, with no clinical or radiographic evidence of progressive disease at 24 to 57+ months following termination of treatment. The usual criteria for terminating phase II chemotherapy in patients with a recurrent brain tumor are evidence of progressive disease or unacceptable toxicity. However, chemotherapeutic success mandates that these criteria be expanded to include patients whose response following the initiation of phase II treatment is followed by prolonged (greater than 1 year) radiographic and clinical stability. Complete response, ie, disappearance of all evidence of disease, is unusual in patients with recurrent primary brain tumors, even with highly effective therapy. Continued improvement in the therapy of patients with these tumors will allow wider application of these criteria.

Treatment of platelet alloimmunization with intravenous immunoglobulin. Two case reports and review of the literature.

Two pediatric patients with severe aplastic anemia, elevated antiplatelet antibody levels, refractoriness to human lymphocyte antigen-matched platelet transfusions, and sustained bleeding problems were treated with intravenous immunoglobulin (IVIG), pH 4.25, for three to over nine months. Improved responses to platelet infusions and improved hemostasis were demonstrated in both patients. A review of the published literature analyzing the role of IVIG in the treatment of platelet alloimmunization is presented.

Efficacy of intravenous gamma globulin in autoimmune-mediated pediatric blood dyscrasias.

Sixteen pediatric patients diagnosed with a variety of autoimmune-mediated hematocytopenias were treated with one to 50 courses of intravenous gamma globulin (IVIG), pH 4.25, over the course of one to 30 months. Thirteen patients had immune thrombocytopenic purpura (ITP), two had autoimmune neutropenia, and one had autoimmune hemolytic anemia. In one patient, chronic ITP was associated with systemic lupus erythematosis, and in a second patient, acute ITP was the presenting manifestation of infection with human immunodeficiency virus. Initial therapy consisted of 400 mg/kg/dose daily for five days for the first seven patients treated, and 1,000 mg/kg/dose daily for two days for the remaining nine patients. In 15 of 16 patients, there was a response to IVIG therapy. In nine of 16 patients, maintenance IVIG therapy for two to more than 30 months was required. Minimal toxicity was experienced in four of 210 separate infusions. Data are presented to support the use of IVIG in the management of childhood autoimmune disorders.

Laboratory correlates and prognostic significance of granular acute lymphoblastic leukemia in children. A Pediatric Oncology Group study.

As part of a comprehensive prospective clinicopathologic study by the Pediatric Oncology Group (POG), 2,092 children with acute lymphoblastic leukemia (ALL) were evaluated by uniform morphologic, cytochemical, and immunologic methods to assess the frequency and implications of granular lymphoblasts. All cases were Sudan black or myeloperoxidase negative and met French-American-British (FAB) morphologic criteria for ALL. Granular ALL, characterized by the presence of more than 5% marrow blasts with at least three clearly defined azurophilic cytoplasmic granules, was identified in 56 of the 1,252 fully studied cases (4.5%). The frequency of granular features did not differ among early pre-B (4.3%), pre-B (3.6%), and T (5.8%) ALL; no cases were identified among the 12 patients with B ALL. Within the early pre-B/pre-B group, granular ALL was equally distributed between good- and poor-risk clinical groups but was more frequent among FAB L2 than FAB L1 cases (12% vs. 2%; P less than or equal to 0.001). Patients were treated with standard POG protocols for early pre-B/pre-B and T ALL. Complete remission (CR) rates were significantly lower for those with granular lymphoblasts, regardless of risk group, immunophenotype, or FAB type. Analysis of event-free survival (EFS) showed a significantly poorer outcome for granular early pre-B/pre-B cases with FAB L2 morphologic characteristics (P less than 0.001) and for those classified as poor risk (P = 0.015). These findings suggest a relationship between granules and L2 morphologic characteristics in childhood ALL and indicate that the presence of granular lymphoblasts conveys a worse prognosis for certain subgroups of children with ALL.

Pediatric oncology group utilization of immunologic markers in the designation of acute lymphocytic leukemia subgroups: influence on treatment response.

The clinical application of blast cell immunophenotype testing is important in childhood ALL for the following reasons. (1) Knowledge of the immunologic group is important in predicting prognosis. Prognostic grouping may prove to be accomplished best by using a combination of traditional risk factors and immunologic phenotyping. However, definition of traditional risk factors may vary within the immunologic groups of ALL. (2) In assessing the relative effectiveness of different treatment regimens for children with ALL it is important to make comparisons among patients within the same major immunologic groups of ALL. (3) Identification of specific immunologic groups of patients within ALL may help in designing therapy for each group. The POG has already made preliminary attempts in this direction for T-ALL and B-ALL. However, leukemia species-specific therapy is still only a long-range goal. Laboratory research must endeavor to identify additional biologic characteristics peculiar to each major immunologic group of ALL. These characteristics may dictate therapeutic maneuvers in the future.

9p- in a girl with acute lymphocytic leukemia and sickle cell disease.

A 4 year old girl with sickle cell disease developed acute lymphocytic leukemia null cell type. The bone marrow karyotype was 46,XX,del(9)(p13). This girl is among the few patients with acute lymphocytic leukemia and abnormalities of #9 to have an isolated 9p-.

Treatment of trilateral retinoblastoma with vincristine and cyclophosphamide.

Current therapy for patients with trilateral retinoblastoma, consisting primarily of surgical intervention and radiotherapy, has resulted in no long-term survivors. The use of adjuvant chemotherapy has not improved this outcome. After observing a tumor response to cyclophosphamide in a patient with suprasellar retinoblastoma, we treated a subsequent patient with trilateral retinoblastoma with both vincristine and cyclophosphamide. Objective tumor regression resulted. Although the tumor ultimately progressed in both patients, these findings suggest that vincristine and cyclophosphamide are active in patients with intracranial (trilateral) retinoblastoma.

Efficacy of vincristine and cyclophosphamide in the therapy of recurrent medulloblastoma.

We conducted a Phase II study of combination therapy with vincristine and cyclophosphamide in the treatment of patients with recurrent or metastatic medulloblastoma. Fourteen patients were treated with vincristine 2 mg/m2 (2.0-mg maximal dose) by intravenous bolus on Day 1 and cyclophosphamide 1 g/m2 by intravenous infusion on Days 1 and 2, with cycles repeated every 4 weeks. All 4 patients with extraneural disease (biopsy-proven bony metastases) responded (duration of responses 2+, 6+, 8, and 16+ months) and 4 of 8 evaluable patients with neuraxis disease responded (duration of response 2, 2+, 2+, and 21+ months). Toxicity was limited to neutropenia without any episodes of infection. These therapeutic results compare favorably with other reports of therapy for recurrent medulloblastoma and support the inclusion of vincristine and cyclophosphamide in randomized adjuvant therapy trials of patients with medulloblastoma.

Leukemias and lymphomas of thymic differentiation.

Neoplasms of thymic T-cell derivation include two closely related malignancies: T-cell acute lymphoblastic leukemia (T-ALL) and T-cell lymphoblastic lymphoma. The recognition of these tumors as distinct biologic entities dates back to the early 1970s, when patients with these diseases were found to have tumor cells that formed spontaneous rosettes with sheep erythrocytes. In the last decade, however, the growth of new technologies and availability of new reagents has enabled us to characterize this group of diseases with more precision. When studied with a panel of monoclonal antibodies, there is tremendous phenotypic diversity in the types of T-cell leukemias that are encountered. In spite of this diversity, a few general facts have become apparent. To a first approximation, thymic T-cell malignancies can be related to stages of normal T-cell development. Surprisingly, in spite of the overall similarity between T-ALL and T-lymphoblastic lymphoma, the antigenic phenotypes encountered suggest a biologic difference between these two diseases. Although there is not currently any single reagent that permits recognition of T-ALL or lymphoblastic lymphoma in all cases, a combination of technologic approaches using conventional morphology and histochemistry, immunologic studies, and, in some cases, newer genetic studies should permit great precision in the definition of this disease. The clinical picture of T-cell ALL or lymphoblastic lymphoma has traditionally been one of a poor prognosis disease with high WBC count, bulky adenopathy, and mediastinal mass. Although encountering this clinical presentation should suggest the T-cell phenotype, not all patients with T-cell leukemia will fit this stereotype. Clinical studies have also served to provide support for the expanding biologic definition of T-cell neoplasia, particularly insofar as it has been demonstrated that patients with T antigen-positive but E rosette-negative ALL behave like other patients with T-cell disease. In short, patients with thymic T-cell malignancies not only have distinctive biologic characteristics to their blasts, but also have a distinctive pattern of clinical presentation, response to therapy, and sites of relapse. These differences have prompted the search for specific therapies and also directed approaches to understanding the variable clinical outcome of patients with these malignancies.

Pulmonary septic emboli mimicking metastatic rhabdomyosarcoma.

Central venous catheters have proven to be an important aid for the care of pediatric patients with malignancies receiving chemotherapy. A rare complication of such catheters is pulmonary septic emboli. This report describes a 15-year-old white girl with rhabdomyosarcoma who developed pulmonary nodules while on chemotherapy. These lesions appeared to be metastatic rhabdomyosarcoma. However, an excisional biopsy showed the lesions to be septic emboli. The patient was placed on antibiotic therapy and responded well. She was able to continue with her "front-line" therapy because the nodules were confirmed not to be metastatic disease.

Retinoblastoma metastatic to bone marrow. A case with florid spread.

A 28-month-old white male, 7 months status postenucleation for retinoblastoma, presented with lethargy, irritability, anemia, and thrombocytopenia. Bone marrow examination revealed almost total replacement of marrow elements with clumps of small round basophilic cells. Electron microscopic study of the marrow revealed clumps of cohesive tumor cells with intermediate junctions, establishing a diagnosis of metastatic retinoblastoma.