Childhood cancer: patterns of protocol participation in a national survey.

Cancer is still the chief cause of death by disease in children, ages one to 14. As improved survival rates have been reported for pediatric cancer patients who are treated on controlled clinical trials, it is important to understand the national utilization of such protocols. In 1993, a survey of childhood cancer was conducted by the Commission on Cancer of the American College of Surgeons. Data regarding type of disease, protocol participation, age, sex, race, insurance, and geographical region were voluntarily submitted by more than 200 hospital cancer registries. Included in this study were 2,208 children and adolescents 21 years of age or younger who were diagnosed in 1987, and 2,293 who were diagnosed in 1992. Pediatric centers (i.e., members of the Pediatric Oncology Group or Children's Cancer Group) submitted 55.1% of the cases and other institutions, 44.9%. It was found that more patients treated at pediatric centers were on protocols (53.8%) than were those treated at other institutions (25.1%). In general, the younger the patient (five years of age or younger), the greater the chance of being on protocol (pediatric centers, 63.7%; others, 42.0%), with very poor adolescent protocol participation (pediatric centers, 34.8%; others, 12.1%). Nevertheless, overall protocol participation was still lower than expected, even in children younger than five years of age, and adolescent participation in controlled clinical trials was low and similar to adult figures. The percentage of childhood cancer cases seen at pediatric centers was smaller than in other series. It was concluded that pediatric cancer centers need to continue to encourage patient participation in controlled clinical trials, with special emphasis on adolescents.

Epidemiology of osteosarcoma and Ewing's sarcoma in childhood: a study of 305 cases by the Children's Cancer Group.

BACKGROUND: The Children's Cancer Group conducted a case-control study to determine the role of a broad range of environmental and familial factors in the etiology of Ewing's sarcoma and osteosarcoma in children. These factors included radiation exposure and, for children with osteosarcoma, parental exposure to beryllium. METHODS: The parents of 152 children with osteosarcoma and 153 children with Ewing's sarcoma were interviewed by telephone. Controls were obtained by random digit dialing and were matched to cases by age and race. RESULTS: Female osteosarcoma patients had earlier onset of breast development (age 11.4 vs. 11.8 years, P=0.03) and menarche (age 12.1 vs. 12.5 years, P=0.002) but no significant differences in growth, whereas male osteosarcoma patients were similar in age at the onset of secondary sexual characteristics but reported significantly less weight gain during their growth spurt (6.6 vs. 11.7 kg, P=0.003). For children with Ewing's sarcoma, the growth spurt began earlier (age 12.1 vs. 12.7 years, P=0.12) and resulted in less weight and height gain (5.2 vs. 9.7 kg, P=0.002, and 10.2 vs. 12.7 cm, P=0.02, respectively) for males, but no differences were observed among females. For factors not related to growth and development (including a wide range of occupational, medical, and household exposures), there was little evidence of an etiologic role with respect to either tumor type. CONCLUSIONS: Differences between cases and controls with respect to growth and development showed no consistent pattern. This study did not identify any important risk factors for either type of childhood bone tumor.

High dose chemotherapy with autologous peripheral blood progenitor cell transplantation in an anephric child with multiply recurrent Wilms tumor.

PURPOSE: An autologous peripheral blood progenitor cell (APBPC) transplant in an anephric child with multiply recurrent Wilms tumor using a conditioning regimen of high dose chemotherapy in conjunction with hemodialysis (HD) and peritoneal dialysis is described. PATIENT AND METHODS: The child had a left nephrectomy at 9 months of age for a stage II Wilms tumor. At 6 years of age, she required a right nephrectomy because of progressive, recurrent disease unresponsive to treatment with doxorubicin, actinomycin, and vincristine. She was maintained on peritoneal dialysis. Salvage chemotherapy consisted of 5 cycles of carboplatin and cyclophosphamide after APBPCs were collected after granulocyte colony-stimulating factor mobilization. After a preparative regimen of carboplatin, cyclophosphamide, and etoposide with closely timed HD, peripheral blood progenitor cells were infused and peritoneal dialysis was resumed. RESULTS: No nonhematopoietic toxicity occurred. Pharmacokinetic studies demonstrated that HD effectively eliminated carboplatin and provided safe, effective plasma concentrations in this anephric patient. Trilineage engraftment occurred by day +10 and the child was discharged from the hospital on day +14. She had a local recurrence on day +194 and died of progressive disease on day +660. CONCLUSIONS: With dialysis support and dose modification, high-dose chemotherapy followed by APBPC transplantation can be successfully performed in the anephric child. Given the lack of organ toxicity in this patient, increased doses of the drugs used in this preparative regimen may be possible for anephric children.

Treatment of nonmetastatic osteosarcoma of the extremity with preoperative and postoperative chemotherapy: a report from the Children's Cancer Group.

PURPOSE: The specific aims of this study were to improve event-free survival (EFS) in patients with newly diagnosed nonmetastatic osteosarcoma of an extremity using the histologic response to neoadjuvant chemotherapy to determine postoperative chemotherapy; to evaluate a uniform histologic grading system that measures tumor response; and to identify patient characteristics that might influence EFS and survival. PATIENTS AND METHODS: Two hundred sixty-eight patients with nonmetastatic osteosarcoma of the extremity were entered between August 1983 and October 1986. Preoperative chemotherapy consisted of four courses of high-dose methotrexate (MTX) and one course of bleomycin, cyclophosphamide, and dactinomycin (BCD). Histologic response to preoperative chemotherapy was determined by morphometric analysis. Good histologic responders (< 5% residual viable tumor) were treated postoperatively with MTX, BCD, and doxorubicin (DOX); poor histologic responders were treated with BCD, DOX, and cisplatin (CDDP). RESULTS: The 8-year EFS and survival rates were 53% and 60%, respectively. Two hundred six patients had their tumors assessed for histologic response: 28% displayed a good histologic response to preoperative chemotherapy. Good histologic responders had an 8-year postoperative EFS rate of 81% and survival rate of 87%; those with a poor histologic response had an 8-year postoperative EFS rate of 46% and survival rate of 52%. A primary tumor site in the proximal humerus or proximal femur and an elevated serum alkaline phosphatase level were associated with an increased risk of an adverse event, whereas the type of surgical procedure was not. CONCLUSION: EFS and survival appear to be directly related to histologic response to neoadjuvant chemotherapy.

MR of intracranial Langerhans cell histiocytosis.

Langerhans cell histiocytosis (LCH) is a disease of children characterized by idiopathic proliferation of histiocytes in the reticuloendothelial system. Intracranial LCH involving the brain is uncommon. We present a case of LCH involving the dural venous sinuses and choroid plexus. Contrast MRI provided an excellent means of identifying the extent of tumor involvement and showed that the patient was at risk for venous sinus thrombosis.

Disseminated nonlymphoblastic lymphoma of childhood: a Childrens Cancer Group study, CCG-552.

PURPOSE: To assess the efficacy of a chemotherapy-only regimen in pediatric patients with disseminated non-lymphoblastic lymphoma and acute B-cell leukemia (B-ALL). PATIENTS AND METHODS: Sixty-eight eligible patients with previously untreated disseminated non-lymphoblastic lymphoma were enrolled on a Childrens Cancer Group study. Therapy included cycles of chemotherapy, systemic and intrathecal (IT), ever 3 weeks for a total maximal duration of 57 weeks. Fifty-five patients had small non-cleaved cell lymphoma (SNCCL) and 13 had diffuse large cell lymphoma (DLCL). Forty-seven were stage III, six were stage IV, and 15 had B-ALL; 13 had central nervous system (CNS) involvement. RESULTS: Four year event-free survival (EFS) was 53% (SE +/- 12%). Stage III SNCCL patients with LDH < 500 IU/L achieved an improved EFS compared to other SNCCL patients (86% vs. 42% 4 year EFS, P = .072). The primary site of failure for advanced stage SNCCL patients was the CNS. All Ki-1-positive DLCL patients relapsed. Patterns of failure, time to relapse, and outcome following relapse differed between SNCCL and DLCL patients. CONCLUSIONS: Advanced stage SNCCL requires better CNS-directed chemotherapy to reduce the CNS failure rate; however, the achievement of durable disease-free survival in four of 11 patients with CNS disease without use of cranial irradiation suggests merit for further evaluation of chemotherapy-only strategies. DLCL patients do not need intensive CNS-directed chemotherapy.

Two Down syndrome patients with an acquired translocation, t(8;14)(q11;q32), in early B-lineage acute lymphoblastic leukemia.

Two males with Down syndrome and acute lymphoblastic leukemia with the acquired translocation, t(8;14)(q11;q32), are described. In each case the constitutional karyotype was 47,XY,+21. The patients were, respectively, aged 3 years 11 months and 32 years, with presenting white blood counts 34 and 1.9 x 10(9)/L with blasts of FAB L1 and L2. In each case immunophenotype of the blasts was C-ALL. The child is alive and well and in first remission 6 years from diagnosis. In contrast, the adult patient died in first remission 8.5 months from diagnosis with severe pancytopenia. These are to our knowledge the second and third cases of ALL with t(8;14)(q11-12;q32) associated with a constitutional genetic disorder.

Two additional cases of t dic(9:12) in acute lymphocytic leukemia (ALL): prognosis in ALL with dic(9:12).

We report two occurrences of dic(9;12) in acute lymphoblastic leukemia and review previous cases. Cases of dic(9;12) share common features with cases of 9p and 12p rearrangements, but prognosis seems particularly good in cases of dic(9;12). The persistence of a specific dicentric in stable clones is remarkable and points to unusual centromeric behavior and/or marked selective advantage of the anomaly.

Biphenotypic leukemic lymphocyte precursors in CD2+CD19+ acute lymphoblastic leukemia and their putative normal counterparts in human fetal hematopoietic tissues.

During detailed immunophenotypic analyses of marrow blasts from 336 acute lymphoblastic leukemia (ALL) patients, a very small percentage of cases reactive with B-cell-directed as well as T-cell-directed monoclonal antibodies (MoAbs) were identified. Five ALL cases were biphenotypic since they coexpressed CD2 (Tp50) and CD19 (Bp95) antigens at the single-cell level. The composite immunophenotype of these biphenotypic ALL cases was [TdT+HLA-ABC+CD2+CD3-CD10+CD13-CD14-CD16-CD19+CD20+ ++-CD21-CD33-CD34+Bgp95-C mu- slg-]. Low-molecular-weight B-cell growth factor (LMW-BCGF), recombinant interleukin-2 (rIL-2), and rIL-3 stimulated the proliferative activity of biphenotypic leukemic lymphocyte precursors without inducing differentiation. In the presence of the phorbol ester TPA, leukemic blasts from two cases differentiated along the B precursor pathway to the [CD2-CD10+CD19+CD20+C mu+slg-] pre-B cell stage. Biphenotypic ALL cases did not share a common configuration and gene rearrangement pattern of the immunoglobulin heavy chain genes or T-cell receptor (TCR) genes. Three cases had rearranged C mu genes but germline TCR genes, one case showed rearrangement of both C mu and TCR genes, and the remaining case had rearranged TCR genes but germline C mu genes. All five patients attained prompt remission after standard induction chemotherapy. Three to four years after initial diagnosis, four patients are now off chemotherapy and remain alive in their first remission. One patient relapsed at 3 years, 7 months, but promptly achieved complete remission after reinduction chemotherapy and remains in second remission off chemotherapy greater than 3 years after her reinduction therapy. With two-color immunofluorescence staining techniques and multiparameter flow cytometric analyses, we identified a small population of CD2+CD19+ lymphoid cells in fetal livers (FLs) and fetal bone marrows (FBMs), which may represent the putative normal counterparts of biphenotypic ALL blasts. A CD2+CD19+ normal biphenotypic lymphoid precursor cell line, designated FL 8.2 CD2+, was established from an FL of 8-weeks of gestational age by Epstein-Barr virus (EBV)-induced blastoid transformation. The composite immunophenotype of FL 8.2 CD2+ cell line was [TdT+HLA-ABC+HLA-DR+ CD2+CD5-CD7-CD10+/-CD13-CD19+CD20-CD21+ CD22+CD33-CD34+/-Bgp95-CDw40+C mu-slgD-slgM-]. FL 8.2 CD2+ cells showed germline patterns of immunoglobulin heavy-chain joining region, heavy-chain constant region, kappa light-chain constant region genes, and TCR beta-chain genes. Cross-linking of CD2 as well as CD19 antigens on FL 8.2 CD2+ cells caused an increase of intracellular ionized calcium.(ABSTRACT TRUNCATED AT 400 WORDS)

Immunophenotype-karyotype associations in human acute lymphoblastic leukemia.

The present study is a detailed analysis of the cytogenetic features of leukemic cells from 104 immunologically classified acute lymphoblastic leukemia (ALL) (78 B lineage and 26 T lineage) cases. Clonal chromosomal abnormalities were found in marrow blasts from 77 of 104 (74%) cases. Hyperdiploidy was much more frequent in B-lineage ALL cases, whereas normal diploidy was more common in T-lineage ALL cases. Fifty-nine of 104 cases (46 of 78 B-lineage ALL and 13 of 26 T-lineage ALL cases) had structural chromosomal abnormalities. Structural abnormalities involving 2p11, 7p13, 7p22, proximal q arm of 7 (7q11 or 7q22), 11q23-24, and translocations involving 12p11-13 appeared to be B-lineage specific. By comparison, structural abnormalities involving 7p15, 7q32, and 14q11 displayed T-lineage specificity. Structural abnormalities involving 9p22-p23 or 14q32, del (6)(q21-q23), del (12)(p11-p13), and the Philadelphia chromosome were found in B-lineage as well as T-lineage ALL cases. This study expands the current knowledge about immunophenotype-karyotype associations in ALL.

Chest wall resection and reconstruction for malignant conditions in childhood.

This report evaluates the efficacy of extensive chest wall resection and prosthetic reconstruction in 15 children with chest wall malignancies. There were nine boys and six girls, with a mean age of 9.6 years. Eleven patients had primary chest wall tumors including Ewing's sarcoma (ES), six; rhabdomyosarcoma (RH), two; chondrosarcoma (CS), one; Askin's malignant neuroectodermal tumor, one; and mesenchymal sarcoma, one. Four children had metastases to chest wall and lung from Wilms' tumor (WT), two; osteogenic sarcoma (OS), one; and neuroblastoma (NB), one. Chest wall resection of two to six ribs and reconstruction with Marlex mesh (seven), lattisimus flap (two), prolene mesh (one), and more recently, a Gortex patch (five), was performed. Eight of the patients required concomitant en-bloc pulmonary resection (wedge, five; lobectomy, two; pneumonectomy, one) and two required resection of diaphragm. Fourteen received adjunctive therapy (chemotherapy, 14; irradiation, eight [preoperative, five; postoperative, three]. Six patients had second-look resections after chemotherapy. There was no operative mortality. Early pulmonary function was normal; however, pulmonary restrictive disease and scoliosis occurred with growth. One ES patient developed a radiation-induced second malignant tumor at age 10 and one ES child died at age 6 (no evidence of disease) of meningitis. Average survival length for ES patients was 77 months (range, 18 to 132 months.) Currently, eight patients are alive and five are free of disease. Extensive chest wall resection and reconstruction is useful in the treatment of primary chest wall tumors, but is palliative in metastatic cases. The Gortex patch is the current prosthetic of choice.

Heterogeneity of cultured leukemic lymphoid progenitor cells from B cell precursor acute lymphoblastic leukemia (ALL) patients.

Colony assays were performed for 50 patients with B cell precursor acute lymphoblastic leukemia (ALL). Blast colony formation was observed for 33 patients, and the plating efficiency (PE) showed a marked interpatient variation, which indicates a pronounced biological heterogeneity at the level of leukemic progenitor cells. Notably, the mean PE of leukemic B cell precursors from patients with a pseudodiploid or near-diploid karyotype with structural chromosomal abnormalities (SCA) was significantly higher than the mean PE of normal diploid or hyperdiploid cases. All patients who had SCA involving 7p13, 11q23-24, or 12p11-13, and patients with a Philadelphia chromosome had high PE values. The S phase percentage, expression of CD19 antigen, and relapse status were also correlated with PE. Significantly, colony blasts had slightly different surface marker profiles in each case and were common ALL antigen negative in 33% of cases, which indicates the existence of a marked immunological heterogeneity at the level of leukemic progenitor cells.

MR imaging of osteogenic and Ewing's sarcoma.

Twenty patients with biopsy-proven osteogenic (11 cases) or Ewing's (nine cases) sarcoma were evaluated by MR imaging on a 0.15-T resistive unit to determine the value of MR in the diagnosis and treatment of these two neoplasms and to develop the best protocol for MR imaging. In all 20 cases, MR identified tumor spread into bone marrow, and it was superior to CT in five cases. Extension of tumor into the soft tissues adjacent to bone was shown better by MR than CT in six cases. Improved anatomic information from MR is the result of the ability to image in the axial, coronal, and sagittal planes. Compared with CT, MR identifies cortical disease but has inferior spatial resolution and defines calcium poorly. MR can be used to monitor tumor response to chemotherapy, and the relationship of tumor to adjacent vasculature can be determined without the use of contrast agents. Two pulse sequences are necessary for maximum display of disease, since, in general, tumor involvement of the bone marrow is best assessed on T1-weighted sequences, and tumor involvement of the soft tissue is best seen on T2-weighted sequences. Additional information about bone-marrow involvement, soft-tissue tumor extent, and the relationship of tumor to blood vessels makes MR a valuable adjunct to CT in the evaluation of these neoplasms.

Efficacy of magnetic resonance imaging in 139 children with tumors.

One hundred thirty-nine children with neoplasms were studied using magnetic resonance imaging (MRI). This procedure was as accurate as computed tomography in predicting tumor histology, except that MRI was unable to detect small areas of tumor calcification. Magnetic resonance imaging could accurately identify the organ of origin of tumor masses and differentiate soft tissue from fat, fluid, or hemorrhage. In addition, MRI was helpful in planning surgery in many cases: It was better than computed tomography in defining the size and extent of soft-tissue tumor masses. It was accurate in defining the extent of the spread of bone sarcomas in the bone marrow. Without requiring the injection of intravenous contrast agents, it accurately defined displacement, encasement, or invasion of major abdominal blood vessels by Wilms' tumors and neuroblastomas. As a means of evaluating pediatric neoplasms, MRI is noninvasive, painless, and well tolerated by children, and it uses no radiation.

Hodgkin disease and non-Hodgkin lymphomas in children: utilization of radiological modalities.

If costs of medical care are to be reduced, the choice of which imaging modality to use must be made as carefully as possible. This study was done to show how radiological modalities were used to evaluate patients with Hodgkin disease and non-Hodgkin lymphoma. We kept a record of every radiological study performed on 66 children with both diseases seen in the past 6 1/3 years. The results of these studies were analyzed to see which areas of the body were studied, which imaging modality was used, how frequently the studies were repeated, and how frequently the studies gave abnormal results. Our findings disclosed that radiological studies have been appropriately performed in anatomic regions of the body in which disease is present. New imaging modalities have been introduced, and the use of some of the older modalities has been decreased. With some modalities, such as skeletal survey, liver/spleen scan, whole-lung tomography, contrast studies of the bowel, and excretory urography, utilization is higher than it ought to be in view of the fact that the yield of positive results is low and the information is obtainable in many cases from other more sensitive procedures. These studies should not be performed as a routine on initial evaluation or follow-up of all patients with Hodgkin or non-Hodgkin lymphomas. On initial presentation all patients should undergo chest radiography and CT scanning of both chest and abdomen. A problem area is that the timing of follow-up studies has been somewhat erratic, with some inappropriate studies particularly 3 or 4 years after diagnosis. Too many imaging procedures have probably been done in follow-up of our patients.

Radiation nephritis following total-body irradiation and cyclophosphamide in preparation for bone marrow transplantation.

Two children prepared for bone marrow transplantation with total-body irradiation and cyclophosphamide developed hypertension, microscopic hematuria, proteinuria, diminished renal function, and anemia six months after transplantation. Light microscopy of the kidneys revealed mesangial expansion, glomerular capillary wall thickening, and lumenal thrombosis. Electron microscopy demonstrated widening of the subendothelial space due to the deposition of amorphous fluffy material. In one patient, immunofluorescence microscopy revealed glomerular capillary wall deposition of fibrin and immunoglobulins. The clinical and histologic findings support the diagnosis of radiation nephritis. Patients prepared for bone marrow transplantation with total-body irradiation and cyclophosphamide should be followed closely after transplantation for the development of hypertension, proteinuria, and renal insufficiency.

Parent to child transmission of the thrombocytopenia absent radius (TAR) syndrome.

We report on cases of the thrombocytopenia absent radius syndrome (TAR) in a family with the first documented occurrence of parent-to-child transmission. At least three other families have been reported in which TAR has been transmitted across generations. The pattern of transmission in these cases is not consistent with the simple autosomal recessive mode of inheritance which has been proposed. TAR syndrome may be a genetically heterogeneous disorder of the result of one of a group of related alleles. Given the increasing evidence for genetic and causal heterogeneity in TAR together with its similarity to conditions such as Holt-Oram, WT Limb-Blood and SC-Roberts Phocomelia syndromes it may be reasonable to view TAR as a developmental field defect rather than a genetic syndrome. Genetic counseling of affected individuals and their families should be modified to reflect the possibility of a recurrence risk as high as 50%.

Sequential high-dose cytosine arabinoside-asparaginase treatment in advanced childhood leukemia.

Sequential high-dose cytosine arabinoside (ara-C) and asparaginase were given to 41 children age six months to 21 years of age with advanced leukemia. Ten of 22 patients with acute lymphocytic leukemia (ALL) and eight of 19 patients with acute nonlymphocytic leukemia (ANLL) obtained complete remissions. The most significant toxicity seen was infection in 22 patients. In addition, patients given intrathecal chemotherapy within 24 hours of ara-C developed neurologic toxicity. The high response rate seen in these patients with advanced leukemia indicates that a trial of this regimen is warranted in children with less advanced ALL and ANLL.

Leukaemic transformation of engrafted bone marrow cells.

Recurrent leukaemia following bone marrow transplantation is most often due to the regrowth of original host leukaemia cells, but may also be due to the malignant transformation of normal donor marrow cells after transplantation into a leukaemia patient. We report the ninth case of malignant change in cells of donor origin in a 12-year-old boy who was originally diagnosed as having Ph1+ CML. He remained Ph1+ during lymphoid blast crisis. After transplantation with marrow from a cytogenetically normal sister, he relapsed to Ph1- ALL in the female donor cells. The marrow showed a mixed karyotype of 46,XX/46,XX,inv(9)(p12q12). It would appear that, haematologically, the patient showed different manifestations of the same disease state. Cytogenetically, however, the pre- and post-transplant leukaemias were different.