Search

Purpose: Survivors of childhood and adolescent cancer are at risk for long-term effects of disease and treatment. The Childhood Cancer Survivor Study assessed overall and cause-specific mortality in a retrospective cohort of 20,227 5-year survivors., Patients and Methods: Eligible subjects were individuals diagnosed with cancer (from 1970 to 1986) before the age of 21 who had survived 5 years from diagnosis. Underlying cause of death was obtained from death certificates and other sources and coded and categorized as recurrent disease, sequelae of cancer treatment, or non-cancer-related. Age and sex standardized mortality ratios (SMRs) were calculated using United States population mortality data., Results: The cohort, including 208,947 person-years of follow-up, demonstrated a 10.8-fold excess in overall mortality (95% confidence interval, 10.3 to 11.3). Risk of death was statistically significantly higher in females (SMR = 18.2), individuals diagnosed with cancer before the age of 5 years (SMR = 14.0), and those with an initial diagnosis of leukemia (SMR = 15.5) or CNS tumor (SMR = 15.7). Recurrence of the original cancer was the leading cause of death among 5-year survivors, accounting for 67% of deaths. Statistically significant excess mortality rates were seen due to subsequent malignancies (SMR = 19.4), along with cardiac (SMR = 8.2), pulmonary (SMR = 9.2), and other causes (SMR = 3.3). Treatment-related associations were present for subsequent cancer mortality (radiation, alkylating agents, epipodophyllotoxins), cardiac mortality (chest irradiation, bleomycin), and other deaths (radiation, anthracyclines). No excess mortality was observed for external causes (SMR = 0.8)., Conclusion: While recurrent disease remains a major contributor to late mortality in 5-year survivors of childhood cancer, significant excesses in mortality risk associated with treatment-related complications exist up to 25 years after the initial cancer diagnosis.

Objective: The etiology and pathogenesis of Langerhans cell histiocytosis (LCH) remain poorly understood. We conducted an exploratory epidemiologic study to investigate potential risk factors associated with LCH., Study Design: We used a case-control study design to obtain data from parents of children with LCH (n = 459) who were members of the Histiocytosis Association of America and Canada. The two control groups consisted of 683 community control subjects and 3719 children with childhood cancers treated at participating Children's Cancer Group institutions., Results: The median age at diagnosis of LCH was 1.8 years (range 0.1 to 14.6 years). Cases were categorized as multisystem LCH (MS-LCH) (n = 208) and single-system LCH (SS-LCH) (n = 198). Statistically significant associations included the following: infections in the neonatal period (MS-LCH, odds ratio (OR) = 2.2), solvent exposure (SS-LCH, OR = 54.9), childhood vaccinations (MS-LCH and SS-LCH, OR = 0.4), thyroid disease in the proband (MS-LCH and SS-LCH, OR = 21.6), and family history of thyroid disease (MS-LCH and SS-LCH, OR = 1.4). The association with thyroid disease in the proband was explained partially by the involvement of the pituitary, with the relative risk decreasing when patients with diabetes insipidus and thyroid involvement were excluded from analysis., Conclusions: This large hypothesis-generating study provides directions for future investigations in well-designed population-based or hospital-based epidemiologic studies.

Langerhans cell histiocytosis is a disease which frustrates both clinician and scientist. Its aetiology is unknown, its pathogenesis is ill understood and the clinical course is unpredictable. Historically, the different nomenclatures reflecting the first clinical descriptions by Hand (1893, 1921), Schuller (1915) and Christian (1920), and subsequently by Letterer (1924) and Siwe (1933), led to confusion only partially resolved by Lichtenstein (1953) who recognised that the disease in each of these clinical syndromes were components of a spectrum of disease involving the histiocyte. He proposed his unifying concept of Histiocytosis X--'X' being the unknown aetiological factor. In 1973, Nezelof recognised the lesional cell as a 'Langerhans-like' cell but it took another decade for the disease to be recognised as a single entity and the term Langerhans cell histiocytosis to be internationally accepted. The publication, by the Histiocyte Society (1987), of their classification of the histiocyte disorders together with criteria for pathological diagnosis and clinical evaluation of Langerhans cell histiocytosis have consolidated the position. This article details the wide variety of clinical manifestations of the disease and its sequelae and discusses possible epidemiological factors. Finally it looks at the potential implications of recent scientific research on the management of the disease.

We report 12 years' experience with histocompatible, related donor marrow transplantation for 123 patients with acute lymphoblastic leukaemia; 104 > or = second remission. Four regimens were studied: cyclophosphamide (Cy)-+total body irradiation (TBI) (n = 35); Cy+fractionated TBI (n = 45); TBI+high-dose cytarabine (n = 15); and hyperfractionated TBI+Cy (n = 28). 45 patients survive (34 +/- 9%; 95% confidence interval) between 1 and 12.7 years (median 7.8 years) following BMT and 29 +/- 8% survive leukaemia-free. Significantly improved disease-free survival was observed in patients with an initial WBC < 50 x 10(9)/l (P = 0.02). Conditioning regimens tested yielded similar outcomes, though TBI/cytarabine led to greater treatment-associated mortality. Leukaemia relapse was the most frequent cause of failure in 56 +/- 11%; median time of relapse 8 months following BMT, none beyond 2.2 years. Relapse was more frequent with higher WBC, shorter initial remission and previous CNS leukaemia. Acute and/or chronic GVHD was associated with a strong trend (P = 0.06) towards less relapse. Allogeneic BMT may be curative for a substantial fraction of patients with ALL, but additional anti-leukaemic measures beyond these conditioning modifications tested will be required to prevent post-transplant leukaemia recurrence.

Purpose: In an effort to evaluate the usefulness of bone marrow transplantation, the Childrens Cancer Group (CCG) initiated a multiinstitutional study comparing bone marrow transplantation versus chemotherapy after successful induction of remission for previously untreated children and young adults with acute myeloid leukemia., Patients and Methods: From 1979 to 1983, 508 patients were entered onto this study and 490 were treated. After induction, patients with an HLA mixed leukocyte culture (MLC)-compatible sibling underwent bone marrow transplantation. Patients not eligible for bone marrow transplantation were eligible for randomization to two chemotherapy maintenance regimens. All patients undergoing bone marrow transplantation were conditioned with cyclophosphamide and total-body irradiation (TBI). Methotrexate was used to prevent or modify graft-versus-host disease (GVHD)., Results: Three hundred eighty-one patients achieved bone marrow remission (78%). Eighty-nine patients had an HLA/MLC-compatible sibling donor and were eligible for bone marrow transplantation, and 252 had no match. Comparison of survival estimates for patients eligible for transplantation versus not eligible at 3 years (52% v 41%), 5 years (50% v 36%), and 8 years (47% v 34%) showed a significant difference in favor of bone marrow transplantation (P < .05). Disease-free survival (DFS) demonstrated similar results. Application of a cure model to the results showed a better outcome for those eligible for transplantation (P = .04). Patients randomized between the two chemotherapy regimens did not show any significant difference between those treated with a continuous maintenance versus a cyclic regimen (P = .16)., Conclusion: Children and young adults who successfully achieved a remission with multiple-agent chemotherapy who had an HLA/MLC-compatible donor and were thus eligible for an allogeneic bone marrow transplant had better survival than those not eligible for transplantation.

With the advances in the therapy of childhood cancers over the past 30 years, many children who are now cured of their cancer are moving into adulthood. These patients have, in many cases, been exposed to multiple therapeutic modalities (chemotherapy, radiation, and/or surgery), and in recent years have experienced more and more intensive therapies. Potential late sequelae can involve almost any organ system, but can be predicted, in part, by the chemotherapy or radiation that individuals may have received. These complications may be categorized by their timing relative to the discontinuation of therapy: early (under 5 years), intermediate (5-20 years), or very late (over 20 years). Four potential late sequelae are reviewed (thyroid, cataracts, renal, and osteoporosis), and recommendations are made for screening of at risk individuals for these long-term complications. The need for long-term follow-up of this unique group of individuals is critical as we attempt to completely define the risks and benefits of our therapeutic efforts.

The approaches to treatment of Langerhans' cell histiocytosis (LCH) have been as varied as the clinical presentation of the disease. The clinical course of localized LCH of bone is generally benign, and it tends to heal spontaneously in a period of months to years. If treatment is required, the disease can be controlled by local measures such as surgical curettement, low-dose irradiation, or intralesional infiltration with corticosteroids. We reviewed 15 children treated with intralesional infiltration of corticosteroids, either primarily for disease of bone (8 patients) or as adjunctive therapy for disseminated LCH (7 patients). Two patients developed complications as a result of this treatment method.

Patients undergoing bone marrow transplantation often receive total body or total lymphoid irradiation as part of the conditioning regimen prior to marrow infusion. The cytogenetic effects of this therapy on skin fibroblasts were studied. Fibroblast cultures from eight skin biopsies were harvested in early passages for G-banded chromosome analysis. Four biopsies were from three patients who had high-dose cyclophosphamide and total body radiotherapy; one was from within and one was from outside the radiation field of a patient who had high-dose cyclophosphamide and lymphoid radiotherapy, one was from a patient who had combination chemotherapy alone, and one was from a normal control. No abnormal mitoses were found in the control or the patient who had chemotherapy alone, and only two of 30 mitoses from skin outside the lymphoid radiotherapy field were abnormal. However, most cells (49-88%) from five biopsies within radiotherapy fields were abnormal. Typically, abnormal karyotypes were pseudodiploid and contained multiple balanced rearrangements, of which reciprocal translocations were most common. The data indicate that the radiotherapy used for bone marrow transplantation induces extensive, sustained chromosome abnormalities in vivo in skin fibroblasts.

The survival of children with acute myeloid leukemia has improved with the identification of active chemotherapeutic agents and intensification of the post remission therapy using intensive chemotherapy early in the therapy. Other reports in this symposium will report equally good results with intensification early in the treatment using bone marrow transplantation. Additional factors such as long term complications and cost will become important variables to be considered, when considering the appropriate treatment for children with acute myeloid leukemia.

A total of 342 previously untreated eligible children were entered into the first Intergroup Ewing's Sarcoma Study (IESS) between May 1973 and November 1978. In group I institutions, patients were randomized between treatment 1 (radiotherapy to primary lesion plus cyclophosphamide, vincristine, dactinomycin, and Adriamycin [doxorubicin; Adria Laboratories, Columbus, OH] [VAC plus ADR]) or treatment 2 (same as treatment 1 without ADR), and group II institutions randomized patients between treatment 2 or treatment 3 (same as treatment 2 plus bilateral pulmonary radiotherapy [VAC plus BPR]). The percentages of patients relapse-free and surviving (RFS) at 5 years for treatments 1, 2, and 3 were 60%, 24%, and 44%, respectively. There was strong statistical evidence of a significant advantage in RFS for treatment 1 (VAC plus ADR) versus 2 (VAC alone) (P less than .001) and 3 (P less than .05) and also of treatment 3 versus 2 (P less than .001). Similar significant results were observed with respect to overall survival. Patients with disease at pelvic sites have significantly poorer survival at 5 years than those with disease at nonpelvic sites (34% v 57%; P less than .001). Among pelvic cases, there was no evidence of differing survival by treatment (P = .81), but among nonpelvic cases, there was strong evidence of differing survival by treatment (P less than .001). The overall percentage of patients developing metastatic disease was 44%; the percentages by treatments 1, 2, and 3 were 30%, 72%, and 42%, respectively. The overall incidence of local recurrence was 15%, and there was no evidence that local recurrence rate differed by treatment. Patient characteristics related to prognosis, both with respect to RFS and overall survival experience, were primary site (nonpelvic patients were most favorable) and patient age (younger patients were more favorable).

In recent years there has been a significant improvement in the survival rate of children with malignant solid tumors. With Wilms' tumor, the survival rate has risen to 80%, but a subset of these patients with unfavorable histologies and therefore a higher rate of relapse need a different strategy. For those patients with soft tissue sarcoma, brain tumors, and bone tumors the combination of preoperative chemotherapy, surgery, and radiotherapy followed by maintenance multiagent chemotherapy has resulted in a survival rate of 45% to 70%. In the case of neuroblastoma, a similar aggressive approach has not resulted in an improved survival. A different approach that uses screening of infants by urinary testing for VMA and HVA to detect earlier and potentially less malignant tumors has begun in Japan and North America in the hope that preclinical detection will reduce mortality.

Review of 5406 children with acute lymphoblastic (ALL) or nonlymphoblastic leukemia (ANLL) registered with Childrens Cancer Study Group (CCSG) since 1972 identified 115 patients (2.1%) with Down syndrome. The proportion of patients with Down syndrome was the same for ALL (2.1%) and ANLL (2.1%). Patients with ALL with and without Down syndrome did not differ significantly with respect to age at diagnosis, sex, race, morphology (FAB classification), cell surface markers, initial white blood cell count, pretreatment hemoglobin value, hepatomegaly, lymphadenopathy, presence of mediastinal mass, CNS disease at diagnosis, or prognostic group as defined by age and initial white blood cell count. Patients with ALL-Down syndrome less frequently had splenomegaly, had lower pretreatment platelet counts, and more often had normal or elevated IgG or IgA levels. In addition, they had a significantly lower rate of remission (81% versus 94%), a higher mortality during induction therapy (14% versus 3%), and a poorer overall survival with 5-year life table rates of 50% versus 65% (P less than 0.001). If an initial remission was achieved, there were no significant differences with respect to remission duration, survival, or disease-free survival. Patients with ANLL-Down syndrome were younger at diagnosis than those without Down syndrome. There was no significant difference in the remission rates between these patients. Analysis of findings in patients with ANLL provided results similar to those obtained for patients with ALL with regard to clinical outcome after achievement of an initial remission.

Multimodal therapy consisting of radiation therapy to all areas of gross disease and intensive combination chemotherapy was administered to 44 patients with Ewing's sarcoma. Seven of these patients had regional disease and the others had clinical evidence of distant metastases. The median duration of time on study for all patients was 75 weeks. A complete response occurred in 31 of the patients and 17 are currently free of disease. Four deaths resulted from complications of therapy; 2 were due to infection and 2 due to adriamycin-related cardiomyopathy.

Allogeneic bone marrow transplantation was performed in 10 patients with disseminated Burkitt's lymphoma or poor-prognosis T-cell lymphoblastic lymphoma. All patients received a cytoreduction regimen consisting of cyclophosphamide, cytosine arabinoside, bis-chloro-nitroso-urea, and total-body irradiation. Eight patients received marrow from HLA-matched sibling donors. One patient received marrow from a parent donor and one patient died during initial cytoreduction and did not undergo total-body irradiation or marrow infusion. Six patients had Burkitt's lymphoma stages III and IV at diagnosis, and three of the six are alive at 18, 28, and 73 months. Four patients had T-cell lymphoblastic lymphoma, stages III and IV at diagnosis, and two of the four are alive at 29 and 49 months. Overall survival in the nine patients who underwent transplantation is 56 percent by life-table analysis. Follow up for the surviving patients ranges from 18 to 73 months (median 29 months). All five survivors are at home with unmaintained remissions.

The histiocytosis syndromes consist of a heterogeneous group of disorders referred to as histiocytosis X or differentiated histiocytosis. Although a large proportion of cases of histiocytosis remains to be of an idiopathic nature, there are cases in which the etiologic mechanism appears to be a defect in the immune system. Provided is a brief review of the literature regarding the immune system in histiocytic disease and a review of the experience at the University of Minnesota with immunologic evaluation of children with histiocytic reactions. Two general hypotheses on the relationship between the immune system and histiocytosis syndromes are discussed.

Of 395 male pediatric patients with previously untreated acute lymphoblastic leukemia, 20 (5%) exhibited testicular infiltration prior to or concurrent with their first bone marrow relapse. Fourteen occurred as an isolated relapse and six occurred concomitant with bone marrow and/or central nervous system relapse. Nine of the 20 relapses were in patients who had discontinued therapy after completing three years of continuous complete remission. Factors found to be independently associated with an increased risk of testicular relapse during maintained remission included pretreatment lymphadenopathy, and to a lesser extent, initial hemoglobin level and initial platelet count. Pretreatment splenomegaly and lymphadenopathy appear to imply an increased risk of testicular relapse for those patients who have their maintenance therapy discontinued. Time from testicular relapse to bone marrow relapse or death was significantly shorter for patients with testicular involvement while receiving chemotherapy when compared to patients with testicular relapse after discontinuing therapy. In those patients achieving three years of continuous complete remission, subsequent testicular relapse occurred significantly more often in patients who discontinued therapy than a similar group who continued therapy. In a group of 76 males who received presymptomatic gonadal radiation immediately after achieving an initial marrow remission, protection appears to have been provided against the manifestation of testicular leukemia during maintained remission.

To identify factors which might be associated with intellectual function following treatment for childhood acute lymphoblastic leukemia, 50 long-term survivors were studied using the Wechsler Intelligence Scale for Children-Revised. All patients were diagnosed between 1972 and 1974 and were treated on a single clinical trial protocol with identical induction and maintenance chemotherapy plus central nervous system prophylaxis that included cranial radiation. The mean full scale IQ score for the group was 95 (SEM 2.0), with mean verbal IQ of 94.4 and mean performance IQ of 96.9. Factors which were found to be closely associated with a lower IQ score included female sex (in both verbal IQ and full-scale IQ), longer duration of chemotherapy (in performance IQ), and younger age at the time of radiation (in both verbal IQ and full-scale IQ). The age at the time of radiation was found to be significantly correlated with discrepancy between verbal and performance IQ, with younger age being associated with verbal IQ scores higher than performance IQ scores. When analyses were performed within specific subgroups of patients defined by sex and age at the time of radiation, dose of cranial radiation, concomitant intrathecal methotrexate therapy, and duration of therapy were all found to be correlated with a lower level of intellectual function. These preliminary findings provide direction for future studies to help identify high-risk patients.

Acute graft-versus-host disease is a major problem in allogeneic bone-marrow transplantation. We performed a randomized study to compare the effectiveness of two regimens in the prevention of acute graft-versus-host disease. Thirty-five patients received methotrexate alone, and 32 received methotrexate, antithymocyte globulin, and prednisone. Of the patients who received methotrexate alone, 48 per cent had acute graft-versus-host disease, as compared with 21 per cent of those who received methotrexate, antithymocyte globulin, and prednisone (P = 0.01). The age of the recipient was a significant factor in the development of acute graft-versus-host disease: Older patients had a higher incidence of the disease (P = 0.001). We conclude that the combination of methotrexate, antithymocyte globulin, and prednisone significantly decreased the incidence of acute graft-versus-host disease and should be used to prevent this disorder in patients receiving allogeneic marrow transplants.

Thirty-four cases of childhood lymphoblastic leukemia that were complicated by CNS and peripheral thrombosis or hemorrhage associated with L-asparaginase (L-asp) therapy were reviewed to determine the effect of the events on the subsequent clinical status. There was no predilection for any site in the CNS cases; all but one of the peripheral events occurred in the lower extremities. The median time for 28 CNS and eight peripheral events from the beginning of L-asp therapy was 17 and 16 days, respectively. One patient died as a result of the CNS event. Twenty-six patients were surviving with a median follow-up of 27 months at the close of the study. Of the patients with peripheral thromboses, only the patient with a dorsal pedal artery occlusion had a significant problem (autoamputation of a toe). Although eight patients received L-asp subsequently without recurrence of the complication, two had transient neurological deterioration associated with the repeat administration of L-asp. Twenty-two patients received CNS prophylaxis consisting of intrathecal methotrexate, CNS radiation, or both, following the CNS event without deterioration. In general, clinical status was not compromised after thrombotic or hemorrhagic events. Although most patients had gross recovery of their neurological impairment, detailed neurological and neuropsychological testing is needed to elucidate possible defects.

Crucial questions for health professionals include what constitutes social support, the sources of social support, and the parameters of social support. The preliminary findings from a research project that focused on the care of children dying of cancer indicate that these questions have concerned primary care nurses and physicians. Data acquired in personal interviews administered to 27 physicians and 32 nurses who participated in the first year of the Home Care for the Child with Cancer project provided descriptions of individual sources of social support. The results reveal a range of supportive mechanisms and networks within varied institutional contexts. While there were some within-group similarities in the forms of social support used by nurses and those used by physicians, numerous individual differences were evident. This is an area for extensive further study.

This paper is a progress report on the role of radiation therapy (RT) in local tumor control and the decreased incidence of pulmonary metastasis in 251 patients entered in the Intergroup Ewing's Sarcoma Study. All were followed for more that 1 year, and their RT records were reviewed. Doses to the primary tumor in the range of 4,500--6,500 rad were administered over approximately 5 to 6 weeks in combination with 4 drugs, i.e., vincristine (VCR), dactinomycin (DAC), cyclophosphamide (CY), and adriamycin, or only the first 3. One group of patients received the 3 drugs and bilateral pulmonary irradiation (approximately 1,500 rad in 2 wk). Preliminary analysis showed a local primary tumor control of approximately 90%. Patients with lesions in the pelvis and humerus had local failure rates of 13% (7 of 54) and 21.4% (6 of 28), respectively. The treatment groups differed significantly in the incidence of pulmonary metastasis. Patients treated with the 4 drugs (regimen 1) had a 14% incidence, whereas 42% of those treated with only 3 drugs (regimen 2) developed pulmonary metastases. Of all patients treated with 3 drugs and pulmonary irradiation (regimen 3), 18% showed lung metastases. The study indicated that intensive chemotherapy and RT significantly improved the local control and survival of patients with localized Ewing's sarcoma. However, the high incidence of metastasis indicated the need for more effective systemic chemotherapy for further improvement of treatment results. More studies are needed so we can define the volume to be treated and the optimal dose of irradiation to determine a therapeutic strategy that will yield optimal survival and tumor control with the fewest sequelae.

The prognostic significance of kidney size at diagnosis of acute lymphoblastic leukemia (ALL) was assessed in a population of 142 children. Kidney size was determined using three different methodologies, and its significance was determined by univariate and multivariate life-table methods. Enlarged kidney size (as determined by any of the three methods used) was not associated with an overall poorer survival. These findings were consistent when kidney size at diagnosis was analyzed as a singled variable and when it was considered after adjustment for the known prognostic factors of age, sex, and initial WBC count. Assessment of renal size at the time of diagnosis of childhood ALL is not indicated for the purpose of predicting subsequent prognosis.

L-Asparaginase was added to vincristine and prednisone for induction of first remission in 815 children with acute lymphocytic or acute undifferentiated leukemia. This combination resulted in an overall remission rate of 93%. The addition of L-asparaginse to the standard induction regimen using prednisone and vincristine did not significantly increase the morbidity or mortality rate during the induction period. The most common side effect was transient L-asparaginase-induced hyperglycemia. The safe administration of L-asparaginase i.m. and the dose efficacy of 6000 I.U./sq m were confirmed. For these reasons, L-asparaginase should be combined with vincristine and prednisone for the initial induction of children with acute lymphocytic or acute undifferentiated leukemia.

Previous series including our earlier study of survivors of childhood acute lymphoblastic leukemia have documented the presence of nonclonal chromosome abnormalities in peripheral blood lymphocytes. To investigate whether or not these abnormalities persist, we restudied nine patients, all of whom had received radiotherapy and a minimum of 3 years of systemic chemotherapy. Therapy had been discontinued a median of 3.9 years prior to study in our first report and a median of 7.2 years prior to study in this follow-up report. Thirty metaphases from short-term cultures of phytohemagglutinin-stimulated peripheral blood from each of nine patients and nine matched controls were analyzed using G-banding. Nonclonal chromosome abnormalities were present in cells from six of the nine patients and 3.0% of patients' cells overall, as compared to seven of ten patients and 3.5% of patients' cells in the earlier study. All patients studied twice had abnormalities on one or both occasions. No evidence for the development of cytogenetically abnormal clones was found. Combined data from the two evaluations indicate that all of the patients have a small population of long-lived lymphocytes with nonclonal chromosome abnormalities, the frequency of these cells appears to remain remarkably constant over time, and the proportion of cells with chromosome abnormalities is approximately threefold greater in patients than in controls. It has become apparent that survivors of acute lymphoblastic leukemia are at increased risk for development of second malignant neoplasms. The relationship between therapy-induced chromosome damage and the development of second malignant neoplasms is currently unknown. We speculate that some cells, possibly in tissues other than peripheral blood, are preneoplastic by virtue of therapy-induced chromosome rearrangements involving critical genes and, following a long latent period, may undergo subsequent genetic or cellular changes that result in malignant transformation. Unfortunately, however, estimation of genetic damage through cytogenetic studies of peripheral blood T-lymphocytes does not appear to be a useful method for prediction of second malignant neoplasms following acute lymphoblastic leukemia, since most or all of the patients have a low level of abnormal cells.

One hundred forty-three children with refractory lymphoblastic and undifferentiated leukemia (ALL/AUL) were treated with cytosine arabinoside (Ara-C) and prednisone (Pred). The dose and duration of Ara-C was escalated during induction depending on the response seen in the peripheral blood and/or bone marrow. For those achieving a remission, Ara-C was also used to determine its maintenance capabilities. Of the 143 children, 79 attained a clinical remission, 45 having a complete bone marrow remission and 34 having a partial remission. Maintenance of remission with twice weekly Ara-C was short and did not appear to depend on the amount of Ara-C given during induction. The major toxicity of Ara-C was myelosuppression.

One hundred eighty-seven patients diagnosed with acute lymphoblastic leukemia (ALL) between 1972 and 1975 were evaluated for height 6.4-8.8 years (median 7.2 years) from the time of diagnosis of their disease. All patients had been treated on protocols CCG-101/143 conducted by the Childrens Cancer Study Group. After induction of remission, patients received either cranial radiation plus six doses of intrathecal methotrexate, craniospinal radiation, or craniospinal radiation plus abdominal radiation, followed by systemic maintenance chemotherapy for either 3 or 5 years. No significant difference was observed in the distribution of height percentiles at the time of diagnosis compared to expected population standards. After treatment an excess (P less than 0.001) was observed in the proportion of patients in the lower percentiles in conjunction with a decrease in the proportion of patients in the higher percentiles. After adjustment for height at diagnosis, the only factor found to have significant impact on attained height percentile was exposure to craniospinal plus abdominal radiation (P less than 0.001) where there was a fivefold excess in the proportion of patients below the fifth percentile for height. Craniospinal radiation only was not associated with a greater reduction in attained height percentile when compared to cranial radiation only.

Histiocytosis X (HX) follows a variable course from the self-limited eosinophilic granuloma (EG) to the aggressive disseminated disease in infants. Some classifications place EG in a well-differentiated category and the disseminated infantile form in a morphologically atypical group. However, criteria for determining prognosis from biopsy material have not received widespread acceptance. We retrospectively reviewed 51 cases of HX, emphasizing the cytological atypia and mitotic activity of the Langerhans' histiocytes, as well as the presence of other parameters. Ten patients died. We were unable to predict clinical outcome from the histopathological findings. Some cases of EG showed mild atypia and high proliferative rates while some fatal disseminated cases had a bland appearance. The prognosis is best predicted by clinical parameters. The findings favor HX being a reactive, nonneoplastic proliferation of the Langerhans' cells.

Thyroid function was measured serially in 28 children with Hodgkin disease diagnosed from 1971 to 1978. The patients' ages ranged from 4 to 16 years at diagnosis, and treatment consisted of chemotherapy only (four patients), radiation alone (15), or radiation plus chemotherapy (nine). None of the four children given chemotherapy only developed thyroid hypofunction, in contrast to 21 (88%) of the 24 children given high doses of radiation (P less than 0.001). Thyroid function in three patients with compensated hypothyroidism and in one child with primary hypothyroidism reverted to normal without thyroid replacement. One child given chemotherapy only and one child given radiation only became transiently hyperthyroid. These results indicate that patients given combined modality therapy for Hodgkin disease are at high risk for thyroid abnormalities. The results of long-term follow-up of thyroid function demonstrate, however, that all such thyroid abnormalities may not necessarily be permanent.

Between 1972 and 1975 the Children's Cancer Study Group conducted two clinical trials for the treatment of newly diagnosed patients with acute lymphoblastic leukemia. Upon achieving 3 yr of continuous complete remission, 316 children and young adults were randomly allocated either to discontinue chemotherapy or to continue chemotherapy for an additional 24 mo. With a median follow-up from the time of randomization of 50 mo, those patients who received 3 yr of therapy have demonstrated a statistically non-significant yet higher incidence of bone marrow relapse as compared to those patients treated for 5 yr (p = 0.09). However, the proportion of patients surviving 5 yr from randomization is 93% for the 3-yr treatment group and 89% for the 5-yr treatment group (p = 0.27). No significant difference was observed between the randomized groups for the occurrence of testicular relapse (p = 0.12), central nervous system relapse (p = 0.17), or first occurrence of relapse or death (p = 0.24). The relapse-free survival of patients treated for 5 yr as compared to those treated for 3 yr was not significantly higher in males (81% versus 75%, p = 0.14) or females (89% versus 89%, p = 0.95). This randomized study did not demonstrate a significant difference between treatment for either 3 or 5 yr.

We report four children with acute megakaryoblastic leukaemia (AMKL) and compare their clinical course with 16 previously reported cases of AMKL in children. In adults, AMKL has been reported as a rapidly progressive disease characterized by pancytopenia associated with bone marrow fibrosis, absence of organomegaly, and unresponsiveness to therapy. Although some of the childhood cases present with these features, the clinical course can be quite variable, particularly in young children, with both organomegaly and leucocytosis occurring. Down syndrome, or other constitutional abnormalities of chromosome 21 were present in four of 20 reported cases. Two of the four cases reported herein were initially diagnosed cytologically as childhood acute lymphoblastic leukaemia (ALL). All four patients achieved a complete remission, and three remain in remission from 34 to 56 months from diagnosis. Greater recognition of AMKL in the future will help to clarify the disease characteristics, prognosis and optimal treatment of this unusual form of leukaemia.

Patients with acute lymphoblastic leukemia who have a mediastinal mass at the time of diagnosis are said to have a poor prognosis. However, many factors which may not be independent contribute to the success of treatment. We compared the disease characteristics and results of therapy in children having large mediastinal masses and lymphoblastic leukemia without mediastinal mass. Patients with a mediastinal mass had less evidence of marrow failure but were burdened with considerably more leukemic cells as measured by peripheral blood white count and extent of lymphadenopathy. Since the presence of mediastinal mass was strongly associated with these and other poor prognostic characteristics, we used multivariate techniques to determine which characteristics were independently associated with an increased risk for relapse. White count, extent of lymphadenopathy, age, and sex were significant predictors of early relapse, but when controlled for these variables the presence of a mass did not predict prognosis.

A randomized study of 264 children and adults with previously untreated localized Ewing's sarcoma of bone was undertaken between 1973 and 1978 by 83 institutions of three national study groups: Children's Cancer Study Group, Southwest Oncology Group, and Cancer and Leukemia Group B. The Intergroup Study was designed to determine if the addition of adriamycin (ADR) or bilateral pulmonary radiotherapy (RT) to vincristine, dactinomycin, and cyclophosphamide (VAC therapy) would improve survival and reduce local recurrences and metastases. All patients received RT to the primary lesion, and the survival rate after 3 years was 65%. The most effective treatment regimen was VAC plus ADR; 74% of the patients were free of disease at 2 years. The lengths of disease-free status and survival of patients treated with VAC plus ADR or VAC plus RT did not differ. However, both regimens were significantly superior to treatment with VAC alone. The addition of ADR or bilateral pulmonary RT to VAC was highly advantageous to patients with nonpelvic primaries. Bone and lung were the major sites of distant relapse, but the addition of bilateral pulmonary RT showed no advantage over that of ADR in reducing the occurrence of lung metastases. These recent results should eliminate some of the pessimism that has accompanied a diagnosis of Ewing's sarcoma, although distant metastases continued to be a major reason for failure in the control of this tumor. Survival of these patients can be improved through well-controlled clinical trials designed to determine optimal adjuvant chemotherapy and treatment of the primary lesion.

Clinical research has by and large been responsible for the success achieved in treating pediatric cancer during the last 20 years. An important milestone has recently been reached with the passing of the halfway mark in the goal of curing all childhood cancer. It is important to re-evaluate our priorities and set future goals. The large multi-institutional cooperative groups have been the mainstay of past successes and should as their major goal continue work towards improvements in survival, particularly for those malignancies which continue to have a poor prognosis. The second priority should be the identification of potential long-term effects of childhood cancer and the effects associated with therapy. Concomitant with improvements in the cure rate it is our responsibility to ensure that cured patients can have the opportunity to enjoy productive, useful and happy lives. The third priority is to foster research of pilot clinical research to serve as a source of ideas to be used for future Phase III clinical trials. Moreover, increased efforts should be directed towards aspects of preventive oncology which requires increased knowledge regarding the etiology of childhood cancers.

Sudden cerebrovascular insults occurred during or immediately following remission induction therapy in 4 children with acute lymphoblastic leukemia. In 3, cerebral infarction was due to thrombosis. In the fourth, an intracerebral hematoma developed representing either frank hemorrhaging or a hemorrhagic infarction. None of the patients had central nervous system leukemia or extreme leukocytosis at the time of diagnosis. Symptoms were obtundation, hemiparesis, seizures, and headache. The induction chemotherapy included L-asparaginase which causes deficiencies of antithrombin, plasminogen, fibrinogen, and factors IX and XI. These hemostatic abnormalities may explain the thromboses and bleeding observed in these children.