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Purpose: Risk stratification and molecular targeting have been key to increasing cure rates for pediatric cancers in high-income countries. Precise diagnosis and successful treatment of pediatric cancer in low-resourced settings is often hindered by insufficient pathology infrastructure, including lack of laboratory platforms for molecular analysis. Given the high frequency of gene fusions in pediatric cancers, identifying such fusions would greatly aid cost-effective pediatric cancer diagnosis, risk stratification, and precision medicine in low-resourced settings. Methods: To allow for implementation of gene fusion detection at Global HOPE sites in Sub-Saharan Africa (SSA), methodologies were reviewed to consider minimal technical expertise required, the ability to utilize samples with sub-optimal RNA quality, and rapid turn-around-time. Literature review, clinical laboratory results, public databases, and large-scale genomic studies were used to obtain exact breakpoint sequence information for gene fusions associated with pediatric and adolescent cancers. Results: Two custom pediatric gene fusions panels were designed using the NanoString Elements technology. The hematologic malignancy panel was designed to detect 439 breakpoints for 223 non-IGH/TCR fusions reported in ALL, AML, lymphomas, and histiocytosis. The solid tumor panel was designed to detect 204 breakpoints for 436 fusions associated with pediatric sarcomas, brain tumors, and renal malignancies. Each panel was tested using 96 samples with known fusion status at Texas Children's Hospital to determine specificity, sensitivity, precision, and ease of workflow. Conclusions: The design, testing, and implementation of a rapid assay to detect gene fusions with diagnostic, prognostic, and therapeutic impact would be transformational in the care of pediatric cancer patients in low-resourced settings. The custom designed panels will allow for large-scale fusion detection in 2-3 days with only 15 minutes of technician time after RNA isolation. Additional steps are needed to identify and address any challenges upon initiation in SSA to fully realize the potential of such technology. Citation Format: Julie Gastier-Foster, Fredrick Lutwama, Joseph Lubega, Kevin Fisher, Dolores Lopez-Terrada, Angshumoy Roy, Nmazuo Ozuah, Jeremy Slone, Peter Wasswa, Carl Allen, David Poplack. Custom Gene Fusion Assays for the Rapid Diagnosis of Pediatric Cancers in Low-Resourced Settings [abstract]. In: Proceedings of the 9th Annual Symposium on Global Cancer Research; Global Cancer Research and Control: Looking Back and Charting a Path Forward; 2021 Mar 10-11. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2021;30(7 Suppl):Abstract nr 98.

Although 80% of pediatric cancer cases occur in low- and middle-income countries, specialists in the field of pediatric hematology and oncology (PHO) are scarce, which is a major reason for the dismal survival rates of children with cancer and blood disorders in sub-Saharan Africa (SSA) compared

Between 1977 and 1991, the Children's Cancer Group and the National Cancer Institute conducted three trials of very high-dose methotrexate (33.6 g/m2; VHD-MTX) in place of cranial radiation (CRT) as central nervous system (CNS) preventive therapy, and assessed efficacy, acute toxicity and long-term neurocognitive outcome. CCG-191P compared VHD-MTX to CRT plus intrathecal methotrexate (IT-MTX) in 181 patients and demonstrated equivalent survival. However, patients treated with CRT had poorer performance on neurocognitive testing over time. CCG-134P evaluated the addition of intensified systemic and intrathecal therapy to VHD-MTX in 128 patients with high-risk acute lymphoblastic leukemia (ALL) and demonstrated reduced CNS relapse compared to the CCG-191P trial, but equivalent survival. CCG-144P compared VHD-MTX to IT-MTX alone in 175 patients with average-risk ALL and demonstrated equivalent survival. VHD-MTX was associated with significant toxicities, particularly neutropenia, transient hepatic dysfunction and sepsis. VHD-MTX achieved similar survival to other CNS-directed therapies without the long-term impact on intelligence, but with substantial acute toxicities.

Approximately 12,000 children in the United States are diagnosed with cancer each year, and roughly 75% of these patients become long-term survivors. The Passport for Care was developed to support these survivors and their health care providers.

BACKGROUND Intraventricular chemotherapy results in more uniform drug distribution within the subarachnoid space and allows for more flexible drug administration schedules. The authors report their experience with an intraventricular concentration times time (C × T) chemotherapy regimen for recurrent meningeal leukemia and lymphoma. METHODS Twenty-one patients (median age, 11.6 years) received C × T therapy for meningeal acute lymphoblastic leukemia (n = 18), Burkitt's lymphoma (n = 2), or undifferentiated leukemia (n = 1). Prior therapy included standard intrathecal (IT) methotrexate and cytarabine, cranial or craniospinal radiation (median, 24 Gy), and 0–5 experimental treatment modalities. C × T induction therapy consisted of 2 mg of intraventricular methotrexate administered daily for 3 days every 10 days, for 4 courses. Patients were then consolidated with 4 courses of alternating intraventricular cytarabine (15 mg/day) or methotrexate (2 mg/day) daily for 3 days every 2 weeks (2 courses of methotrexate and 2 courses of cytarabine). Maintenance therapy consisted of alternating monthly courses of C × T methotrexate or cytarabine. RESULTS Ninety-three percent of patients (14 of 15) who were evaluable for response achieved a complete remission in a median of 10 days (range, 2–40 days). Median remission duration was 15 months. Fourteen patients died of recurrent disease or systemic treatment–related complications; 2 patients are alive, off treatment, and in continuous complete remission for 59+ and 89+ months; 1 patient experienced a meningeal relapse at 24 months on C × T therapy but was reinduced with the C × T regimen, received craniospinal radiation, and is in remission at 142+ months; and 3 are alive with disease at 32+, 72+, and 81+ months. One patient was lost to follow-up. CONCLUSIONS This regimen appears to be an effective and well-tolerated palliative treatment for patients with recurrent meningeal leukemia and lymphoma. Cancer 1999;85:511–6. © 1999 American Cancer Society.

We prospectively assessed the pharmacokinetics of methotrexate, mercaptopurine, and erythrocyte thioguanine nucleotide levels in a homogenous population of children with lower risk acute lymphoblastic leukemia and correlated pharmacokinetic parameters with disease outcome. The maintenance therapy regimen included daily oral mercaptopurine (75 mg/m2) and weekly oral methotrexate (20 mg/m2). One hundred ninety-one methotrexate doses and 190 mercaptopurine doses were monitored in 89 patients. Plasma drug concentrations of both agents were highly variable. The area under the plasma concentration-time curve (AUC) of methotrexate ranged from 0.63 to 12 μmol•h/L, and the AUC of mercaptopurine ranged from 0.11 to 8 μmol•h/L. Drug dose, patient age, and duration of therapy did not account for the variability. Methotrexate AUC was significantly higher in girls than boys (P = .007). There was considerable intrapatient variability for both agents. Erythrocyte thioguanine nucleotide levels were also highly variable (range, 0 to 10 pmol/g Hgb) and did not correlate with mercaptopurine dose or AUC. A Cox regression analysis showed that mercaptopurine AUC was a marginally significant (P = .043) predictor of outcome, but a direct comparison of mercaptopurine AUC in the remission and relapsed patient groups failed to show a significant difference. Methotrexate and mercaptopurine plasma concentrations and erythrocyte thioguanine nucleotide levels were highly variable, but measurement of these pharmacokinetic parameters at the start of maintenance will not distinguish patients who are more likely to relapse.

It has been estimated that approximately 80% of the world's pediatric population lives in countries with limited resources, and that 43% of these children are malnourished. In children with cancer, malnutrition may antedate the diagnosis or be a result of aggressive chemotherapeutic regimens. Studies have shown that children with cancer and malnutrition have a less favorable prognosis, a higher risk of early relapse, and tolerate chemotherapy poorly when compared with children with normal nutritional status. Improvements in nutritional status may improve tolerance to chemotherapy. An understanding of the mechanisms responsible for the effects of malnutrition on drug disposition and pharmacodynamic response is important, especially for anti-neoplastic agents, which have a narrow therapeutic index and may be associated with potentially severe or life-threatening side-effects. Several factors related to malnutrition have been suggested to alter drug disposition. Diminished protein "status" in malnourished children results in lower amounts of plasma proteins, increasing the concentration of free drug available to exert its cytotoxic effect. Severely malnourished individuals also exhibit decreased oxidative metabolism and reduced glomerular filtration rate (GFR), potentially increasing concentrations of parent drug or active metabolites. Malnourished children receiving chemotherapy for the treatment of an underlying malignancy may need specifically "tailored" protocols to achieve therapeutic response while minimizing adverse acute and long-term side effects. The role of specific interventions, such as correction of nutritional status or pharmacokinetic drug monitoring, should be evaluated in this context.

BACKGROUND Topotecan is a topoisomerase I inhibitor that has good penetration across the blood-brain barrier and significant antitumor activity against human brain tumor xenografts. In a Phase I trial in children with refractory cancer, topotecan was well tolerated when administered as a 24-hour infusion. The maximum tolerated dose was 5.5 mg/m2 and the dose-limiting toxicity was myelosuppression. This Phase II study of topotecan was performed to assess the activity of topotecan against childhood brain tumors. METHODS Forty-five children with either a previously treated primary brain tumor that was refractory to standard therapy, or an untreated brain stem glioma or glioblastoma multiforme, received topotecan administered as a 24-hour intravenous infusion every 21 days. The initial dose was 5.5 mg/m2 with escalation to 7.5 mg/m2 on the second and subsequent doses in patients who did not experience dose-limiting toxicity. RESULTS There were no complete or partial responses in the patients with high grade glioma (n = 9), medulloblastoma (n = 9), or brain stem glioma (n = 14). One of 2 patients with a low grade glioma had a partial response lasting more than 17 months; 3 patients with a brain stem glioma had stable disease for 12 to 28 weeks; and 1 patient with a malignant neuroepithelial tumor and 1 patient with an optic glioma had stable disease for 41 weeks and 22 weeks, respectively. Dose esalation from 5.5 mg/m2 to 7.5 mg/m2 was well tolerated in the first 11 patients enrolled on this study who had not received prior craniospinal radiation therapy. The starting dose was subsequently increased to 7.5 mg/m2 for patients without prior craniospinal radiation. CONCLUSIONS Topotecan administered as a 24-hour infusion every 21 days is inactive in high grade gliomas, medulloblastomas, and brain stem tumors. Cancer 1996;78:527-31.

Meningeal metastasis from cancer has become an increasingly frequent problem as the treatment of systemic disease improves. Leukemia, lymphoma and solid tumors may all metastasize to the meninges, where the blood-brain barrier may provide a sanctuary from cytotoxic concentrations of chemotherapeutic agents. Because meningeal disease may be clinically silent or may present with unusual signs and symptoms, it is important to maintain a high index of suspicion for this problem. Diagnosis is usually made by cerebrospinal fluid cytologic testing, magnetic resonance imaging, or both. Treatment options include radiation therapy, systemic chemotherapy and intrathecal chemotherapy. Systemic therapy usually requires administration of either very high drug doses or prolonged infusions in order to overcome the poor penetration of most anticancer agents into the central nervous system. Thus, systemic toxicity is often a major drawback to this approach. Intrathecal chemotherapy results in delivery of anticancer agents directly into the cerebrospinal fluid, usually with minimal systemic toxicity. Intrathecal chemotherapy may be administered by lumbar puncture or by use of an Ommaya reservoir with the tip in the ventricle. Studies are under way to evaluate new agents for both systemic and intrathecal administration. Further research is required to overcome this difficult clinical challenge.

The treatment of central nervous system (CNS) leukemia still poses a significant challenge to the clinical oncologist despite significant advances in therapeutic strategies that are directly targeted at the CNS. This article reviews the evolving definition of CNS leukemia, the current status of therapy for the prevention and treatment of overt CNS leukemia, pharmacological considerations in the treatment of CNS leukemia, and the longterm sequelae of CNS-directed therapy, focusing on articles that have been published in the past 2 years. New agents and treatment strategies for the treatment and prevention of CNS leukemia are also discussed.

A Phase II study of thioTEPA was performed by the Children's Cancer Group. ThioTEPA was administered intravenously every three weeks, at a dose of 65 mg/m2. Pediatric patients with recurrent sarcomas were targeted, but patients with other tumor diagnoses were also eligible. Toxicity was primarily hematopoietic, with thrombocytopenia being predominant. ThioTEPA did not demonstrate significant activity in the target tumor groups evaluated.

High-dose methotrexate with leucovorin rescue (HDMTX-LCV) is an important component of regimens used in the treatment of osteosarcoma. As of this writing the commercially available form of leucovorin is a racemic mixture of d- and l-diastereoisomers; the l-isomer is the active component. This study describes the efficacy and safety of l-leucovorin in HDMTX-LCV regimens. Fifteen patients with osteosarcoma who were enrolled into or treated according to Pediatric Oncology Group protocols 8759 and 8651 received l-leucovorin (7.5 mg every 6 hours) in place of d,l-leucovorin following high-dose methotrexate. Safety data were collected for 1 week after each course or until any toxicities resolved. The mean number of l-leucovorin doses per course was 16.2 and the mean total dose per course was 126 mg. Adverse experiences were generally mild or moderate and occurred in 54 (60%) of 90 courses of l-leucovorin therapy. One l-leucovorin patients, who had inadequate methotrexate rescue, developed severe typhlitis. There were no instances of severe, acute methotrexate toxicity. Myelosuppression was seen but, in general, was not severe. These results support the conclusion that l-leucovorin effectively rescues patients from the toxicity of high-dose methotrexate.

Quinolinic acid (QUIN) is a neurotoxin implicated in the neurologic deficits associated with human immunodeficiency virus type 1 (HIV-1) infection. Forty children with symptomatic HIV-1 disease had elevated (P < .001) cerebrospinal fluid (CSF) QUIN levels (55.8 +/- 8.9 nM) compared with controls (14.9 +/- 3.0 nM). Age-adjusted CSF QUIN concentrations in HIV-1-infected children were predicted by the general index of mental abilities (GIMA, from an age-appropriate intelligence test; r = -0.45, P < .01). Zidovudine therapy reduced CSF QUIN from 64.1 +/- 16.3 to 19.7 +/- 5.2 nM (P < .01; N = 16) and increased GIMA from 76.8 +/- 5.2 to 87.2 +/- 6.3 (P < .001). Encephalopathic HIV-1-infected patients had higher CSF QUIN levels than patients without encephalopathy (79.6 +/- 16.1 vs. 32.7 +/- 6.7 nM, P < .01). CSF QUIN concentrations were also higher (P < .001) in patients who died < or = 3 years after their baseline assessment, compared with those who were still alive. These results warrant further investigation of CSF QUIN in HIV-infected children as a mediator of neurologic dysfunction and a supplemental marker of neurologic disease, particularly when combined with measures of neurocognitive functioning.

Background. Both thiotepa and its active metabolite, tepa, efficiently cross the blood-brain barrier. After intravenous administration, the cerebrospinal fluid concentrations achieved are nearly identical to those in olasma. This provides a strong rationale for testing this agent against brain tumors. Methods. Sixty pediatric patients with recurrent primary brain tumors were treated on a multiinstitutional Phase II study of intravenous thiotepa at a dose of 5 mg/m2 administered every 3 weeks. This dose is the result of a prior pediatric Phase I trial and is significantly higher than those previously recommended. Results. Three of 13 assessable patients with medul-oblastoma had partial responses lasting 22, 25, and 54 weeks. Although no objective responses were observed in 6 assessable patients with malignant gliomas and 14 with brain stem gliomas, 5 of 16 and 4 of 14 patients in elese respective strata had prolonged periods of stable isease (SD) lasting from 12 to more than 33 weeks. Nine ssessable patients with ependymoma had no objective esponse, but two had SD, both for more than 33 weeks. Myelosuppression was the principle toxic effect encoun-ered and appeared to be more severe in patients who had received prior craniospinal radiation therapy or nitro-urea therapy. Conclusions. By conventional Phase II criteria, thiotepa appears to have activity in medulloblastoma. Based on several patients with prolonged SD, it also may possess some limited activity in brain stem and malignant gliomas. The steep in vitro dose-response curve of thiotepa and the long durations of response or SD observed with the dose reported here suggest that moderate-dose to high-dose thiotepa with cytokine support or autologous bone marrow rescue may be associated with an improved response rate to this agent. Cancer 1993; 72:271–5.

Recombinant interleukin-2 (IL-2) produces clinical responses in approximately 20% of adult patients with renal cell carcinoma and melanoma, with both high-dose bolus and continuous infusion regimens. Because of the lower toxicity of continuous infusion, we elected to investigate in a Phase I trial a 5-day continuous infusion repeated for three weeks in children with malignancies refractory to standard therapy. Nineteen children with solid tumors and eight children with hematologic malignancies were entered into the study. The maximum tolerated dose was 3 x 10(6) U/m2/day, with dose-limiting toxicities occurring in five of seven patients treated at the 5 x 10(6) U/m2/day dose level. Dose-limiting toxicities included hypotension, hyperbilirubinemia, thrombocytopenia, pulmonary/pleural effusion, and nephrotoxicity. Serum IL-2 levels were detectable at the higher dose levels and were comparable to those observed in adult patients. Hematologic changes at the higher dose levels included rebound lymphocytosis occurring within 48 h of discontinuation of IL-2, eosinophilia, and decreased platelet counts. No objective responses to therapy were seen. We have identified a dose and schedule of administration for IL-2 in pediatric patients that can be given without intensive care unit support. Pediatric Phase II trials examining the anti-tumor activity of IL-2 given by this schedule are in progress.

Until relatively recently the standard treatment for the child diagnosed with a brain tumor was surgical resection followed by radiation therapy. If initial treatment failed patients were rarely referred for chemotherapy. This, in large part, was owing to the therapeutic nihilism that resulted from the disappointing experience with chemotherapy in the treatment of adults with glioblastoma multiforme. Following encouraging reports of clinical responses to chemotherapy in children with recurrent medulloblastoma, however, the value of adjuvant chemotherapy has become more accepted.

A significant percentage of relapse occurs in children with solid tumors despite advances in treatment. This article discusses reasons for failure of primary therapy, evaluation of the relapsed patient, treatment of the relapsed patient, as well as questionable cancer therapies and therapy cessation.

Objective: To determine whether a short course of 2′,3′-dideoxycytidine (ddC) could provide safe antiretroviral activity in children with symptomatic human immunodeficiency virus infection and whether it could be used with azidothymidine (AZT, zidovudine). The goal was to maintain uninterrupted antiretroviral therapy while sparing AZT-related myelosuppression and ddC-related neuropathy. Methods: In a pilot study, we evaluated four dosage levels of ddC-0.015, 0.02, 0.03, and 0.04 mg/kg, given orally every 6 hours-in 15 children between 6 months and 13 years of age with Centers for Disease Control P2 (i.e., symptomatic) human immunodeficiency virus infection. Thirteen patients had not had any prior antiretroviral therapy; two patients had received and benefited from AZT, but dose-limiting neutropenia had developed. At each dosage level, ddC was given for 8 consecutive weeks and then stopped. After a 30-day rest, a schedule of ddC for 1 week was followed by 3 weeks of AZT therapy (180 mg/m 2 every 6 hours); this alternating schedule was repeated for as long as tolerated. Age-appropriate psychometric testing was performed before the start of ddC therapy and after 8 weeks. Results: During the 8 weeks of therapy with ddC alone, no neutropenia or anemia was observed; 6 of 9 patients had decreases in p24 antigen levels, and 8 of 15 had an increased CD4 cell count. At the 0.04 mg/kg level, a rash developed in three patients; mild mouth sores developed in 9 of 15 patients. On the alternating ddC/AZT schedule, no neuropathy was observed. Conclusions: 2′,3′-Dideoxycytidine has antiretroviral activity in some children and appears to be safe for short intervals. Longer courses of ddC at lower dosage levels, and schedules integrating ddC into combination regimens, deserve to be explored.

A systematic study of verbal and nonverbal memory and learning was undertaken in long-term survivors of acute lymphoblastic leukemia to assess the incidence and pattern of impairments and to determine the relationship between these deficits and computed tomography (CT) brain scan abnormalities. Twenty-three children who had received cranial irradiation (2,400 cGy) and intrathecal chemotherapy as central nervous system (CNS) preventive therapy and who were off all therapy for at least 4 years were evaluated. On the basis of their CT brain scan findings, patients were divided into three groups: those with intracerebral calcifications (n = 5), those with cortical atrophy (n = 8), and those with normal CT findings (n = 10). Significant deficits in verbal memory (p less than 0.025) and verbal learning (p less than 0.05) were observed that were associated with the presence and type of CT brain scan abnormalities; the greatest impairments were observed in patients with calcifications. No significant differences between CT scan groups were found for nonverbal memory and learning. Previous evaluation of attentional processing in these patients using reaction time tests had revealed the presence of deficits primarily in the ability to sustain attention. Combining those data with findings from the present study showed that memory impairments, particularly those in short-term memory, were primarily attributable to an underlying attentional defect that affect the encoding stage of memory processing.

Surveillance and management for therapy-related normal tissue damage in survivors of both childlhood and adult-onset cancer is necessary to maximize health-related quality of life. Progress by the (Children’s Oncology Group (COG) can be modeled or adapted for a adult malignancy, and is described in this report. Investigators from COG developed risk-based, exposure-related guidelines to provide recommendations for screening and management of late effects that may arise as a result of therapeutic exposures used during treatment for childhood, adolescent and young adult cancer. The guidelines are both evidences-based and grounded in the collective clinical experience of experts providing clinical care to thesw patient populations. A therapy-based design was choses to permit modular formatting of the guidelines by therapeutic exposure and based on the patient’s age presenting features, and treatment era. Multidisciplinary system-based (e.g., cardiovascular, neurocognitive, reproductive, etc.) task forces organized within the COG Late Effects Committee are responsible for monitoring the literature, evaluating guideline content, and providing recommendations for guideline revision as new information becomes available.

Purpose: A phase I trial of intrathecal (IT) topotecan was performed to determine the optimal dose, the dose-limiting toxic effects, and the incidence and severity of other toxic effects in patients 3 years and older with neoplastic meningitis. Patients and Methods: Twenty-three assessable patients received IT topotecan administered by means of either lumbar puncture or an indwelling ventricular access device (Ommaya reservoir). Intrapatient dose escalation from 0.025 mg to 0.2 mg was performed in the first cohort of patients. Subsequent cohorts of patients were treated at fixed dose levels of 0.2 mg, 0.4 mg, or 0.7 mg. Serial samples of CSF for pharmacokinetic studies were obtained in a subset of patients with Ommaya reservoirs. Results: Arachnoiditis, characterized by fever, nausea, vomiting, headache, and back pain, was the dose-limiting toxic effect in two of four patients enrolled at the 0.7 mg dose level. The maximum-tolerated dose (MTD) was 0.4 mg. Six of the 23 assessable patients had evidence of benefit manifested as prolonged disease stabilization or response. Conclusion: The MTD and recommended phase II dose of IT topotecan in patients who are 3 years or older is 0.4 mg. A phase II trial of IT topotecan in children with neoplastic meningitis is in progress.

A phase II pediatric trial of a continuous intravenous infusion of 6-mercaptopurine (6MP) in patients with refractory leukemia was performed. The dosing schedule, 50 mg m-2 h-1 for 48 h, was based on the results of a previous phase I trial of this approach. Among the 40 children treated for acute lymphoblastic leukemia (ALL), all of whom had received prior therapy with oral 6MP, 1 complete and 1 partial response were achieved. No response was observed in 17 patients with refractory acute nonlymphocytic leukemia (ANLL). Reversible hepatotoxicity, the primary dose-limiting toxicity, was observed in approximately 50% of cases. Mucositis was encountered infrequently and was usually not severe. 6MP given on the present continuous intravenous infusion schedule overcomes the limited and variable bioavailability of oral 6MP but shows limited activity as induction agent in children with recurrent ALL.

A child with acute lymphoblastic leukemia (ALL) whose predominant leukemic clone demonstrated double minute chromosomes (dmin) is presented. The patient had no history of mutagen or carcinogen exposure and responded well to combination chemotherapy. Although dmin have been described in acute myelogenous leukemia and various solid tumors in adults, their presence in childhood neoplasms is less frequent and limited primarily to neurogenic tumors. This is the first documentation of dmin in childhood ALL, suggesting that there may be an unrecognized subgroup of ALL patients with gene amplification.

PURPOSE To define the maximum-tolerated dose (MTD), quantitative and qualitative toxicities, recommended phase II dose, and pharmacokinetics of pyrazoloacridine (PZA) administered as a 1- or 24-hour infusion in children and young adults with refractory cancers. PATIENTS AND METHODS Twenty-two patients received PZA as a 1-hour infusion at doses of 380 mg/m2 (n = 3), 495 mg/m2 (n = 6), 640 mg/m2 (n = 6), and 835 mg/m2 (n = 7). An additional four patients received PZA as a 24-hour infusion at the MTD (640 mg/m2) for the 1-hour infusion schedule. Plasma samples were obtained for pharmacokinetic analysis in 17 patients. PZA concentration in plasma was measured by reverse-phase high-performance liquid chromatography (HPLC). A two-compartment pharmacokinetic model was fit to the PZA plasma concentration data. RESULTS On the 1-hour infusion schedule, dose-limiting myelosuppression (neutropenia more than thrombocytopenia) was observed in two of seven patients at the 835-mg/m2 dose level. Myelosuppression did not appear to be ameliorated by prolonging the infusion to 24 hours. Nonhematologic toxicities were minor. Significant neurotoxicity, which was dose-limiting in adults treated with a 1-hour infusion of PZA, was observed in one patient treated at 640 mg/m2, but was not dose-limiting. There was marked interpatient variability in plasma PZA concentrations at all dose levels. The pharmacokinetic profile of PZA was characterized by an initial rapid decline (alpha half-life [t(1/2)alpha], 0.5 hours) followed by a prolonged elimination phase (t(1/2)beta, 30 hours). The volume of distribution at steady-state (Vd(ss)) was 700 L/m2 and the clearance was 300 mL/min/m2. There was no evidence of dose-dependent clearance. The area under the PZA concentration-time curve (AUC) correlated poorly with dose and was more predictive of the degree of myelosuppression than was PZA dose. CONCLUSION PZA administered as 1- or 24-hour infusion is well tolerated by children and young adults. The dose-limiting toxicity (DLT) is myelosuppression. Neurotoxicity is not prominent in this age group. There was marked interpatient variation in plasma concentrations of PZA. The recommended dose for phase II studies is 640 mg/m2.

PURPOSE A phase I trial of docetaxel was performed to determine the maximum-tolerated dose (MTD), the dose-limiting toxicities, and the incidence and severity of other toxicities in children with refractory solid tumors. PATIENTS AND METHODS Forty-four children received 103 courses of docetaxel administered as a 1-hour intravenous infusion every 21 days. Doses ranged from 55 to 150 mg/m2, MTD was defined in heavily pretreated and less heavily pretreated (< or = 2 prior chemotherapy regimens, no prior bone marrow transplantation [BMT], and no radiation to the spine, skull, ribs, or pelvic bones) patients. RESULTS Dose-related neutropenia was the primary dose-limiting toxicity. The MTD in the heavily pretreated patient group was 65 mg/m2, but the less heavily pretreated patients tolerated a significantly higher dose of docetaxel (maximum-tolerated dose, 125 mg/m2). Neutropenia and constitutional symptoms consisting of malaise, myalgias, and anorexia were the dose-limiting toxicities at 150 mg/m2 in the less heavily pretreated patients. Thrombocytopenia was not prominent, even in patients who experienced dose-limiting neutropenia. Common nonhematologic toxicities of docetaxel included skin rashes, mucositis, and mild elevations of serum transaminases. Neuropathy was uncommon. Peripheral edema and weight gain were observed in two of five patients who received more than three cycles of docetaxel. A complete response (CR) was observed in one patient with rhabdomyosarcoma, a partial response (PR) in one patient with peripheral primitive neuroectodermal tumor (PPNET), and a minimal response (MR) in two patients with PPNET. Three of the four responding patients were treated at doses > or = 100 mg/m2. CONCLUSION The recommended phase II dose of docetaxel administered as a 1-hour intravenous infusion in children with solid tumors in 125 mg/m2. Because neutropenia was the dose-limiting toxicity and thrombocytopenia was mild, further escalation of the dose should be attempted with granulocyte colony-stimulating factor (G-CSF) support.

There have been significant strides in the treatment and prevention of meningeal cancer, particularly meningeal leukemia, during the past thirty years. These advantages are a direct result of innovative therapeutic approaches specifically designed to overcome the limitations of systemically administered chemotherapy. Such approaches include the administration of intrathecal chemotherapy by intralumbar or intraventricular injection, the administration of very high-dose systemic chemotherapy, and the administration of cranial or craniospinal irradiation. A better understanding of the central nervous system pharmacokinetics of commonly used anticancer agents has also resulted in improvements in the treatment of meningeal cancer. In this article, the clinical pharmacology of the most commonly used intrathecal agents and pharmacologic strategies for the treatment of meningeal cancer will be discussed. In addition, an overview of new agents for intrathecal administration and other novel CNS targeted therapies will be presented.

PURPOSE Cyclophosphamide is commonly used in the treatment of children with malignant brain tumors. The purpose of this study was to develop a multicycle, high-dose intensity cyclophosphamide regimen with granulocyte-macrophage colony-stimulating factor (GM-CSF) and to assess its activity against malignant glioma and primitive neuroectodermal tumor (PNET). METHODS Twenty-three patients with brain tumors, including 15 with malignant glioma and six with PNET, were enrolled. Cyclophosphamide (1.8-2.25 g/m2/day for 2 days i.v.; total dose 3.6-4.5 g/m2) was administered and was followed by recombinant human GM-CSF (5 micrograms/kg/day s.c.) on days 3-11 or until the absolute granulocyte count reached 1.5 x 10(9)/L. RESULTS With a total of 83 cycles administered, the mean dose intensity of cyclophosphamide ranged from 1.5 g/m2/week through cycle 2 (22 patients) to 0.8 g/m2/week through cycle 8 (two patients). No activity was seen against malignant glioma, and five of six patients with PNET had partial responses. The mean duration of a neutrophil count of < 0.5 x 10(9)/L was only 8 days; the platelet recovery was substantially longer. Fever during neutropenia occurred in 54 of 83 cycles. One patient died from transfusion-related graft-versus-host disease. CONCLUSIONS A cyclophosphamide regimen equal to twice the dose intensity of that used in conventional therapy was administered. The regimen was active against PNET but inactive against malignant glioma.

The cerebrospinal fluid (CSF) pharmacokinetics of topotecan were studied in a nonhuman primate model following intraventricular administration of 0.1 mg. Lactone and total drug concentrations were measured using a reverse-phase HPLC method with fluorescence detection. The mean peak concentrations of lactone and total drug in ventricular CSF were 83 +/- 18 microM and 88 +/- 25 microM, respectively. CSF drug elimination of the lactone was bi-exponential with a terminal half-life of 1.3h. The mean clearance from ventricular CSF was 0.075 ml/min for the lactone and 0.043 ml/min for total drug. The ventricular CSF drug exposure (AUC) to lactone was 450-fold greater following intraventricular administration of 0.1 mg topotecan than after systemic intravenous administration of a 40-fold higher dose (10 mg/m2). Peak lumbar concentrations (n = 1), which occurred 2 h after intraventricular drug administration, were 0.98 microM and 2.95 microM for the lactone and total drug, respectively. A transient CSF pleocytosis was observed in one animal following intralumbar topotecan administration and in one animal following intralumbar topotecan administration. No other acute or chronic neurologic or systemic toxicities were observed following a single intraventricular dose or weekly (x4) intralumbar topotecan. Compared with systemic topotecan, intrathecal administration provided a significant pharmacokinetic advantage in terms of CSF drug exposure and did not produce any significant neurotoxicity in a nonhuman primate model. Intrathecal topotecan should be evaluated clinically as a potential alternative therapy for refractory meningeal tumors.

PURPOSE We performed a phase I trial of piroxantrone with and without granulocyte colony-stimulating factor (G-CSF) to determine whether the use of this cytokine would enable us to increase the dose-intensity of piroxantrone. PATIENTS AND METHODS Thirty-eight patients received 121 courses of piroxantrone administered once every 21 days. Initial patient cohorts received piroxantrone alone starting at 150 mg/m2 and the dose was escalated in subsequent patients until dose-limiting toxicity (DLT) was reached. Patient cohorts then received escalating doses of piroxantrone starting at 185 mg/m2 administered with G-CSF beginning day 2. RESULTS Dose-limiting neutropenia occurred in three of six patients treated with 185 mg/m2 piroxantrone; the maximum-tolerated dose (MTD) of piroxantrone alone was 150 mg/m2. Three of six patients treated with piroxantrone and G-CSF exhibited dose-limiting thrombocytopenia at 445 mg/m2; the MTD of piroxantrone with G-CSF was thus 355 mg/m2. Seven patients developed symptomatic congestive heart failure (CHF) at cumulative piroxantrone doses ranging from 855 to 2,475 mg/m2 and two have died of cardiotoxicity. Of these patients, six of seven had previously received doxorubicin. Other nonhematologic toxicity was mild. CONCLUSION The use of G-CSF results in a more than twofold increase in the MTD of piroxantrone. However, symptomatic cardiotoxicity is prominent, especially in patients who have received prior treatment with anthracyclines.

Background Orally administered all-trans-retinoic acid (all-trans-RA) can induce complete remission in a high proportion of patients with acute promyelocytic leukemia. A previous pharmacokinetic study in patients with acute promyelocytic leukemia raised the possibility that the absorption of orally administered all-trans-RA is a saturable process that would have significant clinical impact on dosing strategies. Purpose This study was specifically designed to examine the saturability of all-trans-RA absorption by measuring the effect of doubling the oral dose of all-trans-RA on plasma drug concentration in patients receiving long-term oral therapy. Methods Six patients with solid tumors received oral doses of 10-mg gelatin capsules of all-trans-RA. Patients were studied on 2 consecutive days after they received 28 days of all-trans-RA administered as two daily 78-mg/m2 doses. The study assigned the patients to two groups. Three patients took a 156-mg/m2 dose on day 28 and a 78-mg/m2 dose on day 29; the other three patients took the lower dose on day 28 and the double dose on day 29. Blood samples for the determination of all-trans-RA plasma concentration were obtained at 30-minute intervals starting just prior to drug administration and continuing for a total of 7 hours. The plasma concentration of all-trans-RA was measured by high-performance liquid chromatography. Results Plasma concentrations following an oral dose of all-trans-RA were highly variable, with peak concentrations ranging from 0.07 to 1.2 microM for the 78-mg/m2 dose level. Doubling the dose from 78 to 156 mg/m2 increased plasma concentration in all six patients, but the increase was unpredictable and not related to dose, ranging from less than a 1.2-fold to more than a 10-fold increase. Conclusion The current study does not support the hypothesis that the gastrointestinal absorption of all-trans-RA involves a saturable process but instead suggests that absorption is highly variable among patients. This wide interpatient variability suggests that pharmacokinetic drug monitoring may have an important role in the management of patients receiving all-trans-RA.

Background Orally administered all-trans-retinoic acid (all-trans-RA) can induce remission in a high proportion of patients with acute promyelocytic leukemia. Purpose To further define the drug's pharmacokinetics, a study of intravenous all-trans-RA was performed in rhesus monkeys. Methods A total of nine monkeys received intravenous bolus injections of all-trans-RA. Three different doses (20, 50, and 100 mg/m2) were each tested in three monkeys. Blood samples for determination of all-trans-RA concentration were obtained prior to drug administration and at 5, 10, 15, 30, 45, 60, 75, 90, 120, 150, 180, 240, 360, and 480 minutes after drug administration. Results Plasma disappearance of all-trans-RA was characterized by three distinct phases: a brief, initial exponential decline, followed by a relative plateau in the disappearance curve (the duration of which was dose dependent), and finally a terminal exponential decay. This profile is consistent with a capacity-limited (saturable) elimination process. The first-order (terminal) half-life for all-trans-RA averaged 19 minutes, and the mean clearances were 77, 52, and 59 mL/min for the 20-, 50-, and 100-mg/m2 dose groups, respectively. The mean +/- SD Michaelis constant (Km) for the capacity-limited process was 3.2 +/- 1.9 microM. Conclusions Peak plasma concentrations following oral administration of 45 mg/m2 all-trans-RA in humans approach the Km for the capacity-limited process; thus, the dose-dependent pharmacokinetics of all-trans-RA described here may occur within the clinically used dosage range.

The p53 gene was examined in primary lymphoblasts of 25 pediatric patients with acute lymphoblastic leukemia by the RNase protection assay and by single strand conformation polymorphism analysis in 23 of 25 cases. p53 mutations were found to occur, but at a low frequency (4 of 25). While all four mutations were identified by single strand conformation polymorphism, the comparative sensitivity of RNase protection was 50% (2 of 4). Heterozygosity was retained at mutated codons in 3 of 4 cases. One pedigree was consistent with the Li-Fraumeni syndrome, and bone marrow from both diagnosis and remission indicated a germline G to T transversion at codon 272 (valine to leucine). Although members of another family were affected with leukemia, a 2-bp deletion in exon 6 was nonhereditary. The other two nonhereditary p53 mutations included a T to G transversion at codon 270 (phenylalanine to cysteine) and a G to C transversion at codon 248 (arginine to proline). These data support the role of both hereditary and acquired p53 mutations in the pathogenesis and/or progression of some cases of childhood acute lymphoblastic leukemia.

The carboxypeptidase G class of enzymes rapidly hydrolyze methotrexate (MTX) into the inactive metabolites 4-deoxy-4-amino-N10-methylpteroic acid (DAMPA) and glutamate. This study evaluated the use of carboxypeptidase-G2 (CPDG2) as a potential intrathecal (IT) rescue agent for massive IT MTX overdose. The CSF pharmacokinetics of MTX with and without CPDG2 rescue was studied in adult rhesus monkeys (Macaca mulatta) using a nontoxic IT 5 mg dose (equivalent to 50 mg in humans). Without CPDG2 rescue, peak CSF MTX concentration was 2,904 +/- 340 mumol/L. Within 5 minutes of administration of 30 U IT CPDG2, CSF MTX concentrations decreased greater than 400-fold to 6.55 +/- 6.7 microM. Subsequently, groups of three monkeys received either 25 mg IT MTX (equivalent to 250 mg in humans) followed by 150 U IT CPDG2 or 50 mg IT MTX (equivalent to 500 mg in humans) followed by 300 U IT CPDG2. All animals survived without neurotoxicity. Our studies suggest that CPDG2 may prove to be an important addition to the currently recommended strategy for the management of IT MTX overdose.

We evaluated serum thyroid hormone and thyroid antibody levels, the serum TSH response to TRH, and the circadian pattern of serum TSH in 10 children and adolescents after radiation therapy for acute lymphoblastic leukemia. Four patients had received central nervous system preventive cranial irradiation and intrathecal chemotherapy, and the remaining 6 patients were treated with craniospinal irradiation for central nervous system relapse. Serum total T4 and T3 concentrations were within the normal range and thyroid antibodies were negative in all patients. Four patients who had received craniospinal irradiation had low free T4 levels. Prior to TRH administration, the overall mean serum TSH concentration was 5.4±1.3 mU/l, and the mean peak response to TRH was 33±6.5 mU/l. Both were significantly increased when compared to the levels observed in our control population (p

To treat children with acute lymphoblastic leukemia, the pediatric oncologist must have a basic understanding and appreciation of the clinical pharmacology of vincristine, methotrexate, 6-mercaptopurine, cytarabine (cytosine arabinoside), and corticosteroids. The treating physician should be cognizant of the inter- and intrapatient variabilities in the pharmacokinetics and clinical effects of each of the drugs. The pharmacokinetics of other cancer chemotherapy agents used in the treatment of childhood leukemia should also be known (doxorubicin, asparaginase, teniposide, and cyclophosphamide), but these agents are less commonly used or administered for a short period of the total treatment. Recent laboratory studies and clinical observations have suggested ways in which the agents could be administered more optimally. For the antimetabolites, these include limited bioavailability and the absence of a diurnal variation in oral methotrexate and 6-mercaptopurine, new antifolates with better pharmacological characteristics for oral administration, intravenous therapy with 6-mercaptopurine, and subcutaneous therapy with methotrexate. For corticosteroid therapy, dexamethasone appears to have an advantage over prednisone and prednisolone in treating leukemic cells in the central nervous system. Intrathecal chemotherapy for the prevention of meningeal leukemia is more effective if the dosage is based on the volume of the central nervous system instead of the body surface area. Exposure of systemic tissue to cytotoxic drug concentrations after intrathecal chemotherapy is substantial with methotrexate and negligible with cytarabine.

Neuropsychologic function was assessed in 13 children with symptomatic human immunodeficiency virus disease (Centers for Disease Control Class P2), ranging in age from 14 months to 12 years. Before the initiation of treatment, eight patients were classified as having encephalopathy. Psychologic tests were administered both before and after 6 and 12 months of continuous-infusion azidothymidine (AZT; zidovudine) treatment. After 6 months of treatment a significant increase of 15.5 (+/- 3.3) IQ points was demonstrated in general cognitive functioning (p less than 0.001). Follow-up for 10 of these patients indicated that after 12 months of AZT therapy, they had maintained their gains in IQ points. Improvements in adaptive behavior after 6 months of therapy, assessed with a standardized interview, paralleled the findings on the IQ data. No significant differences in the amount of change was observed for the different subgroups. The magnitude of these improvements could not be explained by practice effects, environmental changes, or general improvement in physical state. We conclude that neuropsychologic function was significantly improved with continuous infusion AZT treatment.

A phase II pediatric trial of a continuous intravenous infusion of 6-mercaptopurine (6-MP) in patients with refractory solid tumors or lymphoma was performed. The dosing schedule of 50 mg/m2 per hour for 48 h was chosen to produce optimal cytotoxic concentrations of 6-MP. There were no complete or partial responses in the 40 patients entered in the trial. Accrual was sufficient for the conclusion to be drawn that there was greater than 95% probability that the true response rate was no greater than 22% and 26% in osteosarcoma and Ewing's sarcoma, respectively. Dose-limiting toxicity was observed in one-third of the patients and included reversible hepatotoxicity, myelosuppression, and mucositis. The excellent penetration of drug into the cerebrospinal fluid (CSF) suggests that future trials of this intravenous dosing schedule should be conducted on tumors of the CNS.

We undertook a phase II trial of sequential MTX (with leucovorin rescue) and 5-FU administered by continuous infusion. Thirty-one patients with refractory solid tumors (targeted to patients with Ewing's sarcoma and rhabdomyosarcoma) were entered on this trial

HISTORICALLY, the classification of lymphoid cancer has been based on morphologic assessment with the light microscope. The observation that lymphoid cells can be categorized according to immunolog...

The expression of the interleukin-2 (IL-2) receptor was studied in neoplastic cells derived from acute leukemias, T-cell lymphoblastic lymphomas, peripheral T-cell lymphomas, chronic lymphocytic leukemias, well-differentiated lymphocytic lymphomas, and established cell lines by both flow cytometric analysis and sodium dodecyl sulfate/polyacrylamide gel electrophoresis (SDS-PAGE) after affinity crosslinking of radiolabeled IL-2. Cells from most acute leukemias (19 of 22), irrespective of their subtype (T, common or nonlymphoid leukemias), as well as T-cell lymphoblastic lymphomas and peripheral T- cell lymphomas expressed only the p70–75 beta subunit of the IL-2 receptor. Cells from the more mature B-cell neoplasms, chronic lymphocytic leukemia, and well-differentiated lymphocytic lymphoma, expressed predominantly alpha beta IL-2 receptors (11 of 14). In contrast to these results, most cell lines established from hematopoietic malignancies do not express either chain of the IL-2 receptor. Further studies are necessary to determine the exact function of the IL-2R p70–75 beta subunit in immature hematopoietic cells, but its wide distribution throughout the hematopoietic system suggests that IL-2 may play a role in the early stages of hematopoiesis.

Intracellular lactate dehydrogenase (LD) isoenzyme patterns were studied in the malignant cells of patients with a variety of lymphoid malignancies. These were compared with intracellular LD isoenzyme patterns of normal lymphoid cells and were also correlated with immunologic cell surface marker characteristics. Results showed that, in general, the malignant B cells of Burkitt's lymphoma and the lymphoblasts of T-cell acute lymphoblastic leukemia had isoenzyme patterns similar to those of normal B and T cells, respectively. The isoenzyme patterns of malignant lymphoid cells from patients with non- T, and non-B acute lymphoblastic leukemia, cutaneous T-cell lymphoma, and chronic lymphocytic leukemia were more heterogeneous. These data, although based on small numbers of patients, are consistent with the hypothesis that LD isoenzymes may reflect differences in the maturational status of cells within a single diagnostic category.

To address the problem of drug dosage as a limiting factor for successful chemotherapy, seven patients with Stage IV neuroblastoma were treated with very high dose cyclophosphamide with imidazole carboximide (DTIC) and vincristine sulfate in conjunction with intensive supportive care. None of the patients experienced a complete response. The major toxicity was myelosuppression, complicated by significant infections. Toxicity was significantly more severe in this study than in similar regimens using these three drugs at conventional doses. Although the number of patients in this study was small and most had received prior therapy, our data do not support the efficacy of very high dose cyclophosphamide in the treatment of Stage IV neuroblastoma.

Fourteen children (aged 3 to 14 years) with average-risk acute lymphoblastic leukemia were studied after an oral dose of 6-mercaptopurine (6-MP) (75 mg/m2) administered alone and, on the next day, concurrently with oral methotrexate (20 mg/m2). When 6-MP was administered alone, both the peak plasma concentration (15 to 150 ng X ml-1) and the AUC (36 to 340 ng X ml-1 X hr) were highly variable. Concurrent methotrexate resulted in a 31% increase in the AUC (P less than 0.01) and a 26% increase in peak plasma levels (P less than 0.05) of 6-MP. The AUC of methotrexate correlated with the degree of increase in 6-MP plasma concentrations. These findings are consistent with previous in vitro studies demonstrating that methotrexate is an inhibitor of xanthine oxidase, the enzyme that catabolizes 6-MP to the inactive metabolite thiouric acid. Although the increases in 6-MP AUC and peak plasma concentrations resulting from concurrent methotrexate administration were statistically significant, this interaction is probably not clinically significant at standard low oral doses of methotrexate in light of the wide interpatient variability in these pharmacokinetic parameters of 6-MP.

A prolonged decrease in circulating granulocytes accompanied transfusions of HL-A-incompatible platelet concentrates in two afebrile patients with aplastic anemia. The median granulocyte count measured at 20 hours after incompatible platelet concentrates was reduced by 30.8 per cent and remained depressed below pretransfusion levels for as long as four days (median of two days). HL-A-matched platelet concentrates obtained either from siblings or from nonfamily donors did not cause granulocytopenia. The rebound granulocytosis that usually follows transfusion reactions was not observed in these patients presumably because of severely comprised bone-marrow reserves. The prolonged delay in recovery of circulating granulocytes caused by incompatible platelet concentrates may lower host defenses and thus increase the risk of infection. (N Engl J Med 290:1220–1223, 1974)

To better characterize the disposition of cytosine arabinoside (Ara-C) in cerebrospinal fluid (CSF), its kinetics were studied in seven patients with meningeal leukemia in complete remission. After intraventricular injection of 30 mg Ara-C, CSF and plasma samples were obtained over a 24-hr period. Ara-C levels were measured by a reverse-phase HPLC assay (with a sensitivity of 0.5 microM in CSF and 1.0 microM in plasma) that readily separated Ara-C from its major metabolite uracil arabinoside (Ara-U). Elimination of Ara-C from CSF followed a biphasic pattern, with an initial t1/2 of 1 hr and a terminal t1/2 of 3.4 hr. Ara-C clearance from CSF was 0.42 ml/min, suggesting that drug elimination was primarily by CSF bulk flow. The ratio of the AUC of Ara-U to the AUC of Ara-C was 0.08, indicating only minor metabolism of Ara-C to Ara-U in CSF, in contrast to that after systemic Ara-C. Despite initial CSF Ara-C concentrations exceeding 2 mM, Ara-C was not detectable in plasma in any patient. Intraventricular Ara-C results in very high levels in CSF, but systemic tissues are relatively spared from exposure to Ara-C.

A four-year-old child with recurrent infections and increasing hepatosplenomegaly over a three-year period was evaluated. Increased numbers of myeloid precursors packed the bone marrow and infiltrated the peripheral blood. A diagnosis of chronic myelogenous leukemia (CML) was considered but could not be confirmed by laboratory studies appropriate for the types of CML usually observed in childhood. Examination of the patient's peripheral blood smears revealed many atypical monocytoid cells with unipolar hairy projections. Scanning electron microscopy showed these to be leukemic monoblasts with characteristic broad-based ruffles on the cell surface. A population of myeloid precursors possessing narrow ridge-like profiles was also observed. Progressive infiltration of the spleen caused hypersplenism which necessitated splenectomy. Subsequently, massive liver and bone marrow involvement led to the patient's death. Terminally, the proliferating blast cells were demonstrated to be leukemic monoblasts by analysis of cytochemical staining patterns, surface immunoglobulins, serum lysozyme levels, and monocyte-mediated antibody-dependent cellular cytotoxicity studies. The findings in this case are most compatible with a diagnosis of chronic myelomonocytic leukemia (CMML), a condition not previously described in childhood. Several myeloproliferative disorders with prolonged survival have been reported in children, but special studies were not performed to determine which cell lines were abnormally proliferating. The similarities between these children and our patient with CMML suggest that monocyte studies may be useful in the diagnosis of these unusual disorders, provide insights into their pathogenesis, and aid in the selection of appropriate therapy.

A 4-year-old boy with orbital rhabdomyosarcoma developed central nervous system (CNS) metastases as a meningeal disease without clinically apparent local recurrence. Abnormal cells in the cerebrospinal fluid (CSF) antedated the symptoms and signs of increased intracranial pressure. This suggests that the CSF of patients with rhabdomyosarcoma should be monitored and that prophylactic therapy of the CNS might be indicated, especially in those patients with head and neck or metastatic disease.

Testing of paired serum samples of 12 children with the Wiskott-Aldrich syndrome for the presence of hepatitis B surface antigen (HB s Ag), antibody to HB s Ag, and antibody to the hepatitis B core antigen revealed evidence of hepatitis B virus infection in three. None of the three, however, developed overt clinical hepatitis or the chronic HB s Ag carrier state. These data suggest that the immunologic defects seen in the Wiskott-Aldrich syndrome permit adequate immune responses to the hepatitis B virus and do not predispose to the chronic HB s Ag carrier state.