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The Children's Oncology Group Long-Term Follow-Up Guidelines provide exposure-based risks and recommendations for late effects screening of survivors of childhood cancer. Passport for Care (PFC) is a web-based clinical decision support tool for generating a personalized survivorship care plan (SCP) derived from the Guidelines and user-entered exposures. We assessed PFC clinician user practices and perceptions of PFC impact on clinic workflow, guidelines application, and survivor shared decision-making.A 35-item REDCap survey was emailed to all PFC users (n = 936) in 146 current and former PFC user clinics. Anonymous responses were permitted. Results were summarized and compared with a 2012 survey.Data were available from 148 respondents representing 64 out of 146 PFC user clinics (minimum clinic response rate 44%, excluding 49 anonymous responses). Generation of a personalized SCP was the most common application of PFC, followed by determination of surveillance recommendations and use as a survivor database. Twenty-five respondents (17%) felt data entry was a significant or insurmountable barrier to PFC application. Sixty-nine percent of respondents attributed PFC with a very high/high impact on guidelines adherence in their clinical practice, compared with 40% who attributed PFC with having a significant impact on adherence in 2012 (p .001).The survey results provide valuable insights on patterns of SCP delivery and Survivor Clinic workflow. User-perceived benefits to PFC included facilitating clinician ability to follow guidelines recommendations in clinical practice. Importantly, some barriers to resource utilization were also identified, suggesting a need for user-informed adaptations to further improve uptake.

The extreme disparity in pediatric cancer outcomes in low- and middle-income countries (LMICs, 20%) vs. the US (80%) can only be solved by addressing the inequities of access to high quality healthcare, including a precise diagnosis. In the US, excellent outcomes depend on treatments tailored to risk groups or specific characteristics of each child's cancer. Unfortunately, most pediatric cancer patients live in LMICs, where physicians often diagnose cancer based on clinical findings due to limited access to pathology and molecular genomic services. The goal of the Texas Children’s Hospital (TCH) Global HOPE program is to improve outcomes for pediatric cancer in Sub-Saharan Africa (SSA), and improved diagnostics is a key component. The aim of this study was to design and validate a cost-effective assay to improve pediatric cancer diagnoses in low resourced settings. The NanoString nCounter platform was chosen due to minimal technical expertise required, ability to test sub-optimal RNA, and rapid turn-around-time (2-3 days). Custom panels were designed to detect 439 specific breakpoints of gene fusions associated with pediatric hematologic malignancies and 436 with pediatric solid tumors. Validation was performed using >140 samples with known fusion status. The NanoString results were consistent with a 99% accuracy after follow-up sequncing of any potential false negative/positive results (see table). Implementing this platform will greatly impact the ability to treat pediatric cancer in SSA by providing a more precise diagnosis. Testing will allow children to be treated according to the specific molecular characteristics of their cancers to maximize their chances of a cure, the same approach now considered standard-of-care in the United States. This work will also form the basis for establishing training in molecular and pediatric pathology in these LMICs, a critical need for long-term sustainability and reducing inequities of pediatric cancer care. Custom Pediatric Cancer Fusion Panel Validation Custom Panel Unique Evaluable Samples Initial False Negatives Initial False Positives True False Negatives True False Positives Accuracy by NanoString Panles Heme 1 48 1 2 0 0 48 (100%) Heme 2 34 0 1 0 0 23 (100%) Heme 3 33 0 1 0 1 32 (97%) Heme 4 28 1 1 0 1 27 (96%) Total 143 2 5 0 2 141 (99%) Citation Format: Julie M. Gastier-Foster, E. Faith Hollingsworth, Dolores H. Lopez-Terrada, Kevin E. Fisher, Angshumoy Roy, Peter M. Wasswa, Nmazuo W. Ozuah, Parth Mehta, Joseph Lubega, Carl E. Allen, David G. Poplack, Fredrick Lutwama. Custom gene fusion assay for the rapid diagnosis of pediatric cancer in Sub-Saharan Africa [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1021.

e24058 Background: Survivors of childhood cancer are at lifelong risk for late effects. The Children’s Oncology Group evidence-based guidelines provide exposure-based risks and recommendations for late effects screening. The Passport for Care (PFC) was developed in 2007 as a web-based clinical decision support tool that uses advanced algorithms to generate a personalized survivorship care plan (SCP), derived from the guidelines and user-entered exposures. Over 150 Long-Term Survivor (LTS) clinics utilize PFC, generating over 47,000 SCPs to date. Our objective was to assess PFC user practices and perceptions of PFC’s impact on clinic workflow, guideline application, and survivor shared decision-making. Methods: We designed a 35-item survey based on a 2012 PFC survey and expanded to include items related to interval website improvements. In June 2021, a REDCap™ survey was sent via email to 935 PFC users in 145 clinics: 107 active PFC clinics and 38 inactive (no data entry in the preceding 6 months). Responses were anonymous, but those who provided an email address were given a $5 gift card. Survey results were reviewed, summarized, and compared with data from 2012 using a Chi square test, when applicable. Results: There were 148 respondents of whom 104 declined anonymity, representing 64 clinics (44%): 58 of the active (54%) and 6 of the inactive clinics (16%). Respondents were largely physicians (n = 46), advanced practice providers (APPs, n = 42), and nurses (n = 49). Of the 148 respondents, 142 provided valid data for the remaining items. PFC was most often used to generate a personalized SCP (n = 131, 93%), compared with 63% in 2012. Other common uses were as a clinical database (59%) and to document late effects (51%). Seventy-one respondents (50%) used PFC to generate an SCP at entry to LTS, and 54 (38%) used PFC at every survivor visit. Most used PFC for > 75% of survivors (n = 103, 73%). Nurses (n = 89, 63%), APPs (n = 63, 44%), physicians (n = 37, 26%), and data managers (n = 13, 9%) performed data entry. Sixty-four respondents (45%) estimated requiring over 30 minutes/patient for data abstraction and entry, and 67 respondents (48%) felt data entry was a modest or significant barrier to PFC application. The majority of respondents were very or generally satisfied with PFC (87%), unchanged from previous (90%). The perceived impact of PFC on accurate application of the guidelines improved from 41% to 72% (p < 0.001), and on fostering conversations with survivors about risk for late effects and screening improved from 44% to 70% (p < 0.001). Conclusions: These results underscore the PFC’s role in increasing guidelines utilization and facilitating conversations with survivors about screening needs. The burden of data entry was a noted limitation, particularly when this responsibility fell to the physician or APP, and was further corroborated by user prioritization of ‘exposure data pre-population by treatment protocol’ for future PFC modifications.

The Inaugural Symposium on Childhood Cancer Health Disparities was held in Houston, Texas, on November 2, 2016. The symposium was attended by 109 scientists and clinicians from diverse disciplinary back-grounds with interests in pediatric cancer disparities and focused on reviewing our current knowledge of disparities in cancer risk and out-comes for select childhood cancers. Following a full day of topical sessions, everyone participated in a brainstorming session to develop a working strategy for the continued expansion of research in this area. This meeting was designed to serve as a springboard for examination of childhood cancer disparities from a more unified and systematic approach and to enhance awareness of this area of need.

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

PURPOSE Specialized multidisciplinary care is central to childhood cancer control. Expertise and infrastructure in the pediatric disciplines of hematology, surgery, critical care, nursing, and pathology are as critical as pediatric oncology. Survival of the majority of children with cancer globally remains dismal because of the scarcity of multidisciplinary pediatric subspecialty services. We present the innovative approach and impact of Texas Children’s Global HOPE initiatives to cost-effectively develop capacity for specialized multidisciplinary cancer care for children in sub-Sahara Africa (SSA). METHODS Global HOPE designed and supports subspecialty training and contingent infrastructure building in SSA in the following disciplines that are critical to pediatric cancer care: pediatric hematology and oncology (PHO), pediatric surgery, pediatric critical care, anatomic and molecular pathology, and pediatric oncology nursing. Key principles underlying the design of each disciplinary program are that it enables the implementation of current best evidence-based practices, primarily uses a problem-based learning approach, and is integrated and accredited by the local health sciences university. Training primarily occurs at an African hub where Global HOPE also supports infrastructure for clinical care and research, in addition to onsite faculty and offsite telemedicine support from the headquarters in Houston, TX. RESULTS The PHO and pediatric surgery fellowship programs based at Makerere University, Kampala, are the most advanced thus far. Twenty pediatricians from 6 African countries have enrolled and 8 have graduated from the 2-year PHO program. One surgeon enrolled in the 3-year pediatric surgery fellowship annually and 6 have graduated since inception. The fellowship programs have directly affected patient outcomes because of evidence-based clinical rigor and enhanced clinical infrastructure. All graduates from the 2 fellowships are currently practicing in SSA. CONCLUSION Formal in situ pediatric subspecialty training is feasible in low- and middle-income countries and carries the critical advantages of infrastructure development, direct patient impact, and is less susceptible to brain drain.

Survivors of childhood cancer are at increased risk for late effects of cancer therapy, but evidence suggests that adherence to follow-up care is suboptimal. Here, we review the barriers to adherence, including those unique to childhood cancer survivors, and the rationale for distribution of a survivorship care plan. We also discuss advantages and potential limitations of delivering survivorship care plans via web-based platforms, and describe the unique features of one of these platforms, Passport for Care. A baseline survey directed toward survivors and conducted through Passport for Care found that a significant proportion of survivors are unaware of their specific health risks resulting from cancer and its treatment, and compared with their parents, are less afraid of the risks of recurrence and of cancer therapy-associated late effects (n = 528). Web-based platforms such as Passport for Care have enormous potential for improving access to health information, as well as for enhancing patient, family caregiver, and healthcare provider awareness of both risks of late effects and recommended surveillance. Results from this survey also suggest the potential utility of leveraging these tools to conduct additional research on consenting survivors.

Background Diversity is necessary for the survival and success of both biological and social systems including societies. There is a lack of diversity, particularly the proportion of women and minorities in leadership positions, within medicine.1;2 In 2009 a group of ASPHO members recognized the need to support the career advancement of women and minority members. This article reports the results of a survey designed to characterize the comparative career pathway experience of women and minority ASPHO members.

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.

Survivors of childhood cancer are at risk of long-term adverse effects and late effects of the disease and/or its treatment. In response to national recommendations to improve evidence-based follow-up care, a web-based support system for clinical decision making, the Passport for Care (PFC), was developed for use at the point of care to produce screening recommendations individualized to the survivor. To date, the PFC has been implemented in over half of the nearly 200 clinics affiliated with the Children's Oncology Group across the USA. Most clinician users report that the PFC has been integrated into clinic workflows, and that it fosters improved conversations with survivors about the potential late effects a survivor might experience and about the screening and/or behavioural interventions recommended to improve health status. Furthermore, clinicians using the PFC have indicated that they adhered more closely to follow-up care guidelines. Perspectives on the challenges encountered and lessons learned during the development and deployment of the PFC are reviewed and contrasted with other nationwide approaches to the provision of guidance on survivor follow-up care; furthermore, the implications for the care of childhood cancer survivors are discussed.

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.

PURPOSE Idarubicin (4-demethoxy-daunorubicin) is more potent and less cardiotoxic than the commonly used anthracyclines, doxorubicin and daunorubicin. In addition, idarubicin is metabolized to an active metabolite, idarubicinol, in contrast to other anthracyclines whose alcohol metabolites are much less active than the parent drug. The current study was performed in nonhuman primates to determine the plasma and cerebrospinal fluid (CSF) pharmacokinetics of idarubicin and idarubicinol and to compare them to the pharmacokinetics of daunorubicin and daunorubicinol. METHODS A dose of 30 mg/m2 of daunorubicin or 8 mg/m2 of idarubicin was administered intravenously over 15 minutes. Plasma and CSF were sampled frequently from the end of the infusion to 72 to 96 hours after infusion. Drug and metabolite concentrations were measured using high-pressure liquid chromatography (HPLC). RESULTS Daunorubicin elimination from plasma was triphasic with a terminal half-life of 5.9 +/- 1.8 hours, area under the concentration-time curve (AUC) 22.5 +/- 9.2 mumol/L.min, and clearance 2790 +/- 960 mL/min/m2. Daunorubicinol elimination was biphasic with a terminal half-life 10.2 +/- 2.3 hours and an AUC 74.5 +/- 5.3 mumol/L.min. Idarubicin elimination was triphasic with terminal half-life of 12.3 +/- 11.4 hours, a AUC 10.8 +/- 3.7 mumol/L.min, and clearance 1650 +/- 610 mL/min/m2. Idarubicinol elimination was biphasic with a terminal half-life 28.7 +/- 4.2 hours and AUC 67 +/- 9.8 mumol/L.min. CSF penetration was low for both parent drugs and their metabolites. CSF idarubicin was measurable at a single time point (1 hour after administration) for 2 animals, and was not measurable for the third. The CSF to plasma concentration ratio at that time point was 8% in 1 animal and 15% in the other. Idarubicinol was detected in 2 to 4 samples at various times, appearing as early as 1 hour in 1 animal and persisting as late as 48 hours in another. The CSF to plasma concentration ratio at corresponding time points was 1.9 +/- 0.6%. Daunorubicin was measurable for < 6 hours after intravenous administration. For individual animals, the mean CSF to plasma concentration ranged from 4% to 12%. Daunorubicinol was detectable by 1 hour in 2 of 3 animals and by 3 hours in the other, and remained detectable at 24 hours in 2 of 3. The terminal half-life of daunorubicinol in CSF was 8.8 +/- 1.3 hours, the AUC was 1.8 +/- 1.5 mumol/L.min, and the AUCCSF to AUCplasma ratio was 2.4 +/- 1.9%. CONCLUSION Idarubicin, idarubicinol, daunorubicin, and daunorubicinol penetrate poorly into the CSF after intravenous administration.

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.

The bacterial enzyme carboxypeptidase G2 (CPDG2) rapidly hydrolyzes methotrexate to inactive metabolites. We administered recombinant CPDG2 (2000 U) intrathecally to seven cancer patients 3 to 9 hours after they had received an accidental overdose of intrathecal methotrexate (median dose = 364 mg; range = 155-600 mg). Four of the seven patients had cerebrospinal fluid (CSF) exchange to remove methotrexate before CPDG2 administration. Immediate symptoms of the methotrexate overdoses included seizures (n = 5), coma (n = 2), and cardiopulmonary compromise (n = 2). Before CPDG2 administration, the median concentrations of methotrexate in CSF were 264 microM (range = 97-510 microM) among patients who had CSF exchange and 8050 microM (range = 2439-16 500 microM) among patients who did not. After intrathecal CPDG2 administration, methotrexate concentrations in CSF declined by more than 98%. All patients recovered completely from the intrathecal methotrexate overdose except for two patients who had memory impairments. Antibodies to CPDG2 were not detected in plasma after treatment with intrathecal CPDG2. Intrathecal CPDG2 is well tolerated, rapidly decreases CSF methotrexate concentrations, and appears to be efficacious for treating accidental intrathecal methotrexate overdoses.

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.

3. Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . _, 3.1. Radiation therapy . . . . . 3.2. Chemotherapy . . . . . 3.2.

The pharmacokinetics of 2',3'-dideoxyadenosine (ddA), didanosine, 2',3'-dideoxyguanosine (ddG), and 6-halogenated prodrugs of ddG, 6-chloro-ddG and 6-iodo-ddG, in plasma and cerebrospinal fluid (CSF) were studied in a non-human primate model. ddA was rapidly and completely deaminated to didanosine, such that didanosine concentration profiles in plasma and CSF were identical following administration of ddA and didanosine. The mean clearance of didanosine was 0.50 liters/h/kg, the terminal half-life was 1.8 h, and the CSF-to-plasma ratio was 4.8%. The disposition of ddG was similar, with a clearance of 0.70 liters/h/kg and a half-life of 1.7 h. The adenosine deaminase-mediated conversion of the 6-halogenated-ddG prodrugs to ddG was rapid but incomplete (48% for 6-chloro-ddG and 29% for 6-iodo-ddG). The CSF-to-plasma ratios of ddG with equimolar doses of ddG, 6-chloro-ddG, and 6-iodo-ddG were 8.5, 24, and 17%, respectively, but the actual ddG exposures in CSF (area under the CSF concentration-time curve) were comparable for ddG (12.1 microM.h) and the 6-halogenated-ddG prodrugs (18.8 microM.h for 6-chloro-ddG, 9.3 microM.h for 6-iodo-ddG).6-Chloro-ddG was not detectable in plasma or CSF, and the CSF-to-plasma ratio of 6-iodo-ddG was 9.4%, so the higher CSF-to-plasma ratios of ddG with the administration of the 6-halogenated-ddG prodrugs does not appear to be the result of enhanced penetration of the prodrug and subsequent dehalogenation to ddG. The penetration of ddG into CSF exceeds that of didanosine and is enhanced by administration of the 6-halogenated prodrugs, although the mechanism of this enhanced penetration is unclear.

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.

We have demonstrated previously decreased melphalan accumulation in a human breast cancer cell line selected for resistance to melphalan (MelR MCF-7). Cross-resistance studies of MelR MCF-7 cells revealed that this cell line was 6.7-fold cross-resistant to methotrexate, but only 2-fold resistant to trimetrexate. Methotrexate transport studies in MelR MCF-7 cells showed a 2-fold decrease in initial methotrexate uptake and a 2-fold decrease in the Vmax for methotrexate uptake in the resistant cells. Methotrexate resistance in MelR MCF-7 cells was also associated with a decrease in non-effluxable methotrexate following incubation with radiolabeled drug for 24 hr. Characterization of intracellular methotrexate after accumulation for 24 hr demonstrated decreased levels of free methotrexate in MelR MCF-7 cells. Analysis of methotrexate polyglutamate formation in MelR MCF-7 cells indicated that the decrease in non-effluxable, non-protein-bound methotrexate was associated with a 3-fold decrease in higher order methotrexate polyglutamate formation. No difference was noted in folylpolyglutamate synthetase activity between the resistant and parental cell lines. Therefore, the observed decrease in methotrexate polyglutamate formation in MelR MCF-7 cells appeared to result from decreased availability of substrate. There was no evidence of any alteration in the amount of the catalytic activity of dihydrofolate reductase in MelR MCF-7 cells compared with parental MCF-7 (WT MCF-7) cells; moreover, the binding affinity of dihydrofolate reductase for methotrexate and the percentage of protein-bound methotrexate were similar in both cell lines. In addition, the total amounts of thymidylate synthase protein and thymidylate synthase catalytic activity in MelR MCF-7 cells were unchanged. Thus, acquired methotrexate resistance in MCF-7 cells selected for resistance to melphalan appears to result from down-regulation of methotrexate uptake.

The use of mercaptopurine (MP) rather than thioguanine (TG) in the treatment of childhood acute lymphoblastic leukemia (ALL) has occurred for historical reasons, but does not have a pharmacologic basis. The purpose of this study was to begin to address whether TG would be more efficacious than MP in the treatment of childhood ALL. Preclinical cytotoxicity studies were performed using human leukemic cell lines and leukemic cells from patients with ALL. First, the concentration-survival curves for MP and TG in three human leukemic cell lines (MOLT-4, CCRF-CEM and Wilson) were determined. The second group of experiments determined the concentration-time dependence for cytotoxicity of MP and TG. The final group of experiments compared the in vitro cytotoxicity of MP to TG in leukemic cells from patients with ALL. The thiopurines displayed classical anti-metabolite cytotoxicity profiles, exhibiting a cytotoxicity threshold concentration and demonstrating an increase in cell kill with prolongation of exposure to the drug. For MP, the cytotoxicity threshold was approximately 1 microM, with maximum cytotoxicity occurring with 10 microM concentrations. For TG, the threshold was only 0.05 microM with maximum cytotoxicity occurring at 0.5 microM. Exposure to MP for more than 8 h was necessary to produce cytotoxicity, whereas exposures as short as 4 h were required for TG. Leukemic cells from children with ALL were also more sensitive to TG than to MP. The median IC50 for TG (20 microM) was significantly lower than that for MP (> or = 206 microM). The data presented here provide a strong rationale for evaluating TG in place of MP in the treatment of childhood ALL. The more direct intracellular activation pathway, higher potency, and shorter duration of drug exposure necessary for cytotoxicity all suggest that TG may have an advantage over MP.

Survival in acute lymphoblastic leukemia (ALL) has improved in recent decades due to recognition of the biologic heterogeneity of ALL, utilization of risk-adapted therapy, and development of protocols that include optimized chemotherapy combinations, effective central nervous system (CNS) prophylaxis, post-induction intensification of therapy, and a prolonged maintenance phase of treatment. Recent molecular studies have yielded novel insights into both leukemia biology and host pharmacogenetic factors; also, large cooperative group clinical research studies have successively refined effective treatment strategies. While children have higher remission and cure rates than adults, both populations have benefited from these discoveries and innovations. Future challenges in this field include improving outcomes for high-risk patients and those with relapsed disease, and developing and integrating novel targeted therapeutic agents into current regimens to reduce toxicities while further improving outcomes.

Piroxantrone is an anthrapyrazole derivative with broad anti-tumor activity in vitro and less cardiac toxicity than the anthracyclines. The metabolic pathways and central nervous system penetration of piroxantrone have not been determined. In this study we examined the pharmacokinetic behavior of piroxantrone in plasma and cerebrospinal fluid in a non-human primate model. In addition, a urinary metabolite of piroxantrone was isolated and its cytotoxicity evaluated in vitro. The disappearance of piroxantrone from plasma after an intravenous dose of 150 mg/m2 given over 60 minutes was biexponential with mean t1/2 alpha of 1.0 minutes and a mean t1/2 beta of 180 minutes. The mean area under the curve was 220 microM.min and the clearance was 1420 ml/min/m2. Piroxantrone was not detectable in the cerebrospinal fluid. Piroxantrone and three other compounds not present in pre-treatment samples were detected in urine. The major urinary metabolite was isolated. Its cytotoxicity against MOLT-4 cells in vitro was at least one log less than that of piroxantrone. In addition, one of the other compounds detected in urine was determined to be a glucuronide conjugation product of the major metabolite. The results of this study may be useful in the interpretation of the activity and toxicity of piroxantrone in clinical trials.

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.

The thiopurines have a wide array of effects on purine metabolism, but the primary mechanism of cytotoxicity for both 6-mercaptopurine (6-MP) and 6-thioguanine (6-TG) appears to be incorporation of drug into DNA following conversion to the thioguanylate form. In murine leukemic cell lines exposed to a range of thiopurine concentrations in vitro, cell survival curves have displayed a phenomenon termed paradoxical cytotoxicity, defined as a decrease in cytotoxicity with increasing drug concentration. The paradoxical cytotoxicity of thiopurines has usually been attributed to concentration-dependent perturbations in the cell cycle. The present study assessed whether the paradoxical cytotoxicity of 6-MP occurred in cultured human leukemic cells, and investigated the biochemical and cell-cycle alterations occurring in these lines at thiopurine concentrations associated with the reverse of cytotoxicity. Paradoxical cytotoxicity was observed in the two human leukemic cell lines examined, but only when 6-MP concentrations exceeded 100 microM. The extent of incorporation of 6-MP metabolites into DNA as thiol-versus non-thiol-containing metabolites was analyzed by performing parallel experiments with 14C- and 35S-radiolabeled drug. With 5 microM 6-MP, approximately 50% of drug was incorporated into DNA as a thionucleotide; however, with increasing drug concentrations, the degree of thionucleotide incorporation remained unchanged or decreased, and the amount incorporated as the desulfurated metabolite (presumably adenylate or guanylate) increased. With 500 microM 6-MP, less than 10% of the drug was incorporated as the thionucleotide. Perturbations in cell cycle reflected the relative amounts of thiol- and non-thiol-containing nucleotide formed at various concentrations of 6-MP. These results suggest that thiopurines may be vulnerable to a unique mechanism of detoxification, in which a human cell can metabolize a cytotoxic drug to a comparatively potent "self-rescue" agent.

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.

Arabinosyl-5-azacytosine (AAC), a new nucleoside antimetabolite, is broadly active in preclinical tumor screening evaluations. To assess the potential for intrathecal use of this drug, we studied the toxicity and pharmacokinetics of intrathecal and intraventricular administration in nonhuman primates. Four adult male rhesus monkeys were given single 10 mg intrathecal (n = 1) or intraventricular (n = 3) doses of AAC to determine its acute toxicity and pharmacokinetic parameters. An additional 3 animals were given four weekly 10 mg intrathecal doses to assess the systemic and neurologic toxicity associated with chronic administration. Disappearance from the cerebrospinal fluid (CSF) was biexponential, and CSF clearance was 0.2 ml/min, which exceeds the rate of CSF bulk flow by 5-fold. The peak CSF concentration and area under the concentration x time curve achieved with the intraventricular administration of 10 mg were one hundred, and fifty fold greater, respectively, than those achieved after an intravenous dose of 200 mg/kg (1500-2400 mg) in prior experiments. No clinically evident neurotoxicity was observed in either the single or the weekly x 4 dose groups. A slight, transient CSF pleocytosis and increased CSF protein was observed. Systemic toxicity was limited to one animal in the weekly x 4 dose group who demonstrated a mild and transient decrease in his peripheral leukocyte count unassociated with a change in his hematocrit or platelet count. These studies in nonhuman primates demonstrate a clear pharmacokinetic advantage for intrathecal vs systemic administration of AAC. This is demonstrated by a 50-fold greater CSF drug exposure with an intrathecal or intraventricular dose 1/200th of that which can be given systemically.(ABSTRACT TRUNCATED AT 250 WORDS)

SUMMARY Pediatric hematologist/oncologists lead in a variety of roles and settings: at the bedside, in private or academic practice, in the laboratory, and in wider society. Whether their leadership is the result of innate ability, technical expertise, or educational experience, patients, colleagues, academic centers, and communities turn to physicians for leadership. But where do these physicians learn this complex skill? Physicians do acquire leadership skills, but mainly through interaction with role models and in a hit or miss fashion. This article provides a theoretical framework for medical leadership education and describes a leadership-focused educational seminar that has been offered to pediatric hematology-oncology fellows at Texas Children's Cancer Center since 1995. Retrospective pre/post evaluations by fellows indicated significant improvement in self-rated ability for all 24 dimensions assessed, including a variety of items drawn from the roster of the Accreditation Council for Graduate Medical Education Core Competencies. In this article we extend the concept of physician leadership from its roots in practice and present a comprehensive model that prepares pediatric hematologist/oncologists for leadership in clinical, research, and educational arenas.

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.

Using an enzyme-linked immunosorbent assay (ELISA), we have measured serum levels of a soluble form of the p55 subunit of the interleukin-2 receptor complex, soluble CD25 (sCD25), at regular intervals in the sera of 51 pediatric and adult cancer patients receiving recombinant human interleukin-2 (IL-2). The IL-2 was administered in repetitive weekly cycles alone or in combination with lymphokine-activated killer (LAK) cells. Levels of CD25 correlated with clinical toxicities reflected by nadir blood pressures, percentages of weight gained, and minimum Karnofsky performances during IL-2 therapy. Coadministration of autologous in vitro activated LAK cells together with IL-2 did not significantly affect the pattern of sCD25 release relative to administration of IL-2 alone. Examination of sCD25 release in response to different doses of IL-2 revealed a statistically significant dose effect of IL-2 on the sCD25 levels in patient sera. In addition, the level of sCD25 in patient sera also correlated strongly with expression of CD25 on the surface of peripheral blood lymphocytes (PBL) obtained from patients following IL-2 therapy. These studies demonstrate the utility of the sCD25 ELISA as a clinical tool for monitoring patients on treatment regimens that include IL-2.

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.

Significant advances in the treatment and prevention of meningeal leukaemia have been made in the past 3 decades. This progress has resulted from the development of innovative approaches to treatment as well as a better understanding of the pharmacokinetics and pharmacodynamics of the commonly used antileukaemic agents. Intrathecal therapy, via the intralumbar or intraventricular route, is a form of regional therapy that results in the delivery of very high drug concentrations to the principle target tumour site (the meninges) using a relatively small drug dose, thereby minimising both systemic drug exposure and systemic toxicity. The dosage and schedules, clinical pharmacology and toxicities of the commonly used intrathecal agents, methotrexate and cytarabine (cytosine arabinoside; Ara-C) are discussed in detail. Another approach which has been used to overcome the poor penetration of antileukaemic drugs into the CNS has been the use of high-dose systemic therapy. This strategy has been successfully applied in the treatment of meningeal leukaemia using both high-dose methotrexate and high-dose cytarabine. The clinical pharmacology, toxicities, and potential limitations of this approach are outlined. Finally, new agents that are currently undergoing clinical evaluation and future directions for research are also discussed.

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.

Immunoglobulin (Ig) and T-cell receptor (TCR) genes were examined in the lymphoblasts of 70 children with immunophenotypically defined B-cell precursor acute lymphoblastic leukemia (ALL). The most frequent genes to rearrange were Ig heavy (H) chain (93%) and TCR delta (79%), followed by TCR gamma (49%), Ig kappa and/or lambda light (L) chain (46%), TCR alpha (46%), and TCR beta (29%). Thus, despite their putative "B-cell precursor" lineage, these leukemias manifest a remarkably high incidence of TCR gene rearrangements. While certain patterns predominate, there is considerable heterogeneity in Ig and TCR genotypes in this disease. No significant associations were found between Ig and TCR genotype and commonly used prognostic factors including age, sex, race, WBC, French-American-British (FAB) subtype, or cytogenetics. However, the lymphoblasts of three of six patients who failed to achieve initial remission had germline patterns of every Ig and TCR gene, a genotype not observed in the leukemic cells from any of the 64 patients who achieved complete remission (p2 = .0007). This study suggests that particular Ig and TCR genotypes may be of clinical relevance in childhood B-cell precursor ALL. The finding of rearranged TCR genes in a large proportion of cases raises fundamental questions about early lineage commitment and lymphocyte differentiation along B-cell and T-cell pathways.

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.