Variable Clinical Courses of Varicella Zoster Virus Infection-related or Vaccination-related Bone Marrow Failure.

We report 5 children with bone marrow failure (BMF) after primary varicella zoster virus (VZV) infection or VZV vaccination, highlighting the highly variable course. Two patients were treated with intravenous immunoglobulins; one had a slow hematologic recovery, and the other was rescued by allogeneic hematopoietic stem cell transplantation (HSCT). Of the 2 patients treated with immunosuppressive therapy with antithymocyte globulin and cyclosporine, one had a complete response, and the other was transplanted for nonresponse. One patient underwent a primary allograft. All patients are alive. This study demonstrated that VZV-associated BMF is a life-threatening disorder that often requires HSCT.

Nerve ultrasound reference values in children and adolescents: Echogenicity and influence of anthropometric factors including hand volume.

Background: Nerve cross-sectional area (CSA) reference values in high-resolution ultrasound for children and adolescents are influenced by demographic and anthropometric factors such as age, height and weight. Objectives: The influence of hand volume as an additional morphometric factor was evaluated and nerve echogenicity was analyzed in a prospective cross-sectional study. Methods: CSA were measured in 30 healthy children and adolescents from 2 to 17 years in the median, ulnar, radial, tibial, peroneal and sural nerves. Height, weight, age, handedness and gender were recorded, the volume of the hands was measured using the water displacement method. The intra-nerve CSA variability (INV), left/right ratios and absolute differences were calculated. Age groups were compared by the Kruskal-Wallis test. The influence of demographic factors was analyzed using Spearman correlation and multiple linear regression. Echogenicity and fraction of black were determined for each nerve segment. Results: Nerve CSA values were consistently lower than those reported for adults and correlated in all measured nerve sites with age, height, weight and hand volume. Weight showed the highest correlation coefficient (R = .95) with the best fitting model predicting CSA. Correlation coefficients were higher in a linear than in a logarithmic model. Ratios were stable, the absolute differences increased with age and were significantly different between age groups. Most nerves showed a mixed or hypoechogenic pattern in echogenicity analysis, hyperechogenicity is less frequently observed. Conclusions: Nerve CSA in children and adolescents is lower than in adults and increases proportionally during growth with a constant INV and left/right ratio in different age groups. Weight and age are predominant anthropometric factors predicting nerve size. Hand volume is correlated with nerve size, but does not predict CSA independently. Echogenicity can provide additional information on nerve structure.

A Complex Intervention to Prevent Medication-Related Hospital Admissions.

BACKGROUND: Children are often treated off-label and are at a disadvantage in pharmacotherapy. The aim of this study was to implement and evaluate a quality assurance measure (PaedPharm) for pediatric pharmacotherapy whose purpose is to reduce medication-related hospitalizations among children and adolescents. METHODS: PaedPharm consisted of the digital pediatric drug information system PaedAMIS, pediatric pharmaceutical quality circles (PaedZirk), and an adverse drug event (ADE) reporting system (PaedReport). The intervention was implemented in a cluster-randomized trial (DRKS 00013924) in 12 regions, with a pediatric and adolescent medicine clinic in each and a total of 152 surrounding private practitioners, in 6 sequences over 8 quarters. In addition to the proportion of ADE-related hospital admissions (primary endpoint), comprehensive process evaluation included other endpoints such as coverage, user acceptance, and relevance to practice. RESULTS: 41 829 inpatient admissions were recorded, of which 5101 were patients of physicians who participated in our study. 4.1% of admissions were ADE-related under control conditions, and 3.1% under intervention conditions (95% CI: [2.3; 5.9] and [1.8; 4.5], respectively). A model-based comparison yielded an intervention effect of 0.73 (population-based odds ratio; [0.39; 1.37]; p = 0.33). PaedAMIS achieved moderate user acceptance and PaedZirk achieved high user acceptance. CONCLUSION: The introduction of PaedPharm was associated with a decrease in medication-related hospitalizations that did not reach statistical significance. The process evaluation revealed broad acceptance of the intervention in outpatient pediatrics and adolescent medicine.

Hyperacute treatment of childhood stroke in Lyme neuroborreliosis: report of two cases and systematic review of the literature.

The safety and efficacy of hyperacute reperfusion therapies in childhood stroke due to focal cerebral arteriopathy (FCA) with an infectious and inflammatory component is unknown. Lyme neuroborreliosis (LNB) is reported as a rare cause of childhood stroke. Intravenous thrombolysis (IVT) and endovascular therapy (EVT) have not been reported in LNB-associated stroke in children. We report two children with acute stroke associated with LNB who underwent hyperacute stroke treatment. A systematic review of the literature was performed to identify case reports of LNB-associated childhood stroke over the last 20 years. Patient 1 received IVT within 73 min after onset of acute hemiparesis and dysarthria; medulla oblongata infarctions were diagnosed on magnetic resonance imaging (MRI). Patient 2 received successful EVT 6.5 hr after onset of progressive tetraparesis, coma, and decerebrate posturing caused by basilar artery occlusion with bilateral pontomesencephalic infarctions. Both patients exhibited a lymphocytic cerebrospinal fluid (CSF) pleocytosis and elevated antibody index (AI) to Borrelia burgdorferi. Antibiotic treatment, steroids, and platelet inhibitors including tirofiban infusion in patient 2 were administered. No side effects were observed. On follow-up, patient 1 showed good recovery and patient 2 was asymptomatic. In the literature, 12 cases of LNB-associated childhood stroke were reported. LNB-associated infectious and inflammatory FCA is not a medical contraindication for reperfusion therapies in acute childhood stroke. Steroids are discussed controversially in inflammatory FCA due to LNB. Intensified antiplatelet regimes may be considered; secondary prophylaxis with acetyl-salicylic acid (ASA) is recommended because of a high risk of early stroke recurrence.

An H3F3A K27M-mutation in a sonic hedgehog medulloblastoma.

Medulloblastomas are malignant embryonal brain tumours that may harbour mutations in histone-modifying genes, while mutations in histone genes have not been detected to date. We here describe the first SHH medulloblastoma with H3 K27M mutation. This may have diagnostic implications as H3 K27M mutations are the hallmark of diffuse midline gliomas, H3 K27M mutant, WHO grade IV. Medulloblastomas arise in midline structures and thus must not be mistaken for DMG when using an antibody detecting the H3 K27M mutation.

Supratentorial ependymoma in childhood: more than just RELA or YAP.

Two distinct genetically defined entities of ependymoma arising in the supratentorial compartment are characterized by the presence of either a C11orf95-RELA or a YAP-MAMLD1 fusion, respectively. There is growing evidence that supratentorial ependymomas without these genetic features exist. In this study, we report on 18 pediatric non-RELA/non-YAP supratentorial ependymomas that were systematically characterized by means of their histology, immunophenotype, genetics, and epigenomics. Comprehensive molecular analyses included high-resolution copy number analysis, methylation profiling, analysis of fusion transcripts by Nanostring technology, and RNA sequencing. Based upon histological and immunohistochemical features two main patterns were identified-RELA-like (n = 9) and tanycytic ependymomas (n = 6). In the RELA-like group histologically assigned to WHO grade III and resembling RELA-fused ependymomas, tumors lacked nuclear expression of p65-RelA as a surrogate marker for a pathological activation of the NF-κB pathway. Three tumors showed alternative C11orf95 fusions to MAML2 or NCOA1. A methylation-based brain tumor classifier assigned two RELA-like tumors to the methylation class "EP, RELA-fusion"; the others demonstrated no significant similarity score. Of the tanycytic group, 5/6 tumors were assigned a WHO grade II. No gene fusions were detected. Methylation profiling did not show any association with an established methylation class. We additionally identified two astroblastoma-like tumors that both presented with chromothripsis of chromosome 22 but lacked MN1 breaks according to FISH analysis. They revealed novel fusion events involving genes in chromosome 22. One further tumor with polyploid cytogenetics was interpreted as PFB ependymoma by the brain tumor methylation classifier but had no relation to the posterior fossa. Clinical follow-up was available for 16/18 patients. Patients with tanycytic and astroblastoma-like tumors had no relapse, while 2 patients with RELA-like ependymomas died. Our data indicate that in addition to ependymomas discovered so far, at least two more supratentorial ependymoma types (RELA-like and tanycytic) exist.

Social inequalities in the participation and activity of children and adolescents with leukemia, brain tumors, and sarcomas (SUPATEEN): a protocol for a multicenter longitudinal prospective observational study.

BACKGROUND: About 2000 children and adolescents under the age of 18 are diagnosed with cancer each year in Germany. Because of current medical treatment methods, a high survival rate can be reached for many types of the disease. Nevertheless, patients face a number of long-term effects related to the treatment. As a result, physical and psychological consequences have increasingly become the focus of research in recent years. Social dimensions of health have received little attention in health services research in oncology so far. Yet, there are no robust results that allow an estimation of whether and to what extent the disease and treatment impair the participation of children and adolescents and which factors mediate this effect. Social participation is of great importance especially because interactions with peers and experiences in different areas of life are essential for the development of children and adolescents. METHODS: Data are collected in a longitudinal, prospective, observational multicenter study. For this purpose, all patients and their parents who are being treated for cancer in one of the participating clinics throughout Germany will be interviewed within the first month after diagnosis (t1), after completion of intensive treatment (t2) and half a year after the end of intensive treatment (t3) using standardized questionnaires. Analysis will be done by descriptive and multivariate methods. DISCUSSION: The results can be used to identify children and adolescents in high-risk situations at an early stage in order to be able to initiate interventions tailored to the needs. Such tailored interventions will finally reduce the risk of impairments in the participation of children and adolescents and increase quality of life. TRIAL REGISTRATION: ClinicalTrials.gov: NCT04101123.

Impact of rs12917 MGMT Polymorphism on [18F]FDG-PET Response in Pediatric Hodgkin Lymphoma (PHL).

PURPOSE: The enzyme O6-methylguanine-DNA methyltransferase (MGMT) is an important component of the DNA repair machinery. MGMT removes O6-methylguanine from the DNA by transferring the methyl group to a cysteine residue in its active site. Recently, we detected the single nucleotide polymorphism (SNP) rs12917 (C/T) in the MGMT sequence adjacent to the active site in Hodgkin lymphoma (HL) cell line KM-H2. We now investigated whether this SNP is also present in other HL cell lines and patient samples. Furthermore, we asked whether this SNP might have an impact on metabolic response in 2-deoxy-2-[18F]fluoro-D-glucose positron emission tomography ([18F]FDG-PET), and on overall treatment outcome based on follow-up intervals of at least 34 months. PROCEDURES: We determined the frequency of this MGMT polymorphism in 5 HL cell lines and in 29 pediatric HL (PHL) patients. The patient cohort included 17 female and 12 male patients aged between 4 and 18 years. After characterization of the sequence, we tested a possible association between rs12917 and age, gender, Ann Arbor stage, treatment group, metabolic response following two courses of OEPA (vincristine, etoposide, prednisone, and doxorubicin) chemotherapy, radiotherapy indication, and relapse status. RESULTS: We detected the minor T allele in four of five HL cell lines. 11/29 patients carried the minor T allele whereas 18/29 patients showed homozygosity for the major C allele. Interestingly, we observed significantly better metabolic response in PHL patients carrying the rs12917 C allele resulting in a lower frequency of radiotherapy indication. CONCLUSION: MGMT polymorphism rs12917 seems to affect chemotherapy response in PHL. The prognostic value of this polymorphism should be investigated in a larger patient cohort.

Osteonecrosis in children with acute lymphoblastic leukemia at initial diagnosis and prior to any chemotherapy.

Osteonecrosis (ON) is a common and debilitating side effect of anti-leukemic treatment in children with acute lymphoblastic leukemia (ALL). However, the impact of leukemia itself on ON development remains elusive. We analyzed 76 children enrolled in the ongoing OPAL trial, who had magnetic resonance imaging (MRI) studies at diagnosis. MRI screening revealed 14 osteonecrotic lesions (5 × hips, 9 × knees) of any grade (I-III) in 7 (9.2%) patients. Six months on, the number of ON per patient increased (1 patient), remained constant (2), and decreased (2). The severity increased from grade I to II in two patients, remained constant (1), completely resolved (2), and decreased from grade III to osteoedema (1). No differences between adolescents initially presenting with/without ON were observed concerning age, pubertal stage, body mass index, leukemia characteristics, and clinical presentation. In MRI screening, a remarkable number of adolescents with ALL present with ON at diagnosis. The course of these ON remains highly unpredictable.

Childhood supratentorial ependymomas with YAP1-MAMLD1 fusion: an entity with characteristic clinical, radiological, cytogenetic and histopathological features.

Ependymoma with YAP1-MAMLD1 fusion is a rare, recently described supratentorial neoplasm of childhood, with few cases published so far. We report on 15 pediatric patients with ependymomas carrying YAP1-MAMLD1 fusions, with their characteristic histopathology, immunophenotype and molecular/cytogenetic, radiological and clinical features. The YAP1-MAMLD1 fusion was documented by RT-PCR/Sanger sequencing, and tumor genomes were studied by molecular inversion probe (MIP) analysis. Significant copy number alterations were identified by GISTIC (Genomic Identification of Significant Targets in Cancer) analysis. All cases showed similar histopathological features including areas of high cellularity, presence of perivascular pseudo-rosettes, small to medium-sized nuclei with characteristic granular chromatin and strikingly abundant cells with dot-like cytoplasmic expression of epithelial membrane antigen. Eleven cases presented features of anaplasia, corresponding to WHO grade III. MRI showed large supratentorial multinodular tumors with cystic components, heterogeneous contrast enhancement, located in the ventricular or periventricular region. One of two variants of YAP1-MAMLD1 fusions was detected in all cases. The MIP genome profiles showed balanced profiles, with focal alterations of the YAP1 locus at 11q22.1-11q21.2 (7/14), MAMLD1 locus (Xp28) (10/14) and losses of chromosome arm 22q (5/14). Most patients were female (13/15) and younger than 3 years at diagnosis (12/15; median age, 8.2 months). Apart from one patient who died during surgery, all patients are alive without evidence of disease progression after receiving different treatment protocols, three without postoperative further treatment (median follow-up, 4.84 years). In this to date, largest series of ependymomas with YAP1-MAMLD1 fusions we show that they harbor characteristic histopathological, cytogenetic and imaging features, occur mostly in young girls under 3 years and are associated with good outcome. Therefore, this genetically defined neoplasm should be considered a distinct disease entity. The diagnosis should be confirmed by demonstration of the specific fusion. Further studies on large collaborative series are warranted to confirm our findings.

Monitoring proteins using in vivo near-infrared time-domain optical imaging after 2-O-hexyldiglycerol-mediated transfer to the brain.

PURPOSE: The aim of the present study was to gain insight into the penetration, biodistribution, and fate of globulins in the brain after 2-O-hexyldiglycerol-induced blood-brain barrier opening. PROCEDURES: The spatial distribution of fluorescence probes was investigated after blood-brain barrier opening with intracarotid 2-O-hexyldiglycerol injection. Fluorescence intensity was visualized by microscopy (mice and rats) and by in vivo time-domain optical imaging. RESULTS: There was an increased 2-O-hexyldiglycerol-mediated transfer of fluorescence-labeled globulins into the ipsilateral hemisphere. Sequential in vivo measurements revealed that the increase in protein concentration lasted at least 96 h after administration. Ex vivo detection of tissue fluorescence confirmed the results obtained in vivo. CONCLUSION: Globulins enter the healthy brain in conjunction with 2-O-hexyldiglycerol. Sequential in vivo near-infrared fluorescence measurements enable the visualization of the spatial distribution of antibodies in the brain of living small animals.

Tumor localization of an anti-TGF-ß antibody and its effects on gliomas.

Even with current standard-of-care therapies, the prognosis for patients with malignant gliomas is very poor and several new treatment modalities for glioblastomas are currently under investigation. Given the role of TGF-ß in gliomas, anti-TGF-ß strategies against gliomas are currently being investigated. Biodistribution of intravenously injected AF680-labeled 1D11, a pan-neutralizing TGF-ß antibody, was monitored in mice bearing either subcutaneous or orthotopic gliomas using in vivo imaging and fluorescence microscopy. AF680-labeled 1D11 entered both the subcutaneous and intracranial tumors and the antibody was detected within the tumor tissue for several days whereas only low fluorescence was found in organs. The effects of 1D11 on subcutaneous versus orthotopic U87MG and GL261 gliomas in immunocompetent C57BL/6J versus immunodeficient CD1-Foxn1nu mice were observed by direct tumor size measurement, H&E staining and immunohistochemistry. Treatment of immunocompetent mice bearing subcutaneous GL261 tumors with 1D11 resulted in complete remission. In immune deficient mice, the growth of subcutaneous GL261 tumors was increased following treatment with 1D11. Intracranially implanted gliomas in C57Bl/6J mice showed no size reduction after 1D11 treatment but there was reduced invasion of the glioma cells into the adjacent normal brain. Together these data demonstrate that TGF-ß plays different roles in combating the tumor depending on subcutaneous versus orthotopic implantation site.

Intensive chemotherapy improves survival in pediatric high-grade glioma after gross total resection: results of the HIT-GBM-C protocol.

BACKGROUND: The authors hypothesized that intensified chemotherapy in protocol HIT-GBM-C would increase survival of pediatric patients with high-grade glioma (HGG) and diffuse intrinsic pontine glioma (DIPG). METHODS: Pediatric patients with newly diagnosed HGG and DIPG were treated with standard fractionated radiation and simultaneous chemotherapy (cisplatin 20 mg/m2 x 5 days, etoposide 100 mg/m2 x 3 days, and vincristine, and 1 cycle of cisplatin + etoposide + ifosfamide 1.5 g/m x 5 days [PEI] during the last week of radiation). Subsequent maintenance chemotherapy included further cycles of PEI in Weeks 10, 14, 18, 22, 26, and 30, followed by oral valproic acid. RESULTS: Ninety-seven (pons, 37; nonpons, 60) patients (median age, 10 years; grade IV histology, 35) were treated. Resection was complete in 21 patients, partial in 29, biopsy only in 26, and not performed in 21. Overall survival rates were 91% (standard error of the mean [SE] +/- 3%), 56%, and 19% at 6, 12, and 60 months after diagnosis, respectively. When compared with previous protocols, there was no significant benefit for patients with residual tumor, but the 5-year overall survival rate for patients with complete resection treated on HIT-GBM-C was 63% +/- 12% SE, compared with 17% +/- 10% SE for the historical control group (P = .003, log-rank test). CONCLUSIONS: HIT-GBM-C chemotherapy after complete tumor resection was superior to previous protocols.

Expression of the water channel protein aquaporin-9 in malignant brain tumors.

Recently, many studies seen concerning the expression and distribution of aquaporins and K channels in the central nervous system, and their physiological and pathophysiologic roles in water and ion homeostasis. Whereas most data were collected on aquaporin-4 (AQP4) in astrocytes, only little attention was paid to AQP9 which is a water channel transporting glycerol, mannitol, and urea as well. This is the first study describing AQP9 in human brain and human brain tumors. For comparison, we also investigated the immunohistochemical distribution of AQP9 in the rat glioma RG2. Whereas in the normal rat brain AQP9 is only weakly expressed by astrocytes, the anti-AQP9 immunoreactivity was found to be increased at the tumor border, but not within the tumor. In contrast, in human glioblastoma, most glioma cells throughout the tumor revealed a strong anti-AQP9 immunoreactivity across the whole surface of the cell. In the discussion, the increase of the anti-AQP9 immunoreactivity in glioma cells is suggested to reflect an upregulation and to counteract the glioma-associated lactic acidosis by clearance of glycerol and lactate from the extracellular space. In addition, the increased level of AQP9 immunoreactivity could be involved in the energy metabolism of the glioma and/or surrounding neuronal cells.

Keratoepithelin suppresses the progression of experimental human neuroblastomas.

Neuroblastoma is the most common extracranial childhood tumor. High expression of activin A is associated with a favorable prognosis, but the contributing mechanisms have remained unclear. Our previous demonstration of the activin A-mediated up-regulation of keratoepithelin led to the consideration that keratoepithelin could modulate neuroblastoma growth and/or progression. We report here that enhanced keratoepithelin expression in human neuroblastoma cells suppresses neuroblastoma cell cohesion and adhesion to various extracellular matrix proteins and that it inhibits neuroblastoma cell proliferation and invasion in vitro and in vivo. Using microarray analysis, we identified several keratoepithelin-regulated genes that may contribute to these biological changes. Together with the observation that keratoepithelin is expressed in human neuroblastomas in vivo, our data suggest that keratoepithelin could play a beneficial role in neuroblastoma development and/or progression.

Models of monocytic invasion into glioma cell aggregates.

BACKGROUND: In order to investigate why human gliomas are abundantly infiltrated by monocytic cells without signs of antitumor activity, experimental models were established in vitro and in vivo. MATERIALS AND METHODS: Peripheral human blood monocytes were added to A172 or U118 glioma cell spheroids and probes analyzed after 72 h by immunohistochemistry. Fluorescence-labelled peritoneal macrophages were administered to syngeneic RG2-glioma-bearing Fischer rats by intravenous or intracarotid injection. RESULTS: Spheroids of both cell lines were infiltrated by monocytes, which took on a chronic inflammatory phenotype with co-expression of MRP8 and MAC 387/MRP14 and positivity to 25F9, but not to 27E10. After both intra-arterial and intravenous injection, labelled monocytes accumulated within the tumor parenchyma of the rat gliomas, while the surrounding brain was only sparsely infiltrated. CONCLUSION: The experimental models described here allow for further investigation of the interactions between monocytes and glioma cells, both in vitro and in vivo. Moreover, monocytes that infiltrate from the peripheral blood into brain tumors may serve as carriers for targeted therapies.

Blood-brain barrier opening with alkylglycerols: Biodistribution of 1-O-pentylglycerol after intravenous and intracarotid administration in rats.

Short-chain alkylglycerols have been described to increase the penetration of drugs and macromolecules across the blood-brain barrier (BBB) into the central nervous system (CNS) and were considered to be of potential value in the pharmaceutical treatment of CNS disorders. Due to the lack of information on the pharmacological behavior of these compounds in vivo, pharmacokinetics and biodistribution of [14C]- and [3H]-labeled 1-O-pentylglycerol (49 mg/kg, 100 mM) was investigated in normal male Wistar rats after intravenous as well as intracarotid administration. There was a rapid and predominant renal elimination of 1-O-pentylglycerol and more than 70% of administered dose was found in the urine within 270 min. Analysis of the pharmacokinetic parameters after a single i.v. bolus injection of 1-O-pentylglycerol resulted in a peak blood concentration of 0.58+/-0.06 micromol/ml, an initial half life of 23+/-7 min and a terminal half life of 18.8+/-4.1 h. No accumulation of 1-O-pentylglycerol was observed in the brain or other organs while highest concentrations were found in liver and thymus. This was confirmed by autoradiographic studies. Five minutes after intracarotid administration, high radioactivity was found in the ipsilateral brain, whereas after 30 min radioactivity in the brain has dramatically decreased. Autoradiographic images gave evidence of biliary excretion in addition to the renal elimination. There were no signs of cleavage of the O-alkyl bond in vivo as demonstrated by HPLC analysis. In conclusion, 1-O-pentylglycerol is characterized by pharmacological properties appearing very favorable for in vivo use as a permeabilizing drug for increased drug delivery to the brain.

MAP kinase pathways involved in glioblastoma response to erucylphosphocholine.

Erucylphosphocholine (ErPC) is a promising antineoplastic drug for the treatment of malignant brain tumors. It exerts strong anticancer activity and induces apoptosis even in chemoresistant glioma cells. In the present study, A172 and U373MG glioma cells were treated with ErPC to explore the contribution of MAP kinase family members ERK, JNK and p38 kinase to ErPC-induced cell death. The exposure to ErPC led to activation of JNK and concurrent inhibition of ERK in both cell lines. Using specific MAP kinase inhibitors we confirmed that in U373MG cells ERK was blocked and JNK was activated upon ErPC treatment. Both effects were dependent on caspase activation. In A172 cells, ErPC treatment resulted in an activation of the JNK pathway, whereas the situation with respect to ERK signalling was more complex. We conclude that inhibition of the ERK pathway by ErPC may be related to antiproliferative effects, while activation of the JNK pathway may be responsible for its pro-apoptotic action.

Oral topotecan in children with recurrent or progressive high-grade glioma: a Phase I/II study by the German Society for Pediatric Oncology and Hematology.

BACKGROUND: Continuous oral treatment with topotecan may be more effective than the typical 1-day and 5-day treatment schedules. In previous studies of continuous treatment with topotecan, increased intestinal side effects were reported in adult patients; however, the experience in pediatric patients and patients with high-grade glioma is quite limited. METHODS: Thirty-two pediatric patients with recurrent high-grade glioma (16 females and 16 males; median age, 9.5 years) were enrolled in the current Phase I/II study. Tumor locations included the cerebral cortex (n = 5), pons (n = 18), and other sites (n = 9). An injectable formulation of topotecan was administered orally, in ice-cold orange juice, once daily. The starting dose of 0.4 mg/m(2) per day was escalated on a patient-by-patient basis. At each patient's maximum dose, blood samples were obtained for the determination of plasma hydroxytopotecan and topotecan lactone concentrations and for the calculation of pharmacokinetic quantities. RESULTS: The toxicity criteria for a maximum tolerated topotecan dose were met in only 19 patients. The primary toxicity type was hematologic. The median maximum tolerated dose was 0.9 mg/m(2) per day (n = 19). The calculated maximum total plasma topotecan concentration was 3.8 ng/mL (n = 7), with an area under the concentration-time curve of 38.4 ng. hours/mL and a half-life of 4.1 hours, which would result in the complete disappearance of topotecan from the plasma after 12 hours. Objective responses were observed in 2 of 13 evaluable patients and lasted for 2.5 and 9 months, respectively (continuous clinical remission, 1 of 14 patients; partial response, 2 of 14 patients; stable disease, 7 of 14 patients; progressive disease, 4 of 14 patients). CONCLUSIONS: Oral topotecan (median dose, 0.9 mg/m(2) per day) administered once daily was well tolerated and somewhat effective in children with recurrent high-grade glioma. A schedule in which the daily dose is split so that dosing is performed twice daily may be superior to the current schedule.