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Hospital-based studies have reported long delays in the diagnosis of paediatric brain tumours. Our objective was to describe the duration between onset of symptoms and diagnosis of medulloblastoma in children and study their clinical determinants in a population-based study. This retrospective cohort study included all paediatric medulloblastoma from a region of France from 1990 to 2005. The median interval from symptom onset until diagnosis for these 166 patients was 65 days and did not decrease during the study period. The most frequent manifestations were: vomiting (88%), headaches (79%), psychomotor regression (60% of children under 3 years), psychological symptoms (27%), strabismus (26%), and asthenia (25%). For one third of the children under 3 years, the diagnosis was made only after life-threatening signs of intracranial hypertension appeared. The prediagnosis interval was significantly longer (median 91 vs. 60 days, p = 0.001) in children with psychological symptoms (27%). Causes for intervals that exceeded the median (65 days) included inconsistent (25%) or late (36%) combination of headaches and vomiting, a period of spontaneous symptom remission (14%-20%), no (24%) or late (57%) neurological signs, psychological symptoms (35%), and a normal neurological examination (27%). Time to medulloblastoma diagnosis in children remains fairly long, despite advances in imaging. Primary-care physicians must be suspicious not only of suggestive neurological signs, but also of non-specific symptoms that persist or are multiple. A meticulous neurological examination and cerebral imaging for such patients might facilitate earlier diagnosis. [ABSTRACT FROM AUTHOR]

Anthracyclines are widely used in paediatric oncology, but their use is limited by the risk of cumulative cardiac toxicity. Encapsulating anthracyclines in liposomes may reduce cardiac toxicity and possibly increase drug availability to tumours. A phase I study in paediatric patients was designed to establish the dose limiting toxicity (DLT) and maximum tolerated dose (MTD) after a single course of liposomal daunorubicin, ‘DaunoXome’, as a 1 h infusion on day 1 of a 21 day cycle. Patients were stratified into two groups according to prior treatment: Group A (conventional) and group B (heavily pretreated patients). Dose limiting toxicity was expected to be haematological, and a two-step escalation was planned, with and without G-CSF support. Pharmacokinetic studies were carried out in parallel. In all, 48 patients aged from 1 to 18 years were treated. Dose limiting toxicity was neutropenia for both groups. Maximum tolerated dose was defined as 155 mg m−2 for Group A and 100 mg m−2 for Group B. The second phase with G-CSF was interrupted because of evidence of cumulative cardiac toxicity. Cardiac toxicity was reported in a total of 15 patients in this study. DaunoXome shares the early cardiotoxicity of conventional anthracyclines in paediatric oncology. This study has successfully defined a haematological MTD for DaunoXome, but the significance of this is limited given the concerns of delayed cardiac toxicity. The importance of longer-term follow-up in patients enrolled into phase I studies has been underestimated previously, and may lead to an under-recognition of important adverse events.British Journal of Cancer (2006) 95, 571–580. doi:10.1038/sj.bjc.6603288 www.bjcancer.com Published online 1 August 2006 [ABSTRACT FROM AUTHOR]

Aims: To assess parental understanding and memorisation of the information given when seeking for consent to their child's participation to clinical research, and to identify the factors of significant influence on parents' decision making process.Methods: Sixty eight parents who had been approached for enrolling their child in a clinical oncology or HIV study were asked to complete an interview. Their understanding was measured by a score which included items required to obtain a valid consent according to French legislation.Results: Items that were best understood by parents were the aims of the study (75%), the risks (70%), the potential benefits to their child (83%), the potential benefits to other children (70%), the right to withdraw (73%), and voluntariness (84%). Items that were least understood were the procedures (44%), the possibility of alternative treatments (53%), and the duration of participation (39%). Less than 10% of the parents had understood all these points. Ten parents (15%) did not remember that they had signed up for a research protocol. Thirty three parents (48%) reported no difficulty in making their decision. Twenty four parents (38%) declared that they made their decision together with the investigator; 26 (41%) let the physician decide. Fifty four parents (78%) felt that the level of information given was satisfactory.Conclusion: There was an apparent discrepancy between parents' evaluation of the adequacy of the information delivered and evaluation of their understanding and memorisation. The majority of parents preferred that the physician take as much responsibility as possible in the decision making process. [ABSTRACT FROM AUTHOR]

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Copyright of EMC-Ophtalmologie is the property of Elsevier B.V. and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

To evaluate the potential differential effect of pretreatment with pharmacologic doses of the trace element zinc on the chemosensitivity of glioma cells and bone marrow cells for carmustine (BCNU), we performed in vitro and in vivo studies of zinc toxicity as well as of the combined treatment with zinc and the anticancer drug. We studied the in vitro effects on established human and rat glioma cell lines using a microcolorimetric growth assay and on murine bone marrow using a clonogenic assay for committed progenitor cells of the granulocyte-monocyte lineage. Zinc exposures of up to 100 microM for 120 h did not influence the growth of six of seven human glioma cell lines. Only U87MG demonstrated statistically significant toxicity during high zinc exposure (100 microM over 120 h). Dose-response growth curves generated for BCNU did not show protection against the anticancer agents by a 48-h pretreatment with different zinc concentrations. The clonogenic capacity of bone marrow cells was slightly reduced by in vitro culture for 24 and 48 h. Although this effect appeared to be more prominent in the presence of zinc supplementation, overall a statistically significant inhibition was seen only after exposure to a concentration of 100 microM zinc over 48 h. As compared with chemotherapy alone, in vitro pretreatment with 50 microM zinc over 48 h followed by chemotherapy resulted in an increased number of colony-forming unit-granulocyte monocyte (CFU-GM): CFU-GM increased by a factor of 2 for BCNU (60 microM x 2 h). This statistically significant in vitro chemoprotection would translate into a dose-protection factor of 1.5, i.e., for the same level of myelosuppression, zinc pretreatment would allow administration of a 50% increased dose of BCNU. The in vivo studies were performed in an s.c. xenograft model of the human glioma cell line U87MG in athymic mice. The maximal tolerable pretreatment with zinc was determined to be a 10-day course of daily i.p. injections of 10 mg/kg ZnCl2. The subsequent i.p. administration of the dose lethal to 10% of the mice (LD10) and of a 1.5 x LD10 dose of BCNU resulted in less bone marrow toxicity in pretreated animals than in non-zinc-pretreated mice as determined in a CFU-GM assay. Glioma colony-forming efficiency (CFE) assays, on the other hand, did not show any zinc-related difference in the BCNU sensitivity of U87MG.(ABSTRACT TRUNCATED AT 400 WORDS) [ABSTRACT FROM AUTHOR]

Metallothionein (MT), a ubiquitous intracellular protein, confers resistance to the toxic effects of platinum compounds. Since a high-zinc diet has been shown to induce MT synthesis in extracerebral tissues but not in brain, we investigated whether it could provide an experimental basis for decreasing the hematotoxicity of carboplatin without impairing its activity against brain tumors. After 2 weeks on either a high-zinc diet or a control diet (zinc content, 180 vs 10 ppm), mice and rats received various doses of carboplatin or Hanks' balanced salt solution by i.p. injection. The hematotoxicity of carboplatin was evaluated with an assay of colony-forming units of granulocytes and mononuclear cells in mice. The high-zinc diet enabled a 50% increase in the carboplatin dose without increasing hematotoxicity. The antitumor activity was evaluated with an assay of the colony-forming efficiency of gliosarcoma cells from 9L brain tumors in rats. The high-zinc diet did not alter the efficacy of carboplatin against this brain tumor. Northern blot analysis confirmed that the high-zinc diet induced MT mRNA in the kidney but not in the brain of mice and rats; it also showed MT mRNA induction in bone marrow cells of mice but not in rat 9L brain tumors. These results suggest that increasing the dietary intake of zinc might increase the therapeutic index of carboplatin in the treatment of brain tumors. [ABSTRACT FROM AUTHOR]

Background TRK fusions are oncogenic drivers of a variety of tumors, many of which can involve the central nervous system (CNS). Larotrectinib is an FDA-approved selective TRK inhibitor for the treatment of TRK fusion cancer (Drilon et al. NEJM 2018). Here we report on the clinical activity of larotrectinib in an expanded set of TRK fusion-positive primary CNS tumors. Methods Patients with primary CNS tumors harboring an NTRK gene fusion detected by local molecular testing who were treated with larotrectinib in two clinical trials (NCT02637687 and NCT02576431) were identified. Larotrectinib was administered until disease progression, withdrawal, or unacceptable toxicity. Disease status was investigator assessed (RANO). Data cutoff: February 19, 2019. Results 18 patients with various histological types of glial tumors (11 high grade, 4 low grade, 3 unknown) were identified. The patients had gene fusions involving NTRK2 (n = 13), NTRK1 (n = 3) and NTRK3 (n = 2). Median age was 10.5 years (range 1.3–79.0); 14 patients were pediatric (< 18). In 14 evaluable patients, the objective response rate was 36% (2 CR [pending confirmation], 3 PR), with responses seen in high- and low-grade disease and across histologies. Nine patients had SD. The 24-week disease control rate was 71%. The duration of treatment ranged from 0.03+ to 16.6+ months. Conclusions Larotrectinib is active in patients with TRK fusion cancer with intracranial disease. Objective responses and durable disease control were seen in primary CNS tumors of various grades and histologies. These results further support expanded testing for NTRK gene fusions in patients with primary CNS tumors. Clinical trial identification NCT02637687 and NCT02576431. Legal entity responsible for the study Bayer. Funding Bayer. Disclosure All authors have declared no conflicts of interest. [ABSTRACT FROM AUTHOR]

Background/aims: Diagnosis of retinoblastoma is mainly based on indirect ophthalmoscopy, but additional imaging techniques are indispensable for the staging of the disease. A new high resolution magnetic resonance imaging (MRI) technique for the examination of the eye was evaluated. A new surface coil with a diameter of 5 cm allows a field of view of 60 mm with an in-plane resolution of 0.8 mm. We compared preoperative MRI scans with the histology after enucleation in 21 cases of retinoblastoma. Parameters studied were appearance of retinoblastoma, choroidal and scleral infiltration, extraocular extension, optic nerve infiltration, and vitreous seeding. Results: All retinoblastomas could be visualised as hypointense to vitreous on T2 weighted images and slightly hyperintense to vitreous on plain T1 weighted images with a moderate enhancement after contrast application. Histology revealed seven cases with infiltration of the optic disc or optic nerve. Preoperative MRI scans depict juxtapapillary tumour masses, but it was impossible to differentiate between a juxtapapillary retinoblastoma, a prelaminar infiltration of the optic disc, or a just postlaminar optic nerve infiltration. In five of 14 cases with a proved tumour infiltration of the choroid, MRI scans showed an inhomogeneous contrast enhancement of the choroid in enhanced T1 weighted sequences beneath the retinoblastoma. Whether this sign is specific for a choroidal infiltration or is just an artefact remains unclear. High resolution MRI scans did not allow the exclusion of this form of intraocular tumour extension. All nine cases with proved vitreous seeding were not detected by MRI scans. None of these cases showed scleral infiltration or orbital tumour extension. Therefore, it is not possible to judge the rank of this technique in detecting orbital tumour growth. Conclusion: The new MRI technique is of limited value in visualisation of prelaminar or postlaminar infiltration of the optic nerve. Advanced... [ABSTRACT FROM AUTHOR]

We tested an experimental strategy to decrease the dose-limiting hematotoxicity of carboplatin without compromising its activity against brain tumors. The effect of pretreatment with WR-1065, a chemomodifier that penetrates brain poorly, on carboplatin's cytotoxicity was evaluated in human hematopoietic granulocyte-monocyte progenitor cells and in three human glioblastoma cell lines. WR-1065 reduced bone marrow toxicity without decreasing carboplatin's activity against glioblastoma cells. These results suggest that the therapeutic index of carboplatin might be increased in the treatment of malignant brain tumors. [ABSTRACT FROM AUTHOR]

The central neurotoxicity of cytotoxic drugs depends on their ability to cross the blood-brain barrier (BBB). The drugs with the highest neurotoxicity are therefore those that cross the BBB most easily: alkylating agents (metabolites of cyclophosphamide and ifosfamide, thiotepa and high-dose melphalan), busulfan, platinum derivatives, aracytine and methotrexate. Apart from aracytine-induced cerebellar toxicity, the clinical signs suggestive of chemotherapy neurotoxicity are relatively nonspecific: altered level of consciousness, seizures, behavioural disorders and motor deficits. Nevertheless, a good knowledge of the various neurological syndromes likely to occur can allow them to be attributed to a drug-induced cause. However, as patients may be receiving several potentially neurotoxic treatments (chemotherapy, concomitant drugs, neurosurgery, radiotherapy), it is difficult to formally confirm the responsibility of the drug, which should only be considered after confirming the absence of radiological and metabolic abnormalities. A specific antagonist treatment can be administered in rare cases (ifosfamide-induced encephalopathy). [Copyright &y& Elsevier]

Peripheral blood stem cells (PBSC) harvest may be difficult in young children. Extracorporeal separator line priming by red blood cells is usually required to improve haemodynamic tolerance and efficacy of collection. We present our experience with 24 children weighing less than 15?kg treated between January 1997 and September 1999, in whom we tried to avoid systematic blood priming. The median age and weight at the time of apheresis were 2.4 years and 12?kg, respectively. A total of 48 PBSC were performed. When haemoglobin was less than 12?g/dl, packed red cells were transfused before collection (40% of aphereses). The median cell yield per apheresis was 7.1 (2.2-30.6)x106/kg CD34+ cells and 16.0 (3.3-44.3)x105 CFU-GM/kg. Initial collection failed in three cases. Four children required an additional haematopoietic progenitor mobilization. This procedure allowed PBSC collection without transfusion in 37.5% of children, and was safe (two serious and five mild transient side effects) and effective (median CD34+ cells collected per child: 7.1x106/kg (4.6-30.6) and CFU-GM: 15.1x105/kg (4.7-44.3)). Despite their low weight, insertion of a femoral catheter was avoided in 43% of children.Bone Marrow Transplantation (2003) 31, 171-174. doi:10.1038/sj.bmt.1703825 [ABSTRACT FROM AUTHOR]

We report a 40-year-old patient with familial retinoblastoma also affecting his elder son, who developed multiple fibromas on the periungual or subungual areas of all the fingers. Molecular analysis disclosed a loss of heterozygosity for the RB1 gene in the larger tumour, with disappearance of the normal allele and persistence of the mutated allele only. The similarity of this observation with distal fibrous tumours encountered in other diseases with germline mutations of tumour-suppressor genes such as neurofibromatosis type 1, tuberous sclerosis and multiple endocrine neoplasia type 1 led to the hypothesis that multiple acral benign tumours with a fibrous component might be a cutaneous marker of tumour suppressor gene germline mutation with low sensitivity but high specificity. [ABSTRACT FROM AUTHOR]