Hepatitis E Virus Infection in Pediatric Oncology.

BACKGROUND: In the 2016 ESPGHAN recommendations on how to deal with hepatitis E virus infection in immunocompromised children, patients treated with chemotherapy were not specifically mentioned. OBSERVATIONS: Two teenagers treated with chemotherapy for acute leukemia and medulloblastoma, respectively, were diagnosed with hepatic cytolysis. After numerous investigations hepatitis E was found, limiting the good progress of the chemotherapy treatment. CONCLUSION: In the case of liver cytolysis in immunocompromised children treated with chemotherapy, hepatitis E virus infection has to be promptly diagnosed.

Paediatric palliative care: why transfuse?

Should indication for transfusion in paediatric palliative care be based on the child's perspective rather than the biological results? An 8-year-old boy presenting a relapse of a stage IV neuroblastoma received regular blood transfusions. A severe exophtalmia led the doctors to question the transfusion strategy. Over 7.5 months, the child received 56 red blood cell units and 31 platelet units. He was hospitalised 50 times. Indication for blood test and transfusion may be regularly and collegially reassessed. Transfusion needs in a palliative strategy can be as high as in a curative strategy. Practices, benefits but also ethical and public health dimensions should be more studied.

Posterior fossa ependymoma H3 K27-mutant: an integrated radiological and histomolecular tumor analysis.

Posterior fossa group A ependymomas (EPN_PFA) are characterized by a loss of H3 K27 trimethylation due to either EZHIP overexpression or H3 p.K27M mutation, similar to H3 K27-altered diffuse midline gliomas (DMG), but in reverse proportions. Very little data is available in the literature concerning H3 K27M-mutant EPN_PFA. Here, we retrospectively studied a series of nine pediatric tumors initially diagnosed as H3 K27M-mutant EPN_PFA to compare them to EZHIP-overexpressing EPN_PFA in terms of radiology, follow-up, histopathology, and molecular biology (including DNA-methylation profiling). Seven tumors clustered within EPN_PFA by DNA-methylation analysis and t-distributed stochastic neighbor embedding. Among the two remaining cases, one was reclassified as a DMG and the last was unclassified. H3 K27M-mutant EPN_PFA cases were significantly older than their counterparts with an EZHIP overexpression. Radiological and histopathological central review of our seven H3 K27M-mutant EPN_PFA cases found them to be similar to their counterparts with an EZHIP overexpression. Sequencing analyses revealed HIST1H3B (n = 2), HIST1H3C (n = 2), H3F3A (n = 1), and HIST1H3D (n = 1) K27M mutations (no sequencing analysis available for the last case which was immunopositive for H3K27M). Consequently, HIST1H3C/D mutations are more frequently observed in EPN_PFA than in classic pontine DMG, H3K27-mutant. Overall survival and event-free survival of EZHIP-overexpressing and H3 K27M-mutant EPN_PFA were similar. After surgery and radiation therapy, 5/7 patients were alive at the end of the follow-up. In summary, the diagnosis of EPN_PFA must include tumor location, growth pattern, Olig2 expression, and DNA-methylation profiling before it can be differentiated from DMG, H3 K27-altered.

Dysplastic gangliocytoma of the cerebellum (Lhermitte-Duclos disease) presenting as a prenatally heterotopic hamartoma.

Dysplastic gangliocytoma of the cerebellum (DGC), also called Lhermitte-Duclos disease, is a rare lesion of the posterior fossa consisting of a diffuse hypertrophy of the cerebellar cortex. DGC frequently presents in young adults and rarely in childhood. Only 3 cases have been previously described in newborns. We present an uncommon case of DGC which was diagnosed in utero. The radiological presentation prenatally and at birth was similar to a heterotopic neuroglial brain tissue. MRI aspects evolved from T1/T2 isointense signals to hypoT1 and hyperT2 signals at the age of 1 year. The girl was then operated on total removal of the lesion which was performed with no postoperative complication. Genetics did not demonstrate any germline PTEN mutation or family history suggesting Cowden disease. Two years later, the child was doing well and MRI confirmed complete resection. This case illustrates the difficulties of diagnosing intracranial lesions in foetuses and newborns. Physicians caring for pregnant women and pediatrics should be aware that neoplasm-like lesions such as DGC may present as hamartomas. Surgical resection could then be discussed whenever possible.

Prognostic relevance of clinical and molecular risk factors in children with high-risk medulloblastoma treated in the phase II trial PNET HR+5.

BACKGROUND: High-risk medulloblastoma is defined by the presence of metastatic disease and/or incomplete resection and/or unfavorable histopathology and/or tumors with MYC amplification. We aimed to assess the 3-year progression-free survival (PFS) and define the molecular characteristics associated with PFS in patients aged 5-19 years with newly diagnosed high-risk medulloblastoma treated according to the phase II trial PNET HR+5. METHODS: All children received postoperative induction chemotherapy (etoposide and carboplatin), followed by 2 high-dose thiotepa courses (600 mg/m2) with hematological stem cell support. At the latest 45 days after the last stem cell rescue, patients received risk-adapted craniospinal radiation therapy. Maintenance treatment with temozolomide was planned to start between 1-3 months after the end of radiotherapy. The primary endpoint was PFS. Outcome and safety analyses were per protocol (all patients who received at least one dose of induction chemotherapy). RESULTS: Fifty-one patients (median age, 8 y; range, 5-19) were enrolled. The median follow-up was 7.1 years (range: 3.4-9.0). The 3 and 5-year PFS with their 95% confidence intervals (95% CI) were 78% (65-88) and 76% (63-86), and the 3 and 5-year OS were 84% (72-92) and 76% (63-86), respectively. Medulloblastoma subtype was a statistically significant prognostic factor (P-value = 0.039) with large-cell/anaplastic being of worse prognosis, as well as a molecular subgroup (P-value = 0.012) with sonic hedgehog (SHH) and group 3 being of worse prognosis than wingless (WNT) and group 4. Therapy was well tolerated. CONCLUSIONS: This treatment based on high-dose chemotherapy and conventional radiotherapy resulted in a high survival rate in children with newly diagnosed high-risk medulloblastoma.

Edema of the optic tract in patients with tumors of the sellar region: clinical and visual implications in the pediatric population.

OBJECTIVE Tumor-related edema of the optic tract (EOT) corresponds to a preferential posterior distribution of peritumoral edema along the white matter tract of the visual system. To date, the consequences of EOT have never been evaluated specifically in the pediatric population. In this study, the authors attempted to identify clinical and radiological features associated with the development of EOT and the specific influence of this edema on visual function. METHODS A retrospective review was performed of data collected from patients younger than 18 years who underwent surgery for a tumor in the sellar region at the authors' institution between January 2005 and January 2016. Data were collected on patient characteristics, ophthalmological evaluations, and neuroimaging findings. To evaluate and compare visual function impairment, ophthalmological data were converted to a global visual function score, which took into account visual acuity, visual field evaluations, and laterality deficiencies. The visual acuity score was defined according to the International Classification of Diseases, 10th Revision. Visual field deficiencies were converted to a score of 0-2. Two opposing groups were then distinguished according to the presence or absence of EOT. Visual acuity, visual field results, and global scores were compared between groups before and after treatment. RESULTS Twenty-six patients were included in the study: 17 patients with craniopharyngioma, 3 patients with pilocytic astrocytoma, 2 patients with ganglioglioma, 2 patients with germ cell tumor, 1 patient with macroprolactinoma, and 1 patient with Rathke's cleft cyst. There were 11 children in the group with edema and 15 children in the group without edema. None of the following criteria were statistically different between the 2 groups: age, sex, clinical symptoms at presentation (endocrine deficiency or intracranial hypertension signs), incidence of hydrocephalus, compression of the optic tracts and mass effect on the optic chiasm, tumor size and localization, presence of intratumoral cysts, treatment, type of tumor, or recurrence. The median global visual function and visual acuity scores were not significantly different between the groups either at presentation or at final evaluation. The visual field score was lower (i.e., more deficiency) in the group with edema than in the group without edema (p < 0.05); 89% of the patients with edema had severe or mild visual field impairment versus only 40% of the patients without edema. At the final examination after treatment, the visual field scores were not different between the 2 groups. Although not significant, the number of patients with optic disc pallor was greater in the group without edema both at diagnosis and at final examination. CONCLUSIONS This study confirms that EOT in the context of sellar region tumor in children is not necessarily associated with a less-favorable visual prognosis.

Contribution of de novo and mosaic TP53 mutations to Li-Fraumeni syndrome.

BACKGROUND: Development of tumours such as adrenocortical carcinomas (ACC), choroid plexus tumours (CPT) or female breast cancers before age 31 or multiple primary cancers belonging to the Li-Fraumeni (LFS) spectrum is, independently of the familial history, highly suggestive of a germline TP53 mutation. The aim of this study was to determine the contribution of de novo and mosaic mutations to LFS. METHODS AND RESULTS: Among 328 unrelated patients harbouring a germline TP53 mutation identified by Sanger sequencing and/or QMPSF, we could show that the mutations had occurred de novo in 40 cases, without detectable parental age effect. Sanger sequencing revealed two mosaic mutations in a child with ACC and in an unaffected father of a child with medulloblastoma. Re-analysis of blood DNA by next-generation sequencing, performed at a depth above 500X, from 108 patients suggestive of LFS without detectable TP53 mutations, allowed us to identify 6 additional cases of mosaic TP53 mutations, in 2/49 children with ACC, 2/21 children with CPT, in 1/31 women with breast cancer before age 31 and in a patient who developed an osteosarcoma at age 12, a breast carcinoma and a breast sarcoma at age 35. CONCLUSIONS: This study performed on a large series of TP53 mutation carriers allows estimating the contribution to LFS of de novo mutations to at least 14% (48/336) and suggests that approximately one-fifth of these de novo mutations occur during embryonic development. Considering the medical impact of TP53 mutation identification, medical laboratories in charge of TP53 testing should ensure the detection of mosaic mutations.

Management of hydrocephalus in pediatric metastatic tumors of the posterior fossa at presentation.

PURPOSE: Presence of metastases in newly diagnosed pediatric posterior fossa tumors (PFT) is not a rare situation, but optimal treatment of associated hydrocephalus in these children has remained undetermined. METHODS: Twenty-nine children treated between January 2005 and December 2015 for a metastatic PFT associated with hydrocephalus constituted the study cohort. Patients were divided into three groups: ventriculoperitoneal shunt (VPS), endoscopic third ventriculostomy (ETV), and temporary ventricular drainage before or during tumor resection (PVD). RESULTS: There were 4 VPS, 18 ETV, and 7 PVD. The global incidence of CSF diversion failure was 52%. No case of dysfunction or dissemination of metastatic cells occurred in the VPS group. Recurrence of hydrocephalus occurred in 55% of the ETV group. Presence of multiple macroscopic metastases and CSF metastatic cells after tumor surgery was associated with ETV failure. Fifty-seven percent of the children in the PVD group were reoperated after an average time of 53 days. Specific oncologic treatment was initiated earlier in the VPS group (11 days) compared to ETV (27 days) and PVD (23 days) groups. CONCLUSIONS: ETV should be avoided in cases of multiple macroscopic metastases, and children who underwent ETV must be followed carefully when metastatic cells are present in CSF after tumor surgery. External ventricular drainage before or during surgical removal should not be considered as a final option to treat hydrocephalus. VPS remains a safe alternative in this situation and allows an early specific oncologic treatment.

Hearing loss during osteosarcoma chemotherapy: when acute ifosfamide toxicity revealed unnoticed methotrexate encephalopathy.

Ifosfamide and methotrexate are widely used for the treatment of pediatric osteosarcoma. However, both these chemotherapeutic drugs can cause encephalopathy. A 17-year-old girl presented with profound hearing loss and dizziness during a postoperative course of ifosfamide, 20 days after a course of methotrexate. Cerebral magnetic resonance imaging (MRI) showed bilateral white matter hypersignal in Fluid Attenuated Inversion Recovery sequences. The clinical evolution was rapidly favorable after methylene blue infusion. This is the second reported case of acute deafness, possibly associated with ifosfamide, whereas MRI data revealed unnoticed chronic methotrexate toxicity. Systematic MRI screening and hearing evaluation may be useful in such cases.

MLL-SEPT5 fusion transcript in infant acute myeloid leukemia with t(11;22)(q23;q11).

Chromosomal rearrangements involving the MLL gene at band 11q23 are the most common genetic alteration encountered in infant acute myeloid leukemia. Reciprocal translocation represents the most frequent form of MLL rearrangement. Currently, more than 60 partner genes have been identified. We report here a case of de novo acute myeloid leukemia with a t(11;22)(q23;q11) in a 23-month-old child. Fluorescence in situ hybridization study revealed that the 3'MLL segment was translocated onto the derivative chromosome 22 and the breakpoint on chromosome 22 was located in or near the SEPT5 gene at 22q11.21. Long distance inverse-polymerase chain reaction was used to identify precisely the MLL partner gene and confirmed the MLL-SEPT5 fusion transcript. Involvement of the SEPT5 gene in MLL rearrangement occurs very rarely. Clinical, cytogenetic and molecular features of acute myeloid leukemia with a MLL-SEPT5 fusion gene are reviewed.

Evidence for new targets and synergistic effect of metronomic celecoxib/fluvastatin combination in pilocytic astrocytoma.

BACKGROUND: Pilocytic astrocytomas occur predominantly in childhood. In contrast to the posterior fossa location, hypothalamo-chiasmatic pilocytic astrocytomas display a worse prognosis often leading to multiple surgical procedures and/or several lines of chemotherapy and radiotherapy to achieve long-term control. Hypothalamo-chiasmatic pilocytic astrocytomas and cerebellar pilocytic astrocytomas have a distinctive gene signature and several differential expressed genes (ICAM1, CRK, CD36, and IQGAP1) are targets for available drugs: fluvastatin and/or celecoxib. RESULTS: Quantification by RT-Q-PCR of the expression of these genes was performed in a series of 51 pilocytic astrocytomas and 10 glioblastomas: they were all significantly overexpressed in hypothalamo-chiasmatic pilocytic astrocytomas relative to cerebellar pilocytic astrocytomas, and CRK and ICAM1 were significantly overexpressed in pilocytic astrocytomas versus glioblastomas.We used two commercially available glioblastoma cell lines and three pilocytic astrocytoma explant cultures to investigate the effect of celecoxib/fluvastatin alone or in combination. Glioblastoma cell lines were sensitive to both drugs and a combination of 100 µM celecoxib and 240 µM fluvastatin was the most synergistic. This synergistic combination was used on the explant cultures and led to massive cell death of pilocytic astrocytoma cells.As a proof of concept, a patient with a refractory multifocal pilocytic astrocytoma was successfully treated with the fluvastatin/celecoxib combination used for 18 months. It was well tolerated and led to a partial tumor response. CONCLUSION: This study reports evidence for new targets and synergistic effect of celecoxib/fluvastatin combination in pilocytic astrocytoma. Because it is non-toxic, this new strategy offers hope for the treatment of patients with refractory pilocytic astrocytoma.

[Glial and glioneuronal tumors in adults and children: main genetic alterations and towards a histomolecular classification]. / Les tumeurs gliales et glioneuronales de l'adulte et de l'enfant: principales altérations génétiques et classification histomoléculaire.

Glial and glioneuronal tumors in children and adult demonstrate distinctive clinical, neuroradiological and molecular features depending on the pathological subtype and within a same subgroup according to the age. In children, gliomas are mainly located in the infratentorial part of the brain. They are most often benign and circumscribed but infiltrative tumors with dismal prognosis are recorded within the pons (DIGP) or the thalamus. Glioblastomas are very rare in children. In contrast, gliomas in adult mainly occur in the cerebral hemispheres and the most frequent subtype is glioblastoma. Glioneuronal tumors mainly occurred in children and young adults. In addition, although pilocytic astrocytomas, pleomorphic xanthoastrocytomas and gangliogliomas are classified into different subgroups according to the WHO 2007 classification, these tumors demonstrate similar neuroradiological findings: they are cystic with contrast enhancement of a mural nodule. Major advances have been made these last five years in the discovery of some master genes that are involved in gliomagenesis and point out differences between children and adults. In adults, infiltrative gliomas can be classified into two major subgroups depending on the existence or not of IDH mutations. IDH-dependent gliomagenesis encompasses diffuse grade II and grade III (they can also show additional molecular alterations such as TP53 mutation or 1p19q codeletion) and secondary glioblastomas. IDH-independent gliomagenesis include triple negative grade II gliomas, gliomatosis cerebri (grade III) and de novo glioblastomas. Pilocytic astrocytomas, pleomorphic xanthoastrocytomas and gangliogliomas share in common BRAF alterations. However, KIAA1549-BRAF fusion characterizes pilocytic astrocytomas whereas V600E BRAF mutation is mainly recorded in pleomorphic xanthoastrocytomas and gangliogliomas.

Dysembryoplastic neuroepithelial tumors share with pleomorphic xanthoastrocytomas and gangliogliomas BRAF(V600E) mutation and expression.

Pediatric cortical glioneuronal benign tumors mainly include gangliogliomas (GG) [differential diagnoses pilocytic astrocytomas (PA) and pleomorphic xanthoastrocytomas (PXA)] and dysembryoplastic neuroepithelial tumor (DNT). DNT include the specific form and the controversial non-specific form that lack the specific glioneuronal element. Our aims were to search for BRAF(V600E) mutation and CD34 expression in DNT, PXA, GG and PA to correlate BRAF(V600E) mutation with BRAF(V600E) expression and to evaluate their diagnostic and prognostic values. Ninety-six children were included. BRAF(V600E) mutation was studied by sequencing and immunohistochemistry; CD34 expression was analyzed by immunohistochemistry. BRAF(V600E) mutation was detected in PXA (60%), GG (38.7%), DNT (30%, including 3/11 specific and 3/9 non-specific forms) and PA (12.5%). BRAF(V600E) expression was recorded in PXA (60%), GG (45.2%) and DNT (30%). CD34 expression was recorded in PXA (60%), GG (58.1%), DNT (25%) and PA (12.5%). Neither CD34 expression nor BRAF(V600E) status was predictive of prognosis, except for PA tumors where CD34 expression was associated with a shorter overall survival. In conclusion, DNT shared with PXA and GG, BRAF(V600E) mutation and/or CD34 expression, which represent molecular markers for these tumors, and we recommend searching for CD34 expression and BRAF(V600E) mutation in all DNT, especially the non-specific forms.

Primary gliomatosis cerebri involving gray matter in pediatrics: a distinct entity? A multicenter study of 14 cases.

BACKGROUND AND PURPOSE: Gliomatosis cerebri (GC) is a rare neoplasm including a variety of tumors, with extremely variable evolution and heterogeneity of prognosis. It may appear either de novo or after a focal glioma, involve predominantly the white or the gray matter, and concern either pediatric or adult patients. We focused on primary GC involving exclusively gray matter in a pediatric population in order better to define the presentation and outcome of this disease. PATIENTS AND METHODS: We reviewed the databases of seven Departments of Pediatric Oncology to identify pediatric cases of GC between 1990 and 2007. Patients were included if they demonstrated a diffuse infiltrative process involving gray matter in magnetic resonance imaging (MRI) and histological tissue analyses, confirming a proliferative glial disorder. RESULTS: Fourteen patients with a median age of 8 years were identified. Epilepsy was the main presenting symptom. Brain MRI showed a lesion of the temporal and insular cerebral cortex associated with tumoral infiltration of the thalami and the basal ganglia. Histological examination confirmed the diagnosis of high-grade glioma. Prognosis was always very gloomy in the short term, with a median survival of less than a year. CONCLUSION: This rare entity, whose prognosis is appalling whatever the treatment proposed, should be clearly identified within the heterogeneous group of GC in the same way as diffuse intrinsic pontine gliomas have been identified among brain stem tumors. Systematic biopsies appear essential to permit the molecular studies which will assist in guiding the choice of future targeted treatments.

Astrovirus and digestive disorders in neonatal units.

AIM: To describe clinical signs associated with Human Astrovirus (HAstV) in stools in neonatal units. METHODS: During 2005-2006, all stool virology performed for isolated digestive symptoms or suspicion of neonatal infection was tested for HAstV by an amplified enzyme-linked immunoassay (IDEIA™ Astrovirus test, Dako Cytomation). Each newborn with a positive result (HAstV+ group) was retrospectively matched with the first following symptomatic newborn in the same care unit having a negative stool virology (HAstV- group). Clinical data were collected during two 3-day periods (just after faecal samples collection and 1 week before) and compared within and between each group. RESULTS: Human astrovirus was detected in faeces of 68 newborns [gestational age: 31.4(28.8-34) weeks] at a post-natal age of 23 (15-42) days without seasonal dominance. Human astrovirus+ and HAstV- groups were comparable. Bloody stool (54.4% versus 14.7%, p < 0.01) and stage II-III necrotizing enterocolitis (20.6% versus 4.4%, p < 0.05) were more frequently observed in HAstV+ than in HAstV- group; these associations were confirmed by logistic regression analysis. CONCLUSION: This descriptive study argues for a possible association between HAstV and digestive symptoms in newborns specifically in preterm infants.

School performance of childhood cancer survivors: mind the teenagers!

OBJECTIVE: To assess school performance in an unselected group of childhood cancer survivors and study risk factors for impairment. STUDY DESIGN: Rates of repeating a grade were compared for patients with cancer, their siblings, and the general population. Phone questionnaires were administered to patients about the school career of their child in remission and their siblings. Responses about cancer survivors were compared with those concerning their siblings and various registries provided by the national board of education. The primary outcome was the rate of repeating a grade. RESULTS: A total of 148 children in remission with a mean age of 15 ± 5.3 years and a mean follow-up period since diagnosis of 6.3 ± 1.3 years were included. More patients than siblings repeated a grade (33% versus 21%; P = .02), with a mean delay since diagnosis of 2 years. Risk factors were an older age at diagnosis, attending a secondary school, low education level of parents, bone marrow transplantation, cerebral surgery, and physical sequelae. In multivariate analysis, risk for repeating was associated with low educational level of the father, attending secondary school at diagnosis, and requiring school-organized educational support on return to school. CONCLUSION: After cancer, repeating a grade is not an exceptional occurrence, especially for teenagers; follow-up and supportive interventions before returning to school would be beneficial.