Alterations in ALK/ROS1/NTRK/MET drive a group of infantile hemispheric gliomas.

Infant gliomas have paradoxical clinical behavior compared to those in children and adults: low-grade tumors have a higher mortality rate, while high-grade tumors have a better outcome. However, we have little understanding of their biology and therefore cannot explain this behavior nor what constitutes optimal clinical management. Here we report a comprehensive genetic analysis of an international cohort of clinically annotated infant gliomas, revealing 3 clinical subgroups. Group 1 tumors arise in the cerebral hemispheres and harbor alterations in the receptor tyrosine kinases ALK, ROS1, NTRK and MET. These are typically single-events and confer an intermediate outcome. Groups 2 and 3 gliomas harbor RAS/MAPK pathway mutations and arise in the hemispheres and midline, respectively. Group 2 tumors have excellent long-term survival, while group 3 tumors progress rapidly and do not respond well to chemoradiation. We conclude that infant gliomas comprise 3 subgroups, justifying the need for specialized therapeutic strategies.

An Adolescent Presenting With Seizures as a Symptom of Gliomatosis Cerebri.

Gliomatosis cerebri is a diffuse infiltrating glioma of neuroepithelial origin that affects more than 2 cerebral lobes. This is rarely seen in pediatric patients. The clinical presentation and imaging are very unspecific, and a biopsy is typically needed for the diagnosis. Given the widespread nature of the disease, surgical treatment is not possible and has a poor overall prognosis. A pediatric patient presented with elevated intracranial pressure. All initial studies were negative, and the imaging showed a symmetrical affection involving the supratentorial and infratentorial regions. A biopsy ultimately confirmed gliomatosis cerebri. This case describes a unique clinical presentation of gliomatosis cerebri in a pediatric patient.

Management and outcome of children and adolescents with non-medulloblastoma CNS embryonal tumors in Spain: room for improvement in standards of care.

Non-medulloblastoma CNS embryonal tumors (former PNET/Pineoblastomas) are aggressive malignancies with poor outcome that have been historically treated with medulloblastoma protocols. The purpose of this study is to present a tumor-specific, real-world data cohort of patients with CNS-PNET/PB to analyze quality indicators that can be implemented to improve the outcome of these patients. Patients 0-21 years with CNS-PNET treated in eight large institutions were included. Baseline characteristics, treatment and outcome [progression-free and overall survival (PFS and OS respectively)] were analyzed. From 2005 to 2014, 43 patients fulfilled entry criteria. Median age at diagnosis was 3.6 years (range 0.0-14.7). Histology was pineoblastoma (9%), ependymoblastoma (5%), ETANTR (7%) and PNET (77%). Median duration of the main symptom was 2 weeks (range 0-12). At diagnosis, 28% presented with metastatic disease. Seventeen different protocols were used on frontline treatment; 44% had gross total resection, 42% craniospinal radiotherapy, 86% chemotherapy, and 33% autologous hematopoietic stem cell transplantation (aHSCT). Median follow-up for survivors was 3.5 years (range 1.7-9.3). 3-year PFS was 31.9% (95% CI 17-47%) and OS 35.1% (95% CI 20-50%). Age, extent of resection and radiotherapy were prognostic of PFS and OS in univariate analysis (p < 0.05). Our series shows a dismal outcome for CNS-PNET, especially when compared to patients included in clinical trials. Establishing a common national strategy, implementing referral circuits and collaboration networks, and incorporating new molecular knowledge into routine clinical practice are accessible measures that can improve the outcome of these patients.

Contribution of Altered Endocannabinoid System to Overactive mTORC1 Signaling in Focal Cortical Dysplasia.

Alterations of the PI3K/Akt/mammalian target of rapamycin complex 1 (mTORC1) signaling pathway are causally involved in a subset of malformations of cortical development (MCDs) ranging from focal cortical dysplasia (FCD) to hemimegalencephaly and megalencephaly. These MCDs represent a frequent cause of refractory pediatric epilepsy. The endocannabinoid system -especially cannabinoid CB1 receptor- exerts a neurodevelopmental regulatory role at least in part via activation of mTORC1 signaling. Therefore, we sought to characterize the possible contribution of endocannabinoid system signaling to FCD. Confocal microscopy characterization of the CB1 receptor expression and mTORC1 activation was conducted in FCD Type II resection samples. FCD samples were subjected to single nucleotide polymorphism screening for endocannabinoid system elements, as well as CB1 receptor gene sequencing. Cannabinoid CB1 receptor levels were increased in FCD with overactive mTORC1 signaling. CB1 receptors were enriched in phospho-S6-positive cells including balloon cells (BCs) that co-express aberrant markers of undifferentiated cells and dysplastic neurons. Pharmacological regulation of CB1 receptors and the mTORC1 pathway was performed in fresh FCD-derived organotypic cultures. HU-210-evoked activation of CB1 receptors was unable to further activate mTORC1 signaling, whereas CB1 receptor blockade with rimonabant attenuated mTORC1 overactivation. Alterations of the endocannabinoid system may thus contribute to FCD pathological features, and blockade of cannabinoid signaling might be a new therapeutic intervention in FCD.

Vulvar fetal rhabdomyoma mimicking 46XX sex differentiation disorder.

Rhabdomiomas are rare mesenchymal benign tumors of striated muscle origin. Setting aside the cardiac (most atrial) rhabdomiomas typically associated to neurocutaneous syndromes (tuberous sclerosis), extracardiac rhabdomyomas appear clinically as a subcutaneous nodule or as a submucosal polypoid lesion. Among them, three main histologic subtypes can be differentiated on the basis of the degree of tumor differentiation: 1) fetal rhabdomioma, usually diagnosed during childhood and almost exclusively located in the in the head and neck region with rare reports in other locations; 2) adult rhabdomioma; and 3) genital rhabdomioma, reported to occur in the lower genital tract of young and middle-aged women and, exceptionally, in children (5).

A phase I/II trial of interleukin-15--stimulated natural killer cell infusion after haplo-identical stem cell transplantation for pediatric refractory solid tumors.

BACKGROUND AIMS: Preliminary data suggest that T-cell-depleted haplo-identical stem cell transplantation (haplo-SCT) has a clinically beneficial allograft-versus-tumor effect associated with natural killer (NK) cell immune reconstitution. METHODS: This phase I/II trial descriptively evaluates the feasibility of interleukin (IL)-15-stimulated NK cell infusion after haplo-SCT in pediatric patients with refractory solid tumors. RESULTS: Six patients received an IL-15-stimulated NK cell infusion at 30 days after haplo-SCT. The mean number of infused NK cells per product was 11.3 × 10(6)/kg (range, 3-27 × 10(6)/kg). The T-cell count was <1 × 10(3)/kg in all patients (range, 0-0.75 × 10(3)/kg). No toxic effects related to IL-15--stimulated NK cell infusion were observed. Four of the six patients showed a clinical response (one achieved very good partial remission, two achieved partial remission and one had stable disease). One patient had progressive disease, and the response was not evaluated in the remaining patient. After a median follow-up period of 310 days, all patients had died: four of cancer relapse, one of cancer-associated thrombotic micro-angiopathy and one of acute graft-versus-host disease. CONCLUSIONS: The adoptive transfer of allogeneic IL-15--stimulated NK cells might be feasible and safe in heavily pretreated pediatric patients with refractory solid tumors, though the advanced stage of disease and toxic effects of haplo-SCT may limit the efficacy of NK cell infusion in this population.

Desmoplastic Trichoepithelioma: An Infrequent Entity not to be Missed: Report of Two Cases.

Desmoplastic trichoepitheliomas are rare benign tumors with follicular differentiation. They have rarely been described in children. We report two children with this uncommon condition.

Hemicerebellitis: Report of three paediatric cases and review of the literature.

Acute inflammation of a single cerebellar hemisphere (hemicerebellitis) is a rare disorder of unknown origin. The clinical presentation is mainly characterized by headache, ataxia, dysmetria, and vomiting. In addition, some children may develop severe intracranial hypertension. The neuroimaging of hemicerebellitis raises a challenging differential diagnosis, particularly with posterior fossa tumours. Although there is no standard treatment for hemicerebellitis, its outcome is usually favourable. However, ipsilateral hemicerebellar atrophy develops in up to half of cases, and a minority of children may show persisting fine motor and/or neurocognitive sequelae. In this article, we contribute with three new reports and review a total of 35 cases of hemicerebellitis.

Inferior vena cava aneurysm in an infant presenting with a renal mass.

Aneurysm of the inferior vena cava is a rare finding in the pediatric population. We report the case of a 5-month-old infant presenting with anemia, hypertension, and dehydration in the emergency room. A renal mass was found with ultrasound and MRI and a renal tumor was first considered. Histopathologic review of the surgical specimen led to the diagnosis of aneurysmal dilatation of the vena cava.

Rituximab in lymphomatoid granulomatosis.

BACKGROUND: Lymphomatoid granulomatosis (LG) is an Epstein-Barr virus-associated, multisystemic disease that combines a granulomatous inflammatory process with lymphoproliferative potential. It is a rare disorder with a variable clinical presentation ranging from an indolent process to an aggressive B-cell lymphoma. Outcome is unpredictable, and a standard treatment has not yet been established. Cases treated with rituximab, an anti-CD20 monoclonal antibody, have been reported with variable results. OBSERVATION: We report on 2 children with LG treated with rituximab and review the literature. The first patient had good response but the second did not. CONCLUSIONS: Rituximab is a treatment option for LG.

Ataxia-telangiectasia and wilms tumor: reduced treatment but early relapse.

Ataxia-telangiectasia (A-T) is an autosomal recessive disease characterized by progressive cerebellar ataxia, oculocutaneous telangiectasia, immunodeficiency, a high incidence of lymphoreticular tumors, and an increased sensitivity to chemoradiotherapy-induced DNA damage. The appropriate cancer therapy remains unknown because of high toxicity rates with full-dose conventional protocols. We present a patient with A-T and nephroblastoma, who received an adapted treatment regimen. To our knowledge this is the second report on nephroblastoma in a patient with A-T but the first with confirmed premortem studies. Although the patient tolerated the chemotherapy regimen well, the patient relapsed and died a year after initial diagnosis.

In vitro Natural Killer Cell Immunotherapy for Medulloblastoma.

How the immune system attacks medulloblastoma (MB) tumors effectively is unclear, although natural killer (NK) cells play an important role in immune defense against tumor cells. Interactions between receptors on NK cells and ligands expressed by tumor cells are critical for tumor control by immunotherapy. In this study, we analyzed tumor samples from 54 MB patients for expression of major histocompatibility complex class I-related chains A (MICA) and UL16 binding protein (ULPB-2), which are ligands for the NK group 2 member D activatory receptor (NKG2D). The percentage of MICA and ULBP-2 positive cells was higher than 25% in 68% and 6% of MB patients, respectively. A moderate-high intensity of MICA cytoplasmic staining was observed in 46% MB patients and weak ULBP-2 staining was observed in 8% MB patients. No correlation between MICA/ULBP-2 expression and patient outcome was found. We observed that HTB-186, a MB cell line, was moderately resistant to NK cell cytotoxicity in vitro. Blocking MICA/ULBP-2 on HTB-186, and NKG2D receptor on NK cells increased resistance to NK cell lysis in vitro. However, HLA class I blocking on HTB-186 and overnight incubation with IL-15 stimulated NK cells efficiently killed tumor cells in vitro. We conclude that although NKG2D/MICA-ULBP-2 interactions have a role in NK cell cytotoxicity against MB, high expression of HLA class I can protect MB from NK cell cytotoxicity. Even so, our in vitro data indicate that if NK cells are appropriately stimulated, they may have the potential to target MB in vivo.

Pleuropulmonary blastoma as characteristic cause of pneumothorax.

BACKGROUND: Pleuropulmonary blastoma (PPB) is the most common lung neoplasms in childhood. Usually presents as recurrent respiratory infections and in some cases as pneumothorax. CASE REPORT: We report the case of a 2-year-old patient that was diagnosed with PPB, that first manifested as recurrent pneumothorax. Three chest computed tomography were necessary for the diagnosis. The first 2 tomographies showed no abnormalities suggestive of malignancy. The patient had a family history of both PPB and leukemia. Three years and a half after completion of treatment, the patient is in complete remission. CONCLUSIONS: PPB is an uncommon disease but is the most common pulmonary neoplasms in childhood. We must suspect it in patients with a suggestive family history and recurrent pneumothorax in the same location.

Systemic juvenile xanthogranuloma with fatal outcome.

Juvenile xanthogranuloma is a benign and self-limited disease which usually appears in the skin of children. Visceral involvement has been rarely reported, as has fatal outcome in some affected individuals. We report a case of systemic juvenile xanthogranuloma in a female newborn with mainly skin, bone marrow, and liver involvement, leading to death at the age of 2 months.

Perforating neutrophilic and granulomatous dermatitis of the newborn--a clue to immunodeficiency.

We report two newborns with a widespread cutaneous eruption consisting of discrete papules which evolved into vesicles, pustules, crusts, and ulcers. These healed over a 2-week period with scarring. Histopathology showed three main features--histiocytic granulomas, neutrophilic infiltration, and transepidermal elimination of degenerated collagen and debris through hair follicles. Both patients had congenital immunodeficiency. This skin condition of the newborn, with distinct clinical and histopathologic features, is a manifestation of immunodeficiency that has not been previously described.

[Congenital botryoid rhabdomyosarcoma of the vulva]. / Rabdomiosarcoma botrioides congénito de vulva.

Rhabdomyosarcoma is the most frequent malignant soft tissue tumor in pediatric patients; however, the vulvar location and congenital appearance are exceptional. We present the case of a newborn girl with botryoid rhabdomyosarcoma of the vulva, treated with chemotherapy, conservative surgery and autologous transplant. Botryoid rhabdomyosarcoma is a variation of embryonal rhabdomyosarcoma that typically grows in mucosa-lined hollow organs, from where it can spread to the body surface. The treatment of botryoid rhabdomyosarcoma in the genito-urinary area is based on polychemotherapy, and it can be complemented with radiotherapy and conservative surgery if necessary, thus resulting in an excellent prognosis and few long-term functional sequelae.

Basal cell carcinoma in childhood after radiation therapy: case report and review.

We describe 2 patients who received ionizing radiation as part of a curative regimen for childhood malignancy which later developed basal cell carcinoma at an early age. They do not occur within the context of well-defined syndromes, such like basal cell nevus syndrome, albinism, or xeroderma pigmentosum. Basal cell carcinomas appears on radiated areas in older individuals, less often in younger patients, in which the period of latency between exposure to radiation and the appearance of basal cell carcinomas is shorter than in older patients. Our 2 cases presented a period of latency of 11 and 10 years. Radiated skin areas must be explored as part of the follow-up in children who received radiotherapy and should probably be maintained for life. The basal cell carcinoma in childhood is best treated by excision.