Infant High-Grade Gliomas Comprise Multiple Subgroups Characterized by Novel Targetable Gene Fusions and Favorable Outcomes.

Infant high-grade gliomas appear clinically distinct from their counterparts in older children, indicating that histopathologic grading may not accurately reflect the biology of these tumors. We have collected 241 cases under 4 years of age, and carried out histologic review, methylation profiling, and custom panel, genome, or exome sequencing. After excluding tumors representing other established entities or subgroups, we identified 130 cases to be part of an "intrinsic" spectrum of disease specific to the infant population. These included those with targetable MAPK alterations, and a large proportion of remaining cases harboring gene fusions targeting ALK (n = 31), NTRK1/2/3 (n = 21), ROS1 (n = 9), and MET (n = 4) as their driving alterations, with evidence of efficacy of targeted agents in the clinic. These data strongly support the concept that infant gliomas require a change in diagnostic practice and management. SIGNIFICANCE: Infant high-grade gliomas in the cerebral hemispheres comprise novel subgroups, with a prevalence of ALK, NTRK1/2/3, ROS1, or MET gene fusions. Kinase fusion-positive tumors have better outcome and respond to targeted therapy clinically. Other subgroups have poor outcome, with fusion-negative cases possibly representing an epigenetically driven pluripotent stem cell phenotype.See related commentary by Szulzewsky and Cimino, p. 904.This article is highlighted in the In This Issue feature, p. 890

Long-term survival in a case of ETANTR with histological features of neuronal maturation after therapy.

Embryonal tumor with abundant neuropil and true rosettes (ETANTR) is a rare subtype of primitive neuroectodermal tumors and one of the most aggressive brain tumors in children. The neoplasm harbors a specific genetic alteration, amplification of the miRNA cluster C19MC at 19q13.42. We report a case of a 21-month-old boy with a mass in the left fronto-opercular region. The lesion was partially resected and pathology examination revealed an ETANTR with immunoreativity for LIN28A protein and amplification of the C19MC locus. The child received the PNET infant indications followed by high-dose thiotepa which resulted in a significant reduction of the mass. Subsequently, a second operation was carried out and the residual mass removed. Histology at this time showed a low-grade lesion composed of neuronal cells ranging from neurocytes to ganglion cells embedded in abundant neuropil with no immature embryonal component and multilayered rosettes. In addition to these features, a decrease in the number of nuclei with amplification of the C19MC locus was also observed. Thirty-one months after the second operation, the patient is alive and well. Such long-term survival could be explained by neuronal maturation induced by therapy associated with reduction of neoplastic cells with amplification of C19MC locus. This case suggests that the induction of differentiation may represent an optimal treatment strategy for very aggressive malignancies as ETANTR

Fungal infections of the lung in children

Fungal infections of the lungs are relatively common and potentially life-threatening conditions in immunocompromised children. The role of imaging in children with lung mycosis is to delineate the extension of pulmonary involvement, to assess response to therapy, and to monitor for adverse sequelae such as bronchiectasis and cavitation. The aim of this paper is to show imaging findings in a series of patients with fungal pneumonia from two tertiary children's hospitals, to discuss differential diagnoses and to show how imaging findings can vary depending on the host immune response

Metastatic Group 3 Medulloblastoma in a Patient With Tuberous Sclerosis Complex: Case Description and Molecular Characterization of the Tumor

Medulloblastoma is the most common pediatric brain tumor. We describe a child with tuberous sclerosis complex that developed a Group 3, myc overexpressed, metastatic medulloblastoma (MB). Considering the high risk of treatment-induced malignancies, a tailored therapy, omitting radiation, was given. Based on the evidence of mammalian target of rapamycin mTORC, mTOR Complex; RAS, Rat sarcoma; RAF, rapidly accelerated fibrosarcoma (mTOR) pathway activation in the tumor, targeted therapy was applied resulting in complete remission of disease. Although the PI3K/AKT/mTOR signaling pathway plays a role in MB, we did not find TSC1/TSC2 (TSC, tuberous sclerosis complex) mutation in our patient. We speculate that a different pathway resulting in mTOR activation is the basis of both TSC and MB in this child; H&E, haematoxilin and eosin; Gd, gadolinium

Value of structured reporting in neuromuscular disorders.

Abstract OBJECTIVE: To assess whether structured reports (SRs) of MRI in patients with inherited neuromuscular disorders (IND) provide more clinically relevant information than non-structured reports (NSRs) and whether neuroradiologists' expertise affects completeness of reports. MATERIAL AND METHODS: Lower limbs' MRI reports of patients with IND produced by neuroradiologists with different level of expertise (>\u200915 years vs.\u2009<\u200915 years of experience in reading IND-MRI) before and after implementation of a SR template were included. Reports were assessed for the presence of 9 key features relevant for IND management. Reports and images were evaluated by neurologists who assessed: disease-specific muscular involvement pattern; presence of sufficient information to order the appropriate genetic/diagnostic tests; presence of sufficient information to make therapeutic decision/perform biopsy and necessity to review MRI images. Mann-Whitney and Fisher's exact tests were used to compare the number of key features for NSR and SR and neurologists' answers for reports produced by neuroradiologists with different experience. RESULTS: Thirty-one SRs and 101 NSRs were reviewed. A median of 8 and 6 key features was present in SR and NSR, respectively (p value\u2009<\u20090.0001). When reports were produced by less expert neuroradiologists, neurologists recognized muscular involvement pattern, had sufficient information for clinical decision-making/perform biopsy more often with SR than NSR (p values:\u2009<\u20090.0001), and needed to evaluate images less often with SR (p value: 0.0001). When reports produced by expert neuroradiologists were evaluated, no significant difference in neurologists' answers was observed. CONCLUSION: SR of IND-MRI contained more often clinically relevant information considered important for disease management than NSR. Radiologist's expertise affects completeness of NSR reports

Infant High-Grade Gliomas Comprise Multiple Subgroups Characterized by Novel Targetable Gene Fusions and Favorable Outcomes.

Infant high-grade gliomas appear clinically distinct from their counterparts in older children, indicating that histopathologic grading may not accurately reflect the biology of these tumors. We have collected 241 cases under 4 years of age, and carried out histologic review, methylation profiling, and custom panel, genome, or exome sequencing. After excluding tumors representing other established entities or subgroups, we identified 130 cases to be part of an "intrinsic" spectrum of disease specific to the infant population. These included those with targetable MAPK alterations, and a large proportion of remaining cases harboring gene fusions targeting ALK (n = 31), NTRK1/2/3 (n = 21), ROS1 (n = 9), and MET (n = 4) as their driving alterations, with evidence of efficacy of targeted agents in the clinic. These data strongly support the concept that infant gliomas require a change in diagnostic practice and management. SIGNIFICANCE: Infant high-grade gliomas in the cerebral hemispheres comprise novel subgroups, with a prevalence of ALK, NTRK1/2/3, ROS1, or MET gene fusions. Kinase fusion-positive tumors have better outcome and respond to targeted therapy clinically. Other subgroups have poor outcome, with fusion-negative cases possibly representing an epigenetically driven pluripotent stem cell phenotype.See related commentary by Szulzewsky and Cimino, p. 904.This article is highlighted in the In This Issue feature, p. 890