Treatment Refractory Soft Tissue Myoepithelial Carcinoma With an ARID1A Mutation.

Soft tissue myoepithelial carcinoma is a rare tumor first reported in the salivary gland. There is considerable tumor heterogeneity between pathology findings, tumor aggressiveness, and response to treatment. Recent molecular testing has identified recurrent genetic changes with PLAG mutations in salivary gland primary tumors and loss of SMARCB1 and EWSR1/FUS gene changes in myoepithelial carcinoma. SMARCB1 is a component of the switch/sucrose nonfermentable (SWI/SNF) complex, an essential cellular regulator. ARID1A is another SWI/SNF complex subunit and is a potent oncogenic driver in other tumor types. In this case, we describe the case of an adolescent/young adult patient with treatment refractory soft tissue myoepithelial carcinoma and a previously unreported ARID1A mutation.

Healthcare providers' promotion of physical activity among child and adolescent cancer survivors: strategies and challenges.

PURPOSE: This study aims to investigate how healthcare providers (HCPs) promote physical activity (PA) to child and adolescent cancer survivors. METHODS: Semi-structured interviews were conducted with HCPs (n = 16; women n = 12; men n = 4) who provide care for cancer survivor youth (age 3 to 18). Participants represented 7 professions, including child life specialists, oncologists, nurse practitioners, physical therapists, and social workers. A reflexive thematic analysis was conducted to explore the techniques that HCPs use to promote PA for this patient population and ways PA promotion can improve. RESULTS: HCPs use five strategies to promote PA to cancer survivor youth: (1) broadening the definition of PA, (2) tailoring PA recommendations, (3) including families, (4) connecting patients to programming, and (5) promoting patient motivation. CONCLUSIONS: This research highlights techniques that HCPs use to promote PA to young cancer survivors and reveals the need for additional ways to support HCPs to improve PA promotion for child and adolescent cancer survivors. While HCPs emphasized the importance of PA for this patient population, they navigate barriers that limit the quality of PA discussions. IMPLICATIONS FOR CANCER SURVIVORS: Further research should explore interventions to improve PA promotion and PA participation among child and adolescent cancer survivors. By understanding the perspectives of HCPs, patients, and their families, PA promotion strategies can be improved, and more programs that support both patients and practitioners may be developed.

Malignant Giant Cell Tumor of Bone With a KRAS G12V Mutation.

Malignant giant cell tumor of bone (GCTB) is a rare, aggressive, sarcoma occurring in adolescent and young adults. It is characterized by the presence of multinucleated giant cells and an aggressive clinical course. Because of the rarity of this tumor, no standard therapies have been identified. Current treatment regimens often include osteosarcoma chemotherapy protocols. We present a case of a malignant GCTB with a KRAS G12V mutation. This mutation is a known oncogenic driver that has not previously been reported on patients with malignant GCTB.

Pediatric Myelodysplastic Syndrome With Germline RRAS Mutation: Expanding the Phenotype of RASopathies.

The RAS/mitogen-activated protein kinase pathway plays a significant role in cell cycle regulation. Germline mutation of this pathway leads to overlapping genetic disorders, RASopathies, and is also an important component of tumorigenesis. Here we describe a rare case of myelodysplastic syndrome with monosomy 7 in a pediatric patient with a germline RRAS mutation. RRAS mutations have been implicated in the development of juvenile myelomonocytic leukemia, but our case suggests RRAS mutations display a broader malignant potential. Our case supports the recommendation that genetic testing should include RRAS in suspected RASopathy patients and if identified, these patients undergo surveillance for hematologic malignancy.

Oncogenic GOPC-ROS1 Fusion Identified in a Congenital Glioblastoma Case.

Congenital glioblastoma (GBM) is a rare brain tumor of infancy. While histologically they resemble pediatric and adult GBM, growing evidence suggests a distinct molecular profile. We report the case of a 7-day-old infant female with congenital GBM found to harbor a GOPC-ROS1 fusion. She underwent surgical resection, moderate-intensity chemotherapy without radiation, and remains disease-free 4 years from completion of therapy. While the frequency of this mutation is not known, the identification of this oncogenic driver may provide insight into the pathogenesis of GBM in this age group and may serve as a molecular target for select patients.

Targetable molecular alterations in congenital glioblastoma.

INTRODUCTION: Congenital glioblastomas (cGBMs) are uncommon tumors presenting in early infancy, variably defined as diagnosed at birth or at age less than 3 months by strict criteria, or more loosely, as occurring in very young children less than 12 months of age. Previous studies have shown that cGBMs are histologically indistinguishable from GBMs in older children or adults, but may have a more favorable clinical outcome, suggesting biological differences between congenital versus other GBMs. Due to the infrequency of cGBMs, especially when employing strict inclusion criteria, molecular features have not been sufficiently explored. METHODS: Archer FusionPlex Solid Tumor Kit, Archer VariantPlex Solid Tumor Kit, Illumina RNAseq were utilized to study cGBMs seen at our institution since 2002. A strict definition for cGBM was utilized, with only infants less than age 3 months at clinical presentation sought for this study. RESULTS: Of the 8 cGBM cases identified in our files, 7 had sufficient materials for molecular analyses, and 3 of 7 cases analyzed showed fusions of the ALK gene (involving MAP4, MZT2Bex2 and EML4 genes as fusion partners). One case showed ROS1 fusion. Somatic mutations in TSC22D1, BMG1 and DGCR6 were identified in 1 case. None of the cases showed alterations in IDH1/2, histone genes, or the TERT gene, alterations which can be associated with GBMs in older children or adults. CONCLUSIONS: Our results show that cGBMs are genetically heterogeneous and biologically different from pediatric and adult GBMs. Identification of ALK and ROS1 raise the possibility of targeted therapy with FDA-approved targeted inhibitors.

Ovarian Sertoli-Leydig Cell Tumor with Elevated Inhibin B as a Cause of Secondary Amenorrhea in an Adolescent with Germ Line DICER1 Mutation.

BACKGROUND: Ovarian tumors, although uncommon in children, can retain endocrine function that disrupts normal feedback mechanisms leading to amenorrhea. Inheritance of germline DICER1 mutations can lead to increased risk for development of ovarian Sertoli-Leydig cell tumors (SLCTs). CASE: We report, to our knowledge, the first case of secondary amenorrhea due to elevated inhibin B levels in a female adolescent with an ovarian SLCT. SUMMARY AND CONCLUSION: Ovarian tumors should be included in the differential diagnosis for pediatric patients who present with menstrual irregularities. Early evaluation of the hypothalamic-pituitary-ovarian axis and inhibin levels is appropriate. Our case also emphasizes the need for testing for DICER1 mutations in pediatric patients with ovarian SLCTs.

Tuberous sclerosis complex: Five new things.

PURPOSE OF REVIEW: Tuberous sclerosis complex (TSC) is a variably expressed neurocutaneous genetic disorder characterized by hamartomatous growths in multiple organ systems. Neurologic involvement often confers the most severe symptoms, and can include epilepsy, increased intracranial pressure from hydrocephalus, intellectual deficits, and autism. The purpose of this review is to provide a neurologically focused update in the diagnosis and treatment of these complications in patients with TSC. RECENT FINDINGS: We highlight 5 new areas of understanding in TSC: the neurobiology of TSC and its translation into clinical practice, vigabatrin in the treatment of infantile spasms, the role of tubers and epilepsy surgery, the treatment of subependymal giant cell astrocytomas, and TSC-related neuropsychiatric disorders. SUMMARY: These recent advances in diagnosis and treatment give our patients with TSC and their families hope for the future for improved care and possible preventive cures, to the end goal of improving quality of life.

Maternal cautopyreiophagia as a rare cause of neonatal hemolysis: a case report.

Hyperbilirubinemia in the first 24 hours of life in a newborn is pathologic, necessitating additional evaluation. We report the first case of hemolysis and subsequent hyperbilirubinemia in an otherwise normal term neonate resulting from oxidative stress in the form of maternal cautopyreiophagia: the ingestion of burnt matchstick heads. During the third trimester of pregnancy, the infant's mother consumed more than 300 burnt matchstick heads weekly for 4 weeks. Matches contain potassium chlorate, a powerful oxidant that when ingested can ultimately lead to the destruction of erythrocytes, disseminated intravascular coagulation, kidney injury, or death. The infant's bilirubin rose as high as 17 mg/dL at 22 hours of life; however, the infant did well with a brief course of phototherapy. This case highlights the importance of prenatal questioning about maternal ingestion of potentially oxidative substances and assessing the possible risk for the infant.

Inhibition of cyclin-dependent kinase 6 suppresses cell proliferation and enhances radiation sensitivity in medulloblastoma cells.

Medulloblastoma accounts for 20 % of all primary pediatric intracranial tumors. Current treatment cures 50-80 % of patients but is associated with significant long-term morbidity and thus new therapeutic targets are needed. One such target is cyclin-dependent kinase 6 (CDK6), a serine/threonine kinase that plays a vital role in cell cycle progression and differentiation. CDK6 is overexpressed in medulloblastoma patients and is associated with an adverse prognosis. To investigate the role of CDK6 in medulloblastoma, we assayed the effect of CDK6 inhibition on proliferation by depleting expression with RNA interference (RNAi) or by inhibiting kinase function with a small molecule inhibitor, PD0332991. Cell proliferation was assessed by colony focus assay or by the xCELLigence system. We then investigated the impact of CDK6 inhibition on differentiation of murine neural stem cells by immunofluorescence of relevant markers. Finally we evaluated the effects of PD0332991 treatment on medulloblastoma cell cycle and radiosensitivity using colony focus assays. Gene expression analysis revealed that CDK6 mRNA expression is higher than normal cerebellum in fifteen out of sixteen medulloblastoma patient samples. Inhibition of CDK6 by RNAi significantly decreased medulloblastoma cell proliferation and colony forming potential. Interestingly, CDK6 inhibition by RNAi increased differentiation in murine neural stem cells. PD0332991 treatment significantly decreased medulloblastoma cell proliferation and led to a G0/G1 cell cycle arrest. Furthermore, PD0332991 pretreatment sensitized medulloblastoma cells to ionizing radiation. Our findings suggest that targeting CDK6 with small molecule inhibitors may prove beneficial in the treatment of medulloblastoma, especially when combined with radiation.