Sclerosing Epithelioid Fibrosarcoma Harboring the EWSR1-CREB3L1 Gene Fusion: The Importance of Molecular Classification in Pediatric Sarcomas.

BACKGROUND: Sclerosing epithelioid fibrosarcoma (SEF) is a very rare soft tissue sarcoma that most commonly presents in middle-aged and elderly adults but has been rarely seen in children. SEF is a very aggressive tumor with over 50% of patients experiencing local recurrence and 40% to 80% of patients experiencing distant metastatic spread. This disease has been shown to be resistant to chemotherapy and is classically treated with surgical excision. CASE: We describe the case of a 10-year-old girl with Graves' disease who presented with protruding eyes (to a greater extent on the left side) and was found to have a large mass in her left inferior rectus muscle that was diagnosed as SEF. After treatment with incomplete resection, due to the benign-appearing nature of the tumor on imaging, and proton radiation therapy, she remains disease-free at 18 months post-therapy. DISCUSSION: SEF is typically identified via genetic testing and recognition of the EWSR1-CREB3L1 gene fusion as well as MUC4 expression via immunohistochemistry. DNA methylation profiling, which has traditionally been used in brain tumors, can also efficiently identify this tumor, and we recommend expanding the use of this technology for difficult to classify pediatric sarcomas.

Race and Ethnicity Reporting in Occupational Therapy Research Among Autistic Youth.

Historically marginalized racial and ethnic groups are underrepresented in autism research broadly; however, patterns of inclusion in occupational therapy research are unknown.In this secondary data analysis, we examined race and ethnicity reporting across articles included in a systematic review of evidence related to occupational therapy practice with autistic individuals <18 years (2013-2021).Two team members reached >90% interrater coding agreement in race and ethnicity reporting across articles in ADLs/IADLs, education/work, play, sleep, and social participation in clinics, homes/communities, and schools.Intervention outcomes of ADL/IADLs (66.7%) and play (66.7%) had low rates of reporting, while social participation in schools (100%) and education/work (100%) had higher rates of reporting. Sample diversity was greatest among research in schools and most limited in clinic-based settings.Systemic racism that limits individuals' participation in occupational therapy research perpetuates racial and ethnic health inequities among autistic children and adolescents.

Who is included in occupational therapy research among autistic youth?In research that guides occupational therapy practice with autistic youth, we need an understanding of the participants that were included in the research. Historically marginalized racial and ethnic groups are typically not included in the research, so we examined articles that informed occupational therapy practice for autistic youth. We found that different areas of intervention (e.g., play, education/work) had different rates of reporting. The most diverse samples were included in schools and were most limited in clinic-based settings. This is important because systemic racism can influence occupational therapy research and practice.

Interventions to Support Participation in Play for Autistic Children and Youth (Dates of Review: 2013-2021).

Systematic Review Briefs provide a summary of the findings from systematic reviews developed in conjunction with the American Occupational Therapy Association's Evidence-Based Practice Program. Each systematic review brief summarizes the evidence on a theme related to a systematic review topic. This systematic review brief presents findings to support participation in play for autistic1 children and adolescents (birth to 18 yr).

Interventions to Support Participation in Sleep for Autistic Children and Adolescents (2013-2021).

Systematic Review Briefs provide a summary of the findings from systematic reviews developed in conjunction with the American Occupational Therapy Association's Evidence-Based Practice Program. Each systematic review brief summarizes the evidence on a theme related to a systematic review topic. This systematic review brief presents findings from the systematic review on interventions to support participation in sleep for autistic1 children and adolescents (birth to 18 yr).

Interventions to Support Participation in Education for Autistic Students (2013-2021).

Systematic Review Briefs provide a summary of the findings from systematic reviews developed in conjunction with the American Occupational Therapy Association's Evidence-Based Practice Program. Each systematic review brief summarizes the evidence on a theme related to a systematic review topic. This systematic review brief presents findings from the systematic review on interventions to support autistic1 children and youth (up to 18 yr old) and focuses on participation in education settings.

Interventions to Support Participation in Basic and Instrumental Activities of Daily Living for Autistic Children and Adolescents (2013-2021).

Systematic Review Briefs provide a summary of the findings from systematic reviews developed in conjunction with the American Occupational Therapy Association's Evidence-Based Practice Program. Each systematic review brief summarizes the evidence on a theme related to a systematic review topic. This systematic review brief presents findings from the systematic review on interventions to support participation in basic and instrumental activities of daily living by autistic1 children and adolescents (birth to 18 yr).

Interventions to Support Social Participation for Autistic Children and Adolescents in Homes and Communities (2013-2021).

Systematic review briefs provide a summary of the findings from systematic reviews developed in conjunction with the American Occupational Therapy Association's Evidence-Based Practice Program. Each systematic review brief summarizes the evidence on a theme related to a systematic review topic. This systematic review brief presents findings to support social participation for autistic1 children and adolescents (birth to 18 yr) in homes and communities.

Clinic-Based Interventions to Support Social Participation for Autistic Children and Adolescents (2013-2021).

Systematic review briefs provide a summary of the findings from systematic reviews developed in conjunction with the American Occupational Therapy Association's Evidence-Based Practice Program. Each systematic review brief summarizes the evidence on a theme related to a systematic review topic. This systematic review brief presents findings from clinic-based studies to support social participation for autistic1 children and adolescents (birth to 18 yr).

Interventions to Support Social Participation for Autistic Children and Adolescents in Schools (2013-2021).

Systematic review briefs provide a summary of the findings from systematic reviews developed in conjunction with the American Occupational Therapy Association's Evidence-Based Practice Program. Each systematic review brief summarizes the evidence on a theme related to a systematic review topic. This systematic review brief presents findings to support social participation in school contexts for autistic1 children and adolescents (birth to 18 yr).

Respiratory Failure in a Child With Pulmonary Metastatic Osteosarcoma and COVID-19.

The novel coronavirus, SARS-CoV-2, causes much more severe disease in adults than in children. Although it is anticipated that immune compromised children and children with cancer may be at higher risk of developing severe or fatal COVID-19, there are no currently published reports of fatal disease in a child with cancer. Because of the discrepancy in disease severity between adult and pediatric patients, we report the case of an adolescent with pulmonary metastatic osteosarcoma who died of COVID-19 early in the course of the pandemic in New York City in the hope that heightening awareness that pulmonary metastatic disease may predispose to a more severe outcome will increase surveillance in this vulnerable population.

Inhibition of porcupine prolongs metastasis free survival in a mouse xenograft model of Ewing sarcoma.

The most pressing unmet clinical need for patients with Ewing sarcoma (ES) is the prevention and treatment of metastasis. The Wnt signaling pathway regulates a number of cellular functions associated with metastasis, including proliferation, motility, and stem cell self-renewal. Functional interaction between Wnt ligands and their receptors requires palmitoylation by Porcupine (Porcn), making this an ideal therapeutic target. We studied the effect of WNT974, a potent, selective Porcn inhibitor, on ES metastasis. In vitro, WNT974 does not affect ES proliferation or sarcosphere formation, but suppresses multiple transcriptional regulators of metastasis and inhibits cell migration. In vivo, in an orthotopic implantation/amputation model of spontaneous distant metastasis, single agent WNT974 treatment leads to a significant delay in formation of lung metastasis and a substantial improvement in post-amputation survival without a major effect on primary tumor growth. The drug produces no survival benefit in a tail vein injection model, supporting the hypothesis that WNT974 inhibits early steps in the metastatic cascade, such as migration and invasion. Our findings strongly implicate Wnt signaling in the early steps of ES metastasis and demonstrate that WNT974 has the potential to significantly improve the survival of ES patients through the specific inhibition of metastasis.

Visual diagnosis: 4-month-old girl with diffuse, varied dermatitis and bullae.

Pediatric autoimmune blistering disorders are exceedingly rare. Of these, childhood bullous pemphigoid (CBP) is the most common IgG-mediated subepidermal bullous disease in the pediatric population. Tense acral blisters, especially on the soles and palms, are characteristic of the infantile presentation. Patients with CBP present with varied dermatoses, making clinical diagnosis alone difficult. Definitive diagnosis is made with direct immunofluorescence revealing linear deposition of IgG and/or C3 at the basement membrane zone (BMZ) or indirect immunofluorescence revealing IgG antibodies reacting with the BMZ. First-line treatment is oral prednisolone dosed at 1 to 2 mg/kg and then tapered slowly to avoid rebound disease. The length of treatment depends on the rate of remission.

An oncogenic role for ETV1 in melanoma.

Copy gains involving chromosome 7p represent one of the most common genomic alterations found in melanomas, suggesting the presence of "driver" cancer genes. We identified several tumor samples that harbored focal amplifications situated at the peak of common chromosome 7p gains, in which the minimal common overlapping region spanned the ETV1 oncogene. Fluorescence in situ hybridization analysis revealed copy gains spanning the ETV1 locus in >40% of cases, with ETV1 amplification (>6 copies/cell) present in 13% of primary and 18% of metastatic melanomas. Melanoma cell lines, including those with ETV1 amplification, exhibited dependency on ETV1 expression for proliferation and anchorage-independent growth. Moreover, overexpression of ETV1 in combination with oncogenic NRAS(G12D) transformed primary melanocytes and promoted tumor formation in mice. ETV1 overexpression elevated microphthalmia-associated transcription factor expression in immortalized melanocytes, which was necessary for ETV1-dependent oncogenicity. These observations implicate deregulated ETV1 in melanoma genesis and suggest a pivotal lineage dependency mediated by oncogenic ETS transcription factors in this malignancy.

Profiling critical cancer gene mutations in clinical tumor samples.

BACKGROUND: Detection of critical cancer gene mutations in clinical tumor specimens may predict patient outcomes and inform treatment options; however, high-throughput mutation profiling remains underdeveloped as a diagnostic approach. We report the implementation of a genotyping and validation algorithm that enables robust tumor mutation profiling in the clinical setting. METHODOLOGY: We developed and implemented an optimized mutation profiling platform ("OncoMap") to interrogate approximately 400 mutations in 33 known oncogenes and tumor suppressors, many of which are known to predict response or resistance to targeted therapies. The performance of OncoMap was analyzed using DNA derived from both frozen and FFPE clinical material in a diverse set of cancer types. A subsequent in-depth analysis was conducted on histologically and clinically annotated pediatric gliomas. The sensitivity and specificity of OncoMap were 93.8% and 100% in fresh frozen tissue; and 89.3% and 99.4% in FFPE-derived DNA. We detected known mutations at the expected frequencies in common cancers, as well as novel mutations in adult and pediatric cancers that are likely to predict heightened response or resistance to existing or developmental cancer therapies. OncoMap profiles also support a new molecular stratification of pediatric low-grade gliomas based on BRAF mutations that may have immediate clinical impact. CONCLUSIONS: Our results demonstrate the clinical feasibility of high-throughput mutation profiling to query a large panel of "actionable" cancer gene mutations. In the future, this type of approach may be incorporated into both cancer epidemiologic studies and clinical decision making to specify the use of many targeted anticancer agents.

Modeling genomic diversity and tumor dependency in malignant melanoma.

The classification of human tumors based on molecular criteria offers tremendous clinical potential; however, discerning critical and "druggable" effectors on a large scale will also require robust experimental models reflective of tumor genomic diversity. Here, we describe a comprehensive genomic analysis of 101 melanoma short-term cultures and cell lines. Using an analytic approach designed to enrich for putative "driver" events, we show that cultured melanoma cells encompass the spectrum of significant genomic alterations present in primary tumors. When annotated according to these lesions, melanomas cluster into subgroups suggestive of distinct oncogenic mechanisms. Integrating gene expression data suggests novel candidate effector genes linked to recurrent copy gains and losses, including both phosphatase and tensin homologue (PTEN)-dependent and PTEN-independent tumor suppressor mechanisms associated with chromosome 10 deletions. Finally, sample-matched pharmacologic data show that FGFR1 mutations and extracellular signal-regulated kinase (ERK) activation may modulate sensitivity to mitogen-activated protein kinase/ERK kinase inhibitors. Genetically defined cell culture collections therefore offer a rich framework for systematic functional studies in melanoma and other tumors.

High-throughput oncogene mutation profiling in human cancer.

Systematic efforts are underway to decipher the genetic changes associated with tumor initiation and progression. However, widespread clinical application of this information is hampered by an inability to identify critical genetic events across the spectrum of human tumors with adequate sensitivity and scalability. Here, we have adapted high-throughput genotyping to query 238 known oncogene mutations across 1,000 human tumor samples. This approach established robust mutation distributions spanning 17 cancer types. Of 17 oncogenes analyzed, we found 14 to be mutated at least once, and 298 (30%) samples carried at least one mutation. Moreover, we identified previously unrecognized oncogene mutations in several tumor types and observed an unexpectedly high number of co-occurring mutations. These results offer a new dimension in tumor genetics, where mutations involving multiple cancer genes may be interrogated simultaneously and in 'real time' to guide cancer classification and rational therapeutic intervention.

Incomplete penetrance of susceptibility genes for MHC-determined immunoglobulin deficiencies in monozygotic twins discordant for type 1 diabetes.

Incomplete intrinsic penetrance is the failure of some genetically susceptible individuals (e.g., monozygotic twins of those who have a trait) to exhibit that trait. For the first time, we examine penetrance of susceptibility genes for multiple MHC gene-determined traits in the same subjects. Serum levels of IgA, IgD, IgG3, but not IgG4, in 50 pairs of monozygotic twins discordant for type 1 diabetes (T1D) correlated more closely in the twins than in random paired controls. The frequencies of subjects deficient in IgA (6%), IgD (33%) and IgG4 (12%), but not in IgG3, were higher in the twins than in controls. We postulate that this was because the MHC haplotypes (and possible non-MHC genes) that predispose to T1D also carry susceptibility genes for certain immunoglobulin deficiencies. Immunoglobulin deficiencies were not associated with T1D. Pairwise concordance for the deficiencies in the twins was 50% for IgA, 57% for IgD and 50% for IgG4. There were no significant associations among the specific immunoglobulin deficiencies except that all IgA-deficient subjects had IgD deficiency. Thus, intrinsic penetrance is a random process independently affecting different MHC susceptibility genes. Because multiple different external triggers would be required to explain the results, differential environmental determinants appear unlikely.