Bioinformatic Analysis of Recurrent Genomic Alterations and Corresponding Pathway Alterations in Ewing Sarcoma.

Ewing Sarcoma (ES) is an aggressive, mesenchymal malignancy associated with a poor prognosis in the recurrent or metastatic setting with an estimated overall survival (OS) of <30% at 5 years. ES is characterized by a balanced, reciprocal chromosomal translocation involving the EWSR1 RNA-binding protein and ETS transcription factor gene (EWS-FLI being the most common). Interestingly, murine ES models have failed to produce tumors phenotypically representative of ES. Genomic alterations (GA) in ES are infrequent and may work synergistically with EWS-ETS translocations to promote oncogenesis. Aberrations in fibroblast growth factor receptor (FGFR4), a receptor tyrosine kinase (RTK) have been shown to contribute to carcinogenesis. Mouse embryonic fibroblasts (MEFs) derived from knock-in strain of homologous Fgfr4G385R mice display a transformed phenotype with enhanced TGF-induced mammary carcinogenesis. The association between the FGFRG388R SNV in high-grade soft tissue sarcomas has previously been demonstrated conferring a statistically significant association with poorer OS. How the FGFR4G388R SNV specifically relates to ES has not previously been delineated. To further define the genomic landscape and corresponding pathway alterations in ES, comprehensive genomic profiling (CGP) was performed on the tumors of 189 ES patients. The FGFR4G388R SNV was identified in a significant proportion of the evaluable cases (n = 97, 51%). In line with previous analyses, TP53 (n = 36, 19%), CDK2NA/B (n = 33, 17%), and STAG2 (n = 22, 11.6%) represented the most frequent alterations in our cohort. Co-occurrence of CDK2NA and STAG2 alterations was observed (n = 5, 3%). Notably, we identified a higher proportion of TP53 mutations than previously observed. The most frequent pathway alterations affected MAPK (n = 89, 24% of pathological samples), HRR (n = 75, 25%), Notch1 (n = 69, 23%), Histone/Chromatin remodeling (n = 57, 24%), and PI3K (n = 64, 20%). These findings help to further elucidate the genomic landscape of ES with a novel investigation of the FGFR4G388R SNV revealing frequent aberration.

Underreporting of SMARCB1 alteration by clinical sequencing: Integrative patho-genomic analysis captured SMARCB1/INI-1 deficiency in a vulvar yolk sac tumor.

•SMARCB1/INI1-deficient gynecologic tumors are rare and clinically aggressive. A subset shows primitive yolk sac tumor features.•Due to technical limitation of next generation sequencing (NGS) and interlaboratory variability in sequencing methodologies and analytical pipelines, SMARCB1 deficiency caused by somatic copy number variations (SCNV) may be underreported by NGS.•To improve identification of SMARCB1/INI1-deficient neoplasm, we propose the following strategy: First, careful pathology slide review and detection of rhabdoid cells should raise the possibility of SMARCB1/INI1 deficiency. Second, INI1 IHC is a useful complementary test to exclude clinical suspicion of SMARCB1 deficiency in the context of negative molecular reporting. Third, knowledge of potential underreporting of SMARCB1 mutation would avoid underdiagnosis.

The Midwest Sarcoma Trials Partnership: Bridging Academic and Community Networks in a Collaborative Approach to Sarcoma.

The treatment of sarcoma necessitates a collaborative approach, given its rarity and complex management. At a single institution, multidisciplinary teams of specialists determine and execute treatment plans involving surgical, radiation, and medical management. Treatment guidelines for systemic therapies in advanced or nonresectable soft tissue sarcoma have advanced in recent years as new immunotherapies and targeted therapies become available. Collaboration between institutions is necessary to facilitate accrual to clinical trials. Here, we describe the success of the Midwest Sarcoma Trials Partnership (MWSTP) in creating a network encompassing large academic centers and local community sites. We propose a new model utilizing online platforms to expand the reach of clinical expertise for the treatment of advanced soft tissue sarcoma.

Cardiovascular toxicities with pediatric tyrosine kinase inhibitor therapy: An analysis of adverse events reported to the Food and Drug Administration.

We sought to examine cardiovascular toxicities associated with tyrosine kinase inhibitors in pediatrics. We examined 1624 pediatric adverse events with imatinib, dasatinib, sorafenib, pazopanib, crizotinib, and ruxolitinib reported to the Food and Drug Administration between January 1, 2015, and August 14, 2020. There were 102 cardiovascular event reports. Hypertension was the most commonly reported cardiovascular event and was most frequently associated with sorafenib and pazopanib. The presence of infection increased the reporting odds of cardiovascular events overall and specifically cardiac arrest, heart failure, and hypertension. These data provide early insight into cardiovascular toxicities with tyrosine kinase inhibitor use in pediatrics.

Entrectinib in children and young adults with solid or primary CNS tumors harboring NTRK, ROS1, or ALK aberrations (STARTRK-NG).

BACKGROUND: Entrectinib is a TRKA/B/C, ROS1, ALK tyrosine kinase inhibitor approved for the treatment of adults and children aged ≥12 years with NTRK fusion-positive solid tumors and adults with ROS1 fusion-positive non-small-cell lung cancer. We report an analysis of the STARTRK-NG trial, investigating the recommended phase 2 dose (RP2D) and activity of entrectinib in pediatric patients with solid tumors including primary central nervous system tumors. METHODS: STARTRK-NG (NCT02650401) is a phase 1/2 trial. Phase 1, dose-escalation of oral, once-daily entrectinib, enrolled patients aged <22 years with solid tumors with/without target NTRK1/2/3, ROS1, or ALK fusions. Phase 2, basket trial at the RP2D, enrolled patients with intracranial or extracranial solid tumors harboring target fusions or neuroblastoma. Primary endpoints: phase 1, RP2D based on toxicity; phase 2, objective response rate (ORR) in patients harboring target fusions. Safety-evaluable patients: ≥1 dose of entrectinib; response-evaluable patients: measurable/evaluable baseline disease and ≥1 dose at RP2D. RESULTS: At data cutoff, 43 patients, median age of 7 years, were response-evaluable. In phase 1, 4 patients experienced dose-limiting toxicities. The most common treatment-related adverse event was weight gain (48.8%). Nine patients experienced bone fractures (20.9%). In patients with fusion-positive tumors, ORR was 57.7% (95% CI 36.9-76.7), median duration of response was not reached, and median (interquartile range) duration of treatment was 10.6 months (4.2-18.4). CONCLUSIONS: Entrectinib resulted in rapid and durable responses in pediatric patients with solid tumors harboring NTRK1/2/3 or ROS1 fusions.

Severe vincristine-induced polyneuropathy in a teenager with anaplastic medulloblastoma and undiagnosed Charcot-Marie-Tooth disease.

Severe neuropathy is a known adverse effect of vincristine in patients with Charcot-Marie-Tooth disease (CMT). We present the case of a 16-year-old girl with anaplastic medulloblastoma treated with gross total resection and high-dose craniospinal radiation with adjuvant vincristine chemotherapy who developed acute-onset severe quadriplegia and vocal cord paralysis. Vincristine and radiation therapy were discontinued. Although her neuropathy slowly improved over several weeks, she developed metastatic extraneural medulloblastoma and died 5 months after diagnosis. Subsequent genetic testing revealed previously asymptomatic and undiagnosed CMT1A. Our case highlights the importance of early recognition of acute vincristine neurotoxicity that should raise suspicion of an underlying hereditary neuropathy.

Secondary Hemophagocytic Lymphohistiocytosis in a Patient With Favorable Histology Wilms Tumor.

Secondary hemophagocytic lymphohistiocytosis (HLH) is most commonly associated with malignancy, infection, or an underlying autoimmune disorder. Malignancy-associated hemophagocytic syndrome is responsible for most secondary HLH cases, but it has not been well described in children. We present a case of a 4-year-old female with favorable histology of Wilms tumor who developed secondary HLH after unsuccessful resection of the tumor and initiation of chemotherapy.

Atypical Teratoid Rhabdoid Tumor in a Teenager with Unusual Infiltration Into the Jugular Foramen.

BACKGROUND: Atypical teratoid rhabdoid tumor is a rare malignant neoplasm that represents 1%-2% of all pediatric central nervous system tumors. Immunohistochemistry plays an important role in establishing the diagnosis with a loss of INI-1 staining in tumor cells. In this case report, we describe a teenager with an unusual presentation and pattern of infiltration of the tumor. CASE DESCRIPTION: A 13-year-old boy presented with a history over several months of progressive nausea, weight loss, and hoarseness of voice associated with multiple lower cranial nerve palsies on neurologic examination. Magnetic resonance imaging revealed a large heterogeneously enhancing extra-axial neoplasm with extension and bony expansion of the jugular foramen. After near total resection, neuropathology demonstrated the absence of INI-1 expression consistent with a diagnosis of atypical teratoid rhabdoid tumor. CONCLUSIONS: This case highlights the diverse clinical presentation and infiltrative potential of atypical teratoid rhabdoid tumors, thus expanding the differential diagnosis of extra-axial tumors invading the jugular foramen.

Glioblastoma multiforme arising from dysembryoplastic neuroepithelial tumor in a child in the absence of therapy.

Dysembryoplastic neuroepithelial tumors (DNETs) are considered as low-grade tumors commonly associated with intractable seizures. We report a case of an unusual hemispheric DNET in a young child presenting with new-onset focal seizures. The tumor was notable for its atypical neuroimaging features and very rapid malignant transformation into a glioblastoma multiforme in the absence of radiation or chemotherapy, 1-year postdiagnosis. Our case highlights the malignant potential of atypical DNETs in the absence of therapy.

Anti-tumor activity of the HSP90 inhibitor SNX-2112 in pediatric cancer cell lines.

BACKGROUND: HSP90 plays a central role in stabilizing client proteins involved in malignant processes. SNX-2112 is an orally administered potent HSP90 inhibitor that has demonstrated pre-clinical anti-tumor activity in adult malignancies. As many childhood tumors depend upon HSP90 client proteins, we sought to test the pre-clinical efficacy of SNX-2112 in a panel of pediatric cancer cell lines both as a single-agent and in combination with cisplatin (CP). PROCEDURE: Eight cell lines (from osteosarcoma, neuroblastoma, hepatoblastoma, and lymphoma) were studied. Short- and long-term effects of SNX-2112 were assessed by MTT and clonogenic assays. Cell cycling was measured using flow cytometry. Status of HSC70, HSP72, AKT1, C-Raf, and PARP was assessed by immunoblotting. Efficacy of SNX-2112 in combination with CP was assessed using median-effect analysis. RESULTS: Cell lines studied demonstrated sensitivity to SNX-2112 with IC(50) values ranging from 10-100 nM. Low dose treatments (12 nM) resulted in a cytostatic response with a minimal increase in sub-G1 content. A higher dose (70 nM) exhibited a more prolonged inhibition and larger sub-G1 accumulation. Observed levels of AKT1 and C-Raf were markedly reduced over time along with an increase in PARP cleavage. In concurrently administered combination treatments, SNX-2112 and CP synergistically inhibited cell growth. CONCLUSIONS: SNX-2112 showed marked single-agent activity in pediatric cancer cell lines with downstream effects on HSP90 client proteins. The combination of SNX-2112 and CP showed synergistic activity in two cell lines tested. Further studies of HSP90 inhibitors such as SNX-2112 as a single agent or in combination with chemotherapy are warranted in pediatric cancer.

A novel mutation in a Fijian boy with Shwachman-Diamond syndrome.

Shwachman-Diamond syndrome (SDS) is an autosomal recessive disorder characterized by pancreatic insufficiency, bone marrow dysfunction, and metaphyseal chondrodysplasia. SDS is associated with mutations in the Shwachman-Bodian-Diamond Syndrome gene, with 90% of reported mutations in exon 2. We present a Fijian boy with SDS who has a novel A>G substitution in exon 1 of the Shwachman-Bodian-Diamond Syndrome gene that has not been reported in the literature. This patient's unique clinical course includes the presence of a cleft lip and episodic hypoglycemia. SDS lacks a clear genotype-phenotype correlation, as is showed by the heterogeneity in its clinical presentation.

Treatment of infantile choriocarcinoma of the liver.

Primary choriocarcinoma of the liver is an extremely rare childhood malignancy frequently associated with clinical instability at initial presentation. It often mimics other benign and malignant childhood liver tumors. Prompt diagnosis and initiation of treatment are necessary to attain a successful outcome. We describe a critically ill infant with metastatic choriocarcinoma whose diagnosis was based on radiographic and tumor marker findings, without an initial biopsy, and her successful management with neo-adjuvant chemotherapy and delayed surgery. She is currently in continuous remission 24 months from diagnosis.

Modifying the soil to affect the seed: role of stromal-derived matrix metalloproteinases in cancer progression.

In the 1980's, as the importance of matrix metalloproteinases (MMPs) in cancer progression was discovered, it was recognized that in most tumors these proteases were abundantly and sometimes exclusively expressed not by tumor cells, but by normal host-derived cells like fibroblasts, vascular endothelial cells, myofibroblasts, pericytes or inflammatory cells that contribute to the tumor microenvironment. Later experiments in mice deficient in specific MMPs revealed that host-derived MMPs play a critical role not only in tumor cell invasion, but also in carcinogenesis, angiogenesis, vasculogenesis and metastasis. Tumor cells secrete many factors, cytokines and chemokines that directly or indirectly increase the expression of these MMPs in the tumor microenvironment where they exert extracellular matrix (ECM) degrading and sheddase activities. The knowledge of the complex role that stromal-derived MMPs play in the interaction between tumor cells and stromal cells should allow us to consider specific windows in cancer treatment when MMP inhibition could have a valuable therapeutic effect.