Immunocompetent murine model of Ewing sarcoma reveals role for TGFβ inhibition to enhance immune infiltrates in Ewing tumors during radiation.

Ewing sarcoma (ES) is an aggressive cancer diagnosed in adolescents and young adults. The fusion oncoprotein (EWSR1::FLI1) that drives Ewing sarcoma is known to downregulate expression (part of the TGFβ receptor). Because is downregulated, it was thought that TGFβ likely plays an inconsequential role in Ewing biology.

RNA-sequencing predicts a role of androgen receptor and aldehyde dehydrogenase 1A1 in osteosarcoma lung metastases.

One-third of pediatric patients with osteosarcoma (OS) develop lung metastases (LM), which is the primary predictor of mortality. While current treatments of patients with localized bone disease have been successful in producing 5-year survival rates of 65-70%, patients with LM experience poor survival rates of only 19-30%. Unacceptably, this situation that has remained unchanged for 30 years.

Therapeutic Hope on the Surface of Ewing Sarcoma.

A detailed analysis of the Ewing sarcoma surfacesome has arrived. Robust expression of surface CDH11 and ENPP1 was identified. This "comprehensive catalog" of the Ewing surfacesome serves as a fresh roadmap to development of new therapeutic approaches, including immunotherapies and multi-modality therapeutic combinations, to target aggressive Ewing tumor subpopulations.

Innovations in Cancer Treatment of Children.

Pediatric cancer outcomes have significantly improved, and yet this success is not spread equally across cancer types or patients. Disparities data in pediatric oncology highlight needed improvements in access to care, including clinical trials and advanced testing for all patients. For cancers such as brain tumors and sarcomas, continued advancement in understanding the biology of tumor heterogeneity is an essential step toward finding new therapeutic combinations to improve outcomes.

Successful Treatment of Patient With Ewing Sarcoma in the Setting of Inherited Cholestatic Liver Disease.

Progressive familial intrahepatic cholestasis type 1 (PFIC1) is an inherited, progressive cholestatic liver disease. Here, we present an approach to the treatment of Ewing sarcoma in a patient with PFIC1. The diagnosis of PFIC1 presents a unique challenge in the treatment of Ewing sarcoma, as the standard-of-care vincristine, doxorubicin, cyclophosphamide/ifosfamide and etoposide chemotherapy backbone for Ewing sarcoma therapy treatment relies heavily on intact hepatic metabolism.

ETV6 dependency in Ewing sarcoma by antagonism of EWS-FLI1-mediated enhancer activation.

The EWS-FLI1 fusion oncoprotein deregulates transcription to initiate the paediatric cancer Ewing sarcoma. Here we used a domain-focused CRISPR screen to implicate the transcriptional repressor ETV6 as a unique dependency in this tumour. Using biochemical assays and epigenomics, we show that ETV6 competes with EWS-FLI1 for binding to select DNA elements enriched for short GGAA repeat sequences.

Harnessing immunomodulation during DNA damage in Ewing sarcoma.

Ewing sarcoma is a fusion-oncoprotein-driven primary bone tumor most commonly diagnosed in adolescents. Given the continued poor outcomes for patients with metastatic and relapsed Ewing sarcoma, testing innovative therapeutic approaches is essential. Ewing sarcoma has been categorized as a 'BRCAness' tumor with emerging data characterizing a spectrum of DNA damage repair defects within individual Ewing tumors, including the presence of EWSR1::FLI1 itself, recurrent somatic mutations, and rare germline-based defects.

BRCA1-associated RING domain-1 (BARD1) loss and GBP1 expression enhance sensitivity to DNA damage in Ewing sarcoma.

Ewing sarcoma is a fusion oncoprotein-driven primary bone tumor. A subset of patients (~10%) with Ewing sarcoma are known to harbor germline variants in a growing number of genes involved in DNA damage repair. We recently reported our discovery of a germline mutation in the DNA damage repair protein (BRCA1-associated RING domain-1) in a patient with Ewing sarcoma.

An international working group consensus report for the prioritization of molecular biomarkers for Ewing sarcoma.

The advent of dose intensified interval compressed therapy has improved event-free survival for patients with localized Ewing sarcoma (EwS) to 78% at 5 years. However, nearly a quarter of patients with localized tumors and 60-80% of patients with metastatic tumors suffer relapse and die of disease. In addition, those who survive are often left with debilitating late effects.

Ewing Sarcoma and Osteosarcoma Have Distinct Immune Signatures and Intercellular Communication Networks.

Purpose: Ewing sarcoma and osteosarcoma are primary bone sarcomas occurring most commonly in adolescents. Metastatic and relapsed disease are associated with dismal prognosis. Although effective for some soft tissue sarcomas, current immunotherapeutic approaches for the treatment of bone sarcomas have been largely ineffective, necessitating a deeper understanding of bone sarcoma immunobiology.

A Druggable Rheostat for Ewing Sarcoma?

The posterior HOXD enhancer is an EWSR1::FLI1-dependent regulator of HOXD13 expression in Ewing sarcoma. HOXD13 expression promotes a mesenchymal cell state. Through antagonistic transcriptional programs, EWSR1::FLI1 and HOXD13 serve as master regulators of Ewing cell plasticity.

The effects of subacute exposure to a water-soluble cannabinol compound in male mice.

Background: Cannabinol (CBN) is one of the many cannabinoids present in Cannabis sativa and has been explored as a potential treatment for sleeplessness. The purpose of this study was to determine the physiological and behavioral effects of subacute exposure to therapeutic and low pharmacological levels of a mechanically formed, stabilized water-soluble cannabinol nano-emulsion (CBNight™).

Methods: Sixty-two male mice were randomly assigned to one of six treatment groups given CBNight™ at dosages designed to deliver 0mg (control) to 4 mg/kg of CBN daily via oral gavage for 14 days.

Cutaneous Ewing Sarcoma Presenting as a Second Primary Malignancy in a Child.

Ewing sarcoma is an EWS-ETS family member-driven malignancy that most commonly arises from bone. Cutaneous Ewing sarcoma is a rare variant which harbors an EWS-ETS family fusion but demonstrates an immunohistochemical staining pattern distinct from classic Ewing tumors. EWSR1 fluorescence in situ hybridization testing interpretation can be challenging in the setting of cutaneous Ewing sarcoma, making an integrated histologic and sequencing approach key for an accurate diagnosis.

Influence of female coalitionary aggressive behavior on the success of male introductions to female groups of rhesus macaques ().

Migration patterns of wild rhesus macaque males are often mimicked in captivity by introducing unfamiliar males to female groups every few years. This strategy prevents inbreeding and has been shown to encourage group stability once males are fully integrated. The current study focused on female coalitionary aggressive behavior directed toward males during introductions to describe factors that predict its frequency and any relationship with introduction success.

Evaluation of barriers to referral for cancer predisposition syndromes in pediatric oncology patients in the United States.

Cancer predisposition syndromes (CPS) are underdiagnosed in the pediatric population, though the diagnosis of a CPS has important implications for the child and their family. CPS are often diagnosed by geneticists or oncologists with expertise in CPS following a malignancy. This requires a member of the care team, most commonly, the treating oncologist to suspect a CPS and refer the patient for CPS assessment.

Factors influencing the success of male introductions into groups of female rhesus macaques: Introduction technique, male characteristics and female behavior.

In captive populations of rhesus macaques, novel adult males are commonly introduced to female groups every few years to prevent inbreeding, which mimics male dispersal in wild macaque populations. However, introducing adult males is challenging because macaques are aggressive to newcomers, which can result in serious injuries. Efforts to reduce trauma risk during the introduction process and increase the probability of success are needed.

Effects of medroxyprogesterone acetate on social behavior in female rhesus macaques (Macaca mulatta) depend on male breeding season introductions.

Background: Although medroxyprogesterone acetate (MPA) is used commonly as a contraceptive in women and female non-human primates, its effects on social behavior remain unclear. This study examined whether MPA treatment and introduction of new adult males during the breeding season influence the social behaviors of group-housed adult female rhesus macaques.

Methods: Subjects were 12 MPA-treated and 12 matched case-control females.

Primary small cell carcinoma of the adrenal gland: Case presentation of a rare extrapulmonary small cell carcinoma.

Small cell carcinoma (SCC) is an aggressive histologic subtype of neuroendocrine tumor and is most commonly of bronchogenic origin. However, it can present in an extrapulmonary fashion. Primary extrapulmonary small cell carcinoma (EPSCC) is a rare disease entity, especially within the genitourinary system and furthermore of the adrenal gland.

Use of Introduction Enclosures to Integrate Multimale Cohorts into Groups of Female Rhesus Macaques ().

Integrating animals into a new group is a challenge for both free-ranging and captive adult male rhesus monkeys (), and for females in groups receiving new males. To ensure the genetic viability of the population, however, male transfers must occur in both natural and captive settings. To facilitate the introduction of groups of adult males to adult females, we designed a new enclosure that is attached to the outdoor compound where females are housed.

The spectrum of rare central nervous system (CNS) tumors with EWSR1-non-ETS fusions: experience from three pediatric institutions with review of the literature.

The group of CNS mesenchymal (non-meningothelial) and primary glial/neuronal tumors in association with EWSR1-non-ETS rearrangements comprises a growing spectrum of entities, mostly reported in isolation with incomplete molecular profiling. Archival files from three pediatric institutions were queried for unusual cases of pediatric (≤21 years) CNS EWSR1-rearranged tumors confirmed by at least one molecular technique. Extra-axial tumors and cases with a diagnosis of Ewing sarcoma (EWSR1-ETS family fusions) were excluded.

Efficacy of FGFR Inhibitors and Combination Therapies for Acquired Resistance in FGFR2-Fusion Cholangiocarcinoma.

The fibroblast growth factor receptor (FGFR) signaling pathway is aberrantly activated in approximately 15% to 20% of patients with intrahepatic cholangiocarcinoma. Currently, several FGFR kinase inhibitors are being assessed in clinical trials for patients with FGFR-altered cholangiocarcinoma. Despite evidence of initial responses and disease control, virtually all patients eventually develop acquired resistance.

Microenvironmental Factors Drive Tenascin C and Src Cooperation to Promote Invadopodia Formation in Ewing Sarcoma.

Ewing sarcoma is a bone tumor most commonly diagnosed in adolescents and young adults. Survival for patients with recurrent or metastatic Ewing sarcoma is dismal and there is a dire need to better understand the mechanisms of cell metastasis specific to this disease. Our recent work demonstrated that microenvironmental stress leads to increased Ewing sarcoma cell invasion through Src activation.

MALT1 is a critical mediator of PAR1-driven NF-κB activation and metastasis in multiple tumor types.

Protease-activated receptor 1 (PAR1), a thrombin-responsive G protein-coupled receptor (GPCR), is implicated in promoting metastasis in multiple tumor types, including both sarcomas and carcinomas, but the molecular mechanisms responsible remain largely unknown. We previously discovered that PAR1 stimulation in endothelial cells leads to activation of NF-κB, mediated by a protein complex comprised of CARMA3, Bcl10, and the MALT1 effector protein (CBM complex). Given the strong association between NF-κB and metastasis, we hypothesized that this CBM complex could play a critical role in the PAR1-driven metastatic progression of specific solid tumors.

EWS-FLI1 low Ewing sarcoma cells demonstrate decreased susceptibility to T-cell-mediated tumor cell apoptosis.

Metastatic and relapsed Ewing sarcoma typically afflicts the adolescent population and is largely fatal. These bone tumors are most commonly driven by the fusion oncoprotein EWS-FLI1. Ewing tumors demonstrate significant intra-tumoral heterogeneity, and individual tumor cells can express highly variable and dynamic levels of EWS-FLI1.