CD103 cDC1 Dendritic Cell Vaccine Therapy for Osteosarcoma Lung Metastases.

Background: We generated a CD103DC vaccine using K7M3 OS cell lysates (cDCV) and investigated its ability to induce regression of primary tumors, established lung metastases, and a systemic immune response.

Methods: A bilateral tumor model was used to assess cDCV therapy efficacy and systemic immunity induction. K7M3 cells were injected into mice bilaterally.

Early skeletal muscle loss in adolescent and young adult cancer patients treated with anthracycline chemotherapy.

Background: Early skeletal muscle loss has been observed in adolescent and young adult (AYA) sarcoma patients undergoing treatment. Identification of individuals within the AYA populace that are at greatest risk of anthracycline-induced skeletal muscle loss is unknown. Moreover, investigations which seek out underlying causes of skeletal muscle degradation during chemotherapy are critical for understanding, preventing, and reducing chronic health conditions associated with poor skeletal muscle status.

Adolescent and young adult Hodgkin lymphoma patients at risk for subcutaneous fat gain during early cancer treatment: a brief report.

Computed tomography scans were assessed for subcutaneous fat area and density at thoracic vertebra 4 in 65 adolescent and young adult (AYA) patients with Hodgkin lymphoma. Subcutaneous fat was quantified over 3 timepoints; (1) baseline, (2) end of initial anthracycline treatment (EOT) and (3) 1 year. Fat area increased at EOT (62.

Poor Sit-to-Stand Performance in Adolescent and Young Adult Patients with Sarcoma.

Adolescents and young adult (AYA) patients with sarcoma are at heightened risk of reduced physical capacity and disease-related weakness. Sit-to-stand (STS) performance correlates with lower extremity functionality and activities of daily living; however, little is known regarding the relationship between muscular status and STS performance in patients with sarcoma. This study assessed STS performance in patients with sarcoma and the association between STS performance and the skeletal muscle index (SMI) and skeletal muscle density (SMD).

The Innate Immune System in Cardiovascular Diseases and Its Role in Doxorubicin-Induced Cardiotoxicity.

Innate immune cells are the early responders to infection and tissue damage. They play a critical role in the initiation and resolution of inflammation in response to insult as well as tissue repair. Following ischemic or non-ischemic cardiac injury, a strong inflammatory response plays a critical role in the removal of cell debris and tissue remodeling.

Pramlintide: A Novel Therapeutic Approach for Osteosarcoma through Metabolic Reprogramming.

Despite aggressive combination chemotherapy and surgery, outcomes for patients with osteosarcoma have remained stagnant for more than 25 years, and numerous clinical trials have identified no new therapies. p53 deletion or mutation is found in more than 80% of osteosarcoma tumors. In p53-deficient cancers with structurally altered p63 and p73, interfering with tumor cell metabolism using Pramlintide (an FDA-approved drug for type 2 diabetes) results in tumor regression.

Retrospective observational studies in ultra-rare sarcomas: A consensus paper from the Connective Tissue Oncology Society (CTOS) community of experts on the minimum requirements for the evaluation of activity of systemic treatments.

Background: In ultra-rare sarcomas (URS) the conduction of prospective, randomized trials is challenging. Data from retrospective observational studies (ROS) may represent the best evidence available. ROS implicit limitations led to poor acceptance by the scientific community and regulatory authorities.

Prognostic Value of Cell-Surface Vimentin-Positive CTCs in Pediatric Sarcomas.

Background: Despite advances in care, the 5 year overall survival for patients with relapsed and or metastatic sarcoma remains as low as < 35%. Currently, there are no biomarkers available to assess disease status in patients with sarcomas and as such, disease surveillance remains reliant on serial imaging which increases the risk of secondary malignancies and heightens patient anxiety.

Methods: Here, for the first time reported in the literature, we have enumerated the cell surface vimentin (CSV+) CTCs in the blood of 92 sarcoma pediatric and adolescent and young adult (AYA) patients as a possible marker of disease.

Nucleus-mitochondria positive feedback loop formed by ERK5 S496 phosphorylation-mediated poly (ADP-ribose) polymerase activation provokes persistent pro-inflammatory senescent phenotype and accelerates coronary atherosclerosis after chemo-radiation.

The incidence of cardiovascular disease (CVD) is higher in cancer survivors than in the general population. Several cancer treatments are recognized as risk factors for CVD, but specific therapies are unavailable. Many cancer treatments activate shared signaling events, which reprogram myeloid cells (MCs) towards persistent senescence-associated secretory phenotype (SASP) and consequently CVD, but the exact mechanisms remain unclear.

Exercise intervention decreases acute and late doxorubicin-induced cardiotoxicity.

Background: Doxorubicin (Dox) is one of the most effective chemotherapy agents used to treat adolescent and young adult sarcoma patients. Unfortunately, Dox causes cardiotoxicities that compromise long-term survival. We investigated whether exercise prevented cardiotoxicity and increased survival following myocardial infarction.

Short-Term Changes in Skeletal Muscle Mass After Anthracycline Administration in Adolescent and Young Adult Sarcoma Patients.

Identification of anthracycline-induced muscle loss is critical for maintaining health in adolescent and young adult (AYA) cancer patients. We used routine chest computed tomography (CT) scans to investigate changes in skeletal muscle of 16 AYA sarcoma patients at thoracic vertebrae 4 (T4) after anthracycline treatment. CT images were examined at three time points (prechemotherapy, postchemotherapy, and 1 year).

Exercise Inhibits Doxorubicin-Induced Damage to Cardiac Vessels and Activation of Hippo/YAP-Mediated Apoptosis.

Dose-related cardiomyopathy is a major side effect following doxorubicin (Dox). To investigate whether exercise (Ex)-induced vasculogenesis plays a role in reducing Dox-induced cardiotoxicity, GFP bone marrow (BM) cells from GFP transgenic mice were transplanted into wild-type mice. Transplanted mice were treated with Dox, Ex, Dox+Ex, or control.

Up-regulation of pro-angiogenic molecules and events does not relate with an angiogenic switch in metastatic osteosarcoma cells but to cell survival features.

Osteosarcoma (OS) is the most frequent malignant bone tumor, affecting predominantly children. Metastases represent a major clinical challenge and an estimated 80% would present undetectable micrometastases at diagnosis. The identification of metastatic traits and molecules would impact in micrometastasis management.

Assessment of drug transporters involved in the urinary secretion of [Tc]dimercaptosuccinic acid.

Introduction: We clarified the renal uptake and urinary secretion mechanism of [Tc]dimercaptosuccinic acid ([Tc]DMSA) via drug transporters in renal proximal tubules.

Methods: [Tc]DMSA was added to human embryonic kidney 293 cells expressing human multidrug and toxin extrusion (MATE)1 and MATE2-K, carnitine/organic cation transporter (OCTN)1 and OCTN2, and organic cation transporter (OCT)2; to Flp293 cells expressing human organic anion transporter (OAT)1 and OAT3; and to vesicles expressing P-glycoprotein (P-gp), multidrug resistance associated protein (MRP)2, MRP4, or breast cancer resistance protein with and without probenecid (OAT inhibitor for both OATs and MRPs). Time activity curves of [Tc]DMSA with and without probenecid were established using LLC-PK cells.

Bempegaldesleukin (BEMPEG; NKTR-214) efficacy as a single agent and in combination with checkpoint-inhibitor therapy in mouse models of osteosarcoma.

Survival of patients with relapsed/refractory osteosarcoma has not improved in the last 30 years. Several immunotherapeutic approaches have shown benefit in murine osteosarcoma models, including the anti-programmed death-1 (anti-PD-1) and anti-cytotoxic T-lymphocyte antigen-4 (anti-CTLA-4) immune checkpoint inhibitors. Treatment with the T-cell growth factor interleukin-2 (IL-2) has shown some clinical benefit but has limitations due to poor tolerability.

[I]MIBG exports via MRP transporters and inhibition of the MRP transporters improves accumulation of [I]MIBG in neuroblastoma.

Introduction: I-labeled m-iodobenzylguanidine ([I]MIBG) has been used to treat neuroblastoma patients, but [I]MIBG may be immediately excreted from the cancer cells by the adenosine triphosphate binding cassette transporters, similar to anticancer drugs. The purpose of this study was to clarify the efflux mechanism of [I]MIBG in neuroblastomas and improve accumulation by inhibition of the transporter in neuroblastomas.

Methods: [I]MIBG was incubated in human embryonic kidney (HEK)293 cells expressing human organic anion transporting polypeptide (OATP)1B1, OATP1B3, OATP2B1, organic anion transporter (OAT)1 and OAT2, organic cation transporter (OCT)1 and OCT2, and sodium taurocholate cotransporting polypeptide, and in vesicles expressing P-glycoprotein (MDR1), multidrug resistance associated protein (MRP)1-4, or breast cancer resistance protein with and without MK-571 and probenecid (MRP inhibitors).

Exosomes: Dynamic Mediators of Extracellular Communication in the Tumor Microenvironment.

It is becoming increasingly recognized that the tumor microenvironment significantly contributes to the development, progression, and metastasis of cancer and also plays a role in response to treatment. The tumor microenvironment is a complex and heterogeneous niche comprised of stromal cells, cancer cells, blood vessels, areas of hypoxia and necrotic tissue, fibrosis, and extracellular matrix. Cellular communication takes place within the tumor microenvironment, both via cell to cell contact, and through extracellular mechanisms such as exosomal signaling.

The Fas/FasL Signaling Pathway: Its Role in the Metastatic Process and as a Target for Treating Osteosarcoma Lung Metastases.

Understanding how the tumor microenvironment participates in inhibiting or supporting tumor growth is critical for the development of novel therapies. Osteosarcoma (OS) metastasizes almost exclusively to the lung, an organ where Fas ligand (FasL) is constitutively expressed. This chapter focuses on our studies dedicated to the interaction of OS cells with the lung microenvironment.

Neuronal Repressor REST Controls Ewing Sarcoma Growth and Metastasis by Affecting Vascular Pericyte Coverage and Vessel Perfusion.

Survival rates for Ewing sarcoma (ES) patients with metastatic disease have not improved in over 20 years. Tumor growth and metastasis are dependent on tumor vasculature expansion; therefore, identifying the regulators that control this process in ES may provide new therapeutic opportunities. ES expresses high levels of repressor element 1 silencing transcription factor (REST), which is regulated by the EWS-FLI-1 fusion gene.

Anthracycline-Induced Cardiotoxicity: Causes, Mechanisms, and Prevention.

Doxorubicin is an anthracycline and one of the more effective chemotherapy agents used in the treatment of children, adolescents, and adults with osteosarcoma. Despite its effectiveness, cardiotoxicity is a major late effect that compromises the survival and quality of life of survivors of this and other cancers. Cardiotoxicity is the inability of the heart to pump blood through the body effectively.

Exosomal communication by metastatic osteosarcoma cells modulates alveolar macrophages to an M2 tumor-promoting phenotype and inhibits tumoricidal functions.

Osteosarcoma metastasizes to the lung, and there is a link between the predominance of tumor-promoting immunosuppressive M2 macrophages in the metastases and poor patient survival. By contrast, M1 macrophage predominance correlates with longer survival. M2 macrophages can be induced by various stimuli in the tumor microenvironment, including exosomes, which are 40- to 150-nm vesicles that are involved in intercellular communication and contribute to tumor progression and immune evasion.