Colony-stimulating factor 1 (CSF1) is a primary regulator of the survival, proliferation, and differentiation of monocyte/macrophage that sustains the protumorigenic functions of tumor-associated macrophages (TAMs). Considering current advances in understanding the role of the inflammatory tumor microenvironment, targeting the components of the sarcoma microenvironment, such as TAMs, is a viable strategy. Here, we investigated the effect of PLX3397 (pexidartinib) as a potent inhibitor of the CSF1 receptor (CSF1R). PLX3397 was recently approved by the Food and Drug Administration (FDA) to treat tenosynovial giant cell tumor and reprogram TAMs whose infiltration correlates with unfavorable prognosis of sarcomas. First, we confirmed by cytokine arrays of tumor-conditioned media (TCM) that cytokines including CSF1 are secreted from LM8 osteosarcoma cells and NFSa fibrosarcoma cells. The TCM, like CSF1, stimulated ERK1/2 phosphorylation in bone marrow–derived macrophages (BMDMs), polarized BMDMs toward an M2 (TAM-like) phenotype, and strikingly promoted BMDM chemotaxis. In vitro administration of PLX3397 suppressed pERK1/2 stimulation by CSF1 or TCM, and reduced M2 polarization, survival, and chemotaxis in BMDMs. Systemic administration of PLX3397 to the osteosarcoma orthotopic xenograft model significantly suppressed the primary tumor growth and lung metastasis, and thus improved metastasis-free survival. PLX3397 treatment concurrently depleted TAMs and FOXP3+ regulatory T cells and, surprisingly, enhanced infiltration of CD8+ T cells into the microenvironments of both primary and metastatic osteosarcoma sites. Our preclinical results show that PLX3397 has strong macrophage- and T-cell–modulating effects that may translate into cancer immunotherapy for bone and soft-tissue sarcomas.

Background Giant cell tumor of bone is a benign, locally aggressive neoplasm. Surgical resection is the preferred treatment method. However, for cases in which resection poses an increased risk to the patient, denosumab (anti-RANKL monoclonal antibody) is considered. Secukinumab is an anti-IL-17 antibody that is used in psoriatic arthritis to reduce bone resorption and articular damage. Case presentation One case of giant cell tumor of bone (GCTB) in a patient treated with secukinumab for psoriatic arthritis demonstrated findings significant for intra-lesional calcifications. Histologic examination showed ossification, new bone formation, and remodeling. A paucity of osteoclast type giant cells was noted. Real-time quantitative polymerase-chain-reaction (qRT-PCR) analysis revealed decreased osteoclast function compared to treatment-naive GCTB. Conclusions Secukinumab may play a role in bone remodeling for GCTB. Radiologists, surgeons, and pathologists should be aware of this interaction, which can cause lesional ossification. Further research is required to define the therapeutic potential of this drug for GCTB and osteolytic disease.

Context The percent of underrepresented minority (URM) students who apply to medical school has changed minimally in the past 40 years. Due to the lack of URM applicants, the consequent matriculation of URMs is grossly disproportionate from their percent representation of the US population. Increasing diversity among medical students and physicians has previously been identified as essential to decreasing healthcare disparities among US minorities. Objectives The objective of our study was to recognize the barriers of applying to medical school among URMs in high school. Methods To identify and assess the prevalence of barriers, surveys were distributed to participants of Med-Achieve, a mini-medical school program of diverse high school students in New York City during the 2019–2020 academic year. Results Among students who will be first in their immediate family to attend college, 80.0% perceived a barrier to pursuing medical school. Specified barriers indicated include the cost of medical school (77%), a lack of guidance/role models (53.9%), and the predicted inability to do well in medical school classes (53.9%). At the end of the program, a statistically significant reduction in the barrier of lack of guidance/role models was seen. Conclusions This study highlights the benefit of mini-medical school programs, especially programs with a mentoring component, to decrease the perceived barriers of applying to medical school among URMs. It also suggests the potential role of similar programs to increase diversity in medicine and to decrease healthcare disparities among minorities in the United States.