Retrospective review of safety and efficacy of anlotinib in advanced osteosarcoma with metastases after failure of standard multimodal therapy.

AIM: To study the safety and efficacy of anlotinib, a multitargeted tyrosine kinase inhibitor, in the treatment of advanced osteosarcoma (OSS) with metastases. METHODS: We retrospectively studied patients with advanced OSS and metastases who received anlotinib treatment in our hospital from June 2018 to April 2020. All patients had received standard multimodal therapies, before taking anlotinib. Therapeutic doses of anlotinib were 12 mg for adults and 10 mg for children and adolescents once a day for 2 consecutive weeks, followed by a week of withdrawal. This 3-week cycle of treatment was continued until the tumor progressed rapidly or the patients failed to tolerate the side effects. Adverse drug reactions were recorded, and therapeutic efficacy was evaluated based on progression-free survival (PFS), disease control rate (DCR), overall survival (OS), and objective response rate (ORR). RESULTS: The median PFS was 9.8 ± .9 months, and the 6- and 10-month PFS rates were 73% and 33%, respectively. The median OS was 11.4 ± .6 months. No patients achieved complete response. After 6 months of treatment, the DCR and ORR were 80% and 13%, respectively. No drug-related deaths or Grade 4 adverse events occurred in the patients. Five patients (33%) had Grade 3 adverse events. The most common drug-related adverse events were hand-food syndrome, fatigue, high blood pressure, anorexia, and pneumothorax. CONCLUSIONS: Anlotinib had a modest therapeutic effect in patients with advanced OSS after the failure of standard treatment. The adverse events were mostly tolerable or relieved after treatment.

Endothelial Cells Promote Migration of Mesenchymal Stem Cells via PDGF-BB/PDGFRß-Src-Akt in the Context of Inflammatory Microenvironment upon Bone Defect.

Homing of mesenchymal stem cells (MSCs) to the defect site is indispensable for bone repair. Local endothelial cells (ECs) can recruit MSCs; however, the mechanism remains unclear, especially in the context of the inflammatory microenvironment. This study was aimed to investigate the role of ECs in MSCs migration during the inflammatory phase of bone repair. The inflammatory microenvironment was mimicked in vitro via adding a cytokine set (IL-1ß, IL-6, and TNF-α) to the culture medium of ECs. The production of PDGF-BB from ECs was measured by ELISA. Transwell and wound healing assays were employed to assess MSCs migration toward ECs and evaluate the implication of PDGF-BB/PDGFRß. A series of shRNA and pathway inhibitors were used to screen signal molecules downstream of PDGF-BB/PDGFRß. Then, mouse models of femoral defects were fabricated and DBM scaffolds were implanted. GFP+ MSCs were injected via tail vein, and the relevance of PDGF-BB/PDGFRß, as well as screened signal molecules, in cell homing was further verified during the early phase of bone repair. In the mimicked inflammatory microenvironment, MSCs migration toward ECs was significantly promoted, which could be abrogated by pdgfrb knockout in MSCs. Inhibition of Src or Akt led to negative effects analogous to pdgfrb knockout. Blockade of JNK, MEK, and p38 MAPK had no impact. Meanwhile, the secretion of PDGF-BB from ECs was evidently motivated by the inflammatory microenvironment. Adding recombinant PDGF-BB protein to the culture medium of ECs phenocopied the inflammatory microenvironment with regard to attracting MSCs, which was abolished by pdgfb, src, or akt in MSCs. Moreover, pdgfb knockout suppressed the expression and phosphorylation of Src and Akt in migrating MSCs. Src knockout impaired Akt expression but not vice versa. In vivo, reduced infiltration of CD31+ ECs was correlated with diminished PDGF-BB in local defect sites, and silencing pdgfb, src, or akt in MSCs markedly hampered cell homing. Together, these findings suggest that in the inflammatory microenvironment, MSCs migrate toward ECs via PDGF-BB/PDGFRß and the downstream Src-Akt signal pathway.

Comparison of Individual Tissue-Engineered Bones and Allogeneic Bone in Treating Bone Defects: A Long-Term Follow-Up Study.

The treatment of bone defects has always been a challenge for orthopedic surgeons. The development of tissue engineering technology provides a novel method for repairing bone defects and has been used in animal experiments and clinical trials. However, there are few clinical studies on comparing the long-term outcomes of tissue-engineered bones (TEBs) and other bone grafts in treating bone defects, and the long-term efficiency of TEBs remains controversial. Therefore, a study designed by us was aimed to compare the long-term efficacy and safety of individual tissue-engineered bones (iTEBs) and allogeneic bone granules (ABGs) in treating bone defects caused by curettage of benign bone tumors and tumor-like lesions. From September 2003 to November 2009, 48 patients who received tumor curettage and bone grafting were analyzed with a mean follow-up of 122 mo (range 60 to 173 mo). Based on implant style, patients were divided into groups of iTEBs (n = 23) and ABGs (n = 25). Postoperatively, the healing time, healing quality, incidence of complications, and functional scores were compared between the two groups. The Musculoskeletal Tumor Society functional evaluation system and Activities of Daily Living Scale scores were significantly improved in both groups with no significant difference. The average healing time of ABGs was longer than that of iTEBs (P < 0.05). At the final follow-up, iTEBs had a better performance in the bone healing quality evaluated by modified Neer classification (P < 0.05). In the group of iTEBs, the complication and reoperation rate was lower than that in the group of ABGs, with no tumorigenesis or immune rejection observed. In summary, for treating bone defects caused by tumor curettage, iTEBs were safe, effective, and tagged with more rapid healing speed, better healing outcome, and lower complication and reoperation rate, in comparison with ABGs.