Background: Osteosarcoma (OS) is the most frequent primary malignant tumor of bone in children and adolescents. Although immune checkpoint inhibitor, anti-programmed death protein 1 (PD-1) antibody, has dramatically improved the clinical outcome in some cancer patients, OS patients are less sensitive to PD-1 blockade due to poor immune responses. Recently, oncolytic virotherapy has been shown to stimulate the immune system through induction of immunogenic cell death (ICD). We recently developed a RGD fiber-modified telomerase-specific oncolytic adenovirus OBP-502, which can enter into tumor cells by binding to cell surface integrin and induce oncolytic cell death in a telomerase-dependent manner. In this study, we assessed the in vitro and in vivo antitumor efficacy of combination therapy with PD-1 blockade and OBP-502 in OS cells.Methods: We used 2 murine OS cell lines, K7M2 and NHOS. The expression of PD-L1, coxsackie and adenovirus receptor (CAR), and integrin on the cell surface was analyzed by flow cytometric analysis. We analyzed the in vitro antitumor effect of OBP-502 using XTT assay and western blot analysis. Virus-induced ICD was assessed by analyzing the level of extracellular ATP and high-mobility group box protein B1 (HMGB1). To evaluate the therapeutic potential of oncolytic immunotherapy, we investigated the in vivo antitumor effect of combination therapy with anti-PD-1 antibody and OBP-502 using a subcutaneous K7M2 xenograft tumor model. Moreover, the number of tumor-infiltrating CD8+, CD4+ and Foxp3+ T cells was analyzed by immunohistochemistry.Results: Flow cytometric analysis demonstrated that K7M2 and NHOS cells had the expression of PD-L1 and integrin, but not CAR. XTT assay showed that OBP-502 efficiently suppressed the viability of K7M2 and NHOS cells in a dose-dependent manner. Western blot analysis revealed that OBP-502 induced the apoptosis-related cell death in K7M2 and NHOS cells. ELISA assay demonstrated that OBP-502 significantly increased the level of extracellular ATP and HMGB1 in K7M2 and NHOS cells. In vivo experiment using a subcutaneous K7M2 xenograft tumor model showed that combination of anti-PD-1 antibody and OBP-502 significantly reduced tumor growth compared to mock treatment or monotherapy. Immunohistochemical analysis revealed that OBP-502 significantly increased the number of tumor-infiltrating CD8+ T cells compared to mock treatment or monotherapy. By contrast, OBP-502 did not affect the number of CD4+ and Foxp3+ T cells in tumor tissues.Conclusion: These results suggest that oncolytic immunotherapy with PD-1 blockade and telomerase-specific oncolytic adenovirus is a promising antitumor strategy to promote the therapeutic potential of PD-1 blockade in OS through stimulation of antitumor immune response.Citation Format: Koji Demiya, Hiroshi Tazawa, Yusuke Mochizuki, Miho Kure, Joe Hasei, Toshiyuki Kunisada, Yasuo Urata, Toshifumi Ozaki, Toshiyoshi Fujiwara. Oncolytic immunotherapy with PD-1 blockade and telomerase-specific oncolytic adenovirus in osteosarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3231.
Minimally invasive orthopedic surgery using a milling machine presents challenges. The milling machine we developed has a redundant axis to minimize cutting-tool contact with surrounding soft tissue. Important components are modeled based on physical requirements, and model-based geometric optimization improves performance. Here we discuss the protective mechanism, hardware, and software we developed to cover the nonworking cutting-edge portion and to protect against soft-tissue damage. We evaluated the effectiveness of this approach using cadaveric bone.
The aim of this study is to evaluate whether thallium-201 (201-Tl) scintigraphy can differentiate malignant from benign soft-tissue tumors.Between April 1995 and December 2005, 192 patients with soft-tissue tumors (85 malignant and 107 benign) underwent 201-Tl scintigraphy before treatment. Isotope uptake was used as a proxy for tumor-to-background ratio (TBR). The accuracy of TBR on early and delayed imaging was evaluated using the Mann-Whitney U and χ(2) tests.There was a statistically significant difference in mean TBR on early and delayed imaging of malignant and benign soft-tissue tumors (124% ± 109% vs. 22% ± 42%, and 82% ± 83% vs. 12% ± 25%, P < 0.0001). A TBR cutoff of 20% indicated the probability of malignancy on early and delayed imaging (82% sensitivity and 77% specificity; 82% sensitivity and 84% specificity, P < 0.0001). Well-differentiated liposarcomas showed low isotope accumulation, while pigmented villonodular synovitis and giant cell tumors of the tendon sheath showed high isotope accumulation.Thallium-201 scintigraphy can distinguish malignant from benign tumors with relatively high accuracy. With the exception of low grade liposarcomas and locally aggressive benign tumors, 201-Tl scintigraphy may be an effective diagnostic modality to differentiate malignant from benign soft-tissue tumors.
Early sarcopenia detection using screening tools, such as SARC-F and SARC-CalF, has been proven reliable. However, the relationship between chronic musculoskeletal pain with sarcopenia is unknown. This study assessed sarcopenia morbidity as well as the reliability of sarcopenia screening with SARC-F and SARC-CalF in patients with chronic musculoskeletal pain.Overall, 172 patients with chronic musculoskeletal pain were included in this cross-sectional study. All participants completed the SARC-F, SARC-CalF, numeric rating scale (NRS), and pain disability assessment scale (PDAS) assessments. Sarcopenia was diagnosed using the Asian Working Group for Sarcopenia criteria 2019. Correlations between SARC-F and SARC-CalF scores and each measured variable were evaluated using univariate and multiple linear regression analyses. A receiver operating characteristic curve analysis was conducted, and reliabilities of SARC-F and SARC-CalF scores for diagnosing sarcopenia were compared.Thirty-nine patients were diagnosed with sarcopenia. Among these, 10 patients were <65 years old, and 29 were >65 years old. Both SARC-F and SARC-CalF scores significantly correlated with grip power, gait speed, skeletal mass index, numeric rating scale score, and PDAS score. In multiple linear regression analysis, SALC-F and SALC-CalF scores significantly correlated with PDAS score, skeletal mass index, and gait speed. The area under the curve were 0.70 for SARC-F and 0.88 for SARC-CalF; SARC-CalF had a significantly higher area under the curve than SARC-F.Sarcopenia was diagnosed in patients aged <65 years with chronic musculoskeletal pain. SALC-F and SARC-CalF scores showed a significant correlation with disability due to pain and were reliable sarcopenia screening tools for chronic musculoskeletal pain. SARC-CalF was more reliable than SARC-F.
