Overall survival rates for patients with advanced osteosarcoma have remained static for over three decades. An in vitro analysis of osteosarcoma cell lines for sensitivity to an array of approved cancer therapies revealed that panobinostat, a broad spectrum histone deacetalyase (HDAC) inhibitor, is highly effective at triggering osteosarcoma cell death. Using in vivo models of orthotopic and metastatic osteosarcoma, here we report that panobinostat impairs the growth of primary osteosarcoma in bone and spontaneous metastasis to the lung, the most common site of metastasis for this disease. Further, pretreatment of mice with panobinostat prior to tail vein inoculation of osteosarcoma prevents the seeding and growth of lung metastases. Additionally, panobinostat impaired the growth of established lung metastases and improved overall survival, and these effects were also manifest in the lung metastatic SAOS2-LM7 model. Mechanistically, the efficacy of panobinostat was linked to high expression of HDAC1 and HDAC2 in osteosarcoma, and silencing of HDAC1 and 2 greatly reduced osteosarcoma growth in vitro. In accordance with these findings, treatment with the HDAC1/2 selective inhibitor romidepsin compromised the growth of osteosarcoma in vitro and in vivo. Analysis of patient-derived xenograft osteosarcoma cell lines further demonstrated the sensitivity of the disease to panobinostat or romidepsin. Collectively, these studies provide rationale for clinical trials in osteosarcoma patients using the approved therapies panobinostat or romidepsin.

Background: The COVID-19 pandemic significantly altered medical practice and public behavior in the USA. In spring of 2020, elective surgery including most joint replacement was suspended and much of the public asked to stay at home. As elective surgery resumes, it is unknown how the public will respond. Questions/Purposes: We sought to describe public interest in knee replacement during the onset of the COVID-19 pandemic. Methods: Google Trends was used to obtain the daily number of searches for "knee replacement," "coronavirus," and "knee pain" from December 19, 2019, to May 14, 2020. The number is on a term-specific scale weighted to the highest number of daily searches for that term. Seven-day weighted averages were used to smooth the data. Results: The number of daily searches for "knee replacement" was stable until around March 8, 2020, after which it decreased through late March, plateauing at less than half the number of searches. At the same time, searches for "coronavirus" spiked. By early May, searches for "knee replacement" had not meaningfully increased, though at the end of the search period the slope turned positive and coronavirus searches decreased. Searches for "knee pain" initially followed a similar pattern to "knee replacement," though the decline was not as steep, and by late April searches for "knee pain" had meaningfully increased. Conclusion: Public interest in knee replacement, assessed through internet search queries, decreased during the onset of the COVID-19 pandemic. While interest in pain has returned, the continued decreased level of interest in surgery may represent a fear of surgery among the general public in the setting of COVID-19. Surgeons may wish to focus outreach and education efforts on the safety and efficacy of knee replacement. Keywords COVID-19. arthroplasty. replacement. knee. public health. health services research HSSJ

Background Clinical research in orthopaedics typically reports the presence of an association after rejecting a null hypothesis of no association using an alpha threshold of 0.05 at which to evaluate a calculated p value. This arbitrary value is a factor that results in the current difficulties reproducing research findings. A proposal is gaining attention to lower the alpha threshold to 0.005. However, it is currently unknown how alpha thresholds are used in orthopaedics and the distribution of p values reported. Questions/purposes We sought to describe the use of alpha thresholds in two orthopaedic journals by asking (1) How frequently are alpha threshold values reported? (2) How frequently are power calculations reported? (3) How frequently are p values between 0.005 and 0.05 reported for the main hypothesis? (4) Are p values less than 0.005 associated with study characteristics such as design and reporting power calculations? Methods The 100 most recent original clinical research articles from two leading orthopaedic journals at the time of this proposal were reviewed. For studies without a specified primary hypothesis, a main hypothesis was selected that was most consistent with the title and abstract. The p value for the main hypothesis and lowest p value for each study were recorded. Study characteristics including details of alpha thresholds, beta, and p values were recorded. Associations between study characteristics and p values were described. Of the 200 articles (100 from each journal), 23 were randomized controlled trials, 141 were cohort studies or case series (defined as a study in which authors had access to original data collected for the study purpose), 31 were database studies, and five were classified as other. Results An alpha threshold was reported in 166 articles (83%) with all but two reporting a value 0.05. Forty-two articles (21%) reported performing a power calculation. The p value for the main hypothesis was less than 0.005 for 88 articles (44%), between 0.05 and 0.005 for 67 (34%), and greater than 0.05 for 29 (15%). The smallest p value was between 0.05 and 0.005 for 39 articles (20%), less than 0.005 for 143 (72%), and either not provided or greater than 0.05 for 18 (9%). Although 50% (65 of 130) cohort and database papers had a main hypothesis p value less than 0.005, only 26% (6 of 23) randomized controlled trials did. Only 36% (15 of 42) articles reporting a power calculation had a p value less than 0.005 compared with 51% (73 of 142) that did not report one. Conclusions Although a lower alpha threshold may theoretically increase the reproducibility of research findings across orthopaedics, this would preferentially select findings from lower-quality studies or increase the burden on higher quality ones. A more-nuanced approach could be to consider alpha thresholds specific to study characteristics. For example, randomized controlled trials with a prespecified primary hypothesis may still be best evaluated at 0.05 while database studies with an abundance of statistical tests may be best evaluated at a threshold even below 0.005. Clinical Relevance Surgeons and scientists in orthopaedics should understand that the default alpha threshold of 0.05 represents an arbitrary value that could be lowered to help reduce type-I errors; however, it must also be appreciated that such a change could increase type-II errors, increase resource utilization, and preferentially select findings from lower-quality studies.