Histone deacetylase inhibition prevents the growth of primary and metastatic osteosarcoma

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.     

Public Interest in Knee Replacement Fell During the Onset of the COVID-19 Pandemic: A Google Trends Analysis

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.