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Background: Despite the encouraging results of the SCORAD trial, single fraction radiotherapy (SFRT) remains underused for patients with complicated bone metastases with rates as low as 18-39%. We aimed to evaluate the incidence and treatment patterns of these metastases in patients being referred to a tertiary centre for palliative radiotherapy., Materials and Methods: We performed a retrospective review of all bone metastases treated at our centre from January 2013 until December 2017. Lesions were classified as uncomplicated or complicated. Complicated was defined as associated with (impending) fracture, existing spinal cord or cauda equina compression. Our protocol suggests using SFRT for all patients with complicated bone metastases, except for those with symptomatic neuraxial compression and a life expectancy of ≥28 weeks., Results: Overall, 37 % of all bone metastases were classified as complicated. Most often as a result of an (impending) fracture (56 %) or spinal cord compression (44 %). In 93 % of cases, complicated lesions were located in the spine, most commonly originating from prostate, breast and lung cancer (60 %). Median survival of patients with complicated bone metastases was 4 months. The use of SFRT for complicated bone metastases increased from 51 % to 85 % over the study period, reaching 100 % for patients with the poorest prognosis., Conclusions: Approximately 37 % of bone metastases are classified as complicated with the majority related to (impending) fracture. Patients with complicated bone metastases have a median survival of 4 months and were mostly treated with SFRT., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Authors.)

Background: Single-fraction radiotherapy (SFRT) offers equal pain relief for uncomplicated painful bone metastases as compared to multiple-fraction radiotherapy (MFRT). Despite this evidence, the adoption of SFRT has been poor with published rates of SFRT for uncomplicated bone metastases ranging from <10% to 70%. We aimed to evaluate the adoption of SFRT and its evolution over time following the more formal endorsement of the international guidelines in our centre starting from 2013., Materials and Methods: We performed a retrospective review of fractionation schedules at our centre for painful uncomplicated bone metastases from January 2013 until December 2017. Only patients treated with 1 × 8 Gy (SFRT-group) or 10 × 3 Gy (MFRT-group) were included. We excluded other fractionation schedules, primary cancer of the bone and post-operative radiotherapy. Uncomplicated was defined as painful but not associated with impending fracture, existing fracture or existing neurological compression. Temporal trends in SFRT/MFRT usage and overall survival were investigated. We performed a lesion-based patterns of care analysis and a patient-based survival analysis. Mann-Whitney U and Chi-square test were used to assess differences between fractionation schedules and temporal trends in prescription, with Kaplan-Meier estimates used for survival analysis (p-value <0.05 considered significant)., Results: Overall, 352 patients and 594 uncomplicated bone metastases met inclusion criteria. Patient characteristics were comparable between SFRT and MFRT, except for age. Overall, SFRT was used in 92% of all metastases compared to 8% for MFRT. SFRT rates increased throughout the study period from 85% in 2013 to 95% in 2017 (p = 0.06). Re-irradiation rates were higher in patients treated with SFRT (14%) as compared to MFRT (4%) (p = 0.046). Four-week mortality and median overall survival did not differ significantly between SFRT and MFRT (17% vs 18%, p = 0.8 and 25 weeks vs 38 weeks, p = 0.97, respectively)., Conclusions: Adherence to the international guidelines for SFRT for uncomplicated bone metastasis was high and increased over time to 95%, which is the highest reported rate in literature., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2021 The Authors.)

Resistance to all-trans retinoic acid (ATRA) remains a clinical problem in the treatment of acute promyelocytic leukemia (APL) and provides a model for the development of novel therapies. Molecular alterations in the ligand-binding domain (LBD) of the PML/RARalpha fusion gene that characterizes APL constitute one mechanism of acquired resistance to ATRA. We identified missense mutations in PML/RARalpha from an additional ATRA-resistant patient at relapse and in a novel ATRA-resistant cell line, NB4-MRA1. These cause altered binding to ligand and transcriptional coregulators, leading to a dominant-negative block of transcription. These mutations are in regions of the LBD that appear to be mutational hot spots occurring repeatedly in ATRA-resistant APL patient cells. We evaluated whether histone deacetylase (HDAC) inhibition could overcome the effects of these mutations on ATRA-induced gene expression. Cotreatment with ATRA and TSA restored RARbeta gene expression in NB4-MRA1 cells, whose PML/RARalpha mutation is in helix 12 of the LBD, but not in an APL cell line harboring the patient-derived PML/RARalpha mutation, which was between helix 5 and 6. Furthermore, ATRA combined with TSA increases histone 4 acetylation on the RARbeta promoter only in NB4-MRA1 cells. Consistent with these results, the combined treatment induces differentiation of NB4-MRA1 only. Thus, the ability of an HDAC inhibitor to restore ATRA sensitivity in resistant cells may depend on their specific molecular defects. The variety of PML/RARalpha mutations arising in ATRA-resistant patients begins to explain how APL patients in relapse may differ in response to transcription therapy with HDAC inhibitors.