Fracture rate after conventional external beam radiation therapy to the spine in multiple myeloma patients

Background Context: Conventional external beam radiation therapy (cEBRT) is used in multiple myeloma (MM) to treat severe pain, spinal cord compression, and disease-related bone disease. However, radiation may be associated with an increased risk of vertebral compression fractures (VCFs), which could substantially impair survival and quality of life. Additionally, the use of the Spinal Instability Neoplastic Score (SINS) in MM is debated in MM. Purpose: To determine the incidence of VCFs after cEBRT in patients with MM and to assess the applicability of the SINS score in the prediction of VCFs in MM. Study Design: Retrospective multicenter cohort study. Patient Sample: MM patients with spinal myeloma lesions who underwent cEBRT between January 2010 and December 2021. Outcome Measures: Frequency of new or progressed VCFs and subdistribution hazard ratios for potentially associated factors. Methods: Patient and treatment characteristics were manually collected from the patients’ electronic medical records. Computed tomography (CT) scans from before and up to 3 years after the start of radiation were used to score radiographic variables at baseline and at follow-up. Multivariable Fine and Gray competing risk analyses were performed to evaluate the diagnostic value of the SINS score to predict the post-radiation VCF rate. Results: A total of 127 patients with 427 eligible radiated vertebrae were included in this study. The mean age at radiation was 64 years, and 66.1% of them were male. At the start of radiation, 57 patients (44.9%) had at least one VCF. There were 89 pre-existing VCFs (18.4% of 483 vertebrae). Overall, 39 of 127 patients (30.7%) reported new fractures (number of vertebrae (n)=12) or showed progression of existing fractures (n=36). This number represented 11.2% of all radiated vertebrae. Five of the 39 (12.8%) patients with new or worsened VCFs received an unplanned secondary treatment (augmentation [n=2] or open surgery [n=3]) within 3 years. Both the total SINS score (SHR 1.77; 95% confidence interval (CI) 1.54–2.03; p<.001) and categorical SINS score (SHR 10.83; 95% CI 4.20–27.94; p<.001) showed an independent association with higher rates of new or progressed VCFs in adjusted analyses. The use of bisphosphonates was independently associated with a lower rate of new or progressed VCFs (SHR 0.47 [95% CI 0.24–0.92; p=.027]). Conclusions: This study demonstrated that new or progressed VCFs occurred in 30.7% of patients within 3 years, in a total of 11.2% of vertebrae. The SINS score was found to be independently associated with the development or progression of VCFs and could thus be applied in MM for fracture prediction and possibly prevention

Metal enrichment processes

There are many processes that can transport gas from the galaxies to their environment and enrich the environment in this way with metals. These metal enrichment processes have a large influence on the evolution of both the galaxies and their environment. Various processes can contribute to the gas transfer: ram-pressure stripping, galactic winds, AGN outflows, galaxy-galaxy interactions and others. We review their observational evidence, corresponding simulations, their efficiencies, and their time scales as far as they are known to date. It seems that all processes can contribute to the enrichment. There is not a single process that always dominates the enrichment, because the efficiencies of the processes vary strongly with galaxy and environmental properties.Comment: 18 pages, 8 figures, accepted for publication in Space Science Reviews, special issue "Clusters of galaxies: beyond the thermal view", Editor J.S. Kaastra, Chapter 17; work done by an international team at the International Space Science Institute (ISSI), Bern, organised by J.S. Kaastra, A.M. Bykov, S. Schindler & J.A.M. Bleeke

Non-invasive cardiac assessment in high risk patients (The GROUND study): rationale, objectives and design of a multi-center randomized controlled clinical trial

Background: Peripheral arterial disease (PAD) is a common disease associated with a considerably increased risk of future cardiovascular events and most of these patients will die from coronary artery disease (CAD). Screening for silent CAD has become an option with recent non-invasive developments in CT (computed tomography)-angiography and MR (magnetic resonance) stress testing. Screening in combination with more aggressive treatment may improve prognosis. Therefore we propose to study whether a cardiac imaging algorithm, using non-invasive imaging techniques followed by treatment will reduce the risk of cardiovascular disease in PAD patients free from cardiac symptoms. Design: The GROUND study is designed as a prospective, multi-center, randomized clinical trial. Patients with peripheral arterial disease, but without symptomatic cardiac disease will be asked to participate. All patients receive a proper risk factor management before randomization. Half of the recruited patients will enter the 'control group' and only undergo CT calcium scoring. The other half of the recruited patients (index group) will undergo the non invasive cardiac imaging algorithm followed by evidence-based treatment. First, patients are submitted to CT calcium scoring and CT angiography. Patients with a left main (or equivalent) coronary artery stenosis of > 50% on CT will be referred to a cardiologist without further imaging. All other patients in this group will undergo dobutamine stress magnetic resonance (DSMR) testing. Patients with a DSMR positive for ischemia will also be referred to a cardiologist. These patients are candidates for conventional coronary angiography and cardiac interventions (coronary artery bypass grafting (CABG) or percutaneous cardiac interventions (PCI)), if indicated. All participants of the trial will enter a 5 year follow up period for the occurrence of cardiovascular events. Sequential interim analysis will take place. Based on sample size calculations about 1200 patients are needed to detect a 24% reduction in primary outcome. Implications: The GROUND study will provide insight into the question whether non-invasive cardiac imaging reduces the risk of cardiovascular events in patients with peripheral arterial disease, but without symptoms of coronary artery disease. Trial registration: Clinicaltrials.gov NCT0018911

Challenges in the Treatment of Spinal Lesions in Patients with Multiple Myeloma

Due to improved systemic therapies, the life expectancy of patients suffering from multiple myeloma (MM) has increased significantly over the past few years. Patients who suffer from the disease for a longer period of time have an increased chance of developing skeletal-related events (SREs), i.e. a pathologic fracture, epidural spinal cord compression (ESCC), radiation (for pain or impending fracture) or surgery to the bone. No definitive guidelines exist on how to treat patients with spinal myeloma disease. Most patients with minimal neurologic deficits can be treated with systemic therapy. Unfortunately, some patients need an intervention like radiotherapy or surgery to relieve their symptoms (i.e. pain or neurologic deficits). However, both radiation and surgery are not without risks in the MM population. The emergence of innovative and highly effective systemic treatment options requires an evaluation of the benefits and adverse effects of radiation and surgery to create a better framework for optimal patient selection for these treatments. A comprehensive understanding of when certain treatment options should or should not be used is essential to achieve the best possible functional outcomes for these patients. As such, this thesis aims to provide insights into the magnitude of the problem of spinal instability and vertebral fractures (part I), and the effect and outcomes of radiation therapy (part II) and surgery (part III)

Stereodivergent S_N2@P Reactions of Borane Oxazaphospholidines: Experimental and Theoretical Studies

The stereodivergent ring-opening of 2-phenyl oxazaphospholidines with alkyl lithium reagents is reported. N-H oxazaphospholidines derived from both (+)-<i>cis</i>-1-amino-2-indanol and (−)-norephedrine provide inversion products in a highly stereoselective process. In contrast, N-Me oxazaphospholidines yield ring-opening products with retention of configuration at the P center, as previously reported by Jugé and co-workers. As a result, from a single amino alcohol auxiliary, both enantiomers of key P-stereogenic intermediates could be synthesized. Theoretical studies of ring-opening with model oxazaphospholidines at the DFT level have elucidated the streochemical course of this process. N-H substrates react in a single step via preferential backside S_N2@P substitution with inversion at phosphorus. N-methylated substrates react preferentially via a two-step frontside S_N2@P, yielding a ring-opened product in which the nucleophilic methyl binds to P with retention of configuration. DFT calculations have shown that the BH₃ unit is a potent directing group to which the methyl lithium reagent coordinates via Li in all the reactions studied

Stereodivergent S_N2@P Reactions of Borane Oxazaphospholidines: Experimental and Theoretical Studies

The stereodivergent ring-opening of 2-phenyl oxazaphospholidines with alkyl lithium reagents is reported. N-H oxazaphospholidines derived from both (+)-<i>cis</i>-1-amino-2-indanol and (−)-norephedrine provide inversion products in a highly stereoselective process. In contrast, N-Me oxazaphospholidines yield ring-opening products with retention of configuration at the P center, as previously reported by Jugé and co-workers. As a result, from a single amino alcohol auxiliary, both enantiomers of key P-stereogenic intermediates could be synthesized. Theoretical studies of ring-opening with model oxazaphospholidines at the DFT level have elucidated the streochemical course of this process. N-H substrates react in a single step via preferential backside S_N2@P substitution with inversion at phosphorus. N-methylated substrates react preferentially via a two-step frontside S_N2@P, yielding a ring-opened product in which the nucleophilic methyl binds to P with retention of configuration. DFT calculations have shown that the BH₃ unit is a potent directing group to which the methyl lithium reagent coordinates via Li in all the reactions studied

A Machine Learning Algorithm for Predicting 6-Week Survival in Spinal Metastasis: An External Validation Study Using 2,768 Taiwanese Patients

INTRODUCTION: There are predictive algorithms for predicting 3-month and 1-year survival in patients with spinal metastasis. However, advance in surgical technique, immunotherapy, and advanced radiation therapy has enabled shortening of postoperative recovery, which returns dividends to the overall quality-adjusted life-year. As such, the Skeletal Oncology Research Group machine learning algorithm (SORG-MLA) was proposed to predict 6-week survival in patients with spinal metastasis, whereas its utility for patients treated with nonsurgical treatment was untested externally. This study aims to validate the survival prediction of the 6-week SORG-MLA for patients with spinal metastasis and provide the measurement of model consistency (MC). METHODS: Discrimination using area under the receiver operating characteristic curve, calibration, Brier score, and decision curve analysis were conducted to assess the model's performance in the Taiwanese-based cohort. MC was also applied to detect the proportion of paradoxical predictions among 6-week, 3-month, and 1-year survival predictions. The long-term prognosis should not be better than the shorter-term prognosis in that of an individual. RESULTS: The 6-week survival rate was 84.2%. The SORG-MLA retained good discrimination with an area under the receiver operating characteristic curve of 0.78 (95% confidence interval, 0.75 to 0.80) and good prediction accuracy with a Brier score of 0.11 (null model Brier score 0.13). There is an underestimation of the 6-week survival rate when the predicted survival rate is less than 50%. Decision curve analysis showed that the model was suitable for use over all threshold probabilities. MC showed suboptimal consistency between 6-week and 90-day survival prediction (78%). CONCLUSIONS: The results of this study supported the utility of the algorithm. The online tool (https://sorg-apps.shinyapps.io/spinemetssurvival/) can be used by both clinicians and patients in informative decision-making discussion before management of spinal metastasis

Preoperative embolization in surgical treatment of spinal metastases originating from non–hypervascular primary tumors: a propensity score matched study using 495 patients

BACKGROUND CONTEXT: Preoperative embolization (PE) reduces intraoperative blood loss during surgery for spinal metastases of hypervascular primary tumors such as thyroid and renal cell tumors. However, most spinal metastases originate from primary breast, prostate, and lung tumors and it remains unclear whether these and other spinal metastases benefit from PE. PURPOSE: To assess the (1) efficacy of PE on the amount of intraoperative blood loss and safety in patients with spinal metastases originating from non-hypervascular primary tumors, and (2) secondary outcomes including perioperative allogeneic blood transfusion, anesthesia time, hospitalization, postoperative complication within 30 days, reoperation, 90-day mortality, and 1-year mortality. STUDY DESIGN: Retrospective propensity-score matched, case-control study at 2 academic tertiary medical centers. PATIENT SAMPLE: Patients 18 years of age or older undergoing surgery for spinal metastases originating from primary non-thyroid, non-renal cell, and non-hepatocellular tumors between January 1, 2002 and December 31, 2016 were included. OUTCOME MEASURES: The primary outcomes were estimated amount of intraoperative blood loss and complications attributable to PE, such as neurologic injury, wound infection, thrombosis, or dissection. The secondary outcomes included perioperative allogeneic blood transfusion, anesthesia time, hospitalization, postoperative complication within 30 days, reoperation, 90-day mortality, and 1-year mortality. METHODS: In total, 495 patients were identified, of which 54 (11%) underwent PE. After propensity score matching on 21 variables, including primary tumor, number of spinal levels, and surgical treatment, 53 non-PE patients were matched to 53 PE patients. Matching was adequate measured by comparing the matched variables, testing the standardized mean differences (<0.25), and inspecting Kernel density plots. The degree of embolization was noted to be complete, until stasis, or successful in 43 (80%) patients. RESULTS: Intraoperative blood loss did not differ between both groups with a median blood loss in liters of 0.6 (IQR, 0.4-1.2) for non-PE patients and 0.9 (IQR, 0.6-1.2) for PE patients (p=.32). No complications occurred during embolization or the time between embolization and surgery. No differences were found in terms of the secondary outcomes. CONCLUSIONS: Our data suggest that, although no complications occurred and the embolization procedure can be considered safe, patients with non-hypervascular spinal metastases might not benefit from PE. A larger, prospective study could confirm or refute these study findings and aid in elucidating a subset of spinal metastases that might benefit from PE

Supplemental Material - Neurological Outcomes and the Need for Retreatments Among Multiple Myeloma Patients With High-Grade Spinal Cord Compression: Radiotherapy vs Surgery

Supplemental Material for Neurological Outcomes and the Need for Retreatments Among Multiple Myeloma Patients With High-Grade Spinal Cord Compression: Radiotherapy vs Surgery by Hester Zijlstra, MD, Alexander M. Crawford, MD, Brendan M. Striano, MD, Robert-Jan Pierik, BSc, Daniel G. Tobert, MD, Nienke Wolterbeek, PhD, Diyar Delawi, MD, PhD, Wim E. Terpstra, MD, PhD, Diederik H. R. Kempen, MD, PhD, Jorrit-Jan Verlaan, MD, PhD, and Joseph H. Schwab, MD, MS in Global Spine Journal</p