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Multiple myeloma is characterised by monoclonal paraprotein production and osteolytic lesions, commonly leading to skeletal-related events (spinal cord compression, pathological fracture, or surgery or radiotherapy to affected bone). Denosumab, a monoclonal antibody targeting RANKL, reduces skeletal-related events associated with bone lesions or metastases in patients with advanced solid tumours. This study aimed to assess the efficacy and safety of denosumab compared with zoledronic acid for the prevention of skeletal-related events in patients with newly diagnosed multiple myeloma. In this international, double-blind, double-dummy, randomised, active-controlled, phase 3 study, patients in 259 centres and 29 countries aged 18 years or older with symptomatic newly diagnosed multiple myeloma who had at least one documented lytic bone lesion were randomly assigned (1:1; centrally, by interactive voice response system using a fixed stratified permuted block randomisation list with a block size of four) to subcutaneous denosumab 120 mg plus intravenous placebo every 4 weeks or intravenous zoledronic acid 4 mg plus subcutaneous placebo every 4 weeks (both groups also received investigators' choice of first-line antimyeloma therapy). Stratification was by intent to undergo autologous transplantation, antimyeloma therapy, International Staging System stage, previous skeletal-related events, and region. The clinical study team and patients were masked to treatment assignments. The primary endpoint was non-inferiority of denosumab to zoledronic acid with respect to time to first skeletal-related event in the full analysis set (all randomly assigned patients). All safety endpoints were analysed in the safety analysis set, which includes all randomly assigned patients who received at least one dose of active study drug. This study is registered with ClinicalTrials.gov, number NCT01345019. From May 17, 2012, to March 29, 2016, we enrolled 1718 patients and randomly assigned 859 to each treatment group. The study met the primary endpoint; denosumab was non-inferior to zoledronic acid for time to first skeletal-related event (hazard ratio 0·98, 95% CI 0·85–1·14; pnon-inferiority=0·010). 1702 patients received at least one dose of the investigational drug and were included in the safety analysis (850 patients receiving denosumab and 852 receiving zoledronic acid). The most common grade 3 or worse treatment-emergent adverse events for denosumab and zoledronic acid were neutropenia (126 [15%] vs 125 [15%]), thrombocytopenia (120 [14%] vs 103 [12%]), anaemia (100 [12%] vs 85 [10%]), febrile neutropenia (96 [11%] vs 87 [10%]), and pneumonia (65 [8%] vs 70 [8%]). Renal toxicity was reported in 85 (10%) patients in the denosumab group versus 146 (17%) in the zoledronic acid group; hypocalcaemia adverse events were reported in 144 (17%) versus 106 (12%). Incidence of osteonecrosis of the jaw was not significantly different between the denosumab and zoledronic acid groups (35 [4%] vs 24 [3%]; p=0·147). The most common serious adverse event for both treatment groups was pneumonia (71 [8%] vs 69 [8%]). One patient in the zoledronic acid group died of cardiac arrest that was deemed treatment-related. In patients with newly diagnosed multiple myeloma, denosumab was non-inferior to zoledronic acid for time to skeletal-related events. The results from this study suggest denosumab could be an additional option for the standard of care for patients with multiple myeloma with bone disease. Amgen.

Degenerative cervical myelopathy (DCM) is the leading cause of spinal cord dysfunction in adults worldwide. DCM encompasses various acquired (age-related) and congenital pathologies related to degeneration of the cervical spinal column, including hypertrophy and/or calcification of the ligaments, intervertebral discs and osseous tissues. These pathologies narrow the spinal canal, leading to chronic spinal cord compression and disability. Owing to the ageing population, rates of DCM are increasing. Expeditious diagnosis and treatment of DCM are needed to avoid permanent disability. Over the past 10 years, advances in basic science and in translational and clinical research have improved our understanding of the pathophysiology of DCM and helped delineate evidence-based practices for diagnosis and treatment. Surgical decompression is recommended for moderate and severe DCM; the best strategy for mild myelopathy remains unclear. Next-generation quantitative microstructural MRI and neurophysiological recordings promise to enable quantification of spinal cord tissue damage and help predict clinical outcomes. Here, we provide a comprehensive, evidence-based review of DCM, including its definition, epidemiology, pathophysiology, clinical presentation, diagnosis and differential diagnosis, and non-operative and operative management. With this Review, we aim to equip physicians across broad disciplines with the knowledge necessary to make a timely diagnosis of DCM, recognize the clinical features that influence management and identify when urgent surgical intervention is warranted.Degenerative cervical myelopathy is the leading cause of spinal cord dysfunction in adults worldwide. In this Review, the authors provide a comprehensive pathophysiological and clinical overview of the condition to equip physicians across broad disciplines with the knowledge needed for its diagnosis and management.

Degenerative cervical myelopathy represents the most common form of non-traumatic spinal cord injury. This trial investigated whether riluzole enhances outcomes in patients undergoing decompression surgery for degenerative cervical myelopathy. This multicentre, double-blind, placebo-controlled, randomised, phase 3 trial was done at 16 university-affiliated centres in Canada and the USA. Patients with moderate-to-severe degenerative cervical myelopathy aged 18–80 years, who had a modified Japanese Orthopaedic Association (mJOA) score of 8–14, were eligible. Patients were randomly assigned (1:1) to receive either oral riluzole (50 mg twice a day for 14 days before surgery and then for 28 days after surgery) or placebo. Randomisation was done using permuted blocks stratified by study site. Patients, physicians, and outcome assessors remained masked to treatment group allocation. The primary endpoint was change in mJOA score from baseline to 6 months in the intention-to-treat (ITT) population, defined as all individuals who underwent randomisation and surgical decompression. Adverse events were analysed in the modified intention-to-treat (mITT) population, defined as all patients who underwent randomisation, including those who did not ultimately undergo surgical decompression. This study is registered with ClinicalTrials.gov, NCT01257828. From Jan 31, 2012, to May 16, 2017, 408 patients were screened. Of those screened, 300 were eligible (mITT population); 290 patients underwent decompression surgery (ITT population) and received either riluzole (n=141) or placebo (n=149). There was no difference between the riluzole and placebo groups in the primary endpoint of change in mJOA score at 6-month follow-up: 2·45 points (95% CI 2·08 to 2·82 points) versus 2·83 points (2·47 to 3·19), difference −0·38 points (−0·90 to 0·13; p=0·14). The most common adverse events were neck or arm or shoulder pain, arm paraesthesia, dysphagia, and worsening of myelopathy. There were 43 serious adverse events in 33 (22%) of 147 patients in the riluzole group and 34 serious adverse events in 29 (19%) of 153 patients in the placebo group. The most frequent severe adverse events were osteoarthrosis of non-spinal joints, worsening of myelopathy, and wound complications. In this trial, adjuvant treatment for 6 weeks perioperatively with riluzole did not improve functional recovery beyond decompressive surgery in patients with moderate-to-severe degenerative cervical myelopathy. Whether riluzole has other benefits in this patient population merits further study. AOSpine North America.

Malignant spinal cord compression (MSCC) is one of the most devastating complications of cancer. Patients often present with a history of progressive pain, paralysis, sensory loss, progressive spinal deformity, and loss of sphincter control. It is an emergency that requires rapid decision making on the part of several specialists, given the risk of permanent spinal cord injury or death. The goals of treatment in spinal metastases are pain control and improvement of neurological function in order to achieve better quality of life (QoL). The standard of care in most cases is rapid initiation of corticosteroids in combination with either surgical decompression in case of an operable candidate, followed by radiation therapy (RT) or RT alone. Surgery is associated with improved outcomes, but is not appropriate for many patients presenting with advanced symptoms of MSCC, such as paralysis, or those with a poor performance status, or cachexic state, as well as altered mental conditions, co-morbidities, surgical risks, and limited life expectancy. On the other hand, aggressive surgical treatment and post-operative RT is advocated for those with more favorable prognosis, or who are expected to have higher neurological recovery potential. Many candidates may require for combined anterior and posterior approaches to effectively deal with the compressive pathology and stabilize the spine. Most patients are presently treated by primary RT, given with the aim of improving function and symptom management. However, there is still debate regarding the most appropriate RT schedule. Rehabilitation can serve to relieve symptoms, QoL, enhance functional independence, and prevent further complications. Ambulatory status has been found to be an important prognostic factor for patients with MSCC.

Malignant spinal cord compression (MSCC) can lead to immediate neurological impairment. In order to preserve and, optimally, restore neurological functions, urgent treatment (usually, within 24 h) is necessary. Treatment options mainly consist of decompressive surgery (DS) and / or radiotherapy (RT) combined with steroids. Whereas historically, RT was the treatment of choice, DS has become standard of care, where applicable. Despite a variety of excellent studies, real world data of treatment in a large academic center is currently underrepresented. We performed a retrospective analysis of patients treated for MSCC in our department of radiotherapy between 1998 and 2018 ( n  = 131), evaluating treatment, achievement of clinically determined improvement of neurological functions as well as overall survival (OS) and treatment-related toxicity. Kaplan-Meier estimator was used for survival statistics, log rank test for survival time comparisons, univariable and multivariable Cox regression and logistic regression for assessing potential impacts of variables on survival and symptom relief. 42.7% of patients had DS before RT ( n  = 56), 57.3% ( n  = 75) received RT without DS. Symptom relief was achieved in 41.2% of all patients ( n  = 54, n  = 26 of those had DS before RT, p  = 0.12). RT completed as intended ( p  < 0.001) was statistically significant for symptom relief, wherein symptom relief ( p  < 0.001), completion of RT course as intended ( p  = 0.01) and more recent treatment dates ( p  = 0.002) were independent predictors for OS. We herein present a large cohort of patients treated for MSCC in our academic center, representing real world treatment data currently lacking in literature.

Intradural spinal cord compression impairs perfusion pressure and is putatively rate-limiting for recovery after traumatic spinal cord injury (tSCI). After cervical tSCI, even minimally improved tissue preservation may help promote neurological recovery. To assess the nature and extent of spinal cord swelling and compression post-acute cervical tSCI, we evaluated several baseline MRI parameters including BASIC score, intramedullary lesion (IML) length, maximal canal compromise (MCC), maximal spinal cord compression (MSCC), extent of cord compression (ECC), maximal swollen anteroposterior diameter adjacent to injury site (Dmax), and maximal cord swelling (MCS) in 169 consecutive patients across 2 centers. In patients with either primarily intradural or combined (MSCC ≤5% or >5%, respectively) cord compression, we examined the predictive value of clinical and imaging admission parameters on American Spinal Injury Association Impairment Scale (AIS) severity and conversion up to 1-year follow-up. 37 (21.9%) patients presented with primarily intradural while 132 (78.1%) had combined cord compression. MSCC, MCS, and Dmax values differed significantly between the two groups (p < 0.0001, < 0.01 and < 0.001, respectively). MSCC was associated with age, MCC and MCS at baseline, while MCS was associated with age, MSCC and Dmax, on multivariable analysis. Logistic regression analysis of areas under receiver operating characteristic curve (AUROC) confirmed ECC (AUC 0.678) and MCS (AUC 0.922) as good and excellent predictors, respectively of AIS-conversion at 1-year for intradural compression participants. Additionally, MCS was significantly more accurate in predicting AIS-conversion in intradural group and the probability of AIS-conversion significantly decreased with each 1% increase in MCS (p = 0.003; OR 0.949), for both compression subtypes. In conclusion, baseline measures of cord swelling predict AIS-conversion likelihood up to 1-year. The deleterious effects of intradural cord compression, either isolated or presenting with extradural compression, may benefit from supplemental decompression strategies in addition to current standard-of-care.

Early diagnosis of malignant spinal cord compression (SCC) is crucial because pretreatment neurological status is the major determinant of outcome. In metastatic castration-resistant prostate cancer, SCC is a clinically significant cause of disease-related morbidity and mortality. We investigated whether screening for SCC with spinal MRI, and pre-emptive treatment if radiological SCC (rSCC) was detected, reduced the incidence of clinical SCC (cSCC) in asymptomatic patients with metastatic castration-resistant prostate cancer and spinal metastasis. We did a parallel-group, open-label, randomised, controlled, phase 3, superiority trial. Patients with metastatic castration-resistant prostate cancer were recruited from 45 National Health Service hospitals in the UK. Eligible patients were aged at least 18 years, with an Eastern Co-operative Oncology Group performance status of 0–2, asymptomatic spinal metastasis, no previous SCC, and no spinal MRI in the past 12 months. Participants were randomly assigned (1:1), using a minimisation algorithm with a random element (balancing factors were treatment centre, alkaline phosphatase [normal vs raised, with the upper limit of normal being defined at each participating laboratory], number of previous systemic treatments [first-line vs second-line or later], previous spinal treatment, and imaging of thorax and abdomen), to no MRI (control group) or screening spinal MRI (intervention group). Serious adverse events were monitored in the 24 h after screening MRI in the intervention group. Participants with screen-detected rSCC were offered pre-emptive treatment (radiotherapy or surgical decompression was recommended per treating physician's recommendation) and 6-monthly spinal MRI. All patients were followed up every 3 months, and then at month 30 and 36. The primary endpoint was time to and incidence of confirmed cSCC in the intention-to-treat population (defined as all patients randomly assigned), with the primary timepoint of interest being 1 year after randomisation. The study is registered with ISRCTN, ISRCTN74112318, and is now complete. Between Feb 26, 2013, and April 25, 2017, 420 patients were randomly assigned to the control (n=210) or screening MRI (n=210) groups. Median age was 74 years (IQR 68 to 79), 222 (53%) of 420 patients had normal alkaline phosphatase, and median prostate-specific antigen concentration was 48 ng/mL (IQR 17 to 162). Screening MRI detected rSCC in 61 (31%) of 200 patients with assessable scans in the intervention group. As of data cutoff (April 23, 2020), at a median follow-up of 22 months (IQR 13 to 31), time to cSCC was not significantly improved with screening (hazard ratio 0·64 [95% CI 0·37 to 1·11]; Gray's test p=0·12). 1-year cSCC rates were 6·7% (95% CI 3·8–10·6; 14 of 210 patients) for the control group and 4·3% (2·1–7·7; nine of 210 patients) for the intervention group (difference −2·4% [95% CI −4·2 to 0·1]). Median time to cSCC was not reached in either group. No serious adverse events were reported within 24 h of screening. Despite the substantial incidence of rSCC detected in the intervention group, the rate of cSCC in both groups was low at a median of 22 months of follow-up. Routine use of screening MRI and pre-emptive treatment to prevent cSCC is not warranted in patients with asymptomatic castration-resistant prostate cancer with spinal metastasis. Cancer Research UK.

Background The optimal EBRT schedule for MSCC is undetermined. Our aim was to determine whether a single fraction (SF) was non-inferior to five daily fractions (5Fx), for functional motor outcome. Methods Patients not proceeding with surgical decompression in this multicentre non-inferiority, Phase 3 trial were randomised to 10 Gy/SF or 20 Gy/5Fx. A change in mobility from baseline to 5 weeks for each patient, was evaluated by a Modified Tomita score: 1 = ‘Walk unaided’, 2 = ‘With walking aid’ and 3 = ‘Bed-bound’. The margin used to establish non-inferiority was a detrimental change of −0.4 in the mean difference between arms. Results One-hundred and twelve eligible patients were enrolled. Seventy-three patients aged 30–87 were evaluated for the primary analysis. The 95% CI for the difference in the mean change in mobility scores between arms was −0.12 to 0.6. Since −0.4 is not included in the interval, there is evidence that 10 Gy/SF is non-inferior to 20 Gy/5Fx. One grade 3 AE was reported in the 5Fx arm. Twelve (26%) patients in the 5Fx arm had a Grade 2–3 AE compared with six (11%) patients in the SF arm ( p  = 0.093). Conclusion For mobility preservation, one 10-Gy fraction is non-inferior to 20 Gy in five fractions, in patients with MSCC not proceeding with surgical decompression. Clinical Trial Registration Cancer Trials Ireland ICORG 05-03; NCT00968643; EU-20952.

Compression of the spinal cord can result from trauma, cancer, epidural abscess, or epidural hematoma and can have a variety of clinical manifestations based on the anatomical level and completeness of the compression. Treatment approaches are outlined. Acute compression of the spinal cord is a devastating but treatable disorder. Diseases that cause acute spinal cord compression constitute a special category because they originate in the spinal column and narrow the spinal canal. This review addresses the disorders that account for most instances of acute spinal cord compression: trauma, tumor, epidural abscess, and epidural hematoma. The pathophysiological features and management of these disorders are similar to those of other acute and serious spinal conditions. The medical context of spinal cord compression determines the diagnosis and directs treatment. Traumatic cord compression is often self-evident. Cord compression in patients with . . .

Bone metastases are a major cause of morbidity in metastatic castration-resistant prostate cancer. Abiraterone acetate potently disrupts intracrine androgen receptor signalling pathways implicated in the progression of the disease, including bone metastases. We assessed data for pain control and skeletal-related events prospectively collected as part of the randomised, phase 3 COU-AA-301 trial of abiraterone acetate plus prednisone versus placebo plus prednisone in patients with metastatic castration-resistant prostate cancer after docetaxel chemotherapy. The COU-AA-301 trial enrolled patients with metastatic castration-resistant prostate cancer in whom one or two lines of chemotherapy (one docetaxel based) had been unsuccessful and who had Eastern Cooperative Oncology Group performance statuses of 2 or less. Pain intensity and interference of pain with daily activities were assessed with the Brief Pain Inventory-Short Form questionnaire at baseline, day 15 of cycle 1, and day 1 of each treatment cycle thereafter until discontinuation. We assessed, with prospectively defined response criteria that incorporated analgesic use, clinically meaningful changes in pain intensity and interference with daily living. We measured time to first occurrence of skeletal-related events, which we defined as pathological fracture, spinal cord compression, palliative radiation to bone, or bone surgery, and regularly assessed them throughout the study. Pain palliation was assessed in patients who had clinically significant baseline pain, whereas all other analyses were done in the overall intention-to-treat population. COU-AA-301 is registered with ClinicalTrials.gov, number NCT00638690. Median follow-up was 20·2 months (IQR 18·4–22·1). In patients with clinically significant pain at baseline, abiraterone acetate and prednisone resulted in significantly more palliation (157 of 349 [45·0%] patients vs 47 of 163 [28·8%]; p=0·0005) and faster palliation (median time to palliation 5·6 months [95% CI 3·7–9·2] vs 13·7 months [5·4–not estimable]; p=0·0018) of pain intensity than did prednisone only. Palliation of pain interference (134 of 223 [60·1%] vs 38 of 100 [38·0%], p=0·0002; median time to palliation of pain interference 1·0 months [95% CI 0·9–1·9] vs 3·7 months [2·7–not estimable], p=0·0004) and median duration of palliation of pain intensity (4·2 months [95% CI 3·0–4·9] vs 2·1 months [1·4–3·7]; p=0·0056) were significantly better with abiraterone acetate and prednisone than with prednisone only. In the overall population, median time to occurrence of first skeletal-related event was significantly longer with abiraterone acetate and prednisone than with prednisone only (25·0 months [95% CI 25·0–not estimable] vs 20·3 months [16·9–not estimable]; p=0·0001). In patients with metastatic castration-resistant prostate cancer previously treated with docetaxel, abiraterone acetate and prednisone offer significant benefits compared with prednisone alone in terms of pain relief, delayed pain progression, and prevention of skeletal-related events. Janssen Research & Development and Janssen Global Services.