Search

Background The aim of this paper is to describe the utility of various recruitment modalities utilized in the Working to Increase Stability through Exercise (WISE) study. WISE is a pragmatic randomized trial that is testing the impact of a 3-year, multicomponent (strength, balance, aerobic) physical activity program led by trained volunteers or delivered via DVD on the rate of serious fall-related injuries among adults 65 and older with a past history of fragility fractures (e.g., vertebral, fall-related). The modified goal was to recruit 1130 participants over 2 years in three regions of Pennsylvania. Methods The at-risk population was identified primarily using letters mailed to patients of three health systems and those over 65 in each region, as well as using provider alerts in the health record, proactive recruitment phone calls, radio advertisements, and presentations at community meetings. Results Over 24 months of recruitment, 209,301 recruitment letters were mailed, resulting in 6818 telephone interviews. The two most productive recruitment methods were letters (72% of randomized participants) and the research registries at the University of Pittsburgh (11%). An average of 211 letters were required to be mailed for each participant enrolled. Of those interviewed, 2854 were ineligible, 2,825 declined to enroll and 1139 were enrolled and randomized. Most participants were female (84.4%), under age 75 (64.2%), and 50% took an osteoporosis medication. Not having a prior fragility fracture was the most common reason for not being eligible (87.5%). The most common reason provided for declining enrollment was not feeling healthy enough to participate (12.6%). Conclusions The WISE study achieved its overall recruitment goal. Bulk mailing was the most productive method for recruiting community-dwelling older adults at risk of serious fall-related injury into this long-term physical activity intervention trial, and electronic registries are important sources and should be considered.

Cladribine tablets 10 mg (3.5 mg/kg cumulative dose over 2 years) are approved for the treatment of relapsing forms of multiple sclerosis (MS), including relapsing-remitting MS and active secondary progressive MS. However, real-world data on cladribine tablets are limited. CLICK-MS and MASTER-2 are single arm, observational, 30-month, Phase IV studies in the US evaluating the effectiveness and safety of cladribine tablets 3.5 mg/kg in patients with relapsing-remitting MS or active secondary progressive MS who had suboptimal response to prior injectable (CLICK-MS), or infusion/oral (MASTER-2) disease-modifying therapy. The primary end point is 24-month annualized relapse rate. Key secondary end points include patient-reported outcomes on quality of life measures, treatment adherence and adverse events. Studies began in 2019 and are expected to be completed in 2023. Trial registration number • CLICK-MS: NCT03933215 (ClinicalTrials.gov) Full title; CLadribine tablets: observational evaluation of effectIveness and patient-reported outcomes in suboptimally Controlled patients previously taKing injectable disease-modifying drugs for relapsing forms of Multiple Sclerosis • MASTER-2: NCT03933202 (ClinicalTrials.gov) Full title; Cladribine tablets: observational evaluation of effectiveness and patient-reported outcomes in suboptiMAlly controlled patientS previously Taking oral or infusion disEase-modifying dRugs for relapsing forms of multiple sclerosis

Summary Background In conflict settings, data to guide humanitarian and development responses are often scarce. Although geospatial analyses have been used to estimate health-care access in many countries, such techniques have not been widely applied to inform real-time operations in protracted health emergencies. Doing so could provide a more robust approach for identifying and prioritising populations in need, targeting assistance, and assessing impact. We aimed to use geospatial analyses to overcome such data gaps in Yemen, the site of one of the world's worst ongoing humanitarian crises. Methods We derived geospatial coordinates, functionality, and service availability data for Yemen health facilities from the Health Resources and Services Availability Monitoring System assessment done by WHO and the Yemen Ministry of Public Health and Population. We modelled population spatial distribution using high-resolution satellite imagery, UN population estimates, and census data. A road network grid was built from OpenStreetMap and satellite data and modified using UN Yemen Logistics Cluster data and other datasets to account for lines of conflict and road accessibility. Using this information, we created a geospatial network model to deduce the travel time of Yemeni people to their nearest health-care facilities. Findings In 2018, we estimated that nearly 8·8 million (30·6%) of the total estimated Yemeni population of 28·7 million people lived more than 30-min travel time from the nearest fully or partially functional public primary health-care facility, and more than 12·1 million (42·4%) Yemeni people lived more than 1 h from the nearest fully or partially functional public hospital, assuming access to motorised transport. We found that access varied widely by district and type of health service, with almost 40% of the population living more than 2 h from comprehensive emergency obstetric and surgical care. We identified and ranked districts according to the number of people living beyond acceptable travel times to facilities and services. We found substantial variability in access and that many front-line districts were among those with the poorest access. Interpretation These findings provide the most comprehensive estimates of geographical access to health care in Yemen since the outbreak of the current conflict, and they provide proof of concept for how geospatial techniques can be used to address data gaps and rigorously inform health programming. Such information is of crucial importance for humanitarian and development organisations seeking to improve effectiveness and accountability. Funding Global Financing Facility for Women, Children, and Adolescents Trust Fund; Development and Data Science grant; and the Yemen Emergency Health and Nutrition Project, a partnership between the World Bank, UNICEF, and WHO.

Summary Background Satralizumab, a humanised monoclonal antibody targeting the interleukin-6 receptor, reduced the risk of relapse in patients with neuromyelitis optica spectrum disorder (NMOSD) when added to immunosuppressant therapy. This study assessed the safety and efficacy of satralizumab monotherapy in patients with the disorder. Methods In this phase 3, double-blind, placebo-controlled, parallel-group trial, we enrolled adults aged 18–74 years with aquaporin-4 antibody seropositive or seronegative NMOSD at 44 investigational sites in 13 countries. Eligible participants had experienced at least one documented NMOSD attack or relapse in the past 12 months and had a score of 6·5 or less on the Expanded Disability Status Scale. Exclusion criteria included clinical relapse 30 days or fewer before baseline. Participants were randomly assigned (2:1) to receive satralizumab 120 mg or visually matched placebo subcutaneously at weeks 0, 2, 4, and every 4 weeks thereafter. Taking immunosuppressants concomitantly was prohibited. The primary endpoint was time to the first protocol-defined relapse, based on the intention-to-treat population and analysed with stratification for two randomisation factors (previous therapy for prevention of attacks and nature of the most recent attack). Safety was assessed in all participants who received at least one dose of satralizumab or placebo. The double-blind phase was due to last until 44 protocol-defined relapses occurred or 1·5 years after random assignment of the last patient enrolled, whichever occurred first; participants could enter an open-label phase after the occurrence of a protocol-defined relapse or at the end of the double-blind phase. The study is registered with ClinicalTrials.gov , NCT02073279 . Findings 95 (57%) of 168 screened participants were randomly assigned to treatment (63 to satralizumab; 32 to placebo) between Aug 5, 2014, and April 2, 2017. Protocol-defined relapses occurred in 19 (30%) patients receiving satralizumab and 16 (50%) receiving placebo (hazard ratio 0·45, 95% CI 0·23–0·89; p=0·018). 473·9 adverse events per 100 patient-years occurred in the satralizumab group, as did 495·2 per 100 patient-years in the placebo group; the incidence of serious adverse events and adverse events leading to withdrawal was similar between groups. Interpretation Satralizumab monotherapy reduced the rate of NMOSD relapse compared with placebo in the overall trial population, with a favourable safety profile. The patient population included a ratio of aquaporin-4 antibody seropositive and seronegative patients that was reflective of clinical practice. Satralizumab has the potential to become a valuable treatment option for patients with NMOSD. Funding Chugai Pharmaceutical (Roche).

Background: Ublituximab, a novel monoclonal antibody (mAb) targeting a unique epitope on the CD20 antigen, is glycoengineered for enhanced B-cell targeting through antibody-dependent cellular cytotoxicity (ADCC). Greater ADCC may allow lower doses and shorter infusion times versus other anti-CD20 mAbs. Objective: The objective was to determine optimal dose, infusion time, and activity of ublituximab in relapsing multiple sclerosis. Methods: This is a phase 2, placebo-controlled study. Patients received three ublituximab infusions (150 mg over 1–4 hours on day 1 and 450–600 mg over 1–3 hours on day 15 and week 24) in six dosing cohorts. The primary endpoint was B-cell depletion. Results: In all cohorts ( N = 48), median B-cell depletion was >99% by week 4, maintained at weeks 24 and 48. Most common adverse events (AEs) were infusion-related reactions (all grade 1–2), with no apparent increased incidence at shorter infusion times. There were no AE-related discontinuations. At weeks 24 and 48, no T1 gadolinium-enhancing lesions ( p = 0.003) and a 10.6% decrease in T2 lesion volume ( p = 0.002) were detected. The annualized relapse rate was 0.07; 93% remained relapse free on study. Overall, 74% of patients had no evidence of disease activity (NEDA). Conclusion: Ublituximab was safely infused as rapid as 1 hour, producing robust B-cell depletion and profound reductions in magnetic resonance imaging (MRI) activity and relapses.

The objectives of this study were to characterize the risk of death (1) from the primary cancer vs competing cause of death; and (2) from various causes of death vs the general poplation. The relative risk of death after a pediatric cancer diagnosis versus the general population and the risk of death from a primary cancer diagnosis versus competing causes of death.This retrospective, population-based study used the Surveillance, Epidemiology, and End Results database (1980-2015) and included patients aged 0 to 19 years at the time of diagnosis. Observed deaths were calculated; the risk of death versus the general population was assessed with standardized mortality ratios (SMRs). Competing risk models for the cause of death were performed.There were 58,356 patients who were diagnosed, and the mortality rate was 22.8%. To assess causes of death, 6996 patients who died during the study period were included (45,580 total person-years at risk): 5128 (73%) died of their primary cancer, and 1868 (27%) died of a competing cause. Among all patients, the rate of death from the index cancer was higher than the rate of death from another cause within the first 5 years after diagnosis. The risk of death from a nonprimary cancer began to supersede the rate of death from the primary cancer 10 years after diagnosis for patients with germ cell tumors, lymphomas, and sarcomas. SMRs for the primary cancer were highest within the first 5 years after diagnosis for all cancers (SMRs, 100-50,000; P .0001). The risk of death from competing causes (heart disease, suicide, and sepsis) was elevated (SMR,100; P .001). The risk of dying of heart disease was high, especially for patients with astrocytomas (SMR, 47.84; 95% confidence interval [CI], 27.87-76.59) and neuroblastomas (SMR, 98.59; 95% CI, 47.28-181.32). The risk of dying of suicide was high in most patients, particularly for those with osteosarcomas (SMR, 111.40; 95% CI, 2.82-620.69), Hodgkin lymphomas (SMR, 62.35; 95% CI, 34.89-102.83), and gonadal germ cell tumors (SMR, 28.97; 95% CI, 12.51-57.09).The cause of death for patients with gonadal germ cell tumors, lymphomas, and sarcomas is more commonly a secondary cancer or noncancerous cause than the primary disease; their risk of death from competing causes (heart disease, suicide, and sepsis) rises throughout life.

Sciatic nerve impingement via a tumor of or trauma to the proximal subgluteal region creates a considerable surgical challenge that is debated in the literature. The neurosurgery literature favors the infragluteal approach, while in orthopaedics, the transgluteal approach is preferred. The goal of our study was to present an operative technique for the infragluteal approach to the subgluteal region with a step-by-step procedural guide to increase awareness among orthopaedic surgeons of alternative surgical approaches to the sciatic notch. We retrospectively reviewed the case of a 62-year-old female found to have a subgluteal myxoma who underwent the infragluteal approach for tumor excision. We then highlighted the anatomic considerations via cadaveric dissection photographs, artistic renditions, and intra-operative images. Our patient underwent tumor resection and sciatic nerve exploration via the infragluteal approach with a successful outcome. In comparison to other approaches in the literature, the infragluteal approach provides a safer dissection with more options for an extension of the exposure and potentially fewer functional deficits. We conclude that orthopaedic surgeons should strongly consider utilizing this approach to the sciatic notch rather than a transgluteal approach.

Background Challenging emerging entities with distinctive molecular signatures may benefit from algorithms for diagnostic work-up. Methods Fusion sarcomas (2020–2021, during pandemic) were diagnosed by clinicoradiology, morphology, phenotype, and next-generation sequencing (NGS). Results Six fusion sarcomas in two males and four females involved the chest-wall, neck, or extremities; ages ranged 2-73, median 18 years. Sizes ranged 5.3-25.0, median 9.1 cm. These include high grade 1) TPR-NTRK1 of proximal femur with a larger rounded soft tissue mass, previously considered osteosarcoma yet without convincing tumor matrix. A pathologic fracture necessitated emergency hemipelvectomy (NED) and 2) novel KANK1-NTRK2 sarcoma of bone and soft tissue with spindled pleomorphic to epithelioid features (AWD metastases). 3) Novel ERC1-ALK unaligned fusion, a low grade infiltrative deep soft tissue hand sarcoma with prominent-vascularity, myopericytoid/lipofibromatosis-like ovoid cells, and collagenized stroma, was successfully treated with ALK-inhibitor (Crizotinib), avoiding amputation. These NTRK and ALK tumors variably express S100 and CD34 and were negative for SOX10. 4) and 5) CIC-DUX4 round cell tumors (rapid metastases/demise), one with COVID superinfection, were previously treated as Ewing sarcoma. These demonstrated mild pleomorphism and necrosis, variable myxoid change and CD99 reactivity, and a distinctive dot-like-Golgi WT1 immunostaining pattern. 6) A chest wall/thoracic round cell sarcoma, focal CD34/ keratins/CK7, revealed nuclear-STAT6, STAT6-NAB2 by NGS, confirming malignant solitary fibrous tumor, intermediate-risk-stratification (AWD metastases). Conclusions Recent fusion sarcomas include new KANK1-NTRK2 and ERC1-ALK, the latter successfully treated by targeted-therapy. ALK/NTRK fusion partners TPR and KANK1 suggest unusual high-grade morphology/behavior. Clinicoradiologic, morphologic, and phenotypic algorithms can prompt molecular-targeted immunostains or NGS for final classification and promising inhibitor therapy.

Neurofibromatosis type 1 (NF1) is one of the most common inherited neurological disorders. It can cause plexiform neurofibromas, leading to diffuse enlargement of a nerve or nerves within the body. There are benign in general, however, can cause significant symptoms due to their size, including bony erosion, pain, and joint instability. Unfortunately, they also have the capacity to become malignant by internal transformation into a malignant peripheral nerve sheath tumor (MPNST). The case presented here is a 27-year-old male with NF1 that was followed for years with a pelvic girdle plexiform neurofibroma whose course was complicated by transformation to MPNST and a spontaneous hip dislocation. He underwent excision, Girdlestone procedure, chemotherapy, and radiation. Unfortunately, he subsequently developed lung metastases and is part of a clinical trial with an MDM2 inhibitor and pembrolizumab.

Anti-CD20 therapies have demonstrated considerable efficacy in the treatment of relapsing multiple sclerosis, constituting a high-efficacy treatment approach for reducing relapse risk and mitigating disability progression. These therapies have been shown to strongly deplete circulating B cells and small subsets of CD3+ CD4 and CD8 T cells that express low levels of CD20. While the clinical profiles of the various anti-CD20 monoclonal antibodies used in treating multiple sclerosis are well-described in the literature, greater understanding of the implications of their distinct molecular and pharmacological attributes is needed. In this review, we focus on four anti-CD20 monoclonal antibodies—rituximab, ocrelizumab, ofatumumab, and ublituximab—that are currently used, approved, or in late-stage clinical development for the treatment of multiple sclerosis. We provide clinical perspectives on the potential implications of differences in molecular structures, target epitopes, dosing regimens, mechanisms and impact on B-cell depletion and reconstitution, immunogenicity, administration-related reactions, and infection risks. Supplementary Information The online version contains supplementary material available at 10.1007/s40263-021-00843-8.

Carboplatin is a chemotherapy drug used to treat solid tumors but also causes bone loss and muscle atrophy and weakness. Bone loss contributes to muscle weakness through bone-muscle crosstalk, which is prevented with the bisphosphonate zoledronic acid (ZA). We treated mice with carboplatin in the presence or absence of ZA to assess the impact of bone resorption on muscle. Carboplatin caused loss of body weight, muscle mass, and bone mass, and also led to muscle weakness as early as 7 days after treatment. Mice treated with carboplatin and ZA lost body weight and muscle mass but did not lose bone mass. In addition, muscle function in mice treated with ZA was similar to control animals. We also used the anti-TGFβ antibody (1D11) to prevent carboplatin-induced bone loss and showed similar results to ZA-treated mice. We found that atrogin-1 mRNA expression was increased in muscle from mice treated with carboplatin, which explained muscle atrophy. In mice treated with carboplatin for 1 or 3 days, we did not observe any bone or muscle loss, or muscle weakness. In addition, reduced caloric intake in the carboplatin treated mice did not cause loss of bone or muscle mass, or muscle weakness. Our results show that blocking carboplatin-induced bone resorption is sufficient to prevent skeletal muscle weakness and suggests another benefit to bone therapy beyond bone in patients receiving chemotherapy. © 2019 American Society for Bone and Mineral Research.

Objective To assess real-world durability of reduction in relapse rates among patients with multiple sclerosis (MS) receiving fingolimod therapy over a longer-term period of follow-up. Methods Patients with MS who initiated fingolimod were identified from a US claims database (January 1, 2009 to September 30, 2016) and followed for 3 years post-initiation. Annualized relapse rates (ARRs) were calculated during the 1-year pre-initiation period, and during each year over the 3-year follow-up period. Time from fingolimod initiation to discontinuation (≥60-day treatment gap) was also summarized. Results Among 1599 fingolimod initiators, 1158 (72%) had continuous fingolimod use up to the start of year 2 and 937 (59%) had continuous fingolimod use up to the start of year 3. The mean baseline ARR during the 1-year pre-initiation period for all initiators was 0.51. After fingolimod initiation, mean ARRs were consistently lower in each year of follow-up: 0.25 (95% CI: 0.22, 0.28) in year 1 for all fingolimod initiators, 0.22 (0.18, 0.25) in year 2 for patients with continuous fingolimod use up to the start of year 2, and 0.23 (0.19, 0.27) in year 3 for patients with continuous fingolimod use up to the start of year 3. Median time on treatment was 33 months for all patients initiating fingolimod. Conclusions Patients with MS who received continuous fingolimod therapy experienced a sustained reduction in relapse rates (>50% vs. baseline) during each year of a 3-year follow-up period.

BACKGROUND: We propose a predictive model that identifies patients at greatest risk of death after palliative radiotherapy, which can help medical professionals choose treatments that better align with patient choice and prognosis. METHODS: The National Cancer Database was queried for recipients of palliative radiotherapy during first course of treatment. Cox regression models and adjusted hazard ratios with 95% confidence intervals were used to evaluate survival predictors. The mortality risk index was calculated using predictors from the estimated Cox regression model, with higher values indicating higher mortality risk. Based on tertile cutpoints, patients were divided into low, medium, and high risk groups. RESULTS: A total of 68,505 patients were included from 2010–2014 (median age 65.7 years, standard deviation 11.8 years, IQR 16, median 66). Upon univariable and multivariable analyses, several risk factors were found to predict survival: (1) location of metastases (liver, bone, lung, and brain); (2) age >65 years; (3) tumor primary (prostate, breast, and lung); (4) male; (5) Charlson-Deyo comorbidity score of 3+; and (6) radiotherapy site, including bone, brain and eye, thorax, and stomach, liver, pancreas, kidney, and abdomen. The median survival times were 11.66 months, 5.09 months, and 3.28 months in the low (n=22,621), medium (n=22,638), and high risk groups (n=22,611), respectively. A nomogram was created and validated to predict survival, available online, https://tinyurl.com/METSSSmodel. CONCLUSION: We created a predictive nomogram for survival of patients receiving palliative radiotherapy during their first course of treatment (named METSSS), based on Metastases location, Elderly (>65 years), Tumor primary, Sex, Sickness/comorbidity, and Site of radiotherapy.

Introduction: Osteoporosis affects nearly half of the U.S. population. Screening methods are improving but remain inadequate, leaving the disease underdiagnosed and undertreated. The purpose of this study is to determine the effectiveness of an EMR implemented system that identifies patients at risk for osteoporosis via an OST (osteoporosis screening tool) score in prompting patients toward osteoporosis evaluation. Methods: OST scores are generated on every patient 50 years of age and older that is admitted to the Penn State Hershey Medical Center (PSHMC) and recorded in their electronic medical record. An OST score < 2 indicates that a patient has a potential risk for osteoporosis. Information Technology (IT) implemented the EMR OST calculation, which currently generates a daily filtered list of all patients with an OST score Results: In the intervention group, 67 (58.26%) of 115 did not schedule a follow-up, while the remaining 48 (41.74%) did seek a follow-up. Thus, the patient follow-up response rate improved with letter intervention using the OST score as an indicator (P < .0001) compared to historical controls (14.29%). Conclusion: Implementing an EMR OST score which identifies patients at risk for osteoporosis, which generates an automatic letter to the patient, significantly promotes patient driven osteoporosis evaluation compared to historical controls.

In clinical trials, disability progression in multiple sclerosis (MS) is measured by the Kurtzke expanded disability status scale (EDSS), which is not captured in routine clinical care in the U.S. This study developed a claims-based disability score (CDS) based on the EDSS for assigning MS disability level in a U.S. claims database.This retrospective cohort study of patients with MS in the U.S., utilized adjudicated health plan claims data linked to electronic medical records (EMRs) data. Patients were identified between 1 January 2012 and 31 December 2016 and indexed on the first date of MS diagnosis. The CDS was developed to assign disability level at baseline using claims and ambulatory EMR records observed over the 1-year baseline period. All-cause healthcare costs were assessed by baseline disability level to validate the CDS.In total, 45,687 patients were identified in claims (full sample) and 1,599 linked to EMR (core sample). Over half of patients in both samples were classified with mild disability at baseline. Adjusted healthcare costs in patients with moderate and severe disability were 15% (The CDS is the first claims-based measure of MS disability utilizing data from EMR. This novel measure advances the opportunity to examine outcomes by disability accumulation in the absence of standard markers of disease progression. Although formal validation of the CDS was not possible due to lack of available EDSS in the EMR, the economic burden results align with prior publications and show that healthcare costs increase with increasing disability. Future validation studies of the CDS are warranted.

Background: There is an unmet need to develop therapeutic interventions directed at the neurodegeneration that underlies progression in multiple sclerosis. High-dose, pharmaceutical-grade biotin (MD1003) might enhance neuronal and oligodendrocyte energetics, resulting in improved cell function, repair, or survival. The MS-SPI randomised, double-blind, placebo-controlled study found that MD1003 improved disability outcomes over 12 months in patients with progressive multiple sclerosis. The SPI2 study was designed to assess the safety and efficacy of MD1003 in progressive forms of multiple sclerosis in a larger, more representative patient cohort. Methods: SPI2 was a randomised, double-blind, parallel-group, placebo-controlled trial done at 90 academic and community multiple sclerosis clinics across 13 countries. Patients were aged 18-65 years, had a diagnosis of primary or secondary progressive multiple sclerosis fulfilling the revised International Panel criteria and Lublin criteria, a Kurtzke pyramidal functional subscore of at least 2 (defined as minimal disability), an expanded disability status scale (EDSS) score of 3·5-6·5, a timed 25-foot walk (TW25) of less than 40 s, evidence of clinical disability progression, and no relapses in the 2 years before enrolment. Concomitant disease-modifying therapies were allowed. Patients were randomly assigned (1:1) by an independent statistician using an interactive web response system, with stratification by study site and disease history, to receive MD1003 (oral biotin 100 mg three times daily) or placebo. Participants, investigators, and assessors were masked to treatment assignment. The primary endpoint was a composite of the proportion of participants with confirmed improvement in EDSS or TW25 at month 12, confirmed at month 15, versus baseline. The primary endpoint was assessed in the intention-to-treat analysis set, after all participants completed the month 15 visit. Safety analyses included all participants who received at least one dose of MD1003. This trial is registered with ClinicalTrials.gov (NCT02936037) and the EudraCT database (2016-000700-29). Findings: From Feb 22, 2017, to June 8, 2018, 642 participants were randomly assigned MD1003 (n=326) or placebo (n=316). The double-blind, placebo-controlled phase of the study ended when the primary endpoint for the last-entered participant was assessed on Nov 15, 2019. The mean time in the placebo-controlled phase was 20·1 months (SD 5·3; range 15-27). For the primary outcome, 39 (12%) of 326 patients in the MD1003 group compared with 29 (9%) of 316 in the placebo group improved at month 12, with confirmation at month 15 (odds ratio 1·35 [95% CI 0·81-2·26]). Treatment-emergent adverse events occurred in 277 (84%) of 331 participants in the MD1003 group and in 264 (85%) of 311 in the placebo group. 87 (26%) of 331 participants in the MD1003 group and 82 (26%) of 311 participants in the placebo group had at least one serious treatment-emergent adverse event. One (

Background: This study evaluated the incidence of de novo bone metastasis across all primary cancer sites and their impact on survival by primary cancer site, age, race, and sex. Questions/purposes: Our objectives were (I) characterize the epidemiology of de novo bone metastasis with respect to patient demographics, (II) characterize the incidence by primary site, age, and sex (2010–2015), and (III) compare survival of de novo metastatic cancer patients with and without bone metastasis. Methods: This is a retrospective, population-based study using nationally representative data from the Surveillance, Epidemiology, and End Results program, 2010–2015. Incidence rates by year of diagnosis, annual percentage changes, Kaplan-Meier, univariate and multiple Cox regression models are included in the analysis. Results: Of patients with cancer in the SEER database, 5.1% were diagnosed with metastasis to bone, equaling ~18.8 per 100,000 bone metastasis diagnoses in the US per year (2010–2015). For adults >25, lung cancer is the most common primary site (2015 rate: 8.7 per 100,000) with de novo bone metastases, then prostate and breast primaries (2015 rates: 3.19 and 2.38 per 100,000, respectively). For patients

Introduction:In 2014, we implemented a geriatric hip fracture patient care pathway at our institution which was designed to improve outcomes and decrease time to surgery.Materials and Methods:We analyzed retrospective data from 463 patients, aged greater than 50, who had surgical treatment for a closed hip fracture due to a low-energy injury between 2013 and 2016 at an academic institution. Objective outcome measures included time to surgery, mortality rate, and total hospital length of stay. Our primary goal was to decrease the time to surgery for definitive fracture fixation to within 24 hours of admission to the hospital for patients who were medically fit for surgery.Results:We implemented a multidisciplinary, collaborative approach to address the needs of this specific patient population. Prior to implementing the pathway in 2013, our baseline time to surgery within 24 hours was 74.67%. After implementation, we had incremental yearly increases in the percentage of patients operated on within 24 hours, 82.31% in 2014 ( P = .10) and 84.14% in 2015 ( P = .04). During the study period, our overall time to surgery was reduced by 27% with an initial average of 20.22 hours in 2013, decreasing to 15.33 hours in 2014, and 14.63 hours in 2015. Our mortality rate at 1 year was 16% in 2013, 17% in 2014, and 15% in 2015.Conclusion:With implementation of the pathway, we were able to expedite surgical care for our patients and demonstrate a 10% improvement in the percentage of patients able to have surgery within 24 hours over a 3-year period. Our mortality and hospital length of stay, however, remained the same. Through this collaborative process and system standardization, we believe we have significantly improved not only direct patient care but their overall hospital experience. We continue to make improvements in our pathway.

Background: Upper extremity (UE) impairment is common with primary progressive multiple sclerosis (PPMS). Objective: This exploratory analysis examined the effects of ocrelizumab on confirmed progression (CP) and confirmed improvement (CI) in UE impairment in patients from ORATORIO. Methods: Patients with PPMS received ocrelizumab 600 mg or placebo every 24 weeks for ⩾120 weeks. The Nine-Hole Peg Test (9HPT) was administered at baseline (BL) and every 12 weeks thereafter. Prespecified exploratory endpoints included change in 9HPT time and proportion of patients with CP of ⩾20% in 9HPT. Analysis populations included intention-to-treat (ITT) patients and subgroups stratified by BL 9HPT time and Expanded Disability Status Scale. Post hoc analyses included the proportion of patients achieving more severe thresholds of CP and the proportion achieving CI in 9HPT. Results: Among ITT patients, ocrelizumab significantly reduced the change in 9HPT time over 120 weeks, the risk of CP of ⩾20% in 9HPT time for both hands and the risk of more severe 9HPT progression versus placebo. Numerical trends also favoured ocrelizumab versus placebo with respect to achieving CI. Consistent directional trends were observed in subgroup analyses. Conclusion: Ocrelizumab reduces the risk of UE disability progression and may increase the possibility of improvement versus placebo in PPMS.

Background Ocrelizumab, an anti-CD20 humanized monoclonal antibody, reduced disease progression in pivotal trials of patients with relapsing (OPERA I, OPERA II) and primary progressive (ORATORIO) multiple sclerosis (MS). These effects may be particularly important among patients with increased disability. Objective In this post hoc exploratory analysis, we evaluated the efficacy of ocrelizumab on disability progression among a subgroup of patients with MS who had increased baseline disability levels (Expanded Disability Status Scale scores ≥4.0) in the pivotal trials. Methods During the double-blind period, patients received ocrelizumab 600 mg intravenously every 24 weeks for 96 weeks in the OPERA trials (versus interferon β-1a 44 μg subcutaneously three times per week) and for 120 weeks in ORATORIO (versus placebo). Kaplan–Meier and Cox survival analyses were used to assess disability outcome measures. Results Baseline demographic, disease, and treatment characteristics were generally comparable across treatment groups in patients with increased disability from the OPERA and ORATORIO trials. Ocrelizumab treatment numerically, and in some instances significantly, reduced confirmed disability progression versus the comparator in these patients. Conclusions In patients with increased baseline disability, ocrelizumab reduced the risk of confirmed disability progression versus interferon β-1a in patients with relapsing-onset MS and versus placebo in patients with progression-onset MS.

ObjectiveTo evaluate lymphocyte counts and incidences of infections in patients with primary progressive MS (PPMS) receiving fingolimod 0.5 mg/d or placebo over 5 years during the INFORMS study, to assess infection rates with longer-term treatment.MethodsINFORMS was a randomized, multicenter, double-blind, placebo-controlled, parallel-group, phase 3 study of the sphingosine 1-phosphate receptor modulator fingolimod in patients with PPMS. Lymphocyte counts and incidences of infections were compared in patients receiving fingolimod or placebo. Infection rates were assessed in patients receiving fingolimod according to nadir and mean absolute lymphocyte count (ALC).ResultsOverall, 336 patients received fingolimod 0.5 mg/d (total exposure: 908.1 patient-years), and 487 received placebo (1,423.5 patient-years). In patients receiving fingolimod, mean ALC decreased by approximately 70% in the 2 weeks following treatment initiation and remained stable throughout the study. The incidences of all infections in the fingolimod and placebo groups were similar (53.6 vs 51.9 per 100 patient-years). The most common infections in patients receiving fingolimod were urinary tract infections (5.7 per 100 patient-years), upper respiratory tract infections (4.2 per 100 patient-years), and influenza (3.2 per 100 patient-years); incidences were similar in the placebo group (5.9, 4.2, and 3.1 per 100 patient-years, respectively). There was no apparent association between nadir or mean ALC and incidence of infection-related adverse events.ConclusionsIn patients with PPMS, long-term treatment with fingolimod 0.5 mg/d for up to 5 years led to an expected decrease of approximately 70% in mean ALC and did not appear to correlate with increased risk of infection.Classification of evidenceBecause this is a secondary analysis, this study provides Class II evidence that long-term PPMS treatment with fingolimod decreased mean ALC by approximately 70%, but did not significantly increase infection risk.

This paper explores the benefits and the costs of strengthening infrastructure assets to make them more resilient, reducing the repair costs and infrastructure disruptions caused by natural hazards. Strengthening infrastructure assets in low- and middle-income countries would increase investment needs in power, transport, and water and sanitation by between $11 billion and $65 billion a year, i.e. 3 percent of baseline infrastructure investment needs. The uncertainty pertaining to the costs and benefits of infrastructure resilience makes it difficult to provide a single estimate for the benefit-cost ratio of strengthening exposed infrastructure assets. To manage this uncertainty, this paper explores the benefit-cost ratio in 3,000 scenarios, combining uncertainties in all parameters of the analysis. The benefit-cost ratio is higher than 1 in 96 percent of the scenarios, larger than 2 in 77 percent of them, and higher than 4 in half of them. The net present value of these investments over the lifetime of new infrastructure assets -- or, equivalently, the cost of inaction -- exceeds $2 trillion in 75 percent of the scenarios and $4.2 trillion in half of them. Moreover, climate change makes the strengthening of infrastructure assets even more important, doubling the median benefit-cost ratio.

ObjectiveThe phase IIIb A Study to Evaluate the Effects of Ocrelizumab on Immune Responses in Participants With Relapsing Forms of Multiple Sclerosis (VELOCE) study (NCT02545868) assessed responses to selected vaccines in ocrelizumab (OCR)-treated patients with relapsing multiple sclerosis.MethodsPatients were randomized 2:1 into the OCR group (n = 68; OCR 600 mg) or control group (n = 34; interferon beta or no disease-modifying therapy). All received tetanus toxoid (TT)-containing vaccine, Pneumovax (23-valent pneumococcal polysaccharide vaccine [23-PPV]), and keyhole limpet hemocyanin (KLH). The OCR group was subdivided into OCR1 (n = 33) and OCR2 (n = 35) at randomization. The OCR1 group received Prevnar (13-valent conjugate pneumococcal vaccine) 4 weeks after 23-PPV; the OCR2 and control groups received influenza vaccine. Vaccinations started 12 weeks after OCR initiation (OCR group) or on day 1 (control group).ResultsPositive response rate to TT vaccine at 8 weeks was 23.9% in the OCR vs 54.5% in the control group. Positive response rate to ≥5 serotypes in 23-PPV at 4 weeks was 71.6% in the OCR and 100% in the control group. Prevnar did not enhance response to pneumococcal serotypes in common with Pneumovax. Humoral response to KLH was decreased in the OCR vs control group. Seroprotection rates at 4 weeks against 5 influenza strains ranged from 55.6% to 80.0% in the OCR2 group and 75.0% to 97.0% in the control group.ConclusionPeripherally B-cell–depleted OCR recipients mounted attenuated humoral responses to clinically relevant vaccines and the neoantigen KLH, suggesting that use of standard nonlive vaccines while on OCR treatment remains a consideration. For seasonal influenza vaccines, it is recommended to vaccinate patients on OCR because a potentially protective humoral response, even if attenuated, can be expected.Classification of evidenceThis study provides Class II evidence confirming that the humoral response to nonlive vaccines in patients with relapsing multiple sclerosis after OCR treatment is attenuated compared with untreated or interferon beta–treated patients, but they can still be expected to be protective.Clinicaltrials.gov identifierNCT02545868.

Rural accessibility is the only metric used in the Sustainable Development Goals to track progress toward better transport services in low- and middle-income countries. This paper estimates the rural accessibility index, defined as the proportion of the rural population who live within 2 kilometers of an all-season road, in 166 countries using open data. It then explores the cost of increasing the rural accessibility index in 19 countries, using an algorithm that prioritizes rural roads investments based on their impact on rural access and connectivity. Investment costs quickly balloon as the rural accessibility index increases, questioning the affordability of universal access to paved roads for many countries by 2030. If countries spent 1 percent of their gross domestic product annually on the upgrade of rural roads, even under optimistic assumptions on growth of gross domestic product, rural accessibility would only increase from 39 to 52 percent by 2030 across all developing countries. Alternative solutions to rural integration must thus be implemented in the short run until countries can afford to increase significantly access to all weather roads. For example, drones that supply regular food and medicine supply to remote communities are much more affordable than roads in the short term.

Importance Doses of fingolimod lower than 0.5 mg per day were not investigated during the fingolimod clinical development program. Whether lower doses of fingolimod might retain efficacy with fewer safety risks remains unknown. Objective To evaluate the efficacy and safety of fingolimod, 0.5 mg, and fingolimod, 0.25 mg, compared with glatiramer acetate and to assess whether these doses of fingolimod show superior efficacy to glatiramer acetate in adult patients with relapsing-remitting multiple sclerosis. Interventions Fingolimod, 0.5 mg, or fingolimod, 0.25 mg, orally once per day or glatiramer acetate, 20 mg, subcutaneously once per day. Design, Setting, and Participants The Multiple Sclerosis Study Evaluating Safety and Efficacy of Two Doses of Fingolimod Versus Copaxone (ASSESS) was a phase 3b multicenter randomized rater-blinded and dose-blinded 12-month clinical trial conducted between August 9, 2012, and April 30, 2018 (including the time required to recruit participants). A total of 1461 patients aged 18 to 65 years with relapsing-remitting multiple sclerosis were screened, and 1064 participants were randomized. These participants had at least 1 documented relapse during the previous year or 2 documented relapses during the previous 2 years and an Expanded Disability Status Scale score of 0 to 6 at screening. Data were analyzed between September and November 2018. Main Outcomes and Measures The superiority of the fingolimod doses was tested hierarchically, with fingolimod, 0.5 mg, vs glatiramer acetate, 20 mg, tested first, followed by fingolimod, 0.25 mg, vs glatiramer acetate, 20 mg. The primary end point was the reduction in annualized relapse rate (ARR). Magnetic resonance imaging parameters, safety, and tolerability were also assessed. Results Of 1461 adult patients screened, 1064 participants (72.8%) were randomized (mean [SD] age, 39.6 [11.0] years; 792 women [74.4%]) to 3 treatment groups: 352 participants received fingolimod, 0.5 mg, 370 participants received fingolimod, 0.25 mg, and 342 participants received glatiramer acetate, 20 mg. In total, 859 participants (80.7%) completed the study. Treatment with fingolimod, 0.5 mg, was superior to treatment with glatiramer acetate, 20 mg, in reducing ARR (40.7% relative reduction); the relative reduction with fingolimod, 0.25 mg, was 14.6%, which was not statistically significant (for fingolimod, 0.5 mg, ARR, 0.15; 95% CI, 0.11-0.21; for fingolimod, 0.25 mg, ARR, 0.22; 95% CI, 0.17-0.29; for glatiramer acetate, 20 mg, ARR, 0.26; 95% CI, 0.20-0.34). Treatment with both fingolimod doses (0.5 mg and 0.25 mg) significantly reduced new or newly enlarging T2 and gadolinium-enhancing T1 lesions compared with treatment with glatiramer acetate. Adverse events were reported in similar proportions across treatment groups (312 participants [90.4%] in the fingolimod, 0.5 mg, group, 323 participants [88.3%] in the fingolimod, 0.25 mg, group, and 283 participants [87.3%] in the glatiramer acetate group). Conclusions and Relevance Fingolimod, 0.5 mg, demonstrated superior clinical efficacy compared with glatiramer acetate, 20 mg, and had a superior benefit-risk profile compared with fingolimod, 0.25 mg, in adult participants with relapsing-remitting multiple sclerosis. Trial Registration ClinicalTrials.gov Identifier:NCT01633112

Background Individual functional system scores (FSS) of the Expanded Disability Status Scale (EDSS) play a central role in determining the overall EDSS score in patients with early-stage multiple sclerosis (MS). Alemtuzumab treatment improves preexisting disability for many patients; however, it is unknown whether improvement is specific to certain functional systems. Objective We assessed the effect of alemtuzumab on individual FSS of the EDSS. Methods CAMMS223 was a 36-month, rater-blinded, phase 2 trial; treatment-naive patients with active relapsing-remitting MS, EDSS ≤3, and symptom onset within 3 years were randomized to annual courses of alemtuzumab or subcutaneous interferon beta-1a (SC IFNB-1a) 44 μg three times weekly. Results Alemtuzumab-treated patients had improved outcomes versus SC IFNB-1a patients on most FSS at Month 36; the greatest effect occurred for sensory, pyramidal, and cerebellar FSS. Among patients who experienced 6-month sustained accumulation of disability, clinical worsening occurred most frequently in the brainstem and sensory systems. For patients with 6-month sustained reduction in preexisting disability, pyramidal and sensory systems contributed most frequently to clinical improvement. Conclusions Alemtuzumab demonstrated a broad treatment effect in improving preexisting disability. These findings may influence treatment decisions in patients with early, active relapsing-remitting MS displaying neurological deficits. ClinicalTrials.gov Identifier NCT00050778.

Background: In phase 3 trials, delayed-release dimethyl fumarate (DMF; also known as gastroresistant DMF) demonstrated efficacy in relapsing-remitting multiple sclerosis (MS). Gastrointestinal (GI) events were associated with DMF treatment. The single-arm, open-label MANAGE study examined the incidence, severity, duration, and management of GI events in adults with relapsing MS initiating DMF treatment in clinical practice in the United States shortly after marketing approval. Patients and Methods: Patients (N = 233) took DMF for up to 12 weeks and recorded information regarding GI events using an eDiary and numerical rating scales. Results: Overall, 54.1% of patients used symptomatic therapy and had GI symptoms. The incidence of GI events was highest in the first month of treatment. The duration of GI events varied by event type, and severity was generally mild to moderate. Decreased severity was seen in patients treated with antacids, bismuth subsalicylate, acid-secretion blockers, antidiarrheals, and antiemetics. Less than 10% of patients were using symptomatic therapy for GI events by week 12 of DMF treatment. A modest reduction in severe GI events was observed in patients who regularly took DMF with food compared with patients who did not. The incidence of GI-related events was comparable in patients with or without a history of GI abnormalities and in patients who did or did not use alcohol or tobacco. Conclusions: Gastrointestinal events associated with DMF are generally transient, mild to moderate in severity, and manageable. Symptomatic therapy and dosing with food may mitigate these events.

Background Monomethyl fumarate (MMF) is the pharmacologically active metabolite of dimethyl fumarate (DMF). MMF formulated as Bafiertam™ 190 mg and DMF formulated as Tecfidera 240 mg deliver bioequivalent exposure of MMF and therefore possess the same efficacy/safety profiles. DMF is a widely used oral treatment for relapsing-remitting forms of multiple sclerosis (RRMS) but is limited in some patients, primarily female, by issues with gastrointestinal (GI) tolerability. Methods This was a randomized, double-blind, head-to-head, 5-week study evaluating the GI tolerability of MMF 190 mg vs DMF 240 mg, administered twice daily in healthy subjects, using a derivative of the self-administered Modified Overall Gastrointestinal Symptom Scale (MOGISS). Subjects were stratified (3:1, female:male) and randomized (1:1) to the treatments. The primary endpoint was the Area Under the Curve (AUC) in each of the individual symptoms in the MOGISS over the 5-week treatment period. Other endpoints included the AUC over the 5-week treatment period in the MOGISS composite and total scores; duration and severity of GI events; Number and percentage of subjects reporting GI events during the overall treatment period, and assessment of safety/tolerability. Results Inferential analysis of the hierarchical testing of overall treatment differences in each MOGISS symptom AUC occurred in a predefined sequence starting with Abdominal Pain. For each symptom, LSMean AUC values were lower for MMF than DMF, however, the first primary endpoint, Abdominal Pain, was not statistically different between treatments; thus, all subsequent statistical analyses were considered exploratory. The side effects and safety profiles observed were consistent with the known profiles of DMF, with no new or unique safety concerns noted. Conclusions Bafiertam showed an improved gastrointestinal tolerability profile compared with Tecfidera, with less severe GI events and fewer days of self-assessed GI symptoms, fewer GI adverse events, and lower discontinuation rates because of GI adverse events.

e23573 Background: Surgery still remains the mainstay of treatment with curative intent for high grade extremity soft tissue non rhabdomyosarcoma sarcomas (HG ESTS). Adjuvant/neoadjuvant Chemotherapy (CT) is still debatable, but most experts agree about its role in HG-ESTS in combination with radiation (R). Interdigitated CT+R is an attractive method of delivering these modalities of treatment in short time prior to surgery, however safety of using growth factor (GF) while administering CT+R in HG ESTS is largely unknown. We conducted a retrospective study of the toxicities associated with GF administration in this setting at a single institution. Methods: Electronic medical records at one institution were reviewed to identify patients having a diagnosis of extremity STS between October 2017- January 2020. Demographics, details of tumor characteristics, and treatment details were noted. Details of Interdigitated (ID)CRT were noted; the intended CT regimen was doxorubicin/ifosphamide/mesna (MAI) at 100% of the intended dosing. Data regarding the toxicities associated with GF administration were also evaluated in these patients; specifically, the development of febrile neutropenia, thrombocytopenia and pulmonary toxicity were evaluated. Patients who presented with metastatic disease were excluded from this analysis. Results: 22 patients were identified. Median age was 63 years. Of these, 9 patients (40%) were smokers. At diagnosis, 6 patients (27%) had metastatic disease. The most common site of primary disease was the thigh (50%). The most common histology was undifferentiated pleomorphic sarcoma (59%). CT monotherapy was administered in 3 patients. RT was administered in 14 patients, out of whom interdigitated CRT was administered in 10 patients. 60% of patients who initiated were able to receive 3 cycles of ID-CRT prior to Surgery. GF was administered in 14 patients who received regimens including CT. Of patients receiving ID-CRT who received GF, 60% completed ID-CRT without delays. No delays occurred due to thrombocytopenia. Febrile neutropenia occured in 22% of patients who received GF. Only 1 patient who received GF suffered prolonged thrombocytopenia. No patients who received GF were noted to have pulmonary toxicity. Conclusions: For adults with HG ESTS, GF administration with ID-CRT does not appear to cause any additional delay in treatment due to prolonged thrombocytopenia or lung toxicity. Inclusion of GF administration in further prospective trials of ID-CRT appears feasible.

A 54-year-old man presented with a painful lesion on the right posterior calf with MRI identifying a 5 cm lesion in the medial head of the gastrocnemius. He underwent wide local excision of the tumour, and the final pathology was consistent with atypical granular cell tumour. Three years later, he developed a recurrent right popliteal mass. Complete staging workup also identified multiple lung nodules and a caecal polyp that were consistent with metastatic granular cell tumour. He was started on pazopanib and deemed a poor candidate for palliative resection due to encasement of the popliteal vessels. The patient refused above-the-knee amputation (AKA) at that point and was evaluated for isolated limb infusion as an alternative. He received three cycles of isolated limb infusion within a 2-year period and achieved good response from the first two cycles. He underwent AKA 4 years after his diagnosis of malignant granular cell tumours and is currently doing well.

A gentleman in his late 40s developed a “pins and needles” sensation and numbness in his left hand that was exacerbated by leaning on his left arm or hyperextending his neck. The numbness developed over a few weeks. Over the next 2 months, the numbness spread proximally in the left arm, then to the right arm, and in patches over his bilateral upper chest and next to the bilateral posterior thighs. He denied pain, weakness, fatigue, cognitive changes, vision changes, dysarthria, or dysphagia or changes in bladder or bowel function. A review of systems was otherwise negative or normal. Past medical history was notable for hyperlipidemia, treated with atorvastatin 20 mg daily. There was no family history of neurologic or autoimmune disease. Vital signs and general physical examination were normal. Neurologic examination was notable for normal mental status and cranial nerve examinations. Gait, coordination, and the remainder of the motor examinations were normal. Sensation was mildly reduced to light touch circumferentially throughout both arms, in patches over the anterior chest, and over the posterior thighs, with preserved sensation to vibration, pinprick, and temperature. The Romberg sign was not present. Deep tendon reflexes were normal. The plantar response was flexor bilaterally. The authors wish to express their gratitude to their medical illustrator, Mr. Jason Ooi, for his evidence-based rendition of the putative mechanisms underlying noncaseating granulomatous inflammation in neurosarcoidosis. The authors also wish to acknowledge the UCSF MS EPIC Study Team. The National Multiple Sclerosis Society Case Conference Proceedings is a peer review publishing initiative from the monthly; Diagnostic and Treatment Challenges in MS and Neuroimmunology Webinars; sponsored by the National Multiple Sclerosis Society Fellowship Training Program; and Directed by Elliot M Frohman, MD, PhD.

Background: Several different classes of medications have been shown to be efficacious at preventing fractures in patients with osteoporosis. No study has compared real world efficacy at preventing fractures between all currently approved medications. Objectives: To directly compare the efficacy of all currently available osteoporosis medications by using a large population claims database. Methods: The Truven Health Analytics MarketScan® database from 2008 - 2012 was used to identify all patients who started a new osteoporosis medication. Patients who experienced a fracture after at least 12 months of treatment were identified and risk factors for fracture for all patients were recorded. Logistic regression was used to account for and quantify the contribution of risk factors, and to make direct comparisons between different osteoporosis medications. Results: A total of 51649 patients were included in the cohort, with an average age of 56 years. The overall incidence rate of fracture was 1.55 per 100 person - years of treatment. Orally administered medications had the lowest fracture rates, led by raloxifene and alendronate (1.24 and 1.54 respectively), while parenterally administered medications including teriparatide and zolerdonic acid had the highest rates (3.90 and 1.98 respectively). No statistically significant differences found between oral or parenterally administered bisphosphonate medications. Conclusions: While patients taking orally administered drugs including bisphosphonates had less frequent incident fracture no statistically significant differences were found between most drugs in head - to - head comparisons, even considering the route of administration of bisphosphonates. These findings support previous evidence that minimal differences in efficacy exist between different osteoporosis medications. This is the first study using a large database to compare all currently available osteoporosis treatments and will hopefully be augmented by further study to provide more evidence to make clinical decisions on osteoporosis medication use.

Objective: In relapsing–remitting multiple sclerosis (RRMS), suboptimal adherence to injectable disease-modifying therapies (iDMTs; interferon β-1a/b, glatiramer acetate) is common, reducing their effectiveness. Patient retention on oral fingolimod and iDMTs was evaluated in PREFER MS , a randomized, parallel-group, active-controlled, open-label, 48-week study. Methods: Patients were included if they had RRMS, were aged 18–65 years and had Expanded Disability Status Scale score up to 6, enrolled at 117 US study sites, were treatment naïve or had received only one iDMT class. Patients were randomized 1:1 (fingolimod 0.5 mg/day; preselected iDMT) by interactive voice-and-web-response system without blinding, followed up quarterly, and allowed one study-approved treatment switch after 12 weeks, or earlier for efficacy or safety reasons. The primary outcome was patient retention on randomized treatment over 48 weeks. Secondary endpoints included patient-reported outcomes, brain volume loss (BVL), and cognitive function. Results: Analysis of 433/436 patients receiving fingolimod and 428/439 receiving iDMTs showed that patient retention rate was significantly higher with fingolimod than with iDMTs [352 (81.3%) versus 125 (29.2%); 95% confidence interval 46.4–57.8%; p < 0.0001]. The most common treatment switch was from iDMT to fingolimod for injection-related reasons. Patient satisfaction was greater and BVL less with fingolimod than with iDMTs, with no difference in cognitive function. Adverse events were consistent with established tolerability profiles for each treatment. Conclusions: In RRMS, fingolimod was associated with better treatment retention, patient satisfaction and BVL outcomes than iDMTs. Patients may persist with iDMTs, but many may switch treatment if permitted. Treatment satisfaction fosters adherence, a prerequisite for optimal outcomes.

Iatrogenic seeding of sarcoma cells into a joint is a feared, although uncommon, phenomenon. In 1983, Joyce and Mankin described twelve patients who had undergone arthroscopy for suspected intra-articular pathology and were later determined to have extra-articular malignancies. Failure to appreciate the extra-articular lesion in eight of these patients led to delays in definitive treatment as well as the introduction of diseased tissue into the joint space1. In 2003, Musculo et al. reported a similar series of twenty-five patients with suspected athletic injuries who were operated on first and only later diagnosed with benign or malignant bone tumors2. Microscopic seeding of a joint with tumor cells from an undiagnosed malignancy is a risk in treating bone and soft-tissue tumors3-5. Iatrogenic spread of a tumor by arthroscopy is a rare complication that can substantially alter surgical outcomes for patients, leading to more aggressive surgical treatment when conservative therapy may have initially been possible6-8. In a busy clinical practice, orthopaedic surgeons must remain vigilant in assessing all patients with musculoskeletal pain, particularly patients with an equivocal etiology. We report the case of a young man with osteosarcoma who had arthroscopy-related complications. The patient’s family was informed that data concerning this case would be submitted for publication, and they provided consent. A previously healthy nineteen-year-old man presented to his primary physician with knee pain, swelling, and limited weight-bearing. The patient offered a reportedly “vague” history of trauma to the knee, sustained while playing with the family dog. After evaluation, the physician decided on empiric treatment with rest and nonsteroidal anti-inflammatory drugs. Despite the medication, the pain continued to worsen, and the patient was subsequently referred for orthopaedic evaluation. The patient presented to the orthopaedist with poorly localized pain about the knee …

Case: During orthopaedic open reduction and internal fixation, early fatigue failure of a Mizuho OSI Orthopedic Trauma Table Top occurred. The patient fell toward the ground but was uninjured. A material failure characterized by a crack in the spar tube leading to complete table component separation was identified. To our knowledge, this report is the first of its kind to specifically highlight surgical table device failure intraoperatively. Conclusion: Although rare, early fatigue failure of operating tables is possible, leading to hazardous intraoperative situations and the potential for serious patient injury or death. Operating tables and equipment should be inspected rigorously and with proper documentation to prevent such events.

This article provides an overview of the current burden of osteoporosis and its complications in today's health care system. The impact of osteoporosis on patients' quality of life and direct financial consequences to the entire health care system are emphasized to highlight the need for increased knowledge and awareness of its complications if left untreated or treated incorrectly. Special attention is given to hip fracture and vertebral compression fracture, stressing the importance of diagnosing osteoporosis before fragility fractures occur. Models for improved care of fragility fractures during follow-up in the outpatient setting and the use of pharmacologic agents are discussed.

A 54-year-old woman presented with complaints of myalgias, fatigue, and progressive leg weakness of several weeks duration, followed by acute loss of vision in her left eye. Her medical history was notable for long-standing systemic lupus erythematosus (SLE) that was actively treated with prednisone, mycophenolate mofetil, and quinacrine. The National Multiple Sclerosis Society Case Conference Proceedings are both a live educational Webinar, in conjunction with a peer review publishing initiative from the monthly “Diagnostic and Treatment Challenges in MS and Neuroimmunology Webinars,” sponsored by the National Multiple Sclerosis Society Fellowship Training Program and Directed by Elliot M. Frohman, MD, PhD, and Teresa C. Frohman, MPAS, MSCS, PA-C, from the Dell Medical School at the University of Texas at Austin.

Purpose of reviewTo provide neurologists with an update on the proposed mechanisms of action (MOAs) of disease-modifying therapies (DMTs) for the treatment of relapsing MS, and their effect on peripheral blood leukocytes, in order to inform treatment decisions.Recent findingsDMTs have vastly differing MOAs, including effects on peripheral blood leukocyte counts, particularly lymphocytes. The clinical implications of changes in lymphocyte counts need to be understood in the context of the underlying MOAs of each respective DMT, with treatment tailored to individual patient needs.SummaryDMTs can alter lymphocyte counts, subsets, activation, and distribution, and thus can influence immune surveillance. Serial monitoring of total leukocytes and absolute lymphocyte counts (ALCs) is advisable in patients receiving DMTs. ALCs should be interpreted regarding expected immunologic changes and individual patient characteristics. Any decision to switch DMTs should consider these factors, along with drug efficacy, safety, and effect on quality of life.

Objective:To evaluate 5-year efficacy and safety of alemtuzumab in patients with active relapsing-remitting multiple sclerosis and inadequate response to prior therapy.Methods:In the 2-year Comparison of Alemtuzumab and Rebif Efficacy in Multiple Sclerosis (CARE-MS) II study (NCT00548405), alemtuzumab-treated patients received 2 courses (baseline and 12 months later). Patients could enter an extension (NCT00930553), with as-needed alemtuzumab retreatment for relapse or MRI activity. Annualized relapse rate (ARR), 6-month confirmed disability worsening (CDW; ≥1-point Expanded Disability Status Scale [EDSS] score increase [≥1.5 if baseline EDSS = 0]), 6-month confirmed disability improvement (CDI; ≥1-point EDSS decrease [baseline score ≥2.0]), no evidence of disease activity (NEDA), brain volume loss (BVL), and adverse events (AEs) were assessed.Results:Most alemtuzumab-treated patients (92.9%) who completed CARE-MS II entered the extension; 59.8% received no alemtuzumab retreatment. ARR was low in each extension year (years 3–5: 0.22, 0.23, 0.18). Through 5 years, 75.1% of patients were free of 6-month CDW; 42.9% achieved 6-month CDI. In years 3, 4, and 5, proportions with NEDA were 52.9%, 54.2%, and 58.2%, respectively. Median yearly BVL remained low in the extension (years 1–5: −0.48%, −0.22%, −0.10%, −0.19%, −0.07%). AE exposure-adjusted incidence rates in the extension were lower than in the core study. Thyroid disorders peaked at year 3, declining thereafter.Conclusions:Alemtuzumab provides durable efficacy through 5 years in patients with an inadequate response to prior therapy in the absence of continuous treatment.Classification of evidence:This study provides Class III evidence that alemtuzumab provides efficacy and slowing of brain atrophy through 5 years.

Multiple hereditary exostoses (MHE) is a rare autosomal dominant condition that results in the growth of cartilage-capped prominences that often cause nerve compression and injury. Many patients suffer from continued and debilitating chronic pain which leads some to advocate avoiding surgical intervention in patients with multiple hereditary exostoses. We present a review of the literature as well as a case series at our institution in order to evaluate the role of surgery in multiple hereditary exostoses. We searched the literature for reports of patients with multiple hereditary exostoses undergoing surgery for nerve compression. We then reviewed the recent experience at our institution which revealed two patients with multiple hereditary exostoses. Our literature search revealed that there have been several case series and retrospective analyses in the literature that assess the benefit of surgery in the case of nerve compression caused by exostoses. The majority of these reports are of solitary exostoses. Few reports expand on the role of surgery in patients with multiple hereditary exostoses suffering from nerve compressions secondary to bony overgrowth. A recent review of the experience at our institution revealed two patients with multiple hereditary exostoses who together underwent a total of four surgeries for treatment of peripheral nerve compression resulting in pain or weakness. Postoperative evaluation revealed improvement in pain and/or motor strength following each operation. Based on our experience and literature review, we advocate that nerve compression in selected individuals with multiple hereditary exostoses that results in neurological injury should be considered for nerve decompression and resection of the offending exostosis.

The anti-CD52 monoclonal antibody alemtuzumab reduces disease activity in previously untreated patients with relapsing-remitting multiple sclerosis. We aimed to assess efficacy and safety of alemtuzumab compared with interferon beta 1a in patients who have relapsed despite first-line treatment.In our 2 year, rater-masked, randomised controlled phase 3 trial, we enrolled adults aged 18-55 years with relapsing-remitting multiple sclerosis and at least one relapse on interferon beta or glatiramer. Eligible participants were randomly allocated in a 1:2:2 ratio by an interactive voice response system, stratified by site, to receive subcutaneous interferon beta 1a 44 μg, intravenous alemtuzumab 12 mg per day, or intravenous alemtuzumab 24 mg per day. Interferon beta 1a was given three-times per week and alemtuzumab was given once per day for 5 days at baseline and for 3 days at 12 months. The 24 mg per day group was discontinued to aid recruitment, but data are included for safety assessments. Coprimary endpoints were relapse rate and time to 6 month sustained accumulation of disability, comparing alemtuzumab 12 mg and interferon beta 1a in all patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, number NCT00548405.202 (87%) of 231 patients randomly allocated interferon beta 1a and 426 (98%) of 436 patients randomly allocated alemtuzumab 12 mg were included in the primary analyses. 104 (51%) patients in the interferon beta 1a group relapsed (201 events) compared with 147 (35%) patients in the alemtuzumab group (236 events; rate ratio 0·51 [95% CI 0·39-0·65]; p0·0001), corresponding to a 49·4% improvement with alemtuzumab. 94 (47%) patients in the interferon beta 1a group were relapse-free at 2 years compared with 278 (65%) patients in the alemtuzumab group (p0·0001). 40 (20%) patients in the interferon beta 1a group had sustained accumulation of disability compared with 54 (13%) in the alemtuzumab group (hazard ratio 0·58 [95% CI 0·38-0·87]; p=0·008), corresponding to a 42% improvement in the alemtuzumab group. For 435 patients allocated alemtuzumab 12 mg, 393 (90%) had infusion-associated reactions, 334 (77%) had infections (compared with 134 [66%] of 202 patients in the interferon beta 1a group) that were mostly mild-moderate with none fatal, 69 (16%) had thyroid disorders, and three (1%) had immune thrombocytopenia.For patients with first-line treatment-refractory relapsing-remitting multiple sclerosis, alemtuzumab could be used to reduce relapse rates and sustained accumulation of disability. Suitable risk management strategies allow for early identification of alemtuzumab's main adverse effect of secondary autoimmunity.Genzyme (Sanofi) and Bayer Schering Pharma.

Background: The purpose of the present study was to evaluate musculoskeletal knowledge among graduating medical students and physician assistant students with use of a National Board of Medical Examiners (NBME) examination. We hypothesized that there would be no difference in scores between the two groups. In addition, we looked for relationships between examination scores and both the student-reported musculoskeletal experiences and the school-reported musculoskeletal curriculum. Methods: One hundred and forty-four students from three medical schools and ninety-one students from four physician assistant schools were included in the present study; both groups were graduating students in the final semester of education. The National Board of Medical Examiners Musculoskeletal Subject Examination (NBME MSK) was utilized to assess musculoskeletal knowledge. Results: The mean examination score (and standard deviation) was 73.8% ± 9.7% for medical students and 62.3% ± 11% for physician assistant students (95% confidence interval [CI], −13.8 to 0.00; p < 0.05). Medical students with an interest in orthopaedics as a career scored significantly higher than those without an expressed orthopaedic interest, and medical students without an expressed career interest in orthopaedics scored significantly higher than physician assistant students (p < 0.05). Among medical students, a longer duration of a clinical rotation in orthopaedics was associated with a higher examination score (p < 0.05). The average number of hours of preclinical musculoskeletal education in the first two years of school was significantly higher for medical schools (122.1 ± 25.1 hours) than for physician assistant schools (89.8 ± 74.8 hours) (p < 0.05). Conclusions: Graduating medical students scored significantly higher than graduating physician assistant students on the NBME MSK. This may be related to multiple factors, and further studies are necessary to evaluate the overall musculoskeletal clinical competence of both groups of students.

Background: Tovaxin is an autologous T-cell immunotherapy under investigation for the treatment of MS. The product consists of in vitro expanded myelin-reactive T-cells manufactured against up to six immunodominant peptides derived from three myelin antigens. Methods: A Phase 2b placebo controlled study (TERMS) was conducted in 150 subjects to gather safety and efficacy data in relapsing-remitting MS and clinically isolated syndrome subjects. Results: Tovaxin had a favorable safety profile. Although no statistically significant clinical or radiological benefit of Tovaxin immunotherapy was identified in the modified intent-to-treat population, a prospective analysis of subjects with more active disease favored Tovaxin in terms of annualized relapse rate (ARR) and disability progression. An analysis also found a possible legacy effect of prior disease-modifying treatment (DMT) which may have contributed to a lowered ARR in the placebo group. DMT-naïve subjects treated with Tovaxin had a lower ARR compared to the placebo group, particularly in those with active baseline disease (ARR≥1, ARR>1). However, clinical benefit was not was accompanied by a treatment-dependent improvement in MRI measures. Conclusions: Previous DMT exposure may reduce effect size and study power. Limiting subject selection to DMT-treatment-naïve individuals may be a reasonable approach to phase 2 or proof-of-concept studies of limited duration.

Background: Alemtuzumab (CD52-specific humanized monoclonal antibody) was found to be an effective therapy for treatment-naive patients with relapsing-remitting multiple sclerosis. Objective: Evaluate alemtuzumab’s effects in patients with treatment-refractory relapsing-remitting multiple sclerosis. Methods: Forty-five relapsing-remitting multiple sclerosis patients who experienced ≥2 relapses during 2 years prior to the study entry whilst receiving interferon therapy were administered 24 mg IV alemtuzumab/day for 5 days at baseline and 3 days 12 months later. Patients received premedication with 1 g IV methylprednisolone on days 1–3 at both times. Results: After 2-year follow-up, the annualized relapse rate was reduced by 94% compared to pre-treatment levels, from 1.6 (2 years prior to treatment) to 0.17 for the 2 years following (P

Multiple sclerosis (MS) is an autoimmune disorder characterized by CNS inflammation, demyelination and cellular damage with atrophy. Most patients with MS initially present with a relapsing-remitting course, with periodic episodes of neurologic symptomatology that do not follow a predictable pattern. In order to maintain a stable clinical course, it is felt to be important to control the number and severity of relapses, as disability, at least in part, is a cumulative effect of damage from multiple lesions within the brain and spinal cord. Historically, MS has not been considered curable, because the immune system could not be adequately normalized over the course of a lifetime. Alemtuzumab (Campath-1H; Campath(®), Genzyme, MA, USA) has recently been investigated in a Phase II clinical trial in the treatment of relapsing-remitting MS. The results observed in the study are very encouraging and multiple insights have been made into the nature of autoimmunity in general based on the clinical response to this monoclonal antibody. Enrollment in two pivotal Phase III clinical trials of alemtuzumab in MS is now complete.

Purpose Mutations leading to constitutive activation of the FMS-like tyrosine kinase 3 receptor (FLT3) occur in blasts of 30% of patients with acute myeloid leukemia (AML). Midostaurin (PKC412; N-benzoylstaurosporin) is a multitargeted tyrosine kinase inhibitor, with demonstrated activity in patients with AML/myelodysplastic syndrome (MDS) with FLT3 mutations. Patients and Methods Ninety-five patients with AML or MDS with either wild-type (n = 60) or mutated (n = 35) FLT3 were randomly assigned to receive oral midostaurin at 50 or 100 mg twice daily. The drug was discontinued in the absence of response at 2 months, disease progression, or unacceptable toxicity. Response was defined as complete response, partial response (PR), hematologic improvement, or reduction in peripheral blood or bone marrow blasts by ≥ 50% (BR). Results The rate of BR for the population in whom efficacy could be assessed (n = 92) was 71% in patients with FLT3-mutant and 42% in patients with FLT3 wild-type. One PR occurred in a patient with FLT3-mutant receiving the 100-mg dose regimen. Both doses were well-tolerated; there were no differences in toxicity or response rate according to the dose of midostaurin. Conclusion These results suggest that midostaurin has hematologic activity in both patients with FLT3-mutant and wild-type. The degree of clinical activity observed supports additional studies that combine midostaurin and other agents such as chemotherapy especially in FLT3-mutant AML.