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Over the past decade, our understanding of the molecular drivers of pediatric low-grade glioma (PLGG) has expanded dramatically. These tumors are predominantly driven by RAS/MAPK pathway activating alterations (fusions and point mutations), most frequently in BRAF, FGFR1, and NF1. Furthermore, additional second hits in tumor suppressor genes (TP53, ATRX, CDKN2A) can portend more aggressive behaviour. Accordingly, comprehensive molecular profiling-specifically genetic sequencing, often plus copy number profiling-has become critical for guiding the diagnosis and management of PLGG. In this review, we discuss the most important genetic alterations that inform on classification and prognosis of PLGG, highlighting their diagnostic and therapeutic relevance., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

With the success of immunotherapy in cancer, understanding the tumor immune microenvironment (TIME) has become increasingly important; however in pediatric brain tumors this remains poorly characterized. Accordingly, we developed a clinical immune-oncology gene expression assay and used it to profile a diverse range of 1382 samples with detailed clinical and molecular annotation. In low-grade gliomas we identify distinct patterns of immune activation with prognostic significance in BRAF V600E-mutant tumors. In high-grade gliomas, we observe immune activation and T-cell infiltrates in tumors that have historically been considered immune cold, as well as genomic correlates of inflammation levels. In mismatch repair deficient high-grade gliomas, we find that high tumor inflammation signature is a significant predictor of response to immune checkpoint inhibition, and demonstrate the potential for multimodal biomarkers to improve treatment stratification. Importantly, while overall patterns of immune activation are observed for histologically and genetically defined tumor types, there is significant variability within each entity, indicating that the TIME must be evaluated as an independent feature from diagnosis. In sum, in addition to the histology and molecular profile, this work underscores the importance of reporting on the TIME as an essential axis of cancer diagnosis in the era of personalized medicine., (© 2024. The Author(s).)

Introduction: There is no published information on the epidemiology of wilderness rescues in California outside of national parks. The objective of this study was to investigate the epidemiology of wilderness search and rescue (SAR) missions in California and identify risk factors for individuals requiring rescue due to accidental injury, illness, or navigation errors in the California wilderness., Methods: A retrospective review of SAR missions in California from 2018 to 2020 was conducted. This was done from a database of information collected by the California Office of Emergency Services and the Mountain Rescue Association from SAR teams, who submitted voluntarily. The subject demographics, activity, location, and outcomes of each mission were analyzed., Results: Eighty percent of the initial data were excluded because of incomplete or inaccurate data. Seven hundred forty-eight SAR missions involving 952 subjects were included in the study. The demographics, activities, and injuries of our population were consistent with those reported from other epidemiological SAR studies, and there were significant differences in outcomes based on the subject's activity. For example, water activities were highly correlated with a fatal outcome., Conclusions: The final data show interesting trends, but it is difficult to draw firm conclusions because so much of the initial data had to be excluded. A uniform system for reporting SAR missions in California may be helpful for further research, which may aid both SAR teams and the recreational public in understanding risk factors. A proposed SAR form for easy entry is included in the discussion section., (Copyright © 2023 Wilderness Medical Society. Published by Elsevier Inc. All rights reserved.)

The color variation of hematoxylin and eosin (H&E)-stained tissues has presented a challenge for applications of artificial intelligence (AI) in digital pathology. Many color normalization algorithms have been developed in recent years in order to reduce the color variation between H&E images. However, previous efforts in benchmarking these algorithms have produced conflicting results and none have sufficiently assessed the efficacy of the various color normalization methods for improving diagnostic performance of AI systems. In this study, we systematically investigated eight color normalization algorithms for AI-based classification of H&E-stained histopathology slides, in the context of using images both from one center and from multiple centers. Our results show that color normalization does not consistently improve classification performance when both training and testing data are from a single center. However, using four multi-center datasets of two cancer types (ovarian and pleural) and objective functions, we show that color normalization can significantly improve the classification accuracy of images from external datasets (ovarian cancer: 0.25 AUC increase, p = 1.6 e-05; pleural cancer: 0.21 AUC increase, p = 1.4 e-10). Furthermore, we introduce a novel augmentation strategy by mixing color-normalized images using three easily accessible algorithms that consistently improves the diagnosis of test images from external centers, even when the individual normalization methods had varied results. We anticipate our study to be a starting point for reliable use of color normalization to improve AI-based, digital pathology-empowered diagnosis of cancers sourced from multiple centers. © 2021 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd., (© 2021 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.)

Sarcomatoid mesothelioma is an aggressive malignancy that can be challenging to distinguish from benign spindle cell mesothelial proliferations based on biopsy, and this distinction is crucial to patient treatment and prognosis. A novel deep learning based classifier may be able to aid pathologists in making this critical diagnostic distinction. SpindleMesoNET was trained on cases of malignant sarcomatoid mesothelioma and benign spindle cell mesothelial proliferations. Performance was assessed through cross-validation on the training set, on an independent set of challenging cases referred for expert opinion ('referral' test set), and on an externally stained set from outside institutions ('externally stained' test set). SpindleMesoNET predicted the benign or malignant status of cases with AUC's of 0.932, 0.925, and 0.989 on the cross-validation, referral and external test sets, respectively. The accuracy of SpindleMesoNET on the referral set cases (92.5%) was comparable to the average accuracy of 3 experienced pathologists on the same slide set (91.7%). We conclude that SpindleMesoNET can accurately distinguish sarcomatoid mesothelioma from benign spindle cell mesothelial proliferations. A deep learning system of this type holds potential for future use as an ancillary test in diagnostic pathology., (© 2021. The Author(s), under exclusive licence to United States & Canadian Academy of Pathology.)

Competing Interests: Conflict of InterestElena Gkrouzman, MD; Melanie H. Smith, MD, PhD; Nilasha Ghosh, MD; John L. Vaughn, MD; Alana B. Levine, MD; Anne R. Bass, MD; and Doruk Erkan, MD, MPH, declare that they have no conflict of interest. Surya V. Seshan, MB, BS, reports fees as a member of the speakers bureau at Alexion, outside the submitted work. Jeffrey C. Laurence, MD, reports research grants from Omeros, Inc., and Jazz Pharmaceuticals, outside the submitted work, as well as personal fees as a consultant from Alexion, during the conduct of this case study. Doruk Erkan, MD, MPH, reports grants from the ACR/EULAR, the National Institutes of Health, and the Lupus Clinical Trials Consortium, grants and personal fees from GlaxoSmithKline, and personal fees from UCB Pharmaceuticals and Exagen, outside the submitted work.

Background: Aberrations in Capicua (CIC) have recently been implicated as a negative prognostic factor in a multitude of cancer types through the derepression of targets downstream of the mitogen-activated protein kinase (MAPK) signaling cascade, such as oncogenic E26 transformation-specific (ETS) transcription factors. The Ataxin-family protein ATXN1L has previously been reported to interact with CIC in both developmental and disease contexts to facilitate the repression of CIC target genes and promote the post-translational stability of CIC. However, little is known about the mechanisms at the base of ATXN1L-mediated CIC post-translational stability., Results: Functional in vitro studies utilizing ATXN1L KO human cell lines revealed that loss of ATXN1L leads to the accumulation of polyubiquitinated CIC protein, promoting its degradation through the proteasome. Although transcriptomic signatures of ATXN1L KO cell lines indicated upregulation of the mitogen-activated protein kinase pathway, ERK activity was found to contribute to CIC function but not stability. Degradation of CIC protein following loss of ATXN1L was instead observed to be mediated by the E3 ubiquitin ligase TRIM25 which was further validated using glioma-derived cell lines and the TCGA breast carcinoma and liver hepatocellular carcinoma cohorts., Conclusions: The post-translational regulation of CIC through ATXN1L and TRIM25 independent of ERK activity suggests that the regulation of CIC stability and function is more intricate than previously appreciated and involves several independent pathways. As CIC status has become a prognostic factor in several cancer types, further knowledge into the mechanisms which govern CIC stability and function may prove useful for future therapeutic approaches.

Ependymoma and chordoma are 2 tumors that occur throughout the craniospinal axis, and for which the extent of neurosurgical resection has a key prognostic role. Both tumors have distinctive pathologic features, yet can present significant diagnostic challenges to pathologists in cases without classical histology. The molecular understanding of ependymoma has had significant advances in the past decade, with the identification of 9 molecular groups with significant prognostic and clinical implications, while a comprehensive study of chordoma further emphasized the key role of brachyury overexpression in its pathogenesis. In this review, we discuss the pathogenesis, radiology and gross pathology, histology, and molecular features of these 2 tumors, as well as active research into targeted therapies, with an emphasis on practical diagnostic challenges, and the use of immunohistochemical and molecular tests in routine diagnostic practice., (Copyright © 2020 by the Congress of Neurological Surgeons.)

Deep learning-based computer vision methods have recently made remarkable breakthroughs in the analysis and classification of cancer pathology images. However, there has been relatively little investigation of the utility of deep neural networks to synthesize medical images. In this study, we evaluated the efficacy of generative adversarial networks to synthesize high-resolution pathology images of 10 histological types of cancer, including five cancer types from The Cancer Genome Atlas and the five major histological subtypes of ovarian carcinoma. The quality of these images was assessed using a comprehensive survey of board-certified pathologists (n = 9) and pathology trainees (n = 6). Our results show that the real and synthetic images are classified by histotype with comparable accuracies and the synthetic images are visually indistinguishable from real images. Furthermore, we trained deep convolutional neural networks to diagnose the different cancer types and determined that the synthetic images perform as well as additional real images when used to supplement a small training set. These findings have important applications in proficiency testing of medical practitioners and quality assurance in clinical laboratories. Furthermore, training of computer-aided diagnostic systems can benefit from synthetic images where labeled datasets are limited (e.g. rare cancers). We have created a publicly available website where clinicians and researchers can attempt questions from the image survey (http://gan.aimlab.ca/). © 2020 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd., (© 2020 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.)

Objective: To evaluate the longitudinal responsiveness (sensitivity to change) of the Patient-Reported Outcomes Measurement Information System (PROMIS) Global Health Short Form (PROMIS10) in outpatients with systemic lupus erythematosus (SLE)., Methods: Outpatients with SLE who were receiving care at an academic medical center completed the PROMIS10 at 2 visits that were a minimum of 1 month apart. Responsiveness of the PROMIS10 global physical and mental health domains to Patient-Reported improvement or deterioration of health status was evaluated, as measured by standard validated instruments. Effect sizes of changes in PROMIS10 scores between visits were evaluated using Kruskal-Wallis testing., Results: A total of 223 SLE patients enrolled and completed baseline surveys, with 186 (83.4%) completing a second set of questionnaires. The PROMIS10 demonstrated mild-to-moderate responsiveness to Patient-Reported improvement (effect size 0.29) and worsening (effect sizes -0.27 and -0.54) of health status for both global physical health and global mental health. Changes in the PROMIS10 correlated poorly with changes in physician-reported measures of disease activity., Conclusion: The PROMIS10 showed responsiveness over time to Patient-Reported changes in SLE health status, but not physician-assessed changes. These data suggest that the PROMIS10 can be used to efficiently measure and monitor important aspects of the SLE patient experience that are not captured by standard physician-derived metrics. Further studies are needed to evaluate the role of the PROMIS10 in optimizing longitudinal disease management in SLE and to determine its responsiveness in other chronic health conditions., (© 2019, American College of Rheumatology.)

Effective management of brain and spine tumors relies on a multidisciplinary approach encompassing surgery, radiation, and systemic therapy. In the era of personalized oncology, the latter is complemented by various molecularly targeting agents. Precise identification of cellular targets for these drugs requires comprehensive profiling of the cancer genome coupled with an efficient analytic pipeline, leading to an informed decision on drug selection, prognosis, and confirmation of the original pathological diagnosis. Acquisition of optimal tumor tissue for such analysis is paramount and often presents logistical challenges in neurosurgery. Here, we describe the experience and results of the Personalized OncoGenomics (POG) program with a focus on tumors of the central nervous system (CNS). Patients with recurrent CNS tumors were consented and enrolled into the POG program prior to accrual of tumor and matched blood followed by whole-genome and transcriptome sequencing and processing through the POG bioinformatic pipeline. Sixteen patients were enrolled into POG. In each case, POG analyses identified genomic drivers including novel oncogenic fusions, aberrant pathways, and putative therapeutic targets. POG has highlighted that personalized oncology is truly a multidisciplinary field, one in which neurosurgeons must play a vital role if these programs are to succeed and benefit our patients., (© 2019 Wong et al.; Published by Cold Spring Harbor Laboratory Press.)

Deep learning refers to a set of computer models that have recently been used to make unprecedented progress in the way computers extract information from images. These algorithms have been applied to tasks in numerous medical specialties, most extensively radiology and pathology, and in some cases have attained performance comparable to human experts. Furthermore, it is possible that deep learning could be used to extract data from medical images that would not be apparent by human analysis and could be used to inform on molecular status, prognosis, or treatment sensitivity. In this review, we outline the current developments and state-of-the-art in applying deep learning for cancer diagnosis, and discuss the challenges in adapting the technology for widespread clinical deployment., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Objective The aims of this study were to assess the feasibility of administering Patient-Reported Outcomes Measurement Information System (PROMIS®) computerized adaptive tests (CATs) to outpatients with systemic lupus erythematosus (SLE). Methods Adults with SLE were recruited during routine outpatient visits at an SLE Center of Excellence. Participants completed 14 PROMIS CATs and provided feedback on their experience. Differences in socio-demographic and clinical characteristics between participants and non-participants were evaluated. Results A total of 204 (86%) of 238 socioeconomically and racially diverse SLE patients completed PROMIS CATs. There were no significant differences between participants and non-participants. Time constraints were cited most frequently as reasons for non-participation. More than 75% of individuals submitted positive comments, including approval of the content and format of questions, and the survey's promotion of self-reflection. A minority of participants cited challenges, most often related to question phrasing (8%) and technical difficulties (6%). Conclusions The administration of PROMIS CATs was feasible and positively received in a diverse cohort of SLE outpatients. Neither socio-demographic nor disease characteristics were significant barriers to successful completion of PROMIS CATs. PROMIS CATs have great potential for efficiently measuring important patient-centered outcomes in routine clinical care of a wide range of SLE patients.

Background: Primary central nervous system lymphoma (PCNSL) is a rare malignancy that usually arises in the context of severe immunosuppression but has incompletely understood etiology, limiting effective treatments., Case Description: We present the case of an 81-year-old immunocompetent man who developed a PCNSL in the right temporal lobe, at the site of a remote episode of herpes simplex virus (HSV) encephalitis 8 years prior. There are numerous viruses with known oncogenic associations; however, to our knowledge, this is the first reported case of PCNSL with an antecedent HSV infection., Conclusions: We discuss this case in the context of our current understandings of the pathogenesis of HSV encephalitis and PCNSL and postulate mechanisms through which the 2 could be associated., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Objective: To assess the feasibility, validity, and reliability of the Patient Reported Outcomes Measurement Information System Global Health Short Form (PROMIS10) in outpatients with systemic lupus erythematosus (SLE)., Methods: SLE outpatients completed PROMIS10, Medical Outcomes Study Short Form-36 (SF-36), LupusQoL-US, and selected PROMIS computerized adaptive tests (CAT) at routine visits at an SLE Center of Excellence. Construct validity was evaluated by correlating PROMIS10 physical and mental health scores with PROMIS CAT, legacy instruments, and physician-derived measures of disease activity and damage. Test-retest reliability was determined among subjects reporting stable SLE activity at 2 assessments 1 week apart using intraclass correlation coefficients (ICC)., Results: A diverse cohort of 204 out of 238 patients with SLE (86%) completed survey instruments. PROMIS10 physical health scores strongly correlated with physical function, pain, and social health domains in PROMIS CAT, SF-36, and LupusQoL, while mental health scores strongly correlated with PROMIS depression CAT, SF-36, and LupusQoL mental health domains (Spearman correlations ≥ 0.70). Active arthritis, comorbid fibromyalgia (FM), and anxiety were associated with worse PROMIS10 scores, but sociodemographic factors and physician-assessed flare status were not. Test-retest reliability for PROMIS10 physical and mental health scores was high (ICC ≥ 0.85). PROMIS10 required < 2 minutes to complete., Conclusion: PROMIS10 is valid and reliable, and can efficiently screen for impaired physical function, pain, and emotional distress in outpatients with SLE. With strong correlations to LupusQoL and SF-36 but significantly reduced responder burden, PROMIS10 is a promising tool for measuring patient-reported outcomes in routine SLE clinical care and value-based healthcare initiatives.

Objective: The aims of this study were to assess the construct validity and the test-retest reliability of Patient Reported Outcomes Measurement Information System (PROMIS) computerized adaptive tests (CAT) in patients with systemic lupus erythematosus (SLE)., Methods: Adults with SLE completed the Medical Outcomes Study Short Form-36, LupusQoL-US version ("legacy instruments"), and 14 selected PROMIS CAT. Using Spearman correlations, PROMIS CAT were compared with similar domains measured with legacy instruments. CAT were also correlated with the Safety of Estrogens in Lupus Erythematosus National Assessment-Systemic Lupus Erythematosus Disease Activity Index (SELENA-SLEDAI) disease activity and the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SDI) scores. Test-retest reliability was evaluated using ICC., Results: There were 204 outpatients with SLE enrolled in the study and 162 completed a retest. PROMIS CAT showed good performance characteristics and moderate to strong correlations with similar domains in the 2 legacy instruments (r = -0.49 to 0.86, p < 0.001). However, correlations between PROMIS CAT and the SELENA-SLEDAI disease activity and SDI were generally weak and statistically insignificant. PROMIS CAT test-retest ICC were good to excellent, ranging from 0.72 to 0.88., Conclusion: To our knowledge, these data are the first to show that PROMIS CAT are valid and reliable for many SLE-relevant domains. Importantly, PROMIS scores did not correlate well with physician-derived measures. This disconnect between objective signs and symptoms and the subjective patient disease experience underscores the crucial need to integrate patient-reported outcomes into clinical care to ensure optimal disease management.

Background: Spinal cord stimulation (SCS) is a well-established treatment for chronic neuropathic pain in the lower limbs. However, some patients have pain in distributions that are difficult to target specifically and consistently with SCS. This often involves pain in the groin or upper limbs, or pain limited to a specific dermatome. We hypothesized that dorsal nerve root stimulation (DNRS) would provide similar pain relief for these patients, compared to our results using SCS., Objectives: In this study we report our experience treating patients with chronic neuropathic pain using SCS and DNRS., Study Design: Open label, prospective study that includes all patients treated with a new trial stimulator system at a single center between July 1, 2011, and October 31, 2013., Setting: Academic university neurosurgical pain center., Methods: One hundred thirty-two consecutive patients had trials of spinal stimulation. Seventy-six patients went on to permanent implants, of which 26 received only DNRS, 47 only SCS, and 3 both. The technique was selected based on clinical assessment and intraoperative test stimulation. Other than pain location and diagnosis, the DNRS and SCS groups had similar baseline characteristics. Follow-up is reported at 12 months. Patients were assessed using a visual analogue scale (VAS) for pain, the SF-36 for quality of life, and the morphine equivalent daily dose (MEDD)., Results: At 12 months, the average VAS score for the DNRS group had decreased from 7.5 (SD 1.4) to 4.4 (SD 2.6) and 47% of patients with permanent implants achieved > 50% pain reduction. There were improvements in all subscores and component summary scores of the SF-36. The MEDD had been reduced in 55% of the patients with available data. There was no significant difference in complication or revision rates between the 2 groups., Limitations: Patients were not randomized to treatment groups, and instead were assigned to SCS or DNRS based on what was expected to provide superior pain coverage. There is incomplete follow-up data for some patients due to missed clinic visits., Conclusions: In our study, DNRS provided excellent pain reduction, quality of life improvement, and opioid medication use decreases. We conclude that it is an effective long-term treatment for chronic neuropathic pain.Key words: Spinal cord stimulation, dorsal nerve root stimulation, lumbar, thoracic, cervical, neuropathic pain, neuromodulation, clinical effectiveness, chronic pain, visual analogue scale.

Background: Spinal cord stimulation (SCS) is a well-established treatment for chronic neuropathic pain in the lower limbs. Upper limb pain comprises a significant proportion of neuropathic pain patients, but is often difficult to target specifically and consistently with paresthesias. We hypothesized that the use of dorsal nerve root stimulation (DNRS), as an option along with SCS, would help us better relieve pain in these patients., Methods: All 35 patients trialed with spinal stimulation for upper limb pain between July 1, 2011, and October 31, 2013, were included. We performed permanent implantation in 23/35 patients based on a visual analogue scale pain score decrease of ≥50% during trial stimulation., Results: Both the SCS and DNRS groups had significant improvements in average visual analogue scale pain scores at 12 months compared with baseline, and the majority of patients in both groups obtained ≥50% pain relief. The majority of patients in both groups were able to reduce their opioid use, and on average had improvements in Short Form-36 quality of life scores. Complication rates did not differ significantly between the two groups., Conclusions: Treatment with SCS or DNRS provides meaningful long-term relief of chronic neuropathic pain in the upper limbs.

Background: Chronic neuropathic groin pain is a common problem. It can arise following surgery or trauma, or spontaneously as part of various pelvic pain syndromes. A number of different stimulation techniques have been reported in the literature to treat this area, but due to the complex anatomy of the region, it can be difficult to target effectively with paresthesias., Objectives: In this study we report our results treating patients with chronic neuropathic groin, pelvic, and abdominal pain, using spinal cord stimulation and dorsal nerve root stimulation., Study Design: Open label, prospective study that includes all patients treated with a new trial stimulator system at a single center between July 1, 2011, and October 31, 2013., Setting: Academic university neurosurgical pain center, Canada., Methods: Thirty-two patients had trials of spinal cord stimulation and/or dorsal nerve root stimulation in the thoracic or lumbar spine. Patients were evaluated on visual analog scale pain scores, SF-36, and morphine equivalent daily dose. Data were recorded at the pre-implant visit, and 3, 6, and 12 months following permanent implant., Results: The 15 patients who went on to permanent implants had, on average, significant pain reduction and improvements in quality of life at the 12 month follow-up. The majority of patients who were taking opioids at the initial assessment were able to reduce their dose with treatment. Three patients with successful trials were long-term non-responders, of whom 2 had the permanent device removed., Limitations: This study would benefit from a larger sample size that would have adequate power for comparisons between patient subgroups and stimulation techniques., Conclusion: Dorsal nerve root stimulation is an effective long-term treatment for neuropathic groin pain.

Background: Deep brain stimulation (DBS) of the ventrocaudalis nucleus of the thalamus is a last resort treatment for chronic refractory pain. DBS is generally a safe procedure, although it can result in functional disturbances depending on the site of stimulation. There has been 1 previous report of stuttering induced by microlesioning of the thalamus, as well as several reports of stuttering induced by stimulation of the thalamus and other related structures in the brain., Case Description: We describe the case of a patient with trigeminal deafferentation face pain who was treated with DBS of the ventrocaudalis nucleus thalamus and developed a reversible stutter immediately on insertion of the electrode. The stutter improved significantly over 12 days after implant; however, the device was not effective in relieving the patient's pain and was removed., Conclusions: Stuttering is a rare complication of deep brain exploration of the sensory thalamus. Our coordinates are near to but in a distinct anatomic region compared with cases previously described as having similar effects on speech., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Objective: In a 3-year randomized, double-blind, osteoporosis treatment study (N = 7,492), bazedoxifene 20 mg and bazedoxifene 40 mg significantly (P < 0.05) reduced the risk of new vertebral fractures by 42% and 37%, respectively, compared with placebo in postmenopausal women with osteoporosis. This study evaluated the long-term (7-y) efficacy and safety of bazedoxifene in generally healthy postmenopausal women with osteoporosis., Methods: This was a second 2-year extension of the 3-year multicenter outpatient core study. During extension I (years 4-5), women receiving bazedoxifene 40 mg transitioned to bazedoxifene 20 mg. In extension II (years 6-7; N = 1,530), all bazedoxifene-treated women continued bazedoxifene 20 mg. Main outcome measures included year 7 endpoints: incidences of new vertebral and nonvertebral fractures, bone mineral density changes, and safety assessments., Results: At 7 years, the cumulative incidences of new vertebral fractures were significantly lower in the bazedoxifene (6.4%) and bazedoxifene 20 mg (7.6%) groups than in the placebo group (9.9%); the relative risk reductions were 36.5% and 30.4%, respectively (both P < 0.001). Bazedoxifene had no effect on the overall incidence of nonvertebral fractures (bazedoxifene, 11.2%; bazedoxifene 20 mg, 12.0%; placebo, 10.8%). The mean changes from baseline in lumbar spine bone mineral density were 2.95%, 2.73%, and 2.19%, respectively. Seven-year decreases in total hip bone mineral density were significantly smaller in the bazedoxifene (-1.15%) and bazedoxifene 20 mg (-1.19%) groups than in the placebo group (-2.53%; P ≤ 0.002). Bazedoxifene showed a favorable safety/tolerability profile across 7 years, with similar adverse events, serious adverse events, and study discontinuations in all groups., Conclusions: Efficacy and safety of bazedoxifene are sustained across 7 years in postmenopausal women with osteoporosis.

Bazedoxifene (BZA) is a selective estrogen receptor modulator that has been shown to prevent and treat postmenopausal osteoporosis. Hip structure analysis (HSA) can be used to extract bone structural properties related to strength from hip bone mineral density (BMD) scans. This exploratory analysis used HSA to evaluate changes in hip structural geometry in postmenopausal women enrolled in a phase 3 osteoporosis treatment study who were treated with BZA 20mg or placebo for 2 years. This analysis cohort included women at increased fracture risk based on known skeletal risk factors (n = 521); 1 or more moderate or severe fractures or 2 or more mild vertebral fractures and/or femoral neck BMD T-score ≤ -3.0 at baseline combined with additional women from the overall study population (n = 475); a subgroup analysis included just those women at increased fracture risk. HSA was applied to duplicate hip dual-energy X-ray absorptiometry (DXA) scans acquired at screening and 24 months. Percent change from baseline was evaluated using an analysis of covariance for BMD and geometric parameters including section modulus (SM), cross-sectional area (CSA), outer diameter (OD), and buckling ratio (BR). In all regions, BZA was associated with increased BMD and improvements in hip structural geometry. In the narrow neck, BZA 20mg significantly increased SM, CSA, OD, and BMD compared with placebo (P < 0.05 for all). In the intertrochanter region, BZA 20mg significantly increased CSA and BMD and decreased BR compared with placebo (P < 0.05 for all). Other than BMD (P < 0.05), effects of BZA 20mg at the shaft did not reach statistical significance. Similar trends toward improvement in structural geometry with BZA 20mg were observed in all three regions of the hip for the subgroup of women at increased fracture risk. Overall, BZA was associated with geometry-related improvements in bone strength with regard to resistance to bending and compressive forces and to local buckling. These improvements were evident at common fracture locations such as the femoral neck and intertrochanter regions, and are consistent with the significant treatment effect reported for BZA on nonvertebral fractures in higher-risk postmenopausal women with osteoporosis., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Objective: To determine frequency, demographic and treatment characteristics of patients with an overlapping second autoimmune illness (2nd AI)., Methods: We analysed two cohorts containing 897 patients with 'pure' systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), Sjögren's syndrome or antiphospholipid syndrome (APS) and 424 patients with one of these diagnoses plus at least one 2nd AI., Results: A 2nd AI occurred in 38% of all patients diagnosed as having SLE (with or without a 2nd AI), 30% with RA, 52% with Sjögren's syndrome and 43% with APS. Compared to those without 2nd AI, patients with 2nd AI differ in age, sex, race and treatment at last visit., Intepretation: These differences may have important implications for understanding treatments, outcomes and mechanisms of SLE and related diseases.