The Impact of On-Target Resistance Mediated by EGFR-T790M or EGFR-C797S on EGFR Exon 20 Insertion Mutation Active Tyrosine Kinase Inhibitors.

Introduction: Mechanisms of resistance to EGFR exon 20 insertion mutation active inhibitors have not been extensively studied in either robust preclinical models or patient-derived rebiopsy specimens. We sought to characterize on-target resistance mutations identified in EGFR exon 20 insertion-mutated lung cancers treated with mobocertinib or poziotinib and evaluate whether these mutations would or would not have cross-resistance to next-generation inhibitors zipalertinib, furmonertinib, and sunvozertinib. Methods: We identified mechanisms of resistance to EGFR exon 20 insertion mutation active inhibitors and then used preclinical models of EGFR exon 20 insertion mutations (A767_V769dupASV, D770_N771insSVD, V773_C774insH) plus common EGFR mutants to probe inhibitors in the absence/presence of EGFR-T790M or EGFR-C797S. Results: Mobocertinib had a favorable therapeutic window in relation to EGFR wild type for EGFR exon 20 insertion mutants, but the addition of EGFR-T790M or EGFR-C797S negated the observed window. Zipalertinib had a favorable therapeutic window for cells driven by EGFR-A767_V769dupASV or EGFR-D770_N771insSVD in the presence or absence of EGFR-T790M. Furmonertinib and sunvozertinib had the most favorable therapeutic windows in the presence or absence of EGFR-T790M in all cells tested. EGFR-C797S in cis to all EGFR mutations evaluated generated dependent cells that were resistant to the covalent EGFR tyrosine kinase inhibitors mobocertinib, zipalertinib, furmonertinib, sunvozertinib, poziotinib, and osimertinib. Conclusions: This report highlights that poziotinib and mobocertinib are susceptible to on-target resistance mediated by EGFR-T790M or -C797S in the background of the most prevalent EGFR exon 20 insertion mutations. Furmonertinib, sunvozertinib, and to a less extent zipalertinib can overcome EGFR-T790M compound mutants, whereas EGFR-C797S leads to covalent inhibitor cross-resistance-robust data that support the limitations of mobocertinib and should further spawn the development of next-generation covalent and reversible EGFR exon 20 insertion mutation active inhibitors with favorable therapeutic windows that are less vulnerable to on-target resistance.

Heritability and variance component estimation for feed and water intake behaviors of feedlot cattle.

Feed and water intake are two important aspects of cattle production that greatly impact the profitability, efficiency, and sustainability of producers. Feed and, to a lesser degree, water intake have been studied previously; however, there is little research on their associated animal behaviors and there is a lack of standardized phenotypes for these behaviors. Feed and water intakes obtained with an Insentec system (Hokofarm Group, The Netherlands) from 830 crossbred steers were used to compute five intake behaviors for both feed and water: daily sessions (DS), intake rate (IR), session size (SS), time per session (TS), and session interval (SI). Variance components and heritabilities were estimated for each trait. Heritabilities for feed intake behaviors were 0.50 ±â€…0.12, 0.63 ±â€…0.12, 0.40 ±â€…0.13, 0.35 ±â€…0.12, and 0.60 ±â€…0.12 for DS, IR, SS, TS, and SI, respectively. Heritabilities for water intake behaviors were 0.56 ±â€…0.11, 0.88 ±â€…0.07, 0.70 ±â€…0.11, 0.54 ±â€…0.12, and 0.80 ±â€…0.10 for NS, IR, SS, TS, and SI, respectively. Daily dry matter intake (DDMI) and daily water intake (DWI) had heritabilities of 0.57 ±â€…0.11 and 0.44 ±â€…0.11. Phenotypic correlations varied between pairs of traits (-0.83 to 0.82). Genetic correlations between DDMI and feed intake behaviors were moderate to high, while genetic correlations between DWI and water intake behaviors were low to moderate. Several significant single nucleotide polymorphisms (SNP) were identified for the feed and water intake behaviors. Genes and previously reported quantitative trait loci near significant SNPs were evaluated. The results indicated that feed and water intake behaviors are influenced by genetic factors and are heritable, providing one additional route to evaluate or manipulate feed and water intake.

Feed and water intake are important aspects of cattle production to understand because they impact producer profitability and sustainability. While feed intake and, to a lesser degree, water intake have previously been studied, the associated feeding and drinking behaviors are relatively unknown and lack standardized phenotypes. Using individual animal feed and water intake records, five behaviors were evaluated for feed and water intake from crossbred feedlot steers. The behaviors evaluated were daily sessions (no./d), session size (kg), time per session (s), intake rate (g/s), and session interval (min). The impact of season (winter vs. summer) and bunk management (ad libitum vs. slick) on feeding and drinking behaviors was evaluated. Heritability and variance components were estimated for all feeding and drinking behaviors. Pairwise phenotypic correlations between behaviors were discussed. The relationship between intake and feeding or drinking behaviors was evaluated with genetic correlations. A genome-wide association study identified several significant single nucleotide polymorphisms for feeding and drinking behaviors. The results indicate that feeding and drinking behaviors are heritable and may be one additional route to evaluate feed and water intake.

EGFR exon 19 insertion EGFR-K745_E746insIPVAIK and others with rare XPVAIK amino-acid insertions: Preclinical and clinical characterization of the favorable therapeutic window to all classes of approved EGFR kinase inhibitors.

BACKGROUND: The epidermal growth factor receptor (EGFR)-K745_E746insIPVAIK and others with XPVAIK amino-acid insertions are exon 19 insertion mutations, which, at the structural modeling level, resemble EGFR tyrosine kinase inhibitor (TKI)-sensitizing mutants. An important unmet need is the characterization of therapeutic windows plus clinical outcomes of exon 19 XPVAIK amino-acid insertion mutations to available EGFR TKIs. METHODS: We used preclinical models of EGFR-K745_E746insIPVAIK and more typical EGFR mutations (exon 19 deletion, L858R, L861Q, G719S, A763_Y764insFQEA, other exon 20 insertion mutations) to probe representative 1st (erlotinib), 2nd (afatinib), 3rd generation (osimertinib), and EGFR exon 20 insertion active (mobocertinib) TKIs. We also compiled outcomes of EGFR exon 19 insertion mutated lung cancers-from our institution plus the literature-treated with EGFR TKIs. RESULTS: Exon 19 insertions represented 0.3-0.8% of all EGFR kinase domain mutation in two cohorts (n = 1772). Cells driven by EGFR-K745_E746insIPVAIK had sensitivity to all classes of approved EGFR TKIs when compared to cells driven by EGFR-WT in proliferation assays and at the protein level. However, the therapeutic window of EGFR-K745_E746insIPVAIK driven cells was most akin to those of cells driven by EGFR-L861Q and EGFR-A763_Y764insFQEA than the more sensitive patterns seen with cells driven by an EGFR exon 19 deletion or EGFR-L858R. The majority (69.2%, n = 26) of patients with lung cancers harboring EGFR-K745_E746insIPVAIK and other mutations with rare XPVAIK amino-acid insertions responded to clinically available EGFR TKIs (including icotinib, gefitinib, erlotinib, afatinib and osimertinib), with heterogeneous periods of progression-free survival. Mechanisms of acquired EGFR TKI resistance of this mutant remained underreported. CONCLUSIONS: This is the largest preclinical/clinical report to highlight that EGFR-K745_E746insIPVAIK and other mutations with exon 19 XPVAIK amino-acid insertions are rare but sensitive to clinically available 1st, 2nd, and 3rd generation as well as EGFR exon 20 active TKIs; in a pattern that mostly resembles the outcomes of models with EGFR-L861Q and EGFR-A763_Y764insFQEA mutations. These data may help with the off-label selection of EGFR TKIs and clinical expectations of outcomes when targeted therapy is deployed for these EGFR mutated lung cancers.

Biologic Association Annual Summit: 2020 Report.

Interest and research in biologic approaches for tissue healing are exponentially growing for a variety of musculoskeletal conditions. The recent hype concerning musculoskeletal biological therapies (including viscosupplementation, platelet-rich plasma, and cellular therapies, or "stem cells") is driven by several factors, including demand by patients promising regenerative evidence supported by substantial basic and translational work, as well as commercial endeavors that complicate the scientific and lay understanding of biological therapy outcomes. While significant improvements have been made in the field, further basic and preclinical research and well-designed randomized clinical trials are needed to better elucidate the optimal indications, processing techniques, delivery, and outcome assessment. Furthermore, biologic treatments may have potential devastating complications when proper methods or techniques are ignored. For these reasons, an association comprising several scientific societies, named the Biologic Association (BA), was created to foster coordinated efforts and speak with a unified voice, advocating for the responsible use of biologics in the musculoskeletal environment in clinical practice, spearheading the development of standards for treatment and outcomes assessment, and reporting on the safety and efficacy of biologic interventions. This article will introduce the BA and its purpose, provide a summary of the 2020 first annual Biologic Association Summit, and outline the future strategic plan for the BA.

Harmonized outcome measures for use in degenerative lumbar spondylolisthesis patient registries and clinical practice.

OBJECTIVE: The development of new treatment approaches for degenerative lumbar spondylolisthesis (DLS) has introduced many questions about comparative effectiveness and long-term outcomes. Patient registries collect robust, longitudinal data that could be combined or aggregated to form a national and potentially international research data infrastructure to address these and other research questions. However, linking data across registries is challenging because registries typically define and capture different outcome measures. Variation in outcome measures occurs in clinical practice and other types of research studies as well, limiting the utility of existing data sources for addressing new research questions. The purpose of this project was to develop a minimum set of patient- and clinician-relevant standardized outcome measures that are feasible for collection in DLS registries and clinical practice. METHODS: Nineteen DLS registries, observational studies, and quality improvement efforts were invited to participate and submit outcome measures. A stakeholder panel was organized that included representatives from medical specialty societies, health systems, government agencies, payers, industries, health information technology organizations, and patient advocacy groups. The panel categorized the measures using the Agency for Healthcare Research and Quality's Outcome Measures Framework (OMF), identified a minimum set of outcome measures, and developed standardized definitions through a consensus-based process. RESULTS: The panel identified and harmonized 57 outcome measures into a minimum set of 10 core outcome measure areas and 6 supplemental outcome measure areas. The measures are organized into the OMF categories of survival, clinical response, events of interest, patient-reported outcomes, and resource utilization. CONCLUSIONS: This effort identified a minimum set of standardized measures that are relevant to patients and clinicians and appropriate for use in DLS registries, other research efforts, and clinical practice. Collection of these measures across registries and clinical practice is an important step for building research data infrastructure, creating learning healthcare systems, and improving patient management and outcomes in DLS.

Osteoporosis: Recent Recommendations and Positions of the American Society for Bone and Mineral Research and the International Society for Clinical Densitometry.

➤: Osteoporosis is common in orthopaedic patients, not only in those sustaining fragility fractures but also in patients ≥50 years old who are having elective orthopaedic surgery. ➤: The American Society for Bone and Mineral Research (ASBMR) has developed consensus-based recommendations for secondary fracture prevention for all patients who are ≥65 years old with a hip or spine fracture. ➤: The ASBMR encourages orthopaedic surgeons to "Own the Bone," by beginning prevention of a secondary fracture during hospitalization for a fragility fracture, if practicable, and arranging follow-up for continued bone health care after discharge. ➤: The International Society for Clinical Densitometry (ISCD) recognized that many poor outcomes and complications of elective orthopaedic surgery are related to osteoporosis. ➤: The ISCD used an evidence-based approach to create official positions to identify which patients ≥50 years old who are having elective orthopaedic surgery should undergo assessment of bone health and how this should be performed.

Atypical Presentation of Extramedullary Plasmacytoma.

BACKGROUND: Plasmacytomas are monoclonal proliferations of plasma cells that typically affect the intramedullary axial skeleton. Imaging findings of an extramedullary plasmacytoma on radiograph and computed tomography can be nonspecific and can resemble other entities such as lymphoma, metastases, chondrosarcomas, or giant cell tumors. CASE REPORT: A 60-year-old female with a medical history of partial complex seizures, hypertension, diabetes, glaucoma, and hyperlipidemia presented with complaints of superficial abdominal pain associated with erythema and swelling for 3 weeks. Computed tomography of her abdomen at time of presentation revealed a 5.8 × 2.7-cm irregularly marginated soft-tissue density just below the umbilicus with an adjacent defect in the midline rectus abdominis. The final pathologic diagnosis was extramedullary plasmacytoma. Treatment during the next year included local radiation, systemic chemotherapy, and an autologous peripheral blood stem cell transplant. Three years after initial diagnosis, the patient presented to the emergency department, and testing revealed new plasmacytomas. The decision was made to proceed with palliative care. CONCLUSION: This case is a unique example of a patient with an extramedullary plasmacytoma with no diagnostic signs of multiple myeloma.

Mitochondrial Encephalomyopathy With Lactic Acidosis and Stroke-Like Episodes-MELAS Syndrome.

BACKGROUND: Mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS) syndrome is a rare inherited disorder that results in waxing and waning nervous system and muscle dysfunction. MELAS syndrome may overlap with other neurologic disorders but shows distinctive imaging features. CASE REPORT: We present the case of a 28-year-old female with atypical stroke-like symptoms, a strong family history of stroke-like symptoms, and a relapsing-remitting course for several years. We discuss the imaging features distinctive to the case, the mechanism of the disease, typical presentation, imaging diagnosis, and disease management. CONCLUSION: This case is a classic example of the relapse-remitting MELAS syndrome progression with episodic clinical flares and fluctuating patterns of stroke-like lesions on imaging. MELAS is an important diagnostic consideration when neuroimaging reveals a pattern of disappearing and relapsing cortical brain lesions that may occur in different areas of the brain and are not necessarily limited to discrete vascular territories. Future studies should investigate disease mechanisms at the cellular level and the value of advanced magnetic resonance imaging techniques for a targeted approach to therapy.

Cannabis use in people with Parkinson's disease and Multiple Sclerosis: A web-based investigation.

OBJECTIVES: Cannabis has been used for medicinal purpose for thousands of years; however the positive and negative effects of cannabis use in Parkinson's disease (PD) and Multiple Sclerosis (MS) are mostly unknown. Our aim was to assess cannabis use in PD and MS and compare results of self-reported assessments of neurological disability between current cannabis users and non-users. METHODS: An anonymous web-based survey was hosted on the Michael J. Fox Foundation and the National Multiple Sclerosis Society webpages from 15 February to 15 October 2016. The survey collected demographic and cannabis use information, and used standardized questionnaires to assess neurological function, fatigue, balance, and physical activity participation. Analysis of variance and chi-square tests were used for the analysis. RESULTS: The survey was viewed 801 times, and 595 participants were in the final data set. Seventy-six percent and 24% of the respondents reported PD and MS respectively. Current users reported high efficacy of cannabis, 6.4 (SD 1.8) on a scale from 0 to 7 and 59% reported reducing prescription medication since beginning cannabis use. Current cannabis users were younger and less likely to be classified as obese (P < 0.035). Cannabis users reported lower levels of disability, specifically in domains of mood, memory, and fatigue (P<0.040). CONCLUSIONS: Cannabis may have positive impacts on mood, memory, fatigue, and obesity status in people with PD and MS. Further studies using clinically and longitudinally assessed measurements of these domains are needed to establish if these associations are causal and determine the long-term benefits and consequences of cannabis use in people with PD and MS.

Persistent Sciatic Artery: A Favorable Anatomic Variant in a Setting of Trauma.

BACKGROUND: Persistent sciatic artery (PSA) is a rare congenital anomaly of the circulation of the lower limb that results from the persistence of an artery that normally regresses early in embryonic development. PSA is usually an incidental finding and is exceedingly rare to find bilaterally. CASE REPORT: We present the case of a rare presentation of PSA that resulted in a favorable outcome for a patient who sustained a gunshot wound to his midthigh and discuss the history, embryology, anatomy, classification schema, imaging evaluation, complications, diagnosis, and management of PSA. CONCLUSION: PSAs are of doubtful clinical significance when found incidentally at imaging; however, individual patient symptoms, unique arterial anatomy, and the PSA classification best determine the appropriate treatment options.

The Medicare Access and CHIP Reauthorization Act (MACRA) of 2015: What's New?

The Centers for Medicare and Medicaid Services (CMS) released its Final Rule on the Medicare Access and CHIP [Children's Health Insurance Program] Reauthorization Act (MACRA) in November 2016. The Rule finalizes the details of the merit-based incentive payment system (MIPS) and the alternative payment model (APM), which will now collectively be referred to as the Quality Payment Program (QPP). This article offers the orthopaedic community a summary of the alterations in healthcare policy that will affect practices nationwide.

Understanding Value-based Reimbursement Models and Trends in Orthopaedic Health Policy: An Introduction to the Medicare Access and CHIP Reauthorization Act (MACRA) of 2015.

In 2015, the US Congress passed legislation entitled the Medicare Access and CHIP [Children's Health Insurance Program] Reauthorization Act (MACRA), which led to the formation of two reimbursement paradigms: the merit-based incentive payment system (MIPS) and alternative payment models (APMs). The MACRA effectively repealed the Centers for Medicare and Medicaid Services (CMS) sustainable growth rate (SGR) formula while combining several CMS quality-reporting programs. As such, MACRA represents an unparalleled acceleration toward reimbursement models that recognize value rather than volume. The first pathway, MIPS, consolidates several Medicare quality-reporting programs into one composite score that will be derived by four performance categories, including quality (30%), resource utilization (30%), meaningful use (25%), and clinical practice improvement activities (15%). The APM pathway includes the following programs: Medicare accountable care organizations as part of the Medicare Shared Savings Program, Bundled Payments for Care Improvement, and Comprehensive Primary Care initiative. Existing APMs have yet to be determined as eligible. We provide a contextual framework of the healthcare legislation that has led to the formation of current health policy and offer recommendations regarding SGR how orthopaedic surgeons may best steer through such reimbursement models.

An evidence-based clinical guideline for antibiotic prophylaxis in spine surgery.

BACKGROUND CONTEXT: The North American Spine Society's (NASS) Evidence-Based Clinical Guideline on Antibiotic Prophylaxis in Spine Surgery provides evidence-based recommendations to address key clinical questions regarding the efficacy and the appropriate antibiotic prophylaxis protocol to prevent surgical site infections in patients undergoing spine surgery. The guideline is intended to address these questions based on the highest quality clinical literature available on this subject as of June 2011. PURPOSE: Provide an evidence-based educational tool to assist spine surgeons in preventing surgical site infections. STUDY DESIGN: Systematic review and evidence-based clinical guideline. METHODS: This guideline is a product of the Antibiotic Prophylaxis in Spine Surgery Work Group of NASS Evidence-Based Guideline Development Committee. The work group consisted of neurosurgeons and orthopedic surgeons who specialize in spine surgery and are trained in the principles of evidence-based analysis. A literature search addressing each question and using a specific search protocol was performed on English language references found in MEDLINE (PubMed), ACP Journal Club, Cochrane Database of Systematic Reviews Database of Abstracts of Reviews of Effectiveness, Cochrane Central Register of Controlled Trials, EMBASE (Drugs and Pharmacology), and Web of Science to identify articles published since the search performed for the original guideline. The relevant literature was then independently rated using the NASS-adopted standardized levels of evidence. An evidentiary table was created for each of the questions. Final recommendations to answer each clinical question were developed via work group discussion, and grades were assigned to the recommendations using standardized grades of recommendation. In the absence of Levels I to IV evidence, work group consensus statements have been developed using a modified nominal group technique, and these statements are clearly identified as such in the guideline. RESULTS: Sixteen clinical questions were formulated and addressed, and the answers are summarized in this article. The respective recommendations were graded by the strength of the supporting literature, which was stratified by levels of evidence. CONCLUSIONS: The clinical guideline for antibiotic prophylaxis in spine surgery has been created using the techniques of evidence-based medicine and best available evidence to aid practitioners in the care of patients undergoing spine surgery. The entire guideline document, including the evidentiary tables, suggestions for future research, and all the references, is available electronically on the NASS Web site at http://www.spine.org/Pages/PracticePolicy/ClinicalCare/ClinicalGuidlines/Default.aspx and will remain updated on a timely schedule.

An evidence-based clinical guideline for the diagnosis and treatment of degenerative lumbar spinal stenosis (update).

BACKGROUND CONTEXT: The evidence-based clinical guideline on the diagnosis and treatment of degenerative lumbar spinal stenosis by the North American Spine Society (NASS) provides evidence-based recommendations to address key clinical questions surrounding the diagnosis and treatment of degenerative lumbar spinal stenosis. The guideline is intended to reflect contemporary treatment concepts for symptomatic degenerative lumbar spinal stenosis as reflected in the highest quality clinical literature available on this subject as of July 2010. The goals of the guideline recommendations are to assist in delivering optimum efficacious treatment and functional recovery from this spinal disorder. PURPOSE: Provide an evidence-based educational tool to assist spine care providers in improving quality and efficiency of care delivered to patients with degenerative lumbar spinal stenosis. STUDY DESIGN: Systematic review and evidence-based clinical guideline. METHODS: This report is from the Degenerative Lumbar Spinal Stenosis Work Group of the NASS's Evidence-Based Clinical Guideline Development Committee. The work group consisted of multidisciplinary spine care specialists trained in the principles of evidence-based analysis. The original guideline, published in 2006, was carefully reviewed. A literature search addressing each question and using a specific search protocol was performed on English language references found in MEDLINE, EMBASE (Drugs and Pharmacology), and four additional, evidence-based, databases to identify articles published since the search performed for the original guideline. The relevant literature was then independently rated by a minimum of three physician reviewers using the NASS-adopted standardized levels of evidence. An evidentiary table was created for each of the questions. Final recommendations to answer each clinical question were arrived at via work group discussion, and grades were assigned to the recommendations using standardized grades of recommendation. In the absence of Levels I to IV evidence, work group consensus statements have been developed using a modified nominal group technique, and these statements are clearly identified as such in the guideline. RESULTS: Sixteen key clinical questions were assessed, addressing issues of natural history, diagnosis, and treatment of degenerative lumbar spinal stenosis. The answers are summarized in this document. The respective recommendations were graded by the strength of the supporting literature that was stratified by levels of evidence. CONCLUSIONS: A clinical guideline for degenerative lumbar spinal stenosis has been updated using the techniques of evidence-based medicine and using the best available clinical evidence to aid both practitioners and patients involved with the care of this condition. The entire guideline document, including the evidentiary tables, suggestions for future research, and all references, will be available electronically at the NASS Web site (www.spine.org) and will remain updated on a timely schedule.