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Showing papers by "Oregon Health & Science University published in 2019"


Journal ArticleDOI
TL;DR: Enough evidence was available to conclude that specific doses of aerobic, combined aerobic plus resistance training, and/or resistance training could improve common cancer-related health outcomes, including anxiety, depressive symptoms, fatigue, physical functioning, and health-related quality of life.
Abstract: PurposeThe number of cancer survivors worldwide is growing, with over 15.5 million cancer survivors in the United States alone—a figure expected to double in the coming decades. Cancer survivors face unique health challenges as a result of their cancer diagnosis and the impact of treatments

1,174 citations


Journal ArticleDOI
TL;DR: The GVG proposes a new Global Anatomic Staging System (GLASS), which involves defining a preferred target artery path (TAP) and then estimating limb-based patency (LBP) resulting in three stages of complexity for intervention.

993 citations


Journal ArticleDOI
TL;DR: The metabolic circuitries whereby TAMs condition the TME to support tumor growth and how such pathways can be therapeutically targeted are discussed.

752 citations


Journal ArticleDOI
03 May 2019
TL;DR: The estimated percentages of patients who are eligible for and who respond to checkpoint inhibitor drugs are higher than reported estimates for drugs approved for genome-driven oncology but remain modest.
Abstract: Importance Immunotherapy checkpoint inhibitors have generated considerable interest because of durable responses in a number of hitherto intractable tumor types. Objective To estimate the percentage of patients with cancer in the United States who are eligible for and respond to checkpoint inhibitor drugs approved for oncology indications by the US Food and Drug Administration (FDA). Design, Setting, and Participants Retrospective cross-sectional study performed from June 2018 through October 2018 using publicly available data to determine (1) demographic characteristics of patients with advanced or metastatic cancer, (2) FDA data on checkpoint inhibitors approved from January 2011 through August 2018, (3) measures of response from drug labels, and (4) published reports estimating the frequency of various inclusion criteria. Main Outcomes and Measures The estimated percentages of US patients with cancer who are eligible for and who respond to immunotherapy checkpoint inhibitor drugs, by year. Results Six checkpoint inhibitor drugs were approved for 14 indications between March 25, 2011, and August 17, 2018. The estimated percentage of patients with cancer who were eligible for checkpoint inhibitor drugs increased from 1.54% (95% CI, 1.51%-1.57%) in 2011 to 43.63% (95% CI, 43.51%-43.75%) in 2018. The percentage of patients with cancer estimated to respond to checkpoint inhibitor drugs was 0.14% (95% CI, 0.13%-0.15%) in 2011 when ipilimumab was approved for unresectable or metastatic melanoma and increased to 5.86% (95% CI, 5.80%-5.92%) by 2015. By 2018, the estimated percentage of responders increased to 12.46% (95% CI, 12.37%-12.54%). Conclusions and Relevance The estimated percentages of patients who are eligible for and who respond to checkpoint inhibitor drugs are higher than reported estimates for drugs approved for genome-driven oncology but remain modest. Future research should explore biomarkers to maximize the benefit of immunotherapy among patients receiving it.

719 citations


Journal ArticleDOI
TL;DR: There are also potential challenges with DL application in ophthalmology, including clinical and technical challenges, explainability of the algorithm results, medicolegal issues, and physician and patient acceptance of the AI ‘black-box’ algorithms.
Abstract: Artificial intelligence (AI) based on deep learning (DL) has sparked tremendous global interest in recent years. DL has been widely adopted in image recognition, speech recognition and natural language processing, but is only beginning to impact on healthcare. In ophthalmology, DL has been applied to fundus photographs, optical coherence tomography and visual fields, achieving robust classification performance in the detection of diabetic retinopathy and retinopathy of prematurity, the glaucoma-like disc, macular oedema and age-related macular degeneration. DL in ocular imaging may be used in conjunction with telemedicine as a possible solution to screen, diagnose and monitor major eye diseases for patients in primary care and community settings. Nonetheless, there are also potential challenges with DL application in ophthalmology, including clinical and technical challenges, explainability of the algorithm results, medicolegal issues, and physician and patient acceptance of the AI ‘black-box’ algorithms. DL could potentially revolutionise how ophthalmology is practised in the future. This review provides a summary of the state-of-the-art DL systems described for ophthalmic applications, potential challenges in clinical deployment and the path forward.

669 citations


Journal ArticleDOI
TL;DR: The HPO’s interoperability with other ontologies has enabled it to be used to improve diagnostic accuracy by incorporating model organism data and plays a key role in the popular Exomiser tool, which identifies potential disease-causing variants from whole-exome or whole-genome sequencing data.
Abstract: The Human Phenotype Ontology (HPO)-a standardized vocabulary of phenotypic abnormalities associated with 7000+ diseases-is used by thousands of researchers, clinicians, informaticians and electronic health record systems around the world. Its detailed descriptions of clinical abnormalities and computable disease definitions have made HPO the de facto standard for deep phenotyping in the field of rare disease. The HPO's interoperability with other ontologies has enabled it to be used to improve diagnostic accuracy by incorporating model organism data. It also plays a key role in the popular Exomiser tool, which identifies potential disease-causing variants from whole-exome or whole-genome sequencing data. Since the HPO was first introduced in 2008, its users have become both more numerous and more diverse. To meet these emerging needs, the project has added new content, language translations, mappings and computational tooling, as well as integrations with external community data. The HPO continues to collaborate with clinical adopters to improve specific areas of the ontology and extend standardized disease descriptions. The newly redesigned HPO website (www.human-phenotype-ontology.org) simplifies browsing terms and exploring clinical features, diseases, and human genes.

532 citations


Journal ArticleDOI
TL;DR: This study shows that clinical response to anti-PD-1 immunotherapy in GBM is associated with specific molecular alterations, immune expression signatures, and immune infiltration that reflect the tumor’s clonal evolution during treatment.
Abstract: Immune checkpoint inhibitors have been successful across several tumor types; however, their efficacy has been uncommon and unpredictable in glioblastomas (GBM), where <10% of patients show long-term responses. To understand the molecular determinants of immunotherapeutic response in GBM, we longitudinally profiled 66 patients, including 17 long-term responders, during standard therapy and after treatment with PD-1 inhibitors (nivolumab or pembrolizumab). Genomic and transcriptomic analysis revealed a significant enrichment of PTEN mutations associated with immunosuppressive expression signatures in non-responders, and an enrichment of MAPK pathway alterations (PTPN11, BRAF) in responders. Responsive tumors were also associated with branched patterns of evolution from the elimination of neoepitopes as well as with differences in T cell clonal diversity and tumor microenvironment profiles. Our study shows that clinical response to anti-PD-1 immunotherapy in GBM is associated with specific molecular alterations, immune expression signatures, and immune infiltration that reflect the tumor’s clonal evolution during treatment. Genomic, transcriptomic, and microenvironmental analyses of samples from patients with glioblastoma treated with nivolumab or pembrolizumab identifies features associated with treatment response that may help in refining patient stratification.

519 citations


Journal ArticleDOI
TL;DR: It is shown that monocyte subpopulation distribution and transcriptomes are significantly altered by the presence of endometrial and breast cancer and an auto-regulatory loop between TAMs and cancer cells driven by tumor necrosis factor alpha involving SIGLEC1 and CCL8 is identified.

511 citations


Journal ArticleDOI
TL;DR: The authors showed that PCSK9 (proprotein convertase subtilisin/kexin 9) inhibitors have been shown to significantly reduce plasma Lp(a) concen...
Abstract: Background: Lipoprotein(a) [Lp(a)] may play a causal role in atherosclerosis. PCSK9 (proprotein convertase subtilisin/kexin 9) inhibitors have been shown to significantly reduce plasma Lp(a) concen...

442 citations


Journal ArticleDOI
02 May 2019-Cell
TL;DR: Comparative proteomic and phosphoproteomic analysis of paired tumor and normal adjacent tissues produced a catalog of colon cancer-associated proteins and phosphosites, including known and putative new biomarkers, drug targets, and cancer/testis antigens, which suggested glycolysis as a potential target to overcome the resistance of MSI-H tumors to immune checkpoint blockade.

439 citations


Journal ArticleDOI
Donald J. Hagler1, Sean N. Hatton1, M. Daniela Cornejo1, Carolina Makowski2, Damien A. Fair3, Anthony Steven Dick4, Matthew T. Sutherland4, B. J. Casey5, M Deanna6, Michael P. Harms6, Richard Watts5, James M. Bjork7, Hugh Garavan8, Laura Hilmer1, Christopher J. Pung1, Chelsea S. Sicat1, Joshua M. Kuperman1, Hauke Bartsch1, Feng Xue1, Mary M. Heitzeg9, Angela R. Laird4, Thanh T. Trinh1, Raul Gonzalez4, Susan F. Tapert1, Michael C. Riedel4, Lindsay M. Squeglia10, Luke W. Hyde9, Monica D. Rosenberg5, Eric Earl3, Katia D. Howlett11, Fiona C. Baker12, Mary E. Soules9, Jazmin Diaz1, Octavio Ruiz de Leon1, Wesley K. Thompson1, Michael C. Neale7, Megan M. Herting13, Elizabeth R. Sowell13, Ruben P. Alvarez11, Samuel W. Hawes4, Mariana Sanchez4, Jerzy Bodurka14, Florence J. Breslin14, Amanda Sheffield Morris14, Martin P. Paulus14, W. Kyle Simmons14, Jonathan R. Polimeni15, Andre van der Kouwe15, Andrew S. Nencka16, Kevin M. Gray10, Carlo Pierpaoli11, John A. Matochik11, Antonio Noronha11, Will M. Aklin11, Kevin P. Conway11, Meyer D. Glantz11, Elizabeth Hoffman11, Roger Little11, Marsha F. Lopez11, Vani Pariyadath11, Susan R.B. Weiss11, Dana L. Wolff-Hughes, Rebecca DelCarmen-Wiggins, Sarah W. Feldstein Ewing3, Oscar Miranda-Dominguez3, Bonnie J. Nagel3, Anders Perrone3, Darrick Sturgeon3, Aimee Goldstone12, Adolf Pfefferbaum12, Kilian M. Pohl12, Devin Prouty12, Kristina A. Uban17, Susan Y. Bookheimer18, Mirella Dapretto18, Adriana Galván18, Kara Bagot1, Jay N. Giedd1, M. Alejandra Infante1, Joanna Jacobus1, Kevin Patrick1, Paul D. Shilling1, Rahul S. Desikan19, Yi Li19, Leo P. Sugrue19, Marie T. Banich20, Naomi P. Friedman20, John K. Hewitt20, Christian J. Hopfer20, Joseph T. Sakai20, Jody Tanabe20, Linda B. Cottler21, Sara Jo Nixon21, Linda Chang22, Christine C. Cloak22, Thomas Ernst22, Gloria Reeves22, David N. Kennedy23, Steve Heeringa9, Scott Peltier9, John E. Schulenberg9, Chandra Sripada9, Robert A. Zucker9, William G. Iacono24, Monica Luciana24, Finnegan J. Calabro25, Duncan B. Clark25, David A. Lewis25, Beatriz Luna25, Claudiu Schirda25, Tufikameni Brima26, John J. Foxe26, Edward G. Freedman26, Daniel W. Mruzek26, Michael J. Mason27, Rebekah S. Huber28, Erin McGlade28, Andrew P. Prescot28, Perry F. Renshaw28, Deborah A. Yurgelun-Todd28, Nicholas Allgaier8, Julie A. Dumas8, Masha Y. Ivanova8, Alexandra Potter8, Paul Florsheim29, Christine L. Larson29, Krista M. Lisdahl29, Michael E. Charness30, Michael E. Charness31, Michael E. Charness15, Bernard F. Fuemmeler7, John M. Hettema7, Hermine H. Maes7, Joel L. Steinberg7, Andrey P. Anokhin6, Paul E.A. Glaser6, Andrew C. Heath6, Pamela A. F. Madden6, Arielle R. Baskin-Sommers5, R. Todd Constable5, Steven Grant11, Gayathri J. Dowling11, Sandra A. Brown1, Terry L. Jernigan1, Anders M. Dale1 
TL;DR: The baseline neuroimaging processing and subject-level analysis methods used by the Adolescent Brain Cognitive Development Study are described to be a resource of unprecedented scale and depth for studying typical and atypical development.

Journal ArticleDOI
TL;DR: To update evidence‐based recommendations for the treatment of patients with ankylosing spondylitis (AS) and nonradiographic axial spONDyloarthritis (SpA).
Abstract: Objective To update evidence-based recommendations for the treatment of patients with ankylosing spondylitis (AS) and nonradiographic axial spondyloarthritis (SpA). Methods We conducted updated systematic literature reviews for 20 clinical questions on pharmacologic treatment addressed in the 2015 guidelines, and for 26 new questions on pharmacologic treatment, treat-to-target strategy, and use of imaging. New questions addressed the use of secukinumab, ixekizumab, tofacitinib, tumor necrosis factor inhibitor (TNFi) biosimilars, and biologic tapering/discontinuation, among others. We used the Grading of Recommendations, Assessment, Development and Evaluation methodology to assess the quality of evidence and formulate recommendations and required at least 70% agreement among the voting panel. Results Recommendations for AS and nonradiographic axial SpA are similar. TNFi are recommended over secukinumab or ixekizumab as the first biologic to be used. Secukinumab or ixekizumab is recommended over the use of a second TNFi in patients with primary nonresponse to the first TNFi. TNFi, secukinumab, and ixekizumab are favored over tofacitinib. Co-administration of low-dose methotrexate with TNFi is not recommended, nor is a strict treat-to-target strategy or discontinuation or tapering of biologics in patients with stable disease. Sulfasalazine is recommended only for persistent peripheral arthritis when TNFi are contraindicated. For patients with unclear disease activity, spine or pelvis magnetic resonance imaging could aid assessment. Routine monitoring of radiographic changes with serial spine radiographs is not recommended. Conclusion These recommendations provide updated guidance regarding use of new medications and imaging of the axial skeleton in the management of AS and nonradiographic axial SpA.

Journal ArticleDOI
TL;DR: There is a call to action for key stakeholders to create the infrastructure and cultural adaptations needed so that all people living with and beyond cancer can be as active as is possible for them.
Abstract: Multiple organizations around the world have issued evidence-based exercise guidance for patients with cancer and cancer survivors. Recently, the American College of Sports Medicine has updated its exercise guidance for cancer prevention as well as for the prevention and treatment of a variety of cancer health-related outcomes (eg, fatigue, anxiety, depression, function, and quality of life). Despite these guidelines, the majority of people living with and beyond cancer are not regularly physically active. Among the reasons for this is a lack of clarity on the part of those who work in oncology clinical settings of their role in assessing, advising, and referring patients to exercise. The authors propose using the American College of Sports Medicine's Exercise Is Medicine initiative to address this practice gap. The simple proposal is for clinicians to assess, advise, and refer patients to either home-based or community-based exercise or for further evaluation and intervention in outpatient rehabilitation. To do this will require care coordination with appropriate professionals as well as change in the behaviors of clinicians, patients, and those who deliver the rehabilitation and exercise programming. Behavior change is one of many challenges to enacting the proposed practice changes. Other implementation challenges include capacity for triage and referral, the need for a program registry, costs and compensation, and workforce development. In conclusion, there is a call to action for key stakeholders to create the infrastructure and cultural adaptations needed so that all people living with and beyond cancer can be as active as is possible for them.

Journal ArticleDOI
TL;DR: There is consistent, compelling evidence that physical activity plays a role in preventing many types of cancer and for improving longevity among cancer survivors, although the evidence related to higher risk of melanoma demonstrates the importance of sun safe practices while being physically active.
Abstract: Introduction The American College of Sports Medicine convened an International Multidisciplinary Roundtable on Exercise and Cancer in March 2018 to evaluate and translate the evidence linking physical activity and cancer prevention, treatment, and control. This article discusses findings from the Roundtable in relation to the biologic and epidemiologic evidence for the role of physical activity in cancer prevention and survival. Results The evidence supports that there are a number of biologically plausible mechanisms, whereby physical activity can influence cancer risk, and that physical activity is beneficial for the prevention of several types of cancer including breast, colon, endometrial, kidney, bladder, esophageal, and stomach. Minimizing time spent in sedentary behavior may also lower risk of endometrial, colon and lung cancers. Conversely, physical activity is associated with higher risk of melanoma, a serious form of skin cancer. Further, physical activity before and after a cancer diagnosis is also likely to be relevant for improved survival for those diagnosed with breast and colon cancer; with data suggesting that postdiagnosis physical activity provides greater mortality benefits than prediagnosis physical activity. Conclusions Collectively, there is consistent, compelling evidence that physical activity plays a role in preventing many types of cancer and for improving longevity among cancer survivors, although the evidence related to higher risk of melanoma demonstrates the importance of sun safe practices while being physically active. Together, these findings underscore the importance of physical activity in cancer prevention and control. Fitness and public health professionals and health care providers worldwide are encouraged to spread the message to the general population and cancer survivors to be physically active as their age, abilities, and cancer status will allow.

Journal ArticleDOI
19 Jul 2019-Science
TL;DR: The role of pericytes in Alzheimer’s disease is examined by examining cerebral capillaries in humans and mice developing AD, and by applying amyloid-β in the oligomeric form, which is thought to contribute to cognitive decline.
Abstract: Cerebral blood flow is reduced early in Alzheimer’s disease (AD). Because most of the vascular resistance within the brain is in capillaries, this could reflect dysfunction of contractile pericytes on capillary walls. Here we used live and rapidly-fixed biopsied human tissue to establish disease-relevance, and rodent experiments to define mechanism. We found that, in humans with cognitive decline, amyloid β (Aβ) constricts brain capillaries at pericyte locations. This was caused by Aβ generating reactive oxygen species, which evoked the release of endothelin-1 (ET) that activated pericyte ETA receptors. Capillary, but not arteriole, constriction also occurred in vivo in a mouse model of AD. Thus, inhibiting the capillary constriction caused by Aβ could potentially reduce energy lack and neurodegeneration in AD.

Journal ArticleDOI
TL;DR: It is shown that two classes of cytotoxic drugs broadly employed in pre-operative (neoadjuvant) breast cancer therapy, taxanes and anthracyclines, elicit tumour-derived EVs with enhanced pro-metastatic capacity.
Abstract: Cytotoxic chemotherapy is an effective treatment for invasive breast cancer. However, experimental studies in mice also suggest that chemotherapy has pro-metastatic effects. Primary tumours release extracellular vesicles (EVs), including exosomes, that can facilitate the seeding and growth of metastatic cancer cells in distant organs, but the effects of chemotherapy on tumour-derived EVs remain unclear. Here we show that two classes of cytotoxic drugs broadly employed in pre-operative (neoadjuvant) breast cancer therapy, taxanes and anthracyclines, elicit tumour-derived EVs with enhanced pro-metastatic capacity. Chemotherapy-elicited EVs are enriched in annexin A6 (ANXA6), a Ca2+-dependent protein that promotes NF-κB-dependent endothelial cell activation, Ccl2 induction and Ly6C+CCR2+ monocyte expansion in the pulmonary pre-metastatic niche to facilitate the establishment of lung metastasis. Genetic inactivation of Anxa6 in cancer cells or Ccr2 in host cells blunts the pro-metastatic effects of chemotherapy-elicited EVs. ANXA6 is detected, and potentially enriched, in the circulating EVs of breast cancer patients undergoing neoadjuvant chemotherapy.

Journal ArticleDOI
TL;DR: Lenvatinib plus pembrolizumab showed anti-tumour activity in patients with advanced recurrent endometrial cancer with a safety profile that was similar to those previously reported for lenvatinIB and pembrology monotherapies, apart from an increased frequency of hypothyroidism.
Abstract: Summary Background Lenvatinib is a multikinase inhibitor of VEGFR1, VEGFR2, and VEGFR3, and other receptor tyrosine kinases. Pembrolizumab, an antibody targeting PD-1, has moderate efficacy in biomarker-unselected endometrial cancer. We aimed to assess the combination of lenvatinib plus pembrolizumab in patients with advanced endometrial carcinoma, after establishing the maximum tolerated dose in a phase 1b study. Methods In this open-label, single-arm, phase 2 study done at 11 centres in the USA, eligible patients were aged 18 years or older and had metastatic endometrial cancer (unselected for microsatellite instability or PD-L1), had an Eastern Cooperative Oncology Group performance status of 0 or 1, had received no more than two previous systemic therapies, had measurable disease according to the immune-related Response Evaluation Criteria In Solid Tumors (irRECIST), and had a life expectancy of 12 weeks or longer. Patients received 20 mg oral lenvatinib daily plus 200 mg intravenous pembrolizumab every 3 weeks. Treatment continued until disease progression, development of unacceptable toxic effects, or withdrawal of consent. The primary endpoint of this interim analysis was the proportion of patients with an objective response at week 24 as assessed by investigators according to irRECIST in the per-protocol population. This trial is registered with ClinicalTrials.gov , number NCT02501096 . Findings Between Sept 10, 2015, and July 24, 2017, 54 patients were enrolled, 53 of whom were included in the analysis. At the cutoff date for anti-tumour activity data (Dec 15, 2017), median study follow-up was 13·3 months (IQR 6·7–20·1). 21 (39·6% [95% CI 26·5–54·0]) patients had an objective response at week 24. Serious treatment-related adverse events occurred in 16 (30%) patients, and one treatment-related death was reported (intracranial haemorrhage). The most frequently reported any-grade treatment-related adverse events were hypertension (31 [58%]), fatigue (29 [55%]), diarrhoea (27 [51%]), and hypothyroidism (25 [47%]). The most common grade 3 treatment-related adverse events were hypertension (18 [34%]) and diarrhoea (four [8%]). No grade 4 treatment-related adverse events were reported. Five (9%) patients discontinued study treatment because of treatment-related adverse events. Interpretation Lenvatinib plus pembrolizumab showed anti-tumour activity in patients with advanced recurrent endometrial cancer with a safety profile that was similar to those previously reported for lenvatinib and pembrolizumab monotherapies, apart from an increased frequency of hypothyroidism. Lenvatinib plus pembrolizumab could represent a new potential treatment option for this patient population, and is being investigated in a randomised phase 3 study. Funding Eisai and Merck.

Journal ArticleDOI
TL;DR: Tumors with TP53 mutations differ from their non-mutated counterparts in RNA, miRNA, and protein expression patterns, with mutant TP53 tumors displaying enhanced expression of cell cycle progression genes and proteins.

Journal ArticleDOI
TL;DR: It is shown that PARPi-mediated modulation of the immune response contributes to their therapeutic effects independently of BRCA1/2 mutations, providing a mechanistic rationale for using PARPi as immunomodulatory agents to harness the therapeutic efficacy of immune checkpoint blockade.
Abstract: Poly-(ADP-ribose) polymerase (PARP) inhibitors (PARPi) have shown remarkable therapeutic efficacy against BRCA1/2 mutant cancers through a synthetic lethal interaction. PARPi exert their therapeutic effects mainly through the blockade of single-stranded DNA damage repair, which leads to the accumulation of toxic DNA double-strand breaks specifically in cancer cells with DNA repair deficiency (BCRAness), including those harboring BRCA1/2 mutations. Here we show that PARPi-mediated modulation of the immune response contributes to their therapeutic effects independently of BRCA1/2 mutations. PARPi promoted accumulation of cytosolic DNA fragments due to unresolved DNA lesions, which in turn activated the DNA sensing cGAS-STING pathway and stimulated production of type I interferons to induce antitumor immunity independent of BRCAness. These effects of PARPi were further enhanced by immune checkpoint blockade. Overall, these results provide a mechanistic rationale for using PARPi as immunomodulatory agents to harness the therapeutic efficacy of immune checkpoint blockade.

Journal ArticleDOI
01 Sep 2019-Leukemia
TL;DR: Patients with MM refractory to CD38 MoAB have poor prognosis and this study provides benchmark for new therapies to be tested in this population.
Abstract: The introduction of CD38-targeting monoclonal antibodies (CD38 MoABs), daratumumab and isatuximab, has significantly impacted the management of patients with multiple myeloma (MM). Outcomes of patients with MM refractory to CD38 MoABs have not been described. We analyzed outcomes of 275 MM patients at 14 academic centers with disease refractory to CD38 MoABs. Median interval between MM diagnosis and refractoriness to CD38 MoAB (T0) was 50.1 months. The median overall survival (OS) from T0 for the entire cohort was 8.6 [95% C.I. 7.5–9.9] months, ranging from 11.2 months for patients not simultaneously refractory to an immunomodulatory (IMiD) agent and a proteasome inhibitor (PI) to 5.6 months for “penta-refractory” patients (refractory to CD38 MoAB, 2 PIs and 2 IMiDs). At least one subsequent treatment regimen was employed after T0 in 249 (90%) patients. Overall response rate to first regimen after T0 was 31% with median progression-free survival (PFS) and OS of 3.4 and 9.3 months, respectively. PFS was best achieved with combinations of carfilzomib and alkylator (median 5.7 months), and daratumumab and IMiD (median 4.5 months). Patients with MM refractory to CD38 MoAB have poor prognosis and this study provides benchmark for new therapies to be tested in this population.

Journal ArticleDOI
TL;DR: The 2018 ACR/NPF guideline as mentioned in this paper provides evidence-based guidelines for the pharmacologic and non-pharmacologic treatment of psoriatic arthritis (PsA) using the GRADE (Grading of Recommendations Assessment, Development and Evaluation) methodology.
Abstract: Objective To develop an evidence-based guideline for the pharmacologic and nonpharmacologic treatment of psoriatic arthritis (PsA), as a collaboration between the American College of Rheumatology (ACR) and the National Psoriasis Foundation (NPF). Methods We identified critical outcomes in PsA and clinically relevant PICO (population/intervention/comparator/outcomes) questions. A Literature Review Team performed a systematic literature review to summarize evidence supporting the benefits and harms of available pharmacologic and nonpharmacologic therapies for PsA. GRADE (Grading of Recommendations Assessment, Development and Evaluation) methodology was used to rate the quality of the evidence. A voting panel, including rheumatologists, dermatologists, other health professionals, and patients, achieved consensus on the direction and the strength of the recommendations. Results The guideline covers the management of active PsA in patients who are treatment-naive and those who continue to have active PsA despite treatment, and addresses the use of oral small molecules, tumor necrosis factor inhibitors, interleukin-12/23 inhibitors (IL-12/23i), IL-17 inhibitors, CTLA4-Ig (abatacept), and a JAK inhibitor (tofacitinib). We also developed recommendations for psoriatic spondylitis, predominant enthesitis, and treatment in the presence of concomitant inflammatory bowel disease, diabetes, or serious infections. We formulated recommendations for a treat-to-target strategy, vaccinations, and nonpharmacologic therapies. Six percent of the recommendations were strong and 94% conditional, indicating the importance of active discussion between the health care provider and the patient to choose the optimal treatment. Conclusion The 2018 ACR/NPF PsA guideline serves as a tool for health care providers and patients in the selection of appropriate therapy in common clinical scenarios. Best treatment decisions consider each individual patient situation. The guideline is not meant to be proscriptive and should not be used to limit treatment options for patients with PsA.

Journal ArticleDOI
24 Jan 2019-Cell
TL;DR: The structure of the CB1-Gi signaling complex bound to the highly potent agonist MDMB-Fubinaca (FUB) is presented, which compose the structural framework to explain CB1 activation by different classes of ligands and provide insights into the G protein coupling and selectivity mechanisms adopted by the receptor.

Journal ArticleDOI
TL;DR: To develop an evidence‐based guideline for the pharmacologic and nonpharmacologic treatment of psoriatic arthritis (PsA), as a collaboration between the American College of Rheumatology and the National Psoriasis Foundation (NPF).
Abstract: Objective:To develop an evidence-based guideline for the pharmacologic and nonpharmacologic treatment of psoriatic arthritis (PsA), as a collaboration between the American College of Rheumatology (...

Journal ArticleDOI
TL;DR: These data support the continued value of PC expertise and need for specialized medical toxicology information to manage more serious exposures and are a model system for the near real-time surveillance of national and global public health.
Abstract: Introduction: This is the 36th Annual Report of the American Association of Poison Control Centers' (AAPCC) National Poison Data System (NPDS). As of 1 January, 2018, 55 of the nation's poison centers (PCs) uploaded case data automatically to NPDS. The upload interval was 7.72 [6.90, 12.0] (median [25%, 75%]) minutes, creating a near real-time national exposure and information database and surveillance system.Methods: We analyzed the case data tabulating specific indices from NPDS. The methodology was similar to that of previous years. Where changes were introduced, the differences are identified. Cases with medical outcomes of death were evaluated by a team of medical and clinical toxicologist reviewers using an ordinal scale of 1-6 to assess the Relative Contribution to Fatality (RCF) of the exposure.Results: In 2018, 2,530,238 closed encounters were logged by NPDS: 2,099,751 human exposures, 57,017 animal exposures, 368,025 information requests, 5,346 human confirmed nonexposures, and 99 animal confirmed nonexposures. United States PCs also made 2,621,242 follow-up calls in 2018. Total encounters showed a 2.96% decline from 2017, while health care facility (HCF) human exposure cases remained nearly steady with a slight decrease of 0.261%. All information requests decreased by 15.5%, medication identification (Drug ID) requests decreased by 30.2%, and human exposure cases decreased by 0.729%. Human exposures with less serious outcomes have decreased 2.33% per year since 2008, while those with more serious outcomes (moderate, major or death) have increased 4.45% per year since 2000.Consistent with the previous year, the top 5 substance classes most frequently involved in all human exposures were analgesics (10.8%), household cleaning substances (7.28%), cosmetics/personal care products (6.53%), sedatives/hypnotics/antipsychotics (5.53%), and antidepressants (5.22%). For cases with more serious outcomes, sedative/hypnotics/antipsychotics exposures were the class that increased most rapidly, by 1,828 cases/year (9.21%/year) over the past 18 years. Over just the past 10 years (for cases with the most serious outcomes) antidepressant exposures increased most rapidly, by 1,887 cases/year (7.02%/year).The top 5 most common exposures in children age 5 years or less were cosmetics/personal care products (12.1%), household cleaning substances (10.7%), analgesics (9.04%), foreign bodies/toys/miscellaneous (6.87%), and topical preparations (4.69%). Drug identification requests comprised 18.2% of all information requests. NPDS documented 3,111 human exposures resulting in death; 2,582 (83.0%) of these were judged as related (RCF of 1-Undoubtedly responsible, 2-Probably responsible, or 3-Contributory).Conclusions: These data support the continued value of PC expertise and need for specialized medical toxicology information to manage more serious exposures. Unintentional and intentional exposures continue to be a significant cause of morbidity and mortality in the US. The near real-time status of NPDS represents a national public health resource to collect and monitor US exposure cases and information requests. The continuing mission of NPDS is to provide a nationwide infrastructure for surveillance for all types of exposures (e.g., foreign body, infectious, venomous, chemical agent, or commercial product), and the identification and tracking of significant public health events. NPDS is a model system for the near real-time surveillance of national and global public health.

Journal ArticleDOI
12 Feb 2019-JAMA
TL;DR: It is concluded with moderate certainty that providing or referring pregnant or postpartum women at increased risk to counseling interventions has a moderate net benefit in preventing perinatal depression.
Abstract: Importance Perinatal depression, which is the occurrence of a depressive disorder during pregnancy or following childbirth, affects as many as 1 in 7 women and is one of the most common complications of pregnancy and the postpartum period. It is well established that perinatal depression can result in adverse short- and long-term effects on both the woman and child. Objective To issue a new US Preventive Services Task Force (USPSTF) recommendation on interventions to prevent perinatal depression. Evidence Review The USPSTF reviewed the evidence on the benefits and harms of preventive interventions for perinatal depression in pregnant or postpartum women or their children. The USPSTF reviewed contextual information on the accuracy of tools used to identify women at increased risk of perinatal depression and the most effective timing for preventive interventions. Interventions reviewed included counseling, health system interventions, physical activity, education, supportive interventions, and other behavioral interventions, such as infant sleep training and expressive writing. Pharmacological approaches included the use of nortriptyline, sertraline, and omega-3 fatty acids. Findings The USPSTF found convincing evidence that counseling interventions, such as cognitive behavioral therapy and interpersonal therapy, are effective in preventing perinatal depression. Women with a history of depression, current depressive symptoms, or certain socioeconomic risk factors (eg, low income or young or single parenthood) would benefit from counseling interventions and could be considered at increased risk. The USPSTF found adequate evidence to bound the potential harms of counseling interventions as no greater than small, based on the nature of the intervention and the low likelihood of serious harms. The USPSTF found inadequate evidence to assess the benefits and harms of other noncounseling interventions. The USPSTF concludes with moderate certainty that providing or referring pregnant or postpartum women at increased risk to counseling interventions has a moderate net benefit in preventing perinatal depression. Conclusions and Recommendation The USPSTF recommends that clinicians provide or refer pregnant and postpartum persons who are at increased risk of perinatal depression to counseling interventions. (B recommendation)

Journal ArticleDOI
TL;DR: Avelumab demonstrated antitumor activity and acceptable safety in heavily pretreated patients with recurrent or refractory ovarian cancer in an expansion cohort of a phase 1b, open-label study.
Abstract: Importance Current treatment options for progressive ovarian cancer provide limited benefit, particularly in patients whose disease has become resistant to platinum-based chemotherapy. Objective To assess the efficacy and safety of avelumab, an anti–programmed death-ligand 1 agent, in a cohort of patients with previously treated recurrent or refractory ovarian cancer. Design, Setting, and Participants In an expansion cohort of a phase 1b, open-label study (JAVELIN Solid Tumor), 125 patients with advanced ovarian cancer who had received chemotherapy including a platinum agent were enrolled between November 6, 2013, and August 27, 2015. Statistical analysis was performed from December 31, 2016, to October 9, 2018. Intervention Patients received avelumab, 10 mg/kg, every 2 weeks until disease progression, unacceptable toxic effects, or withdrawal from the study. Main Outcomes and Measures Prespecified end points in this cohort included confirmed best overall response (per Response Evaluation Criteria In Solid Tumors, version 1.1), immune-related best overall response, duration of response, progression-free survival, overall survival, results of programmed death-ligand 1 expression–based analyses, and safety. Results A total of 125 women (median age, 62.0 years [range, 27-84 years]) who had received a median of 3 prior lines of treatment (range, 0-10) for advanced disease were enrolled in the study. Patients received avelumab for a median of 2.8 months (range, 0.5-27.4 months), with a median follow-up of 26.6 months (range, 16-38 months). A confirmed objective response occurred in 12 patients (9.6%; 95% CI, 5.1%-16.2%), including a complete response in 1 patient (0.8%) and a partial response in 11 patients (8.8%). The 1-year progression-free survival rate was 10.2% (95% CI, 5.4%-16.7%) and median overall survival was 11.2 months (95% CI, 8.7-15.4 months). Infusion-related reactions occurred in 25 patients (20.0%). Other frequent treatment-related adverse events (any grade event occurring in ≥10% of patients) were fatigue (17 [13.6%]), diarrhea (15 [12.0%]), and nausea (14 [11.2%]). Grade 3 or higher treatment-related adverse events occurred in 9 patients (7.2%), of which only the level of lipase increased (3 [2.4%]) occurred in more than 1 patient. Twenty-one patients (16.8%) had an immune-related adverse event of any grade. No treatment-related deaths occurred. Conclusions and Relevance Avelumab demonstrated antitumor activity and acceptable safety in heavily pretreated patients with recurrent or refractory ovarian cancer. Trial Registration ClinicalTrials.gov identifier:NCT01772004

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TL;DR: Global eye disease burden, unmet needs and common conditions of public health importance for which AI and DL systems may be applicable are described and the potential challenges for clinical adoption are discussed.

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TL;DR: A cross‐PIA white paper that provides both a concise “state‐of‐the‐science” report of ethnoracial factors across PIA foci and updated recommendations to address immediate needs to advance ADRD science across ethnorracial populations is synthesized.
Abstract: Alzheimer's disease and related dementias (ADRDs) are a global crisis facing the aging population and society as a whole. With the numbers of people with ADRDs predicted to rise dramatically across the world, the scientific community can no longer neglect the need for research focusing on ADRDs among underrepresented ethnoracial diverse groups. The Alzheimer's Association International Society to Advance Alzheimer's Research and Treatment (ISTAART; alz.org/ISTAART) comprises a number of professional interest areas (PIAs), each focusing on a major scientific area associated with ADRDs. We leverage the expertise of the existing international cadre of ISTAART scientists and experts to synthesize a cross-PIA white paper that provides both a concise "state-of-the-science" report of ethnoracial factors across PIA foci and updated recommendations to address immediate needs to advance ADRD science across ethnoracial populations.

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TL;DR: Nanoparticle-based contrast agents employed in most common biomedical imaging modalities, including fluorescence imaging, MRI, CT, US, PET and SPECT are reviewed, addressing their structure related features, advantages and limitations.
Abstract: An urgent need for early detection and diagnosis of diseases continuously pushes the advancements of imaging modalities and contrast agents. Current challenges remain for fast and detailed imaging of tissue microstructures and lesion characterization that could be achieved via development of nontoxic contrast agents with longer circulation time. Nanoparticle technology offers this possibility. Here, we review nanoparticle-based contrast agents employed in most common biomedical imaging modalities, including fluorescence imaging, MRI, CT, US, PET and SPECT, addressing their structure related features, advantages and limitations. Furthermore, their applications in each imaging modality are also reviewed using commonly studied examples. Future research will investigate multifunctional nanoplatforms to address safety, efficacy and theranostic capabilities. Nanoparticles as imaging contrast agents have promise to greatly benefit clinical practice.

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TL;DR: The CDC’s 2016 Guideline for Prescribing Opioids for Chronic Pain has been embraced by the medical and health policy communities, but some policies and practices purportedly derived from the guideline have been inconsistent with its recommendations.
Abstract: No Shortcuts to Safer Opioid Prescribing The CDC’s 2016 Guideline for Prescribing Opioids for Chronic Pain has largely been embraced by the medical and health policy communities. Unfortunately, some policies and practices purportedly derived from the guideline have been inconsistent with its recommendations.