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PURPOSE: To evaluate the prevalence and characteristics of different HER2 categories among patients with advanced breast cancer (aBC) and describe treatment patterns and outcomes of those with HER2-low disease. METHODS: A retrospective cohort study was conducted via chart review at the Huntsman Cancer Institute, including patients diagnosed with aBC (stages IIIB, IIIC and IV) between 2010 and 2019. All patients with IHC1+ were considered HER2-low unless FISH was positive. Patients with IHC2+ were only classified as HER2-low if a negative FISH was documented. The prevalence and characteristics of each HER2 category were reported. Treatment patterns and survival outcomes of HER2-low patients who received first line treatment in 2017 or later were presented. RESULTS: A total of 240 of 414 patients (58%) with aBC were HER2-low, with the majority of patients (83%) classified as hormone receptor (HR)-positive. In first line, most HR-positive patients received endocrine therapy with chemotherapy for stage IIIB/IIIC (47%) and with CDK4/6 inhibitors for stage IV breast cancer (50%) Most HR-negative patients received chemotherapy alone (92% for stage IIIB/IIIC, 60% for stage IV). In second line, chemotherapy alone was the most common modality (21.4% for HR-positive; 45.5% for HR-negative). Median overall survival was 37.7 months while median progression-free survival from first line was 18.0 months, decreasing to 8.0 months in second line. CONCLUSION: A substantial proportion of patients previously classified as HER2-negative have low but detectable HER2 expression and may benefit from novel HER2-directed agents, which have demonstrated clinical benefit in this population post-chemotherapy.
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This study used COTA de-identified data (2010-2021) of patients in the US to explore outcomes of novel therapies in relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) in real-world settings. Demographics, clinical characteristics, and clinical outcomes of patients with R/R DLBCL who received novel treatments including chimeric antigen receptor T-cell (CAR T) therapy and tafasitamab- or polatuzumab-based therapies were evaluated. Overall, 175 patients with R/R DLBCL were analyzed; 73, 69, and 27 received CAR T therapy, polatuzumab-based regimens, and tafasitamab-based regimens, respectively. In patients who had ≥1 prior lines of therapy (i.e. starting second-line or later therapy; 2 L+), CAR T, polatuzumab-based regimens, and tafasitamab-based regimens achieved a median overall survival of 26.5, 7.8, and 6.3 months, respectively. Outcomes were particularly poor for patients with relapse following CAR T, indicating that polatuzumab- and tafasitamab-based regimens in 2 L + R/R DLBCL have suboptimal outcomes in the real world. Additional treatment options are needed.
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BACKGROUND: With advancements in CF drug development, people with cystic fibrosis (PwCF) now take a median of seven medications daily, increasing treatment complexity, risk of drug therapy problems (DTPs), and interference with treatment goals. Given that some of these DTPs can be prevented with preemptive pharmacogenetic testing, the overall goal of this study was to test the clinical utility of a multi-gene pharmacogenetics (PGx) panel in potentially reducing DTPs in PwCF. METHODS: A population based retrospective study of patients with CF was conducted at the University of Utah Health Care System. The patients were genotyped for CYP450 enzymes using a pharmacogenomic assay, and their drug utilization information was obtained retrospectively. This pharmacogenomic information was combined with clinical guidelines to predict the number of actionable PGx interventions in this patient cohort. RESULTS: A total of 52 patients were included in this study. In the patient sample, a minimum of one order of actionable PGx medication was observed in 75 % of the cases. Results revealed that 4.2 treatment modifications per 10 patients can be enabled with the help of a PGx intervention in this patient population. Additionally, our findings suggest that polymorphisms in CYP2D6 and CYP2C19 are most likely to be the primary contributors to DTP's within PwCF. CONCLUSION: This study provides evidence that the PGx panel has the potential to help alleviate the clinical burden of DTPs in PwCF and can assist in informing pharmacotherapy recommendations. Future research should validate these findings and evaluate which subgroups of PwCF would most benefit from pharmacogenetic testing.
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BACKGROUND: Pneumonia is a global disorder and a common reason for prolonged hospitalization. Angiotensin-converting enzyme inhibitors (ACEi) have pleiotropic effects that support a role in modulating pneumonia, but results have been controversial. OBJECTIVES: The present study was conducted to elucidate an ACEi-induced pneumonia benefit in at-risk neurologically impaired population and to determine whether a mortality benefit exists. METHODS: A cohort study using a large health-system of 29,011 unique ACEi users and 1635 case patients 65 years of age or older without neurological disorders affecting swallowing who were admitted with community-acquired pneumonia hospitalization and followed up from January 1, 2015 to December 31, 2019 (5 years). The association between ACEi use and pneumonia hospitalization and mortality were determined after propensity score matching using Cox and logistic regression. RESULTS: The experimental cohort was 74.9 ± 7.3 years and 51% were male. ACEi users had lower odds of acquiring pneumonia versus ACEi non-users (odds ratio) 0.72 [95% Confidence Interval (CI) 0.51 to 0.99]; p = 0.048. The risk of short-term mortality (<30 days) (HR) 0.42, p < 0.001 and long-term mortality (≥30 day) (HR) 0.83, p < 0.002 was significantly lower for ACEi users compared with the ACEi non-users. CONCLUSIONS: ACEi use in patients at risk of pneumonia without neurological swallowing disorders is associated with reduction in hospitalization and lowering of short- and long-term mortality. Given the high incidence of morbidity and mortality associated with pneumonia, and the susceptibility in older populations with underlying cardiovascular or renal disease or social dependencies, our data support the prescribing of ACEi in these populations to reduce pneumonia hospitalization risk as well as short- and long-term mortality.
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Inibidores da Enzima Conversora de Angiotensina , Pneumonia , Humanos , Masculino , Idoso , Feminino , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Estudos de Coortes , Pneumonia/tratamento farmacológicoRESUMO
INTRODUCTION: There is increasing evidence that COVID-19 has unmasked the true magnitude of health inequity worldwide. Policies and guidance for containing the infection and reducing the COVID-19 related deaths have proven to be effective, however the extent to which health inequity factors were considered in these policies is rather unknown. The aim of this study is to measure the extent to which COVID-19 related policies reflect equity considerations by focusing on the global policy landscape around wearing masks and personal protection equipment (PPE). METHODS: A systematic search for published documents on COVID-19 and masks/PPE was conducted across six databases: PubMed, EMBASE, CINAHL, ERIC, ASSIA and Psycinfo. Reviews, policy documents, briefs related to COVID-19 and masks/PPE were included in the review. To assess the extent of incorporation of equity in the policy documents, a guidance framework known as 'PROGRESS-Plus': Place of residence, Race/ethnicity, Occupation, Gender/sex, Religion, Education, Socioeconomic status, Social capital, Plus (age, disability etc.) was utilized. RESULTS: This review included 212 policy documents. Out of 212 policy documents, 190 policy documents (89.62%) included at least one PROGRESS-plus component. Most of the policy documents (n = 163, 85.79%) focused on "occupation" component of the PROGRESS-plus followed by personal characteristics associated with discrimination (n = 4;2.11%), place of residence (n = 2;1.05%) and education (n = 1;0.53%). Subgroup analysis revealed that most of the policy documents (n = 176, 83.01%) were focused on "workers" such as healthcare workers, mortuary workers, school workers, transportation workers, essential workers etc. Of the remaining policy documents, most were targeted towards whole population (n = 30; 14.15%). Contrary to "worker focused" policy documents, most of the 'whole population focused' policy documents didn't have a PROGRESS-plus equity component rendering them equity limiting for the society. CONCLUSION: Our review highlights even if policies considered health inequity during the design/implementation, this consideration was often one dimensional in nature. In addition, population wide policies should be carefully designed and implemented after identifying relevant equity related barriers in order to produce better outcomes for the whole society.
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COVID-19 , Equidade em Saúde , Humanos , Equipamento de Proteção Individual , Políticas , SARS-CoV-2RESUMO
OBJECTIVES: FOLFIRINOX, gemcitabine/nab-paclitaxel (gem-nab/P), and gemcitabine-capecitabine (gem-cap) demonstrated superiority over gemcitabine monotherapy for pancreatic cancer (PC). It is still unclear which chemotherapy regimen is the most optimal. This study aimed to conduct a systematic review (SR) and indirect comparison to compare safety and efficacy of FOLFIRINOX versus gem-nab/P and gem-cap in PC. METHODS: An SR was conducted in several databases from inception to November 2020. RCTs investigating resectable or advanced PC were included. Primary outcomes including overall survival (OS), disease-free survival (DFS)/progression-free survival (PFS)/relapse-free survival (RFS), and grade 3/4 adverse events (AEs) were pooled using a random effects model. Indirect comparisons were done to compare FOLFIRINOX versus gem-cap and gem-nab/P. Heterogeneity was evaluated using Cochran's Q test and I2 statistics. RESULTS: Nine studies were identified involving 6,564 patients. Indirect comparisons showed FOLFIRINOX had significantly better OS (resectable: HR 0.78 [0.61-0.99]; advanced: HR 0.71 [0.60-0.85]) and RFS/DFS/PFS (resectable: HR 0.67 [0.55-0.82]; advanced: HR 0.65 [0.57-0.74]) compared to gem-cap as well as OS (resectable: HR 0.78 [0.61-1.00]; advanced: HR 0.73 [0.54-0.98]) and DFS/PFS (resectable: HR 0.66 [0.53-0.82]; advanced: HR 0.64 [0.49-0.83]) compared to gem-nab/P. FOLFIRINOX increased grade 3/4 AE risk compared to gem-cap and gem-nab/P. CONCLUSIONS: FOLFIRINOX is associated with significant survival benefits compared to gem-nab/P and gem-cap. However, it is important to consider the increased grade 3/4 AE risk associated with FOLFIRINOX.
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Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias Pancreáticas , Albuminas , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Intervalo Livre de Doença , Humanos , Paclitaxel/efeitos adversos , Neoplasias Pancreáticas/tratamento farmacológicoRESUMO
BACKGROUND: Patients with rheumatoid arthritis (RA) have higher rates of mortality attributed to the inflammatory nature and the associated burden of cardiovascular complications. Previous research indicates that treatment with statin therapy may play a role in reducing the mortality rate of RA patients, but similar evidence in U.S. patients is lacking. OBJECTIVE: To assess the association between statin use and overall mortality among RA patients in the United States. METHODS: A population-based study of RA patients with incident statin use was conducted. Patients aged ≥ 18 years with a diagnosis of RA between January 2007 and December 2015 were included and reviewed for the use of statin medication. Time stratified propensity score matching was used to adequately balance the comparison groups. Logistic regression and Cox proportional hazard models were used to estimate the association. RESULTS: 19,614 people fulfilled the inclusion criteria for the study out of which 2,089 were statin users. There were 1,883 statin users that were matched to 1,883 statin nonusers. Baseline characteristics were well balanced across the 2 groups after matching. The hazards ratio for all-cause mortality in patients with RA for statin users was 0.72 (95% CI = 0.56-0.91; P = 0.008) compared with statin nonusers. CONCLUSIONS: Compared with no use of statins, current statin use is associated with 28% lower risk of mortality in RA patients. Decision makers and providers should consider and support integration of these results into the current clinical guidelines for delivering quality health care to RA patients. DISCLOSURES: No outside funding supported this study. The authors received no financial support for the research, authorship, and/or publication of this article. The authors have no affiliations with or involvement in any organization or entity with any financial interest or nonfinancial interest in the subject matter or materials discussed in this manuscript.
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Artrite Reumatoide/tratamento farmacológico , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Adulto , Artrite Reumatoide/mortalidade , Estudos de Coortes , Feminino , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/administração & dosagem , Incidência , Masculino , Pessoa de Meia-Idade , Mortalidade/tendências , Medição de Risco , Estados Unidos/epidemiologia , Adulto JovemRESUMO
BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) is one of the most common mental disorders affecting children and adults. Previous systematic reviews have provided estimates of ADHD-associated costs but were limited to the USA and Europe. OBJECTIVES: This study aimed to systematically summarise all global evidence on the economic burden of ADHD. METHODS: A systematic search for published studies on costs of ADHD was conducted in EconLit, EMBASE, PubMed, ERIC, and PsycINFO. Additional literature was identified by searching the reference lists of eligible studies. The quality of the studies was assessed using the Larg and Moss checklist. RESULTS: This review included 44 studies. All studies were conducted in high-income countries and were limited to North America and Europe except for four studies: two in Asia and two in Australia. Most studies were retrospective and undertook a prevalence-based study design. Analysis revealed a substantial economic impact associated with ADHD. Estimates based on total costs ranged from $US831.38 to 20,538 for per person estimates and from $US356 million to 20.27 billion for national estimates. Estimates based on marginal costs ranged from $US244.15 to 18,751.00 for per person estimates and from $US12.18 million to 141.33 billion for national estimates. Studies that calculated economic burden across multiple domains of direct, indirect, and education and justice system costs for both children and adults with ADHD reported higher costs and translated gross domestic product than did studies that captured only a single domain or age group. CONCLUSIONS: Despite the wide variation in methodologies in studies reviewed, the literature suggests that ADHD imposes a substantial economic burden on society. There is a dire need for cost-of-illness research in low- and middle-income countries to better inform the treatment and management of ADHD in these countries. In addition, guidelines on the conduct and reporting of economic burden studies are needed as they may improve standardisation of cost-of-illness studies.
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Transtorno do Deficit de Atenção com Hiperatividade , Adulto , Criança , Efeitos Psicossociais da Doença , Europa (Continente) , Humanos , Prevalência , Estudos RetrospectivosRESUMO
Clusterin (CLU), or apolipoprotein J (ApoJ), is the third most predominant genetic risk factor associated with late-onset Alzheimer's disease (LOAD). In this study, we use multiple rodent and human brain tissue and neural cell models to demonstrate that CLU is expressed as multiple isoforms that have distinct cellular or subcellular localizations in the brain. Of particular significance, we identify a non-glycosylated 45 kDa CLU isoform (mitoCLU) that is localized to the mitochondrial matrix and expressed in both rodent and human neurons and astrocytes. In addition, we show that rodent mitoCLU is translated from a non-canonical CUG (Leu) start site in Exon 3, a site that coincides with an AUG (Met) in human CLU. Last, we reveal that mitoCLU is present at the gene and protein level in the currently available CLU-/- mouse model. Collectively, these data provide foundational knowledge that is integral in elucidating the relationship between CLU and the development of LOAD.
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Clusterina/metabolismo , Mitocôndrias/metabolismo , Isoformas de Proteínas/metabolismo , Doença de Alzheimer/metabolismo , Animais , Encéfalo/metabolismo , Feminino , Camundongos , Camundongos Endogâmicos C57BL , Gravidez , Ratos , Ratos Sprague-DawleyRESUMO
BACKGROUND: Depression has been reported to be commonly manifested in patients with Alzheimer's disease (AD) and is considered a risk factor for AD. The human apolipoprotein E (ApoE) gene exists in three major isoforms (coded by ε2, ε3, and ε4), and the ε4 allele has been associated with a greater incidence of both depression and AD. Although mounting evidence points to the potentially complex interaction between these two brain disorders in which ApoE might play a role, the underlying mechanisms are largely unknown. METHODS: Using human ApoE2, ApoE3, and ApoE4 gene-targeted replacement (hApoE-TR) mouse models, we investigated the role of ApoE isoforms and their potential interactions with estrogen receptor ß (ERß) signaling in modulating the brain mechanisms involved in depression. RESULTS: Our initial analyses in 6-month-old female hApoE-TR mice demonstrated that ApoE influenced the expression of brain-derived neurotrophic factor (BDNF) and the 5-hydroxytryptamine 2A (5-HT2A) serotonin receptor in an isoform-dependent manner, with the ApoE4 brain exhibiting the lowest level of BDNF and the highest level of 5-HT2A. In addition, both presynaptic and postsynaptic proteins were downregulated, indicating a synaptic deficit in ApoE4 brains. Our subsequent analyses revealed that a 3-month chronic treatment with an ERß-targeted (83-fold selectivity over ERα) phytoestrogenic diet induced several changes in ApoE2 and ApoE3 brains, including a significant decrease in the expression of 5-HT2A receptors and an increase in BDNF/tropomyosin receptor kinase B and synaptic proteins. In contrast, ApoE4 brains were largely unresponsive to the treatment, with an increase only in select synaptic proteins in the treated group. CONCLUSIONS: Taken together, these results indicate that ApoE4 negatively impacts BDNF-5-HT2A signaling in the female brain, which could in part underlie the ApoE4-mediated increased risk for depression. In a larger context, this mechanism could serve as a molecular link between depression and AD associated with ApoE4. Enhancing ERß activity could provide a greater therapeutic benefit to non-ApoE4 carriers than to ApoE4 carriers in interventions for these brain disorders.
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Apolipoproteínas E/metabolismo , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Encéfalo/metabolismo , Receptor beta de Estrogênio/metabolismo , Isoformas de Proteínas/metabolismo , Receptor 5-HT2A de Serotonina/metabolismo , Sinapses/fisiologia , Animais , Apolipoproteínas E/genética , Encéfalo/efeitos dos fármacos , Proteína 4 Homóloga a Disks-Large/genética , Proteína 4 Homóloga a Disks-Large/metabolismo , Receptor beta de Estrogênio/genética , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/genética , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Proteínas dos Microfilamentos , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Isoformas de Proteínas/genética , Moduladores Seletivos de Receptor Estrogênico/farmacologia , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia , Sinaptofisina/genética , Sinaptofisina/metabolismo , Proteína 2 Associada à Membrana da Vesícula/genética , Proteína 2 Associada à Membrana da Vesícula/metabolismoRESUMO
Depression currently affects 350 million people worldwide and 19 million Americans each year. Women are 2.5 times more likely to experience major depression than men, with some women appearing to be at a heightened risk during the menopausal transition. Estrogen signaling has been implicated in the pathophysiology of mood disorders including depression; however, the underlying mechanisms are poorly understood. In this study, the role of estrogen receptor (ER) subtypes, ERα and ERß, in the regulation of brain-derived neurotrophic factor (BDNF) and serotonin (5-HT) signaling was investigated; two pathways that have been hypothesized to be interrelated in the etiology of depression. The analyses in ERα-/- and ERß-/- mouse models demonstrated that BDNF was significantly downregulated in ERß-/- but not ERα-/- mice, and the ERß-/--mediated effect was brain-region specific. A 40% reduction in BDNF protein expression was found in the hippocampus of ERß-/- mice; in contrast, the changes in BDNF were at a much smaller magnitude and insignificant in the cortex and hypothalamus. Further analyses in primary hippocampal neurons indicated that ERß agonism significantly enhanced BDNF/TrkB signaling and the downtream cascades involved in synaptic plasticity. Subsequent study in ERß mutant rat models demonstrated that disruption of ERß was associated with a significantly elevated level of 5-HT2A but not 5-HT1A in rat hippocampus, indicating ERß negatively regulates 5-HT2A. Additional analyses in primary neuronal cultures revealed a significant association between BDNF and 5-HT2A pathways, and the data showed that TrkB activation downregulated 5-HT2A whereas activation of 5-HT2A had no effect on BDNF, suggesting that BDNF/TrkB is an upstream regulator of the 5-HT2A pathway. Collectively, these findings implicate that the disruption in estrogen homeostasis during menopause leads to dysregulation of BDNF-5-HT2A signaling and weakened synaptic plasticity, which together predispose the brain to a vulnerable state for depression. Timely intervention with an ERß-targeted modulator could potentially attenuate this susceptibility and reduce the risk or ameliorate the clinical manifestation of this brain disorder.
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Fator Neurotrófico Derivado do Encéfalo/metabolismo , Receptor beta de Estrogênio/metabolismo , Menopausa/metabolismo , Receptor 5-HT2A de Serotonina/metabolismo , Animais , Encéfalo/metabolismo , Fator Neurotrófico Derivado do Encéfalo/fisiologia , Córtex Cerebral/metabolismo , Depressão/etiologia , Depressão/fisiopatologia , Transtorno Depressivo Maior/metabolismo , Receptor beta de Estrogênio/genética , Feminino , Hipocampo/metabolismo , Hipocampo/patologia , Glicoproteínas de Membrana/metabolismo , Camundongos , Neurônios/metabolismo , Cultura Primária de Células , Ratos , Receptor 5-HT1A de Serotonina/metabolismo , Receptor trkB/metabolismo , Serotonina/metabolismo , Agonistas do Receptor 5-HT2 de Serotonina/metabolismo , Lobo Temporal/metabolismoRESUMO
Alzheimer's disease (AD) disproportionally affects women and men. The female susceptibility for AD has been largely associated with the loss of ovarian sex hormones during menopause. This review examines the current understanding of the role of estrogen receptor ß (ERß) in the regulation of neurological health and its implication in the development and intervention of AD. Since its discovery in 1996, research conducted over the last 15-20 years has documented a great deal of evidence indicating that ERß plays a pivotal role in a broad spectrum of brain activities from development to aging. ERß genetic polymorphisms have been associated with cognitive impairment and increased risk for AD predominantly in women. The role of ERß in the intervention of AD has been demonstrated by the alteration of AD pathology in response to treatment with ERß-selective modulators in transgenic models that display pronounced plaque and tangle histopathological presentations as well as learning and memory deficits. Future studies that explore the potential interactions between ERß signaling and the genetic isoforms of human apolipoprotein E (APOE) in brain aging and development of AD-risk phenotype are critically needed. The current trend of lost-in-translation in AD drug development that has primarily been based on early-onset familial AD (FAD) models underscores the urgent need for novel models that recapitulate the etiology of late-onset sporadic AD (SAD), the most common form of AD representing more than 95% of the current human AD population. Combining the use of FAD-related models that generally have excellent face validity with SAD-related models that hold more reliable construct validity would together increase the predictive validity of preclinical findings for successful translation into humans.