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OBJECTIVE: The objective was to evaluate the efficacy/safety of pirtobrutinib in the treatment of B-cell malignancies and distinguish it from other available Bruton's tyrosine kinase (BTK) inhibitors. DATA SOURCES: A literature search of PubMed (January 2021 through November 2023) and Clinicaltrials.gov was conducted using terms pirtobrutinib, Jaypirca, and LOXO 305. Licensing trials of available BTK inhibitors were also reviewed. STUDY SELECTION AND DATA EXTRACTION: Relevant English-language clinical trials were evaluated. DATA SYNTHESIS: Pirtobrutinib was approved by the US Food and Drug Administration for the treatment of relapsed/refractory mantle cell lymphoma (MCL) and chronic lymphocytic leukemia (CLL) based largely on a phase 1/2 study in B-cell malignancies. Pirtobrutinib demonstrated a 73% overall response rate (ORR) in the CLL population and 58% in MCL. Pirtobrutinib has activity in patients resistant to earlier-generation, covalent BTK inhibitors. In fact, the ORRs were similar in BTK-pretreated and naïve patients. Adverse effects include fatigue, diarrhea, bleeding, and infection. Atrial fibrillation, a class effect of BTK inhibitors, may be less common with pirtobrutinib. RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE IN COMPARISON WITH EXISTING DRUGS: Compared with earlier-generation BTK inhibitors, pirtobrutinib is more selective for BTK and binds noncovalently to the receptor. Ongoing studies are evaluating pirtobrutinib's use in multiple B-cell malignancies and comparing it with other BTK inhibitors. CONCLUSION: The characteristics of pirtobrutinib render it useful in the treatment of B-cell malignancies no longer responding to a previous BTK inhibitor, and results from ongoing clinical trials may support future expanded use.
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BACKGROUND: Anxiety and depression in cardiac rehabilitation (CR) are associated with greater morbidity, mortality, and increased healthcare costs. Current psychological interventions within CR have small effects based on low-quality studies of clinic-based interventions with limited access to home-based psychological support. We tested the effectiveness of adding self-help metacognitive therapy (Home-MCT) to CR in reducing anxiety and depression in a randomised controlled trial (RCT). METHODS AND FINDINGS: We ran a single-blind, multi-centre, two-arm RCT. A total of 240 CR patients were recruited from 5 NHS-Trusts across North West England between April 20, 2017 and April 6, 2020. Patients were randomly allocated to Home-MCT+CR (n = 118, 49.2%) or usual CR alone (n = 122, 50.8%). Randomisation was 1:1 via randomised blocks within hospital site, balancing arms on sex and baseline Hospital Anxiety and Depression Scale (HADS) scores. The primary outcome was the HADS total score at posttreatment (4-month follow-up). Follow-up data collection occurred between August 7, 2017 and July 20, 2020. Analysis was by intention to treat. The 4-month outcome favoured the MCT intervention group demonstrating significantly lower end of treatment scores (HADS total: adjusted mean difference = -2.64 [-4.49 to -0.78], p = 0.005, standardised mean difference (SMD) = 0.38). Sensitivity analysis using multiple imputation (MI) of missing values supported these findings. Most secondary outcomes also favoured Home-MCT+CR, especially in reduction of post-traumatic stress symptoms (SMD = 0.51). There were 23 participants (19%) lost to follow-up in Home-MCT+CR and 4 participants (3%) lost to follow-up in CR alone. No serious adverse events were reported. The main limitation is the absence of longer term (e.g., 12-month) follow-up data. CONCLUSION: Self-help home-based MCT was effective in reducing total anxiety/depression in patients undergoing CR. Improvement occurred across most psychological measures. Home-MCT was a promising addition to cardiac rehabilitation and may offer improved access to effective psychological treatment in cardiovascular disease (CVD) patients. TRIAL REGISTRATION: NCT03999359.
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Doenças Cardiovasculares , Humanos , Doenças Cardiovasculares/terapia , Depressão/psicologia , Ansiedade/diagnóstico , Transtornos de Ansiedade , Inglaterra , Análise Custo-Benefício , Qualidade de VidaRESUMO
BACKGROUND: The NHS Diabetes Prevention Programme (NDPP) is a behaviour change programme for adults who are at risk of developing type 2 diabetes mellitus (T2DM): people with raised blood glucose levels, but not in the diabetic range, diagnosed with nondiabetic hyperglycaemia (NDH). We examined the association between referral to the programme and reducing conversion of NDH to T2DM. METHODS AND FINDINGS: Cohort study of patients attending primary care in England using clinical Practice Research Datalink data from 1 April 2016 (NDPP introduction) to 31 March 2020 was used. To minimise confounding, we matched patients referred to the programme in referring practices to patients in nonreferring practices. Patients were matched based on age (≥3 years), sex, and ≥365 days of NDH diagnosis. Random-effects parametric survival models evaluated the intervention, controlling for numerous covariates. Our primary analysis was selected a priori: complete case analysis, 1-to-1 practice matching, up to 5 controls sampled with replacement. Various sensitivity analyses were conducted, including multiple imputation approaches. Analysis was adjusted for age (at index date), sex, time from NDH diagnosis to index date, BMI, HbA1c, total serum cholesterol, systolic blood pressure, diastolic blood pressure, prescription of metformin, smoking status, socioeconomic status, a diagnosis of depression, and comorbidities. A total of 18,470 patients referred to NDPP were matched to 51,331 patients not referred to NDPP in the main analysis. Mean follow-up from referral was 482.0 (SD = 317.3) and 472.4 (SD = 309.1) days, for referred to NDPP and not referred to NDPP, respectively. Baseline characteristics in the 2 groups were similar, except referred to NDPP were more likely to have higher BMI and be ever-smokers. The adjusted HR for referred to NDPP, compared to not referred to NDPP, was 0.80 (95% CI: 0.73 to 0.87) (p < 0.001). The probability of not converting to T2DM at 36 months since referral was 87.3% (95% CI: 86.5% to 88.2%) for referred to NDPP and 84.6% (95% CI: 83.9% to 85.4%) for not referred to NDPP. Associations were broadly consistent in the sensitivity analyses, but often smaller in magnitude. As this is an observational study, we cannot conclusively address causality. Other limitations include the inclusion of controls from the other 3 UK countries, data not allowing the evaluation of the association between attendance (rather than referral) and conversion. CONCLUSIONS: The NDPP was associated with reduced conversion rates from NDH to T2DM. Although we observed smaller associations with risk reduction, compared to what has been observed in RCTs, this is unsurprising since we examined the impact of referral, rather than attendance or completion of the intervention.
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Diabetes Mellitus Tipo 2 , Hiperglicemia , Adulto , Humanos , Pré-Escolar , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/epidemiologia , Diabetes Mellitus Tipo 2/prevenção & controle , Hiperglicemia/diagnóstico , Medicina Estatal , Estudos de Coortes , Inglaterra/epidemiologia , Encaminhamento e ConsultaRESUMO
OBJECTIVE: The aim of this article is to assess available data regarding use of nivolumab/relatlimab for adult and pediatric patients 12 years of age and older with unresectable or metastatic melanoma. DATA SOURCES: A search of PubMed conducted from August 2019 to August 2022 with the search terms Opdualag, nivolumab AND relatlimab, and BMS-986016 resulted in 14 publications. STUDY SELECTION AND DATA EXTRACTION: Relevant clinical trials written in English language were analyzed. DATA SYNTHESIS: Nivolumab/relatlimab was approved by the Food and Drug Administration following results of a phase 1/2 trial and phase 2/3 RELATIVITY-047 trial. Nivolumab/relatlimab demonstrated a median progression free survival (PFS) of 10.1 months in the first-line setting without new safety signals. The PFS benefits appear greatest in those with programmed cell death-ligand 1 (PD-L1) <1% and lymphocyte activation gene-3 (LAG-3) ≥1%. Adverse effects commonly experienced were immune related in nature and require early identification and prompt management. Grade 3 or 4 adverse effects occurred in 18.9% of patients. RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE: For patients 12 years of age and older with unresectable or metastatic melanoma, nivolumab/relatlimab offers a new first-line treatment option. Evaluation of PD-L1 expression along with concomitant use of medications with potential interactions should be evaluated when deciding if nivolumab/relatlimab is the most appropriate treatment option. CONCLUSIONS: Nivolumab/relatlimab adds an additional first-line treatment option demonstrating promising improved PFS for patients with unresectable or metastatic melanoma, particularly those with PD-L1 <1% and/or LAG 3 ≥1%. Additional uses of nivolumab/relatlimab may be on the horizon as further clinical trials are ongoing.
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Antineoplásicos , Melanoma , Adulto , Humanos , Criança , Nivolumabe/efeitos adversos , Antineoplásicos/uso terapêutico , Anticorpos Monoclonais/efeitos adversos , Inibidores de Checkpoint Imunológico/uso terapêutico , Antígeno B7-H1 , Melanoma/tratamento farmacológico , Melanoma/metabolismo , Melanoma/patologia , Ensaios Clínicos Fase II como Assunto , Ensaios Clínicos Fase I como AssuntoRESUMO
OBJECTIVE: To evaluate clinical data regarding the use of amivantamab and mobocertinib for epidermal growth factor receptor (EGFR) exon 20 insertion mutation non-small cell lung cancer (NSCLC) and assess their potential impact on the care of patients. DATA SOURCES: A comprehensive literature search of PubMed and Clinicaltrials.gov was conducted using the terms amivantamab, Rybrevant, JNJ-61186372, mobocertinib, Exkivity, TAK-788. STUDY SELECTION AND DATA EXTRACTION: Relevant English-language clinical trials were evaluated. DATA SYNTHESIS: Amivantamab and mobocertinib were Food and Drug Administration (FDA) approved based on phases 1 and 2 studies. Amivantamab demonstrated an overall response rate (ORR) of 40% and median progression-free survival (PFS) of 8.3 months. Patients commonly experienced rash (86%), paronychia (45%), and stomatitis (21%). Mobocertinib demonstrated an ORR of 28% and median PFS of 7.3 months in phase 1/2 study. Patients frequently experienced diarrhea (91%), rash (45%), and paronychia (38%). Cardiac monitoring is recommended with mobocertinib due to risk of QTc prolongation and cardiac failure. RELEVANCE TO PATIENT CARE: For NSCLC patients who possess an EGFR exon 20 insertion mutation, amivantamab and mobocertinib are indicated as second-line therapy. Ongoing studies are evaluating these therapies as first-line monotherapy and as part of combination regimens in multiple cancer types. Dosage forms, drug interactions, and patient comorbidities should be considered when deciding which of the 2 agents may be most appropriate. CONCLUSION: Amivantamab and mobocertinib target an uncommon NSCLC mutation that has historically marked a poor prognosis because of innate resistance to previously approved EGFR tyrosine kinase inhibitors. Promising results from early phase trials supported accelerated FDA approval.
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Carcinoma Pulmonar de Células não Pequenas , Exantema , Neoplasias Pulmonares , Paroniquia , Humanos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Mutagênese Insercional , Paroniquia/tratamento farmacológico , Inibidores de Proteínas Quinases/efeitos adversos , Receptores ErbB/genética , Éxons , Mutação , Ensaios Clínicos Fase II como Assunto , Ensaios Clínicos Fase I como AssuntoRESUMO
PURPOSE: To examine the impact of diabetes (type 2) and glycemic control on healthcare-related outcomes (healthcare utilization, adverse effects, and treatment modifications) in non-metastatic breast cancer (NMBC) patients during chemotherapy treatment. METHODS: This was a retrospective study of 243 NMBC patients (stages 1-3) with/without diabetes receiving neoadjuvant or adjuvant cytotoxic chemotherapy. The primary study endpoint was to compare healthcare utilization between NMBC patients with and without diabetes. Secondary study endpoints included adverse events and chemotherapy treatment modifications. Additional analyses were conducted to compare these health-related outcomes by glycemic control status. RESULTS: NMBC patients with diabetes had higher utilization of emergency department (ED) services (52% vs. 33%, p = 0.013) and a higher frequency of unplanned inpatient admissions (35% vs. 19%, p = 0.014). Additionally, NMBC patients with diabetes had a higher incidence of infection and treatment modifications. NMBC patients, regardless of diabetes diagnosis, who had poor glycemic control, specifically hyperglycemia (per random blood glucose), during the study period also had increased healthcare utilization, adverse effects, and treatment modifications. Patients with a baseline HbA1c ≥ 7 had a greater number of ED visits and a higher incidence of infection than those without diabetes. CONCLUSION: Diabetes and glycemic control may impact the health-related outcomes of NMBC patients. Additional studies are needed to confirm these findings and determine optimal monitoring and management strategies for NMBC patients with diabetes and/or poor glycemic control during cytotoxic chemotherapy.
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Neoplasias da Mama , Diabetes Mellitus Tipo 2 , Hiperglicemia , Humanos , Feminino , Estudos Retrospectivos , Neoplasias da Mama/patologia , Controle Glicêmico , Hiperglicemia/induzido quimicamente , Hiperglicemia/epidemiologia , Hiperglicemia/prevenção & controle , GlicemiaRESUMO
BACKGROUND: The prevention of type 2 diabetes (T2DM) is a major concern for health services around the world. The English NHS Diabetes Prevention Programme (NHS-DPP) offers a group face-to-face behaviour change intervention, based around exercise and diet, to adults with non-diabetic hyperglycaemia (NDH), referred from primary care. Previous analysis of the first 100,000 referrals revealed just over half of those referred to the NHS-DPP took up a place. This study aimed to identify the demographic, health and psychosocial factors associated with NHS-DPP uptake to help inform the development of interventions to improve uptake and address inequities between population groups. METHODS: Drawing on the Behavioral Model of Health Services Utilization we developed a survey questionnaire to collect data on a wide range of demographic, health and psychosocial factors that might influence uptake of the NHS-DPP. We distributed this questionnaire to a cross-sectional random sample of 597 patients referred to the NHS-DPP across 17 general practices, chosen for variation. Multivariable regression analysis was used to identify factors associated with NHS-DPP uptake. RESULTS: 325 out of 597 questionnaires were completed (54%). Only a third of responders took up the offer of a place. The best performing model for uptake (AUC = 0.78) consisted of four factors: older age; beliefs concerning personal vulnerability to T2DM; self-efficacy for reducing T2DM risk; and the efficacy of the NHS-DPP. After accounting for these, demographic and health-related factors played only a minor role. CONCLUSION: Unlike fixed demographic characteristics, psychosocial perceptions may be amenable to change. NHS-DPP uptake rates may be improved by targeting the beliefs of patients about their risk of developing T2DM, their ability to carry out and sustain behaviours to reduce this risk, and the efficacy of the NHS-DPP in providing the necessary understanding and skills required. The recently introduced digital version of the NHS DPP could help address the even lower uptake amongst younger adults. Such changes could facilitate proportional access from across different demographic strata.
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Diabetes Mellitus Tipo 2 , Hiperglicemia , Adulto , Humanos , Diabetes Mellitus Tipo 2/prevenção & controle , Medicina Estatal , Estudos Transversais , DemografiaRESUMO
BACKGROUND: Depression and anxiety in cardiovascular disease are significant, contributing to poor prognosis. Unfortunately, current psychological treatments offer mixed, usually small improvements in these symptoms. The present trial tested for the first time the effects of group metacognitive therapy (MCT; 6 sessions) on anxiety and depressive symptoms when delivered alongside cardiac rehabilitation (CR). METHODS: A total of 332 CR patients recruited from 5 National Health Service Trusts across the North-West of England were randomly allocated to MCT+CR (n=163, 49.1%) or usual CR alone (n=169, 50.9%). Randomization was 1:1 via minimization balancing arms on sex and Hospital Anxiety and Depression Scale scores within hospital site. The primary outcome was Hospital Anxiety and Depression Scale total after treatment (4-month follow-up). Secondary outcomes were individual Hospital Anxiety and Depression Scales, traumatic stress symptoms, and psychological mechanisms including metacognitive beliefs and repetitive negative thinking. Analysis was intention to treat. RESULTS: The adjusted group difference on the primary outcome, Hospital Anxiety and Depression Scale total score at 4 months, significantly favored the MCT+CR arm (-3.24 [95% CI, -4.67 to -1.81], P<0.001; standardized effect size, 0.52 [95% CI, 0.291 to 0.750]). The significant difference was maintained at 12 months (-2.19 [95% CI, -3.72 to -0.66], P=0.005; standardized effect size, 0.33 [95% CI, 0.101 to 0.568]). The intervention improved outcomes significantly for both depression and anxiety symptoms when assessed separately compared with usual care. Sensitivity analysis using multiple imputation of missing values supported these findings. Most secondary outcomes favored MCT+CR, with medium to high effect sizes for psychological mechanisms of metacognitive beliefs and repetitive negative thinking. No adverse treatment-related events were reported. CONCLUSIONS: Group MCT+CR significantly improved depression and anxiety compared with usual care and led to greater reductions in unhelpful metacognitions and repetitive negative thinking. Most gains remained significant at 12 months. Study strengths include a large sample, a theory-based intervention, use of longer-term follow-up, broad inclusion criteria, and involvement of a trials unit. Limitations include no control for additional contact as part of MCT to estimate nonspecific effects, and the trial was not intended to assess cardiac outcomes. Nonetheless, results demonstrated that addition of the MCT intervention had broad and significant beneficial effects on mental health symptoms. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: ISRCTN74643496.
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Ansiedade/terapia , Reabilitação Cardíaca/métodos , Depressão/terapia , Metacognição/fisiologia , Intervenção Psicossocial/métodos , Psicoterapia de Grupo/métodos , Idoso , Ansiedade/psicologia , Reabilitação Cardíaca/psicologia , Depressão/psicologia , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Método Simples-Cego , Resultado do TratamentoRESUMO
Offshore platforms, subsea pipelines, wells and related fixed structures supporting the oil and gas (O&G) industry are prevalent in oceans across the globe, with many approaching the end of their operational life and requiring decommissioning. Although structures can possess high ecological diversity and productivity, information on how they interact with broader ecological processes remains unclear. Here, we review the current state of knowledge on the role of O&G infrastructure in maintaining, altering or enhancing ecological connectivity with natural marine habitats. There is a paucity of studies on the subject with only 33 papers specifically targeting connectivity and O&G structures, although other studies provide important related information. Evidence for O&G structures facilitating vertical and horizontal seascape connectivity exists for larvae and mobile adult invertebrates, fish and megafauna; including threatened and commercially important species. The degree to which these structures represent a beneficial or detrimental net impact remains unclear, is complex and ultimately needs more research to determine the extent to which natural connectivity networks are conserved, enhanced or disrupted. We discuss the potential impacts of different decommissioning approaches on seascape connectivity and identify, through expert elicitation, critical knowledge gaps that, if addressed, may further inform decision making for the life cycle of O&G infrastructure, with relevance for other industries (e.g. renewables). The most highly ranked critical knowledge gap was a need to understand how O&G structures modify and influence the movement patterns of mobile species and dispersal stages of sessile marine species. Understanding how different decommissioning options affect species survival and movement was also highly ranked, as was understanding the extent to which O&G structures contribute to extending species distributions by providing rest stops, foraging habitat, and stepping stones. These questions could be addressed with further dedicated studies of animal movement in relation to structures using telemetry, molecular techniques and movement models. Our review and these priority questions provide a roadmap for advancing research needed to support evidence-based decision making for decommissioning O&G infrastructure.
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Ecossistema , Peixes , Animais , Invertebrados , Larva , Oceanos e MaresRESUMO
PURPOSE OF REVIEW: Recent advances in oncologic therapies have significantly improved overall survival for patients with malignancy. However, cardiovascular complications have not only increased in this population due to shared risk factors and pathophysiology, but also due to the therapies themselves. One key mechanism that warrants further attention is accelerated atherosclerosis due to these agents. RECENT FINDINGS: Here we review recent studies focusing on four classes of anticancer agents with the potential to accelerate atherosclerosis, including breakpoint cluster region-Ableson (BCR-ABL) tyrosine kinase inhibitors, immunotherapies, androgen deprivation therapies, and vascular endothelial growth factor inhibitors. In addition to drug therapy, radiation therapy may also accelerate atherosclerosis. SUMMARY: In order to optimize outcomes for patients with malignancy, enhanced efforts need to focus on mitigating common risk factors, but also recognizing enhanced atherosclerotic risk with certain oncologic therapies. For patients exposed to these agents, risk reduction with agents such as aspirin and/or statins prior to, during, and after cancer treatment may provide opportunities to improve overall outcomes.
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Antineoplásicos , Aterosclerose , Neoplasias da Próstata , Antagonistas de Androgênios , Antineoplásicos/efeitos adversos , Aterosclerose/induzido quimicamente , Humanos , Masculino , Neoplasias da Próstata/induzido quimicamente , Neoplasias da Próstata/tratamento farmacológico , Fator A de Crescimento do Endotélio VascularRESUMO
BACKGROUND: Immune checkpoint inhibitors (ICIs) used in cancer treatment cause immune-related adverse effects (irAEs), including thyroiditis leading to hypothyroidism. The management and outcomes of this irAE are not well established. OBJECTIVE: The purpose of this analysis is to describe the onset, management, and outcomes of patients experiencing hypothyroidism from ICI. METHODS: A retrospective study was conducted of adults receiving ICI therapy at a community cancer center between January 1, 2017, and February 1, 2020. The primary endpoint was to describe onset (timing) of hypothyroidism (thyroid-stimulating hormone [TSH] > 10 µIU/mL). Secondary outcomes included describing hypothyroidism symptoms and levothyroxine use, time to documented disease progression, and occurrence of additional adverse effects (AEs). RESULTS: Of the 200 patients included in the study, 19% developed clinical hypothyroidism (TSH > 10 µIU/mL, or required initiation of or dose increase in levothyroxine). Median time to TSH higher than 10 µIU/mL was 13.3 weeks and symptoms of hypothyroidism occurred in 34% of patients developing clinical hypothyroidism. The median final daily levothyroxine dose was 88 mcg (0.88 mcg/kg). Time to disease progression was longer in those with clinical hypothyroidism (27.4 months vs. 6.8 months, respectively, P = .015). Additional AEs occurred in 68% of those developing hypothyroidism versus 49% without hypothyroidism (P = .029). CONCLUSION AND RELEVANCE: Patients with clinical hypothyroidism during ICI treatment may have improved cancer outcomes, but they also are more likely to develop other AEs. Patients requiring thyroid replacement therapy with levothyroxine may benefit from a starting dose between 50 and 100 mcg/day, approximately 0.88 mcg/kg/day.
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Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Hipotireoidismo , Adulto , Progressão da Doença , Humanos , Hipotireoidismo/induzido quimicamente , Hipotireoidismo/tratamento farmacológico , Inibidores de Checkpoint Imunológico/efeitos adversos , Estudos Retrospectivos , Tireotropina/uso terapêutico , Tiroxina/uso terapêuticoRESUMO
BACKGROUND: Vascular endothelial growth factor (VEGF) inhibitors are known to cause hypertension. The purpose of this study was to assess the impact of blood pressure (BP) elevations on outcomes in patients receiving VEGF inhibitors. METHODS: This retrospective chart review analyzed patients receiving treatment with VEGF inhibitors. The primary endpoint was time to progression (TTP) in those with or without significant increase in BP (increase in systolic BP greater than 20 mm Hg or greater than 10 mm Hg increase in diastolic BP). Secondary endpoints included treatment interruption, therapy discontinuation due to documented adverse effect, and time to BP elevation. Subgroup analyses were completed in those receiving bevacizumab and oral tyrosine kinase inhibitors. RESULTS: A total of 155 patients were included and 93 patients (60%) experienced a significant increase in BP. Median time to development of an elevated BP was 47 days. Patients with significant increases in BP had a longer median TTP compared to patients without (8.1 months vs 4.4 months, p = 0.002). No differences were present between groups in treatment interruption or discontinuation due to a documented adverse effect and outcomes were similar in those receiving bevacizumab and oral tyrosine kinase inhibitors. In the analysis of the impact of severity of BP elevations, those with severe BP elevations were more likely to have treatment interrupted but discontinuation rates were similar across groups. CONCLUSION: Development of significant BP elevations may be a marker of therapeutic response to VEGF inhibitors and does not limit treatment duration, even in those with severe elevations.
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Hipertensão , Fator A de Crescimento do Endotélio Vascular , Inibidores da Angiogênese/efeitos adversos , Pressão Sanguínea , Humanos , Hipertensão/induzido quimicamente , Hipertensão/tratamento farmacológico , Estudos RetrospectivosRESUMO
INTRODUCTION: Motor vehicle crashes (MVC) are the second leading cause of death for adolescents in the United States, with drowsy driving a major contributing factor. Early school start times have been identified as a significant factor that reduces adolescent sleep duration, which in turn contributes to drowsy driving and MVC. This paper examined the longitudinal impact of delaying secondary school start times on self-reported student drowsy driving and teen MVC. METHODS: Secondary school students (10th and 11th grade, 51.7% female, 67.8% White) in the United States completed annual surveys 1 year before and 2 years after implementation of later school start times (70-min delay, n range 1642-2452 per year), reporting frequency of drowsy driving (less than once/week vs. at least once/week). Teen (16-18 years) MVC data from the Colorado Department of Transportation for the 2 years before and 2 years after later start time implementation were compared for Arapahoe County (where start times changed) and neighboring Adams County and Douglas County (where start times did not change). RESULTS: With later start times, there was a significant drop in the percent of students who reported frequent drowsy driving (pre-change: 32.6%, post-change: 21.9%, follow-up: 22.8%). Weekday teen MVC rates went down in Arapahoe County (p = .04) during the school year, while no change or increases in MVC rates were seen in neighboring counties. CONCLUSIONS: Healthy school start times are important for adolescent health and safety, with study findings highlighting the downstream effects of increased sleep duration following a 70-min delay in secondary school start times on adolescent drowsy driving and teen MVC rates.
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Acidentes de Trânsito , Condução de Veículo , Adolescente , Feminino , Humanos , Masculino , Veículos Automotores , Instituições Acadêmicas , Inquéritos e Questionários , Estados Unidos/epidemiologiaRESUMO
BACKGROUND: Hypoalbuminemia is commonly observed in cancer patients. Given the pharmacokinetic interactions between serum proteins and protein bound medications, administration of highly protein bound targeted oral oncolytic drugs may result in elevated unbound drug levels and decreased tolerability in those with hypoalbuminemia. OBJECTIVE: To describe the impact of hypoalbuminemia on oral oncolytic drug tolerability. METHODS: A retrospective study was conducted of adult patients receiving treatment with targeted oral oncolytic drugs with ≥95% protein binding. The primary end point of this study was to compare time to discontinuation resulting from documented toxicity in those with and without hypoalbuminemia. RESULTS: The study included 143 patients receiving 16 targeted oral oncolytic drugs (42% with hypoalbuminemia, 58% without hypoalbuminemia). Adverse events were common, with similar incidence among patients with and without hypoalbuminemia (73% vs 76%, respectively; P = 0.727). Median time to therapy discontinuation resulting from documented toxicity was significantly shorter in those with hypoalbuminemia (22 months vs not reached; P = 0.003). Cox regression demonstrated that hypoalbuminemia was the only significant risk factor for shorter time to discontinuation resulting from documented adverse effects (hazard ratio = 3.0; 95% CI = 1.15-8.0; P = 0.025). CONCLUSION AND RELEVANCE: This represents the first report of the impact of hypoalbuminemia on tolerability of highly protein bound oral oncolytic drugs, demonstrating that patients with hypoalbuminemia may be at increased risk for early discontinuation resulting from toxicity. Given the importance of maintaining dose intensity in patients receiving oncolytic therapy, albumin levels should be monitored throughout treatment and supportive care maximized in those developing hypoalbuminemia.
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Antineoplásicos/metabolismo , Tolerância a Medicamentos , Hipoalbuminemia/tratamento farmacológico , Albumina Sérica/metabolismo , Administração Oral , Adulto , Idoso , Antineoplásicos/administração & dosagem , Antineoplásicos/uso terapêutico , Feminino , Humanos , Hipoalbuminemia/sangue , Incidência , Masculino , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Ligação Proteica , Estudos Retrospectivos , Fatores de RiscoRESUMO
OBJECTIVE: To assess the clinical application of lurbinectedin and its role in the therapy of small-cell lung cancer (SCLC). DATA SOURCES: PubMed database and ClincialTrials.gov were utilized to perform a comprehensive literature search from August 2011 to mid-November 2020 with the terms lurbinectedin and PM01183. STUDY SELECTION AND DATA EXTRACTION: English-language clinical trials of lurbinectedin were evaluated. DATA SYNTHESIS: Lurbinectedin, as second-line therapy in SCLC, demonstrated an overall response (OR) rate of 35.2% and median overall survival of 9.3 months. Phase II studies in multiple cancers revealed myelosuppression (>95%), increased liver enzymes (>70%), nausea (up to 80%), vomiting (54%), and fatigue (>50%) as the most common adverse events associated with lurbinectedin. CYP3A4 drug interactions affect lurbinectedin exposure (severe pancytopenia occurred after coadministration with aprepitant), and protein binding can affect its clearance. Patients with cardiac comorbidities were not included in published lurbinectedin trials because of cardiotoxicity associated with trabectedin. RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE: Lurbinectedin is an option in SCLC after failure of a platinum-based regimen. Dose adjustments, drug interactions, antiemetic regimen choice, and patient comorbidities are important clinical considerations with lurbinectedin use. Likewise, its place in therapy in the era of immune checkpoint inhibitors requires further exploration. CONCLUSIONS: With a promising OR compared with other second-line options, lurbinectedin should be considered in patients who have failed first-line therapy. Studies are ongoing with lurbinectedin in combination with other agents in SCLC, and a phase III trial is assessing use in combination with doxorubicin compared with other second-line regimens.
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Neoplasias Pulmonares , Recidiva Local de Neoplasia , Protocolos de Quimioterapia Combinada Antineoplásica , Carbolinas/uso terapêutico , Compostos Heterocíclicos de 4 ou mais Anéis/efeitos adversos , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológicoRESUMO
The original article [1] contains an omitted grant acknowledgement and affiliation as relates to the contribution of co-author, Rafael Perera-Salazar. As such, the following two amendments should apply to the original article.
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OBJECTIVES: Tracheostomy is a very common clinical intervention in critically ill adult patients. The indications for tracheostomy procedures in pediatric patients with complex conditions have increased dramatically in recent years, but there are currently no guidelines on the optimal timing of tracheostomy in pediatric patients undergoing prolonged ventilation. DATA SOURCES: We performed a systematic search of the existing literature in MEDLINE via PubMed and Embase databases and the Cochrane Library to identify clinical trials, observational studies, and cohort studies that compare early and late tracheostomy in children. The date of the last search was August 27, 2018. Included articles were subjected to manual searching. STUDY SELECTION: Studies in mechanically ventilated children that compared early with late tracheostomy were included. DATA EXTRACTION: Data were extracted into a spreadsheet and copied into Review Manager 5.3 (The Cochrane Collaboration, Copenhagen, Denmark). DATA SYNTHESIS: Data were meta-analyzed using an inverse variance, random effects model. Continuous outcomes were calculated as mean differences with 95% CIs, and dichotomous outcomes were calculated as Mantel-Haenszel risk ratios with 95% CIs. We included eight studies (10 study arms). These studies were all retrospective cohort studies. Early tracheostomy was associated with significant reductions in mortality, days on mechanical ventilation, and length of intensive care and total hospital stay, although the lack of randomized, controlled trials limits the validity of these findings. Although variance was imputed for some studies, these conclusions did not change after removing these studies from the analysis. CONCLUSIONS: In children on mechanical ventilation, early tracheostomy may improve important medical outcomes. However, our data demonstrate the urgent need for high-quality, randomized controlled trials in the pediatric population.
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Respiração Artificial/estatística & dados numéricos , Traqueostomia/métodos , Adolescente , Criança , Pré-Escolar , Cuidados Críticos , Estado Terminal , Humanos , Lactente , Unidades de Terapia Intensiva , Tempo de Internação , Estudos Retrospectivos , Fatores de Tempo , Traqueostomia/mortalidadeRESUMO
OBJECTIVE: To assess the use of subcutaneous trastuzumab/hyaluronidase-oysk (SQ trastuzumab) in comparison to intravenous (IV) trastuzumab. DATA SOURCES: A comprehensive PubMed literature search was performed from August 2012 to August 2019 using search terms Herceptin Hylecta, trastuzumab, hyaluronidase, subcutaneous, preference, safety, efficacy, and cost. STUDY SELECTION & DATA EXTRACTION: English-language clinical trials focusing on SQ trastuzumab were evaluated. DATA SYNTHESIS: In phase III trials, adverse event (AE) rates ranged from 64% to 97.6% of patients receiving SQ trastuzumab in 3 studies compared to 94.6% of patients receiving IV trastuzumab. In the phase III trial comparing SQ trastuzumab to IV trastuzumab, six-year overall survival (OS) was 84% in both groups. In pharmacokinetic analyses, trough concentrations and AUC0-21 were slightly higher in patients receiving SQ trastuzumab and differences were larger at the extremes of body weight. Two pharmacoeconomic analyses reported cost-savings associated with a 52-week treatment cycle of trastuzumab of $2,090 USD and $4,600 USD. RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE: Food and Drug Administration (FDA)-approved in February 2019, SQ trastuzumab, a monoclonal antibody that binds to human epidermal growth factor receptor 2 (HER2) protein in combination with hyaluronidase, offers an alternative dosage form for patients with breast tumors overexpressing HER2. CONCLUSIONS: SQ trastuzumab has a similar safety profile to IV trastuzumab. Although it may be slightly more cost-effective, its role in the treatment of HER2-overexpressing tumors requires further study in those at the extremes of body weight due to differences in drug exposure compared to IV trastuzumab.
Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Hialuronoglucosaminidase/uso terapêutico , Receptor ErbB-2/metabolismo , Trastuzumab/uso terapêutico , Adulto , Antineoplásicos Imunológicos/administração & dosagem , Antineoplásicos Imunológicos/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias da Mama/imunologia , Neoplasias da Mama/metabolismo , Neoplasias da Mama/mortalidade , Ensaios Clínicos Fase III como Assunto , Intervalo Livre de Doença , Feminino , Humanos , Hialuronoglucosaminidase/administração & dosagem , Hialuronoglucosaminidase/efeitos adversos , Injeções Intravenosas , Injeções Subcutâneas , Pessoa de Meia-Idade , Trastuzumab/administração & dosagem , Trastuzumab/efeitos adversosRESUMO
BACKGROUND: Oral mucositis, a common complication of several different anticancer therapies, causes significant morbidity in cancer patients. It is characterized by the destruction of the mucosa throughout the gastrointestinal tract including the oral cavity. Limited data exist regarding the treatment of established oral mucositis with oral mucoadhesive hydrogel (MuGard) or supersaturated calcium phosphate oral rise (Caphosol) compared to standard topical therapies. OBJECTIVES: To evaluate the effects of MuGard and Caphosol compared to standard topical therapy in the treatment of established oral mucositis. METHODS: A retrospective chart review was performed including adults receiving MuGard, Caphosol, and/or standard topical therapy for the treatment of established oral mucositis while admitted to a community teaching hospital. A post hoc propensity score was used to match patients receiving newer agents (Mugard/Caphosol) to those receiving standard topical therapy (ST). RESULTS: One hundred and forty-seven patients were included for analysis (125 ST, 15 MuGard, 7 Caphosol). From this population, 14 patients in each group were matched. The primary endpoint of median change in average daily pain score at days 3 and 7, compared to baseline, demonstrated no difference between matched groups at day 3 (ST 0, MuGard/Caphosol 0.18, p = 0.830) or day 7 (ST 0, MuGard/Caphosol 0.8, p = 0.494). No differences were noted between groups in opioid usage, oral mucositis symptom duration or progression, or incidence of documented infection. CONCLUSION: MuGard and Caphosol did not demonstrate any benefits compared to standard topical therapy at reducing pain scores or increasing mucosal recovery in the treatment of oral mucositis.
Assuntos
Antineoplásicos/efeitos adversos , Fosfatos de Cálcio/administração & dosagem , Estomatite/induzido quimicamente , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/uso terapêutico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias/tratamento farmacológico , Dor/etiologia , Estudos Retrospectivos , Estomatite/terapia , Adulto JovemRESUMO
BACKGROUND: The presence of additional chronic conditions has a significant impact on the treatment and management of type 2 diabetes (T2DM). Little is known about the patterns of comorbidities in this population. The aims of this study are to quantify comorbidity patterns in people with T2DM, to estimate the prevalence of six chronic conditions in 2027 and to identify clusters of similar conditions. METHODS: We used the Clinical Practice Research Datalink (CPRD) linked with the Index of Multiple Deprivation (IMD) data to identify patients diagnosed with T2DM between 2007 and 2017. 102,394 people met the study inclusion criteria. We calculated the crude and age-standardised prevalence of 18 chronic conditions present at and after the T2DM diagnosis. We analysed longitudinally the 6 most common conditions and forecasted their prevalence in 2027 using linear regression. We used agglomerative hierarchical clustering to identify comorbidity clusters. These analyses were repeated on subgroups stratified by gender and deprivation. RESULTS: More people living in the most deprived areas had ≥ 1 comorbidities present at the time of diagnosis (72% of females; 64% of males) compared to the most affluent areas (67% of females; 59% of males). Depression prevalence increased in all strata and was more common in the most deprived areas. Depression was predicted to affect 33% of females and 15% of males diagnosed with T2DM in 2027. Moderate clustering tendencies were observed, with concordant conditions grouped together and some variations between groups of different demographics. CONCLUSIONS: Comorbidities are common in this population, and high between-patient variability in comorbidity patterns emphasises the need for patient-centred healthcare. Mental health is a growing concern, and there is a need for interventions that target both physical and mental health in this population.