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Interleukin-23 (IL-23) and IL-17 are cytokines currently being targeted in clinical trials. Although inhibition of both of these cytokines is effective for treating psoriasis, IL-12 and IL-23 p40 inhibition attenuates Crohn's disease, whereas IL-17A or IL-17 receptor A (IL-17RA) inhibition exacerbates Crohn's disease. This dichotomy between IL-23 and IL-17 was effectively modeled in the multidrug resistance-1a-ablated (Abcb1a(-/-)) mouse model of colitis. IL-23 inhibition attenuated disease by decreasing colonic inflammation while enhancing regulatory T (Treg) cell accumulation. Exacerbation of colitis by IL-17A or IL-17RA inhibition was associated with severe weakening of the intestinal epithelial barrier, culminating in increased colonic inflammation and accelerated mortality. These data show that IL-17A acts on intestinal epithelium to promote barrier function and provide insight into mechanisms underlying exacerbation of Crohn's disease when IL-17A or IL-17RA is inhibited.
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Colitis/inmunología , Interleucina-17/fisiología , Interleucina-23/fisiología , Receptores de Interleucina-17/fisiología , Subfamilia B de Transportador de Casetes de Unión a ATP/deficiencia , Animales , Colitis/tratamiento farmacológico , Colitis/etiología , Colitis/microbiología , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Epitelio/fisiopatología , Femenino , Factores de Transcripción Forkhead/análisis , Regulación de la Expresión Génica/inmunología , Infecciones por Helicobacter/complicaciones , Infecciones por Helicobacter/inmunología , Inmunización Pasiva , Inmunoglobulina G/uso terapéutico , Subunidad p40 de la Interleucina-12/antagonistas & inhibidores , Interleucina-17/inmunología , Interleucina-23/inmunología , Subunidad p19 de la Interleucina-23/antagonistas & inhibidores , Subunidad p19 de la Interleucina-23/inmunología , Mucosa Intestinal/fisiopatología , Ratones , Ratones Noqueados , Permeabilidad , Receptores de Interleucina-17/antagonistas & inhibidores , Receptores de Interleucina-17/inmunología , Subgrupos de Linfocitos T/inmunología , Linfocitos T Reguladores/inmunología , TranscriptomaRESUMEN
BACKGROUND: National studies reporting the prevalence of cannabis use have focused on individuals with a history of cancer without distinction by their treatment status, which can impact symptom burden. While pain is a primary motivation to use cannabis in cancer, the magnitude of its association with cannabis use remains understudied. METHODS: We examined cannabis use and pain management among 5523 respondents of the Behavioral Risk Factor Surveillance System with a cancer history. Survey-weighted prevalence proportions of respondents' cannabis use are reported, stratified on cancer treatment status. Regression models estimated odds ratios (ORs) and 95% confidence intervals (CIs) of cancer-related pain and cannabis use. RESULTS: Cannabis use was slightly more prevalent in those undergoing active treatment relative to those who were not undergoing active treatment (9.3% vs. 6.2%; P=0.05). Those under active treatment were more likely to use cannabis medicinally (71.6% vs. 50.0%; P=0.03). Relative to those without cancer-related pain, persons with pain under medical control (OR 2.1, 95% CI, 1.4-3.2) or uncontrolled pain were twice as likely to use cannabis (OR 2.0, 95% CI, 1.1-3.5). CONCLUSIONS: Use of cannabis among cancer patients may be related to their treatment and is positively associated with cancer-related pain. Future research should investigate the associations of cannabis use, symptom burden, and treatment regimens across the treatment spectrum to facilitate interventions.
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Dolor en Cáncer , Cannabis , Neoplasias , Humanos , Manejo del Dolor , Dolor en Cáncer/tratamiento farmacológico , Dolor en Cáncer/epidemiología , Dolor en Cáncer/etiología , Dolor/tratamiento farmacológico , Dolor/epidemiología , Dolor/etiología , Motivación , Neoplasias/complicaciones , Neoplasias/epidemiologíaRESUMEN
Blocking chemokine receptor C-C chemoattractant cytokine (chemokine) receptor (CCR) 6-dependent T cell migration has therapeutic promise in inflammatory diseases. PF-07054894 is a novel CCR6 antagonist that blocked only CCR6, CCR7, and C-X-C chemoattractant cytokine (chemokine) receptor (CXCR) 2 in a ß-arrestin assay panel of 168 G protein-coupled receptors. Inhibition of CCR6-mediated human T cell chemotaxis by (R)-4-((2-(((1,4-Dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpicolinamide (PF-07054894) was insurmountable by CCR6 ligand, C-C motif ligand (CCL) 20. In contrast, blockade of CCR7-dependent chemotaxis in human T cells and CXCR2-dependent chemotaxis in human neutrophils by PF-07054894 were surmountable by CCL19 and C-X-C motif ligand 1, respectively. [3H]-PF-07054894 showed a slower dissociation rate for CCR6 than for CCR7 and CXCR2 suggesting that differences in chemotaxis patterns of inhibition could be attributable to offset kinetics. Consistent with this notion, an analog of PF-07054894 with fast dissociation rate showed surmountable inhibition of CCL20/CCR6 chemotaxis. Furthermore, pre-equilibration of T cells with PF-07054894 increased its inhibitory potency in CCL20/CCR6 chemotaxis by 10-fold. The functional selectivity of PF-07054894 for inhibition of CCR6 relative to CCR7 and CXCR2 is estimated to be at least 50- and 150-fold, respectively. When administered orally to naïve cynomolgus monkeys, PF-07054894 increased the frequency of CCR6+ peripheral blood T cells, suggesting that blockade of CCR6 inhibited homeostatic migration of T cells from blood to tissues. PF-07054894 inhibited interleukin-23-induced mouse skin ear swelling to a similar extent as genetic ablation of CCR6. PF-07054894 caused an increase in cell surface CCR6 in mouse and monkey B cells, which was recapitulated in mouse splenocytes in vitro. In conclusion, PF-07054894 is a potent and functionally selective CCR6 antagonist that blocks CCR6-mediated chemotaxis in vitro and in vivo. SIGNIFICANCE STATEMENT: The chemokine receptor, C-C chemoattractant cytokine (chemokine) receptor 6 (CCR6) plays a key role in the migration of pathogenic lymphocytes and dendritic cells into sites of inflammation. (R)-4-((2-(((1,4-Dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpicolinamide (PF-07054894) is a novel CCR6 small molecule antagonist that illustrates the importance of binding kinetics in achieving pharmacological potency and selectivity. Orally administered PF-07054894 blocks homeostatic and pathogenic functions of CCR6, suggesting that it is a promising therapeutic agent for the treatment of a variety of autoimmune and inflammatory diseases.
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Quimiocinas CC , Interleucina-23 , Humanos , Animales , Ratones , Quimiocinas CC/genética , Receptores CCR7 , Ligandos , Linfocitos T , Inflamación , Receptores CCR6RESUMEN
The current study evaluated formal training around spiritual care for healthcare providers and the relationships between that training, perceived barriers to spiritual care, and frequency of inquiry around spiritual topics. A mixed methods explanatory sequential design was used. Quantitative methods included an online survey administered to providers at The Ohio State University Comprehensive Cancer Center. Main and interactive effects of formal training and barriers to spiritual care on frequency of inquiry around spiritual topics were assessed with two-way ANOVA. Qualitative follow-up explored provider strategies to engage spiritual topics. Among 340 quantitative participants, most were female (82.1%) or White (82.6%) with over one-half identifying as religious (57.5%). The majority were nurses (64.7%) and less than 10% of all providers (n = 26) indicated formal training around spiritual care. There were main effects on frequency of inquiry around spiritual topics for providers who indicated "personal discomfort" as a barrier (p < 0.001), but not formal training (p = 0.526). Providers who indicated "personal discomfort" as a barrier inquired about spirituality less frequently, regardless of receiving formal training (M = 8.0, SD = 1.41) or not (M = 8.76, SD = 2.96). There were no interactive effects between training and "may offend patients" or "personal discomfort" (p = 0.258 and 0.125, respectively). Qualitative analysis revealed four strategies with direct and indirect approaches: (1) permission-giving, (2) self-awareness/use-of-self, (3) formal assessment, and (4) informal assessment. Training for providers should emphasize self-awareness to address intrapersonal barriers to improve the frequency and quality of spiritual care for cancer patients.
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Terapias Espirituales , Espiritualidad , Humanos , Femenino , Masculino , Personal de Salud/educación , Encuestas y Cuestionarios , OhioRESUMEN
Communication failure within health care teams is a major cause of patient harm across health care settings. Factors which contribute to communication failure include actual or perceived 'power'. Whilst a great deal of ergonomics research has focussed on teamwork in health care, the role of power in relation to measurable patient safety and performance outcomes remains relatively unknown. This article presents the findings from a review of the literature on power within multidisciplinary health care team settings. Following a systematic literature search, nineteen studies were evaluated in terms of research design, methods and analyses across the included studies. The main impacts resulting from power imbalances include negative effects on team collaboration, decision-making, communication and overall performance. Wider patient safety research, and more specifically the ergonomics discipline, is encouraged to address the complex interplay between power and teamwork in the health care sector.Practitioner Statement: We conducted a review of studies focussed on the influence of power on teamwork in health care. The findings show that power can have negative impacts on collaboration, decision-making, communication, and team performance. We conclude that power represents an important area for ergonomics, both in health care and other settings.Abbreviations: CRM: crew resource management; TEM: threat and error management; SNA: social network analysis; EAST: event analysis of systemic teamwork.
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Atención a la Salud , Grupo de Atención al Paciente , Comunicación , Humanos , Seguridad del PacienteRESUMEN
BACKGROUND: Gemogenovatucel-T is an autologous tumour cell vaccine manufactured from harvested tumour tissue, which specifically reduces expression of furin and downstream TGF-ß1 and TGF-ß2. The aim of this study was to determine the safety and efficacy of gemogenovatucel-T in front-line ovarian cancer maintenance. METHODS: This randomised, double-blind, placebo-controlled, phase 2b trial involved 25 hospitals in the USA. Women aged 18 years and older with stage III/IV high-grade serous, endometrioid, or clear cell ovarian cancer in clinical complete response after a combination of surgery and five to eight cycles of chemotherapy involving carboplatin and paclitaxel, and an Eastern Cooperative Oncology Group status of 0 or 1 were eligible for inclusion in the study. Patients were randomly assigned (1:1) to gemogenovatucel-T or placebo by an independent third party interactive response system after successful screening using randomly permuted block sizes of two and four and stratified by extent of surgical cytoreduction and neoadjuvant versus adjuvant chemotherapy. Gemogenovatucel-T (1â×â107 cells per injection) or placebo was administered intradermally (one per month) for a minimum of four and up to 12 doses. Patients, investigators, and clinical staff were masked to patient allocation until after statistical analysis. The primary endpoint was recurrence-free survival, analysed in the per-protocol population. All patients who received at least one dose of gemogenovatucel-T were included in the safety analysis. The study is registered with ClinicalTrials.gov, NCT02346747. FINDINGS: Between Feb 11, 2015, and March 2, 2017, 310 patients consented to the study at 22 sites. 217 were excluded. 91 patients received gemogenovatucel-T (n=47) or placebo (n=44) and were analysed for safety and efficacy. The median follow-up from first dose of gemogenovatucel-T was 40·0 months (IQR 35·0-44·8) and from first dose of placebo was 39·8 months (35·5-44·6). Recurrence-free survival was 11·5 months (95% CI 7·5-not reached) for patients assigned to gemogenovatucel-T versus 8·4 months (7·9-15·5) for patients assigned to placebo (HR 0·69, 90% CI 0·44-1·07; one-sided p=0·078). Gemogenovatucel-T resulted in no grade 3 or 4 toxic effects. Two patients in the placebo group had five grade 3 toxic events, including arthralgia, bone pain, generalised muscle weakness, syncope, and dyspnea. Seven patients (four in the placebo group and three in the gemogenovatucel-T group) had 11 serious adverse events. No treatment-related deaths were reported in either of the groups. INTERPRETATION: Front-line use of gemogenovatucel-T immunotherapy as maintenance was well tolerated but the primary endpoint was not met. Further investigation of gemogenovatucel-T in patients stratified by BRCA mutation status is warranted. FUNDING: Gradalis.
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Vacunas contra el Cáncer/administración & dosificación , Carcinoma Endometrioide/terapia , Neoplasias Ováricas/terapia , Anciano , Vacunas contra el Cáncer/efectos adversos , Carcinoma Endometrioide/inmunología , Carcinoma Endometrioide/patología , Método Doble Ciego , Femenino , Humanos , Persona de Mediana Edad , Recurrencia Local de Neoplasia , Estadificación de Neoplasias , Neoplasias Ováricas/inmunología , Neoplasias Ováricas/mortalidad , Neoplasias Ováricas/patología , Factores de Tiempo , Resultado del Tratamiento , Estados UnidosRESUMEN
BACKGROUND: Oncologists often struggle with managing the unique care needs of older adults with cancer. This study sought to determine the feasibility of delivering a transdisciplinary intervention targeting the geriatric-specific (physical function and comorbidity) and palliative care (symptoms and prognostic understanding) needs of older adults with advanced cancer. METHODS: Patients aged ≥65 years with incurable gastrointestinal or lung cancer were randomly assigned to a transdisciplinary intervention or usual care. Those in the intervention arm received 2 visits with a geriatrician, who addressed patients' palliative care needs and conducted a geriatric assessment. We predefined the intervention as feasible if >70% of eligible patients enrolled in the study and >75% of eligible patients completed study visits and surveys. At baseline and week 12, we assessed patients' quality of life (QoL), symptoms, and communication confidence. We calculated mean change scores in outcomes and estimated intervention effect sizes (ES; Cohen's d) for changes from baseline to week 12, with 0.2 indicating a small effect, 0.5 a medium effect, and 0.8 a large effect. RESULTS: From February 2017 through June 2018, we randomized 62 patients (55.9% enrollment rate [most common reason for refusal was feeling too ill]; median age, 72.3 years; cancer types: 56.5% gastrointestinal, 43.5% lung). Among intervention patients, 82.1% attended the first visit and 79.6% attended both. Overall, 89.7% completed all study surveys. Compared with usual care, intervention patients had less QoL decrement (-0.77 vs -3.84; ES = 0.21), reduced number of moderate/severe symptoms (-0.69 vs +1.04; ES = 0.58), and improved communication confidence (+1.06 vs -0.80; ES = 0.38). CONCLUSIONS: In this pilot trial, enrollment exceeded 55%, and >75% of enrollees completed all study visits and surveys. The transdisciplinary intervention targeting older patients' unique care needs showed encouraging ES estimates for enhancing patients' QoL, symptom burden, and communication confidence.
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Evaluación Geriátrica/métodos , Neoplasias/terapia , Cuidados Paliativos/métodos , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Medición de Resultados Informados por el Paciente , Proyectos PilotoRESUMEN
OBJECTIVE: The purpose of this study is to summarize the data on the incidence, clinical behavior and overall survival of patients with glassy cell cervical carcinoma (GCCC). METHODS: Twenty-four case series and fifteen case reports identified by searching PubMed database qualified for inclusion in this study. The published cases were combined with data from a retrospective chart review of patients with GCCC in two major teaching hospitals in Brooklyn, NY. RESULTS: A total of 292 cases were collected through our literature and chart review. Median age at diagnosis was 45 years old (range 12-87 years of age). GCCC incidence ranges from 0.2 to 9.3% of all cervical cancers and 2 to 30.2% of cervical adenocarcinomas. The stage distribution is similar to squamous cell carcinoma with 79% of the patients being diagnosed with Stage I or II disease. Most common sites of recurrence for Stage I patients are the vagina and pelvis. In Stage II patients locoregional and distant metastases are equally common. Recurrence rate was higher among patients treated only with surgery (32.7%), as compared to patients treated with surgery followed by radiation (11%) or patients treated with radiation only (10%). Median overall survival (OS) was 25 months (95% CI 8.4-41.6). Overall 5-year survival for all stages is lower when compared to all cervical cancers (54.8% vs 75%). There was no interaction between race and OS (p=0.66). CONCLUSION: GCCC is a rare histologic type of cervical cancer that presents at a younger age, is associated with high risk for distant failure and carries worse prognosis as compared to the squamous cell type. Radiation therapy is associated with decreased risk of recurrence.
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Antineoplásicos/uso terapéutico , Carcinoma Adenoescamoso/terapia , Recurrencia Local de Neoplasia , Neoplasias del Cuello Uterino/terapia , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Carcinoma Adenoescamoso/mortalidad , Carcinoma Adenoescamoso/patología , Niño , Terapia Combinada/métodos , Femenino , Humanos , Histerectomía , Persona de Mediana Edad , Estadificación de Neoplasias , Pronóstico , Radioterapia , Estudios Retrospectivos , Neoplasias del Cuello Uterino/mortalidad , Neoplasias del Cuello Uterino/patología , Neoplasias del Cuello Uterino/secundario , Adulto JovenRESUMEN
INTRODUCTION: Confirming abstinence during smoking cessation clinical trials is critical for determining treatment effectiveness. Several biological methods exist for verifying abstinence (e.g., exhaled carbon monoxide [CO], cotinine), and while cotinine provides a longer window of detection, it is not easily used in trials involving nicotine replacement therapy. The Society for Research on Nicotine and Tobacco's Subcommittee on Biochemical Verification cite 8-10 parts per million (ppm) for CO as a viable cutoff to determine abstinence; however, recent literature suggests this cutoff is likely too high and may overestimate the efficacy of treatment. METHODS: This study examined the relationship between CO and cotinine in a sample of 662 individuals participating in a smoking cessation clinical trial. A receiver operating characteristics curve was calculated to determine the percentage of false positives and false negatives at given CO levels when using cotinine as confirmation of abstinence. Differences were also examined across race and gender. RESULTS: A CO cutoff of 3 ppm (97.1% correct classification) most accurately distinguished smokers from nonsmokers. This same cutoff was accurate for both racial and gender groups. The standard cutoffs of 8 ppm (14.0% misclassification of smokers as abstainers) and 10 ppm (20.6% misclassification of smokers as abstainers) produced very high false-negative rates and inaccurately identified a large part of the sample as being abstinent when their cotinine test identified them as still smoking. CONCLUSIONS: It is recommended that researchers and clinicians adopt a more stringent CO cutoff in the range of 3-4 ppm when complete abstinence from smoking is the goal.
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Monóxido de Carbono/análisis , Cotinina/orina , Cese del Hábito de Fumar/métodos , Fumar/orina , Adulto , Biomarcadores/análisis , Biomarcadores/orina , Pruebas Respiratorias/métodos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estándares de Referencia , Fumar/epidemiologíaRESUMEN
INTRODUCTION: Racial and gender disparities for smoking cessation might be accounted for by differences in expectancies for tobacco interventions, but few studies have investigated such differences or their relationships with motivation to quit and abstinence self-efficacy. METHODS: In this cross-sectional study, 673 smokers (African American: n = 443, 65.8%; women: n = 222, 33.0%) under criminal justice supervision who enrolled in a clinical smoking cessation trial in which all received bupropion and half received counseling. All participants completed pretreatment measures of expectancies for different tobacco interventions, motivation to quit, and abstinence self-efficacy. The indirect effects of race and gender on motivation to quit and abstinence self-efficacy through expectancies for different tobacco interventions were evaluated. RESULTS: African Americans' stronger expectancies that behavioral interventions would be effective accounted for their greater motivation to quit and abstinence self-efficacy. Women's stronger expectancies for the effectiveness of pharmacotherapy accounted for their greater motivation to quit, whereas their stronger expectancies for the effectiveness of behavioral treatments accounted for their greater abstinence self-efficacy. CONCLUSIONS: Findings point to the mediating role of expectancies for treatment effectiveness and suggest the importance of exploring expectancies among African Americans and women as a way to augment motivation and self-efficacy.
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Negro o Afroamericano/psicología , Motivación , Autoeficacia , Factores Sexuales , Cese del Hábito de Fumar/psicología , Adulto , Bupropión/uso terapéutico , Consejo , Estudios Transversales , Femenino , Humanos , Masculino , Persona de Mediana Edad , Cese del Hábito de Fumar/métodos , NicotianaRESUMEN
Self-discrepancy theory (SDT) is one framework for understanding how goal failure is associated with depressive symptoms. The present studies sought to examine the variance in depressive symptoms explained by actual:ideal discrepancies, beyond what is accounted for by actual-self ratings. Additionally, gender and grade were examined as potential moderators in the relationship. In Study 1 (N = 228), discrepancies accounted for additional variance in the level of depressive symptoms beyond what was explained by actual-self ratings in a college sample. In Study 2 (N = 192), while similar global patterns were found, gender and grade differences emerged. For boys, the relationship between actual:ideal discrepancies and depressive symptoms was due to actual-self ratings. For girls, a developmental pattern suggested that actual:ideal discrepancies become more important to the prediction of depressive symptoms among older girls. Implications for the emergence of the discrepancy-depression association are discussed.
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Depresión/etiología , Autoevaluación (Psicología) , Adolescente , Factores de Edad , Niño , Depresión/psicología , Femenino , Objetivos , Humanos , Masculino , Escalas de Valoración Psiquiátrica , Teoría Psicológica , Autoimagen , Factores Sexuales , Encuestas y Cuestionarios , Adulto JovenRESUMEN
Individual differences in higher-order cognitive abilities may be an important piece to understanding how and when self-discrepancies lead to negative emotions. In the current study, three measures of reasoning abilities were considered as potential moderators of the relationship between self-discrepancies and depression and anxiety symptoms. Participants (N = 162) completed measures assessing self-discrepancies, depression and anxiety symptoms, and were administered measures examining formal operational thought, and verbal and non-verbal abstract reasoning skills. Both formal operational thought and verbal abstract reasoning were significant moderators of the relationship between actual:ideal discrepancies and depressive symptoms. Discrepancies predicted depressive symptoms for individuals with higher levels of formal operational thought and verbal abstract reasoning skills, but not for those with lower levels. The discussion focuses on the need to consider advanced reasoning skills when examining self-discrepancies.
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Emociones , Autoimagen , Pensamiento , Adolescente , Adulto , Ansiedad/psicología , Depresión/psicología , Femenino , Humanos , Masculino , Adulto JovenRESUMEN
Advance care planning (ACP) supports individuals in aligning their medical care with personal values and preferences in the face of serious illness. The variety of ACP tools available reflects diverse strategies intended to facilitate these critical conversations, yet evaluations of their effectiveness often show mixed results. Following the Arskey and O'Malley framework, this scoping review aims to synthesize the range of ACP tools targeted at patients and families, highlighting their characteristics and delivery methods to better understand their impact and development over time. Studies included focused on patient-facing ACP tools across all settings and mediums. Exclusions were applied to studies solely targeting healthcare providers or those only aiming at completion of advance directives without broader ACP discussions. Searches were conducted across PubMed, Embase, CINAHL, The Cochrane Library, and Web of Science. Data were extracted using a predesigned spreadsheet, capturing study population, setting, intervention modality, and intervention theme. Tools were categorized by delivery method and further analyzed through a year-wise distribution to track trends and developments. We identified 99 unique patient-facing tools, with those focusing on counseling (31) and video technologies (21) being the most prevalent while others incorporated online platforms, print materials, games, or some combination of different delivery methods. Over half the tools were designed for specific patient groups, especially for various diseases and racial or ethnic communities. Recent years showed a surge in tool variety and innovation, including integrated patient portals and psychological techniques. The review demonstrates a broad array of innovative ACP tools that facilitate personalized and effective ACP. Our findings contribute to an enhanced understanding of their utilization and potential impacts, offering valuable insights for future tool development and policy making in ACP.
Scanning the landscape of tools to assist patients with advance care planning This review investigates the variety of tools, programs, and interventions designed to help patients plan their healthcare in advance, a process known as advance care planning (ACP). ACP is crucial because it ensures individuals receive medical care aligned with their wishes, especially during serious illness or near the end of life. Our study gathered information from various sources, focusing on tools aimed directly at patients and their families. We found 99 unique tools that assist in ACP, including individual counseling sessions, video-based tools, and digital platforms. Some tools are designed specifically for certain patient groups, such as those with particular diseases or belonging to diverse racial and ethnic communities. Our review highlights the recent surge in the variety and innovation of these tools, such as integrated patient portals and methods incorporating psychological techniques, suggesting a growing effort to make ACP more accessible and tailored to individual needs. However, despite this variety, more research is needed to understand how these tools impact healthcare outcomes and how they can be effectively implemented in different care settings. Our findings aim to guide future development of ACP tools, improve their integration into healthcare practices, and ensure they meet the diverse needs of patients and families.
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Comorbid dementia complicates cancer therapy decision-making in older adults. We aimed to synthesize the recent literature (<5 years) on the challenges associated with cancer therapy decision-making among older people living with dementia (PLWD) and their caregivers. Of the 20,763 references, 8767 had their title and abstract screened, and eight met the inclusion criteria. Six studies were qualitative, one study employed mixed methods, and one study was quasi-experimental. Most studies were conducted in the UK (89%) and reported homogeneity in race and geography. Breast (56%) and prostate (45%) were the most frequent reported cancers. Five studies (56%) reported multiple types of dementia, with two (22%) indicating stages. The studies indicated that communication between patients, caregivers, and clinical teams might alleviate stress caused by worsening health prospects and potential ethical concerns. Information from this review can lead to better-informed, patient-centered treatment decision processes among older PLWD and cancer, their caregivers, and clinicians.
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Cuidadores , Toma de Decisiones , Demencia , Neoplasias , Humanos , Demencia/terapia , Demencia/epidemiología , Neoplasias/terapia , Anciano , Comorbilidad , Masculino , FemeninoRESUMEN
Ritlecitinib is a small molecule in clinical development that covalently and irreversibly inhibits Janus kinase 3 (JAK3) and the TEC family of kinases (BTK, BMX, ITK, TXK, and TEC). This phase 1, open-label, parallel-group study assessed target occupancy and functional effects of ritlecitinib on JAK3 and TEC family kinases in healthy participants aged 18-60 years who received 50 or 200 mg single doses of ritlecitinib on day 1. Blood samples to assess ritlecitinib pharmacokinetics, target occupancy, and pharmacodynamics were collected over 48 hours. Target occupancy was assessed using mass spectroscopy. Functional inhibition of JAK3-dependent signaling was measured by the inhibition of the phosphorylation of its downstream target signal transducer and activator of transcription 5 (pSTAT5), following activation by interleukin 15 (IL-15). The functional inhibition of Bruton's tyrosine kinase (BTK)-dependent signaling was measured by the reduction in the upregulation of cluster of differentiation 69 (CD69), an early marker of B-cell activation, following treatment with anti-immunoglobulin D. Eight participants received one 50 mg ritlecitinib dose and 8 participants received one 200 mg dose. Ritlecitinib plasma exposure increased in an approximately dose-proportional manner from 50 to 200 mg. The maximal median JAK3 target occupancy was 72% for 50 mg and 64% for 200 mg. Ritlecitinib 50 mg had >94% maximal target occupancy of all TEC kinases, except BMX (87%), and 200 mg had >97% for all TEC kinases. For BTK and TEC, ritlecitinib maintained high target occupancy throughout a period of 48 hours. Ritlecitinib reduced pSTAT5 levels following IL-15- and BTK-dependent signaling in a dose-dependent manner. These target occupancy and functional assays demonstrate the dual inhibition of the JAK3- and BTK-dependent pathways by ritlecitinib. Further studies are needed to understand the contribution to clinical effects of inhibiting these pathways.
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Interleucina-15 , Janus Quinasa 3 , Humanos , Agammaglobulinemia Tirosina Quinasa , Transducción de Señal , Inhibidores de Proteínas Quinasas/farmacología , Factores InmunológicosRESUMEN
Background: Individuals who have metastatic cancer experience substantial physical and psychological distress (e.g., pain, depression, anxiety) from their disease and its treatment compared to patients with less advanced disease. As the burden of symptoms varies over time, ecological momentary assessment (EMA) may be used to better understand patients' symptom trajectories, complimenting traditional longitudinal data collection methods. However, few have used EMA in patients with metastatic disease. The current study adds to the existing literature by exploring interrelated, common cancer-related symptoms of pain, anxiety, and depression and use of cannabis-based products, opioid medications, other (nonopioid) pain medications, and medications for anxiety or depression. Methods: An eight-day prospective observational feasibility study was conducted among 50 patients with metastatic cancer recruited from seven solid cancer clinics at The Ohio State University Comprehensive Cancer Center. Participants completed a week of interval-contingent mobile EMA, administered daily at 9 a.m., 3 p.m., and 8 p.m., and a comprehensive interviewer-administered questionnaire on Day 8. Participants were queried on their symptom burden and management strategies (i.e., use of medications and cannabis). We considered EMA to be feasible if a priori retention (80%) and adherence goals (75%) were met. Results: Seventy-nine percent of eligible patients contacted enrolled in the study (n = 50 of 63). Among those enrolled, 92% were retained through Day 8 and 80% completed >90% of EMAs, exceeding a priori objectives. Participants' average pain, anxiety, and depressive symptoms across the week of EMA ranged from 1.7 to 1.8 (1 to 5 scale). Symptoms varied little by day or time of administration. On Day 8, significant proportions of participants reported past-week use of medications and cannabis for symptom management. Conclusions: Participants exceeded a priori adherence and retention objectives, indicating that mobile EMA is feasible among metastatic cancer patients, addressing a gap in the existing literature and informing future research. Restricting eligibility to participants with a minimum cutoff of symptom burden may be warranted to increase observations of symptom variability and provide opportunities for future health interventions. Future research is needed to test the acceptability and quality of data over a longer study period in this patient population.
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BACKGROUND: Older cancer survivors in general are at greater risk for cancer-related cognitive impairment (CRCI), yet few studies have explored its association with health outcomes. This study examined the association between subjective and objective measures of cognitive function and physical function, frailty, and quality of life (QoL) among older breast cancer survivors. MATERIALS AND METHODS: Older breast cancer survivors who reported cognitive concerns completed surveys on patient-reported cognitive function, physical function, frailty, and QoL as well as objective tests of visuospatial working memory and sustained attention. Data were analyzed using descriptive statistics and separate linear regression models. RESULTS: A total of 219 female breast cancer survivors completed the study. Perceived cognitive abilities were associated with better physical function, frailty, and QoL (p ≤ 0.001) while cognitive concerns were negatively related with these metrics (p ≤ 0.001). Poorer visuospatial working memory and sustained attention were linked to increased frailty (p ≤ 0.001-0.01), whereas poorer sustained attention was associated with poorer physical function (p < 0.01). CONCLUSIONS: Older breast cancer survivors with perceived cognitive impairment and poorer cognitive performance reported poorer physical functioning, increased frailty, and poorer QoL. These findings underscore the importance of assessing cognitive concerns and their associated outcomes in older breast cancer survivors.
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BACKGROUND: The objective of this study was to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of PF06835375, a potent selective afucosyl immunoglobulin G1 antibody targeting C-X-C chemokine receptor type 5 (CXCR5) that potentially depletes B cells, follicular T helper (Tfh) cells, and circulating Tfh-like (cTfh) cells, in patients with systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). METHODS: This first-in-human, multicenter, double-blind, sponsor-open, placebo-controlled Phase 1 study recruited patients aged 18-70 years with SLE or RA. In Part A, patients received single doses of intravenous PF-06835375 (dose range: 0.03-6 mg) or placebo in six sequential single ascending dose (SAD) cohorts. In Part B, patients received repeat doses of subcutaneous PF-06835375 (dose range: 0.3-10 mg) or placebo on Days 1 and 29 in five multiple ascending dose (MAD) cohorts. Tetanus/Diphtheria (Td) and Meningococcal B (MenB/Trumenba™) vaccines were administered at Day 4 (Td and MenB) and Week 8 (MenB only) to assess PF-06835375 functional effects. Endpoints included treatment-emergent adverse events (TEAEs), pharmacokinetic parameters, pharmacodynamic effects on B and cTfh cells, and biomarker counts, vaccine response, and exploratory differential gene expression analysis. Safety, pharmacokinetic, and pharmacodynamic endpoints are summarized descriptively. The change from baseline of B and Tfh cell-specific genes over time was calculated using a prespecified mixed-effects model, with a false discovery rate < 0.05 considered statistically significant. RESULTS: In total, 73 patients were treated (SAD cohorts: SLE, n = 17; RA, n = 14; MAD cohorts: SLE, n = 22; RA, n = 20). Mean age was 53.3 years. Sixty-two (84.9%) patients experienced TEAEs (placebo n = 17; PF-06835375 n = 45); most were mild or moderate. Three (9.7%) patients experienced serious adverse events. Mean t1/2 ranged from 3.4-121.4 h (SAD cohorts) and 162.0-234.0 h (MAD cohorts, Day 29). B and cTfh cell counts generally showed dose-dependent reductions across cohorts (range of mean maximum depletion: 67.3-99.3%/62.4-98.7% [SAD] and 91.1-99.6%/89.5-98.1% [MAD], respectively). B cell-related genes and pathways were significantly downregulated in patients treated with PF-06835375. CONCLUSIONS: These data support further development of PF-06835375 to assess the clinical potential for B and Tfh cell depletion as a treatment for autoimmune diseases. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT03334851.
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Artritis Reumatoide , Lupus Eritematoso Sistémico , Receptores CXCR5 , Humanos , Persona de Mediana Edad , Adulto , Método Doble Ciego , Femenino , Masculino , Lupus Eritematoso Sistémico/tratamiento farmacológico , Lupus Eritematoso Sistémico/inmunología , Artritis Reumatoide/tratamiento farmacológico , Artritis Reumatoide/inmunología , Anciano , Adulto Joven , Relación Dosis-Respuesta a Droga , Adolescente , Anticuerpos Monoclonales Humanizados/farmacocinética , Anticuerpos Monoclonales Humanizados/administración & dosificación , Anticuerpos Monoclonales Humanizados/efectos adversos , Anticuerpos Monoclonales Humanizados/uso terapéutico , Antirreumáticos/farmacocinética , Antirreumáticos/administración & dosificación , Antirreumáticos/uso terapéutico , Antirreumáticos/efectos adversosRESUMEN
The 17th Workshop on Recent Issues in Bioanalysis (17th WRIB) took place in Orlando, FL, USA on 19-23 June 2023. Over 1000 professionals representing pharma/biotech companies, CROs, and multiple regulatory agencies convened to actively discuss the most current topics of interest in bioanalysis. The 17th WRIB included 3 Main Workshops and 7 Specialized Workshops that together spanned 1 week to allow an exhaustive and thorough coverage of all major issues in bioanalysis of biomarkers, immunogenicity, gene therapy, cell therapy and vaccines.Moreover, in-depth workshops on "EU IVDR 2017/746 Implementation and impact for the Global Biomarker Community: How to Comply with these NEW Regulations" and on "US FDA/OSIS Remote Regulatory Assessments (RRAs)" were the special features of the 17th edition.As in previous years, WRIB continued to gather a wide diversity of international, industry opinion leaders and regulatory authority experts working on both small and large molecules as well as gene, cell therapies and vaccines to facilitate sharing and discussions focused on improving quality, increasing regulatory compliance, and achieving scientific excellence on bioanalytical issues.This 2023 White Paper encompasses recommendations emerging from the extensive discussions held during the workshop and is aimed to provide the bioanalytical community with key information and practical solutions on topics and issues addressed, in an effort to enable advances in scientific excellence, improved quality and better regulatory compliance. Due to its length, the 2023 edition of this comprehensive White Paper has been divided into three parts for editorial reasons.This publication (Part 2) covers the recommendations on Biomarkers, IVD/CDx, LBA and Cell-Based Assays. Part 1A (Mass Spectrometry Assays and Regulated Bioanalysis/BMV), P1B (Regulatory Inputs) and Part 3 (Gene Therapy, Cell therapy, Vaccines and Biotherapeutics Immunogenicity) are published in volume 16 of Bioanalysis, issues 9 and 7 (2024), respectively.
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Biomarcadores , Tratamiento Basado en Trasplante de Células y Tejidos , Vacunas , Humanos , Biomarcadores/análisis , Vacunas/inmunología , Citometría de Flujo , Bioensayo/métodos , Unión Europea , BlancoRESUMEN
Cynomolgus monkeys dosed with a therapeutic monoclonal antibody (mAbY.1) at ≥ 50 mg/kg had unexpected acute thrombocytopenia (nadir ~3,000 platelets/µl), sometimes with decreases in red cell mass. Increased activated macrophages, mitotic figures, and erythrophagocytosis were observed in the spleen. Binding of mAbY.1 to cynomolgus peripheral blood cells could not be detected in vitro. mAbY.1 induced phagocytosis of platelets by peripheral blood monocytes from cynomolgus monkeys, but not from humans. mAbs sharing the same constant domain (Fc) sequences, but differing from mAbY.1 in their variable domains, bound competitively to and had similar biological activity against the intended target. None of these antibodies had hematologic liabilities in vitro or in vivo. Neither the F(ab')2 portion of mAbY.1 nor the F(ab')2 portion on an aglycosylated Fc (IgG1) framework caused phagocytosis of platelets in vitro. These data suggest that the hematologic effects of mAbY.1 in cynomolgus monkeys likely occurred through an off-target mechanism, shown to be driven by 1 to 3 amino acid differences in the light chain. The hematologic effects made mAbY.1 an unsuitable candidate for further development as a therapeutic agent. This example demonstrates that nonclinical safety studies may be essential for understanding off-target effects of mAbs prior to clinical trials.