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PROBLEM: Medical students experience psychological distress more frequently than age-matched peers. Tracking medical student well-being has typically been limited to once- or twice-per-year questionnaires. Ongoing, real-time assessment of student behavior and well-being could facilitate individualized, timely interventions. APPROACH: Faculty at the University of Vermont, in conjunction with the Larner College of Medicine Office of Medical Education, developed a novel smartphone app in 2021 called WE MD to track and support medical student wellness. The app included the following features: (1) nightly surveys assessing wellness-related behaviors (e.g., social interaction, sleep, exercise) and outcomes (i.e., mood, focus, stress, overall well-being); (2) health reports that enabled users to graph various combinations of their own behaviors and outcomes, allowing them to visualize trends and understand possible correlations between behaviors and outcomes; (3) a resource library with articles and educational videos related to specific wellness behaviors or outcomes; and (4) research-based "insights" or brief tips intended to promote healthy habits. Participants also received virtual "coins" for interacting with the app that could be exchanged for various items in an online store. OUTCOMES: The WE MD program enrolled a substantial portion of the medical school population (43%); most of the students used the app on a regular basis. Students found the app to be acceptable and appreciated many features and also provided feedback on how to improve the app. Information from the nightly survey data converged with established measures but also identified variability over time in wellness behaviors and outcomes. NEXT STEPS: Data from the WE MD program suggest that app-based daily tracking of wellness behaviors and outcomes is a feasible, promising approach to promote student wellness and identify real-time patterns and risk periods for medical students. The app will be revised based on student feedback and adapted for use by students, residents, and faculty.
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Aplicaciones Móviles , Estudiantes de Medicina , Humanos , Estudiantes de Medicina/psicología , Femenino , Masculino , Encuestas y Cuestionarios , Promoción de la Salud/métodos , Conductas Relacionadas con la Salud , Teléfono Inteligente , Vermont , AdultoRESUMEN
BACKGROUND: Novel combination therapies to overcome anti-PD-1 resistance are required. Enadenotucirev, a tumor-selective blood stable adenoviral vector, has demonstrated a manageable safety profile and ability to increase tumor immune-cell infiltration in phase I studies in solid tumors. METHODS: We conducted a phase I multicenter study of intravenous enadenotucirev plus nivolumab in patients with advanced/metastatic epithelial cancer not responding to standard therapy. Co-primary objectives were safety/tolerability and maximum tolerated dose and/or maximum feasible dose (MTD/MFD) of enadenotucirev plus nivolumab. Additional endpoints included response rate, cytokine responses, and anti-tumor immune responses. RESULTS: Overall, 51 heavily pre-treated patients were treated, 45/51 (88%) of whom had colorectal cancer (35/35 patients with information available were microsatellite instability-low/microsatellite stable) and 6/51 (12%) had squamous cell carcinoma of the head and neck. The MTD/MFD of enadenotucirev plus nivolumab was not reached, with the highest dose level tested (1×1012 vp day 1; 6×1012 vp days 3 and 5) shown to be tolerable. Overall, 31/51 (61%) patients experienced a grade 3-4 treatment-emergent adverse event (TEAE), most frequently anemia (12%), infusion-related reaction (8%), hyponatremia (6%), and large intestinal obstruction (6%). Seven (14%) patients experienced serious TEAEs related to enadenotucirev; the only serious TEAE related to enadenotucirev occurring in >1 patient was infusion-related reaction (n=2). Among the 47 patients included in efficacy analyses, median progression-free survival was 1.6 months, objective response rate was 2% (one partial response for 10 months), and 45% of patients achieved stable disease. Median overall survival was 16.0 months; 69% of patients were alive at 12 months. Persistent increases in Th1 and related cytokines (IFNγ, IL-12p70, IL-17A) were seen from ~day 15 in two patients, one of whom had a partial response. Among the 14 patients with matching pre-tumor and post-tumor biopsies, 12 had an increase in intra-tumoral CD8+ T-cell infiltration and 7 had increased markers of CD8 T-cell cytolytic activity. CONCLUSIONS: Intravenously dosed enadenotucirev plus nivolumab demonstrated manageable tolerability, an encouraging overall survival and induced immune cell infiltration and activation in patients with advanced/metastatic epithelial cancer. Studies of next-generation variants of enadenotucirev (T-SIGn vectors) designed to further re-program the tumor microenvironment by expressing immune-enhancer transgenes are ongoing. TRIAL REGISTRATION NUMBER: NCT02636036.
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Neoplasias Primarias Secundarias , Neoplasias , Humanos , Nivolumab/uso terapéutico , Neoplasias/tratamiento farmacológico , Adenoviridae , Terapia Combinada , Citocinas , Neoplasias Primarias Secundarias/tratamiento farmacológico , Microambiente TumoralRESUMEN
Tumor-selective viruses are a novel therapeutic approach for treating cancer. Tumor-Specific Immuno Gene Therapy (T-SIGn) vectors are tumor-selective adenoviral vectors designed to express immunomodulatory transgenes. Prolonged activated partial thromboplastin time (aPTT), associated with the presence of antiphospholipid antibodies (aPL), has been observed in patients with viral infections, and following administration of adenovirus-based medicines. aPL may be detected as lupus anticoagulant (LA), anti-cardiolipin (aCL) and/or anti-beta 2 glycoprotein antibodies (aß2GPI). No subtype alone is definitive for development of clinical sequalae, however, patients who are 'triple positive' have a greater thrombotic risk. Additionally, isolated aCL and aß2GPI IgM do not appear to add value in thrombotic association to aPL positivity, rather IgG subtypes must also be present to confer an increased risk. Here we report induction of prolonged aPTT and aPL in patients from eight Phase 1 studies who were treated with adenoviral vectors (n = 204). Prolonged aPTT (≥ Grade 2) was observed in 42% of patients, with a peak at 2-3 weeks post-treatment and resolution within ~ 2 months. Among patients with aPTT prolongation, LA, but not aCL IgG nor aß2GPI IgG, was observed. The transience of the prolongation and discordance between positive LA and negative aCL/aß2GPI IgG assays is not typical of a prothrombotic state. Among the patients with prolonged aPTT there was no evidence of an increased rate of thrombosis. These findings elucidate the relationship between viral exposure and aPL in the context of clinical trials. They suggest a framework in which hematologic changes can be monitored in patients receiving similar treatments.Clinical trial registration:NCT02028442, NCT02636036, NCT02028117, NCT03852511, NCT04053283, NCT05165433, NCT04830592, NCT05043714.
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Síndrome Antifosfolípido , Neoplasias , Trombosis , Humanos , Anticuerpos Antifosfolípidos , Síndrome Antifosfolípido/complicaciones , Inhibidor de Coagulación del Lupus , Anticuerpos Anticardiolipina , Trombosis/etiología , Inmunoglobulina G , Neoplasias/terapia , Neoplasias/complicacionesRESUMEN
Introduction: The US Medical Licensing Examination (USMLE) Step 1 exam has proven a difficult stressor for medical students during their training, even with the advent of pass-fail scoring. The preparation period before the exam places students at high risk for burnout and depression, leading to impaired exam performance and other serious consequences including suicide. Many medical schools already provide academic support for students during USMLE Step 1 preparation, yet to date, there are no published programs specifically geared towards mental health support during this time. Methods: Students from the Larner College of Medicine at the University of Vermont developed the "Step-Siblings" program to partner pre-clinical level students preparing for Step 1 (Little Sibs) with clinical-level students (Big Sibs) in an effort to promote near-peer mentorship and support for those studying. Big Sibs were trained to offer emotional support and wellness advice, but specifically not to provide academic counselling. The pilot program was evaluated by student surveys. Results: Our program successfully paired Little Sibs (n = 125) with Big Sibs (n = 75) several months preceding the Step 1 dedicated study period, achieving the intended effect of reducing burnout and fostering a supportive community during a notoriously isolating and emotionally challenging time. Survey results indicated that a majority of Little and Big Sibs found the program helpful. Conclusions: This student-driven mentorship model is simple to implement, easily generalizable to other medical schools and other board exams, and bears the lasting benefit of combatting the stress and burnout so prevalent in medical education. Supplementary Information: The online version contains supplementary material available at 10.1007/s40670-022-01571-4.
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PURPOSE: Larotrectinib is a highly selective and CNS-active tropomyosin receptor kinase (TRK) inhibitor that has demonstrated efficacy across TRK fusion-positive cancers, regardless of the tumor type. The aim of this study was to assess the efficacy and safety of larotrectinib in patients with TRK fusion-positive lung cancers. MATERIALS AND METHODS: Data from two global, multicenter, registrational clinical trials of patients treated with larotrectinib were analyzed: a phase II adult and young adult basket trial (NCT02576431) and a phase I adult trial (NCT02122913). The primary end point was objective response rate (ORR). RESULTS: By July 20, 2020, 20 patients with TRK fusion-positive lung cancer had been treated. The ORR by investigator assessment among 15 evaluable patients was 73% (95% CI, 45 to 92); one (7%) patient had a complete response, 10 (67%) had a partial response, three (20%) had stable disease, and one (7%) had progressive disease as best response. The median duration of response, progression-free survival, and overall survival were 33.9 months (95% CI, 5.6 to 33.9), 35.4 months (95% CI, 5.3 to 35.4), and 40.7 months (95% CI, 17.2 to not estimable), respectively. Among patients with baseline CNS metastases, the ORR was 63% (95% CI, 25 to 91). Adverse events were mainly grade 1 or 2. CONCLUSION: Larotrectinib is highly active with rapid and durable responses, extended survival benefit, and a favorable long-term safety profile in patients with advanced lung cancer harboring NTRK gene fusions, including those with CNS metastases. These findings support routine testing for NTRK fusions in patients with lung cancer.
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Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Proteínas Quinasas/genética , Pirazoles/uso terapéutico , Pirimidinas/uso terapéutico , Adulto , Anciano , Femenino , Fusión Génica , Humanos , Masculino , Persona de Mediana Edad , Pirazoles/efectos adversos , Pirimidinas/efectos adversos , Resultado del TratamientoRESUMEN
PURPOSE: Guidelines support early integration of palliative care (PC) into standard oncology practice; however, little is known as to whether outcomes can be improved by modifying health care delivery in a real-world setting. METHODS: We report our 6-year experience of embedding a nurse practitioner in an oncology clinic (March 2014-March 2020) to integrate early, concurrent advance care planning and PC. RESULTS: Compared with patients with advanced cancer not enrolled in the palliative care nurse practitioner program, in March 2020, patients who are enrolled are more likely to have higher quality of PC (eg, goals of care note documentation [82% v 15%; P < .01], referral to the psychosocial oncology program [67% v 37%; P < .01], and referral to hospice [61% v 34%; P < .01]) and less inpatient utilization in the last 6 months of life (eg, hospital days [12 v 18; P < .01] and intensive care unit days [1.2 v 2.3; P < .01]). The program expanded over time with the support of faculty skills training for advance care planning and PC, supporting a shared mental model of PC delivery within the oncology clinic. CONCLUSION: Embedding a trained palliative care nurse practitioner in oncology clinics to deliver early integrated PC can lead to improved quality of care for patients with advanced cancer.
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Neoplasias , Enfermeras Practicantes , Humanos , Oncología Médica , Neoplasias/psicología , Neoplasias/terapia , Cuidados Paliativos , Mejoramiento de la CalidadRESUMEN
PURPOSE: Most gastrointestinal stromal tumors (GIST) are driven by KIT/PDGFRa mutations. Tyrosine kinase inhibitor benefit is progressively less after imatinib failure. This phase II trial analyzed the efficacy of nivolumab (N) or nivolumab + ipilimumab (N + I) in patients with refractory GIST. PATIENTS AND METHODS: Patients with advanced/metastatic GIST refractory to at least imatinib were randomized 1:1 in a noncomparative, parallel group, unblinded phase II trial of N (240 mg every 2 weeks) or N + I (240 mg every 2 weeks + 1 mg/kg every 6 weeks). The primary endpoint was the objective response rate of N alone or N+I by RECIST 1.1 in the intent-to-treat population. RESULTS: A total of 36 patients with a median of 3 (1-6) prior lines of therapies were enrolled. Ten of 19 (52.6%) patients had stable disease (SD) for a clinical benefit rate (CBR) of 52.6% in the N arm and the median progression-free survival (PFS) was 11.7 weeks [95% confidence interval (CI), 7.0-17.4]. In the N+I arm, 1 of 16 (6.7%) patients had a complete response (CR) and 4/16 (25.0%) had SD for a CBR of 31.3% and a median PFS of 8.3 weeks (95% CI, 5.6-22.2). The 4- and 6-month PFS were 42.1% and 26.3%, respectively for N, and 31.3% and 18.8%, respectively for N+I. The most common adverse events (AE) attributed to N and N+I were fatigue: 13.9% and 22.2%, respectively. There were nine total attributable grade 3-4 AEs. CONCLUSIONS: The primary endpoint of response rate > 15% was not observed for N or N + I. In a heavily pretreated GIST population, responses and long-term disease control with both N and N+I were observed. No new safety signals have been observed.
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Tumores del Estroma Gastrointestinal , Nivolumab , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Tumores del Estroma Gastrointestinal/tratamiento farmacológico , Tumores del Estroma Gastrointestinal/genética , Humanos , Mesilato de Imatinib , Ipilimumab/uso terapéutico , Nivolumab/efectos adversos , Inhibidores de Proteínas QuinasasRESUMEN
Colorectal cancer (CRC) is a leading cause of cancer mortality. Creatine metabolism was previously shown to critically regulate colon cancer progression. We report that RGX-202, an oral small-molecule SLC6A8 transporter inhibitor, robustly inhibits creatine import in vitro and in vivo, reduces intracellular phosphocreatine and ATP levels, and induces tumor apoptosis. RGX-202 suppressed CRC growth across KRAS wild-type and KRAS mutant xenograft, syngeneic, and patient-derived xenograft (PDX) tumors. Antitumor efficacy correlated with tumoral expression of creatine kinase B. Combining RGX-202 with 5-fluorouracil or the DHODH inhibitor leflunomide caused regressions of multiple colorectal xenograft and PDX tumors of distinct mutational backgrounds. RGX-202 also perturbed creatine metabolism in patients with metastatic CRC in a phase 1 trial, mirroring pharmacodynamic effects on creatine metabolism observed in mice. This is, to our knowledge, the first demonstration of preclinical and human pharmacodynamic activity for creatine metabolism targeting in oncology, thus revealing a critical therapeutic target.
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Antineoplásicos , Neoplasias del Colon , Neoplasias Colorrectales , Animales , Antineoplásicos/farmacología , Línea Celular Tumoral , Proliferación Celular , Neoplasias del Colon/tratamiento farmacológico , Neoplasias del Colon/genética , Neoplasias Colorrectales/patología , Creatina/metabolismo , Creatina/farmacología , Creatina/uso terapéutico , Humanos , Proteínas de Transporte de Membrana , Ratones , Ratones Desnudos , Mutación , Proteínas del Tejido Nervioso/metabolismo , Proteínas de Transporte de Neurotransmisores en la Membrana Plasmática/genética , Proteínas de Transporte de Neurotransmisores en la Membrana Plasmática/farmacología , Proteínas Proto-Oncogénicas p21(ras)/metabolismoRESUMEN
PURPOSE: Trifluridine/tipiracil (FTD/TPI) is approved for advanced colorectal and gastric/gastroesophageal cancer; however, data in patients with renal impairment (RI) are limited. This phase I study evaluated FTD/TPI in patients with advanced solid tumors and varying degrees of RI to develop dosing guidance. METHODS: Patients were enrolled into normal renal function (CrCl ≥ 90 mL/min), mild RI (CrCl 60-89 mL/min), or moderate RI (CrCl 30-59 mL/min) cohorts and administered the recommended FTD/TPI dose (35 mg/m2 twice daily, days 1-5 and 8-12; 28-day cycle). Based on interim pharmacokinetics/safety data, patients with severe RI (CrCl 15-29 mL/min) were enrolled and received FTD/TPI 20 mg/m2 twice daily. RESULTS: Forty-three patients (normal renal function [n = 12]; mild RI [n = 12]; moderate RI [n = 11]; severe RI [n = 8]) were enrolled and treated. At steady state, compared to values in patients with normal renal function, FTD area under the curve (AUC) was not significantly different in patients with RI, but TPI AUC was significantly higher and increased with RI severity. FTD/TPI safety profile was consistent with prior experience, but grade ≥ 3 adverse events (AEs) were more frequent in the RI cohorts (83.3% [mild], 90.9% [moderate], 75.0% [severe], and normal [50.0%]). Hematologic AEs (anemia and neutropenia) were more frequent with RI. Overall, seven patients discontinued because of unrelated, nonhematologic AEs. CONCLUSION: FTD/TPI is safe and tolerable at the recommended 35 mg/m2 dose in patients with mild/moderate RI and at the reduced 20 mg/m2 dose in patients with severe RI. TRIAL REGISTRATION: NCT02301117, registration date: November 21, 2014.
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Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Enfermedades Renales/fisiopatología , Neoplasias/tratamiento farmacológico , Pirrolidinas/administración & dosificación , Timina/administración & dosificación , Trifluridina/administración & dosificación , Adulto , Anciano , Anciano de 80 o más Años , Anemia/inducido químicamente , Anemia/epidemiología , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Área Bajo la Curva , Estudios de Cohortes , Combinación de Medicamentos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Neutropenia/inducido químicamente , Neutropenia/epidemiología , Pirrolidinas/efectos adversos , Pirrolidinas/farmacocinética , Índice de Severidad de la Enfermedad , Timina/efectos adversos , Timina/farmacocinética , Trifluridina/efectos adversos , Trifluridina/farmacocinéticaRESUMEN
OBJECTIVES: Blockade of programmed cell death-1 (PD-1) and its ligand (PD-L1) has transformed the treatment of NSCLC. In a first-in-human, Phase 1, dose escalation and cohort expansion study, cemiplimab, a monoclonal antibody directed against PD-1, was evaluated for the treatment of patients with advanced solid tumors (NCT02383212). Here, we report results in patients with advanced NSCLC from the dose expansion cohort. MATERIALS AND METHODS: Immune-checkpoint inhibitor naive patients with advanced NSCLC (stage III/IV), irrespective of PD-L1 status, who had progressed after, or were refractory to first- or later-line therapy were enrolled and received cemiplimab 200 mg every 2 weeks intravenously for up to 48 weeks. Primary study objectives were to assess safety and tolerability, and to evaluate clinical activity of cemiplimab. RESULTS: Twenty patients with NSCLC were enrolled. Median age was 64.0 years (range: 50-82); 65.0 % were male; 80.0 % had an ECOG performance status of 1; 60.0 % had a histology of adenocarcinoma. Median number of prior lines of systemic therapy was 2 (range: 1-4). Median duration of follow-up was 7.0 months (range: 1.0-18.2). All patients experienced ≥1 treatment-emergent adverse event (TEAE) of any grade. Most common TEAEs were arthralgia, asthenia, cough, and dyspnea (each 4/20; 20.0 %). Grade ≥3 TEAEs occurred in 60.0 % (12/20) of patients. Of patients with measurable disease per independent central review (ICR), five had partial response (PR), four had stable disease (SD) and 10 had progressive disease. Objective response rate (ORR; complete response + PR) was 25.0 % (95 % CI: 8.7-49.1 %). Duration of response exceeded 8 months in four of the five responding patients at the time of data cut-off (April 30, 2019). The disease control rate per ICR (ORR + SD) was 50.0 % (95 % CI: 27.2-72.8 %). CONCLUSION: Cemiplimab showed an acceptable safety profile and demonstrated antitumor activity in pretreated patients with NSCLC.
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Antineoplásicos Inmunológicos , Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Anticuerpos Monoclonales Humanizados/uso terapéutico , Antineoplásicos Inmunológicos/efectos adversos , Antígeno B7-H1 , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Femenino , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Masculino , Persona de Mediana EdadRESUMEN
INTRODUCTION: For students studying anatomy, dissection of the human body can elicit a wide range of intellectual and emotional responses that are subject to change over the duration of a course. The purpose of this study was to determine how overall emotional responses change over time, if there are differences in responses by gender and previous laboratory exposure, and if these responses impact course performance. METHODS: First-year medical students enrolled in the Human Structure and Function course at the University of Vermont, and in the Organ Systems 1, 2, and 3 courses at Morehouse School of Medicine were given a series of four surveys across the first-year curriculum. Data were gathered regarding age, gender, and previous laboratory exposure. Students were asked to rate their level of 15 positive and negative emotions, and their desire to avoid or approach the laboratory and donors. These responses were translated to three measures: (a) a positive response index (PRI), (b) a negative response index (NRI), and (c) an avoid-approach index (AAI). Responses were followed longitudinally and matched with anatomy practical examination grades. RESULTS: Gender and previous laboratory exposure status were both significantly related to emotional responses at different points throughout the year, and unique patterns of responses across the year emerged within each group. Higher PRI and AAI were positively correlated with some practical examination scores. CONCLUSIONS: Data suggest that gender and previous laboratory exposure status influence emotional responses to dissection, and that these responses may have an effect on course performance.
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Anatomía/educación , Disección/educación , Disección/psicología , Emociones , Estudiantes de Medicina/psicología , Adulto , Cadáver , Curriculum , Femenino , Cuerpo Humano , Humanos , Masculino , Factores Sexuales , Adulto JovenRESUMEN
PURPOSE: This first-in-human study assessed the safety, tolerability, dose-limiting toxicities (DLT), antitumor activity, and pharmacokinetics of cemiplimab, a monoclonal anti-programmed cell death-1 (PD-1), as monotherapy and in combination with hypofractionated radiotherapy (hfRT) and/or cyclophosphamide (CPA) in patients with advanced solid tumors. PATIENTS AND METHODS: Patients were enrolled in 1 of 10 dose escalation cohorts and received cemiplimab 1, 3, or 10 mg/kg every 2 weeks intravenously for up to 48 weeks. Depending on the cohort, patients received hfRT and/or low-dose (200 mg/m2) CPA. Safety was evaluated. Antitumor activity was assessed by Response Evaluation Criteria in Solid Tumors version 1.1. RESULTS: Sixty patients were enrolled. The median duration of follow-up was 19.3 weeks (range, 2.3-84.3). There were no DLTs. The most common treatment-emergent adverse events (TEAEs) of any grade were fatigue (45.0%), nausea (36.7%), and vomiting (25.0%). The most common immune-related adverse events (irAEs) of any grade were arthralgia (10.0%), hypothyroidism (8.3%), and maculopapular rash (8.3%). Cemiplimab pharmacokinetic parameters increased in a close to dose-proportional manner and were similar regardless of combination therapy regimen. Two patients (one with cutaneous squamous cell carcinoma and one with cervical cancer) experienced a complete response; 7 had a partial response. Observed duration of response was ≥12 months in 6 patients. CONCLUSIONS: The safety profile of cemiplimab was comparable with other anti-PD-1 agents. Addition of hfRT and/or CPA did not appear to increase grade ≥3 irAEs, suggesting that cemiplimab can be safely administered with hfRT and/or CPA. Cemiplimab exhibited encouraging antitumor activity with 2 complete responses and 7 partial responses observed; responses were also durable.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Quimioradioterapia/mortalidad , Neoplasias/terapia , Criterios de Evaluación de Respuesta en Tumores Sólidos , Adulto , Anciano , Anticuerpos Monoclonales Humanizados/administración & dosificación , Ciclofosfamida/administración & dosificación , Relación Dosis-Respuesta a Droga , Fatiga/inducido químicamente , Femenino , Humanos , Masculino , Persona de Mediana Edad , Náusea/inducido químicamente , Estadificación de Neoplasias , Neoplasias/patología , Seguridad del Paciente , Resultado del TratamientoRESUMEN
BACKGROUND AND OBJECTIVES: The expanding population of older adults in the United States, coupled with provider hesitance to work with this population, is expected to result in a large service gap, particularly in the health care field. Research on provider hesitancy has largely focused on the impact of attitudes toward older adults and professional competency, with some recent explorations of social influences. There is currently no comprehensive measure that includes all of these areas. RESEARCH DESIGN AND METHODS: The present study outlines the development of the Working with Older Adults Scale (WOAS), which is grounded in the theory of planned behavior as applied to working with older adults. The WOAS is composed of 20 items, rated on a 7-point Likert scale, that make up four subscales: (i) Attitude, (ii) Subjective Norm, (iii) Perceived Behavioral Control, and (iv) Intention. RESULTS: Results indicated that, for the young adult college student sample it was developed with, the measure has an excellent factor structure and good internal reliability and construct validity. Consistent with the theory of planned behavior model, intention to work with older adults was significantly predicted by attitudes, subjective norm, and perceived behavioral control. Subjective norm accounted for the greatest amount of variance. Further analyses revealed differential effects of age, gender, and experience on the WOAS subscales. DISCUSSION AND IMPLICATIONS: The WOAS, and underlying theory, offers new insights and ideas for future exploration of the service gap between older adults' needs and professional availability across health service fields.
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Actitud , Intención , Anciano , Humanos , Reproducibilidad de los Resultados , Estudiantes , Encuestas y CuestionariosRESUMEN
Background PF-06650808 is a novel anti-Notch3 antibody-drug conjugate (ADC) able to deliver an auristatin-based cytotoxic payload to target cells. In this first-in-human, dose-finding, phase I study (NCT02129205), we investigated safety, pharmacokinetics, immunogenicity, and preliminary antitumor activity of single-agent PF-06650808 in 40 patients with advanced breast cancer (BC) and other solid tumors unselected for Notch3 expression. Primary endpoint was dose-limiting toxicity (DLT). PF-06650808 was administered intravenously every 3 weeks at a starting dose of 0.2 mg/kg, escalated up to 6.4 mg/kg following the modified continual reassessment method. An additional dose level, 2.0 mg/kg, was evaluated in patients with advanced, estrogen receptor-positive (ER+) BC. Results The majority of patients had advanced BC (60%) and almost all (90%) had received ≥3 prior lines of anticancer therapy. Treatment with PF-06650808 was generally well tolerated at dose levels ≤2.0 mg/kg with no DLTs. The maximum tolerated dose (MTD) was estimated to be 2.4 mg/kg. The most common treatment-related AEs in all patients were fatigue (40.0%), decreased appetite (37.5%), nausea (35.0%), alopecia (32.5%), abdominal pain (25.0%), pruritus (25.0%), and vomiting (25.0%). Five patients achieved a partial response (PR), including 2 unconfirmed PRs; 4 of the responders had ER+/PR+/HER2- BC. Sixteen (51.6%) patients achieved stable disease, including 8 (57.1%) of 14 patients with ER+ BC. Tumor samples from all responders tested positive for NOTCH3 expression in a retrospective, exploratory analysis. Conclusions The anti-Notch3 ADC PF-06650808 has demonstrated a manageable safety profile and early signs of antitumor activity in patients with advanced BC.
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Anticuerpos Monoclonales Humanizados/uso terapéutico , Antineoplásicos Inmunológicos/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Inmunoconjugados/química , Neoplasias/tratamiento farmacológico , Oligopéptidos/uso terapéutico , Receptor Notch3/antagonistas & inhibidores , Adulto , Anciano , Anciano de 80 o más Años , Anticuerpos Monoclonales Humanizados/farmacocinética , Antineoplásicos Inmunológicos/farmacocinética , Neoplasias de la Mama/secundario , Femenino , Estudios de Seguimiento , Humanos , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Neoplasias/patología , Oligopéptidos/farmacocinética , Pronóstico , Receptor Notch3/inmunología , Estudios Retrospectivos , Distribución Tisular , Adulto JovenRESUMEN
Among educators who teach in the human anatomy laboratory, there has been lively debate about sharing information about anatomical donors. One consideration in this debate is concern about the emotional effect of personalizing donors on the students. The purpose of this study was to evaluate student responses to being exposed to donor information (DI). Three cohorts of first-year medical students (n = 284) were surveyed at four time points throughout the year. Surveys queried students about positive and negative responses to working in the laboratory, wanting to know specific DI, and if knowing this DI would/did affect their responses to working with donors. Analyses examined the relationships between desire to know DI and indices of the following: positive response index (PRI), negative response index (NRI), avoid-approach index (AAI), and compassion-respect index. Across all surveys, a majority of respondents wanted to know some form of DI. At all time points, a majority of respondents felt that knowing all types of DI would increase their positive responses to working with donors. A greater PRI and AAI tended to be associated with wanting to know more personal DI (e.g., names and personal histories). A greater NRI tended to be associated with anticipating that learning personal DI would increase their negative responses before entering the laboratory, which did not persist after dissection began. These data suggest that for a majority of students, knowing personal DI increases their positive response and does not elicit negative responses to dissection or working with anatomical donors. Clin. Anat. 32:1019-1032, 2019. © 2019 Wiley Periodicals, Inc.
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Anatomía/educación , Cadáver , Disección/psicología , Estudiantes de Medicina/psicología , Donantes de Tejidos , Adulto , Femenino , Registros de Salud Personal , Humanos , Masculino , Adulto JovenRESUMEN
AIMS: Trifluridine/tipiracil (FTD/TPI) prolongs survival in refractory metastatic colorectal cancer, but limited data exist on its use in patients with hepatic impairment. This Phase I, open-label, nonrandomized study investigated the safety, tolerability and pharmacokinetics of FTD/TPI in patients with advanced solid tumours (except breast cancer) and varying degrees of hepatic impairment, to provide dosing recommendations. METHODS: Patients aged ≥18 years with advanced solid tumours and normal hepatic function, or mild, moderate or severe hepatic impairment according to National Cancer Institute criteria, were planned to be enrolled. Patients received FTD/TPI 35 mg/m2 orally twice daily on days 1-5 and 8-12 of each 28-day cycle. RESULTS: Twenty-four patients were enrolled to the normal hepatic function (n = 8) and mild (n = 10) and moderate (n = 6) hepatic impairment cohorts. Overall, 12 patients (50.0%) had at least 1 adverse event leading to study discontinuation. In the moderate hepatic impairment cohort, 5 of 6 patients experienced grade ≥ 3 elevation in bilirubin. No patients with severe hepatic impairment were enrolled. FTD area under the curve at steady state decreased by 18% and 22% in the mild and moderate cohorts, respectively; however, no clear change was observed in TPI area under the curve. CONCLUSIONS: FTD/TPI can be safely administered in patients with normal hepatic function and mild hepatic impairment, with no initial dose adjustment. FTD/TPI is not recommended for use in patients with moderate hepatic impairment because of findings of grade 3 or 4 increased blood bilirubin. Therefore, FTD/TPI is not recommended for patients with moderate or severe hepatic impairment.
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Antineoplásicos/farmacocinética , Hepatopatías/complicaciones , Hígado/metabolismo , Neoplasias/tratamiento farmacológico , Pirrolidinas/farmacocinética , Trifluridina/farmacocinética , Uracilo/análogos & derivados , Administración Oral , Adulto , Anciano , Antineoplásicos/administración & dosificación , Antineoplásicos/efectos adversos , Bilirrubina/sangre , Esquema de Medicación , Combinación de Medicamentos , Cálculo de Dosificación de Drogas , Femenino , Humanos , Hepatopatías/diagnóstico , Hepatopatías/metabolismo , Masculino , Persona de Mediana Edad , Modelos Biológicos , Neoplasias/complicaciones , Neoplasias/diagnóstico , Pirrolidinas/administración & dosificación , Pirrolidinas/efectos adversos , Índice de Severidad de la Enfermedad , Timina , Resultado del Tratamiento , Trifluridina/administración & dosificación , Trifluridina/efectos adversos , Estados Unidos , Uracilo/administración & dosificación , Uracilo/efectos adversos , Uracilo/farmacocinéticaRESUMEN
PURPOSE: MINT1526A is a monoclonal antibody that blocks the interaction of integrin alpha 5 beta 1 (α5ß1) with its extracellular matrix ligands. This phase I study evaluated the safety and pharmacokinetics of MINT1526A with or without bevacizumab in patients with advanced solid tumors. METHODS: MINT1526A was administered every 3 weeks (Q3W) as monotherapy (arm 1) or in combination with bevacizumab 15 mg/kg, Q3W (arm 2). Each arm included a 3 + 3 dose-escalation stage and a dose-expansion stage. RESULTS: Twenty-four patients were enrolled in arm 1 (dose range 2-30 mg/kg) and 30 patients were enrolled in arm 2 (dose range 3-15 mg/kg). Monocyte α5ß1 receptor occupancy was saturated at a dose of 15 mg/kg. No dose-limiting toxicities were observed, and the maximum tolerated dose was not reached in either arm. The most common adverse events, regardless of causality, included abdominal pain (25%), diarrhea (25%), nausea (21%), vomiting (21%), and fatigue (21%) in arm 1 and nausea (40%), fatigue (33%), vomiting (30%), dehydration (30%), headache (30%), and hypertension (30%) in arm 2. No grade ≥ 3 bleeding events were observed in either arm. No confirmed partial responses (PR) were observed in arm 1. In arm 2, one patient with thymic carcinoma experienced a confirmed PR and two patients with hepatocellular carcinoma (HCC) experienced durable minor radiographic responses. CONCLUSIONS: MINT1526A, with or without bevacizumab, was well-tolerated. Preliminary evidence of combination efficacy, including in patients with HCC, was observed, but cannot be distinguished from bevacizumab monotherapy in this phase I study.
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Antineoplásicos Inmunológicos/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Neoplasias/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos Inmunológicos/inmunología , Protocolos de Quimioterapia Combinada Antineoplásica/inmunología , Bevacizumab/administración & dosificación , Bevacizumab/inmunología , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Integrina alfa5beta1/antagonistas & inhibidores , Integrina alfa5beta1/inmunología , Masculino , Persona de Mediana Edad , Neoplasias/inmunologíaRESUMEN
This corrects the article DOI: 10.1038/bjc.2017.327.
RESUMEN
Background The signaling protein p38 mitogen-activated protein kinase (MAPK) regulates the tumor cell microenvironment, modulating cell survival, migration, and invasion. This phase 1 study evaluated the safety of p38 MAPK inhibitor LY3007113 in patients with advanced cancer to establish a recommended phase 2 dose. Methods In part A (dose escalation), LY3007113 was administered orally every 12 h (Q12H) at doses ranging from 20 mg to 200 mg daily on a 28-day cycle until the maximum tolerated dose (MTD) was reached. In part B (dose confirmation), patients received MTD. Safety, pharmacokinetics, pharmacodynamics, and tumor response data were evaluated. Results MTD was 30 mg Q12H. The most frequent treatment-related adverse events (>10%) were tremor, rash, stomatitis, increased blood creatine phosphokinase, and fatigue. Grade ≥ 3 treatment-related adverse events included upper gastrointestinal haemorrhage and increased hepatic enzyme, both occurring at 40 mg Q12H and considered dose-limiting toxicities. LY3007113 exhibited an approximately dose-proportional increase in exposure and time-independent pharmacokinetics after repeated dosing. Maximal inhibition (80%) of primary biomarker MAPK-activated protein kinase 2 in peripheral blood mononuclear cells was not reached, and sustained minimal inhibition (60%) was not maintained for 6 h after dosing to achieve a biologically effective dose (BED). The best overall response in part B was stable disease in 3 of 27 patients. Conclusions The recommended phase 2 dosage of LY3007113 was 30 mg Q12H. Three patients continued treatment after the first radiographic assessment, and the BED was not achieved. Further clinical development of this compound is not planned as toxicity precluded achieving a biologically effective dose.