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Early and Sustained Improvements in Symptoms and Quality of Life with Upadacitinib in Adults and Adolescents with Moderate-to-Severe Atopic Dermatitis: 52-Week Results from Two Phase III Randomized Clinical Trials (Measure Up 1 and Measure Up 2)
No full textBACKGROUND: Atopic dermatitis is a chronic inflammatory disease characterized by increased itch, skin pain, poor sleep quality, and other symptoms that negatively affect patient quality of life. Upadacitinib, an oral selective Janus kinase (JAK) inhibitor with greater inhibitory potency for JAK1 than JAK2, JAK3, or tyrosine kinase 2, is approved to treat moderate-to-severe atopic dermatitis.
OBJECTIVE: We aimed to evaluate the effect of upadacitinib on patient-reported outcomes over 52 weeks in adults and adolescents with moderate-to-severe atopic dermatitis.
METHODS: Data from two phase III monotherapy trials of upadacitinib (Measure Up 1, NCT03569293; Measure Up 2, NCT03607422) were integrated. Changes in pruritus, pain, other skin symptoms, sleep, quality of life, mental health, and patient impression were evaluated. Patient-reported outcome assessments included the Worst Pruritus Numerical Rating Scale, Patient-Oriented Eczema Measure, Dermatology Life Quality Index, Atopic Dermatitis Symptom Scale, Atopic Dermatitis Impact Scale, Hospital Anxiety and Depression Scale, SCORing Atopic Dermatitis index, Patient Global Impression of Severity, Patient Global Impression of Change, and Patient Global Impression of Treatment. Minimal clinically important differences, achievement of scores representing minimal disease burden, and the change from baseline were evaluated in patients who received upadacitinib through week 52 and in patients who received placebo through week 16.
RESULTS: This analysis included 1609 patients (upadacitinib 15 mg, N = 557; upadacitinib 30 mg, N = 567; placebo, N = 485). Baseline demographics and disease characteristics were generally similar across all arms. The proportion of patients treated with upadacitinib reporting improvements in itch increased rapidly by week 1, increased steadily through week 8, and was sustained through week 52. Patients receiving upadacitinib also experienced improvements in pain and other skin symptoms by week 1, which continued through week 16; improvements were maintained through week 52. Patient reports of improved sleep increased rapidly from baseline to week 1, increased steadily through week 32, and were sustained through week 52. Patients experienced quality-of-life improvements through week 8, which were maintained through week 52. By week 1, patients in both upadacitinib groups experienced rapid improvements in emotional state, and by week 12, patients also achieved meaningful improvements in anxiety and depression. Improvements in mental health continued steadily through week 32 and were maintained through week 52. Patients treated with upadacitinib 30 mg generally experienced improvements in patient-reported outcomes earlier than those treated with upadacitinib 15 mg. Through week 16, patients receiving upadacitinib experienced greater improvements versus those receiving placebo in all assessed patient-reported outcomes.
CONCLUSIONS: Adults and adolescents with moderate-to-severe atopic dermatitis treated with once-daily upadacitinib 15 or 30 mg experienced early improvements in itch, pain, other skin symptoms, sleep, quality of life, and mental health that were sustained through week 52.
CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov identifiers NCT03569293 (13 August 2018) and NCT03607422 (27 July 2018)
For Squamous Cancers, the Streetlamps Shine on Occasional Keys, Most Baskets Are Empty, and the Umbrellas Cannot Keep Us Dry: A Call for New Models in Precision Oncology
No full textA Phase II Trial of Pevonedistat and Docetaxel in Patients With Previously Treated Advanced Non-Small-Cell Lung Cancer
No full textBACKGROUND: Postimmunotherapy (IO) treatment options for stage IV non-small-cell lung cancer (NSCLC) remain limited. Docetaxel alone or in combination with ramucirumab remains a standard of care, but response rates and survival benefit are suboptimal. Cullin-RING ligases (CRL) catalyze degradation of tumor suppressor proteins and are overactivated in NSCLC. Neddylation, which is catalyzed by the NEDD8 activating enzyme (NAE), is required for the activation of CRLs. Pevonedistat, a first-in-class small molecule NAE inhibitor, exerted antitumor activity when combined with docetaxel in preclinical studies.
METHODS: We conducted a phase II, single-arm, investigator-initiated study evaluating the efficacy of pevonedistat plus docetaxel in patients with relapsed/refractory stage IV NSCLC. Patients received docetaxel 75 mg/m(2) on day 1 and pevonedistat 25 mg/m(2) on days 1, 3 and 5 of a 21-day cycle. The primary endpoint was objective response rate (ORR).
RESULTS: From March 5, 2018 to January 26, 2021, we enrolled 31 patients. The ORR was 22% (1 CR, 5 PR), median PFS was 4.1 months, and median OS was 13.2 months. The incidence of Grade ≥3 adverse events (AE) was 53% in patients (n = 30) who received at least 1 dose of both drugs, with the most frequent being neutropenia and AST/ALT elevation. One patient was taken off study for a Grade 4 transaminase elevation. There were no Grade 5 toxicities.
CONCLUSION: Our data suggest that the combination of docetaxel and pevonedistat is safe and exerts activity in patients with relapsed NSCLC. These encouraging results suggest that the neddylation pathway is an antitumor pathway that should be further studied
Psychosocial evaluation of living liver donors-State of current practices in the United States
No full textWe surveyed living donor liver transplant programs in the United States to describe practices in the psychosocial evaluation of living donors focused on (1) composition of psychosocial team; (2) domains, workflow, and tools of the psychosocial assessment; (3) absolute and relative mental health-related contraindications to donation; and (4) postdonation psychosocial follow-up. We received 52 unique responses, representing 33 of 50 (66%) of active living donor liver transplant programs. Thirty-one (93.9%) provider teams included social workers, 22 (66.7%) psychiatrists, and 14 (42.4%) psychologists. Validated tools were rarely used, but domains assessed were consistent. Respondents rated active alcohol (93.8%), cocaine (96.8%), and opioid (96.8%) use disorder, as absolute contraindications to donation. Active suicidality (97%), self-injurious behavior (90.9%), eating disorders (87.9%), psychosis (84.8%), nonadherence (71.9%), and inability to cooperate with the evaluation team (78.1%) were absolute contraindications to donation. There were no statistically significant differences in absolute psychosocial contraindications to liver donation between geographical areas or between large and small programs. Programs conduct postdonation psychosocial follow-up (57.6%) or screening (39.4%), but routine follow-up of declined donors is rarely conducted (15.8%). Psychosocial evaluation of donor candidates is a multidisciplinary process. The structure of the psychosocial evaluation of donors is not uniform among programs though the domains assessed are consistent. Psychosocial contraindications to living liver donation vary among the transplant programs. Mental health follow-up of donor candidates is not standardized
Impact of obesity on in-hospital mortality and morbidity among patients admitted for antineoplastic chemotherapy: a nationwide analysis
No full textBACKGROUND: Obesity is a complex and multifactorial medical condition that can have far reaching consequences on cancer patients, particularly those undergoing treatment such as chemotherapy. Our study focuses to comprehensively explore the various adverse outcomes in obese patients receiving chemotherapy during hospitalization.
METHODS: The National Inpatient Sample 2020 was used using the ICD-10 codes to identify patients hospitalized with a primary discharge diagnosis of neoplastic chemotherapy with or without a secondary diagnosis of obesity. Statistical analysis using Stata software was done, and primary and secondary outcomes were obtained after adjusting for confounders using multivariate regression analysis.
RESULTS: Mortality was similar in both obese and non-obese patients. Length of stay and total hospitalization charges were increased in obese patients. Obese patients had higher odds of developing acute respiratory failure and were more likely to require non-invasive and invasive mechanical ventilation.
CONCLUSION: Our study concluded that obesity could be considered an independent predictor of worse outcomes in patients admitted for neoplastic chemotherapy. Notably, addressing obesity could help to improve the efficacy of treatment for cancer patients while simultaneously reducing any negative consequences associated with being obese
Fidelity to the Consensus Auditory-Perceptual Analysis of Voice (CAPE-V): A Pilot Study
No full textOBJECTIVES: Auditory-perceptual measurements of voice are among the most common diagnostic tools used during a voice evaluation and are considered a gold standard for documenting voice disorders. The goal of this pilot study was to examine the fidelity of clinicians in the administration of the Consensus Auditory-Perceptual Evaluation of Voice (CAPE-V) and its published protocol. This investigation aimed to determine how the CAPE-V is being used by clinicians and researchers and the extent to which users deviate from the published procedure.
STUDY DESIGN: Survey
METHODS: Data were collected by surveying a group (N = l7) of speech-language pathologists who regularly evaluate and treat patients with voice disorders. Survey results revealed that few of the sampled speech-language pathologists follow exactly the standardized instructions for administering the CAPE-V. Considerable variability in CAPE-V administration, including tasks and stimuli examined, was found across respondents.
CONCLUSIONS: This exploratory project may be used to develop a larger national survey study investigating fidelity to the CAPE-V and to motivate recommendations for possible revisions to the instrument and its protocol for administration
The Glymphatic Response to the Development of Type 2 Diabetes
No full textThe glymphatic system has recently been shown to be important in neurological diseases, including diabetes. However, little is known about how the progressive onset of diabetes affects the glymphatic system. The aim of this study is to investigate the glymphatic system response to the progressive onset of diabetes in a rat model of type 2 diabetic mellitus. Male Wistar rats (n = 45) with and without diabetes were evaluated using MRI glymphatic tracer kinetics, functional tests, and brain tissue immunohistochemistry. Our data demonstrated that the contrast agent clearance impairment gradually progressed with the diabetic duration. The MRI data showed that an impairment in contrast clearance occurred prior to the cognitive deficits detected using functional tests and permitted the detection of an early DM stage compared to the immuno-histopathology and cognitive tests. Additionally, the quantitative MRI markers of brain waste clearance demonstrated region-dependent sensitivity in glymphatic impairment. The improved sensitivity of MRI markers in the olfactory bulb and the whole brain at an early DM stage may be attributed to the important role of the olfactory bulb in the parenchymal efflux pathway. MRI can provide sensitive quantitative markers of glymphatic impairment during the progression of DM and can be used as a valuable tool for the early diagnosis of DM with a potential for clinical application
Does Tighter Glycemic Control Beyond Hemoglobin A1c of 8% Improve Outcome for Lumbar Spine Surgery? A MSSIC Study
No full textBACKGROUND AND OBJECTIVES: Diabetes mellitus is associated with increased risk of postoperative adverse outcomes. Previous studies have emphasized the role of glycemic control in postoperative complications. This study aims to ascertain whether controlling hemoglobin A1c (HbA1c) lower than 8% preoperatively results in meaningful risk reduction or improved outcomes.
METHODS: We used patient-level data from the Michigan Spine Surgery Improvement Collaborative registry, focusing on patients who underwent elective lumbar spine surgery between 2018 and 2021. The primary outcomes were length of stay and the occurrence of postoperative adverse events. Secondary outcomes included patient satisfaction, achievement of a minimum clinically important difference (MCID) of Patient-Reported Outcomes Measurement Information System-Physical Function, the EuroQol-5D and NRS of leg and back pain, and return to work.
RESULTS: A total of 11 348 patients were included in this analysis. Patients with HbA1c above the thresholds before surgery had significantly higher risks of urinary retention for all 3 possible threshold values (incidence rate ratio [IRR] = 1.30, P = .015; IRR = 1.35, P = .001; IRR = 1.25, P = .011 for the HbA1c cutoffs of 8%, 7.5%, and 7%, respectively). They also had longer hospital stay (IRR = 1.04, P = .002; IRR = 1.03, P = .001; IRR = 1.03, P \u3c .001 for the HbA1c cutoffs of 8%, 7.5%, and 7%, respectively) and had higher risks of developing any complication with HbA1c cutoff of 7.5% (IRR = 1.09, P = .010) and 7% (IRR = 1.12, P = .001). Diabetics with preoperative HbA1c above all 3 thresholds were less likely to achieve Patient-Reported Outcomes Measurement Information System MCID at the 90-day follow-up (IRR = .81, P \u3c .001; IRR = .86, P \u3c .001; IRR = .90, P = .007 for the HbA1c cutoffs of 8%, 7.5%, and 7%, respectively) and less likely to achieve EuroQol-5D MCID at the 2-year follow-up (IRR = .87, P = .027; IRR = .84, P = .005 for the HbA1c cutoffs of 7.5% and 7%, respectively).
CONCLUSION: Our study suggests that reducing HbA1c below 8% may have diminishing returns regarding reducing complications after spine surgery
Discontinuation of Antiseizure Medications in Patients With Brain Tumors
No full textPatients with brain tumors will experience seizures during their disease course. While providers can use antiseizure medications to control these events, patients with brain tumors can experience side effects, ranging from mild to severe, from these medications. Providers in subspecialties such as neurology, neuro-oncology, neurosurgery, radiation oncology, and medical oncology often work with patients with brain tumor to balance seizure control and the adverse toxicity of antiseizure medications. In this study, we sought to explore the problem of brain tumor-related seizures/epilepsy in the context of how and when to consider antiseizure medication discontinuation. Moreover, we thoroughly evaluate the literature on antiseizure medication discontinuation for adult and pediatric patients and highlight recommendations relevant to patients with both brain tumors and seizures
When Do Patients Achieve PROMIS Milestones After Rotator Cuff Repair?
No full textBACKGROUND: Given the variability of the questions asked, the Patient-Reported Outcomes Measurement Information System (PROMIS) upper extremity (UE) computer adaptive test (CAT) Version 2.0 item bank aids in the evaluation of rotator cuff repair (RCR) rehabilitation by determining when recovery milestones are possible based on the quality of patient responses at certain time points.
PURPOSE: To assess the time point at which patients with RCR were able to achieve specific functional milestones, determined as positive responses to the 5 most frequently asked items on the PROMIS UE CAT Version 2.0.
STUDY DESIGN: Case series; Level of evidence, 4.
METHODS: The postoperative PROMIS UE CAT Version 2.0 scores of patients who underwent RCR between February 16, 2017, and July 30, 2019, were reviewed with respect to individual PROMIS item, response, and timing of response. A functional milestone was considered achieved if the patient response was without any difficulty or with a little difficulty to any of the 5 most frequently asked PROMIS items. The percentage of patients in each monthlong postoperative interval who answered with either response was recorded. The logit generalized estimating equations method was used to analyze the association between milestone achievement for each PROMIS item and predictor variables (age, sex, body mass index, smoking status, race, ethnicity, and employment status).
RESULTS: A total of 1131 responses from 371 patients were included. The majority of patients attained milestone achievement on 4 of the 5 most frequently asked PROMIS items at time points ranging from 1 to 5 months postoperatively: Are you able to carry a shopping bag or briefcase? (by 1 month), Are you able to put on and take off a coat or jacket? (by 3 months), Are you able to pour liquid from a bottle into a glass? (by 3 months), and Are you able to carry a heavy object (over 10 pounds/5 kg)? (by 5 months). For the item Are you able to put on a shirt or blouse? , the majority of patients did not achieve the milestone by 1 year.
CONCLUSION: These findings support the application of PROMIS UE CAT Version 2.0 milestone achievement in the shared decision-making process and postoperative monitoring, as patients can use this information to determine when they can return to certain activities and providers can apply these standards to identify patients needing additional clinical support