Citations

Background: The management of patients with locally advanced or metastatic differentiated thyroid cancer (DTC) that is refractory to radioiodine (RAI) remains a therapeutic challenge. The multi-tyrosine kinase inhibitors (TKIs) sorafenib and lenvatinib have been approved based on phase 3 clinical trials. Patients and Methods: We aimed at describing the efficacy and safety of TKI treatment of RAI-refractory DTC in a real-world setting at six German referral centers. One hundred and one patients with locally advanced or metastatic RAI-refractory DTC treated with sorafenib, lenvatinib, and/or pazopanib were included. Progression-free survival (PFS) and overall survival (OS) probabilities were estimated by using the Kaplan-Meier method. Results: Ninety-seven of 101 patients had progressive disease before TKI initiation. The median PFS for first-line treatment with sorafenib ( n = 33), lenvatinib ( n = 53), and pazopanib ( n = 15) was 9 (95% confidence interval 5.2–12.8), 12 (4.4–19.6), and 12 months (4.4–19.6), respectively. The median OS for first-line treatment was 37 (10–64) for sorafenib, 47 (15.5–78.5) for lenvatinib, and 34 months (20.2–47.8) for pazopanib. Serious complications (e.g., hemorrhage, acute coronary syndrome, and thrombosis/venous thromboembolism) occurred in 16 out of 75 (21%) patients taking lenvatinib, in 3 out of 42 (7%) patients taking sorafenib, and in 3 out of 24 (13%) patients taking pazopanib. Conclusions: Sorafenib, lenvatinib, and pazopanib are effective treatment options in the majority of patients with RAI-refractory DTC. The PFS and six-month survival rate in patients treated with lenvatinib und pazopanib appear to compare favorably with sorafenib in the first-line treatment setting. However, a more advanced disease stage at treatment initiation in sorafenib- and pazopanib-treated patients in the era before TKI-approval and the retrospective nature of this study precludes a direct comparison of TKIs.

Abstract Aims The causes of distinct patterns of reduced cortical thickness in the common human epilepsies, detectable on neuroimaging and with important clinical consequences, are unknown. We investigated the underlying mechanisms of cortical thinning using a systems‐level analysis. Methods Imaging‐based cortical structural maps from a large‐scale epilepsy neuroimaging study were overlaid with highly spatially resolved human brain gene expression data from the Allen Human Brain Atlas. Cell‐type deconvolution, differential expression analysis and cell‐type enrichment analyses were used to identify differences in cell‐type distribution. These differences were followed up in post‐mortem brain tissue from humans with epilepsy using Iba1 immunolabelling. Furthermore, to investigate a causal effect in cortical thinning, cell‐type‐specific depletion was used in a murine model of acquired epilepsy. Results We identified elevated fractions of microglia and endothelial cells in regions of reduced cortical thickness. Differentially expressed genes showed enrichment for microglial markers and, in particular, activated microglial states. Analysis of post‐mortem brain tissue from humans with epilepsy confirmed excess activated microglia. In the murine model, transient depletion of activated microglia during the early phase of the disease development prevented cortical thinning and neuronal cell loss in the temporal cortex. Although the development of chronic seizures was unaffected, the epileptic mice with early depletion of activated microglia did not develop deficits in a non‐spatial memory test seen in epileptic mice not depleted of microglia. Conclusions These convergent data strongly implicate activated microglia in cortical thinning, representing a new dimension for concern and disease modification in the epilepsies, potentially distinct from seizure control.

Abstract The burden of senescent cells (SnCs), which do not divide but are metabolically active and resistant to death by apoptosis, is increased in older adults and those with chronic diseases. These individuals are also at the greatest risk for morbidity and mortality from SARS‐CoV‐2 infection. SARS‐CoV‐2 complications include cytokine storm and multiorgan failure mediated by the same factors as often produced by SnCs through their senescence‐associated secretory phenotype (SASP). The SASP can be amplified by infection‐related pathogen‐associated molecular profile factors. Senolytic agents, such as Fisetin, selectively eliminate SnCs and delay, prevent, or alleviate multiple disorders in aged experimental animals and animal models of human chronic diseases, including obesity, diabetes, and respiratory diseases. Senolytics are now in clinical trials for multiple conditions linked to SnCs, including frailty; obesity/diabetes; osteoporosis; and cardiovascular, kidney, and lung diseases, which are also risk factors for SARS‐CoV‐2 morbidity and mortality. A clinical trial is underway to test if senolytics decrease SARS‐CoV‐2 progression and morbidity in hospitalized older adults. We describe here a National Institutes of Health‐funded, multicenter, placebo‐controlled clinical trial of Fisetin for older adult skilled nursing facility (SNF) residents who have been, or become, SARS‐CoV‐2 rtPCR‐positive, including the rationale for targeting fundamental aging mechanisms in such patients. We consider logistic challenges of conducting trials in long‐term care settings in the SARS‐CoV‐2 era, including restricted access, consent procedures, methods for obtaining biospecimens and clinical data, staffing, investigational product administration issues, and potential solutions for these challenges. We propose developing a national network of SNFs engaged in interventional clinical trials.

Background: It is standard of care and an accreditation requirement to screen for and address distress and psychosocial needs in patients with cancer. This study assessed the availability of mental health (MH) and chemical dependency (CD) services at US cancer centers. Methods: The 2017–2018 American Hospital Association (AHA) survey, Area Health Resource File, and Centers for Medicare & Medicaid Services Hospital Compare databases were used to assess availability of services and associations with hospital-level and health services area (HSA)–level characteristics. Results: Of 1,144 cancer centers surveyed, 85.4% offered MH services and 45.5% offered CD services; only 44.1% provided both. Factors associated with increased adjusted odds of offering MH services were teaching status (odds ratio [OR], 1.76; 95% CI, 1.18–2.62), being a member of a hospital system (OR, 2.00; 95% CI, 1.31–3.07), and having more beds (OR, 1.04 per 10-bed increase; 95% CI, 1.02–1.05). Higher population estimate (OR, 0.98; 95% CI, 0.97–0.99), higher percentage uninsured (OR, 0.90; 95% CI, 0.86–0.95), and higher Mental Health Professional Shortage Area level in the HSA (OR, 0.99; 95% CI, 0.98–1.00) were associated with decreased odds of offering MH services. Government-run (OR, 2.85; 95% CI, 1.30–6.22) and nonprofit centers (OR, 3.48; 95% CI, 1.78–6.79) showed increased odds of offering CD services compared with for-profit centers. Those that were members of hospital systems (OR, 1.61; 95% CI, 1.14–2.29) and had more beds (OR, 1.02; 95% CI, 1.01–1.03) also showed increased odds of offering these services. A higher percentage of uninsured patients in the HSA (OR, 0.92; 95% CI, 0.88–0.97) was associated with decreased odds of offering CD services. Conclusions: Patients’ ability to pay, membership in a hospital system, and organization size may be drivers of decisions to co-locate services within cancer centers. Larger organizations may be better able to financially support offering these services despite poor reimbursement rates. Innovations in specialty payment models highlight opportunities to drive transformation in delivering MH and CD services for high-need patients with cancer.

Abstract Background Bamlanivimab and casirivimab-imdevimab are authorized for treatment of mild to moderate coronavirus disease 2019 (COVID-19) in high-risk patients. We compared the outcomes of patients who received these therapies to identify factors associated with hospitalization and other clinical outcomes. Methods Adult patients who received monoclonal antibody from 19 November 2020 to 11 February 2021 were selected and divided into those who received bamlanivimab (n = 2747) and casirivimab-imdevimab (n = 849). The 28-day all-cause and COVID-19–related hospitalizations were compared between the groups. Results The population included 3596 patients; the median age was 62 years, and 50% were female. All had ≥1 medical comorbidity; 55% had multiple comorbidities. All-cause and COVID-19–related hospitalization rates at 28 days were 3.98% and 2.56%, respectively. After adjusting for medical comorbidities, there was no significant difference in all-cause and COVID-19–related hospitalization rates between bamlanivimab and casirivimab-imdevimab (adjusted hazard ratios [95% confidence interval], 1.4 [.9–2.2] and 1.6 [.8–2.7], respectively). Chronic kidney, respiratory and cardiovascular diseases, and immunocompromised status were associated with higher likelihood of hospitalization. Conclusions This observational study on the use of bamlanivimab and casirivimab-imdevimab in high-risk patients showed similarly low rates of hospitalization. The number and type of medical comorbidities are associated with hospitalizations after monoclonal antibody treatment.

Abstract There is growing evidence showing that sex disparity in lung cancer risk cannot be fully explained by sex differences in smoking behavior, implying existence of genetic and molecular basis for sex disparity in lung cancer development. However, the information about sex dimorphism in lung cancer risk is quite limited despite the great success in lung cancer association studies. By adopting a stringent two-stage analysis strategy, we performed a genome-wide gene-sex interaction analysis using genotype from a lung cancer cohort including ~ 47,000 individuals with European ancestry. Three low-frequency variants (minor allele frequency < 0.05), rs17662871 (OR=0.71, p=4.29x10-8); rs79942605 (OR=2.17, p=2.81x10-8); and rs208908 (OR=0.70, p=4.54x10-8), were identified with different risk effect of lung cancer between men and women. Further eQTL and functional annotation analysis suggested rs208908 affect lung cancer risk through differential regulation of CXADR (Coxsackie Virus And Adenovirus Receptor) gene expression in lung tissues between men and women. Our study is one of the first studies to provide novel insights about the genetic and molecular basis for sex disparity in lung cancer development.

Background We sought to determine the occurrence of major bleeding events in a population-based cohort of stroke patients with atrial fibrillation in a population-based cohort who were risk-stratified at baseline, one and five years, following initiation of warfarin treatment. Methods The resources of the Rochester Epidemiology Project Medical Linkage System were used to identify acute ischemic stroke patients with atrial fibrillation undergoing warfarin treatment for secondary stroke prevention from 1980 to 1995. These patients were risk-stratified according to the HAS-BLED and HEMORRHAGES scores prior to warfarin initiation following stroke onset; these scores were reassessed one and five years later. Major bleeding was considered in patients with fatal or clinically overt bleeding associated with either transfusion of >2 units of blood or >2 g/dl decrease in hemoglobin. Results One hundred patients (mean age, 79.3 years; 68% women) were studied. Median duration of warfarin treatment was 2.4 years (interquartile range, 0.4-6.6) and duration from stroke onset to death was 3.7 years (1.1-8.8). Major bleeding events occurred in 41 patients at a median duration of 19 months (5-58) following warfarin initiation. Sixteen events occurred within a year of treatment, 25 events from years 1-5, and 14 events in patients treated for >5 years. Patients with baseline HAS-BLED scores ≥2 had higher life-time risks of major bleeding events compared with those ≤1 (95% vs 5%, p=0.002), while those with HEMORRHAGES score ≥2 had higher life-time risks of major bleeding events compared with those ≤1 (90% vs 10%, p=0.030). Periodic reassessments of these risks were associated with a higher detection of major bleeding events. Patients with an increase in the HAS-BLED scores had a higher subsequent risk of major bleeding events compared with those with no change (year one, 64% vs 34%, p=0.043; year five, 75% vs 29%, p=0.018). Similarly, patients with an increase in the HEMORRHAGES scores had a higher risks of major bleeding events compared to those with no change (year one, 57% vs 33%, p=0.063; year five, 71% vs 10%, p<0.001). Conclusions Periodic assessments of bleeding risks using prognostic scales are associated with a higher detection of major bleeding events. These scales should be periodically reassessed in the years following warfarin initiation to determine if the benefit of ongoing use outweighs the bleeding risk.

Introduction: Patients with intracerebral cavernous malformations (ICMs) may present with or later develop seizures. There are limited data regarding the clinical demographics of these patients, predictors of medically treatable versus medically refractory seizures, and long term seizure outcome. Objective: We aimed to characterize the clinical and radiographic features of supratentorial ICMs that present with seizures and describe their response to medical treatment. Methods: Patients with supratentorial ICMs were identified from a radiographic database for cases seen between 1989 and 1999. Clinical and radiographic information was abstracted and prospective follow up was obtained. Medically refractory seizures were defined as patients who were not seizure-free at last follow up, or who underwent surgery for refractory seizures. Results: A total of 206 patients were identified with a radiographic diagnosis of supratentorial ICM, 103 (50%) of whom presented with seizures and 7 (3%) who later developed seizures. Compared to those with seizures, patients without seizures were more likely to have a subcortical supratentorial ICM and to be on an antithrombotic agent. Intracerebral hemorrhage (ICH) at diagnosis did not predict presentation with seizure at diagnosis. Among the 59 patients treated with antiepileptics only, 16 (27%) were seizure-free at last follow up, 7 of whom no longer required medication and 8 of whom were controlled on a single agent. In the remainder of patients who were not seizure-free, seizure frequency was reduced in 37%, unchanged in 12%, increased in 5%, and unknown in 19%. Of the total 110 patients with seizures, 46 (42%) underwent at least one surgical removal of an ICM for medically refractory seizures. Conclusions: To date this study is one of the largest cohorts of ICM patients with seizures. Seizure is a common presentation in patients with cortical supratentorial ICMs. The presence of ICH at ICM diagnosis is not related to an increased occurrence of seizures at presentation. One-fourth of patients treated with antiepileptics alone eventually become seizure-free, almost half of which do not require medication at follow-up, suggesting that some non-surgical patients may not require life-long antiepileptic therapy.