Karolinska Institutet Innovations (Sweden)

Brain metastases following esophagectomy for cancer are rare but can greatly affect quality of life. To date, risk factors for, time to development of, and treatment strategies for brain metastasis are not well defined. Consecutive patients treated with esophagectomy for clinical stage I-IVA esophageal cancer from 2010 to 2021 across five centers were included. Logistic regression analyses were performed to identify risk factors for development of solitary brain metastases. Overall survival was assessed using Kaplan-Meier analysis. Of 3191 included patients, 91 (2.9%) developed solitary brain metastasis. Multivariable analysis identified increasing clinical nodal stage, adenocarcinoma (adjusted odds ratio [aOR] 4.00; 95% confidence interval [CI] 1.91-10), neoadjuvant chemoradiotherapy (aOR 2.18; 95% CI 1.19-4.28), and adjuvant therapy (OR 2.48; 95% CI 1.10-5.18) as risk factors for developing solitary brain metastases. Complete pathological responders were more likely to develop brain metastases than distant metastases (aOR 2.43; 95% CI 1.23-4.55). Patients with early solitary brain metastasis had the worst median overall survival (4.4 months, 95% CI 2.2-17) compared with classic (11 months, 95% CI 8.3-18) or late (7.4 months, 95% CI 2.1-not reached) (p = 0.20). Treatment involving surgery combined with radiation (adjusted hazard ratio [aHR] 0.10; 95% CI 0.05-0.20) resulted in better median overall survival (18 months, 95% CI 13-26) than did radiation (aHR 0.20; 95% CI 0.11-0.36) (10 months, 95% CI 6.1-14) or best supportive care (1.3 months, 95% CI 0.39-2.8) (p < 0.001). After esophagectomy for cancer, nodal involvement, adenocarcinoma, neoadjuvant and adjuvant therapy, and complete pathologic response appear to be risk factors for developing solitary brain metastases. Survival of selected patients with solitary brain metastasis is possible, especially if they are able to undergo surgery combined with radiation therapy.

To assess risks of adverse pregnancy outcomes (APOs) in a contemporary cohort of women with systemic sclerosis (SSc) in relation to the timing of SSc diagnosis and by parity. From the nationwide Swedish Medical Birth Register, we assembled pregnancies with births in women with SSc and in comparator women from the general population (1998-2021). We classified pregnancies according to the timing of SSc diagnosis at birth: post-SSc (after SSc diagnosis [n = 94]) and pre-SSc (zero to three years [n = 39] or more than three years [n = 839] before diagnosis of SSc). We used regression models estimating relative risks (RRs) and odds ratios of APOs with 95% confidence intervals (CIs) in post-SSc and pre-SSc pregnancies, respectively. For post-SSc pregnancies, RRs of preeclampsia (3.8, 95% CI 1.8-7.8), preterm birth (3.3; 95% CI 1.8-6.1), and cesarean delivery (2.5; 95% CI 1.8-3.5) were increased. By contrast, there were no indications of increased proportions of maternal or neonatal death or stillbirth. Stratifying on parity, risks were considerably higher among primiparous post-SSc women (preeclampsia RR 7.5, 95% CI 3.5-16.1; preterm birth RR 5.1, 95% CI 2.5-10.5). We also noted increased odds of APOs in pre-SSc pregnancies, with the highest estimates in the zero to three years' pre-SSc pregnancies. Contemporary women with SSc displayed markedly increased risks of several APOs after SSc diagnosis; the risks of some APOs were already increased before diagnosis, particularly within three years. Our findings suggest that both preclinical and overt SSc have a substantial impact on pregnancy outcomes, especially in the first pregnancy, highlighting the importance of specialized care and close monitoring.

Endothelial dysfunction is an early consequence of vascular inflammation and a driver of coronary atherosclerotic disease leading to myocardial infarction. The red blood cells (RBCs) mediate endothelial dysfunction in patients at cardiovascular risk, but their role in patients with acute myocardial infarction is unknown. This study aimed to investigate if RBCs from patients with ST-elevation myocardial infarction (STEMI) induced endothelial dysfunction and the role of systemic inflammation in this effect. RBCs from patients with STEMI and aged-matched healthy controls were coincubated with rat aortic segments for 18 h followed by evaluation of endothelium-dependent (EDR) and endothelium-independent relaxation (EIDR). RBCs and aortic segments were also analyzed for arginase and oxidative stress. The patients were divided into groups depending on C-reactive protein (CRP) levels at admission. RBCs from patients with STEMI and CRP levels ≥2 mg/L induced impairment of EDR, but not EIDR, compared with RBCs from STEMI and CRP <2 mg/L and healthy controls. Aortic expression of arginase 1 was increased following incubation with RBCs from patients with STEMI and CRP ≥2, and arginase inhibition prevented the RBC-induced endothelial dysfunction. RBCs from patients with STEMI and CRP ≥2 had increased reactive oxygen species compared with RBCs from patients with CRP <2 and healthy controls. Vascular inhibition of NADPH oxidases and increased dismutation of superoxide improved EDR. RBCs from patients with STEMI and low-grade inflammation induce endothelial dysfunction through a mechanism involving arginase 1 as well as increased RBC and vascular superoxide by NADPH oxidases.NEW & NOTEWORTHY Red blood cells from patients with STEMI and systemic inflammation induce endothelial dysfunction ex vivo. The RBC-induced endothelial dysfunction is mediated through increased arginase 1 and a shift in the redox balance toward oxidative stress. Inhibition of arginase or free radicals attenuates the impairment of endothelial function. The study suggests that red blood cells deserve attention as a key player in systemic inflammation and STEMI.

IntroductionPersons with dementia experience time‐related problems, but there is a lack of instruments evaluating their time processing ability and daily time management. This study aimed to evaluate the psychometric properties of the instruments KaTid®‐Senior measuring time processing ability, and Time‐S© Senior and Time‐Proxy© measuring daily time management for persons with dementia.MethodsPersons with dementia (n = 53) and their significant others (n = 49) participated in the study. Rasch analyses were used to evaluate the instruments' rating scale functioning; internal scale validity; person‐response validity; unidimensionality; person‐separation reliability; and internal consistency. Versions excluding items with poor fit to the Rasch model were also evaluated.ResultsOverall, the Rasch analyses showed acceptable psychometric properties. All instruments met the criteria for unidimensionality and the reliability was good. More challenging items should be added in KaTid‐Senior for better targeting of persons with mild dementia. Person‐response validity issues in Time‐S Senior need to be addressed.ConclusionThe instruments can validly and reliably be used to assess time processing ability and daily time management in persons with dementia in clinical research and healthcare settings. In turn, this can contribute to the development of methods to compensate for impaired time processing ability and daily time management. The assessments can also increase the possibility of early detection of impaired time processing ability and daily time management, thereby facilitating adequate timing of interventions and enhanced occupational performance.

BackgroundLorlatinib is a third-generation anaplastic lymphoma kinase (ALK)/c-ros oncogene 1 (ROS1) tyrosine kinase inhibitor (TKI) with efficacy in patients with ALK-rearranged non-small-cell lung cancer (NSCLC) previously treated with a second-generation ALK inhibitor or with first- and second-generation ALK inhibitors. We examined the cost-effectiveness of second- or third-line+ (2L+ or 3L+) lorlatinib in Sweden, versus chemotherapy.MethodsA partitioned survival model with three health states (progression free, progressed, or death) was used. Lorlatinib relative efficacy versus chemotherapy was derived using unanchored matching adjusted indirect treatment comparisons from a phase 2 clinical trial. Utility data were derived from the same trial and published studies. Costs (year 2019) were obtained from Swedish national data. Costs and benefits were discounted at 3% per annum using a societal perspective (base case). Model robustness was evaluated with deterministic and probabilistic sensitivity analyses.ResultsFor 2L+, the average discounted total quality-adjusted life year (QALY) gain was 1.29 years. Total incremental costs were Swedish krona (SEK) 731,791, resulting in an incremental cost-effectiveness ratio (ICER) of SEK 566,278 per QALY gained. Non-discounted survival gain amounted to 1.94 years. For 3L+, the average discounted total QALY gain was 1.25 years. Total incremental costs were SEK 754,801, resulting in an ICER of SEK 603,934 per QALY gained. Non-discounted survival gain was 1.88 years. Sensitivity analyses were consistent.ConclusionsICERs ranged from SEK 421,000 to SEK 384,066 less than the boundary for a cost-effective treatment for a high-severity disease in Sweden (SEK 988,000), suggesting 2L+ or 3L+ lorlatinib is a cost-effective treatment for ALK-positive NSCLC versus chemotherapy.Supplementary InformationThe online version contains supplementary material available at 10.1007/s40273-021-01015-8.