Lymphocytes and sinus histiocytosis in tumor and matched lymph nodes as predictors of survival in non-small-cell lung cancer

Aim: To analyze immune cell populations in non-small-cell lung cancer (NSCLC) tumors and matched tumor-bearing and non-tumor-bearing lymph nodes (ntbLNs) to predict prognosis. Patients & methods: 71 patients with long-term disease-free survival and 80 patients with relapse within 3 years were included in this study. We used Cox regression to identify factors associated with overall survival (OS) and progression-free survival (PFS). Results: Sinus histiocytosis and tumor-infiltrating lymphocyte density in the tumor were positively associated with PFS and OS. CD4 expression in N1 (hazard ratio = 0.72; p = 0.02) and N2 (hazard ratio = 0.91; p = 0.04) ntbLNs were positively correlated with OS and PFS, respectively. Discussion: Immunological markers in ntbLNs could be used to predict survival in NSCLC.

Carotid Artery Stiffness Mechanisms Associated With Cardiovascular Disease Events and Incident Hypertension: the MESA

Background: Elastic arteries stiffen via 2 main mechanisms: (1) load-dependent stiffening from higher blood pressure and (2) structural stiffening due to changes in the vessel wall. It is unknown how these different mechanisms contribute to incident cardiovascular disease (CVD) events. Methods: The MESA (Multi-Ethnic Study of Atherosclerosis) is a longitudinal study of 6814 men and women without CVD at enrollment, from 6 communities in the United States. MESA participants with B-mode carotid ultrasound and brachial blood pressure at baseline Exam in (2000–2002) and CVD surveillance (mean follow-up 14.3 years through 2018) were included (n=5873). Peterson’s elastic modulus was calculated to represent total arterial stiffness. Structural stiffness was calculated by adjusting Peterson’s elastic modulus to a standard blood pressure of 120/80 mm Hg with participant-specific models. Load-dependent stiffness was the difference between total and structural stiffness. Results: In Cox models adjusted for traditional risk factors, load-dependent stiffness was significantly associated with higher incidence of CVD events (hazard ratio/100 mm Hg, 1.21 [95% CI, 1.09–1.34] P <0.001) events while higher structural stiffness was not (hazard ratio, 1.03 [95% CI, 0.99–1.07] P =0.10). Analysis of participants who were normotensive (blood pressure <130/80, no antihypertensives) at baseline exam (n=2122) found higher load-dependent stiffness was also associated with significantly higher incidence of hypertension (hazard ratio, 1.53 [95% CI, 1.35–1.75] P <0.001) while higher structural stiffness was not (hazard ratio, 1.03 [95% CI, 0.99–1.07] P =0.16). Conclusions: These results provide valuable new insights into mechanisms underlying the association between arterial stiffness and CVD. Load-dependent stiffness was significantly associated with CVD events but structural stiffness was not.

Association of ROX Index with Mechanical Ventilator Use in Sepsis Patients in the Emergency Department

Detecting sepsis patients who are at a high-risk of mechanical ventilation is important in emergency departments (ED). The respiratory rate oxygenation (ROX) index is the ratio of tissue oxygen saturation/fraction of inspired oxygen to the respiratory rate. This study aimed to investigate whether the ROX index could predict mechanical ventilator use in sepsis patients in an ED. This retrospective observational study included quick sequential organ failure assessment (qSOFA) ≥ 2 sepsis patients that presented to the ED between September 2019 and April 2020. The ROX and ROX-heart rate (HR) indices were significantly lower in patients with mechanical ventilator use within 24 h than in those without the use of a mechanical ventilator (4.0 [3.2–5.4] vs. 10.0 [5.9–15.2], p < 0.001 and 3.9 [2.7–5.8] vs. 10.1 [5.4–16.3], p < 0.001, respectively). The area under the receiver operating characteristic (ROC) curve of the ROX and ROX-HR indices were 0.854 and 0.816 (both p < 0.001). The ROX and ROX-HR indices were independently associated with mechanical ventilator use within 24 h (adjusted hazard ratio = 0.78, 95% CI: 0.68–0.90, p < 0.001 and adjusted hazard ratio = 0.87, 95% CI 0.79–0.96, p = 0.004, respectively). The 28-day mortality was higher in the low ROX and low ROX-HR groups. The ROX and ROX-HR indices were associated with mechanical ventilator use within 24 h in qSOFA ≥ 2 patients in the ED.

Vascular risk factors and stroke risk across the life span: A population-representative study of half a million people

Background: The incidence of stroke in developed countries is increasing selectively in young individuals, but whether this is secondary to traditional vascular risk factors is unknown. Methods: We used the Canadian Community Health Survey from 2000 to 2016 to create a large population-representative cohort of individuals over the age of 30 and free from prior stroke. All analyses were stratified by age decile. We linked with administrative databases to determine emergency department visits or hospitalizations for acute stroke until December 2017. We calculated time trends in risk factor prevalence (hypertension, diabetes, obesity, and smoking) using meta-regression. We used Cox proportional hazard models to evaluate the association between vascular risk factors and stroke risk, adjusted for demographic, co-morbid, and social variables. We used competing risk regression to account for deaths and calculated population-attributable fractions. In a sensitivity analysis, we excluded those with prior heart disease or cancer. Results: We included 492,400 people in the analysis with 8865 stroke events over a median follow-up time of 8.3 years. Prevalence of hypertension, diabetes, and obesity increased over time while smoking decreased. Associations of diabetes, hypertension, and obesity with stroke risk were progressively stronger at younger age (adjusted hazard ratio for diabetes was 4.47, 95% confidence interval (CI) = 1.95–10.28 at age 30–39, vs 1.21, 95% CI = 0.93–1.57 at age 80+), although the obesity association was attenuated with adjustment. Smoking was associated with higher risk of stroke without a gradient across age deciles, although had the greatest population-attributable fraction at younger age. The hazard ratio for stroke with multiple concurrent risk factors was much higher at younger age (adjusted hazard ratio for 3–4 risk factors was 8.60, 95% CI = 2.97–24.9 at age 30–39 vs 1.61, 95% CI = 0.88–2.97 at age 80+) and results were consistent when accounting for the competing risk of death and excluding those with prior heart disease or cancer. Conclusions: Diabetes and hypertension were associated with progressively elevated relative risk of stroke in younger individuals and prevalence was increasing over time. The association of obesity with stroke was not significant after adjustment for other factors. Smoking had the greatest prevalence and population-attributable fraction for stroke at younger age. Our findings assist in understanding the relationship between vascular risk factors and stroke across the life span and planning public health measures to lower stroke incidence in the young.

Uveitis as a Risk Factor for Developing Acute Myocardial Infarction in Ankylosing Spondylitis: A National Population-Based Longitudinal Cohort Study

BackgroundAnkylosing spondylitis (AS) is a chronic inflammatory disease. Excess cardiovascular risks were well recognized in patients with AS and were attributed to prolonged systemic inflammation. Uveitis is one of the most common extra-articular symptoms of AS and is also considered an indicator of systemic inflammation. This study aimed to investigate whether uveitis was a risk factor for developing acute myocardial infarction (AMI) in patients with AS using the National Health Insurance Research Database (NHIRD).MethodsData were collected from the NHIRD over a fifteen-year period. Variables were analyzed using the Pearson chi-square test and Fisher’s exact test. Risk factors for the occurrence of AMI were examined by calculating hazard ratio. Kaplan-Meier analysis was performed to compare the cumulative incidence of AMI in the uveitis and non-uveitis cohorts.ResultsA total of 5905 patients with AS were enrolled, including 1181 patients with uveitis (20%) and 4724 patients without uveitis (80%). The Kaplan–Meier method with the log-rank test showed that the uveitis group had a significantly higher cumulative hazard for patients with AMI than the non-uveitis group (p &lt; 0.001). The adjusted hazard ratio (aHR) of AMI was higher in the uveitis group than in the non-uveitis group (aHR = 1.653, p &lt; 0.001). Stratified analysis revealed that patients with uveitis had an increased risk of developing AMI regardless of their sex (male/female aHR = 1.688/1.608, p &lt; 0.001). Patients with uveitis in all age groups were independently associated with an increased risk of developing AMI compared to those without uveitis (20–39 years/40–59 years/≥ 60 years, aHR = 1.550, 1.579, 3.240, p &lt; 0.001). Patients with uveitis had a higher probability of developing AMI regardless of comorbidities. Uveitis patients with comorbidities had a higher risk of developing AMI compared to uveitis patients without comorbidities.ConclusionUveitis is a significant risk factor for developing AMI in patients with AS. Physicians should be aware of the potential cardiovascular risk in AS patients with uveitis, especially simultaneously with other traditional risk factors of AMI. Further prospective studies are needed to elucidate the underlying mechanism between uveitis and AMI in patients with AS.

The Thromboembolic Predictability of CHA2DS2-VASc Scores Using Different Echocardiographic Criteria for Congestive Heart Failure in Korean Patients with Nonvalvular Atrial Fibrillation

The association between congestive heart failure (CHF) of the CHA2DS2-VASc scores and thromboembolic (TE) events in patients with atrial fibrillation (AF) is a topic of debate due to conflicting results. As the importance of diastolic impairment in the occurrence of TE events is increasingly recognized, it is crucial to evaluate the predictive power of CHA2DS2-VASc scores with C criterion integrating diastolic parameters. We analyzed 4200 Korean nonvalvular AF patients (71 years of age, 59% men) to compare multiple echocardiographic definitions of CHF. Various guideline-suggested echocardiographic parameters for systolic or diastolic impairment, including left ventricular ejection fraction (LVEF) ≤ 40%, the ratio of early diastolic mitral inflow velocity to early diastolic velocity of the mitral annulus (E/E’) ≥ 11, left atrial volume index > 34 mL/m2, and many others were tested for C criteria. Multivariate-adjusted Cox regression analysis showed that CHA2DS2-VASc score was an independent predictor for composite thromboembolic events only when CHF was defined as E/E’ ≥ 11 (hazard ratio, 1.26; p = 0.044) but not with other criteria including the original definition (hazard ratio, 1.10; p = 0.359). Our findings suggest that C criterion defined as diastolic impairment, such as E/E’ ≥ 11, may improve the predictive value of CHA2DS2-VASc scores.

Multiomic characterisation of high grade serous ovarian carcinoma enables high resolution patient stratification

Background: High grade serous ovarian carcinoma (HGSOC) is the most common type of ovarian cancer; most patients experience disease recurrence which accumulates chemoresistance, leading to treatment failure. Previous investigations have characterised HGSOC at the genomic and transcriptomic level, identifying subtypes of patients with differential outcome and treatment response. However, the relationship between molecular events identified at the gene sequence, gene copy number and gene expression levels remains poorly defined. Methods: We perform multi-layer molecular characterisation of a large retrospective HGSOC cohort (n=362) with detailed clinical annotation to interrogate the relationship between patient groups defined by gene mutation, copy number events, gene expression patterns and infiltrating immune cell burden. We construct a high resolution picture of the molecular landscape in HGSOC and identify features of tumours associated with distinct clinical behaviour in patients. Results: BRCA2-mutant (BRCA2m) and EMSY-overexpressing cases demonstrated prolonged survival (multivariable hazard ratio 0.40 and 0.53) and higher chemotherapy response rates at first- and second-line treatment. CCNE1-gained (CCNE1g) cases demonstrated shorter survival (multivariable hazard ratio 1.52, 95% CI 1.10-2.10), under-representation of FIGO stage IV cases (P=0.017) and no significant difference in treatment response. We demonstrate marked overlap between the TCGA- and derived subtypes: the TCGA DIF, IMR, PRO and MES subtypes correlated with the Tothill C4, C2, C5 and C1 subtypes (P<0.001). IMR/C2 cases displayed higher BRCA1/2m frequency (25.5% and 32.5%) and significantly greater infiltration of immune cells (P<0.001), while PRO/C5 cases had the highest CCNE1g rate (23.9% and 22.2%) and were uniformly low in immune cell infiltration. The survival benefit for cases with aberrations in homologous recombination repair (HRR) genes was apparent across all transcriptomic subtypes (hazard ratio range 0.48-0.68). There was significant co-occurrence of RB loss and HRR gene aberrations (P=0.005); RB loss was further associated with favourable survival within cases harbouring HRR aberrations (multivariable hazard ratio 0.50, 95% CI 0.30-0.84). Conclusions: These data paint a high resolution picture of the molecular landscape in HGSOC, better defining patients who may benefit most from specific molecular therapeutics and highlighting those for whom novel treatment strategies are needed to improve outcomes.

Efficacy and safety of recombinant human endostatin during peri-radiotherapy period in advanced non-small-cell lung cancer

Background: This study aimed to retrospectively investigate the efficacy and safety of recombinant human endostatin (Rh-endostatin) combined with radiotherapy in advanced non-small-cell lung cancer (NSCLC). Methods: Patients with unresectable stage III and IV NSCLC who treated with radiotherapy were enrolled. Patients who received Rh-endostatin infusion throughout the whole peri-radiotherapy period formed the Endostar group, and those who received no Rh-endostatin infusion were the control group. Results: The median progression-free survival was 8.0 and 4.4 months (hazard ratio: 0.53; 95% CI: 0.32–0.90; p = 0.019) and median overall survival was 40.0 and 13.1 months (hazard ratio: 0.53; 95% CI: 0.28–0.98; p = 0.045) for the Endostar and control groups, respectively. The Endostar group exhibited a numerically lower rate of radiation pneumonitis relapse, radiation pneumonitis death and pulmonary fibrosis. Conclusion: Rh-endostatin infusion throughout the peri-radiotherapy period enhanced radiosensitivity and showed better survival outcomes and a tendency toward fewer radiation-related pulmonary events in patients with NSCLC.

Prescription medication use after congenital heart surgery

Background: Improvements in mortality after congenital heart surgery have necessitated a shift in focus to postoperative morbidity as an outcome measure. We examined late morbidity after congenital heart surgery based on prescription medication use. Methods: Between 1953 and 2009, 10,635 patients underwent congenital heart surgery at <15 years of age in Finland. We obtained 4 age-, sex-, birth-time, and hospital district-matched controls per patient. The Social Insurance Institution of Finland provided data on all prescription medications obtained between 1999 and 2012 by patients and controls. Patients were assigned one diagnosis based on a hierarchical list of cardiac defects and dichotomised into simple and severe groups. Medications were divided into short- and long-term based on indication. Follow-up started at the first operation and ended at death, emigration, or 31 December, 2012. Results: Totally, 8623 patients met inclusion criteria. Follow-up was 99.9%. In total, 8126 (94%) patients required prescription medications. Systemic anti-bacterials were the most common short-term prescriptions among patients (93%) and controls (88%). Patients required betablockers (simple hazard ratio 1.9, 95% confidence interval 1.7–2.1; severe hazard ratio 6.5, 95% confidence interval 5.3–8.1) and diuretics (simple hazard ratio 3.2, 95% CI 2.8–3.7; severe hazard ratio 38.8, 95% CI 27.5–54.7) more often than the general population. Both simple and severe defects required medication for cardiovascular, gastrointestinal, psychiatric, neurologic, metabolic, autoimmune, and infectious diseases more often than the general population. Conclusions: The significant risk for postoperative cardiovascular and non-cardiovascular disease warrants close long-term follow-up after congenital heart surgery for all defects.

An electrocardiography score predicts heart failure hospitalization or death beyond that of cardiovascular magnetic resonance imaging

Background: The electrocardiogram (ECG) and cardiovascular magnetic resonance imaging (CMR) both provide powerful prognostic information. The aim was to determine the relative prognostic value of ECG and CMR, respectively. Methods: Consecutive patients (n=783) undergoing CMR and resting 12-lead ECG with a QRS duration <120 ms were included. CMR measures included feature tracking global longitudinal strain (GLS), extracellular volume fraction (ECV), left ventricular mass and volumes, and ischemic and non-ischemic scar size. Prognosis scores for one-year event-free survival were derived using continuous ECG or CMR measures, and multinomial logistic regression, and compared with regards to the combined outcome of survival free from hospitalization for heart failure or death. Results: Patients (median [interquartile range] age 55 [43-64] years, 44% female) had 155 events during 5.7 [4.4-6.6] years. The ECG prognosis score included 1) the frontal plane QRS-T angle, and 2) the heart rate corrected QT duration (QTc) (log-rank 55, p<0.001). The CMR prognosis score included 1) GLS, and 2) ECV (log-rank 85, p<0.001). The combination of positive scores for both ECG and CMR yielded the highest prognostic value (log-rank 105, p<0.001). Multivariable analysis showed an association with outcomes for both the ECG prognosis score (log-rank 8.4, hazard ratio [95% confidence interval] 1.29 [1.09-1.54], p=0.004) and the CMR prognosis score (log-rank 47, hazard ratio 1.90 [1.58-2.28], p<0.001). Conclusions: An ECG prognosis score predicted outcomes independently of, and beyond CMR. Combining the results of ECG and CMR using both prognosis scores improved the overall prognostic performance.