Pulmonary vasodilation in acute pulmonary embolism - a systematic review

Acute pulmonary embolism is the third most common cause of cardiovascular death. Pulmonary embolism increases right ventricular afterload, which causes right ventricular failure, circulatory collapse and death. Most treatments focus on removal of the mechanical obstruction caused by the embolism, but pulmonary vasoconstriction is a significant contributor to the increased right ventricular afterload and is often left untreated. Pulmonary thromboembolism causes mechanical obstruction of the pulmonary vasculature coupled with a complex interaction between humoral factors from the activated platelets, endothelial effects, reflexes and hypoxia to cause pulmonary vasoconstriction that worsens right ventricular afterload. Vasoconstrictors include serotonin, thromboxane, prostaglandins and endothelins, counterbalanced by vasodilators such as nitric oxide and prostacyclins. Exogenous administration of pulmonary vasodilators in acute pulmonary embolism seems attractive but all come with a risk of systemic vasodilation or worsening of pulmonary ventilation-perfusion mismatch. In animal models of acute pulmonary embolism, modulators of the nitric oxide-cyclic guanosine monophosphate-protein kinase G pathway, endothelin pathway and prostaglandin pathway have been investigated. But only a small number of clinical case reports and prospective clinical trials exist. The aim of this review is to give an overview of the causes of pulmonary embolism-induced pulmonary vasoconstriction and of experimental and human investigations of pulmonary vasodilation in acute pulmonary embolism

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

Searching for stochastic gravitational waves using data from the two colocated LIGO Hanford detectors

Searches for a stochastic gravitational-wave background (SGWB) using terrestrial detectors typically involve cross-correlating data from pairs of detectors. The sensitivity of such cross-correlation analyses depends, among other things, on the separation between the two detectors: the smaller the separation, the better the sensitivity. Hence, a colocated detector pair is more sensitive to a gravitational-wave background than a noncolocated detector pair. However, colocated detectors are also expected to suffer from correlated noise from instrumental and environmental effects that could contaminate the measurement of the background. Hence, methods to identify and mitigate the effects of correlated noise are necessary to achieve the potential increase in sensitivity of colocated detectors. Here we report on the first SGWB analysis using the two LIGO Hanford detectors and address the complications arising from correlated environmental noise. We apply correlated noise identification and mitigation techniques to data taken by the two LIGO Hanford detectors, H1 and H2, during LIGO’s fifth science run. At low frequencies, 40–460 Hz, we are unable to sufficiently mitigate the correlated noise to a level where we may confidently measure or bound the stochastic gravitational-wave signal. However, at high frequencies, 460–1000 Hz, these techniques are sufficient to set a 95% confidence level upper limit on the gravitational-wave energy density of Ω(f) < 7.7 × 10[superscript -4](f/900  Hz)[superscript 3], which improves on the previous upper limit by a factor of ~180. In doing so, we demonstrate techniques that will be useful for future searches using advanced detectors, where correlated noise (e.g., from global magnetic fields) may affect even widely separated detectors.National Science Foundation (U.S.)United States. National Aeronautics and Space AdministrationCarnegie TrustDavid & Lucile Packard FoundationAlfred P. Sloan Foundatio

Effects of Anacetrapib in Patients with Atherosclerotic Vascular Disease

BACKGROUND: Patients with atherosclerotic vascular disease remain at high risk for cardiovascular events despite effective statin-based treatment of low-density lipoprotein (LDL) cholesterol levels. The inhibition of cholesteryl ester transfer protein (CETP) by anacetrapib reduces LDL cholesterol levels and increases high-density lipoprotein (HDL) cholesterol levels. However, trials of other CETP inhibitors have shown neutral or adverse effects on cardiovascular outcomes. METHODS: We conducted a randomized, double-blind, placebo-controlled trial involving 30,449 adults with atherosclerotic vascular disease who were receiving intensive atorvastatin therapy and who had a mean LDL cholesterol level of 61 mg per deciliter (1.58 mmol per liter), a mean non-HDL cholesterol level of 92 mg per deciliter (2.38 mmol per liter), and a mean HDL cholesterol level of 40 mg per deciliter (1.03 mmol per liter). The patients were assigned to receive either 100 mg of anacetrapib once daily (15,225 patients) or matching placebo (15,224 patients). The primary outcome was the first major coronary event, a composite of coronary death, myocardial infarction, or coronary revascularization. RESULTS: During the median follow-up period of 4.1 years, the primary outcome occurred in significantly fewer patients in the anacetrapib group than in the placebo group (1640 of 15,225 patients [10.8%] vs. 1803 of 15,224 patients [11.8%]; rate ratio, 0.91; 95% confidence interval, 0.85 to 0.97; P=0.004). The relative difference in risk was similar across multiple prespecified subgroups. At the trial midpoint, the mean level of HDL cholesterol was higher by 43 mg per deciliter (1.12 mmol per liter) in the anacetrapib group than in the placebo group (a relative difference of 104%), and the mean level of non-HDL cholesterol was lower by 17 mg per deciliter (0.44 mmol per liter), a relative difference of -18%. There were no significant between-group differences in the risk of death, cancer, or other serious adverse events. CONCLUSIONS: Among patients with atherosclerotic vascular disease who were receiving intensive statin therapy, the use of anacetrapib resulted in a lower incidence of major coronary events than the use of placebo. (Funded by Merck and others; Current Controlled Trials number, ISRCTN48678192 ; ClinicalTrials.gov number, NCT01252953 ; and EudraCT number, 2010-023467-18 .)

Derivation and Validation of a 4-Level Clinical Pretest Probability Score for Suspected Pulmonary Embolism to Safely Decrease Imaging Testing

Importance: In patients with suspected pulmonary embolism (PE), overuse of diagnostic imaging is an important point of concern. Objective: To derive and validate a 4-level pretest probability rule (4-Level Pulmonary Embolism Clinical Probability Score [4PEPS]) that makes it possible to rule out PE solely on clinical criteria and optimized D-dimer measurement to safely decrease imaging testing for suspected PE. Design, setting, and participants: This study included consecutive outpatients suspected of having PE from US and European emergency departments. Individual data from 3 merged management studies (n = 11 114; overall prevalence of PE, 11%) were used for the derivation cohort and internal validation cohort. The external validation cohorts were taken from 2 independent studies, the first with a high PE prevalence (n = 1548; prevalence, 21.5%) and the second with a moderate PE prevalence (n = 1669; prevalence, 11.7%). A prior definition of pretest probability target values to achieve a posttest probability less than 2% was used on the basis of the negative likelihood ratios of D-dimer. Data were collected from January 2003 to April 2016, and data were analyzed from June 2018 to August 2019. Main outcomes and measures: The rate of PE diagnosed during the initial workup or during follow-up and the rate of imaging testing. Results: Of the 5588 patients in the derivation cohort, 3441 (61.8%) were female, and the mean (SD) age was 52 (18.5) years. The 4PEPS comprises 13 clinical variables scored from-2 to 5. It results in the following strategy: (1) very low probability of PE if 4PEPS is less than 0: PE ruled out without testing; (2) low probability of PE if 4PEPS is 0 to 5: PE ruled out if D-dimer level is less than 1.0 μg/mL; (3) moderate probability of PE if 4PEPS is 6 to 12: PE ruled out if D-dimer level is less than the age-adjusted cutoff value; (4) high probability of PE if 4PEPS is greater than 12: PE ruled out by imaging without preceding D-dimer test. In the first and the second external validation cohorts, the area under the receiver operator characteristic curves were 0.79 (95% CI, 0.76 to 0.82) and 0.78 (95% CI, 0.74 to 0.81), respectively. The false-negative testing rates if the 4PEPS strategy had been applied were 0.71% (95% CI, 0.37 to 1.23) and 0.89% (95% CI, 0.53 to 1.49), respectively. The absolute reductions in imaging testing were-22% (95% CI,-26 to-19) and-19% (95% CI,-22 to-16) in the first and second external validation cohorts, respectively. The 4PEPS strategy compared favorably with all recent strategies in terms of imaging testing. Conclusions and relevance: The 4PEPS strategy may lead to a substantial and safe reduction in imaging testing for patients with suspected PE. It should now be tested in a formal outcome study.</p

Safety and efficacy of the novel BRAF inhibitor FORE8394 in patients with advanced solid and CNS tumors: Results from a phase 1/2a study

3006 Background: FORE8394 is an investigational inhibitor (i) of class 1 (V600) and 2 (activating non-V600) BRAF-altered tumors. FORE8394 did not have paradoxical activation of the MAPK pathway in nonclinical studies. Methods: In a phase 1/2a study, patients (pts) aged ≥3 years with BRAF-altered, advanced solid or CNS tumors received FORE8394 (900-3600 mg/day or mg/m 2 dosing) with or without a pharmacokinetic booster (cobicistat 150 mg/day). CNS metastases and prior treatment with other BRAFi were allowed. Besides standard safety assessments, skin and eye exams were required. Objective response was assessed by RECIST v1.1 or RANO criteria. Efficacy was evaluated in pts with class 1/2 BRAF alterations and ≥1 post-baseline assessment, with mg/m 2 dosing (n=4) reported separately. Results: On 21Nov2022, 110 pts had received ≥1 dose of FORE8394. 85% completed ≥1 4-week cycle. 10 (9%) and 3 (3%) received FORE8394 ≥2 and ≥6 years, respectively; 14 (13%) are ongoing. Pts included 61 (55%) class 1 mutations, 19 (17%) class 2 mutations (excluding fusions), and 17 (15%) BRAF fusions. 64 pts (58%) had ≥2 prior lines of systemic therapy; 28 (25%) received prior MAPKi. Increased ALT (39%), increased AST (35%), fatigue (34%), nausea (27%), diarrhea (22%), and vomiting (20%) were the most frequently reported treatment-emergent adverse events (TEAEs); most were grade (G) 1/2. G3+ TEAEs were reported in 49% (54/110), the most common being increased ALT (9%), increased blood bilirubin (6%), and hyponatremia (5%). Transient G1 pyrexia was observed in 8 (7%) pts. All rashes were G1; none required a dose change. No TEAE of hyperkeratosis, papilloma, uveitis, retinal detachment, or LVEF reduction were reported. 1 pt discontinued due to FORE8394-related TEAE. Antitumor activity was observed in pts with MAPKi-naïve, V600 mutant tumors (excluding colorectal cancer [CRC]), 39% (9/23) having a PR (median duration of response [DoR]: 32 months). In 17 pts with V600 mutated tumors (excluding CRC) treated with prior MAPKi, 3 (18%) had PR and 5 (29%) had SD. In V600 mutated tumors, PRs occurred in 6 (55%) gliomas, 3 (100%) ovarian cancers, and 1 each in CRC (7%), small bowel (50%), papillary thyroid (13%) and anaplastic thyroid (25%) cancers. Of pts with BRAF-fusions, a pt with AGK-BRAF-fused melanoma had CR (DoR 51.8+ months); 46% (6/13) had SD. Of note, 1 child with V600E mutated Langerhans cell histiocytosis had SD with improvement in neurodegenerative changes and a progression-free survival of 55.8+ months. Conclusions: As single agent anticancer therapy, FORE8394 had antitumor activity in various tumors with BRAF alterations, including pts previously treated with MAPKi and pts with BRAF fusions. Durable tolerability was observed, and TEAEs indicative of paradoxical MAPK activation were not observed, consistent with the novel mechanism of action of FORE8394. These results support further evaluation of FORE8394. Clinical trial information: NCT02428712