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Background: Mortality risk assessment informs clinical management of pulmonary arterial hypertension (PAH). The Registry to Evaluate Early and Long-Term PAH Disease Management (REVEAL) Lite 2 is a simplified risk calculator discriminating 1-year mortality risk., Methods: This post-hoc analysis of the phase 3 GRIPHON study assessed changes in REVEAL Lite 2 risk score with selexipag versus placebo and whether changes were prognostic or predictive of time to first morbidity/mortality (M/M) event., Results: REVEAL Lite 2 risk category discriminated M/M risk (landmark concordance indices: 0.68-0.76, selexipag; 0.65-0.70, placebo). Across baseline risk categories, hazard ratios supported a lower risk of M/M events with selexipag versus placebo: low, 0.573 (95% confidence interval [CI] 0.361-0.908; p = 0.0178); intermediate, 0.423 (95% CI 0.274-0.655; p = 0.0001); and high, 0.711 (9% CI 0.520-0.972; p = 0.0326). Odds ratios for risk improvement were 2.0 (95% CI 1.50-2.65), 1.8 (95% CI 1.38-2.43), and 2.0 (95% CI 1.43-2.72) for selexipag versus placebo at 16, 26, and 52 weeks, respectively (all p < 0.001). REVEAL Lite 2 risk improvement at week 16 explained 19.1% of the treatment effect in all patients and 47.0% in patients with REVEAL Lite 2 baseline risk score of ≥7., Conclusions: REVEAL Lite 2 can monitor PAH M/M risk and facilitate treatment optimization. Baseline REVEAL Lite 2 risk score was prognostic of M/M risk in patients with PAH and mediates treatment effect up to 47% for those at higher risk. Lower M/M risk with selexipag versus placebo occurred irrespective of baseline risk category (ClinicalTrials.gov identifier: NCT01106014)., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Morbidity and mortality in pulmonary arterial hypertension (PAH) remain high. Activation of platelet-derived growth factor receptor, colony stimulating factor 1 receptor, and mast or stem cell growth factor receptor kinases stimulates inflammatory, proliferative, and fibrotic pathways driving pulmonary vascular remodelling in PAH. Seralutinib, an inhaled kinase inhibitor, targets these pathways. We aimed to evaluate the efficacy and safety of seralutinib in patients with PAH receiving standard background therapy., Methods: The TORREY trial was a phase 2, randomised, multicentre, multinational, double-blind, placebo-controlled study. Patients with PAH from 40 hospital and community sites were randomly assigned 1:1 via interactive response technologies to receive seralutinib (60 mg twice daily for 2 weeks, then increased to 90 mg twice daily as tolerated) or placebo by dry powder inhaler twice daily for 24 weeks. Randomisation was stratified by baseline pulmonary vascular resistance (PVR; <800 dyne·s/cm 5 and ≥800 dyne·s/cm 5 ). Patients were eligible if classified as WHO Group 1 PH (PAH), WHO Functional Class II or III, with a PVR of 400 dyne·s/cm 5 or more, and a 6 min walk distance of between 150 m and 550 m. The primary endpoint was change in PVR from baseline to 24 weeks. Analyses for efficacy endpoints were conducted in randomly assigned patients (intention-to-treat population). Safety analyses included all patients who received the study drug. TORREY was registered with ClinicalTrials.gov (NCT04456998) and EudraCT (2019-002669-37) and is completed., Findings: From Nov 12, 2020, to April 20, 2022, 151 patients were screened for eligibility, and following exclusions, 86 adults receiving PAH background therapy were randomly assigned to seralutinib (n=44; four male, 40 female) or placebo (n=42; four male, 38 female), and comprised the intention-to-treat population. At baseline, treatment groups were balanced except for a higher representation of WHO Functional Class II patients in the seralutinib group. The least squares mean change from baseline to week 24 in PVR was 21·2 dyne·s/cm 5 (95% CI -37·4 to 79·8) for the placebo group and -74·9 dyne·s/cm 5 (-139·7 to -10·2) for the seralutinib group. The least squares mean difference between the seralutinib and placebo groups for change in PVR was -96·1 dyne·s/cm 5 (95% CI -183·5 to -8·8; p=0·03). The most common treatment-emergent adverse event in both treatment groups was cough: 16 (38%) of 42 patients in the placebo group; 19 (43%) of 44 patients in the seralutinib group., Interpretation: Treatment with inhaled seralutinib significantly decreased PVR, meeting the primary endpoint of the study among patients receiving background therapy for PAH., Funding: Gossamer Bio., Competing Interests: Declaration of interests ARH reports having received consulting fees from United Therapeutics, Tenax Therapeutics, Merck, and Janssen; having served as an advisory committee member for Gossamer Bio; and having held stock from Tenax Therapeutics. CT, DM, EE, EP, J-MB, LSZ, MC, RA, RFR, and RO report stocks or stock options from Gossamer Bio; and employment at Gossamer Bio. LSZ also reported patents related to seralutinib (assigned to Gossamer Bio or Pulmokine); stocks or stock options from Pulmokine. RFR also reported previous consulting fees from Gossamer Bio. H-AG reports having received consulting fees from Gossamer Bio, Aerovate, Altavant, Bayer AG, Attgeno, Janssen and Actelion, MSD and Acceleron, and Pfizer; payment or honoraria for lectures, presentations, speaker bureaus, or educational events from Bayer AG, Janssen and Actelion, and MSD and Acceleron; participated as an advisory committee member for Aerovate, Altavant, Bayer AG, Attgeno, Janssen and Actelion, MSD and Acceleron, and Pfizer; and as a member of a data and safety monitoring board for Insmed. J-LV reports having received consulting fees from Gossamer Bio, ShouTi, Janssen, Enzyvant, Bayer HealthCare, Merck, Liquidia, Aerami, and Insmed; received payment or honoraria (payment to their institution) for lectures, presentations, or educational events from Janssen, Merck, Novartis, and Boehringer Ingelheim; received payment for expert testimony from Actelion Pharmaceuticals; received either support for attending meetings or travel (payment to their institution) from Merck; participated on a data safety monitoring board (payment to their institution) from Janssen, GSK, and Moderna; membership on steering committees for Gossamer Bio, Insmed, Merck, and United Therapeutics. KMC reports having received grants or contracts (payment made to their institution) for clinical studies overseen by her from Gossamer Bio, Janssen, United Therapeutics, Merck, Acceleron, and Altavant; received consulting fees from Acceleron; received fees for participating on an advisory board for Merck; received fees for work as an advisory committee member for Gossamer Bio; received fees for work as a steering committee member for Janssen; received fees for work on an adjudication committee for Arena and United Therapeutics; and received fees for an editorial role with the American Heart Association. LSH reported having received payment or honoraria for speaker bureau membership from Janssen; participated as an advisory board member for Janssen, MSD, Altavant, and United Therapeutics, and as an advisory committee member for Gossamer Bio; and having stock or stock options at ATXA Therapeutics, iOWNA, and Circular. OS reports having received grants or contracts for research (payment made to their institution) from Janssen, MSD, and AOP Orphan; payment or honoraria for lectures or an educational event from AOP Orphan, Ferrer, Janssen, and MSD; support for attending meetings or travel from MSD and Janssen; and participated on an advisory committee for Gossamer Bio, AOP Orphan, Enzyvant, Ferrer, Janssen, and MSD. PES reports having received payment or honoraria for lectures, presentations, speaker bureaus, manuscript writing, or educational events from Janssen, MSD, Ferrer, and AOT; support for either attending meetings or travel from Janssen and MSD; participated in a data safety monitoring board or advisory board for Janssen, MSD, Ferrer, Gossamer Bio, and AOT; and receipt of equipment, materials, drugs, medical writing, gifts, or other services from Gossamer Bio. RLB reports having received consulting fees from Merck, United Therapeutics, KEROS, Aerovate, Insmed, and Cereno; served as an advisory committee member for Gossamer Bio; served as an advisory board member for Altavant, Merck, Janssen, and Insmed; served on a data safety monitoring board for Janssen; and served on a scientific advisory board for Cereno. RLZ reports having received consulting fees from Johnson & Johnson, United Therapeutics, Bayer, and Alnylam. RNC reports having received consulting fees from Gossamer Bio, Janssen, Bayer, United Therapeutics, and Third Pole; payment or honoraria for lectures from Janssen and Bayer; and participated on an advisory committee for Gossamer Bio, Janssen, and Bayer. RPF reports having royalties or licenses from UpToDate; receiving consulting fees from Janssen and Liquidia; participated on a data safety monitoring board or advisory board from Gossamer Bio (as an advisory committee member); participated on an advisory board for Janssen, Liquidia, Tenax Therapeutics, ShouTi, Insmed, and Merck; and participated on a data safety monitoring board for Aerovate. RTZ reports having received grants or contracts for industry-supported research from United Therapeutics, Janssen, Tenax Therapeutics, and Gossamer Bio; consulting fees from Janssen, Vivus, Morphogen-IX, Merck, and Gossamer Bio; and stock or stock options from Selten. SS reports having received a research grant from United Therapeutics; speaker honoraria (received by his institute) from Janssen and United Therapeutics; served as an advisor to Janssen, Bayer, United Therapeutics, Gossamer Bio, Altavant Sciences, and Merck; served as a steering committee member for Bayer, Keros, and Liquidia Technologies; and served as a data safety monitoring board committee member for the National Institutes of Health K23 grant. VVM reports having received grant support from Aerovate, Enzyvant, Gossamer Bio, Janssen, Merck, and Sonovie; consulting fees from Aerami, Aerovate, Caremark, Corvista, Enzyvant, Gossamer Bio, Janssen, Merck, United Therapeutics, and Vertex; and participated as an advisory committee member for Gossamer Bio. All authors report receiving medical writing and editorial support for the present manuscript funded by Gossamer Bio., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Background: Selexipag is an oral prostacyclin receptor agonist, indicated for pulmonary arterial hypertension to delay disease progression and reduce the risk of pulmonary arterial hypertension-related hospitalization. SelexiPag: tHe usErs dRug rEgistry (NCT03278002) was a US-based, prospective, real-world registry of selexipag-treated patients., Methods: Adults with pulmonary hypertension (enrolled 2016-2020) prescribed selexipag were followed for ≤18 months, with data collected at routine clinic visits. Patients were defined as newly or previously initiated if they had started selexipag ≤60 days or >60 days, respectively, before enrollment., Results: The registry included 829 patients (430 newly initiated, 399 previously initiated; 759 with pulmonary arterial hypertension), of whom 55.6% were World Health Organization functional class (FC) 3/4; 57.3% were intermediate or high risk per Registry to Evaluate Early and Long-Term PAH Disease Management (REVEAL) 2.0. In patients with pulmonary arterial hypertension, 18-month discontinuation rates for adverse events were 22.0%, 32.0%, and 11.9%, and 18-month survival rates were 89.4%, 84.2%, and 94.5% in the overall, newly, and previously initiated patient populations, respectively. From baseline to month 18, most patients had stable or improved FC and stable or improved REVEAL 2.0 risk category status. Discontinuation for adverse events, hospitalization, and survival were similar regardless of patients' individually tolerated selexipag maintenance dose. No new safety signals were identified., Conclusions: In this real-world analysis of patients initiating selexipag, most patients had stable or improved FC and REVEAL 2.0 risk category. Similar to the GRIPHON trial, outcomes with selexipag in this real-world study were comparable across maintenance dose strata, with no new safety signals., (Copyright © 2024 International Society for the Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

Background: Echocardiographic parameters are used as prognostic markers in patients with pulmonary arterial hypertension (PAH) receiving parenteral (IV or subcutaneous [IV/SC]) prostacyclin therapy. However, data on how posttreatment echocardiographic results associate with outcomes are limited., Research Question: Are echocardiographic parameters pre- and post-parenteral prostacyclin therapy in patients with PAH associated with long-term outcomes?, Study Design and Methods: In this retrospective cohort study, patients with PAH initiated on IV epoprostenol or IV/SC treprostinil therapy between 2007 and 2016 were included and followed up through May 31, 2020. Survival free from transplant was assessed from the time of IV/SC prostacyclin therapy initiation and from first follow-up echocardiogram following at least 90 days of therapy., Results: Patients with PAH initiated on IV/SC prostacyclin therapy (N = 118) were followed up for a median of 7.3 years. Survival was 86%, 79%, and 69% at 1, 2, and 3 years, respectively. Follow-up echocardiogram in 101 patients (median, 178 days; interquartile range, 140-273 days) showed improvement in five echocardiographic measures: right ventricular function, right ventricular systolic pressure, right ventricular diastolic diameter, left ventricular diastolic diameter, and tricuspid regurgitation (TR) severity. TR severity and pericardial effusion were associated with survival from IV/SC therapy initiation, whereas right ventricular diastolic diameter, right atrial (RA) size, TR severity, and inferior vena cava characteristics were associated with survival from first follow-up. In a multivariable analysis incorporating other prognostic measures at first follow-up, walk distance, functional class, N-terminal pro-B-type natriuretic peptide, and RA size resulted in the best fit model for survival., Interpretation: Echocardiographic variables improved following IV/SC therapy, and multiple echocardiographic measures associated significantly with survival, particularly when reassessed after at least 90 days of therapy. RA size in particular may be useful in prognostication in follow-up of patients with PAH on IV/SC therapy., (Copyright © 2022 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Background: This systematic review and meta-analysis aimed to compare the outcomes of curative therapy (resection, transplantation, ablation) for hepatocellular carcinoma (HCC) arising from non-alcoholic fatty liver disease (NAFLD) and non-NAFLD etiologies., Methods: A systematic search of PubMed, EMBASE and Cochrane Library was conducted for studies comparing survival, peri- and post-operative outcomes. Quality assessment was performed using the Newcastle-Ottawa scale., Results: Findings for 5579 patients were pooled across 9 studies and examined. Analysis demonstrated improved disease-free survival (DFS; HR 0.85, 95% CI 0.74-0.98, p = 0.03) and overall survival (OS; HR 0.87; 95% CI 0.81-0.93; p < 0.0001) in NAFLD-HCC patients undergoing liver resection as compared to non-NAFLD HCC patients. NAFLD-HCC patients undergoing all forms of curative therapy were similarly associated with improved OS (HR 0.96; 95% CI 0.86-1.06; p = 0.40) and DFS (HR 0.85; 95% CI 0.74-0.98; p = 0.03), albeit results being significant only for DFS. Only 2 studies reported higher rates of peri- and post-operative complications in patients with NAFLD-HCC. Significant inter-study heterogeneity precluded further analysis., Conclusion: NAFLD-HCC patients can enjoy long-term survival benefit with aggressive curative therapy. Peri- and post-operative morbidity should be mitigated with pre-operative optimization of comorbidities, and deliberately close post-operative monitoring., Competing Interests: Declarations of interest None to declare., (Copyright © 2021. Published by Elsevier Ltd.)

Background: Early initiation of pulmonary arterial hypertension (PAH) therapies is associated with improved long-term outcomes, yet data on the early use of prostacyclin pathway agents are limited. In these post hoc analyses of the Prostacyclin (PGI 2 ) Receptor Agonist In Pulmonary Arterial Hypertension (GRIPHON) study, the largest randomized controlled trial for PAH to date, the prognostic value of time from diagnosis and its impact on treatment response were examined., Research Question: How does time from diagnosis impact morbidity/mortality events and response to selexipag treatment in patients with PAH?, Study Design and Methods: The GRIPHON study randomly assigned 1,156 patients with PAH to selexipag or placebo treatment. Patients were categorized post hoc into a time from diagnosis of ≤ 6 months and > 6 months at randomization. Hazard ratios (selexipag vs placebo) were calculated for the primary end point of morbidity/mortality by time from diagnosis using Cox proportional hazard models., Results: Time from diagnosis was ≤ 6 months in 34.9% and > 6 months in 65.1% of patients. Time from diagnosis was prognostic of morbidity/mortality, with newly diagnosed patients having a poorer long-term outcome than patients diagnosed for longer. Compared with placebo, selexipag reduced the risk of morbidity/mortality in patients with a time from diagnosis of ≤ 6 months and > 6 months, with a more pronounced effect in newly diagnosed patients (hazard ratio, 0.45 [95% CI, 0.33-0.63] and 0.74 [95% CI, 0.57-0.96], respectively; P = .0219 for interaction)., Interpretation: In the GRIPHON study, newly diagnosed PAH patients had a worse prognosis than patients with a longer time from diagnosis. The benefit of selexipag treatment on disease progression was more pronounced in patients treated earlier than in patients treated later., Trial Registry: ClinicalTrials.gov; No.: NCT01106014; URL: www.clinicaltrials.gov., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

This systematic review and meta-analysis aimed to confirm the prognostic value of lymph node ratio (LNR), and determine an optimal LNR cut-off for overall survival (OS) in patients with distal cholangiocarcinoma (DCC) undergoing curative surgery. We additionally aimed to provide a consolidated review of current evidence regarding prognostic significance of positive lymph node count (PLNC) and total lymph node count (TLNC). A systematic search of PubMed, EMBASE and Cochrane Library was conducted from inception to October 2020. Studies were included into meta-analysis if there was histological diagnosis, curative surgery, restriction to DCC and relevant LNR results. Quality assessment was performed using the Newcastle Ottawa Scale. Findings for 1228 patients were pooled across 6 studies. Meta-analysis delineated a dose-effect gradient in which higher LNR cut-offs correlated with larger pooled hazard ratios: 00.2 (HR 3.26; 95% CI 2.07-5.13; p < 0.00001) and LNR>0.4 (HR 3.59; 95% CI 2.31-5.58; p < 0.00001) when compared against a control group of LNR = 0. LNR of 0.2 (HR 2.12; 95% CI: 1.57-2.86; p < 0.0001) was found to be a significant and ideal cut-off for prognostication of poorer OS. A review of current literature reveals an ongoing debate regarding the comparative prognostic value of differing PLNC cut-offs (0/1/3 versus 0/1/4). TLNC of 10-13 is widely reported to be the minimum necessary to ensure improved long term outcomes. PLNC and LNR are strong prognostic factors for OS in DCC. An ideal LNR cut-off of 0.2 is most significantly associated with poorer OS., Competing Interests: Declaration of competing interest Authors have no financial or personal relationships with other people or organizations that could inappropriately influence or bias their work. There are no conflicts of interest with regards to employment, consultancies, stock ownership, honoraria, paid expert testimony, patent applications or registrations, grants or other forms of funding. There is no ethical problem with this manuscript. There are no sources of outside financial support for the conduct of research and/or the preparation of the article. This includes any funding, equipment and drugs. There is no financial support whatsoever from any industry to acknowledge. There is no involvement of human or animal test subjects in this publication. Subject to acceptance, authors will transfer copyright to the publisher., (Copyright © 2021. Published by Elsevier Ltd.)

Background: Selexipag is a selective oral prostacyclin receptor agonist indicated for pulmonary arterial hypertension (PAH) treatment. SelexiPag: tHe usErs dRug rEgistry (SPHERE) (NCT03278002) is collecting data from selexipag-treated patients in real-world clinical practice to elucidate and describe the clinical characteristics, outcomes, and dosing/titration regimens of patients treated with selexipag in routine clinical practice., Methods: SPHERE is a United States (US)-based, ongoing, multicenter, prospective observational study (target N = 800). This study enrolls patients who are either newly initiated on selexipag (≤60 days before enrollment) or were previously receiving selexipag with documentation of dose titration at study enrollment. Data collection for the study occurs at routine clinic visits. In this paper, we report on the first 500 patients enrolled., Results: Median follow-up was 17.8 months; 77.6% of patients completed the planned 18 months follow-up, and 22.4% discontinued early from the study. At diagnosis, 94.8% of patients had PAH (World Health Organization [WHO] Group 1), most commonly idiopathic (49.2%) and connective tissue disease associated (26.4%). Most patients (72.4%) initiated selexipag more than 60 days before enrollment. At initiation, 31.0% of patients had WHO functional class (FC) II disease, and 49.6% had WHO FC II or III disease. In addition, 55.0% of patients were receiving double therapy (most commonly an endothelin receptor antagonist plus phosphodiesterase type 5 inhibitor [42.3%]), whereas 30.6% were receiving monotherapy. Despite most patients already receiving PAH-specific therapy, at selexipag initiation, 67.2% (336 of 500) were at intermediate risk, and 9.6% (48 of 500) were at high risk of 1-year mortality. Risk scores remained stable in ∼55% of patients and improved in ∼20% at the end of the study. In total, 72.2% of patients had at least 1 adverse event (AE), and 37.6% reported a serious AE. The median selexipag maintenance dose was 1,200 µg twice daily (interquartile range: 800-1,600 µg twice daily)., Conclusions: Real-world, US-based patients with PAH initiating selexipag typically have WHO FC II/III disease and are at intermediate risk, despite receiving PAH-specific treatment. Selexipag was prescribed as part of a combination regimen in most patients. The study identified no unexpected adverse effects., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Approaches to risk assessment in pulmonary arterial hypertension (PAH) include the noninvasive French risk assessment approach (number of low-risk criteria based on the European Society of Cardiology and European Respiratory Society guidelines) and Registry to Evaluate Early and Long-term PAH Disease Management (REVEAL) 2.0 risk calculator. The prognostic and predictive value of these methods for morbidity/mortality was evaluated in the predominantly prevalent population of GRIPHON, the largest randomized controlled trial in PAH., Methods: GRIPHON randomized 1,156 patients with PAH to selexipag or placebo. Post-hoc analyses were performed on the primary composite end-point of morbidity/mortality by the number of low-risk criteria (World Health Organization functional class I-II; 6-minute walk distance >440 m; N-terminal pro-brain natriuretic peptide <300 ng/liter) and REVEAL 2.0 risk category. Hazard ratios and 95% confidence intervals were calculated using Cox proportional hazard models., Results: Both the number of low-risk criteria and the REVEAL 2.0 risk category were prognostic for morbidity/mortality at baseline and any time-point during the study. Patients with 3 low-risk criteria at baseline had a 94% reduced risk of morbidity/mortality compared to patients with 0 low-risk criteria and were all categorized as low-risk by REVEAL 2.0. The treatment effect of selexipag on morbidity/mortality was consistent irrespective of the number of low-risk criteria or the REVEAL 2.0 risk category at any time-point during the study. Selexipag-treated patients were more likely to increase their number of low-risk criteria from baseline to week 26 than placebo-treated patients (odds ratio 1.69, p = 0.0002); similar results were observed for REVEAL 2.0 risk score., Conclusions: These results support the association between risk profile and long-term outcome and suggest that selexipag treatment may improve risk profile., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: The use of an endovascular approach for treatment of abdominal aortic aneurysms has gained traction over the past 2 decades. One of the major drawbacks of the endovascular approach is the increased rates of reintervention, with the majority arising from endoleaks that occur up to 20% of the time. Although type II endoleak is the most common subtype (25-45% of all endoleaks), it is associated with the greatest dilemma and debate with regard to indications and modalities of treatment. The open surgical approach to management of type II endoleak has gained interest and popularity over the years because of issues associated with the endovascular approach., Methods: We present a case of a patient with type II endoleak undergoing transperitoneal sacotomy, endoaneurysmorrhaphy, and stent-graft preservation, after having failed endovascular intervention. In addition, we describe the difficulties associated with posteriorly located backbleeding lumbar arteries and a unique case of iatrogenically created type III endoleak intraoperatively., Results: A literature review was performed with regard to the risk factors, indications for intervention, and modalities of treatment for type II endoleaks. In addition, suggestions are provided for future improvements in surgical technique., Conclusions: Type II endoleak is a common complication of endovascular aortic repair. In spite of this, management strategies are poorly standardized with no definitive gold standard. More collective data and pooled experience will be needed to further refine the open surgical technique and objectively assess its benefits and shortcomings vis-à-vis other alternatives., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: A long-term trial showed that the oral prostacyclin (PGl 2 ) receptor (IP) agonist, selexipag, delayed disease progression in patients with pulmonary arterial hypertension (PAH). Transition to selexipag in patients treated with more burdensome inhaled therapies that target the prostacyclin pathway may be considered by patients and physicians. The Phase 3b, prospective, open-label TRANSIT-1 (Tolerability and Safety of the Transition From Inhaled Treprostinil to Oral Selexipag in Patients With Pulmonary Arterial Hypertension) study evaluated the safety and tolerability of transition from inhaled treprostinil to oral selexipag., Methods: Patients receiving non-prostanoid oral PAH therapy and inhaled treprostinil at stable doses, in World Health Organization Functional Class II/III, with 6-minute walk distance ≥ 300 meters were enrolled. The 16-week main treatment period included downtitration of inhaled treprostinil over 8 weeks and parallel uptitration of selexipag over 12 weeks. Sustained treatment transition at Week 16 was defined as (1) receiving selexipag at Week 16; (2) no selexipag interruption(s) totaling ≥ 8 days; and (3) no inhaled treprostinil or other prostanoids after Week 8. Clinical parameters and patient-reported treatment satisfaction outcomes were assessed at Week 16., Results: All 34 enrolled patients completed the study. At Week 16, 32 patients (94.1%) had stopped inhaled treprostinil and were receiving selexipag. Twenty-eight patients (82.4%) met all criteria for sustained treatment transition. During the study, 3 patients discontinued selexipag due to adverse events. Overall, most adverse events were typical of prostanoid therapies and started during the uptitration phase. In general, patients remained clinically stable throughout treatment and reported improved convenience., Conclusions: Transition to oral selexipag from inhaled treprostinil in PAH patients was successful and well tolerated in most patients, and associated with greater convenience., Clinical Trial Number: NCT02471183., (Copyright © 2018. Published by Elsevier Inc.)

Background: Disease-specific patient-reported outcome (PRO) instruments are important in assessing the impact of disease and treatment. The Pulmonary Arterial Hypertension-Symptoms and Impact Questionnaire is the first instrument for quantifying pulmonary arterial hypertension (PAH) symptoms and impacts developed according to the 2009 US Food and Drug Administration PRO guidance; previous qualitative research in patients with PAH supported its initial content validity., Methods: Content finalization and psychometric validation were conducted by using data from A Study of Macitentan in Pulmonary Arterial Hypertension to Validate the PAH-SYMPACT (SYMPHONY), a single-arm, 16-week trial with macitentan 10 mg in US patients with PAH. Item performance, Rasch analysis, and factor analyses were used to select the final item content of the PRO and to define its domain structure. Internal consistency, test-retest reliability, known-group and construct validity, sensitivity to change, and influence of oxygen on item performance were evaluated., Results: Data from 278 patients (79% female; mean age: 60 years) were analyzed. Following removal of redundant/misfitting items, the final questionnaire has 11 symptom items across two domains (cardiopulmonary and cardiovascular symptoms) and 11 impact items across two domains (physical and cognitive/emotional impacts). Differential item function analysis confirmed that PRO scoring is unaffected by oxygen use. For all four domains, internal consistency reliability was high (Cronbach's alpha > 0.80), and scores were highly reproducible in stable patients (intraclass correlation coefficient: 0.84-0.94). Correlations with the Cambridge Pulmonary Hypertension Outcome Review questionnaire and the 36-item Medical Outcomes Study Short Form Survey were moderate to high ([r] = 0.34-0.80). The questionnaire differentiated well between patients with varying disease severity levels and was sensitive to improvements in clinician- and patient-reported disease severity., Conclusions: The Pulmonary Arterial Hypertension-Symptoms and Impact Questionnaire is a brief, disease-specific PRO instrument possessing good psychometric properties that can be administered in clinical practice and clinical studies., Trial Registry: ClinicalTrials.gov; No.: NCT01841762; URL: www.clinicaltrials.gov., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Parenteral prostanoids are considered the treatment of choice for patients with severe pulmonary arterial hypertension (PAH). Prognostic studies for patients treated in the modern era are limited., Methods: In this retrospective cohort study, patients initiating IV epoprostenol or IV or subcutaneous (SC) treprostinil therapy for PAH from 2007 to 2016 at UT Southwestern and The Ohio State University were included. Transplant-free survival was assessed from the time of IV/SC therapy initiation and from the time of first follow-up. The utility of traditional prognostic measures was assessed by using categories (lower, intermediate, and higher risk) recommended in the 2015 European Society of Cardiology/European Respiratory Society guidelines for functional class, 6-min walk distance, brain natriuretic peptide or N-terminal pro-brain natriuretic peptide level, and hemodynamic results., Results: Patients with group 1 PAH receiving IV epoprostenol (n = 132), IV treprostinil (n = 25), or SC treprostinil (n = 38) were included. Survival from IV/SC prostanoid initiation was 84%, 77%, and 67% at 1, 2, and 3 years. Follow-up assessment was performed after a minimum of 90 days' therapy (mean, 356 ± 247 days) in 163 patients. After treatment with an IV/SC prostanoid, better functional class, 6-min walk distance, brain natriuretic peptide/N-terminal pro-brain natriuretic peptide level, and mixed venous O 2 saturation (but not cardiac index) was associated with survival, as was the total number of lower risk and higher risk findings. Having zero lower risk findings or two or more higher risk findings was associated with particularly poor outcomes., Conclusions: In patients with PAH receiving treatment with a parenteral prostanoid, survival was significantly associated with the number of guideline-recommended lower risk and higher risk criteria achieved at first follow-up., (Copyright © 2018 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Forsterite (Mg2SiO4) because of its exceptionally high fracture toughness which is close to that of cortical bones has been nominated as a possible successor to calcium phosphate bioceramics. Recent in vitro studies also suggest that forsterite possesses good bioactivity and promotes osteoblast proliferation as well as adhesion. However studies on preparation and sinterability of nanocrystalline forsterite remain scarce. In this work, we use a solid-state reaction with magnesium oxide (MgO) and talc (Mg3Si4(OH)2) as the starting precursors to synthesize forsterite. A systematic investigation was carried out to elucidate the effect of preparatory procedures including heat treatment, mixing methods and sintering temperature on development of microstructures as well as the mechanical properties of the sintered forsterite body., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Background: Thrombocytopenia develops in some patients with advanced pulmonary arterial hypertension (PAH) while receiving IV epoprostenol therapy. In this study, we evaluate whether epoprostenol use, other PAH medication use, hemodynamics, or PAH etiology are associated with thrombocytopenia in PAH., Methods: Platelet counts were evaluated in 47 PAH patients receiving IV epoprostenol, and in 44 patients with an inadequate response to initial therapy with oral agents in a cross-sectional study. Associations between thrombocytopenia (platelet count < 150,000/mL) and epoprostenol use, hemodynamics, PAH etiology, and use of other PAH medications were evaluated in univariable and multivariable analyses., Results: PAH subtypes included idiopathic (69%), fenfluramine (18%), connective tissue disease (10%), and congenital heart disease (2%)-associated PAH. Thrombocytopenia was observed in 34% of patients treated with epoprostenol, compared with 15% of patients receiving oral therapy (odds ratio [OR], 2.9; p < 0.05), and the association between epoprostenol and thrombocytopenia remained significant after adjustment for differences in hemodynamics (OR, 5.0; p < 0.05). Right atrial pressure (OR, 1.12 per mm Hg; p < 0.05) and mixed venous oxygen saturation (Svo(2)) [OR, 0.92 per percentage; p < 0.05] were also associated with thrombocytopenia in univariable analyses; after logistic regression analysis, both the use of epoprostenol and Svo(2) were independently associated with thrombocytopenia. In a separate analysis including only patients with current or prior epoprostenol use, epoprostenol dose and right atrial pressure were inversely associated with platelet count., Conclusion: Epoprostenol use and severity of hemodynamic abnormalities are associated with thrombocytopenia in PAH, and these effects appear to be independent and additive.

Background: IV epoprostenol is a highly effective therapy for pulmonary arterial hypertension (PAH). However, monitoring the efficacy and adjusting the dose of epoprostenol often requires serial invasive hemodynamic measurements. This study investigated whether superior vena cava (SVC) oxygen saturation measured from the indwelling catheter and brain natriuretic peptide (BNP) level would predict right heart catheterization markers associated with lower survival rates (right atrial pressure [RAP], > 10 mm Hg; pulmonary artery [PA] oxygen saturation, < 62%) in epoprostenol-treated patients with PAH., Methods: Twenty-seven epoprostenol-treated PAH patients had a BNP level and SVC oxygen saturation measured from their indwelling central venous catheters. The results were compared with cardiac catheterization results., Results: SVC oxygen saturation and BNP level both showed significant correlation with hemodynamic variables. BNP level correlated best with RAP (r = 0.66; p < 0.001), while SVC oxygen saturation correlated most closely with PA oxygen saturation (r = 0.91; p < 0.001). All patients with a BNP level of >or= 117 pg/mL had an elevated RAP (specificity, 100% [defined as a RAP of > 10 mm Hg]), but sensitivity was only 65%. An SVC oxygen saturation of < 64% showed a sensitivity of 89% and a specificity of 78% in predicting a PA oxygen saturation of < 62%., Conclusions: SVC oxygen saturation and BNP level predict hemodynamics associated with lower survival rates and may be useful as "noninvasive" markers of prognosis in epoprostenol-treated PAH patients. BNP levels have a lower sensitivity relative to specificity, and a normal BNP level did not exclude a high RAP or low PA oxygen saturation.

Background: Amphetamine, methamphetamine, and cocaine are suspected of being pulmonary hypertension risk factors based on a small number of case reports along with pharmacologic similarities to fenfluramine, a diet drug associated with pulmonary arterial hypertension (PAH). We sought to determine whether rates of stimulant use are increased in patients believed to have idiopathic PAH compared with patients with PAH and known risk factors and patients with chronic thromboembolic pulmonary hypertension (CTEPH)., Methods: In this retrospective study, rates of stimulant use were determined for 340 patients with idiopathic PAH, PAH and known risk factors, or CTEPH seen between November 2002 and April 2004. "Stimulant" use was defined as any reported use of amphetamine, methamphetamine, or cocaine. Odds of stimulant use were calculated using a polychotomous logistic regression model., Results: A history of stimulant use was found in 28.9% of patients with a diagnosis of idiopathic PAH, compared with 3.8% of patients with PAH and a known risk factor, and 4.3% of patients with CTEPH. After adjustment for differences in age, patients with idiopathic PAH were 10.14 times (95% confidence interval, 3.39 to 30.3; p < 0.0001) more likely to have used stimulants than patients with PAH and known risk factors, and 7.63 times (95% confidence interval, 2.99 to 19.5; p < 0.0001) more likely to have used stimulants than patients with CTEPH., Conclusions: Patients with idiopathic PAH are significantly more likely to have used stimulants than patients with other forms of pulmonary hypertension.