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Elizabeth Ashley Hardin,1 Kelly M Chin2 1Department of Internal Medicine, Division of Cardiology, 2Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA Abstract: Pulmonary arterial hypertension is characterized by abnormalities in the small pulmonary arteries including increased vasoconstriction, vascular remodeling, proliferation of smooth muscle cells, and in situ thrombosis. Selexipag, a novel, oral prostacyclin receptor agonist, has been shown to improve hemodynamics in a phase II clinical trial and reduce clinical worsening in a large phase III clinical trial involving patients with pulmonary arterial hypertension. In this paper, we describe the prostacyclin signaling pathway, currently available oral prostanoid medications, and the development and clinical use of selexipag. Keywords: selexipag, pulmonary arterial hypertension, prostacyclin

Background: This study evaluated long-term outcomes in patients with pulmonary arterial hypertension (PAH) undergoing treatment with ambrisentan monotherapy, a selective oral endothelin-1 receptor antagonist.Methods and Results: Patients who participated in the Ambrisentan in Pulmonary Arterial Hypertension: A Phase 3, Randomized, Double-Blind, Placebo-Controlled Multicenter Efficacy Study (ARIES-1) clinical trial and extension phase at our institution were included. Cardiac catheterization, 6-minute walk distance (6MWD), and cardiac magnetic resonance (MRI) data were retrospectively reviewed. Twelve patients with PAH (11 idiopathic, 1 fenfluramine) had follow-up from 3 to 5.5 years from the initiation of ARIES-1. Patients received ambrisentan therapy throughout the study period and were on ambrisentan monotherapy for the first 2 years. At year 1, improvements in median mean pulmonary arterial pressure (PA), cardiac output, and pulmonary vascular resistance (PVR) were seen (P = .02, P = .03, P < .01), and the improvement in PVR persisted at 2 years. 6MWD also improved significantly between baseline (350 m) and 1 and 2 years (397 m, P < .01 and 393 m, P = .01). Cardiac MRI results were more varied, with an increase in RV ejection fraction from 29% at baseline to 46% at 2 years (P = .02), but other MRI variables did not improve.Conclusions: Ambrisentan monotherapy led to improvements in catheterization, 6MWD, and RV ejection fraction, and shows promise as a long-term treatment for pulmonary arterial hypertension. [ABSTRACT FROM AUTHOR]

Rationale: Heterozygous mutations in the coding regions of the telomerase genes, TERT and TERC, have been found in familial and sporadic cases of idiopathic interstitial pneumonia. All affected patients with mutations have short telomeres.Objectives: To test whether telomere shortening is a frequent mechanism underlying pulmonary fibrosis, we have characterized telomere lengths in subjects with familial or sporadic disease who do not have coding mutations in TERT or TERC.Methods: Using a modified Southern blot assay, the telomerase restriction fragment length method, and a quantitative polymerase chain reaction assay we have measured telomere lengths of genomic DNA isolated from circulating leukocytes from normal control subjects and subjects with pulmonary fibrosis.Measurements and Main Results: All affected patients with telomerase mutations, including case subjects heterozygous for newly reported mutations in TERT, have short telomere lengths. A significantly higher proportion of probands with familial pulmonary fibrosis (24%) and sporadic case subjects (23%) in which no coding mutation in TERT or TERC was found had telomere lengths less than the 10th percentile when compared with control subjects (P = 2.6 x 10(-8)). Pulmonary fibrosis affectation status was significantly associated with telomerase restriction fragment lengths, even after controlling for age, sex, and ethnicity (P = 6.1 x 10(-11)). Overall, 25% of sporadic cases and 37% of familial cases of pulmonary fibrosis had telomere lengths less than the 10th percentile.Conclusions: A significant fraction of individuals with pulmonary fibrosis have short telomere lengths that cannot be explained by coding mutations in telomerase. Telomere shortening of circulating leukocytes may be a marker for an increased predisposition toward the development of this age-associated disease. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Overnight inpatient monitoring is common following balloon pulmonary angioplasty (BPA) for chronic thromboembolic pulmonary hypertension (CTEPH). We describe our institutional experience in same-day discharge (SDD) after BPA. Across 78 BPA sessions, there were only 2 (2.6%) admissions for hemoptysis with no reperfusion lung injury or deaths at 30 days., Competing Interests: The authors declare no conflicts of interest., (© 2024 The Author(s). Pulmonary Circulation published by John Wiley & Sons Ltd on behalf of Pulmonary Vascular Research Institute.)

Introduction: Data on real-world clinical practice and outcomes of patients with pulmonary arterial hypertension (PAH) associated with congenital heart disease (CHD) are scarce. The OPUS/OrPHeUS studies enrolled patients with PAH newly initiating macitentan, including those with PAH associated with CHD (CHD-PAH)., Methods: OPUS was a prospective, United States, multicenter, long-term, observational drug registry (April 2014-June 2020). OrPHeUS was a retrospective, United States, multicenter medical chart review (October 2013-March 2017). The characteristics, treatment patterns, safety, and outcomes during macitentan treatment of patients with CHD-PAH and the subgroups Eisenmenger syndrome, left-to-right shunts and small/coincidental CHD were descriptively compared., Results: The combined OPUS/OrPHeUS population included 272 (6.1%) patients with CHD-PAH (80 patients with Eisenmenger syndrome; 82 patients with left-to-right shunts and 92 patients with small/coincidental defects). Most patients across the CHD-PAH subgroups were in World Health Organization Functional Class II/III (82.9-94.6%). Macitentan was initiated as combination therapy in 65.0% of patients with CHD-PAH. During follow-up, 81.4% of patients experienced ≥ 1 adverse event (AE), the most common being dyspnea (23.5%), nausea (13.7%), dizziness (12.7%), headache (12.7%) and edema (10.8%). The 1- and 2-year Kaplan-Meier (95% confidence limits) estimates of patients with CHD-PAH being free from hospitalization were 64.5% (57.9, 70.4) and 49.3% (41.9, 56.3); for survival, the 1- and 2-year Kaplan-Meier estimates were 93.5% (89.3, 96.1) and 90.2% (84.9, 93.7)., Conclusions: Macitentan was used in clinical practice in patients with CHD-PAH and its subgroups, including as combination therapy in the majority of patients. Safety in this population was consistent with the known profile of macitentan., Trial Registration: OPsumit ® Users Registry (OPUS): NCT02126943; Opsumit ® Historical Users cohort (OrPHeUS): NCT03197688; URL www., Clinicaltrials: gov ., Competing Interests: Declarations. Conflict of Interest: Kelly M Chin has served as a Scientific Committee member for Johnson & Johnson; has received research grants/support from Johnson & Johnson, Altavant, Acceleron, United Therapeutics, Pfizer, Merck, Gossamer Bio; has received support for travel to meetings from Johnson & Johnson; and has received consultancy fees from Johnson & Johnson, Altavant, Acceleron, United Therapeutics and Gossamer Bio. Richard Channick served as a Scientific Committee member for Johnson & Johnson; served on an advisory board for Johnson & Johnson and Bayer; received research grants/support from Johnson & Johnson and United therapeutics; received speaker fees from Johnson & Johnson, and Bayer; received consultancy fees from Johnson & Johnson, Bayer and Third pole. Nick H Kim served as a Scientific Committee member for Johnson & Johnson; received research grants/support from Enzyvant and Lung Biotechnology; received consultant fees from Johnson & Johnson, Bayer, Merck, United Therapeutics, Gossamer Bio, Pulnovo and Polarean; and received speaker fees from Johnson & Johnson, Bayer and Merck. Rose Ong is an employee of Johnson & Johnson; has received support for travel to meetings from Johnson & Johnson; holds stock or stock options with Johnson & Johnson; and spouse is an employee of Roche. Stefano Turricchia, Nicolas Martin and Lada Mitchell are employees of Johnson & Johnson. Vallerie V McLaughlin served as a Scientific Committee member from Johnson & Johnson; received research grants from Aerovate, Altavant, Gossamer Bio, Johnson & Johnson, Merck, and SoniVie; and received consultant fees from Aerami, Aerovate, Altavant, Bayer, Caremark, Corvista, Gossamer Bio, Johnson & Johnson, L.L.C, Merck and United Therapeutics. Ethical Approval: OPUS and OrPHeUS were executed in accordance with Good Pharmacoepidemiology Practices [29] and the 2008 Declaration of Helsinki ethical principles. Ethical approval was obtained from independent ethics committees/institutional review boards (IRB) of participating centers (see Supplementary Methods 1 for a full site list including local ethical review boards) and overseen by an Independent Scientific Committee (Supplementary Methods 2) with protocols reviewed by the US FDA. IRB approvals were provided by the Western IRB and Quorum (now Advarra) (OPUS registry; Western IRB approval number 2014‐0816, Quorum Review File number 29120/Advarra Pro00035124) and WCG‐IRB (OrPHeUS study; IRB numbers 2017‐8051 and 2017‐2348). In OPUS, written informed consent was obtained from all patients, including for publication of anonymized patient data (in OrPHeUS, an IRB waiver for informed consent was obtained). The informed consent form in OPUS included a confidentiality clause that all records and documents pertaining to the participation of patients in the OPUS registry would be held strictly confidential and their names would not be reported in any publications resulting from the OPUS registry. Following the approval of macitentan by the US FDA for the long-term treatment of PAH, OPUS and OrPHeUS were initiated as a post-marketing requirement to evaluate the potential risks for liver toxicity with macitentan use. This post-marketing requirement was completed in September 2019., (© 2024. The Author(s).)

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: MK-5475 is an investigational inhaled soluble guanylate cyclase stimulator hypothesised to avoid most side-effects of systemic vasodilation., Methods: The phase 2 INSIGNIA-PAH (NCT04732221) trial randomised adults with pulmonary arterial hypertension (PAH) on stable background therapy 1:1:1:1 to once-daily dosing with placebo, MK-5475 32 µg, 100 µg or 380 µg via dry powder inhalation for 12 weeks., Objectives: The objectives were to evaluate pulmonary vascular resistance (PVR; primary), 6-min walk distance (6MWD; secondary), additional selected haemodynamic parameters, and safety and tolerability in participants with PAH., Results: 168 participants were randomised to placebo (n=41), MK-5475 32 µg (n=42), 100 µg (n=44), and 380 µg (n=41). Median age was 51 years. Most participants were female (73.8%), diagnosed with idiopathic PAH (63.7%), receiving concomitant phosphodiesterase type 5 inhibitors (PDE5i; 93.5%), and treated with double or triple combination therapy (85.1%). At week 12, the placebo-corrected changes in PVR by least-squares means were -9.2% (95% CI -21.3%, 2.9%; p=0.068) with 32 µg, -22.0% (95% CI -33.7%, -10.3%; p<0.001) with 100 µg, and -19.9% (95% CI -33.4%, -6.4%; p=0.002) with 380 µg MK-5475. No treatment differences versus placebo were observed in 6MWD. Treatment-related adverse events and serious adverse events were similar across treatment groups. Three participants died: two on placebo and one on MK-5475 100 µg. One participant had symptomatic hypotension and one had haemoptysis (both on MK-5475 100 µg)., Conclusions: In participants with PAH on stable background therapy, including PDE5i, inhaled MK-5475 reduced PVR and was well tolerated, without evidence of systemic side-effects such as hypotension, suggesting a pulmonary selective pharmacodynamic effect., Competing Interests: Conflict of interest: M. Humbert reports grants/contracts from Gossamer Bio and Merck & Co., Inc., Rahway, NJ, USA, consultancy for 35 Pharma, Aerovate Therapeutics, Inc., AOP Orphan Pharmaceuticals, Bayer, Chiesi Farmaceutici SpA, Ferrer Internacional SA, Gossamer Bio, Janssen Pharmaceuticals, Keros Therapeutics, Liquidia Corp., Merck & Co., Inc., Rahway, NJ, USA, Novartis, Respira Therapeutics, Roivant Sciences Ltd and United Therapeutics Corp., honoraria from Janssen Pharmaceuticals and Merck & Co., Inc., Rahway, NJ, USA, and participation on a data safety monitoring or advisory board for 35 Pharma, Aerovate Therapeutics, Inc., Janssen Pharmaceuticals, Keros Therapeutics, Merck & Co., Inc., Rahway, NJ, USA, Novartis and United Therapeutics Corp. P.M. Hassoun reports participation on a scientific steering committee for MSD and participation on a scientific advisory board for ARIA-CV. K.M. Chin reports fees for work on steering, advisory or adjudication committees from Gossamer Bio, Janssen, Merck & Co., Inc., Rahway, NJ, USA, and United Therapeutics, and research support to institution for clinical studies overseen by her from Altavant, Gossamer Bio, Janssen, Merck & Co., Inc., Rahway, NJ, USA, and United Therapeutics. G. Bortman reports consultancy for Biosidus Argentina, Tuteur SA, Aerovate Therapeutics Inc., Baliarda Argentina, Merck & Co, Inc., Glaxo Inc. and Tecnopharma/Raffo, Inc. M.J. Patel, C. La Rosa, W. Fu and M.J. Loureiro are current employees of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, and may hold stock and/or stock options in Merck & Co., Inc., Rahway, NJ, USA. M.M. Hoeper reports consultancy for Acceleron Pharma, Inc., Actelion Pharmaceuticals, Aerovate, AOP Orphan Pharmaceuticals, Bayer HealthCare, Ferrer Internacional SA, Gossamer Bio, Janssen Global Services, LLC, Keros, Merck & Co., Inc., Rahway, NJ, USA, and Novartis., (Copyright ©The authors 2024.)

Introduction: Historically, patients recently (≤ 6 months) diagnosed with pulmonary arterial hypertension (PAH; incident) have had poorer survival than those with a longer (> 6 months) time from PAH diagnosis (prevalent). Despite guideline recommendations for initial combination therapy for most patients with PAH, many are initiated and maintained on monotherapy. Real-world evidence to evaluate the benefit of early combination treatment in newly-diagnosed patients is lacking., Methods: Patients with PAH initiating combination therapy with the endothelin receptor antagonist macitentan and the phosphodiesterase-5 inhibitor tadalafil (M+T) were identified from the combined dataset of the US, multicenter OPUS (prospective, observational drug registry; NCT02126943) and OrPHeUS (retrospective, medical chart review; NCT03197688) studies (2013-2020). Descriptive analyses were performed for the incident and prevalent cohorts, as well as the subcohort of incident patients who received M+T as first-line combination therapy (incident initial combination)., Results: In OPUS/OrPHeUS, 1336 patients with PAH received M+T during the observation period. For the incident [n = 453 (33.9%)], incident initial combination [n = 272 (20.4%)], and prevalent [n = 837 (62.6%)] cohorts: median (Q1, Q3) M+T exposure was 14.2 (4.2, 27.5), 12.2 (3.2, 25.5), and 14.7 (4.5, 28.0) months. 12-month Kaplan-Meier estimates (95% confidence limits) for survival were 91.2% (87.7, 93.7), 88.5% (83.2, 92.2), and 92.9% (90.6, 94.6), for patients free from hospitalization were 59.4% (54.1, 64.4), 56.3% (49.1, 62.9), and 62.3% (58.5, 65.9), and for patients persisting on combination therapy were 68.6% (63.9, 72.8), 65.0% (58.8, 70.6) and 66.9% (63.5, 70.0). Adverse events (OPUS only) were reported in 77.8%, 80.2%, and 80.3% of patients, respectively, with no unexpected adverse events observed., Conclusions: Despite a historically worse prognosis, incident patients receiving M+T, including as initial combination therapy, had similar survival and hospitalization as prevalent patients. Safety profiles were similar across cohorts. Together, these data support the use of early combination therapy with macitentan and tadalafil., (© 2024. The Author(s).)

Pulmonary arterial hypertension leads to significant impairment in haemodynamics, right heart function, exercise capacity, quality of life and survival. Current therapies have mechanisms of action involving signalling via one of four pathways: endothelin-1, nitric oxide, prostacyclin and bone morphogenetic protein/activin signalling. Efficacy has generally been greater with therapeutic combinations and with parenteral therapy compared with monotherapy or nonparenteral therapies, and maximal medical therapy is now four-drug therapy. Lung transplantation remains an option for selected patients with an inadequate response to therapies., Competing Interests: Conflict of interest: K.M. Chin reports grants and consultancy fees from Janssen, Merck, Gossamer Bio and United Therapeutics, support for attending meetings from Janssen, and is an associate editor for Circulation. S.P. Gaine reports grants from Janssen, Aerovent and Gossamer Bio, consultancy fees from Janssen, Merck, Gossamer Bio, United Therapeutics and Altavent, payment or honoraria for lectures, presentations, manuscript writing or educational events and support for attending meetings from Janssen, and participation on a data safety monitoring board or advisory board with Janssen. C. Gerges reports grants from OrphaCare, payment or honoraria for lectures, presentations, manuscript writing or educational events from AOPHealth, AstraZeneca, Janssen and Ferrer, and support for attending meetings from AOPHealth, AstraZeneca, Cordis, Janssen and MSD. Z-C. Jing has no potential conflicts of interest to disclose. S.C. Mathai reports consultancy fees from Janssen, United Therapeutics, Merck and Acceleron, participation on a data safety monitoring board or advisory board with Bayer, and a leadership role on the Patient Centered Outcomes Research Institute Rare Disease Advisory Panel. Y. Tamura reports grants from Nippon Shinyaku Co. Ltd and Mochida, consultancy fees from MSD, and payment or honoraria for lectures, presentations, manuscript writing or educational events from Nippon Shinyaku Co. Ltd and Janssen Pharmaceuticals. V.V. McLaughlin reports grants from Aerovate, Gossamer-Bio, Janssen, Keros, Merck and Sonovie, and consultancy fees from 35Pharma, Aerami, Aerovate, Caremark, L.L.C., Corvista, Gossamer Bio, Janssen, Keros, Merck, Riovant and United Therapeutics. O. Sitbon reports grants from Aerovate, AOP Orphan, Ferrer, Janssen and MSD, consultancy fees from Altavant/Enzyvant, AOP Orphan, Ferrer, Gossamer Bio, Janssen, Liquidia, MSD, Respira Therapeutics and Roivant Sciences, payment or honoraria for lectures, presentations, manuscript writing or educational events from Aerovate, AOP Orphan, Janssen, Ferrer and MSD, and participation on a data safety monitoring board or advisory board with Altavant/Enzyvant, Gossamer Bio, Janssen and Respira Therapeutics., (Copyright ©The authors 2024.)

Introduction: Despite the increasing widespread adoption and experience in minimally invasive liver resections (MILR), open conversion occurs not uncommonly even with minor resections and as been reported to be associated with inferior outcomes. We aimed to identify risk factors for and outcomes of open conversion in patients undergoing minor hepatectomies. We also studied the impact of approach (laparoscopic or robotic) on outcomes., Methods: This is a post-hoc analysis of 20,019 patients who underwent RLR and LLR across 50 international centers between 2004-2020. Risk factors for and perioperative outcomes of open conversion were analysed. Multivariate and propensity score-matched analysis were performed to control for confounding factors., Results: Finally, 10,541 patients undergoing either laparoscopic (LLR; 89.1%) or robotic (RLR; 10.9%) minor liver resections (wedge resections, segmentectomies) were included. Multivariate analysis identified LLR, earlier period of MILR, malignant pathology, cirrhosis, portal hypertension, previous abdominal surgery, larger tumor size, and posterosuperior location as significant independent predictors of open conversion. The most common reason for conversion was technical issues (44.7%), followed by bleeding (27.2%), and oncological reasons (22.3%). After propensity score matching (PSM) of baseline characteristics, patients requiring open conversion had poorer outcomes compared with successful MILR cases as evidenced by longer operative times, more blood loss, higher requirement for perioperative transfusion, longer duration of hospitalization and higher morbidity, reoperation, and 90-day mortality rates., Conclusions: Multiple risk factors were associated with conversion of MILR even for minor hepatectomies, and open conversion was associated with significantly poorer perioperative outcomes., (© 2024. Society of Surgical Oncology.)

Aims: According to current guidelines, initial monotherapy should be considered for pulmonary arterial hypertension (PAH) patients with cardiopulmonary comorbidities. This analysis of combined data from the TRITON and REPAIR clinical trials, assesses efficacy and safety of initial double combination therapy in patients without vs. with 1-2 cardiac comorbidities., Methods and Results: Data were combined for patients from TRITON (NCT02558231) and REPAIR (NCT02310672) on initial macitentan and tadalafil double combination therapy (overall set, n = 148) and two subgroups defined as patients without cardiac comorbidities (n = 62) and those with 1-2 cardiac comorbidities (n = 78). Patients with ≥3 comorbidities were excluded from these studies. For the overall set, the median (Q1-Q3) duration of combined macitentan and tadalafil exposure was 513.0 (364.0-778.0) days, and was similar between subgroups. Change from baseline to Week 26 for pulmonary vascular resistance was -55% and -50% for patients without and with 1-2 cardiac comorbidities, respectively; marked improvements in other hemodynamic and functional parameters were also observed, although functional parameters improved to a lesser extent in patients with comorbidities. At Week 26, the majority of patients had improved PAH risk status, according to the non-invasive four-strata and REVEAL Lite 2.0 methods. The safety profile of initial macitentan plus tadalafil combination therapy was consistent with the known profiles of the two drugs, and similar between the subgroups., Conclusions: Initial double combination therapy with macitentan plus tadalafil is efficacious in patients with PAH with 1-2 cardiac comorbidities and those without, with similar safety and tolerability profiles between the two groups., (© 2024 Actelion Pharmaceuticals Ltd. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

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.)

Introduction: Data on real-world clinical practice and outcomes of patients with pulmonary arterial hypertension associated with connective tissue disease (CTD-PAH) are scarce. The OPUS/OrPHeUS studies enrolled patients newly initiating macitentan, including those with CTD-PAH. This analysis describes patient characteristics, treatment patterns, outcomes, and safety profiles of patients with CTD-PAH newly initiating macitentan in the US using the OPUS/OrPHeUS combined dataset., Methods: OPUS was a prospective, US, multicenter, long-term, observational drug registry (April 2014-June 2020). OrPHeUS was a retrospective, US, multicenter medical chart review (October 2013-March 2017). The characteristics, treatment patterns, safety, and outcomes during macitentan treatment of patients with CTD-PAH and its subgroups systemic sclerosis (SSc-PAH), systemic lupus erythematosus (SLE-PAH), and mixed CTD (MCTD-PAH) were descriptively compared to patients with idiopathic/heritable PAH (I/HPAH)., Results: The combined OPUS/OrPHeUS population included 2498 patients with I/HPAH and 1192 patients with CTD-PAH (708 SSc-PAH; 159 SLE-PAH; 124 MCTD-PAH, and 201 other CTD-PAH etiologies). At macitentan initiation for patients with I/HPAH and CTD-PAH, respectively: 61.2 and 69.3% were in World Health Organization functional class (WHO FC) III/IV; median 6-min walk distance was 289 and 279 m; and 58.1 and 65.2% received macitentan as combination therapy. During follow-up, for patients with I/HPAH and CTD-PAH, respectively: median duration of macitentan exposure observed was 14.0 and 15.8 months; 79.0 and 83.0% experienced an adverse event; Kaplan-Meier estimates (95% confidence limits [CL]) of patients free from all-cause hospitalization at 1 year were 60.3% (58.1, 62.4) and 59.3% (56.1, 62.3); and Kaplan-Meier estimates (95% CL) of survival at 1 year were 90.5% (89.1, 91.7) and 90.6% (88.6, 92.3)., Conclusions: Macitentan was used in clinical practice in patients with CTD-PAH and its subgroups, including as combination therapy. The safety and tolerability profile of macitentan in patients with CTD-PAH was comparable to that of patients with I/HPAH., Trial Registration: OPsumit® Users Registry (OPUS): NCT02126943; Opsumit® Historical Users cohort (OrPHeUS): NCT03197688; www., Clinicaltrials: gov Graphical abstract available for this article., (© 2024. The Author(s).)

Introduction: Portopulmonary hypertension (PoPH) carries a worse prognosis than other forms of pulmonary arterial hypertension (PAH). Data regarding use of PAH-specific therapies in patients with PoPH are sparse as they are usually excluded from clinical trials. This analysis describes patient characteristics, treatment patterns, outcomes, and safety profiles in patients with PoPH newly initiating macitentan in the USA using the OPUS/OrPHeUS combined dataset., Methods: OPUS was a prospective, US, multicenter, observational drug registry (April 2014-June 2020); OrPHeUS was a retrospective, US, multicenter chart review (October 2013-March 2017). Additional information regarding patients' liver disease was retrospectively collected for patients with PoPH in OPUS., Results: The OPUS/OrPHeUS dataset included 206 patients with PoPH (median age 58 years; 52.4% female), with baseline cirrhosis and liver test abnormalities reported in 72.8% and 31.6% of patients respectively. Macitentan was initiated as combination therapy in 74.8% of patients and median (Q1, Q3) exposure to macitentan was 11.9 (3.1, 26.0) months. One-year Kaplan-Meier estimates (95% confidence limit, CL) of patients free from all-cause hospitalization and survival were 48.6% (40.7, 56.0) and 82.2% (75.1, 87.4). Of the 96 patients with PoPH in OPUS, 29.2% were classified as in need of liver transplant due to underlying liver disease during the study; transplant waitlist registration was precluded because of PAH severity for 32.1% and 17.9% were transplanted. Hepatic adverse events (HAE) were experienced by 49.0% of patients; the most common being increased bilirubin (16.0%), ascites (7.3%), and hepatic encephalopathy (5.8%); 1.5% and 21.8% of patients discontinued macitentan as a result of HAE and non-hepatic adverse events., Conclusion: There were no unexpected safety findings in patients with PoPH treated with macitentan. These data add to the evidence supporting the safety and tolerability of macitentan in patients with PoPH. A graphical abstract is available with this article., Trial Registration: OPsumit® Users Registry (OPUS): NCT02126943; OPsumit® Historical Users cohort (OrPHeUS): NCT03197688; www., Clinicaltrials: gov ., (© 2024. The Author(s).)

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: Endothelin receptor antagonist (ERA) and phosphodiesterase 5 inhibitor (PDE5i) combination therapy is recommended for low-/intermediate-risk pulmonary arterial hypertension (PAH) patients. A fixed-dose combination of the ERA macitentan and PDE5i tadalafil (M/T FDC) in a once-daily, single tablet would simplify treatment., Objectives: The multicenter, double-blind, adaptive phase 3 A DUE study investigated the efficacy and safety of M/T FDC vs macitentan 10 mg and vs tadalafil 40 mg monotherapies in PAH patients, including treatment-naïve and prior ERA or PDE5i monotherapy-treated patients., Methods: World Health Organization functional class II-III patients were randomized to M/T FDC, macitentan, or tadalafil depending on their PAH treatment (treatment-naïve, ERA, or PDE5i monotherapy) at baseline. The primary endpoint was change in pulmonary vascular resistance (PVR) at week 16., Results: In total, 187 patients were randomized to single-tablet M/T FDC (n = 108), macitentan (n = 35), or tadalafil (n = 44). PVR reduction with M/T FDC was significantly greater vs macitentan (29%; geometric mean ratio 0.71; 95% CL: 0.61-0.82; P < 0.0001) and vs tadalafil (28%; geometric mean ratio 0.72; 95% CL: 0.64-0.80; P < 0.0001). Three patients died in the M/T FDC arm (judged unrelated to treatment). Adverse events (AEs) leading to discontinuation, serious AEs, and those of special interest (anemia, hypotension, and edema) were more frequent with M/T FDC., Conclusions: Macitentan and tadalafil FDC significantly improved PVR vs monotherapies in PAH patients, with a safety and tolerability profile consistent with the individual components. The A DUE study supports M/T FDC as a once-daily, single-tablet combination for initial therapy and escalation to double combination therapy in patients with PAH. (Clinical Study to Compare the Efficacy and Safety of Macitentan and Tadalafil Monotherapies With the Corresponding Fixed-dose Combination Therapy in Subjects With Pulmonary Arterial Hypertension [PAH]) [A DUE]; NCT03904693)., Competing Interests: Funding Support and Author Disclosures This study was funded by Actelion Pharmaceuticals Ltd, a Janssen Pharmaceutical Company of Johnson and Johnson. Prof Grünig has received fees for lectures and/or consultations from Bayer/Merck Sharp & Dohme, Ferrer, GEBRO, GlaxoSmithKline, Janssen Pharmaceutical Companies of Johnson and Johnson, and OMT; and has received research grants to his institution from Acceleron, BayerHealthCare, Merck Sharp & Dohme, Bellerophon, GossamerBio, GlaxoSmithKline, Janssen Pharmaceutical Companies of Johnson and Johnson, Novartis, OMT, Pfizer, REATE, and United Therapeutics outside of the submitted work. Prof Jansa has received fees and grants from Janssen Pharmaceutical Companies of Johnson and Johnson, Janssen AOP Orphan, Bayer Healthcare, Merck Sharp & Dohme, and Arena Pharmaceuticals Inc. Prof Fan has served as a scientific committee member for Janssen Pharmaceutical Companies of Johnson and Johnson. Dr Hauser, Ms Morganti, and Dr Rofael are employees of Janssen Pharmaceutical Companies of Johnson and Johnson. Mr Pannaux is an employee of a company contracted by Janssen Pharmaceutical Companies of Johnson and Johnson. Dr Chin has served as a scientific committee member for Janssen Pharmaceutical Companies of Johnson and Johnson; has received research grants/support from Janssen Pharmaceutical Companies of Johnson and Johnson, Altavant, Acceleron, United Therapeutics, Pfizer, Merck, and Gossamer Bio; has received support for travel to meetings from Janssen Pharmaceutical Companies of Johnson and Johnson; and has received consultancy fees from Janssen Pharmaceutical Companies of Johnson and Johnson, Altavant, Acceleron, United Therapeutics, Gossamer Bio, and Merck., (Copyright © 2024. Published by Elsevier Inc.)

Background: The impact of cirrhosis and portal hypertension on perioperative outcomes of minimally invasive left lateral sectionectomies remains unclear. We aimed to compare the perioperative outcomes between patients with preserved and compromised liver function (noncirrhotics versus Child-Pugh A) when undergoing minimally invasive left lateral sectionectomies. In addition, we aimed to determine if the extent of cirrhosis (Child-Pugh A versus B) and the presence of portal hypertension had a significant impact on perioperative outcomes., Methods: This was an international multicenter retrospective analysis of 1,526 patients who underwent minimally invasive left lateral sectionectomies for primary liver malignancies at 60 centers worldwide between 2004 and 2021. In the study, 1,370 patients met the inclusion criteria and formed the final study group. Baseline clinicopathological characteristics and perioperative outcomes of these patients were compared. To minimize confounding factors, 1:1 propensity score matching and coarsened exact matching were performed., Results: The study group comprised 559, 753, and 58 patients who did not have cirrhosis, Child-Pugh A, and Child-Pugh B cirrhosis, respectively. Six-hundred and thirty patients with cirrhosis had portal hypertension, and 170 did not. After propensity score matching and coarsened exact matching, Child-Pugh A patients with cirrhosis undergoing minimally invasive left lateral sectionectomies had longer operative time, higher intraoperative blood loss, higher transfusion rate, and longer hospital stay than patients without cirrhosis. The extent of cirrhosis did not significantly impact perioperative outcomes except for a longer duration of hospital stay., Conclusion: Liver cirrhosis adversely affected the intraoperative technical difficulty and perioperative outcomes of minimally invasive left lateral sectionectomies., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Introduction: Minimally invasive liver resection (MILR) is widely recognized as a safe and beneficial procedure in the treatment of both malignant and benign liver diseases. Hepatolithiasis has traditionally been reported to be endemic only in East Asia, but has seen a worldwide uptrend in recent decades with increasingly frequent and invasive endoscopic instrumentation of the biliary tract for a myriad of conditions. To date, there has been a woeful lack of high-quality evidence comparing the laparoscopic (LLR) and robotic (RLR) approaches to treatment hepatolithiasis., Methods: This is an international multicenter retrospective analysis of 273 patients who underwent RLR or LRR for hepatolithiasis at 33 centers in 2003-2020. The baseline clinicopathological characteristics and perioperative outcomes of these patients were assessed. To minimize selection bias, 1:1 (48 and 48 cases of RLR and LLR, respectively) and 1:2 (37 and 74 cases of RLR and LLR, respectively) propensity score matching (PSM) was performed., Results: In the unmatched cohort, 63 (23.1%) patients underwent RLR, and 210 (76.9%) patients underwent LLR. Patient clinicopathological characteristics were comparable between the groups after PSM. After 1:1 and 1:2 PSM, RLR was associated with less blood loss (p = 0.003 in 1:2 PSM; p = 0.005 in 1:1 PSM), less patients with blood loss greater than 300 ml (p = 0.024 in 1:2 PSM; p = 0.027 in 1:1 PSM), and lower conversion rate to open surgery (p = 0.003 in 1:2 PSM; p < 0.001 in 1:1 PSM). There was no significant difference between RLR and LLR in use of the Pringle maneuver, median Pringle maneuver duration, 30-day readmission rate, postoperative morbidity, major morbidity, reoperation, and mortality., Conclusion: Both RLR and LLR were safe and feasible for hepatolithiasis. RLR was associated with significantly less blood loss and lower open conversion rate., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Few studies have evaluated the effects of pulmonary arterial hypertension therapies on pericardial effusion. We evaluated hemodynamics, echocardiograms, and outcomes for 119 parenteral prostanoid-treated patients. We discovered an increased frequency of pericardial effusions posttreatment, and that a moderate-large pericardial effusion at initiation, but not at 1st follow-up, was significantly associated with mortality., Competing Interests: The authors declare no conflict of interest., (© 2023 The Authors. Pulmonary Circulation published by John Wiley & Sons Ltd on behalf of Pulmonary Vascular Research Institute.)

Further understanding of when to initiate therapies in pulmonary arterial hypertension (PAH) is important to improve long-term outcomes. Post hoc analyses of GRIPHON (NCT01106014) and exploratory analyses of TRITON (NCT02558231) suggested benefit of early selexipag initiation on long-term outcomes, despite no additional benefit versus initial double combination on haemodynamic and functional parameters in TRITON. Post hoc analyses investigated the effect of early selexipag initiation on disease progression and survival in a large, pooled PAH cohort. Data from newly diagnosed (≤6 months) PAH patients from GRIPHON and TRITON were pooled. Patients on active therapy with selexipag (pooled selexipag group) were compared with those on control therapy with placebo (pooled control group). Disease progression end-points were defined as per the individual studies. Hazard ratios (HR) and 95% CI for time to first disease progression event up to end of double-blind treatment (selexipag/placebo) +7 days and time to all-cause death up to end of study were estimated using Cox regression models. The pooled dataset comprised 649 patients, with 44% on double background therapy. Selexipag reduced the risk of disease progression by 52% versus control (HR: 0.48; 95% CI: 0.35-0.66). HR for risk of all-cause death was 0.70 (95% CI: 0.46-1.10) for the pooled selexipag versus control group. Sensitivity analyses accounting for the impact of PAH background therapy showed consistent results, confirming the appropriateness of data pooling. These post hoc , pooled analyses build on previous insights, further supporting selexipag use within 6 months of diagnosis, including as part of triple therapy, to delay disease progression., Competing Interests: Conflicts of interest: J.G. Coghlan has received grants, speaker fees and support for attending meetings from Janssen Pharmaceutical Companies of Johnson & Johnson; and has received consulting fees from Janssen Pharmaceutical Companies of Johnson & Johnson, Acceleron, Bayer and Vicore. Conflicts of interest: S. Gaine has served as a steering committee member for Janssen Pharmaceutical Companies of Johnson & Johnson; has received speaker fees from Janssen Pharmaceutical Companies of Johnson & Johnson, Bayer and AOP; and has served on advisory boards/data safety monitoring boards for Janssen Pharmaceutical Companies of Johnson & Johnson, United Therapeutics, Gossamer Bio and Altavant. Conflicts of interest: R. Channick has served as a steering committee member for Janssen Pharmaceutical Companies of Johnson & Johnson; has served on an advisory board for Janssen Pharmaceutical Companies of Johnson & Johnson and Bayer; has received consultancy fees from Bayer, Gossamer, Third Pole, Acceleron, Arena Pharmaceuticals and Janssen Pharmaceutical Companies of Johnson & Johnson; and has received speaker fees from Janssen Pharmaceutical Companies of Johnson & Johnson and Bayer. Conflicts of interest: K.M. Chin has served as a steering committee member for Janssen Pharmaceutical Companies of Johnson & Johnson; has received research grants from Janssen Pharmaceutical Companies of Johnson & Johnson, Altavant, Acceleron, United Therapeutics, Pfizer, Merck, Gossamer Bio; has received support for travel to meetings from Janssen Pharmaceutical Companies of Johnson & Johnson; and has received consultancy fees from Janssen Pharmaceutical Companies of Johnson & Johnson, Altavant, Acceleron, United Therapeutics and Gossamer Bio. Conflicts of interest: C. du Roure is an employee of Janssen Pharmaceutical Companies of Johnson & Johnson. Conflicts of interest: J.S.R. Gibbs has served as a steering committee member for Janssen Pharmaceutical Companies of Johnson & Johnson, Complexa and Acceleron/Merck; has received consultancy fees from Acceleron/Merck; has served as a clinical endpoints committee member for Pfizer, Aerovate, Janssen Pharmaceutical Companies of Johnson & Johnson and United Therapeutics; and has served as a data and safety monitoring board member for Janssen Pharmaceutical Companies of Johnson, Merck Sharp & Dohme, Gossamer Bio and Bial. Conflicts of interest: M.M. Hoeper has served as a steering committee member for Janssen Pharmaceutical Companies of Johnson & Johnson; has received speaker and consultancy fees from Janssen Pharmaceutical Companies of Johnson & Johnson, Bayer, GlaxoSmithKline, Merck Sharp & Dohme, and Pfizer; and has received research grants from Janssen Pharmaceutical Companies of Johnson & Johnson. Conflicts of interest: I.M. Lang has served as a steering committee member for Janssen Pharmaceutical Companies of Johnson & Johnson; has received research grants from Janssen Pharmaceutical Companies of Johnson & Johnson and AOP Orphan Pharmaceuticals; has received consultancy fees from Janssen Pharmaceutical Companies of Johnson & Johnson, AOP Health, Bayer, Ferrer and United Therapeutics; has received speaker fees from Janssen Pharmaceutical Companies of Johnson & Johnson, AOP Health and Bayer; has received support for attending meetings from Janssen Pharmaceutical Companies of Johnson & Johnson, AOP Health, Bayer, Ferrer and Medtronic. Conflicts of interest: S.C. Mathai has served as a steering committee member for Janssen Pharmaceutical Companies of Johnson & Johnson; has received consultancy fees from Acceleron, Bayer, United Therapeutics and Janssen Pharmaceutical Companies of Johnson & Johnson; has received speaker fees from Practice Point CME; has participated on an advisory board for United Therapeutics; and has had a leadership role on the PCORI, Rare Disease Advisory Panel and served as ACCP PVD Network Chair. Conflicts of interest: V.V. McLaughlin has served as a steering committee member for Janssen Pharmaceutical Companies of Johnson & Johnson; reports grant support from Aerovate, Altavant, Gossamer-Bio, Janssen Pharmaceutical Companies of Johnson & Johnson, Merck and Sonovie; and has received consultancy fees from Aerami, Aerovate, Altavant, Bayer, Caremark, L.L.C., Corvista, Gossamer Bio, Janssen Pharmaceutical Companies of Johnson & Johnson, Merck and United Therapeutics. Conflicts of interest: L. Mitchell is an employee of Janssen Pharmaceutical Companies of Johnson & Johnson. Conflicts of interest: G. Simonneau has served as a steering committee member for and received research grants from Janssen Pharmaceutical Companies of Johnson & Johnson; and has received speaker and consultancy fees from Janssen Pharmaceutical Companies of Johnson & Johnson, Bayer, GlaxoSmithKline, Merck Sharp & Dohme and Pfizer. Conflicts of interest: O. Sitbon has served as a steering committee member for Janssen Pharmaceutical Companies of Johnson & Johnson and Gossamer Bio; has received research grants from Janssen Pharmaceutical Companies of Johnson & Johnson, Acceleron Pharmaceuticals, GlaxoSmithKline, and Merck Sharp & Dohme; has received consultancy fees from Janssen Pharmaceutical Companies of Johnson & Johnson, AOP Orphan, Ferrer Gossamer Bio and Merck Sharp & Dohme and United Therapeutics; has received speaker fees from Janssen Pharmaceutical Companies of Johnson & Johnson, AOP Orphan, Ferrer and Merck Sharp & Dohme; and has served on an advisory board for Acceleron Pharmaceuticals, Altavant Pharmaceuticals, Gossamer Bio, Janssen Pharmaceutical Companies of Johnson & Johnson and Merck Sharp & Dohme. Conflicts of interest: V.F. Tapson has served as a steering committee member for Janssen Pharmaceutical Companies of Johnson & Johnson, Bayer and United Therapeutics; has received consultancy fees from Janssen Pharmaceutical Companies of Johnson & Johnson, Arena Pharmaceuticals, Bayer, Daiichi-Sankyo, EKOS/BTG and United Therapeutics; has received research grants from Arena Pharmaceuticals, Arena, and Bayer; has received speaker fees from Janssen Pharmaceutical Companies of Johnson & Johnson; and serves as Vice President of Medical Affairs at Inari Medical. Conflicts of interest: N. Galiè is a steering committee member for Janssen Pharmaceutical Companies of Johnson & Johnson; has received grant support from Janssen Pharmaceutical Companies of Johnson & Johnson; has received consulting fees and speaker fees from Janssen Pharmaceutical Companies of Johnson & Johnson, Ferrer and Pfizer., (Copyright ©The authors 2023.)

Macitentan is an oral endothelin receptor antagonist for the management of pulmonary arterial hypertension (PAH). The OPsumit® USers Registry (OPUS) and the OPsumit® Historical USers cohort (OrPHeUS) medical chart review provide real-world data for patients newly initiating macitentan. This study aims to describe the characteristics, safety profile, and clinical outcomes of PAH patients newly treated with macitentan in the combined OPUS/OrPHeUS data set. OPUS was a prospective, multicenter, long-term, observational drug registry from April 2014 to June 2020. OrPHeUS was a retrospective, US, multicenter chart review: observation period October 2013 to March 2017. All analyses were descriptive. At registry closure in June 2020, the combined population consisted of 5654 patients, of whom 81.9% were diagnosed with PAH. For these 4626 patients, median duration of macitentan exposure observed was 14.5 (Q1 = 5.2, Q3 = 29.0) months; idiopathic PAH (54.8%) was the most common form of PAH; macitentan was initiated as monotherapy (37.9%), or as part of double (48.0%) or triple therapy (14.1%); discontinuation due to nonhepatic/hepatic adverse events occurred in 17.1%/0.3% of patients; 9.9% of patients experienced ≥1 hepatic adverse events; Kaplan-Meier estimates showed that at 1 year 59.9% (95% confidence interval: 58.3, 61.5) of patients were free from hospitalization and survival was 90.4% (89.3, 91.3). This analysis of real-world data from the combined OPUS and OrPHeUS populations demonstrated that macitentan is well tolerated in a large, diverse population of PAH patients, with overall and hepatic safety profiles consistent with previous macitentan clinical trials., Competing Interests: V. V. M. reports serving as a steering committee member, as well as receiving consultant fees, and research grants/support from Janssen Pharmaceutical Companies of Johnson & Johnson; consultant fees and research grants/support from United Therapeutics, Bayer, and Acceleron Pharma, Inc.; consultant fees from Altavant, Caremark, CiVi Biopharma Inc., and Gossamer Bio; and research grants/support from Reata Pharmaceuticals and SoniVie. R. C. serves as a steering committee member, served on an advisory board, and received research grants/support, and speaker fees from Janssen Pharmaceutical Companies of Johnson & Johnson; has served on an advisory board for Bayer; has received consultancy and speaker fees from Bayer and Arena Pharmaceuticals; and has received research grants from United Therapeutics. N. H. K. has served a steering committee member and received research grants/support and speaker fees from Janssen Pharmaceutical Companies of Johnson & Johnson; has received research grants/support from Bellerophon, Eiger, Gossamer Bio, Lung Biotechnology, and SoniVie; consultant fees from Bayer, Merck, and United Therapeutics; and speaker fees from Bayer. R. P. F has served as a steering committee and advisory board member for Janssen Pharmaceutical Companies of Johnson & Johnson, Gossamer Bio, Liquidia, and Tenax; and as an advisory board member for Altavant Sciences and ShoTi; and received royalties from UptoDate. J.W. M. received financial support, research grants and personal fees from Janssen Pharmaceutical Companies of Johnson & Johnson; personal fees and financial support from Bayer Pharmaceuticals, United Therapeutics, Reata Pharmaceuticals and Arena Pharmaceuticals; and financial support from Eiger Pharmaceuticals, and Bellerophon. L. M. G. has served on advisory boards and received speaker fees from Janssen Pharmaceutical Companies of Johnson & Johnson, has received speaker fees from United Therapeutics, Gilead, and Bayer Pharmaceuticals; and served on advisory boards for United Therapeutics and Bayer Pharmaceuticals. C. M. reports personal fees from Janssen Pharmaceutical Companies of Johnson & Johnson, United Therapeutics, Gilead, and Bayer. A. R. reports speaker fees from Janssen Pharmaceutical Companies of Johnson & Johnson, Bayer Pharmaceuticals, United Therapeutics. J. R. L. has served on an advisory board for and received research support from Janssen Pharmaceutical Companies of Johnson & Johnson; has received research support from United Therapeutics and Bayer, and has served on an advisory board for Bayer. M. B. and S. L. are employees of Janssen Pharmaceutical Companies of Johnson & Johnson and in the past held stock/stock options for Actelion Pharmaceuticals Ltd. and currently hold stock/stock options in the parent company Johnson & Johnson. G. W. was an employee of Janssen Pharmaceutical Companies of Johnson & Johnson at the time that the analyses and this publication were developed. K. C. has served as a steering committee member, on an advisory board, and has received research grants/support, and consultancy fees from Janssen Pharmaceutical Companies of Johnson & Johnson; has received research grants from United Therapeutics and Ironwood Pharmaceuticals; has served on an advisory board for Bayer Healthcare; and has received consultancy fees from United Therapeutics., (© 2022 Actelion Pharmaceuticals Ltd. Pulmonary Circulation published by John Wiley & Sons Ltd on behalf of Pulmonary Vascular Research Institute.)

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.)

Competing Interests: Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. ICMJE forms for all authors are available online.

Background: The majority of evidence with regards to minimally invasive liver resection (MILR) favors its application in minor hepatectomies. We conducted a propensity score-matched (PSM) analysis to determine its feasibility and safety in major hepatectomies (MIMH) for liver malignancies., Methods: Retrospective review of 130 patients who underwent MIMH and 490 patients who underwent open major hepatectomy (OMH) for malignant pathologies was performed. PSM in a 1:1 ratio identified two groups of patients with similar baseline clinicopathological characteristics. Perioperative outcomes were then compared. Major hepatectomies included traditional major (>3 segments) and technical major hepatectomies (right anterior and right posterior sectionectomies)., Results: Both cohorts were well-matched for baseline characteristics after PSM. Of 130 MIMH cases, there were 12 conversions to open. Comparison of perioperative outcomes demonstrated a significant association of MIMH with longer operation time and more frequent application of Pringle's maneuver (PM), but decreased postoperative stay. These results were consistent on a subgroup analysis that only included patients undergoing traditional major hepatectomies. A second subgroup analysis restricted to cirrhotic patients demonstrated that while perioperative outcomes were equivalent, MIMH was similarly associated with a longer operative time. Subset analyses of resections performed after 2015 demonstrated that MIMH was additionally associated with a lower postoperative morbidity compared to OMH., Conclusion: Comparison of perioperative and short-term oncological outcomes between MIMH and OMH for malignancies demonstrated that MIMH is feasible and safe. It is associated with a shorter hospital stay at the expense of a longer operation time compared to OMH., (© 2021. The Society for Surgery of the Alimentary Tract.)

Background: Minimally invasive surgery for the treatment of hallux valgus deformities has become increasingly popular. Knowledge of the location of the hallux metatarsophalangeal (MTP) proximal capsular origin on the metatarsal neck is essential for surgeons in planning and executing extracapsular corrective osteotomies. A cadaveric study was undertaken to further study this anatomic relationship., Methods: Ten nonpaired fresh-frozen frozen cadaveric specimens were used for this study. Careful dissection was performed, and the capsular origin of the hallux MTP joint was measured from the central portion of the metatarsal head in the medial, lateral, dorsal, plantarmedial, and plantarlateral dimensions., Results: The ten specimens had a mean age of 77 years, with 5 female and 5 male. The mean distances from the central hallux metatarsal head to the MTP capsular origin were 15.2 mm dorsally, 8.4 mm medially, 9.6 mm laterally, 19.3 mm plantarmedially, and 21.0 mm plantarlaterally., Conclusion: The MTP capsular origin at the hallux metatarsal varies at different anatomic positions. Knowledge of this capsular anatomy is critical for orthopaedic surgeons when planning and performing minimally invasive distal metatarsal osteotomies for the correction of hallux valgus., Type of Study: Cadaveric Study.

Introduction: In the event-driven GRIPHON randomised-controlled trial, the oral prostacyclin receptor agonist selexipag significantly reduced the risk of disease progression (composite primary endpoint of morbidity/mortality), compared with placebo, in patients with pulmonary arterial hypertension (PAH). The ongoing open-label extension study (GRIPHON OL) collects further data on long-term safety, tolerability, and survival of PAH patients treated with selexipag., Methods: Patients randomised to selexipag or placebo in GRIPHON could enter GRIPHON OL either after experiencing a morbidity event during double-blind treatment or at the end of the study. Patients were followed for adverse events (AE) and survival from selexipag initiation up to 3 days and 30 days after end of treatment, respectively. Data are presented up to a cut-off date of 1 September 2019., Results: Overall, 953 patients in GRIPHON and GRIPHON OL were treated with selexipag. At the time of selexipag initiation, 81.2% of patients were receiving background PAH therapy. Median (min, max) exposure to selexipag was 31.7 months (0, 106), corresponding to a total of 3054.4 patient-years. The most frequently reported AEs were related to known prostacyclin-related effects or underlying disease. There were 305 (32.0%) patients who experienced an AE leading to treatment discontinuation. Survival during GRIPHON and GRIPHON OL was assessed for the 574 patients randomised to selexipag in GRIPHON. Kaplan-Meier survival estimates (95%CI) at 1, 3, 5 and 7 years were 92.0% (89.4, 94.0), 79.3% (75.4, 82.6), 71.2% (66.5, 75.3) and 63.0% (57.4, 68.1), respectively., Conclusions: These results provide the longest follow-up period published to date for a PAH therapy. The safety profile of selexipag over this extended treatment period was consistent with that observed in GRIPHON. A large proportion of the population was receiving background therapy at selexipag initiation, providing further insight into the long-term safety of selexipag as part of a combination therapy regimen., Trial Registration: ClinicalTrials.gov Identifiers: NCT01106014 and NCT01112306., (© 2021. The Author(s).)

Aims: The number of pulmonary arterial hypertension (PAH) patients with comorbidities is increasing and there are limited data on response to PAH-targeted therapies in this population. These post hoc analyses explored the effect of selexipag in PAH patients with cardiovascular comorbidities in the GRIPHON study., Methods and Results: Randomized patients (n = 1156) were classified using three methods: (i) by subgroups defined according to previously published comorbidity count and restrictive haemodynamic criteria: Subgroup A (<3 comorbidities and haemodynamic criteria met; n = 962) and Subgroup B (≥3 comorbidities and/or haemodynamic criteria not met; n = 144); comorbidities included body mass index ≥30 kg/m 2 , essential hypertension, diabetes, history of coronary artery disease; (ii) by number of comorbidities, with addition of atrial fibrillation (0, 1, 2, 3, 4, or 5); (iii) by presence of individual comorbidities. Selexipag to placebo hazard ratios (HR) and 95% confidence intervals (CI) for morbidity/mortality (primary composite endpoint) were estimated using Cox regression adjusting selexipag effect for baseline covariates. Approximately half of the patients in GRIPHON (n = 584; 50.5%) had comorbidities. Selexipag reduced the risk of a morbidity/mortality event compared with placebo in both Subgroup A (HR 0.66, 95% CI 0.53, 0.82) and Subgroup B (HR 0.50, 95% CI 0.26, 0.96), with no evidence of an inconsistent treatment effect between subgroups (interaction p = 0.432). Consistent results were observed in analyses by number and by specific type of comorbidity., Conclusion: Selexipag reduces the risk of a morbidity/mortality event vs. placebo irrespective of patient comorbidity status, suggesting that comorbidity status does not influence the treatment effect of selexipag., (© 2021 Actelion Pharmaceuticals Ltd and Janssen Pharmaceuticals Company of Johnson & Johnson. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Background: In pulmonary arterial hypertension (PAH), there are no data comparing initial triple oral therapy with initial double oral therapy., Objectives: TRITON (The Efficacy and Safety of Initial Triple Versus Initial Dual Oral Combination Therapy in Patients With Newly Diagnosed Pulmonary Arterial Hypertension; NCT02558231), a multicenter, double-blind, randomized phase 3b study, evaluated initial triple (macitentan, tadalafil, and selexipag) versus initial double (macitentan, tadalafil, and placebo) oral therapy in newly diagnosed, treatment-naive patients with PAH., Methods: Efficacy was assessed until the last patient randomized completed week 26 (end of main observation period). The primary endpoint was change in pulmonary vascular resistance (PVR) at week 26., Results: Patients were assigned to initial triple (n = 123) or initial double therapy (n = 124). At week 26, both treatment strategies reduced PVR compared with baseline (by 54% and 52%), with no significant difference between groups (ratio of geometric means: 0.96; 95% confidence interval: 0.86-1.07; P = 0.42). Six-minute walk distance and N-terminal pro-brain natriuretic peptide improved by week 26, with no difference between groups. Risk for disease progression (to end of main observation period) was reduced with initial triple versus initial double therapy (hazard ratio: 0.59; 95% confidence interval: 0.32-1.09). Most common adverse events with initial triple therapy included headache, diarrhea, and nausea. By the end of the main observation period, 2 patients in the initial triple and 9 in the initial double therapy groups had died., Conclusions: In patients with newly diagnosed PAH, both treatment strategies markedly reduced PVR by week 26, with no significant difference between groups (primary endpoint not met). Exploratory analyses suggested a possible signal for improved long-term outcomes with initial triple versus initial double oral therapy., Competing Interests: Funding Support and Author Disclosures This study was funded by Actelion Pharmaceuticals, a Janssen Pharmaceutical Company of Johnson & Johnson. Dr Chin has served as a steering committee member for Janssen Pharmaceutical Companies of Johnson & Johnson; has received research grants from Janssen Pharmaceutical Companies of Johnson & Johnson, the National Institutes of Health, Ironwood Pharmaceuticals, and SoniVie; has served on advisory boards for Bayer Healthcare (through the University of California, San Diego) and Flowonix; has served as an adjudication committee member for Arena Pharmaceuticals; is an associate editor of Circulation for the American Heart Association; and has received consultancy fees from Janssen Pharmaceutical Companies of Johnson & Johnson. Prof Sitbon has served as a steering committee member for Janssen Pharmaceutical Companies of Johnson & Johnson; and has served as an advisory board member for and received research grants from Janssen Pharmaceutical Companies of Johnson & Johnson. Dr Doelberg is an employee of Actelion Pharmaceuticals. Dr Feldman has received speaker and consultancy fees from Bayer and United Therapeutics; and has received consultancy fees from Gilead, Gossamer, Acceleron, Altavant, Janssen Pharmaceutical Companies of Johnson & Johnson, and Bellerophon. Dr Gibbs has served as a steering committee member for Janssen Pharmaceutical Companies of Johnson & Johnson, Complexa, and Acceleron; has received consultancy fees from Arena; has received speaker fees from GlaxoSmithKline and Merck Sharp & Dohme; has served as a clinical endpoints committee member for Pfizer, Bayer, Bellerophon, Janssen Pharmaceutical Companies of Johnson & Johnson, and United Therapeutics; and has served as a data and safety monitoring board member for Janssen Pharmaceutical Companies of Johnson & Johnson. Prof Grünig has received grants and personal fees from Bayer, Janssen Pharmaceutical Companies of Johnson & Johnson, Merck Sharp & Dohme, and GlaxoSmithKline; and has received grants from Janssen Pharmaceutical Companies of Johnson & Johnson, Bayer/Merck Sharp & Dohme, GlaxoSmithKline, and United Therapeutics. Prof Hoeper has served as a steering committee member for Janssen Pharmaceutical Companies of Johnson & Johnson; has received speaker and consultancy fees from Janssen Pharmaceutical Companies of Johnson & Johnson, Bayer, GlaxoSmithKline, Merck Sharp & Dohme, and Pfizer; and has received research grants from Janssen Pharmaceutical Companies of Johnson & Johnson. Mr Martin is an employee of Actelion Pharmaceuticals. Dr Mathai has served as a steering committee member for Janssen Pharmaceutical Companies of Johnson & Johnson; and has served as a consultant for Arena, Liquidia, and United Therapeutics. Prof McLaughlin has served as a steering committee member for Janssen Pharmaceutical Companies of Johnson & Johnson; has received grants, personal fees, and nonfinancial support from Janssen Pharmaceutical Companies of Johnson & Johnson and Bayer; has received grants from Eiger and SoniVie; and has received personal fees from United Therapeutics, Arena, Caremark, Medtronic, and Merck Sharp & Dohme. Dr Perchenet is an employee of Actelion Pharmaceuticals; has previously held stock and stock options with Actelion Pharmaceuticals; and currently holds stock and stock options in the parent company Johnson & Johnson. Dr Poch has received speaker and consultancy fees from Bayer Healthcare. Dr Saggar has received consultancy fees and research funding from United Therapeutics and Janssen Pharmaceutical Companies of Johnson & Johnson. Prof Simonneau has served as a steering committee member for and received research grants from Janssen Pharmaceutical Companies of Johnson & Johnson and Bayer; and has received speaker and consultancy fees from Janssen Pharmaceutical Companies of Johnson & Johnson, Bayer, GlaxoSmithKline, Merck Sharp & Dohme, and Pfizer. Prof Galiè is a steering committee member for Janssen Pharmaceutical Companies of Johnson & Johnson; has received grant support, personal fees, and nonfinancial support from Janssen Pharmaceutical Companies of Johnson & Johnson; and has received grant support and personal fees from Bayer Healthcare, Pfizer, and GlaxoSmithKline., (Copyright © 2021 The Authors. 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.)

Purpose: The CLASSICAL-Lung clinical trial tested the combination of pepinemab, an IgG4 humanized mAb targeting semaphorin 4D, with the PD-L1 inhibitor avelumab to assess the effects of coupling increased T-cell infiltration and reversal of immune suppression via pepinemab with sustained T-cell activation via checkpoint inhibition., Patients and Methods: This phase Ib/II, single-arm study was designed to evaluate the safety, tolerability, and efficacy of pepinemab in combination with avelumab in 62 patients with advanced non-small cell lung cancer (NSCLC), including immunotherapy-naïve (ION) patients and patients whose tumors progressed following anti-PD-1/L1 monotherapy (IOF). The main objectives were to evaluate safety/tolerability, establish a recommended phase 2 dose (RP2D), obtain a preliminary evaluation of antitumor activity, and investigate candidate biomarker activity., Results: The combination was well tolerated with no major safety signals identified. Pepinemab, 10 mg/kg with avelumab, 10 mg/kg, every 2 weeks, was selected as the RP2D. Among 21 evaluable ION patients, 5 patients experienced partial responses (PR), 4 patients evidenced clinical benefit ≥1 year, and the disease control rate (DCR) was 81%. Notably, overall response rate with the combination therapy was higher than previously reported for single-agent avelumab in the PD-L1-negative/low population. Among 29 evaluable IOF patients, the combination resulted in a DCR of 59%, including 2 PR and 7 patients with durable clinical benefit of ≥23 weeks. Biomarker analysis of biopsies demonstrated increased CD8 T-cell density correlating with RECIST response criteria., Conclusions: The combination of pepinemab with avelumab was well tolerated in NSCLC and showed signs of antitumor activity in immunotherapy-resistant and PD-L1-negative/low tumors., (©2021 American Association for Cancer Research.)

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: Chronic thromboembolic pulmonary hypertension (CTEPH) is a rare sequela of acute pulmonary embolism that is treatable when recognized. Awareness of this disease has increased with recent advancements in therapeutic options, but delays in diagnosis remain common, and diagnostic and treatment guidelines are often not followed. Data gathered from international registries have improved our understanding of CTEPH, but these data may not be applicable to the US population owing to differences in demographics and medical practice patterns., Objective: The US CTEPH Registry (US-CTEPH-R) was developed to provide essential information to better understand the demographics, risk factors, evaluation, and treatment of CTEPH in the United States, as well as the short- and long-term outcomes of surgical and nonsurgical therapies in the modern treatment era., Methods: Thirty sites throughout the United States enrolled 750 subjects in this prospective, longitudinal, observational registry of patients newly diagnosed with CTEPH. Enrollment criteria included a mean pulmonary artery pressure ≥25 mmHg by right heart catheterization and radiologic confirmation of CTEPH by a multidisciplinary adjudication committee. Following enrollment, subjects were followed biannually until the conclusion of the study. Quality of life surveys were administered at enrollment and biannually, and all other testing was at the discretion of the treating clinician. Details regarding surgical therapy, balloon pulmonary angioplasty, and medical therapy were collected at enrollment and at follow-up, as well as information related to health care utilization and survival., Results: Data from this registry will improve understanding of the demographics, risk factors, and treatment patterns of patients with CTEPH, and the longitudinal impact of therapies on quality of life, health care utilization, and survival., Conclusions: This manuscript details the methodology and design of the first large, prospective, longitudinal registry of patients with CTEPH in the United States., Trial Registration: ClinicalTrials.gov NCT02429284; https://www.clinicaltrials.gov/ct2/show/NCT02429284., International Registered Report Identifier (irrid): DERR1-10.2196/25397., (©Kim M Kerr, C Greg Elliott, Raymond L Benza, Richard N Channick, Kelly M Chin, R Duane Davis, Sonia Jain, Andrea Z LaCroix, Michael M Madani, Vallerie V McLaughlin, Myung H Park, Victor F Tapson, William R Auger. Originally published in JMIR Research Protocols (https://www.researchprotocols.org), 25.05.2021.)

Background: The utility of minimally-invasive liver resection (MILR) for deep centrally located tumours (CLT) remains controversial. We aimed to review our institution's experience and outcomes with minimally invasive central hepatectomy (CH) and right anterior sectionectomy (RAS) for CLT in a propensity score-matched (PSM) analysis., Methods: Retrospective review of a prospectively maintained surgical database revealed 23 patients who underwent MILR (6 CH, 17 RAS) and 53 patients who underwent open liver resection (OLR; 24 CH, 29 RAS) for CLT. PSM in a 1:1 ratio identified two groups of patients with similar baseline clinicopathological characteristics. Peri-operative outcomes were then compared., Results: There was one laparoscopic-assisted, one robot-assisted and two laparoscopic-converted-open procedures in the MILR cohort. Across the unmatched cohort, there was only one mortality (MILR) and five patients with major morbidity (all OLR). MILR was associated with a longer operating time (P < 0.001), but shorter post-operative hospital stay (P = 0.002) and decreased morbidity (P = 0.018) in the unmatched cohort. Examination of peri-operative outcomes after PSM revealed that MILR was similarly associated with a longer operating time (P = 0.001) and shortened post-operative hospital stay (P = 0.043). OLR was associated with a significantly reduced application of Pringle manoeuvre (P = 0.004). There were no significant differences between MILR and OLR with regards to blood loss, blood transfusions, morbidity and margin status in the PSM analysis., Conclusion: MILR for CLT is safe and feasible when performed by experienced surgeons. It is associated with shorter hospital stays but at the expense of longer operation times and more frequent application of Pringle manoeuver., (© 2021 Royal Australasian College of Surgeons.)

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: Group 3 pulmonary hypertension (PH) is a common complication in patients with lung diseases but there are currently no FDA-approved therapies. The data is conflicting, but a few small studies suggest potential benefits in using Group 1 PH therapies in these patients, particularly in severe PH with right ventricular (RV) dysfunction., Methods: A retrospective cohort study of patients with severe Group 3 PH with RV dysfunction who received parenteral prostanoids from 2007-2018 at our institution was undertaken. Severe PH was defined as mean pulmonary arterial pressure (mPAP) ≥35 mmHg or mPAP 25-34 with cardiac index (CI) <2.4 L/min/m 2 . Routine prognostic studies including N-terminal prohormone of brain natriuretic peptide (NT-proBNP), 6-minute walk distance (6MWD), WHO Functional Class assessment, oxygen requirement, arterial oxygen saturation, right ventricular systolic pressure (RVSP) and right heart catheterization (RHC) pressures, were obtained before initiation of parenteral therapy and at first clinical follow-up., Results: Nine patients were included. Five were female (55.6%) with a median [interquartile range (IQR)] of 69 [54-71] years. Median CI was 1.8 (1.6-2.4) L/min/m 2 and median pulmonary vascular resistance (PVR) was 14.7 (10.7-17.1) Wood units (WU). We found no statistically significant improvement in NT-proBNP levels, exercise capacity, or functional class. Resting oxygen requirement worsened from 4 to 6 L/min (P=0.04) and exertional oxygen saturation nadir worsened from 90% to 83% (P=0.01) despite the increase in FiO 2 with exertion. Overall results were heterogenous: several patients demonstrated clinical stabilization, with two undergoing lung transplantation and one showing long-term stability with medical therapy. Symptoms remained severe for most: three patients discontinued prostanoid therapy, choosing to pursue hospice care., Conclusions: We found no statistically significant improvement in NT-proBNP levels, exercise capacity, or functional class, while oxygen requirement at rest and oxygen saturation during exertion significantly worsened. Our results suggest that parenteral prostanoids should not generally be considered in the treatment of Group 3 PH patients., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/jtd-20-1635). TS reports grants from National Institutes of Health, grants from Actelion Pharmaceuticals, grants from Liquidia Technologies, grants from Bayer, grants from United Therapeutics, grants, personal fees and other from Gilead Sciences, outside the submitted work. SB reports grants from United Therapeutics, grants from Reata, grants from PhaseBio, grants from National Institutes of Health, grants from Complexa, grants from Pfizer, personal fees from Bayer, personal fees from Actelion Pharmaceuticals, outside the submitted work. FT reports grants from Liquida Technologies, grants from Bellerophon, grants from Altavant, grants from GSK, grants from Complexa, grants from PhaseBio, grants from Cyclerion, personal fees from Bayer, personal fees from Reata, personal fees from United Therapeutics, personal fees from Janssen (Actelion), personal fees from Pfizer, personal fees from Genentech, outside the submitted work. KC reports grants from Actelion, grants from SoniVie, grants from Ironwood, personal fees from Actelion, personal fees from United Therapeutics, personal fees from Bayer, personal fees from University of California San Diego, personal fees and other from American Heart Association, outside the submitted work. The other author has no conflicts of interest to disclose., (2021 Journal of Thoracic Disease. All rights reserved.)

Background: The oral IP receptor agonist selexipag is approved for the long-term treatment of pulmonary arterial hypertension (PAH). Treatment interruptions should be avoided due to the progressive nature of the disease. An intravenous (IV) formulation of selexipag was developed to provide a treatment option for short-term interruptions to oral selexipag. In this prospective, multicenter, open-label study, the safety, tolerability, and pharmacokinetics of temporarily switching between oral and IV selexipag were investigated (NCT03187678, ClinicalTrials.gov)., Methods: PAH patients receiving stable oral selexipag doses were enrolled. Following three consecutive IV selexipag infusions patients resumed oral selexipag. Corresponding IV and oral doses were selected to achieve comparable exposure to the active metabolite of selexipag. Safety outcomes were monitored throughout, and pharmacokinetic samples were obtained after oral and IV administration., Results: All 20 patients completed the study. Fifteen patients had adverse events (AEs), most were mild, and none resulted in discontinuation. Headache was the most common AE throughout the study (four patients). Three serious AEs occurred in two patients with underlying comorbidities when oral dosing had resumed. There were no changes in WHO functional class for any patient and no clinically symptomatic changes in blood pressure were observed. Comparable exposure to the active metabolite of selexipag was demonstrated following corresponding oral and IV selexipag doses., Conclusions: Temporarily switching between corresponding doses of oral and IV selexipag was well-tolerated with no unexpected safety findings and comparable exposure to the active metabolite. Treatment with IV selexipag is a feasible option to bridge temporary oral selexipag treatment interruptions.

Background: Minimally invasive liver resection (MILR) has been increasingly adopted over the past decade, and its application has been expanded to the management of extrapancreatic biliary malignancies (EPBMs). We aimed to evaluate the peri- and post-operative outcome of patients undergoing MILR for suspected EPMB., Methods: Forty-four consecutive patients who underwent MILR with a curative intent for EPBM at Singapore General Hospital between 2011 and 2018 were identified from a prospectively maintained surgical database. Clinical and operative data were analysed and compared to provide information and make comparisons on peri- and post-operative outcomes., Results: A total of 26, 5 and 13 patients underwent MILR for intrahepatic cholangiocarcinoma (ICC), perihilar cholangiocarcinoma (PHC) and gallbladder carcinoma (GBCA), respectively. Six major hepatectomies were performed, of which one was laparoscopic assisted and another was robot assisted. Ten patients underwent posterosuperior segmentectomies. There was one open conversion. The mean operative time was 266.5 min, and the mean blood loss was 379 ml. The mean length of hospital stay was 4.7 days with no incidences of 30- and 90-day mortality. The rate of recurrence-free survival (RFS) was 75% (at least 12-month follow-up). There was a significantly higher rate of robot-assisted procedures in patients undergoing MILR for GBCA/PHC as compared to ICC (P = 0.034). Patients undergoing posterosuperior segmentectomies required longer operative time (P = 0.018) with an increased need for (P = 0.001) and duration of (P = 0.025) Pringles manoeuvre. There were no differences in operative time, blood loss, morbidity, mortality or RFS between the above groups., Conclusion: Minimally invasive surgery can be adopted safely with a low open conversion rate for EPBMs., Competing Interests: None

Background: Liver resection (LR) is the main modality of treatment for hepatocellular carcinoma (HCC) and colorectal liver metastasis (CRLM). Post-hepatectomy liver failure (PHLF) remains the most dreaded complication. We aim to create a prognostic score for early risk stratification of patients undergoing LR., Methodology: Clinical and operative data of 472 patients between 2000 and 2016 with HCC or CRLM undergoing major hepatectomy were extracted and analysed from a prospectively maintained database. PHLF was defined using the 50-50 criteria., Results: Liver cirrhosis and fatty liver were histologically confirmed in 35.6% and 53% of patients. 4.7% (n = 22) of patients had PHLF. A 90-day mortality was 5.1% (n = 24). Pre-operative albumin-bilirubin score (p = 0.0385), prothrombin time (p < 0.0001) and the natural logarithm of the ratio of post-operative day 1 to pre-operative serum bilirubin (SB) (ln( POD1 Bil/ pre-op Bil); p < 0.0001) were significantly independent predictors of PHLF. The PHLF prognostic nomogram was developed using these factors with receiver operating curve showing area under curve of 0.88. Excellent sensitivity (94.7%) and specificity (95.7%) for the prediction of PHLF (50-50 criteria) were achieved at cut-offs of 9 and 11 points on this model. This score was also predictive of PHLF according to Peak Bil > 7 and International Study Group for Liver Surgery criteria, intensive care unit admissions, length of stay, all complications, major complications, re-admissions and mortality (p < 0.05)., Conclusions: The PHLF nomogram ( https://tinyurl.com/SGH-PHLF-Risk-Calculator ) can serve as a useful tool for early identification of patients at high risk of PHLF before the 'point of no return'. This allows enforcement of closer monitoring, timely intervention and mitigation of adverse outcomes.

In order to evaluate the therapeutic potential of fluoxetine in pulmonary arterial hypertension, 13 patients with pulmonary arterial hypertension underwent catheterization before and after 12 (N = 5) or 24 (N = 8) weeks fluoxetine therapy. No change was seen in the primary endpoint of pulmonary vascular resistance, other hemodynamic values, or any secondary endpoints., (© The Author(s) 2020.)

Background: This study aimed to determine pre- and peri-operative parameters with significant predictive value for post-operative outcomes in patients with recurrent colorectal cancer presenting as peritoneal carcinomatosis undergoing cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS-HIPEC), and to develop a novel prognostic scoring system for prediction of survival outcomes., Methods: A single-institution review of prospectively collected data from all patients who underwent CRS-HIPEC between October 2005 and October 2017 was conducted. Univariate and multivariate analyses were used to identify significant parameters for prediction of post-CRS-HIPEC disease-free survival and overall survival (OS)., Results: A total of 278 patients underwent CRS-HIPEC, of whom 72 were for peritoneal carcinomatosis from recurrent colorectal cancer. Disease-free interval (DFI; P = 0.006), peritoneal cancer index (PCI; P = 0.001) and left upper quadrant disease (P = 0.023) were significant independent predictors of 3-year OS. DFI (0.007), PCI (P < 0.001) and intraoperative blood loss (BL; P = 0.001) were significant independent predictors of 5-year OS. PCI and BL were significant independent predictors of both 3-year (P = 0.026, PCI; P = 0.009, BL) and 5-year (P = 0.002, PCI; P = 0.011, BL) disease-free survival. Predictive models were developed for risk stratification of OS., Conclusion: PCI, DFI, left upper quadrant disease and BL have significant predictive value for post-CRS-HIPEC outcomes. Risk stratification models allow for more prudent patient selection and ultimately more accurate prognostication of post-operative outcomes., (© 2020 Royal Australasian College of Surgeons.)

The authors assessed the effects of forearm rotation on the proximity of the radial nerve and medial collateral ligament (MCL) to a proximal and a more distal arthroscopic anterior elbow capsulectomy. Arthroscopy was performed on 10 cadaveric specimens. Sutures were passed lateral to medial at the level of the radiocapitellar joint and at the proximal edge of the annular ligament. Dissection measured the distance to the radial nerve from the lateral starting point and to the MCL from the medial exit point in varying degrees of forearm rotation. The extent of brachialis muscle coverage of the radial nerve was documented. The distance from the starting point to the radial nerve increased in pronation at both levels. The medial extent of the capsulectomy remained a safe distance from the MCL. Brachialis muscle covered the radial nerve at both levels. Pronation increases the capsulectomy safe zone, including more distally, before encountering the radial nerve; the MCL is not at risk. [Orthopedics. 2020;43(5):e399-e403.]., (Copyright 2020, SLACK Incorporated.)