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Pulmonary hypertension (PH) is highly heterogeneous and despite treatment advances it remains a life‐shortening condition. There have been significant advances in imaging technologies, but despite evidence of their potential clinical utility, practice remains variable, dependent in part on imaging availability and expertise. This statement summarizes current and emerging imaging modalities and their potential role in the diagnosis and assessment of suspected PH. It also includes a review of commonly encountered clinical and radiological scenarios, and imaging and modeling‐based biomarkers. An expert panel was formed including clinicians, radiologists, imaging scientists, and computational modelers. Section editors generated a series of summary statements based on a review of the literature and professional experience and, following consensus review, a diagnostic algorithm and 55 statements were agreed. The diagnostic algorithm and summary statements emphasize the key role and added value of imaging in the diagnosis and assessment of PH and highlight areas requiring further research.

There are physiological consequences of overeating that can lead to increased morbidity and mortality. The purpose of this review article is to acquaint the reader with the current state of the art in the non–cardiac-gated, noncontrast chest computed tomographic (NCCT) imaging biomarkers of the metabolic syndrome and their prognostic significance found in the lower neck and chest. NCCT imaging biomarkers associated with metabolic syndrome in the chest include premature coronary artery calcification, acceleration of large vessel arterial and valvular calcifications associated with atherosclerosis, and pulmonary arterial enlargement from pulmonary hypertension associated with sleep apnea. These easily identified imaging biomarkers have prognostic implications for major adverse cardiac events (MACE). These NCCT chest-imaging biomarkers are likely targets for artificial intelligence algorithms to harvest for longitudinal assessment of their individual and multifactorial contributions to chronic disease, MACE, and mortality. Early recognition and treatment of these common disorders may help improve patient outcomes and quality of life while decreasing medical costs.

TPS462 Background: Dysregulation of fibroblast growth factor receptor (FGFR) signaling by FGFR genetic alterations is implicated in many cancers, including cholangiocarcinoma (CCA). FGFR2 translocations with fusion partners occur in ≈10% to 20% of intrahepatic CCA tumors. Pemigatinib is a selective oral inhibitor of FGFR-1, 2, 3. Preliminary data from the ongoing phase 2 study show efficacy and tolerable safety in patients (pts) with CCA with FGFR2 translocations. We present the design for a phase 3, open-label, randomized trial investigating pemigatinib monotherapy versus gemcitabine plus cisplatin chemotherapy in the first-line treatment of pts with advanced/metastatic or unresectable CCA with FGFR2 rearrangement. Methods: Eligible pts (target, N = 432) are ≥ 18 years (≥ 20 years for Japanese pts) and have ECOG performance status ≤ 1 and histologically confirmed advanced (locally advanced, metastatic, or recurrent) CCA with a documented FGFR2 rearrangement. Key exclusion criteria include prior systemic therapy, excluding adjuvant/neoadjuvant treatment completed ≥ 6 months before enrollment; current evidence of clinically significant corneal or retinal disorder; history of calcium and phosphate homeostasis disorder or systemic mineral imbalance with ectopic calcification of soft tissues; and known, untreated CNS metastases or history of uncontrolled seizures. Pts are randomized 1:1 and stratified by geographic region and tumor burden into 2 treatment groups: pemigatinib starting dose 13.5 mg once daily continuously on a 3-week cycle; or gemcitabine (1000 mg/m2) and cisplatin (25 mg/m2) administered intravenously on days 1 and 8 of every 3-week cycle for up to 8 cycles until disease progression or unacceptable toxicity. Crossover to pemigatinib may be allowed once progressive disease is confirmed. The primary endpoint is progression-free survival (based on independent central review using RECIST v1.1). Secondary endpoints include overall response rate, overall survival, duration of response, disease control rate, safety and tolerability, and impact on quality of life. Clinical trial information: NCT03656536.

TPS545 Background: Advanced cholangiocarcinoma (CC) is a life-threatening disease with limited effective chemotherapy options. Mutations in isocitrate dehydrogenase 1 (mIDH1) occur in 13–15% of CC cases, and up to 25% of intrahepatic CC cases, leading to epigenetic and genetic changes that promote oncogenesis via production of the oncometabolite 2-hydroxyglutarate (2-HG). AG-120 (ivosidenib), a first-in-class oral mIDH1 inhibitor, displayed a favorable safety profile and clinical activity in a phase 1 study enrolling 73 mIDH1 CC patients who had received ≥1 prior systemic regimen. As of 10 Mar 2017, 4/73 (5%) had a partial response and 41/73 (56%) stable disease. Progression free survival (PFS) rates at 6 months and 12 months were 38.5% and 20.7%, respectively. The 500 mg once daily dose level of AG-120 was selected for further development in mIDH1 CC. Methods: ClarIDHy is a global, phase 3, multicenter, double-blind, randomized (2:1) study of AG-120 (500 mg once daily) vs. matched placebo in 186 mIDH1 CC patients (ClinicalTrials.gov NCT02989857). Key eligibility criteria: non-resectable or metastatic CC, documented mIDH1 by central laboratory testing, ECOG performance status 0–1, measurable disease (RECIST v1.1), documented disease progression after ≤2 prior systemic therapies in the advanced setting including at least 1 gemcitabine- or 5-fluorouracil-containing regimen, and no prior mIDH inhibitor therapy. Crossover from placebo to AG-120 will be allowed at time of radiographic disease progression. Primary endpoint: PFS assessed by independent radiologists. Secondary endpoints: safety, tolerability, overall response rate (RECIST 1.1), overall survival, pharmacokinetic/pharmacodynamic analyses, and quality of life (EORTC QLQ-C30 and QLQ-BIL21 scales). An independent data monitoring committee will monitor the data during study conduct. The ClarIDHy study is currently activated at participating sites in the US, UK, EU, and S. Korea. R eused with permission from the American Society of Clinical Oncology (ASCO). This abstract was accepted and previously presented at the 2017 ASCO Annual Meeting. All rights reserved. Clinical trial information: NCT02989857.

TPS4142 Background: Advanced cholangiocarcinoma (CC) is a life-threatening disease for which there are limited therapeutic options. Mutations in isocitrate dehydrogenase 1 (mIDH1) occur in up to 25% of intrahepatic CC cases. mIDH1 lead to epigenetic and genetic changes that promote oncogenesis via production of the oncometabolite, D-2-hydroxyglutarate (2-HG). AG-120 is a first-in-class oral inhibitor of the mIDH1 enzyme, and is being tested in a phase 1 study that enrolled 73 patients (pts) with mIDH1 CC who had received a median of 2 prior therapies (range 1–5). AG-120 has demonstrated a favorable safety profile and clinical activity in this study. Among the 72 efficacy evaluable pts (≥1 post-baseline response assessment or discontinued prematurely), 6% (n = 4) had a confirmed partial response and 56% (n = 40) had stable disease. Progression-free survival (PFS) rate at 6 months was 40% as of Dec 16, 2016. The 500 mg once daily (QD) dose of AG-120 was selected for the ongoing phase 3 study in mIDH1 CC described here. Methods: ClarIDHy is a global, phase 3, multicenter, double-blind study randomizing 186 pts with mIDH1 CC in a 2:1 ratio to AG-120 (500 mg QD) or matched placebo (NCT02989857). Key eligibility criteria: nonresectable or metastatic CC; documented mIDH1 based on central laboratory testing; ECOG 0–1; measurable disease (RECIST v1.1); documented disease progression following ≤2 prior systemic therapies in the advanced setting, including at least 1 gemcitabine- or 5-fluorouracil-containing regimen; and no prior mIDH inhibitor therapy. Crossover from the placebo arm to the AG-120 arm will be permitted. The primary endpoint is PFS as assessed by an independent review. Secondary endpoints include safety, tolerability, overall response rate, overall survival, pharmacokinetic and pharmacodynamic analyses on plasma, and quality of life as assessed by the EORTC QLQ-C30, EORTC QLQ-BIL21, and EQ-5D-5L instruments. An independent data monitoring committee will monitor the data throughout the study. The ClarIDHy study is currently activated at participating sites in the US and will be activated in centers throughout Europe and in South Korea. Clinical trial information: NCT02989857.

Prostacyclin (PGI2) and Ibuprofen (IP) may preserve platelet integrity and function during cardiopulmonary bypass (CPB). Platelet consumption on bubble and membrane oxygenator, platelet lysis, and platelet microembolism were studied in 7 control, 6 PGI2-, and 5 IP-treated dogs undergoing CPB. At 18 hours after I.V. administration of autologous In-Ill-labeled platelets (300 μCi), 7 heparinized dogs (300 u/kg), and 6 dogs treated with I.V. infusion of PGI2 (25 ng/kg/min) and heparin (100 u/kg), and 5 dogs with I.V. IP (12.5 mg/kg) 15 min prior to bypass procedure underwent CPB for 1 hour. In-111 in plasma obtained from platelet lysis was determined by centrifugation at 200,000 G of serial blood samples at 5-min intervals during CPB. Hemodilution was measured with I-125-labeled serum albumin (10 μCi). Platelet deposition on oxygenator was imaged with a gamma camera and quantitated with an ionization chamber. An insignificant amount of platelet (<0.2%) was found in the heat exchanger. In-111-labeled platelet level in blood of control dogs 20 min after CPB initiation decreased to 23 ± 5% of prebypass level, 38 ± 5% in PGI2 group, and 25 ± 5% in the IP group. Plasma In-111 increased to 34±7% in control, 15±5% in PGI2 group, and 17±3% in IP group (p< 0.01). Platelet deposition on the oxygenator amounted to 20±5% of In-111 platelets in control, 11±3% of PGI2, and 13±4% in IP group (p< 0.01). These results indicate that both PGI2 and IP significantly reduce platelet consumption in oxygenator and platelet lysis during CPB. Thus PGI2 may reduce postoperative bleeding. Ibuprofen, although preserving platelet function, has a longer duration of action and, hence, systemic administration prior to CPB is not practical. Surface coating of extracorporeal surfaces with IP might be beneficial.

PURPOSE: We evaluated the safety and efficacy of weekly paclitaxel therapy in women with metastatic breast cancer in a phase II multicenter trial. Entry criteria were relatively liberal to reflect the heterogeneity of metastatic breast cancer in clinical practice. PATIENTS AND METHODS: Patients had histologically confirmed and measurable metastatic breast cancer. Up to two prior chemotherapy regimens for metastatic disease, including prior therapy with anthracyclines and taxanes and prior high-dose therapy, were allowed. Paclitaxel 80 mg/m2 was administered weekly for 4 weeks per 4-week cycle. RESULTS: We enrolled 212 patients; 211 were assessable for toxicity and 177 were assessable for response. Ninety percent of patients had received prior chemotherapy (adjuvant, metastatic, or both), 46% of patients had three or more involved metastatic sites, and 60% of patients had visceral-dominant disease. Responses were documented on two occasions and were independently reviewed. The overall response rate (complete plus partial response) was 21.5% (95% confidence interval, 15.4% to 27.5%), with 41.8% of patients having disease stabilization. Median time to progression was 4.7 months, and overall survival in all 212 patients enrolled was 12.8 months. Therapy was well tolerated, with a 15% incidence of grade 3/4 hematologic toxicity and a 9% incidence of grade 3 neurotoxicity; other serious toxicities were rare. The response rate and toxicity profile in the 34% of patients ≥ 65 years of age were similar to that of younger patients. CONCLUSION: Weekly paclitaxel therapy was well tolerated and demonstrated reasonable activity in this relatively heavily pretreated population with advanced disease. Further study of weekly paclitaxel in combination therapy is warranted.

Early diagnosis of males with X-linked adrenoleukodystrophy (X-ALD) is essential for preventing loss of life due to adrenal insufficiency and for timely therapy of the childhood cerebral form of X-ALD with hematopoietic cell transplantation. This article describes X-ALD, the current therapies, the history of the development of the newborn screening test, the approval by the Secretary of Health and Human Services for the addition of X-ALD newborn screening to the recommended uniform panel of disorders screened as newborns (RUSP) and the successful implementation of X-ALD newborn screening in the state of New York beginning on 30 December 2013. Follow-up guidelines that have been established in New York are outlined. Based on the success of newborn screening in New York, and early results in Connecticut, where X-ALD newborn screening started in December 2015, and in California, where X-ALD newborn screening began in September 2016, we are confident and hopeful that X-ALD newborn screening will expand to include all US states and to countries that have established neonatal screening programs. The Minster of Health in the Netherlands has approved the addition of X-ALD to the newborn screening program with a start date expected in 2017. The states, such as Massachusetts, Illinois, Minnesota, New Jersey, Florida and Washington, that have legislative approval will commence screening as soon as budgetary resources, testing and follow-up procedures are in place.

Abstract Breast, ovarian, and prostate cancers are hormone-related and may have a shared genetic basis, but this has not been investigated systematically by genome-wide association (GWA) studies. Meta-analyses combining the largest GWA meta-analysis data sets for these cancers totaling 112,349 cases and 116,421 controls of European ancestry, all together and in pairs, identified at P &lt; 10−8 seven new cross-cancer loci: three associated with susceptibility to all three cancers (rs17041869/2q13/BCL2L11; rs7937840/11q12/INCENP; rs1469713/19p13/GATAD2A), two breast and ovarian cancer risk loci (rs200182588/9q31/SMC2; rs8037137/15q26/RCCD1), and two breast and prostate cancer risk loci (rs5013329/1p34/NSUN4; rs9375701/6q23/L3MBTL3). Index variants in five additional regions previously associated with only one cancer also showed clear association with a second cancer type. Cell-type–specific expression quantitative trait locus and enhancer–gene interaction annotations suggested target genes with potential cross-cancer roles at the new loci. Pathway analysis revealed significant enrichment of death receptor signaling genes near loci with P &lt; 10−5 in the three-cancer meta-analysis. Significance: We demonstrate that combining large-scale GWA meta-analysis findings across cancer types can identify completely new risk loci common to breast, ovarian, and prostate cancers. We show that the identification of such cross-cancer risk loci has the potential to shed new light on the shared biology underlying these hormone-related cancers. Cancer Discov; 6(9); 1052–67. ©2016 AACR. This article is highlighted in the In This Issue feature, p. 932

AbstractThe Patient‐Centered Outcomes Research Institute (PCORI) was established by Congress in 2010 to promote the conduct of research that could better inform patients in making decisions that reflect their desired health outcomes. PCORI has established five national priorities for research around which specific funding opportunities are issued: 1) assessment of prevention, diagnosis, and treatment options; 2) improving healthcare systems; 3) communication and dissemination research; 4) addressing disparities; and 5) improving methods for conducting patient‐centered outcomes research. To date, implementation of patient‐centered research in the emergency care setting has been limited, in part because of perceived challenges in meeting PCORI priorities such as the need to focus on a specific disease state or to have planned follow up. We suggest that these same factors that have been seen as challenges to performing patient‐centered research within the emergency setting are also potential strengths to be leveraged to conduct PCORI research. This paper explores factors unique to patient‐centered emergency care research and highlights specific areas of potential alignment within each PCORI priority.