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Rebecca J Lee, Anne C Armstrong, Andrew M WardleyDepartment of Medical Oncology, The Christie NHS Foundation Trust, Wilmslow Road, Manchester, UKAbstract: The number of targeted treatments has risen exponentially over the last few years and is an important concept in the fight against cancer. This review will concentrate on some of the main treatments targeting aberrant pathways which have been tested mainly in the Phase I/II setting. These include human epidermal growth factor receptor 2 inhibitors, drug-antibody conjugates, epidermal growth factor receptor inhibitors, vascular endothelial growth factor inhibitors, reticular activating system, mammalian target of rapamycin and multi-kinase inhibitors. Further knowledge of these pathways and the predictors of response to them will enable personalized medicine to become a reality.Keywords: breast cancer, targeted therapy, tyrosine kinase, receptor

PARTNER is a prospective, phase II-III, randomized controlled clinical trial that recruited patients with triple-negative breast cancer 1,2 , who were germline BRCA1 and BRCA2 wild type 3 . Here we report the results of the trial. Patients (n = 559) were randomized on a 1:1 basis to receive neoadjuvant carboplatin-paclitaxel with or without 150 mg olaparib twice daily, on days 3 to 14, of each of four cycles (gap schedule olaparib, research arm) followed by three cycles of anthracycline-based chemotherapy before surgery. The primary end point was pathologic complete response (pCR) 4 , and secondary end points included event-free survival (EFS) and overall survival (OS) 5 . pCR was achieved in 51% of patients in the research arm and 52% in the control arm (P = 0.753). Estimated EFS at 36 months in the research and control arms was 80% and 79% (log-rank P > 0.9), respectively; OS was 90% and 87.2% (log-rank P = 0.8), respectively. In patients with pCR, estimated EFS at 36 months was 90%, and in those with non-pCR it was 70% (log-rank P < 0.001), and OS was 96% and 83% (log-rank P < 0.001), respectively. Neoadjuvant olaparib did not improve pCR rates, EFS or OS when added to carboplatin-paclitaxel and anthracycline-based chemotherapy in patients with triple-negative breast cancer who were germline BRCA1 and BRCA2 wild type. ClinicalTrials.gov ID: NCT03150576 ., (© 2024. The Author(s).)

Purpose: Here, we report the sensitivity of a personalized, tumor-informed circulating tumor DNA (ctDNA) assay (Signatera) for detection of molecular relapse during long-term follow-up of patients with breast cancer., Methods: A total of 156 patients with primary breast cancer were monitored clinically for up to 12 years after surgery and adjuvant chemotherapy. Semiannual blood samples were prospectively collected, and analyzed retrospectively to detect residual disease by ultradeep sequencing using ctDNA assays, developed from primary tumor whole-exome sequencing data., Results: Personalized Signatera assays detected ctDNA ahead of clinical or radiologic relapse in 30 of the 34 patients who relapsed (patient-level sensitivity of 88.2%). Relapse was predicted with a lead interval of up to 38 months (median, 10.5 months; range, 0-38 months), and ctDNA positivity was associated with shorter relapse-free survival ( P < .0001) and overall survival ( P < .0001). All relapsing triple-negative patients (n = 7/23) had a ctDNA-positive test within a median of 8 months (range, 0-19 months), while the 16 nonrelapsed patients with triple-negative breast cancer remained ctDNA-negative during a median follow-up of 58 months (range, 8-99 months). The four patients who had negative tests before relapse all had hormone receptor-positive (HR+) disease and conversely, five of the 122 nonrelapsed patients (all HR+) had an occasional positive test., Conclusion: Serial postoperative ctDNA assessment has strong prognostic value, provides a potential window for earlier therapeutic intervention, and may enable more effective monitoring than current clinical tests such as cancer antigen 15-3. Our study provides evidence that those with serially negative ctDNA tests have superior clinical outcomes, providing reassurance to patients with breast cancer. For select cases with HR+ disease, decisions about treatment management might require serial monitoring despite the ctDNA-positive result.

Purpose: ER+/HER2- advanced breast cancer (ABC) with visceral crisis (VC) or impending VC (IVC) is commonly treated with chemotherapy instead of CDK4/6 inhibitors (CDK4/6i). However, there is little evidence to confirm which treatment is superior. This study compared outcomes of patients with ER+/HER2- ABC and IVC/VC treated with CDK4/6i or weekly paclitaxel., Methods: Patients with ER+/HER2- ABC receiving first line treatment at a large tertiary UK cancer centre from 1-Mar-2017 to 30-Jun-2021 were retrospectively identified. Hospital records were screened for IVC/VC affecting the liver, lungs/mediastinum, gastrointestinal tract and/or bone marrow. Baseline demographics, clinical data and survival outcomes were recorded up to 30-Jul-2022., Results: 27/396 (6.8%) patients with ABC who received CDK4/6i and 32/86 (37.2%) who received paclitaxel had IVC/VC. Median time to treatment failure (TTF), progression-free survival (PFS) and overall survival (OS) were significantly longer in the CDK4/6i compared to paclitaxel cohort: TTF 17.3 vs. 3.5 months (HR 0.33, 95%CI 0.17-0.61, p = 0.0002), PFS 17.8 vs. 4.5 months (HR 0.38, 95%CI 0.21-0.67, p = 0.002), OS 24.6 vs. 6.7 months (HR 0.37, 95%CI 0.20-0.68, p = 0.002). The median time to first improvement in IVC/VC was similar in patients receiving CDK4/6i compared to paclitaxel (3.9 vs. 3.6 weeks, p = 0.773). Disease control at 4 months was not significantly different in the CDK4/6i and paclitaxel cohorts (77.8% vs. 59.4%, p = 0.168). In multivariate analysis, treatment with CDK4/6i was independently associated with a longer PFS compared to paclitaxel (HR 0.31, 95%CI 0.12-0.78, p = 0.015)., Conclusion: In this retrospective study, patients with ER+/HER2- ABC and IVC/VC treated with CDK4/6i had a significantly better survival compared to those treated with weekly paclitaxel. Further prospective studies that minimise possible selection bias are recommended., (© 2023. The Author(s).)

Background: Pre-clinical models demonstrate that platelet activation is involved in the spread of malignancy. Ongoing clinical trials are assessing whether aspirin, which inhibits platelet activation, can prevent or delay metastases., Methods: Urinary 11-dehydro-thromboxane B 2 (U-TXM), a biomarker of in vivo platelet activation, was measured after radical cancer therapy and correlated with patient demographics, tumour type, recent treatment, and aspirin use (100 mg, 300 mg or placebo daily) using multivariable linear regression models with log-transformed values., Results: In total, 716 patients (breast 260, colorectal 192, gastro-oesophageal 53, prostate 211) median age 61 years, 50% male were studied. Baseline median U-TXM were breast 782; colorectal 1060; gastro-oesophageal 1675 and prostate 826 pg/mg creatinine; higher than healthy individuals (~500 pg/mg creatinine). Higher levels were associated with raised body mass index, inflammatory markers, and in the colorectal and gastro-oesophageal participants compared to breast participants (P < 0.001) independent of other baseline characteristics. Aspirin 100 mg daily decreased U-TXM similarly across all tumour types (median reductions: 77-82%). Aspirin 300 mg daily provided no additional suppression of U-TXM compared with 100 mg., Conclusions: Persistently increased thromboxane biosynthesis was detected after radical cancer therapy, particularly in colorectal and gastro-oesophageal patients. Thromboxane biosynthesis should be explored further as a biomarker of active malignancy and may identify patients likely to benefit from aspirin., (© 2023. The Author(s).)

Background: Coronary artery calcium (CAC) scanning can be performed using non-contrast computed tomography to predict cardiovascular events, but has less value for risk stratification in symptomatic patients., Objective: To identify and validate predictors of significant coronary obstruction (SCO) in symptomatic patients without coronary artery calcification., Methods: A total of 4,258 participants were screened from the CORE64 and CORE320 studies that enrolled patients referred for invasive angiography, and from the Quanta Registry that included patients referred for coronary computed tomography angiography (CTA). Logistic regression models evaluated associations between cardiovascular risk factors, CAC, and SCO. An algorithm to assess the risk of SCO was proposed for patients without CAC. Significance level of 5% was used in the analyses., Results: Of the 509 participants of the CORE study, 117 (23%) had zero coronary calcium score; 13 (11%) patients without CAC had SCO. Zero calcium score was related to younger age, female gender, lower body mass index, no diabetes, and no dyslipidemia. Being a current smoker increased ~3.5 fold the probability of SCO and other CV risk factors were not significantly associated. Considering the clinical findings, an algorithm to further stratify zero calcium score patients was proposed and had a limited performance in the validation cohort (AUC 58; 95%CI 43, 72)., Conclusion: A lower cardiovascular risk profile is associated with zero calcium score in a setting of high-risk patients. Smoking is the strongest predictor of SCO in patients without CAC.

Background: The randomized, double-blind OlympiA trial compared 1 year of the oral poly(adenosine diphosphate-ribose) polymerase inhibitor, olaparib, to matching placebo as adjuvant therapy for patients with pathogenic or likely pathogenic variants in germline BRCA1 or BRCA2 (gBRCA1/2pv) and high-risk, human epidermal growth factor receptor 2-negative, early breast cancer (EBC). The first pre-specified interim analysis (IA) previously demonstrated statistically significant improvement in invasive disease-free survival (IDFS) and distant disease-free survival (DDFS). The olaparib group had fewer deaths than the placebo group, but the difference did not reach statistical significance for overall survival (OS). We now report the pre-specified second IA of OS with updates of IDFS, DDFS, and safety., Patients and Methods: One thousand eight hundred and thirty-six patients were randomly assigned to olaparib or placebo following (neo)adjuvant chemotherapy, surgery, and radiation therapy if indicated. Endocrine therapy was given concurrently with study medication for hormone receptor-positive cancers. Statistical significance for OS at this IA required P < 0.015., Results: With a median follow-up of 3.5 years, the second IA of OS demonstrated significant improvement in the olaparib group relative to the placebo group [hazard ratio 0.68; 98.5% confidence interval (CI) 0.47-0.97; P = 0.009]. Four-year OS was 89.8% in the olaparib group and 86.4% in the placebo group (Δ 3.4%, 95% CI -0.1% to 6.8%). Four-year IDFS for the olaparib group versus placebo group was 82.7% versus 75.4% (Δ 7.3%, 95% CI 3.0% to 11.5%) and 4-year DDFS was 86.5% versus 79.1% (Δ 7.4%, 95% CI 3.6% to 11.3%), respectively. Subset analyses for OS, IDFS, and DDFS demonstrated benefit across major subgroups. No new safety signals were identified including no new cases of acute myeloid leukemia or myelodysplastic syndrome., Conclusion: With 3.5 years of median follow-up, OlympiA demonstrates statistically significant improvement in OS with adjuvant olaparib compared with placebo for gBRCA1/2pv-associated EBC and maintained improvements in the previously reported, statistically significant endpoints of IDFS and DDFS with no new safety signals., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Patients with cancer have been shown to have increased risk of COVID-19 severity. We previously built and validated the COVID-19 Risk in Oncology Evaluation Tool (CORONET) to predict the likely severity of COVID-19 in patients with active cancer who present to hospital. We assessed the differences in presentation and outcomes of patients with cancer and COVID-19, depending on the wave of the pandemic. We examined differences in features at presentation and outcomes in patients worldwide, depending on the waves of the pandemic: wave 1 D614G (n = 1430), wave 2 Alpha (n = 475), and wave 4 Omicron variant (n = 63, UK and Spain only). The performance of CORONET was evaluated on 258, 48, and 54 patients for each wave, respectively. We found that mortality rates were reduced in subsequent waves. The majority of patients were vaccinated in wave 4, and 94% were treated with steroids if they required oxygen. The stages of cancer and the median ages of patients significantly differed, but features associated with worse COVID-19 outcomes remained predictive and did not differ between waves. The CORONET tool performed well in all waves, with scores in an area under the curve (AUC) of >0.72. We concluded that patients with cancer who present to hospital with COVID-19 have similar features of severity, which remain discriminatory despite differences in variants and vaccination status. Survival improved following the first wave of the pandemic, which may be associated with vaccination and the increased steroid use in those patients requiring oxygen. The CORONET model demonstrated good performance, independent of the SARS-CoV-2 variants.

Nearly all estrogen receptor (ER)-positive (POS) metastatic breast cancers become refractory to endocrine (ET) and other therapies, leading to lethal disease presumably due to evolving genomic alterations. Timely monitoring of the molecular events associated with response/progression by serial tissue biopsies is logistically difficult. Use of liquid biopsies, including circulating tumor cells (CTC) and circulating tumor DNA (ctDNA), might provide highly informative, yet easily obtainable, evidence for better precision oncology care. Although ctDNA profiling has been well investigated, the CTC precision oncology genomic landscape and the advantages it may offer over ctDNA in ER-POS breast cancer remain largely unexplored. Whole-blood (WB) specimens were collected at serial time points from patients with advanced ER-POS/HER2-negative (NEG) advanced breast cancer in a phase I trial of AZD9496, an oral selective ER degrader (SERD) ET. Individual CTC were isolated from WB using tandem CellSearch ® /DEPArray™ technologies and genomically profiled by targeted single-cell DNA next-generation sequencing (scNGS). High-quality CTC (n = 123) from 12 patients profiled by scNGS showed 100% concordance with ctDNA detection of driver estrogen receptor α (ESR1) mutations. We developed a novel CTC-based framework for precision medicine actionability reporting (MI-CTCseq) that incorporates novel features, such as clonal predominance and zygosity of targetable alterations, both unambiguously identifiable in CTC compared to ctDNA. Thus, we nominated opportunities for targeted therapies in 73% of patients, directed at alterations in phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA), fibroblast growth factor receptor 2 (FGFR2), and KIT proto-oncogene, receptor tyrosine kinase (KIT). Intrapatient, inter-CTC genomic heterogeneity was observed, at times between time points, in subclonal alterations. Our analysis suggests that serial monitoring of the CTC genome is feasible and should enable real-time tracking of tumor evolution during progression, permitting more combination precision medicine interventions., (© 2021 The Authors. Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.)

Purpose: Patients with cancer are at increased risk of severe COVID-19 disease, but have heterogeneous presentations and outcomes. Decision-making tools for hospital admission, severity prediction, and increased monitoring for early intervention are critical. We sought to identify features of COVID-19 disease in patients with cancer predicting severe disease and build a decision support online tool, COVID-19 Risk in Oncology Evaluation Tool (CORONET)., Methods: Patients with active cancer (stage I-IV) and laboratory-confirmed COVID-19 disease presenting to hospitals worldwide were included. Discharge (within 24 hours), admission (≥ 24 hours inpatient), oxygen (O 2 ) requirement, and death were combined in a 0-3 point severity scale. Association of features with outcomes were investigated using Lasso regression and Random Forest combined with Shapley Additive Explanations. The CORONET model was then examined in the entire cohort to build an online CORONET decision support tool. Admission and severe disease thresholds were established through pragmatically defined cost functions. Finally, the CORONET model was validated on an external cohort., Results: The model development data set comprised 920 patients, with median age 70 (range 5-99) years, 56% males, 44% females, and 81% solid versus 19% hematologic cancers. In derivation, Random Forest demonstrated superior performance over Lasso with lower mean squared error (0.801 v 0.807) and was selected for development. During validation (n = 282 patients), the performance of CORONET varied depending on the country cohort. CORONET cutoffs for admission and mortality of 1.0 and 2.3 were established. The CORONET decision support tool recommended admission for 95% of patients eventually requiring oxygen and 97% of those who died (94% and 98% in validation, respectively). The specificity for mortality prediction was 92% and 83% in derivation and validation, respectively. Shapley Additive Explanations revealed that National Early Warning Score 2, C-reactive protein, and albumin were the most important features contributing to COVID-19 severity prediction in patients with cancer at time of hospital presentation., Conclusion: CORONET, a decision support tool validated in health care systems worldwide, can aid admission decisions and predict COVID-19 severity in patients with cancer., Competing Interests: Rebecca J. LeeSpeakers' Bureau: AstraZenecaResearch Funding: Bristol Myers Squibb (Inst), AstraZeneca/MedImmune (Inst) Rohan ShottonHonoraria: ServierTravel, Accommodations, Expenses: Servier Laurence AlbigesConsulting or Advisory Role: Bristol Myers Squibb (Inst), Ipsen (Inst), Roche (Inst), Novartis (Inst), Pfizer (Inst), Astellas Pharma (Inst), Merck (Inst), MSD (Inst), AstraZeneca (Inst), Janssen (Inst), Eisai (Inst), Corvus Pharmaceuticals (Inst), Bellerophon Therapeutics (Inst)Research Funding: Bristol Myers Squibb (Inst)Travel, Accommodations, Expenses: BMS, MSD Dirk ArnoldEmployment: Asklepios KlinikenHonoraria: Bayer, Merck Serono, Roche/Genentech, Servier, Bristol Myers Squibb, Merck Sharp and Dome, AstraZeneca, Amgen, Boston Scientific, Pierre Fabre, IpsenConsulting or Advisory Role: Bayer, Merck Serono, Biocompatibles, Terumo, Bristol Myers Squibb, MSD Oncology, AstraZenecaResearch Funding: Roche/Genentech (Inst), Sanofi (Inst), Oncolytics (Inst)Travel, Accommodations, Expenses: Boston ScientificUncompensated Relationships: ESMO Council, ESMO Journals (Ann Oncol, ESMO Open), German Society for Hematology and Medical Oncology, German Cancer Society, European Organisation for Research and Treatment of Cancer (EORTC) Kathryn BanfillStock and Other Ownership Interests: Roche (I)Honoraria: AstraZeneca Mark BaxterHonoraria: IpsenTravel, Accommodations, Expenses: Ipsen Fabrice BarlesiHonoraria: Genentech/Roche, Pfizer, Pierre Fabre, AstraZeneca, Bristol Myers Squibb, Boehringer Ingelheim, Lilly, Novartis, Merck Serono, MSD Oncology, Takeda, Bayer, Seattle Genetics, Mirati TherapeuticsConsulting or Advisory Role: Roche/Genentech, Pfizer, Novartis, Pierre Fabre, Bristol Myers Squibb, AstraZeneca/MedImmune, Boehringer Ingelheim, Lilly, Merck Serono, MSD Oncology, Takeda, Bayer, Mirati TherapeuticsResearch Funding: Roche/Genentech (Inst), AstraZeneca/MedImmune (Inst), Bristol Myers Squibb (Inst), Pierre Fabre (Inst), AbbVie (Inst), Amgen (Inst), Bayer (Inst), Boehringer Ingelheim (Inst), Eisai (Inst), Lilly (Inst), Ipsen (Inst), Innate Pharma (Inst), Novartis (Inst), Merck Serono (Inst), MSD Oncology (Inst), Pfizer (Inst), Sanofi/Aventis (Inst), Takeda (Inst)Travel, Accommodations, Expenses: Roche/Genentech, Bristol Myers Squibb, AstraZeneca/MedImmune, MSD Oncology Benjamin BesseResearch Funding: AstraZeneca (Inst), Pfizer (Inst), Lilly (Inst), Onxeo (Inst), Inivata (Inst), AbbVie (Inst), Amgen (Inst), Blueprint Medicines (Inst), Celgene (Inst), GlaxoSmithKline (Inst), Sanofi (Inst), Takeda (Inst), Cristal Therapeutics (Inst), Daiichi Sankyo (Inst), Janssen Oncology (Inst), OSE Immunotherapeutics (Inst), BeiGene (Inst), Boehringer Ingelheim (Inst), Roche/Genentech (Inst), Tolero Pharmaceuticals (Inst), 4D Pharma (Inst), Aptitude Health (Inst), Cergentis (Inst), Chugai Pharma (Inst), Genzyme (Inst), Ipsen (Inst), Turning Point Therapeutics (Inst), Eisai (Inst) Antonio CallesHonoraria: AstraZeneca, Boehringer Ingelheim, Pfizer, Roche/Genentech, Lilly, Novartis, Merck Sharp & Dohme, Bristol Myers Squibb, Amgen, Bayer, Takeda, Sanofi/RegeneronConsulting or Advisory Role: Boehringer Ingelheim, Roche/Genentech, Lilly, Merck Sharp & Dohme, Novartis, Pfizer, Bristol Myers Squibb, Takeda, Igen Biotech, Sanofi/RegeneronResearch Funding: MSD Oncology Ellen CopsonHonoraria: Roche, Pfizer, AstraZeneca, Lilly, NovartisConsulting or Advisory Role: Lilly, NanoString Technologies, Pfizer, Sanofi/Aventis, RocheSpeakers' Bureau: Roche, Pfizer, AstraZeneca, Sanofi/AventisResearch Funding: SECA, AstraZeneca (Inst)Travel, Accommodations, Expenses: Roche, AstraZeneca Adina E. CroitoruConsulting or Advisory Role: Ipsen, Pfizer, MSD OncologyResearch Funding: Bristol Myers Squibb (Inst), Amgen (Inst), Astellas Pharma (Inst), Exelixis (Inst), Merck (Inst), Merck KGaA (Inst)Travel, Accommodations, Expenses: Merck, ServierUncompensated Relationships: Lilly, Roche, Bayer, Pfizer, Sanofi Leonie EastlakeTravel, Accommodations, Expenses: Servier Paul FitzpatrickStock and Other Ownership Interests: AstraZeneca/MedImmuneResearch Funding: AstraZeneca/MedImmune (Inst)Other Relationship: Pistoia Alliance, EHDEN IMI project Henrik FrederiksenResearch Funding: AbbVie (Inst), Gilead Sciences (Inst), Sanofi (Inst) Hannah FrostResearch Funding: AstraZeneca (Inst) Sarju GanatraExpert Testimony: Haymarket Medical EducationTravel, Accommodations, Expenses: Haymarket Medical Education Andreas GlenthøjHonoraria: Novo NordiskConsulting or Advisory Role: Novartis, Celgene/Bristol Myers Squibb, Bluebird Bio, Sanofi, Novo Nordisk, AgiosResearch Funding: Sanofi, Saniona A/STravel, Accommodations, Expenses: Agios Fabio GomesHonoraria: AstraZeneca, Merck Serono, Roche Donna M. GrahamConsulting or Advisory Role: Clinigen GroupSpeakers' Bureau: Cancer Drug Development ForumResearch Funding: Pfizer (Inst) Kevin HarringtonHonoraria: Arch Oncology (Inst), AstraZeneca (Inst), BMS (Inst), Boehringer Ingelheim (Inst), Merck Serono (Inst), MSD (Inst), Oncolys BioPharma (Inst), Pfizer (Inst), Replimune (Inst), Inzen Therapeutics (Inst), Codiak Biosciences (Inst)Consulting or Advisory Role: Arch Oncology (Inst), AstraZeneca (Inst), BMS (Inst), Boehringer Ingelheim (Inst), Merck Serono (Inst), MSD (Inst), Oncolys BioPharma (Inst), Replimune (Inst), Inzen Therapeutics (Inst)Speakers' Bureau: BMS (Inst), Merck Serono (Inst), MSD (Inst)Research Funding: AstraZeneca (Inst), Merck Sharp & Dohme (Inst), Replimune (Inst), Boehringer Ingelheim (Inst) Lasse H. JakobsenHonoraria: Takeda, Roche Khurum KhanHonoraria: ServierConsulting or Advisory Role: Bayer Health Christophe MassardConsulting or Advisory Role: Amgen, Astellas Pharma, AstraZeneca, Bayer, BeiGene, BMS, Celgene, Debiopharm Group, Genentech/Roche, Ipsen, Janssen, Lilly, MSD, Novartis, Pfizer, Sanofi, ORION, Taiho Pharmaceutical, Blueprint Medicines, Innate Pharma, PharmaMar, Faron Pharmaceuticals Olivier MichielinConsulting or Advisory Role: Bristol Myers Squibb, MSD, Novartis, Roche, Amgen, Pierre FabreResearch Funding: MSD, Bristol Myers Squibb, NeraCare GmbHExpert Testimony: Bristol Myers SquibbTravel, Accommodations, Expenses: Bristol Myers Squibb, MSD Anne C. MosenthalHonoraria: Springer Nature Berta ObispoHonoraria: Sanofi, Lilly, Angelini, LEO Pharma, RoviConsulting or Advisory Role: Rovi George PentheroudakisHonoraria: Roche, Amgen, Bristol Myers Squibb, MSD, MerckConsulting or Advisory Role: Roche, AmgenResearch Funding: Roche (Inst), Amgen (Inst), Bristol Myers Squibb (Inst), Merck (Inst), AstraZeneca (Inst), Novartis (Inst), Pfizer (Inst)Travel, Accommodations, Expenses: Sanofi, MSD, Roche, Amgen, BMS Solange PetersHonoraria: Roche (Inst), Bristol Myers Squibb (Inst), Novartis (Inst), Pfizer (Inst), MSD (Inst), AstraZeneca (Inst), Takeda (Inst), Illumina (Inst), Medscape (Inst), Prime Oncology (Inst), RMEI Medical Education (Inst), Research to Practice (Inst), PER (Inst), Imedex (Inst), ecancer (Inst)Consulting or Advisory Role: Roche/Genentech (Inst), Novartis (Inst), Bristol Myers Squibb (Inst), Pfizer (Inst), MSD (Inst), Amgen (Inst), AstraZeneca (Inst), Janssen (Inst), Regeneron (Inst), Merck Serono (Inst), Boehringer Ingelheim (Inst), Takeda (Inst), Lilly (Inst), AbbVie (Inst), Bayer (Inst), Biocartis (Inst), Debiopharm Group (Inst), Illumina (Inst), PharmaMar (Inst), Sanofi (Inst), Seattle Genetics (Inst), Blueprint Medicines (Inst), Daiichi Sankyo (Inst), Incyte (Inst), Bioinvent (Inst), Clovis Oncology (Inst), Vaccibody (Inst), Phosplatin Therapeutics (Inst), Foundation Medicine (Inst)Research Funding: Roche (Inst), BMS (Inst), MSD (Inst), Amgen (Inst), Lilly (Inst), AstraZeneca (Inst), Pfizer (Inst), Illumina (Inst), Merck Serono (Inst), Novartis (Inst), Biodesix (Inst), Boehringer Ingelheim (Inst), Iovance Biotherapeutics (Inst), Phosplatin Therapeutics (Inst)Travel, Accommodations, Expenses: Roche, Bristol Myers Squibb, MSD, Sanofi, IncyteUncompensated Relationships: Journal of Thoracic Oncology, ESMO, European Thoracic Oncology Platform (ETOP), Annals of Oncology (I) Kimberly Rieger-ChristResearch Funding: Veracyte, Ravel, Grail, Exact Sciences, Nucleix Timothy RobinsonTravel, Accommodations, Expenses: Daiichi Sankyo/Lilly Emanuela RomanoConsulting or Advisory Role: AstraZeneca/MedImmune (Inst), Bristol Myers Squibb (Inst), Roche/Genentech (Inst)Research Funding: Bristol Myers Squibb, AmgenTravel, Accommodations, Expenses: AstraZeneca/MedImmune, Bristol Myers Squibb, Roche Michael RoweHonoraria: MSDSpeakers' Bureau: ServierTravel, Accommodations, Expenses: Astellas Pharma Anne ThomasConsulting or Advisory Role: BMSSpeakers' Bureau: Bristol Myers SquibbExpert Testimony: BMS Lance TurtleSpeakers' Bureau: Eisai (Inst) David ViñalSpeakers' Bureau: ServierTravel, Accommodations, Expenses: Merck Caroline WilsonConsulting or Advisory Role: Roche, Pfizer Carlo PalmieriHonoraria: PfizerConsulting or Advisory Role: Pfizer, Daiichi-Sankyo, Lilly, Novartis, Seattle GeneticsResearch Funding: Pfizer, Daiichi-SankyoTravel, Accommodations, Expenses: Roche Donal LandersEmployment: AstraZeneca, AthenexLeadership: DeLondra OncologyStock and Other Ownership Interests: DeLondra OncologyResearch Funding: AstraZeneca (Inst) Timothy CooksleyHonoraria: Bristol Myers Squibb Foundation Caroline DiveConsulting or Advisory Role: Biocartis, Merck, AstraZeneca, GRAIL, Boehringer IngelheimResearch Funding: AstraZeneca, Astex Pharmaceuticals, Bioven, Amgen, Carrick Therapeutics, Merck, Taiho Oncology, GlaxoSmithKline, Bayer, Boehringer Ingelheim, Roche, BMS, Novartis, Celgene, Epigene Therapeutics, Angle, Menarini, Clearbridge Biomedics, Thermo Fisher Scientific, NeoMed André FreitasResearch Funding: AstraZeneca (Inst) Anne C. ArmstrongStock and Other Ownership Interests: AstraZeneca (I)Consulting or Advisory Role: Gilead Sciences, MSDResearch Funding: AstraZeneca/MedImmune (Inst)Travel, Accommodations, Expenses: Gilead Sciences, MSD OncologyNo other potential conflicts of interest were reported.

Background: Little is known about the timing of preclinical heart failure (HF) development, particularly among blacks. The primary aims of this study were to delineate age-related left ventricular (LV) structure and function evolution in a biracial cohort and to test the hypothesis that young-adult LV parameters within normative ranges would be associated with incident stage B-defining LV abnormalities over 25 years, independent of cumulative risk factor burden., Methods: Data from the Coronary Artery Risk Development in Young Adults study were analyzed. Participants (n = 2,833) had a mean baseline age of 30.1 years; 45% were black, and 56% were women. Generalized estimating equation logistic regression was used to estimate age-related probabilities of stage B LV abnormalities (remodeling, hypertrophy, or dysfunction) and logistic regression to examine risk factor-adjusted associations between baseline LV parameters and incident abnormalities. Cox regression was used to assess whether baseline LV parameters associated with incident stage B LV abnormalities were also associated with incident clinical (stage C/D) HF events over >25 years' follow-up., Results: Probabilities of stage B LV abnormalities at ages 25 and 60 years were 10.5% (95% CI, 9.4%-11.8%) and 45.0% (95% CI, 42.0%-48.1%), with significant race-sex disparities (e.g., at age 60, black men 52.7% [95% CI, 44.9%-60.3%], black women 59.4% [95% CI, 53.6%-65.0%], white men 39.1% [95% CI, 33.4%-45.0%], and white women 39.1% [95% CI, 33.9%-44.6%]). Over 25 years, baseline LV end-systolic dimension indexed to height was associated with incident systolic dysfunction (adjusted odds ratio per 1 SD higher, 2.56; 95% CI, 1.87-3.52), eccentric hypertrophy (1.34; 95% CI, 1.02-1.75), concentric hypertrophy (0.69; 95% CI, 0.51-0.91), and concentric remodeling (0.68; 95% CI, 0.58-0.79); baseline LV mass indexed to height 2.7 was associated with incident eccentric hypertrophy (1.70; 95% CI, 1.25-2.32]), concentric hypertrophy (1.63; 95% CI, 1.19-2.24), and diastolic dysfunction (1.24; 95% CI, 1.01-1.52). Among the entire cohort with baseline echocardiographic data available (n = 4,097; 72 HF events), LV end-systolic dimension indexed to height and LV mass indexed to height 2.7 were significantly associated with incident clinical HF (adjusted hazard ratios per 1 SD higher, 1.56 [95% CI, 1.26-1.93] and 1.42 [95% CI, 1.14-1.75], respectively)., Conclusions: Stage B LV abnormalities and related racial disparities were present in young adulthood, increased with age, and were associated with baseline variation in indexed LV end-systolic dimension and mass. Baseline indexed LV end-systolic dimension and mass were also associated with incident clinical HF. Efforts to prevent the LV abnormalities underlying clinical HF should start from a young age., (Copyright © 2020 American Society of Echocardiography. All rights reserved.)

Background: Cancer patients are at increased risk of death from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Cancer and its treatment affect many haematological and biochemical parameters, therefore we analysed these prior to and during coronavirus disease 2019 (COVID-19) and correlated them with outcome., Patients and Methods: Consecutive patients with cancer testing positive for SARS-CoV-2 in centres throughout the United Kingdom were identified and entered into a database following local governance approval. Clinical and longitudinal laboratory data were extracted from patient records. Data were analysed using Mann-Whitney U test, Fisher's exact test, Wilcoxon signed rank test, logistic regression, or linear regression for outcomes. Hierarchical clustering of heatmaps was performed using Ward's method., Results: In total, 302 patients were included in three cohorts: Manchester (n = 67), Liverpool (n = 62), and UK (n = 173). In the entire cohort (N = 302), median age was 69 (range 19-93 years), including 163 males and 139 females; of these, 216 were diagnosed with a solid tumour and 86 with a haematological cancer. Preinfection lymphopaenia, neutropaenia and lactate dehydrogenase (LDH) were not associated with oxygen requirement (O 2 ) or death. Lymphocyte count (P < 0.001), platelet count (P = 0.03), LDH (P < 0.0001) and albumin (P < 0.0001) significantly changed from preinfection to during infection. High rather than low neutrophils at day 0 (P = 0.007), higher maximal neutrophils during COVID-19 (P = 0.026) and higher neutrophil-to-lymphocyte ratio (NLR; P = 0.01) were associated with death. In multivariable analysis, age (P = 0.002), haematological cancer (P = 0.034), C-reactive protein (P = 0.004), NLR (P = 0.036) and albumin (P = 0.02) at day 0 were significant predictors of death. In the Manchester/Liverpool cohort 30 patients have restarted therapy following COVID-19, with no additional complications requiring readmission., Conclusion: Preinfection biochemical/haematological parameters were not associated with worse outcome in cancer patients. Restarting treatment following COVID-19 was not associated with additional complications. Neutropaenia due to cancer/treatment is not associated with COVID-19 mortality. Cancer therapy, particularly in patients with solid tumours, need not be delayed or omitted due to concerns that treatment itself increases COVID-19 severity., Competing Interests: Disclosure RJL speaker fees BMS and Astrazeneca, MR honoraria from Astellas Pharma, speaker fees MSD and Servier. CW consultancy and speaker fees Pfizer, Amgen, Novartis, AA conference fee Merck, spouse shares in Astrazeneca. TR financial support to attend educational workshops from Amgen and Daiichi-Sankyo. JT is now working at Astra Zeneca. CD, outside of this scope of work, has received research funding from AstraZeneca, Astex Pharmaceuticals, Bioven, Amgen, Carrick Therapeutics, Merck AG, Taiho Oncology, Clearbridge Biomedics, Angle PLC, Menarini Diagnostics, GSK, Bayer, Boehringer Ingelheim, Roche, BMS, Novartis, Celgene, Thermofisher. CD is on advisory boards for, and has received consultancy fees/honoraria from, AstraZeneca, Biocartis and Merck KGaA. The remaining authors have no conflicts of interest to declare., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Cyclin-dependent kinase 4/6 (CDK4/6) and PI3K inhibitors synergize in PIK3CA -mutant ER-positive HER2-negative breast cancer models. We conducted a phase Ib trial investigating the safety and efficacy of doublet CDK4/6 inhibitor palbociclib plus selective PI3K inhibitor taselisib in advanced solid tumors, and triplet palbociclib plus taselisib plus fulvestrant in 25 patients with PIK3CA -mutant, ER-positive HER2-negative advanced breast cancer. The triplet therapy response rate in PIK3CA- mutant, ER-positive HER2-negative cancer was 37.5% [95% confidence interval (CI), 18.8-59.4]. Durable disease control was observed in PIK3CA -mutant ER-negative breast cancer and other solid tumors with doublet therapy. Both combinations were well tolerated at pharmacodynamically active doses. In the triplet group, high baseline cyclin E1 expression associated with shorter progression-free survival (PFS; HR = 4.2; 95% CI, 1.3-13.1; P = 0.02). Early circulating tumor DNA (ctDNA) dynamics demonstrated high on-treatment ctDNA association with shorter PFS (HR = 5.2; 95% CI, 1.4-19.4; P = 0.04). Longitudinal plasma ctDNA sequencing provided genomic evolution evidence during triplet therapy. SIGNIFICANCE: The triplet of palbociclib, taselisib, and fulvestrant has promising efficacy in patients with heavily pretreated PIK3CA -mutant ER-positive HER2-negative advanced breast cancer. A subset of patients with PIK3CA -mutant triple-negative breast cancer derived clinical benefit from palbociclib and taselisib doublet, suggesting a potential nonchemotherapy targeted approach for this population. This article is highlighted in the In This Issue feature, p. 1 ., (©2020 American Association for Cancer Research.)

Objective: To evaluate the association of cigarette smoking and right ventricular (RV) systolic and diastolic functions in a population-based cohort of individuals at middle age., Methods: This cross-sectional study included participants who answered the smoking questionnaire and underwent echocardiography at the Coronary Artery Risk Development in Young Adulthood year 25 examination. RV systolic function was assessed by echocardiographic-derived tricuspid annular plane systolic excursion (TAPSE) and by right ventricular peak systolic velocity (RVS'), while RV diastolic function was evaluated by early right ventricular tissue velocity (RVE'). Multivariable linear regression models assessed the relationship of smoking with RV function, adjusting for age, sex, race, body mass index, systolic blood pressure, total cholesterol, high-density lipoprotein (HDL) cholesterol, diabetes mellitus, alcohol consumption, pulmonary function, left ventricular systolic and diastolic function and coronary artery calcium score., Results: A total of 3424 participants were included. The mean age was 50±4 years; 57% were female; and 53% were black. There were 2106 (61%) never smokers, 750 (22%) former smokers and 589 (17%) current smokers. In the multivariable analysis, current smokers had significantly lower TAPSE (β=-0.082, SE=0.031, p=0.008), RVS' (β=-0.343, SE=0.156, p=0.028) and RVE' (β=-0.715, SE=0.195, p<0.001) compared with never smokers. Former smokers had a significantly lower RVE' compared with never smokers (β=-0.414, SE=0.162, p=0.011), whereas no significant difference in RV systolic function was found between former smokers and never smokers., Conclusions: In a large multicenter community-based biracial cohort of middle-aged individuals, smoking was independently related to both worse RV systolic and diastolic functions., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY. Published by BMJ.)

Breast cancer remains a leading cause of death worldwide. Our increased understanding of cellular mechanisms inherent to cancer has led to the development of new therapeutic targets. One such therapy is that of poly(ADP-ribose) polymerase (PARP) inhibitors, with PARP playing a key role in the repair of single stranded DNA breaks. The development of drugs able to inhibit PARP led to their investigation in tumors that have defective DNA repair, including that of BRCA1/2 -associated cancers. The PARP inhibitor Olaparib, has recently been evaluated in the Phase III OlympiAD trial, and demonstrated a significant progression-free survival advantage in patients with HER2-negative metastatic breast cancer and a germline BRCA-mutation. This article will review the findings and potential implications of the trial.

Forests and woodlands worldwide are being severely impacted by invasive Phytophthora species, with initial outbreaks in some cases occurring on host trees located in public parks and gardens. These highly disturbed sites with diverse planting practices may indeed act as harbours for invasive Phytophthora pathogens which are particularly well adapted to surviving in soil. High throughput Illumina sequencing was used to analyse Phytophthora species diversity in soil samples collected from 14 public garden/amenity woodland sites in northern Britain. Bioinformatic analyses revealed some limitations to using internal transcribed spacer as the barcode region; namely reporting of false positives and ambiguous species matches. Taking this into account, 35 distinct sequences were amplified across the sites, corresponding to 23 known Phytophthora species as well as twelve oomycete sequences with no match to any known Phytophthora species. Phytophthora pseudosyringae and P. austrocedri , both of which cause serious damage to trees and are regarded as fairly recent introductions to Britain, were the two most abundant Phytophthora species detected. There was no evidence that any of the detected Phytophthora species were more associated with any one type of host, healthy or otherwise. This study has demonstrated the ubiquity and diversity of Phytophthora species endemic in highly managed, extensively planted soil environments in Britain. Suggested improvements to the methodology and the practical implications of the findings in terms of mitigating Phytophthora spread and impact are discussed., Competing Interests: The authors declare that they have no competing interests.

Background: BEECH investigated the efficacy of capivasertib (AZD5363), an oral inhibitor of AKT isoforms 1-3, in combination with the first-line weekly paclitaxel for advanced or metastatic estrogen receptor-positive (ER+)/human epidermal growth factor receptor 2-negative (HER2-) breast cancer, and in a phosphoinositide 3-kinase, catalytic, alpha polypeptide mutation sub-population (PIK3CA+)., Patients and Methods: BEECH consisted of an open-label, phase Ib safety run-in (part A) in 38 patients with advanced breast cancer, and a randomised, placebo-controlled, double-blind, phase II expansion (part B) in 110 women with ER+/HER2- metastatic breast cancer. In part A, patients received paclitaxel 90 mg/m2 (days 1, 8 and 15 of a 28-day cycle) with capivasertib taken twice daily (b.i.d.) at two intermittent ascending dosing schedules. In part B, patients were randomly assigned, stratified by PIK3CA mutation status, to receive paclitaxel with either capivasertib or placebo. The primary end point for part A was safety to recommend a dose and schedule for part B; primary end points for part B were progression-free survival (PFS) in the overall and PIK3CA+ sub-population., Results: Capivasertib was well tolerated, with a 400 mg b.i.d. 4 days on/3 days off treatment schedule selected in part A. In part B, median PFS in the overall population was 10.9 months with capivasertib versus 8.4 months with placebo [hazard ratio (HR) 0.80; P = 0.308]. In the PIK3CA+ sub-population, median PFS was 10.9 months with capivasertib versus 10.8 months with placebo (HR 1.11; P = 0.760). Based on the Common Terminology Criteria for Adverse Event v4.0, the most common grade ≥3 adverse events in the capivasertib group were diarrhoea, hyperglycaemia, neutropoenia and maculopapular rash. Dose intensity of paclitaxel was similar in both groups., Conclusions: Capivasertib had no apparent impact on the tolerability and dose intensity of paclitaxel. Adding capivasertib to weekly paclitaxel did not prolong PFS in the overall population or PIK3CA+ sub-population of ER+/HER2- advanced/metastatic breast cancer patients.ClinicalTrials.gov: NCT01625286., (© The Author(s) 2019. Published by Oxford University Press on behalf of the European Society for Medical Oncology.)

Aims: To evaluate the association of cumulative blood pressure (BP) from young adulthood to middle age with left atrial (LA) structure/function as assessed by three-dimensional echocardiography (3DE) in a large longitudinal bi-racial population study., Methods and Results: We conducted a prospective post hoc analysis of individuals enrolled at the Coronary Artery Risk Development in Young Adults, which is a multi-centre bi-racial cohort with 30 years of follow-up. Cumulative systolic and diastolic BP levels were defined by summing the product of average millimetres of mercury and the years between each two consecutive clinic visits over 30 years of follow-up. Multivariable linear regression analyses were used to assess the relationship between cumulative systolic and diastolic BP with 3DE LA structure and function, adjusting for demographics and traditional cardiovascular risk factors. A total of 1033 participants were included, mean age was 55.4 ± 3.5 years, 55.2% women, 43.9% blacks. Cumulative systolic BP had stronger correlations than cumulative diastolic BP. Higher cumulative systolic BP was independently associated with higher 3D LA volumes: maximum (β = 1.74, P = 0.004), pre-atrial contraction (β = 1.87, P < 0.001), minimum (β = 0.76, P = 0.04), total emptying (β = 0.98, P = 0.006), active emptying (β = 1.12, P < 0.001), and lower magnitude 3D LA early diastolic strain rate (β = 0.05, P = 0.02). Higher cumulative diastolic BP was independently associated with higher 3D LA active emptying volume (β = 0.66, P = 0.002), lower magnitude 3D LA early diastolic strain rate (β = 0.05, P = 0.004), and higher magnitude 3D LA late diastolic strain rate (β = -0.04, P = 0.05)., Conclusion: Higher cumulative BP from early adulthood throughout middle age was associated with adverse LA remodelling evaluated by 3D echocardiography.

Purpose: AZD9496 is an oral nonsteroidal, small-molecule inhibitor of estrogen receptor alpha (ERα) and a potent and selective antagonist and degrader of ERα. This first-in-human phase I study determined the safety and tolerability of ascending doses of oral AZD9496 in women with estrogen receptor (ER) + /HER2 - advanced breast cancer, characterized its pharmacokinetic (PK) profile, and made preliminary assessment of antitumor activity. Patients and Methods: Forty-five patients received AZD9496 [20 mg once daily (QD) to 600 mg twice daily (BID)] in a dose-escalation, dose-expansion "rolling 6" design. Safety, tolerability, and PK activity in each cohort were reviewed before escalating to the next dose. PK was determined by mass spectrometry. Adverse events (AEs) were graded according to the Common Terminology Criteria for Adverse Events (CTCAE) v4.0. Objective tumor response was evaluated by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. Results: Most common causally related AEs were diarrhea (35.6%), fatigue (31.1%), and nausea (22.2%), and seven patients had grade ≥3 AEs. Three patients experienced a dose-limiting toxicity: one each at 150 mg BID (abnormal hepatic function), 400 mg BID (diarrhea and elevated liver function tests), and 600 mg BID (diarrhea), and all were reversible. The maximum tolerated dose was not reached. Partial response was confirmed in one patient, who also had decreased tumor marker Ca15.3. Four patients had stable disease at 12 months' follow-up. Conclusions: AZD9496 is well tolerated with an acceptable safety profile, showing evidence of prolonged disease stabilization in heavily pretreated patients with ER + /HER2 - advanced breast cancer. Clin Cancer Res; 24(15); 3510-8. ©2018 AACR See related commentary by Jordan, p. 3480 ., (©2018 American Association for Cancer Research.)

Background: We investigated whether cardiac parameters in young adulthood are associated with indicators of brain health in midlife., Methods and Results: This study includes 648 participants from the CARDIA (Coronary Artery Risk Development in Young Adults) study (52% women, 38% black). We studied associations of cardiac parameters assessed by echocardiography (left ventricular ejection fraction, left atrial volume, and left ventricular mass) in young adulthood (mean age: 30 years) with brain measures obtained by magnetic resonance imaging (total brain, gray and white matter volume, white matter integrity, abnormal white matter) in midlife (mean age: 50 years). In 406 individuals with complete measurements, higher left atrial volume was associated with lower white matter fractional anisotropy, independent of traditional cardiovascular risk factors (β=-0.002; P <0.02). The association was strongest in black participants and in men., Conclusions: Higher left atrial volume in early adulthood is associated with impairment of white matter integrity in midlife. Interventions to improve cardiac function in young adults may benefit brain health and should be targeted in particular at black men., (© 2017 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.)

Phytophthora austrocedri is causing widespread mortality of Austrocedrus chilensis in Argentina and Juniperus communis in Britain. The pathogen has also been isolated from J. horizontalis in Germany. Isolates from Britain, Argentina, and Germany are homothallic, with no clear differences in the dimensions of sporangia, oogonia, or oospores. Argentinian and German isolates grew faster than British isolates across a range of media and had a higher temperature tolerance, although most isolates, regardless of origin, grew best at 15°C and all isolates were killed at 25°C. Argentinian and British isolates caused lesions when inoculated onto both A. chilensis and J. communis; however, the Argentinian isolate caused longer lesions on A. chilensis than on J. communis and vice versa for the British isolate. Genetic analyses of nuclear and mitochondrial loci showed that all British isolates are identical. Argentinian isolates and the German isolate are also identical but differ from the British isolates. Single-nucleotide polymorphisms are shared between the British and Argentinian isolates. We concluded that British isolates and Argentinian isolates conform to two distinct clonal lineages of P. austrocedri founded from the same as-yet-unidentified source population. These lineages should be recognized and treated as separate risks by international plant health legislation.

Background: ExteNET showed that 1 year of neratinib, an irreversible pan-HER tyrosine kinase inhibitor, significantly improves 2-year invasive disease-free survival after trastuzumab-based adjuvant therapy in women with HER2-positive breast cancer. We report updated efficacy outcomes from a protocol-defined 5-year follow-up sensitivity analysis and long-term toxicity findings., Methods: In this ongoing randomised, double-blind, placebo-controlled, phase 3 trial, eligible women aged 18 years or older (≥20 years in Japan) with stage 1-3c (modified to stage 2-3c in February, 2010) operable breast cancer, who had completed neoadjuvant and adjuvant chemotherapy plus trastuzumab with no evidence of disease recurrence or metastatic disease at study entry. Patients who were eligible patients were randomly assigned (1:1) via permuted blocks stratified according to hormone receptor status (hormone receptor-positive vs hormone receptor-negative), nodal status (0 vs 1-3 vs or ≥4 positive nodes), and trastuzumab adjuvant regimen (given sequentially vs concurrently with chemotherapy), then implemented centrally via an interactive voice and web-response system, to receive 1 year of oral neratinib 240 mg/day or matching placebo. Treatment was given continuously for 1 year, unless disease recurrence or new breast cancer, intolerable adverse events, or consent withdrawal occurred. Patients, investigators, and trial funder were masked to treatment allocation. The predefined endpoint of the 5-year analysis was invasive disease-free survival, analysed by intention to treat. ExteNET is registered with ClinicalTrials.gov, number NCT00878709, and is closed to new participants., Findings: Between July 9, 2009, and Oct 24, 2011, 2840 eligible women with early HER2-positive breast cancer were recruited from community-based and academic institutions in 40 countries and randomly assigned to receive neratinib (n=1420) or placebo (n=1420). After a median follow-up of 5·2 years (IQR 2·1-5·3), patients in the neratinib group had significantly fewer invasive disease-free survival events than those in the placebo group (116 vs 163 events; stratified hazard ratio 0·73, 95% CI 0·57-0·92, p=0·0083). The 5-year invasive disease-free survival was 90·2% (95% CI 88·3-91·8) in the neratinib group and 87·7% (85·7-89·4) in the placebo group. Without diarrhoea prophylaxis, the most common grade 3-4 adverse events in the neratinib group, compared with the placebo group, were diarrhoea (561 [40%] grade 3 and one [<1%] grade 4 with neratinib vs 23 [2%] grade 3 with placebo), vomiting (grade 3: 47 [3%] vs five [<1%]), and nausea (grade 3: 26 [2%] vs two [<1%]). Treatment-emergent serious adverse events occurred in 103 (7%) women in the neratinib group and 85 (6%) women in the placebo group. No evidence of increased risk of long-term toxicity or long-term adverse consequences of neratinib-associated diarrhoea were identified with neratinib compared with placebo., Interpretation: At the 5-year follow-up, 1 year of extended adjuvant therapy with neratinib, administered after chemotherapy and trastuzumab, significantly reduced the proportion of clinically relevant breast cancer relapses-ie, those that might lead to death, such as distant and locoregional relapses outside the preserved breast-without increasing the risk of long-term toxicity. An analysis of overall survival is planned after 248 events., Funding: Wyeth, Pfizer, and Puma Biotechnology., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Background: The human aorta dilates with advancing age. However, the association between progressive aortic dilation with aging and cardiac remodeling has not been established in studies of community-dwelling adults. The aim of this study was to test the hypothesis that there would be a relationship between aortic size increase over the early adult life span with left ventricular (LV) structural remodeling and subclinical LV dysfunction in middle age, even in the absence of overt cardiovascular and valvular disease., Methods: Included were Coronary Artery Risk Development in Young Adults study participants (N = 2,933) aged 23 to 35 years with available transthoracic echocardiographic measurements during 20 years of follow-up. Multivariate linear regression models assessed sex-specific associations between 20-year change in aortic root diameter with LV structure and function., Results: Larger aortic root diameter at 20-year follow-up was associated with greater LV mass (2.77 vs 2.18 g/mm in men and women, respectively, P < .001). In longitudinal analyses, increase in aortic root diameter over 20-year follow-up was associated with a greater 20-year increase in LV mass and ratio of LV mass to LV end-diastolic volume ratio in both sexes. In women but not in men, increased aortic root diameter over 20 years was associated with increased left atrial dimension, impaired E/E', and impaired early diastolic longitudinal and circumferential strain rates assessed by speckle-tracking echocardiography., Conclusions: Progressive increase in aortic root diameter from early adulthood to middle age was associated with increased LV mass and LV concentric remodeling in both sexes and impaired diastolic function predominantly in women., (Copyright © 2017 American Society of Echocardiography. Published by Elsevier Inc. All rights reserved.)

Introduction: Relations between heart failure and clinically manifested stroke are well known, but the associations between heart and brain early abnormalities are not totally clear., Aims: We explore relations of subclinical brain abnormalities with early cardiac dysfunction in a large healthy middle-aged biracial cohort., Methods: The CARDIA study enrolled 5115 young adults aged 18-30 years at baseline (1985-1986). We assessed 719 Caucasian and African American participants of the CARDIA study, with echocardiograms and brain MRI at follow-up year 25 (2010-2011). Echocardiography assessed aortic root diameter; LVEF; circumferential, longitudinal, and radial deformation. Cerebral MRI DTI, and, on a subset, ASL perfusion sequences were used to assess white matter fractional anisotropy and gray matter cerebral blood flow (CBF). Linear regression explored relations between cardiac parameters and cerebral measures, adjusting for anthropometrics, risk factors, and brain constitutional variation., Results: Mean age 50 ± 4 years, SBP 118 ± 15 mm Hg; 60% white, and 48% men. Mean CBF was 46 ± 9 mL/100 g/min, and white matter fractional anisotropy was 0.31 ± 0.02. Worse circumferential deformation and larger aortic root were related to worse white matter fractional anisotropy. Worse radial systolic deformation was related to worse CBF in multivariable models. LVEF did not relate to early brain abnormalities., Conclusions: In spite of no apparent effect of LV ejection fraction, early subclinical cardiac dysfunction and brain abnormalities are present and associated in middle-aged generally healthy individuals., (© 2017, Wiley Periodicals, Inc.)

Background: Strain and strain rate are sensitive markers of left ventricular (LV) myocardial function. The aim of this study was to assess reference ranges and regional patterns of LV strain and strain rate using two-dimensional speckle-tracking echocardiography in a large population of black and white subjects., Methods: This study involved a retrospective review of prospectively collected images in 557 participants in the Coronary Artery Risk Development in Young Adults study who remained healthy at the year 25 examination. LV deformation parameters were measured in apical four-chamber, apical two-chamber, and parasternal short-axis views in 509, 391, and 521 subjects, respectively., Results: Patients' mean age was 49.6 ± 3.6 years, 61.6% were women, and 69.5% were white. White women showed the highest LV systolic and diastolic deformation values, reflected by a more negative reference range for apical four-chamber longitudinal strain (-16.4%; 95% prediction interval [PI], -20.8% to -12.0%) and a higher positive reference range for early diastolic strain rate (0.93 1/sec; 95% PI, 0.41 to 1.46 1/sec), respectively. The lowest LV systolic and diastolic deformation values were found in black men, with apical four-chamber longitudinal strain (14.7%; 95% PI, -19.1% to -10.3%) and early diastolic strain rate (0.79 1/sec; 95% PI, 0.42 to 1.16 1/sec). Absolute strain increased from the epicardium toward the endocardium. A base-to-apex gradient of longitudinal strain toward the apex was exhibited in inferior and inferoseptal regions and, in contrast, in the opposite direction in anterior and anterolateral walls. Sex had the strongest influence on LV deformation variability., Conclusions: Strain and strain rate reference values were sex and race related. White women showed the highest reference ranges for LV deformation, while the lowest values were found in black men. Significant layer- and level-specific patterns in regional LV deformation were identified., (Copyright © 2017 American Society of Echocardiography. All rights reserved.)

Objective: We investigated the association of cardiovascular risk factors and myocardial fibrosis with early cardiac dysfunction in type 1 diabetes., Research Design and Methods: Participants with type 1 diabetes aged 13-39 years without a known history of cardiovascular disease (CVD) ( n = 1,441) were recruited into the Diabetes Control and Complications Trial (1983-1993) and subsequently followed in the Epidemiology of Diabetes Interventions and Complications study (1994 to present). Seven hundred fourteen participants underwent cardiac magnetic resonance (CMR) imaging (2007-2009) with late gadolinium enhancement sequences to assess ischemic and nonischemic scars and tagging sequences to evaluate circumferential strain. CMR-derived T1 mapping also was used to assess interstitial fibrosis. The influence of cardiovascular risk factors and myocardial scar on circumferential strain was assessed using linear regression., Results: Circumferential dysfunction was consistently associated with older age, male sex, smoking history, obesity, higher blood pressure, lower HDL cholesterol, and higher mean HbA 1c . Participants with nonischemic scars ( n = 16) had the worst circumferential function compared with those without scars (β ± SE 1.32 ± 0.60; P = 0.03). In sex-adjusted models, the correlation between T1 times and circumferential strain was not significant. In the fully adjusted models, a trend toward circumferential dysfunction in participants with nonischemic scars was found. Left ventricular ejection fraction was not associated with risk factors but was significantly lower if a myocardial scar was present., Conclusions: Traditional CVD risk factors and elevated HbA 1c levels are major factors related to early cardiac dysfunction in type 1 diabetes. Nonischemic myocardial scar, possibly as a marker of chronic exposure to known risk factors, may predict early cardiac dysfunction mediated by diffuse myocardial fibrosis as seen in diabetic cardiomyopathy., (© 2017 by the American Diabetes Association.)

Objectives: This study sought to investigate how cumulative exposure to glycemic abnormalities and trajectories of insulin resistance (IR) relate to left ventricular (LV) remodeling and function during young to middle adulthood., Background: Cumulative exposure to glycemic abnormalities and trajectories of IR may adversely influence LV remodeling and function over a 25-year period in subjects who were young adults, predisposing individuals to heart failure later in life., Methods: In the CARDIA (Coronary Artery Risk Development in Young Adults) Year 25 examination, 3,179 participants were identified with information on glucose metabolism; these participants were stratified into 4 subgroups: group 1 normal glucose tolerance (NGT), group 2 impaired glucose tolerance (IGT) or impaired fasting glucose, group 3 late diabetes mellitus (DM) (DM diagnosed at year 15 or later), and group 4 early DM (DM diagnosed at year 0 to year 15). Among the subgroup without DM, 3 trajectory groups of change in the homeostasis model assessment of IR were identified: low IR, moderate IR, and high IR. LV mass, relative wall thickness, LV ejection fraction (LVEF), longitudinal systolic strain (Ell), and early diastolic strain rate (Ell&#95;SRe) at year 25 were assessed by echocardiography. Clinically relevant systolic and diastolic dysfunction were defined as LVEF <50% for systolic dysfunction, and E/e' ≥13 for diastolic dysfunction., Results: The early DM group had less favorable LV mass (coefficient = 11.04; p < 0.001), LVEF (coefficient = -2.72; p < 0.05), Ell (coefficient = 1.53; p < 0.001), and Ell&#95;SRe (coefficient = -0.09; p < 0.05) than did the NGT group. Being in the early DM group and having high hemoglobin A 1c were independently associated with greater odds of having systolic dysfunction (odds ratio = 5.44; p < 0.005) compared with the NGT group. High IR was associated with worse relative wall thickness (coefficient = 0.019; p < 0.0001) and worse Ell, E', and Ell&#95;SRe, depending on obesity level., Conclusions: Cumulative exposure to DM or higher IR beginning in early adulthood adversely impacts LV remodeling and function at middle age., (Copyright © 2017 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background:: Cardiac Magnetic Resonance is in need of a simple and robust method for diastolic function assessment that can be done with routine protocol sequences., Objective:: To develop and validate a three-dimensional (3D) model-based volumetric assessment of diastolic function using cardiac magnetic resonance (CMR) imaging and compare the results obtained with the model with those obtained by echocardiography., Methods:: The study participants provided written informed consent and were included if having undergone both echocardiography and cine steady-state free precession (SSFP) CMR on the same day. Guide points at the septal and lateral mitral annulus were used to define the early longitudinal relaxation rate (E'), while a time-volume curve from the 3D model was used to assess diastolic filling parameters. We determined the correlation between 3D CMR and echocardiography and the accuracy of CMR in classifying the diastolic function grade., Results:: The study included 102 subjects. The E/A ratio by CMR was positively associated with the E/A ratio by echocardiography (r = 0.71, p < 0.0001). The early diastolic relaxation velocity by tissue Doppler and longitudinal relaxation rate for the lateral mitral annulus displacement were positively associated (p = 0.007), as were the ratio between Doppler E/e' and CMR E/E' (p = 0.01). CMR-determined normalized peak E (NE) and deceleration time (DT) were able to predict diastolic dysfunction (areas under the curve [AUCs] = 0.70 and 0.72, respectively). In addition, the lateral E/E' ratio showed good utility in identifying diastolic dysfunction (AUC = 0.80). Overall, echocardiography and CMR interobserver and intraobserver agreements were excellent (intraclass correlation coefficient range 0.72 - 0.97)., Conclusion:: 3D modeling of standard cine CMR images was able to identify study subjects with reduced diastolic function and showed good reproducibility, suggesting a potential for a routine diastolic function assessment by CMR., Fundamento:: A ressonância magnética cardíaca necessita de um método simples e robusto para a avaliação da função diastólica que pode ser feito com sequências protocolares de rotina., Objetivo:: Desenvolver e validar a avaliação volumétrica da função diastólica através de um modelo tridimensional (3D) com utilização de imagens de ressonância magnética cardíaca (RMC) e comparar os resultados obtidos com este modelo com os obtidos por ecocardiografia., Métodos:: Os participantes do estudo assinaram um termo de consentimento e foram incluídos se tivessem sido submetidos no mesmo dia tanto à ecocardiografia quanto à cine RMC com precessão livre no estado estacionário (steady-state free precession, SSFP). Pontos-guia foram utilizados no anel mitral septal e lateral para definir a velocidade de estiramento no início da diástole (E'), enquanto curvas de volume-tempo do modelo 3D foram utilizadas para avaliar os parâmetros de enchimento diastólico. Foram determinadas a correlação entre a RMC 3D e a ecocardiografia, além da acurácia da RMC em classificar o grau de função diastólica., Resultados:: Ao todo, 102 sujeitos foram incluídos no estudo. A razão E/A pela RMC esteve positivamente associada com a razão E/A obtida pela ecocardiografia (r = 0,71, p < 0,0001). Estiveram positivamente associadas a velocidade de relaxamento diastólico inicial ao Doppler tecidual e a velocidade de relaxamento longitudinal de deslocamento do anel mitral lateral (p = 0,007), bem como a razão entre E/e' por Doppler e E/E' pela RMC (p = 0,01). A velocidade normalizada de pico de enchimento (EM) determinada pela RMC e o tempo de desaceleração (TD) foram capazes de predizer a disfunção diastólica (áreas sob a curva [AUCs] = 0,70 e 0,72, respectivamente). Além disso, a razão E/E' lateral mostrou boa utilidade para a identificação da disfunção diastólica (AUC = 0,80). No geral, a ecocardiografia e a RMC apresentaram excelente concordância interobservador e intraobservador (coeficiente de correlação intraclasse 0,72 - 0,97)., Conclusão:: Uma modelagem 3D de imagens padrões de cine RMC foi capaz de identificar os indivíduos do estudo com função diastólica reduzida e mostrou uma boa reprodutibilidade, sugerindo ter potencial na avaliação rotineira da função diastólica por RMC.

Breast cancer specific mortality results from tumour cell dissemination and metastatic colonisation. Identification of the cells and processes responsible for metastasis will enable better prevention and control of metastatic disease, thus reducing relapse and mortality. To better understand these processes, we prospectively collected 307 patient-derived breast cancer samples (n = 195 early breast cancers (EBC) and n = 112 metastatic samples (MBC)). We assessed colony-forming activity in vitro by growing isolated cells in both primary (formation) and secondary (self-renewal) mammosphere culture, and tumour initiating activity in vivo through subcutaneous transplantation of fragments or cells into mice. Metastatic samples formed primary mammosphere colonies significantly more frequently than early breast cancers and had significantly higher primary mammosphere colony formation efficiency (0.9 % vs. 0.6 %; p < 0.0001). Tumour initiation in vivo was significantly higher in metastatic than early breast cancer samples (63 % vs. 38 %, p = 0.04). Of 144 breast cancer samples implanted in vivo, we established 20 stable patient-derived xenograft (PDX) models at passage 2 or greater. Lung metastases were detected in mice from 14 PDX models. Mammosphere colony formation in vitro significantly correlated with the ability of a tumour to metastasise to the lungs in vivo (p = 0.05), but not with subcutaneous tumour initiation. In summary, the breast cancer stem cell activities of colony formation and tumour initiation are increased in metastatic compared to early samples, and predict metastasis in vivo. These results suggest that breast stem cell activity will predict for poor outcome tumours, and therapy targeting this activity will improve outcomes for patients with metastatic disease., Competing Interests: Compliance with Ethical StandardsFundingThis study was funded by Cancer Research UK and Breast Cancer Now. MK was funded by S cience and Technology Development Fund fellowship No. 6123.Research involving Human ParticipantsAll patients underwent fully informed consent in accordance with local research ethics committee guidelines. Ethical approval for metastatic samples was granted by the Central Office for Research Ethics Committee study number 05/Q1402/25. Early breast cancer samples were collected via the Manchester Cancer Research Centre Biobank which is licensed by the Human Tissue Authority (licence number: 30,004) and has been ethically approved as a research tissue bank by the South Manchester Research Ethics Committee (Ref: 07/H1003/161 + 5).Conflict of InterestThe authors declare that they have no conflict of interest.

This open-label, multicenter, phase 1B/2 trial assessed AUY922 plus trastuzumab in patients with locally advanced or metastatic HER2-positive breast cancer previously treated with chemotherapy and anti-HER2 therapy. This study was composed of a dose-escalation part with AUY922 administered weekly at escalating doses with trastuzumab 2 mg/kg/week (phase 1B), followed by a phase 2 part using the same regimen at recommended phase 2 dose (RP2D). The primary objectives were to determine the maximum tolerated dose (MTD) and/or RP2D (phase 1B), and to evaluate preliminary antitumor activity (phase 2) of AUY922 plus trastuzumab at MTD/RP2D. Forty-five patients were treated with AUY922 plus trastuzumab (4 in phase 1B with AUY922 at 55 mg/m2 and 41 in phase 1B/2 with AUY922 at 70 mg/m2 [7 in phase 1B and 34 in phase 2]). One patient in phase 1B (70 mg/m2) experienced a dose-limiting toxicity (grade 3 diarrhea); the RP2D was weekly AUY922 70 mg/m2 plus trastuzumab. Of the 41 patients in the 70 mg/m2 cohort, the overall response rate (complete or partial responses) was 22.0% and 48.8% patients had stable disease. Study treatment-related adverse events occurred in 97.8% of patients; of these, 31.1% were grade 3 or 4. Forty-one patients (91.1%) reported ocular events (82.3% had grade 1 or 2 events). Two patients (4.4%) had ocular events leading to the permanent discontinuation of study treatment. AUY922 at 70 mg/m2 plus trastuzumab standard therapy is well tolerated and active in patients with HER2-positive metastatic breast cancer who progressed on trastuzumab-based therapy., Competing Interests: AK has served as an Advisory board member for GlaxoSmithKline. DR received honoraria from Novartis. SA has served as a consultant for Novartis, Pfizer, Boehringer Ingelheim, Pierre Fabre, and Eisai. EA has served as an Advisory board member for Roche, and Celgene, and served as speaker for Roche, Novartis, and Celgene. MC has served as a consultant for Novartis, Servier, Menarini, Sanofi, Astra-Zeneca, and Roche, attended speaker bureaus for Novartis, and received grant from Novartis. MAk, S-FH, CL are employees of Novartis. S-CL received honoraria from Novartis. All remaining authors have declared no conflicts of interest.

Background: High-dose oestrogen (HDE) is effective but toxic in postmenopausal women with advanced breast cancer (ABC). Prolonged oestrogen deprivation sensitises BC cell lines to estrogen and we hypothesised that third-generation aromatase inhibitors (AIs) would sensitise BCs to low-dose estradiol (LDE)., Methods: A single-arm phase II study of LDE (2 mg estradiol valerate daily) in postmenopausal women with estrogen receptor-positive (ER+) ABC. The primary end-point was clinical benefit (CB) rate. If LDE was ineffective, HDE was offered. If LDE was effective, retreatment with the pre-LDE AI was offered on progression., Results: Twenty-one patients were recruited before the trial was closed early due to slow accrual; 19 were assessable for efficacy and toxicity. CB was seen in 5 in 19 patients (26%; 95% confidence interval 9.1-51.2%), all with prolonged SD (median duration 16.8 months; range 11.0-29.6). Treatment was discontinued for toxicity in 4 in 19 patients (21%) and 8 in 11 women without hysterectomy experienced vaginal bleeding (VB). After primary LDE failure, three patients received HDE and one achieved a partial response (PR). Following CB on LDE, four patients restarted pre-LDE AI and three achieved CB including one PR. Those with CB to LDE had a significantly longer duration of first-line endocrine therapy for ABC than those without (54.9 versus 16.8 months; p < 0.01) CONCLUSION: LDE is an effective endocrine option in women with evidence of prolonged sensitivity to AI therapy. LDE is reasonably well tolerated although VB is an issue. Re-challenge with the pre-LDE AI following progression confirms re-sensitisation as a true phenomenon., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Introduction: Few large studies describe quality control procedures and reproducibility findings in cardiovascular ultrasound, particularly in novel techniques such as speckle tracking echocardiography (STE). We evaluate the echocardiography assessment performance in the Coronary Artery Risk Development in Young Adults (CARDIA) study Year 25 (Y25) examination (2010-2011) and report findings from a quality control and reproducibility program conducted to assess Field Center image acquisition and reading center (RC) accuracy., Methods: The CARDIA Y25 examination had 3475 echocardiograms performed in 4 US Field Centers and analyzed in a RC, assessing standard echocardiography (LA dimension, aortic root, LV mass, LV end-diastolic volume [LVEDV], ejection fraction [LVEF]), and STE (two- and four-chamber longitudinal, circumferential, and radial strains). Reproducibility was assessed using intraclass correlation coefficients (ICC), coefficients of variation (CV), and Bland-Altman plots., Results: For standard echocardiography reproducibility, LV mass and LVEDV consistently had CV above 10% and aortic root below 6%. Intra-sonographer aortic root and LV mass had the most robust values of ICC in standard echocardiography. For STE, the number of properly tracking segments was above 80% in short-axis and four-chamber and 58% in two-chamber views. Longitudinal strain parameters were the most robust and radial strain showed the highest variation. Comparing Field Centers with echocardiography RC STE readings, mean differences ranged from 0.4% to 4.1% and ICC from 0.37 to 0.66, with robust results for longitudinal strains., Conclusion: Echocardiography image acquisition and reading processes in the CARDIA study were highly reproducible, including robust results for STE analysis. Consistent quality control may increase the reliability of echocardiography measurements in large cohort studies., (© 2014, Wiley Periodicals, Inc.)

Background: In some countries, the public health system has less availability when compared to the population covered by health insurance. In addition, inappropriate referrals for treadmill exercise stress test increase spending and lead to unnecessary interventions. We aim to determine the prevalence and characteristics of inappropriate referrals for treadmill exercise stress tests in the assessment of coronary artery disease (CAD), considering public and private health systems scenarios., Methods: A cross-sectional design was used to describe the frequency of inappropriate use of exercise testing in the diagnosis of CAD and to determine its predictors. We consecutively enrolled 191 patients from two outpatient facilities in Northeast Brazil. For inclusion, the exercise testing should be referred for the assessment of CAD. We performed logistic regression models to identify independent predictors of inappropriate use., Results: Treadmill exercise stress tests were rated as inappropriate in 150 (78 %) patients. The majority of patients had low or very low pre-test probability of CAD. Presence of hypertension, diabetes and dyslipidemia were more frequent in the appropriate than inappropriate indications (71 %, 19 % and 29 % versus 43 %, 8 % and 16 %, respectively). Tests performed both at the public and private system showed high prevalence of inappropriate examinations, higher in the latter (57 % versus 87 %, P < 0.001). The private health system was the major independent predictor of inappropriate referral, consistent in all regression models (when adjusting for clinical variables, OR = 4.3; P < 0.001)., Conclusion: The vast majority of treadmill exercise stress test referrals in the assessment of CAD were inappropriate. The availability of the method and not the estimate probability of CAD appear to be the underlying condition for a treadmill test referral.

Background: We investigated race-ethnic and sex-specific relationships of left ventricular (LV) structure and LV function in African American and white men and women at 43 to 55 years of age., Methods and Results: The Coronary Artery Risk Development in Young Adults (CARDIA) Study enrolled African American and white adults, age 18 to 30 years, from 4 US field centers in 1985-1986 (Year-0) who have been followed prospectively. We included participants with echocardiographic assessment at the Year-25 examination (n=3320; 44% men, 46% African American). The end points of LV structure and function were assessed using conventional echocardiography and speckle-tracking echocardiography. In the multivariable models, we used, in addition to race-ethnic and gender terms, demographic (age, physical activity, and educational level) and cardiovascular risk variables (body mass index, systolic blood pressure, diastolic blood pressure, heart rate, presence of diabetes, use of antihypertensive medications, number of cigarettes/day) at Year-0 and -25 examinations as independent predictors of echocardiographic outcomes at the Year-25 examination (LV end-diastolic volume [LVEDV]/height, LV end-systolic volume [LVESV]/height, LV mass [LVM]/height, and LVM/LVEDV ratio for LV structural indices; LV ejection fraction [LVEF], Ell, and Ecc for systolic indices; and early diastolic and atrial ratio, mitral annulus early peak velocity, ratio of mitral early peak velocity/mitral annulus early peak velocity; ratio, left atrial volume/height, longitudinal peak early diastolic strain rate, and circumferential peak early diastolic strain rate for diastolic indices). Compared with women, African American and white men had greater LV volume and LV mass (P<0.05). For LV systolic function, African American men had the lowest LVEF as well as longitudinal (Ell) and circumferential (Ecc) strain indices among the 4 sex/race-ethnic groups (P<0.05). For LV diastolic function, African American men and women had larger left atrial volumes; African American men had the lowest values of Ell and Ecc for diastolic strain rate (P<0.05). These race/sex differences in LV structure and LV function persisted after adjustment., Conclusions: African American men have greater LV size and lower LV systolic and diastolic function compared to African American women and to white men and women. The reasons for these racial-ethnic differences are partially but not completely explained by established cardiovascular risk factors., (© 2015 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.)

Purpose: To investigate the association between left atrial ( LA left atrium ) function and left ventricular myocardial fibrosis using cardiac magnetic resonance (MR) imaging in a multi-ethnic population., Materials and Methods: For this HIPAA-compliant study, the institutional review board at each participating center approved the study protocol, and all participants provided informed consent. Of 2839 participants who had undergone cardiac MR in 2010-2012, 143 participants with myocardial scar determined with late gadolinium enhancement and 286 age-, sex-, and ethnicity-matched control participants were identified. LA left atrium volume, strain, and strain rate were analyzed by using multimodality tissue tracking from cine MR imaging. T1 mapping was applied to assess diffuse myocardial fibrosis. The association between LA left atrium parameters and myocardial fibrosis was evaluated with the Student t test and multivariable regression analysis., Results: The scar group had significantly higher minimum LA left atrium volume than the control group (mean, 22.0 ± 10.5 [standard deviation] vs 19.0 ± 7.8, P = .002) and lower LA left atrium ejection fraction (45.9 ± 10.7 vs 51.3 ± 8.7, P < .001), maximal LA left atrium strain ( Smax maximum LA strain ) (25.4 ± 10.7 vs 30.6 ± 10.6, P < .001) and maximum LA left atrium strain rate ( SRmax maximum LA strain rate ) (1.08 ± 0.45 vs 1.29 ± 0.51, P < .001), and lower absolute LA left atrium strain rate at early diastolic peak ( SRE LA strain rate at early diastolic peak ) (-0.77 ± 0.42 vs -1.01 ± 0.48, P < .001) and LA left atrium strain rate at atrial contraction peak ( SRA LA strain rate at atrial contraction peak ) (-1.50 ± 0.62 vs -1.78 ± 0.69, P < .001) than the control group. T1 time 12 minutes after contrast material injection was significantly associated with Smax maximum LA strain (β coefficient = 0.043, P = .013), SRmax maximum LA strain rate (β coefficient = 0.0025, P = .001), SRE LA strain rate at early diastolic peak (β coefficient = -0.0016, P = .027), and SRA LA strain rate at atrial contraction peak LA strain rate at atrial contraction peak (β coefficient -0.0028, P = .01) in the regression model. T1 time 25 minutes after contrast material injection was significantly associated with SRmax maximum LA strain rate (β coefficient = 0.0019, P = .016) and SRA LA strain rate at atrial contraction peak (β coefficient = -0.0022, P = .034)., Conclusion: Reduced LA left atrium regional and global function are related to both replacement and diffuse myocardial fibrosis processes. Clinical trial registration no.: NCT00005487, (© RSNA, 2014 Online supplemental material is available for this article.)

Objectives: The goal of this study was to investigate the relationship of body mass index (BMI) and its 25-year change to left ventricular (LV) structure and function., Background: Longstanding obesity may be associated with clinical cardiac dysfunction and heart failure. Whether obesity relates to cardiac dysfunction during young adulthood and middle age has not been investigated., Methods: The CARDIA (Coronary Artery Risk Development in Young Adult) study enrolled white and black adults ages 18 to 30 years in 1985 to 1986 (Year-0). At Year-25, cardiac function was assessed by conventional echocardiography, tissue Doppler imaging (TDI), and speckle tracking echocardiography (STE). Twenty-five-year change in BMI (classified as low: <27 kg/m(2) and high: ≥27 kg/m(2)) was categorized into 4 groups (Low-Low, High-Low, Low-High, and High-High). Multiple linear regression was used to quantify the association between categorical changes in BMI (Low-Low as reference) with LV structural and functional parameters obtained in middle age, adjusting for baseline and 25-year change in risk factors., Results: The mean BMI was 24.4 kg/m(2) in 3,265 participants included at Year-0. Change in BMI adjusted for risk factors was directly associated with incipient myocardial systolic dysfunction assessed by STE (High-High: β-coefficient = 0.67; Low-High: β-coefficient = 0.35 for longitudinal peak systolic strain) and diastolic dysfunction assessed by TDI (High-High: β-coefficient = -074; Low-High: β-coefficient = -0.45 for e') and STE (High-High: β-coefficient = -0.06 for circumferential early diastolic strain rate). Greater BMI was also significantly associated with increased LV mass/height (High-High: β-coefficient = 26.11; Low-High: β-coefficient = 11.87)., Conclusions: Longstanding obesity from young adulthood to middle age is associated with impaired LV systolic and diastolic function assessed by conventional echocardiography, TDI, and STE in a large biracial cohort of adults age 43 to 55 years., (Copyright © 2014 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Aims: We investigated whether the addition of left atrial (LA) size determined by echocardiography improves cardiovascular risk prediction in young adults over and above the clinically established Framingham 10-year global CV risk score (FRS)., Methods and Results: We included white and black CARDIA participants who had echocardiograms in Year-5 examination (1990-91). The combined endpoint after 20 years was incident fatal or non-fatal cardiovascular disease: myocardial infarction, heart failure, cerebrovascular disease, peripheral artery disease, and atrial fibrillation/flutter. Echocardiography-derived M-mode LA diameter (LAD; n = 4082; 149 events) and 2D four-chamber LA area (LAA; n = 2412; 77 events) were then indexed by height or body surface area (BSA). We used Cox regression, areas under the receiver operating characteristic curves (AUC), and net reclassification improvement (NRI) to assess the prediction power of LA size when added to calculated FRS or FRS covariates. The LAD and LAA cohorts had similar characteristics; mean LAD/height was 2.1 ± 0.3 mm/m and LAA/height 9.3 ± 2.0 mm(2)/m. After indexing by height and adjusting for FRS covariates, hazard ratios were 1.31 (95% CI 1.12, 1.60) and 1.43 (95% CI 1.13, 1.80) for LAD and LAA, respectively; AUC was 0.77 for LAD and 0.78 for LAA. When LAD and LAA were indexed to BSA, the results were similar but slightly inferior. Both LAD and LAA showed modest reclassification ability, with non-significant NRIs., Conclusion: LA size measurements independently predict clinical outcomes. However, it only improves discrimination over clinical parameters modestly without altering risk classification. Indexing LA size by height is at least as robust as by BSA. Further research is needed to assess subgroups of young adults who may benefit from LA size information in risk stratification., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2014. For permissions please email: journals.permissions@oup.com.)

Objectives: The strain relaxation index (SRI), a novel diastolic functional parameter derived from tagged magnetic resonance imaging (MRI), is used to assess myocardial deformation during left ventricular relaxation. We investigated whether diastolic function indexed by SRI predicts heart failure (HF) and atrial fibrillation (AF) over an 8-year follow-up., Methods: As a part of the multi-ethnic study of atherosclerosis, 1544 participants free of known cardiovascular disease (CVD) underwent tagged MRI in 2000-02. Harmonic phase analysis was used to compute circumferential strain. Standard parameters, early diastolic strain rate (EDSR) and the peak torsion recoil rate were calculated. An SRI was calculated as difference between post-systolic and systolic times of the strain peaks, divided by the EDSR peak. It was normalized by the total interval of relaxation. Over an 8-year follow-up period, we defined AF (n = 57) or HF (n = 36) as combined (n = 80) end-points. Cox regression assessed the ability of SRI to predict events adjusted for risk factors and markers of subclinical disease. Integrated discrimination index (IDI) and net reclassification index (NRI) of SRI, compared with conventional indices, were also assessed., Results: The hazard ratio for SRI remained significant for the combined HF and AF end-points as well as for HF alone after adjustment. For the combined end-point, IDI was 1.5% (P < 0.05) and NRI was 11.4% (P < 0.05) for SRI. Finally, SRI was more robust than all other existing cardiovascular magnetic resonance diastolic functional parameters., Conclusion: SRI predicts HF and AF over an 8-year follow-up period in a large population free of known CVD, independent of established risk factors and markers of subclinical CVD.

Background: Framingham risk score (FRS) underestimates risk in young adults. Left ventricular mass (LVM) relates to cardiovascular disease (CVD), with unclear value in youth. In a young biracial cohort, we investigate how FRS predicts CVD over 20 years and the incremental value of LVM. We also explore the predictive ability of different cut-points for hypertrophy., Methods: We assessed FRS and echocardiography-derived LVM (indexed by body surface area or height2.7) from 3980 African-American and white Coronary Artery Risk Development in Young Adults (CARDIA) participants (1990-1991); and followed over 20 years for a combined endpoint: cardiovascular death; nonfatal myocardial infarction, heart failure, cerebrovascular disease, and peripheral artery disease. We assessed the predictive ability of FRS for CVD and also calibration, discrimination, and net reclassification improvement for adding LVM to FRS., Results: Mean age was 30±4 years, 46% males, and 52% white. Event incidence (n=118) across FRS groups was, respectively, 1.3%, 5.4%, and 23.1% (p<0.001); and was 1.4%, 1.3%, 3.7%, and 5.4% (p<0.001) across quartiles of LVM (cut-points 117 g, 144 g, and 176 g). LVM predicted CVD independently of FRS, with the best performance in normal weight participants. Adding LVM to FRS modestly increased discrimination and had a statistically significant reclassification. The 85th percentile (≥116 g/m2 for men; ≥96 g/m2 for women) showed event prediction more robust than currently recommended cut-points for hypertrophy., Conclusion: In a biracial cohort of young adults, FRS and LVM are helpful independent predictors of CVD. LVM can modestly improve discrimination and reclassify participants beyond FRS. Currently recommended cut-points for hypertrophy may be too high for young adults., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Left ventricular (LV) mass and the LV ejection fraction (LVEF) are major independent predictors of future cardiovascular disease. The association of LV mass with the future LVEF in younger populations has not been studied. The aim of this study was to investigate the relation of LV mass index (LVMI) at ages 23 to 35 years to LV function after 20 years of follow-up in the Coronary Artery Risk Development in Young Adults (CARDIA) study. CARDIA is a longitudinal study that enrolled young adults in 1985 and 1986. In this study, participants with echocardiographic examinations at years 5 and 25 were included. LVMI and the LVEF were assessed using M-mode echocardiography at year 5 and using M-mode and 2-dimensional imaging at year 25. Statistical analytic models assessed the correlation between LVMI and LV functional parameters cross-sectionally and longitudinally. A total of 2,339 participants were included. The mean LVEF at year 25 was 62%. Although there was no cross-sectional correlation between LVMI and the LVEF at year 5, there was a small but statistically significant negative correlation between LVMI at year 5 and the LVEF 20 years later (r = -0.10, p <0.0001); this inverse association persisted for LVMI in the multivariate model. High LVMI was an independent predictor of systolic dysfunction (LVEF <50%) 20 years later (odds ratio 1.46, p = 0.0018). In conclusion, LVMI in young adulthood in association with chronic risk exposure affects systolic function in middle age; the antecedents of heart failure may occur at younger ages than previously thought., (Copyright © 2014 Elsevier Inc. All rights reserved.)