Temporal Trends of Enrollment by Sex and Race in Major Cardiovascular Randomized Clinical Trials.

Background: Women and racialized minorities continue to be underrepresented in cardiovascular (CV) trial outcomes data, despite comprising a significant global burden of CV disease. This study evaluated the impact of trial characteristics on the temporal enrollment of women and racialized minorities in prominent CV trials published in the period 1986-2023. Methods: MEDLINE was searched for CV trials published in The Lancet, the Journal of the American Medical Association, and the New England Journal of Medicine. Participant and investigator demographics, types of interventions, clinical indications, and funding sources were compared according to the enrollment of women or racialized minorities. Results: From 799 studies, including 4,071,921 patients, the enrollment of women and racialized minorities significantly increased from 1986 to 2023 (both P ≤ 0.001). Although the enrollment of women varied by trial indication, comprising 25.0% of coronary artery disease, 35.2% of noncoronary and/or vascular disease, 13.8% of heart failure, 17.0% of arrhythmia, and 28.7% of other CV trials (P ≤ 0.001), it did not differ by peer-reviewed vs industry funding. First authors who were women were more likely than first authors who were men to enroll significantly more women (P = 0.01). Conclusions: Active efforts to increase diverse enrollment, along with improved reporting, including of sex and race, in future CV trials may increase the generalizability of their findings and applicability to global populations.

Contexte: Les femmes et les groupes racisés demeurent sous-représentés dans les données de résultats d'essais cliniques sur les maladies cardiovasculaires (CV) malgré l'important fardeau global associé à ces maladies. Cette étude visait à évaluer l'effet des caractéristiques des essais sur la sélection temporelle des femmes et des membres de groupes racisés dans les essais portant principalement sur les maladies CV durant la période de 1986 à 2023. Méthodologie: La base de données MEDLINE a été consultée à la recherche d'essais sur les maladies CV publiés dans The Lancet, Journal of the American Medical Association et New England Journal of Medicine. Les données démographiques des participants et des chercheurs, les types d'interventions, les indications cliniques et les sources de financement ont été comparés en fonction de la sélection des femmes ou des membres de groupes racisés. Résultats: Dans 799 études cumulant 4 071 921 patients, la sélection des femmes et des membres de groupes racisés a augmenté significativement entre 1986 et 2023 (p ≤ 0,001 dans les deux cas). Bien que la sélection des femmes variait en fonction des indications des essais, soit 25,0 % dans les essais portant sur les coronaropathies, 35,2 % pour les maladies non coronariennes et/ou vasculaires, 13,8 % pour l'insuffisance cardiaque, 17,0 % pour l'arythmie et 28,7 % pour d'autres maladies CV (p ≤ 0,001), elle ne différait pas selon que les études étaient révisées par des pairs ou qu'elles étaient financées par l'industrie. Lorsqu'une femme était l'autrice principale, le nombre de femmes sélectionnées était susceptible d'être plus élevé que lorsque l'auteur principal était un homme (p = 0,01). Conclusions: Des efforts actifs pour diversifier davantage la sélection des participants et mieux rendre compte des différences, notamment en ce qui concerne le sexe et la race, pourraient élargir la portée des conclusions des futurs essais sur les maladies CV et leur application à l'ensemble de la population.

Indolent lymphoma care delivery and outcomes during the COVID-19 pandemic in Ontario, Canada.

The treatment pattern and outcomes in patients with indolent B-cell lymphoma treated during the coronavirus disease 2019 (COVID-19) pandemic period compared to the prepandemic period are unclear. This was a retrospective population-based study using administrative databases in Ontario, Canada (follow-up to 31 March 2022). The primary outcome was treatment pattern; secondary outcomes were death, toxicities, healthcare utilization (emergency department [ED] visit, hospitalization) and SARS-CoV-2 outcomes. Adjusted hazard ratios (aHR) from Cox proportional hazards models were used to estimate associations. We identified 4143 patients (1079 pandemic, 3064 prepandemic), with a median age of 69 years. In both time periods, bendamustine (B) + rituximab (BR) was the most frequently prescribed regimen. During the pandemic, fewer patients received R maintenance or completed the full 2-year course (aHR 0.81, 95% CI 0.71-0.92, p = 0.001). Patients treated during the pandemic had less healthcare utilization (ED visit aHR 0.77, 95% CI 0.68, 0.88, p < 0.0001; hospitalization aHR 0.81, 95% CI 0.70-0.94, p = 0.0067) and complications (infection aHR 0.69, 95% CI 0.57-0.82, p < 0.0001; febrile neutropenia aHR 0.66, 95% CI 0.47-0.94, p = 0.020), with no difference in death. Independent of vaccination, active rituximab use was associated with a higher risk of COVID-19 complications. Despite similar front-line regimen use, healthcare utilization and admissions for infection were less in the pandemic cohort.

Comparative effectiveness of salvage chemotherapy regimens and chimeric antigen T-cell receptor therapies in relapsed and refractory diffuse large B cell lymphoma: a network meta-analysis of clinical trials.

The optimal salvage chemotherapy regimen (SC) for relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) prior to autologous stem cell transplant remains unclear. Moreover, although chimeric antigen receptor T cell (CAR-T) therapies were recently approved for primary refractory DLBCL, head-to-head comparisons are lacking. We searched MEDLINE, EMBASE and CENTRAL to July 2022, for randomized trials that enrolled adult patients with R/R DLBCL and performed network meta-analyses (NMA) to assess the efficacy of SC and CAR-T therapies. NMA of SC (6 trials, 7 regimens, n = 1831) indicated that rituximab with gemcitabine, dexamethasone, cisplatin (R-GDP) improved OS and PFS over compared regimens. NMA of 3 CAR-T trials (n = 865) indicated that both axi-cel and liso-cel improved PFS over standard of care, with no difference in OS. Our results indicate that R-GDP may be preferred for R/R DLBCL over other SC compared. Longer follow-up is required for ongoing comparative survival analysis as data from CAR-T trials matures.

Mortality among patients with diffuse large B-cell lymphoma and mental disorders: a population-based study.

BACKGROUND: Mental disorders have been reported in patients with diffuse large B-cell lymphoma (DLBCL), but studies examining their association with mortality are lacking. METHODS: We conducted a population-based study using linked administrative health-care databases from Ontario, Canada. All patients with DLBCL 18 years of age or older treated with rituximab-based therapy between January 1, 2005, and December 31, 2017, were identified and followed until March 1, 2020. Mental disorders were defined as either preexisting or postdiagnosis (after lymphoma treatment initiation). Cox proportional hazards models were used to estimate the adjusted hazard ratio (HR) between mental disorders and 1-year and all-cause mortality while controlling for covariates. RESULTS: We identified 10 299 patients with DLBCL. The median age of the cohort was 67 years; 46% of patients were female, and 28% had a preexisting mental disorder. At 1-year follow-up, 892 (9%) had a postdiagnosis mental disorder, and a total of 2008 (20%) patients died. Preexisting mental disorders were not associated with 1-year mortality (adjusted HR = 1.06, 95% confidence interval [CI] = 0.96 to 1.17, P = .25), but postdiagnosis disorders were (adjusted HR = 1.51, 95% CI = 1.26 to 1.82, P = .0001). During a median follow-up of 5.2 years, 2111 (22%) patients had a postdiagnosis mental disorder, and 4084 (40%) patients died. Both preexisting and postdiagnosis mental disorders were associated with worse all-cause mortality (preexisting adjusted HR = 1.12, 95% CI = 1.04 to 1.20, P = .0024; postdiagnosis adjusted HR = 1.63, 95% CI = 1.49 to 1.79, P < .0001). CONCLUSIONS: Patients with DLBCL and mental disorders had worse short-term and long-term mortality, particularly those with postdiagnosis mental disorders. Further studies are needed to examine mental health service utilization and factors mediating the relationship between mental disorders and inferior mortality.

Fracture risk among patients with cancer compared to individuals without cancer: a population-based study.

BACKGROUND: Patients with cancer may be at increased risk of osteoporosis and fracture; however, gaps exist in the existing literature and the association between cancer and fracture requires further examination. METHODS: We conducted a population-based cohort study of Ontario patients with cancer (breast, prostate, lung, gastrointestinal, haematologic) diagnosed between January 2007 to December 2018 and 1:1 matched non-cancer controls. The primary outcome was incident fracture (end of follow-up December 2019). Multivariable Cox regression analysis was used to estimate the relative fracture risk with sensitivity analysis accounting for competing risk of death. RESULTS: Among 172,963 cancer patients with non-cancer controls, 70.6% of patients with cancer were <65 years old, 58% were female, and 9375 and 8141 fracture events were observed in the cancer and non-cancer group, respectively (median follow-up 6.5 years). Compared to non-cancer controls, patients with cancer had higher risk of fracture (adjusted HR [aHR] 1.10, 95% CI 1.07-1.14, p < 0.0001), which was also observed for both solid (aHR 1.09, 95% CI 1.05-1.13, p < 0.0001) and haematologic cancers (aHR 1.20, 95% CI 1.10-1.31, p < 0.0001). Sensitivity analysis accounting for competing risk of death did not change these findings. CONCLUSIONS: Our study indicates that patients with cancer are at modest risk of fractures compared to non-cancer controls.

Association of COVID-19 Vaccination With Breakthrough Infections and Complications in Patients With Cancer.

Importance: Patients with cancer are known to have increased risk of COVID-19 complications, including death. Objective: To determine the association of COVID-19 vaccination with breakthrough infections and complications in patients with cancer compared to noncancer controls. Design, Setting, and Participants: Retrospective population-based cohort study using linked administrative databases in Ontario, Canada, in residents 18 years and older who received COVID-19 vaccination. Three matched groups were identified (based on age, sex, type of vaccine, date of vaccine): 1:4 match for patients with hematologic and solid cancer to noncancer controls (hematologic and solid cancers separately analyzed), 1:1 match between patients with hematologic and patients with solid cancer. Exposures: Cancer diagnosis. Main Outcomes and Measures: Outcomes occurring 14 days after receipt of second COVID-19 vaccination dose: primary outcome was SARS-CoV-2 breakthrough infection; secondary outcomes were emergency department visit, hospitalization, and death within 4 weeks of SARS-CoV-2 infection (end of follow-up March 31, 2022). Multivariable cumulative incidence function models were used to obtain adjusted hazard ratio (aHR) and 95% CIs. Results: A total of 289 400 vaccinated patients with cancer (39 880 hematologic; 249 520 solid) with 1 157 600 matched noncancer controls were identified; the cohort was 65.4% female, and mean (SD) age was 66 (14.0) years. SARS-CoV-2 breakthrough infection was higher in patients with hematologic cancer (aHR, 1.33; 95% CI, 1.20-1.46; P < .001) but not in patients with solid cancer (aHR, 1.00; 95% CI, 0.96-1.05; P = .87). COVID-19 severe outcomes (composite of hospitalization and death) were significantly higher in patients with cancer compared to patients without cancer (aHR, 1.52; 95% CI, 1.42-1.63; P < .001). Risk of severe outcomes was higher among patients with hematologic cancer (aHR, 2.51; 95% CI, 2.21-2.85; P < .001) than patients with solid cancer (aHR, 1.43; 95% CI, 1.24-1.64; P < .001). Patients receiving active treatment had a further heightened risk for COVID-19 severe outcomes, particularly those who received anti-CD20 therapy. Third vaccination dose was associated with lower infection and COVID-19 complications, except for patients receiving anti-CD20 therapy. Conclusions and Relevance: In this large population-based cohort study, patients with cancer had greater risk of SARS-CoV-2 infection and worse outcomes than patients without cancer, and the risk was highest for patients with hematologic cancer and any patients with cancer receiving active treatment. Triple vaccination was associated with lower risk of poor outcomes.

Left atrial volume and function measured by cardiac magnetic resonance imaging as predictors of shocks and mortality in patients with implantable cardioverter-defibrillators.

Left atrial (LA) volume and function (LA ejection fraction, LAEF) have demonstrated prognostic value in various cardiovascular diseases. We investigated the incremental value of LA volume and LAEF as measured by cardiovascular magnetic resonance imaging (CMR) for prediction of appropriate implantable cardioverter defibrillator (ICD) shock or all-cause mortality, in patients with ICD. We conducted a retrospective, multi-centre observational cohort study of patients who underwent CMR prior to primary or secondary prevention ICD implantation. A single, blinded reader measured maximum LA volume index (maxLAVi), minimum LA volume index (minLAVi), and LAEF. The primary outcome was a composite of independently adjudicated appropriate ICD shock or all-cause death. A total of 392 patients were enrolled. During a median follow-up time of 61 months, 140 (35.7%) experienced an appropriate ICD shock or died. Higher maxLAVi and minLAVi, and lower LAEF were associated with greater risk of appropriate ICD shock or death in univariate analysis. However, in multivariable analysis, LAEF (HR 0.92 per 10% higher, 95% CI 0.81-1.04, p = 0.17) and maxLAVi (HR 1.02 per 10 ml/m2 higher, 95% CI 0.93-1.12, p = 0.72) were not independent predictors of the primary outcome. In conclusion, LA volume and function measured by CMR were univariate but not independent predictors of appropriate ICD shocks or mortality. These findings do not support the routine assessment of LA volume and function to refine risk stratification to guide ICD implant. Larger studies with longer follow-up are required to further delineate the clinical implications of LA size and function.

Association between diabetes and haematological malignancies: a population-based study.

AIMS/HYPOTHESIS: Contemporary data for the association of diabetes with haematological malignancies are lacking. We evaluated the risk of developing haematological malignancies and subsequent mortality in individuals with diabetes compared with those without diabetes. METHODS: We conducted a population-based observational study using healthcare databases from Ontario, Canada. All Ontario residents 30 years of age or older free of cancer and diabetes between 1 January 1996 and 31 December 2015 were eligible for inclusion. Using Cox regression analyses, we explored the association between diabetes and the risk and mortality of haematological malignancies (leukaemia, lymphoma, multiple myeloma). The impact of timing on associations was evaluated with analyses stratified by time since diabetes diagnosis (<3 months, 3 months to 1 year, ≥1 year). RESULTS: We identified 1,003,276 individuals with diabetes and age and sex matched these to 2,006,552 individuals without diabetes. Compared with individuals without diabetes, those with diabetes had a modest but significantly higher risk of a haematological malignancy (adjusted HR 1.10 [95% CI 1.08, 1.12] p < 0.0001). This association persisted across all time periods since diabetes diagnosis. Among those with haematological malignancies, diabetes was associated with a higher all-cause mortality (HR 1.36 [95% CI 1.31, 1.41] p < 0.0001) compared with no diabetes, as well as cause-specific mortality. CONCLUSIONS/INTERPRETATION: Diabetes is associated with a higher risk of haematological malignancies and is an independent risk factor of all-cause and cause-specific mortality. Greater efforts for lifestyle modification may not only reduce diabetes burden and its complications but may also potentially lower risk of malignancy and mortality. Graphical abstract.

Levothyroxine dose and risk of atrial fibrillation: A nested case-control study.

Contemporary data on the effect of levothyroxine dose on the occurrence of atrial fibrillation (AF) are lacking, particularly in the older population. Our objective was to determine the effect of cumulative levothyroxine exposure on risk of AF and ischemic stroke in older adults. METHODS: We conducted a population-based observational study using health care databases from Ontario, Canada. We identified adults aged ≥66 years without a history of AF who filled at least 1 levothyroxine prescription between April 1, 2007, and March 31, 2016. Cases were defined as cohort members who had incident AF (emergency room visit or hospitalization) between the date of first levothyroxine prescription and December 31, 2017. Index date was date of AF. Cases were matched with up to 5 controls without AF on the same index date. Secondary outcome was ischemic stroke. Cumulative levothyroxine exposure was estimated based on total milligrams of levothyroxine dispensed in the year prior to index date. Using nested case-control approach, we compared outcomes between older adults who received high (≥0.125 mg/d), medium (0.075-0.125 mg/d), or low (0-0.075 mg/d) cumulative levothyroxine dose. We compared outcomes between current, recent past, and remote past levothyroxine use. RESULTS: Of 183,360 older adults treated with levothyroxine (mean age 82 years; 72% women), 30,560 (16.1%) had an episode of AF. Compared to low levothyroxine exposure, high and medium exposure was associated with significantly increased risk of AF after adjustment for covariates (adjusted odds ratio [aOR] 1.29, 95% CI 1.23-1.35; aOR 1.08, 95% CI 1.04-1.11; respectively). No association was observed between levothyroxine exposure and ischemic stroke. Compared with current levothyroxine use, older adults with remote levothyroxine use had lower risks of AF (aOR 0.56, 95% CI 0.52-0.59) and ischemic stroke (aOR 0.61, 95% CI 0.56-0.67). CONCLUSIONS: Among older persons treated with levothyroxine, levothyroxine at doses >0.075 mg/d is associated with an increased risk of AF compared to lower exposure.

Outcomes of patients with hematologic malignancies and COVID-19: a systematic review and meta-analysis of 3377 patients.

Outcomes for patients with hematologic malignancy infected with COVID-19 have not been aggregated. The objective of this study was to perform a systematic review and meta-analysis to estimate the risk of death and other important outcomes for these patients. We searched PubMed and EMBASE up to 20 August 2020 to identify reports of patients with hematologic malignancy and COVID-19. The primary outcome was a pooled mortality estimate, considering all patients and only hospitalized patients. Secondary outcomes included risk of intensive care unit admission and ventilation in hospitalized patients. Subgroup analyses included mortality stratified by age, treatment status, and malignancy subtype. Pooled prevalence, risk ratios (RRs), and 95% confidence intervals (CIs) were calculated using a random-effects model. Thirty-four adult and 5 pediatric studies (3377 patients) from Asia, Europe, and North America were included (14 of 34 adult studies included only hospitalized patients). Risk of death among adult patients was 34% (95% CI, 28-39; N = 3240) in this sample of predominantly hospitalized patients. Patients aged ≥60 years had a significantly higher risk of death than patients <60 years (RR, 1.82; 95% CI, 1.45-2.27; N = 1169). The risk of death in pediatric patients was 4% (95% CI, 1-9; N = 102). RR of death comparing patients with recent systemic anticancer therapy to no treatment was 1.17 (95% CI, 0.83-1.64; N = 736). Adult patients with hematologic malignancy and COVID-19, especially hospitalized patients, have a high risk of dying. Patients ≥60 years have significantly higher mortality; pediatric patients appear to be relatively spared. Recent cancer treatment does not appear to significantly increase the risk of death.

Comparison of outcomes in a population-based cohort of metastatic breast cancer patients receiving anti-HER2 therapy with clinical trial outcomes.

PURPOSE: Little data exist for comparing cardiac safety and survival outcomes of trastuzumab/pertuzumab or ado-T emtansine (TDM1) in metastatic breast cancer (MBC) patients enrolled in randomized clinical trial (RCT) vs the real-world. METHODS: This was a retrospective population-based cohort of all patients with MBC treated with trastuzumab/pertuzumab or TDM1 (2012-2017) in Ontario, Canada. Outcomes were incident heart failure (HF) and overall survival (OS). RCT data were obtained from digitizing survival curves and compared with cohort data using Kaplan-Meier analysis. Age-based comparison of outcomes was conducted for patients ≥ 65 years old vs younger than 65. RESULTS: The two cohorts composed of 833 and 397 patients treated with trastuzumab/pertuzumab and TDM1, of whom 5.5% and 7.6% had baseline HF, respectively. Incident HF following trastuzumab/pertuzumab or TDM1 was low (trastuzumab/pertuzumab 1.8 events/100 person years; TDM1 0.02 events/100 person years). The median OS was 39.2 and 56.4 months in the trastuzumab/pertuzumab population-based cohort and CLEOPATRA, respectively. The median OS was 15.4 and 30.9 months in the TDM1 population-based cohort and EMILIA, respectively. Cohort OS was significantly worse than RCT OS (trastuzumab/pertuzumab HR 1.67, 95% CI 1.37-2.03, p < 0.0001; TDM1 HR 2.80, 95% CI 2.27-3.44, p < 0.0001). Older patients had worse OS than younger patients for trastuzumab/pertuzumab (HR 1.60, 95% CI 1.19-2.16, p = 0.0018), but not for TDM1 (HR 1.16, 95% CI 0.81-1.66, p = 0.43). CONCLUSION: HF incidence during trastuzumab/pertuzumab or TDM1 therapy in this real-world cohort was low. Survival in this cohort was worse compared to RCT, suggesting that recruitment of patients similar to the real-world population is required.

Temporal Trends of Women Enrollment in Major Cardiovascular Randomized Clinical Trials.

BACKGROUND: Although it is known that women do not participate in trials as frequently as men, there are limited recent data examining how women recruitment has changed over time. METHODS: We conducted MEDLINE search using a validated strategy for randomized trials published in New England Journal of Medicine, Lancet, and Journal of the American Medical Association between 1986 and 2015, and included trials evaluating pharmacologic or nonpharmacologic therapies. We abstracted data on demographics, intervention type, clinical indication, and trial design characteristics, and examined their relationships with women enrollment. RESULTS: In total, 598 trials met inclusion criteria. Women enrollment increased significantly over time (21% between 1986 and 1990 to 33% between 2011 and 2015; Pfor trend < 0.001) and did not differ by journal or funding source. Women enrollment varied with clinical indication, comprising 37% for non-coronary artery disease vascular trials, 30% for coronary artery disease trials, 28% for heart failure trials, and 28% for arrhythmia trials (P < 0.001), which were all significantly lower than the expected proportion in disease populations (P < 0.001). Women enrollment varied with trial type (31%, 29%, and 26% for pharmacologic, device, and procedural trials, respectively; P = 0.001). These findings were corroborated using multivariable analysis. We found significant positive correlations between women enrolled, and mean age and total number of participants. Fewer women were enrolled in trials reporting statistically significant results than those who did not (P = 0.001). CONCLUSIONS: Although enrollment of women has increased over time, it remains lower than the relative proportion in the disease population. Future studies should elucidate the reasons for persistent under-representation of women in clinical trials.

Differences in Warfarin Pharmacodynamics and Predictors of Response Among Three Racial Populations.

BACKGROUND: Population differences in warfarin dosing requirement have been reported; however, unlike the pharmacokinetics (PK) of warfarin, the quantitative influences of pharmacodynamic (PD) factors on the anticoagulation response to warfarin in different ethnic populations are totally unknown. METHODS: Using population PK/PD analysis, we attempted to identify predictors of S-warfarin clearance [CL(S)] and half maximal effective concentration (EC50) to quantify racial differences in both PK and PD parameters, and to assess the contribution of these parameters to the international normalized ratio (INR) and over-anticoagulation response (INR ≥ 4) in a cohort of 309 White, Asian and African American patients. RESULTS: Similar to our previous findings, the median CL(S) was 30% lower in African American patients than Asian and White patients (169 vs. 243 and 234 mL/h, p < 0.01). EC50 showed a greater racial difference than CL(S) [1.03, 1.70 and 2.76 µg/mL for Asian, White and African American patients, respectively, p < 0.01). Significant predictors of INR included demographic/clinical (age, body weight, creatinine clearance and sex) and genotypic (CYP2C9*3,*8 and VKORC1 -1639G>A) factors, as well as African American ethnicity. In all three racial groups, genetic predictors of INR appeared to have greater influence than demographic/clinical predictors. Both CL(S) and EC50 contributed to the over-anticoagulation response to warfarin. Patients having VKORC1 -1639 G>A and/or factors associated with reduced CYP2C9 activity were more likely to have an INR ≥ 4. CONCLUSIONS: Although there were contrasting racial differences in CL(S) and EC50 that impacted on the INR, the racial difference in EC50 was greater than that for CL(S), thus explaining the higher warfarin requirement for African American patients.

Early diastolic strain rate measurements by cardiac MRI in breast cancer patients treated with trastuzumab: a longitudinal study.

We evaluated temporal changes in early diastolic strain rates by cardiovascular magnetic resonance (CMR) as an early detector of trastuzumab-induced ventricular dysfunction. We conducted a prospective, multi-centre, longitudinal observational study of 41 trastuzumab-treated breast cancer women who underwent serial CMR (baseline, 6, 12, and 18 months). Two blinded readers independently measured left ventricular ejection fraction (LVEF), peak systolic strain parameters (global longitudinal strain [GLS] and global circumferential strain [GCS]), and early diastolic strain rate parameters (global longitudinal diastolic strain rate [GLSR-E], global circumferential diastolic strain rate [GCSR-E], and global radial diastolic strain rate [GRSR-E]), by feature tracking (FT-CMR) using CMR42. There was a significant decline in peak systolic strain GLS and GCS at 6 months (p = 0.024 and p < 0.001, respectively) and 12 months (p = 0.002 and p < 0.001, respectively), followed by recovery at 18 months, which paralleled decline in LVEF at 6 months (p = 0.034) and 12 months (p = 0.012). Conversely, early diastolic strain rates GLSR-E and GCSR-E did not significantly change over 18 months (p > 0.10), while GRSR-E was marginally significant at 12 months (p = 0.021). There was no significant correlation between changes at 6 months in LVEF and GLSR-E or GRSR-E (p > 0.10), and a marginally significant weak correlation between LVEF and GCSR-E (p = 0.046). Among trastuzumab-treated patients without overt cardiotoxicity, there was no consistent temporal change in FT-CMR-derived diastolic strain rate parameters up to 18 months, in contrast to decline in systolic strain and LVEF. Systolic strains by FT-CMR are likely more useful than diastolic strain rates for monitoring subclinical trastuzumab-related myocardial dysfunction.ClinicalTrials.gov identifier NCT01022086.

Effect of CYP4F2, VKORC1, and CYP2C9 in Influencing Coumarin Dose: A Single-Patient Data Meta-Analysis in More Than 15,000 Individuals.

The cytochrome P450 (CYP)4F2 gene is known to influence mean coumarin dose. The aim of the present study was to undertake a meta-analysis at the individual patients level to capture the possible effect of ethnicity, gene-gene interaction, or other drugs on the association and to verify if inclusion of CYP4F2*3 variant into dosing algorithms improves the prediction of mean coumarin dose. We asked the authors of our previous meta-analysis (30 articles) and of 38 new articles retrieved by a systematic review to send us individual patients' data. The final collection consists of 15,754 patients split into a derivation and validation cohort. The CYP4F2*3 polymorphism was consistently associated with an increase in mean coumarin dose (+9% (95% confidence interval (CI) 7-10%), with a higher effect in women, in patients taking acenocoumarol, and in white patients. The inclusion of the CYP4F2*3 in dosing algorithms slightly improved the prediction of stable coumarin dose. New pharmacogenetic equations potentially useful for clinical practice were derived.

Cardiovascular magnetic resonance left ventricular strain in end-stage renal disease patients after kidney transplantation.

BACKGROUND: Cardiovascular disease is a significant cause of morbidity and mortality in patients with end-stage renal disease (ESRD) and kidney transplant (KT) patients. Compared with left ventricular (LV) ejection fraction (LVEF), LV strain has emerged as an important marker of LV function as it is less load dependent. We sought to evaluate changes in LV strain using cardiovascular magnetic resonance imaging (CMR) in ESRD patients who received KT, to determine whether KT may improve LV function. METHODS: We conducted a prospective multi-centre longitudinal study of 79 ESRD patients (40 on dialysis, 39 underwent KT). CMR was performed at baseline and at 12 months after KT. RESULTS: Among 79 participants (mean age 55 years; 30% women), KT patients had significant improvement in global circumferential strain (GCS) (p = 0.007) and global radial strain (GRS) (p = 0.003), but a decline in global longitudinal strain (GLS) over 12 months (p = 0.026), while no significant change in any LV strain was observed in the ongoing dialysis group. For KT patients, the improvement in LV strain paralleled improvement in LVEF (57.4 ± 6.4% at baseline, 60.6% ± 6.9% at 12 months; p = 0.001). For entire cohort, over 12 months, change in LVEF was significantly correlated with change in GCS (Spearman's r = - 0.42, p < 0.001), GRS (Spearman's r = 0.64, p < 0.001), and GLS (Spearman's r = - 0.34, p = 0.002). Improvements in GCS and GRS over 12 months were significantly correlated with reductions in LV end-diastolic volume index and LV end-systolic volume index (all p < 0.05), but not with change in blood pressure (all p > 0.10). CONCLUSIONS: Compared with continuation of dialysis, KT was associated with significant improvements in LV strain metrics of GCS and GRS after 12 months, which did not correlate with blood pressure change. This supports the notion that KT has favorable effects on LV function beyond volume and blood pessure control. Larger studies with longer follow-up are needed to confirm these findings.

Prediction of early breast cancer patient survival using ensembles of hypoxia signatures.

BACKGROUND: Biomarkers are a key component of precision medicine. However, full clinical integration of biomarkers has been met with challenges, partly attributed to analytical difficulties. It has been shown that biomarker reproducibility is susceptible to data preprocessing approaches. Here, we systematically evaluated machine-learning ensembles of preprocessing methods as a general strategy to improve biomarker performance for prediction of survival from early breast cancer. RESULTS: We risk stratified breast cancer patients into either low-risk or high-risk groups based on four published hypoxia signatures (Buffa, Winter, Hu, and Sorensen), using 24 different preprocessing approaches for microarray normalization. The 24 binary risk profiles determined for each hypoxia signature were combined using a random forest to evaluate the efficacy of a preprocessing ensemble classifier. We demonstrate that the best way of merging preprocessing methods varies from signature to signature, and that there is likely no 'best' preprocessing pipeline that is universal across datasets, highlighting the need to evaluate ensembles of preprocessing algorithms. Further, we developed novel signatures for each preprocessing method and the risk classifications from each were incorporated in a meta-random forest model. Interestingly, the classification of these biomarkers and its ensemble show striking consistency, demonstrating that similar intrinsic biological information are being faithfully represented. As such, these classification patterns further confirm that there is a subset of patients whose prognosis is consistently challenging to predict. CONCLUSIONS: Performance of different prognostic signatures varies with pre-processing method. A simple classifier by unanimous voting of classifications is a reliable way of improving on single preprocessing methods. Future signatures will likely require integration of intrinsic and extrinsic clinico-pathological variables to better predict disease-related outcomes.