Association of neighbourhood-level material deprivation with adverse outcomes and processes of care among patients with heart failure in a single-payer healthcare system: A population-based cohort study.

AIM: We studied the association between neighbourhood material deprivation, a metric estimating inability to attain basic material needs, with outcomes and processes of care among incident heart failure patients in a universal healthcare system. METHODS AND RESULTS: In a population-based retrospective study (2007-2019), we examined the association of material deprivation with 1-year all-cause mortality, cause-specific hospitalization, and 90-day processes of care. Using cause-specific hazards regression, we quantified the relative rate of events after multiple covariate adjustment, stratifying by age ≤65 or ≥66 years. Among 395 763 patients (median age 76 [interquartile range 66-84] years, 47% women), there was significant interaction between age and deprivation quintile for mortality/hospitalization outcomes (p ≤ 0.001). Younger residents (age ≤65 years) of the most versus least deprived neighbourhoods had higher hazards of all-cause death (hazard ratio [HR] 1.19, 95% confidence interval [CI] 1.10-1.29]) and cardiovascular hospitalization (HR 1.29 [95% CI 1.19-1.39]). Older individuals (≥66 years) in the most deprived neighbourhoods had significantly higher hazard of death (HR 1.11 [95% CI 1.08-1.14]) and cardiovascular hospitalization (HR 1.13 [95% CI 1.09-1.18]) compared to the least deprived. The magnitude of the association between deprivation and outcomes was amplified in the younger compared to the older age group. More deprived individuals in both age groups had a lower hazard of cardiology visits and advanced cardiac imaging (all p < 0.001), while the most deprived of younger ages were less likely to undergo implantable cardioverter-defibrillator/cardiac resynchronization therapy-pacemaker implantation (p = 0.023), compared to the least deprived. CONCLUSION: Patients with newly-diagnosed heart failure residing in the most deprived neighbourhoods had worse outcomes and reduced access to care than those less deprived.

Prolonged ketosis and glycosuria secondary to SGLT2 inhibitor therapy.

Clinicians should be aware of the potential for the pharmacologic activity of SGLT2 inhibitors to persist long after the standard drug clearance period of five half-lives, the typical duration used to guide pre-operative medication recommendations.

Coronary artery disease in patients with cancer: challenges and opportunities for improvement.

PURPOSE OF REVIEW: Coronary artery disease (CAD) is a common comorbidity in patients with cancer. We review shared risk factors between the two diseases and cancer treatments that increase the risk of CAD. We also discuss outcomes and management considerations of patients with cancer who develop CAD. RECENT FINDINGS: Several traditional and novel risk factors promote the development of both CAD and cancer. Several cancer treatments further increase the risk of CAD. The presence of cancer is associated with a higher burden of comorbidities and thrombocytopenia, which predisposes patients to higher bleeding risks. Patients with cancer who develop acute coronary syndromes are less likely to receive timely revascularization or appropriate medical therapy, despite evidence showing that receipt of these interventions is associated with substantial benefit. Accordingly, a cancer diagnosis is associated with worse outcomes in patients with CAD. The risk-benefit balance of revascularization is becoming more favorable due to the improving prognosis of many cancers and safer revascularization strategies, including shorter requirements for dual antiplatelet therapy after revascularization. SUMMARY: Several factors increase the complexity of managing CAD in patients with cancer. A multidisciplinary approach is recommended to guide treatment decisions in this high-risk and growing patient group.

Statin Exposure and Risk of Heart Failure After Anthracycline- or Trastuzumab-Based Chemotherapy for Early Breast Cancer: A Propensity Score‒Matched Cohort Study.

Background Statins are hypothesized to reduce the risk of cardiotoxicity associated with anthracyclines and trastuzumab. Our aim was to study the association of statin exposure with hospitalization or emergency department visits (hospital presentations) for heart failure (HF) after anthracycline- and/or trastuzumab-containing chemotherapy for early breast cancer. Methods and Results Using linked administrative databases, we conducted a retrospective cohort study of women aged ≥66 years without prior HF who received anthracyclines or trastuzumab for newly diagnosed early breast cancer in Ontario between 2007 to 2017. Statin-exposed and unexposed women were matched 1:1 using propensity scores. Trastuzumab-treated women were also matched on anthracycline exposure. We matched 666 statin-discordant pairs of anthracycline-treated women and 390 pairs of trastuzumab-treated women (median age, 69 and 71 years, respectively). The 5-year cumulative incidence of HF hospital presentations after anthracyclines was 1.2% (95% CI, 0.5%-2.6%) in statin-exposed women and 2.9% (95% CI, 1.7%-4.6%) in unexposed women (P value, 0.01). The cause-specific hazard ratio associated with statins in the anthracycline cohort was 0.45 (95% CI, 0.24-0.85; P value, 0.01). After trastuzumab, the 5-year cumulative incidence of HF hospital presentations was 2.7% (95% CI, 1.2%-5.2%) in statin-exposed women and 3.7% (95% CI, 2.0%-6.2%) in unexposed women (P value 0.09). The cause-specific hazard ratio associated with statins in the trastuzumab cohort was 0.46 (95% CI, 0.20-1.07; P value, 0.07). Conclusions Statin-exposed women had a lower risk of HF hospital presentations after early breast cancer chemotherapy involving anthracyclines, with non-significant trends towards lower risk following trastuzumab. These findings support the development of randomized controlled trials of statins for prevention of cardiotoxicity.

The Yield of Routine Cardiac Imaging in Breast Cancer Patients Receiving Trastuzumab-Based Treatment: A Retrospective Cohort Study.

BACKGROUND: There are limited data on the yield of routine cardiac imaging for trastuzumab-treated patients with breast cancer. METHODS: We conducted a retrospective cohort study of patients with breast cancer treated with adjuvant trastuzumab between 2007 and 2012 at Princess Margaret Cancer Centre (Toronto, Canada). We classified imaging tests as clinically prompted or routinely ordered and determined whether each test led to changes in patient care. A generalized estimating equation model was used to determine if patient characteristics predicted routine studies more likely to change care. We analysed routine tests that were exclusively preceded by consecutive tests that did not change care to determine if their yield differed by time since trastuzumab start and the number of prior tests that did not change care. RESULTS: We identified 448 patients who received 1735 cardiac imaging studies after trastuzumab initiation. Of 1555 routine tests, 44 led to changes in care (2.8%) for 43 patients, whereas 50 of 180 clinically prompted tests (27.8%) altered care in 29 patients (P-value < 0.001). Earlier stage cancer, diabetes, prior anthracyclines, and prior cardiovascular disease were associated with a higher likelihood of changes in care following routine tests (P-value < 0.05). Among routine tests that were exclusively preceded by consecutive tests that did not change care, tests ordered outside months 3-9 and those that followed ≥ 3 tests were even less likely to change care. CONCLUSIONS: Routine cardiac imaging tests rarely changed care for trastuzumab-treated patients with breast cancer, particularly among lower risk anthracycline-naïve women who had multiple prior tests that did not change care.

In Vitro Self-Renewal Assays for Brain Tumor Stem Cells.

Early development of human organisms relies on stem cells, a population of non-specialized cells that can divide symmetrically to give rise to two identical daughter cells, or divide asymmetrically to produce one identical daughter cell and another more specialized cell. The capacity to undergo cellular divisions while maintaining an undifferentiated state is termed self-renewal and is responsible for the maintenance of stem cell populations during development. In addition, self-renewal plays a crucial role in the homeostasis of developed organism through replacement of defective cells.Similar to their non-malignant counterparts, it has been postulated that tumor cells follow a differentiation hierarchy, with the least differentiated cells termed cancer stem cells (CSCs) at the apex. These tumor stem cells possess the ability to self-renew, have a higher capacity to initiate tumor growth when xenografted into an animal model, and can recapitulate the cell heterogeneity of the tumor they originate from. Hence, further investigation of mechanisms governing the self-renewal in cancer can lead to development of novel therapies targeting CSCs.In this chapter, we described the soft agar assay and the limiting dilution assay (LDA) as two easy-to-implement and inexpensive assays to measure the stemness properties of brain tumor stem cells (BTSCs). These techniques constitute useful tools for the preclinical evaluation of therapeutic strategies targeting BTSCs clonogenicity.

Cotargeting Ephrin Receptor Tyrosine Kinases A2 and A3 in Cancer Stem Cells Reduces Growth of Recurrent Glioblastoma.

Glioblastoma (GBM) carries a dismal prognosis and inevitably relapses despite aggressive therapy. Many members of the Eph receptor tyrosine kinase (EphR) family are expressed by GBM stem cells (GSC), which have been implicated in resistance to GBM therapy. In this study, we identify several EphRs that mark a therapeutically targetable GSC population in treatment-refractory, recurrent GBM (rGBM). Using a highly specific EphR antibody panel and CyTOF (cytometry by time-of-flight), we characterized the expression of all 14 EphR in primary and recurrent patient-derived GSCs to identify putative rGBM-specific EphR. EPHA2 and EPHA3 coexpression marked a highly tumorigenic cell population in rGBM that was enriched in GSC marker expression. Knockdown of EPHA2 and EPHA3 together led to increased expression of differentiation marker GFAP and blocked clonogenic and tumorigenic potential, promoting significantly higher survival in vivo Treatment of rGBM with a bispecific antibody against EPHA2/A3 reduced clonogenicity in vitro and tumorigenic potential of xenografted recurrent GBM in vivo via downregulation of AKT and ERK and increased cellular differentiation. In conclusion, we show that EPHA2 and EPHA3 together mark a GSC population in rGBM and that strategic cotargeting of EPHA2 and EPHA3 presents a novel and rational therapeutic approach for rGBM.Significance: Treatment of rGBM with a novel bispecific antibody against EPHA2 and EPHA3 reduces tumor burden, paving the way for the development of therapeutic approaches against biologically relevant targets in rGBM. Cancer Res; 78(17); 5023-37. ©2018 AACR.

Short report: Follow-up of Bahamian women with a BRCA1 or BRCA2 mutation.

PURPOSE: We sought to determine to what extent the knowledge of carrying a BRCA1 or BRCA2 mutation influences the uptake of preventive surgeries in Bahamian women, including bilateral salpingo-oophorectomy and bilateral mastectomy. PATIENTS AND METHODS: The study population consisted of 78 female residents of the Bahamas for whom a BRCA1 or BRCA2 mutation had been detected between 2004 and 2014. The mean age of the 78 participants at the time of genetic testing was 46 years (age range 22-73 years). The mean time of follow-up was 4.4 years. RESULTS: Of the 78 study participants, 19 women had a bilateral salpingo-oophorectomy (24%). Seven out of 37 patients who had unilateral breast cancer chose to remove the unaffected contralateral breast (19%). Three of 13 patients with no history of breast cancer chose to have a prophylactic bilateral mastectomy (23%). CONCLUSION: Preventive surgery is an acceptable option for a significant proportion of Bahamian women with a BRCA1 or BRCA2 mutation. It will be important to identify and reduce barriers to preventive surgery in the Bahamas in order that the benefit of getting testing can be fully realized.