Mechanisms and clinical course of cardiovascular toxicity of cancer treatment I. Oncology

The opening session of Second International Colloquium on Cardio-Oncology addressed two areas of vital interest. The first reviewed new thoughts related to established agents. While anthracycline cardiotoxicity has been studied and reviewed extensively, ongoing research attempting to understand why it appears the mechanism(s) of toxicity differs from that of oncologic efficacy continue to evoke comment and intriguing speculation. Better understanding of the role of β-topoisomerase II in toxicity has advanced our understanding of the cascade of events that lead to heart failure. Additionally, the cardioprotective role of dexrazoxane fits well with our new understanding of how β-topoisomerase II works. Beyond the anthracyclines, new insight is providing us insight to better understand the impact on cardiac function seen with other agents including those targeting HER2 and several tyrosine-kinase inhibitors. Unlike the anthracyclines, these agents affect cardiac function in ways that are less direct, and therefore have different characteristics and should be thought of in alternate ways. This new knowledge regarding established agents furthers our understanding of the spectrum of cardiotoxicity and cardiac dysfunction in the cancer patient. The session also addressed cardiovascular toxicities of newer and established agents beyond myocardial dysfunction including effects on the vasculature. These agents cause changes that may be temporary or permanent, and that range from subclinical to life-threatening. The session ended with a discussion of the cardiac effects of immune checkpoint inhibitors. These agents can cause rare and sometimes fatal cardiac inflammation, for which long-term follow up may be required.     

Successful Treatment for BK Virus Nephropathy by Leflunomide in a Kidney Transplant Patient: A Case Report

IntroductionThe immunosuppressant agents in kidney transplantation (KT) may lead to various complications such as opportunistic infections and malignancies. BK virus associated nephropathy is a significant complication following KT, and it can result in graft failure. BK virus causes tubulointerstitial nephritis, ureter stenosis, and even graft failure in KT recipients with impaired immune system. We described a 63-year-old woman, who was a hepatitis C carrier and on dialysis for 22 years before KT, who received cadaveric-donor KT 2 years previously. She reported decreasing urine output and general weakness. The serum creatinine level was slightly increased from 2.94 to 4.38 mg/dL.MethodsImmunosuppressant medications including prednisolone, everolimus, cyclosporin, and mycophenolate sodium were continued as maintenance therapy post KT. Kidney biopsy was performed due to deterioration of graft function.ResultsThe kidney biopsy showed consistent results with early-stage polyomavirus nephropathy, characterized by focal viral cytopathic changes with positive immunohistochemical signals and mesangial proliferative glomerulonephritis, immune-complex-mediated (Fig 1 and Fig 2). Negative C4d staining at peritubular capillary was reported. The dosage of mycophenolate sodium was tapered from 720 to 360 mg daily and that of everolimus increased from 0.5 to 1.0 mg daily due to BK viral infection with BK nephropathy. The serum creatinine level was 2.75 mg/dL after treatment.ConclusionEarly detection of BK nephropathy and decreasing immunosuppressant agents are the mainstay of treatment. Substituting leflunomide for mycophenolate sodium and increasing dosage of everolimus has been proposed to solve BK nephropathy. We presented that the use of leflunomide in such situation is in a timely manner.     

Outcomes following the percutaneous coronary intervention in contemporary Vietnamese practice: Insight from a single centre prospective cohort

BackgroundEvidence regarding the outcomes of percutaneous coronary intervention (PCI) in low-and-middle incomes countries remains limited.ObjectivesTo report the outcomes post PCI at discharge, 30 days and 12 months in Vietnam and identify the key factors associated with adverse outcomes at 12 months.MethodsWe used data from a single centre prospective cohort in Vietnam. Data regarding demographics, clinical presentation, procedural information, and outcomes of patients were collected and analysed. Primary outcomes were mortality and major adverse cardiac and cerebrovascular events.ResultsIn total, 926 patients were included. Poor outcomes were relatively low in those undergoing PCI. Predictors of mortality and major adverse cardiac and cerebrovascular events at 12 months post-PCI included being older than 75, being male, having acute myocardial infarction, left ventricular ejection fraction ≤ 40%, prior cerebral vascular disease and having an unsuccessful PCI.ConclusionsAdverse outcomes of patients undergoing PCI in Vietnam are relatively low in comparison with those reported in other countries across the Asia Pacific region. Identification of factors associated with poor outcomes is beneficial for improving the quality of cardiac care and developing the prediction model of outcomes post-PCI in Vietnam.     

LncRNA GAS5 upregulates Smad4 to suppress the apoptosis of chondrocytes induced by lipopolysaccharide

Background: Osteoarthritis (OA) is closely correlated with inflammation. It has been reported that lncRNA GAS5 plays an important role in inflammation, indicating the potential involvement of GAS5 in OA. This study was carried out to investigate the function of GAS5 in OA.Methods: Expression levels of GAS5 in synovial fluid from 45 OA patients and 45 healthy controls were measured by RT-qPCR. Cell transfections were performed to explore the potential interactions among GAS5, miR-146a, and Smad4 in chondrocytes. Lipopolysaccharide (LPS)-induced cell apoptosis after overexpression of GAS5, miR-146a, and Smad4 was analyzed by cell apoptosis assay.Results: GAS5 was downregulated in OA. Moreover, LPS treatment downregulated GAS5 in chondrocytes. Interaction between GAS5 could with miR-146a was predicted by bioinformatics analysis and further confirmed by RNA-RNA pulldown assay. However, overexpression of GAS5 and miR-146a did not affect the expression of each other. GAS5 overexpression increased Smad4 expression in chondrocytes. In contrast, miR-146a overexpression downregulated Smad4 in chondrocytes. Moreover, GAS5 and Smad4 overexpression inhibited LPS- induced chondrocytes apoptosis, while miR-146a overexpression played an opposite role and attenuated the effects of GAS5 and Smad4 overexpression on cell apoptosis.Conclusion: GAS5 might sponge miR-146a to upregulate Smad4, thereby suppressing LPS- induced chondrocytes apoptosis.     

Neighborhood resources associated with frailty trajectories over time among community-dwelling older adults in China

Background and objectivesRecent research has identified neighborhoods as an important contributor to later-life frailty. However, little is known about how neighborhood resources are associated with frailty trajectories over time, especially in developing countries. This study examines the impact of neighborhood physical and social resources on the trajectories of frailty over time among older people in China.Research design and methodsUsing the four waves of the China Health and Retirement Longitudinal Study (2011–2018), 5673 respondents aged 60 and above at baseline were included for analyses. Multilevel growth modeling was fitted to estimate the effects of neighborhood resources on frailty trajectories over a 7-year period, controlling for individual-level characteristics.ResultsOlder Chinese people who lived in neighborhoods with better basic infrastructures and a greater number of voluntary organizations were less frail at baseline. Accessible exercise facilities were associated with a lower initial level of frailty only among rural older adults, while higher community-level socioeconomic status (SES) was associated with a lower initial level of frailty only among urban older adults. Over the 7-year follow-up period, better basic infrastructures and accessible exercise facilities were associated with a slower increase rate of frailty scores among rural residents.Discussion and implicationsNeighborhood resources are important contributors to the level of frailty among older Chinese people. Our findings of significant urban-rural differences have important implications for designing and implementing infrastructure development and community building programs in rural and urban China.     

Epidemiology of Connectional Silence in specialist serious illness conversations

ContextHuman connection can reduce suffering and facilitate meaningful decision-making amid the often terrifying experience of hospitalization for advanced cancer. Some conversational pauses indicate human connection, but we know little about their prevalence, distribution or association with outcomes.PurposeTo describe the epidemiology of Connectional Silence during serious illness conversations in advanced cancer.MethodsWe audio-recorded 226 inpatient palliative care consultations at two academic centers. We identified pauses lasting 2+ seconds and distinguished Connectional Silences from other pauses, sub-categorized as either Invitational (ICS) or Emotional (ECS). We identified treatment decisional status pre-consultation from medical records and post-consultation via clinicians. Patients self-reported quality-of-life before and one day after consultation.ResultsAmong all 6769 two-second silences, we observed 328 (4.8%) ECS and 240 (3.5%) ICS. ECS prevalence was associated with decisions favoring fewer disease-focused treatments (OR_adj: 2.12; 95% CI: 1.12, 4.06). Earlier conversational ECS was associated with improved quality-of-life (p = 0.01). ICS prevalence was associated with clinicians' prognosis expectations.ConclusionsConnectional Silences during specialist serious illness conversations are associated with decision-making and improved patient quality-of-life. Further work is necessary to evaluate potential causal relationships.Practice implicationsPauses offer important opportunities to advance the science of human connection in serious illness decision-making.