Risk factors and survival outcomes in children with early cardiotoxicity after allogeneic hematopoietic stem cell transplantation.

Cardiotoxicity in children is a potentially fatal complication after allogeneic hematopoietic stem cell transplantation (allo-HSCT); therefore, early identification of risk factors can improve patient prognosis. However, there are few data on the clinical characteristics of early-stage cardiotoxicity in children after allo-HSCT. We conducted a retrospective single-center study of pediatric patients who underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT) between January 2016 and December 2022 at the Children's Hospital Affiliated with Chongqing Medical University to evaluate the clinical characteristics of early cardiac events (ECEs) after allo-HSCT and their impact on survival outcomes. We enrolled 444 patients who underwent allo-HSCT-304 males (68%) and 140 females (32%)-with a median age of 3.3 years (1.8-6.5 years) at transplantation. We found that 73 patients (16.4%) had ECEs after allo-HSCT. The ECEs included valvular disease (n = 46), pericardial effusion (n = 38), arrhythmia (n = 9), heart failure (n = 16), and dilated cardiomyopathy (n = 1). Female sex, age ≥ 6 years, body mass index (BMI) < 16 kg/m2 and HLA-type mismatches were risk factors for ECEs. We designed a stratified cardiac risk score that included these risk factors, and the higher the score was, the greater the cumulative incidence of ECEs. The occurrence of an ECE was closely associated with a lower overall survival (OS) rate and greater nonrelapse mortality (NRM). In addition, stratified analysis based on the number of combined ECEs showed that the greater the number of combined ECEs was, the more significant the negative impact on OS rates.

Comparison of Surgical or Medical Castration-Related Cardiotoxicity in Patients with Prostate Cancer.

PURPOSE: Androgen deprivation therapy (ADT) includes bilateral orchiectomy or long-acting gonadotropin-releasing hormone (GnRH) agonists/antagonists. It remains controversial with respect to ADT associated cardiovascular outcomes. Hereby, we compared the risk of major adverse cardiovascular and cerebrovascular events (MACCEs) in patients with prostate cancer receiving either surgical castration or GnRH therapies. MATERIALS AND METHODS: Using the Taiwan Cancer Registry and Taiwan's National Health Insurance Research Database, we identified 8,413 patients receiving GnRH therapies compared with 694 receiving surgical castration from 2008 to 2017. The median followup duration was 3 years. RESULTS: The crude incidences of 3-year mortality and MACCEs were 19.90% vs 26.51% and 8.23% vs 8.65% in patients receiving GnRH therapies or surgical castration, respectively. After adjusting for age, cancer stage and comorbidities, despite no significant differences in MACCEs between groups there was a slight increase in the incidence of acute myocardial infarction (AMI) in patients receiving surgical castration compared with those receiving GnRH therapies. The mortality adjusted hazard ratios of MACCEs and AMI among patients receiving surgical castration were 1.11- and 1.8-fold higher than those receiving GnRH therapies. Notably, in subgroup analysis regarding cancer stage, patients with cancer stage IV showed the most significantly increasing risk of AMI in those receiving surgical castration compared with GnRH therapies. CONCLUSIONS: Collectively, we indicated an increased risk of AMI in patients with prostate cancer, especially in patients receiving surgical castration rather than those receiving GnRH therapies. Our findings highlight concerns regarding the cardiac safety of surgical castration compared with GnRH therapies.

Protective role of beta-blockers in chemotherapy-induced cardiotoxicity-a systematic review and meta-analysis of carvedilol.

Some randomized controlled trials (RCTs) have tested the efficacy of beta-blockers as prophylactic agents on cancer therapy-induced cardiotoxicity; however, the quality of this evidence remains undetermined. This systematic review and meta-analysis study aims to evaluate the prophylactic effects of beta-blockers, especially carvedilol, on chemotherapy-induced cardiotoxicity. RCTs were identified by searching the MEDLINE (PubMed), Embase (OvidSP), Cochrane CENTRAL (OvidSP), etc., until December 2017. Inclusion criteria were randomized clinical trial and adult cancer patients started beta-blockers before chemotherapy. We evaluated the mean differences (MD) by fixed- or random-effects model and the odds ratio by Peto's method. Primary outcome was the left ventricular ejection fraction (LVEF) of patients after chemotherapy, and secondary outcomes were all-cause mortality, clinically overt cardiotoxicity, and other echocardiographic measurements. In total, we included six RCTs that used carvedilol as a prophylactic agent in patients receiving chemotherapy. The LVEF was not significantly distinct between those using carvedilol and placebo after chemotherapy (MD, 1.74; 95% confidence interval (CI), - 0.18 to 3.66; P = 0.08). The incidence of clinically overt cardiotoxicity was lower in the carvedilol group compared with the control group (Peto OR, 0.42; 95% CI, 0.20-0.89; P = 0.02). Furthermore, after chemotherapy, the LV end-diastolic diameter did not increase in the carvedilol group compared with the placebo group (MD, - 1.41; 95% CI, - 2.32 to - 0.50; P = 0.002). The prophylactic use of carvedilol exerted no impact on the early asymptomatic LVEF decrease but seemed to attenuate the frequency of clinically overt cardiotoxicity and prevent ventricular remodeling.

Association of pazopanib-induced toxicities with outcome of patients with advanced soft tissue sarcoma; a retrospective analysis based on the European Organisation for Research and Treatment of Cancer (EORTC) 62043 and 62072 clinical trials.

Background: There is an unmet need for markers predicting the outcome of patients with advanced soft tissue sarcoma (STS) treated with pazopanib. Since toxicity might be related to the anti-tumor activity of the drug, the aim of this study was to determine whether pazopanib-induced proteinuria, hypothyroidism and cardiotoxicity grade 3-4 were associated with outcome. Methods: The combined results of the EORTC 62043 and 62072 trials were retrospectively assessed and used in a landmark analysis to evaluate the effect of the toxicities on progression-free survival (PFS) and overall survival (OS), using the Kaplan-Meier method and Cox regression models. Results: Of the 333 eligible patients, 259 patients were included in the analyses, for which a landmark time point of 60 days after randomization/registration was selected. Proteinuria occurred in 25.1%, hypothyroidism in 22.0% and cardiotoxicity grade 3-4 in 5.8% of the patients (any grade in 41.7%). There was no effect of the occurrence of proteinuria (6-months PFS 35.4% for patients with vs. 38.3% for patients without proteinuria, HR 1.01, p = .953), hypothyroidism (41.2% vs. 36.5%, HR 0.82, p = .210) or cardiotoxicity grade 3-4 (26.7% vs. 38.2%, HR 0.97, p = .897) on PFS. Nor was there an effect of proteinuria (6-months OS 63.2% for patients with vs. 74.4% for patients without proteinuria, HR 1.22, p = .196), hypothyroidism (76.2% vs. 70.5%, HR 0.75, p = .093) or cardiotoxicity grade 3-4 (80.0% vs. 77.2%, HR 0.93, p = .801) on OS. Conclusion: There was no association between the occurrence of pazopanib-induced proteinuria, hypothyroidism and cardiotoxicity and outcome. Therefore, these toxicities cannot be used as predictors for pazopanib activity in patients with advanced STS.

Dioscorea bulbifera L. delays the excretion of doxorubicin and aggravates doxorubicin-induced cardiotoxicity and nephrotoxicity by inhibiting the expression of P-glycoprotein in mice liver and kidney.

We aimed to investigate the drug-drug interaction (DDI) between doxorubicin (DOX) and Dioscorea bulbifera L. (DB) solution in mice, and to explore the effect of P-glycoprotein (P-gp) on this type of DDI. The toxicity of DOX in the liver, kidneys, and heart was assessed with alanine aminotransferase (ALT), aspartate aminotransferase (AST), creatinine (Cr), urea nitrogen (BUN), creatine kinase MB (CK-MB), creatine kinase (CK) and histopathology. High-performance liquid chromatography tandem mass spectrometry (HPLC-MS/MS) was used to determine the concentrations of DOX in the serum, liver, kidneys and heart. Immunohistochemistry and western blots were used to determine the expression levels of P-gp in these tissues. Our results demonstrated that, after co-administration of DOX and DB, survival was significantly decreased compared with either administration of DOX or DB alone, or water. Co-administration of DOX and DB induced elevated levels of toxicity in the heart and kidneys, but not the liver, compared with DOX alone. We conclude that concurrent treatment with DOX and DB results in increased levels of toxicity due to the accumulation of DOX in the body. Delayed excretion of DOX is associated with inhibition of P-gp in liver and kidneys.

Cumulative anthracycline exposure and risk of cardiotoxicity; a Danish nationwide cohort study of 2440 lymphoma patients treated with or without anthracyclines.

Cardiotoxicity is a known risk of anthracycline treatment. However, the relative contribution of anthracyclines to the development of congestive heart failure (CHF), when included in a poly-chemotherapy regimen, is unclear. We examined cardiotoxicity in adult patients with diffuse large B-cell lymphoma and follicular lymphoma undergoing first-line immunochemotherapy from 2000-2012. In total, 2440 patients without previous heart disease were identified from the Danish Lymphoma Registry, of which 1994 (81·7%) were treated with anthracycline-containing chemotherapy [R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisolone) or R-CHOEP (R-CHOP + etoposide)] and 446 (18·3%) were treated without anthracyclines (reference group). Compared to the reference group, the adjusted hazard ratio of CHF after 3-5 cycles of R-CHOP/CHOEP was 5·0 [95% confidence interval (CI) 1·4; 18·5], 6 cycles 6·8 (95% CI 2·0; 23·3) and >6 cycles 13·4 (95% CI 4·0; 45·0). The cumulative 5-year risk of CHF with all-cause mortality as competing risk was 4·6% after 3-5 cycles of R-CHOP/CHOEP, 4·5% after 6 and 7·9% after more than 6 cycles. Cumulative 5-year risk for patients treated without anthracyclines was 0·8%. Using anthracyclines in first-line lymphoma treatment increases risk of CHF in patients without previous history of heart disease. In particular, treatment with >6 cycles of R-CHOP/CHOEP is associated with a significant increase in CHF rate.

Dexrazoxane Significantly Reduces Anthracycline-induced Cardiotoxicity in Pediatric Solid Tumor Patients: A Systematic Review.

Cardiotoxicity is a dose-limiting and potentially lethal complication of anthracycline administration. Previous studies failed to determine definitive toxic doses or cardioprotective factors. Current dosing strategies may utilize unnecessarily high anthracycline doses, such that survival benefit may not outweigh increased toxicity rates. A systematic review of randomized controlled trials and prospective/retrospective studies investigating anthracycline treatment in pediatric solid tumors was performed from PubMed/MEDLINE and Cochrane databases. Generalized linear models mapping survival, cardiotoxicity, and cardiotoxicity-free survival adjusted for male-to-female ratio, follow-up time, and concomitant chemotherapeutic drugs or cardioprotective agents (dexrazoxane) were generated using R. Survival rose linearly with increasing cumulative anthracycline dose whereas cardiotoxicity demonstrated exponential increases both without (dose, >200 mg/m) and with (dose, >400 mg/m) dexrazoxane. Maximum cardiotoxicity-free survival was 268.2 mg/m without and 431.8 mg/m with dexrazoxane. Despite increasing cardiotoxicity-free dose by >150 mg/m, dexrazoxane minimally improved projected survival (71.9% vs. 75.4%). Cardiotoxicity increased linearly as a function of follow-up time with rates doubling from 5 to 20 years, without evidence of plateau. On the basis of our model, current dosing regimens-doxorubicin doses >375 mg/m without dexrazoxane-overvalue increased anthracycline administration and may contribute to devastating cardiotoxicity. The linear increase of cardiotoxicity without evidence of plateau confirms the necessity for lifelong cardiac monitoring.

Sub-acute vs. Late-onset Presentation of Oncotherapy Related Cardiotoxicity: Predictors of Cardiac Function Recovery and Long-Term Outcome.

BACKGROUND: Cardiac damage caused by oncological therapy may manifest early or many years after the exposure. OBJECTIVES: To determine the differences between sub-acute and late-onset cardiotoxicity in left ventricular ejection fraction (LVEF) recovery as well as long-term prognosis. METHODS: We studied 91 patients diagnosed with impaired systolic function and previous exposure to oncological therapy. The study population was divided according to sub-acute (from 2 weeks to ≤ 1 year) and late-onset (> 1 year) presentation cardiotoxicity. Recovery of LVEF of at least 50% was defined as the primary end point and total mortality was the secondary end point. RESULTS: Fifty-three (58%) patients were classified as sub-acute, while 38 (42%) were defined as late-onset cardiotoxicity. Baseline clinical characteristics were similar in the two groups. The mean LVEF at presentation was significantly lower among patients in the late-onset vs. sub-acute group (28% vs. 37%, respectively, P < 0.001). Independent predictors of LVEF recovery were trastuzumab therapy and a higher baseline LVEF. Although long-term mortality rates were similar in the groups with sub-acute and late-onset cardiotoxicity, improvement of LVEF was independently associated with reduced mortality. CONCLUSIONS: Our findings suggest that early detection and treatment of oncological cardiotoxicity play an important role in LVEF recovery and long-term prognosis.

Folic acid reduces doxorubicin-induced cardiomyopathy by modulating endothelial nitric oxide synthase.

The use of doxorubicin (DOXO) as a chemotherapeutic drug has been hampered by cardiotoxicity leading to cardiomyopathy and heart failure. Folic acid (FA) is a modulator of endothelial nitric oxide (NO) synthase (eNOS), which in turn is an important player in diseases associated with NO insufficiency or NOS dysregulation, such as pressure overload and myocardial infarction. However, the role of FA in DOXO-induced cardiomyopathy is poorly understood. The aim of this study was to test the hypothesis that FA prevents DOXO-induced cardiomyopathy by modulating eNOS and mitochondrial structure and function. Male C57BL/6 mice were randomized to a single dose of DOXO (20 mg/kg intraperitoneal) or sham. FA supplementation (10 mg/day per oral) was started 7 days before DOXO injection and continued thereafter. DOXO resulted in 70% mortality after 10 days, with the surviving mice demonstrating a 30% reduction in stroke volume compared with sham groups. Pre-treatment with FA reduced mortality to 45% and improved stroke volume (both P < 0.05 versus DOXO). These effects of FA were underlain by blunting of DOXO-induced cardiomyocyte atrophy, apoptosis, interstitial fibrosis and impairment of mitochondrial function. Mechanistically, pre-treatment with FA prevented DOXO-induced increases in superoxide anion production by reducing the eNOS monomer:dimer ratio and eNOS S-glutathionylation, and attenuated DOXO-induced decreases in superoxide dismutase, eNOS phosphorylation and NO production. Enhancing eNOS function by restoring its coupling and subsequently reducing oxidative stress with FA may be a novel therapeutic approach to attenuate DOXO-induced cardiomyopathy.

Novel approaches to the prediction, diagnosis and treatment of cardiac late effects in survivors of childhood cancer: a multi-centre observational study.

BACKGROUND: Anthracycline-induced cardiac toxicity is a cause of significant morbidity and early mortality in survivors of childhood cancer. Current strategies for predicting which children are at greatest risk for toxicity are imperfect and diagnosis of cardiac injury is usually made relatively late in the natural history of the disease. This study aims to identify genomic, biomarker and imaging parameters that can be used as predictors of risk or aid in the early diagnosis of cardiotoxicity. METHODS: This is a prospective longitudinal cohort study that recruited two cohorts of pediatric cancer patients at six participating centres: (1) an Acute Cohort of children newly diagnosed with cancer prior to starting anthracycline therapy (n = 307); and (2) a Survivor Cohort of long-term survivors of childhood cancer with past exposure to anthracycline (n = 818). The study team consists of three collaborative cores. The Genomics Core is identifying genomic variations in anthracycline metabolism and in myocardial response to injury that predispose children to treatment-related cardiac toxicity. The Biomarker Core is identifying existing and novel biomarkers that allow for early diagnosis and prognosis of anthracycline-induced cardiac toxicity. The Imaging Core is identifying echocardiographic and cardiac magnetic resonance (CMR) imaging parameters that correspond to early signs of cardiac dysfunction and remodeling and precede global dysfunction and clinical symptoms. The data generated by the cores will be combined to create an integrated risk-prediction model aimed at more accurate identification of children who are most susceptible to anthracycline toxicity. DISCUSSION: We aim to identify genomic risk factors that predict risk for anthracycline cardiotoxicity pre-exposure and imaging and biomarkers that facilitate early diagnosis of cardiac injury. This will facilitate a personalized approach to identifying at-risk children with cancer who may benefit from cardio- protective strategies during therapy, and closer surveillance and earlier initiation of medications to preserve heart function after cancer therapy. TRIAL REGISTRATION: NCT01805778 . Registered 28 February 2013; retrospectively registered.

Assessment of late anthracycline-induced cardiotoxicity by 123I-mIBG cardiac scintigraphy in patients treated during childhood and adolescence.

PURPOSE: The goal of this study was to evaluate late cardiotoxic effects of anthracyclines (ATC) by evaluating cardiac sympathetic activity in a cohort of asymptomatic patients previously treated with ATC for childhood cancers. METHODS: We studied 89 asymptomatic patients previously treated with ATC with a normal echocardiogram (49 men and 40 women) and a control group of 40 healthy individuals (26 men and 14 women). Both groups underwent planar myocardial 123I-meta-iodobenzylguanidine scintigraphy (123I-mIBG). From these images, the early and late heart-to-mediastinum (H/M) ratio and washout rate (WR) were assessed. RESULTS: The mean survival at the time of the 123I-mIBG scintigraphy was 5.3 ± 3.4 years. Patients treated with ATC had a lower but clinical normal left ventricular ejection fraction (LVEF) compared to controls (60.44 ± 6.5 vs 64.1 ± 6.0%, P < 0.01). Both the late H/M ratio and WR were not able to discriminate ATC treated patients from controls. The cumulative ATC dose was the only independent predictor of the LVEF, explaining approximately 12% of the variation in LVEF (P = 0.01). CONCLUSIONS: Although the pathophysiology behind ATC cardiotoxicity is most likely multifactorial, myocardial sympathetic activity is not associated with a reduction in LVEF 5-years after completion of chemotherapy.

On the mechanisms of melatonin in protection of aluminum phosphide cardiotoxicity.

Aluminum phosphide (AlP), one of the most commonly used pesticides worldwide, has been the leading cause of self-poisoning mortalities among many Asian countries. The heart is the main organ affected in AlP poisoning. Melatonin has been previously shown to be beneficial in reversing toxic changes in the heart. The present study reveals evidence on the probable protective effects of melatonin on AlP-induced cardiotoxicity in rats. The study groups included a control (almond oil only), ethanol 5% (solvent), sole melatonin (50 mg/kg), AlP (16.7 mg/kg), and 4 AlP + melatonin groups which received 20, 30, 40 and 50 mg/kg of melatonin by intraperitoneal injections following AlP treatment. An electronic cardiovascular monitoring device was used to record the electrocardiographic (ECG) parameters. Heart tissues were studied in terms of oxidative stress biomarkers, mitochondrial complexes activities, ADP/ATP ratio and apoptosis. Abnormal ECG records as well as declined heart rate and blood pressure were found to be related to AlP administration. Based on the results, melatonin was highly effective in controlling AlP-induced changes in the study groups. Significant improvements were observed in the activities of mitochondrial complexes, oxidative stress biomarkers, the activities of caspases 3 and 9, and ADP/ATP ratio following treatment with melatonin at doses of 40 and 50 mg/kg. Our results indicate that melatonin can counteract the AlP-induced oxidative damage in the heart. This is mainly done by maintaining the normal balance of intracellular ATP as well as the prevention of oxidative damage. Further research is warranted to evaluate the possibility of using melatonin as an antidote in AlP poisoning.

Incidence, time of occurrence and response to heart failure therapy in patients with anthracycline cardiotoxicity.

BACKGROUND: Anthracyclines are commonly used chemotherapeutic medications. AIM: In the current analysis, we evaluated all-cause mortality and incidence, timing and response to medical therapy of anthracycline cardiotoxicity. METHODS: Left ventricular ejection fraction (LVEF) was serially assessed using gated heart pool scan/echocardiography in patients receiving anthracycline-based chemotherapy from January 2009 to December 2014. RESULTS: A total of 1204 patients was administered anthracyclines during the study period. During a median follow up of 32 (interquartile range: 15-58) months, all-cause mortality was 38% (n = 463), with the incidence of cardiotoxicity 10.2% (n = 123). Only 15.4% (n = 19) patients required heart failure hospitalisation, with 48% (n = 59) of patients commenced on beta blockade therapy and/or angiotensin-converting enzyme inhibitors. The majority of patients (73.2%, n = 90) experienced cardiotoxicity within 1 year of anthracycline initiation. The proportion of patients with complete, partial and no LVEF recovery were 16.3% (n = 20), 29.3% (n = 36) and 54.4% (n = 67) respectively. Mortality was higher in the cardiotoxicity group (49% vs 37%, P < 0.01). History of coronary artery disease, leukaemia, idarubicin use and high cumulative anthracycline dose were predictors of cardiotoxicity. CONCLUSIONS: Cardiotoxicity after anthracycline use predictably occurs within the first year of therapy and is dose-related, with variable degrees of recovery. While the need for hospitalisation for heart failure was uncommon, medical therapy appears underutilised, suggesting there may be a role for improved surveillance and early initiation of treatment.

The clinical features of fatal cyclophosphamide-induced cardiotoxicity in a conditioning regimen for allogeneic hematopoietic stem cell transplantation (allo-HSCT).

Cyclophosphamide (CY) cardiotoxicity induces a rare lethal complication associated with its use. The minimum dose for cardiac toxicity is still not known, although there are no reports of CY toxicity at doses of less than 100 mg/kg. There are few studies of CY cardiotoxicity that included a large number of patients who received high-dose CY for conditioning for allogeneic stem cell transplant (allo-HSCT). To elucidate the clinical course, complications, true incidence, and risk factors, the cardiac events of 811 patients who received more than a total of 100 mg/kg of CY as conditioning for allo-HSCT were analyzed. Twelve of 811 recipients (1.5 %) developed fatal cardiac failure induced by CY at a median of 4 (range 2-8) days after the first administration of CY. Regarding the dose of CY, 8.5, 1.2, and 0 % of the patients developed cardiac failure among the patients treated with a total of 200, 120, and 100 mg/kg CY, respectively. On echocardiography, the E/A ratio shows diastolic dysfunction but not the ejection fraction changed in the early course. Moreover, a short time to the first symptom after the administration of CY tended to be associated with early death (p = 0.09). Eleven patients died from progressive acute cardiac failure at day 7 (5-30) after the first administration of CY, and only one patient survived. In summary, fatal CY cardiotoxicity with allo-HSCT is a rare complication, but it is associated with high mortality. The possibility of CY-induced cardiotoxicity must be considered early after the administration of CY.

Late radiation toxicity in Hodgkin lymphoma patients: proton therapy's potential.

In 2010, all young patients treated for intrathoracic Hodgkin lymphoma (HL) at one of 10 radiotherapy centers in the province of Quebec received 3D conformal photon therapy. These patients may now be at risk for late effects of their treatment, notably secondary malignancies and cardiac toxicity. We hypothesized that more complex radiotherapy, including intensity-modulated proton therapy (IMPT) and possibly IMRT (in the form of helical tomotherapy (HT)), could benefit these patients. With institutional review board approval at 10 institutions, all treatment plans for patients under the age of 30 treated for HL during a six-month consecutive period of 2010 were retrieved. Twenty-six patients were identified, and after excluding patients with extrathoracic radiation or treatment of recurrence, 20 patients were replanned for HT and IMPT. Neutron dose for IMPT plans was estimated from published measurements. The relative seriality model was used to predict excess risk of cardiac mortality. A modified linear quadratic model was used to predict the excess absolute risk for induction of lung cancer and, in female patients, breast cancer. Model parameters were derived from published data. Predicted risk for cardiac mortality was similar among the three treatment techniques (absolute excess risk of cardiac mortality was not reduced for HT or IMPT (p > 0.05, p > 0.05) as compared to 3D CRT). Predicted risks were increased for HT and reduced for IMPT for secondary lung cancer (p < 0.001, p < 0.001) and breast cancers (p< 0.001, p< 0.001) as compared to 3D CRT.

PLANT POISONING IN THAILAND: A 10-YEAR ANALYSIS FROM RAMATHIBODI POISON CENTER.

Plant poisoning is not uncommon in Thailand. The objective of this study was to determine the incidence, type, clinical manifestations, severity and outcomes of plant poisoned patients in Thailand over a 10-year period. We retrospectively reviewed data from the Ramathibodi Poison Center Toxic Exposure Surveillance System for 2001-2010. A total of 2,901 poisonous plant exposure cases were identified, comprising 3.1% of the 92,392 poison cases recorded during the study period. This was the fifth most common type of poisoning recorded. Children aged < 13 years comprised the largest percent (69.8%) of the cases. The major type of exposure was unintentional ingestion. Ninety-nine types of poisonous plants were recorded as the causative agents among 99.1%of the cases. Gastrointestinal symptoms were reported in 72.0% of cases with Jatropha curcas (physic nut) comprising 54.1% of these. Most patients had only minor signs and symptoms. The mortality rate among the total plant poisoning cases was 0.9%, with 26 deaths. Thirteen deaths occurred in children aged < 13 years. The greatest number of fatalities were due to ingestion of Manihot esculenta (cassava), primarily due to multi-system organ failure. Children aged < 13 years are at the greatest risk for plant poisoning in Thailand; mostly unintentional. Most cases were minor and the mortality rate was low. Jatropha curcas was the most common cause of poisoning and Manihot esculenta was the most common cause of death. Public education is important to minimize these poisonings.

Paroxetine mitigates cardiac remodelling by doxorubicin and increases survival.

Doxorubicin (DOX) is an effective anticancer drug. However, its use is hampered by the development of very mortal cardiomyopathy. Here, we investigate whether the co-administration of the antidepressant paroxetine (P), known to exert beneficial cardiovascular effects, would provide effective cardioprotection. Experiments were performed in male Wistar rats randomly assigned to control group (0.5 mL/kg 0.9% NaCl, i.v., n = 7), DOX group (DOX 5 mg /kg i.v., n = 23) and DOX+P group (DOX 5 mg/kg, i.v. plus P 10 mg/kg p.o. daily, beginning five days before DOX administration and during the follow-up period, n = 11). Rats' body weight and echocardiography parameters were monitored before and after drug/vehicle administration. Cardiac histology was performed post-mortem, as well as beta1-adrenergic receptor (ß1-AR), beta2-adrenergic receptor (ß2-AR), G protein-coupled receptor kinases type 2 (GRK2), type 3 (GRK3), beta-arrestin 1, and beta-arrestin 2 gene expression using RT-qPCR. DOX-treated rats exhibited bad general condition, adynamia, loss of body weight, and low survival. Echocardiography revealed two phenotypes: cardiomyopathy with left ventricular (LV) hypertrophy (DOX-HCM) and cardiomyopathy with LV dilation (DOX-DCM). In DOX-HCM rats only, there was an increased GRK2 and GRK3 gene expression and synthesis. DOX+P co-treated rats exhibited good general condition, normal spontaneous behaviour, gained weight over time, had increased survival, and preserved LV morphology and contractility. In these rats, gene expression and synthesis of GRK2 and GRK3 were decreased, while ß1-AR and ß2-AR were increased. Present results show for the first time that P effectively reduces DOX-induced cardiotoxicity and enhances survival.

Heart-related mortality after postoperative breast irradiation in patients with ductal carcinoma in situ in the contemporary radiotherapy era.

Although radiation-induced cardiotoxicity has been addressed, its prognostic relevance to modern radiotherapy (RT) techniques is unclear. This study assessed the impact of adjuvant RT on heart-related deaths in patients with ductal carcinoma in situ. Patients who underwent adjuvant RT after breast-conserving surgery between 1988 and 2008 were identified from the Surveillance, Epidemiology, and End Results database. Kaplan‒Meier and competing risks analyses were conducted after propensity score-matching according to tumor laterality. A total of 41,526 propensity-matched patients were identified (n = 20,763 for either left- or right-sided tumor). In the analysis of the cumulative incidence of heart-related mortality events, there was a greater risk increment in the left-sided group over the first to second decades after RT in patients aged ≤ 50 years (P = 0.048). Competing risks analysis of the young patients showed that left-sided RT was associated with higher heart-related mortality rates (Grey's test, P = 0.049). The statistical significance remained after adjusting for other covariates (subdistribution hazard ratio 2.35; 95% confidence interval 1.09‒5.10). Regarding the intrinsic effect of modern RT techniques, further strategies to reduce heart-related risks are needed for young patients. Close surveillance within an earlier follow-up period should be considered for these patients in clinics.

[Cardiotoxicity of Anti-PD-L1 Antibody and the Effect of Levothyroxine 
in Attenuating the Related Mortality in Mice].

BACKGROUND: Immune checkpoint inhibitors (ICIs) such as antibodies against programmed cell death 1 (PD-1) and programmed cell death ligand 1 (PD-L1), have shown remarkable efficacies in many subtypes of cancers. However, ICIs may also cause severe immune-related adverse events in the recipient patients. Recently, ICI-associated myocarditis have been reported in hundreds of patients worldwide, with a mortality rate of approximately 50% in these cases. This study aims to recapitulate the cardiotoxicity and explore the detoxicifying approaches to attenuate mortality caused by PD-1/PD-L1 inhibitors in healthy mice. METHODS: Six to eight-week-old C57BL/6 mice were inoculated with anti-PD-1 antibody (12.5 µg/g every 5 days for 6 injections), anti-PD-L1 antibody (10 µg/g once a week for 6 weeks), anti-PD-L1 antibody (with the same dosage described above) in combination with levothyroxine (0.25 µg/g, intraperitoneally injected half an hour before anti-PD-L1 antibody injection), or isotype control immunoglobulin IgG (10 µg/g once a week for 6 weeks). The ejection function of the hearts was detected by echocardiography, body temperature and blood pressure were detected by Mouse MonitorTM and non-invassive blood pressure minotor, and serum free thyroxine concentration was detected by The enzyme linked immunosorbent assay (ELISA). RESULTS: PD-L1 was expressed at different levels by the cardiomyocytes of the mice. The isotype control immunoglobulin and anti-PD-1 antibody did not cause death of the mice. The 12 mice receiving 3-6 injections of anti-PD-L1 antibody showed a significant increase in the heart-to-tibial ratio and cardiomyoctye degeneration, hyalinization and extravascular inflammatory cell infiltration. In addition, the serum thyroxine was mardedly decreased to 1/3 of that in the control group mice, and the blood pressure and body temperature were abnormally decreased in mice upon treatment with PD-L1 blockade. Eight of the 12 (66.7%) mice died from multiple intravenous injection of anti-PD-L1 antibody.Intraperitoneal injection of levothyroxine 30 min before the injection of anti-PD-L1 antibody significantly attenuated the mortality rate of the anti-PD-L1 antibody-treated mice. CONCLUSIONS: The anti-PD-L1 antibody is cardiotoxic and lethal, and levothyroxine is able to rescue the mice from this immune checkpoint inhibitor-caused mortality.

Decision Science Can Inform Clinical Trade-Offs Regarding Cardiotoxic Cancer Treatments.

Cancer treatment-related cardiotoxicity (ie, heart failure, coronary artery disease, vascular diseases, arrhythmia) is a growing cancer survivorship concern within oncology practice; heart disease is the leading cause of noncancer death in cancer survivors and surpasses cancer as the leading cause of death for some cancers with higher survival rates. The issue of cardiotoxicity introduces a critical tradeoff that must be acknowledged and reconciled in clinical oncology practice: treating cancer aggressively and effectively in the present vs preventing future cardiotoxicity. Although many cancers must be treated as aggressively as possible, for others, multiple treatment options are available. Yet even when effective and less cardiotoxic treatments are available, they are not always chosen. Wariness to choose equally effective but less cardiotoxic treatment options may result in part from providers' and patients' reliance on "cognitive heuristics," or mental shortcuts that people (including, research shows, medical professionals) use to simplify complex judgments. These heuristics include delay discounting, availability and affect heuristics, and default bias. In the current commentary, we describe relevant research that illuminates how use of heuristics leads to biased medical decision making and translate how this research may apply when the tradeoff between aggressive cancer treatment and preventing future cardiotoxicity is considered. We discuss the implications of these biases in oncology practice, offer potential solutions to reduce bias, and call for future research in this area.