Acute Cardiac Toxicity Research Articles

All-Trans-Retinoic Acid Prevents Carfilzomib-Induced Cardiotoxicity By Decreasing Activation of the Renin-Angiotensin System

INTRODUCTION Bortezomib (BTZ), Carfilzomib (CFZ) and Ixazomib (IXA) are proteasome inhibitors (PI) approved for Multiple Myeloma (MM) treatment. By design, they all target the rate-limiting proteasome ß5 subunit. CFZ treatment increases the survival of patients with relapsed/refractory MM compared to BTZ. However, CFZ treatment is associated with heart failure not commonly observed for BTZ. The molecular basis for CFZ-induced cardiotoxicity is poorly understood. We have shown before that CFZ co-inhibits the ß5 and ß2 proteasome subunits compared to co-inhibition of the ß5/ß1 subunits by BTZ. We hypothesized that the unique ß5/ß2 subunit inhibition pattern of CFZ likewise explains the CFZ related acute cardiotoxicity. METHODS Isolated primary murine cardiomyocytes treated with BTZ, CFZ or ß5, ß2 and ß1 subunit-selective PI were used as in vitro model. Selectivity of proteasome subunit inhibition was confirmed with activity based chemical probes. Cardiomyocyte contractility was assessed in vitro using motion vector image analysis. The accumulation of individual proteins in cardiomyocytes undergoing 1h treatment with different PI was analyzed by liquid chromatography/mass spectrometry (LC/MS). In vivo analysis of the effects of differential proteasome subunit inhibition patterns was performed by electrocardiography (ECG) monitoring and untargeted metabolomics analysis from murine heart and plasma using R v.3.5.1 (2018-07-02) and Matlab 2020a. RESULTS Co-inhibition of ß5/ß2 proteasome subunits by CFZ or by respective subunit-specific PI for 1h resulted in increased proteasome inhibition and proteotoxic stress in cardiomyocytes compared to ß5/ß1 inhibition induced by BTZ. Likewise, CFZ or the ß5/ß2 type co-inhibition of the proteasome impaired contractility of cardiomyocytes in vitro, in contrast to BTZ or to ß5/ß1-selective proteasome inhibition. LC/MS-based proteome analysis of murine primary cardiomyocytes treated with either CFZ-type or BTZ-type proteasome inhibition identified accumulation of Retinal Dehydrogenase 1 (ALDH1A1) in PI-treated cardiomyocytes, with CFZ showing a slightly stronger effect. ALDH1A1 is involved in retinoic acid metabolism. Co-treatment of cardiomyocytes with its enzymatic end-product, all-trans-Retinoic-Acid (atRA), restored contractility of cardiomyocytes undergoing CFZ treatment in vitro. Leucyl-Cistinyl Aminopeptidase (LCAP) was identified as the protein that accumulated in CFZ-versus BTZ-treated cardiomyocytes (Log2 CFZ = 1.1, Log2 BTZ = -0.49, p=0.002). LCAP is involved in the Renin-Angiotensin System (RAS) and its increase suggests selective activation of RAS with increased degradation of RAS metabolites via LCAP in cardiomyocytes undergoing CFZ treatment. Indeed, mRNA expression for angiotensin converting enzyme 2 (Ace2) and angiotensin receptor 1 (Agtr1) was increased in beating cardiomyocytes treated with CFZ. Conversely, treatment with aminopeptidase inhibitor Bestatin prevented CFZ-induced cardiomyocyte toxicity in vitro. Consistent with our model, co-treatment of cardiomyocytes with CFZ and Valsartan, an Agtr1 inhibitor, likewise prevented CFZ- induced toxicity. In vivo, 1h CFZ treatment selectively led to acute bradycardia with local activation of the RAS and accumulation of angiotensin in the heart. CFZ/atRA co-treatment decreased local angiotensin levels and prevented CFZ-induced bradycardia. There were no differences in angiotensin plasma levels in between the treated mice, suggesting that the local RAS in the heart rather than systemic effects of the RAS mediates the cardiotoxicity of CFZ. CONCLUSION Our data suggest that CFZ specifically impairs cardiac contractility in a dose-dependent manner that is caused by its unique ß5/ß2 proteasome subunit co-inhibition pattern. CFZ leads to more efficient functional proteasome inhibition in cardiomyocytes, resulting in accumulation of LCAP that subsequently activates the local RAS and induce acute cardiotoxicity. Based on our findings, CFZ-induced cardiotoxicity may be prevented or mitigated by either blocking RAS activation at the angiotensin II receptor level using selective drugs like Valsartan, or by reducing angiotensin levels with atRA. This provides a rational strategy to prevent CFZ-induced acute cardiac toxicity by modulating the activity of the local RAS with approved drugs. Disclosures No relevant conflicts of interest to declare.

Acute cardiomyopathy following a single dose of doxorubicin in a patient with adult T-Cell leukemia/lymphoma

Anthracycline-based chemotherapy regimens are associated with decreased cardiac function with cumulative dosing, yet there is limited information regarding the acute cardiotoxic potential of these medications and appropriate medical management strategies. Herein, we report a case of cardiomyopathy following a single dose of doxorubicin and describe our pharmacologic management approach. A 37 year old Jamaican male presented for work-up and treatment of HTLV-1 associated T-cell leukemia/lymphoma. Upon diagnosis, the patient received one cycle of CHOEP, which was complicated by tumor lysis syndrome. Subsequently, the treatment was changed to DA-EPOCH, however, immediately after the initiation of DA-EPOCH on day 1, the patient was found to have t-wave inversions on EKG and an ejection fraction (EF) of 20% with new mitral regurgitation. EPOCH infusion was discontinued within 3 hours of initiation.Management and outcome: The chemotherapy regimen was modified to DA-EPOC with the removal of doxorubicin. The patient was started on metoprolol succinate 12.5 mg once daily for 2 days and subsequently switched to carvedilol 3.125 mg twice daily and lisinopril 5 mg once daily; the patient's ejection fraction improved to baseline after 2.5 months of therapy. Though anthracyclines are associated with cardiotoxicity at high cumulative doses, this case highlights the cardiotoxic potential of these medications in the acute setting. Management of anthracycline cardiotoxicity is similar to heart failure management, with data suggesting benefit of using carvedilol and lisinopril. It is unclear if our patient would have benefited from prophylactic angiotensin converting enzymes inhibitors (ACEi) and/or beta-blocker therapy, as he had no known cardiac disease. Acute anthracycline-induced cardiac toxicity is an adverse drug reaction with which providers should be familiar and know how to appropriately manage.

Impact of cytokine release syndrome on cardiac function following CD19 CAR-T cell therapy in children and young adults with hematological malignancies

BackgroundChimeric antigen receptor (CAR) T-cell-associated cytokine release syndrome (CRS) may present with tachycardia, hemodynamic instability and reduced cardiac function. Pediatric CAR studies examining cardiac toxicity are limited.MethodsWe report on cardiac...

Cardiac serum marker alterations after intraoperative radiotherapy with low-energy x-rays in early breast cancer as an indicator of possible cardiac toxicity

PurposeTo assess acute cardiac toxicity caused by intraoperative radiotherapy (IORT) with low-energy x‑rays for early breast cancer.MethodsWe prospectively analyzed pre- and postoperative troponin I and NT-proBNP in 94 women who underwent breast-conserving surgery between 2013 and 2017 at the Department of Gynecology and Obstetrics of the University Medical Center Mannheim, Germany. Thirty-nine women received IORT using low-energy x‑rays during breast-conserving surgery while 55 patients without IORT formed the control group. Demographic and surgical parameters as well as cardiac markers were evaluated.ResultsThere were no significant differences concerning age and side of breast cancer between the groups. Furthermore, no significant difference between the troponin I assays of the IORT and control groups could be found (preoperatively: 0.017 ± 0.006 ng/ml vs. 0.018 ± 0.008 ng/ml; p = 0.5105; postoperatively: 0.019 ± 0.012 ng/ml vs. 0.018 ± 0.010 ng/ml; p = 0.6225). N‑terminal fragment of B‑type natriuretic peptide (NT-proBNP) was significantly higher in the control group 24 h after surgery (preoperatively: 158.154 ± 169.427 pg/ml vs. 162.109 ± 147.343 pg/ml; p = 0.56; postoperatively: 168.846 ± 160.227 pg/ml vs. 232.527 ± 188.957 pg/ml; p = 0.0279).ConclusionTroponin I levels as a marker of acute cardiac toxicity did not show any significant differences in patients who received IORT during breast-conserving surgery compared to those who did not.

Accelerated Hypofractionated Whole Breast Radiotherapy for Early Breast Cancer; ARandomized Phase III Clinical Trial

To compare the cosmetic outcome and acute cutaneous, cardiac, and pulmonary toxicity profile of accelerated hypofractionated and conventional whole breast radiotherapy (WBRT).This was a blocked randomized, clinical trial on women with early-stage node-negative invasive breast cancer after breast conservation surgery (BCS) with clear margins randomly assigned to receive WBRT either at a conventional dose of 50.0 grays (Gy) in 25 fractions (the conventional group) or at a dose of 42.5 Gy in 16 fractions (the hypofractionated group). Boost irradiation was permitted in both groups. Data were analyzed by SPSS V21.0 using Mann–Whitney U, independent-samples t- and Chi-Square/Fisher's exact tests at the level of P≤0.05.The median follows up was 16 months. Forty-one patients in the conventional WBRT arm and 45 patients in the hypofractionated WBRT group were enrolled. No significant difference was observed in terms of left and right ventricle systolic dysfunction and diastolic dysfunction. Pulmonary function tests after 6 and 12 months follow up, were comparable in both groups (P=0.2). Skin toxicity during and after treatment was acceptable in both groups. Breast size change in the conventional and the hypofractionated WBRT groups was 14.3% and 7.1%, respectively (P=0.6). Excellent or good cosmetic outcome was similar in both groups.The results of our study support the use of accelerated hypofractionated WBRT in women with invasive breast cancer less than five cm and node-negative after breast-conserving surgery, which provides a more convenient shorter course of radiotherapy with a comparable cosmetic outcome and cutaneous, cardiac, and pulmonary toxicity profile.

Can rutin ameliorate aluminum phosphide-induced acute cardiac toxicity in adult albino rats?

Current management of rice tablet or aluminium phosphide (AlP) poisoning has remained mostly supportive despite of its fatal outcome and unfortunately no antidote is found yet, therefore, there is a need to search for a treatment that can adequately protect against its toxicity. To the best of our knowledge, there are no studies until now concerning the cardioprotective effect of rutin against AlP cardiac toxicity in rats. For this purpose, this study was carried out to investigate the possible protective effect of rutin against AlP induced cardiotoxicity in rats. Forty male albino rats were randomly divided into four groups. Group I: normal control group was served as untreated rats and received distilled water orally through a gastric tube. Group II: Rutin treated group received a dose of 100 mg/kg rutin dissolved in distilled water and given orally through a gastric tube. Group III: AlP intoxicated rats received AlP oral single sub-lethal dose (2 mg/Kg body weight) dissolved in distilled water and given through a gastric tube. Group IV: AlP intoxicated rats + Rutin treated one hour after receiving AlP in doses as mentioned above. After that we tested the following parameters: ECG changes including HR and ST-segment elevation, serum level of TNF-α, IL-6 and H-FABP (pg/ml), antioxidant and Oxidant parameters in cardiac tissue as GSH, SOD, and MDA, apoptotic factor caspase-3 and histopathological examination of cardiac tissue was also included. The results showed that treatment with rutin caused a significant decrease in heart rate and ST segment elevation, a significant decrease in activity of TNF-α and IL-6 and levels of H-FABP also a significant decrease in the activity of SOD with decreased levels of MDA and caspase-3 level and a significant increase in the level of GSH compared to (AlP) intoxicated group, also histopathological changes induced by AlP improved after treatment with rutin. It is concluded that AlP intoxication caused ECG, biochemical and histopathological changes which were potentially improved with rutin. Â

Metachronous NSCLC in previously irradiated patients: is re-irradiation with SBRT a good option as definitive treatment?

AbstractAim:Treatment of metachronous second primary non-small cell lung cancer (NSCLC) in patients already treated with definitive radiotherapy is a matter of debate, since most patients are excluded from surgical treatment, which remains a therapeutic standard for patients with isolated lung masses. Salvage chemotherapy or immunotherapy alone offers a low probability of disease control. The option of re-irradiation often remains the only viable, but the risks of severe acute or late toxicities affecting the surrounding normal tissues make this a real clinical challenge.Materials and methods:From January 2015 to April 2018, five patients (male/female: 4/1; age 54–81 years, median 68) with previously irradiated NSCLC presented with a second primary lung tumour.Results:A partial response was seen in four patients, one complete responses in the fifth. The toxicity was low: two patients experienced a grade 2 asymptomatic radiation pneumonitis after 6 and 12 months from the end of stereotactic body radiation therapy, resolved with cortisone therapy. No acute or late oesophageal or cardiac toxicity was found.Findings:In this work, we present our initial experience about the use of stereotactic radiotherapy technique in already irradiated patients. We reported a local disease control in all cases with an acceptable toxicity.

The VITAL Trial: Phase II Trial of Vosaroxin and Infusional Cytarabine for Frontline Treatment of acute Myeloid Leukemia

The VITAL Trial: Phase II Trial of Vosaroxin and Infusional Cytarabine for Frontline Treatment of acute Myeloid Leukemia

TREATMENT OF ACUTE BUPROPRIONE TOXICITY WITH LIPID INFUSION AND PLASMAPHERESIS

SESSION TITLE: Plasmapheresis to the Rescue SESSION TYPE: Fellow Case Reports PRESENTED ON: 10/21/2019 3:15 PM - 4:15 PM INTRODUCTION: Bupropion is an atypical antidepressant used to treat major depressive disorder and other psychiatric conditions. The toxic side effects of bupropion include seizures, tachycardia, arrhythmias, and death. These side effects are dose and formulary dependent. We describe a case of acute bupropion toxicity from a suicide attempt with symptoms, which was treated with Intralipid infusion along with serial plasmapheresis. CASE PRESENTATION: A 19-year-old male was transferred from an outside hospital for suicide attempt with ingestion of 40 tablets of 150 mg sustained released (SR) bupropion for a total dose of 9 gm. He was not a candidate for any activated charcoal. The patient developed tonic-clonic seizures and the decision was made to initiate a bolus of 140 mL of 20% Intralipid before and during transport. On admission to our hospital he developed status epilepticus and had QTc prolongation (467 and 487). He was started on 800 mL lipid infusion immediately followed by serial plasmapheresis. The triglyceride levels were closely monitored. The patient received a total of 940 mL (140 mL bolus plus 800 mL continuous infusion) of intralipid along with 3 sessions of plasmapheresis. He remained seizure free and his QTc normalized and was successfully extubated. DISCUSSION: Bupropion is a highly lipid soluble and protein-bound medication. Mild toxicity includes dry mouth, nausea, insomnia, dizziness. Life-threatening toxicities include seizure and arrhythmias. Seizures are generally seen with an overdose of bupropion. Ingestion of 4.5-9 g of bupropion increases the likelihood of seizures. Treatment is mostly symptomatic and with benzodiazepines. Lipid infusions can be used as lipid rescue therapy for acute cardiovascular collapses. The mechanism is the same as the use of lipid infusion as rescue therapy in case of local anesthetic, tricyclic antidepressants or serotonin-specific reuptake inhibitor toxicities. The proposed mechanism involves lipids from the infusion binding to the offending drug and pulling it from the target tissue preventing its accumulation and minimizing the toxic effects. Despite several reports there seem to be increased risks and compilations associated with lipid infusions like acute respiratory distress syndrome, hypertriglyceridemia, pancreatitis, and cardiac toxicity. There are not many reports of the use of plasmapheresis in a timely manner (depending on the half-life of the drug) for an SR drug after lipid infusion to promote removal of all the lipid molecules including those bound to the offending drug thereby preventing toxicity from the drug and lipid infusion as well. In our case combination of both helped in stabilizing and treating the patient. CONCLUSIONS: Use of lipid infusion in conjugation with plasmapheresis for the treatment of acute bupropion toxicity with symptoms allows safe use of lipid infusion and ensures complete removal of offending drug. Reference #1: Tolentino Stephanie; Gharpure, Varsha; Tsifansky, Michael Critical Care Medicine: December 2013 Reference #2: Intravenous lipid emulsion in clinical toxicology Leelach Rothschild,corresponding author1 Sarah Bern,1 Sarah Oswald,1 and Guy Weinbergcorresponding author1,2 DISCLOSURES: No relevant relationships by Praful Tewari, source=Web Response

Cardiac toxicity of Triptergium wilfordii Hook F. may correlate with its inhibition to hERG channel

Tripterygium wilfordii Hook F. (TWHF) is a Chinese traditional medicine with cardiac toxicities. However, the mechanism of acute cardiac toxicity is not very clear. By using patch clamp techniques, we found that 0.05 mg/ml and 0.1 mg/ml of the aqueous crude extract of TWHF inhibit 21.4 ± 1.6% and 86.7 ± 5.7% (n = 5) of hERG current Amplitudes (IhERG) respectively. We further found that Celastrol, one of main components of TWHF, inhibits hERG with an IC50 of 0.83 μM. Additional mutagenesis studies show that mutations of T623A, S624A and F656A significantly alter the inhibition and S624A has the strongest effect, supported by our docking model. Our data suggest that inhibition of hERG channel activity by Celastrol contributed to TWHF cardiotoxicity.

Effect of Radiation Dose to Cardiac Substructures on the Acute Development of New Arrhythmias Following Conventionally Fractionated Radiation Treatment to the Lung

The impact of radiation dose on specific cardiac substructures and its relationship with the development of new cardiac arrhythmias in the acute setting (either during the radiation treatment course itself, or within the month immediately following completion of treatment) is not well-established in the existing literature. We aimed to identify patients who experienced acute cardiac arrhythmic toxicities and determine the dose received by the sinoatrial (SA) node and right atrium in these patients. We conducted a single-institution, retrospective review of patients who received at least 45 Gy of external-beam radiation treatment to the lung between October 2013 and June 2017. 193 patients were identified within this cohort, and these patients’ medical records were reviewed for incidence of new cardiac events during or after radiation treatment. Seven patients were identified as having suffered a Grade 3 acute cardiac arrhythmic toxicity requiring inpatient admission, all of whom had no prior history of arrhythmias. Contouring guidelines for regional cardiac anatomy were created, and cardiac substructures, including the SA node and all four main chambers of the heart, were contoured on these patients. An analysis of the dose received by the SA node and the right atrium, two substructures critical to the electrical conduction system of the heart, was subsequently completed on this patient subset. Of the seven patients with an acute cardiac arrhythmic toxicity, the median age was 65 and the median follow-up from conclusion of radiation treatment was 17 months. The median prescribed dose was 60 Gy in 30 fractions. Two of the patients were prescribed radiation for left-sided lung malignancies, and the other five were treated for right-sided cancers. Two of the seven patients experienced cardiac toxicity during the treatment course, while the other five experienced toxicities within the month following conclusion of radiation. Four of the seven patients experienced atrial fibrillation, and the remaining toxicities (one in each patient) were Mobitz Type 2 heart block, multifocal atrial tachycardia, and atrial flutter. Across all seven patients, the mean SA node dose ranged from 1702 cGy to 6778 cGy and the maximum SA node dose ranged from 3157 cGy to 6904 cGy; the mean right atrial dose ranged from 443 cGy to 4057 cGy and the maximum right atrial dose ranged from 3620 cGy to 6938 cGy. Three patients received over 60 Gy of mean SA node dose, maximum SA node dose, and maximum right atrium dose. While acute development of new cardiac arrhythmias following conventionally fractionated radiation treatment to the lung is an uncommon occurrence, increased radiation dose to the SA node and right atrium may predispose patients to this toxicity; further study is warranted to elucidate specific dose limits to cardiac substructures.

PB1765 CHARACTERISTICS OF ERYTHROLEUKEMIA ABOUT 10 CASES WITH REVIEW OF THE LITERATURE

Background:Acute erythroblastic leukemia (AML‐M6) is a rare entity, accounting for 3‐4% of all LAs. There are two types: erythroleukemia and pure erythroid leukemia. It is most often manifested by signs of cytopenia and infiltration of extrahematopoietic tissues, and is more common in adults than in children with a poor prognosis.Aims:The objective of this study is to describe the clinical, biological and evolutionary aspects of erytholeukemia in a monocentric retrospective study.Methods:the diagnosis is based on a cytological examination of the blood smear (FS) and medullary (PMO) as well as the immunophenotypic examination. We calculated overall survival by Kaplan Meier methodResults:n = 181 (evaluable), n = 10 patients with AML6 according to the FAB classification (5%). • The cytological study of FS and PMO + CMF results led to the diagnosis of erythroleukemia in 08 of our patients and pure erythroid leukemia in 2 patients. Mean age = 47 ± 21.77 years [0‐64]. Sex ratio = 1.5 (6H / 4F). Duration: 40 ± 35 days [01‐90]. Symptoms of bone marrow failure: PCM (100%), hemorrhagic syndrome: 3 cases (30%), infection: 04 cases (40%), splenomegaly: 04 cases (30%), mean WB = 84,300 ± 11.260 giga / l [125.000‐83.400], peripheral blast level (avg = 26 ± 23% [1‐65]), medullary blasts = average 49.5 ± 19% (08‐93) • mean hemoglobin level = 8.06 ± 1.09 g / dl [5‐10], platelets: 21‐151giga / l (avg: 65,900 ± 47,450 / mm3) n = 03 patients had severe thrombocytopenia at 13‐21‐39 giga / respectively (30%), pancytopenia found in n = 05 cases (50%), LDH level (mean) = 905 ± 896 IU / L [12‐2,900], n = 02 patients had 1 metabolic complication at diagnosis (hyperkalemia, hyponatremia). n = 8 patients received induction CT (3 + 7), n = 01 patient received only 2 aracytin‐associated antracycline injections. Newborn LAM, the newborn clinically presents: cutaneous and mucosal paleness and hepatosplenomegaly, on the biological plane: GB: 125giga / l, (EB = 64%, blast = 3%), HB = 10 g / dl, PLQ = 13gigal / l, PMO: infiltration by 68% of dystrophic EB, 08% of MB, the newborn t under aseptic vacuum The specific treatment has not yet been started. The complete remission is obtained (n = 04 cases (40%)) and n = 03 failures (30%), n = 01patient came out against medical advice; one induction death is listed (acute cardiac toxicity) • Overall survival = 27% (fig1)Summary/Conclusion:our data are similar to those of the literature: rare pathologic LAM6 (3‐5 / series, 05% in ours), exceptional in children. The signs of bone marrow failure are almost constant, 1 pancytopenia in 50%. Splenomegaly is found in 1/3 of the cases. The prognosis is reserved (overall survival = 25% at 05 years) from wherethe value of rapid diagnosis and adequate managementimage

BRAIN NATRIURETIC PEPTIDE (BNP) AS A BIOMARKER OF CARDIAC TOXICITY IN CASES OF ACUTE CARBON MONOXIDE POISONING

Background: Acute carbon monoxide (CO) poisoning is a common toxicity emergency that leads in many occasions to morbidity and mortality. Acute myocardial injury is commonly observed among acute carbon monoxide poisoned patients and cardiac toxicity is found to be the cause of mortality in the majority of cases. Some studies recorded normal values of cardiac troponins in cases of acute CO poisoning with cardiac affection. Hence it is important to search for novel and sensitive biomarkers to diagnose cardiac ischemia in these cases. Brain natriuretic peptide (BNP) is a cardiac hormone which is produced mainly in the ventricular myocardium in response to myocardial hypoxia. Aim: The present study aims to investigate the value of BNP measurement in detection of cardiac toxicity in acute carbon monoxide poisoning. Methods: The present study was conducted on 42 patients with acute CO poisoning admitted to the Poison Control Centre of Ain Shams University hospitals (PCC-ASUH). Routine laboratory tests and ECG were done on admission in addition to determination of the level of BNP and determination of troponin I. Results: Analysis of the results showed that there is an increase in the levels of BNP in patients suffering from acute CO poisoning with high levels seen in those with ischemic changes recorded by ECG. Conclusions: The present study concluded that plasma BNP levels could be used as a specific reliable biomarker of cardiac toxicity in patients with acute CO poisoning.

Does Modern Mediastinal Irradiation Cause Acute Subclinical Cardiac Toxicity? The Final Results of the MEDICATE Study (Mediastinal Irradiation and Cardio-Toxic Effects)

Radiation-induced heart disease (RIHD) is a late effect of cardiac irradiation (RT), and has been demonstrated in Hodgkin and non-Hodgkin lymphoma (HL and NHL), as well as in other thoracic cancers. There is no established measurement tool to detect acute cardiac damage, however high sensitivity troponin I and T (HsTnI and HsTNT) and imaging modalities such as echocardiograms have shown promise in some studies. We conducted a prospective trial to characterize acute and subacute cardiac damage in patients with thoracic cancers receiving cardiac radiation therapy. Patients were recruited from Hematology or Lung clinics at our institution if they were to receive cardiac RT of at least 30Gy to 5% of cardiac volume or a mean dose of 4Gy. Following consent and CT simulation, conformal (3D) and intensity modulated radiation therapy (IMRT) plans were created and cardiac structures were contoured. Patients had blood drawn for C-reactive protein (systemic inflammatory marker), HsTnI, HsTnT prior to RT and at 2 and 4 weeks into radiation therapy and completed 3D echocardiograms (3D) prior to RT and one year post-RT. Serum markers levels, imaging results and cardiac RT dose-volume data were analyzed for association. Twenty patients were recruited (including one who withdrew consent). The median value for “mean LV dose” was 3.1 Gy, and the median value for “mean total cardiac dose” was 8.6 Gy. Statistically significant positive associations between hsTnI and hsTnT at all time points, with an apparent decrease in mean value over time, and therewas a positive association between hsTnI increase between week 2 to 4 and maximum cardiac LV dose (ρ= 0.66, p=0.027). Although overall the mean change in LVEF for the whole cohort was non-significant (57.57 pre-RT and 56.4 post –RT), the mean dose to the left ventricle was associated with decrease in ejection fraction from pre-RT to one year echocardiograms (ρ= -0.46, p=0.054). An association was also seen between increase in left ventricular strain (LVS) and cardiac mean dose (ρ= 0.46, p=0.058), and cardiac dose to maximum 5% volume (ρ= 0.48, p=0.043). Our study suggests that hsTnI and hsTnT are intimately related, but detection of acute cardiac damage was not demonstrated potentially due to limitations of these markers, or low radiation therapy doses using modern techniques. Our results also suggest 3D echocardiogram findings may detect subacute damage at one year depending on dose to cardiac volumes. Given limitations of our study, we suggest that techniques to measure subacute cardiac damage including serum biomarkers and imaging modalities require further characterization to optimize their use. Identification early damage could facilitate the ability to closely monitor and intervene in patients at risk for RIHD. The current study is reassuring that modern quality-assured radiation techniques can prevent acute cardiac damage, even after anthracycline chemotherapy.

956P - A phase Ib and randomised phase II trial of pazopanib with or without fosbretabulin in advanced recurrent ovarian cancer

Background: Prospective trials have validated angiogenesis as a treatment target in ovarian cancer although improvements in PFS have been modest. One potential strategy to improve efficacy is to combine anti-vascular agents. Fosbretabulin (F) is an intravenous vascular disrupting agent and pazopanib (P) is an oral VEGFR tyrosine kinase inhibitor. Methods: A multi-centre Phase 1b(P1b)/randomised phase 2 (RP2) trial that recruited women with recurrent epithelial ovarian cancer and a platinum-free interval of 3-12 months. Any Bevacizumab had been received ≥6 months prior to recruitment. Phase 1b dose levels ranged from F = 54mg/m2 d1,8,15q28d + P = 600mg/day (F54+P600) up to F = 60mg/m2 d1,8,15q28d + P = 800mg/day. In RP2 participants received either RP2D or P = 800mg/day (P800). Primary outcome in P1b was safety plus RP2D and in RP2 was RECIST PFS. Results: 12 and 21 patients were recruited to P1b & RP2 respectively. The RP2D was F54+P600. In the RP2 median PFS was 7.6 months (95%CI 4.1-not estimated) in F54+P600 group vs. 3.7 months (95%CI 1.0-8.1) in P800 group (HR 0.30, 95%CI 0.08-1.03, P = 0.06). Four patients who received F+P (2 in P1b and 2 in RP2) developed acute hypertension plus reversible secondary cardiac toxicity. The occurrence of cardiac toxicity resulted in premature discontinuation of the trial. Data on circulating biomarkers of angiogenesis collected in in P1b & RP2 will also be presented. Conclusions: F54+P600 appeared effective but was associated with reversible secondary cardiac toxicity that with better hypertension control might have been avoided. Clinical trial identification: EudraCT: 2013-005471-40. Legal entity responsible for the study: The Christie NHS Foundation Trust. Funding: Novartis & Mateon Therapeutics. Disclosure: G.J.S. Rustin: Advisory board: Mateon, Roche, AstraZeneca in past 3 years, only Roche in past year. All other authors have declared no conflicts of interest.

Cardioprotective role of FA against isoproterenol induced cardiac toxicity.

The present study was designed to investigate the protective effect of ferulic acid (FA) against isoproterenol (ISO)-induced cardiac toxicity in rats. Isoproterenol challenged in a dose of 85mg/kg body weight (b.w.) subcutaneously for two consecutive days in the experimental group resulted in acute cardiac toxicity as evidenced by changes in electrocardiogram (ECG) pattern and marked elevation of serum cardiac enzymes viz aspartate aminotransferase (AST), alanine transaminase (ALT), creatinine kinase (CK-MB) and lactate dehydrogenase (LDH) also increases inflammatory cytokines. Moreover, acute toxicity effect was exhibited by disturbance in the antioxidant system as decrease in activities of superoxide dismutase (SOD) and glutathione (GSH) with the rise in activities of malondialdehyde (MDA) and nitric oxide (NO). Pre-treatment with FA at the increasing dose of (10, 20 and 40mg/kg b.w.) orally for 28 consecutive days followed by isoproterenol injection for 2days significantly attenuated changes in serum cardiac enzymes. Furthermore, histopathological evaluation confirmed the restoration of cellular architecture in FA pretreated rats. The cardioprotective effect of FA was comparable with standard drug treatment metoprolol. Taken together, FA demonstrated cardioprotective effect against ISO-induced cardiac toxicity by normalization of serum cardiac biomarkers, alleviating oxidative stress and augmenting endogenous antioxidant system.

Dosimetric comparison between proton beam therapy and photon radiation therapy for locally advanced esophageal squamous cell carcinoma

BackgroundThe purpose of this study was to perform a dosimetric comparison between proton beam therapy (PBT) and photon radiation therapy in patients with locally advanced esophageal squamous cell carcinoma (ESCC) who were treated with PBT in our institution. In addition, we evaluated the correlation between toxicities and dosimetric parameters, especially the doses to normal lung or heart tissue, to clarify the clinical advantage of PBT over photon radiation therapy.MethodsA total of 37 consecutive patients with Stage III thoracic ESCC who had received PBT with or without concurrent chemotherapy between October 2012 and December 2015 were evaluated in this study. The dose distributions of PBT were compared with those of dummy 3-dimensional conformal radiation therapy (3DCRT) and Intensity Modulated Radiation Therapy (IMRT), focusing especially on the doses to organs at risk, such as normal lung and heart tissue.ResultsOf the 37 patients, the data from 27 patients were analyzed. Among these 27 patients, four patients (15%) developed grade 2 pericardial effusion as a late toxicity. None of the patients developed grade 3 or worse acute or late pulmonary and cardiac toxicities. When the dosimetric parameters between PBT and planned 3DCRT were compared, all the PBT domestic variables for the lung dose except for lung V10 GyE and V15 GyE were significantly lower than those for the dummy 3DCRT plans, and the PBT domestic variables for the heart dose were also significantly lower than those for the dummy 3DCRT plans. When the PBT and IMRT plans were compared, all the PBT domestic variables for the doses to the lung and heart were significantly lower than those for the dummy IMRT plans. Regarding the correlation between the grades of toxicities and the dosimetric parameters, no significant correlation was seen between the occurrence of grade 2 pericardial effusion and the dose to the heart.ConclusionsWhen the dosimetric parameters of the dose distributions for the treatment of patients with locally advanced stage III ESCC were compared between PBT and 3DCRT or IMRT, PBT enabled a significant reduction in the dose to the lung and heart, compared with 3DCRT or IMRT.

A feasibility study of neo-adjuvant low-dose fractionated radiotherapy with two different concurrent anthracycline-docetaxel schedules in stage IIA/B-IIIA breast cancer.

The aim of the study was to evaluate the feasibility of neoadjuvant low-dose fractionated radiotherapy, in combination with two anthracycline-docetaxel regimens, in breast cancer treatment. Women with stage IIA/B-IIIA breast cancer were assigned to receive the treatment of low-dose fractionated radiotherapy (0.4 Gy/per fraction, 2 fractions per day, for 2 days, every 21 days for 8-6 cycles) with concomitant neoadjuvant chemotherapy with non-pegylated liposomal doxorubicin and docetaxel. Two chemotherapy schedules were planned to be combined with low-dose fractionated radiotherapy. The first schedule consisted of four cycles of non-pegylated liposomal doxorubicin sequentially followed by four cycles of docetaxel, and the second schedule consisted of six cycles of non-pegylated liposomal doxorubicin plus concomitant docetaxel. Acute toxicity was evaluated according to the Radiation Therapy Oncology Group score system. Pathological response was evaluated by the Mandard score and expressed as tumor regression grade. Between March 2008 and February 2009, 10 patients underwent low-dose fractionated radiotherapy and concomitant chemotherapy. No grade 3-4 breast toxicity was observed. Five patients had a clinical complete response. Seven patients underwent conservative surgery. Overall, tumor regression grade 1 (absence of residual cancer) was achieved in one patient (10%) and grade 2 (residual isolated cells scattered through the fibrosis) in 4 patients (40%). The pathologic major response rate (tumor regression grade 1 + 2) was 20% in patients receiving low-dose fractionated radiotherapy and sequential non-pegylated liposomal doxorubicin and docetaxel and 80% in the group receiving low-dose fractionated radiotherapy and concurrent non-pegylated liposomal doxorubicin and docetaxel treatment. Concomitant low-dose fractionated radiotherapy combined with anthracycline and docetaxel is feasible. The toxicity profile of radio-chemotherapy was similar to that of chemotherapy alone: there was no acute skin or cardiac toxicity. The concurrent application of liposomal doxorubicin and docetaxel with low-dose fractionated radiation led to higher histological response rates compared to the sequential application of the same two drugs.

Combination of Trastuzumab and Radiotherapy in the Adjuvant Treatment of Breast Cancer: A Single Center Experience and Focus on the Cardiac Safety

Background: The main toxicity of trastuzumab, is the alteration of cardiac function. The objective of this study is to examine the acute cardiotoxicity of the combination of Radiotherapy (RT) and trastuzumab in the adjuvant treatment of breast cancer. Materials and Methods: This is a retrospective study of 41 patients followed for localized breast cancer, treated by multimodal strategy combining chemotherapy, Radiotherapy and trastuzumab as adjuvant treatment in the medical oncology department at the Ibn Sina Military hospital of Marrakesh. Results: All patients underwent adjuvant RT on the wall, including 17 on the left side. The median value of the Left Ventricular Ejection Fraction (LVEF) before starting treatment was 64%. The median value of the absolute decrease of LVEF, after the end of RT, was of the order of 4%. All patients received treatment with trastuzumab, during irradiation at usual doses for twelve months. Trastuzumab was stopped temporarily in seven patients, because of the fall in LVEF of more than 10%. After a median followup of 13 months, one patient developed congestive heart failure, imposing the definitive cessation of trastuzumab. Conclusion: The association RT and trastuzumab, does not appear to increase the risk of acute cardiac toxicity, whatever the irradiated side.

Cardioprotective effects of rutin in rats exposed to pirarubicin toxicity

We established both an acute and chronic cardiac toxicity rat model, which showed pretreatment with rutin attenuated pirarubicin-induced myocardial histopathological injury, electrocardiogram abnormalities, and cardiac dysfunction. Rutin also significantly reduced serum levels of MDA, BNP, CK-MB, CTnT, and LDH and increased serum SOD levels. Treatment with rutin and dexrazoxane resulted in an increase in Bcl-2/Bax ratio (p < 0.05) and reduction in JNK and Caspase-3 protein levels, compared to the pirarubicin group (all p < 0.05). Furthermore, rutin at a dose of 50 mg/kg significantly attenuated the above-mentioned alterations. Our study suggests the antioxidant and anti-apoptotic properties of rutin may be responsible for the cardioprotective effects observed.