Cardiac Toxic Effects Research Articles

Development and validation of an LC-MS/MS method for the quantification of free and total doxorubicin in human plasma and its clinical application for a novel doxorubicin hydrochloride liposome injection in Chinese patients with breast cancer

AbstractA novel doxorubicin hydrochloride liposome injection was prepared to reduce toxicity and side effects, as well as extend plasma half-life in the treatment of breast cancer. In this study, a rapid and sensitive bioanalytical method was developed and validated to characterize the pharmacokinetic profile of total and free doxorubicin in plasma of 3 Chinese patients after intravenous infusion of this injection. Plasma samples were prepared by protein precipitation for the determination of total doxorubicin, while solid phase extraction was used to determine free doxorubicin. After plasma sample pre-treatment, total and free concentrations were quantified individually using a validated LC-MS/MS method. The calibration curves were found to be linear in the range of 0.20–500.0 ng mL−1 for total doxorubicin and in the range of 1.00–1,000 ng mL−1 for free doxorubicin. The free concentrations in plasma were only one sixth to one quarter of the total levels. Liposomal doxorubicin had a longer apparent half-life (>50 h) than the non-targeted drug (<10 h) reported in the reference. and a lower volume of distribution. This novel injectable formulation steadily released free doxorubicin from liposomes over a long period of time to reduce cardiac toxicity and side effects, while ensuring a clinical curative effect.

Ecotoxicity and environmental safety assessment of two-dimensional niobium carbides (MXenes)

Two-dimensional (2D) MXenes have gained great interest in water treatment, biomedical, and environmental applications. The antimicrobial activity and cell toxicity of several MXenes including Nb4C3Tx and Nb2CTx have already been explored. However, potential side effects related to Nb-MXene toxicity, especially on aquatic pneuma, have rarely been studied. Using zebrafish embryos, we investigated and compared the potential acute toxicity between two forms of Nb-MXene: the multilayer (ML-Nb4C3Tx, ML-Nb2CTx) and the delaminated (DL-Nb2CTx, and DL-Nb4C3Tx) Nb-MXene. The LC50 of ML-Nb4C3Tx, ML-Nb2CTx, DL-Nb2CTx, and DL-Nb4C3Tx were estimated to be 220, 215, 225, and 128 mg/L, respectively. Although DL-Nb2CTx, and DL-Nb4C3Tx derivatives have similar sizes, DL-Nb4C3Tx not only shows the higher mortality (LC50 = 128 mg/L Vs 225 mg/L), but also the highest teratogenic effect (NOEC = 100 mg/L Vs 200 mg/L). LDH release assay suggested more cell membrane damage and a higher superoxide anion production in DL-Nb4C3Tx than DL-Nb2CTx,. Interestingly, both DL-Nb-MXene nanosheets showed insignificant cardiac, hepatic, or behavioral toxic effects compared to the negative control. Embryos treated with the NOEC of DL-Nb2CTx presented hyperlocomotion, while embryos treated with the NOEC of DL-Nb4C3Tx presented hyperlocomotion, suggesting developmental neurotoxic effect and muscle impairment induced by both DL-Nb-MXene. According to the Fish and Wildlife Service (FSW) Acute Toxicity Rating Scale, all tested Nb-MXene nanosheets were classified as “Practically not toxic”. However, DL-Nb4C3Tx should be treated with caution as it might cause a neurotoxic effect on fauna when it ends up in wastewater in high concentrations.

A clinical study and laboratory evaluation of the cardiac and hepatic toxic effects of paraphenylenediamine

Introduction Paraphenylenediamine is the main component in many commercial hair dyes, and can produce severe local and systemic toxicity reactions after acute ingestion or dermal absorption. The aim of this study was to assess the factors contributing to morbidity and mortality in cases of acute paraphenylenediamine poisoning, with a focus on evaluating the resultant hepatic and cardiac toxicity. Methods This observational study was conducted on patients with acute paraphenylenediamine poisoning presenting to Sohag University Hospitals, and included a retrospective part from February 2021 to January 2022 and a prospective part from February 2022 to July 2022. Clinical data were extracted and receiver operating characteristic curves created to identify prognostic markers. Results Among 50 eligible patients 39 (78 percent) recovered, and 11 (22 percent) died or had permanent complications. Angioedema and anuria were the most frequent features in complicated cases. By receiver operating characteristic analysis, either an increase in aspartate aminotransferase activity greater than 644 IU/L or alanine aminotransferase activity greater than 798 IU/L, a time delay to presentation of greater than 4.5 hours, and a pH of less than 7.32 were associated with a significant increase in morbidity and mortality. While cardiac enzyme activities, and concentrations of blood urea nitrogen and creatinine increased in most cases, they were not associated with mortality. Discussion Management of patients with paraphenylenediamine poisoning is mainly supportive, as there is no specific antidote. Respiratory failure and kidney failure are the most life threatening complications. Hepatoxicity and cardiotoxicity also occur. The ability to predict the events can help guide patient disposition and care. Conclusion Elevated liver enzyme activities, increased time delay to admission, decreased pH, and the presence of angioedema and anuria can be used as predictors of morbidity and mortality in patients with acute paraphenylenediamine poisoning.

Asiatic acid and madecassic acid cause cardiotoxicity via inflammation and production of excessive reactive oxygen species in zebrafish.

Centella asiatica (L.) Urban is a famous Chinese traditional medicine, which is widely used for treating various chronic inflammatory diseases. Although there are reports that Centella total glycosides exhibit heart-protective properties, our previous experiment showed that it has cardiac toxic effects in zebrafish. The components of Centella total glycosides are complex, so we recommend further research to determine their key components and mechanisms. In this study, sample quantification was done using liquid chromatography-tandem mass spectrometry. The cardiotoxicity of Centella total glycosides, asiaticoside, madecassoside, asiatic acid, and madecassic acid was evaluated using zebrafish and cell models. The zebrafish oxidative stress model and myocarditis model were used to explore further the mechanisms through which cardiotoxicity is achieved. Asiatic acid and madecassic acid caused zebrafish cardiotoxicity and H9C2 cell death. However, no toxicity effects were observed for asiaticoside and madecassoside in zebrafish, until the solution was saturated. The results from the cell model study showed that asiatic acid and madecassic acid changed the expression of apoptosis-related genes in myocardial cells. In the zebrafish model, high concentrations of these components raised the levels of induced systemic inflammation, neutrophils gathered in the heart, and oxidative stress injury. Asiatic acid and madecassic acid are the main components causing cardiotoxicity in zebrafish. This may be due to enhanced inflammation and reactive oxygen species injury, which causes myocardial cell apoptosis, which further leads to cardiac toxicity.

Targeting the hERG1 and β1 integrin complex for cancer treatment.

Despite great advances, novel therapeutic targets and strategies are still needed, in particular for some carcinomas in the metastatic stage (breast cancer, colorectal cancer, pancreatic ductal adenocarcinoma and the clear cell renal carcinoma). Ion channels may be considered good cancer biomarkers and targets for antineoplastic therapy. These concepts are particularly relevant considering the hERG1 potassium channel as a novel target for antineoplastic therapy. A great deal of evidence demonstrates that hERG1 is aberrantly expressed in human cancers, in particular in aggressive carcinomas. A relevant cornerstone was the discovery that, in cancer cells, the channel is present in a very peculiar conformation, strictly bound to the β1 subunit of integrin receptors. The hERG1/β1 integrin complex does not occur in the heart. Starting from this evidence, we developed a novel single chain bispecific antibody (scDb-hERG1-β1), which specifically targets the hERG1/β1 integrin complex and exerts antineoplastic effects in preclinical experiments. Since hERG1 blockade cannot be pursued for antineoplastic therapy due to the severe cardiac toxic effects (ventricular arrhythmias) that many hERG1 blockers exert, different strategies must be identified to specifically target hERG1 in cancer. The targeting of the hERG1/β1 integrin complex through the bispecific antibody scDb-hERG1-β1 can overcome such hindrances.

Late Cardiac Toxic Effects Associated With Treatment Protocols for Hodgkin Lymphoma in Children

Contemporary North American trials for children with Hodgkin lymphoma (HL) have decreased radiation therapy (RT) use and increased pharmacologic cardioprotection but also increased the cumulative doxorubicin dose, making overall treatment consequences for late cardiac toxic effects uncertain. To estimate the risk of cardiac toxic effects associated with treatments used in modern pediatric HL clinical trials. For this cohort study, Fine and Gray models were fitted using survivors in the Childhood Cancer Survivor Study who were diagnosed with HL between January 1, 1970, and December 31, 1999, and were followed for a median of 23.5 (range, 5.0-46.3) years. These models were applied to the exposures in the study population to estimate the 30-year cumulative incidence of cardiac disease. The study population comprised patients with intermediate-risk or high-risk HL treated in 4 consecutive Children's Oncology Group clinical trials from September 2002 to October 2022: AHOD0031, AHOD0831, AHOD1331, and S1826. Data analysis was performed from April 2020 to February 2023. All patients received chemotherapy including doxorubicin, and some patients received mediastinal RT, dexrazoxane, or mediastinal RT and dexrazoxane. Estimated 30-year cumulative incidence of grade 3 to 5 cardiac disease. The study cohort comprised 2563 patients, with a median age at diagnosis of 15 (range, 1-22) years. More than half of the patients were male (1357 [52.9%]). All 2563 patients received doxorubicin, 1362 patients (53.1%) received mediastinal RT, and 307 patients (12.0%) received dexrazoxane. Radiation therapy use and the median mean heart dose among patients receiving RT decreased, whereas the planned cumulative dose of doxorubicin and use of dexrazoxane cardioprotection increased. For patients treated at age 15 years, the estimated 30-year cumulative incidence of severe or fatal cardiac disease was 9.6% (95% CI, 4.2%-16.4%) in the AHOD0031 standard treatment group (enrolled 2002-2009), 8.6% (95% CI, 3.8%-14.9%) in the AHOD0831 trial (enrolled 2009-2012), 8.2% (95% CI, 3.6%-14.3%) in the AHOD1331 trial (enrolled 2015-2019), and 6.2% (95% CI, 2.7%-10.9%) in the S1826 trial (enrolled 2019-2022), whereas the expected rate in an untreated population was 5.0% (95% CI, 2.1%-9.3%). Despite the estimated reduction in late cardiac morbidity, the frequency of recommended echocardiographic screening among survivors will increase based on current guidelines. In this cohort study of sequential HL trials, reductions in the proportion of children receiving mediastinal RT and increases in dexrazoxane use were estimated to offset the increased doxorubicin dose and produce a net reduction in late cardiac disease. Further studies on dexrazoxane are warranted to confirm whether its role in reducing cardiac toxic effects is maintained long term. These findings suggest that survivorship follow-up guidelines should be refined to align with the risks associated with treatment.

Accelerated Hypofractionated Chemoradiation Followed by Stereotactic Ablative Radiotherapy Boost for Locally Advanced, Unresectable Non–Small Cell Lung Cancer

Intrathoracic progression remains the predominant pattern of failure in patients treated with concurrent chemoradiation followed by a consolidation immune checkpoint inhibitor for locally advanced, unresectable non-small cell lung cancer (NSCLC). To determine the maximum tolerated dose (MTD) and use of hypofractionated concurrent chemoradiation with an adaptive stereotactic ablative radiotherapy (SABR) boost. This was an early-phase, single-institution, radiation dose-escalation nonrandomized controlled trial with concurrent chemotherapy among patients with clinical stage II (inoperable/patient refusal of surgery) or III NSCLC (American Joint Committee on Cancer Staging Manual, seventh edition). Patients were enrolled and treated from May 2011 to May 2018, with a median patient follow-up of 18.2 months. Patients advanced to a higher SABR boost dose if dose-limiting toxic effects (any grade 3 or higher pulmonary, gastrointestinal, or cardiac toxic effects, or any nonhematologic grade 4 or higher toxic effects) occurred in fewer than 33% of the boost cohort within 90 days of follow-up. The current analyses were conducted from January to September 2023. All patients first received 4 Gy × 10 fractions followed by an adaptive SABR boost to residual metabolically active disease, consisting of an additional 25 Gy (low, 5 Gy × 5 fractions), 30 Gy (intermediate, 6 Gy × 5 fractions), or 35 Gy (high, 7 Gy × 5 fractions) with concurrent weekly carboplatin/paclitaxel. The primary outcome was to determine the MTD. Data from 28 patients (median [range] age, 70 [51-88] years; 16 [57%] male; 24 [86%] with stage III disease) enrolled across the low- (n = 10), intermediate- (n = 9), and high- (n = 9) dose cohorts were evaluated. The protocol-specified MTD was not exceeded. The incidences of nonhematologic acute and late (>90 days) grade 3 or higher toxic effects were 11% and 7%, respectively. No grade 3 toxic effects were observed in the intermediate-dose boost cohort. Two deaths occurred in the high-dose cohort. Two-year local control was 74.1%, 85.7%, and 100.0% for the low-, intermediate-, and high-dose cohorts, respectively. Two-year overall survival was 30.0%, 76.2%, and 55.6% for the low-, intermediate-, and high-dose cohorts, respectively. This early-phase, dose-escalation nonrandomized controlled trial showed that concurrent chemoradiation with an adaptive SABR boost to 70 Gy in 15 fractions with concurrent chemotherapy is a safe and effective regimen for patients with locally advanced, unresectable NSCLC. ClinicalTrials.gov Identifier: NCT01345851.

Emodin attenuates cardiomyocyte pyroptosis in doxorubicin-induced cardiotoxicity by directly binding to GSDMD

BackgroundDoxorubicin (Dox), which is an anticancer drug, has significant cardiac toxicity and side effects. Pyroptosis occurs during Dox-induced cardiotoxicity (DIC), and drug inhibition of this process is one therapeutic approach for treating DIC. Previous studies have indicated that emodin can reduce pyroptosis. However, the role of emodin in DIC and its molecular targets remain unknown. Hypothesis/PurposeWe aimed to clarify the protective role of emodin in mitigating DIC, as well as the mechanisms underlying this effect. MethodsThe model of DIC was established via the intraperitoneal administration of Dox at a dosage of 5 mg/kg per week for a span of 4 weeks. Emodin at two different doses (10 and 20 mg/kg) or a vehicle was intragastrically administered to the mice once per day throughout the Dox treatment period. Cardiac function, myocardial injury markers, pathological morphology of the heart, level of pyroptosis and mitochondrial function were assessed. Protein microarray, biolayer interferometry and pull-down assays were used to confirm the target of emodin. Moreover, GSDMD-overexpressing plasmids were transfected into GSDMD−/− mice and HL-1 cells to further verify whether emodin suppressed GSDMD activation. ResultsEmodin therapy markedly enhanced cardiac function and reduced cardiomyocyte pyroptosis in mice induced by Dox. Mechanistically, emodin binds to GSDMD and inhibits the activation of GSDMD by targeting the Trp415 and Leu290 residues. Moreover, emodin was able to mitigate Dox-induced cardiac dysfunction and myocardial injury in GSDMD−/− mice overexpressing GSDMD, as shown by increased EF and FS, decreased serum levels of CK-MB, LDH and IL-1β and mitigated cell death and cell morphological disorder. Additionally, emodin treatment significantly reduced GSDMD-N expression and plasma membrane disruption in HL-1 cells overexpressing GSDMD induced by Dox. In addition, emodin reduced mitochondrial damage by alleviating Dox-induced GSDMD perforation in the mitochondrial membrane. ConclusionEmodin has the potential to attenuate DIC by directly binding to GSDMD to inhibit pyroptosis. Emodin may become a promising drug for prevention and treatment of DIC.

The Potential Mechanisms behind Loperamide-Induced Cardiac Arrhythmias Associated with Human Abuse and Extreme Overdose.

Loperamide has been a safe and effective treatment for diarrhea for many years. However, many cases of cardiotoxicity with intentional abuse of loperamide ingestion have recently been reported. We evaluated loperamide in in vitro and in vivo cardiac safety models to understand the mechanisms for this cardiotoxicity. Loperamide slowed conduction (QRS-duration) starting at 0.3 µM [~1200-fold (×) its human Free Therapeutic Plasma Concentration; FTPC] and reduced the QT-interval and caused cardiac arrhythmias starting at 3 µM (~12,000× FTPC) in an isolated rabbit ventricular-wedge model. Loperamide also slowed conduction and elicited Type II/III A-V block in anesthetized guinea pigs at overdose exposures of 879× and 3802× FTPC. In ion-channel studies, loperamide inhibited hERG (IKr), INa, and ICa currents with IC50 values of 0.390 µM, 0.526 µM, and 4.091 µM, respectively (i.e., >1560× FTPC). Additionally, in silico trials in human ventricular action potential models based on these IC50s confirmed that loperamide has large safety margins at therapeutic exposures (≤600× FTPC) and confirmed repolarization abnormalities in the case of extreme doses of loperamide. The studies confirmed the large safety margin for the therapeutic use of loperamide but revealed that at the extreme exposure levels observed in human overdose, loperamide can cause a combination of conduction slowing and alterations in repolarization time, resulting in cardiac proarrhythmia. Loperamide's inhibition of the INa channel and hERG-mediated IKr are the most likely basis for this cardiac electrophysiological toxicity at overdose exposures. The cardiac toxic effects of loperamide at the overdoses could be aggravated by co-medication with other drug(s) causing ion channel inhibition.

Non-pegylated liposomal doxorubicin in older adjuvant early breast cancer patients: cardiac safety analysis and final results of the COLTONE study

AimsTo explore the cardiac safety of adjuvant Non-Pegylated Liposomal Doxorubicin (NPL-DOX) plus Cyclophosphamide (CTX) followed by weekly Paclitaxel, in elderly women (≥ 65 years) with high-risk breast cancer. Previously, we described no symptomatic cardiac events within the first 12 months from starting treatment. We now reported the updated results after a median follow-up 76 months.MethodsThe cardiac activity was evaluated with left ventricular ejection fraction (LVEF) echocardiograms assessments, before starting chemotherapy and every 6 months, until 30 months from baseline, then yearly for at least 5 years.ResultsForty-seven women were recruited by two Units of Medical Oncology (Ethics Committee authorization CESM-AOUP, 3203/2011; EudraCT identification number: 2010-024067-41, for Pisa and Pontedera Hospitals). An episode of grade 3 CHF (NCI-CTCAE, version 3.0) occurred after 18 months the beginning of chemotherapy. The echocardiograms assessments were performed comparing the LVEF values of each patient evaluated at fixed period of time, compared to baseline. We observed a slight changed in terms of mean values at 48, 60, 72 and 84 months. At these time points, a statistically significant reduction of − 3.2%, − 4.6%, − 6.4% and − 7.1%, respectively, was observed. However, LVEF remained above 50% without translation in any relevant clinical signs. No other cardiac significant episodes were reported. To this analysis, in 13 patients (28%) occurred disease relapse and, of them, 11 (23%) died due to metastatic disease. Eight patients died of cancer-unrelated causes.ConclusionsThe combination including NPL-DOX in elderly patients revealed low rate of cardiac toxic effects. Comparative trials are encouraged.

Cardiac toxic effect of radiation therapy in patients receiving adjuvant trastuzumab treatment, as examined by LVEF of echocardiography: an experimental research.

This study aimed to evaluate the cardiotoxic consequences of radiotherapy in breast cancer patients who underwent adjuvant trastuzumab treatment by echocardiographic left ventricular ejection fraction (LVEF) measurement. In this retrospective study patients treated with postoperative breast irradiation with adjuvant trastuzumab were examined in terms of LVEF. Eithy five patients with age of 31-76 referred to the radiotherapy department of 5 Azar Hospital of Gorgan, Iran between years 2013 and 2020 were analyzed. Patients were divided into two left sided and right sided breast groups. Patients are routinely assessed every 3 months by echocardiocraphgy. LVEF values was measured at intervals of 3, 6, and 12 months after treatment onset. On the left side, the average of LVEF immediately decreased after treatment, compared to before treatment (∆ LVEF= 0.021), which shows the impact of trastuzumab. The LVEF average 3 months after treatment onset showed a significant decrease (∆ LVEF= 0.043) indicating a synergistic effect of trastuzumab and radiotherapy. LVEF average 6 months and 1 year after treatment onset showed a decrease but not significant (∆ LVEF= 0.009 and 0.013, respectively).In the right breast LVEF average immediately 3 months after treatment showed a significant decrease (∆ LVEF= 0.011 and 0.057, respectively). Nevertheless, LVEF average does not show a significant decrease after 6 months and 1 year after treatment in the right side group (∆ LVEF= 0.0002 and 0.018, respectively). Our results showed LVEF changes within one year following treatment in left sided breast cancer was more than right side , but the difference was not significant ,which may be due to the short period of our study based on the protocol of our department. More changes in the left side must be due to placing of the heart in the path of radiation. The study showed that LVEF may be an indicative measure for assessing radiation and adjuvant treatment effects on cardiac function.

Resveratrol ameliorates penconazole-induced cardiotoxicity by inhibition of oxidative stress and apoptosis in zebrafish larvae

Penconazole (PEN) is a typical systemic triazole fungicide with cardiac toxic effects. Resveratrol (RES) is a natural polyphenolic phytochemical with antioxidation properties. This study aimed to investigate if RES could protect against PEN-induced cardiotoxicity and to determine the underlying mechanisms. Zebrafish embryos were exposed to 0, 0.5, 1 and 2 mg/L of PEN from 4 to 96 h post fertilization (hpf) and cardiac developmental toxicity was assessed. Our results showed that PEN decreased hatching rate, survival rate, heart rate and body length, with increased malformation rate and spontaneous movement. PEN induced pericardial edema and abnormal cardiac structure in myl7:egfp transgenic zebrafish, as well as downregulation of cardiac development related genes (nkx2.5, tbx2.5, gata4, noto, and vmhc). In addition, PEN elevated oxidative stress via reactive oxygen species (ROS) accumulation and triggered cardiomyocytic apoptosis by upregulation of p53, bcl-2, bax and caspase 3. These adverse outcomes were counteracted by RES, indicating that RES ameliorated PEN-induced cardiotoxicity by inhibiting oxidative stress and apoptosis in zebrafish. Taken together, this study revealed the important role of oxidative stress in PEN-induced cardiotoxicity and identified dietary RES supplementation as a novel strategy to mitigate its toxicity.

The role of ginseng derivatives against chemotherapy-induced cardiotoxicity: A systematic review of non-clinical studies.

Although chemotherapy agents are used to treating cancers, they have serious side effects, like their harmful effects on the cardiovascular system, limiting the clinical use of these chemotherapy agents. This study aimed to systematically investigate the potential role of ginseng derivatives in the prevention of chemotherapy-induced cardiac toxicity. This systematic review was performed according to PRISMA guidelines strategy in databases till August 2022. First, identify studies related to using search terms in titles and abstracts. After studying and screening 209 articles, 16 articles were selected in this study according to our inclusion and exclusion criteria. According to the findings of this study, ginseng derivatives showed significant changes in biochemical, histological, and heart weight loss, as well as a reduction in mortality, which occurred in the groups treated with chemotherapy agents compared to the control groups. Co-administration of ginseng derivatives with chemotherapy agents inhibited or reversed these changes to near-moderate levels. The protective effects of ginseng derivatives can be due to their anti-inflammatory, anti-oxidant, and anti-apoptotic action. This systematic review shows evidence that concomitant administration of ginseng derivatives improves chemotherapy-induced cardiac toxicity. However, for better conclusions about the practical mechanisms of ginseng derivatives in reducing the cardiac toxic effects of chemotherapy agents and evaluating the efficacy and safety of the compound simultaneously, it is necessary to design comprehensive studies.

Cardiac and Pulmonary Dosimetric Parameters in Patients With Lung Cancer Undergoing Postoperative Radiation Therapy Across a Statewide Consortium

The recently published Lung Adjuvant Radiotherapy Trial (Lung ART) reported increased rates of cardiac and pulmonary toxic effects in the postoperative radiation therapy (PORT) arm. It remains unknown whether the dosimetric parameters reported in Lung ART are representative of contemporary real-world practice, which remains relevant for patients undergoing PORT for positive surgical margins. The purpose of this study was to examine heart and lung dose exposure in patients receiving PORT for non-small cell lung cancer across a statewide consortium. From 2012 to 2022, demographic and dosimetric data were prospectively collected for 377 patients at 27 academic and community centers within the Michigan Radiation Oncology Quality Consortium undergoing PORT for nonmetastatic non-small cell lung cancer. Dosimetric parameters for target coverage and organ-at-risk exposure were calculated using data from dose-volume histograms, and rates of 3-dimensional conformal radiation therapy (3D-CRT) and intensity modulated radiation therapy (IMRT) utilization were assessed. Fifty-one percent of patients in this cohort had N2 disease at the time of surgery, and 25% had a positive margin. Sixty-six percent of patients were treated with IMRT compared with 32% with 3D-CRT. The planning target volume was significantly smaller in patients treated with 3D-CRT (149.2 vs 265.4 cm3; P < .0001). The median mean heart dose for all patients was 8.7 Gy (interquartile range [IQR], 3.5-15.3 Gy), the median heart volume receiving at least 5 Gy (V5) was 35.2% (IQR, 18.5%-60.2%), and the median heart volume receiving at least 35 Gy (V35) was 9% (IQR, 3.2%-17.7%). The median mean lung dose was 11.4 Gy (IQR, 8.1-14.3 Gy), and the median lung volume receiving at least 20 Gy (V20) was 19.6% (IQR, 12.7%-25.4%). These dosimetric parameters did not significantly differ by treatment modality (IMRT vs 3D-CRT) or in patients with positive versus negative surgical margins. With increased rates of IMRT use, cardiac and lung dosimetric parameters in this statewide consortium were slightly lower than those reported in Lung ART. These data provide useful benchmarks for treatment planning in patients undergoing PORT for positive surgical margins.

Trastuzumab plus FOLFOX for HER2-positive biliary tract cancer refractory to gemcitabine and cisplatin: a multi-institutional phase 2 trial of the Korean Cancer Study Group (KCSG-HB19–14)

HER2 overexpression or amplification, which is present in 15% of all cases of biliary tract cancer, has been identified as a druggable molecular target by genomic profiling. In the phase 3 ABC-06 trial, the folinic acid, fluorouracil, and oxaliplatin (FOLFOX) regimen showed a survival benefit compared with active symptom control as second-line therapy for biliary tract cancer. We aimed to evaluate the clinical activity of FOLFOX plus anti-HER2 antibody trastuzumab as a second-line or third-line treatment for HER2-positive biliary tract cancer. This study was an investigator-initiated, open-label, non-randomised, single-arm, multi institutional, phase 2 trial in participants aged 19 years or older with HER2-positive (defined as immunohistochemistry 3+ or immunohistochemistry 2+ and in-situ hybridisation positive or ERBB2 gene copy number ≥6·0 by next-generation sequencing) biliary tract cancer (intrahepatic cholangiocarcinoma, extrahepatic cholangiocarcinoma, and gallbladder cancer) who progressed on chemotherapy containing gemcitabine and cisplatin (with one or two previous chemotherapy lines permitted). In cycle one, patients received intravenous trastuzumab-pkrb at 6 mg/kg on day 1, and FOLFOX (consisting of intravenous oxaliplatin [85 mg/m2], intravenous leucovorin [200 mg/m2], and fluorouracil [400 mg/m2 bolus] all on day 1, and fluorouracil [2400 mg/m2 infusion] on days 1-2. In cycle two onwards, participants were administered intravenous trastuzumab-pkrb at 4 mg/kg and FOLFOX, every 2 weeks, until unacceptable toxic effects or disease progression. The primary endpoint of the study was objective response rate based on RECIST version 1.1, assessed in the participants who completed at least one study cycle. The response rate threshold for a positive objective response rate was 25%. This trial is registered with ClinicalTrials.gov (NCT04722133) and is ongoing. 34 participants were enrolled between June 26, 2020, and Sept 1, 2021. At the time of data cutoff on May 1, 2022, median follow-up was 13·0 months (IQR 11·0-16·9), with three participants remaining on treatment. Ten patients had a partial response and 17 had stable disease; the overall response rate was 29·4% (95% CI 16·7-46·3) and the disease control rate was 79·4% (95% CI 62·9-89·9). Median progression-free survival was 5·1 months (95% CI 3·6-6·7); median overall survival was 10·7 (95%CI 7·9-not reached). The most common treatment-related grade 3 or 4 adverse events were neutropenia (ten [29%] participants with grade 3 and nine [26%] with grade 4), grade 3 anaemia (five [15%] participants), and grade 3 peripheral sensory neuropathy (four [12%] participants). There were no treatment-related cardiac toxic effects or deaths. The overall health assessment (EuroQoL-VAS) score did not change significantly throughout the treatment. Sensory and motor neuropathy symptoms as assessed by the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Chemotherapy-Induced Peripheral Neuropathy twenty-item scale questionnaire did not change significantly over time. For HER2-positive biliary tract cancer, second-line or third-line trastuzumab biosimilar plus FOLFOX exhibited promising activity with acceptable toxicity, warranting further investigation. Boryung Pharmaceutical, Celltrion, National Research Foundation of Korea, National R&D Program for Cancer Control through the National Cancer Center, Yonsei University College of Medicine.

Late Effects of Craniospinal Irradiation Using Electron Spinal Fields for Pediatric Patients With Cancer

For children, craniospinal irradiation (CSI) with photons is associated with significant toxic effects. The use of electrons for spinal fields is hypothesized to spare anterior structures but the long-term effects remain uncertain. We studied late effects of CSI using electrons for spinal radiation therapy (RT). Records of 84 consecutive patients treated with CSI using electrons for the spine at a single institution between 1983 and 2014 were reviewed. Median age at RT was 5 (range, 1-14) years. The most common histologies were medulloblastoma/primitive neuroectodermal tumor (59%) and ependymoma (8%). The median prescribed dose to the entire spine was 30 Gy (range, 6-45). A subset of 48 (57%) patients aged 2 to 14 at RT with clinical follow-up for ≥5 years was analyzed for late effects. Height z scores adjusted for age before and after CSI were assessed using stature-for-age charts and compared with a t test. At median follow-up of 19 years (range, 0-38 years), the median survival was 22 years (95% confidence interval, 12-28 years) after RT, with 47 patients (56%) alive at last follow-up. On subset analysis for late effects, 19 (40%) patients developed hypothyroidism and 5 (10%) developed secondary malignancies. Other complications reported were esophageal stricture and periaortic hemorrhage in 1 and restrictive pulmonary disease in 1 patient. Median height z score before treatment was -0.4 (36th percentile; interquartile range, -1.0 to 0.0) and at last follow-up was -2.2 (first percentile; interquartile range, -3.1 to -1.6; P < .001). Of 44 patients with spinal curvature assessments, 15 (34%) had scoliosis with median Cobb angle 15° (range, 10°-35°) and 1 (2%) required surgery. Frequent musculoskeletal toxic effects and predominantly decreased height were seen with long-term follow-up. Scoliosis and hypothyroidism were each seen in at least one-third of long-term survivors. However, clinically evident esophageal, pulmonary, and cardiac toxic effects were infrequent.

Osteosarcoma/Ewing Sarcoma

Osteosarcoma/Ewing Sarcoma

Dose to the Left Anterior Descending Artery Correlates With Cardiac Events After Irradiation for Breast Cancer

Although global heart dose has been associated with late cardiac toxic effects in patients who received radiation therapy for breast cancer, data detailing the clinical significance of cardiac substructure dosimetry are limited. We investigated whether dose to the left anterior descending artery (LAD) correlates with adverse cardiac events. We identified 375 consecutively treated female patients from 2012 to 2018 who received left-sided breast or chest wall irradiation (with or without regional nodal irradiation). Medical records were queried to identify cardiac events after radiation therapy. Mean and maximum LAD and heart doses (LAD Dmean, LAD Dmax, heart Dmean, and heart Dmax) were calculated and converted to 2-Gy equivalent doses (EQD2). Univariate and multivariable Cox regression analyses were performed to determine association with cardiac toxic effects. Potential dose thresholds for each of the 4 dose parameters were identified by receiver operating characteristic (ROC) curve analysis, after which Kaplan-Meier analysis was performed to compare cardiac event-free survival based on these constraints. Median follow-up time was 48 months. Thirty-six patients experienced a cardiac event, and 23 patients experienced a major cardiac event. On univariate and multivariable analyses, increased LAD Dmean, LAD Dmax, and heart Dmean were associated with increased risk of any cardiac event and a major cardiac event. ROC curve analysis identified a threshold LAD Dmean EQD2 of 2.8 Gy (area under the ROC curve, 0.69), above which the risk for any cardiac event was higher (P=.001). Similar results were seen when stratifying by LAD Dmax EQD2 of 6.7 Gy (P=.005) and heart Dmean EQD2 of 0.8 Gy (P=.01). Dose to the LAD correlated with adverse cardiac events in this cohort. Contouring and minimizing dose to the LAD should be considered for patients receiving radiation therapy for left-sided breast cancer.

Citalopram Induced Cardiotoxicity in Rats at Repeated Doses

Although the correlation between citalopram and cardiovascular pathologies was realized via case studies, there is no experimental study that was performed independently of other risk factors related to cardiotoxicity. In the study reported here, we aimed to identify the cardiotoxic effects of citalopram by evaluating serum cardiac biomarkers, such as serum aspartate transaminase, creatine kinase-myoglobin binding, lactate dehydrogenase and troponin-T levels as well as electrocardiogram parameters, deoxyribonucleic acid damage in cardiomyocytes and histological findings of heart tissue in rats that were administered oral doses of 5, 10, or 20 mg/kg of citalopram for 28 d. Additionally, to investigate possible mechanisms underlying cardiotoxicity, glutathione and malondialdehyde levels in cardiac tissue were determined to evaluate oxidative stress. According to our results, heart rates were increased, PR intervals were prolonged, and T wave amplitudes were significantly decreased in the 20 mg/kg citalopram-administered groups when compared with the control group. Additionally, serum aspartate transaminase, lactate dehydrogenase and troponin-T levels were significantly increased in the 10 and 20 mg/kg citalopram-administered group compared to the control group. Significant deoxyribonucleic acid damages were observed in the 10 and 20 mg/kg citalopram-administered groups. Histopathological investigations revealed degenerative changes in the 10 and 20 mg/kg citalopram-administered groups. In heart tissues, glutathione levels were decreased in the 10 and 20 mg/kg citalopram-administered groups significantly when compared with the control group. These findings indicated the relationship between high-dose and subtherapeutic-dose citalopram administration and cardiac morphological, biochemical and functional toxic effects.

Effect of Elective Internal Mammary Node Irradiation on Disease-Free Survival in Women With Node-Positive Breast Cancer

The benefit of internal mammary node irradiation (IMNI) for treatment outcomes in node-positive breast cancer is unknown. To investigate whether the inclusion of IMNI in regional nodal irradiation improves disease-free survival (DFS) in women with node-positive breast cancer. This multicenter, phase 3 randomized clinical trial was conducted from June 1, 2008, to February 29, 2020, at 13 hospitals in South Korea. Women with pathologically confirmed, node-positive breast cancer after breast-conservation surgery or mastectomy with axillary lymph node dissection were eligible and enrolled between November 19, 2008, and January 14, 2013. Patients with distant metastasis and those who had received neoadjuvant treatment were excluded. Data analyses were performed according to the intention-to-treat principle. All patients underwent regional nodal irradiation along with breast or chest wall irradiation. They were randomized 1:1 to receive radiotherapy either with IMNI or without IMNI. The primary end point was the 7-year DFS. Secondary end points included the rates of overall survival, breast cancer-specific survival, and toxic effects. A total of 735 women (mean [SD] age, 49.0 [9.1] years) were included in the analyses, of whom 373 received regional nodal irradiation without IMNI and 362 received regional nodal irradiation with IMNI. Nearly all patients underwent taxane-based adjuvant systemic treatment. The median (IQR) follow-up was 100.4 (89.7-112.1) months. The 7-year DFS rates did not significantly differ between the groups treated without IMNI and with IMNI (81.9% vs 85.3%; hazard ratio [HR], 0.80; 95% CI, 0.57-1.14; log-rank P = .22). However, an ad hoc subgroup analysis showed significantly higher DFS rates with IMNI among patients with mediocentrally located tumors. In this subgroup, the 7-year DFS rates were 81.6% without IMNI vs 91.8% with IMNI (HR, 0.42; 95% CI, 0.22-0.82; log-rank P = .008), and the 7-year breast cancer mortality rates were 10.2% without IMNI vs 4.9% with IMNI (HR, 0.41; 95% CI, 0.17-0.99; log-rank P = .04). No differences were found between the 2 groups in the incidence of adverse effects, including cardiac toxic effects and radiation pneumonitis. This randomized clinical trial found that including IMNI in regional nodal irradiation did not significantly improve the DFS in patients with node-positive breast cancer. However, patients with medially or centrally located tumors may benefit from the use of IMNI. ClinicalTrials.gov Identifier: NCT04803266.