Cardiopulmonary Toxicity Research Articles

Role of Adjuvant Radiotherapy in Non-Small Cell Lung Cancer-A Review.

Simple SummaryThe role of postoperative radiotherapy (PORT) in completely resected non-small cell lung cancer (NSCLC) with ipsilateral mediastinal lymph node involvement (pN2) is controversial. The aim of our review was to study the literature relating to PORT for completely resected NSCLC patients with pN2 involvement. The Lung ART and PORT-C trials indicate better locoregional control with PORT, but this has not yet translated into survival benefits. Given the conflicting results, guidelines do not recommend the use of PORT routinely. Future research should focus on identifying subgroups of patients who might benefit from PORT.Background: For patients with completely resected non-small cell lung cancer (NSCLC) with ipsilateral mediastinal lymph node involvement (pN2), the administration of adjuvant chemotherapy is the standard of care. The role of postoperative radiation therapy (PORT) is controversial. Methods: We describe the current literature focusing on the role of PORT in completely resected NSCLC patients with pN2 involvement and reflect on its role in current guidelines. Results: Based on the results of the recent Lung ART and PORT-C trials, the authors conclude that PORT cannot be generally recommended for all resected pN2 NSCLC patients. A substantial decrease in the locoregional relapse rate without translating into a survival benefit suggests that some patients with risk factors might benefit from PORT. This must be balanced against the risk of cardiopulmonary toxicity with potentially associated mortality. Lung ART has already changed the decision making for the use of PORT in daily practice for many European lung cancer experts, with lower rates of recommendations for PORT overall. Conclusions: PORT is still used, albeit decreasingly, for completely resected NSCLC with pN2 involvement. High-level evidence for its routine use is lacking. Further analyses are required to identify patients who would potentially benefit from PORT.

Indications and Parameters Around Postoperative Radiation Therapy for Lung Cancer

Patients with locally advanced resected non–small-cell lung cancer present a high risk of relapse. Although adjuvant platinum–based chemotherapy has become the standard of care, the role of postoperative radiation therapy (PORT) has been controversial for years. In patients with incomplete resection, PORT should be proposed, on the basis of a strong consensus, despite the absence of randomized evidence. In patients with completely resected (R0) non–small-cell lung cancer, a meta-analysis showed poorer outcomes after PORT in the absence of mediastinal involvement (pN0 and pN1). In patients with pN2, the role of PORT was less clear and required further research. The meta-analysis included trials using older radiation techniques and poorer quality of surgery according to today's standards, and selection of patients was not positron emission tomography–based. Newer retrospective and nonrandomized studies and subgroup analyses of randomized trials evaluating adjuvant chemotherapy suggested a survival benefit of PORT in patients with pN2 R0. Two recent randomized trials (Lung ART and PORT-C) evaluating conformal PORT versus no PORT retrieved no disease-free survival advantage for stage IIIA-N2 patients, even if mediastinal relapse was significantly decreased with PORT. PORT had no effect on survival, possibly given the high rate of distant relapse and risk of additional cardiopulmonary toxicity. Ongoing and future analyses are planned in Lung ART to identify patients for whom PORT could be recommended. Incorporation of newer systemic treatments (immune checkpoint inhibitors or targeted therapy in oncogene-addicted patients) is underway in the neoadjuvant and/or adjuvant setting. Better identification of patients at a high risk of disease recurrence, with analysis of circulating tumor DNA, on the basis of the detection of postsurgical minimal (or molecular) residual disease is warranted in future studies.

Cardiopulmonary toxicities after hypofractionated radiotherapy in breast cancer

Cardiopulmonary toxicities after hypofractionated radiotherapy in breast cancer

Randomized trial for cardiopulmonary toxicity with hypofractionated adjuvant radiation in breast cancer: Wasn't blown away by the results!

Randomized trial for cardiopulmonary toxicity with hypofractionated adjuvant radiation in breast cancer: Wasn't blown away by the results!

Randomized study assessing the cardiopulmonary toxicities from postoperative conventional versus hypofractionated radiotherapy in locally advanced left breast carcinoma

Randomized study assessing the cardiopulmonary toxicities from postoperative conventional versus hypofractionated radiotherapy in locally advanced left breast carcinoma

Low Cardiopulmonary Toxicity With Use of IMRT When Delivering Postoperative Radiation Therapy (PORT) in Patients With NSCLC

The role of PORT for patients with resected stage IIIA (N2) NSCLC is controversial. Recently, the Phase III LungART trial reported a significant improvement in mediastinal control with PORT but failed to show an overall survival (OS) benefit, due in part to cardiopulmonary (CP) toxicity (7% early and 20% late grade (G) 3-5). However, LungART employed 3D conformal radiotherapy (3D-CRT) in 90% of patients as well as elective treatment of mediastinal nodal stations. We evaluated the risk of CP toxicity associated with use of postoperative IMRT for this population.We conducted a retrospective study of consecutive patients with NSCLC treated with postoperative IMRT between 2008 and 2019. Patients were eligible if they were found to have incidental pN2 or an R1/2 resection. Targets of PORT for pN2 were bronchial stump, ipsilateral hilum, and involved mediastinal station(s). The primary objective was incidence of CTCAE (v4) G3+ CP toxicities. Secondary objectives were major adverse cardiac events (MACE), defined as cardiac death, myocardial infarction, coronary revascularization or hospitalization due to heart failure; disease-free survival (DFS); and OS. Cumulative incidence and Kaplan-Meier method were used as appropriate.73 patients received PORT with IMRT. Median follow-up was 54 months. Median age at diagnosis was 65 years (range 36 - 81); 33 patients (45%) had pre-existing cardiovascular disease and 48 (65.8%) were current/former smokers. 50 patients had pN2 disease and 23 patients had R1/R2 resection. Among patients with pN2, the median number of involved mediastinal nodes was 1 (range 1 - 12). All patients with pN2 and 70% of patients with R1/R2 resection received chemotherapy, the majority of which was sequential (n = 52, 71.2%). Median RT dose was 54 Gy (range 45 - 66 Gy) in 27 fractions for patients with pN2 and 59.4 Gy (range 45 - 66 Gy) in 30 fractions for patients with R1/R2 resection. 3-year cumulative incidence of G3+ CP toxicity was 2.7%, with an overall incidence of 6.8% (5 events in 73 patients). The rate of G3+ CP toxicity in patients with pN2 was 8%. Three patients developed ≥1 MACE: one died of a cardiac arrest and two underwent coronary revascularization. Two of these patients had a history of coronary artery disease. Two episodes of G3+ toxicity involved valve replacements in patients with pre-existing valvular disease. 3-year DFS was 51.4% (95% CL 46.9 - 55.1%). Two patients with pN2 developed mediastinal failures. 3-year OS was 62.3% (95% CL 50.2 - 74.4%).PORT for pN2 NSCLC using IMRT and no elective nodal irradiation is associated with a low rate of G3+ CP toxicity in patients with pN2, comparable to the chemotherapy only arm of the LungART trial. Our data suggest that highly conformal radiation techniques should be prospectively assessed for their potential to translate the known local control benefit of PORT into a survival advantage.

P40.07 Immunotherapy Toxicity in Lung Cancer & the Impact of Thoracic Radiation Therapy

Immunotherapy is increasingly utilized either alone or in combination with chemotherapy and/or radiation therapy (RT) with improved survival. Immunotherapy related toxicity can appear similar to radiation induced toxicity. The contribution of concurrent or sequential thoracic radiation to immunotherapy related cardiopulmonary toxicity is not well understood. Current literature suggests that combination of immunotherapy and thoracic radiation does not result in an increase in high-grade toxicities, however clinicians continue to approach this combination with caution. All patients that received immunotherapy for non-small cell lung cancer (NSCLC) between 2011 and 2020 were included in the analysis. The electronic medical records were used to collect demographic, treatment, and toxicity data. RTOG toxicity scale was used to grade pneumonitis and CTCAE was used for all other toxicities. The first course of radiation therapy was used for analysis if patients received more than one course. The relationship between thoracic RT and the incidence of cardiopulmonary toxicities was evaluated through pairwise comparisons using Barnard’s exact test of three groups including: patients who received thoracic RT ³ 45 Gy, thoracic RT < 45 Gy, and those who did not receive thoracic RT. To account for the three pairwise comparisons for each toxicity class, Bonferroni adjusted p-values were utilized. Additionally, the impact of RT type (thoracic vs. nonthoracic) and total dose (³ 45 Gy vs. < 45 Gy) over multiple courses of treatment was examined. The cause specific hazard ratios for toxicity outcomes were modeled using the Cox proportional hazards model, with time of treatment initiation designated as the time of origin. Candidate variables for inclusion included: receipt of any thoracic vs. non-thoracic RT, thoracic vs. nonthoracic RT received as most recent therapy relative to time of toxicity, total thoracic RT dose (³ 45 Gy or < 45 Gy), and total non-thoracic RT dose. The toxicity outcomes (all grade occurrences and grade 3-5 events) evaluated included cardiopulmonary toxicities of any type, pleural effusions, and pneumonitis events. 251 patients met the inclusion criteria and were included in the analysis. The majority of patients were locally advanced or metastatic at presentation; 33.5% stage III & 56.6% stage IV. RT was given in 83.3% of patients and 63.7% of patients received thoracic RT. An elevated risk of grade 3-5 pleural effusions was found in patients who received thoracic RT and cumulative dose < 45 Gy, however, the group that received ³ 45 Gy did not reveal an increased risk of grade 3-5 pleural effusions. Overall, the remaining candidate variables were not found to significantly impact the evaluated toxicity outcomes (p > 0.05). An increased risk of pleural effusions was found in patients who received a prior cumulative RT dose of <45 Gy. However, overall, the results of this large single-institution retrospective review do not show an association with thoracic RT and increased risk of cardiopulmonary toxicity in patients receiving immunotherapy for NSCLC. Further dosimetric analysis will be conducted to better characterize cardiopulmonary toxicity outcomes relative to radiation dose to the heart and lung.

Evaluation of Radiation-induced Pleural Effusions after Radiotherapy to Support Development of Animal Models of Radiation Pneumonitis.

Not all animal models develop radiation-induced pleural effusions (RIPEs) as a form of radiation-induced lung injury (RILI). Such effusions are also not well characterized in humans. The purpose of this study is to identify occurrences of RIPE in humans, provide justification for development of relevant animal models, and further characterize its risk factors in cancer patients. We also aim to identify dose thresholds for cardiopulmonary toxicity in humans to shed light on possible pathogenic mechanisms for RIPEs. We carried out a retrospective review of medical records of 96 cancer patients receiving thoracic irradiation (TRT) at our institution. Fifty-three (53%) patients developed a new pleural effusion post TRT; 18 (19%) had RIPE; and 67% developed RIPE ipsilateral to the site irradiated. None developed "contralateral only" effusions. Median time to development was 6 mo (IQR; 4-8 mo). Of 18, 8 patients (44%) had concomitant asymptomatic (radiographic only) or symptomatic radiation pneumonitis and pericardial effusion. Dosimetric factors, including combined and ipsilateral mean lung dose (MLD), were significantly associated with increased risk of RIPE. Angiotensin converting enzyme inhibition, steroids, or concurrent chemotherapy did not modify incidence of RIPE. Our results substantiate the occurrence and incidence of RIPEs in humans. In cancer patients, a median time to development of effusions around 6 mo also supports the onset of RIPEs concurrent with radiation pneumonitis. Future work needs to include large populations of cancer survivors in whom delayed RIPEs can be tracked and correlated with cardiovascular changes in the context of injury to multiple organs.

Dark Side of Cancer Therapy: Cancer Treatment-Induced Cardiopulmonary Inflammation, Fibrosis, and Immune Modulation.

Advancements in cancer therapy increased the cancer free survival rates and reduced the malignant related deaths. Therapeutic options for patients with thoracic cancers include surgical intervention and the application of chemotherapy with ionizing radiation. Despite these advances, cancer therapy-related cardiopulmonary dysfunction (CTRCPD) is one of the most undesirable side effects of cancer therapy and leads to limitations to cancer treatment. Chemoradiation therapy or immunotherapy promote acute and chronic cardiopulmonary damage by inducing reactive oxygen species, DNA damage, inflammation, fibrosis, deregulation of cellular immunity, cardiopulmonary failure, and non-malignant related deaths among cancer-free patients who received cancer therapy. CTRCPD is a complex entity with multiple factors involved in this pathogenesis. Although the mechanisms of cancer therapy-induced toxicities are multifactorial, damage to the cardiac and pulmonary tissue as well as subsequent fibrosis and organ failure seem to be the underlying events. The available biomarkers and treatment options are not sufficient and efficient to detect cancer therapy-induced early asymptomatic cell fate cardiopulmonary toxicity. Therefore, application of cutting-edge multi-omics technology, such us whole-exome sequencing, DNA methylation, whole-genome sequencing, metabolomics, protein mass spectrometry and single cell transcriptomics, and 10 X spatial genomics, are warranted to identify early and late toxicity, inflammation-induced carcinogenesis response biomarkers, and cancer relapse response biomarkers. In this review, we summarize the current state of knowledge on cancer therapy-induced cardiopulmonary complications and our current understanding of the pathological and molecular consequences of cancer therapy-induced cardiopulmonary fibrosis, inflammation, immune suppression, and tumor recurrence, and possible treatment options for cancer therapy-induced cardiopulmonary toxicity.

Acrolein but not its metabolite, 3-Hydroxypropylmercapturic acid (3HPMA), activates vascular transient receptor potential Ankyrin-1 (TRPA1): Physiological to toxicological implications

Acrolein, an electrophilic α,β-unsaturated aldehyde, is present in foods and beverages, and is a product of incomplete combustion, and thus, reaches high ppm levels in tobacco smoke and structural fires. Exposure to acrolein is linked with cardiopulmonary toxicity and cardiovascular disease risk. The hypothesis of this study is the direct effects of acrolein in isolated murine blood vessels (aorta and superior mesenteric artery, SMA) are transient receptor potential ankyrin-1 (TRPA1) dependent. Using isometric myography, isolated aorta and SMA were exposed to increasing levels of acrolein. Acrolein inhibited phenylephrine (PE)-induced contractions (approximately 90%) in aorta and SMA of male and female mice in a concentration-dependent (0.01–100 μM) manner. The major metabolite of acrolein, 3-hydroxypropylmercapturic acid (3HPMA), also relaxed PE-precontracted SMA. As the SMA was 20× more sensitive to acrolein than aorta (SMA EC50 0.8 ± 0.2 μM; aorta EC50 > 29.4 ± 4.4 μM), the mechanisms of acrolein-induced relaxation were studied in SMA. The potency of acrolein-induced relaxation was inhibited significantly by: 1) mechanically-impaired endothelium; 2) Nω-Nitro-L-arginine methyl ester hydrochloride (L-NAME); 3) guanylyl cyclase (GC) inhibitor (ODQ); and, 4) a TRPA1 antagonist (A967079). TRPA1 positive immunofluorescence was present in the endothelium. Compared with other known TRPA1 agonists, including allyl isothiocyanate (AITC), cinnamaldehyde, crotonaldehyde, and formaldehyde, acrolein stimulated a more potent TRPA1-dependent relaxation. Acrolein, at high concentration [100 μM], induced tension oscillations (spasms) independent of TRPA1 in precontracted SMA but not in aorta. In conclusion, acrolein is vasorelaxant at low levels (physiological) yet vasotoxic at high levels (toxicological).

Increasing Heart Dose Reduces Overall Survival in Patients Undergoing Postoperative Radiation Therapy for NSCLC

IntroductionGiven the concern for cardiopulmonary toxicity in patients with NSCLC undergoing postoperative radiation therapy (PORT), the purpose of this study was to evaluate the association between heart dose and overall survival (OS) in patients undergoing PORT with modern techniques. MethodsThis is a retrospective study of consecutive patients with NSCLC treated with PORT between May 2004 and January 2017. Clinical records were reviewed and radiation dose distributions were analyzed for association with OS. ResultsA total of 284 patients were analyzed. At the time of surgery, most patients had pathologic American Joint Committee on Cancer seventh edition stage III disease (91.2 %) and received either preoperative or adjuvant chemotherapy (92.3 %). Most patients underwent a lobectomy (81.3 %) and had R0 (80.6 %) or R1 (19.4 %) resection. PORT was delivered with a median radiation dose of 54 Gy, and 70.4 % of patients were treated with intensity-modulated radiation therapy. Dosimetric variables across a large range of doses to the heart were highly significant (p < 0.05) for OS. The volume of the heart receiving 8 Gy (HV8) was the most significant dosimetric variable (p < 0.001), and the median HV8 was 35.5 %. The median OS was 33.2 versus 53.6 months (p < 0.005) for patients with HV8 above or below 35.5 %, respectively. On multivariable analysis accounting for other potential prognostic confounders, HV8 remained highly significant (p < 0.001). ConclusionsThe data reveal a strong correlation between increasing heart dose and OS in patients with NSCLC undergoing PORT. Taken together with the recently presented LungART trial, lowering heart dose in PORT patients may help to decrease the risk of morbidity and mortality and improve the therapeutic ratio of PORT.

PO53: A Novel Unidirectional Permanent Device for Intraoperative Brachytherapy in Patients with Early Stage Lung Cancer Who Undergo Sub-Lobar Resection

Purpose: While complete surgical resection is considered standard of care for early stage lung cancer, many patients are unable to tolerate radical lung procedures due to poor cardiopulmonary function. In these patients, sub-lobar resection with radiotherapy may be a safe and efficacious compromise. Implanted brachytherapy at the time of surgery is highly conformal and may spare cardiopulmonary toxicity. The CivaSheet (CivaTech Oncology) is a planar, uni-directional device designed to deliver a therapeutic dose of low dose rate radiation.

Normal Tissue Injury Induced by Photon and Proton Therapies: Gaps and Opportunities.

Despite technological advances in radiation therapy (RT) and cancer treatment, patients still experience adverse effects. Proton therapy (PT) has emerged as a valuable RT modality that can improve treatment outcomes. Normal tissue injury is an important determinant of the outcome; therefore, for this review, we analyzed 2 databases: (1) clinical trials registered with ClinicalTrials.gov and (2) the literature on PT in PubMed, which shows a steady increase in the number of publications. Most studies in PT registered with ClinicalTrials.gov with results available are nonrandomized early phase studies with a relatively small number of patients enrolled. From the larger database of nonrandomized trials, we listed adverse events in specific organs/sites among patients with cancer who are treated with photons and protons to identify critical issues. The present data demonstrate dosimetric advantages of PT with favorable toxicity profiles and form the basis for comparative randomized prospective trials. A comparative analysis of 3 recently completed randomized trials for normal tissue toxicities suggests that for early stage non-small cell lung cancer, no meaningful comparison could be made between stereotactic body RT and stereotactic body PT due to low accrual (NCT01511081). In addition, for locally advanced non-small cell lung cancer, a comparison of intensity modulated RTwith passive scattering PT (now largely replaced by spot-scanned intensity modulated PT), PT did not provide any benefit in normal tissue toxicity or locoregional failure over photon therapy. Finally, for locally advanced esophageal cancer, proton beam therapy provided a lower total toxicity burden but did not improve progression-free survival and quality of life (NCT01512589). The purpose of this review is to inform the limitations of current trials looking at protons and photons, considering that advances in technology, physics, and biology are a continuum, and to advocate for future trials geared toward accurate precision RT that need to be viewed as an iterative process in a defined path toward delivering optimal radiation treatment. A foundational understanding of the radiobiologic differences between protons and photons in tumor and normal tissue responses is fundamental to, and necessary for, determining the suitability of a given type of biologically optimized RT to a patient or cohort.

Single Institution Experience of Proton and Photon-based Postoperative Radiation Therapy for Non–small-cell Lung Cancer

IntroductionPostoperative radiation therapy (PORT) for non–small-cell lung cancer remains controversial with studies showing no overall survival (OS) benefit in the setting of excessive cardiopulmonary toxicity. Proton beam therapy (PBT) can potentially reduce toxicity with improved organ-at-risk sparing. We evaluated outcomes of PORT patients treated with PBT and intensity-modulated radiation therapy (IMRT). Materials and MethodsThis is a retrospective review of 136 PORT patients (61 PBT, 75 IMRT) treated from 2003 to 2016. A Kaplan-Meier analysis was performed to assess oncologic outcomes. A Cox regression was conducted to identify associated factors. Total toxicity burden (TTB) was defined as grade ≥ 2 pneumonitis, cardiac, or esophageal toxicity. ResultsMedian OS was 76 and 46 months for PBT and IMRT with corresponding 1- and 5-year OS of 85.3%, 50.9% and 89.3%, 37.2% (P = .38), respectively. V30 Gy heart (odds ratio [OR], 144.9; 95% confidence interval [CI], 2.91-7214; P = .013) and V5 Gy lung (OR, 15.8; 95% CI, 1.22-202.7; P = .03) were predictive of OS. Organ-at-risk sparing was improved with PBT versus IMRT; mean heart 2.0 versus 7.4 Gy (P < .01), V30 Gy heart 2.6% versus 10.7% (P < .01), mean lung 7.9 versus 10.4 Gy (P = .042), V5 Gy lung 23.4% versus 42.1% (P < .01), and V10 Gy lung 20.4% versus 29.6% (P < .01). TTB was reduced with PBT (OR, 0.35; 95% CI, 0.15-0.83; P = .017). Rates of cardiac toxicity were 14.7% IMRT and 4.9% PBT (P = .09). Rates of ≥ grade 2 pneumonitis were 17.0% IMRT and 4.9% PBT (P = .104). ConclusionPBT improved cardiac and lung sparing and reduced toxicity compared with IMRT. Considering the impact of cardiopulmonary toxicity on PORT outcomes, PBT warrants prospective evaluation.

515 Repurposing of FDA-approved lead drugs as potentiators of uterine contractility in postpartum hemorrhage

Current medical options for management of postpartum hemorrhage preclude universal application due to their potential for adverse side effects. The objective of this study was to test the ex vivo efficacy of uterine-selective, FDA-approved drugs with no known cardiopulmonary toxicities repurposed for use at the human myometrial level. Lead drugs that selectively regulate human myometrial contractility were identified in prior studies using in vitro high throughput drug screening for calcium mobilization in myometrial cells. In this study, functional ex vivo isometric contractility was assessed via organ bath assays to determine uterotonic activity of mefloquine and pimavanserin on the human myometrial tissue. Human myometrial tissue was obtained at the time of cesarean delivery from non-laboring women meeting inclusion and exclusion criteria. Myometrial tissue strips (∼6-8 per biopsy) were submerged in organ baths (37°C, 95%O2, 5%CO2) containing Kreb’s Bicarbonate Solution and suspended under 3-gram isometric conditions. Tissues that displayed rhythmic spontaneous contractions were treated with cumulative concentrations (10pM – 0.1mM) of either mefloquine, pimavanserin or vehicle control (DMSO) at 20min intervals. Contractile activity was recorded and analyzed for frequency, amplitude, and area under the curve. Drug response relative to spontaneous contractile activity was analyzed, and non-linear regression models were used to generate concentration-response curves. Comparisons of fit were performed to determine if the non-linear curves of mefloquine and pimavanserin were significantly different (p<0.05) from DMSO. We performed 57 experiments in myometrial samples obtained from 12 women. There was no significant difference in the amplitude, frequency, or area under the curve between the vehicle control, mefloquine, and pimavanserin. Neither mefloquine nor pimavanserin induces ex vivo uterotonic activity in human myometrial tissue.

A Rare Case of Late Presentation of Dasatinib-Induced Cardiopulmonary Toxicity

Tyrosine kinase inhibitors (TKI) (imatinib, dasatinib, and nilotinib) are used for the treatment and long-term control of chronic myeloid leukemia (CML). TKIs rarely cause systemic side effects with atypical presentations, and these must be borne in mind while prescribing these drugs over a prolonged period. Dasatinib-induced cardiopulmonary toxicity should be suspected in patients presenting with new-onset cardiac or pulmonary symptoms, with features of congestive cardiac failure and pulmonary infiltrates. We report a rare presentation of simultaneous occurrence of pleural effusion, interstitial pneumonitis, pulmonary hypertension, and heart failure in a CML patient on dasatinib for >6 years, which was successfully treated with discontinuation of the drug and oral steroids.

A Multi-Institutional Analysis of Radiation Dosimetric Predictors of Toxicity After Trimodality Therapy for Esophageal Cancer

PurposeThis multi-institutional review explored associations between radiation dose-volume histogram (DVH) parameters and cardiopulmonary toxicities with trimodality therapy for esophageal cancer. Methods and MaterialsWe reviewed 465 consecutive patients with esophageal cancer treated with chemoradiation therapy followed by surgery at 2 tertiary-care institutions between 2007 and 2013. Using logistic regression, we assessed associations between lung and heart DVH parameters and cardiopulmonary toxicities and survival. Statistically significant variables were subsequently included in multivariable models, which incorporated age, smoking history, previous history of heart disease, and type of chemotherapy. ResultsThe median age of the patients was 61 years (interquartile range, 54-68 years), and 86% were men. At baseline, 60% of the patients had known cardiac risk factors, 64% were current or former smokers, and 10% had other pulmonary comorbidities. Most patients had stage II to III (96%) adenocarcinoma (94%) of the distal esophagus. The radiation therapy (RT) modalities used were 3-dimensional conformal RT (38%), intensity modulated RT (41%), and proton therapy (20%). An increased heart dose was associated with increased risk of cardiac toxicity on univariable analysis (V20 Gy: odds ratio [OR], 1.20; 95% CI, 1.08-1.33; P = .001) (V30 Gy: OR, 1.24; 95% CI, 1.11-1.38; P < .0001) (V40 Gy: OR, 1.18; 95% CI, 1.03-1.35; P = .018). No lung DVH metrics were associated with lung toxicity. Heart V30 Gy was associated with adverse events on multivariable analysis (OR, 1.15; 95% CI, 1.04-1.26; P = .0047). ConclusionsWe observed an association between heart dose and cardiac toxicity for esophageal cancer. The risk of cardiac toxicity was 5%, 10%, and 15% when the heart V30 Gy dose was 14%, 20%, and 30%, respectively. For every 10% increase in V30 Gy, there was a corresponding 24% increase in the relative risk of cardiac toxicity.

Particulate matter inhalation and the exacerbation of cardiopulmonary toxicity due to metabolic disease.

Particulate matter is a significant public health issue in the United States and globally. Inhalation of particulate matter is associated with a number of systemic and organ-specific adverse health outcomes, with the pulmonary and cardiovascular systems being particularly vulnerable. Certain subpopulations are well-recognized as being more susceptible to inhalation exposures, such as the elderly and those with pre-existing respiratory disease. Metabolic syndrome is becoming increasingly prevalent in our society and has known adverse effects on the heart, lungs, and vascular systems. The limited evaluations of individuals with metabolic syndromehave demonstrated that theymay compose a sensitive subpopulation to particulate exposures. However, the toxicological mechanisms responsible for this increased vulnerability are not fully understood. This review evaluates the currently available literature regarding how the response of an individual's pulmonary and cardiovascular systems is influenced by metabolic syndrome and metabolic syndrome-associated conditions such as hypertension, dyslipidemia, and diabetes. Further, we will discuss potential therapeutic agents and targets for the alleviation and treatment of particulate-matter induced metabolic illness. The information reviewed here may contribute to the understanding of metabolic illness as a risk factor for particulate matter exposure and further the development of therapeutic approaches to treat vulnerable subpopulations, such as those with metabolic diseases.

VRd Versus KRd Safety Profiles in Newly Diagnosed Multiple Myeloma Patients Using Real-World Evidence Data from a Single Institution: VRd Has High Rates of Chronic Neuropathy, and KRd Has Low Rates of Cardiopulmonary or Renal Toxicities When Using Optimized IV Fluid Management Coupled with Baseline Cardiac Workup

VRd Versus KRd Safety Profiles in Newly Diagnosed Multiple Myeloma Patients Using Real-World Evidence Data from a Single Institution: VRd Has High Rates of Chronic Neuropathy, and KRd Has Low Rates of Cardiopulmonary or Renal Toxicities When Using Optimized IV Fluid Management Coupled with Baseline Cardiac Workup

Modulation of Cardiopulmonary Toxicity and Oxidative Stress by Phenolic-Rich Fraction of Croton zambiscus Leaves in Rat Exposed to Chronic Mixture of Environmental Toxicants.

Chronic mixed toxicant exposure has been implicated in the aetiology of lung and heart failure through prolonged free radical generations. This study was carried out to assess the protective effect of naturally occurring phenolic components from Croton zambesicus (400mg/kg C-ZAMB) leaves against cardiopulmonary toxicity induced by chronic mixed toxicant (0.5mL EOMABRSL) in rats. Chronic cardiopulmonary injury via oral administration of 0.5ml EOMABRSL for 98days (non-withdrawal) and 70days (withdrawal) caused unhealthy alteration in the levels of oxidative stress biomarkers [malondialdehyde (MDA), reduced glutathione (GSH), glutathione-S-transferase (GST), superoxide dismutase (SOD) and catalase]. Similarly, both withdrawal and non-withdrawal approaches of EOMABRSL-exposed animals exhibited increase in the activity of eco-51-nucleotidase (51ENT) with corresponding diminution in the activity of lactate dehydrogenase (LDH), i.e. the metabolic fuel for cardiopulmonary wellness. Ultimately, histology examination confirmed hyperplastic, bronchopneumonia and cloudy swelling of cardiovascular cells followed by the accumulation of cellular exudates and haemorrhage in the alveoli and bronchioles. The active antioxidants of 400mg/kg C-ZAMB leaves were responsible for the biological protection of cardiopulmonary toxicity by modulating the activities of 51ENT and LDH. The oxidative stress was also reversed by 400mg/kg phenolic C-ZAMB leaves in the heart and lungs. Hence, 400mg/kg phenolic C-ZAMB leaves may be a natural therapy for the treatment of cardiovascular disorder associated with pulmonary dysfunction in rats.