Detection of Alteration in Carotid Artery Volumetry Using Standard-of-care Computed Tomography Surveillance Scans Following Unilateral Radiation Therapy for Early-stage Tonsillar Squamous Cell Carcinoma Survivors: A Cross-Sectional Internally-Matched Carotid Isodose Analysis.

Purpose: Radiation induced carotid artery disease (RICAD) is a major cause of morbidity and mortality among survivors of oropharyngeal cancer. This study leveraged standard-of-care CT scans to detect volumetric changes in the carotid arteries of patients receiving unilateral radiotherapy (RT) for early tonsillar cancer, and to determine dose-response relationship between RT and carotid volume changes, which could serve as an early imaging marker of RICAD. Methods and Materials: Disease-free cancer survivors (>3 months since therapy and age >18 years) treated with intensity modulated RT for early (T1-2, N0-2b) tonsillar cancer with pre- and post-therapy contrast-enhanced CT scans available were included. Patients treated with definitive surgery, bilateral RT, or additional RT before the post-RT CT scan were excluded. Pre- and post-treatment CTs were registered to the planning CT and dose grid. Isodose lines from treatment plans were projected onto both scans, facilitating the delineation of carotid artery subvolumes in 5 Gy increments (i.e. received 50-55 Gy, 55-60 Gy, etc.). The percent-change in sub-volumes across each dose range was statistically examined using the Wilcoxon rank-sum test. Results: Among 46 patients analyzed, 72% received RT alone, 24% induction chemotherapy followed by RT, and 4% concurrent chemoradiation. The median interval from RT completion to the latest, post-RT CT scan was 43 months (IQR 32-57). A decrease in the volume of the irradiated carotid artery was observed in 78% of patients, while there was a statistically significant difference in mean %-change (±SD) between the total irradiated and spared carotid volumes (7.0±9.0 vs. +3.5±7.2, respectively, p<.0001). However, no significant dose-response trend was observed in the carotid artery volume change withing 5 Gy ranges (mean %-changes (±SD) for the 50-55, 55-60, 60-65, and 65-70+ Gy ranges [irradiated minus spared]: -13.1±14.7, -9.8±14.9, -6.9±16.2, -11.7±11.1, respectively). Notably, two patients (4%) had a cerebrovascular accident (CVA), both occurring in patients with a greater decrease in carotid artery volume in the irradiated vs the spared side. Conclusions: Our data show that standard-of-care oncologic surveillance CT scans can effectively detect reductions in carotid volume following RT for oropharyngeal cancer. Changes were equivalent between studied dose ranges, denoting no further dose-response effect beyond 50 Gy. The clinical utility of carotid volume changes for risk stratification and CVA prediction warrants further evaluation.

Longitudinal changes in the carotid arteries of head and neck cancer patients following radiation therapy: Results from a prospective serial imaging biomarker characterization study.

INTRODUCTION: We prospectively evaluated morphologic and functional changes in the carotid arteries of patients treated with unilateral neck radiation therapy (RT) for head and neck cancer. METHODS: Bilateral carotid artery duplex studies were performed at 0, 3, 6, 12, 18 months and 2, 3, 4, and 5 years following RT. Intima media thickness (IMT); global and regional circumferential, as well as radial strain, arterial elasticity, stiffness, and distensibility were calculated. RESULTS: Thirty-eight patients were included. A significant difference in the IMT from baseline between irradiated and unirradiated carotid arteries was detected at 18 months (median, 0.073 mm vs -0.003 mm; P = 0.014), which increased at 3 and 4 years (0.128 mm vs 0.013 mm, P = 0.016, and 0.177 mm vs 0.023 mm, P = 0.0002, respectively). A significant transient change was noted in global circumferential strain between the irradiated and unirradiated arteries at 6 months (median difference, -0.89, P = 0.023), which did not persist. No significant differences were detected in the other measures of elasticity, stiffness, and distensibility. CONCLUSIONS: Functional and morphologic changes of the carotid arteries detected by carotid ultrasound, such as changes in global circumferential strain at 6 months and carotid IMT at 18 months, may be useful for the early detection of radiation-induced carotid artery injury, can guide future research aiming to mitigate carotid artery stenosis, and should be considered for clinical surveillance survivorship recommendations after head and neck RT.

Longitudinal Changes in the Carotid Arteries of Head and Neck Cancer Patients Following Radiation Therapy: Results from a Prospective Serial Imaging Biomarker Characterization Study.

INTRODUCTION: We prospectively evaluated morphologic and functional changes in the carotid arteries of patients treated with unilateral neck radiation therapy (RT) for head and neck cancer. METHODS: Bilateral carotid artery duplex studies were performed at 0, 3, 6, 12, 18 months and 2, 3, 4, and 5 years following RT. Intima media thickness (IMT); global and regional circumferential, as well as radial strain, arterial elasticity, stiffness, and distensibility were calculated. RESULTS: Thirty-eight patients were included. A significant difference in the IMT from baseline between irradiated and unirradiated carotid arteries was detected at 18 months (median, 0.073mm vs -0.003mm; P =0.014), which increased at 3 and 4 years (0.128mm vs 0.013mm, P =0.016, and 0.177mm vs 0.023mm, P =0.0002, respectively). A > 0.073mm increase at 18 months was significantly more common in patients who received concurrent chemotherapy (67% vs 25%; P =0.03). A significant transient change was noted in global circumferential strain between the irradiated and unirradiated arteries at 6 months (median difference, -0.89, P =0.023), which did not persist. No significant differences were detected in the other measures of elasticity, stiffness, and distensibility. CONCLUSIONS: Functional and morphologic changes of the carotid arteries detected by carotid ultrasound, such as changes in global circumferential strain at 6 months and carotid IMT at 18 months, may be useful for the early detection of radiation-induced carotid artery injury, can guide future research aiming to mitigate carotid artery stenosis, and should be considered for clinical surveillance survivorship recommendations after head and neck RT.

Extensive Painless Aortic Dissection in a Patient With Breast Cancer.

This case illustrates the unusual clinical presentation and natural progression of type A aortic dissection, found incidentally on echocardiogram in a patient with breast cancer. Possible association of tyrosine kinase inhibitor with aortic dissection is reviewed in the light of this case.

Predictors of Recurrence and Survival in Cancer Patients With Pericardial Effusion Requiring Pericardiocentesis.

Aim: This study investigated the factors predicting survival and the recurrence of pericardial effusion (PE) requiring pericardiocentesis (PCC) in patients with cancer. Materials and Methods: We analyzed the data of patients who underwent PCC for large PEs from 2010 to 2020 at The University of Texas MD Anderson Cancer Center. The time to the first recurrent PE requiring PCC was the interval from the index PCC with pericardial drain placement to first recurrent PE requiring drainage (either repeated PCC or a pericardial window). Univariate and multivariate Fine-Gray models accounting for the competing risk of death were used to identify predictors of recurrent PE requiring drainage. Cox regression models were used to identify predictors of death. Results: The study cohort included 418 patients with index PCC and pericardial drain placement, of whom 65 (16%) had recurrent PEs requiring drainage. The cumulative incidences of recurrent PE requiring drainage at 12 and 60 months were 15.0% and 15.6%, respectively. Younger age, anti-inflammatory medication use, and solid tumors were associated with an increased risk of recurrence of PE requiring drainage, and that echocardiographic evidence of tamponade at presentation and receipt of immunotherapy were associated with a decreased risk of recurrence. Factors predicting poor survival included older age, malignant effusion on cytology, non-use of anti-inflammatory agents, non-lymphoma cancers and primary lung cancer. Conclusion: Among cancer patients with large PEs requiring drainage, young patients with solid tumors were more likely to experience recurrence, while elderly patients and those with lung cancer, malignant PE cytology, and non-use of anti-inflammatory agents showed worse survival.

Acute coronary syndrome in patients with cancer.

INTRODUCTION: Improvement in cancer survival has led to an increased focus on cardiovascular disease as the other major determinant of survivorship. As a result, there has been an increasing interest in managing cardiovascular disease during and post cancer treatment. AREAS COVERED: This article reviews the current literature on the pathogenesis, risk factors, presentation, treatment and clinical outcomes of acute coronary syndrome (ACS) in patients with cancer. EXPERT OPINION: There is growing evidence that both medical therapy and invasive management of ACS improve outcomes in patients with cancer. Appropriate patient selection, risk stratification and tailored therapy represents the cornerstone of management in these patients.

Speckle-Tracking Echocardiography in Cardio-Oncology and Beyond.

Speckle-tracking echocardiography has enabled clinicians to detect changes in myocardial function with more sensitivity than that afforded by traditional diastolic and systolic functional measurements, including left ventricular ejection fraction. Speckle-tracking echocardiography enables evaluation of myocardial strain in terms of strain (percent change in length of a myocardial segment relative to its length at baseline) and strain rate (strain per unit of time). Both measurements have potential for use in diagnosing and monitoring the cardiovascular side effects of cancer therapy. Regional and global strain measurements can independently predict outcomes not only in patients who experience cardiovascular complications of cancer and cancer therapy, but also in patients with a variety of other clinical conditions. This review and case series examine the clinical applications and overall usefulness of speckle-tracking echocardiography in cardio-oncology and, more broadly, in clinical cardiology.

Safety of Transesophageal Echocardiography in Patients with Thrombocytopenia.

BACKGROUND: According to current literature and guidelines, thrombocytopenia is considered a relative contraindication for performing transesophageal echocardiogram (TEE). In cancer patients, thrombocytopenia is frequently present. No prior studies have assessed the safety and complications of TEE in a thrombocytopenic population. METHODS: From January 2002 to December 2017, all patients who underwent TEE at MD Anderson Cancer Center in the nonoperative setting were included in the study. Patient characteristics, laboratory data, indications, and complications of TEE were obtained from medical records. Thrombocytopenia was defined as platelet count <100,000/µL prior to procedure. In this retrospective study, medical records were reviewed up to 30 days after procedure to search for possible complications related to TEE. RESULTS: During the study period, 2,345 TEE studies were performed. The mean age was 58.2 ± 15.3 years and 58.8% of patients were male. Thrombocytopenia was found in 814 patients (34.7%). More thrombocytopenic patients had hematologic malignancy, when compared with patients with normal platelet level (79.7% vs 30.2%; P < .001). The most common indication for TEE study was to evaluate for suspected endocarditis (48.0%) and was found more frequently in thrombocytopenic patients compared with those with normal platelet count (69.5% vs 36.5%; P < .001). Overall, 10 patients (0.4%) had complications related to TEE: eight minor oropharyngeal bleeding that did not require transfusion, one transient atrial fibrillation, and one esophageal perforation. There was no major bleeding, respiratory failure, or death related to TEE examination during the study period. Minor oropharyngeal bleeding was the only complication seen in thrombocytopenic patients (seven patients, 0.3%). CONCLUSIONS: Thrombocytopenia is common in cancer patients undergoing TEE. TEE-related complications are minimal in patients with both normal or low platelet count. With appropriate patient preparation and careful probe manipulation, TEE can be safely performed in thrombocytopenic patients.

Feasibility and Outcomes of an Exercise Intervention for Chemotherapy-Induced Heart Failure.

PURPOSE: Cancer treatment-related heart failure (HF) is an emerging health concern, as the number of survivors is increasing rapidly, and cardiac health issues are a leading cause of mortality in this population. While there is general evidence for the efficacy of exercise rehabilitation interventions, more research is needed on exercise rehabilitation interventions for patients specifically with treatment-induced HF and whether such interventions are safe and well-accepted. This study provides feasibility and health outcomes of a pilot exercise intervention for cancer survivors with chemotherapy-induced HF. METHODS: Twenty-five participants were randomized to a clinic-based exercise intervention or a wait-list control group or, alternatively, allowed to enroll in a home-based exercise intervention if they declined the randomized study. For purposes of analysis, both types of exercise programs were combined into a single intervention group. Repeated-measures analysis of variance was conducted to assess for significant time and treatment group main effects separately and time × treatment group interaction effects. RESULTS: Significant improvements in maximum oxygen uptake ((Equation is included in full-text article.)O2max) were observed in the intervention group. Intervention satisfaction and adherence were high for both clinic- and home-based interventions, with no reported serious adverse events. Enrollment was initially low for the clinic-based intervention, necessitating the addition of the home-based program as an intervention alternative. CONCLUSIONS: Results suggest that exercise rehabilitation interventions are feasible in terms of safety, retention, and satisfaction and have the potential to improve (Equation is included in full-text article.)O2max. To maximize adherence and benefits while minimizing participant burden, an ideal intervention may incorporate elements of both clinic-based supervised exercise sessions and a home-based program.

Targeted Cancer Therapies With Pericardial Effusions Requiring Pericardiocentesis Focusing on Immune Checkpoint Inhibitors.

Case reports have reported immune checkpoint inhibitors (ICI), especially nivolumab, are associated with recurrent pericardial effusions. Our objective was to determine how often patients being treated with ICI develop hemodynamically significant pericardial effusion requiring pericardiocentesis compared with other cancer therapeutics and whether the survival of patients who underwent pericardiocentesis differs according to ICI use versus standard cancer therapeutics. Our institutional review board approved catheterization laboratory data collection for all pericardiocenteses performed and all patients receiving ICI from January 1, 2015 to December 31, 2017. Retrospective review of the electronic medical record was performed to identify cancer therapeutics given preceding pericardiocentesis. Log-rank analysis was performed to compare survival in patients requiring pericardiocentesis between those on ICI and those not on ICI. Overall, 3,966 patients received ICI of which only 15 pericardiocenteses were required, including 1 repeat pericardiocentesis in a patient on nivolumab. The prevalence of pericardiocentesis among patients on ICI was 0.38% (15/3,966). Eleven pericardiocenteses were performed after nivolumab infusion, 3 after pembrolizumab, and 1 after atezolizumab, with pericardiocentesis prevalences for each agent of 0.61% (11/1,798), 0.19% (3/1,560), and 0.32% (1/309), respectively. One hundred and twenty pericardiocentesis were performed on patients receiving other cancer therapeutics although no therapeutic agent was associated with more pericardiocenteses than nivolumab. In conclusion, the prevalence of hemodynamically significant pericardial effusions and ICI administration is uncommon, and survival durations after pericardiocentesis for patients receiving ICI and those not receiving ICI are similar, suggesting that frequent echocardiographic monitoring for pericardial effusions is not necessary.

Safety of Diagnostic and Therapeutic Cardiac Catheterization in Cancer Patients With Acute Coronary Syndrome and Chronic Thrombocytopenia.

Little data is available on the bleeding risk and outcomes of cancer patients with chronic thrombocytopenia who underwent cardiac catheterization. We sought to assess the safety of coronary angiography, percutaneous coronary intervention, and antiplatelet therapy in cancer patients with acute coronary syndrome (ACS) and chronic thrombocytopenia. We performed a retrospective study of patients with chronic thrombocytopenia who underwent cardiac catheterization for ACS between November 2009 and November 2015. Preprocedural platelet counts were classified into 3 groups: mild thrombocytopenia (50,000 to 100,000/µL), moderate thrombocytopenia (30,000 to 50,000/µL), and severe thrombocytopenia (<30,000/µL). Postprocedural bleeding complications and overall survival (OS) were recorded. A total of 98 patients were included. Mean platelet count on admission was 47.63 ± 29.85 K/µL. Severe thrombocytopenia was identified in 36 patients (36.7%), moderate thrombocytopenia in 20 patients (20.4%), and mild thrombocytopenia in 42 patients (42.9%). Aspirin therapy (alone or in combination with clopidogrel) was used in 66 patients (67.3%), whereas 27 patients (27.6%) were on dual antiplatelet therapy. One procedure-related retroperitoneal hematoma and 3 procedure-related small hematomas were identified. No cerebrovascular events related to the procedure or the antiplatelet therapy were noted. Moderate thrombocytopenia was associated with decreased OS, whereas aspirin, dual antiplatelet therapy, and statin use showed a trend of improved OS. In conclusion, we suggest that coronary angiography and percutaneous coronary intervention can be performed safely in cancer patients with chronic thrombocytopenia. Aspirin therapy and dual antiplatelet therapy should be considered in cancer patients with chronic thrombocytopenia and ACS.

Interventional Cardio-Oncology: Adding a New Dimension to the Cardio-Oncology Field.

The management of cardiovascular disease in patients with active cancer presents a unique challenge in interventional cardiology. Cancer patients often suffer from significant comorbidities such as thrombocytopenia and coagulopathic and/or hypercoagulable states, which complicates invasive evaluation and can specifically be associated with an increased risk for vascular access complications. Furthermore, anticancer therapies cause injury to the vascular endothelium as well as the myocardium. Meanwhile, improvements in diagnosis and treatment of various cancers have contributed to an increase in overall survival rates in cancer patients. Proper management of this patient population is unclear, as cancer patients are largely excluded from randomized clinical trials on percutaneous coronary intervention (PCI) and national PCI registries. In this review, we will discuss the role of different safety measures that can be applied prior to and during these invasive cardiovascular procedures as well as the role of intravascular imaging techniques in managing these high risk patients.

Chemotherapeutic Agents and the Risk of Ischemia and Arterial Thrombosis.

PURPOSE OF REVIEW: Numerous chemotherapeutic agents have been associated with the development of ischemia and arterial thrombosis. As newer therapies have been developed to treat cancer, some of these chemotherapy drugs have been implicated in the development of vascular disease. In this review, we will summarize the most common chemotherapeutic drug classes that may play a role in the development of ischemic heart disease. RECENT FINDINGS: Angiogenesis inhibitors, alkylating agents, antimetabolites, antimicrotubules, and proteasome inhibitors have a number of cardiovascular toxicities. The possible mechanisms of action of these drugs leading to ischemic complications are varied but include endothelial dysfunction, platelet aggregation, reduced levels of nitrous oxide (NO), and elevated levels of reactive oxygen species (ROS), and vasospasm. While some drugs act through multiple pathways that result in the development of ischemic heart disease, others such as the antimetabolites and antimicrotubules appear to primarily cause vasospasm. Furthermore, while aromatase inhibitors increase the risk of heart disease in comparison to tamoxifen in large studies, this finding likely occurs because of a protective role of tamoxifen on cardiovascular risk factors rather than a direct effect of aromatase inhibitors. Angiogenesis inhibitors, alkylating agents, antimetabolites, antimicrotubules, and proteasome inhibitors can lead to ischemic complications in patients with cancer. Many of these drugs have proven to be effective in improving cancer prognosis, but their possible cardiovascular effects have to be carefully monitored and treated. Treatment of ischemic complications in the setting of cancer therapy should focus on the optimal medical management of known cardiovascular risk factors and follow an evidence-based approach.

Fulminant Cryptococcus neoformans infection with fatal pericardial tamponade in a patient with chronic myelomonocytic leukaemia who was treated with ruxolitinib: Case report and review of fungal pericarditis.

Cryptococcus neoformans is a saprophytic fungal pathogen that can cause serious illness in immune-compromised hosts and it presents with a wide variety of clinical symptoms. We present a fatal case of fulminant C. neoformans infection presenting as pericardial tamponade in a 71-year-old male with chronic myelomonocytic leukaemia undergoing chemotherapy with the JAK-STAT inhibitor ruxolitinib. We also review the published cases of fungal pericarditis/tamponade. In addition to illustrating an atypical presentation of C. neoformans, this case highlights the risk for opportunistic fungal infections in patients with haematological malignancies, especially the ones treated with small molecule kinase inhibitors.

Improvement of Smoking Abstinence Rates With Increased Varenicline Dosage: A Propensity Score-Matched Analysis.

PURPOSE/BACKGROUND: It is unclear whether increasing the dose of varenicline beyond the standard dose of 2 mg/d would improve smoking abstinence. METHODS: We examined the effect of 3 mg/d of varenicline on smoking abstinence among smokers who had reduced their smoking by 50% or more in response to 2 mg/d for at least 6 weeks but had not quit smoking. Of 2833 patients treated with varenicline, dosage of a subset of 73 smokers was increased to 3 mg/d after 6 weeks. We used a propensity score analysis involving multiple baseline covariates to create a comparative sample of 356 smokers who remained on 2 mg/d. All smokers received concurrent and similar smoking-cessation counseling. RESULTS: At 3 months, we found higher 7-day point prevalence smoking-abstinence rate in the 3-mg group (26%) than in the 2-mg group (11.5%, χ = 10.60, P < 0.001; risk ratio [RR], 2.3; 95% confidence interval [CI], 1.4-3.6). The difference in abstinence rates remained significant at the 6-month (P < 0.001; RR, 2.6; 95% CI, 1.6-3.9) and 9-month follow-up (P < 0.001; RR, 2.2; 95% CI, 1.4-3.3). CONCLUSIONS: A relatively small increase in the daily dose of varenicline seems to offer a benefit for those who are not able to achieve total abstinence after approximately 6 weeks of 2 mg/d.

Incidence and Predictors of Pericardial Effusion After Chemoradiation Therapy for Locally Advanced Non-Small Cell Lung Cancer.

PURPOSE: Findings from Radiation Therapy Oncology Group (RTOG) 0617 suggested that collateral radiation to the heart may contribute to early death in patients receiving chemoradiation therapy for non-small cell lung cancer (NSCLC); however, reports of cardiac toxicity after thoracic radiation therapy (RT) remain limited. Because pericardial disease is the most common cardiac complication of thoracic RT, we investigated the incidence of and risk factors for pericardial effusion (PCE) in patients enrolled in a phase 2 prospective randomized study of intensity modulated RT versus proton therapy for locally advanced NSCLC. METHODS AND MATERIALS: From July 2009 through April 2014, 201 patients were prospectively treated with proton beam therapy or intensity modulated RT to 60 to 74 Gy with concurrent chemotherapy. The primary endpoint (grade ≥2 PCE) was diagnosed on review of follow-up images. Clinical characteristics and cardiac dose-volume parameters associated with PCE were identified via Cox proportional hazards modeling and recursive partitioning analysis of null Martingale residuals. Reproducibility was evaluated in a separate retrospective cohort of 301 patients. RESULTS: The cumulative incidence rates of PCE among patients in the trial were 31.4% at 1 year and 45.4% at 2 years, with a median time to PCE of 8.9 months. Several cardiac dose-volume parameters (eg, V20 [volume receiving ≥20 Gy] to V65 [volume receiving ≥65 Gy]) predicted PCE, but heart volume receiving ≥35 Gy (HV35) was the most strongly associated, with a cutoff volume of 10%. On multivariate analysis, HV35 >10% independently predicted PCE (hazard ratio [HR], 2.14; P=.002), a finding that maintained reproducibility in the retrospective validation cohort. Other factors associated with PCE included receipt of adjuvant chemotherapy (HR, 2.82; P<.001) and prior cardiac disease (HR, 1.68; P=.020). CONCLUSIONS: PCE was common after RT for NSCLC, occurring in nearly half of patients even after moderate radiation doses to the heart. Adjuvant chemotherapy may increase the risk of PCE, and HV35 >10% may identify patients at risk of development of this cardiac toxicity.

Progressive and Reversible Conduction Disease With Checkpoint Inhibitors.

Novel antineoplastic therapies are focused on harnessing our own immune system to fight cancer. To that end, cytotoxic T-lymphocyte-associated antigen 4 and programmed death ligand 1 are 2 coinhibitory signals that play central roles in decreasing T-cell response and represent a class of medications termed "checkpoint inhibitors." We present an unusual case of progressive conduction abnormalities induced by checkpoint inhibitors. Prompt medical intervention resulted in full recovery. Despite the anticancer efficacy, the newer antineoplastic agents pose a significant and often life-threatening risk of cardiotoxicity.