A Predictive Model for Cancer-Associated Thrombosis in Japanese Cancer Patients: Findings from the J-Khorana Registry.

Background Although the close relationship between cancer and venous thromboembolism (VTE) has been identified, risk stratification for VTE in Japanese patients with cancer remains unclear. Objectives This study aimed to validate the Khorana VTE risk assessment score (KRS) for VTE diagnosis and establish an optimal predictive model for VTE in Japanese patients with cancer. Methods A total of 7,955 Japanese patients with cancer were subdivided into low- (0), intermediate- (1-2), and high-score (3) groups according to the KRS. Using 37 explanatory variables, a total of 2,833 patients with cancer were divided into derivation and validation cohorts (5:5). A risk model for Japanese participants was developed using the derivation cohort data. Results The prevalence of VTE in low-, intermediate-, and high-score patients was 1.2, 2.5, and 4.3%, respectively. Logistic regression analysis demonstrated that cancer stage (III-IV) and KRS ≥ 2 were independent and significant predictors of VTE onset. The risk model for VTE assigned 1 point to body mass index ≥25 kg/m 2 and 2 points each to the prevalence of osteochondral cancer and D-dimer level ≥1.47 µg/mL. The areas under the curve of the risk model were 0.763 and 0.656 in the derivation and validation cohorts, respectively. Conclusion The KRS was useful in Japanese patients, and our new predictive model may be helpful for the diagnosis of VTE in Japanese patients with cancer.

Tenascin-C as a potential marker for immunohistopathology of doxorubicin-induced cardiomyopathy.

Aims: Doxorubicin is used in classical chemotherapy for several cancer types. Doxorubicin-induced cardiomyopathy (DOX-CM) is a critical issue among cancer patients. However, differentiating the diagnosis of DOX-CM from that of other cardiomyopathies is difficult. Therefore, in this study, we aimed to determine novel histopathological characteristics to diagnose DOX-CM. Methods and results: Twelve consecutive patients with DOX-CM who underwent cardiac histopathological examination in two medical centres were included. Twelve patients with dilated cardiomyopathy, who were matched with DOX-CM patients in terms of age, sex, and left ventricular ejection fraction, formed the control group. Another control group comprised five consecutive patients with cancer therapy-related cardiac dysfunction induced by tyrosine kinase inhibitors or vascular endothelial growth factor inhibitors were the controls. The positive area of tenascin-C, number of infiltrating macrophages, and presence of p62- and ubiquitin-positive cardiomyocytes were evaluated. Human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) were used for in vitro investigation. The myocardium exhibited significantly greater tenascin-C-positive area and macrophage number in the DOX-CM group than in the control groups (P < 0.01). The tenascin-C-positive area correlated with the number of both CD68- and CD163-positive cells (r = 0.748 and r = 0.656, respectively). Immunostaining for p62 was positive in 10 (83%) patients with DOX-CM. Furthermore, western blotting analysis revealed significant increase in tenascin-C levels in hiPSC-CMs upon doxorubicin treatment (P < 0.05). Conclusion: The combined histopathological assessment for tenascin-C, macrophages, and p62/ubiquitin may serve as a novel tool for the diagnosis of DOX-CM. Doxorubicin may directly affect the expression of tenascin-C in the myocardium.

Advancing Cardio-Oncology in Asia.

Cardio-oncology is an emerging multi-disciplinary field, which aims to reduce morbidity and mortality of cancer patients by preventing and managing cancer treatment-related cardiovascular toxicities. With the exponential growth in cancer and cardiovascular diseases in Asia, there is an emerging need for cardio-oncology awareness among physicians and country-specific cardio-oncology initiatives. In this state-of-the-art review, we sought to describe the burden of cancer and cardiovascular disease in Asia, a region with rich cultural and socio-economic diversity. From describing the uniqueness and challenges (such as socio-economic disparity, ethnical and racial diversity, and limited training opportunities) in establishing cardio-oncology in Asia, and outlining ways to overcome any barriers, this article aims to help advance the field of cardio-oncology in Asia.

Prevalence and characteristics of immune checkpoint inhibitor-related myocardial damage: A prospective observational study.

An increasing number of patients with cancer are being treated with immune checkpoint inhibitors. Consequently, the incidence of immune checkpoint inhibitor-related myocarditis has been increasing. Nonetheless, the diagnostic criteria for the immune checkpoint inhibitor-related myocarditis have not been sufficiently established. Therefore, the real-world incidence or prevalence of immune checkpoint inhibitor-related myocardial damage remains unknown. This was a single-center cohort study that included 100 patients admitted for immune checkpoint inhibitor therapy for any type of cancer. The patients underwent monthly measurement of cardiac troponin I and N-terminal pro-brain natriuretic peptide levels with electrocardiography. Additionally, echocardiography was performed every 3 months. Our protocol was continued until 6 months after the initiation of immune checkpoint inhibitors. We defined immune checkpoint inhibitor-related myocardial damage as an increase in cardiac troponin I levels by >0.026 ng/mL and/or a decrease in the left ventricular ejection fraction by >10% to <53% on echocardiography. The mean patient age was 64 years; 71% were men. The most commonly used immune checkpoint inhibitor was nivolumab (47%), followed by pembrolizumab (29%). Overall, 5% of patients received combination therapy. Among 100 patients, 10 (10%) were diagnosed with immune checkpoint inhibitor-related myocardial damage. Among them, five patients underwent endomyocardial biopsy. Of these patients, four were histopathologically observed to have lymphocyte infiltration in their myocardium. In conclusion, serial cardiac troponin I measurement during immune checkpoint inhibitor treatment could help detect early-phase myocardial damage. The prevalence of myocardial damage was much higher than previously expected.

A Case of Lung Cancer with Very-Late-Onset Immune Checkpoint Inhibitor-Related Myocarditis.

Immune checkpoint inhibitor (ICI)-related myocarditis has been reported to appear in the early phase after ICI initiation. Herein, we report the case of a 78-year-old man with non-small cell lung cancer. Pembrolizumab was introduced as first-line therapy. After 9 months, second-line therapy, including bevacizumab, was initiated. After another 7 months, echocardiography showed diffuse left ventricular dysfunction. Based on the histopathologic examination of the myocardium, the patient was diagnosed with ICI-related myocarditis. Initiation of prednisolone therapy improved cardiac function. This case of late-onset ICI-related myocarditis illustrates that endomyocardial biopsy can be useful in the differential diagnosis of cancer-related left ventricular dysfunction.

Il a été rapporté qu'une myocardite pouvait survenir peu après l'instauration d'un traitement par des inhibiteurs des points de contrôle immunitaire (ICI). Nous présentons le cas d'un homme de 78 ans atteint d'un cancer du poumon non à petites cellules. Le pembrolizumab a été administré comme traitement de première intention. Neuf mois plus tard, un traitement de deuxième intention par le bévacizumab a été instauré. Après sept autres mois, l'échocardiographie a montré une dysfonction ventriculaire gauche diffuse. À la suite des résultats de l'examen histopathologique du myocarde, une myocardite liée aux ICI a été diagnostiquée. L'instauration d'un traitement par la prednisolone a amélioré la fonction cardiaque du patient. Ce cas de myocardite tardive liée aux ICI montre l'utilité éventuelle de la biopsie de l'endomyocarde dans le diagnostic différentiel d'une dysfonction ventriculaire gauche liée au cancer.

Sinus Node Dysfunction Co-occurring with Immune Checkpoint Inhibitor-associated Myocarditis.

Immune checkpoint inhibitor (ICI)-induced myocarditis is a potentially life-threatening adverse event. We herein report a rare case of sick sinus syndrome (SSS) co-occurring with ICI-associated myocarditis. A 71-year-old woman with lung cancer undergoing pembrolizumab monotherapy was admitted owing to a fever, worsening kidney function, and sinus bradycardia. She was diagnosed with multi-organ immune-related adverse events, including myocarditis. Pulse steroid therapy was initiated immediately under the support of a temporary pacemaker, which resulted in the resolution of SSS in a few days. Biopsy specimens of the endomyocardium showed active myocarditis. Thus, we should be aware that SSS can co-occur with ICI-induced myocarditis.

Prognostic Impact of Cancer Activity on Clinically Relevant Bleeding Events After Percutaneous Coronary Intervention.

Purpose : Limited data exist about clinically relevant bleeding events related to antiplatelet therapy after percutaneous coronary intervention (PCI) in cancer patients. We investigated the risk factors for clinically relevant bleeding events in patients with cancer after PCI with stent implantation. Patients and Methods : Patients with solid cancer subjected to first PCI were divided into active (n = 45) and non-active cancer groups (n = 44). The active group included non-operable patients on treatment or with metastasis ; the non-active included those already subjected to or for whom radical surgery was planned within 3 months after the index PCI. Results : During a median follow-up of 2.2 years, 11 bleeding events occurred, with only one occurring in the non-active cancer group. Half of them occurred during the dual-antiplatelet therapy (DAPT) period, and the rest occurred during single-antiplatelet therapy (SAPT) period. Kaplan-Meier analysis showed significantly more bleeding events in the active cancer group (p = 0.010). Multivariate Cox regression hazard analysis revealed cancer activity as a significant independent risk factor for bleeding (p = 0.023) ; but not for three-point major adverse cardiovascular events. Conclusion : Clinically relevant bleeding risk after PCI was significantly lower in non-active cancer. Active cancer group had clinically relevant bleeding during both DAPT and SAPT periods. J. Med. Invest. 68 : 29-37, February, 2021.

Serial Changes in Cardiac Strain and Contractility After Hematopoietic Stem Cell Transplantation in Patients with Hematologic Malignancies.

Hematopoietic stem cell transplantation (HSCT) is occasionally associated with cardiac dysfunction during long-term follow-up. Global longitudinal strain (GLS) has emerged as an early predictor of cardiotoxicity associated with cancer therapy; however, the serial changes in GLS before and after HSCT have not been elucidated. To clarify the association between HSCT and GLS, we investigated serial changes in GLS before and after HSCT. We evaluated cardiac function before and 1, 3, and 6 months after HSCT in 38 consecutive HSCT patients enrolled in this study. Overall, GLS and left ventricular (LV) ejection fraction (EF) temporally decreased 1 month post-HSCT. LVEF completely recovered to baseline at 3 months after HSCT, whereas GLS partially recovered 6 months after HSCT. Except for five patients who died within 6 months, GLS values in the low EF group (LVEF ≤ 55% at 6 months post-HSCT, n = 6) were significantly and consistently lower than those in the normal EF group (LVEF > 55% at 6 months post-HSCT, n = 27) at any time during follow-up. These findings suggest that GLS before HSCT might be associated with a decrease in LVEF after HSCT in patients with hematologic malignancies. Further prospective and long-term data will be important for understanding the management of HSCT-associated cardiac dysfunction.

Symptomatic Sinus Bradycardia in a Patient with Solitary Fibrous Tumor/Hemangiopericytoma Treated with Pazopanib.

Pazopanib, a multi-targeted tyrosine kinase inhibitor, is associated with cardiovascular adverse events, such as hypertension, cardiac dysfunction, and thromboembolism. However, symptomatic pazopanib-related bradycardia is uncommon. We herein report a case of symptomatic bradycardia of 35 beats per minute in a patient with solitary fibrous tumor/hemangiopericytoma (SFT/HPC) treated with pazopanib for 1 month. His heart rate recovered to a normal range soon after pazopanib cessation. He restarted pazopanib at a reduced dose, which was continued without SFT/HPC progression or bradycardia recurrence. This case highlights the possibility of bradycardia induced by pazopanib and the importance of monitoring the patient's heart rate.

Multicentre cohort study of the impact of percutaneous coronary intervention on patients with concurrent cancer and ischaemic heart disease.

BACKGROUND: The incidence of concurrent cancer and ischaemic heart disease (IHD) is increasing; however, the long-term patient prognoses remain unclear. METHODS: Five-year all-cause mortality data pertaining to patients in the Osaka Cancer Registry, who were diagnosed with colorectal, lung, prostate, and gastric cancers between 2010 and 2015, were retrieved and analysed together with linked patient administrative data. Patient characteristics (cancer type, stage, and treatment; coronary risk factors; medications; and time from cancer diagnosis to index admission for percutaneous coronary intervention [PCI] or IHD diagnosis) were adjusted for propensity score matching. Three groups were identified: patients who underwent PCI within 3 years of cancer diagnosis (n = 564, PCI + group), patients diagnosed with IHD within 3 years of cancer diagnosis who did not undergo PCI (n = 3058, PCI-/IHD + group), and patients without IHD (n = 27,392, PCI-/IHD- group). Kaplan-Meier analysis was used for comparisons. RESULTS: After propensity score matching, the PCI + group had better prognosis (n = 489 in both groups, hazard ratio 0.64, 95% confidence interval 0.51-0.81, P < 0.001) than the PCI-/IHD + group. PCI + patients (n = 282) had significantly higher mortality than those without IHD (n = 280 in each group, hazard ratio 2.88, 95% confidence interval 1.90-4.38, P < 0.001). CONCLUSIONS: PCI might improve the long-term prognosis in cancer patients with IHD. However, these patients could have significantly worse long-term prognosis than cancer patients without IHD. Since the present study has some limitations, further research will be needed on this important topic in cardio-oncology.

Prognostic Effect of Incidental Pulmonary Embolism on Long-Term Mortality in Cancer Patients.

BACKGROUND: The effect of incidental pulmonary embolism (PE) on long-term prognosis in cancer patients is unclear. This study assessed the characteristics of cancer and venous thromboembolism (VTE) and the effect of incidental PE identified by oncologists on long-term survival of patients with cancer.Methods and Results:This single-center, retrospective, cohort study used hospital-based cancer registry data from the Osaka International Cancer Institute linked with electronic medical records and administrative data from Japan's Diagnosis Procedure Combination Per-diem Payment System. Overall, 15,689 cancer patients underwent contrast-enhanced thoracic computed tomography during 2010-2018. After excluding patients with missing data, symptomatic patients, or patients with suspected PE, 174 with incidental PE (PE+ group) and 13,197 with no PE (PE- group) were identified. The total incidence of incidental PE was 1.3%. No deaths from thrombotic events were identified in the PE+ group. Both groups were adjusted for cancer- and VTE-related characteristics using inverse probability weighting. After adjusting for immortal time bias in the PE+ group, Kaplan-Meier analysis revealed that all-cause mortality was higher in the PE+ group (hazard ratio, 2.26; 95% confidence interval, 1.53-3.33). A Cox proportional hazard model revealed that metastatic cancer and a history of curative treatment were significant prognostic factors, whereas central PE and residual proximal deep vein thrombosis were not. CONCLUSIONS: Incidental PE in cancer patients indicates poorer prognosis. Cancer-related but not thrombosis-related factors determine prognosis.

Osimertinib is associated with reversible and dose-independent cancer therapy-related cardiac dysfunction.

INTRODUCTION: The use of osimertinib is associated with the risk of cancer therapy-related cardiac dysfunction (CTRCD) for EGFR-mutated non-small cell lung cancer (NSCLC) patients. In this study, we aimed to clarify the clinical features of patients with CTRCD associated with osimertinib. METHODS: A total of 183 cases of advanced EGFR-mutated NSCLC who received osimertinib monotherapy from January 2014 to December 2019 were evaluated. Longitudinal changes in LVEF were evaluated in 58 patients by serial echocardiography before and after osimertinib administration. RESULTS: Of 58 patients, 16 patients (8.7%) had decreased LVEF of 10 units or more and 8 patients (4.4%) met the CTRCD criteria. Overall, LVEF significantly decreased after osimertinib treatment from a mean value of 69% (range, 52-82%) at baseline to 66% (26-75%) (p < 0.001). During osimertinib treatment, LVEF remained low but did not decline any further. Discontinuation, dose reduction, or switching to another EGFR tyrosine kinase inhibitors resulted in recovery in 6 out of 8 CTRCD patients. Multivariate analysis showed that history of heart disease was a significant predictor of CTRCD (ORR, 4.97; 95% confidence interval [CI], 1.26-19.6; P = 0.022). CONCLUSIONS: Osimertinib was associated with the risk of CTRCD, which is dose-independent and reversible with drug withdrawal.

Acute myocardial infarction caused by tumor embolus originating from upper tract urothelial carcinoma: a case report.

Coronary emboli from malignant tumors rarely cause acute myocardial infarction. We report the case of a patient with tumor embolism from an upper tract urothelial carcinoma that caused acute myocardial infarction via a patent foramen ovale. Coronary blood flow was restored by embolus aspiration without stenting. Clinicians must consider malignant tumor embolism as a possible cause of acute myocardial infarction.

Coronary spastic angina in a multiple myeloma patient treated with bortezomib, lenalidomide, and dexamethasone.

Adverse cardiovascular events have been reported in patients with multiple myeloma. We present a case of coronary spastic angina during combination therapy with bortezomib, lenalidomide, and dexamethasone for multiple myeloma. A 70-year-old man, newly diagnosed with multiple myeloma, was admitted to our hospital at his fifth therapy cycle due to exertional chest pain. Coronary angiography revealed diffuse spasm in the left coronary artery, which normalized after intracoronary injection of nitroglycerin. Calcium channel blockers were effective in treating his coronary spastic angina and the patient resumed treatment for multiple myeloma. This case highlights the importance of being aware of the possibility of coronary spastic angina when combination therapy with bortezomib, lenalidomide, and dexamethasone is initiated. .

Bisoprolol transdermal patch treatment for patients with atrial fibrillation after noncardiac surgery: A single-center retrospective study of 61 patients.

OBJECTIVES: Atrial fibrillation after surgery is associated with increased rates of heart failure and ischemic stroke, and extension of hospitalization. Bisoprolol is a ß-blocker used to reduce heart rate and manage arrhythmias during atrial fibrillation. However, the safety and efficacy of bisoprolol transdermal patch treatment in patients with postoperative atrial fibrillation remain unclear. METHODS: We retrospectively assessed the electronic health records of our hospital between September 2013 and July 2018 and identified patients with postoperative atrial fibrillation who had been treated with a bisoprolol transdermal patch. We excluded patients with sinus rhythm using bisoprolol transdermal patch to prevent atrial fibrillation recurrence and those with sustained atrial fibrillation before surgery. Data on heart rhythm, heart rate, and blood pressure at the baseline and after 24 h of treatment were obtained from the electronic health records. RESULTS: Of the 603 patients treated with the bisoprolol transdermal patch, 61 patients with postoperative atrial fibrillation after noncardiac surgery were included. The bisoprolol transdermal patch was discontinued due to bradycardia in two patients (3.3%). In both cases, the heart rate increased after the removal of the bisoprolol transdermal patch and no additional treatment was necessary. Among the 61 patients, sinus rhythm was restored within 24 h of bisoprolol treatment in 47 patients (77.0%). The heart rate significantly decreased from 124.8 ± 26.3 bpm at the baseline to 78.9 ± 16.6 bpm at 24 h after treatment (p < 0.001). There were no significant differences in the systolic and diastolic blood pressures between patients before and at 24 h after treatment. CONCLUSION: The results of this study indicate that the bisoprolol transdermal patch is well tolerated and effective in patients with atrial fibrillation after noncardiac surgery.

Cardiac Adverse Events in EGFR-Mutated Non-Small Cell Lung Cancer Treated With Osimertinib.

OBJECTIVES: The purpose of this study was to assess osimertinib-associated cardiac adverse events (AEs) in a real-world setting, using a retrospective single-center cohort study in Japan. BACKGROUND: Cases of osimertinib-associated cardiac AEs have been reported but remain poorly understood. METHODS: A total of 123 cases of advanced non-small cell lung cancer (NSCLC) with confirmed EGFR mutations who received osimertinib monotherapy from 2014 to 2019 at the Osaka International Cancer Institute (Osaka, Japan) were evaluated. Cardiac AEs were defined according to Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. Changes in left ventricular ejection fraction (LVEF) and rates of cancer therapeutics-related cardiac dysfunction (CTRCD), defined as a ≥10 % absolute decline in LVEF from baseline to a value of <53%, were further assessed in 36 patients in whom serial measurements of LVEF were obtained before and during osimertinib treatment. RESULTS: Severe cardiac AEs (CTCAE grade 3 or higher) occurred in 6 patients (4.9%) after osimertinib administration. These AEs included acute myocardial infarction (n = 1), heart failure with reduced LVEF (n = 3), and valvular heart disease (n = 2). Five of the 6 patients had a history of cardiovascular risk factors or disease. Myocardial biopsies in 2 of the patients showed cardiomyocyte hypertrophy and lipofuscin deposition. In 36 patients assessed with serial LVEF, LVEF declined from 69.4 ± 4.2% to 63.4 ± 10.5% with osimertinib therapy (p < 0.001). CTRCD occurred in 4 patients with a nadir LVEF of 40.3 ± 9.1% with osimertinib. CONCLUSIONS: In this retrospective cohort analysis, the incidence of cardiac AEs in patients treated with osimertinib was 4.9%. Additional prospective data collected from patients with NSCLC treated with osimertinib will be important in understanding the incidence, pathophysiology, and management of cardiac AEs with osimertinib.

Fracture of a Retrievable Inferior Vena Cava Filter Placed for Cancer-associated Thrombosis in a Patient with Malignant Lymphoma.

Venous thromboembolism occurs in prothrombotic states, such as malignancy. To prevent fatal pulmonary thromboembolism, an indwelling inferior vena cava (IVC) filter is considered in addition to anticoagulation therapy. We herein report a case of fracture of a retrievable IVC filter in a malignant lymphoma patient. One of the filter arms was fractured and fixed to the IVC wall after one year. Since dislocation of the fractured arm was assessed correctly using three-dimensional computed tomography, we were able to retrieve the main body of the IVC filter successfully. Indications and management of IVC filter fracture should be discussed.

Single-drug approach with rivaroxaban: A case of successful anticoagulation against cancer-associated thrombosis.

We report a patient with pulmonary embolism and deep vein thrombosis induced by cancer chemotherapy who received successful anticoagulation using a single-drug approach with rivaroxaban. Cancer-associated thrombosis (CAT) is a leading cause of non-cancer death in patients with cancer, which is induced by cancer itself and/or chemotherapy agents including cisplatin and gemcitabine. By contrast, hemorrhagic state is another feature of advanced cancer. In these opposite conditions of cancer patients, CAT have to be controlled by appropriate anticoagulation. This case shows potential for single-drug approach with rivaroxaban and direct oral anticoagulants being effective and safety strategy against CAT. .

Oral Anticoagulants in Japanese Patients with Atrial Fibrillation and Active Cancer.

Objective Oral anticoagulants (OACs), which include direct oral anticoagulants (DOACs) and warfarin, are widely used for the prevention of thromboembolic events in patients with atrial fibrillation (AF). Cancer is associated with a prothrombotic state as well as an increased bleeding risk. Few data are available on the efficacy and safety of OACs in Japanese cancer patients with AF. We sought to investigate the efficacy and safety of OACs in this population. Methods This retrospective cohort study included active cancer patients in whom AF was recorded by electrocardiography in our hospital from January 2014 to December 2016 and who were treated with DOACs or warfarin. Patients were followed for 1 year. The study outcomes were stroke or systemic embolism and major bleeding. Result A total of 224 patients with AF and active cancer were treated with OACs (DOACs, n=127; warfarin, n=97). Overall, stroke or systemic embolism and major bleeding occurred in seven (3.8%/year) and eight (4.9%/year) patients, respectively. Stroke or systemic embolism occurred in three patients in the DOAC group (2.8%/year) and four patients in the warfarin group (5.4%/year). Major bleeding occurred in four patients in the DOAC group (4.0%/year) and four patients in the warfarin group (6.5%/year). Conclusion The rates of stroke or systemic embolism and major bleeding events were not negligible among Japanese cancer patients with AF receiving OACs. Further investigations on the optimal management of Japanese patients with AF and cancer are needed.