Home Treatment for Active Cancer Patients With Low-Risk Pulmonary Embolism　- A Predetermined Companion Report From the ONCO PE Trial.

BACKGROUND: Patients with appropriately selected low-risk pulmonary embolism (PE) can be treated at home, although it has been controversial whether applies to patients with cancer, who are considered not to be at low risk.Methods and Results: The current predetermined companion report from the ONCO PE trial evaluated the 3-month clinical outcomes of patients with home treatment and those with in-hospital treatment. The ONCO PE trial was a multicenter, randomized clinical trial among 32 institutions in Japan investigating the optimal duration of rivaroxaban treatment in cancer-associated PE patients with a score of 1 using the simplified version of the Pulmonary Embolism Severity Index (sPESI). Among 178 study patients, there were 66 (37%) in the home treatment group and 112 (63%) in the in-hospital treatment group. The primary endpoint of a composite of PE-related death, recurrent venous thromboembolism (VTE) and major bleeding occurred in 3 patients (4.6% [0.0-9.6%]) in the home treatment group and in 2 patients (1.8% [0.0-4.3%]) in the in-hospital treatment group. In the home treatment group, there were no cases of PE-related death or recurrent VTE, but major bleeding occurred in 3 patients (4.6% [0.0-9.6%]), and 2 patients (3.0% [0.0-7.2%]) required hospitalization due to bleeding events. CONCLUSIONS: Active cancer patients with PE of sPESI score=1 could be potential candidates for home treatment.

Myocarditis associated with immune-checkpoint inhibitors diagnosed by cardiac magnetic resonance imaging.

Myocarditis associated with immune-checkpoint inhibitors (ICIs) is a rare, but critical adverse event. Although endomyocardial biopsy (EMB) is the standard for diagnosis of myocarditis, there is a possibility of false negatives due to sampling errors and local nonavailability of EMB, which may hamper the appropriate diagnosis of myocarditis. Therefore, an alternative criterion based on cardiac magnetic resonance imaging (CMRI) combined with clinical presentation has been proposed, but not emphasized sufficiently. We report a case of myocarditis after ICIs administration, which was diagnosed using CMRI in a 48-year-old male with lung adenocarcinoma. CMRI provides an opportunity to diagnose myocarditis during cancer treatment.

Epidemiological Study Regarding the Incidence of Venous Thromboembolism in Patients After Cancer Remission.

INTRODUCTION: The time course of reduction in the risk of venous thromboembolism (VTE) in patients who were diagnosed with cancer, treated with anticancer therapy, and in remission is unclear. We hypothesized that the risk of VTE will decrease over time after cancer remission. METHODS: We conducted a retrospective analysis using claims data for cancer remission in Japan. Background information of patients who developed VTE after cancer remission was collected, and the VTE incidence rate after cancer remission was analyzed. Subgroup analysis based on VTE history, cancer type, and the presence or absence of surgery during hospitalization was conducted. RESULTS: A total of 638,908 patients were eligible for the analysis. VTE occurred in 5533 of 638,908 cases, pulmonary embolism occurred in 779 cases, and deep vein thrombosis occurred in 5084 cases after cancer remission. The mean age of patients who developed VTE was 70.1 ± 12.5 years, and the proportion of men was 47.5%. All comorbidities and medications were higher in the VTE group (P < 0.001) than in the non-VTE group after cancer remission. The incidence of VTE was 2.4% per year in the first 30 days, 1.35% per year in 31-60 days, and gradually decreased to 0.48% per year in 181-360 days, becoming almost constant (annual rate 0.3%) 2 years after cancer remission. CONCLUSION: Risk of developing VTE decreased to the same level as that in patients without cancer 2 years after cancer remission. Although the guidelines do not specify the duration of anticoagulant prophylaxis for new onset or recurrent VTE after cancer remission and the appropriate duration of such prophylaxis may vary depending on VTE risk factors, determining the period of high risk of VTE for each patient and preventing VTE is considered important.

Relevance of Non-Bridging Therapy with Heparin during Temporary Interruption of Direct Oral Anticoagulants in Patients with Cancer-Associated Venous Thromboembolism.

Objectives: To evaluate the relevance of non-bridging therapy with unfractionated heparin during the temporary, pre-procedural interruption of direct oral anticoagulants (DOACs) in patients with cancer-associated venous thromboembolism (VTE). Materials and Methods: This retrospective study included 142 patients with cancer and VTE who required temporary interruption of DOACs before invasive procedures. Data, including rates of VTE recurrence, non-major bleeding, and major bleeding, were compared between patients who received or not received alternative therapy with unfractionated heparin during interruption. Results: Sixty-eight patients were prescribed heparin, while 74 were not. There were no differences in age, body mass index, white blood cell count, hemoglobin level, or platelet count between the groups. VTE recurrence was observed in four (6%) and one (1%) patient in the heparin bridging and non-bridging groups, respectively (risk ratio [RR]: 4.4, 95% confidence interval [CI]: 0.50-38.0, p=0.19). Non-major bleeding occurred in three (4%) and two (3%) patients in the bridging and non-bridging groups (RR: 1.6, 95%CI: 0.28-9.48, p=0.67), while major bleeding occurred in 0 (0%) and three patients (4%) (p=0.25), respectively. Conclusion: Our findings confirm the relevance of non-bridging therapy with unfractionated heparin for reducing VTE risk during DOAC interruption in patients with cancer.

Effective collaboration between hematologists and cardiologists facilitated successful control of reversible dasatinib-related pulmonary arterial hypertension and treatment-free remission of chronic myeloid leukemia: a case report.

The BCR-ABL1 tyrosine kinase inhibitor dasatinib is effective in chronic myeloid leukemia (CML) treatment. The major known adverse effects of dasatinib include pleural effusion and pulmonary arterial hypertension (PAH); however, the underlying mechanisms remain unclear. This case report describes a two-step dasatinib dose reduction decided by multi-disciplinary collaboration between cardiologists and hematologists for the management of PAH that led to treatment-free remission (TFR), suggesting an important improvement in the field. Herein, a 43-year-old woman with CML was administered 100 mg of dasatinib daily as a first-line therapy from May 2014. There were no evident abnormalities on her electrocardiogram and transthoracic echocardiography (TTE) charts before she started taking dasatinib. She developed leg edema in June 2015, and the TTE showed a high transtricuspid pressure gradient value. Based on these findings, we diagnosed PAH and right-sided heart failure due to dasatinib. However, since it was confirmed that the molecular response (MR4.5) (International Scale: BCR-ABL1IS ≤ 0.0032%) was sustained, the hematologist decided to reduce the dasatinib dose to 70 mg after thorough deliberations with the cardiologists. After the dose reduction, the PAH improved immediately; however, it was observed again in 2017, which improved with a second dose reduction to 50 mg. Additionally, cardiovascular drug therapy was initiated. The PAH was exacerbated again in 2018 with sustained MR4.5. Hence, we decided to discontinue dasatinib as the MR4.5 had been sustained over 4 years. After the discontinuation of dasatinib, PAH improved again, and near MR4.0 (BCR-ABL1IS ≤ 0.01%) level has been sustained for several years now. Thereafter, no apparent deterioration in PAH was observed. We present a case of reversible dasatinib-induced PAH. Successful management of recurrent PAH was possible with several dose reductions, and TFR was achieved. This was partly due to effective collaboration between the hematologists and cardiologists. If needed, dose reduction as a treatment strategy may be considered before discontinuing dasatinib.

Assessment of Pazopanib-Related Heart Failure in Patients With Advanced Soft Tissue Sarcoma　- A Single Institute Analysis.

BACKGROUND: Heart failure (HF) is one of the potential adverse events of pazopanib treatment for soft tissue sarcoma (STS), but detailed reports of such HF cases are scarce. This study determined the incidence and risk factors of HF following pazopanib treatment for STS at our Institute and the clinical outcomes.Methods and Results:This study retrospectively analyzed the cases of STS patients treated with pazopanib (n=151) between 2012 and 2020. HF occurred in 6 patients (3.9%) at the median onset of 137 (range 14-468) days after the treatment initiation. When their HF was diagnosed, pazopanib was interrupted in all 6 patients. No patients experienced HF-related death, and HF development was not a significant factor for poor overall survival. The cumulative doses of anthracyclines (>225 mg/m2) before pazopanib initiation (83% vs. 37%, P=0.031), pazopanib initiation at age ≥60 years (83% vs. 35%, P=0.026), and the baseline B-type natriuretic peptide (BNP) concentration (≥50 pg/mL) before pazopanib (67% vs. 11%, P=0.002) initiation were predictive factors for post-pazopanib treatment HF. CONCLUSIONS: The study findings highlight the effect of past anthracycline exposure and baseline BNP for pazopanib-associated HF. Although the study patients' clinical outcomes were generally favorable, periodic monitoring of cardiac function using ultrasonic echocardiography or serum markers is essential to detect events early and begin therapeutic intervention appropriately under a cardiologist's instructions.

Myocardial dysfunction caused by abemaciclib: a case report.

A 68-year-old female patient with metastatic breast cancer presented 12 weeks after starting chemotherapy with abemaciclib and fulvestrant with breathlessness, peripheral edema, and weight gain. Brain natriuretic peptide (BNP) and troponin I levels were raised above normal, and chest radiography revealed an increase in the cardiothoracic ratio from 47% before chemotherapy to 55%. The transthoracic echocardiogram showed a reduction in left ventricular ejection fraction from 76% before chemotherapy to 68%. Contrast-enhanced cardiac magnetic resonance imaging (MRI) revealed delayed accumulation in the interventricular septum. Under the diagnosis of abemaciclib-induced myocardial dysfunction and heart failure, abemaciclib was discontinued, and enalapril and furosemide were started. Two months later, imaging revealed a cardiothoracic ratio of 47% with a left ventricular ejection fraction of 73%. A cardiac MRI after three months was normal. This case report demonstrates that cardiac dysfunction caused by abemaciclib is reversible if detected early and treated appropriately.

A Rare Case of Reversible Cardiac Dysfunction Associated with Tegafur/Gimeracil/Oteracil (S-1) Therapy.

For the past 20 years, S-1 has been used in the treatment of many types of cancer. However, the clinical importance of myocardial dysfunction attributed to S-1 remains to be unclear. Thus, in this study, we report on a patient with myocardial dysfunction associated with S-1.S-1 postoperative chemotherapy for gastric cancer was included as a treatment for a 65-year-old man. On day 8, S-1 treatment was discontinued after the patient developed an oral ulcer. He was then admitted to the hospital because of diarrhea caused by S-1. At approximately the same time, he developed dyspnea, and his chest X-rays revealed perihilar vascular engorgement and cardiac enlargement. Although his brain natriuretic peptide was 595.8 pg/mL, troponin I and creatine phosphokinase were unremarkable. Electrocardiograms showed no change in atrial fibrillations or new ST-T wave change. As per his transthoracic echocardiogram, noted were expansion of the left ventricle, global hypokinesis, and reduced left ventricular ejection fraction (approximately 40%). The patient was then diagnosed with S-1-related myocardial dysfunction. Furosemide, human atrial natriuretic peptide, dobutamine, enalapril, spironolactone, and bisoprolol were administered. Thirteen days after being diagnosed with heart failure, his symptoms disappeared, his echocardiogram showed that the left ventricular ejection fraction had increased to 65%, and the cardiothoracic ratio improved to 47% according to his chest X-rays.S-1-related myocardial dysfunction may be reversible, as it can improve after approximately 2 weeks.

Cardiotoxicities of 5-Fluorouracil and Other Fluoropyrimidines.

OPINION STATEMENT: Fluoropyrimidine (FP) is used to treat a wide range of cancers; however, it is associated with drug-induced vascular toxicity, as well as angina pectoris and coronary spasm. FP has been administered for many years, although the incidence, mechanisms, and appropriate methods for managing its associated cardiovascular toxicities have not been clarified, and the management of these complications has not been standardized. This lack of evidence is not limited to FP. Many trials of anticancer agents have been conducted, excluding patients with heart diseases. Hence, there is a paucity of epidemiological data on cardiovascular adverse events caused by anticancer agents. There have been remarkable improvements in cancer treatment in recent years, with consequent improvements in prognosis. In this context, new cardiovascular toxicities related to new drugs have emerged. We are now compelled to respond to cardiovascular adverse events despite the lack of evidence regarding optimal management. The result has been establishment and rapid maturation of the new academic field of cardio-oncology. Despite the relative lack of evidence, we must review small pieces of evidence that have accumulated to date and make the utmost efforts to provide patients with effective evidence-based medical care. Simultaneously, we urgently need randomized clinical trials to build strong evidence.

Identification of risk factors for venous thromboembolism and evaluation of Khorana venous thromboembolism risk assessment in Japanese lung cancer patients.

BACKGROUND: The reported incidence of venous thromboembolism (VTE) in cancer patients is 4-20%. The Khorana VTE risk score (KRS) and the Vienna VTE risk score (VRS) have been proposed as scoring models for evaluation of cancer-associated VTE. However, the risk factors of VTE in Japanese lung cancer patients have not been clarified. METHODS: This retrospective study included 682 hospitalized Japanese patients with newly diagnosed lung cancer who were examined for VTE on admission between January 2014 and December 2016. RESULTS: Seventy-one (10.4%) of the 682 patients were diagnosed with VTE. Multivariate logistic regression analysis showed that body mass index (BMI) ≥25 kg/m2 (OR, 2.02; 95% CI, 1.06-3.72), white blood cell (WBC) count >11 × 109/L (OR, 2.31; 95% CI, 1.11-4.61), pre-chemotherapy serum D-dimer concentration ≥1.44 µg/mL (OR, 2.73; 95% CI, 1.49-4.99), and non-small cell lung cancer (OR, 3.13; 95% CI, 1.32-9.23) were significantly associated with VTE in these patients. The cut-off values for BMI, WBC count, and D-dimer concentration determined using receiver operating characteristic curves were 25.4 kg/m2, 11.2 × 109/L, and 1.95 µg/mL, respectively. CONCLUSIONS: In this study, we were able to identify four independent risk factors for cancer-associated VTE in Japanese lung cancer patients for the first time. Moreover, we showed that a cut-off level of ≥25 kg/m2 for BMI was a risk factor for VTE in this cohort.

[Effects of Seven Tyrosine Kinase Inhibitors on the Anticoagulation Activity of Warfarin].

Several studies have reported increased anticoagulation effect of warfarin(WF)when combined with tyrosine kinase inhibitors(TKIs), such as gefitinib and erlotinib. However, effects of TKIs other than gefitinib and erlotinib on the anticoagulation effect of WF have not been clarified. To assess the degree and onset of prothrombin time-international normalized ratio (PT-INR)elevation and changes in WF daily doses in patients additionally receiving TKIs, this retrospective, single-center observational study compared PT-INR values and WF daily doses during WF treatment in the absence and presence of TKIs. Seven different TKIs(afatinib, alectinib, axitinib, crizotinib, pazopanib, regorafenib, and vandetanib)were prescribed during treatment with WF of venous thromboembolism in 10 cancer patients. Compared to baseline PT-INR, significant PT-INR elevations were observed in all patients during the combination therapy. The median PT-INR increased 1.6-fold from the baseline in the presence of TKIs(p<0.01), and the onset of PT-INR elevation was observed at a median of 18 days. As all patients receiving WF with the 7 TKIs showed PT-INR elevation, enhancement of the anticoagulation effect of WF in the presence of TKIs appears to be highly frequent. PT-INR should be carefully monitored, and adjusting the WF dosage may become necessary during the WF and TKI combination therapy.

[Effects of Tyrosine Kinase Inhibitors on Control of PT-INR in Patients Receiving Warfarin].

Few studies have evaluated the influence of anticancer drugs on the anticoagulation response to warfarin(WF). This retrospective, single-center, observationalstudy evaluated the changes in prothrombin time-internationalnormal ized ratio (PT-INR)in patients receiving a combination of WF and anticancer drugs. We compared(a)PT-INR changes between groups receiving WF and concomitantly started on either tyrosine kinase inhibitors(TKI)(WF+TKI group: n=14)or anticancer drugs other than TKI(WF+non-TKI group: n=20)and(b)PT-INR changes between groups that were started on WF concomitantly while receiving either TKI(TKI+WF group: n=16)or anticancer drugs other than TKI(non-TKI+WF group: n=13). (a)PT-INR changes were significantly larger in the WF+TKI group than in the WF+non-TKI group(2.23 vs 0.42, p<0.001). In the WF+TKI group, the WF dose was reduced after all 14 patients(100.0%)showed increased PT-INR.(b)PT-INR changes during the WF induction period were significantly larger in the TKI+WF group than in the non-TKI+WF group(2.18 vs 0.68, p<0.001). In the TKI+WF group, the WF dose was reduced after 12 patients(75.0%)showed increased PT-INR. It might be necessary to consider a reduction in WF dose when WF is administered in combination with TKIs.

Drug interactions between tyrosine kinase inhibitors (gefitinib and erlotinib) and warfarin: Assessment of international normalized ratio elevation characteristics and in vitro CYP2C9 activity.

BACKGROUND: Elevation of the international normalized ratio and bleeding complications has been reported in patients taking warfarin concomitantly with tyrosine kinase inhibitors such as gefitinib and erlotinib. OBJECTIVE: To assess the frequency, degree, and onset of international normalized ratio elevation in patients receiving warfarin with gefitinib or erlotinib, and changes in vitro cytochrome P450 2C9 activity. METHODS: This retrospective, single-center, observational study compared international normalized ratio values during the treatment with warfarin in the absence and presence of the tyrosine kinase inhibitors, gefitinib, and erlotinib. In addition, the inhibitory effect of tyrosine kinase inhibitors on cytochrome P450 2C9 activity was screened in an in vitro study. RESULTS: Compared with international normalized ratio at the baseline significant (P < 0.05) international normalized ratio elevations were observed in the majority of the patients (5/6 patients with gefitinib, 83.3%; 6/7 patients with erlotinib, 85.7%) during concurrent therapy. The international normalized ratio was increased 1.8- and 1.6-fold relative to the baseline value, on median, in the presence of gefitinib and erlotinib, respectively, and the onset of international normalized ratio elevation was observed at a median of seven days and nine days, respectively. In vitro (S)-warfarin 7-hydroxylation activity was inhibited by 36% in the presence of 1 µM gefitinib and 27% by 10 µM erlotinib, which are comparable to the steady-state plasma levels of these tyrosine kinase inhibitors after standard dosing. CONCLUSION: In most patients, international normalized ratio elevation was observed within two weeks of the start of concomitant therapy with warfarin and gefitinib or erlotinib. To avoid excessive anticoagulant response by warfarin, international normalized ratio should be carefully monitored weekly and dosage adjustment of warfarin might be recommended during the first month after the start of concurrent tyrosine kinase inhibitor therapy.

A Case of Recurrent Breast Cancer Identified by Pulmonary Tumor Thrombotic Microangiopathy.

Pulmonary tumor thrombotic microangiopathy (PTTM) is a rare, cancer-related, pulmonary complication that causes hypoxia and pulmonary hypertension. We report on a 42-year-old woman who was diagnosed with recurrent breast cancer that was detected due to the presence of PTTM. Eleven months after surgery for heterochronous bilateral cancer of the left breast, she developed progressive dyspnea but computerized tomography showed no pulmonary thromboembolism, and a transthoracic echocardiography revealed mild pulmonary hypertension. She was diagnosed with PTTM by cytology from pulmonary artery catheterization and perfusion lung scintigraphy. Also, the patients complained of back pain after admission, bone scintigraphy showed multiple bone metastases. Despite the early diagnosis of PTTM, her platelet count decreased, her performance status rapidly deteriorated, and her dyspnea worsened. Thus, we could not treat her with chemotherapy. She died due to respiratory failure 19 days after admission. To the best of our knowledge, this is the first report of recurrent breast cancer identified by the manifestation of PTTM. Although PTTM is a rare phenomenon, it should be considered in the differential diagnosis of acute dyspnea or pulmonary hypertension in patients with breast cancer. Furthermore, upon diagnosis, the patient should be referred to a cardiologist as soon as possible.

Insufficient self-care is an independent risk factor for adverse clinical outcomes in Japanese patients with heart failure.

Self-care is a cornerstone for the successful management of heart failure (HF). The purpose of this study was to examine the impacts of HF self-care on prognosis in Japanese patients with HF. A total of 283 HF outpatients (age 64 ± 14, 70% male, 52% HFrEF) were enrolled. We asked patients to answer about their adhevence to 5 self-care behaviors (medication, eating a low-sodium diet, regular exercise, daily weight check, and treatment seeking behavior). On the basis of the results, we classified patients into a good self-care group and a poor self-care group. The primary outcome was HF hospitalization and/or cardiac death. In total, 65% of patients were classified into the poor self-care group. During a median follow-up of 2 years, cardiac events occurred more frequently in the poor self-care group (22% versus 9.6%, P = 0.013). Poor self-care was an independent risk factor for cardiac events in Cox regression analysis adjusted for clinical parameters (hazard ratio = 2.86, P = 0.005). Poor self-care was also associated with an increased number of HF hospitalizations as well as an extended length of hospital stay for HF. Poor knowledge about HF was an independent determinant for poor self-care in multivariate logistic regression analysis (odds ratio = 0.92, P = 0.019). Insufficient self-care is an independent risk factor for cardiac events in Japanese patients with HF.

Successful weaning from the DuraHeart with a low left ventricular ejection fraction.

We report a case in which the DuraHeart (Terumo Heart, Ann Arbor, MI, USA) was successfully removed despite a low ejection fraction. A 33-year-old man who suffered from dilated cardiomyopathy underwent implantation of the DuraHeart. The assist flow decreased to less than 1.0 l/min 3 months after the implantation. Echocardiography demonstrated a low left ventricular ejection fraction (26 %) and left ventricular dilatation (64 mm). Right heart catheterization revealed a cardiac index of 2.9 l/min/m(2) with a DuraHeart flow of 0.7 l/min. The patient underwent DuraHeart explantation without cardiopulmonary bypass. He was stable at 10 months post-explant.

[Mid-long term result of implantable ventricular assist device treatment for end-stage heart failure in the University of Tokyo Hospital].

Two implantable left ventricular assist devices(I-LVADs)were approved in Japan in 2011. I-LVADs were used for end-stage heart failure of 20 patients in our institute until March 2012. We examine the clinical course of these 20 patients who were treated with I-LVADs. End points are transplantation, death, or weaning from I-LVADs. Mean hospital days after I-LVAD implantation were 58.1 days, and all 20 patients could discharge from hospital alive. Until September 2012, mean follow up interval was 515 days. Five patients reached heart transplantation, 2 died, weaning from an I-LVAD could be done in 1 patient, and 12 continued to wait for heart transplantation. Survival rate was 100% at 1 month, 95% at 3 months, and 89% at 1 year, respectively. Mean follow up duration after discharge were 457 days, and 16 patients(80%)needed a total of 41 times of readmission in this period. Freedom from readmission was 75% at 1 month, 60% at 3 months, and 25% at 1 year, respectively. In conclusion, prognosis of I-LVAD treatment was good, but many patients needed readmission after I-LVAD implantation and follow up system for I-LVAD treatment should be improved immediately.