Edoxaban for 12 Versus 3 Months in Cancer-associated Isolated Distal Deep Vein Thrombosis According to Different Doses: Insights from the ONCO DVT study.

BACKGROUND: The ONCO DVT study revealed the superiority of 12-month relative to 3-month edoxaban treatment for cancer-associated isolated distal deep vein thrombosis (DVT) regarding the thrombotic risk. METHODS: In this pre-specified subgroup analysis of the ONCO DVT study, we stratified the patients into those with a standard edoxaban dose (60 mg/day; N=151) and those with a reduced edoxaban dose (30 mg/day; N=450) and evaluated the clinical outcomes for the 12-month and 3-month treatments. RESULTS: The cumulative 12-month incidence of symptomatic recurrent venous thromboembolism was lower in the 12-month than 3-month group for both the 60 mg (1.3% vs. 11.6%, P=0.02; odds ratio [OR], 0.12; 95% CI, 0.01-0.97) and 30 mg (1.1% vs. 7.6%, P=0.002; OR, 0.14; 95% CI, 0.03-0.60) edoxaban subgroups, which was consistent across the edoxaban doses without a significant interaction (P =0.90). The 12-month cumulative incidence of major bleeding was higher in the 12-month group than 3-month group for the 60 mg edoxaban subgroup (14.3% vs. 4.4%, P=0.046; OR, 3.61; 95% CI, 0.97-13.52), whereas it did not significantly differ between the two groups for the 30 mg edoxaban subgroup (8.7% vs. 8.6%, P=0.89; OR, 0.97; 95% CI, 0.49-1.91), signaling there was a potential interaction (P=0.07). CONCLUSIONS: A 12-month edoxaban regimen for cancer-associated isolated distal DVT was consistently superior to a 3-month regimen, across the edoxaban doses for the thrombotic risk. However, caution was suggested for the standard dose of edoxaban due to the potential for an increased risk of bleeding with prolonged anticoagulation therapy.

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.

The impact of renal function on clinical outcomes of patients with cancer-associated isolated distal deep vein thrombosis: Insights from the ONCO DVT study.

BACKGROUND: The multicenter, open-label, randomized clinical trial ONCO DVT compared 3-month and 12-month edoxaban treatment regimens for isolated distal deep vein thrombosis (DVT) and suggested potential benefits of prolonged edoxaban treatment in terms of thrombotic risk. However, the risk-benefit balance of prolonged edoxaban treatment in patients with renal function remains unclear. OBJECTIVES: To compare the safety and efficacy of 3-month and 12-month edoxaban treatment regimens in patients with cancer-associated isolated distal DVT and different renal functions. METHODS: This pre-specified subgroup analysis of the ONCO DVT study included 601 patients divided into subgroups according to renal function using a 50 mL/min creatinine clearance (Ccr) cutoff. The primary endpoint was symptomatic recurrent venous thromboembolism (VTE) and VTE-related death at 12 months and the major secondary endpoint was major bleeding at 12 months. RESULTS: Among the 601 patients, 131 (21.8 %) comprised the renal dysfunction subgroup. The primary endpoint occurred in 6 (9.7 %) and 1 (1.4 %) patients in the 3-month and 12-month edoxaban groups in the renal dysfunction subgroup, respectively, and in 16 (6.6 %) and 2 (0.9 %) patients in the no renal dysfunction subgroup, respectively. The major secondary endpoint occurred in 9 (14.5 %) and 7 (10.1 %) patients in the 12-month and 3-month edoxaban groups in the renal dysfunction subgroup, and in 13 (5.3 %) and 21 (9.3 %) patients in the no renal dysfunction subgroup, respectively. CONCLUSIONS: A 12-month edoxaban regiment was superior to a 3-month treatment in terms of thrombotic risk irrespective of renal function. A higher bleeding risk was not identified in patients with renal dysfunction who received prolonged edoxaban treatment.

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.

Edoxaban for 12 Months Versus 3 Months in Patients With Cancer With Isolated Distal Deep Vein Thrombosis (ONCO DVT Study): An Open-Label, Multicenter, Randomized Clinical Trial.

BACKGROUND: The optimal duration of anticoagulation therapy for isolated distal deep vein thrombosis in patients with cancer is clinically relevant, but the evidence is lacking. The prolonged anticoagulation therapy could have a potential benefit for prevention of thrombotic events; however, it could also increase the risk of bleeding. METHODS: In a multicenter, open-label, adjudicator-blinded, randomized clinical trial at 60 institutions in Japan, we randomly assigned patients with cancer with isolated distal deep vein thrombosis, in a 1-to-1 ratio, to receive either a 12-month or 3-month edoxaban treatment. The primary end point was a composite of a symptomatic recurrent venous thromboembolism (VTE) or VTE-related death at 12 months. The major secondary end point was major bleeding at 12 months, according to the criteria of the International Society on Thrombosis and Haemostasis. The primary hypothesis was that a 12-month edoxaban treatment was superior to a 3-month edoxaban treatment with respect to the primary end point. RESULTS: From April 2019 through June 2022, 604 patients were randomized, and after excluding 3 patients who withdrew consent, 601 patients were included in the intention-to-treat population: 296 patients in the 12-month edoxaban group and 305 patients in the 3-month edoxaban group. The mean age was 70.8 years, 28% of the patients were men, and 20% of the patients had symptoms of deep vein thrombosis at baseline. The primary end point of a symptomatic recurrent VTE event or VTE-related death occurred in 3 of the 296 patients (1.0%) in the 12-month edoxaban group and in 22 of the 305 patients (7.2%) in the 3-month edoxaban group (odds ratio, 0.13; 95% CI, 0.03-0.44). The major secondary end point of major bleeding occurred in 28 of the 296 patients (9.5%) in the 12-month edoxaban group and in 22 of the 305 patients (7.2%) in the 3-month edoxaban group (odds ratio, 1.34; 95% CI, 0.75-2.41). The prespecified subgroups did not affect the estimates on the primary end point. CONCLUSIONS: In patients with cancer with isolated distal deep vein thrombosis, 12 months was superior to 3 months for an edoxaban treatment with respect to the composite outcome of a symptomatic recurrent VTE or VTE-related death. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03895502.

Cardiovascular Complications Associated with Contemporary Lung Cancer Treatments.

OPINION STATEMENT: Lung cancer is the most common form of cancer in humans and the leading cause of cancer-related death worldwide. Traditionally, lung cancer has been diagnosed as either small cell lung cancer (SCLC) or non-small cell lung cancer (NSCLC). However, recent developments in molecular pathology have revolutionized the diagnosis and treatment of the disease, thus improving patient prognosis and increasing the number of survivors. In advanced NSCLC cases, molecularly targeted drugs for patients with positive driver gene mutation/rearrangement, and immune checkpoint inhibitors for those with a positive biomarker, have changed the standard of care. SCLC is a highly malignant entity. In addition to the chemotherapy and radiotherapy, immune checkpoint inhibitors have recently provided some hope for extended-stage SCLC. Smoking cessation is related to decreased morbidity. However, early metastasis remains a significant challenge. Recently, cancer therapy-related cardiovascular disease (CTRCD) has emerged as diverse pathophysiology, including fulminant myocarditis, fatal arrhythmia, pericarditis, hypertension, and thrombosis, that emerged with modern lung cancer therapies. Cardio-oncology is a new interdisciplinary collaboration to develop methodologies to manage cardiovascular risk factors and CTRCDs with the common goal of minimizing unnecessary interruption of cancer treatment and maximizing outcomes of lung cancer survivors.

Advantages and challenges for noninvasive atrial fibrillation ablation.

PURPOSE: Although catheter ablation is an effective therapy for atrial fibrillation (AF), risks remain and improved efficacy is desired. Stereotactic radiotherapy is a well-established therapy used to noninvasively treat malignancies with precision. We sought to evaluate stereotactic arrhythmia radioablation (STAR) as a therapeutic option for treating AF. METHODS AND RESULTS: Three cancer patients with drug refractory AF were enrolled. Planning software using 3-D CT of the left atrium was used to design a desired ablation volume encompassing antral circumferential pulmonary vein isolation, roof and floor lines to create a "box" lesion set. After planning, patients were treated in the radioablation suite. STAR was able to deliver the intended radiation dose to the target in all 3 patients. No complications were observed over a follow-up period of 24 months. One patient with paroxysmal AF died from deterioration of cancer. The autopsy revealed evidence of fibroblasts and fibrogenesis in the region of atrial tissues targeted with radioablation. In one of these patients, left atrial posterior wall electrograms recorded from the esophagus before and 3 months after STAR indicated successful electrical isolation. CONCLUSIONS: This is the first report of non-invasive radioablation of the left atrium with demonstration of successful electrical isolation. Although STAR may be safe and effective in delivering ablative energy to the left atrium, further evaluation is warranted regarding effectiveness.

A Simple Formula for Predicting the Maintenance Dose of Warfarin with Reference to the Initial Response to Low Dosing at an Outpatient Clinic.

Objective The pharmacodynamic effect of warfarin varies among individuals, and its maintenance dose is widely distributed. Although many formulae for predicting the maintenance dose of warfarin have been developed, most of them are complex and not in practical use. Methods and Materials Among 12,738 new patients visiting the Cardiovascular Institute between 2004 and 2009, we identified 127 patients (66.6±8.8 years, 89 men) with atrial fibrillation for whom warfarin was newly started with an initial dose of 2 mg/day and the international normalized ratio (INR) at 1 year after warfarin was started was within the therapeutic range. The prediction models for the maintenance dose were developed by an exponential equation and a first-order equation. Results The initial response of the INR to the dose of 2 mg/day (initial INR) ranged from 1.00-3.24 (mean 1.43), while the maintenance dose of warfarin ranged from 0.5-14 mg (mean 3.8 mg). The maintenance dose showed an exponential correlation to the initial INR: (predicted maintenance dose) =5.522× (initial INR) -1.556 (R2=0.795, p<0.001). Excluding the patients with a poor response to the initial dose (initial INR <1.1, n=32) permitted a simple correlation with a first-order approximation: (predicted maintenance dose) =-2.009× (initial INR) +6.172 (R2=0.706, p<0.001). Conclusion We developed a simple formula for predicting the maintenance dose of warfarin using the initial response of the INR to low-dose warfarin.

Prospective Registry of Rivaroxaban Management of Cancer-Associated Venous Throboembolism (PRIMECAST) Study.

Background: The incidence of thromboembolism in patients with cancer is approximately 11%, and the risk of thrombosis in patients with malignant tumors is 6-fold higher than that in healthy persons. Thrombosis not only disrupts the treatment of cancer but also induces deterioration of quality of life (QOL). Knowledge about thrombus treatment is limited, and evidence is scarce. Clarification of the status and safety of venous thromboembolism (VTE) treatment in patients with cancer will contribute to active intervention and improvement of prognosis and QOL. In this study, the therapeutic effects of a non-vitamin K antagonist oral anticoagulant for VTE and the prognosis of cancer after treatment will be examined to establish a therapeutic method for VTE in patients with cancer. Methods and Results: A multicenter, non-interventional, observational study will be conducted in patients with cancer who developed VTE and underwent anticoagulant therapy with rivaroxaban (group A) or warfarin (group B) for 24 weeks. The primary endpoint will be the recurrence/aggravation of symptomatic VTE or occurrence/aggravation of deep vein thrombosis. Registration of 500 patients is needed in order to calculate the 95% confidence interval of the event rate at ±1% precision. Conclusions: The investigation period will run from January 2019 to December 2023 with ongoing selection of patients. Trial registration: no. 5-18-32 (approved 1 August 2018).

Improvement in karyomegalic interstitial nephritis three years after ifosfamide and cisplatin therapy by corticosteroid.

Long-term nephrotoxicity of ifosfamide is occasionally progressive, and, in such case, there has been no specific treatment to prevent progression. It has been reported that the presence of karyomegalic interstitial nephritis, which is rare type of interstitial nephritis, may be related to ifosfamide-induced nephropathy with poor prognosis and resistant to the immunosuppressive therapy. A 15-year-old boy presented with progressive nephrotoxicity 3 years after systemic chemotherapy with ifosfamide and cisplatin for the treatment of osteosarcoma. Renal biopsy revealed the severe tubulointerstitial nephritis with tubular atrophy and focal global and segmental glomerular sclerosis. It also showed tubular epithelial cells with variably sized nuclei, some of which were massively enlarged, abnormal hyperchromatic, irregular shaped, and bizarre-appearing. These morphological changes were suggestive of the histology of karyomegalic interstitial nephritis. Corticosteroid retarded the progression of nephrotoxicity. The present case is the first report, suggesting that corticosteroid was effective against the late-onset renal toxicity by ifosfamide therapy. Our case also suggests that karyomegalic interstitial nephritis may be the result of long-term nephrotoxicity of ifosfamide. Since concurrent treatment with cisplatin is one of the risk factors for ifosfamide nephrotoxicity, there is a possibility that cisplatin may have a synergetic effect with ifosfamide for producing karyomegalic interstitial nephritis.

[Complete remission of repeated recurrent membranous nephropathy after non-myeloablative allogeneic peripheral blood stem cell transplantation].

A 64-year-old man with treatment-related myelodysplastic syndrome (MDS) underwent non-myeloablative allogeneic peripheral blood stem cell transplantation from a fully HLA-matched sibling. Seven months after transplantation, he suffered from nephrotic syndrome (proteinuria 16.67 g/day) around two weeks atter tapering tacrolimus (TAC) for the prophylaxis of graft-versus-host disease(GVHD). A renal biopsy revealed membranous nephropathy (Stage I ). Treatment with prednisolone (PSL), starting with 50 mg daily, resulted in incomplete remission type I. Although remission was maintained for 7 months, nephrotic syndrome recurred (proteinuria 7.81 g/day)after tapering PSL(5 mg/day) (18 months after transplantation). His PSL dose was increased again to 50 mg daily, and proteinuria improved again. Two weeks after discontinuation of TAC as it was suspected of worsening his renal function, proteinuria increased again to 6.37 g/day (21.5 months after transplantation). After administration of cyclosporin A (CsA) (30 mg/day) instead of TAC, proteinuria re-improved and complete remission of nephrotic syndrome was achieved. In this case, nephrotic syndrome worsened twice just after tapering or discontinuing immunosuppressive medication, and reinforcement of immunosuppression was effective in improving proteinuria. As hematopoietic cell transplantation (HCT) is an increasingly common treatment worldwide, the opportunities to see patients with nephrotic syndrome after HCT are also increasing. Our case serves as a reference to manage the recurrence of nephrotic syndrome after HCT.

Electrocardiography characteristics of isolated non-compaction of ventricular myocardium in Japanese adult patients.

BACKGROUND: Isolated non-compaction of ventricular myocardium (INVM) is characterized by persistent embryonic myocardial morphology without other cardiac anomalies. Congestive heart failure, critical arrhythmias, and systemic thromboemboli are known as major manifestations during childhood. Recently it was reported that there are some patients who seem apparently healthy in adult INVM. Clinical characteristics including that for electrocardiograms (ECG) of adult INVM, however, are unknown for Japanese subjects. METHODS AND RESULTS: From 24,082 patients who underwent echocardiography between June 2000 and June 2007, 187 patients (0.78%, 41.3+/-16.8 years, 122 male) were identified as having INVM according to the criteria proposed by Oechslin et al. Although fatal ventricular arrythmias and thromboembolic events occurred in 2 patients and in 1 patient, respectively, the rest had no severe cardiac complications. Normal ECG findings were found only in 24.6% of the patients. Most of the ECG abnormalities, however, were non-specific: ST-T changes in 35.2% and bundle branch block in 14.9%. Notably, Brugada-like ECG was frequently seen in the present Japanese INVM patients (3.2%). The incidence of these ECG findings was not dependent upon the extent of non-compaction. CONCLUSIONS: The prevalence and ECG findings of adult Japanese INVM patients in a hospital-based clinical practice have been identified.

Dynamic narrowing of left ventricular outflow tract-Possible mechanism of latent left ventricular outflow tract obstruction.

It has been reported that left ventricular outflow tract (LVOT) obstruction can be provoked in patients even without significant left ventricular hypertrophy. We experienced a 74-year-old man with mild degree of left ventricular hypertrophy and latent LVOT obstruction which was successfully treated by alcohol septal ablation. LVOT was not narrow at end-diastole, but proximal septum was protruding further into LVOT during the ejection period, producing a dynamic narrowing of the LVOT. Alcohol septal ablation did not reduce the interventricular septal thickness nor enlarge LVOT. However, it limited the excursion of proximal septum. The effect of the treatment suggested the importance of the dynamic nature of LVOT in the mechanism of latent LVOT obstruction in this case.

A 10-year retrospective review of airline transport pilots aged 60 to 63 in Japan.

BACKGROUND: On May 14, 1991, the Japanese Ministry of Transport issued an official notice allowing medically certified airline transport pilots aged 60 to 63 yr old (aged pilot) to work on non-scheduled flights. Since September 24, 1996, the official notice was revised to allow them to work on scheduled flights. The regulation requires pilots to pass both routine and additional aviation medical examinations. METHOD: Ten years have passed since the first regulation, so the medical records and the present status of aged pilots were reviewed and summarized. RESULTS: By the end of October 2000, 159 pilots had undergone their first additional examination. Two pilots failed due to coronary ischemia, two due to brain infarction, and one due to complete right bundle branch block (CRBBB) on ECG. One pilot failed the examination at the age of 62 due to coronary ischemia and another at the age of 62.5 due to atrial fibrillation. Thirteen pilots retired prior to the age of 63 for unknown reasons. At the time of review, 44 pilots had reached the age of 63 and retired. Subsequent flight time as aged pilot was 83,872 h in total (617 +/- 483 h; mean +/- SD) with monthly flight time of 41 +/- 27 h. Japan Aircraft Accident Investigation Commision reported 323 accidents, including 27 airtransport accidents in the past 10 yr. There were no accidents involving any of the aged pilots. CONCLUSION: The review suggests that the aged pilots who are deemed medically qualified by the official notice criteria are flying safely without mishap incidence.