Thrombospondin-1 is an endogenous substrate of cereblon responsible for immunomodulatory drug-induced thromboembolism.

ABSTRACT: Immunomodulatory drugs (IMiDs) are key drugs for treating multiple myeloma and myelodysplastic syndrome with chromosome 5q deletion. IMiDs exert their pleiotropic effects through the interaction between cell-specific substrates and cereblon, a substrate receptor of the E3 ubiquitin ligase complex. Thus, identification of cell-specific substrates is important for understanding the effects of IMiDs. IMiDs increase the risk of thromboembolism, which sometimes results in fatal clinical outcomes. In this study, we sought to clarify the molecular mechanisms underlying IMiDs-induced thrombosis. We investigated cereblon substrates in human megakaryocytes using liquid chromatography-mass spectrometry and found that thrombospondin-1 (THBS-1), which is an inhibitor of a disintegrin-like and metalloproteinase with thrombospondin type 1 motifs 13, functions as an endogenous substrate in human megakaryocytes. IMiDs inhibited the proteasomal degradation of THBS-1 by impairing the recruitment of cereblon to THBS-1, leading to aberrant accumulation of THBS-1. We observed a significant increase in THBS-1 in peripheral blood mononuclear cells as well as larger von Willebrand factor multimers in the plasma of patients with myeloma, who were treated with IMiDs. These results collectively suggest that THBS-1 represents an endogenous substrate of cereblon. This pairing is disrupted by IMiDs, and the aberrant accumulation of THBS-1 plays an important role in the pathogenesis of IMiDs-induced thromboembolism.

A rare case of cardiac myxoma with light bulb-like cystic morphology: a case report.

Background: Cystic myxomas are quite rare. Moreover, few reports have evaluated the causes that constituted them. Case summary: A 73-year-old Asian man presented for pre-operative examination of osteoarthritis, and transthoracic echocardiography (TTE) revealed an incidental intracardiac mass. Therefore, he was referred to our department for further evaluation. He had no specific symptoms or family history related to tumours and heart failure. The TTE showed a 32 × 24 mm spherical mass adherent to the left atrial septum. The upper part of the mass was cystic in formation and hypoechoic inside and resembled a light bulb. Transoesophageal echocardiography showed the feeding arteries flowing from the bottom into the cystic part. In addition, two jet strips drained from the cystic part in the direction of the mitral valve. Coronary angiography revealed the feeding arteries, which consisted mainly of the right coronary artery conus branch and the left circumflex branch, and the blood flowed into the saccular area from the feeding arteries and excreted towards the mitral valve. Surgical resection was performed due to the mobility, and the histopathology confirmed a cystic myxoma. Discussion: We described the unique anatomical formation of a cystic myxoma, which consisted of an exquisite balance between the tumour-feeding arteries and the draining outlet vessels.

Evaluation of coronary flow is useful in patients with left coronary cusp thrombus formation after left ventricular assist device implantation.

Left ventricular assist device (LVAD) is essential for patients with severe heart failure, but there is a risk of thrombus formation on the aortic root and cusps, leading to coronary artery occlusion. Even with the narrowing of the echo-window due to LVAD, careful observation of coronary flow by transthoracic echocardiography can evaluate the patency of coronary flow non-invasively and immediately.

Both New-Onset and Pre-Existing Hypertension Indicate Favorable Clinical Outcomes in Patients Treated With Anti-Vascular Endothelial Growth Factor Therapy.

BACKGROUND: Hypertension is a frequent adverse event caused by vascular endothelial growth factor signaling pathway (VSP) inhibitors. However, the impact of hypertension on clinical outcomes during VSP inhibitor therapy remains controversial.Methods and Results: We reviewed 3,460 cancer patients treated with VSP inhibitors from the LIFE Study database, comprising Japanese claims data between 2016 and 2020. Patients were stratified into 3 groups based on the timing of hypertension onset: (1) new-onset hypertension (n=569; hypertension developing after VSP inhibitor administration); (2) pre-existing hypertension (n=1,790); and (3) no hypertension (n=1,101). Time to treatment failure (TTF) was used as the primary endpoint as a surrogate for clinical outcomes. The median (interquartile range) TTF in the new-onset and pre-existing hypertension groups was 301 (133-567) and 170 (72-358) days, respectively, compared with 146 (70-309) days in the non-hypertensive group (P<0.001 among all groups). In an adjusted Cox proportional hazard model, new-onset (hazard ratio [HR] 0.58; 95% confidence interval [CI] 0.50-0.68; P<0.001) and pre-existing (HR 0.85; 95% CI 0.73-0.98; P=0.026) hypertension were independent factors for prolonged TTF. The TTF of new-onset hypertension was longer than that of pre-existing hypertension (HR 0.68; 95% CI 0.62-0.76; P<0.001). CONCLUSIONS: This study highlighted that new-onset hypertension induced by VSP inhibitors was an independent factor for favorable clinical outcomes. Pre-existing hypertension before VSP inhibitor initiation was also a significant factor.

Decreases of ethanolamine plasmalogen and phosphatidylcholine in erythrocyte are a common phenomenon in Alzheimer's, Parkinson's, and coronary artery diseases.

Decreased plasma levels of plasmalogens in neurodegenerative diseases have been watched with interest. We previously reported the decreases of erythrocyte ethanolamine plasmalogen (PlsPE) of blood not only in Alzheimer's disease (AD) and Parkinson's disease (PD), but also in coronary artery disease (CAD). In the present study, by using the same high-performance liquid chromatography (HPLC) method, we investigated the pattern of changes in the phospholipid composition of erythrocyte membrane in AD, PD and CAD compared with healthy individuals. The common patten of changes among them was as follows: The decrease of erythrocyte PlsPE was accompanied by a decrease of phosphatidylcholine although phosphatidylethanolamine remained unchanged. The decreases of PlsPE and phosphatidylcholine were replaced by an increase of sphingomyelin (SM) in the total phospholipids. The dissociated change between PlsPE and phosphatidylethanolamine (PE) may be caused by the differences in molecular structure or in location in the cell membrane. Such special changes provide another piece of biochemical evidence that these different diseases are caused by identical pathological mechanism, suggesting potential biomarkers for these chronic diseases due to aging.

IMPROVE bleeding score predicts major bleeding in advanced gastrointestinal cancer patients with venous thromboembolism.

BACKGROUND: The incidence of venous thromboembolism has been reported as 20% in cancer patients. Anticoagulation therapy is the standard treatment for venous thromboembolism. On the other hand, bleeding should be carefully managed, because advanced cancer, particularly gastrointestinal cancer, carries a high risk of bleeding. However, the optimal management for cancer-associated thromboembolism remains to be clarified. METHODS: We retrospectively examined patients with advanced gastrointestinal cancer, including gastric cancer and colorectal cancer, who were treated with chemotherapy between 2014 and 2018 for the incidence and characteristics of venous thromboembolism and bleeding. RESULTS: In total, 194 patients (120 men, 74 women) were enrolled in this study. The underlying pathology was gastric cancer in 74 cases and colorectal cancer in 120 cases. Of the 194 patients, 40 patients (20.6%) were diagnosed with venous thromboembolism and 10 patients (5.2%) were diagnosed with concomitant pulmonary thromboembolism. Conversely, bleeding was observed in 29 patients (15%). The location of bleeding was the primary tumor in 17 cases, metastatic tumor in 9 and hemorrhagic gastric ulcer in 3. Within the venous thromboembolism group (n = 40), bleeding was observed in 10 patients (25%). Multivariate analysis showed that International Medical Prevention Registry on Venous Thromboembolism (IMPROVE) bleeding score ≥7 correlated significantly with major bleeding (P = 0.01). In patients with a low risk of bleeding, major bleeding was observed in only three patients. CONCLUSIONS: IMPROVE bleeding score may predict the risk for bleeding in gastrointestinal cancer patients with venous thromboembolism. Selecting patients with a low risk of bleeding using with IMPROVE bleeding score is expected to contribute to the safer management of anticoagulation therapy for cancer-associated thromboembolism.

Case Report: Bronchogenic Cyst in the Right Atrium of a Young Woman.

A 31-year-old woman was referred to our hospital for evaluation of a cardiac mass in the right atrium. Cardiac magnetic resonance imaging indicated a cystic mass filled with fluid accumulation in the right atrium. The mass was identified as a cardiac cyst and was surgically removed. Pathological examination revealed an extremely rare bronchogenic cyst. Bronchogenic cysts are benign congenital abnormalities of primitive foregut origins that form in the mediastinum during embryonic development. There is unusual clinical dilemmas surrounding the treatment plan for cardiac surgery or biopsy of cardiac masses, especially in patients with rare cardiac cysts. The anatomical location of the cyst can be related to various clinical symptoms and complications. In cases of indeterminate cardiac cysts, direct cyst removal without prior biopsy is of utmost importance.

Early-onset cardiac dysfunction following allogeneic haematopoietic stem cell transplantation.

OBJECTIVE: Heart failure following allogeneic haematopoietic stem cell transplantation (allo-HSCT) is a serious complication that requires early detection; however, the clinical implications of early-onset cancer therapy-related cardiac dysfunction (CTRCD) following allo-HSCT remain unclear. We investigated the determinants and prognostic impact of early-onset CTRCD in allo-HSCT recipients. METHODS: The records of 136 patients with haematological malignancies who underwent allo-HSCT at our institute were retrospectively reviewed. Early-onset CTRCD was defined as a decrease in left ventricular ejection fraction (LVEF) of ≥10% and an LVEF of ≤53% within 100 days after HSCT. RESULTS: Early-onset CTRCD was diagnosed in 23 out of 136 included patients (17%), and the median duration from HSCT to CTRCD diagnosis was 24 (9-35) days. Patients were followed up for 347 (132-1268) days. In multivariate logistic regression analysis, cumulative doxorubicin dosage (each 10 mg/m2) and severity of acute graft-versus-host disease (GVHD/grade) were independent indicators of early-onset CTRCD (OR (95% CI) 1.04 (1.00 to 1.07); p=0.032; OR (95% CI) 1.87 (1.19 to 2.95), p=0.004, respectively). The overall and primary disease death rates were significantly higher in allo-HSCT recipients with early-onset CTRCD than in those without early-onset CTRCD (HR (95% CI) 1.98 (1.11 to 3.52), p=0.016; HR (95% CI) 2.96 (1.40 to 6.29), p=0.005, respectively), independent of primary disease type, remission status and transplantation type. CONCLUSIONS: Severe acute GVHD and higher cumulative anthracycline are two significant determinants of early-onset CTRCD. Early-onset CTRCD following allo-HSCT regulates survival in patients with haematological malignancies.

Case Report: Cardiac Tamponade in Association With Cytokine Release Syndrome Following CAR-T Cell Therapy.

Chimeric antigen receptor T (CAR-T) cell therapy has been shown to have substantial efficacy against refractory hematopoietic malignancies. However, it frequently causes cytokine release syndrome (CRS) as a treatment-specific adverse event. Although cardiovascular events associated with CAR-T cell therapy have been increasingly reported recently, pericardial disease is a rare complication and its clinical course is not well characterized. Here, we report a case of acute pericardial effusion with cardiac tamponade after CAR-T cell therapy. Case Summary: A 59-year-old man with refractory diffuse large B-cell lymphoma underwent CAR-T cell therapy. Grade 2 CRS was observed on day 0; it progressed to grade 4 on day 7 and was accompanied by a fever over 39°C, hypoxia requiring intubation, hypotension requiring the use of a vasopressor agent, and supraventricular tachycardia. Although cardiac function was preserved, marked pericardial effusion with the collapse of the right heart was detected on echocardiography. Since pericardiocentesis was considered to have a high complication risk due to severe myelosuppression, medications for CRS were prioritized. Tocilizumab, an interleukin-6 inhibitor, and high-dose methylprednisolone (1 g/day for 3 days) were administered for the management of severe CRS. On day 8, the pericardial effusion decreased, and the hemodynamic status markedly stabilized. CRS did not exacerbate after the steroid dose was reduced. Further, lymphoma size reduced after the induction of CAR-T cell therapy, and tumor regrowth was not noted at 3 months after CAR-T cell infusion. Conclusion: Interleukin-6 pathway inhibitors and corticosteroid therapy should be considered in the context of CRS for significant pericardial effusion after CAR-T cell therapy in the acute phase.

Successful transition from intravenous epoprostenol to oral selexipag and inhaled iloprost in a case of severe pulmonary arterial hypertension associated with systemic lupus erythematosus.

A 25-year-old woman was admitted to our hospital with severe pulmonary arterial hypertension associated with systemic lupus erythematosus (SLE-PAH). Her mean pulmonary arterial pressure was 56 mmHg, and her SLE Disease Activity Index-2 K score was 14 on admission. In addition to a strong immunosuppressive regimen, which included steroid pulse therapy followed by high-dose oral prednisolone (1 mg/kg) and intravenous cyclophosphamide, an upfront combination of vasodilator therapy, including oral tadalafil, macitentan, and intravenous epoprostenol, was administered in the early phase. Two months later, her mean pulmonary arterial pressure was 29 mmHg, and her other haemodynamic markers showed significant improvement. She refused to start life-long intravenous epoprostenol therapy and so was switched to oral selexipag and inhaled iloprost. The transition was successful, and she has experienced no exacerbations of SLE-PAH during the 10 months since the onset of pulmonary arterial hypertension. To the best of our knowledge, this is the first report of intravenous epoprostenol being switched to alternative oral and inhaled therapy in a patient with SLE-PAH. In combination with adequate immunosuppressive therapy, it is probably easier to make this transition in patients with SLE-PAH than in those with pulmonary arterial hypertension of a different aetiology. Continuous infusion of epoprostenol can have potentially life-threatening complications and a detrimental effect on the quality of life. Our alternative treatment strategy was successful, and we hope that it will prove beneficial in other cases.

Impact of adaptive cardiac resynchronization therapy in patients with systolic heart failure: Beyond QRS duration and morphology.

BACKGROUND: Mechanical and electrical restoration by cardiac resynchronization therapy (CRT) with adaptive pacing algorithm (aCRT) in heart failure patients with a moderately wide (120-149 ms) QRS has not been fully evaluated. The purpose of this study was to investigate the therapeutic effect of aCRT compared with conventional biventricular CRT (BiV-CRT) regardless of QRS morphology. METHODS: Seventeen consecutive patients with a QRS ≥120 ms, regardless of morphology, underwent CRT device implantation with an aCRT pacing algorithm. Propensity score matched analysis was performed to evaluate the impact of aCRT on the improvement in mechanical and electrical parameters after CRT device implantation using historical controls (HC) from the clinical registry of BiV-CRT (START trial). RESULTS: Left ventricular (LV) volume significantly decreased after CRT in all patients in both the aCRT and HC groups. The difference in relative reduction of LV end-systolic volume (LVESV) was not significantly different between the 2 arms. QRS shortening after CRT was significantly greater in the aCRT group than in the BiV-CRT group, and the difference was prominent in patients with a moderately wide QRS (120-149 ms). In patients with a moderately wide QRS, the relative reduction in LVESV [39 (29-47)% vs. 2 (-6-20)%, p = 0.04] and proportion of LV volume responders (90% vs. 38%, p = 0.04) were significantly greater in the aCRT group than in the HC group. The proportion of volume responders was not significantly different in patients with a wide QRS (≥150 ms). CONCLUSIONS: The aCRT algorithm improved electrical and mechanical parameters in patients with a moderately wide QRS, regardless of QRS morphology.

Effect of renin-angiotensin system inhibitors in patients with cancer treated with anti-VEGF therapy.

BACKGROUND: Cancer treatment with vascular endothelial growth factor signalling pathway (VSP) inhibitors frequently causes hypertension. Although previous reports suggested that the antihypertensive drug renin-angiotensin system inhibitor (RASI) may have a positive synergistic effect with VSP inhibitors, the actual impact on clinical outcomes is unknown. OBJECTIVES: The study aims to clarify whether RASIs exhibit clinical benefits for patients with cancer with hypertension. METHOD: From the Longevity Improvement and Fair Evidence Study database, comprising Japanese claims data between 2016 and 2020, we reviewed 2380 patients treated with VSP inhibitors who received antihypertensive treatment during cancer therapy. The patients were classified into two groups: with-RASI (n=883) and without-RASI (n=1497). In addition, 1803 of these patients treated for hypertension with RASI-only (n=707) or calcium channel blocker-only (n=1096) were also reviewed. The time-to-treatment failure (TTF), the interval from initiation of chemotherapy to its discontinuation, was applied as the primary endpoint. RESULTS: The median TTFs were 167 (60-382) days in the with-RASI group and 161 (63-377) days in the without-RASI group (p=0.587). All models, including Cox proportional hazard models and multiple propensity score models, did not reveal the superiority of with-RASI treatment. In the propensity score matching model, the HR for treatment with-RASI compared with that for without-RASI was 0.96 (95% CI 0.86 to 1.06, p=0.386). In addition, the TTFs of RASI-only were not superior to calcium channel blocker-only (p=0.584). CONCLUSIONS: RASIs for hypertension do not benefit clinical outcomes during cancer therapy with VSP inhibitors. In addition, RASIs and calcium channel blockers have comparable clinical efficacy as first-line antihypertensive.

Refractory constrictive pericarditis caused by an immune checkpoint inhibitor properly managed with infliximab: a case report.

BACKGROUND: Immune checkpoint inhibitors (ICIs) can cause cardiac immune-related adverse events (irAEs), including pericarditis. Cardiovascular events related to pericardial irAE are less frequent, but fulminant forms can be fatal. However, the diagnosis and treatment strategies for pericardial irAE have not established. CASE SUMMARY: A 58-year-old man was diagnosed with advanced non-small-cell lung cancer and nivolumab was administered as 5th-line therapy. Eighteen months after the initiation of nivolumab, the patient developed limb oedema and increased body weight. Although a favourable response of the cancer was observed, pericardial thickening and effusion were newly detected. He was diagnosed with irAE pericarditis after excluding other causes of pericarditis. Nivolumab was suspended and a high-dose corticosteroid was initiated. However, right heart failure (RHF) symptoms were exacerbated during the tapering of corticosteroid because acute pericarditis developed to steroid-refractory constrictive pericarditis. To suppress sustained inflammation of the pericardium, infliximab, a tumour necrosis factor-alfa inhibitor, was initiated. After the initiation of infliximab, the corticosteroid dose was tapered without deterioration of RHF. Exacerbation of lung cancer by irAE treatment including infliximab was not observed. DISCUSSION: IrAE should be considered when pericarditis develops after the administration of ICI even after a long period from its initiation. Infliximab rescue therapy may be considered as a 2nd-line therapy for steroid-refractory irAE pericarditis even with constrictive physiology.

Impaired deformability and association with density distribution of erythrocytes in patients with type 2 diabetes mellitus under treatment.

BACKGROUND: Disturbed microcirculation is related to diabetic complications, and erythrocyte deformability is a critical factor regulating microcirculation. OBJECTIVES: To know the relationship between the impaired deformability and density profile in diabetic erythrocytes. METHODS: We recruited patients with type 2 diabetes (n = 15, diabetic group) and age- and sex-matched non-diabetic subjects (n = 15, control group). Erythrocyte density (ED) profile was obtained by the phthalate ester separation technique. ED distribution was fitted by sigmoidal curve, yielding specific gravity of phthalate ester allowing passage of half erythrocytes population (ED50) and slope factor. Erythrocyte deformability was estimated by our specific filtration technique. RESULTS: Diabetic group showed significantly (p < 0.001) higher HbA1c and fasting blood glucose concentration. Erythrocyte deformability in diabetic group was impaired as compared with that in control group (p < 0.001) and proportional to HbA1c (p = 0.009). However, ED50 and the slope factor in diabetic group did not differ from respective parameters in control group. CONCLUSIONS: This study demonstrated that erythrocyte deformability was impaired in diabetic patients even under treatment. HbA1c up to 7.5% is concluded not to alter the erythrocyte density but to impair the deformability, which might be a warning to clinicians for prevention of diabetic complications.

Acute Decompensated Heart Failure in Patients with Heart Failure with Reduced Ejection Fraction.

Acute decompensated heart failure (ADHF) requires immediate treatments because it impairs perfusion to systemic organs and their function. Half of all patients with ADHF are diagnosed with heart failure with reduced left ventricular ejection fraction (HFrEF). The initial goal of management for ADHF is to stabilize hemodynamic status. Pulmonary edema is treated with vasodilators or diuretics. Inhibitors of the renin-angiotensin-aldosterone system and ß-blockers should be started and/or increased to meet the maximum dose, ideally the target dose, that the patient can tolerate as a treatment of HFrEF. Patients with severe circulatory failure need inotropic drugs or mechanical circulatory support.

Acute and Chronic Effects of Cancer Drugs on the Cardiovascular System.

Several cancer treatments cause cardiotoxicity that can lead to heart failure, coronary artery disease, arrhythmia, and pericardial disease. In this review, representative cases of heart failure following cardiotoxicity caused by trastuzumab, anthracycline, and hematopoietic stem cell transplantation are described with case notes. Additionally, other important points regarding cardiotoxicity related to heart failure are reported. During and after potentially cardiotoxic therapy, periodic cardiac examinations are recommended to detect any cardiovascular disorders; these are ameliorated if appropriately diagnosed at an earlier stage. It is important for cardiologists and oncologists to understand the pathophysiology of representative cardiovascular disease cases following cancer treatment.

Atrial fibrillation observed in a patient with esophageal cancer treated with fluorouracil.

Fluorouracil (5-FU), a commonly used anticancer agent, has potent cardiotoxicity that is mediated by vascular endothelial injury and vasospasm. Here, we report a patient demonstrating atrial fibrillation (AF), which was most likely induced by vasospasm mediated by 5-FU. A 69-year-old man presented with dysphagia and was diagnosed with advanced esophageal cancer. Frequent paroxysms of atrial fibrillation (AF) were observed during combination chemotherapy including 5-FU. AF was refractory to disopyramide, but was sensitive to antianginal agents (nicorandil and nitroglycerin transdermal patch). Coronary angiography performed within the chemotherapeutic period demonstrated moderate stenosis in the right coronary artery (RCA). Severe spasm at the proximal portion of the atrial branch in RCA was induced by provocation test using acetylcholine. Our case indicated that 5-FU predisposed vasospasm in RCA and the subsequent atrial ischemia may lead to AF. .

Association of atrial fibrillation and gastroesophageal reflux disease: Natural and therapeutic linkage of the two common diseases.

Atrial fibrillation (AF) is a common arrhythmia and gastroesophageal reflux disease (GERD) is popular in Japan. The two common diseases share several predisposing factors such as lifestyle and senescence, and inflammation and oxidative stress play an important role in their development and progression. Incidental cases of AF treated successfully by proton pump inhibitor (PPI) applied for coexisting GERD have been sporadically reported. An increasing evidence indicates that GERD induces the initiation and the perpetuation of AF. This is caused by the autonomic nerve influence, mechanical compression, and propagation of local inflammation due to proximity of left atrium (LA) and lower esophagus. Meanwhile, AF also develops GERD by mechanical and inflammatory actions of LA characterized by remodeling and inflammation. The robust association of AF with GERD is not limited to their natural interaction, i.e., pharmacological or nonpharmacological treatment of AF is reported to aggravate GERD. Many cardiac drugs (anticoagulants, calcium antagonists, and nitrates) induce esophageal mucosal damage and lower esophageal sphincter relaxation promoting acid reflux. These drugs are frequently prescribed in patients with AF for stroke prevention, rate control, and for coexisting coronary heart disease. Catheter ablation also yields both GERD and esophageal thermal injury, which is a precursor lesion of atrioesophageal fistula. The notion that AF and GERD are mutually interdependent is widely and empirically recognized. However, mechanistic link of the two common diseases and objective evaluation of PPI as an adjunctive AF treatment warrant future large-scale prospective trials.

Hypoalbuminemia for the prediction of venous thromboembolism and treatment of direct oral anticoagulants in metastatic gastric cancer patients.

BACKGROUND: Venous thromboembolism (VTE) is highly associated with advanced gastric cancer (AGC) and is sometimes lethal. Predictors of VTE have not been identified, and the efficacy and safety of direct oral anticoagulants (DOACs) for AGC-associated VTE remain to be clarified. METHODS: A total of 188 AGC patients who started chemotherapy during the period from January 2014 to December 2017 in our institutions were retrospectively examined for the incidence of VTE, risk factors for VTE, and the efficacy and safety of DOAC-based anticoagulant therapy for VTE. RESULTS: Thirty-four patients (18%) were diagnosed with VTE at the start or during the course of chemotherapy (VTE group). More VTE group patients had a history of abdominal surgery and had moderate-severe ascites (32% versus 17%, 32% versus 14%, respectively) than non-VTE group patients (NVTE group). The mean serum albumin concentrations in the VTE group were significantly lower than NVTE group (3.38 mg/dL vs 3.65 mg/dL, respectively). Multivariate analysis showed that hypoalbuminemia was significantly correlated with VTE (P = 0.012). In the VTE group, 29 patients (85%) received anticoagulant therapy, including 24 patients treated with DOACs. No lethal VTE was observed in any patients. Thirteen patients (45%) terminated DOACs because of anemia or bleeding events, of whom eleven developed major bleeding. Median overall survivals of the VTE and NVTE groups were 9.63 months and 11.5 months, respectively (P = 0.262). CONCLUSION: Hypoalbuminemia appears to be a risk factor for AGC-associated VTE. DOACs are effective to AGC-associated VTE, but careful observation of bleeding events is required.