Altered properties of amyloidogenic prion protein in genetic Creutzfeldt-Jakob disease with PRNP V180I mutation in response to pentosan polysulfate.

Genetic Creutzfeldt-Jakob disease (gCJD) with V180I prion protein gene (PRNP) mutation shows weaker prion protein (PrP) deposition histologically compared with sporadic CJD, and it is more difficult to detect protease-resistant prion protein in immunoblotting. However, we previously reported the autopsy case of a patient with V180I gCJD who was treated with pentosan polysulfate sodium (PPS); this case had increased protease-resistant PrP deposition. It has been suggested that PPS might reduce protease-resistant PrP; however, the detailed pharmacological and histopathological effects of PPS in humans remain unknown. We examined autopsied human brain tissue from four cases with V180I gCJD that were added to our archives between 2011 and 2021: two cases treated with PPS and two cases without PPS. We conducted a neuropathological assessment, including immunohistochemistry for PrP. We also performed immunoblotting for PrP on homogenate samples from each brain to detect protease-resistant PrP using both a conventional procedure and size-exclusion gel chromatography for the purification of oligomeric PrP. Both PPS-treated cases showed long survival time over 5 years from onset and increased PrP deposition with a characteristic pattern of coarse granular depositions and congophilic PrP microspheres, whereas the cases without PPS showed around 1-year survival from onset and relatively mild neuronal loss and synaptic PrP deposition. Although cortical gliosis seemed similar among all cases, aquaporin 4-expression as a hallmark of astrocytic function was increased predominantly in PPS cases. Immunoblotting of non-PPS cases revealed protease-resistant PrP in the oligomeric fraction only, whereas the PPS-treated cases showed clear signals using conventional procedures and in the oligomeric fraction. These unique biochemical and histopathological changes may reflect the progression of V180I gCJD and its modification by PPS, suggesting the possible existence of toxic PrP-oligomer in the pathophysiology of V180I gCJD and beneficial effects of PPS toward the aggregation and detoxication of toxic PrP-oligomer.

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.

Coaptation Reserve Predicts Optimal Reduction in Mitral Regurgitation and Long-Term Survival With Transcatheter Edge-to-Edge Repair.

BACKGROUND: Although transcatheter edge-to-edge repair (TEER) is effective and safe, there is a need for better prediction of optimal outcomes. We aimed to determine predictors of optimal reduction in mitral regurgitation (MR) and survival with TEER. METHODS: We examined mitral anatomy and its change with TEER on outcomes in 183 patients (age, 82 [77-87] years; 53% women). Coaptation reserve was measured as the distance of continuous apposition of the A2 and P2 leaflet segments in 2-dimensional apical long-axis imaging at the site of the predominant jet of MR. Augmentation in coaptation was measured as the total amount of leaflet insertion. Addressable coaptation area was calculated using the physical boundaries of the TEER device. RESULTS: Coaptation reserve, its augmentation, and addressable coaptation area were strong predictors of MR reduction (all P<0.001), as well as heart failure hospitalization and death. For patients with either mild or no residual MR, median values for coaptation reserve, its augmentation, and addressable coaptation area were 3.7 (2.8-4.5) mm, 7.3 (5.2-9.5) mm, and 59.0 (48.0-71.8) mm2, respectively. Receiver operating characteristic analyses determined the best values for optimal MR reduction as a coaptation reserve of >3.0 mm (P<0.001), addressable coaptation area of ≥52 mm2 (P<0.001), and coaptation augmentation of ≥4.7 mm (P<0.001). These values were associated with greater 2-year survival free of all-cause mortality and persisting even in analyses restricted to those with mild or no residual MR after TEER. CONCLUSIONS: Coaptation reserve and its augmentation are simple, independent parameters that predict optimal MR reduction and better survival in patients undergoing TEER. These findings may have implications for patient selection and expanded use of the therapy.

Primary Nondural Central Nervous System Marginal ZoneB-Cell Lymphoma of the Mucosa-Associated Lymphoid Tissue Type Mimicking CNS Inflammatory Diseases.

Marginal zone B-cell lymphomas (MZBCLs) are non-Hodgkin lymphomas arising from postgerminal center marginal zone B cells. MZBCLs are subclassified into extranodal, nodal, and splenic MZBCLs. Primary nondural central nervous system (CNS) MZBCLs of the mucosa-associated lymphoid tissue (MALT) type are among the extranodal examples. Their clinicopathological features are not well characterized. Therefore, the clinicopathological features of 8 primary nondural CNS MZBCLs of the MALT type were assessed to establish their pathological diagnostic criteria. Histologically, all cases of primary nondural CNS MZBCLs of the MALT type showed perivascular expansive monotonous proliferation of small atypical B lymphoid cells with plasma cell differentiation, low Ki-67 labeling index, and minimal invasion from the perivascular space. In addition, no vascular changes such as glomeruloid changes, obliterative fibrointimal proliferation, and intramural lymphocytic infiltration were seen. These key histological characteristics should be considered when diagnosing cases that are suspected to be primary nondural CNS MZBCLs of the MALT type. Additionally, regarding PCR for the detection of immunoglobulin heavy variable gene and T-cell receptor γ gene rearrangements, the former is detected, but the latter is not detected in all cases. Therefore, PCR detection including sequence analysis should be added when diagnosing difficult cases based on the key histological characteristics.

Ischemic Stroke Caused by Carotid Stump at the Common Carotid Artery.

An 84-year-old man developed motor aphasia and right hemiparesis on postoperative day 1 after orchiectomy for suspected malignant lymphoma. He had a history of thoracic endovascular aortic repair for aortic aneurysm using a bypass graft from the right subclavian artery to the left common carotid artery (CCA); however, the graft had become occluded six months later. Brain magnetic resonance imaging revealed acute cerebral infarctions in the left frontal lobe. Carotid ultrasonography revealed a stump at the left CCA, just below the bifurcation, formed by the occluded graft with an oscillating thrombus. This case was rare in that a CCA stump was identified as the embolic source of ischemic stroke.

[Case report: transient ischemic stroke caused by internal carotid artery occlusion due to compression by pituitary apoplexy and hemodynamic mechanism].

An 87-year-old blind man was admitted due to repeatedly disturbed consciousness and fever. Brain CT showed a pituitary tumor with a hematoma and an occlusive lesion of the right internal carotid artery. He experienced consciousness disturbance and left limb weakness with hypotension for a few minutes on the day of admission. We considered pituitary apoplexy caused adrenal failure with hypotension and transient ischemic attack (TIA) induced by a hemodynamic mechanism. An increased dose of hydrocortisone improved the fever and hypotension, and resolved consciousness disturbance. This is a unique example of TIA caused by the occlusive lesion of the internal carotid artery compressed as a result of pituitary apoplexy and a hemodynamic mechanism.

Subvalvular aortic stenosis diagnosed by 3D transesophageal echocardiography.

The patient was a 13-year-old male with chief complaints of exertional chest pain and dyspnea. Cardiac murmur was suspected in a medical checkup at 1 month old, at which time he was diagnosed with subvalvular aortic stenosis. He had subsequently been under follow-up observation at a nearby hospital for subvalvular aortic stenosis. He was admitted to our department for surgery due to aggravation of symptoms that had occurred over the previous year. Transthoracic echocardiography after admission showed an abnormal structure in the subvalvular aortic area, and the maximum pressure gradient between the left ventricle and aortic valve was 84 mmHg. The preoperative valve area was 0.71 cm(2), as measured by the Doppler method. Measurement of valve area by the trace method was difficult. Transesophageal echocardiography (TEE) showed a septum-like structure extending from the ventricular septum in the subvalvular area. On 3D TEE, the valve areas in the systolic and diastolic phases were 0.86 and 0.49 cm(2), respectively. Postoperative echocardiography showed resection of the structure in the subvalvular area, and the postoperative course was favorable.