Long-term safety and efficacy of mogamulizumab (anti-CCR4) for treating virus-associated myelopathy.

Some carriers of human T-cell leukaemia virus type 1 (HTLV-1), a retrovirus that primarily infects CD4+ T cells and causes lifelong infection, develop HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). Current treatments for HAM/TSP are insufficient with problematic long-term side effects. This study evaluated the long-term safety and efficacy of the anti-CCR4 antibody mogamulizumab in patients with HAM/TSP over a 4-year period. We conducted an open-label, extended long-term study (UMIN trial number: UMIN000019942) of a phase 1-2a trial with mogamulizumab for HAM/TSP (UMIN000012655). The study participants were patients with corticosteroid-resistant HAM/TSP who could walk 10 m with or without assistive tools. Mogamulizumab was administered at 0.01, 0.03, 0.1 or 0.3 mg/kg at intervals of ≥8 weeks (0.01 and 0.03 mg/kg) or ≥12 weeks (0.1 and 0.3 mg/kg). HTLV-1 proviral load, CSF inflammatory markers and clinical symptoms were summarized by descriptive statistics. Missing observations were imputed using the last-observation-carried-forward method. As a post hoc analysis, we evaluated the therapeutic effect of mogamulizumab on gait function by comparing it with contemporary control data from a HAM/TSP patient registry. Of the 21 participants in the phase 1-2a, 18 (86%) enrolled in the long-term study and 15 (71%) continued repeated doses of mogamulizumab for 4 years. The median dose was 0.1 mg/kg after 4 years. Seventeen of 21 participants (81%) experienced grade 1-2 skin-related adverse events. Observed grade 3 drug-related adverse effects included three cases of lymphopenia and one case each of microscopic polyangiitis, elevated levels of aspartate aminotransferase, and neutropenia. Four of 21 participants (19%) developed neutralizing antibodies. After 4 years, the peripheral blood proviral load and the number of infected cells in CSF decreased by 60.7% and 66.3%, respectively. Neopterin and CXCL10 CSF concentrations decreased by 37.0% and 31.0%, respectively. Among the 18 participants, spasticity and Osame Motor Disability Score (OMDS) improved in 17 (94%) and four (22%), respectively. However, 10 m walking time worsened by 7.3% on average. Comparison with the contemporary control group demonstrated that mogamulizumab inhibited OMDS progression (P = 0.02). The results of the study suggest that mogamulizumab has long-term safety and inhibitory effects on lower limb motor disability progression in corticosteroid-treated patients with HAM/TSP. This will provide a basis for the application of mogamulizumab in HAM/TSP treatment.

Carotid Ultrasound Using Superb Microvascular Imaging to Identify Patients Developing In-Stent Restenosis After CAS.

BACKGROUND AND PURPOSE: In-stent restenosis (ISR) caused by in-stent intimal hyperplasia (ISH) may develop after carotid artery stenting (CAS), and often necessitates re-stenting. We investigated whether new ultrasound technique is useful for detecting carotid artery plaques prone to ISR. PURPOSE: Superb micro-vascular imaging (SMI) is a new color Doppler imaging technique for assessing low velocity blood flow such as neovascularization in carotid artery plaques. In this study, we attempted to identify associations between findings from carotid ultrasonography with SMI performed prior to CAS and in-stent restenosis after 6 months of CAS. METHODS: This study investigated 19 patients (18 men; mean age, 72.4 years). Preoperative plaque evaluation was performed by magnetic resonance imaging, ultrasonography, and carotid angiography. Follow up angiography was performed in all patients at 6 months after CAS. ISR was defined as ISH resulting in >50% stenosis based on European Carotid Surgery Trialists criteria. We investigated whether SMI was useful as a predictor of ISR by chi-square test. RESULTS: Preoperative mean stenosis rate according to North American Symptomatic Carotid Endarterectomy Trial methods in 19 patients was 61.3%. Neovascularization was observed on SMI in 10 patients (52.6%). Carotid angiography at 6 months after CAS revealed ISR in 4 patients, all of whom had shown neovascularization on SMI. A significant association was seen between findings of neovascularization on SMI and development of ISR (p = 0.033). In predicting ISR, neovascularization findings on SMI offered 100.0% sensitivity and 60.0% specificity. CONCLUSIONS: Preprocedural plaque characterization by carotid ultrasound with SMI appears useful for predicting ISR at 6 months after CAS.

Morphology Changes in Perfluorosulfonated Ionomer from Thickness and Thermal Treatment Conditions.

The morphological changes of Nafion thin films with thicknesses from 10 to 200 nm on Pt substrate with various annealing histories (unannealed to 240 °C) were systematically investigated using grazing incidence small-angle X-ray scattering (GISAXS) and grazing incidence wide-angle X-ray scattering (GIWAXS). The results revealed that the hydrophilic ionic domain and hydrophobic backbone in Nafion thin films changed significantly when the annealing treatment exceeded the cluster transition temperature, which decreased proton conductivity, due to the constrained hydrophilic/hydrophobic phase separation, and increased the crystalline-rich domain. This research contributed to the understanding of ionomer thermal stability in the catalyst layer, which is subjected to thermal annealing during the hot-pressing process.

Preprocedural Carotid Plaque Echolucency as a Predictor of In-Stent Intimal Restenosis after Carotid Artery Stenting.

OBJECTIVES: In-stent intimal restenosis (ISR) caused by neointimal hyperplasia can develop <24 months after carotid artery stenting (CAS). The utility of plaque imaging by carotid ultrasonography (US) or magnetic resonance imaging (MRI) has been investigated for the prediction of ipsilateral stroke. We aimed to investigate whether these imaging techniques are useful for detecting carotid plaques prone to ISR. MATERIALS AND METHODS: We examined 133 patients (mean age of 72.1 ± 8.4 years old) that received CAS at a single hospital from 2014 to 2018. A pre-CAS carotid plaque evaluation was performed by carotid angiography, duplex carotid US, and black-blood carotid artery MRI (BB-MRI). The mean stenosis rate was 71.0 ± 12.3% by the North American Symptomatic Carotid Endarterectomy Trial (NASCET) methods. Follow-up carotid angiography was performed 6 months after CAS in all patients according to a predefined protocol. ISR was defined as in-stent intimal hyperplasia more than 50% stenosed based on the NASCET criteria. The selection of the stent type was at the discretion of the treating physician. Predictors of ISR were determined by multivariate logistic regression analysis. RESULTS: Follow-up angiography demonstrated ISR in 33 patients (24.8%). In 44 patients, more than two stents were deployed. Univariate logistic regression analyses demonstrated echolucent lesion, floating plaque, complete occlusive or pseudo-occlusive lesion, and closed-cell stent use as significantly associated with ISR (>50%). Multivariate logistic regression analysis demonstrated that echolucent lesion (OR 4.667, 95% CI 1.849-11.779) and closed-cell stent use (OR .378, 95% CI .148-.968) were significantly associated with ISR. CONCLUSIONS: Preprocedural plaque characterization by carotid US appeared to be useful to predict ISR 6 months after CAS.

The Risk Factors for Death within 6 Months After Ischemic Stroke in Patients with Cancer.

OBJECTIVES: While the intravenous recombinant tissue plasminogen activator (rt-PA) therapy for acute ischemic stroke patients with cancer is recommended when survival of ≥ 6 months is expected, the risk factors for death and stroke recurrence within 6 months after stroke are not well known. Thus, we aimed to identify markers for death and recurrence risks within six months from stroke onset in patients with cancer. MATERIALS AND METHODS: In a retrospective cohort study, the subjects comprised acute ischemic stroke patients with cancer hospitalized at St. Marianna University hospital from 2008 through 2019. To evaluate the associations between the clinical factors within 24 h of the initial stroke and death or stroke recurrence events within 6 months from stroke onset, Logistic analysis and Cox proportional hazards regression analysis was used respectively. Next, the optimal cutoff point of markers for different mortality groups was determined using the receiver operating characteristic curve analysis and cumulative outcome rate of each group was compared using the Kaplan-Meier method. RESULTS: Among 194 patients with cancer who developed acute stroke, 167 were ultimately selected for analysis. 47 subjects (28.14%) passed away within 6 months following stroke onset, and 20 subjects (11.98%) had stroke recurrence. High D-dimer levels, low fibrinogen levels, high Glasgow prognostic scores (GPS), and multiple vascular territory infarctions was independently associated with death, where higher death rate was significantly confirmed in the group with D-dimer levels of ≥3.95 mg/dl, fibrinogen levels <277.5 mg/dl and GPS scores of 2. Low fibrinogen level, lack of antithrombotic therapy, and the presence of metastasis were associated with stroke recurrence. CONCLUSIONS: When patients with cancer suffer stroke, D-dimer levels, fibrinogen levels, GPS, and multiple vascular territory infarctions would be associated with the risk of death within 6 months. Low fibrinogen levels, lack of antithrombotic therapy, and the presence of metastasis correlated with high risk of stroke recurrence.

The utility of superb-microvascular imaging for evaluating the full length of carotid artery stents.

Transoral carotid ultrasonography (TOCU) is a powerful tool for evaluating internal carotid artery (ICA) lesions located from the carotid bifurcation up to the level of the second cervical vertebra. Superb-microvascular imaging (SMI) is a new Doppler imaging technique whose algorithm analyze tissue movements to minimize motion artifacts by eliminating clutter signals. SMI significantly reduces motion artifacts and allows visualization of low-velocity blood flow even in minute vessels. TOCU with SMI produces clear intraluminal image of the distal extracranial ICA, which is not possible with conventional carotid artery ultrasonography (CUS). CUS with SMI and TOCU with SMI were performed in a patient with a history of carotid artery stenting for symptomatic left ICA stenosis, providing images of the full length of the stents with intimal hyperplasia.

Risk of Hyperglycemia and Hypoglycemia in Patients with Acute Ischemic Stroke Based on Continuous Glucose Monitoring.

BACKGROUND: In patients with acute ischemic stroke, current guidelines recommend maintaining blood glucose levels in a range of 140-180 mg/dL and closely monitoring to prevent hypoglycemia (<60 mg/dL). We aimed to assess glucose variability by continuous glucose monitoring (CGM) and to demonstrate the risk of acute ischemic stroke patients with glucose levels outside of the glucose management recommendations. METHODS: Patients with ischemic stroke admitted within 7 days after onset were prospectively enrolled, and their blood glucose levels were monitored every 15 minutes for 72-hour period using the FreeStyle Libre Pro. Multivariate logistic regression analyses were used to analyze potential predictors for hyperglycemic (>180 mg/dL) and hypoglycemic (<60 mg/dL) events. RESULTS: A total of 39 acute ischemic stroke patients (mean age 75.9 ± 11.5 years) were enrolled, and CGM was started from 58.6 ± 41.9 hours after stroke onset. CGM showed hypoglycemic events in 19 patients and hyperglycemic events in 21 patients, and the frequencies of hypo- and hyperglycemic events during CGM were 10.1 ± 15.7% and 11.9 ± 22.5%, respectively. Hypoglycemic events were mainly observed in the night-time in patients with normoglycemia at admission. Logistic regression analyses demonstrated significant associations between the blood glucose level at admission and hypo- and hyperglycemic events on CGM. CONCLUSIONS: This study of CGM found that many stroke patients have blood glucose levels outside the recommended guideline range in the acute phase. Blood glucose level on admission may be used as a predictor for hypo- and hyperglycemic events after admission.

Intraplaque Microvascular Flow Signal in Superb Microvascular Imaging and Magnetic Resonance Imaging Carotid Plaque Imaging in Patients with Atheromatous Carotid Artery Stenosis.

Carotid artery atherosclerosis is one of the major risk factors for ischemic stroke. Intraplaque neovascularization (IPN) is one of the steps toward the development of vulnerable plaque. Superb microvascular imaging (SMI) is a new ultrasonographic technique for visualizing low-velocity and microvascular flow by clutter suppression to extract flow signals from large to small vessels and enables visualization of intraplaque microvascular flow (IMVF) without echo contrast media. We aimed to investigate the association between IMVF signal in SMI and MRI plaque imaging among patients with atherosclerotic carotid stenosis. We prospectively enrolled patients (>18 years old) with mild to severe carotid stenosis (more than 50% in cross-sectional area) diagnosed by carotid ultrasonography between August 2017 and April 2018, irrespective of sex and history of stroke. A total of 40 patients (31 men, 9 women; mean age, 75.1 ± 10.0 years) were enrolled. SMI revealed IPN findings in 21 patients. SMI clearly visualized the direction of pulsatile flow movement in microvessels and IPN was easily classified into the two types of Type V (n=2) and Type E (n=19). Multivariate logistic regression analysis presented that microvascular flow signal in carotid plaque on SMI was identified as a significant predictor of intraplaque hemorrhage as evaluated by MRI (OR, 8.46; 95%CI, 1.44-49.9; p=0.018). This study demonstrated a significant association between the presence of IMVF signal in SMI and intraplaque hemorrhage characterized by high-intensity lesions on MRI T1-FFE images.

Improvement of cerebral blood flow after balloon angioplasty and stenting for symptomatic middle cerebral artery stenosis.

OBJECTIVE: Although reports of endovascular treatment for intracranial arterial stenosis have been increasing recently, their efficacy remains to be elucidated. This study aimed to investigate the changes in cerebral hemodynamics of severe middle cerebral artery (MCA) stenosis patients by performing CT perfusion (CTP) after endovascular treatment. METHODS: Subjects were those who underwent balloon angioplasty and stenting for symptomatic MCA M1 stenosis refractory to medical therapy at our hospital between 2008 and 2022. We included 36 patients (mean age 63.69 ± 15.24 years, 20 males) who underwent CTP before and within three weeks after treatment. The CTP parameters such as relative cerebral blood flow (rCBF), relative cerebral blood volume (rCBV), and relative mean transit time (rMTT) were calculated as ipsilateral values divided by contralateral value. RESULTS: Endovascular treatment consisted of 26 balloon angioplasty and 10 stenting procedures performed at an average of 1 month from onset. CTP was performed at an average of 5.5 days postoperatively. The mean overall stenosis rate decreased from 79.0% to 30.3%. In the balloon angioplasty group, it decreased from 77.6% to 35.3%, and in the stent group, it decreased from 82.7% to 17.5%. After treatment, rCBF and rMTT measured by CTP improved significantly (both p < 0.001), whereas there was no significant change in rCBV. The improvement rates of rCBF and rMTT were mild higher in the stent group, but not significantly so. CONCLUSION: Balloon angioplasty and stenting for symptomatic MCA improved cerebral hemodynamics, resulting in significantly increased rCBF and decreased rMTT.

Large-Scale Whole-Genome Analysis of HTLV-1-Associated Myelopathy Identified Hereditary Spastic Paraplegias.

Objectives: Distinguishing human T-cell lymphotropic virus type 1 (HTLV-1)-associated myelopathy from hereditary spastic paraplegia in patients infected with HTLV-1 is challenging due to overlapping clinical symptoms. The aim of this study was to explore the possibility that hereditary spastic paraplegia is inherently present in patients diagnosed with HTLV-1-associated myelopathy. Methods: We performed whole-genome sequencing on 315 unrelated patients registered in the HTLV-1-Associated Myelopathy patient registry "HAM-net," from 2013 to 2022 in Japan. CSF inflammatory biomarkers, including CXCL10, were measured. Results: We identified 5 patients with pathogenic variants in the genes RTN2, SPAST, VCP, and UBAP1, which are the known causes of hereditary spastic paraplegia. These patients had no family history of hereditary spastic paraplegia. The levels of CSF inflammatory biomarkers were lower than expected in these patients, compared with disease severity. Discussion: Genetic analysis is useful for the differentiation of hereditary spastic paraplegia patients from HTLV-1-associated myelopathy patients, especially for the patients with low levels of CSF inflammatory markers. Here we report the presence of hereditary spinal cord diseases in patients diagnosed with HTLV-1-associated myelopathy and provides evidence that genetic analysis would be helpful in the diagnostic workflow.

[National Questionnaire Survey on the Actual Use and Content Evaluation of the human T-cell leukemia virus type I (HTLV-1) -associated Myelopathy (HAM) Practice Guidelines 2019].

It is not enough to just create medical practice guidelines; they are also required to be implemented into practice. Therefore, we surveyed specialists to determine the extent of the dissemination of the "HAM Practice Guidelines 2019," to quantify gaps, identify challenges, and understand needs in daily practice. The survey also revealed that the 25% of the specialists were unaware of the tests required for confirming human T-cell leukemia virus type I (HTLV-1) infection. Additionally, they had insufficient knowledge of the HTLV-1 infection. About 90.7% of the specialists agreed with the policy of determining treatment intensity based on disease activity. However, the implementation rate of cerebrospinal fluid marker measurement, which is useful for this assessment, was as low as 27%. Hence, it is important to use the findings of this study to further promote awareness about this issue.

EZH1/2 dual inhibitors suppress HTLV-1-infected cell proliferation and hyperimmune response in HTLV-1-associated myelopathy.

Background: Human T-cell leukemia virus type 1 (HTLV-1) causes HTLV-1-associated myelopathy (HAM), adult T-cell leukemia/lymphoma (ATL), HTLV-1-associated uveitis, and pulmonary diseases. Although both HAM and ATL show proliferation of infected cells, their pathogeneses are quite different. In particular, the pathogenesis of HAM is characterized by hyperimmune responses to HTLV-1-infected cells. Recently, we demonstrated the overexpression of histone methyltransferase EZH2 in ATL cells and the cytotoxic effects of EZH2 inhibitors and EZH1/2 dual inhibitors on these cells. However, these phenomena have never been studied in HAM. Furthermore, what effect these agents have on the hyperimmune response seen in HAM is completely unknown. Methods: In this study, we investigated histone methyltransferase expression levels in infected cell populations (CD4+ and CD4+CCR4+ cells) from patients with HAM using microarray and RT-qPCR analyses. Next, using an assay system that utilizes the spontaneous proliferation characteristic of peripheral blood mononuclear cells derived from patients with HAM (HAM-PBMCs), we investigated the effects of EZH2 selective inhibitors (GSK126 and tazemetostat) and EZH1/2 dual inhibitors (OR-S1 and valemetostat, also known as DS-3201), particularly on cell proliferation rate, cytokine production, and HTLV-1 proviral load. We also examined the effect of EZH1/2 inhibitors on the proliferation of HTLV-1-infected cell lines (HCT-4 and HCT-5) derived from patients with HAM. Results: We found elevated expression of EZH2 in CD4+ and CD4+CCR4+ cells from patients with HAM. EZH2 selective inhibitors and EZH1/2 inhibitors significantly inhibited spontaneous proliferation of HAM-PBMC in a concentration-dependent manner. The effect was greater with EZH1/2 inhibitors. EZH1/2 inhibitors also reduced the frequencies of Ki67+ CD4+ T cells and Ki67+ CD8+ T cells. Furthermore, they reduced HTLV-1 proviral loads and increased IL-10 levels in culture supernatants but did not alter IFN-γ and TNF-α levels. These agents also caused a concentration-dependent inhibition of the proliferation of HTLV-1-infected cell lines derived from patients with HAM and increased annexin-V(+)7-aminoactinomycin D(-) early apoptotic cells. Conclusion: This study showed that EZH1/2 inhibitors suppress HTLV-1-infected cell proliferation through apoptosis and the hyperimmune response in HAM. This indicates that EZH1/2 inhibitors may be effective in treating HAM.

[A case of nasal discharge resulting in recurrent bacterial meningitis].

A 47-year-old man who was previously hospitalized three times due to bacterial meningitis experienced a headache and posterior neck pain in May. He was admitted to our hospital because of a fever 3 h later. He was fully conscious and febrile, with a headache and signs of meningeal irritation. A cerebrospinal fluid examination showed an increased number of cells with polynuclear cell predominance and decreased glucose levels, leading to the diagnosis of bacterial meningitis. Steroid and antibiotic treatment was initiated, at which time, large amounts of nasal discharge were observed. Cisternal scintigraphy was performed, and cerebrospinal fluid was detected in the nasal discharge. The cause was idiopathic, and endoscopic repair was performed. The nasal fluid leakage was suggested to be the cause of the recurrent bacterial meningitis in this case.

Contrast-enhanced carotid ultrasonography and MRI plaque imaging to identify patients developing in-stent intimal hyperplasia after carotid artery stenting.

AIM: In-stent intimal hyperplasia (ISH) observed after carotid artery stenting (CAS) may lead to in-stent restenosis. We aimed to investigate whether contrast-enhanced carotid ultrasonography (CEUS) and magnetic resonance imaging (MRI) plaque imaging prior to CAS are predictive for ISH at 6 months after CAS. MATERIAL AND METHOD: A total of 14 patients (13 men, 1 woman; mean age, 74.2 years) were prospectively enrolled. CEUS and MRI plaque imaging were performed before CAS. ISH was diagnosed by carotid angiography at 6 months after CAS. Patients were divided into two groups based on the thicknessof ISH and age, risk factors, enhancement in CEUS, MRI plaque imaging and number of replaced stents were compared between groups. RESULTS: Carotid angiography at 6 months after CAS revealed ISH in 10 patients. Plaque enhancement on CEUS was observed in 6 patients, all of whom showed ISH. A significant association was seen between plaque enhancement on CEUS and development of ISH (χ2 test, CEUS enhancement (+) 100% vs. CEUS enhancement (-) 50% p=0.040). Carotid plaques in 12 patients were diagnosed as unstable by MRI plaque imaging. Presence of ISH was significantly associated with unstable plaque diagnosed by MRI plaque imaging (χ2 test, unstable 83% vs. stable 0%; p=0.016). CONCLUSION: Carotid plaque MRI and CEUS may be useful to predict ISH after CAS.