Air inflow into vacuum-type immobilization devices impacts setup errors.

We aimed to determine the impact of air inflow into vacuum-type immobilization devices (VIDs) on setup errors. We assigned 70 patients undergoing radiotherapy for head and neck cancer to groups V (n = 34) or N (n = 36) according to whether the VIDs were deflated weekly or not deflated during treatment, respectively. We calculated systematic errors (Σ) as the standard deviations (SDs) of mean errors, and random errors (σ) as the root mean square of SDs in each patient. We compared overall means (µ), SDs (SDoverall), random errors and systematic errors. We also measured temporary pressure changes in VIDs to determine the influence of pressure changes in VIDs on setup errors. The µ was within 0.20 mm and 0.2° in both groups, whereas SDoverall significantly differed between them. The SDoverall differed the most in the Roll axes of groups N (0. 87°) and V (0.58°). The Σ and σ values were lower in all axes of group V than in group N. Despite the initial deflation target of - 70 kPa, the pressure in VIDs reached - 5 kPa at the end of treatment. However, weekly deflation apparently maintained pressure at - 20 kPa. Effective pressure control in VIDs can reduce patient-by-patient variation and improve setup reproducibility for individual patients, consequently resulting in small variations among overall setup errors.

Differentiating non-epileptic seizures from epileptic seizures in Glut1 deficiency syndrome.

AIM: To investigate the clinical characteristics of non-epileptic seizures due to transient brain dysfunction caused by energy deficiency after prolonged fasting or exercise in individuals with glucose transporter type 1 deficiency syndrome (Glut1DS), and then elucidate further the seizure features to distinguish non-epileptic seizures from epileptic seizures. METHOD: This retrospective case-control study included 57 non-epileptic seizures and 23 epileptic seizures (control group) in 14 individuals (11 males, three females; aged 5-44 years, median = 20 years) with Glut1DS, all with a heterozygous pathogenic SLC2A1 mutation. RESULTS: Non-epileptic seizures were classified as paroxysmal altered consciousness (n = 8), movement disorders (n = 35) (eye-head movements, ataxia, spasticity, weakness, involuntary movement), dysaesthesia (n = 8), and vomiting (n = 6) at the peak ages at onset of 5 to 10 years. Ketogenic diet therapy was effective in 33 of 43 (77%) non-epileptic seizures. Providing supplementary food before high-impact exercise or during attacks prevented or mitigated non-epileptic seizures in some individuals. Glut1DS-associated non-epileptic seizures are fundamentally situation-related seizures with specific provoking and ameliorating factors. Non-epileptic seizures can be distinguished from epileptic seizures by the absence of complete consciousness loss and rapid postictal recovery despite prolonged seizures. INTERPRETATION: Non-epileptic seizures are not well recognized but require different therapeutic approaches compared to epileptic seizures. Awareness of the differentiation of non-epileptic seizures from epileptic seizures is essential when performing preventive or therapeutic decision-making for acute exacerbation seizures.

Modeling of a tissue expander with a radiofrequency identification port in postmastectomy radiation therapy planning.

The purpose of this study was to evaluate the dose attenuation of Motiva Flora® (Flora, Establishment Labs, Alajuela, Costa Rica) tissue expander with a radiofrequency identification port locator and to develop a model for accurate postmastectomy radiation therapy planning. Dose attenuation was measured using an EBT3 film (Ashland, Bridgewater, NJ), and the optimal material and density assignment for the radiofrequency identification coil for dose calculation were investigated using the AcurosXB algorithm on the Eclipse (Varian Medical Systems, Palo Alto, CA) treatment planning system. Additionally, we performed in vivo dosimetry analysis using irradiation tangential to the Flora tissue expander to validate the modeling accuracy. Dose attenuations downstream of the Flora radiofrequency identification coil was 1.29% for a 6 MV X-ray and 0.99% for a 10 MV X-ray when the coil was placed perpendicular to the beam. The most suitable assignments for the material and density of the radiofrequency identification coil were aluminum and 2.27 g/cm3, respectively, even though the coil was actually made of copper. Gamma analysis of in vivo dosimetry with criteria of 3% and 2 mm did not fail in the coil region. Therefore, we conclude that the model is reasonable for clinical use.

Evaluation of the four-dimensional motion of lung tumors during end-exhalation breath-hold conditions using volumetric cine computed tomography images.

BACKGROUND AND PURPOSE: This study was performed to evaluate the four-dimensional motion of lung tumors during end-exhalation (EE) breath-holding (BH) using cine computed tomography (CT) and investigate the correlation between tumor and surrogate marker motions. MATERIALS AND METHODS: This study included 28 patients who underwent stereotactic body radiation therapy at our institution and were capable of 15-20 s of EE BH within a ±1.5-mm gating window with external markers. During EE BH with cine CT, 21 s of continuous data were acquired using 320-row multislice CT. Displacements in the tumor position during EE BH were assessed in the left-right (LR), anterior-posterior (AP), and superior-inferior (SI) directions. Pearson's correlation coefficient (r) between tumor motions during EE BH and diaphragm/external marker motions was also determined. RESULTS: The mean absolute maximum displacements of the tumor position during EE BH were 1.3 (range: 0.2-4.0), 1.9 (range: 0.3-12.0), and 1.3 (range: 0.1-7.2) mm in the LR, AP, and SI directions, respectively. The displacement of the tumor position in the AP direction was weakly correlated (|r| < 0.4) with the external marker and diaphragm displacements in many cases (proportions of 50% and 46%, respectively). CONCLUSION: We found some cases showing substantial displacement in lung tumor positions during EE BH, especially in the AP direction. Because these tumor position displacements did not correlate with surrogate markers and were difficult to detect, we recommend pretreatment evaluation of the four-dimensional motions of tumors during BH using cine CT.

Establishment of a flow cytometry screening method for patients with glucose transporter 1 deficiency syndrome.

Objective: We assessed the usefulness of flow cytometry as a functional assay to measure glucose transporter 1 (GLUT1) levels on the surface of red blood cells (RBCs) from Japanese patients with glucose transporter 1 deficiency syndrome (Glut1DS). Methods: We recruited 13 genetically confirmed Glut1DS patients with a solute carrier family 2 member 1 (SLC2A1) mutation (eight missense, one frameshift, two nonsense, and two deletion) and one clinically suspected Glut1DS-like patient without an SLC2A1 mutation, and collected whole blood with informed consent. We stained pelleted RBCs (1 µL) from the patients with a Glut1.RBD ligand and anti-glycophorin A antibody, which recognizes a human RBC membrane protein, and analyzed the cells using flow cytometry. Results: Relative GLUT1 levels quantified by flow cytometry in 11 of 13 patients with definite Glut1DS were 90% below those of healthy controls. Relative GLUT1 levels were not reduced in two of 13 Glut1DS patients who had a missense mutation and no intellectual disability and one Glut1DS-like patient without an SLC2A1 mutation. Relative GLUT1 levels were significantly reduced in Glut1DS patients with an SLC2A1 mutation, more severe intellectual disability, and spasticity. Conclusions: This method to detect GLUT1 levels on RBCs is simple and appears to be an appropriate screening assay to identify severe Glut1DS patients in the early stage before the development of irreversible neurologic damage caused by chronic hypoglycorrhachia.

[Invention and Evaluation of a Novel Air Leak Check System for Vacuum-type Patient Immobilization Device].

PURPOSE: We developed a novel system to measure air leakage in vacuum cushions, which are used in high-precision radiation therapy. The purpose of this study was to verify the usefulness of this system by evaluating the accuracy and the capability for detecting air leakage. METHODS AND RESULTS: The novel system was used to measure pressure in the cushion using a manometer. The advantage of this system was that we can measure the pressure without deformation of the cushion and check the pressure immediately. We confirmed that the pressure measured using this system is proportional to the reading in the reference manometer by the coefficient of 1.0. This system had a higher capability in the leak detection than the capability by checking softness in our sense of touch. We checked the leakage using this system against 18 cushions without air leakage (NL group) and 7 cushions that had problems regarding usage in patients due to the leakage (CW group). Average pressure variations in the NL group and the CW group were 22 kPa and 46 kPa, respectively. This was a significant difference in both groups. We could decide the criteria of pressure in the cushions that may cause troubles in the future use. CONCLUSION: We concluded that this system can detect air leakage in the cushions with a higher detectivity than our tactile sense.

[Brain Calcification].

Brain calcification can be either physiological or pathological. Pathological calcification occurs due to a wide spectrum of causes, including congenital disorders, infections, endocrine/metabolic diseases, cerebrovascular diseases, and neoplasms. The patient's age, localization of the calcification, and association with other imaging findings are useful for the correct diagnosis. Dural arteriovenous fistulas with cortical venous reflux should be included in the differential diagnosis of subcortical calcification via CT. MRA should be conducted subsequently. We recently reported the clinical and imaging characteristics of calcified brain metastases in 20 patients. Hemorrhage, necrosis, or degeneration were detected within the lesions in six patients. Both T1WI and T2WI showed a hyperintense mass surrounded by a hypointense rim in one patient. Hemorrhagic brain metastases can mimic cerebral cavernous malformations. Cancer metastasis should be considered as a differential diagnosis when calcified or hemorrhagic masses are detected in middle-aged and elderly patients. We recommend conducting MRI with Gd enhancement.

Clinical trial of carotid artery stenting using dual-layer CASPER stent for carotid endarterectomy in patients at high and normal risk in the Japanese population.

BACKGROUND: The dual-layer nitinol CASPER stent was designed to prevent plaque prolapse into its strut and periprocedural stroke. OBJECTIVE: To conduct a clinical trial for government approval of the device in patients at either high or normal risk for carotid endarterectomy (CEA). METHODS: Eligible patients had ≥50% symptomatic stenosis or ≥80% asymptomatic stenosis according to the North American Symptomatic Carotid Endarterectomy Trial methods (peak systolic velocity 130 and 230 cm/s on ultrasonography, respectively). The primary endpoint was the lack of major adverse events (MAEs), defined as death, stroke, and myocardial infarction within 30 days, and ipsilateral stroke within 1 year. The performance goal was set at 90.5%. MAE rates were also compared between the CEA high- and normal-risk groups. RESULTS: 140 carotid artery stenting procedures, including 40% of patients at high risk and 60% at normal risk for CEA, were performed in 13 institutes. MAEs occurred in two cases (one intraprocedural and one postprocedural stroke), and the MAE rate was 1.4%. The non-MAE rate was 98.6% according to Kaplan-Meier analysis, which was superior to the previously set performance goal. The deployment success, target lesion revascularization (TLR), in-stent restenosis, and cerebrovascular event rates were 99.3%, 2.4%, 8.5%, and 7.2%, respectively. The MAE rate in patients with normal CEA risk was 1.2%, which was similar to the high-risk CEA group, with no significant difference due to the small number of MAEs. CONCLUSIONS: The MAE rate following use of the CASPER stent was low (1.4%). The MAE, deployment success, TLR, in-stenosis, and cerebrovascular event rates were similar to those of previous reports.

Thrombectomy for Small-Artery Occlusions with the Small-Diameter Stent Retriever, Tron Fx 2 mm × 15 mm: A Case Series.

Objective: The safety and efficacy of thrombectomy for small-artery occlusions is still controversial. In April 2019, Tron Fx, a stent retriever with an expansion diameter of 2 mm, became reimbursed by health insurance in Japan. We report on cases of thrombectomy for small-artery occlusions performed using this device in seven patients. Methods: The subjects were seven patients who underwent thrombectomy between July 2019 and June 2020 using Tron Fx with 2 mm in diameter. We analyzed clinical results including recanalization and complications. Results: The mean age of the seven patients was 80.1 years, and the subjects included six men. The sites of occlusion were the middle cerebral artery M2 (n = 4), M4 (n = 1), anterior cerebral artery A2 (n = 1), and A3 (n = 1). One of the seven patients had an M2 occlusion that was formed during coil embolization for a ruptured cerebral aneurysm. In five cases, four cases were of primary occlusion and one case was of emboli into a new territory, treating with only Tron Fx 2 mm resulted in thrombolysis in cerebral infarction (TICI) 2b-3 in four cases. There was one case of grade 0, which was M4 occlusion. Finally, TICI 2b-3 were achieved in six of seven cases. No symptomatic intracranial hemorrhage occurred. Symptoms improved in five of six patients, excluding a vascular occlusion that occurred during surgery. Conclusion: Tron Fx with 2 mm diameter can be used safely for small-artery occlusion. The introduction of Tron Fx with 2 mm diameter may contribute to expand indications for thrombectomy for small-artery occlusions.

The role of molecular analysis of SLC2A1 in the diagnostic workup of glucose transporter 1 deficiency syndrome.

The study aimed to investigate the role of molecular analysis of SLC2A1 in the diagnostic workup of glucose transporter 1 deficiency syndrome (Glut1DS). During 2006-2020, we received 100 requests for SLC2A1 variant analysis of patients clinically suspected for Glut1DS. Pathogenic variants were detected in 37 patients, among whom 11 were familial cases. Most patients presented with epilepsy (n = 31; 84%), movement disorders (MD) (n = 28; 76%), and intellectual disabilities (ID) (n = 29; 78%). Moreover, paroxysmal dyskinesias (PD) (n = 10; 27%) were more frequently seen in familial cases (55%) than in sporadic cases (15%) (p < .05). The Glut1DS patients with ID typically had either epilepsy or MD. The presence of MD, particularly when associated with epilepsy or ID, indicated Glut1DS (p < .05). The cerebrospinal fluid (CSF) glucose levels were at or below the 10th percentile in all 32 SLC2A1-positive patients but only in 16 of 52 (31%) SLC2A1-negative patients (p < .05). Thus, CSF analysis is an essential tool in the diagnostic workup of Glut1DS. SLC2A1 molecular analysis should be performed in patients with a family history of Glut1DS or with at least one of the following clinical features, such as epilepsy, MD, and PD with or without ID, and low CSF glucose level. This would help in precise molecular diagnosis of the disease and facilitate effective treatment and appropriate genetic counseling.

Preoperative concurrent endocrine therapy with chemotherapy in luminal B-like breast cancer.

PURPOSE: Luminal B-like breast cancer is sensitive to both chemotherapy and endocrine therapy. We aimed to assess the safety and efficacy of concomitant chemotherapy and endocrine therapy compared with chemotherapy alone in the preoperative setting in luminal B-like breast cancer. METHODS: This two-arm randomized clinical trial enrolled patients with luminal B-like human epithelial growth factor 2-negative breast cancer, who were randomly assigned at a 1:1 ratio to receive preoperative chemotherapy alone or preoperative endocrine therapy concurrent with chemotherapy for 24 weeks before surgery. The primary endpoint was the pathological complete response (pCR) rate. The secondary endpoints included the clinical response rate, toxicity, and health-related quality of life (HRQOL). RESULTS: Overall, 70 patients were randomly assigned to the chemotherapy and chemo-endocrine therapy groups. The pCR rates were 9.7% and 3.0% (P = 0.319), and the clinical complete response rates were 5.9% and 5.6% (P = 0.745) in the chemotherapy and chemo-endocrine therapy groups, respectively. There were no clear differences in treatment-related adverse events or HRQOL between the two groups. CONCLUSIONS: In patients with luminal B-like breast cancer, the pCR, clinical response rate, toxicity, and HRQOL with the concomitant administration of endocrine therapy and chemotherapy were not superior to chemotherapy alone in the preoperative setting.

Balloon-assisted Onyx Embolization in the Management of Complicated Dural Arterioevenous Fistula.

Objective: Dural arteriovenous fistula (dAVF) is an abnormal vascular communication between the meningeal artery and vein at the dura mater, with frequent recruitment of collateral arterial pedicles. In recent years, Onyx embolization has become the mainstay intervention for dAVF at various locations, although an unfavorable vascular anatomy often limits effective obliteration of the lesion. Balloon assistance may facilitate curable occlusion of the abnormal shunt with Onyx while preserving the patency of the affected sinus, even in complicated dAVFs. Methods: We retrospectively reviewed the clinical and angiographic findings of patients with dAVF treated endovascularly in our institution between September 2018 and August 2019. Based on the detailed analysis of individual angioarchitecture, we defined complicated dAVF as lesions for which a complete cure is considered difficult to achieve with simple transarterial Onyx embolization alone, primarily due to a high flow and/or diffuse shunt with or without drainage to the functioning but compromised sinus. We evaluated the preoperative symptoms, anatomical classification, endovascular procedure, radiologic results, and clinical outcomes of these patients. Results: Five patients met our criteria, all of whom were treated with balloon-assisted Onyx embolization (two superior sagittal sinus dAVF, two transverse-sigmoid sinus dAVF, and one torcular dAVF). In four cases, Onyx was injected from a tiny branch of the middle meningeal artery under balloon occlusion of the collateral arteries or balloon devascularization of the competitive inflow. In three cases, balloon sinus protection was performed to prevent the inadvertent occlusion of the vital venous outflow with Onyx. In one case, for the complementary occlusion of the remnant shunt through the previously coiled but recanalized occipital artery, Onyx was injected from the wire lumen of a dual-lumen balloon catheter to avoid undesirable reflux. The angiographic results were an anatomical cure in four cases and near-complete occlusion in one case. No procedural complications were observed in any cases. The clinical outcome was a complete cure in four cases and improvement in one case. Conclusion: Our cases suggest that balloon devascularization can improve the unfavorable flow environment and simplify the vascular anatomy. Balloon sinus protection can support not only securing the patency of the normal venous outflow but also encourage aggressive intervention. Onyx injection via a dual-lumen balloon catheter can augment the controllability of embolization while preventing reflux. Each of these techniques can facilitate safe and effective Onyx embolization in the treatment of complicated dAVFs, and their combination may further expand the therapeutic horizon.

Prospective Registry of Embolization of Intracranial Aneurysms Using HydroSoft Coils: Results of the Japanese HydroSoft Registry.

BACKGROUND: The effect of HydroSoft coils on the prevention of recanalization and thrombosis after embolization is unclear. We herein report the results of the single-armed prospective Japanese HydroSoft Registry. METHODS: Aneurysms with a diameter of <10 mm that were treated with a ≥50% length of HydroSoft coils were registered. We evaluated the safety and recanalization rate and analyzed the factors related to their recanalization and thrombosis 1 year later. RESULTS: In total, 122 aneurysms were registered. Their mean maximum diameter and neck length were 6.4 and 3.9 mm, respectively. The mean length of the HydroSoft coils was 84.3%. No intracranial hemorrhage occurred, but 2 patients developed minor ischemic strokes. Angiographic examination immediately after the procedure showed complete obliteration, neck remnant (NR), and body filling (BF) in 20 (16.4%), 32 (26.2%), and 67 (54.9%) cases, respectively. One-year follow-up angiography showed complete obliteration, NR, and BF in 68 (55.7%), 15 (12.3%), and 15 (12.3%) cases, respectively, and 5 aneurysms (4.1%) were recanalized (4 and 1 with BF and NR as their initial angiographic result, respectively). Another 11 aneurysms still showed BF, although their thrombosis was promoted. No significant factors related to recanalization were identified. A high volume embolization ratio and small neck were significantly associated with thrombosis 1 year after embolization with HydroSoft coils. CONCLUSIONS: The safety and prevention of recanalization 1 year after the treatment appeared acceptable. The high volume embolization ratio associated with HydroSoft coils could induce progression of thrombosis for aneurysms characterized by NR and BF during the follow-up period.

Effectiveness of staged angioplasty for avoidance of cerebral hyperperfusion syndrome after carotid revascularization.

OBJECTIVECerebral hyperperfusion syndrome (CHS) is a serious complication after carotid artery stenting (CAS). Staged angioplasty (SAP)-i.e., angioplasty followed by delayed CAS-has been reported as a potential CHS-avoiding procedure. The purpose of this study was to clarify the effectiveness of SAP in avoiding CHS after carotid revascularization for patients at high risk for this complication.METHODSThe authors retrospectively studied cases involving patients at high risk for CHS from 44 Japanese centers who were scheduled for SAP, regular CAS, angioplasty, or staged procedures other than SAP between October 2007 and March 2014. They investigated the rate of CHS in the population scheduled for SAP or regular CAS, and for safety analysis, the composite rate of transient ischemic attack (TIA) and ischemic stroke in the population eventually receiving SAP or regular CAS.RESULTSData from a total of 525 patients (532 lesions, mean age 72.5 ± 7.5 years, 74 women ) were analyzed. Scheduled procedures included SAP for 113 lesions and regular CAS for 419 lesions. The rate of CHS was lower in the SAP group than in the regular CAS group (4.4% vs 10.5%, p = 0.047). Multivariate analysis showed that SAP was negatively related to CHS (OR 0.315; 95% CI 0.120-0.828). In the population eventually receiving SAP (102 lesions) or regular CAS (428 lesions), the composite rate of TIA and ischemic stroke was comparable between the SAP group and the regular CAS group (9.8% vs 9.3%).CONCLUSIONSSAP may be an effective and safe carotid revascularization procedure to avoid CHS.

Multiple aneurysms on the subarcuate artery arising from the anterior inferior cerebellar artery in a patient with a Borden type I transverse-sigmoid dural arteriovenous fistula manifesting as subarachnoid hemorrhage: A case report.

BACKGROUND: Peripheral anterior inferior cerebellar artery (AICA) aneurysms are rare and commonly associated with vascular malformations, such as cerebellar arteriovenous malformations (AVMs). We present a case wherein multiple AICA feeding aneurysms on the subarcuate artery as a feeding artery of a Borden type I transverse-sigmoid dural arteriovenous fistula (dAVF) manifested as subarachnoid hemorrhage. CASE DESCRIPTION: A 67-year-old woman presented with acute severe headache. Brain computed tomography (CT) demonstrated subarachnoid hemorrhage mainly in the posterior fossa. A transverse-sigmoid dAVF was detected on magnetic resonance angiography (MRA) and three-dimensional-CT angiography (3D-CTA), with no cortical venous reflex. The patient underwent conventional angiography, which showed multiple aneurysms on a small branch of the AICA, feeding a transverse-sigmoid dAVF (Borden type I). The AICA aneurysms seemed flow dependent and ruptured owing to high-flow arteriovenous shunts through the dAVF. Based on the source images of the MRA, the small artery arising from the AICA was considered the subarcuate artery, and it was confirmed on 3D-CTA after the artery was successfully embolized with Onyx without any complications. Multiple aneurysms on the subarcuate artery are extremely rare, and the artery has not been identified as a feeding artery of the transverse-sigmoid dAVF. CONCLUSION: A rare case of multiple ruptured aneurysms on the subarcuate artery was reported in a patient with a Borden type I dAVF at the transverse-sigmoid sinuses manifesting as subarachnoid hemorrhage. Onyx embolization of the parent artery occlusion was feasible and useful in treating this type of feeding artery aneurysm of the AICA with a dAVF.

Safety and efficacy of verinurad, a selective URAT1 inhibitor, for the treatment of patients with gout and/or asymptomatic hyperuricemia in the United States and Japan: Findings from two phase II trials.

Objective: Evaluate efficacy/safety of verinurad monotherapy in patients with gout (Japan/US) or asymptomatic hyperuricemia (Japan).Methods: Two randomized, placebo-controlled, phase II studies were conducted (NCT01927198/NCT02078219). Patients were randomized to once-daily doses of placebo or escalating doses of verinurad (study 1: 5-12.5 mg; study 2: 2.5-15 mg). Primary endpoint was percentage change from baseline in serum urate (sUA) at week 12 (study 1)/week 16 (study 2). Safety was also assessed.Results: Most patients in study 1 (n = 171) were white (74.9%); all patients were Japanese in study 2 (n = 204). Least squares means (±SE) estimate of percentage change in sUA levels from baseline in study 1 was 1.2 ± 2.9 for placebo, and -17.5 ± 2.8, -29.1 ± 2.8, -34.4 ± 2.9 for verinurad 5, 10, 12.5 mg, respectively. In study 2, results were -2.4 ± 2.5 and -31.7 ± 2.5, -51.7 ± 2.6,-55.8 ± 2.5, respectively. Difference from placebo was significant for each verinurad dose (p<.0001). The proportion of patients with treatment-emergent adverse events (TEAEs) was similar across all groups. Renal-related TEAEs were more common with verinurad than placebo.Conclusion: Verinurad monotherapy resulted in sustained reductions in sUA in Japanese/US patients but renal AEs occurred, so verinurad alone is not recommended for treatment of hyperuricemia or gout. The renal consequences of excessive uric acid excretion deserve study.

Verinurad combined with febuxostat in Japanese adults with gout or asymptomatic hyperuricaemia: a phase 2a, open-label study.

Objectives: Verinurad (RDEA3170) is a high-affinity inhibitor of the URAT1 transporter in clinical development for treating gout and asymptomatic hyperuricaemia. The aim of this Phase 2a, randomized, open-label study was to investigate the multiple-dose pharmacodynamics, pharmacokinetics and safety of oral verinurad combined with febuxostat vs febuxostat alone and verinurad alone. Methods: Japanese male subjects aged 21-65 years with gout (n = 37) or asymptomatic hyperuricaemia (n = 35) and serum urate (sUA) ⩾8 mg/dl were randomized to febuxostat (10, 20, 40 mg) in combination with verinurad (2.5-10 mg), verinurad alone (2.5-15 mg), febuxostat alone (10, 20, 40 mg) or benzbromarone alone (50 mg). There were four treatment periods per cohort and each treatment period was 7 days. Study drugs were administered once-daily after breakfast. Plasma, serum and urine samples were measured at pre-set intervals on days -1, 7, 14, 21 and 28. Results: Verinurad combined with febuxostat decreased sUA in dose-dependent manner, providing greater sUA lowering than febuxostat alone at the same dose (P < 0.001). Urinary uric acid excretion rate was increased by verinurad, reduced by febuxostat and comparable to baseline for verinurad combined with febuxostat. Verinurad from 2.5 mg to 15 mg was well tolerated, with no withdrawals due to adverse events. Laboratory assessments showed no clinically meaningful changes during combination treatment. Conclusion: Verinurad combined with febuxostat decreased sUA dose-dependently while maintaining uric acid excretion similar to baseline. All dose combinations of verinurad and febuxostat were generally well tolerated. These data support continued investigation of oral verinurad in patients with gout. Trial registration: ClinicalTrials.gov, https://clinicaltrials.gov, NCT02317861.

Regulation of a distinct activated RIPK1 intermediate bridging complex I and complex II in TNFα-mediated apoptosis.

Stimulation of cells with TNFα can promote distinct cell death pathways, including RIPK1-independent apoptosis, necroptosis, and RIPK1-dependent apoptosis (RDA)-the latter of which we still know little about. Here we show that RDA involves the rapid formation of a distinct detergent-insoluble, highly ubiquitinated, and activated RIPK1 pool, termed "iuRIPK1." iuRIPK1 forms after RIPK1 activation in TNF-receptor-associated complex I, and before cytosolic complex II formation and caspase activation. To identify regulators of iuRIPK1 formation and RIPK1 activation in RDA, we conducted a targeted siRNA screen of 1,288 genes. We found that NEK1, whose loss-of-function mutations have been identified in 3% of ALS patients, binds to activated RIPK1 and restricts RDA by negatively regulating formation of iuRIPK1, while LRRK2, a kinase implicated in Parkinson's disease, promotes RIPK1 activation and association with complex I in RDA. Further, the E3 ligases APC11 and c-Cbl promote RDA, and c-Cbl is recruited to complex I in RDA, where it promotes prodeath K63-ubiquitination of RIPK1 to lead to iuRIPK1 formation. Finally, we show that two different modes of necroptosis induction by TNFα exist which are differentially regulated by iuRIPK1 formation. Overall, this work reveals a distinct mechanism of RIPK1 activation that mediates the signaling mechanism of RDA as well as a type of necroptosis.

Efficacy and Safety of REVIVE SE Thrombectomy Device for Acute Ischemic Stroke: River JAPAN (Reperfuse Ischemic Vessels with Endovascular Recanalization Device in Japan).

REVIVE SE (REVIVE) is a closed-ended, self-expanding stent retriever used in the RIVER JAPAN study. We present our early experience with REVIVE for revascularization of acute ischemic stroke (AIS) in patients who have failed or are ineligible for intravenous recombinant tissue plasminogen activator treatment. This prospective, single-arm, non-randomized, multicenter registry study followed up patients undergoing mechanical thrombectomy with REVIVE for 90 days. The primary endpoint was a post-procedure Thrombolysis in Cerebral Infarction (TICI) score ≥2a. Secondary endpoints were clot migration/embolization; recanalization without symptomatic intracranial hemorrhage (ICH) at 24 h; symptomatic ICH; good neurological outcome (modified Rankin Scale score ≤2 National Institute of Health Stroke Scale (NIHSS) score decrease ≥10) at day 90; device- or procedure-related serious adverse events (SAEs) and mortality at day 90. To confirm non-inferiority of REVIVE, results were compared with historical data of the Merci Retriever. About 49 patients were enrolled (median age 73 years; males 46.9%; middle cerebral artery (MCA) occlusion 83.7%; median NIHSS score 17). A post-procedure TICI score ≥2a was observed in 73.5% (36/49, 95% confidence interval [CI] 58.9-85.1) of patients. No post-procedural clot migration/embolization events occurred. Successful recanalization without symptomatic ICH was observed in 62.5% (30/48, 95% CI 47.4-76.0). The good neurological outcome was achieved in 66.7% (32/48) patients. Symptomatic ICH and device- or procedure-related SAEs were reported in 6.3% and 12.2% of patients, respectively. Two deaths were reported. REVIVE demonstrated equivalent efficacy and safety as the Merci Retriever. Results suggest that REVIVE is effective and safe in recanalizing occluded intracranial arteries in AIS.

Questionnaire survey on the current status of ketogenic diet therapy in patients with glucose transporter 1 deficiency syndrome (GLUT1DS) in Japan.

OBJECTIVES: We conducted a questionnaire survey on the efficacy and side effects of ketogenic diet (KD) therapy in patients with glucose transporter 1 deficiency syndrome (GLUT1DS) as well as issues associated with long-term KD therapy from the viewpoint of patients' families. SUBJECTS AND METHODS: The subjects were 34 patients whose ages at the time of the survey ranged between 2 and 50 years (median, 11 years). The ages at the diagnosis ranged between 3 months and 48 years and 5 months (median, 4 years and 10 months), and KD therapy was started within 5 months in all patients. RESULTS: The types of KD therapies used were modified Atkins diet (MAD) in 18 patients (53%), MCT (medium chain triglyceride)-KD in 9 (26%), classic KD in 5 (15%), LGIT (low-glycemic index treatment) in 1 (3%), and unspecified diet in 1 (3%). Epileptic seizures improved by more than 90% in 17 patients, by 50-89% in 9, by less than 50% in 3, and an unknown percentage in 5. Neurological symptoms other than the epileptic seizures improved markedly, moderately, and mildly in 14, 5, and 7 patients, respectively, and did not improve in 2. The side effects of KD therapy were seen in 9 patients and it was subsequently discontinued in one. CONCLUSIONS: The families of patients showed a high level of satisfaction with the efficacy of KD therapy for the neurological symptoms. However, in order to continue KD therapy for a long period of time, its tolerability needs to be improved.