The first-in-human phase I study of a brain-penetrant mutant IDH1 inhibitor DS-1001 in patients with recurrent or progressive IDH1-mutant gliomas.

BACKGROUND: Approximately 70% of lower-grade gliomas harbor isocitrate dehydrogenase 1 (IDH1) mutations, resulting in the accumulation of oncometabolite D-2-hydroxyglutarate (D-2-HG); this leads to epigenetic dysregulation, oncogenesis, and subsequent clonal expansion. DS-1001 is an oral brain-penetrant mutant IDH1 selective inhibitor. This first-in-human study investigated the safety, pharmacokinetics, pharmacodynamics, and efficacy of DS-1001. METHODS: This was a multicenter, open-label, dose-escalation, phase I study of DS-1001 for recurrent/progressive IDH1-mutant (R132) glioma (N = 47) (NCT03030066). DS-1001 was administered orally at 125-1400 mg twice daily. Dose-escalation used a modified continual reassessment method. RESULTS: The maximum tolerated dose was not reached. Eight patients were continuing treatment at the data cutoff. Most adverse events (AEs) were grade 1-2. Twenty patients (42.6%) experienced at least 1 grade 3 AE. No grade 4 or 5 AEs or serious drug-related AEs were reported. Common AEs (>20%) were skin hyperpigmentation, diarrhea, pruritus, alopecia, arthralgia, nausea, headache, rash, and dry skin. The objective response rates were 17.1% for enhancing tumors and 33.3% for non-enhancing tumors. Median progression-free survival was 10.4 months (95% confidence interval [CI], 6.1 to 17.7 months) and not reached (95% CI, 24.1 to not reached) for the enhancing and non-enhancing glioma cohorts, respectively. Seven on-treatment brain tumor samples showed a significantly lower amount of D-2-HG compared with pre-study archived samples. CONCLUSIONS: DS-1001 was well tolerated with a favorable brain distribution. Recurrent/progressive IDH1-mutant glioma patients responded to treatment. A study of DS-1001 in patients with chemotherapy- and radiotherapy-naïve IDH1-mutated WHO grade 2 glioma is ongoing (NCT04458272).

Cerebrospinal Fluid Leakage to the Chest Subcutaneous Pocket Due to Aggressive Brain Edema around the Leads for Deep Brain Stimulation: A Case Report and Literature Review.

Cerebral edema around the lead has been reported as a complication of deep brain stimulation; however, the causes remain unknown. Herein, we present a rare case of sudden cerebral edema around the lead occurring after deep brain stimulation. This was accompanied by cerebrospinal fluid (CSF) leakage into the subcutaneous thoracic pocket around the implantable pulse generator in a 53-year-old man with Parkinson's disease. No such case has been reported thus far. Lumbar drainage was performed to improve CSF leakage. The cerebral edema initially responded to steroids, but then it stopped responding to treatment. The edema appeared alternately on the left and right sides, and cyst formation was noted around the left lead. There are some reports of cyst formation around the lead; however, in our case, images were used to monitor the edema and cyst from their appearance to their disappearance. Our data suggest that cyst formation and cerebral edema are related.

[Stereotactic and Functional Neurosurgery: Complications and Countermeasures].

Stereotactic and functional neurosurgery(deep brain stimulation[DBS]and radiofrequency coagulation)is an established method of treatment for patients with Parkinson's disease, tremor, and/or dystonia. The surgery involves many pitfalls and is similar to other surgeries, requiring experience and skills. Here, we have discussed three categories of DBS-related complications, including surgical procedure-related and device-related complications, and stimulation-induced side effects. In addition, we have discussed the prevention and coping methods, including those not listed in the guidelines for stereotactic and functional neurosurgery.

Foreign body granuloma around implantable pulse generator for deep brain stimulation: Two case reports.

We report two cases of granuloma that occurred around an implantable pulse generator (IPG) for deep brain stimulation. Both cases showed no signs of infection and disappeared after moving the IPG and removing the granulation. If a noninfectious mass is formed, the relocation of IPG may improve it.

An autopsy case of pure nigropathy with TUBA4A nonsense mutation.

We showed the results of pathological and genetic investigation for an autopsy case who was evaluated as longstanding Parkinson's disease (PD) in alive. Neuropathological investigation showed "pure nigropathy" without Lewy and tau pathology, and genetic analyses using next-generation sequencing detected novel TUBA4A nonsence mutation. Subsequent physiological study added to strength the hypothesis that the variant is pathogenic one. Present case showed TUBA4A is not only responsible gene for amyotrophic lateral sclerosis/frontotemporal dementia but also PD associated pure nigropathy. Also we found minimal but significant tau pathology high possibly associated with long-term deep brain stimulation in subthalamic nucleus.

Bilateral Pallidal Stimulation with Directional Leads for Primary Focal Lingual Dystonia.

There have been limited studies regarding stereotactic and functional neurosurgery for lingual dystonia. Here, we report a patient with primary lingual dystonia who showed significant improvement after bilateral deep brain stimulation (DBS). A 42-year-old woman presented with a 5- to 6-year history of tongue protrusion; however, she lacked a significant medical or medication history before onset. She presented with gradually worsening symptoms and was diagnosed with idiopathic lingual dystonia. Her tongue was injected with botulinum toxin on 6 occasions; however, it had a limited effect. Oral medications were ineffective. She underwent DBS since her involuntary tongue movements were causing nocturnal breathing problems. Directional leads were bilaterally inserted into the internal segment of the globus pallidus (GPi). The directional part of each lead was inserted at the GPi bottom on both sides. The posteromedial contacts were used to deliver stimulation. After 1.5 years, the patient's Burke-Fahn-Marsden dystonia rating scale score improved from 9 to 1.5 and 2 to 1 for movement and disability, respectively. This case demonstrated the effectiveness of bilateral GPi-DBS. Placing the directional part of the lead in the GPi bottom could improve the stimulation effects.

The Hanger Reflex: An Inexpensive and Non-invasive Therapeutic Modality for Dystonia and Neurological Disorders.

The hanger reflex is a phenomenon characterized by the involuntary rotation of the head when a wire hanger is worn around the head such that a force is applied to the frontal temporal area by the longer side of the hanger. The application of a shearing force on the skin is thought to be the cause of this phenomenon. Attempts have been made to treat cervical dystonia using equipment designed to induce the hanger reflex. This reflex may have implications in the treatment of headaches, cervical pain, and adhesive capsulitis. The hanger reflex is seen not only in the head region but is also in other parts of the body. Thus, it could be used in the treatment of systemic dystonias. The hanger reflex may help develop inexpensive and non-invasive treatment for dystonia or other neurological diseases and is expected to be the focus of research in the future.

Discovery of a Potent, Selective, and Orally Available MTHFD2 Inhibitor (DS18561882) with in Vivo Antitumor Activity.

We report the discovery of a potent and isozyme-selective MTHFD2 inhibitor, DS18561882 (2). Through investigation of the substituents on our tricyclic coumarin scaffold (1,2,3,4-tetrahydrochromeno[3,4-c]pyridin-5-one), MTHFD2 inhibitory activity was shown to be elevated by incorporating an amine moiety at the 8-position and a methyl group at the 7-position of the initial lead 1. X-ray structure analysis revealed that a key interaction for enhanced potency was salt bridge formation between the amine moiety and the diphosphate linker of an NAD+ cofactor. Furthermore, ortho-substituted sulfonamide in place of benzoic acid of 1 significantly improved cell permeability and cell-based growth inhibition against a human breast cancer cell line. The thus-optimized DS18561882 showed the strongest cell-based activity (GI50 = 140 nM) in the class, a good oral pharmacokinetic profile, and thereby tumor growth inhibition in a mouse xenograft model upon oral administration.

Pilot Study for Considering Subthalamic Nucleus Anatomy during Stimulation Using Directional Leads.

OBJECTIVE: Directional leads are used for deep brain stimulation (DBS). Two of the four contacts of the leads are divided into three parts, enabling controlled stimulation in a circumferential direction. The direction of adverse effects evoked by DBS in the subthalamic nucleus (STN) and stimulation strategies using directional leads were evaluated. METHODS: Directional leads were implanted into the bilateral STN of six parkinsonian patients (1 man, 5 women; mean age 66.2 years). The contact centers were located within the upper border of the STN, and the locations were identified electrically using microrecordings. Adverse effects were evaluated with electrical stimulation (30 µs, 130 Hz, limit 11 mA) using the directional part of each lead after surgery, and the final stimulation direction was investigated. Unified Parkinson's disease rating scale (UPDRS) scores were evaluated before and after DBS. RESULTS: Fifty-six motor and four sensory symptoms were evoked by stimulation; no adverse effect was evoked in 14 contacts. Motor and sensory symptoms were evoked by stimulation in the anterolateral direction and medial to posterolateral direction, respectively. Stimulation in the posteromedial direction produced adverse effects less frequently. The most frequently used contacts were located above the STN (63%), followed by the upper part of the STN (32%). The mean UPDRS part III and dyskinesia scores decreased after DBS from 30.2 ± 11.7 to 7.2 ± 2.9 and 3.3 ± 2.4 to 0.5 ± 0.8, respectively. CONCLUSION: The incidence of adverse effects was low for the posteromedial stimulation of the STN. Placing the directional part of the lead above the STN may facilitate the control of dyskinesia.

Improvement of Writer's Cramp from an Old Lesion in the Contralateral Hemisphere with Transient Gait Disturbance After Thalamotomy.

BACKGROUND: Stereotactic ventro-oral thalamotomy has been performed in cases of focal task-specific dystonia, including writer's cramp, with excellent outcomes. However, no reports have revealed the outcome of ventro-oral thalamotomy in a patient with a contralateral cerebral lesion. We describe a patient with left-hand writer's cramp with an old lesion in the left hemisphere and transient gait disturbance after right ventro-oral thalamotomy. CASE DESCRIPTION: A 43-year-old man had a hemorrhage in the left basal ganglia due to cerebral arteriovenous malformation at 22 years of age, and right hemiparesis remained as a sequela. He developed left-handed writing ability; however, he became aware of the stiffness of his left hand and difficulty in writing. Writer's cramp was diagnosed. Medical treatments were not effective, and right ventro-oral thalamotomy was performed. Although his writing ability improved, he could not walk. After performing rehabilitation, his walking completely improved, reaching the level before surgery, after 3 months, and his writer's cramp was completely cured. CONCLUSIONS: In patients with basal nucleus lesions, gait disturbance may appear transiently after contralateral thalamotomy. It is crucial to fully explain the potential complications, particularly in relation to temporal gait disturbances, and obtain informed consent.

Pilot Study of a Device to Induce the Hanger Reflex in Patients with Cervical Dystonia.

The hanger reflex (HR) is an involuntary head rotation that occurs in response to a clothes hanger encircling the head and compressing the unilateral fronto-temporal area. Here, we developed an elliptical device to induce the HR and examined its utility for the treatment of cervical dystonia (CD). The study included 19 patients with rotational-type CD. The device was applied to each subject's head for at least 30 min/day for 3 months. Severity scores on part 1 of the Toronto Western Spasmodic Torticollis Rating Scale were evaluated at baseline and after the 3-month trial. Mean scores without and with the device were significantly different both at baseline (16.6 vs. 14.7, respectively; P < 0.05) and after the trial (14.9 vs. 13.6, respectively; P < 0.05). This preliminary trial suggests that our device can improve abnormal head rotation in patients with CD.

Full recovery from drummer's dystonia with foot and arm symptoms after stereotactic ventro-oral thalamotomy: a case report.

Ventro-oral (Vo) thalamotomy is effective in patients with focal task-specific dystonias (FTSDs), but only in those with upper-limb symptoms. We describe a patient with drummer's dystonia who completely recovered after Vo thalamotomy. A 37-year-old man who started playing drums at 14 began having difficulty performing fine movements with his right foot when drumming at 22. He experienced right hand cramps while drumming 3 months before visiting our hospital. He was diagnosed with FTSD. Left Vo thalamotomy was performed, which led to complete improvement of symptoms. Vo thalamotomy may be effective for FTSD patients with upper- and lower-extremity symptoms.

Discovery and structure-guided fragment-linking of 4-(2,3-dichlorobenzoyl)-1-methyl-pyrrole-2-carboxamide as a pyruvate kinase M2 activator.

Tumor cells switch glucose metabolism to aerobic glycolysis by expressing the pyruvate kinase M2 isoform (PKM2) in a low active form, providing glycolytic intermediates as building blocks for biosynthetic processes, and thereby supporting cell proliferation. Activation of PKM2 should invert aerobic glycolysis to an oxidative metabolism and prevent cancer growth. Thus, PKM2 has gained attention as a promising cancer therapy target. To obtain novel PKM2 activators, we conducted a high-throughput screening (HTS). Among several hit compounds, a fragment-like hit compound with low potency but high ligand efficiency was identified. Two molecules of the hit compound bound at one activator binding site, and the molecules were linked based on the crystal structure. Since this linkage succeeded in maintaining the original position of the hit compound, the obtained compound exhibited highly improved potency in an in vitro assay. The linked compound also showed PKM2 activating activity in a cell based assay, and cellular growth inhibition of the A549 cancer cell line. Discovery of this novel scaffold and binding mode of the linked compound provides a valuable platform for the structure-guided design of PKM2 activators.

Why a Catheter Can Be Correctly Placed in the Anterior Horn of Lateral Ventricle by Inserting Perpendicular to the Frontal Bone on the Ventricular Drainage? Demonstration of the Accuracy of an Inserting Path by Computed Tomographic Image Study and Clinical Practices.

Why a catheter can be correctly placed in the ventricle by inserting perpendicular to the frontal bone on the ventricular drainage? We performed a study on the accuracy of a path perpendicular to the skull surface into the anterior horn using computed tomography (CT), and a clinical study. Twenty patients were studied on CT images. Using the curved multi-planar reconstruction method, the curved frontal skull and brain were reconstructed to flat structures, and perpendicular lines were drawn from the flat surface to the foramen of Monro on the reconstructed images. In clinical practice, we made a device which guided a catheter inserting perpendicular to the frontal skull surface, and used it in the ventricular drainage surgery for 148 hydrocephalic patients (158 surgeries). We discovered that the curved surface of the frontal bone around Kocher's point represents the surface of a globe (mean radius, 75.9 ± 4.3 mm) centering on the foramen of Monro. The distribution of points ranged from 13.5-43.5 mm (mean, 43.5 ± 6.1 mm) to the midline, with points appearing more laterally as ventricular size increased. A catheter was placed in the ventricle in 148 surgeries (99.4%), and the catheter reached the ventricle with correct orientation toward the foramen of Monro in 128 (81.0%). The reason why the ventricular insertion perpendicular to the frontal bone surface can provide a consistent path toward the foramen of Monro is that the curved surface of the frontal bone around Kocher's point represents the surface of a globe centered on the foramen of Monro.

Improvement of Table Tennis Dystonia by Stereotactic Ventro-Oral Thalamotomy: A Case Report.

BACKGROUND: Task-specific focal dystonia, such as writer's cramp and musician's cramp, is a type of dystonia that affects performance of particular tasks. Such movement disorders have been treated with stereotactic ventro-oral (Vo) thalamotomy with excellent outcomes. However, there has been no previous report of treatment of sport-related or athlete's dystonia by means of stereotactic surgery. We treated a patient with table tennis-related dystonia with Vo thalamotomy, and evaluated the outcome. CASE DESCRIPTION: A 20-year-old, female, left-handed table tennis player complained of difficulty hitting a ping-pong ball. She started playing table tennis at 8 years of age, practiced for more than 4 hours every day, and participated in national tournaments. Abnormal flexion of the left wrist when hitting a ball became apparent when she was 19 years old. The abnormal movement emerged on the forehand stroke and, subsequently, on the backhand, until finally she could not continue playing. The diagnosis was task-specific focal dystonia that did not recover with medication. She visited our hospital and underwent right Vo thalamotomy. The surgery was performed using local anesthesia, with the patient swinging a paddle during stimulation and coagulation of the thalamus. Her symptoms had improved completely the day after surgery, such that she was able to participate in tournaments again. CONCLUSIONS: We applied Vo thalamotomy for the successful treatment of athlete's dystonia, suggesting that this condition has an underlying mechanism similar to that of other task-specific focal dystonias. This provides new hope to patients with athlete's dystonia refractive to other therapies.

Treatment Result in the Initial Stage of Kanazawa Mobile Embolectomy Team for Acute Ischemic Stroke.

Five recent multicenter randomized controlled trials (RCTs) have clearly shown the superiority of mechanical thrombectomy in large vessel occlusion acute ischemic stroke compared to systemic thrombolysis. Although 14 hospitals in Ishikawa prefecture have uninterrupted availability of systemic thrombolysis, mechanical thrombectomy is not available at all of these hospitals. Therefore, we established a Kanazawa mobile embolectomy team (KMET), which could travel to these hospitals and perform the acute reperfusion therapy. In this article, we report early treatment outcomes and validate the effectiveness of a network between affiliated hospitals and KMET. Between January 2014 and December 2015, 48 patients, aged 45-92 years (mean: 73.0 years), underwent acute reperfusion therapy provided by KMET in 10 affiliated hospitals of Kanazawa University Hospital. The pre-treatment NIHSS scores ranged from 5 to 39 (mean: 19.1). ASPECTS+W ranged from 1 to 11 (mean: 7.3). Successful revascularization, defined as thrombolysis in cerebral infarction (TICI) 2b or 3, was achieved in 38/48 cases (80%), and a good outcome, defined as modified Rankin Scale (mRS) score from 0 to 2 at 90 days after the treatment, was achieved in 24/48 cases (50%). There were two cases of intracranial bleeding (4%). Mean time from onset to recanalization was 297 min. These results, which are similar to those of five previous RCTs, suggest that a collaborative network between affiliated hospitals and KMET is effective for acute reperfusion therapy in local areas wherein experienced neuroendovascular specialists are insufficient.

Phase II Trial of Intravenous Low-Dose Granulocyte Colony-Stimulating Factor in Acute Ischemic Stroke.

BACKGROUND: Granulocyte colony-stimulating factor (G-CSF) has shown neuroprotective and neurogenerative activities in experimental studies, and our previous phase I clinical study suggested the safety and potential efficacy of low-dose G-CSF in acute ischemic stroke patients. The present phase II trial is aimed to evaluate the effect of G-CSF administration on neurological function and infarct volume, compared with a placebo group. METHODS: Forty-nine acute ischemic stroke patients (29 males, 20 females; 71 ± 10 years) within 24 hours after onset were recruited. Eligible patients were randomized 2:2:1 to receive G-CSF 150 µg/body/day, G-CSF 300 µg/body/day, and placebo, respectively. We evaluated clinical outcome in terms of the National Institutes of Health Stroke Scale, the modified Rankin Scale, and the Barthel Index at 90 days after onset, together with changes in infarct volume on magnetic resonance imaging. RESULTS: We found no serious adverse event, including change in leukocyte levels, which remained below 31,000/µL, at 150 and 300 µg G-CSF/body/day. Clinical outcome scores did not show any significant difference among the 3 groups. Chronological changes in infarct volume also showed no significant difference. CONCLUSIONS: G-CSF was well-tolerated at 150 and 300 µg/body/day in patients with acute ischemic stroke. However, administration of G-CSF at both 150 and 300 µg/body/day neither contributed to functional recovery nor reduced infarct volume at 3 months after onset, compared with the control group. The apparent lack of effectiveness may have been due to the small sample size. A trial of combination therapy with recombinant tissue plasminogen activator and G-CSF is planned.

Importance of (123)I-ioflupane SPECT and Myocardial MIBG Scintigraphy to Determine the Candidate of Deep Brain Stimulation for Parkinson's Disease.

(123)I-ioflupane SPECT (DaTscan) is an examination that detects presynaptic dopamine neuronal dysfunction, and has been used as a diagnostic tool to identify degenerative parkinsonism. Additionally, myocardial (123)I-metaiodobenzyl guanidine (MIBG) scintigraphy measures the concentration of cardiac sympathetic nerve fibers and is used to diagnose Parkinson's disease (PD). These exams are used as adjuncts in the diagnosis of parkinsonism, however, the relationship of these two examinations are not well-known. We investigated the relationship of these two scanning results specifically for determining the use of deep brain stimulation therapy (DBS). Subjects were Japanese patients with suspected striatonigral degeneration, including PD; DaTscans and myocardial MIBG scintigraphy were performed. The mean values of the left-right specific binding ratios (SBRs) from the DaTscan, and the early/delayed heart-to-mediastinum ratios (HMRs) from the MIBG scintigraphy were calculated. Using simple linear regression analysis, we compared the SBR and early/delayed HMR values. Twenty-four patients were enrolled in this study. Twenty-one patients were positive via the DaTscan, and the MIBG scintigraphy results showed 14 patients were positive. SBR and both early and delayed HMR were positively correlated in cases of PD, but negative in non-PD cases. A mean SBR value less than 3.0 and a delayed HMR value less than 1.7 indicated a Hoehn-Yahr stage 3 or 4 for PD, which is commonly regarded as a level appropriate for initiating DBS therapy. Our results indicate that performing both DaTscan and MIBG scintigraphy is useful for the evaluation of surgical intervention in PD.

A mushroom-derived amino acid, ergothioneine, is a potential inhibitor of inflammation-related DNA halogenation.

Myeloperoxidase (MPO)-generated halogenating molecules, such as hypochlorous acid and hypobromous acid (HOBr), in inflammatory regions are postulated to contribute to disease progression. In this study, we showed that ergothioneine (EGT), derived from an edible mushroom, inhibited MPO activity as well as the formation of 8-bromo-2'-deoxyguanosine in vitro. The HOBr scavenging effect of EGT is higher than those of ascorbic acid and glutathione. We initially observed that the administration of Coprinus comatus, an edible mushroom containing a high amount of EGT, inhibited the UV-B-induced inflammatory responses and DNA halogenation, suggesting that EGT is a promising anti-inflammatory agent from mushrooms.