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.

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.

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 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.

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.

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.

Chronic subdural hematoma infected by propionibacterium acnes: a case report.

We present a very rare case of a patient with an infected subdural hematoma due to Propionibacterium acnes. A 63-year-old male complained of dizziness and was admitted to our hospital. He had a history of left chronic subdural hematoma due to a traffic accident, which had been conservatively treated. Physical, neurological and laboratory examinations revealed no definite abnormality. Plain CT scan demonstrated a hypodense crescentic fluid collection over the surface of the left cerebral hemisphere. The patient was diagnosed with chronic subdural hematoma and underwent burr hole surgery three times and selective embolization of the middle meningeal artery, but the lesion easily recurred. Repeated culture examinations of white sedimentation detected P. acnes. Therefore, he underwent craniotomy surgery followed by intravenous administration of antibiotics. The infected subdural hematoma was covered with a thick, yellowish outer membrane, and the large volume of pus and hematoma was removed. However, the lesion recurred again and a low-density area developed in the left frontal lobe. Craniotomy surgery was performed a second time, and two Penrose drainages were put in both the epidural and subdural spaces. Subsequently, the lesions completely resolved and he was discharged without any neurological deficits. Infected subdural hematoma may be refractory to burr hole surgery or craniotomy alone, in which case aggressive treatment with craniotomy and continuous drainage should be indicated before the brain parenchyma suffers irreversible damage.

[Complete remission of consciousness disturbances and spasticity due to a severe subarachnoid hemorrhage after intrathecal baclofen therapy: a case report].

Typically, intrathecal baclofen therapy(ITB)for spasticity is continuously required because the spasticity can recur if the ITB is stopped. Thus, an infusion pump for the ITB is permanently implanted. Some sporadic cases exhibiting remarkable improvements in their spasticity and consciousness disturbances have been reported after implanting the ITB pump. We experienced a rare case involving removal of the ITB pump after the spasticity resolved and the consciousness disturbances markedly improved. A 15-year-old girl developed a subarachnoid hemorrhage due to rupture of an aneurysm in the right anterior cerebral artery. Her initial Glasgow Coma Scale score was 4(E1V1M2). Trapping of the aneurysm and decompression craniotomy were performed. Subsequently, she underwent a tracheotomy, and a percutaneous gastrostomy(PEG)tube was implanted because of persistent consciousness disturbances. Cranioplasty and lumbar-peritoneal shunt for normal pressure hydrocephalus were performed after 1 month. An ITB pump was implanted to improve the spasticity observed mainly in the lower extremities 61 days after hemorrhage onset. Right hemiparesis remained due to Kernohan's notch. After transfer to the rehabilitation hospital, her consciousness disturbances and spasticity remarkably improved(1.9 to 1.0 and 3.5 to 1.0 on the Ashworth scale for the upper and lower extremities, respectively). The tracheostomy and PEG tubes were removed, and the baclofen dose was gradually reduced. She was completely off baclofen after 7 months, and she was discharged with a short leg brace and a cane for walking. The baclofen pump was then removed. In this case, temporary ITB improved the spasticity and consciousness disturbances.

Stereotactic neurosurgery for writer's cramp: report of two cases with an overview of the literature.

BACKGROUND: Writer's cramp is a specific movement disorder with hand muscle cramps in writing, being classified into focal and action-specific dystonia. Stereotactic surgery, such as thalamotomy and deep brain stimulation (DBS), has been reported for writer's cramp; however, the number of reported cases is still scarce and surgical procedures are also controversial. OBJECTIVES: In this study, therefore, we present 2 patients who underwent thalamotomy for writer's cramp and systematically review the literature on stereotactic surgery for writer's cramp. METHODS: Case reports and literature review are presented. RESULTS: Both patients underwent ventral oral nucleus (Vo) thalamotomy safely. Their symptoms completely disappeared after surgery and did not recur during follow-up periods. In the literature, a total of 31 cases were surgically treated for writer's cramp. Stereotactic surgery included thalamotomy in 25 cases and DBS in 6. The target included the Vo in 17 cases, the ventral intermediate nucleus (Vim) in 3, and both Vo and Vim in 7. Both procedures markedly improved or resolved the symptoms. Transient neurological deficits were observed in 16.0% of patients after thalamotomy. CONCLUSIONS: The Vo may be the most effective target to treat writer's cramp. Both thalamotomy and DBS are feasible and effective, but thalamotomy would be a better option, especially in younger or high-risk patients.

Impact of bilateral subthalamic stimulation on motor/cognitive functions in Parkinson's disease.

It is still unclear whether deep brain stimulation targeted to the bilateral subthalamic nucleus (STN-DBS) affects cognitive function in Parkinson's disease (PD). This prospective study was aimed to systemically evaluate the impact of bilateral STN-DBS on motor and cognitive functions in patients with PD. This study included totally 11 Japanese patients with medically intolerant PD. Neurological and cognitive status was precisely evaluated before and 1 year after bilateral STN-DBS, using unified Parkinson's disease rating scale (UPDRS), levodopa equivalent doses, mini-mental state examination (MMSE), Japanese adult reading test (JART), repeatable battery for the assessment of neuropsychological status (RBANS), and Wechsler adult intelligence scale-revised (WAIS-R). Preoperative RBANS and WAIS-R identified cognitive dysfunction that could not be detected by MMSE and JART. Before surgery, PD patients had significantly impaired immediate memory and attention. Motor function significantly improved 1 year after bilateral STN-DBS. Bilateral STN-DBS did not affect any score on cognitive examinations. However, postoperative improvements of total score on RBANS and performance intelligence quotient (PIQ) scores on WAIS-R were closely related to those of UPDRS part III off (R(2) = 0.61, P < 0.01; R(2) = 0.39, P < 0.05, respectively). These findings strongly suggest that bilateral STN-DBS may significantly improve cognitive function in a certain subgroup of patients whose therapeutic effects on motor function are prominent.

Bilateral subthalamic deep brain stimulation for camptocormia associated with Parkinson's disease.

BACKGROUND: Few multiple case studies of the effects of deep brain stimulation for camptocormia associated with Parkinson's disease have been reported. Although deep brain stimulation was in some cases not effective against camptocormia, it is unclear in which types of patients it was effective in treating camptocormia. OBJECTIVE: We treated 4 Parkinson's disease patients with camptocormia and evaluated their paraspinal muscle status by computed tomography to specify the characteristics of cases of effective treatment. METHODS: The 2 female and 2 male patients in this study were 60-69 years old, with a disease duration from onset to surgery of 7-13 years and a follow-up period of 18-40 months. The electrodes were implanted bilaterally in the subthalamic nuclei. RESULTS: Camptocormia was improved in 3 cases, and was unchanged in the remaining case although other parkinsonian symptoms improved. The computed tomography number of paraspinal muscle in the unimproved patient was much smaller than that in the improved patients. CONCLUSIONS: A relationship may exist between improvement of camptocormia and severity of paraspinal muscle degeneration.

Thoracic vertebral cavernous hemangioma in a schizophrenic patient--case report.

A 55-year-old man presented with gait disturbance, incontinence, and back pain. He had a medical history of schizophrenia for the past 35 years. Computed tomography (CT) and magnetic resonance imaging suggested thoracic vertebral hemangioma. Dynamic CT incidentally detected a hepatic hemangioma. Laminectomy of T3 and T4, resection of the epidural hemangioma, and rigid instrumentation between T1 and T6 using rod and hook systems were performed. Postoperatively, his symptoms completely disappeared and the histological diagnosis was capillary hemangioma. Schizophrenic patients have diminished sensitivity to pain or other symptoms, so neurological symptoms may become severe. However, early and appropriate treatment can result in satisfactory neurological outcome. The patient had a rare association of vertebral hemangioma and hepatic hemangioma, which may be a chance occurrence.

Chemical and immunochemical detection of 8-halogenated deoxyguanosines at early stage inflammation.

Myeloperoxidase (MPO) generates reactive halogenating species that can modify DNA. The aim of this study was to investigate the formation of 8-halogenated 2'-deoxyguanosines (8- halo-dGs) during inflammatory events. 8-Bromo-2'-dG (8-BrdG) and 8-chloro-2'-dG (8-CldG) were generated by treatment of MPO with hydrogen peroxide at physiological concentrations of Cl(-) and Br(-). The formation of 8-halo-dGs with other oxidative stress biomarkers in lipopolysaccharide-treated rats was assessed by liquid chromatography tandem mass spectrometry and immunohistochemistry using a novel monoclonal antibody (mAb8B3) to 8-BrdG-conjugated keyhole limpet hemocyanin. The antibody recognized both 8-BrdG and 8-CldG. In the liver of lipopolysaccharide-treated rats, immunostaining for 8-halo-dGs, halogenated tyrosines, and MPO were increased at 8 h, whereas those of 8-oxo-2'-dG (8-OxodG) and 3-nitrotyrosine were increased at 24 h. Urinary excretion of both 8-CldG and 8-BrdG was also observed earlier than those of 8-OxodG and modified tyrosines (3-nitrotyrosine, 3-chlorotyrosine, and 3- bromotyrosine). Moreover, the levels of the 8-halo-dGs in urine from human diabetic patients were 8-fold higher than in healthy subjects (n = 10, healthy and diabetic, p < 0.0001), whereas there was a moderate difference in 8-OxodG between the two groups (p < 0.001). Interestingly, positive mAb8B3 antibody staining was observed in liver tissue from hepatocellular carcinoma patients but not in liver tissue from human cirrhosis patients. These data suggest that 8-halo-dGs may be potential biomarkers of early inflammation.

Safe removal of glioblastoma near the angular gyrus by awake surgery preserving calculation ability--case report.

A 67-year-old patient presented with progressive agraphia, alexia, and impaired ability to calculate persisting for 4 weeks. He showed preserved ability to do single-digit addition and subtraction. Magnetic resonance imaging demonstrated a tumor in the left parietal lobe. A malignant glioma was suspected, and awake craniotomy was performed to remove the tumor with functional cortical mapping to determine the cortices involved in calculation and language. His calculation ability was mapped on the angular gyrus, and partial resection of the tumor was achieved without deterioration of that ability. The histological diagnosis was glioblastoma multiforme. The patient's calculation ability improved dramatically after the operation.

Mechanical injury of the subthalamic area during stereotactic surgery followed by improvement of trunk, neck, and face tremor--case report--.

A 50-year-old man had undergone right nucleus ventrointermedius (Vim) thalamotomy 1 year previously, resulting in the disappearance of left hand tremor. However, he presented with right distal and proximal tremor including the axial trunk, neck, and head. Deep brain stimulation (DBS) of the left Vim for these symptoms was unsuccessful. Attempts were made to stimulate the left Vim, nucleus ventralis lateralis, and subthalamic nucleus (STN), but no significant improvement was obtained after repeat surgery. However, subsequent improvement of the symptoms including proximal tremor was very marked even without DBS stimulation. Brain magnetic resonance imaging demonstrated lesion and edema in the posteromedial area of the STN. Mechanical injury of the area caused by the surgical procedures may have contributed to the improvement in his persistent symptoms.