Pembrolizumab-associated Neuronopathy with Improved Lower Limb Somatosensory Evoked Potential After Intravenous Methylprednisolone Treatment: A Case Report.

Cases of neuronopathy associated with immune checkpoint inhibitors (ICIs) have rarely been reported. We herein report a case of ICI-associated neuronopathy. A 54-year-old man underwent chemotherapy for right maxillary sinus cancer. Two months after pembrolizumab treatment, diarrhea, worsening of abnormal sensations, and severe ataxia of the lower limbs were observed. Somatosensory evoked potentials (SEPs) with tibial nerve stimulation showed disappearance of the N21 waveform. A colonic biopsy suggested ICI-associated colitis. Based on these findings, the patient was diagnosed with ICI-associated neuronopathy. Clinical symptoms and SEP findings improved markedly after two courses of intravenous methylprednisolone.

Discovery of a potent, selective, and orally available EGFR C797S mutant inhibitor (DS06652923) with in vivo antitumor activity.

The C797S mutation is one of the major factors behind resistance to the third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs). Herein, we describe the discovery of DS06652923, a novel, potent, and orally available EGFR-triple-mutant inhibitor. Through scaffold hopping from the previously reported nicotinamide derivative, a novel biaryl scaffold was obtained. The potency was successfully enhanced by the introduction of basic substituents based on analysis of the docking study results. In addition, the difluoromethoxy group on the pyrazole ring improved the kinase selectivity by inducing steric clash with the other kinases. The most optimized compound, DS06652923, achieved tumor regression in the Ba/F3 allograft model upon its oral administration.

Diagnostic value of lower extremity ultrasonographic nerve enlargement for differentiating demyelinating Charcot-Marie-Tooth disease from chronic inflammatory demyelinating polyneuropathy.

BACKGROUND AND PURPOSE: We previously reported that nerve enlargement assessment by nerve ultrasonography of the intermediate upper limb is applicable for distinguishing demyelinating Charcot-Marie-Tooth disease (CMT) from chronic inflammatory demyelinating polyneuropathy (CIDP). However, differences in the severity and distribution patterns of lower extremity nerve enlargement have not been established for either disease. Therefore, we examined the utility of lower extremity nerve ultrasonography for differentiating between CMT and CIDP. METHODS: Twelve patients with demyelinating CMT and 17 patients with CIDP were evaluated. The median, ulnar, tibial, and fibular nerves were evaluated in three regions: the distal upper extremity, intermediate upper extremity, and lower extremity. Of the 14 selected screening sites, the number of sites that exhibited nerve enlargement (enlargement site number, ESN) in each region was determined. RESULTS: The screening ESNs in the intermediate region and lower extremities were greater in patients with demyelinating CMT than in patients with CIDP and greater than the ESN in the distal region (p = 0.010, p = 0.001, and p = 0.101, respectively). The ESNs in the intermediate region and lower extremities significantly differed among patients with typical CIDP, CIDP variants, and demyelinating CMT (p = 0.084 and p < 0.001). Among the 14 selected screening sites, the combined upper and lower extremity ESNs exhibited the highest AUC (0.92; p < 0.001). CONCLUSIONS: Combining the upper and lower extremities for ultrasonographic nerve measurement more accurately distinguishes CIDP from demyelinating CMT.

Metastatic Maxillary Gingival Angiosarcoma with Aggressive Growth: A Case Report.

Angiosarcoma is a rare malignant tumor of endothelial origin. It is an aggressive neoplasm with early metastasis and poor prognosis and accounts for approximately 2% of all soft tissue sarcomas. Primary tumors arising in the oral cavity account for only 1% of all angiosarcomas. Here, we report a rare case of metastatic angiosarcoma of the gingiva originating from a primary mediastinal lesion. The patient was an 83-year-old man who presented with a maxillary interincisor tumor; it was a painless mass with rounded superficial necrosis measuring 23 mm× 17 mm on the labial side and 20 mm× 17 mm on the palatal side. The histopathological diagnosis was of an epithelioid angiosarcoma. Imaging revealed lesions in the mediastinum, lungs, liver, and skin. The primary lesion was considered a mediastinal lesion. As the tumor had spread throughout the body, palliative therapy was administered. However, the patient's general condition deteriorated rapidly, and he died 3 weeks after the first visit. Identifying oral metastatic malignancies may result in detection of malignant tumors at other sites; thus, oral and maxillofacial surgeons must maintain a heightened awareness of angiosarcoma.

Detection of episodic nocturnal hypercapnia in patients with neurodegenerative disorders.

PURPOSE: Episodic nocturnal hypercapnia (eNH) in transcutaneous carbon dioxide pressure (PtcCO2) corresponding to rapid eye movement sleep hypoventilation is a useful biomarker for detecting nocturnal hypoventilation. However, the relationship between eNH and neurodegenerative diseases with sleep-related breathing disorders (SRBDs) is unknown. The aim of this study was to evaluate the relationship between eNH and nocturnal hypoventilation in neurodegenerative diseases. METHODS: Patients with neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), multiple system atrophy (MSA), Parkinson's disease, progressive supranuclear palsy, corticobasal syndrome, and idiopathic normal pressure hydrocephalus, were enrolled and received overnight PtcCO2 monitoring. The patients were divided into groups for eNH and sleep-associated hypoventilation (SH) prevalence analysis: A (ALS), B (MSA), and C (others). RESULTS: Among 110 patients, twenty-three (21%) and 10 (9%) of the patients met eNH and SH criteria, respectively. eNH and SH were significantly more frequent in groups A and B than in C. The prevalence of SH in the patients with eNH was 39% whereas most of patients with SH (90%) presented with eNH. Among patients with daytime carbon dioxide pressure in arterial blood ≤ 45 mmHg, eNH frequency was 13%, whereas none of the patients met SH criteria. The frequency of noninvasive positive pressure ventilation after PtcCO2 monitoring was significantly higher in those with than without eNH. CONCLUSIONS: eNH is common in patients with MSA and ALS who present with SRBD. eNH with overnight PtcCO2 monitoring is a useful biomarker to detect hypoventilation among neurodegenerative diseases with different SRBD mechanisms.

Synthesis, activity, and their relationships of 2,4-diaminonicotinamide derivatives as EGFR inhibitors targeting C797S mutation.

The C797S mutation is one of the major factors behind resistance to the third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors. Herein, we describe the discovery of the 2,4-diaminonicotinamide derivative 5j, which shows potent inhibitory activity against EGFR del19/T790M/C797S and L858R/T790M/C797S. We also report the structure-activity relationship of the 2,4-diaminonicotinamide derivatives and the co-crystal structure of 5j and EGFR del19/T790M/C797S.

Swallowing sound evaluation using an electronic stethoscope and artificial intelligence analysis for patients with amyotrophic lateral sclerosis.

Background and purpose: Non-invasive, simple, and repetitive swallowing evaluation is required to prevent aspiration pneumonia in neurological care. We investigated the usefulness of swallowing sound evaluation in patients with amyotrophic lateral sclerosis (ALS) using our new electronic stethoscope artificial intelligence (AI) analysis tool. Methods: We studied patients with ALS who provided written informed consent. We used an electronic stethoscope, placed a Bluetooth-enabled electronic stethoscope on the upper end of the sternum, performed a 3-mL water swallow three times, and remotely identified the intermittent sound components of the water flow caused at that time by AI, with the maximum value as the swallowing sound index. We examined the correlation between the swallowing sound index and patient background, including swallowing-related parameters. Results: We evaluated 24 patients with ALS (age 64.0 ± 11.8 years, 13 women, median duration of illness 17.5 months). The median ALS Functional Rating Scale-Revised (ALSFRS-R) score was 41 (minimum 18, maximum 47). In all cases, the mean swallowing sound index was 0.209 ± 0.088. A multivariate analysis showed that a decrease in the swallowing sound index was significantly associated with a low ALSFRS-R score, an ALSFRS-R bulbar symptom score, % vital capacity, tongue pressure, a Mann Assessment of Swallowing Ability (MASA) score, and a MASA pharyngeal phase-related score. Conclusion: Swallowing sound evaluation using an electronic stethoscope AI analysis showed a correlation with existing indicators in swallowing evaluation in ALS and suggested its usefulness as a new method. This is expected to be a useful examination method in home and remote medical care.

Peak expiratory flow, but not tongue pressure, can predict pneumonia development in older adults.

PURPOSE: Pneumonia is the leading cause of mortality and morbidity in aging populations. Major causes of pneumonia in older adults are swallowing dysfunction and decreased airway clearance capacity, including an impaired cough reflex. Maximal tongue pressure is useful for evaluating swallowing function, and peak expiratory flow indirectly reflects cough strength. However, it is unclear whether they can predict pneumonia development in older adults. In this study, we investigated whether tongue pressure and peak expiratory flow could predict pneumonia development in older adults. METHODS: This two-center prospective observational study included older adults aged 65 years or older without respiratory disease or head and neck cancer. We enrolled 383 consenting participants, many of whom had a history of stroke, and followed them for 2 years. The association between time to pneumonia development and tongue pressure or peak expiratory flow at enrollment was examined in a Cox proportional hazards model. RESULTS: The mean age of the participants was 77.1 ± 6.2 years, and 36.0% of them were women. The mean tongue pressure was 35.4 ± 10.5 kPa and median peak expiratory flow was 218 L/min at enrollment. Six patients developed pneumonia during the study period. A low peak expiratory flow at enrollment was significantly associated with pneumonia development in the multivariate Cox proportional hazards model, but this association was not observed for tongue pressure. CONCLUSION: Decreased peak expiratory flow may predict pneumonia development in older adults. Future studies should investigate interventions for peak expiratory flow improvement.

Discovery of DS-9300: A Highly Potent, Selective, and Once-Daily Oral EP300/CBP Histone Acetyltransferase Inhibitor.

Histone acetylation is a post-translational modification of histones that is catalyzed by histone acetyltransferases (HATs) and plays an essential role in cellular processes. The HAT domain of EP300/CBP has recently emerged as a potential drug target for cancer therapy. Here, we describe the identification of the novel, highly potent, and selective EP300/CBP HAT inhibitor DS-9300. Our optimization efforts using a structure-based drug design approach based on the cocrystal structures of the EP300 HAT domain in complex with compounds 2 and 3 led to the identification of compounds possessing low-nanomolar EP300 HAT inhibitory potency and the ability to inhibit cellular acetylation of histone H3K27. Optimization of the pharmacokinetic properties in this series resulted in compounds with excellent oral systemic exposure, and once-daily oral administration of 16 (DS-9300) demonstrated potent antitumor effects in a castrated VCaP xenograft mouse model without significant body weight loss.

[The Myasthenia Gravis Activities of Daily Living score and associated factors to distinguish the refractory phase in generalized myasthenia gravis patients with 5 years or more disease duration].

Associated factors of the Myasthenia Gravis Activities of Daily Living (MG-ADL) score were investigated in 55 patients who had had generalized MG for more than 5 years. In multivariate analysis, correlates of the MG-ADL score at the last follow-up were the total number of fast-acting treatments (FTs) (standardized regression coefficient 0.617，P < 0.001) and Myasthenia Gravis Foundation of America (MGFA) classification (standardized regression coefficient 0.227，P = 0.032) (F = 32.7，P < 0.001). In patients with a score of 5 or more on MG-ADL at the last follow-up, tendency as follows were seen: 1) early-onset (P = 0.002), 2) longer duration (P = 0.014), 3) high frequency of MGFA classification V (P = 0.017), 4) high frequency of the total number of FTs (P < 0.001), and 5) higher dose of prednisolone at the last follow-up (P = 0.003). MGFA V, early-onset without depending on E-L-T classification, or difficulty of reduction for high doses of prednisolone can be the target of novel treatment for MG, and future prospective study will be expected.

The association between nutritional intake one week after admission and outcome in acute ischemic stroke patients.

OBJECTIVES: Although associations between malnutrition status at stroke admission and poor stroke outcomes have been established, the effect of nutritional intake during the acute phase remains unclear. We aimed to evaluate the associations between nutritional intake one week after admission and the outcome at three months among acute ischemic stroke (AIS) patients. MATERIALS AND METHODS: Consecutive AIS patients were investigated. Nutritional status at admission was evaluated using the Controlling Nutritional Status score, calculated from the serum albumin, lymphocyte count, and total cholesterol. We retrospectively evaluated nutritional intake (energy and protein) one week after admission, and the cutoff value of each nutritional intake level for good outcome was defined as the modified Rankin Scale 0-2 at three months after stroke onset using the receiver operating characteristic curve. RESULTS: Of the 205 patients, 146 patients had good outcomes. Mild initial neurological symptoms and good nutritional status at admission were associated with good outcome. The cutoff value of good outcome for protein intake was 0.812 g/kg/day (sensitivity: 0.884, specificity: 0.509) and that for energy intake was 19.0 kcal/kg/day (sensitivity: 0.918, specificity: 0.424). Those nutritional intake indicators were independently associated with good outcome after adjusting for baseline confounders, including stroke severity and nutritional status at admission (protein intake: odds ratio (OR), 4.04; 95% confidence intervals (CIs), 1.14-13.1, and energy intake: OR, 5.00; 95% CIs, 1.41-17.8, respectively). CONCLUSIONS: Adequate nutritional intake at one week after admission was independently associated with good outcome regardless of the nutritional status at admission or stroke severity.

Prognosis Prediction Using Magnetic Resonance Spectroscopy and Oligoclonal Bands in Central Nervous System Methotrexate-associated Lymphoproliferative Disorder.

Central nervous system methotrexate-associated lymphoproliferative disorder (CNS-MTX-LPD) is rare, but its spontaneous regression has been observed in some patients after withdrawal of agents. We herein report three cases of primary CNS-MTX-LPD that received oral MTX for rheumatoid arthritis. Epstein-Barr virus and oligoclonal bands (OCBs) were positive, while proton magnetic resonance spectroscopy (1H-MRS) showed an elevated lipid peak and slightly elevated choline/N-acetylaspartate ratio in common. After MTX withdrawal, brain lesions showed spontaneous regression in all cases. Our patient's 1H-MRS findings and OCBs may reflect a non-monoclonal lymphoproliferative histology as benign-type lesions in CNS-MTX-LPD.

Short-term or long-term outcomes for stroke patients with cancer according to biological markers.

BACKGROUND: Although hypercoagulability using D-dimer levels may be a useful marker for predicting outcomes in ischemic stroke patients with cancer, other biological markers for predicting outcomes are unclear. We aimed to investigate the associations between several biological markers and short-term or long-term outcomes among ischemic stroke patients with cancer. METHODS: Consecutive acute ischemic stroke patients with cancer (n = 309) were registered. Biological markers such as hemoglobin, albumin, C-reactive protein and D-dimer levels were assessed. Stroke outcomes, namely, a 3-month modified Rankin Scale score indicating poor functional outcome (mRS score of 3-6) and 1-year survival, were assessed. RESULTS: Of the 277 patients who could be assessed for 3 months outcome, 131 patients (47.3%) had a poor outcome at 3 months. Multivariable analysis revealed that increased D-dimer levels and decreased albumin levels were independently associated with poor stroke outcomes (adjusted odds ratio [aOR]: 1.04, 95% confidence interval [CI]: 1.00-1.08, and aOR: 0.50, 95% CI: 0.31-0.80, respectively). Of 309 patients, 70 patients (22.7%) died during the follow-up period (median, 241 days). Multivariate Cox proportional hazard analyses showed that high D-dimer levels and hypoalbuminemia were independently associated with mortality (adjusted hazard ratio [aHR]: 2.65, 95% CI: 1.37-5.12, and aHR: 2.29, 95% CI: 1.21-4.49, respectively). The effect of each biological marker on mortality was notably observed among patients with active cancer but not among those with nonactive cancer. CONCLUSION: Low albumin levels were independently associated with short- and long-term outcomes, as were D-dimer levels, in acute ischemic stroke patients with cancer.

Discovery of EP300/CBP histone acetyltransferase inhibitors through scaffold hopping of 1,4-oxazepane ring.

EP300 and its paralog CBP play an important role in post-translational modification as histone acetyltransferases (HATs). EP300/CBP inhibition has been gaining attention as an anticancer treatment target in recent years. Herein, we describe the identification of a novel, highly selective EP300/CBP inhibitor, compound 11 (DS17701585), by scaffold hopping and structure-based optimization of a high-throughput screening hit 1. Compound 11 (DS17701585) shows dose-dependent inhibition of SRY-box transcription factor 2 (SOX2) mRNA expression in a human lung squamous cell carcinoma cell line LK2-xenografted mouse model.

Perioperative Deep Vein Thrombosis and D-dimer Measurement in Patients with Brain Tumor.

We investigated the appropriate D-dimer cutoff value for each brain tumor type for acute or subacute deep vein thrombosis (DVT) following transcranial brain tumor surgery.In this single-center retrospective study, a cumulative total of 128 patients who underwent transcranial brain tumor surgery were enrolled and classified into the glioma group, the other intracranial malignant tumor group, and the intracranial benign tumor group. Venous ultrasonography was performed if the D-dimer plasma levels were positive (≥1 µg/mL) before surgery and on postoperative day (POD) 3 or 7.Of the 128 cases, DVT developed in 32 (25.0%). Among those, acute or subacute DVT was diagnosed in 22 cases on POD 3 and in 8 cases on POD 7. Compared with DVT-negative cases on POD 3, acute or subacute DVT-positive cases on POD 3 revealed a significant increase in the D-dimer level in all groups combined and in the benign tumor group but not in the glioma group. With regard to DVT on POD 3 in all groups, the receiver operating characteristic curve for the D-dimer level on POD 3 demonstrated a cutoff value of 3.3 µg/mL (sensitivity [0.636] and specificity [0.750]). However, if this cutoff value was used in practice, eight cases would be false-negative with a minimum D-dimer level of 1.5 µg/mL.The D-dimer cutoff value for acute or subacute DVT on POD 3 could be set to 3.3 µg/mL; however, the setting resulted in several false-negative cases. Practically, 1.5 µg/mL of the D-dimer cutoff value on POD 3 might be appropriate to avoid false-negative results.

Increased Serum Alkaline Phosphatase and Functional Outcome in Patients with Acute Ischemic Stroke Presenting a Low Ankle-Brachial Index.

AIMS: Elevated serum alkaline phosphatase (ALP) levels are associated with an increased risk of cerebrocardiovascular diseases. However, the associations of ALP with peripheral arterial disease (PAD) and outcomes in patients with acute ischemic stroke (AIS) are not well-known. METHODS: We examined the association between ALP levels and the ankle-brachial index (ABI) in 2111 consecutive patients with AIS. A poor functional outcome was defined as a modified Rankin Scale (mRS) score of 3-6 at 3 months after stroke. A low ABI was defined as a value of ≤ 0.9. RESULTS: Of the total cohort, 482 patients (22.8%) had a low ABI. ALP levels were higher in patients with a low ABI than in those without (p＜0.001). The multivariable logistic analysis revealed that quartiles of ALP levels were significantly associated with a low ABI (odds ratio [OR]: 1.20, 95% confidence interval [CI]: 1.08-1.33). Of the 1322 patients with a premorbid mRS score of 0-2, 434 patients (32.8%) had a poor outcome. The multivariable analysis revealed that elevated serum ALP levels and a low ABI were independently associated with poor stroke outcomes after adjustment for baseline characteristics (OR: 1.21, 95% CI: 1.07-1.38, and OR: 2.00, 95% CI: 1.40-2.84, respectively). CONCLUSIONS: Increased serum ALP levels are significantly associated with a low ABI. These indicators are independent prognostic factors for poor stroke outcomes at 3 months.

Predictors of Stroke Outcome Extracted from Multivariate Linear Discriminant Analysis or Neural Network Analysis.

AIM: The prediction of functional outcome is essential in the management of acute ischemic stroke patients. We aimed to explore the various prognostic factors with multivariate linear discriminant analysis or neural network analysis and evaluate the associations between candidate factors, baseline characteristics, and outcome. METHODS: Acute ischemic stroke patients (n=1,916) with premorbid modified Rankin Scale (mRS) scores of 0-2 were analyzed. The prediction models with multivariate linear discriminant analysis (quantification theory type II) and neural network analysis (log-linearized Gaussian mixture network) were used to predict poor functional outcome (mRS 3-6 at 3 months) with various prognostic factors added to age, sex, and initial neurological severity at admission. RESULTS: Both models revealed that several nutritional statuses and serum alkaline phosphatase (ALP) levels at admission improved the predictive ability. Of the 1,484 patients without missing data, 560 patients (37.7%) had poor outcomes. The patients with poor outcomes had higher ALP levels than those without (294.3±259.5 vs. 246.3±92.5 U/l, P＜0.001). Multivariable logistic analyses revealed that higher ALP levels (1-SD increase) were independently associated with poor stroke outcomes after adjusting for several confounding factors, including the neurological severity, malnutrition status, and inflammation (odds ratio 1.21, 95% confidence interval 1.02-1.49). Several nutritional indicators extracted from prediction models were also associated with poor outcome. CONCLUSION: Both the multivariate linear discriminant and neural network analyses identified the same indicators, such as nutritional status and serum ALP levels. These indicators were independently associated with functional stroke outcome.

Clinical characteristics and tumor markers in ischemic stroke patients with active cancer.

Cancer-associated ischemic stroke (CAS) refers to a hypercoagulation disorder related to malignant tumors, especially adenocarcinoma. Carbohydrate antigen (CA) 125 is a mucinous serum marker that might reflect hypercoagulation status, but the association between CA 125 and CAS is unclear across various types of cancer. The aim of this study was to investigate the associations among tumor markers, coagulation markers, and clinical factors in acute ischemic stroke (AIS) patients with active cancer. Consecutive AIS patients with active cancer (a diagnosis or ongoing active therapy for cancer within 6 months) were prospectively enrolled at four hospitals. D-dimer, C-reactive protein (CRP), carcinoembryonic antigen (CEA), CA19-9, and CA 125 levels were measured. Of 120 AIS patients with active cancer, 47 were diagnosed with CAS. CA 125 had the strongest correlations with D-dimer and CRP (ρ = 0.543, p < 0.001 and ρ = 0.452, p < 0.001, respectively). The areas under the receiver-operating characteristic curves for the diagnosis of CAS were 0.812 (95% CI 0.718-0.878) for CA 125, 0.714 (95% CI 0.602-0.801) for CEA, and 0.663 (95% CI 0.552-0.759) for CA 19-9. Multivariable analysis revealed that CA 125 levels in the highest quartile (OR 2.91, 95% CI 1.68-5.53), multiple lesions in multiple vascular territories observed on diffusion-weighted imaging, the absence of dyslipidemia, and the absence of atrial fibrillation were independently associated with CAS. Increased CA 125 levels, which indicate hypercoagulability, were useful for diagnosing CAS in AIS patients with active cancer.

A 36-year-old Man with Repeated Short-term Transient Hyperammonemia and Impaired Consciousness with a Confirmed Carbamoyl Phosphate Synthase 1 Gene Monoallelic Mutation.

A 36-year-old man experienced severely impaired consciousness twice after drinking because of hyperammonemia. No abnormal blood tests were found other than ammonia levels. However, magnetic resonance imaging (MRI) showed atrophy of the brain parenchyma. One the second occasion, the patient suffered severe impairment of consciousness, and because of seizures and glossoptosis, mechanical ventilation was started. Urea cycle disorders (UCDs) were assumed to be involved. Genetic testing revealed a monoallelic mutation of the carbamoyl phosphate synthase 1 (CPS1) gene. When transient hyperammonemia of unknown cause occurs repeatedly in adults, an active investigation for UCDs should be conducted.