A Cerebral Embolism Caused by a Malignant Peripheral Nerve Sheath Tumor in a Patient with Neurofibromatosis Type 1.

A 31-year-old man with neurofibromatosis type 1 (NF-1) had undergone resection of a malignant peripheral nerve sheath tumor (MPNST) on the buttock 3 months previously. He subsequently underwent mechanical thrombectomy for a hyperacute left middle cerebral artery embolism. Histopathologically, the emboli comprised neurofilament-positive pleomorphic tumor cells with geographic necrosis and conspicuous mitosis and were identified as MPNST. The patient died of respiratory failure due to lung MPNST metastasis on day 15 of hospitalization. To our knowledge, this is the first report of a spontaneous cerebral embolism due to MPNST in a NF-1 patient.

Pulmonary endarterectomy for chronic thromboembolic pulmonary hypertension with bronchial obstruction by a carcinoid tumor.

Pulmonary endarterectomy (PEA) is a standard treatment for chronic thromboembolic pulmonary hypertension (CTEPH). CTEPH combined with bronchial obstruction by a tumor is rare but should be assessed carefully because PEA for obstructed segments can be less therapeutic and make the subsequent surgical resection challenging. This report describes a case of CTEPH with bronchial obstruction by a typical carcinoid tumor in a 75-year-old man. On-site evaluation and removal of the obstructive tumor were performed bronchoscopically, increasing the effectiveness of subsequent PEA for all affected pulmonary segments. This report illustrates a PEA strategy to treat CTEPH with bronchial tumor obstruction.

Impact of providing genetics-based future cardiovascular risk on LDL-C in patients with familial hypercholesterolemia.

BACKGROUND: Familial hypercholesterolemia (FH) is an autosomal dominant monogenic disease characterized by high low-density lipoprotein cholesterol (LDL-C) levels. Although carrying causative FH variants is associated with coronary heart disease (CHD), it remains unclear whether disclosing its associated cardiovascular risk affects outcomes in patients with FH. OBJECTIVE: We aimed to evaluate the efficacy of providing future cardiovascular risk based on genetic testing in addition to a standard FH education program. METHODS: We conducted a randomized, wait-list controlled, open-label, single-center trial. In the intervention group, we reported a future cardiovascular risk based on the genetic testing adding to standard FH education at week 0. In the wait-list control group, we only disseminated standard FH education according to the guidelines at week 0; they later received a genetic testing-based cardiovascular risk assessment at week 24. The primary endpoint of this study was the plasma LDL-C level at week 24. RESULTS: Fifty eligible patients with clinically diagnosed FH, without a history of CHD, were allocated to the intervention group (n = 24) or the wait-list control group (n = 26). At week 24, the intervention group had a significantly greater reduction in LDL-C levels than the wait-list control group (mean changes, -13.1 mg/dL vs. 6.6 mg/dL; difference, -19.7 mg/dL; 95% confidence interval, -34 to -5.6; p = 0.009). This interventional effect was consistent with FH causative variant carriers but not with non-carriers. CONCLUSIONS: In addition to standard FH care, providing future cardiovascular risk based on genetic testing can further reduce plasma LDL-C levels, particularly among FH causal variant carriers. REGISTRATION: Japan Registry of Clinical Trials (jRCTs04218002). URL: https://jrct.niph.go.jp/latest-detail/jRCTs042180027.

Primary Presacral Neuroendocrine Tumor Presenting as Multiple Liver Metastasis: A Case Report.

BACKGROUND Various neoplasms, including neuroendocrine neoplasms (NENs), can arise from the presacral space. Most presacral lesions are detected due to symptoms arising from tumor growth. However, diagnosing small, asymptomatic presacral tumors is challenging because of their unique location. CASE REPORT A 63-year-old woman with chronic hepatitis C underwent follow-up after achieving a sustained virological response. Abdominal ultrasonography revealed multiple new hyperechoic masses in the liver. Physical and laboratory examinations, including tumor marker analysis, yielded unremarkable results. Computed tomography (CT) and magnetic resonance imaging (MRI) indicated metastatic liver tumors but failed to identify the primary site of these lesions. The hepatic mass was biopsied, leading to a diagnosis of grade 2 neuroendocrine tumor. 111In-pentetreotide somatostatin receptor scintigraphy revealed significant radiotracer accumulation in multiple hepatic masses, several bones, and a small presacral space lesion. Pathological examination of the presacral lesion confirmed a grade 2 neuroendocrine tumor, similar to the hepatic mass. Review of a CT scan performed 4 years earlier indicated a small cyst-like lesion in the presacral space suspected of being a developmental cyst; however, the presence of cystic components was not confirmed pathologically. The patient was diagnosed with a primary presacral neuroendocrine tumor, which might have originated from a developmental cyst, with multiple liver metastases. Chemotherapy with everolimus was initiated, and the clinical course has been uneventful. CONCLUSIONS We report a rare neuroendocrine tumor arising from the presacral space with multiple liver metastases. The presacral space should be examined when a NEN with an unknown primary site is found.

Three cases of subcorneal pustular dermatosis with immunohistochemical examinations.

Subcorneal pustular dermatosis, a rare, benign skin disease, is a type of neutrophilic dermatosis. The authors reported three cases of subcorneal pustular dermatosis. In case 1, a 9-year-old girl developed a skin rash with blisters following a mycoplasma infection and had a flare-up due to a common cold. She was successfully treated with a topical corticosteroid. In case 2, a 70-year-old woman who had been treated for rheumatoid arthritis with adalimumab, salazosulfapyridine, and leflunomide developed 3- to 5-mm pustules on her trunk and thighs 4 days after flu vaccination. The rash disappeared with drug withdrawal and treatment with diaminodiphenyl sulfone. In case 3, an 81-year-old man, who was diagnosed with pyoderma gangrenosum at 61 years old, developed multiple small flaccid pustules on his trunk and extremities due to an infection in the arteriovenous shunt area on the forearm. The pustule disappeared with intravenous antibiotic therapy; however, the pustules subsequently flared up along with ulcers typical of pyoderma gangrenosum. He was given oral prednisolone therapy, which was effective for the small pustules and some ulcers. Immunohistochemical examination of the three cases revealed neutrophilic infiltration in the subcorneal layer of the epidermis. The pustules contained neutrophils as well as some CD68+ and a few CD1a+ cells. The epidermis and dermis were more predominantly infiltrated by CD4+ cells than by CD8+ cells. Positive stainings for interleukin 8, interleukin 36γ, and phospho-extracellular signal-regulated kinases 1 and 2 were observed in the upper layers of the epidermis below the pustules. Although the pathogenesis of subcorneal pustular dermatosis has not been clarified, the current results suggest that a variety of inflammatory cells, including those responsible for both innate and acquired immunity, are involved in the accumulation of neutrophils in subcorneal pustular dermatosis.

The utility of zebrafish cardiac arrhythmia model to predict the pathogenicity of KCNQ1 variants.

Genetic testing for inherited arrhythmias and discriminating pathogenic or benign variants from variants of unknown significance (VUS) is essential for gene-based medicine. KCNQ1 is a causative gene of type 1 long QT syndrome (LQTS), and approximately 30% of the variants found in type 1 LQTS are classified as VUS. We studied the role of zebrafish cardiac arrhythmia model in determining the clinical significance of KCNQ1 variants. We generated homozygous kcnq1 deletion zebrafish (kcnq1del/del) using the CRISPR/Cas9 and expressed human Kv7.1/MinK channels in kcnq1del/del embryos. We dissected the hearts from the thorax at 48 h post-fertilization and measured the transmembrane potential of the ventricle in the zebrafish heart. Action potential duration was calculated as the time interval between peak maximum upstroke velocity and 90% repolarization (APD90). The APD90 of kcnq1del/del embryos was 280 ± 47 ms, which was significantly shortened by injecting KCNQ1 wild-type (WT) cRNA and KCNE1 cRNA (168 ± 26 ms, P < 0.01 vs. kcnq1del/del). A study of two pathogenic variants (S277L and T587M) and one VUS (R451Q) associated with clinically definite LQTS showed that the APD90 of kcnq1del/del embryos with these mutant Kv7.1/MinK channels was significantly longer than that of Kv7.1 WT/MinK channels. Given the functional results of the zebrafish model, R451Q could be reevaluated physiologically from VUS to likely pathogenic. In conclusion, functional analysis using in vivo zebrafish cardiac arrhythmia model can be useful for determining the pathogenicity of loss-of-function variants in patients with LQTS.

Children with Severe Hypercholesterolemia Caused by a Pathogenic Mutation in ABCG5.

We herein present a case series of hypercholesterolemia caused by a pathogenic mutation in the ATP-binding cassette sub-family G member 5 (ABCG5). Three unrelated infantile patients who were breastfed and had extremely elevated low-density lipoprotein (LDL) cholesterol levels were referred to our hospital. Their LDL cholesterol levels decreased significantly after weaning. Panel sequencing revealed a pathogenic mutation in ABCG5 in each patient. An 8-year-old girl was also referred due to suspected familial hypercholesterolemia. Panel sequencing revealed a pathogenic mutation in ABCG5. A cholesterol-reduced diet alone significantly reduced the LDL cholesterol levels. Moreover, the administration of ezetimibe was found to be beneficial.

Spontaneous regression of lymphovascular invasion and metastasis of malignant melanoma: ultrasound findings.

This report presents a case of malignant melanoma in a 40-year-old male who underwent resection of the tumor in his right ankle. Eleven months after the resection, a subcutaneous mass was observed on his right femur. Ultrasound examination revealed a hypoechoic tubular structure in the right thigh, with a small amount of blood flow in the lesion. Using ultrasound and fine-needle aspiration, the patient was diagnosed with metastasis and lymphovascular invasion of malignant melanoma. Treatment with an immune checkpoint inhibitor was originally scheduled, but the lesion disappeared spontaneously after the fine-needle aspiration.

Impact of High-Density Lipoprotein Function, Rather Than High-Density Lipoprotein Cholesterol Level, on Cardiovascular Disease Among Patients With Familial Hypercholesterolemia.

BACKGROUND: Recently, the function of high-density lipoprotein (HDL), rather than the HDL cholesterol (HDL-C) level, has been attracting more attention in risk prediction for coronary artery disease (CAD).Methods and Results: Patients with clinically diagnosed familial hypercholesterolemia (FH; n=108; male/female, 51/57) were assessed cross-sectionally. Serum cholesterol uptake capacity (CUC) levels were determined using our original cell-free assay. Linear regression was used to determine associations between CUC and clinical variables, including low-density lipoprotein cholesterol and the carotid plaque score. Multivariable logistic regression analysis was used to test factors associated with the presence of CAD. Among the 108 FH patients, 30 had CAD. CUC levels were significantly lower among patients with than without CAD (median [interquartile range] 119 [92-139] vs. 142 [121-165] arbitrary units [AU]; P=0.0004). In addition, CUC was significantly lower in patients with Achilles tendon thickness ≥9.0 mm than in those without Achilles tendon thickening (133 [110-157] vs. 142 [123-174] AU; P=0.047). Serum CUC levels were negatively correlated with the carotid plaque score (Spearman's r=0.37; P=0.00018). Serum CUC levels were significantly associated with CAD, after adjusting for other clinical variables (odds ratio=0.86, 95% CI=0.76-0.96, P=0.033), whereas HDL-C was not. CONCLUSIONS: HDL function, assessed by serum CUC level, rather than HDL-C level, adds risk stratification information among FH patients.

Whole Exome Sequencing Insufficient for a Definitive Diagnosis of a Patient with Compound Heterozygous Familial Hypercholesterolemia.

Homozygous familial hypercholesterolemia (HoFH) is a rare genetic disorder, and a genetic analysis is important to make a definitive diagnosis. A comprehensive genetic analysis using next generation sequencing (NGS) and whole exome sequencing (WES) is feasible. However, the application of NGS in the assessment of genomic structural variations is generally limited, and a substantial number of control samples are needed for such assessments. Thus, NGS alone is unlikely to detect genomic structural variations in a "singleton." We present the case of a patient with compound HeFH (heterozygous FH), whose causative mutations in the LDLR gene could not be identified by WES, necessitating the application of the multiplex ligation-dependent probe amplification (MLPA) technique.

Case Report: Myocarditis Associated With COVID-19 mRNA Vaccination Following Myocarditis Associated With Campylobacter Jejuni.

We herein present our experience with a case involving a 17-year-old Japanese boy suffering from acute myocarditis after his second coronavirus disease-2019 (COVID-19) messenger RNA (mRNA) vaccine shot. The patients had a history of myocarditis associated with Campylobacter jejuni 3 years prior. This has been the first-ever documented case of myocarditis associated with COVID-19 mRNA vaccination in a patient with a history of myocarditis. We present a series of images and blood biomarkers for different types of myocarditis that developed in this single patient.

Embolization of Skull Base Meningiomas with Embosphere Microspheres: Factors Predicting Treatment Response and Evaluation of Complications.

OBJECTIVE: Preoperative embolization for intracranial meningiomas can cause tumor necrosis, reduce intraoperative blood loss, and facilitate surgery. This study aimed to evaluate the efficacy of tumor embolization using Embosphere microspheres for skull base meningiomas and analyze postembolization plain computed tomography (CT) and magnetic resonance imaging (MRI) scans to identify findings that could potentially predict treatment response. METHODS: Between April 2014 and April 2020, 80 patients with skull base meningiomas presenting at our medical center underwent embolization with Embosphere microspheres. The effects of tumor embolization were evaluated through a comparison of postembolization plain CT and contrast-enhanced MRI. RESULTS: A total of 143 vessels (102 of 108 external carotid artery branches and 41 of 65 internal carotid artery branches) from 80 skull base meningiomas were embolized with Embosphere microspheres. Microspheres 100-300 µm in size were used in 2 cases, microspheres 300-500 µm in size were used in 12 cases, and microspheres 500-700 µm in size were used in 66 cases. Postembolization contrast-enhanced MRI showed reductions in enhancing lesions within the tumor in 55 of 80 cases. Postembolization plain CT scans showed high-density lesions within the tumor in 41 of 55 cases. Thus, reductions in enhancing lesions on postembolization contrast-enhanced MRI were statistically significantly associated with the presence of high-density lesions on postembolization plain CT (P < 0.001). Embolization-related neurological complications occurred in 3 cases. CONCLUSIONS: Embosphere microspheres are user friendly and effective embolic materials for the embolization of skull base meningiomas. Postembolization contrast-enhanced MRI and plain CT findings may be useful for evaluating the effects of tumor embolization.

Explainable Machine Learning for Atrial Fibrillation in the General Population Using a Generalized Additive Model　- A Cross-Sectional Study.

Background: Atrial fibrillation (AF) is the most common arrhythmia and is associated with increased thromboembolic stroke risk and heart failure. Although various prediction models for AF risk have been developed using machine learning, their output cannot be accurately explained to doctors and patients. Therefore, we developed an explainable model with high interpretability and accuracy accounting for the non-linear effects of clinical characteristics on AF incidence. Methods and Results: Of the 489,073 residents who underwent specific health checkups between 2009 and 2018 and were registered in the Kanazawa Medical Association database, data were used for 5,378 subjects with AF and 167,950 subjects with normal electrocardiogram readings. Forty-seven clinical parameters were combined using a generalized additive model algorithm. We validated the model and found that the area under the curve, sensitivity, and specificity were 0.964, 0.879, and 0.920, respectively. The 9 most important variables were the physical examination of arrhythmia, a medical history of coronary artery disease, age, hematocrit, γ-glutamyl transpeptidase, creatinine, hemoglobin, systolic blood pressure, and HbA1c. Further, non-linear relationships of clinical variables to the probability of AF diagnosis were visualized. Conclusions: We established a novel AF risk explanation model with high interpretability and accuracy accounting for non-linear information obtained at general health checkups. This model contributes not only to more accurate AF risk prediction, but also to a greater understanding of the effects of each characteristic.

Genetic mutations, regression of Achilles tendon thickness, and cardiovascular events among patients with familial hypercholesterolemia.

BACKGROUND AND AIMS: Achilles tendon thickness (ATT) can be regressed through LDL-lowering in patients with familial hypercholesterolemia (FH). We aimed to determine factors associated with regression of ATT and its role in development of major adverse cardiovascular events (MACE). METHODS: Patients with clinically diagnosed FH (N = 1,050, male/female = 490/560) were retrospectively assessed. FH-related gene mutations and ATT data using X-ray were collected. Multivariable linear regression analysis was exploited to test the factors associated with deterioration of ATT. Cox proportional hazards models were used to assess factors associated with MACE, including cardiovascular death and acute coronary events. RESULTS: The median follow-up period was 12.6 years. FH-linked mutations were identified in 777 patients. During the follow-up period, 113 MACEs were observed, and median ATT was regressed from 8.7 to 8.5 mm. We found that there was more significant positive correlation between cholesterol-year score and ATT among patients with FH-related gene mutation (p < 2.2 × 10-16; Spearman's r = 0.42). Multivariable linear regression analyses revealed that age (standardized coefficients [SCs] = 0.307, 95% confidence interval [CI] = 0.241-0.373), hypertension (SCs = 0.069, 95%CI = 0.001-0.138), and diabetes (SCs = 0.059, 95% CI = 0.003-0.115) were positively correlated with changes in ATT (progression). Baseline ATT (SCs = -0.474, 95%CI = -0.535-0.413) and FH-related mutations (SCs = -0.058, 95%CI = -0.091-0.024) were negatively correlated with changes in ATT (regression). Considering this confounding factors, regression of ATT was significantly associated with reduced MACE (hazard ratio [HR] = 0.67, 95%CI = 0.51-0.89, per 1.0 mm). CONCLUSIONS: Assessed ATT condition and presence of FH-linked gene mutations represent diagnostic values and risk stratification information among patients with FH.