Utility of pemafibrate in nonalcoholic steatohepatitis model mice induced by a choline-deficient, high-fat diet and dextran sulfate sodium.

Aim: The purpose of this study was to examine the effect of pemafibrate in a murine model of non-alcoholic steatohepatitis (NASH). Methods: Forty-two, 19-week-old, male, C57BL/6J mice were divided into three groups: a Control group (n = 14), a dextran sulfate sodium (DSS) group (n = 14), and a DSS + PEM group (n = 14). All mice were given a standard rodent diet for the first week, followed by a choline-deficient, high-fat diet (CDHF) for the next 12 weeks. The 22nd day after the animals arrived was taken as Day 1 of the experiment. The Control group continued the CDHF diet and MilliQ water. The DSS group continued the CDHF diet, but starting on Day 1, the group received 0.8 % DSS to drink for 7 consecutive days, followed by MilliQ water for 10 days; this was taken as one course, and it was repeated on the same schedule until autopsy. The DSS + PEM group received the CDHF diet with PEM 0.1 mg/kg/day. Their drinking water was the same as that of the DSS group. On Seven animals from each group were autopsied on each of Day 50 and Day 120, and histopathological and immunohistochemical examinations, as well as quantitative RNA and cytokine measurements, of autopsied mice were performed. Results: Pemafibrate improved hepatic steatosis (decreased steatosis area), improved liver inflammation enhanced by DSS (decreased aspartate transaminase and alanine aminotransferase), improved hepatic fibrosis promoted by DSS (decreased fibrotic areas and a marker of fibrosis), inhibited tumorigenesis, and decreased intestinal inflammation in the NASH model mice. Conclusions: In a murine model of NASH, mixing PEM 0.1 mg/kg/day into the diet inhibited disease progression and tumor formation.

[Anatomical Variations to the Vertebral Artery and Posterior Inferior Cerebellar Artery are Associated with the Partial Persistence of Primitive Lateral Basirovertebral Anastomosis].

The angioarchitecture of the hindbrain is homologous to that of the spinal cord, and its vascular system can be analyzed at the longitudinal and axial structures. During embryonic development, there are two main longitudinal arteries: the longitudinal neural artery and the primitive lateral basilovertebral anastomosis. Commonly observed variations are formed by the fenestration and duplication of either the vertebrobasilar artery, or cerebellar artery, which can be observed when the primitive lateral basilovertebral anastomosis partially persists. Understanding the pattern and development of blood supply to the hindbrain provides useful information of various anomalies in the vertebrobasilar junction and cerebellar arteries.

Comparing Three Different Anti-Programmed Death-Ligand 1 Antibodies in Immunohistochemical Evaluation of Combined Chemoimmunotherapy Response in Patients With NSCLC: A Prospective Study.

Introduction: Multiple programmed death-ligand 1 (PD-L1) immunohistochemistry assays performed using different antibodies including DAKO 22C3, DAKO 28-8, and Ventana SP142 PD-L1-predictive markers for response to various immune checkpoint inhibitors in NSCLC-have been approved in several countries. The differences in multiple PD-L1 immunohistochemistry assay results in predicting the therapeutic response to combined chemoimmunotherapy in patients with NSCLC remain unclear. Methods: In this multicenter prospective observational study, we monitored 70 patients with advanced NSCLC treated with combined chemoimmunotherapy at 10 institutions in Japan. The expression of PD-L1 in pretreatment tumors was evaluated using the 22C3, 28-8, and SP142 assays in all patients. Results: The PD-L1 level in tumor cells determined using the 22C3 assay was the highest among the three assays performed with different antibodies. According to the 22C3 assay results, the PD-L1 tumor proportion score greater than or equal to 50% group had a significantly longer progression-free survival period than the PD-L1 tumor proportion score less than 50% group. Nevertheless, the other assays did not reveal remarkable differences in the objective response rate or progression-free survival. Conclusions: In our study, PD-L1 expression determined using the 22C3 assay was more correlated with the therapeutic response of patients with NSCLC treated with combined chemoimmunotherapy than that determined using the 28-8 and SP142 assays. Therefore, the 22C3 assay may be useful for clinical decision-making for patients with NSCLC treated with combined chemoimmunotherapy. Trial registration number: UMIN 000043958.

Utility of ultrasonography in a mouse model of non-alcoholic steatohepatitis induced by a choline-deficient, high-fat diet and dextran sulfate sodium.

Background: Nonalcoholic steatohepatitis (NASH) is a chronic progressive liver disease that can progress to cirrhosis and hepatocellular carcinoma. The prevalence of NASH is increasing year by year. However, the etiology and progression of NASH, along with the processes leading to carcinogenesis, remain poorly understood. A range of animal models are used in research, but investigators have been unable to establish a model that results in tumorigenesis from a stable disease state. The present study aimed to create a stable, low-mortality model of NASH using abdominal ultrasonography (US) to assess NASH stage and diagnose liver tumors. Methods: Thirty-four 19-week-old male C57BL/6J mice were fed a choline-deficient, high-fat (CDHF) diet. Twenty animals were given seven courses of 0.8 % dextran sulfate sodium (DSS) for 7 days followed by 10 days of MilliQ water (CDHF+DSS group). The remaining 14 animals drank only MilliQ water (CDHF group). All animals were weighed weekly and US was performed on Days 35 and 120. After necropsy, samples were taken for biochemical analysis and histopathological evaluation. Results: The CDHF+DSS group had significantly lower body weight on Days 35 and 120, and significantly higher liver/body weight (%) on Day 35 compared to the CDHF group. US on Days 35 and 120 revealed significantly shorter long intestine and higher colonic histological score in the CDHF+DSS group compared to the CDHF group. IL-1ß and IL-6 levels in the large intestinal tissue were significantly higher in the CDHF+DSS group. Conclusions: A stable, low-mortality model of NASH was created with a CDHF diet and intermittent 0.8 % DSS. Abdominal US can assess the degree of fatty degeneration and evaluate liver tumorigenesis without necropsy. This assessment procedure will reduce the number of mice killed unnecessarily during experiments, thereby contributing to animal welfare.

TTF-1 Expression and Clinical Outcomes of Combined Chemoimmunotherapy in Patients With Advanced Lung Adenocarcinoma: A Prospective Observational Study.

Introduction: Lung adenocarcinoma with negative TTF-1 expression is believed to be a poor prognostic factor for certain systemic treatments. Nevertheless, the impact of TTF-1 expression on combined chemoimmunotherapy remains unclear. We aimed to investigate the relationship between tumor TTF-1 expression and the efficacy of combined chemoimmunotherapy in patients with advanced lung adenocarcinoma. Methods: This multicenter prospective observational study included 58 patients with advanced lung adenocarcinoma treated with combined chemoimmunotherapy across 10 institutions in Japan. The expression of TTF-1 in pretreatment tumors was determined using immunohistochemistry. Results: The objective response rate of combined chemoimmunotherapy was significantly higher in TTF-1-positive groups than in TTF-1-negative groups (p = 0.02). The median progression-free survival (PFS) and overall survival were significantly longer in TTF-1-positive groups than in TTF-1-negative groups (10.9 versus 5.0 mo; p = 0.01). Multivariate analysis revealed that TTF-1 expression was an independent favorable prognostic factor for PFS. Moreover, TTF-1 expression in patients with lung adenocarcinoma is significantly associated with programmed death-ligand 1 expression (p = 0.003). The TTF-1-positive group with programmed death-ligand 1 tumor proportion score greater than or equal to 50% had a significantly longer PFS than the other groups (p = 0.02). Conclusions: TTF-1 positivity is associated with better clinical outcomes in patients with advanced lung adenocarcinoma treated with combined chemoimmunotherapy.

Fatal cerebral venous sinus thrombosis with preceding thrombocytopenia in a patient with new-onset eosinophilic granulomatosis with polyangiitis.

A previously healthy, 44-year-old, female patient was hospitalised for acute abdominal pain and bilateral pneumonia. Eosinophilic granulomatosis with polyangiitis (EGPA) was diagnosed on the basis of eosinophilia, eosinophilic tissue inflammation, polyneuropathy, and bilateral pneumonia. She had a fatal cerebral venous sinus thrombosis following thrombocytopenia, which was apparently caused by platelet consumption. It may have been possible to prevent the deterioration of the venous thrombosis by starting immunosuppressive or anticoagulant therapy earlier. If a patient with EGPA presents with unexplained thrombocytopenia, the physician should assess for physical findings or laboratory abnormalities suggestive of thrombosis. Additionally, if the patient complains of headache or nausea with normal head computed tomography findings, magnetic resonance imaging or magnetic resonance venography should be performed to assess for cerebral venous sinus thrombosis.

Sequential Middle Meningeal Artery Embolization after Burr Hole Surgery for Recurrent Chronic Subdural Hematoma.

Middle meningeal artery embolization (MMAE) for chronic subdural hematoma (CSDH) is a novel, minimally invasive treatment. The indications and treatment practices for MMAE are variable and remain controversial. This study aimed to evaluate a strategy involving sequential MMAE after burr hole surgery for treating recurrent CSDH. We performed a retrospective analysis of data from consecutive patients who had undergone MMAE using liquid embolic agents within approximately 2 weeks after burr hole surgery for recurrent CSDH from September 2020 to March 2022. We analyzed patient characteristics, procedural details, CSDH recurrence after MMAE, surgical rescue, and complications. Six of the nine patients who underwent MMAE for CSDH recurrence were male, and the median age was 85 (range, 70-94) years. Five of the nine patients were being administered antithrombotic agents. The median duration between the burr hole surgery and MMAE procedure was 10 (range, 3-25) days. Anterior and posterior convexity branches were targeted for embolization using low-concentration N-butyl cyanoacrylate (NBCA), and the abnormal vascular networks with a cotton wool appearance disappeared after embolization in all cases. The NBCA distribution was observed by high-resolution computed tomography during the procedure; in three of nine cases, the NBCA penetrated not only the MMA but also the inner membrane. No recurrence, surgical rescue, or complications were observed in any patient during the median follow-up period of 3 months. As a minimally invasive treatment for recurrent CSDH, sequential MMAE after burr hole surgery may be a safe and effective option for preventing recurrence.

Early prediction of functional prognosis in neurofibromatosis type 2 patients based on genotype-phenotype correlation with targeted deep sequencing.

Regardless of treatment, the clinical progression of neurofibromatosis type 2 (NF2), particularly in terms of hearing, swallowing, and gait, tend to worsen throughout the patients' lives. We performed a retrospective analysis of functional outcomes in Japanese NF2 patients to predict their functional prognosis. We analyzed genotype-phenotype correlation based on genetic data from a cohort of 57 patients with a mean follow-up of 14.5 ± 6.0 years. Their functional outcomes, including hearing, swallowing, and ambulation, were reviewed. Performing a targeted deep sequencing, germline NF2 mutations were identified in 28 patients (49.1%), and mosaic NF2 was identified in 20 patients (20, 35.0%). The functional preservation period and outcome differed significantly depending on clinical/genetic factors. Among these factors, "Truncating", "Mosaic", and "Age of symptom onset ≥ 25" had the most significant effects on functional disability. By applying a combination of an NF2 mutation type/location, and age of symptom onset, we classified different degrees of functional preservation and progression, schwannoma growth rate and total interventions per year per patient. The prediction of detailed functional outcomes in NF2 patients can plan better strategies for life-long disease management and social integration.

Comparison of the efficiency of endobronchial ultrasound-guided transbronchial needle aspiration using a 22G needle versus 25G needle for the diagnosis of lymph node metastasis in patients with lung cancer: a prospective randomized, crossover study.

BACKGROUND: Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is generally performed for the diagnosis of hilar/mediastinal lymph node metastasis in patients with lung cancer. Recently, a 25-gauge (G) needle became available, but robust evidence of its usefulness in routine clinical practice is still lacking. METHODS: A prospective randomized crossover trial was performed, in which patients with suspected hilar/mediastinal lymph node metastasis of lung cancer underwent EBUS-TBNA. The primary endpoint was the rate of yield histology specimens containing malignant cells. RESULTS: From December 2018 to February 2020, 102 patients were randomly assigned to EBUS-TBNA using a 22G needle first, followed by a 25G needle (n=50) or EBUS-TBNA using a 25G needle first, followed by a 22G needle (n=52). There was no difference in the diagnostic yield of malignancy between the histology specimens obtained by using the 22G and 25G needles (75% vs. 75%, respectively, P=0.37). The sizes of the tissue samples (16.4 vs. 4.9 mm2, respectively) and number of malignant cells in the tissue samples (626 vs. 400, respectively) were both significantly higher when using the 22G needle than when using the 25G needle. CONCLUSIONS: No significant difference in the diagnostic yield between the 22G and 25G needles was observed for the diagnosis of lymph node metastasis of lung cancer, suggesting that needles of either gauge could be used for the biopsy. However, we would recommend use of the 22G needle, because it provided larger specimens and specimens containing larger numbers of malignant cells. TRIAL REGISTRATION: University hospital Medical Information Network Clinical Trial Registry (ID: UMIN000036680).

Delayed Hemiparkinsonism Associated with Kernohan's Notch in a Patient with a Ruptured Arteriovenous Malformation.

A 24-year-old female patient was admitted for a right frontal intracranial hematoma with an uncal herniation due to a ruptured arteriovenous malformation and therefore underwent emergency surgery. Neuroimaging revealed left-sided midbrain notching against the tentorium, indicating Kernohan's notch phenomenon. She denied experiencing any short-term neurological deficits but right-sided delayed hemiparkinsonism developed 18 months later. Dopamine transporter tracer uptake was severely reduced in the left striatum, suggesting nigrostriatal degeneration secondary to Kernohan's notch. Uncal herniations are potentially fatal, but surgery can save the patient's life and improve the functional outcomes. Clinicians should therefore be aware of delayed hemiparkinsonism as a rare complication of Kernohan's notch phenomenon.

Acute Thrombectomy for Contralateral Internal Carotid Artery Occlusion after Revascularization Surgery for Quasi-moyamoya Disease: A Case Report.

Ischemic complications can occur after revascularization surgery for moyamoya disease, but acute contralateral internal carotid artery (ICA) occlusion is an extremely rare complication. The patient was a 51-year-old woman with no medical history. Left frontal lobe infarction and bilateral ICA terminal stenosis were identified by repeated transient right paresis and aphasia. We diagnosed her with quasi-moyamoya disease associated with hyperthyroidism and performed revascularization surgery for the symptomatic left side. Although neurological symptoms did not worsen immediately after the surgery, disturbance of consciousness, right conjugate deviation, and left paresis appeared 4 hr after the surgery. New infarction appeared in the right frontal lobe, and the blood signal beyond the right middle cerebral artery (MCA) disappeared on MRI and MRA. Mechanical thrombectomy (MT) using a suction catheter improved antegrade blood flow in the MCA. The left paresis remained at discharge (modified Rankin Scale score = 4), but she was able to walk independently 3 months after the operation and was independent at home. Acute contralateral ICA occlusion after revascularization for moyamoya disease is an extremely rare complication, but the symptoms can be severe and treatment should be considered. To the best of our knowledge, there have been no reports of MT for postoperative acute contralateral ICA occlusion. Since the results of endovascular treatment such as percutaneous transluminal angioplasty and stent placement for patients with moyamoya disease are poor, MT using an aspiration catheter could be a good treatment option.

Trans-cell Approach through Closed-cell Stent for Middle Meningeal Artery Embolization in Recurrent Chronic Subdural Hematoma.

We report a case of recurrent chronic subdural hematoma (CSDH) treated using the trans-cell approach through a closed-cell stent for middle meningeal artery embolization (MMAE). A 77-year-old man with acute ischemic stroke due to anterior circulation tandem occlusion was treated with intracranial thrombectomy and carotid artery stenting using a closed-cell stent 5 years ago. He experienced head trauma after a fall, which then developed into a CSDH. Burr hole surgery was performed twice, followed by MMAE considering the high possibility of recurrence due to antiplatelet therapy and brain atrophy after ischemic stroke. A distal access catheter was inserted into the external carotid artery through the closed-cell stent, and a microcatheter was navigated in the middle meningeal artery. The anterior and posterior convexity branches were embolized with 16.7% N-butyl cyanoacrylate. The postoperative course was favorable, and CT at 3-month follow-up showed a decrease in the hematoma. Even after the placement of the closed-cell stent, endovascular treatment of the external carotid artery is possible and can be a therapeutic option using the trans-cell approach.

Targeted deep sequencing of DNA from multiple tissue types improves the diagnostic rate and reveals a highly diverse phenotype of mosaic neurofibromatosis type 2.

BACKGROUND: Although 60% of patients with de novo neurofibromatosis type 2 (NF2) are presumed to have mosaic NF2, the actual diagnostic rate of this condition remains low at around 20% because of the existing difficulties in detecting NF2 variants with low variant allele frequency (VAF). Here, we examined the correlation between the genotype and phenotype of mosaic NF2 after improving the diagnostic rate of mosaic NF2. METHODS: We performed targeted deep sequencing of 36 genes including NF2 using DNA samples from multiple tissues (blood, buccal mucosa, hair follicle and tumour) of 53 patients with de novo NF2 and elucidated their genotype-phenotype correlation. RESULTS: Twenty-four patients (45.2%) had the NF2 germline variant, and 20 patients with NF2 (37.7%) had mosaic NF2. The mosaic NF2 phenotype was significantly different from that in patients with NF2 germline variant in terms of distribution of NF2-related disease, tumour growth rate and hearing outcome. The behaviour of schwannoma correlated to the extent of VAF with NF2 variant in normal tissues unlike meningioma. CONCLUSION: We have improved the diagnostic rate of mosaic NF2 compared with that of previous studies by targeted deep sequencing of DNA from multiple tissues. Many atypical patients with NF2 diagnosed with 'unilateral vestibular schwannoma' or 'multiple meningiomas' presumably have mosaic NF2. Finally, we suggest that the highly diverse phenotype of NF2 could result not only from the type and location of NF2 variant but also the extent of VAF in the NF2 variant within normal tissue DNA.

Validity of using immunohistochemistry to predict treatment outcome in patients with non-small cell lung cancer not otherwise specified.

PURPOSE: Histology samples are important for the appropriate administration of tumor type-specific cytotoxic and molecular-targeted therapies for the treatment of non-small cell lung cancer (NSCLC). When biopsy samples lack a definite morphology, a diagnosis can be selected from three subtypes based on immunohistochemistry (IHC) results, as follows: favor adenocarcinoma (ADC), favor squamous cell carcinoma (SQC), or not otherwise specified (NOS)-null. In terms of patient outcome, however, the validity of IHC-based classifications remains unknown. METHODS: A large series of 152 patients with advanced NSCLC whose diagnoses had been made based on morphological findings and who had been homogeneously treated were enrolled. We used IHC staining (TTF-1, SP-A, p40, and CK5/6) to examine tumor samples and refined the diagnoses. We then analyzed the pathological subgroups according to the IHC staining results. RESULTS: IHC profiling resulted in 50% of the cases being classified as favor ADC, 31% being classified as favor SQC, and 19% being classified as NOS-null groups. Compared with the favor ADC and favor SQC groups, the NOS-null group had a significantly poorer outcome. Pemetrexed-containing platinum regimens produced a response rate similar to that of other platinum doublet regimens in the favor ADC group (44% vs. 46%), whereas it produced a poorer response in the favor SQC group (0% vs. 52%) and the NOS-null group (0% vs. 24%). The favor ADC group tended to have a higher percentage of EGFR positivity and ALK positivity than the favor SQC group (25% vs. 11% and 7% vs. 0%, respectively). CONCLUSIONS: These findings support the use of immunohistological subtyping of NSCLC biopsy specimens to select patient-appropriate treatments.

Impressive response to nivolumab of non-small-cell lung cancer containing sarcomatoid components.

We present two cases of pulmonary pleomorphic carcinoma (PPC) treated with Nivolumab. A 57-year-old man presented with a 3.5-cm mass in the left lower lobe. Left lower lobectomy and lymph node dissection were performed. Histological diagnosis was stage IIIA (pT2bN2M0) PPC. The tumour relapsed two months later and he was treated with carboplatin and paclitaxel, but his condition became progressive and nonresponsive after one cycle. We used nivolumab as second line. Repeat chest X-ray showed impressive reduction of relapse lesions seven days after the start of nivolumab therapy. Our second case is a 50-year-old man who presented with a 3.7-cm mass in the right lower lobe and submucosal tumour in the colon. Endobronchial ultrasound-guided transbronchial needle aspiration biopsy (EBUS-TBNA) and colon biopsy yield the diagnosis of PPC and metastatic colon cancer. He was treated with cisplatin plus pemetrexed. His disease proved resistant and we used nivolumab as second line. He showed partial response following four cycles.

Successful endovascular recanalization of massive cerebral venous sinus thrombosis in a patient with tuberous sclerosis and protein S deficiency: a case report.

Here, we report the case of a 27-year-old woman with tuberous sclerosis complex who underwent successful endovascular intervention for cerebral venous thrombosis at the superior sagittal sinus. She had protein S deficiency and a long-term history of anemia caused by menorrhagia from uterine fibroids, possibly leading to a hypercoagulable state. Cerebral venous sinus thrombosis accounts for ~0.5-1% of all strokes. Several cases of venous thrombosis in patients with tuberous sclerosis complex and protein S or protein C deficiency have been reported, but further studies are needed to identify whether an association of this rare combination may be explained.

Thoracoscopic stapler-and-loop technique for left atrial appendage closure in nonvalvular atrial fibrillation: Mid-term outcomes in 201 patients.

BACKGROUND: Left atrial appendage (LAA) closure can be an alternative to oral anticoagulation to prevent cardiogenic thromboembolisms in patients with nonvalvular atrial fibrillation. OBJECTIVE: The purpose of this study was to retrospectively evaluate the safety, completeness, and mid-term prevention of our thoracoscopic stapler-and-loop technique for LAA closure. METHODS: Patients operated on between October 2008 and February 2017 were reviewed. Endoscopic stapler and ligation loops were used. Patients received 1 month of anticoagulation before discontinuation. Hospital death and procedure-related major complications (thromboembolism, hemorrhagic events, phrenic palsy) were the primary composite endpoint for safety, and cardiogenic thromboembolisms were the endpoint for prevention. Brain magnetic resonance imaging investigated new thromboembolic spots 1 year after surgery. RESULTS: There were 201 patients (118 men, 83 women) with a mean age of 74 years (range 68-94) years, mean CHA2DS2-VASc score (± SD) 4.1 ±1.4, and mean HAS-BLED score 2.9 ± 1.0. Mean operation time was 28 minutes. All LAAs were removed, and intraoperative transesophageal echocardiography confirmed completeness of the closure in each patient. No hospital deaths or major procedure-related complications occurred. Follow-up results for 198 patients (98%) over a mean period of 48 months (range 12-110) revealed that 2 patients developed cardiogenic thromboembolisms (0.25 event per 100 patient-years). Magnetic resonance imaging of 51 patients with a mean CHA2DS2-VASc score of 4.7 ± 1.6 revealed 1 new small spot in each of 2 patients (3.9%; 3.9 spots per 100 patient-years). CONCLUSION: Our thoracoscopic stapler-and-loop technique swiftly, safely, and completely closed LAAs in patients with nonvalvular atrial fibrillation and provided acceptable mid-term prevention without anticoagulation.