Atorvastatin Reduces Circulating S100A12 Levels in Patients with Carotid Atherosclerotic Plaques - A Link with Plaque Inflammation

Aims: Inflammation is involved in various processes of atherosclerosis development. Serum C-reactive protein (CRP) levels, a predictor for cardiovascular risk, are reportedly reduced by statins. However, several studies have demonstrated that CRP is a bystander during atherogenesis. While S100A12 has been focused on as an inflammatory molecule, it remains unclear whether statins affect circulating S100A12 levels. Here, we investigated whether atorvastatin treatment affected S100A12 and which biomarkers were correlated with changes in arterial inflammation. Methods: We performed a prospective, randomized open-labeled trial on whether atorvastatin affected arterial (carotid and thoracic aorta) inflammation using¹⁸fluorodeoxyglucose positron emission tomography/computed tomography (¹⁸F-FDG-PET/CT) and inflammatory markers. Thirty-one statin-naïve patients with carotid atherosclerotic plaques were randomized to either a group receiving dietary management (n=15) or one receiving atorvastatin (10mg/day,n=16) for 12weeks.¹⁸F-FDG-PET/CT and flow-mediated vasodilation (FMD) were performed, the latter to evaluate endothelial function. Results: Atorvastatin, but not the diet-only treatment, significantly reduced LDL-cholesterol (LDL-C, -43%), serum CRP (-37%) and S100A12 levels (-28%) and improved FMD (+38%).¹⁸F-FDG-PET/CT demonstrated that atorvastatin, but not the diet-only treatment, significantly reduced accumulation of¹⁸F-FDG in the carotid artery and thoracic aorta. A multivariate analysis revealed that reduction in CRP, S100A12, LDL-C, oxidized-LDL, and increase in FMD were significantly associated with reduced arterial inflammation in the thoracic aorta, but not in the carotid artery. Conclusions: Atorvastatin treatment reduced S100A12/CRP levels, and the changes in these circulating markers mirrored the improvement in arterial inflammation. Our observations suggest that S100A12 may be an emerging therapeutic target for atherosclerosis.     

Diagnostic value of abdominal fat tissue aspirate in familial amyloid polyneuropathy

To confirm amyloid deposition we performed aspiration biopsy of abdominal fat tissue in 14 patients with type I familial amyloid polyneuropathy (FAP). All patients, about half of whom were at an early stage of disease and lacking severe neurological disabilities, showed positive amyloid deposition in preparations stained with Congo red. On light and electron microscopic examinations deposits of amyloid were observed around fat cells and small vascular walls, and among collagen bundles. All patients in the study were demonstrated to have a variant transthyretin in their sera by radioimmunoassay. Abdominal fat tissue aspiration can be easily performed with an ordinary syringe and is very sensitive for detecting amyloid deposition. The procedure is valuable in the diagnosis of type I FAP patients with actual deposition of amyloid substance, even at an early stage.     

A case report of Lhermitte-Duclos disease with systematic AVMs]

We report a case of Lhermitte-Duclos disease (LDD) with huge AVMs of left extremities. The patient is a 46-year-old woman, who was identified heart failure due to AVMs at 13 years old and underwent amputation of left arm and several embolizations for AVM of left leg. Following a loss of consciousness, she was admitted to our hospital at 46 years old. CT scan showed a low-density area in the vermis of cerebellum. MR imaging showed a tumor with characteristic parallel linear striation. She was treated with partial resection of tumor. Pathological findings were dysplastic gangliocytoma. She was diagnosed LDD by MR imaging and pathological findings. Some reports describe an association between LDD and Cowden disease. On the other hand, there are reports of an association between Cowden disease and AVM. However, to our knowledge, there is no report of an association between LDD and AVM. Although this case didn't be revealed an association with Cowden disease, we believe that this case is a very interesting one henceforth suggesting the association between LDD, Cowden disease, and AVM.     

Safe Concurrent Use of Anti-tuberculosis Drugs and Pembrolizumab in a Patient with Non-small-cell Lung Cancer Who Was Infected with Mycobacterium tuberculosis

A 68-year-old Japanese man was diagnosed with lung adenocarcinoma stage IVB. We introduced a first-line chemotherapy of four cycles of carboplatin and pemetrexed and pembrolizumab, followed by pemetrexed and pembrolizumab maintenance therapy. Approximately four months after anticancer therapy, a small nodule appeared in the right peripheral S3 lesion. After five months, the nodule was confirmed as a Mycobacterium tuberculosis (TB) nodule. We initiated anti-TB therapy without stopping pembrolizumab, and the right S3 nodule shrank immediately. This report supports the concurrent use of anti-TB treatment with an immune checkpoint inhibitor when the TB infection area is limited.     

Atypical Shone's Complex Diagnosed at 70 Years Old: Presenting with Double-orifice Mitral Valve,Bicuspid Aortic Valve,and Aortic Coarctation

Atypical Shone''s complex is a rare congenital anomaly involving a left-sided obstructive lesion of two or three cardiovascular levels. A 70-year-old man with dyspnea on exertion was diagnosed with severe aortic stenosis (AS) with a bicuspid valve, complicated by severe aortic coarctation (CoA) and a double-orifice mitral valve. He underwent surgery for AS and CoA in one session. It is important to search for complicated malformations, even in cases of bicuspid aortic valve found in old age.     

Universal Screening for Familial Hypercholesterolemia in Children in Kagawa,Japan

Aim: Familial hypercholesterolemia (FH) is an underdiagnosed autosomal dominant genetic disorder characterized by high levels of plasma low-density lipoprotein cholesterol (LDL-C) from birth. This study aimed to assess the genetic identification of FH in children with high LDL-C levels who are identified in a universal pediatric FH screening in Kagawa, Japan. Method: In 2018 and 2019, 15,665 children aged 9 or 10 years underwent the universal lipid screening as part of the annual health checkups for the prevention of lifestyle-related diseases in the Kagawa prefecture. After excluding secondary hyper-LDL cholesterolemia at the local medical institutions, 67 children with LDL-C levels of ≥ 140 mg/dL underwent genetic testing to detect FH causative mutations at four designated hospitals. Results: The LDL-C levels of 140 and 180 mg/dL in 15,665 children corresponded to the 96.3 and 99.7 percentile values, respectively. Among 67 children who underwent genetic testing, 41 had FH causative mutations (36 in the LDL-receptor, 4 in proprotein convertase subtilisin/kexin type 9, and 1 in apolipoprotein B). The area under the curve of receiver operating characteristic curve predicting the presence of FH causative mutation by LDL-C level was 0.705, and FH causative mutations were found in all children with LDL-C levels of ≥ 250 mg/dL. Conclusion: FH causative mutations were confirmed in almost 60% of the referred children, who were identified through the combination of the lipid universal screening as a part of the health checkup system and the exclusion of secondary hyper-LDL cholesterolemia at the local medical institutions.     

The Simultaneous Onset of Pancreatitis and Colitis as Immune-related Adverse Events in a Patient Receiving Nivolumab Treatment for Renal Cell Carcinoma

Immune checkpoint inhibitors (ICIs), which have anti-tumor effects, are currently approved for treatment of several kinds of advanced malignancies. However, with their increasing use, a variety of immune-related adverse events (irAEs) in administered patients have been reported. We herein report a rare case of the simultaneous onset of acute pancreatitis and colitis as irAEs during nivolumab treatment given to a patient with renal cell carcinoma, who then shown marked improvement with corticosteroid therapy.     

Absolute lymphocyte count and C-reactive protein-albumin ratio can predict prognosis and adverse events in patients with recurrent esophageal cancer treated with nivolumab therapy

Predicting the prognosis and adverse events (AEs) of nivolumab therapy for recurrent esophageal cancer is very important. The present study investigated whether a simple blood biochemical examination could be used to predict prognosis and AEs following nivolumab treatment for relapse of esophageal cancer. A total of 41 patients who received nivolumab treatment for recurrent esophageal cancer after esophagectomy were analyzed. The absolute lymphocyte count (ALC), neutrophil-lymphocyte ratio (NLR), platelet-lymphocyte ratio (PLR), monocyte-lymphocyte ratio (MLR) and C-reactive protein-albumin ratio (CAR) were assessed at the time of nivolumab induction as indices that can be calculated by blood biochemical examinations alone. Median values were 1,015 for ALC, 3.401 for NLR, 242.6 for PLR, 0.458 for MLR and 0.119 for CAR, and patients were divided into two groups according to values. A high ALC, low NLR, low PLR, low MLR and low CAR were associated with a better response to nivolumab. In addition, patients with the aforementioned indices, with the exception of low PLR, or better response were more likely to develop AEs in univariate analysis. In multivariate analysis, a high ALC [odds ratio (OR): 4.857, P=0.043] and low CAR (OR: 9.099, P=0.004) were identified as independent risk factors for AEs. Survival analysis revealed that overall survival and progression-free survival (PFS) rates after nivolumab treatment differed significantly between the high and low groups of ALC, NLR, PLR, MLR and CAR. The multivariate analysis identified a low ALC [hazard ratio (HR): 3.710, P=0.003] and high CAR (HR: 2.953, P=0.007) as independent poor prognostic factors of PFS. In conclusion, ALC and CAR have potential as biomarkers for outcomes of recurrent esophageal cancer following nivolumab treatment.     

Colorectal Cancer Screening Program in Songjiang district,Shanghai between 2015 and 2017: Evaluation of participation rate and the associated factor

Little is known about the participation rate of newly implemented colorectal cancer (CRC) screening programs in China. Our goals were to identify factors associated with nonparticipation for CRC screening in Songjiang District, Shanghai.We analyzed individuals included in an observational cohort study from 4 towns (Xin Qiao, She Shan, Mao Gang, and Zhong Shan) in Songjiang District. The participation rate was calculated for the CRC screening program based on a fecal immunochemical test and a risk assessment questionnaire between 2015 and 2017 inclusive.Of the 27,130 individuals eligible for inclusion in this study, 20,863 (76.9%) participated in CRC screening at least once during 2015 and 2017. The factors linked with nonparticipation were; being male (odds ratio [OR] 0.87, 95% confidence interval [CI] 0.82–0.93, P < .01), unmarried (OR 0.71, 95% CI 0.64–0.80, P < .01), having a high education level (middle school, OR 0.82, 95% CI 0.74–0.90, P < .01, high school or above, OR 0.64, 95% CI 0.57–0.73, P < .01), absence of chronic disease (OR 0.90, 95% CI 0.85–0.96, P < .01), and living in 2 out of the 4 towns covered (Xin Qiao, OR 0.72, 95% CI 0.66–0.78, P < .01, Zhong Shan, OR 0.29, 95% CI 0.26–0.31, P < .01).The current study revealed several associated factors with nonparticipation for the CRC screening in Songjiang district. These findings will help identify target populations that require an individualized approach to increase the participation rate.     

Sandwich Radioimmunometric Assay with Murine Monoclonal Antibody, NCC-ST-439, for Serological Diagnosis of Human Cancers

Sandwich radioimmunometric assay (RIA) for a new tumor-associated carbohydrate antigen defined by a monoclonal antibody (MoAb), NCC-ST-439, was developed and the antigen levels were determined in sera of normal donors, and patients with various malignant and non-malignant disorders. In normal donors, 97.0% (226/233) of sera were antigen-negative (less than 12 units/ml) except for 7 serum samples from young females. In patients with malignant disorders, 34.2% (82/240) were antigen-positive, in particular 64.0% (16/25) of patients with pancreatic carcinoma, 66.7% (16/24) of patients with recurrent colorectal carcinoma and 54,5% (6/11) of patients with recurrent breast carcinoma. In patients with non-malignant disorders, 6.0% (7/116) were antigen-positive. The positive rate in benign hepatobiliary disorders, including gallstones, hepatitis and liver cirrhosis, was especially low at 4.3% (1/23). We concluded that determination of serum NCC-ST-439 antigen would be useful in serodiagnosis of carcinoma patients.