Cohort profile: rationale and design of the Resource Center for Health Science (RECHS) project - a study of health hazards and medical cost burden among the Japanese population.

PURPOSE: The increased global burden of non-communicable diseases and mental disorders is an urgent health challenge for countries around the entire world, especially those experiencing super-ageing societies, where over 21% of the population is age 65 years or older. Japan is the world's most rapidly ageing society, and as a result, medical costs are also rising dramatically. With the aims of establishing a foundational framework for future research efforts, primarily focusing on the development of a personal health record (PHR) system, and creating a long-term repository for bioresources integrated with PHRs, this study investigated potential health risks and future healthcare burdens based on a longitudinal analysis of health records. PARTICIPANTS: The Resource Center for Health Science (RECHS) project is a long-term, prospective biobank project, population and health check-up-based cohort that primarily investigates the associations between lifestyle and environmental factors and some surrogate markers of non-communicable diseases, such as diabetes, hypertension, cardiovascular disease and cancer. Starting in 2010, we initiated an annual cohort study among voluntary participants recruited from health check-up programmes and collected data from the following sources: a self-administered baseline questionnaire that included items on dietary habits and stress, a Brief Self-Administered Diet History Questionnaire, the Centre for Epidemiologic Studies Depression Scale and the General Health Questionnaire-28. FINDINGS TO DATE: For this prospective cohort study, we planned to enrol approximately 10 000 participants. We collected and stored serum samples from all participants for future analyses. The study participants who still were able to participate in these health check-ups and their outcomes were then obtained from the measurements and questionnaire responses. FUTURE PLANS: Insights emerging from the RECHS study can provide researchers and public health policy administrators with evidence to aid in the prevention of non-communicable diseases and clarify the most malleable status to implement preventive measures.

Dataset dependency of low-density lipoprotein-cholesterol estimation by machine learning.

OBJECTIVES: We evaluated the applicability of a machine learning-based low-density lipoprotein-cholesterol (LDL-C) estimation method and the influence of the characteristics of the training datasets. METHODS: Three training datasets were chosen from training datasets: health check-up participants at the Resource Center for Health Science (N = 2664), clinical patients at Gifu University Hospital (N = 7409), and clinical patients at Fujita Health University Hospital (N = 14,842). Nine different machine learning models were constructed through hyperparameter tuning and 10-fold cross-validation. Another test dataset of another 3711 clinical patients at Fujita Health University Hospital was selected as the test set used for comparing and validating the model against the Friedewald formula and the Martin method. RESULTS: The coefficients of determination of the models trained on the health check-up dataset produced coefficients of determination that were equal to or inferior to those of the Martin method. In contrast, the coefficients of determination of several models trained on clinical patients exceeded those of the Martin method. The means of the differences and the convergences to the direct method were higher for the models trained on the clinical patients' dataset than for those trained on the health check-up participants' dataset. The models trained on the latter dataset tended to overestimate the 2019 ESC/EAS Guideline for LDL-cholesterol classification. CONCLUSION: Although machine learning models provide valuable method for LDL-C estimates, they should be trained on datasets with matched characteristics. The versatility of machine learning methods is another important consideration.

Clinical differences among patients with myeloperoxidase-antineutrophil cytoplasmic antibody-positive interstitial lung disease.

INTRODUCTION: Patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis and idiopathic interstitial lung diseases (IIPs) are positive for myeloperoxidase (MPO)-ANCA. MPO-ANCA-positive vasculitis mainly comprises microscopic polyangiitis (MPA) and unclassifiable vasculitis. These diseases are frequently complicated by interstitial lung disease (ILD). Few studies have reported the clinical differences between the subtypes of MPO-ANCA-positive ILD. Therefore, this study aimed to examine the clinical findings and courses of MPO-ANCA-positive ILD. METHOD: This retrospective study enrolled 100 patients with MPO-ANCA-positive ILD who were categorized into three groups: MPA (n = 44), unclassifiable vasculitis (n = 29), and IIP (n = 27). Our study compared the clinical findings and prognosis of these patients and analyzed the poor prognostic factors. Furthermore, we assessed the association between the patients with and without acute exacerbation of ILD (AE-ILD). RESULTS: Our study found clinical differences in serum markers, clinical symptoms, and treatment regimens among the three groups. ILD complications, as the main cause of death, differed among the three groups (P = 0.04). Patients with unclassifiable vasculitis showed higher survival rates than those with IIP (P = 0.046). Patients with AE-ILD showed fewer general symptoms (P = 0.02) and lower survival rates (P < 0.01) than those without AE-ILD. In multivariate analysis, AE-ILD development was a strong poor prognostic factor for MPO-ANCA-positive ILD. CONCLUSIONS: The subtypes of MPO-ANCA-positive ILD have different clinical features and prognoses. Patients who develop AE-ILD require careful evaluation of clinical courses. Key Points • In myeloperoxidase (MPO)-antineutrophil cytoplasmic antibody (ANCA)-positive interstitial lung disease (ILD), patients with unclassifiable vasculitis showed a better prognosis than those with idiopathic ILD.. • Development of acute exacerbation in ILD was a strong poor prognostic factor in patients with MPO-ANCA-positive ILD..

The Trajectory of the COVID-19 Vaccine Antibody Titers Over Time and the Association of Mycophenolate Mofetil in Solid Organ Transplant Recipients.

The COVID-19 vaccine will be safe and effective in solid organ transplant recipients (SOTs). However, the blunted antibody responses were also of concern. Few studies have reported prolonged serologic follow-up after 2 doses of BNT162b2 vaccine in SOTs. We performed a single-center, prospective observational study of 78 SOTs who received 2 doses of BNT162b2 vaccine. We identified the trajectory of antibody titers after vaccination among SOTs with or without mycophenolate mofetil (MMF) or withdrawn from MMF. We found low seroconversion rates (29/42: 69%) and low antibody titers in SOTs treated with MMF. An inverse linear relationship between neutralizing antibody titers and MMF concentration was confirmed in restricted cubic spline plots (P for effect < .01, P for nonlinearity = .08). For the trajectory of antibody responses, seroconversion and improved antibody titers were observed after withdrawal from MMF in SOTs who showed seronegative or low antibody titers at the first visit after 2 doses of vaccine (P for effect < .01, P for nonlinearity < .05, and P for interaction < .01). We identified increased B-cell counts after withdrawal from MMF (P < .01). The recovery of antibody responses was seen in SOTs withdrawn from MMF. The trajectories of antibody responses were modified by MMF administration.

Validation of the Martin method to estimate low-density lipoprotein cholesterol concentrations in Japanese populations and a modified method for laboratory information system application.

OBJECTIVES: High concentrations of low-density lipoprotein cholesterol (LDL-C) are a risk factor for cardiovascular disease. We validated the efficacy of the Martin method is useful in the estimation of LDL-C concentrations was validated in Japanese populations and derived a modified Martin method for easy laboratory information system applications. METHODS: We created 3 subject groups, including 2664 health check-up participants registered with the Resource Center for Health Science, 29,806 clinical patients (A) in the Gifu University Hospital, and 113,716 clinical patients (B) in the Fujita Health University Hospital. Each method to estimate serum LDL-C concentrations (Friedewald formula, Martin method and modified Martin method) was validated by correlation analysis with serum LDL-C concentrations measured using a direct method. RESULTS: The correlation coefficients with the direct method in terms of the Friedewald formula, Martin method, and modified Martin method were 0.963, 0.972 and 0.970 in the health check-up participants; 0.946, 0.962 and 0.961 in clinical patients A; and 0.961, 0.979 and 0.978 in clinical patients B, respectively. Concordance ratios with using the direct method in the Friedewald formula, Martin method and modified Martin method were 82.8%, 85.5% and 85.3% in the health check-up participants; 76.4%, 80.5% and 80.2% in clinical patients A; and 76.1%, 82.6% and 82.6% in clinical patients B, respectively. CONCLUSION: Our results show that the Martin and modified Martin methods display good performance in terms of the estimation of LDL-C concentrations among triglyceride concentrations of a wide range, and they may thus be useful for estimating LDL-C concentrations.

Antibody Responses to BNT162b2 Vaccination in Japan: Monitoring Vaccine Efficacy by Measuring IgG Antibodies against the Receptor-Binding Domain of SARS-CoV-2.

To fight severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which causes coronavirus disease 2019 (COVID-19), mass vaccination has begun in many countries. To investigate the usefulness of a serological assay to predict vaccine efficacy, we analyzed the levels of IgG, IgM, and IgA against the receptor-binding domain (RBD) of SARS-CoV-2 in the sera from BNT162b2 vaccinated individuals in Japan. This study included 219 individuals who received two doses of BNT162b2. The levels of IgG, IgM, and IgA against RBD were measured by enzyme-linked immunosorbent assay before and after the first and second vaccination, respectively. The relationship between antibody levels and several factors, including age, gender, and hypertension were analyzed. Virus-neutralizing activity in sera was measured to determine the correlation with the levels of antibodies. A chemiluminescent enzyme immunoassay (CLEIA) method to measure IgG against RBD was developed and validated for the clinical setting. The levels of all antibody isotypes were increased after vaccination. Among them, RBD-IgG was dramatically increased after the second vaccination. The IgG levels in females were significantly higher than in males. There was a negative correlation between age and IgG levels in males. The IgG levels significantly correlated with the neutralizing activity. The CLEIA assay measuring IgG against RBD showed a reliable performance and a high correlation with neutralizing activity. Monitoring of IgG against RBD is a powerful tool to predict the efficacy of SARS-CoV-2 vaccination and provides useful information in considering a personalized vaccination strategy for COVID-19. IMPORTANCE Mass vaccination campaigns using mRNA vaccines against SARS-CoV-2 have begun in many countries. Serological assays to detect antibody production may be a useful tool to monitor the efficacy of SARS-CoV-2 vaccination in individuals. Here, we reported the induction of antibody isotype responses after the first and second dose of the BNT162b2 vaccine in a well-defined cohort of employees in Japan. We also reported that age, gender, and hypertension are associated with differences in antibody response after vaccination. This study not only provides valuable information with respect to antibody responses after BNT162b2 vaccination in the Japanese population but also the usefulness of serological assays for monitoring vaccine efficacy in clinical laboratories to determine a personalized vaccination strategy for COVID-19.

Serum GP88 as a predictive biomarker for hepatocellular carcinoma in patients with viral hepatitis C after direct-acting antiviral agents.

BACKGROUND: Progranulin (GP88) is an 88-kDa glycoprotein growth factor with important biological effects in tumorigenesis and tumour survival. We investigated the usefulness of measuring serum GP88 concentrations as a predictive biomarker for hepatocellular carcinoma in patients with viral hepatitis C after treatment with direct-acting antiviral agents. METHODS: We measured the serum GP88 concentrations by using a sandwich enzyme-linked immunoassay from 67 healthy control subjects and 29 patients (20 patients who did not develop hepatocellular carcinoma and 9 patients who developed hepatocellular carcinoma after treatment) with viral hepatitis C after treatment with asunaprevir and daclatasvir. RESULTS: The serum GP88 concentrations of patients with chronic hepatitis C prior to antiviral treatment were significantly higher than those of healthy control subjects. After antiviral treatment, the serum GP88 concentrations of patients who eventually developed hepatocellular carcinoma were significantly higher than those who did not develop hepatocellular carcinoma. The changes in the serum GP88 concentrations before and after treatment in patients who developed hepatocellular carcinoma were significantly lower than those in patients who did not develop hepatocellular carcinoma. The cumulative incidence of hepatocellular carcinoma was significantly higher in either patients with high serum GP88 concentrations after treatment or those with small changes of serum GP88 concentrations pre- and post-treatment. CONCLUSIONS: Sustained high concentrations of serum GP88 in patients treated with direct-acting antiviral agents are correlated with the risk of developing hepatocellular carcinoma.

Comparative Analysis of Antigen-Specific Anti-SARS-CoV-2 Antibody Isotypes in COVID-19 Patients.

Serological tests for detection of anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Abs in blood are expected to identify individuals who have acquired immunity against SARS-CoV-2 and indication of seroprevalence of SARS-CoV-2 infection. Many serological tests have been developed to detect Abs against SARS-CoV-2. However, these tests have considerable variations in their specificity and sensitivity, and whether they can predict levels of neutralizing activity is yet to be determined. This study aimed to investigate the kinetics and neutralizing activity of various Ag-specific Ab isotypes against SARS-CoV-2 in serum of coronavirus disease 2019 (COVID-19) patients confirmed via PCR test. We developed IgG, IgM, and IgA measurement assays for each Ag, including receptor-binding domain (RBD) of spike (S) protein, S1 domain, full-length S protein, S trimer, and nucleocapsid (N) domain, based on ELISA. The assays of the S protein for all isotypes showed high specificity, whereas the assays for all isotypes against N protein showed lower specificity. The sensitivity of all Ag-specific Ab isotypes depended on the timing of the serum collection and all of them, except for IgM against N protein, reached more than 90% at 15-21 d postsymptom onset. The best correlation with virus-neutralizing activity was found for IgG against RBD, and levels of IgG against RBD in sera from four patients with severe COVID-19 increased concordantly with neutralizing activity. Our results provide valuable information regarding the selection of serological test for seroprevalence and vaccine evaluation studies.

Interstitial lung disease with myeloperoxidase-antineutrophil cytoplasmic antibody-associated vasculitis in elderly patients.

Anti-neutrophil cytoplasmic antibodies-associated vasculitis (AAV) occurs in elderly people, and patients with anti-myeloperoxidase autoantibodies (MPO-ANCA)-positive AAV are often complicated with interstitial lung disease (ILD). This study aimed to evaluate the age-related clinical features of elderly patients with MPO-ANCA-positive AAV-ILD. This study retrospectively investigated 63 patients with MPO-ANCA-positive AAV-ILD, all of whom were 65 years or older at diagnosis. Clinical characteristics, causes of death and survival rates among three groups stratified by age (65-74 years, n = 29; 75-79 years, n = 18; over 80 years, n = 16) were compared. This study also examined the association with severe infections in these patients. Among the three age groups, there were significant differences in sex (P = 0.032), serum Krebs von den Lungen-6 (P < 0.01), and total ground-glass opacity score (P = 0.011). The causes of death were mainly severe infections and complications of ILD. Kaplan-Meier curve analysis showed a significantly lower 5-year survival rate in the oldest group (P < 0.01). Regarding severe infections in these patients, the 5-year cumulative incidence of severe infections was higher in the patients receiving steroid pulse therapy (P = 0.034). The clinical characteristics of MPO-ANCA-positive AAV-ILD differ with age in elderly patients, with age being an important poor prognostic factor in these patients. The administration of steroid pulse therapy is a significant risk factor of severe infection in MPO-ANCA-positive elderly patients with AAV-ILD.

Pulmonary Vascular Alterations on Computed Tomography Imaging and Outcomes in Heart Failure With Preserved Ejection Fraction: a Preliminary Data.

BACKGROUND: Pulmonary vascular disease may play an important role in the pathophysiology of heart failure (HF) with preserved ejection fraction (HFpEF). However, no study has demonstrated noninvasive quantification of pulmonary vascular alterations in HFpEF. This study sought to determine the association between pulmonary vascular alterations quantified by chest computed tomography scan and clinical outcomes in HFpEF. METHODS AND RESULTS: Pulmonary vascular alterations were quantified in 151 patients with HFpEF who underwent noncontrast chest computed tomography scan by measuring the percentage of total cross-sectional area (CSA) of pulmonary vessels less than 5 mm2 to the total lung area (%CSA<5). We divided the patients by the median value of %CSA<5 (=1.45%) and examined the association between %CSA<5 and a composite outcome of all-cause mortality or HF hospitalization. During a median follow-up of 17.3 months, there were 44 (29%) composite outcomes. Event rates were significantly higher in patients with higher %CSA<5 than those with lower %CSA<5 (log-rank P = .02). %CSA<5 was associated with an increased risk of the outcome (hazard ratio per 1.0% increment, 1.46; 95% confidence interval 1.06-1.98; P = .02) in an unadjusted Cox model, and was independently and incrementally associated with the outcome over age, the presence of atrial fibrillation, E/e' ratio, and estimated pulmonary artery systolic pressure (global χ2 17.3 vs 11.5, P = .02). CONCLUSIONS: A higher %CSA<5 was associated with an increased risk of all-cause mortality or HF hospitalization in patients with HFpEF, with an incremental prognostic value over age, atrial fibrillation, E/e' ratio, and pulmonary artery systolic pressure.

Immune-related adverse events caused by treatment with pembrolizumab in a patient with lung cancer who infected influenza virus.

A 67-year-old man with stage IV B lung adenocarcinoma was treated with pembrolizumab. The patient was admitted to the hospital because of influenza on the day of the second cycle of pembrolizumab treatment. He was diagnosed with pneumonia and was treated with antiviral drugs and steroids. However, the patient eventually died. In this case, treatment with immune checkpoint inhibitors might have affected the immune response caused by influenza virus infection, that might have caused lung injury, which is an immune-related adverse event (irAE). Hence, it is important that, caution should be taken to prevent transmission of viral infection, and Therefore, it is important to prevent viral infections, but caution should also be paid to the possibility that infections may cause irAEs in patients with lung cancer.

Progranulin depletion inhibits proliferation via the transforming growth factor beta/SMAD family member 2 signaling axis in Kasumi-1 cells.

Progranulin is an autocrine growth factor that promotes proliferation, migration, invasion, and chemoresistance of various cancer cells. These mechanisms mainly depend on the protein kinase B (Akt)/mechanistic target of rapamycin (mTOR) pathway. Recent studies have shown that patients with hematopoietic cancer have elevated serum progranulin levels. Thus, the current study aimed to investigate the role of progranulin in hematopoietic cancer cells and how it modulates their proliferation. Both knockdown of progranulin and progranulin neutralizing antibody treatment inhibited proliferation in several human hematopoietic cancer cell lines. Moreover, progranulin depletion not only decreases the phosphorylation level of the Akt/mTOR pathway but also, surprisingly, increases the expression of transforming growth factor-beta (TGF-ß) and phosphorylation of mothers against decapentaplegic homolog 2 (SMAD2) in Kasumi-1 cell. Furthermore, LY2109761, an inhibitor of TGF-ß receptor type I/II kinase, and TGF-ß neutralizing antibody blocked the inhibition of proliferation induced by progranulin depletion. These data provide new insights that progranulin alters cell proliferation via the TGF-ß axis and progranulin could be a new therapeutic target for hematopoietic cancers.

Clinical features of dermatomyositis associated with anti-MDA5 antibodies by age.

OBJECTIVES: Anti-melanoma differentiation-associated gene 5 (MDA5) autoantibody-positive and age at onset ≥60 years are poor prognosis factors in polymyositis (PM) and dermatomyositis (DM) associated with interstitial lung disease (ILD) among Japanese patients. However, the influence of age on the clinical features of anti-MDA5 autoantibody-positive patients with DM remains unclear. METHODS: We retrospectively examined 40 patients with DM and anti-MDA5 autoantibodies according to age. We compared patients aged <60 and ≥60 years with respect to clinical features including laboratory test findings, high-resolution lung computed tomography data, treatment content, and complications such as infections and prognosis. We also examined clinical features between surviving and deceased patients in the older patient group. RESULTS: Of 40 enrolled patients, 13 were classified as old and 27 as young. Older patients had significantly fewer clinical symptoms including arthralgia/arthritis (p < .01), skin ulceration (p = .02), and higher mortality than younger patients (p = .02) complicated with rapidly progressive ILD (RP-ILD), combination immunosuppressive therapy, and strictly controlled infections. CONCLUSION: Clinical features and mortality of anti-MDA5 autoantibody-positive DM patients were influenced by age. Patients aged ≥60 years had a worse prognosis, and combination immunosuppressive therapy was often ineffective for RP-ILD in older patients.

Reliability of serological tests for COVID-19: comparison of three immunochromatography test kits for SARS-CoV-2 antibodies.

BACKGROUND: Several immunochromatographic serological test kits have been developed to detect severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-specific antibodies, but their relative performance and potential clinical utility is unclear. METHODS: Three commercially available serological test kits were evaluated using 99 serum samples collected from 29 patients diagnosed with coronavirus disease 2019 (COVID-19) and 100 serum samples collected from 100 healthy volunteers in 2017 as negative controls. RESULTS: The specificity of the IgM and IgG antibodies showed comparable results among the three immunochromatographic serological test kits. The specificity for IgM antibody was 98.0%, 98.0%, and 97.0%, and the specificity for IgG antibody was identical among the three kits (99.0%). The IgM antibody-positive rates of the three test kits for samples taken at the early stage of the disease (0-4 days after onset) were consistent with all three kits (18.2%); however, the IgM antibody-positive rates thereafter showed considerable differences among the kits, making it difficult to interpret the kinetics of IgM response against SARS-CoV-2. The IgG antibody-positive rates for samples taken after 13 days of onset were 100.0%, 97.6%, and 97.6%, respectively. CONCLUSION: There were large differences among the results of the three test kits. Only few cases showed positive results for IgM, suggesting that at least 2 of these kits used in this study were unsuitable for diagnosis of COVID-19. The IgG antibody was positive in almost all samples after 13 days of onset, suggesting that it may be useful for determining infections in the recent past.

Serum Metabolic Profiles of the Tryptophan-Kynurenine Pathway in the high risk subjects of major depressive disorder.

Previous reports have shown that during chronic inflammation, the tryptophan (TRP)-kynurenine (KYN) pathway plays a pivotal role in the onset of depression. The aim of this study was to investigate the characteristics of the serum TRP-KYN pathway metabolite profile in high-risk subjects of major depressive disorder (HRMDD) defined by depression scores. The concentrations of TRP-KYN pathway metabolites {TRP, KYN, 3-hydroxyanthranilic acid (3HAA), 3-hydroxykynurenine (3HK), kynurenic acid (KYNA) and anthranilic acid (AA)} were assessed in serum from HRMDD, chronic pain disorder patients and healthy controls. In serum from HRMDD, elevated levels of AA and decreased levels of TRP were observed, but the levels of other metabolites were not changed. Furthermore, the change in the AA2nd/AA1st ratio in subjects who progressed from a health. y state to a depressive state was correlated with an increase in the CES-D score. The level of IL-1 receptor antagonist (IL-1RA) was negatively correlated with that of AA. Interestingly, we confirmed AA as a possible biomarker for depression-related symptoms, since the metabolite profiles in the chronic pain disorder group and chronic unpredictable mild stress model mice were similar to those in the HRMDD. These results suggest that AA may be an effective marker for HRMDD.

Clinical features of patients with anti-melanoma differentiation-associated gene-5 antibody-positive dermatomyositis complicated by spontaneous pneumomediastinum.

BACKGROUND: Dermatomyositis (DM) with autoantibody against melanoma differentiation-associated gene-5 (MDA5) is characterized by elevated risk of rapidly progressive interstitial lung disease (RP-ILD) with a potentially fatal course. Pneumomediastinum (PNM) is a common pulmonary manifestation which accompanies ILD. However, the clinical features of the patients with anti-MDA5 antibody-positive DM who develop PNM remain unclear. METHODS: We retrospectively examined 31 patients with DM having anti-MDA5 antibody and compared the clinical features between patients with PNM (PMN(+)) (n = 11) and those without (PNM(-) (n = 20). In addition, we evaluated the treatment-related prognoses in PNM(+) group. RESULTS: CT score (total ground-glass opacity (GGO) score, P = 0.02; total fibrosis score, P = 0.02) before treatment, and mortality (P = 0.04) were significantly higher in PNM(+) group. The cumulative survival rate as assessed by Kaplan-Meier method was significantly lower for the PNM(+) group (P = 0.02). Among 11 PMN(+) patients, 9 patients (9/11, 81.8%) underwent intensive immunosuppression therapy for RP-ILD, and 5 patients (5/11, 45.5%) did not respond to it and died from the respiratory failure. At the time of diagnosis of PNM, nonsurvivors had worse liver function (ALT, P = 0.03; LDH, P = 0.01), worse respiratory status (A-aDO2, P = 0.01), and worse CT score (total GGO score, P < 0.01). CONCLUSIONS: A subgroup of patients with DM having anti-MDA5 antibody complicated by PNM as well as RP-ILD did respond to intensive immunosuppression therapy. Initial aggressive immunosuppressive therapy should be considered for these patients.Key Points• This study clearly demonstrate the presence of PNM was associated with elevated risk of death due to respiratory failure from RP-ILD among patients with DM having circulating anti-MDA5-antibody.•This study demonstrate evaluation of CT image may be helpful to find patients with better response to the intense immunosuppression therapy for the patients with DM having circulating anti-MDA5-antibody and PNM.

Cytokines and biological markers in autoimmune GFAP astrocytopathy: The potential role for pathogenesis and therapeutic implications.

Autoimmune glial fibrillary acidic protein (GFAP) astrocytopathy (GFAP-A) is a corticosteroid-responsive meningoencephalomyelitis with a poorly understood pathogenesis. We examined and compared the levels of cytokines and biological markers in the cerebrospinal fluid (CSF) of patients with GFAP-A and other neurological disorders. We identified four cytokines (tumor necrosis factor alpha [TNFα], Interleukin [IL]-27, IL-6, and chemokine [C-C motif] ligand 20) and three biological markers (GFAP, S100 calcium-binding protein B, and neurofilament light chain) present at elevated levels in CSF samples during the acute phase of GFAP-A. Additionally, we identified significant correlations between CSF TNFα, IL-27, IL-6, and CSF biological markers.

Probe-based confocal laser endomicroscopy for rapid on-site evaluation of transbronchial biopsy specimens.

BACKGROUND: Probe-based confocal laser endomicroscopy (pCLE) is a novel, noninvasive technology that provides real-time lung imaging during bronchoscopy. pCLE shows the elastic fiber network without the use of a fluorescent dye. Elastic fibers produce argon laser-induced autofluorescence at a wavelength of 488 nm, but tumor cells do not produce autofluorescence at this wavelength. As a result, the tumor cells cannot be observed directly. Therefore, we stained transbronchial biopsy (TBB) specimens with acriflavine to evaluate the benign and malignant structures using pCLE of ex vivo samples and to determine whether rapid histopathological diagnosis of TBB specimens could be made via pCLE. METHODS: After bronchoscopy, 36 TBB specimens were stained with acriflavine and observed using pCLE. Benign and malignant lesions were classified by cell density and nuclear magnitude disparity. RESULTS: We defined the confocal laser endomicroscopic atypia classification from the findings of the cells. The sensitivity for malignancy was 91.3%, and the specificity was 76.9%. Both inter-observer (κ = 0.48) and intra-observer (κ = 0.57) agreement confirmed moderate agreement. CONCLUSION: pCLE with acriflavine staining was useful to differentiate malignant from benign TBB specimens, and might be useful as a substitute for rapid on-site evaluation of histopathological diagnosis.

Differential clinical features of patients with clinically amyopathic dermatomyositis who have circulating anti-MDA5 autoantibodies with or without myositis-associated autoantibodies.

BACKGROUND: Anti-melanoma differentiation-associated gene 5 (MDA5) autoantibodies have been identified as myositis-specific autoantibodies that are often associated with clinically amyopathic dermatomyositis (CADM) and a poor prognosis due to rapidly progressive interstitial lung disease (RP-ILD) in East Asian patients. Besides anti-MDA5 autoantibodies, patients with CADM may have myositis-associated autoantibodies (MAAs), which characterize other connective tissue diseases such as rheumatoid arthritis and Sjögren's syndrome. However, the clinical significance of the coexistence of anti-MDA5 autoantibodies and MAAs in patients with CADM remains unclear. METHODS: We retrospectively analyzed 24 patients with CADM who had anti-MDA5 autoantibodies. Their clinical phenotypes including laboratory test results, high-resolution lung computed tomography data, response to therapy, and prognosis were compared between those who were positive and negative for MAAs, such as antinuclear antibody (ANA), anti-cyclic citrullinated peptide (CCP), anti-SSA, and anti-SSB antibodies. RESULTS: Among 24 patients, 9 (37.5%) additionally had at least one of the MAAs examined in this study: 1 patient was positive for ANA, 5 for anti-CCP, 5 for either anti-SSA or anti-SSB, 1 for anti-cardiolipin, and 1 for anti-Scl-70. Although all anti-MDA5-positive patients with CADM had ILD, the MAA-positive patients showed a lower risk of developing RP-ILD (p = 0.03), a more favorable response to combination therapy of corticosteroids and immunosuppressive agents, and a lower mortality rate than patients with no MAAs (p = 0.03). CONCLUSIONS: Our data suggest that anti-MDA5-positive patients with CADM who also have MAAs have a better prognosis than those without MAAs; thus, anti-MDA5 autoantibodies by themselves may not be strong predictors of worse clinical outcomes in patients with CADM. Coexistent MAAs could be biomarkers for a favorable prognosis in anti-MDA5-positive patients with CADM.

Higher levels of progranulin in cerebrospinal fluid of patients with lymphoma and carcinoma with CNS metastasis.

Assessing central nervous system (CNS) involvement in patients with lymphoma or carcinoma is important in determining therapy and prognosis. Progranulin (PGRN) is a secreted glycosylated protein with roles in cancer growth and survival; it is highly expressed in aggressive cancer cell lines and specimens from many cancer types. We examined PRGN levels by Enzyme Immuno-Assay (EIA) in cerebrospinal fluid (CSF) samples from 230 patients, including 18 with lymphoma [12 with CNS metastasis (CNS+); 6 without CNS metastasis (CNS-)], 21 with carcinomas (10 CNS+; 11 CNS-), and 191 control patients with non-cancer neurological diseases, and compared PRGN levels among these disease groups. Median CSF PGRN levels in the CNS+ lymphoma group were significantly higher than in the CNS- lymphoma and control non-cancer groups; and were also significantly higher in the CNS+ carcinoma group than in the CNS- carcinoma and control groups, except for patients with infectious neurological disorders. Receiver operating characteristic curve analyses revealed that CSF PGRN levels distinguished CNS+ lymphoma from CNS- lymphoma and non-cancer neurological diseases [area under curve (AUC): 0.969]; and distinguished CNS+ carcinomas from CNS- carcinomas and non-cancer neurological diseases (AUC: 0.918). We report here, for the first time, that CSF PGRN levels are higher in patients with CNS+ lymphoma and carcinomas compared to corresponding CNS- diseases. This would imply that measuring CSF PGRN levels could be used to monitor CNS+ lymphoma and metastasis.