Medical Centers In Japan Research Articles

Perinatal factors contributing to chronic kidney disease in a cohort of Japanese children with very low birth weight

BackgroundDevelopmental programming of chronic kidney disease (CKD) in young adults is linked to preterm birth and intrauterine growth restriction (IUGR). Which confers a higher risk of progression to chronic kidney damage in children with very low birth weight (VLBW; born weighing < 1500 g): prematurity or IUGR?MethodsThis is a national historical cohort study of children with VLBW cared for in perinatal medical centers in Japan. Predictive factors included three latent variables (prematurity, IUGR, stress during neonatal period) and eight observed variables (gestational age, birth weight Z-score, maternal age, duration of treatment with antibiotics and diuretics, maternal smoking, late-onset circulatory collapse, kidney dysfunction) during the perinatal period. The primary endpoint was estimated glomerular filtration rate (eGFR) at age ≥ 3 years. A structural equation model was used to examine the pathologic constitution.ResultsThe 446 children with VLBW included 253 boys and 193 girls, of mean age 5.8 ± 2.6 years and mean eGFR 111.7 ml/min/1.73 m2 at last encounter. Pathway analyses showed intrauterine malnutrition (β = 0.85) contributed more to chronic kidney damage than stress during the neonatal period (β = − 0.19) and prematurity (β = 0.12), and kidney dysfunction and late-onset circulatory collapse were important observed variables in stress during the neonatal period.ConclusionsIUGR was more harmful to future kidneys of VLBW neonates. Neonatal kidney dysfunction and late-onset circulatory collapse were important risk factors for subsequent CKD development. This emphasizes the need for obstetricians to monitor for fetal growth restriction and neonatologists to minimize neonatal stress to prevent CKD in later life.

Efficacy, safety, and pharmacokinetics of oral valganciclovir in patients with congenital cytomegalovirus infection

ObjectivesValganciclovir (VGCV) has been shown to improve sensorineural hearing loss (SNHL) and neurological outcomes in patients with neonatal symptomatic congenital cytomegalovirus (cCMV) infection. However, reports on the pharmacokinetics, efficacy and safety of oral VGCV are limited. The aim of this study is to evaluate the pharmacokinetics of VGCV for use in the treatment of cCMV. MethodsThis was a single-center, retrospective observational study conducted at Saitama Children's Medical Center in Japan between 2012 and 2017. CMV DNA copy number, maximum plasma VGCV concentration (Cmax), and adverse events (ADEs) during treatment were evaluated. ResultsA total of 26 patients with cCMV who received VGCV were included in this study. The median age at VGCV initiation was 9.5 months (range 0–46). Twenty-one patients (81%) had SNHL at baseline. Of these, five patients (19%) presented with improved SNHL, and none experienced worsened SNHL during treatment. The mean VGCV Cmax was 3.5 μg/mL (range 2–5.3), with no significant variation among individual values, and the values were maintained during treatment. Furthermore, there were no correlations between the Cmax values and age, sex, SNHL improvement or ADEs. Neutropenia (<1000/mm3) was observed in six patients (23%); however, no serious ADEs occurred. ConclusionsVGCV prevented the progression of SNHL without serious ADEs due to its stable pharmacokinetics. This study provides safety and tolerability of VGCV for the treatment of cCMV patients.

Characterization of Ba813 harbouring Bacillus cereus in patients with haematological malignancy and hospital environments at a medical centre in Japan.

Introduction. Bacillus cereus harbouring Ba813, a specific chromosomal marker of Bacillus anthtacis, is found in patients with severe manifestations and causes nosocomial outbreaks.Aim. We assessed the genetic characteristics and virulence of Ba813(+) B. cereus in a hospital setting.Methodology. Three neutropenic patients with haematological malignancy developed B. cereus bacteraemia within a short period. Fifteen B. cereus were isolated from different sites in a haematology ward. A total of 18 isolates were evaluated for Ba813- and B. anthracis-related virulence, food poisoning-related virulence, genetic diversity, bacteria motility and biofilm formation.Results. Ba813(+) B. cereus was detected in 33 % (1/3) of patients and 66 % (9/15) of the hospital environment. The 18 strains were divided into 2 major clusters (clade 1 and clade 2), and 14 strains were classified into clade 1. All Ba813(+) strains, including four sequence types, were classified into clade 1/the cereus III lineage, which is most closely related to the anthracis lineage. Two strains belonging to clade 1/non-cereus III carried the B. anthracis-associated cap gene, but not Ba813. B. cereus, including Ba813(+) strains, had significantly lower prevalence of enterotoxin genes than clade 2 strains. In clade 1, B. cereus, Ba813(+) strains showed significantly higher swimming motility and biofilm formation ability than Ba813(-) strains.Conclusion. Ba813(+) B. cereus, which are genetically closely related to B. anthracis, were abundant in a haematological ward. Ba813(+) B. cereus with high motility and biofilm formation abilities may spread easily in hospital environments, and could become a hospital-acquired infection.

Social withdrawal in major depressive disorder: a case-control study of hikikomori in japan

BackgroundSocial withdrawal is a feature of a number of psychiatric disorders including major depressive disorder (MDD), yet research examining social withdrawal as a feature of MDD is rare. MethodsThis was a retrospective case-control study. Participants (N = 67) were recruited through an outpatient clinic at an academic medical center in Japan. Major depressive disorder (MDD) and social withdrawal were established with the Structured Clinical Interview for DSM-IV Axis I Disorders and a semi-structured psychiatric interview, respectively. Participants also completed self-report measures. ResultsWe classified 24 participants as cases (MDD with social withdrawal) and 43 participants as controls (MDD without social withdrawal). Cases, on average, were more likely to have lower education level, prior episodes of depression, and higher suicidal ideation at baseline than controls. In unadjusted regression models, cases had significantly less social connection, less reward dependence, less self-directedness, and higher scores on scales of modern-type depression and hikikomori. In adjusted regression models, associations between social withdrawal and hikikomori (p<0.01) and reward dependence (p = 0.03) remained significant. LimitationsThe sample was limited in size and drawn from a single site. ConclusionsIn patients with MDD, social withdrawal may have subtle associations with clinical symptoms, social connection, and personality traits. Developing a better understanding of social withdrawal's phenotype in depression requires more in-depth examination.

Highly Bioavailable Curcumin Derivative Ameliorates Crohn's Disease Symptoms: A Randomized, Double-Blind, Multicenter Study.

The new curcumin derivative Theracurmin® has a 27-fold higher absorption rate than natural curcumin powder. Theracurmin® is an inhibitor of nuclear factor-κB, which mediates the expression of inflammatory cytokines. The effect of Theracurmin® on inflammatory bowel disease in humans has not been explored; therefore, we investigated the efficacy and safety of Theracurmin® in patients with Crohn's disease. In this randomized, double-blinded study performed at 5 independent medical centers in Japan, Theracurmin® (360 mg/day, n = 20) or placebo (n = 10) was administered to patients with active mild-to-moderate Crohn's disease for 12 weeks. The agent's efficacy was assessed by evaluating clinical and endoscopic remission, healing of anal lesions, and blood levels of inflammatory markers. In the Theracurmin® group, a significant reduction in clinical disease activity was observed in week 12 relative to that in week 0 (p = 0.005). On intention-to-treat analysis, clinical remission rates were 35%, 40%, and 40% at weeks 4, 8, and 12, respectively, which were significantly higher than those in the placebo group (all 0%; p = 0.033, p = 0.020, and p = 0.020, respectively). Furthermore, reduction in endoscopic Crohn's disease severity (p = 0.032) was observed at week 12 in the Theracurmin® group. The endoscopic remission rates were 15% and 0% in the Theracurmin® and placebo groups, respectively. Significant healing of anal lesions (p = 0.017) was observed at week 8 in the Theracurmin® group. No serious adverse events were observed in either group throughout the study. Theracurmin® shows significant clinical and endoscopic efficacy together with a favorable safety profile in patients with active mild-to-moderate Crohn's disease. UMIN000015770.

A MicroRNA Signature Identifies Pancreatic Ductal Adenocarcinoma Patients at Risk for Lymph Node Metastases

Pancreatic ductal adenocarcinomas (PDACs) frequently metastasize to the lymph nodes; strategies are needed to identify patients at highest risk for lymph node metastases. We performed genome-wide expression profile analyses of PDAC specimens, collected during surgery or endoscopic ultrasound-guided fine-need aspiration (EUS-FNA), to identify a microRNA (miRNA) signature associated with metastasis to lymph nodes. For biomarker discovery, we analyzed miRNA expression profiles of primary pancreatic tumors from 3 public data sets (The Cancer Genome Atlas, GSE24279, and GSE32688). We then analyzed 157 PDAC specimens (83 from patients with lymph node metastases and 74 without) from Japan, collected from 2001 through 2017, for the training cohort and 107 PDAC specimens (63 from patients with lymph node metastases and 44 without) from a different medical center in Japan, from 2002 through 2016, for the validation cohort. We also analyzed samples collected by EUS-FNA before surgery from 47 patients (22 patients with lymph node metastases and 25 without; 17 for the training cohort and 30 from the validation cohort) and 62 specimens before any treatment from patients who received neoadjuvant chemotherapy (9 patients with lymph node metastasis and 53 without) for additional validation. Multivariate logistic regression analyses were used to evaluate the statistical differences in miRNA expression between patients with vs without metastases. We identified an miRNA expression pattern associated with diagnosis of PDAC metastasis to lymph nodes. Using logistic regression analysis, we optimized and trained a 6-miRNA risk prediction model for the training cohort; this model discriminated patients with vs without lymph node metastases with an area under the curve (AUC) of 0.84 (95% confidence interval [CI], 0.77-0.89). In the validation cohort, the model identified patients with vs without lymph node metastases with an AUC of 0.73 (95% CI, 0.64-0.81). In EUS-FNA biopsy samples, the model identified patients with vs without lymph node metastases with an AUC of 0.78 (95% CI, 0.63-0.89). The miRNA expression pattern was an independent predictor of PDAC metastasis to lymph nodes in the validation cohort (odds ratio, 17.05; 95% CI, 2.43-119.57) and in the EUS-FNA cohort (95% CI, 0.65-0.87). Using data and tumor samples from 3 independent cohorts, we identified an miRNA signature that identifies patients at risk for PDAC metastasis to lymph nodes. The signature has similar levels of accuracy in the analysis of resected tumor specimens and EUS-FNA biopsy specimens. This model might be used to select treatment and management strategies for patients with PDAC.

Prospective multicentre study on the safety and utility of transbronchial lung cryobiopsy with endobronchial balloon.

Transbronchial lung cryobiopsy (TBLC) has been increasingly utilised to diagnose diffuse parenchymal lung diseases (DPLDs) and lung cancers; however, TBLC protocols have not yet been standardised and the rate of complications associated with this procedure vary widely. Therefore, this prospective multicentre observational study investigated the safety and utility of the TBLC technique in patients with diffuse and localised respiratory diseases.This study was conducted at multiple medical centres in Japan between July 2018 and April 2019. The study's primary end-point was the rate of severe or serious adverse events associated with TBLC. Adverse events included bronchial bleeding, pneumothorax, pneumonia, respiratory failure, and an acute exacerbation of interstitial pneumonia. Adverse events were graded according to severity. During the TBLC procedure, an endobronchial balloon catheter for bronchial blockade was used in all patients. Pathological confidence and quality of specimens were categorised into three groups.A total of 112 patients were included. Neither severe nor serious adverse events were identified; therefore, the primary end-point was met. Nineteen patients (17%) experienced no bronchial bleeding. Mild or moderate bronchial bleeding was identified in 67% and 16% of patients, respectively. Mild pneumothoraces were identified in four patients (3.6%). The safety profile in patients aged ≥75 years was not significantly different from younger patients. Definite or probable pathological diagnoses were made in 84.9% of patients.This TBLC protocol with routine use of an endobronchial balloon had an acceptable safety profile and diagnostic yield in patients, including elderly ones, with diffuse and localised respiratory diseases.

Mixed 20-peptide cancer vaccine in combination with docetaxel and dexamethasone for castration-resistant prostate cancer: a randomized phase II trial

A novel cancer vaccine consisting of 20 mixed peptides (KRM-20) was designed to induce cytotoxic T lymphocytes (CTL) against twelve different tumor-associated antigens. The aim of this phase II trial was to examine whether KRM-20 in combination with docetaxel and dexamethasone enhances the antitumor effects in patients with castration-resistant prostate cancer (CRPC). In this double-blind, placebo-controlled, randomized phase II study, we enrolled chemotherapy-naïve patients with CRPC from ten medical centers in Japan. Eligible patients were randomly assigned 1:1 centrally to receive either KRM-20 combined with docetaxel and dexamethasone (n = 25) or placebo with docetaxel and dexamethasone (n = 26). The primary endpoint was the difference in prostate-specific antigen (PSA) decline between each treatment. The rates of > 50% PSA decline in the two arms were similar (56.5% versus 53.8%; P = 0.851). Human leukocyte antigen (HLA)-matched peptide-specific immunoglobulin G (P = 0.018) and CTL (P = 0.007) responses in the KRM-20 arm significantly increased after treatment. The addition of KRM-20 did not increase toxicity. There were no between-group differences in progression-free or overall survival (OS). The addition of KRM-20 was safe, and similar PSA decline and HLA-matched peptide-specific CTL and IgG responses increased in combination with docetaxel and dexamethasone in CRPC patients. Subgroup analysis suggested that this treatment is favorable for CRPC patients with ≥ 26% lymphocytes or PSA levels of < 11.2 ng/ml, but further clinical trials comparing OS are required.

Comparison of initial and final diagnoses in children with acute febrile illness: A retrospective, descriptive study: Initial and final diagnoses in children with acute fever

BackgroundThis study aimed to elucidate the etiologies and diagnostic errors of early-phase pediatric fever without an obvious cause. MethodsThis single-center, retrospective, descriptive study included 1334 febrile children hospitalized at Beppu Medical Center in Japan between 2014 and 2018. Eligibility criteria were age ≤12 years, axillary temperature ≥38.0°C, and fever duration ≤7 days at admission. Initial diagnoses on the day of admission and final diagnoses at defervescence were divided into initial fever with identified source (FIS) and initial fever without source (FWS) and final FIS and final FWS, respectively. The etiology of initial FWS and diagnostic discordance between initial FIS and final FIS were investigated. ResultsOf the 1334 participants, 94 (7.0%) were diagnosed with initial FWS. Among patients with initial FWS, final diagnoses were confirmed in 40 (43%), including Kawasaki disease in 17, urinary tract infection in 5, bacteremia in 4, exanthem subitum in 3, and the others in 11. Among the 1275 patients diagnosed with final FIS, diagnostic discordances between initial and final diagnoses were observed in 131 patients (10%). The multiple logistic regression analysis identified increased serum C-reactive protein value at admission (odds ratio [OR]: 1.09; 95% confidence interval [CI]: 1.06–1.13), exanthem subitum (OR: 409; 95% CI: 119–1399), and Kawasaki disease (OR: 14.3; 95% CI: 8.7–23.3) as independent risk factors for diagnostic discordance. ConclusionExanthem subitum and Kawasaki disease may be undiagnosed or misdiagnosed in febrile children with fever duration ≤7 days.

Factors associated with disabling low back pain among nursing personnel at a medical centre in Japan: a comparative cross-sectional survey

ObjectivesLow back pain (LBP) is a common cause of disability among nursing personnel. Although many studies regarding the risk factors for LBP among nursing staff have focused on the physical...

Efficacy and safety of pembrolizumab as first-line therapy in advanced non-small cell lung cancer with at least 50% PD-L1 positivity: a multicenter retrospective cohort study (HOPE-001).

Objectives As first line therapy, pembrolizumab provides longer progression free survival (PFS) and overall survival (OS) than platinum doublets in programmed death ligand 1 (PD-L1)-positive non-small cell lung cancer (NSCLC) with tumor propensity scores (TPS) ≥50%. However, clinical trials do not represent real-world patients. Materials and Methods This multicenter retrospective study conducted across 11 medical centers in Japan analyzed clinical data from patients receiving first-line pembrolizumab for NSCLC between February 1, 2017 and April 30, 2018. The efficacy, safety, and suitability of pembrolizumab monotherapy were evaluated. Results The median age of the 213 enrolled patients was 71 (range: 39-91) years. Among them, 176 (82.6%) were male, 20 (9.4%) were never smokers (median Brinkman index: 900), 172 (80.8%) had an ECOG PS of 0-1, 55 (25.8%) had squamous-cell carcinoma (SQ). PD-L1 TPS were 50-74%, 75-89%, and 90-100% in 97 (45.5%), 47 (22.1%), and 69 (32.4%) patients, respectively. Adverse events (AEs) of grades ≥3 were observed in 39 (18.3%) patients. Pneumonitis was the most common severe AE, occurring in 10 patients (4.7%) including 1 with grade 4 toxicity; no severe AE-related deaths occurred. The overall response rate, median PFS, and median OS was 51.2%, 8.3months, and 17.8months, respectively. On multivariate analysis, ECOG PS (0-1 vs. ≥2: HR: 1.69, 95.0% CI: 1.05-2.72; p = 0.03138), CRP/Alb (<0.3 vs. ≥0.3: HR: 1.92, 95.0% CI: 1.28-2.87; p = 0.00153), steroid usage (not usage vs. usage: HR: 2.94, 95.0% CI: 1.45-5.95; p = 0.00267), and PD-L1 TPS (50-89% vs. 90-100%: HR: 0.65, 95.0% CI: 0.43-1.00; p = 0.04984) were significantly and independently correlated with PFS of pembrolizumab. Conclusion The results confirm the efficacy and safety of pembrolizumab in real-world patients. Poor PS and steroid usage at the time of commencing pembrolizumab treatment indicate poor outcomes. First-line pembrolizumab particularly benefits patients with PD-L1 TPS ≥90% or low inflammatory states (CRP/ALB<0.3).

Abstract 819: DNA methylation genome-wide analysis in remnant gastric cancer

Abstract Purpose: Although primary gastric cancers (PGC) and remnant gastric cancers (RGC) both originate from the same gastrointestinal organ, they have very distinct clinicopathological behaviors. Due to the importance of chronic inflammation in the carcinogenesis of gastric malignancies, we hypothesized that DNA promoter hypermethylation would play a critical role in the carcinogenesis of RGC as well as PGC. Methods: We investigated the genome-wide DNA methylation patterns of PGC and RGC tissues from 48 patients from an academic medical center in Japan using the Infinium HumanMethylation450 BeadChip assay. The results were validated by quantitative methylation-specific PCR (qMSP) in separate, independent cohorts. Results: We found that in our training cohort of 48 patients, genes from the gastric cancer tissues identified by the Infinium HumanMethylation 450 Beadchip clustered into high and low methylation groups on multivariate analysis (p=0.004, OR=12.33). PGCs contributed significantly to the high methylation group suggesting that the DNA promoter methylation status in PGC is higher than that in RGC. Supporting this conclusion was the finding that in a separate qMSP analysis in a test cohort, the gene A had significantly higher DNA promoter methylation in cancer tissues in the validation PGC tissues than in RGC. Conclusion: This study demonstrated that DNA promoter methylation status in PGC is higher than in RGC. This result may reflect the effects of Helicobacter pylori on the induction of DNA methylation in the remnant stomach. Citation Format: Tomoaki Ito, Kiichi Sugimoto, Hajime Orita, Masahiro Maeda, Hiroshi Moro, Toshikazu Ushijima, Hitoshi Katai, Ryo Wada, Kazuhiro Sakamoto, Koichi Sato, Malcolm V. Brock. DNA methylation genome-wide analysis in remnant gastric cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 819.

Personalized Peptide Vaccination for Castration-Resistant Prostate Cancer Progressing after Docetaxel Chemotherapy: A Randomised, Double-Blind, Placebo-Controlled, Phase 3 Trial

Background: To develop a new treatment modality, we conducted a phase 3 randomised trial of personalized peptide vaccination (PPV) for human leukocyte antigen (HLA) -A24-positive patients with castration-resistant prostate cancer (CRPC) for whom docetaxel chemotherapy failed. Methods: This randomized, double-blind, placebo-controlled, phase 3 trial was done at 68 medical centers in Japan. Eligible patents were aged 20 years or older with HLA-A24-positive, CRPC progressing after docetaxel chemotherapy, positive immunoglobulin G (IgG) responses to at least 2 of 12 warehouse peptides, an Eastern Cooperative Oncology Group performance status of 0 or 1, life expectancy of at least 12 weeks, serum testosterone level of ≤ 50 ng/dl, and satisfactory bone marrow function, hepatic function, and renal function. Patients were randomly assigned in a 2:1 ratio to receive PPV or placebo. Four of 12 warehouse peptides selected based on pre-existing peptide-specific IgG levels or the corresponding placebo were subcutaneously injected in 6 doses weekly and then bi-weekly following the maximum of 30 doses until disease progression. The primary end point was overall survival (OS), and secondary end points were progression-free survival (PFS) and immune responses. Efficacy analyses were by the full analysis set. Findings: Between August 2013 and April 2016, 310 patients were randomly assigned (207 to PPV and 103 to placebo), and 306 patients were analyzed by the full analysis set (204 to PPV and 102 to placebo). Baseline characteristics were balanced between groups. The estimated median OS was 16.1 months (95% confidence interval [CI], 13–18·2) with PPV and 16·9 months (95% CI, 13·1–20·4) with placebo (hazard ratio [HR], 1·04; 95% CI, 0·80–1·37; p=0·77). The median PFS was not significantly different between groups. Grade < 3 adverse events were observed in 41% in both groups. The most common AEs were < grade 3 injection site reactions in both groups. The analysis of treatment arm effects among subgroups revealed lower HRs for OS in favor of the PPV arm in patients with < 64% neutrophils (HR, 0·55; 95% CI, 0·33–0·93, p=0·03) or ≥ 26% lymphocytes (HR, 0·70; 95% CI, 0·52–0·92, p=0·02) at base line by the significant interaction test (p=0·003 or p=0·007). Interpretation: PPV did not prolong OS or PFS in HLA-A24-positive patients with CRPC progressing after docetaxel chemotherapy. Subgroup analysis suggested that the patients with a lower proportion of neutrophils or a higher proportion of lymphocytes at base line can receive survival benefits from PPV treatment. Trial Regstration: This study is registered with UMIN Clinical Trials Registry (UMI11308), and patient enrollment is complete. Funding Statement: This study was supported by grants from the Japan Agency for Medical Research and Development (No. 18im0110802h0008) and Fujifilm Company. Declaration of Interests: MN has served as an advisory board consultant for BrightPath biotherapeutics Co. Ltd. KI received research funding from Taiho Pharmaceutical Company. SN has served as a consultant to BrightPath biotherapeutics Co. Ltd and received an honorarium from Sanofi. All other authors declare no competing interests. Ethics Approval Statement: The trial was conducted in accordance with the Declaration of Helsinki and Good Clinical Practice guidelines. The protocol was approved by institutional review boards or ethical committees at all of the institutions. All patients were Japanese and provided written informed consent before participating in this study.

Present status of prophylactic thyroidectomy in pediatric multiple endocrine neoplasia 2: a nationwide survey in Japan 1997-2017.

Background In Japan, prophylactic thyroidectomy involves out-of-pocket expense. The American Thyroid Association (ATA) recommends prophylactic thyroidectomy for medullary thyroid carcinoma (MTC) during early childhood in patients with multiple endocrine neoplasia type 2 (MEN2). The ATA reports a high frequency of postoperative complications in childhood, which also influenced the delay of prophylactic thyroidectomy in Japan. Methods This retrospective study of multiple medical centers in Japan included individuals aged <20 years diagnosed with germline RET mutations between 1997 and 2017. The onset and onset possibility were defined based on confirmed lesions or calcitonin levels. The definition of risk and prophylactic thyroidectomy were based on the ATA 2015 revised guideline. Results Twenty-one patients with MEN2 were enrolled (highest risk, n = 5; high risk, n = 5; and moderate risk, n = 11). The cumulative incidence of the onset/onset possibility reached 50% at 5 and 8 years and 100% at 9 years and 17 years in high- and moderate-risk patients, respectively. Of 7 patients with MEN2A, 71% underwent prophylactic thyroidectomy. Only one 5-year-old patient (C634Y) had increased serum calcitonin level after prophylactic thyroidectomy in the MEN2A group. The only permanent complication, which did not occur in patients who underwent total thyroidectomy alone, was hypoparathyroidism (33% of patients). This permanent complication occurred with clinically developed MTC. No permanent postoperative complications occurred in patients aged 5-6 years. Conclusions Prophylactic thyroidectomy reduces recurrence and postoperative complications in pediatric patients with MEN2. Early thyroidectomy based on only calcitonin level could possibly reduce thyroidectomy delay.

Nomogram based on multivariable regression model estimates the overall survival of patients with nivolumab who were previously treated for advanced non-small cell lung cancer.

e20683 Background: Nivolumab (Nivo) has demonstrated with its efficacy against metastatic non-small cell lung cancer (NSCLC). However, it has been also reported that Nivo does not show beneficial effects in approximately 80% of patients. The predictive ability of biomarkers still is yet unclear; thus identifying biomarkers which better predict overall survival (OS) of such patients treated with Nivo is crucial. In this study, we conducted multivariable cox regression analysis including biomarkers and clinical factors measured at the time of initiating treatment with Nivo to assess predictive ability of OS of patients. Results of the multivariable analysis were elucidated with a nomogram which estimates the OS of Nivo in previously treated patients with advanced NSCLC. Methods: In this study, data for 201 patients treated with nivolumab during 17 December 2015 to 31 July 2016 at three respiratory medical centers in Japan were retrospectively reviewed. We collected clinical data at the time of nivolumab treatment commencement, and we evaluated two programmed cell death ligand 1 (PD-L1) immunohistochemistry (IHC) assay systems (22C3 and 28-8). Results: The median age at the time of administration nivolumab was 68 years, 135 patients were male, 157 patients had a smoking history, and 152 patients had a performance status (PS) score of 0–1. 39 patients had EGFR (37) or ALK (2) mutation positive. For 22C3 and 28-8, 36.3% and 36.8% of patients were negative, 17.4% and 14.4% had PD-L1 status of 1-49%, and 11.9% and 14.9% had PD-L1 status of ≥50%, 34.3% and 33.8% had PD-L1 status of missing, respectively. Kendall’s rank correlation coefficient between 22C3 and 28-8 was 0.8414. The median OS of all patients was 333 (95% confidence interval (CI): 116-520) days. In the multivariate analysis, PS score ≥2 (hazard ratio (HR): 2.23; 95%CI: 1.36-3.66 p &lt; 0.001), high LDH level at baseline (HR: 1.13 95%CI: 1.03-1.24; p = 0.008, and progression disease (PD) of pre-treatment response (HR: 3.64 95%CI: 2.29-5.79 p &lt; 0.001) were significantly associated with poor OS. There was not significant distance between PD-L1 status and OS of Nivo. Based on these analyses, we created the nomogram to estimate the OS of Nivo in previously treated patients with advanced NSCLC. Conclusions: PS score ≥2, high LDH levels at baseline, and PD of pre-treatment response were predictive of poor OS of Nivo, moreover the nomogram might be useful to estimate the OS of Nivo in previously treated patients with advanced NSCLC.

Abstract B081: Serum antibody against NY-ESO-1 and XAGE1 predicts clinical responses to anti-PD-1 therapy in non-small cell lung cancer

Abstract Introduction: Lung cancer is the leading cause of death from cancer worldwide. Most lung cancers, especially non-small-cell lung cancer (NSCLC), are diagnosed in the advanced stages and are resistant to conventional chemotherapy, resulting in poor prognosis. Programmed death-1 (PD-1) inhibitors effectively treat NSCLC; however, robust biomarkers for predicting clinical benefits with anti-PD-1 therapy have yet to be identified. NSCLC expresses NY-ESO-1 and/or XAGE1 antigens which belongs to cancer-testis (CT) antigen. NY-ESO-1 is broadly expressed in various human malignancies and has been extensively investigated as a target of cancer vaccines and T-cell therapy, because it exhibits the highest immunogenicity among CT antigens. XAGE1 is expressed in approximately 40~60% of lung adenocarcinoma (LAD), and the XAGE1 serum antibody is a good prognostic marker in advanced LAD patients, as we reported previously. Thus, NY-ESO-1 and XAGE1 may be major immuno-dominant antigens in NSCLC, and spontaneous immune responses against these antigens are considered to play important roles in the immune surveillance of NSCLC. Then, we hypothesized that NY-ESO-1 and XAGE1 antibody have potential as response and monitoring biomarkers in anti-PD-1 therapy for NSCLC, and conducted a prospective study to verify this hypothesis. Methods: A prospective study of biomarkers for anti-PD-1 therapy was performed using patients with advanced NSCLC from five medical centers in Japan. Prior to the administration of nivolumab or pembrolizumab, serum NY-ESO-1 and XAGE1 antibody responses were measured using ELISA, and patients in the discovery cohort were then stratified by their antibody status for enrollment in observational study. To assess the status of the antibody response, sera from patients were collected within two months before anti-PD-1 therapy, and antibody titers were serially measured during anti-PD-1 therapy. In the multicenter study (the validation and the additional cohorts), clinical responses to anti-PD-1 therapy and the antibody status were double-blinded with each other by clinicians and laboratory scientists. The primary endpoint was the objective responses rate (ORR) to anti-PD-1 therapy according to the NY-ESO-1 and XAGE1 antibody status. Secondary endpoints included progression-free survival (PFS) and overall survival (OS). Results: In the discovery cohort (n=13), NY-ESO-1 and/or XAGE1 antibody-positive NSCLC responded to anti-PD-1 therapy, whereas antibody-negative NSCLC did not. Furthermore, the antibody titers before anti-PD-1 therapy strongly correlated with tumor reduction rates (P&amp;lt;0.0001), and the titers in responders gradually decreased with tumor shrinkage. Antibody-positive patients obtained clinical benefits with anti-PD-1 therapy; Hazard ratios (HR) of OS and PFS between antibody-positive and -negative patients were 0.15 (95% CI 0.03 to 0.51, P=0.005) and 0.17 (95% CI 0.02 to 0.31, P=0.001), respectively. Antibody positivity was associated with good response and survival, regardless of tumor PD-ligand1 (PD-L1) expression, mutation burden, and CD8 T-cell infiltration. In independent multicenter study (n=40), five (50%; 3 CR and 2 PR) out of ten antibody-positive patients responded to anti-PD-1 therapy, in contrast to only two (6.7%; 2 PR) out of 30 antibody-negative patients (ORR 50% vs. 6.7%, P&amp;lt;0.006), resulting in 18% (7/40) ORR in the multicenter study. OS in antibody-positive patients were significantly longer than those in antibody-negative patients (HR 0.20, 95% CI 0.13 to 0.76, P=0.01). CT antibody-positive NSCLC patients recognized and responded to significantly more tumor antigens than CT antibody-negative patients. Conclusions: NY-ESO-1 and/or XAGE1 serum antibodies are useful biomarkers for predicting clinical benefits and monitoring tumor burden in anti-PD-1 therapy for NSCLC. Citation Format: Koji Kurose, Yoshihiro Ohue, Takahiro Karasaki, Junichiro Futami, Isao Irei, Takeshi Masuda, Masaaki Fukuda, Akitoshi Kinoshita, Hirokazu Matsushita, Katsuhiko Shimizu, Hiroyuki Yamaguchi, Minoru Fukuda, Kazuhiro Kakimi, Mikio Oka. Serum antibody against NY-ESO-1 and XAGE1 predicts clinical responses to anti-PD-1 therapy in non-small cell lung cancer [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr B081.

Comparison of USA300 with non-USA300 methicillin-resistant Staphylococcus aureus in a neonatal intensive care unit

ObjectivesReports of USA300 methicillin-resistant Staphylococcus aureus (MRSA) strain were still scarce in neonatal intensive care units (NICUs) and the relationship of USA300 MRSA to clinical infections is still controversial. The primary outcome was the incidence of MRSA infections caused by the USA300 and non-USA300 strains at a NICU in Japan. MethodsThis retrospective cohort study was conducted between November 2011 and October 2016 at Tokyo Metropolitan Children’s Medical Center in Japan. All MRSA isolated after 48h of hospitalization were included for analysis by pulsed-field gel electrophoresis (PFGE) using the standard USA300 strain. Genes were tested for Panton-Valentine leukocidin (PVL) and arginine catabolic mobile element (ACME). A whole genome sequence was performed for representative isolates of USA300. ResultsIn total, 109 MRSA isolates were included for analysis. PFGE classified 34 and 75 isolates of USA300 and non-USA300 MRSA, respectively. Both PVL and ACME genes were detected in USA300 and non-USA300 strains at rate of 100% (34/34) and 5.3% (4/75), respectively (P<0.05). There was no statistically significant difference in the proportion of clinical diseases between USA- 300 and non-USA 300 strains. ConclusionsInfants with USA300 MRSA infection did not differ significantly from those with non-USA300 MRSA infection.

Quantification of Residual Bone Marrow Plasma Cells By Eight-Color Flow Cytometry in Patients with Multiple Myeloma: Comparison between the Dura Clone RE PC Panel (Beckman Coulter) and the Euro Flow MM-MRD Panel (Cytognos)

【Background】The use of novel agents with different mechanisms of action has resulted in high complete response (CR) rates and improved the survival of patients with multiple myeloma (MM). Obtaining minimal residual disease (MRD) negativity following treatment is an important determinant for longer survival in patients with MM. The EuroFlow MM-MRD panel (EuroFlow panel) using the Infinicyt software (Cytognos, Salamanca, Spain) is a two-tube six-color antibody panel. By the addition of two drop-in antibodies (CD138, CD27; vendor of user's choice) into both tubes, an eight-color configuration, which has been validated by the EuroFlow consortium is obtained. The DuraClone RE PC kit (DuraClone panel) is a recently developed one-tube eight-color dry antibody panel using the Kaluza software (Beckman Coulter, Miami, USA) for manual identification of abnormal plasma cells (PCs) to detect MRD in MM. Although both methods are available, a comparison between them has yet to be performed. This study aimed to compare the EuroFlow panel and the DuraClone panel analysis of residual abnormal plasma cells by eight-color flow cytometry.【Methods】Patients with International Myeloma Working Group defined symptomatic MM treated at Kanazawa University Hospital and Kameda Medical Center in Japan from January 2017 to July 2018 were included. Bone marrow samples were obtained as part of routine clinical practice for evaluating treatment response when appropriate. Bone marrow aspirates (4 mL; first pull of bone marrow aspiration) anti-coagulated with ethylenediamine tetraacetic acid were evenly split (2 mL each) for the EuroFlow panel and the DuraClone panel. PC quantification by the EuroFlow panel was performed at Kanazawa University Hospital and the DuraClone panel was performed at Kameda Medical Center. The monoclonal antibodies used in the EuroFlow and the DuraClone panels are detailed in Table 1. Identification of neoplastic PCs required ≥ 20 cells. Sample processing and measurement of PCs were performed within 48 hours of collection.The correlation of total leukocyte acquisition, total plasma cells and MRD were analyzed for both methods. Qualitative comparison of MRD negativity was also performed. Spearman's correlation coefficient was used for evaluating the correlation of paired data. The Bland-Altman plot was used for detection of fixed bias and proportional bias.【Results】A total of 79 samples were analyzed. We first assessed the number of total leukocytes using the EuroFlow panel and the DuraClone panel. The median number of total leukocytes acquired with the EuroFlow panel was significantly higher than with the DuraClone panel (median: 8,505,172 cells, interquartile range [IQR]: 6,164,094 - 9,105,097 cells and median: 2,858,026 cells, IQR: 1,466,004 - 4,284,926 cells, respectively; p < 0.01), but the percentage of total plasma cells showed good concordance between both methods (regression coefficient = 0.91, p < 0.01). The median percentage of abnormal plasma cells was 0.0035% (IQR: 0.0005 - 0.05) and 0.0046% (IQR: 0.0005 - 0.05) using the EuroFlow panel and the DuraClone panel, respectively. Figure 1A shows scatter plots comparing the percentage of abnormal cells analyzed using the EuroFlow panel and the DuraClone panel. Both methods showed a high degree of concordance (regression coefficient = 0.90, p < 0.01). Bland-Altman plots also showed good agreement between both methods. There was no statistically significant fixed bias with a mean difference of 10% (95% confidence interval [CI]: -12~14%). In addition, no significant proportional bias was detected between the two methods (regression coefficient: -0.01, p = 0.85; Figure 1B).Qualitative analysis of MRD negativity also showed substantial agreement between the two methods (kappa = 0.7); 11 of 79 (13.9 %) samples showed discrepancy for determination of MRD negativity (< 1 × 10-5). Nine of these samples were MRD negative by the EuroFlow panel, but MRD positive by the DuraClone panel, and two samples were MRD positive by the EuroFlow panel, but MRD negative by the DuraClone panel. However, all discrepancies occurred near the limit of detection of both methods (1.0 × 10-5).【Conclusion】Our findings indicate that the DuraClone panel has good overall concordance with the EuroFlow panel for the detection of abnormal PCs in MM samples. The one-tube DuraClone panel enables to reduce processing time and test cost compared with the two-tube EuroFlow panel. [Display omitted] DisclosuresTakamatsu:Celgene: Honoraria, Research Funding; Janssen: Honoraria; Bristol-Myers Squibb: Research Funding; Ono: Research Funding. Nakao:Alexion Pharmaceuticals, Inc.: Consultancy, Honoraria; Kyowa Hakko Kirin Co., Ltd.: Honoraria; Novartis: Honoraria.

Abstract 275: Arterial Hyperoxia Exposure and Survival Among Resuscitated Patients With Out-of-Hospital Cardiac Arrest. Jaam-ohca Registry in Japan

Background: The effect of hyperoxia for outcomes in resuscitated patients with out-of-hospital cardiac arrest (OHCA) is still controversial. Objective: To assess the relationship between the post-ROSC hyperoxia exposure volume (HEV) and survival among resuscitated OHCA patients. Methods: The JAAM-OHCA Registry was a multicenter prospective observation using the OHCA database obtained from 73 critical care medical centers in Japan, and the study period were between June 2014 and December 2015. In this study, patients who sustained a cardiac arrest in a prehospital setting, for whom resuscitation was attempted, and who were then transported to participating institutions were included. Patients receiving extracorporeal cardiopulmonary resuscitation and who was dead in emergency room were excluded. Arterial blood gases were sampled on hospital arrival, ROSC, ICU admission, and at least 24-hours post-ROSC. In addition to the 4 sampling times mentioned above, arterial blood gases were sampled, as and when required. Hyperoxia was defined as a PaO2 value of &gt;=300 mm Hg. Hyperoxia exposure time (HET) was defined as the time of a sustained PaO2 value of &gt;=300 mmHg, and hyperoxia excess level (HEL) was defined as the highest PaO2 level from hospital arrival to 24-hours post-ROSC. HEV was calculated by HET*HEV/2. Primary outcome was one-month survival. Multivariable logistic regression adjusting for age, sex, initial shockable rhythm, bystander witness, bystander CPR, time from call to hospital arrival, tracheal intubation, and targeted temperature management was performed to assess the association between HEV and survival. Results: A total of 1751 patients were included and 414 (23.6%) had hyperoxia. Among the hyperoxia patients, survival gradually decreased from 50.0% to 44.2% as HEV increased. The adjusted odds ratio of minimum HEV groups or maximum HEV groups for one-month survival compared with non-hyperoxia group was 2.50 (95% confidence interval [CI], 1.33-4.70) and 1.16 (95% CI, 0.62-2.18), respectively. Conclusions: Among resuscitated OHCA patients, excessive amounts of HEV was associated with decreased one-month survival.

A Japanese survey of malignant disease in pregnancy

In recent years, the incidence of malignant disease in pregnancy has been increasing, but there are few large-scale surveys of malignant disease in pregnancy in Japan. The aim of this study was to survey malignant disease occurring during pregnancy in Japan. Malignant disease in pregnancy was defined as diagnosis or treatment for malignant disease, except in situ carcinoma during pregnancy, or within 1-year postpartum. First, a primary survey questionnaire of the incidence of malignant disease in pregnancy and the number of deliveries over the course of 2014 was sent to 510 medical centers in Japan. Second, the survey questionnaires on the incidence of malignant diseases in pregnancy were collected and analyzed in detail. Of the 510 medical centers, 411 (81%) responded to the survey. There were 215,372 deliveries and 189 incidents (0.09%) of malignant disease in pregnancy. Of the 189 patients with malignancy, 157 detailed responses about the patients were received. The most frequently encountered cancer types were cervical cancer (36%), breast cancer (24%), and ovarian cancer (15%). During the 2years after delivery, 15 patients (1 with breast cancer, 2 with ovarian cancer, 3 with hematologic malignancy, 4 with intestinal cancer, and 5 with others) died of the disease; most of them had advanced disease. In particular, 88% of the patients with intestinal cancers at diagnosis had advanced disease, and half of them died of disease. In Japan, the most common malignancies in pregnancy in order of frequency are cervical cancer, breast cancer, and ovarian cancer. Early diagnosis and appropriate management of cancer during pregnancy are important for improving maternal and neonatal outcomes, because advanced diseases have a poor prognosis.