Cervical Spinal Alignment Change Accompanying Spondylosis Exposes Harmonization Failure with Total Spinal Balance: A Japanese Cohort Survey Randomly Sampled from a Basic Resident Registry

The relationship between spinal posture and quality of life has garnered considerable attention with the increase in older community-dwelling residents. However, details of this association remain insufficient. A recent Japanese population cohort epidemiological locomotion survey (the Obuse study) revealed that the C2–C7 cervical sagittal vertical axis (CSVA) began to increase in males from their 60s, but not in females. This study aimed to clarify the pathology of these cervical spondylotic changes. A total of 411 participants (202 male and 209 female) aged between 50 and 89 years were selected by random sampling from a cooperating town’s resident registry. All participants underwent lateral X-ray photography in a standing position for the measurement of several sagittal spinal alignment parameters, including CSVA, C2–C7 cervical lordosis (CL), T1 slope (T1S), and sagittal vertical axis (SVA). The presence of cervical spondylotic changes was also recorded. Associations of cervical sagittal spinal alignment with cervical spondylosis and between cervical and total sagittal spinal alignment were examined. The prevalence of cervical spondylosis was significantly higher in males (81%) than in females (70%) (p = 0.01). CL was significantly smaller in cervical spondylosis subjects when adjusted by age (3.4 degrees less; p = 0.01). T1S minus CL displayed a moderate positive correlation with CSVA in both males and females (r = 0.49 and 0.48, respectively, both p < 0.01). In males only, CSVA and CL showed weak positive correlations with SVA (r = 0.31 and 0.22, respectively, both p < 0.01) independently of age. Cervical spinal misalignment was more clearly associated with diminished SF-8TM scores in females than in males. In community-dwelling elderly residents, cervical sagittal spinal alignment change accompanying cervical spondylosis manifested as hypofunction to compensate for whole-spine imbalance.

Mutational and clinical spectrum of Japanese patients with hereditary hemorrhagic telangiectasia

Background Hereditary hemorrhagic telangiectasia (HHT) is a dominantly inherited vascular disorder characterized by recurrent epistaxis, skin/mucocutaneous telangiectasia, and organ/visceral arteriovenous malformations (AVM). HHT is mostly caused by mutations either in the ENG or ACVRL1 genes, and there are regional differences in the breakdown of causative genes. The clinical presentation is also variable between populations suggesting the influence of environmental or genetic backgrounds. In this study, we report the largest series of mutational and clinical analyses for East Asians. Methods Using DNAs derived from peripheral blood leukocytes of 281 Japanese HHT patients from 150 families, all exons and exon–intron boundaries of the ENG, ACVRL1, and SMAD4 genes were sequenced either by Sanger sequencing or by the next-generation sequencing. Deletions/amplifications were analyzed by the multiplex ligation-dependent probe amplification analyses. Clinical information was obtained by chart review. Results In total, 80 and 59 pathogenic/likely pathogenic variants were identified in the ENG and ACVRL1 genes, respectively. No pathogenic variants were identified in the SMAD4 gene. In the ENG gene, the majority (60/80) of the pathogenic variants were private mutations unique to a single family, and the variants were widely distributed without any distinct hot spots. In the ACVRL1 gene, the variants were more commonly found in exons 5–10 which encompasses the serine/threonine kinase domain. Of these, 25/59 variants were unique to a single family while those in exons 8–10 tended to be shared by multiple (2–7) families. Pulmonary and cerebral AVMs were more commonly found in ENG-HHT (69.1 vs. 14.4%, 34.0 vs. 5.2%) while hepatic AVM was more common in ACVRL1-HHT (31.5 vs. 73.2%). Notable differences include an increased incidence of cerebral (34.0% in ENG-HHT and 5.2% in ACVRL1-HHT), spinal (2.5% in ENG-HHT and 1.0% in ACVL1-HHT), and gastric AVM (13.0% in ENG-HHT, 26.8% in ACVRL1-HHT) in our cohort. Intrafamilial phenotypic heterogeneity not related to the age of examination was observed in 71.4% and 24.1% of ENG- and ACVRL1-HHT, respectively. Conclusions In a large Japanese cohort, ENG-HHT was 1.35 times more common than ACVRL1-HHT. The phenotypic presentations were similar to the previous reports although the cerebral, spinal, and gastric AVMs were more common.

Notable Patterns in the Genomic Landscape of Adult T-Cell Leukemia/Lymphoma Encountered in HTLV-1 Endemic Western World Regions

Background: Adult T-cell leukemia/lymphoma (ATLL) is an aggressive malignancy with dismal prognosis and associated with clonal T-cell expansion driven by Human T-Lymphotropic Virus 1 (HTLV-1) infection. Comprehensive genomic studies in Japan have identified recurrent alterations affecting TCR-NF-kB signaling (i.e. PRKCB, PLCG1, CARD11, VAV1, and IRF4), T-cell trafficking pathways (i.e. CCR4 and CCR7), and the tumor suppressor genes CDKN2A and TP53. HTLV-1 endemic regions include Africa, the Caribbean, and South America in addition to Japan. Retrospective studies from the Western population have reported distinctive features from the Japanese cohort, e.g. younger age, more common lymphomatous presentation, and worse outcomes. Our group sought to evaluate the unique molecular features of ATLL in a large cohort of patients from the Caribbean and South America. Methods: We performed a multimodal genomic study on specimens from 169 patients encountered in the United States (Miami), Peru, Brazil, France, and Spain. Data types included Oncoscan/Copy Number Variation (CNV) data for 129 patients, RNA-seq data for 97 patients, and whole exome sequencing (WES) data for 125 patients. Patients were ethnically classified based upon single nucleotide polymorphisms, under 3 main groups: African (n=80), native American (n= 32), or South Asian/Islander (n=12). 46 specimens without WES data could not be ethnically classified. Somatic variants were called using Mutect. Putative driver mutations were identified by frequency-based criteria. CNV significance was determined using GISTIC2.0. Data were compared to whole exome and targeted sequencing data published by Kataoka et al. Results: Our cohort replicated trends reported in Japanese datasets but included several distinctive findings. South American and Caribbean patients had fewer mutations in CCR4 and CD58. Three putative tumor suppressors not previously implicated in ATLL were identified based on recurrent damaging mutations. These included ANKRD11 (n=3), DGKZ (n=3), and PTPN6 (n=3). Both ANKRD11 and PTPN6 were only mutated in Afro-Caribbean patients with aggressive (acute and lymphomatous) cases. CNV analysis revealed ANKRD11 deletions in a significant portion of cases (n=16). As previously reported, STAT3 mutations were more common in indolent subtypes. IRF4 mutations (n=14) or amplifications (n=19) were only observed in aggressive ATLL subtypes. L70V was the most common IRF4 variant (n=5). Among Japanese samples, K59R mutations were seen twice as often as L70V mutations. Both K59R and L70V are located within the IRF4 DNA binding domain. In samples from patients with disease relapse (N = 10), IRF4 was the only gene mutated significantly more often (p = 0.03). 3 of 10 patients who were previously treated with interferon (IFN)-based therapy relapsed with new IRF4 mutations (L70V n=2, and K59R n=1), suggesting IRF4 may be associated with IFN resistance. A total of 11 patients in the Western cohort had FOXO3 mutations including R177W (n=7) and D199N (n=3) variants. These only occurred in Afro-Caribbean patients with aggressive subtypes. R177W is located within the FOXO3DNA binding domain, suggesting that dysregulation of its transcriptional targets may contribute to disease. In the Japanese cohort, only one patient had a FOXO3 mutation, (D199N). The majority of primary ATLL samples analyzed by Western Blot showed significantly reduced or no expression of FOXO3, or ANKRD11. Conclusion: The genomic landscape of ATLL encountered in patients from South America and the Caribbean resembles that of ATLL in Japanese patients. However, our study identified novel variants and tumor suppressor genes not previously implicated in ATLL that differ from the Japanese population. Furthermore, we correlate our genomic analysis with clinical findings to implicate ATLL driver genes in IFN resistance and disease prognosis. Functional Studies to determine the prognostic and functional roles of the gene alterations we identified in ATLL are ongoing. Disclosures Gru: StemLine: Honoraria, Research Funding, Speakers Bureau; CRISPT Therapeutics: Research Funding; Innate Pharma: Research Funding.

824. Analysis of Comorbidities and Use of Co-medications in 28,089 HIV-positive Patients: A Nationwide Cohort Study From 2009 to 2019 in Japan

Background Comorbidities are associated with a high burden of disease in human immunodeficiency virus (HIV)- positive patients. The objective was to investigate the prevalence of chronic comorbidities and the use of co-medications in HIV-positive patients in Japan. Methods This longitudinal cohort study retrospectively analyzed clinical information from HIV-positive patients using antiretroviral therapy (ART) between April 2009 and April 2019. Demographic characteristics, numbers and types of chronic comorbidities and numbers and types of co-medications, were described by age groups. This is the first report to analyze comorbidities and the polypharmacy of all patients in the cross-sectional National Database of Health Insurance Claims and Specific Health Checkups of Japan (NDB), which contains data on the largest number of HIV-positive patients in Japan, available to date. Results Overall, 28,089 HIV-positive patients (male 91·9%) who used ART were identified. About 40% of 28,089 patients had at least one chronic comorbidity. The number of acquired immunodeficiency syndrome (AIDS)-defining cancers and non-AIDS-defining cancers in this Japanese cohort was 2,432 (8·7%) and 2,485 (8·8%), respectively. The incidence of AIDS-defining cancers was 6·4% for non-Hodgkin lymphoma and 2·5% for Kaposi’s sarcoma, with bronchus or lung cancer being the most common of the non-AIDS-defining cancers. Syphilis was the most common infection (47·2%). The cumulative burden of vascular disease and AIDS-free cancer increased with age. The most common therapeutic categories of co-medications were systemic antibacterials (42%) and antacids, antiflatulents and antiulcerants (38·8%). Most of the patients used at least one co-medication (71·4%), and the numbers of co-medications used were greater in the older age groups. Conclusion The burden of chronic comorbidities and co-medication were found to be greater in older than younger patients, among 28,089 HIV-positive patients in a nationwide study in Japan. This finding suggests the need to identify elderly persons living with HIV and to appropriately manage their HIV and comorbidities. Disclosures All Authors: No reported disclosures

Hypertensive Disorders during Pregnancy and Anthropometric Measurement of Children Up to 7 Years of Age: The Hokkaido Birth Cohort Study in Japan

Hypertensive disorders during pregnancy (HDP) increase the risk of offspring with a low birth weight, preterm birth and small-for-gestational age; however, evidence of the anthropometric measurements during early childhood remains limited. We aimed to understand the associations between maternal HDP and anthropometric measurements of children aged up to seven years in a Japanese cohort. In total, 20,926 mother–infant pairs participated in the Hokkaido Study on Environment and Children’s Health, Japan, from 2002 to 2013. Medical reports were used to confirm HDP exposure, while weight, height, height z score, and weight z score were the outcomes. The prevalence of HDP in the study population was 1.7%. The birth height of male children born to HDP mothers was smaller as compared to those born to non-HDP mothers. When adjusted with covariates, the linear regressions showed significant changes in birth weight (b: −79.3; 95% confidence interval [CI]: −154.8, −3.8), birth height (−0.67; 95% CI: −1.07, −0.26), weight at seven years (1.21; 95% CI: 0.13, 2.29), and weight gain between four and seven years (1.12; 95% CI: 0.28, 1.96) of male children exposed to HDP. Differences were more significant in male children than female. Our study showed that despite low birth weight, male children exposed to HDP caught up with their growth and gained more weight by seven years of age compared with male children not exposed to HDP, whereas no such differences were observed in female children; however, this finding requires replication.

Potential application of measuring serum infliximab levels in rheumatoid arthritis management: A retrospective study based on KURAMA cohort data

Infliximab (IFX) therapy has considerably improved the treatment of rheumatoid arthritis (RA). However, some patients still do not respond adequately to IFX therapy, or the efficacy of the treatment diminishes over time. Although previous studies have reported a relationship between serum IFX levels and therapeutic efficacy, the potential applications of IFX therapeutic drug monitoring (TDM) in clinical practice remain unclear. The purpose of this study was to investigate the potential applications of IFX TDM by analyzing a Japanese cohort database. Data were collected retrospectively from the Kyoto University Rheumatoid Arthritis Management Alliance cohort between January 1, 2011, and December 31, 2018. Serum IFX levels were measured using a liquid chromatography-tandem mass spectrometer. Out of the 311 RA patients that used IFX, 41 were eligible for the analysis. Serum IFX levels were significantly higher in responders than in non-responders. An optimal cut-off value was determined to be 0.32 μg/mL based on a receiver operating characteristic curve. At the IFX measurement point, a better therapeutic response was observed in the high IFX group (n = 32) than in the low IFX group (n = 9). Conversely, at the maximum effect point, when DAS28-ESR was the lowest between IFX introduction and measurement points, there were no differences in responder proportions between the low and high IFX groups. IFX primary ineffectiveness could be avoided with appropriate dose escalation without blood concentration measurement in clinical practice. In conclusion, IFX TDM could facilitate the identification of secondary non-responders and in turn, proper IFX use.

Functional Effects of Four or Fewer Critical Genes Linked to Lung Cancers and New Subtypes Detected by A New Machine Learning Classifier

Finding genes biologically directly or indirectly related to lung cancer has been drawing much attention, and many genes directly related to lung cancer have been reported. However, it has not been confirmed whether those published 'key' genes are truly critical to lung cancer formation, i.e., they may be with very limited useful information. As a result, finding essential genes remains a challenging lung cancer research problem. Using a recently developed competing linear factor analysis method in differentially expressed gene detection, we advance the study of lung cancer critical genes detection to a uniformly informative level. A set of common four genes and their functional effects are detected to be differentially expressed in tumor and non-tumor samples with 100% sensitivity and 100% specificity in one study of lung adenocarcinoma (LUAD) and one study of squamous cell lung cancers (LUSC) (two North American cohorts with 20429 genes, 576 and 552 samples respectively). Two additional analyses also gain accuracy of 97.8% sensitivity and 100% specificity in one study of non-small cell lung carcinomas (NSCLC, a European cohort with 20356 genes and 156 samples), and an accuracy of 100% sensitivity and 95% specificity (1 out of 20 non-tumor samples) in one study of ALK-positive and EGFR/KRAS/ALK-negative lung adenocarcinomas (LUAD, a Japanese cohort with 20356 genes and 224 samples). There are some common genes, but different functional effects, within each set of four genes among two North American cohorts and a European cohort and among North American cohorts and the Japanese cohort. These results show the four-gene-based classifiers are robust with different types of lung cancers and different race cohorts and accurate. The functional effects of four genes disclose significantly other mechanisms (mysteries) between LUAD and LUSC. These sets of four genes and their functional effects are considered to be essential for lung cancer studies and practice. These genes' functional effects naturally classify patients into different groups (more than seven subtypes). Subtype information is useful for personalized therapies. The new findings can motivate new lung cancer research in more focused and targeted directions to save lives, protect people, and reduce enormous economic costs in research and lung cancer treatments.

A risk model for detecting clinically significant prostate cancer based on bi-parametric magnetic resonance imaging in a Japanese cohort

Selective identification of men with clinically significant prostate cancer (sPC) is a pivotal issue. Development of a risk model for detecting sPC based on the prostate imaging reporting and data system (PI-RADS) for bi-parametric magnetic resonance imaging (bpMRI) and clinical parameters in a Japanese cohort is expected to prove beneficial. We retrospectively analyzed clinical parameters and bpMRI findings from 773 biopsy-naïve patients between January 2011 and December 2016. A risk model was established using multivariate logistic regression analysis and presented on a nomogram. Discrimination of the risk model was compared using the area under the receiver operating characteristic curve. Statistical differences between the predictive model and clinical parameters were analyzed using DeLong test. sPC was detected in 343 men (44.3%). Multivariate logistic regression analysis to predict sPC revealed age (P = 0.002), log prostate-specific antigen (P < 0.001), prostate volume (P < 0.001) and PI-RADS scores (P < 0.001) as significant contributors to the model. Area under the curve was higher for the risk model (0.862), than for age (0.646), log prostate-specific antigen (0.652), prostate volume (0.697) or imaging score (0.822). DeLong test results also showed that the novel risk model performed significantly better than those parameters (P < 0.05). This novel risk model performed significantly better compared with PI-RADS scores and other parameters alone, and is thus expected to prove beneficial in making decisions regarding biopsy on suspicion of sPC.

Detection of mild cognitive impairment by spinal posture assessment in health exams of the general older population: A Japanese cohort survey randomly sampled from a basic resident registry

The recent increase in the older adult population has led to a higher prevalence of cognitive impairment, which is often overlooked in routine health examinations. Citizens aged 50 to 89 years were targeted for this cohort survey by random sampling from the resident registry of a cooperating town in 2014. A total of 413 participants (203 male and 210 female) were enrolled. We analyzed the distribution of cognitive function test scores as determined by Montreal Cognitive Assessment and Mini-Mental State Examination tests in each age (50’s, 60’s, 70’s and 80’s) and sex group to examine whether mild cognitive impairment (MCI) could be detected by sagittal spinal balance measurement based on a radiological approach. Sagittal spinal balance was quantitatively measured as sagittal vertical axis (SVA). We observed significant associations for higher age and/or SVA anteriorization with lower cognitive function. In men, spinal balance anteriorization was associated with MCI independently of age, with combinations of age and SVA also making valid MCI determinations; male cases of SVA ≥ 100 mm at any age, SVA ≥ 90 mm at ≥ 70 years, and SVA ≥ 70 mm at ≥ 80 years were all more likely to have MCI than cases below those values. For women, MCI was more likely in cases of SVA ≥ 70 mm, regardless of age. Thus, spinal balance anteriorization can be regarded as an easily visible indicator of latent MCI in community-dwelling older people.