Background: We compared the temporal changes of immunoglobulin M (IgM), IgG, and IgA antibodies against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) nucleoprotein (N), spike 1 subunit (S1), and receptor-binding domain (RBD), and neutralizing antibodies (NAbs) against SARS-CoV-2 in patients with coronavirus disease 2019 (COVID-19) to understand the humoral immunity in COVID-19 patients for developing drugs and vaccines for COVID-19. Methods: A total of five confirmed COVID-19 cases in Nissan Tamagawa Hospital in early August 2020 were recruited in this study. Using a fully automated chemiluminescence immunoassay analyzer, we measured the levels of IgG, IgA, and IgM against SARS-CoV-2 N, S1, and RBD and NAbs against SARS-CoV-2 in COVID-19 patients' sera acquired multiple times in individuals from 0 to 76 days after symptom onset.Results: IgG levels against SARS-CoV-2 structural proteins increased over time in all cases but IgM and IgA levels against SARS-CoV-2 showed different increasing trends
The objective of this study was to clarify the impact of adverse reactions on immune dynamics. We investigated the pattern of systemic adverse reactions after the second and third coronavirus disease 2019 (COVID-19) vaccinations and their relationship with immunoglobulin G against severe acute respiratory syndrome coronavirus 2 spike 1 protein titers, neutralizing antibody levels, peak cellular responses, and the rate of decrease after the third vaccination in a large-scale community-based cohort in Japan. Participants who received a third vaccination with BNT162b2 (Pfizer/BioNTech) or mRNA-1273 (Moderna), had two blood samples, had not had COVID-19, and had information on adverse reactions after the second and third vaccinations (n = 2198) were enrolled. We collected data on sex, age, adverse reactions, comorbidities, and daily medicine using a questionnaire survey. Participants with many systemic adverse reactions after the second and third vaccinations had significantly higher humoral and cellular immunity in the peak phase. Participants with multiple systemic adverse reactions after the third vaccination had small changes in the geometric values of humoral immunity and had the largest geometric mean of cellar immunity in the decay phase. Systemic adverse reactions after the third vaccination helped achieve high peak values and maintain humoral and cellular immunity. This information may help promote uptake of a third vaccination, even among those who hesitate due to adverse reactions.
1551 Background: Cancer genomic profiling (CGP) tests have been approved in Japan since June 2019, with the requisite that all test results be discussed by molecular tumor boards (MTBs). More than 20,000 patients in over 200 designated hospitals have taken CGP tests by December 2021. As CGP tests have entered clinical practice, streamlining decision making by MTBs and standardizing interpretation of test results and treatment recommendations have become urgent issues. Here, we evaluated the utility of Chrovis, an annotation algorithm for reporting CGP tests to support MTBs make their recommendations. Methods: We retrospectively reviewed the reporting process of all approved CGP tests done at The University of Tokyo Hospital between December 2019 and November 2021. Chrovis provided annotation for each genetic variant by incorporating biologic, clinical, and therapeutic information by referencing several public knowledge databases and using natural language processing, and generated reports using the automated program. The MTB reviewed and made any necessary changes before finalizing the report. Changes in disclosure of germline findings were made according to the recommendations of a national guideline with consideration of past and family history. Results: Of the 243 tests, 91 changes in 81 Chrovis reports (33% of all reports) were made by the MTB. The most common type of change was germline disclosure with 26 changes (29%), followed by clinical trial information in Japan (18 changes, 20%) and recommendation of the patient-proposed national basket trial with multiple targeted agents (17 changes, 19%). Changes in germline disclosure increased from June 2021, when an update to a national guideline was released, while the proportion of changes in the latter two types remained unchanged. Gene alterations that led to the highest number of changes was TP53, with 13 changes. Changes in therapeutic recommendations were frequently observed in the RAS/MAPK pathway ( BRAF, KRAS, NF1, NRAS) with 12 changes. More changes were required with a tumor-only tissue CGP panel (57 of 149) compared with a matched tumor/normal tissue CGP panel (24 of 94, p = 0.04), mostly due to germline disclosure (24 vs. 2 changes). Conclusions: We observed that automated algorithm-based reporting was sufficient in 67% of reports. Recommendation for germline disclosure still requires manual supervision, particularly with tumor-only tissue CGP panels if algorithms do not incorporate medical history. The process of recommending clinical trials needs improvement, e.g., standardizing database formats for inclusion and exclusion criteria.
Ependymomas encompass multiple, clinically relevant tumor types based on localization, genetic alterations, and epigenetic and transcriptomic profiles. Tumors belonging to the methylation class of spinal ependymoma (SP-EPN) represent the most common intramedullary neoplasms in children and adults. However, molecular data of SP-EPN are scarce, and clear treatment recommendations are lacking. The only known recurrent genetic events in SP-EPN are loss of chromosome 22q and NF2 mutations. Yet, it remains unclear whether SP-EPN with germline or sporadic NF2 mutations or with NF2 wild type status differ clinically or molecularly. To provide a comprehensive molecular profile of SP-EPN, we integrated epigenetic, genomic, transcriptomic, and histological analyses of up to 237 cases. Clustering of methylation data revealed two distinct molecular SP-EPN subtypes. The distribution of NF2 mutated cases differed significantly across these subtypes (p <0.0001): The vast majority of tumors harboring either a previously known NF2 germline mutation or a sporadic mutation were assigned to subtypes A, whereas subtype B tumors mainly contained NF2 wild type sequences. In addition, subtype A tumors showed a lower frequency of MGMT promoter methylation (p= 0.018) and contained almost all pediatric patients of the cohort. Whole-exome sequencing (30 cases) identified numerous mutations in NF2 wild type and mutated tumors. Mutated genes in NF2 wild type tumors were enriched for genes associated with cell cycle and cytoskeleton. RNA sequencing revealed two distinct transcriptional groups with upregulation of proliferative genes in one group and upregulation of cilial genes in the other group. The molecular subtypes displayed subtle, but significant differences in the appearance of histopathological characteristics, such as surfaces, inflammation, and hyalinized vessels. Investigation of clinical parameters is ongoing and will complete the picture of SP-EPN heterogeneity as an important basis for future clinical decision-making.
Introduction: Comprehensive cancer genomic profiling tests have been implemented in the clinic to guide patients and physicians to decide optimal treatments. Most tests analyze genomic DNA to detect genomic alterations in a few hundred genes. RNA panels have advantages over DNA panels when detecting fusion and exon skipping events. Methods: Between April 2017 and March 2022, non-small cell lung cancer samples were analyzed by Todai OncoPanel (TOP), a dual targeted DNA/RNA panel with matched tumor/normal pair analysis. Informed consent was obtained from all patients. Publicly available genomic data from approved panels in Japan, all of which are DNA-only panels, was downloaded from the Center for Cancer Genomics and Advanced Therapeutics (C-CAT) database on 2022/11/3. Results: Sixty-one samples were analyzed. The median age of the patients was 62, and 35 were men. The histology of the samples included 52 adenocarcinoma and 9 squamous cell carcinoma. Of the 52 adenocarcinoma samples, pathogenic or likely pathogenic mutations were detected in 46 (88%), and 40 samples (77%) harbored potentially druggable targets. With the DNA panel, 23 (44%) TP53 loss-of-function mutations, 17 (33%) EGFR activating mutations, 6 (12%) ERBB2 activating mutations, 5 (10%) KRAS activating mutations, 5 (10%) RB1 loss-of-function mutations, 3 (6%) BRAF activating mutations, and 3 (6%) MET exon 14 splice site mutation were detected. Meanwhile, with the RNA panel, three MET exon 14 skipping and 15 fusion genes in 16 patients (16/61 = 26%) were detected, all in adenocarcinoma. Specifically, EML4-ALK, KIF5B-RET, and CD47-MET were detected from one sample each, and 12 others were all novel fusions with unknown pathogenicity. Overall, 5 out of 61 (8.1%) non-small cell lung cancer samples harbored MET exon 14 skipping or fusion. Using the C-CAT database, 37 MET exon 14 splice site mutations and 2 rearrangements were found in 1,514 non-small cell lung cancer samples (2.6%) from the C-CAT database (p = 0.009). One BRCA1 and one BRCA2 pathogenic germline variants were detected from the TOP germline panel. Conclusion: Analysis of non-small cell lung cancer using TOP led to detection of a high percentage of druggable targets. TOP RNA panel may detect MET exon 14 skipping and fusions at higher sensitivity. Citation Format: Hidenori Kage, Shinji Kohsaka, Kenji Tatsuno, Aya Shinozaki-Ushiku, Hideaki Isago, Kousuke Watanabe, Motohiro Kato, Tetsuo Ushiku, Kiyoshi Miyagawa, Takahide Nagase, Jun Nakajima, Hiroyuki Aburatani, Hiroyuki Mano, Katsutoshi Oda. Detection of METexon 14 skipping and fusions in non-small cell lung cancer by comprehensive genomic profiling using a dual targeted DNA/RNA panel [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 256.
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