Annals of Laboratory Medicine最新文献

Background: The function of CD69 expressed on T cells in chronic hepatitis B (CHB) remains unclear. We aimed to elucidate the roles of CD69 on T cells in the disease process and in antiviral therapy for CHB.

Methods: We enrolled 335 treatment-naive patients with CHB and 93 patients with CHB on antiviral therapy. CD69, antiviral cytokine production by T cells, T-helper (Th) cells, and inhibitory molecules of T cells were measured using flow cytometry, and clinical-virological characteristics were examined dynamically during antiviral therapy.

Results: CD69 expression on CD3+, CD4+, and CD8+ T cells was the lowest in the immune-active phase and was negatively correlated with liver transaminase activity, fibrosis features, inflammatory cytokine production by T cells, and Th-cell frequencies but positively with inhibitory molecules on T cells. CD69 expression on CD3+, CD4+, and CD8+ T cells decreased after 48 weeks of antiviral therapy, and patients with hepatitis B e antigen (HBeAg) seroconversion in week 48 showed lower CD69 expression on T cells at baseline and week 48. The area under the ROC curve of CD69 expression on T cells at baseline for predicting HBeAg seroconversion in week 48 was 0.870, the sensitivity was 0.909, and the specificity was 0.714 (P =0.002).

Conclusions: CD69 negatively regulates T-cell immunity during CHB, and its expression decreases with antiviral therapy. CD69 expression predicts HBeAg seroconversion in week 48. CD69 may play an important negative role in regulating T cells and affect the efficacy of antiviral therapy.

In the era of precision medicine, pharmacogenetics has substantial potential for addressing inter-individual variability in drug responses. Although pharmacogenetics has been a research focus for many years, resulting in the establishment of several formal guidelines, its clinical implementation remains limited to several gene-drug combinations in most countries, including Korea. The main causes of delayed implementation are technical challenges in genotyping and knowledge gaps among healthcare providers; therefore, clinical laboratories play a critical role in the timely implementation of pharmacogenetics. This paper presents an update of the Clinical Pharmacogenetic Testing and Application guidelines issued by the Korean Society for Laboratory Medicine and aims to provide the necessary information for clinical laboratories planning to implement or expand their pharmacogenetic testing. Current knowledge regarding nomenclature, gene-drug relationships, genotyping technologies, testing strategies, methods for clinically relevant information delivery, QC, and reimbursements has been curated and described in this guideline.

Background: The Molecular International Prognostic Scoring System (IPSS-M) has improved the prediction of clinical outcomes for myelodysplastic syndromes (MDS). The Artificial Intelligence Prognostic Scoring System for MDS (AIPSS-MDS), based on classical clinical parameters, has outperformed the IPSS, revised version (IPSS-R). For the first time, we validated the IPSS-M and other molecular prognostic models and compared them with the established IPSS-R and AIPSS-MDS models using data from South American patients.

Methods: Molecular and clinical data from 145 patients with MDS and 37 patients with MDS/myeloproliferative neoplasms were retrospectively analyzed.

Results: Prognostic power evaluation revealed that the IPSS-M (Harrell's concordance [C]-index: 0.75, area under the receiver operating characteristic curve [AUC]: 0.68) predicted overall survival better than the European MDS (EuroMDS; C-index: 0.72, AUC: 0.68) and Munich Leukemia Laboratory (MLL) (C-index: 0.70, AUC: 0.64) models. The IPSS-M prognostic discrimination was similar to that of the AIPSS-MDS model (C-index: 0.74, AUC: 0.66) and outperformed the IPSS-R model (C-index: 0.70, AUC: 0.61). Considering simplified low- and high-risk groups for clinical management, after restratifying from IPSS-R (57% and 32%, respectively, hazard ratio [HR]: 2.8; P=0.002) to IPSS-M, 12.6% of patients were upstaged, and 5% were downstaged (HR: 2.9; P=0.001). The AIPSS-MDS recategorized 51% of the low-risk cohort as high-risk, with no patients being downstaged (HR: 5.6; P<0.001), consistent with most patients requiring disease-modifying therapy.

Conclusions: The IPSS-M and AIPSS-MDS models provide more accurate survival prognoses than the IPSS-R, EuroMDS, and MLL models. The AIPSS-MDS model is a valid option for assessing risks for all patients with MDS, especially in resource-limited centers where molecular testing is not currently a standard clinical practice.

Hypertrophic cardiomyopathy (HCM) is a genetic cardiac muscle disease characterized by clinical and genetic heterogeneity. Genetic testing can reveal the presence of disease-causing variants in genes encoding sarcomere proteins. However, it yields inconclusive or negative results in 40-60% of HCM cases, owing to, among other causes, technical limitations such as the inability to detect pathogenic intronic variants. Therefore, we aimed to increase the diagnostic yield of molecular analysis for HCM by improving the in-silico detection of intronic variants in MYBPC3 that may escape detection by algorithms normally used with tagged diagnostic panels. We included 142 HCM probands with negative results in Illumina TruSight Cardio panel analysis, including exonic regions of 174 cardiomyopathy genes. Raw data were re-analyzed using existing bioinformatics tools. The spliceogenic variant c.1224-80G>A was detected in three patients (2.1%), leading us to reconsider their molecular diagnosis. These patients showed late onset and mild symptoms, although no peculiar phenotypic characteristics were shared. Collectively, rare spliceogenic MYBPC3 variants may play a role in causing HCM, and their systematic detection should be performed to provide more comprehensive solutions in genetic testing using multigenic panels.

Background: MUTYH-associated polyposis is an autosomal recessive disorder associated with an increased lifetime risk of colorectal cancer and a moderately increased risk of ovarian, bladder, breast, and endometrial cancers. We analyzed the carrier frequency and estimated the incidence of MUTYH-associated polyposis in East Asian and Korean populations, for which limited data were previously available.

Methods: We examined 125,748 exomes from the gnomAD database, including 9,197 East Asians, and additional data from 5,305 individuals in the Korean Variant Archive and 1,722 in the Korean Reference Genome Database. All MUTYH variants were interpreted according to the American College of Medical Genetics and Genomics and Association for Molecular Pathology guidelines and the Sequence Variant Interpretation guidelines from ClinGen.

Results: The global carrier frequency of MUTYH-associated polyposis was 1.29%, with Europeans (non-Finnish) having the highest frequency of 1.86% and Ashkenazi Jews the lowest at 0.06%. East Asians and Koreans had a carrier frequency of 0.35% and 0.37% and an estimated incidence of 1 in 330,409 and 1 in 293,304 in Koreans, respectively, which were substantially lower than the global average of 1 in 24,160 and the European (non-Finnish) incidence of 1 in 11,520.

Conclusions: This was the first study to investigate the frequency of carriers of MUTYH-associated polyposis in East Asians, including specific subgroups, utilizing gnomAD and a Korean genome database. Our data provide valuable reference information for future investigations of MUTYH-associated polyposis to understand the genetic diversity and specific variants associated with this condition in East Asian populations.

Background: NUP98 rearrangements (NUP98r), associated with various hematologic malignancies, involve more than 30 partner genes. Despite their clinical significance, reports on the clinicopathological characteristics of rare NUP98r remain limited. We investigated the characteristics of patients with myeloid neoplasms harboring NUP98r among those identified as having 11p15 translocation in chromosomal analysis.

Methods: We retrospectively reviewed results from bone marrow chromosomal analyses conducted between 2011 and 2023 and identified 15 patients with 11p15 translocation. Subsequently, NUP98r were evaluated using FISH and/or reverse transcription PCR, and clinical and laboratory data of the patients were analyzed.

Results: NUP98r were identified in 11 patients initially diagnosed as having AML (N=8), myelodysplastic syndrome (N=2), or chronic myelomonocytic leukemia (N=1), with a median age of 44 yrs (range, 4-77 yrs). Three patients had a history of chemotherapy. In total, five NUP98 fusions were identified: NUP98::DDX10 (N=3), NUP98::HOXA9 (N=2), NUP98::PSIP1 (N=2), NUP98::PRRX1 (N=1), and NUP98::HOXC11 (N=1). Patients with NUP98r exhibited a poor prognosis, with a median overall survival of 12.0 months (95% confidence interval [CI], 3.4-29.6 months) and a 5-yr overall survival rate of 18.2% (95% CI, 5.2%-63.7%).

Conclusions: Our study revealed the clinical and genetic characteristics of patients with myeloid neoplasms harboring rare and non-cryptic NUP98r. Given its association with poor prognosis, a comprehensive evaluation is crucial for identifying previously underdiagnosed NUP98r in patients with myeloid neoplasms.

Background: Bacteroides fragilis group (BFG) isolates are the most frequently isolated gram-negative anaerobic bacteria and exhibit higher levels of antimicrobial resistance than other anaerobic bacteria. Reliable susceptibility testing is needed because of reports of resistance to the most active antibiotics. Recently, the European Committee on Antimicrobial Susceptibility Testing (EUCAST) introduced disk zone diameter breakpoints. We evaluated the disk diffusion test (DDT) for susceptibility testing of BFG isolates compared with the agar dilution method.

Methods: In total, 150 BFG isolates were collected from three institutes in Korea. The agar dilution method was conducted according to the CLSI guidelines. DDT was performed following the EUCAST guideline. Fastidious anaerobe agar supplemented with 5% defibrinated horse blood was used as the culture medium. Nine antimicrobials were evaluated: penicillin, cefoxitin, cefotetan, imipenem, meropenem, piperacillin-tazobactam, clindamycin, moxifloxacin, and metronidazole.

Results: The categorical agreement (CA) between the two methods was >90.0% for imipenem, meropenem, clindamycin, and metronidazole. However, the CA for piperacillintazobactam was low, at 83.2%. Major errors were found: 5.4% for imipenem, 7.4% for meropenem, and 12.8% for piperacillin-tazobactam. All minor errors were <10%. We propose using the area of technical uncertainty (ATU) zone-overlapping area for susceptible and resistant strains to reduce errors in the DDT. Outside the ATU, the CAs of cefoxitin, cefotetan, and piperacillin-tazobactam were >90.0%, whereas that of moxifloxacin was increased to 88.5%.

Conclusions: The DDT can be a useful alternative antimicrobial susceptibility test for BFG isolates when using the ATU zone to reduce errors.