JAK2 Loss Arising From Tumor-Spread-Through-Air-Spaces (STAS) Promotes Tumor Progression by Suppressing CD8+ T Cells in Lung Adenocarcinoma: A Machine Learning Approach.

BACKGROUND: Tumor spread through air spaces (STAS) is a recently discovered risk factor for lung adenocarcinoma (LUAD). The aim of this study was to investigate specific genetic alterations and anticancer immune responses related to STAS. By using a machine learning algorithm and drug screening in lung cancer cell lines, we analyzed the effect of Janus kinase 2 (JAK2) on the survival of patients with LUAD and possible drug candidates. METHODS: This study included 566 patients with LUAD corresponding to clinicopathological and genetic data. For analyses of LUAD, we applied gene set enrichment analysis (GSEA), in silico cytometry, pathway network analysis, in vitro drug screening, and gradient boosting machine (GBM) analysis. RESULTS: The patients with STAS had a shorter survival time than those without STAS (P < 0.001). We detected gene set-related downregulation of JAK2 associated with STAS using GSEA. Low JAK2 expression was related to poor prognosis and a low CD8+ T-cell fraction. In GBM, JAK2 showed improved survival prediction performance when it was added to other parameters (T stage, N stage, lymphovascular invasion, pleural invasion, tumor size). In drug screening, mirin, CCT007093, dihydroretenone, and ABT737 suppressed the growth of lung cancer cell lines with low JAK2 expression. CONCLUSION: In LUAD, low JAK2 expression linked to the presence of STAS might serve as an unfavorable prognostic factor. A relationship between JAK2 and CD8+ T cells suggests that STAS is indirectly related to the anticancer immune response. These results may contribute to the design of future experimental research and drug development programs for LUAD with STAS.

Diagnostic Assessment of Endoscopic Ultrasonography-Fine Needle Aspiration Cytology in the Pancreas: A Comparison between Liquid-Based Preparation and Conventional Smear.

Background and Objectives: This study aimed to elucidate the cytologic characteristics and diagnostic usefulness of endoscopic ultrasonography-fine needle aspiration cytology (EUS-FNAC) by comparing it with liquid-based preparation (LBP) and conventional smear (CS) in pancreas. Methods: The diagnostic categories (I through VII) were classified according to the World Health Organization Reporting System for Pancreaticobiliary Cytopathology. Ten cytologic features, including nuclear and additional features, were evaluated in 53 cases subjected to EUS-FNAC. Nuclear features comprised irregular nuclear contours, nuclear enlargement, hypochromatic nuclei with parachromatin clearing, and nucleoli. Additional cellular features included isolated atypical cells, mucinous cytoplasm, drunken honeycomb architecture, mitosis, necrotic background, and cellularity. A decision tree analysis was conducted to assess diagnostic efficacy. Results: The diagnostic concordance rate between LBP and CS was 49.1% (26 out of 53 cases). No significant differences in nuclear features were observed between categories III (atypical), VI (suspicious for malignancy), and VII (malignant). The decision tree analysis of LBP indicated that cases with moderate or high cellularity and mitosis could be considered diagnostic for those exhibiting nuclear atypia. Furthermore, in CS, mitosis, isolated atypical cells, and necrotic background exerted a more significant impact on the diagnosis of EUS-FNAC. Conclusions: Significant parameters for interpreting EUS-FNAC may differ between LBP and CS. While nuclear atypia did not influence the diagnosis of categories III, VI, and VII, other cytopathologic features, such as cellularity, mitosis, and necrotic background, may present challenges in diagnosing EUS-FNAC.

Clinicopathological significances of cribriform pattern in lung adenocarcinoma.

The present study aimed to investigate the clinicopathological and prognostic implications of the cribriform pattern in lung adenocarcinoma through a meta-analysis. The estimated rates of cribriform pattern in lung adenocarcinomas were investigated. The correlations between cribriform pattern and clinicopathological characteristics, including genetic alterations and prognosis were evaluated. The estimated rate of cribriform pattern was 0.150 (95% confidence interval [CI], 0.101-0.218) in lung adenocarcinoma. The estimated rates of cribriform pattern in the 5% and 10% criteria were 0.230 (95% CI 0.125-0.386) and 0.130 (95% CI 0.062-0.252), respectively. The presence of cribriform pattern was significantly correlated with larger tumor size (> 30 mm), spread through air spaces, and lymph node metastasis (P < 0.001, P < 0.001, and P = 0.007, respectively, in the meta-regression test). There were no significant differences between cribriform pattern, smoking history, and vascular and lymphatic invasion. In lung adenocarcinoma with cribriform pattern, the estimated rates of ALK rearrangement, KRAS, and EGFR mutations were 0.407 (95% CI 0.165-0.704), 0.330 (95% CI 0.117-0.646), and 0.249 (95% CI 0.125-0.437), respectively. ALK rearrangement was significantly more frequent in lung adenocarcinomas with cribriform pattern than in those without. The overall survival rate was significantly worse in lung adenocarcinomas with a cribriform pattern than in those without (hazard ratio 2.051, 95% CI 1.369-3.075). In conclusion, the presence of a cribriform pattern can be a useful predictor of the clinicopathological characteristics and prognosis of patients with lung adenocarcinoma.

Comparison between Peritumoral and Intratumoral Budding in Colorectal Cancer.

Tumor budding (TB) is classified, based on location, into peritumoral budding (PTB) or intratumoral budding (ITB). This study aimed to evaluate the relationship between PTB and ITB in colorectal cancers (CRCs). PTB and ITB were investigated and subsequently divided into high and low groups. CRCs were divided into three groups: (1) high PTB/ITB, (2) high PTB or ITB, and (3) low PTB/ITB. The clinicopathological and prognostic significances were evaluated according to the three tumor budding (TB) groups. High PTB/ITB and low PTB/ITB were identified in 32 (12.0%) and 135 (50.8%) patients, respectively. A total of 99 patients (37.2%) were found to have high PTB or ITB. TB was significantly correlated with lymphatic and perineural invasion, lymph node metastasis, metastatic lymph node ratio, distant metastasis, and a higher pTNM stage. A significant correlation was found between high PTB and high ITB (p = 0.010). The amount of PTB was found to increase significantly with the amount of ITB (p < 0.001) in a linear regression test. Patients with high PTB/ITB had worse overall and recurrence-free survival than those with high PTB or ITB. Conversely, patients with low PTB/ITB had better overall and recurrence-free survival rates than those with high PTB or ITB. However, there was no significant difference in overall and recurrence-free survival between patients with high PTB/low ITB and high ITB/low PTB (p = 0.336 and p = 0.623, respectively). In summary, the presence of TB, regardless of PTB or ITB, was significantly correlated with aggressive tumor behavior and a worse prognosis than the absence of TB. Additionally, the present study demonstrated that it is feasible to stratify the prognosis of patients based on whether they have both PTB and ITB or only one of the two.

Significant Genes Associated with Mortality and Disease Progression in Grade II and III Glioma.

BACKGROUND: The Wnt/ß-catenin pathway plays a critical role in the tumorigenesis and maintenance of glioma stem cells. This study aimed to evaluate significant genes associated with the Wnt/ß-catenin pathway involved in mortality and disease progression in patients with grade II and III glioma, using the Cancer Genome Atlas (TCGA) database. METHODS: We obtained clinicopathological information and mRNA expression data from 515 patients with grade II and III gliomas from the TCGA database. We performed a multivariate Cox regression analysis to identify genes independently associated with glioma prognosis. RESULTS: The analysis of 34 genes involved in Wnt/ß-catenin signaling demonstrated that four genes (CER1, FRAT1, FSTL1, and RPSA) related to the Wnt/ß-catenin pathway were significantly associated with mortality and disease progression in patients with grade II and III glioma. We also identified additional genes related to the four significant genes of the Wnt/ß-catenin pathway mentioned above. The higher expression of BMP2, RPL18A, RPL19, and RPS12 is associated with better outcomes in patients with glioma. CONCLUSIONS: Using a large-scale open database, we identified significant genes related to the Wnt/ß-catenin signaling pathway associated with mortality and disease progression in patients with grade II and III gliomas.

CLDN18: Clinical, Pathological, and Genetic Signatures with Drug Screening in Gastric Adenocarcinoma.

INTRODUCTION: The CLDN18 gene, encoding claudin 18.1 and claudin 18.2, is a key component of tight junction strands in epithelial cells that form a paracellular barrier that is critical in Stomach Adenocarcinoma (STAD). METHODS: Our study included 1,095 patients with proven STAD, 415 from The Cancer Genome Atlas (TCGA) cohort and 680 from the Gene Expression Omnibus database. We applied various analyses, including gene set enrichment analysis, pathway analysis, and in vitro drug screening to evaluate survival, immune cells, and genes and gene sets associated with cancer progression, based on CLDN18 expression levels. Gradient boosting machine learning (70% for training, 15% for validation, and 15% for testing) was used to evaluate the impact of CLDN18 on survival and develop a survival prediction model. RESULTS: High CLDN18 expression correlated with worse survival in lymphocyte-poor STAD, accompanied by decreased helper T cells, altered metabolic genes, low necrosis-related gene expression, and increased tumor proliferation. CLDN18 expression showed associations with gene sets associated with various stomach, breast, ovarian, and esophageal cancers, while pathway analysis linked CLDN18 to immunity. Incorporating CLDN18 expression improved survival prediction in a machine learning model. Notably, nutlin-3a and niraparib effectively inhibited high CLDN18-expressing gastric cancer cells in drug screening. CONCLUSION: Our study provides a comprehensive understanding of the biological role of CLDN18-based bioinformatics and machine learning analysis in STAD, shedding light on its prognostic significance and potential therapeutic implications. To fully elucidate the molecular intricacies of CLDN18, further investigation is warranted, particularly through in vitro and in vivo studies.

The Association of Chronic Periodontitis as a Potential Risk Factor with Rheumatoid Arthritis: A Nested Case-Control Study Using a Korean National Health Screening Cohort.

Growing research has proposed that rheumatoid arthritis (RA) and chronic periodontitis (CP) share similar pathophysiological mechanisms involving inflammation and tissue destruction. However, the potential correlation of CP as a contributing factor for the occurrence of RA warrants validation in the Korean population, where both diseases are prevalent, especially considering the increasingly aging demographic in Korea. This study examined 5139 RA cases and 509,727 matched controls from a Korean national cohort dataset (2002-2019) by carefully employing propensity score matching to ensure comparability between groups. Baseline characteristics were compared using standardized differences, and logistic regression was employed to estimate the impact of CP history on RA likelihood while controlling for covariates. We fully examined medical records documenting CP occurrences within the two-year period leading up to the index date, conducting comprehensive subgroup analyses. While a 1-year history of CP did not show a significant association with likelihood of RA, a 2-year history of CP increased RA likelihood by 12%, particularly among older adults, females, rural residents, and those with certain comorbidities such as hypercholesterolemia. Interestingly, this association persisted even among individuals with non-smoking habits, normal weight, and infrequent alcohol consumption. These findings suggest that chronic CP exposure for at least 2 years may independently elevate RA risk in Korean adults. The association in certain subgroups appears to suggest a predisposition toward genetic susceptibilities over lifestyle and environmental factors. Predicting RA in CP patients may be challenging, emphasizing the importance of regular RA screening, especially in high-risk subgroups.

Low CDKN1B Expression Associated with Reduced CD8+ T Lymphocytes Predicts Poor Outcome in Breast Cancer in a Machine Learning Analysis.

The cyclin-dependent kinase inhibitor 1B (CDKN1B) gene, which encodes the p27Kip1 protein, is important in regulating the cell cycle process and cell proliferation. Its role in breast cancer prognosis is controversial. We evaluated the significance and predictive role of CDKN1B expression in breast cancer prognosis. We investigated the clinicopathologic factors, survival rates, immune cells, gene sets, and prognostic models according to CDKN1B expression in 3794 breast cancer patients. We performed gene set enrichment analysis (GSEA), in silico cytometry, pathway network analyses, gradient boosting machine (GBM) learning, and in vitro drug screening. High CDKN1B expression levels in breast cancer correlated with high lymphocyte infiltration signature scores and increased CD8+ T cells, both of which were associated with improved prognosis in breast cancer. which were associated with a better prognosis. CDKN1B expression was associated with gene sets for the upregulation of T-cell receptor signaling pathways and downregulation of CD8+ T cells. Pathway network analysis revealed a direct link between CDKN1B and the pathway involved in the positive regulation of the protein catabolic process pathway. In addition, an indirect link was identified between CDKN1B and the T-cell receptor signaling pathway. In in vitro drug screening, BMS-345541 demonstrated efficacy as a therapeutic targeting of CDKN1B, effectively impeding the growth of breast cancer cells characterized by low CDKN1B expression. The inclusion of CDKN1B expression in GBM models increased the accuracy of survival predictions. CDKN1B expression plays a significant role in breast cancer progression, implying that targeting CDKN1B might be a promising strategy for treating breast cancer.

Prognostic Implications of Intratumoral Budding in Colorectal Cancer: Detailed Analysis Based on Tumor-Infiltrating Lymphocytes.

BACKGROUND: This study aims to understand the clinical and pathological importance of intratumoral budding (ITB) in colorectal cancer (CRC) and its relationship with tumor-infiltrating lymphocytes (TILs). CRCs can be classified into hot (high immunoscore (IS)) and cold (low IS) tumors. METHODS: We investigated the number of ITBs in a hotspot area and categorized them into high-ITB (≥5) and low-ITB (<5) groups. The clinicopathological significance of ITB in human CRCs was evaluated, and a detailed analysis based on tumor-infiltrating lymphocytes (TILs) was also performed. RESULTS: High ITB was identified in 59 of 266 CRC cases (22.2%). High ITB significantly correlated with a poorly differentiated tumor, lympho-vascular invasion, perineural invasion, higher pT stage, lymph node metastasis, and higher metastatic lymph node ratio. High ITB was also significantly correlated with a low IS and low CD8-positive lymphocytic infiltrate. The number of ITBs was substantially higher in the low-IS group than in the high-IS group (3.28 ± 3.31 vs. 2.19 ± 2.59; p = 0.005). High ITB significantly correlated with worse overall survival (p = 0.004). In the low-IS group, CRCs with high ITB had a significantly worse prognosis than those with low ITB (p = 0.021). However, there was no significant difference in prognosis between the high- and low-ITB groups in the high-IS group (p = 0.498). CONCLUSIONS: Taken together, high ITB was significantly correlated with aggressive tumor behaviors and worse survival in patients with CRCs. In addition, ITB can be useful for the prognostic stratification of CRCs with low IS.