The Importance of HHLA2 in Solid Tumors-A Review of the Literature.

Cancer immunotherapy is a rapidly developing field of medicine that aims to use the host's immune mechanisms to inhibit and eliminate cancer cells. Antibodies targeting CTLA-4, PD-1, and its ligand PD-L1 are used in various cancer therapies. However, the most thoroughly researched pathway targeting PD-1/PD-L1 has many limitations, and multiple malignancies resist its effects. Human endogenous retrovirus-H Long repeat-associating 2 (HHLA2, known as B7H5/B7H7/B7y) is the youngest known molecule from the B7 family. HHLA2/TMIGD2/KIRD3DL3 is one of the critical pathways in modulating the immune response. Recent studies have demonstrated that HHLA2 has a double effect in modulating the immune system. The connection of HHLA2 with TMIGD2 induces T cell growth and cytokine production via an AKT-dependent signaling cascade. On the other hand, the binding of HHLA2 and KIR3DL3 leads to the inhibition of T cells and mediates tumor resistance against NK cells. This review aimed to summarize novel information about HHLA2, focusing on immunological mechanisms and clinical features of the HHLA2/KIR3DL3/TMIGD2 pathway in the context of potential strategies for malignancy treatment.

Prognostic Value of HHLA2 in Patients with Solid Tumors: A Meta-Analysis.

HHLA2 is a checkpoint from the B7 family that can play a co-stimulatory or co-inhibitory role in cancer, depending on the binding receptor. The aim of this meta-analysis was to assess the relationship between HHLA2 levels and its impact on the prognosis of patients with solid cancers. The study used data from PubMed, Embase, Web of Science (WOS), Cochrane and SCOPUS databases. The R studio software was used for the data analysis. The study assessed overall survival (OS), disease-specific survival (DSS), progression-free survival (PFS), recurrence-free survival (RFS), and disease-free survival (DFS) by pooling appropriate hazard ratios (HR). Eighteen studies (2880 patients' data) were included. High expression of HHLA2 was associated with worse OS (HR = 1.58, 95% CI: 1.23-2.03), shorter RFS (HR = 1.95, 95% CI: 1.38-2.77) and worse DFS (HR = 1.45, 95% CI: 1.01-2.09) in patients with solid cancers. The current study suggests that high expression of HHLA2 is associated with poorer prognosis in patients with solid cancers.

Prognostic Value of B7H4 Expression in Patients with Solid Cancers: A Systematic Review and Meta-Analysis.

V-set domain-containing T-cell activation inhibitor 1 (aliases VTCN1, B7H4) participates in tumour immune escape by delivering inhibitory signals to T cells. The purpose of this article was to assess the B7H4 prognostic value in solid cancers. Three databases were searched for relevant articles. The main endpoints were overall survival (OS), disease-specific survival (DSS), progression-free survival (PFS), recurrence-free survival (RFS), and disease-free survival (DFS). Appropriate hazard ratios (HRs) were pooled. The R studio software (version 4.0.3) was used for data analysis. Thirty-one studies met the inclusion criteria. High expression of B7H4 was associated with worse OS (HR = 1.52, 95% CI: 1.37-1.68) but not with DSS (HR = 1.14, 95% CI: 0.49-2.63), RFS (HR = 1.77, 95% CI: 0.75-4.18), DFS (HR = 1.29, 95% CI: 0.8-2.09), or PFS (HR = 1.71, 95% CI: 0.91-3.2) in patients with solid cancers. High expression of B7H4 is associated with a poorer prognosis in patients with solid cancers. B7H4 is a promising prognostic biomarker and immunotherapeutic target for various solid cancers because of its activity in cancer immunity and tumourigenesis.

Digital Subtraction Angiography of Cerebral Arteries: Influence of Cranial Dimensions on X-ray Tube Performance.

(1) Background. Digital subtraction angiography (DSA) is indispensable for diagnosing cerebral aneurysms due to its superior imaging precision. However, optimizing X-ray parameters is crucial for accurate diagnosis, with X-ray tube settings significantly influencing image quality. Understanding the relationship between skull dimensions and X-ray parameters is pivotal for tailoring imaging protocols to individual patients. (2) Methods. A retrospective analysis of DSA data from a single center was conducted, involving 251 patients. Cephalometric measurements and statistical analyses were performed to assess correlations between skull dimensions and X-ray tube parameters (voltage and current). (3) Results. The study revealed significant correlations between skull dimensions and X-ray tube parameters, highlighting the importance of considering individual anatomical variations. Gender-based differences in X-ray parameters were observed, emphasizing the need for personalized imaging protocols. (4) Conclusions. Personalized approaches to DSA imaging, integrating individual anatomical variations and gender-specific differences, are essential for optimizing diagnostic outcomes. While this study provides valuable insights, further research across multiple centers and diverse imaging equipment is warranted to validate these findings.

Will ChatGPT pass the Polish specialty exam in radiology and diagnostic imaging? Insights into strengths and limitations.

Purpose: Rapid development of artificial intelligence has aroused curiosity regarding its potential applications in medical field. The purpose of this article was to present the performance of ChatGPT, a state-of-the-art language model in relation to pass rate of national specialty examination (PES) in radiology and imaging diagnostics within Polish education system. Additionally, the study aimed to identify the strengths and limitations of the model through a detailed analysis of issues raised by exam questions. Material and methods: The present study utilized a PES exam consisting of 120 questions, provided by Medical Exami-nations Center in Lodz. Questions were administered using openai.com platform that grants free access to GPT-3.5 model. All questions were categorized according to Bloom's taxonomy to assess their complexity and difficulty. Following the answer to each exam question, ChatGPT was asked to rate its confidence on a scale of 1 to 5 to evaluate the accuracy of its response. Results: ChatGPT did not reach the pass rate threshold of PES exam (52%); however, it was close in certain question categories. No significant differences were observed in the percentage of correct answers across question types and sub-types. Conclusions: The performance of the ChatGPT model in the pass rate of PES exam in radiology and imaging diagnostics in Poland is yet to be determined, which requires further research on improved versions of ChatGPT.

B7H3 Role in Reshaping Immunosuppressive Landscape in MSI and MSS Colorectal Cancer Tumours.

The study aimed to assess the expression of B7H3 concerning clinicopathological and histological parameters, including MSI/MSS status, CD-8 cells, tumour-infiltrating lymphocytes (TILs), budding, TNM scale and grading. Moreover, we analyzed the B7H3-related pathways using available online datasets and the immunological context of B7H3 expression, through the 48-cytokine screening panel of cancer tissues homogenates, immunogenic features and immune composition. The study included 158 patients diagnosed with CRC. To assess B7H3 levels, we performed an immunohistochemistry method (IHC) and enzyme-linked immunosorbent assay (ELISA). To elucidate the immune composition of colorectal cancer, we performed the Bio-Plex Pro Human 48-cytokine panel. To study biological characteristics of B7H3, we used online databases. Expression of B7H3 was upregulated in CRC tumour tissues in comparison to adjacent noncancerous margin tissues. The concentrations of B7H3 in tumours were positively associated with T parameter of patients and negatively with tumour-infiltrating lymphocytes score. Additionally, Principal Component Analysis showed that B7H3 expression in tumours correlated positively with cytokines associated with M2-macrophages and protumour growth factors. The expression of B7H3 in tumours was independent of MSI/MSS status. These findings will improve our understanding of B7H3 role in colorectal cancer immunity. Our study suggests that B7-H3 is a promising potential target for cancer therapy. Further studies must clarify the mechanisms of B7H3 overexpression and its therapeutic importance in colorectal cancer.

Do Elevated YKL-40 Levels Drive the Immunosuppressive Tumor Microenvironment in Colorectal Cancer? Assessment of the Association of the Expression of YKL-40, MMP-8, IL17A, and PD-L1 with Coexisting Type 2 Diabetes, Obesity, and Active Smoking.

The influence of chitinase-3-like protein 1 (YKL-40 or CHI3L1) expression on the immunological properties of the tumor microenvironment, which may affect the effectiveness of immunotherapy, is currently not sufficiently understood in colorectal cancer (CRC). The aim of this study was to investigate the relationship between YKL-40 expression and the immunological properties of the tumor microenvironment in CRC. We performed in silico analysis, including analysis of immune cell infiltration scores and the immune landscape depending on YKL-40 expression, gene set enrichment analysis (GSEA), and analysis of three Gene Expression Omnibus (GEO) datasets. In 48 CRC tissue homogenates and the surgical margin, we analyzed the expression of YKL-40, MMP8, IL17A, and PD-L1. Moreover, we analyzed the expression of YKL-40 in tissue homogenates retrieved from patients with coexisting diabetes, obesity, and smoking. The expression of YKL-40 was significantly higher in CRC tumor tissue compared to healthy tissue and correlated with MMP-8, IL17A, and PD-L1 expression. In silico analysis revealed an association of YKL-40 with disease recurrence, and GSEA revealed a potential link between elevated YKL-40 expression and immunosuppressive properties of the tumor microenvironment in CRC.

Overexpression and Role of HHLA2, a Novel Immune Checkpoint, in Colorectal Cancer.

The study aimed to investigate correlations between HHLA2 levels and parameters, including microsatellite instability (MSI) status, CD8+ cells, and histopathological features: budding, tumor-infiltrating lymphocytes (TILs), TNM scale, grading, cytokines, chemokines, and cell signaling moleculesin colorectal cancer (CRC). Furthermore, the immune infiltration landscape and HHLA2-related pathways in colorectal cancer using available online datasets were analyzed. The study included 167 patients diagnosed with CRC. Expression of HHLA2 was detected by immunohistochemistry method (IHC) and enzyme-linked immunosorbent assay (ELISA). The IHC was used to evaluate the MSI and CD8+ status. The budding and TILs were measured using a light microscope. The concentrations of cytokines, chemokines, and cell signaling molecules were measured to analyze the data by the Bio-Plex Pro Human cytokine screening panel, 48 cytokine assay, and principal component analysis (PCA). Geneset enrichment analysis (GSEA) was conducted to identify HHLA2-related pathways. The biological function of HHLA2 was predicted by Gene Ontology (GO). Analysis of the immune infiltration landscape of HHLA2 in colorectal cancer was made by the web-based tool Camoip. High HHLA2 expression was detected in CRC tumor tissues compared to the adjacent noncancerous tissues. The percentage of HHLA2-positive tumors was 97%. GSEA and GO showed that HHLA2 upregulation correlated with cancer-related pathways and several biological functions. Tumor-infiltrating lymphocytes score correlated positively with IHC HHLA2 expression level percentage. There was a negative correlation between HHLA2, anti-tumor cytokines and pro-tumor growth factors. This study provides a valuable insight into the role of HHLA2 in CRC. We reveal the role of HHLA2 expression as well as a stimulatory and inhibitory immune checkpoint in colorectal cancer. Further research may verify the therapeutic values of the HHLA2-KIR3DL3/TMIGD2 pathway in colorectal cancer.

B7H4 Expression Is More Frequent in MSS Status Colorectal Cancer and Is Negatively Associated with Tumour Infiltrating Lymphocytes.

The immunotherapies based on ICIs in CRC are nowadays limited to microsatellite unstable tumours which are approximately 15% of all CRC cases. There are a few new immune checkpoints belonging to the B7 family, including B7H4. B7H4 expression is associated with so-called "cold tumours", and its function is linked to the downregulation of various immune cell populations. Our study aimed to investigate whether B7H4 expression is dependent on microsatellite status in CRC and on elucidating the immunological context in which the expression of B7H4 occurs. We enrolled 167 patients in the study. We prepared the homogenates from tumour tissues and healthy adjacent tissue to assess the B7H4 levels and the Bio-Plex Pro Human 48-cytokine panel. We assessed the microsatellite status of the tumour, B7H4 expression, CD8+ T cell population, and the TILs and budding in H + E stained slides by the IHC method. We used an online available database for further exploring the biological characteristics of B7H4. The expression of B7H4 was more frequent in microsatellite stable tumours, and was negatively associated with TILs. B7H4 is positively correlated with antitumour immunosuppressive iTME, thus contributing to the immunosuppressive environment in CRC.

Assessment of the RANTES Level Correlation and Selected Inflammatory and Pro-Angiogenic Molecules Evaluation of Their Influence on CRC Clinical Features: A Preliminary Observational Study.

Background and Objectives: Assessment of RANTES level and concentrations of inflammatory cytokines: programmed death ligand 1 (PD-L1), interferon gamma IFN-γ, tumor necrosis factor alpha (TNF-α), transforming growht factor ß (TGF-ß) (and angiogenesis factors: vascular endothelial growth factor A (VEGF-A) and vascular endothelial growth factor C (VEGF C) in tumor and margin tissues of colorectal cancer (CRC,) and evaluation of RANTES influence on histopathological parameters (microvessel density (MVD), budding, tumor-infiltrating lymphocytes (TILs)), in relation to patients' clinical features. Materials and Methods: The study used 49 samples of tumor and margin tissues derived from CRC patients. To determinate the concentration of RANTES, PD-L1, IFN-γ, TNF-α, TGF-ß, VEGF-A, and VEGF-C, we used the commercially available enzyme-linked immunosorbent assay kit. Additionally, RANTES and PD-L1 expression was assessed with the use of IHC staining in both tumor cells and TILS in randomly selected cases. MVD was assessed on CD34-stained specimens. The MVD and budding were assessed using a light microscope. Results: We found significantly higher levels of RANTES, PD-L1, IFN-γ, TNF-α, TGF-ß, VEGF-A, and VEGF-C in the tumor in comparison with the margin. The RANTES tumor levels correlated significantly with those of PD-L1, TNF-α, TGF-ß, VEGF-A, and VEGF-C. The RANTES margin levels were significantly associated with the margin levels of all proteins investigated-PD-L1, IFN-γ, TNF-α, TGF-ß, VEGF-A, and VEGF-C. Additionally, we observed RANTES- and PD-L1-positive immunostaining in TILs. In a group of 24 specimens, 6 different CRC tumors were positive for RANTES and PD-L1 immunostaining. The IFN-gamma concentration in both tumor and margin and TGF-ß in tumor correlated with TILs. TILs were negatively associated with the patients' disease stage and N parameter. Conclusions: RANTES activity might be associated with angiogenesis, lymphogenesis, and immune escape in CRC. RANTES is an important chemokine that is a part of the chemokine-cytokine network involved in the modulation of TME composition in CRC. Further research may verify which processes are responsible for the associations observed in the study.

Periostin in Angiogenesis and Inflammation in CRC-A Preliminary Observational Study.

Background and Objectives: To assess the periostin level and the concentrations of pro-inflammatory cytokines: TNFα, IFN-γ, IL-1ß and IL-17 in tumor and marginal tissues of CRC and to investigate the influence of periostin on angiogenesis by MVD (microvessel density) and concentration of VEGF-A in relation to clinicopathological parameters of patients. Materials and Methods: The study used 47 samples of tumor and margin tissues derived from CRC patients. To determinate the concentration of periostin, VEGF-A, TNFα, IFNγ, IL-1ß and IL-17, we used the commercially available enzyme- linked immunosorbent assay kit. MVD was assessed on CD34-stained specimens. The MVD and budding were assessed using a light microscope Results: We found significantly higher concentrations of periostin, VEGF-A, IFN-γ, IL-1 ß, IL-17 and TNFα in the tumor samples compared with surgical tissue margins. The tumor concentrations of periostin were correlated with tumor levels of VEGF-A, IFN-γ, IL-1ß and TNFα. We observed significant correlation between margin periostin and VEGF-A, IFN-γ, IL-17 and TNFα in tumor and margin specimens. Additionally, we found a significantly negative correlation between periostin tumor concentration and microvessel density at the invasive front. Tumor periostin levels were also correlated positively with tumor budding. Conclusions: Periostin activity may be associated with pro-inflammatory cytokine levels: TNFα, IFN-γ, IL-1ß and IL-17. Our results also suggest the role of periostin in angiogenesis in CRC and its upregulation in poorly vascularized tumors. Further research on the regulations between periostin and cytokines are necessary to understand the interactions between tumor and immune tumor microenvironment, which could be helpful in the development of new targeted therapy.

The Concentration of CMKLR1 Expression on Clinicopathological Parameters of Colorectal Cancer: A Preliminary Study.

Background and Objectives: Colorectal cancer (CRC) is the second-most common cause of cancer-related deaths worldwide. Angiogenesis is crucial for cancer growth, infiltration of surrounding tissues, and metastasis and plays a key role in the pathogenesis of CRC. Chemerin/chemokine-like receptor 1 (CMKLR1) is one of the biochemical pathways involved in the regulation of angiogenesis in solid tumors. The aim of the study was to assess the CMKLR1 level in tumor and margin tissues of CRC in relation to histopathological parameters: microvessel density (MVD), budding, tumor-infiltrating lymphocytes (TILs), TNM scale, and grading. Materials and Methods: The study involved 43 samples of tumor and margin tissues obtained from CRC patients. To assess the concentration of CMKLR1 a commercially available enzyme-linked immunosorbent assay kit was used. For 35 cases, we performed CD34 immunostaining. The MVD, budding, and TILs were assessed using a light microscope. Results: The levels of CMKLR1 in both tumor and margin were negatively correlated with MVD and budding. CMKLR1 concentration in margin was higher in tissues with lymphocytic infiltration. Conclusions: Low vascularity and low budding are associated with higher CMKLR1 expression. CMKLR1 might play a multifunctional role in CRC pathogenesis by influencing tumor budding and peritumoral lymphocytic infiltration.

GDF-15 Level Correlates with CMKLR1 and VEGF-A in Tumor-free Margin in Colorectal Cancer.

Colorectal cancer (CRC) is the third most frequently diagnosed cancer worldwide, responsible for over 880 000 deaths each year. Growth/differentiation factor 15 (GDF-15) is reported to be a promising diagnostic and prognostic factor in CRC. It induces pleiotropic effects in tumor cells: proliferation, stemness, invasion and metastasis. Some studies indicate that GDF-15 may stimulate angiogenesis in malignant neoplasms. However, it has not been investigated in CRC yet. The aim of our study was to determine the level of GDF-15 and the concentrations of hypoxia-inducible factor-1α (HIF-1α), VEGF-A and chemokine-like receptor 1 (CMKLR1) in tumor and margin specimens of CRC in relation to histological grade and TNM staging. The study comprised 33 samples of tumor and margin tissues obtained from CRC patients. To assess the concentration of GDF-15, HIF-1α, VEGF-A and CMKLR1, commercially available enzyme-linked immunosorbent assay (ELISA) kits were used. We found significantly increased levels of GDF-15 and CMKLR1 in tumor tissue compared to margin tissue and higher concentrations of HIF-1α and VEGF-A in margin tissue than in tumor tissue. The levels of GDF-15 and HIF-1α were significantly correlated with VEGF-A and CMKLR1 in margin tissue. In CRC, the increased level of GDF-15 might stimulate angiogenesis through upregulation of HIF-1α, VEGF A and CMKLR1 expression. Our study is the first one to reveal the correlation between the levels of GDF-15 and CMKLR1 in CRC. The elevated levels of HIF-1α and VEGF-A in tumor-free margin tissues suggest that noncancer cells in the tumor microenvironment are an important source of proangiogenic factors.

miREIA - an immunoassay method in assessment of microRNA levels in tumor tissue-pilot study. The impact of miR-93-5p, miR-142-5p and IFNγ on PD-L1 level in colorectal cancer.

Colorectal cancer is the second and third most common cancer in females and males, respectively. The PD-L1/PD-1 immune checkpoint is an important source of immunosuppression in the tumor microenvironment and is associated with IFNγ. Recent studies have revealed that a significant number of tumor suppressive miRNAs can regulate the expression of PD-L1.                The objective quantification of selected microRNAs using the miREIA method in CRC tissue was performed. We investigated the roles of miR-93-5p and miR-142-5p expression and the levels of IFNγ in regulating the expression of PD-L1 in tumor and margin tissues of CRC in relation to the histological grade, TNM classification, and tumor localization. 37 samples of tumor and margin tissues from CRC patients were evaluated. MiR-93-5p and miR-142-5p levels were measured by a method for quantitative measurement of human microRNA (miREIA). The concentrations of PD-L1 and IFNγ were determined by the ELISA kit. We found higher concentrations of miR-93-5p, PD-L1 and IFNγ in tumor samples compared to tumor margin samples. A significant correlation was found between PD-L1 and IFNγ in tumor and margin specimens; between miR-142-5p and miR-93-5p levels  in tumor and margin specimens. A higher level of miR-93-5p was found in tumor margin tissues on the left side of the colon. Patients with distant metastases were characterized by higher miR-93-5p concentration compared to patients without metastases. CRC is an important source of PD-L1, IFNγ and miR-93-5p expression. Understanding the mechanisms underlying intratumoral PD-L1 expression may open new opportunities for targeted immunotherapy for colorectal cancer.