The Impact of KPNA2 on Prognosis of Colorectal Cancer Patients: A Meta-Analysis

Background and purpose: Colorectal cancer (CRC) is one of the most common malignant tumors with the highest mortality globally. At present, there is no exact biomarker to predict the prognosis and clinicopathological monitoring of CRC patients. Recent studies on the relationship of Karyopherin α 2 (KPNA2) expression and the prognosis of CRC has gradually become a hot spot while the results are still controversial. The aim of this study was to analyze and assess the prognostic role of KPNA2 in CRC patients. Methods: PubMed, Web of Science, Medline, EMBASE, CNKI, Wanfang, VIP, and Chinese Medical Database were systematically searched. The cohort study of high-level expression of KNPA2 and low-level expression of KPNA2 in CRC patients was included, the relevant data were extracted and the literature quality was evaluated. At the same time, the relationship between KPNA2 expression level and the overall survival (OS), the clinicopathological stage of CRC patients was studied. Meta-analysis was carried out by Stata MP 17.0 (Stata Corporation, College Station, TX, USA) software. Results: A total of 7 cohort studies involving 1166 patients were included. The analysis results showed that higher KPNA2 expression was significantly associated with higher tumor stage (OR=1.90, 95% CI 1.42–2.54), higher degree of tumor invasion (OR=2.14，95% CI 1.55-2.94), more lymph node metastasis (OR=2.20, 95% CI 1.68-2.88) and more distant metastasis (OR=3.66，95% CI 1.81-7.40). Moreover, higher KPNA2 expression was significantly associated with the shorter OS (HR=2.31, 95%CI 1.46-3.68).Conclusion: KPNA2 overexpression is an unfavorable prognostic factor for CRC patients. It could serve as a prognostic biomarker and as a potential therapeutic target for CRC.

Reappraisal of Grading in Intestinal-Type Sinonasal Adenocarcinoma: Tumor Budding as an Independent Prognostic Parameter

Since sinonasal intestinal-type adenocarcinomas (ITAC) show resemblance to colorectal adenocarcinomas, we aimed to investigate novel prognostic factors of outcome, with particular focus on the role of tumor budding (TB). Retrospective clinico-pathological single-institution study on consecutive ITAC patients between 1996 and 2020. Histopathological parameters including conventional subtypes and TB features (low, intermediate, high) were evaluated with the aid of pancytokeratin (AE1/AE3) immunohistochemical staining. Parameters were correlated to clinical data and outcome. A total of 31 ITAC patients were included. Overall, 19/31 patients (61.3%) presented with stage III/IV disease. Presence of lymph node or distant metastases was rare (1/31 patient, 3.2%). Treatment protocols consisted of tumor resection in 30/31 patients (96.8%) and primary radiochemotherapy in 1/31 patient (3.2%). Adjuvant radiation therapy was conducted in 20/30 surgically treated patients (66.7%). The 3- and 5-year overall survival (OS) was 83.9% and 78.3% and the 3- and 5-years disease-specific survival (DSS) 83.7% % and 78.5%, respectively. The presence of intermediate/high TB (defined as ≥ 5 buds) was associated with both, worse DSS (log rank p = 0.03) and OS (log rank p = 0.006). No patient with low TB revealed progressive disease or died of the disease. No association between TB and tumor stage or conventional tumor subtype was found. Tumor budding seems to be an independent prognostic factor of worse outcome in ITAC.

Significant co-expression of putative cancer stem cell markers, EpCAM and CD166, correlates with tumor stage and invasive behavior in colorectal cancer

Background The crucial oncogenic role of cancer stem cells (CSCs) in tumor maintenance, progression, drug resistance, and relapse has been clarified in different cancers, particularly in colorectal cancer (CRC). The current study was conducted to evaluate the co-expression pattern and clinical significance of epithelial cell adhesion molecules (EpCAM) and activated leukocyte cell adhesion (CD166 or ALCAM) in CRC patients. Methods This study was carried out on 458 paraffin-embedded CRC specimens by immunohistochemistry on tissue microarray (TMA) slides. Results Elevated expression of EpCAM and CD166 was observed in 61.5% (246/427) and 40.5% (164/405) of CRC cases. Our analysis showed a significant positive association of EpCAM expression with tumor size (P = 0.02), tumor stage (P = 0.007), tumor differentiate (P = 0.005), vascular (P = 0.01), neural (P = 0.01), and lymph node (P = 0.001) invasion. There were no significant differences between CD166 expression and clinicopathological parameters. Moreover, the combined analysis demonstrated a reciprocal significant correlation between EpCAM and CD166 expression (P = 0.02). Interestingly, there was a significant positive correlation between EpCAM/CD166 phenotypes expression and tumor stage (P = 0.03), tumor differentiation (P = 0.05), neural, and lymph node invasion (P =0.01). Conclusions The significant correlation of EpCAM and CD166 expression and their association with tumor progression and aggressive behavior is the reason for the suggestion of these two CSC markers as promising targets to promote novel effective targeted-therapy strategies for cancer treatment in the present study.

Biomarker dynamics and prognosis in breast cancer after neoadjuvant chemotherapy

Breast cancer is a biologically diverse disease with treatment modalities selected based on tumor stage and tumor biology. Distinct intrinsic subtypes and surrogate biomarker profiles play a major role for therapeutic decisions. Response rates to systemic and local treatments as well as the interaction with epidemiological risk factors have been validated in clinical trials and translational studies. This retrospective study addresses the question how biomarker profiles and treatment modalities in the neoadjuvant chemotherapy setting have changed during the past 15 years and what prognostic impact these changes implicate. 342 female breast cancer stage I-IV patients receiving neoadjuvant chemotherapy between 2003 and 2017 were analyzed. Overall survival (OS) was correlated with preoperative clinical stage, postoperative pathological stage, treatment modalities and tumor biology before and after chemotherapy. Two subgroups were separated using an arbitrary cut-off year at 2009/2010, due to 2010 when platinum containing regimens were first administered. Median follow-up was 54 months. 57 (17%) patients died; recurrences occurred in 103 of 342 (30%) patients. Nodal stage and intrinsic subtypes (pre- and postoperative) significantly correlated with OS (p < 0.001). Preoperative histological grading lacked prognostic power. When comparing the patient characteristics of the subgroups, we found significant difference in the following characteristics: cT, ypT, ypN, pCR and chemotherapy regimens (p < 0.001). There was no difference in OS when comparing the two subgroups. Pathological complete response (pCR) rates had a significant impact on OS and disease-free survival (DFS) in HER2+ and triple negative subtypes (p = 0.03). In multivariate analysis, high proliferation index (> 30%), clinical metastatic stage and pathological tumor stage had prognostic impact on OS (p < 0.001, p = 0.0001, p = 0.002). Clinico-pathological factors and distinct therapy regiments especially in triple negative and HER2+ subtypes have prognostic impact on pCR, OS and DFS after neoadjuvant chemotherapy.

A Pan-Cancer Analysis of Tumor-Infiltrating B Cell Repertoires

Tumor-infiltrating B cells can play an important role in anti-tumor responses but their presence is not well understood. In this study, we extracted the B cell receptor repertoires from 9522 tumor and adjacent non-tumor samples across 28 tumor types in the Cancer Genome Atlas project and performed diversity and network analysis. We identified differences in diversity and network statistics across tumor types and subtypes and observed a trend towards increased clonality in primary tumors compared to adjacent non-tumor tissues. We also found significant associations between the repertoire features and mutation load, tumor stage, and age. Our V-gene usage analysis identified similar V-gene usage patterns in colorectal and endometrial cancers. Lastly, we evaluated the prognostic value of the repertoire features and identified significant associations with survival in seven tumor types. This study warrants further research into better understanding the role of tumor-infiltrating B cells across a wide range of tumor types.

The Valuable Role of Armc1 in Invasive Breast Cancer as a Novel Biomarker

Background: Invasive breast carcinoma (BRCA) is a common type of breast cancer with high incidence in clinics, so it is significant to find an effective biomarker for BRCA diagnosis and treatment. Although some Armadillo (Arm)-repeat proteins families are confirmed to be biomarkers in cancers, the role of Armadillo repeat-containing 1 (ARMC1) in BRCA remains unknown.Methods: We analyzed the ARMC1 expression in normal breast tissues and BRCA samples, and its association with overall survival by the public database. χ² test evaluated the risks associated with ARMC1 expression in TCGA-BRCA patient samples. The ARMC1 mutations in BRCA were explored in the cBioportal database. Besides, the GO and KEGG analysis was used to explore the potential signaling pathways of ARMC1 in BRCA. Lastly, Immunohistochemistry and immunohistochemistry were performed to validate the ARMC1 expression in BRCA.Results: ARMC1 level in tumor sample was significantly higher than that in normal tissue, and it was also related to lower survival. The factors in clinical patients such as tumor stage and grade and histology were associated with ARMC1 expression. There were 32% of ARMC1 genetic mutations in BRCA, and the amplification and high expression made up the majority of them. Also, ARMC1 might regulate BRCA by involving in the cell cycle. Increased ARMC1 expression was found in clinical breast carcinoma tissues by our confirmatory experiments.Conclusions: All the results revealed that ARMC1 may play a significant role in BRCA as a biomarker, it provides valuable clues for the treatment and diagnosis of invasive breast cancer.

Downregulation of MTHFD2 Inhibits the Progression of Bladder Cancer Through PI3K/AKT Signaling Pathways

Background: Methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) is related to the pathogenesis of many human malignant tumors, but its role in bladder cancer remains poorly understood. We aimed to determine the effect of downregulation of MTHFD2 on the progression of bladder cancer. First, the relationship between MTHFD2 expression and survival time in patients with bladder cancer was analyzed by GEPIA and the UALCAN online database. The expression of MTHFD2 in bladder cancer and adjacent tissues was detected by reverse transcription-quantitative PCR (RT-PCR), Western blot (WB), and tissue microarray. Second, the effects of low expression of MTHFD2 on the proliferation of bladder cancer cell lines were evaluated by CCK-8, Transwell, cell wound scratch, cell cloning, and flow cytometry assays. In vivo, the effect of MTHFD2 silencing on tumorigenicity was determined in nude mice. Furthermore, the phosphoinositide 3‑kinase (PI3K)/protein kinase B (Akt) signaling pathway was confirmed by western blotting after RNA sequencing (RNA-seq). Results: The expression of MTHFD2 in bladder cancer tissues was significantly higher and positively correlated with tumor stage and negatively correlated with overall survival. The expression of MTHFD2 in bladder cancer lines was significantly higher and the proliferation, migration, and clone formation ability of bladder cancer cells with low expression of MTHFD2 were significantly decreased in vitro and in vivo. RNA-seq showed that the differential genes were enriched in the PI3K/Akt signaling pathway. WB revealed that the expression of PI3K/AKT protein was downregulated. Conclusions: Our findings indicated that downregulation of MTHFD2 can reduce the progression of bladder cancer through inhibited PI3K-AKT signal pathway and may be provided a new approach for the diagnosis and treatment of bladder cancer.

Sarcopenia, Precardial Adipose Tissue and High Tumor Volume as Outcome Predictors in Surgically Treatedpleural Mesothelioma

Background: We evaluated the prognostic value of Sarcopenia, low precardial adipose-tissue (PAT), and high tumor-volume in the outcome of surgically-treated pleural mesothelioma (PM). Methods: From 2005 to 2020, consecutive surgically-treated PM-patients having a pre-operative computed tomography (CT) scan were retrospectively included. Sarcopenia was assessed by CT-based parameters measured at the level of the fifth thoracic vertebra (TH5) by excluding fatty-infiltration based on CT-attenuation. The findings were stratified for gender, and a threshold of the 33rd percentile was set to define sarcopenia. Additionally, tumor volume as well as PAT were measured. The findings were correlated with progression-free survival and long-term mortality. Results: Two-hundred-seventy-eight PM-patients (252 male; 70.2 ± 9 years) were included. The mean progression-free survival was 18.6 ± 12.2 months, and the mean survival time was 23.3 ± 24 months. Progression was associated with chronic obstructive pulmonary disease (COPD) (p = <0.001), tumor-stage (p = 0.001), and type of surgery (p = 0.026). Three-year mortality was associated with higher patient age (p = 0.005), presence of COPD (p < 0.001), higher tumor-stage (p = 0.015), and higher tumor-volume (p < 0.001). Kaplan-Meier statistics showed that sarcopenic patients have a higher three-year mortality (p = 0.002). While there was a negative correlation of progression-free survival and mortality with tumor volume (r = 0.281, p = 0.001 and r = −0.240, p < 0.001; respectively), a correlation with PAT could only be shown for epithelioid PM (p = 0.040). Conclusions: Sarcopenia as well as tumor volume are associated with long-term mortality in surgically treated PM-patients. Further, while there was a negative correlation of progression-free survival and mortality with tumor volume, a correlation with PAT could only be shown for epithelioid PM.