Poor Pathological Differentiation Research Articles

Clinicopathological features and genomic profiles of prostate cancer with elevated carbohydrate antigen 19-9.

e17003 Background: The elevated carbohydrate antigen 19-9 (CA199) is commonly observed in digestive system tumors, but rarely in prostate cancer (PCa). Due to the rarity and the poor understanding of the special subtype of PCa, the clinicopathological and genomic characteristics and survival outcomes in PCa patients with elevated CA199 in our center were analyzed. Methods: Cases were collected retrospectively from 2012 to 2023 in Sun Yat-sen University Cancer Center. The tumor genomic profiles were analyzed by R (http://www.rproject.org). Kaplan-Meier survival analyses were performed to compare survival outcomes. All statistical analyses were performed using SPSS version 26.0 and GraphPad Prism version 8.0. All analyses were two‐tailed, and the significance level was set at P<0.05. Results: A total of 137 PCa patients with elevated CA199 (>35ng/ml) were identified, with an exclusion of 47 patients with secondary cancers and 40 patients with other diseases that may cause elevated CA199, finally 50 cases (22 with primary and 28 with secondary elevated CA199) were included. The median initial PSA and the median time from diagnosis to CRPC were 102ng/ml and 14 months. Most patients were with a high GS score (GS≥8: 82%) and an advanced stage (M1: 84%). Poorly differentiated adenocarcinoma (22%) was frequently observed. Compared with patients with primary elevated CA199, patients with secondary elevated CA199 had higher levels of CA199 (102ng/ml vs. 78ng/ml, p=0.0456), lower levels of PSA at diagnosis (65ng/ml vs. 132ng/ml, p=0.0131) and higher proportion of poorly differentiated adenocarcinoma (36% vs. 5%, p=0.0138). The level of CA199 in patients with primary elevated CA199 was correlated with the level of CEA (R2=0.2658, p=0.0168), but not with the level of NSE or PSA. At a median follow-up of 31 months, the median OS of the whole group, primary elevated CA199 and secondary elevated CA199 subgroups was 49 months, 31 months and not reached. Secondary elevated CA199 (p=0.0009), abiraterone treatment (p<0.0001) and chemotherapy treatment (p=0.0331) were significant prognostic factors of OS. To study the genomic characteristics of PCa patients with elevated CA199, 29 PCa patients with normal CA199 were included as a control (genomic data available in 13 and 29 cases respectively). Patients with elevated CA199 were more likely to have mutations in castration resistant associated genes (AR, FOXA1, ASXL1, KMT2B, JAK2 and AKT1), malignant progression associated genes (RARA, BLM, PIK3R1) and CA199 metabolism associated gene (ERBB2). Conclusions: PCa with elevated CA199 is highly malignant and with poor prognosis. Intensive treatment with abiraterone and chemotherapy could benefit such patients. Poor pathological differentiation and the gene mutation profile may partly explain the clinical outcome.

Prognostic value of PD‑L1 expression and CD68 macrophages in tumor nest of patients with primary gastric cancer.

The programmed death receptor 1/programmed death receptor ligand 1 axis (PD-1/PD-L1) is involved in tumor immune escape and is a potential prognostic biomarker and anti-tumor immunotherapy target in patients with gastric cancer (GC). However, the results of studies obtained in recent years have been inconsistent. The present study aimed to determine the possible predictive significance of PD-L1 in conjunction with three proteins linked with PD-L1 regulation in patients with primary GC. In the present study, the PD-L1, human epidermal growth factor receptor 2 (HER2), cluster of differentiation (CD)133 and microphage-associated CD68 expression levels were identified by multiplexed immunohistochemistry and assessed by automated pathological analysis system in 93 GC tumors and neighboring normal tissues arrayed on the same tissue microarray. All four proteins were statistically analyzed in relation to the clinicopathological characteristics. The expression levels of HER2, CD133 and CD68 were considerably higher in cancer tissues compared with neighboring normal tissues (P<0.05), however, the reverse trend was detected for PD-L1 expression (P=0.0577), particularly in tumor nest (TN; P<0.05). There was no significant correlation between the HER2 and CD133 expression levels and clinicopathological factors. However, significant relationships were found between PD-L1 expression and the TNM stage, pathological differentiation and survival status of patients (P<0.05). Moreover, survival time was prolonged in individuals with elevated PD-L1 expression in TN and GC tissues, but no significant correlation was identified (P=0.0881). The CD68 expression level in tumor stroma, but not in TN, was significantly correlated with poor pathological differentiation in patients with GC (P<0.05). However, PD-L1+CD68+ macrophages were strongly related to lower tumor size (diameter <5 cm), early TNM stage (stage I+II), good pathological differentiation and overall survival in TN (P<0.05). In conclusion, PD-L1+CD68+ macrophage infiltration in TN might be a potential indicator of prognosis in patients with primary GC and merits further investigation.

The impact of indirect notification of a cancer diagnosis and a risk model based on it to predict the prognosis of postoperative stage T3 esophageal cancer patients.

Chinese doctors are required to inform patients' direct relatives of a cancer diagnosis rather than the patients themselves. The disease may be hidden from patients by their family members, which could result in severe outcomes. We selected postoperative T3 esophageal cancer (EsC) patients hospitalized from June 2015 to December 2019 as research subjects. The patients were divided into a direct-notification group and an indirect-notification group. Several variables were used to evaluate both groups' 36-month progress-free survival (PFS). A risk prediction model of prognosis based on the risk score was established, which was assessed using the area under the curve (AUC) of the receiver operating characteristic curve. One hundred and thirteen patients were enrolled in the training group and forty-eight in the validation group. Cox multivariate regression analysis revealed that males, late stage, poor pathological differentiation, and indirect notification were independent worse risk factors for postoperative T3 stage EsC patients at 36-month PFS (hazard ratio (HR) = 0.454, 95% confidence interval (CI): 0.254-0.812, P = .008; HR = 1.560, 95% CI: 1.006-2.420, P = .047; HR = 0.595, 95% CI: 0.378-0.936, P = .025; HR = 2.686, 95% CI: 1.679-4.297, P < 0.001, respectively). The type of notification was the best correlation factor. The risk score was calculated as follows: risk score = 0.988 × cancer notification (indirect = 1, direct = 0)-0.790 × sex (female = 1, Male = 0) + 0.445 × stage (IIIB = 1, IIA + IIB = 0)-0.519 × pathological differentiation (moderately + well = 1, poorly = 0). The model had a sensitivity of 64.8% and specificity of 81.8%, with the AUC at 0.717 (95% CI: 0.614-0.810) in internal verification, and a sensitivity of 56.8% and specificity of 100%, with the AUC at 0.705 (95% CI: 0.651-0.849) in external validation. The model had good internal and external stability. The model showed a Brier score of 0.18. Indirect notification of a cancer diagnosis was an important negative predictor of postoperative EsC patients' PFS. The model displayed good accuracy and stability in the prediction of risk for cancer progression.

Yin Yang 1-Induced Long Noncoding RNA DUXAP9 Drives the Progression of Oral Squamous Cell Carcinoma by Blocking CDK1-Mediated EZH2 Degradation.

LncRNAs play a critical role in oral squamous cell carcinoma (OSCC) progression. However, the function and detailed molecular mechanism of most lncRNAs in OSCC are not fully understood. Here, a novel nuclear-localized lncRNA, DUXAP9 (DUXAP9), that is highly expressed in OSCC is identified. A high level of DUXAP9 is positively associated with lymph node metastasis, poor pathological differentiation, advanced clinical stage, worse overall survival, and worse disease-specific survival in OSCC patients. Overexpression of DUXAP9 significantly promotes OSCC cell proliferation, migration, invasion, and xenograft tumor growth and metastasis, and upregulates N-cadherin, Vimentin, Ki67, PCNA, and EZH2 expression and downregulates E-cadherin in vitro and in vivo, whereas knockdown of DUXAP9 remarkably suppresses OSCC cell proliferation, migration, invasion, and xenograft tumor growth in vitro and in vivo in an EZH2-dependent manner. Yin Yang 1 (YY1) is found to activate the transcriptional expression of DUXAP9 in OSCC. Furthermore, DUXAP9 physically interacts with EZH2 and inhibits EZH2 degradation via the suppression of EZH2 phosphorylation, thereby blocking EZH2 translocation from the nucleus to the cytoplasm. Thus, DUXAP9 can serve as a promising target for OSCC therapy.

Brain glucose metabolism on [18F]-FDG PET/CT: a dynamic biomarker predicting depression and anxiety in cancer patients.

To explore the correlation between the incidence rates of depression and anxiety and cerebral glucose metabolism in cancer patients. The experiment subjects consisted of patients with lung cancer, head and neck tumor, stomach cancer, intestinal cancer, breast cancer and healthy individuals. A total of 240 tumor patients and 39 healthy individuals were included. All subjects were evaluated by the Hamilton depression scale (HAMD) and Manifest anxiety scale (MAS), and were examined by whole body Positron Emission Tomography/Computed Tomography (PET/CT) with 18F-fluorodeoxyglucose (FDG). Demographic, baseline clinical characteristics, brain glucose metabolic changes, emotional disorder scores and their relations were statistically analyzed. The incidence rates of depression and anxiety in patients with lung cancer were higher than those in patients with other tumors, and Standard uptake values (SUVs) and metabolic volume in bilateral frontal lobe, bilateral temporal lobe, bilateral caudate nucleus, bilateral hippocampus, left cingulate gyrus were lower than those in patients with other tumors. We also found that poor pathological differentiation, and advanced TNM stage independently associated with depression and anxiety risk. SUVs in the bilateral frontal lobe, bilateral temporal lobe, bilateral caudate nucleus, bilateral hippocampus, left cingulate gyrus were negatively correlated with HAMD and MAS scores. This study revealed the correlation between brain glucose metabolism and emotional disorders in cancer patients. The changes in brain glucose metabolism were expected to play a major role in emotional disorders in cancer patients as psychobiological markers. These findings indicated that functional imaging can be applied for psychological assessment of cancer patients as an innovative method.

Systematically Prognostic Analyses of Gastric Cancer Patients with Ovarian Metastasis.

Ovarian metastasis of gastric cancer indicates that the disease has reached the late stage and the opportunity for radical surgery is restricted. However, the clinical characteristics and prognosis of patients with gastric cancer ovarian metastasis (GCOM) remain to be illustrated. Here, we retrieved the information of 780 GCOM cases from the Surveillance, Epidemiology, and End Results (SEERs) database and analyzed their clinicopathological characteristics as well as their survival. According to our data, most GCOM patients showed poor pathological differentiation, advanced T and N stages. The prognostic factors include patients' age, tumor size, surgical resection, and chemotherapy treatment. Of note, the marriage status was also identified as an independent prognostic factor. Besides the identification of prognostic factors, we established nomograms to help predict the overall survival and cancer-specific survival of GCOM, respectively.

Abstract 4721: Yin Yang 1-induced long non-coding RNA DUXAP9 drives oral squamous cell carcinoma by blocking CDK1-mediated EZH2 degradation

Abstract Background: lncRNAs play a critical role in oral squamous cell carcinoma (OSCC) progression and metastasis. However, the detailed molecular mechanism is not fully understood. Methods: Differential-expressed lncRNAs between OSCCs and paired adjacent tissues were identified by microarray. The expression of lncRNADUXAP9 (DUXAP9) was detected by RNAscope and quantitative real-time PCR (qRT-PCR). The gain-of-function and loss-of-function of DUXAP9 were evaluated in vitro and in vivo assays. Chromatin immunoprecipitation (ChIP)and luciferase assays were performed to analyze the transcriptional regulation of DUXAP9. RNA pull-down assays, LS-MS/MS analysis, RNA immunoprecipitation assays, and Co-immunoprecipitation (Co-IP) were performed to address the molecular mechanism through which DUXAP9promotes OSCC progression. Results: By analyzing lncRNA microarray data, we identified a novel nuclear-localized DUXAP9, which is upregulated in OSCC. The high level of DUXAP9is positively associated with lymph-node metastasis, poor pathological differentiation, advanced clinical stage, worse overall survival, and worse disease-specific survival in OSCC patients. DUXAP9 significantly promotes cell proliferation, migration/invasion, and metastasis in vitro and in vivo through an EZH2-dependent manner. Yin Yang 1(YY1) was found to activate the transcriptional expression of DUXAP9 in OSCC. Furthermore, DUXAP9was proven to physically interact with EZH2 and inhibit EZH2 degradation via the suppression of the phosphorylation of EZH2, thereby blocking EZH2nucleus to cytoplasm translocation. Conclusions: Here we demonstrated a novel mechanism mediated by lncRNA DUXAP9 at the posttranslational level, which contributes to OSCC progression, thus providing a promising target for OSCC therapy. Keywords: LncRNA DUXAP9, YY1, EZH2, Ubiquitination, Oral squamous cell carcinoma Citation Format: Wei Cao, Wenkai Zhou. Yin Yang 1-induced long non-coding RNA DUXAP9 drives oral squamous cell carcinoma by blocking CDK1-mediated EZH2 degradation. [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 4721.

The Prognostic Utilities of Various Risk Factors for Laryngeal Squamous Cell Carcinoma: A Systematic Review and Meta-Analysis.

Objective: To assess the prognostic utilities of various risk factors for laryngeal squamous cell carcinoma. Methods: Six databases were searched to January 2022. Hazard ratios for overall survival and disease-free survival were collected and study characteristics were recorded. The risk of bias was evaluated using the Newcastle-Ottawa scale. Results: Twenty-eight studies involving 32,128 patients were finally included. In terms of overall survival, older age, a history of alcohol consumption, a high Charlson comorbidity index score, a high TNM stage (III and IV), a high tumor stage (III and IV), nodal involvement, poor pathological differentiation, primary chemoradiotherapy and radiotherapy were associated with increased risks of death. In terms of disease-free survival, older age (≥60 years), TNM stages III and IV, tumor stages III and IV, supraglottic tumors, and nodal involvement all increased the risk of death. Conclusions: The TNM stage importantly predicts overall survival, and tumor location predicts the disease-free survival of patients with laryngeal squamous cell carcinoma. Of patients with risk factors, the Charlson comorbidity index usefully predicts overall survival.

Penile metastasis from rectal carcinoma: A case report

BACKGROUNDMetastasis to the penis is an unusual event, and penile metastasis from rectal carcinoma (PMRC) is extremely rare and associated with a dismal prognosis. Thus far, approximately 80 cases have been reported.CASE SUMMARYHerein, we report the case of a 49-year-old man with PMRC. The patient presented to the urology clinic with a complaint of penile pain during urination. The patient underwent the Dixon operation for rectal carcinoma 2 mo before the presentation. During hospitalisation, abdominal computed tomography revealed a nodular lesion on the left penis. The postoperative pathological examination revealed a typical intestinal-type adenocarcinoma. Previous cases of PMRC were retrieved from PubMed to characterise the clinicopathological features and identify the prognostic factors of PMRC.CONCLUSIONThe analysis suggested that approximately 24 mo is the median time to metastasis occurrence and 150 d is the survival time after diagnosis. Furthermore, poor pathological differentiation, lymph node involvement of the primary RC, metastasis time < 6 mo, penile metastatic nodule diameter > 1 cm, and treatment abandonment are negative predictors of survival outcomes. Close follow-up, surgical resection, chemotherapy, and radiotherapy may potentially improve the prognosis of patients.

Prognostic value of preoperative peripheral blood neutrophil-to-lymphocyte ratio and γ-glutamyl transpeptidase-to-platelet ratio index in patients with hepatitis B virus related intrahepatic cholangiocarcinoma after radical resection

Objective: To explore the value of preoperative neutrophil-to-lymphocyte ratio (NLR) and γ-glutamyl transpeptidase-to-platelet ratio index (GPRI) for predicting the prognosis of patients with HBV-related intrahepatic cholangiocarcinoma (ICC) after radical resection. Methods: The data of 79 patients who underwent radical resection for HBV-related ICC in the Department of Hepatobiliary Surgery of the First Affiliated Hospital of Xi'an Jiaotong University from January 2010 to December 2018 were retrospectively analyzed. Among them, 48(60.8%) patients were male and 31 (39.2%) patients were female, (56.9±11.2) years old. X-Tile statistical software was used to determine the best cut-off values of NLR and GPRI. The χ2 test was conducted to analyze the relationship between preoperative NLR and GPRI and the clinicopathological characteristics, and the Cox proportional hazard regression model was conducted for multivariate analysis. A nomogram prognostic prediction model was established based on independent risk factors screened by Cox regression model. Results: The best cut-off values of NLR and GPRI were 3.13 and 1.31 determined by the X-Tile software, respectively. With the best cut-off value, 79 patients were divided into NLR≤3.13 group (45 cases) and NLR>3.13 group (34 cases). GPRI≤1.31 group (54 cases) and GPRI>1.31 group (25 cases). Compared with the preoperative NLR ≤3.13 group, the proportion of patients with liver cirrhosis and atrophy, poor pathological differentiation, tumor diameter>5 cm and late TNM stage was significantly increased in the NLR>3.13 group (all P<0.05); Compared with preoperative GPRI ≤1.31 group, the proportion of patients with liver cirrhosis and atrophy was significantly increased in the GPRI>1.31 group (P=0.025). The postoperative overall survival time of the included patients was 2 to 126 months, with the median survival time being 18 months, and the 1, 3-year overall survival rates were 63.3%, 32.8%, respectively. Multivariate analysis showed that NLR, GPRI, liver cirrhosis and atrophy, and lymphatic metastasis were independent risk factors affecting the overall survival of patients with HBV-related ICC after radical resection (P<0.05). A nomogram prediction model was established based on independent risk factors, with the C-index of 0.750, and the prediction effect was close to the actual survival outcome of the patients. Conclusion: Preoperative peripheral blood NLR and GPRI can be used to predict the prognosis of patients with HBV-related ICC after radical resection.

Serum GGT/ALT ratio predicts vascular invasion in HBV-related HCC

BackgroundThe gamma-glutamyl transferase (GGT) to alanine aminotransferase (ALT) ratio has been reported as an effective predictor of the severity of hepatitis and HCC. The purpose of this study was to determine the role of the GGT/ALT ratio in the prediction of vascular invasion and survival outcomes in patients with hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC).MethodsThe risk factors for vascular invasion were determined by univariate/multivariate logistic analysis. The cut-off value of GGT/ALT in predicting vascular invasion was calculated using the receiver operating characteristic (ROC) curve. The prognostic value of GGT/ALT was examined by Cox analysis and Kaplan–Meier curves. Sensitivity analysis, such as subgroup analysis and propensity score matching (PSM), was performed to reduce potential confounding bias.ResultsA high GGT/ALT ratio was identified as an independent risk factor for vascular invasion (P = 0.03). The correlation analysis suggested that higher GGT/ALT was associated with more severe tumour burdens, including vascular invasion (P < 0.001), tumour volume > 5 cm (P < 0.001), poor pathological differentiation (P = 0.042), more severe BCLC (P < 0.001) and ALBI grade (P = 0.007). In the survival analysis, a high GGT/ALT ratio was associated with poor overall survival (OS) (HR: 1.38; 95% CI 1.03, 1.87; P < 0.0001) and disease-free survival (DFS) (HR: 1.32; 95% CI 1.03, 1.87; P < 0.0001). In the subgroup analysis, similar results were consistently observed across most subgroups. In PSM analysis, GGT/ALT remained independently associated with vascular invasion (OR, 186; 95% CI 1.23, 3.33).ConclusionThe GGT/ALT ratio was a potential effective factor in the prediction of vascular invasion and prognosis in patients with HBV-related HCC.

ID4 predicts poor prognosis and promotes BDNF-mediated oncogenesis of colorectal cancer.

Inhibitors of DNA binding and cell differentiation (ID) proteins regulate cellular differentiation and tumor progression. Whether ID family proteins serve as a linkage between pathological differentiation and cancer stemness in colorectal cancer is largely unknown. Here, the expression of ID4, but not other ID family proteins, was enriched in LGR5-high colon cancer stem cells. Its high expression was associated with poor pathological differentiation of colorectal tumors and shorter survival in patients. Knockdown of ID4 inhibited the growth and dissemination of colon cancer cells, while enhancing chemosensitivity. Through gene expression profiling analysis, brain-derived neurotrophic factor (BDNF) was identified as a downstream target of ID4 expression in colorectal cancer. BDNF knockdown decreased the growth and migration of colon cancer cells, and its expression enhanced dissemination, anoikis resistance and chemoresistance. ID4 silencing attenuated the epithelial-to-mesenchymal transition pattern in colon cancer cells. Gene cluster analysis revealed that ID4 and BDNF expression was clustered with mesenchymal markers and distant from epithelial genes. BDNF silencing decreased the expression of mesenchymal markers Vimentin, CDH2 and SNAI1. These findings demonstrated that ID4-BDNF signaling regulates colorectal cancer survival, with the potential to serve as a prognostic marker in colorectal cancer.

Overexpression of GINS4 Is Associated With Tumor Progression and Poor Survival in Hepatocellular Carcinoma.

PurposeOur research was aimed to identify the expression, clinical value and biological significance of GINS complex subunit 4 (GINS4) in hepatocellular carcinoma (HCC).Materials and MethodsGINS4 was initially screened through weighted gene co-expression network analysis (WGCNA). The TCGA, GEO, and TIMER databases were applied for analyzing the GINS4 mRNA expression in HCC. GINS4 protein levels were detected via immunohistochemistry (IHC). Receiver operating characteristic (ROC) curve was applied for estimating the diagnostic significance of GINS4 in HCC. Kaplan-Meier plots, Cox model, and nomogram were used to assess the prognostic performance of GINS4 in HCC. Nomogram validation was conducted through time-dependent ROC and decision curve analysis (DCA). The Wanderer, UALCAN, and DiseaseMeth databases were utilized to identify GINS4 methylation levels in HCC. Genes co-expressed with GINS4 in HCC were estimated through the TCGA, cBioPortal, and GEPIA. GO, KEGG, and GSEA unraveled the possible biological mechanisms of GINS4 in HCC.ResultsWGCNA confirmed that GINS4 was one of hub genes significantly associated with histological grade of HCC. Multiple databases confirmed the significant upregulation of GINS4 in HCC tissues compared with non-tumor controls. IHC analysis of 35 HCC patients demonstrated that overexpressed GINS4 positively correlated with advanced TNM stage and poor pathological differentiation. GINS4 could effectively differentiate HCC cases from healthy individuals, with an AUC of 0.865. Increased GINS4 expression predicted unsatisfactory prognosis in HCC patients, especially in age >60 years, histological grade 1, HBV infection-negative, and occurring relapse subgroup. Nomogram incorporating GINS4 level and TNM stage displayed satisfactory predictive accuracy and clinical utility in predicting HCC prognosis. Upregulated GINS4 exhibited hypomethylated levels in HCC. Functional analysis indicated that GINS4 potentially positively modulated cell cycle and PI3K/AKT/mTOR pathway.ConclusionGINS4 is overexpressed in HCC and is correlated with undesirable survival of HCC patients.

Independent Risk Factors of Early Recurrence After Curative Resection for Perihilar Cholangiocarcinoma: Adjuvant Chemotherapy May Be Beneficial in Early Recurrence Subgroup.

PurposeIn current clinical practice, early recurrence (ER) is not commonly discussed in perihilar cholangiocarcinoma (pCCA), and its risk factors for this disease have not been well clarified. We carried out this study to analyze the risk factors contributing to ER and explored the prognostic factors after curative resection for pCCA.Patients and MethodsA total of 335 consecutive pCCA patients were retrospectively analyzed. Risk factors contributing to ER were evaluated using univariate and multivariate logistic regression analyses. Prognostic factors of the ER group were determined by univariate and multivariate Cox regression models. The overall survival (OS) rate was calculated using the Kaplan–Meier method. The Log rank test was used for OS comparison.ResultsOf the 335 cases, 258 patients (77.0%) developed tumor recurrence, 136 patients (40.6%) developed ER, and 122 patients (36.4%) developed late recurrence (LR) postoperatively. The median OS of the ER and LR groups was 15 months and 36 months, respectively (P<0.001). The multivariate analysis revealed that poor pathological differentiation (P=0.006; moderate vs well, odds ratio [OR]=2.162, 95% confidence interval [CI] 0.753–6.208, P=0.152; poor vs well, OR=4.839, 95% CI 1.544–15.170, P=0.007), perineural invasion (OR=4.797, 95% CI 1.586–14.510, P=0.005), and high levels of preoperative carbohydrate antigen 19–9 (CA19-9) (OR=2.205, 95% CI 1.208–4.026, P=0.010) were independent risk factors of developing ER after resection. Adjuvant chemotherapy (HR=0.383, 95% CI 0.154–0.953, P=0.039) remained as the independent protective factor of OS in patients with ER.ConclusionIt is recommended that patients with poorly differentiated tumors, presence of perineural invasion, and high levels of preoperative CA19-9 receive closer follow-up and adjuvant chemotherapy following surgery.

Differential analysis of gene expression profiles in hepatocellular carcinoma patients with high and low levels of alpha-fetoprotein

Objective: To investigate the differential gene expression profiles of alpha-fetoprotein (AFP) high- and low-expressing hepatocellular carcinoma (HCC), and to provide a theoretical basis for the molecular mechanism and prognosis analysis of HCC. Methods: The transcriptome data and related clinical information from 368 HCC cases were obtained from the Cancer Gene Atlas (TCGA) public database. The samples were divided into AFP high expression (AFP(high)) group and low expression (AFP(low)) group according to the quartile of AFP mRNA expression, with 92 cases in each group. The differential gene analysis was carried out using the DEseq2 package in the R software. The functional and KEGG pathway enrichment analysis of the differential genes was performed using ClusterProfiler package. The protein-protein interaction network was constructed to screen hub genes using the String database and Cytoscape software. The single-sample GSEA analysis was performed to enrich and score signature gene sets using the GSVA package. And then RNAseq data and real-time quantitative polymerase chain reaction (RT-qPCR) were used for independent dataset validation and tissue validation. Results: The clinical analysis showed that high expression of AFP was significantly associated with poor pathological differentiation and ethnicity (P<0.05 for both). A total of 1 382 differential genes were obtained by bioinformatics analysis, of which 931 genes were up-regulated and 451 genes were down-regulated in AFP(high) group. GO enrichment analysis showed that the highly expressed genes were mainly correlated with the processes of appendage development, limb development, and skeletal system development, while lowly expressed genes were related to metabolic-related processes such as xenobiotic metabolism, steroid metabolism, and cellular response to xenobiotic stimuli. KEGG pathway enrichment analysis revealed that highly expressed genes were mainly involved in primary immunodeficiency, neuroactive ligand-receptor interaction, and cytokine-cytokine receptor interaction, while lowly expressed genes were mainly involved in retinol metabolism, chemical carcinogenesis, steroid hormone biosynthesis and other pathways. A prognostic related gene set that was consisted of AURKB, TTK, CENPA, UBE2C, HJURP, and KIF15 was identified. And the high expression of this gene set was related to the shorter recurrence-free survival and overall survival time in HCC patients, and its enrichment score was positively correlated with AFP expression (r=0.475, P<0.001). The validation results of RNAseq data were basically consistent with the TCGA data. The RT-qPCR results showed that AURKB, KIF15, and UBE2C were significantly overexpressed in HCC tissues with high AFP expression. Although the expression of AURKB, TTK, KIF15, and UBE2C was not related to recurrence-free survival and overall survival of HCC patients, there was a tendency that the patients with high AFP levels showed relatively shorter recurrence-free survival time and overall survival time. Conclusions: There is a large difference in gene expression profiles between AFP(high) and AFP(low) HCC. The prognostic signature may cooperate with AFP to promote the initiation and development of HCC. It also may explain the tumorigenesis in HCC with different AFP levels, and provide new clues for the prognosis of HCC.

Incidence and prognosis of patients with pulmonary metastases at diagnosis of primary extrapulmonary malignancy: A population-based study.

e19353 Background: As a sign of advanced malignancy, pulmonary metastases often predict poor prognosis and are notoriously difficult to treat, requiring an interdisciplinary combination of chemotherapy, surgery and radiotherapy. Large-scale and generalizable studies examining the incidence and prognosis of patients with pulmonary metastases are still lacking. Methods: We identified 2,649,261 patients with diagnoses of nonhematologic malignancies originating outside of the pulmonary between 2010 and 2016 from the Surveillance, Epidemiology, and End Results (SEER) program. We described the incidence proportion and survival of patients with pulmonary metastases, and determined risk factors and prognostic factors of for pulmonary metastasis. Results: We identified 68,474 patients with pulmonary metastases at diagnosis, accounting for 3.19% of all patients with cancer and 35.94% of those patients with metastatic disease. Tumors with higher lung metastasis rates were pancreas cancer, esophageal cancer, sarcoma, renal cancer, hepatobiliary cancer, all other type of cancer, ovarian cancer and gastric cancer (10.54%, 9.32%, 8.75%, 7.48%, 6.43%, 5.96%, 5.79% and 5.26%, respectively). When considering only patients with distant metastases at diagnosis, The top five types of cancer with pulmonary metastasis were testicular cancer (82.82%), thyroid cancer (72.80%), endometrial cancer (66.87%), renal cancer (66.59%) and cervical cancer (64.89%). Multivariable logistic regression identified several oncology characteristics, such as synchronal bone, brain or liver metastasis (vs without), higher N-stage, and tumor poor pathological differentiation were associated with higher risk of pulmonary metastases. Similar to the risk factors for incidence, more distant metastasis, poor differentiation, higher staging, positive lymph node might also associate with shorter overall survival and cancer-specific survival. Surgery of primary site was a protect factor for survival. Conclusions: For the first time, we provided current generalizable estimates of the incidence and prognosis of patients with pulmonary metastases at diagnosis of an extrapulmonary malignancy. This data may lead to evaluation of early screening of the pulmonary using chest CT scan among patients with newly diagnosed primary extrapulmonary malignancies, and further shape the development of screening and treatment guidelines about pulmonary metastases.

The Characteristics and Nomogram for Primary Lung Papillary Adenocarcinoma.

BackgroundPrimary pulmonary papillary adenocarcinoma (PA) is a specific and rare subtype of invasive pulmonary adenocarcinoma (ADC). The knowledge concerning the clinicopathologic features and prognosis of patients with primary pulmonary PA has not been clarified because of its rarity.MethodsThe clinical data of a total of 3391 patients with primary pulmonary PA were retrospectively analyzed to confirm their clinical characteristics and factors influencing prognosis and were in comparison with 3236 patients with non- PA pulmonary adenocarcinoma. All patients were histologically diagnosed between 1988 and 2015 in The Surveillance Epidemiology and End Results (SEER) database. A nomogram with satisfactory predictive performance was established to visually predict long-term survival of these patients.Results and conclusionCollectively, primary pulmonary PA is a rare pathological cancer and its prognosis is analogous to that of non-PA pulmonary adenocarcinoma. Older age, larger lesions, distant metastases, lymph node invasion, and poor pathological differentiation are correlative with unacceptable prognosis. Surgical intervention is conducive to reaping favorable prognosis. Unfortunately, radiotherapy or chemotherapy results of no significant effects on patient survival. In our study, a nomogram with prognostic function is formulated to confer individual prediction of overall survival (OS).

Protein Kinase D1 Is Increased in Tumor Tissue, Correlates With Advanced Tumor Features and Worse Prognosis of Non-Small Cell Lung Cancer.

Objective:This study aimed to assess protein kinase D1 expression and its association with tumor characteristics as well as prognosis in patients with non-small cell lung cancer.Methods:Protein kinase D1 expression in tumor tissues and adjacent tissues from 172 patients with non-small cell lung cancer who underwent surgical resection were analyzed by immunohistochemical staining. Based on the total immunohistochemical score, protein kinase D1 expression was classified as protein kinase D1 high expression (further divided into protein kinase D1 high+++, protein kinase D1 high++, and protein kinase D1 high+ expressions) and protein kinase D1 low expression. Clinical characteristics of patients with non-small cell lung cancer were acquired from the database. Accumulating disease-free survival and overall survival were calculated based on patients’ relapse/survival status.Results:Protein kinase D1 expression was increased in tumor tissues compared to adjacent tissues (P < .001). Tumor protein kinase D1 high expression correlated with poorer pathological differentiation (P = .041), increased tumor size (P = .003), the presence of lymph node metastasis (P = .001), and elevated tumor, nodes and metastases stage (P < .001). Besides, both accumulating disease-free survival and overall survival were decreased in patients with tumor protein kinase D1 high expression compared to patients with tumor protein kinase D1 low expression (P = .010 for disease-free survival and P = 0.005 for overall survival). Moreover, they were lowest in patients with tumor protein kinase D1 high+++ expression, followed by patients with tumor protein kinase D1 high++ expression, then patients with tumor protein kinase D1 high+ expression, and highest in patients with tumor protein kinase D1 low expression (P < .001 for disease-free survival and P = .001 for overall survival). Notably, higher tumor protein kinase D1 expression was an independent predictive factor for decreased disease-free survival (P = .001) and overall survival (P = .004).Conclusions:Protein kinase D1 might be a potential marker to identify patients with non-small cell lung cancer with worse tumor features and prognosis.

C-X-C chemokine receptor 2 correlates with unfavorable prognosis and facilitates malignant cell activities via activating JAK2/STAT3 pathway in non-small cell lung cancer

ABSTRACT This study aimed to investigate the correlation of C-X-C chemokine receptor 2 (CXCR2) with clinicopathological characteristics and survival in non-small cell lung cancer (NSCLC) patients and further explore its effect on proliferation, apoptosis, invasion, stemness, chemosensitivity as well as JAK2/STAT3 pathway in NSCLC cells. The expression of CXCR2 in tumor tissues and adjacent tissues from 340 NSCLC patients received surgery was detected by immunohistochemistry. CXCR2 overexpression and knockdown were constructed through plasmid transfection and the effect of CXCR2 dysregulation on cell proliferation, apoptosis, invasion, stemness, chemosensitivity as well as its regulatory effect on JAK2/STAT signaling pathway was assessed in NCI-H1437 cells and NCI-H1299 cells. CXCR2 expression was higher in tumor tissues than that in paired adjacent tissues, and it was correlated with poor pathological differentiation, greater tumor size, lymph node metastasis, higher TNM stage and poor survival in NSCLC patients. In vitro, CXCR2 expression was increased in human NSCLC cell lines compared with human normal lung bronchus epithelial cells. CXCR2 promoted cell proliferation and invasion, while suppressed cell apoptosis in NCI-H1437/NCI-H1299 cells. Additionally, CXCR2 increased CD133+ cell rate and cell sphere-forming ability, while reduced chemosensitivity to cisplatin and gemcitabine in NCI-H1437/NCI-H1299 cells. Besides, CXCR2 activated the JAK2/STAT3 signaling pathway in NCI-H1437/NCI-H1299 cells. In conclusion, the clinical implication and the molecular function of CXCR2 discovered in our study reveal the potential of CXCR2 as a future target for disease monitoring and treatment of NSCLC.

SETD3 is regulated by a couple of microRNAs and plays opposing roles in proliferation and metastasis of hepatocellular carcinoma.

A previous study reported that histone methyltransferase SETD3 is up-regulated in tumor tissues of hepatocellular carcinoma (HCC) and is associated with the growth of HCC. However, the clinical significance and the effect of SETD3 on HCC metastasis remain unclear. In the present study, both the protein and mRNA expression levels of SETD3 were measured in a larger cohort of HCC patients. The results showed that the protein level of SETD3 in HCC tissues was significantly higher than that in non-tumorous tissues, which was inconsistent with the mRNA expression level of SETD3. The high protein level of SETD3 in HCC tissues was significantly associated with male gender, poor pathological differentiation, liver cirrhosis and unfavorable prognosis of HCC patients. Subsequently, we demonstrated that SETD3 could be regulated at post-transcriptional step by a couple of miRNAs (miR-16, miR-195 and miR-497). Additionally, in vitro and in vivo experiments revealed that SETD3 played opposing roles in proliferation and metastasis of HCC: promoting proliferation but inhibiting metastasis. Mechanistic experiments revealed that doublecortin-like kinase 1 (DCLK1) was a downstream target of SETD3. SETD3 could increase the DNA methylation level of DCLK1 promoter to inhibit the transcription of DCLK1. Further study revealed that DCLK1/PI3K/matrix metalloproteinase (MMP) 2 (MMP-2) was an important pathway that mediated the effect of SETD3 on HCC metastasis. In conclusion, the present study revealed that SETD3 is associated with tumorigenesis and is a promising biomarker for predicting the prognosis of HCC patients after surgical resection. In addition, SETD3 plays inhibitory role in HCC metastasis partly through DCLK1/PI3K/MMP-2 pathway.