Development and validation of prognostic nomogram for T1-3N0M0 non-small cell lung cancer after curative resection.

BACKGROUND: Radical resection plus lymph node dissection is a common treatment for patients with T1-3N0M0 non-small cell lung cancer (NSCLC). Few models predicted the survival outcomes of these patients. This study aimed to developed a nomogram for predicting their overall survival (OS). MATERIALS AND METHODS: This study involved 3002 patients with T1-3N0M0 NSCLC after curative resection between January 1999 and October 2013. 1525 Patients from Sun Yat-sen University Cancer Center were randomly allocated to training cohort and internal validation cohort in a ratio of 7:3. 1477 patients from ten institutions were recruited as external validation cohort. A nomogram was constructed based on the training cohort and validated by internal and external validation cohort to predict the OS of these patients. The accuracy and practicability were tested by Harrell's C-indexes, calibration plots and decision curve analyses (DCA). RESULTS: Age, sex, histological classification, pathological T stage, and HI standard were independent factors for OS and were included in our nomogram. The C-index of the nomogram for OS estimates were 0.671 (95% CI, 0.637-0.705),0.632 (95% CI, 0.581-0.683), and 0.645 (95% CI, 0.617-0.673) in the training cohorts, internal validation cohorts, and external validation cohort, respectively. The calibration plots and DCA for predictions of OS were in excellent agreement. An online version of the nomogram was built for convenient clinical practice. CONCLUSIONS: Our nomogram can predict the OS of patients with T1-3N0M0 NSCLC after curative resection. The online version of our nomogram offer opportunities for fast personalized risk stratification and prognosis prediction in clinical practice.

A 20-gene mutation signature predicts the efficacy of immune checkpoint inhibitor therapy in advanced non-small cell lung cancer patients.

BACKGROUND: There is an unmet need to identify novel predictive biomarkers that enable more accurate identification of individuals who can benefit from immune checkpoint inhibitor (ICI) therapy. The US FDA recently approved tumor mutational burden (TMB) score of ≥ 10 mut/Mb as a threshold for pembrolizumab treatment of solid tumors. Our study aimed to test the hypothesis that specific gene mutation signature may predict the efficacy of ICI therapy more precisely than high TMB (≥ 10). METHODS: We selected 20 candidate genes that may predict for the efficacy of ICI therapy by the analysis of data from a published cohort of 350 advanced non-small cell lung cancer (NSCLC) patients. Then, we compared the influences of various gene mutation signatures on the efficacy of ICI treatment. They were also compared with PD-L1 and TMB. The Kaplan-Meier method was utilized to evaluate the prognosis univariates, while selected univariates were adopted to develop a systematic nomogram. RESULTS: A high mutation signature, where three or more of the 20 selected genes were mutated, was associated with the significant benefits of ICI therapy. Specifically, patients with high mutation signature were confirmed to have better prognosis for ICI treatment, compared with those with wild type (the median PFS: 7.17 vs. 2.90 months, p = 0.0004, HR = 0.47 (95% [CI]:0.32-0.68); the median OS: unreached vs. 9 months, p = 1.8E-8, HR = 0.17 (95% [CI]:0.11-0.25)). Moreover, those patients with the high mutation signature achieved significant ICI treatment benefits, while there was no difference of OS and PFS between patients without the signature but TMB-H (≥ 10) and those without the signature and low TMB(< 10). Finally, we constructed a novel nomogram to evaluate the efficacy of ICI therapy. CONCLUSION: A high mutational signature with 3 or more of the 20-gene panel could provide more accurate predictions for the outcomes of ICI therapy than TMB ≥ 10 in NSCLC patients.

Covered versus uncovered stent insertion for malignant superior vena cava obstruction.

Purpose: To determine whether covered or uncovered stent insertion achieved better clinical efficacy when used to treat malignant superior vena cava (SVC) obstruction (SVCO).Material and methods: A total of 64 patients with malignant SVCO underwent stent insertion between January 2011 and March 2018 at our center. Of these, 34 were treated via uncovered stent insertion while 30 were treated via covered stent insertion. We compared the clinical effectiveness, patency of the stent, and overall survival between these two groups.Results: Both treatments achieved a 100% technical and clinical success rate, without any incidence of complications relating to the procedure. Stent dysfunction was found in one and six patients in the covered and uncovered groups during the follow-up period (1/30 vs. 6/34, p = .153), respectively. The covered stent patency period was significantly longer in the group treated with covered stents (374 vs. 317 days, p = .049), while median survival following stent insertion was 175 and 159 days, respectively, for the covered and uncovered groups (p = .784).Conclusion: Uncovered and covered stent insertion are both safe means of effectively treating patients with malignant SVCO, but covered stents achieve better patency for long-term periods than uncovered stents.

Effect of vascular endothelial growth factor rs35569394 in esophageal cancer and response to chemotherapy.

The objective of this study was to investigate the possible association between the single nucleotide polymorphism (SNP), rs35569394, of the vascular endothelial growth factor gene (VEGF) and the risk of esophageal cancer (EC) in the Han Chinese population. A total of 290 EC subjects and 322 ethnically matched unrelated healthy controls free from the esophageal disease were studied. Genomic DNA was isolated from peripheral blood by salting out. Genotyping of VEGF rs35569394 polymorphism was carried out via polymerase chain reaction followed by agarose gel electrophoresis. The results showed that the distribution of genotypes was significantly different across the gender groups (p=0.032) and clinical stages (p=0.034). VEGF rs35569394 was associated with EC risk (p= 0.012, OR=1.34). A gender analysis break-down showed that rs35569394-D allele frequency was significantly higher in females than in the controls (p=0.0004, OR=1.81). Moreover, significant associations were also found in females under the dominant model (II versus ID+DD: χ2=8.18, p=0.003, OR=2.12) and the recessive model (II+ID versus DD: χ2=8.25, p=0.004, OR=2.39). Additionally, we found that the genotype, rs35569394-DD, was associated with a complete response + partial response to chemotherapy when compared with rs35569394-II (χ2=4.67, p=0.030, OR=0.47). In conclusion, our case-control study showed that the VEGF rs35569394 was significantly associated with the clinical stages and the increased risk of EC in Han Chinese females. In addition, the genotype rs35569394-DD showed a better response to chemotherapy.

A prognosis model for predicting immunotherapy response of esophageal cancer based on oxidative stress-related signatures.

Oxidative stress (OS) is intimately associated with tumorigenesis and has been considered a potential therapeutic strategy. However, the OS-associated therapeutic target for esophageal squamous cell carcinoma (ESCC) remains unconfirmed. In our study, gene expression data of ESCC and clinical information from public databases were downloaded. Through LASSO-Cox regression analysis, a risk score (RS) signature map of prognosis was constructed and performed external verification with the GSE53625 cohort. The ESTIMATE, xCell, CIBERSORT, TIMER, and ImmuCellAI algorithms were employed to analyze infiltrating immune cells and generate an immune microenvironment (IM). Afterward, functional enrichment analysis clarified the underlying mechanism of the model. Nomogram was utilized for forecasting the survival rate of individual ESCC cases. As a result, we successfully constructed an OS-related genes (OSRGs) model and found that the survival rate of high-risk groups was lower than that of low-risk groups. The AUC of the ROC verified the strong prediction performance of the signal in these two cohorts further. According to independent prognostic analysis, the RS was identified as an independent risk factor for ESCC. The nomogram and follow-up data revealed that the RS possesses favorable predictive value for the prognosis of ESCC patients. qRT-PCR detection demonstrated increased expression of MPC1, COX6C, CYB5R3, CASP7, and CYCS in esophageal cancer patients. In conclusion, we have constructed an OSRGs model for ESCC to predict patients' prognosis, offering a novel insight into the potential application of the OSRGs model in ESCC.

Deletion of osteopontin in non-small cell lung cancer cells affects bone metabolism by regulating miR-34c/Notch1 axis: a clue to bone metastasis.

Lung cancer is prone to bone metastasis, and osteopontin (OPN) has an important significance in maintaining bone homeostasis. The goal of this study was to explore the impact of OPN level on bone metabolism and the molecular mechanism of inhibiting bone metastasis in non-small cell lung cancer (NSCLC). The expression of OPN in NSCLC was ascertained by Western blot and immunohistochemistry, and the correlation between the expression level of OPN and survival of patients was analyzed. Then the shRNA technology was applied to reduce the expression of OPN in NSCLC cells, and CCK-8 assay was carried out to investigate the effect of low expression of OPN on the proliferation of NSCLC cells. In addition, the effects of low expression of OPN on osteoclast differentiation, osteoblast generation and mineralization were studied using osteoclast precursor RAW264.7 and human osteoblast SaOS-2 cells, and whether OPN could regulate miR-34c/ Notch pathway to affect bone metabolism was further explored. The findings showed that the high level of OPN in NSCLC was closely related to the poor prognosis of patients and the abnormal proliferation of NSCLC cell lines. The suppression of OPN was beneficial to inhibit the differentiation of osteoclasts and promote the mineralization of osteoblasts. Besides, this study confirmed that the deletion of OPN can regulate bone metabolism through the regulation of miR-34c/Notch1 pathway, which will contribute to inhibiting the occurrence of osteolytic bone metastasis in NSCLC.

C-X-C motif chemokine ligand 12 (CXCL12)/C-X-C motif chemokine receptor 7(CXCR7) regulates epithelial-mesenchymal transition process and promotes the metastasis of esophageal cancer by activating signal transducer and activator of transcription 3 (STAT3) pathway.

Esophageal cancer is a malignant tumor of the digestive system that is prone to metastasis. Chemokines and their receptors act an essential role in the occurrence and development of tumors. Here, we investigated the regulatory mechanism of CXCL12/CXCR7 in the growth and metastasis of esophageal cancer. CXCR7 was found highly expressed in clinical tissues and cells of esophageal cancer. Knockdown of CXCR7 inhibited the proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT) process of esophageal cancer cells. The knockdown of chemokine CXCL12 also inhibited the expression of EMT-related proteins and the mesenchymal morphology changes of esophageal cancer cells, but the knockdown of C-X-C motif chemokine receptor 4 (CXCR4) had no such effect. Furthermore, the knockdown of CXCR7 attenuated the enhanced EMT process induced by CXCL12 overexpression, while the knockdown of CXCR4 cannot inhibit this process. In addition, overexpressed CXCL12/CXCR7 activated the downstream STAT3 pathway, but had little effect on the extracellular regulated protein kinase (ERK) or serine-threonine kinase (AKT) pathways. Inhibition of the STAT3 pathway using AZD9150 weakened the accelerated effects of CXCL12/CXCR7 on the growth and metastasis of esophageal cancer in vitro and in vivo. In conclusion, our research revealed that CXCL12/CXCR7 regulates EMT and other malignant processes by activating the STAT3 pathway to accelerate the growth and metastasis of esophageal cancer.

Treatment paradigms and survival outcomes in esophageal adenocarcinoma with liver metastasis: a retrospective cohort study using the SEER database.

Background: Esophageal adenocarcinoma with liver metastasis (EACLM) at the time of diagnosis has a poor prognosis and few therapeutic options. The best treatment options and prognostic factors for EACLM patients are unclear. The present study sought to explore the optimal treatment modalities for and the prognosis of these patients. Methods: Patients diagnosed with EACLM at the time of diagnosis were identified from the Surveillance, Epidemiology and End Results (SEER) database between 2010 and 2015. The last follow-up date was December 31, 2018. Treatment patterns were divided into four groups: local therapy (surgery/radiation), systemic therapy [chemotherapy (CT)], combination therapy (surgery/radiation + CT), and no treatment. The Kaplan-Meier (K-M) method and log-rank test were used for overall survival (OS) and disease-specific survival (DSS). Univariable and multivariable Cox regression were performed to identify the prognostic factors. Propensity score-matching (PSM) analyses were performed for sensitive analyses. Results: A total of 925 patients diagnosed with EACLM were included in the study. The median OS was 12, 10, 3, and 2 months for combination therapy, systemic therapy, local therapy, and no treatment, respectively (P<0.001). After PSM, the patients who received systemic treatment had a better OS (median 9 vs. 2 months; P<0.001) and DSS (median 9 vs. 3 months; P<0.001) than those who received no treatment. Compared to systemic therapy, combination therapy did not increase patients' OS (median 13 vs. 12 months, P=0.069) but did improve their DSS (median 19 vs. 13 months, P=0.048). Conclusions: EACLM patients might benefit the most from systemic therapy and combination therapy. For patients who are well-tolerated, combination therapy should be considered as a preferable option.

Comprehensive Bioinformatics Analysis to Identify the Gene HMMR Associated With Lung Adenocarcinoma Prognosis and Its Mechanism of Action in Multiple Cancers.

BACKGROUND: Lung cancer is the third most frequently diagnosed cancer in the world, with lung adenocarcinoma (LUAD) as the most common pathological type. But studies on the predictive effect of a single gene on LUAD are limited. We aimed to discover new predictive markers for LUAD. METHODS: Differentially high-expressed genes at each stage were obtained from the TCGA and GTEx databases. The functions of these genes were investigated through GO enrichment and KEGG pathway analyses. Then, the key genes were selected by applying whole gene overall survival time. The expression of the key gene was studied in LUAD, and survival analysis was performed using Kaplan-Meier mapper, followed by univariate and multifactorial COX analysis. Finally, the gene expression and its prognostic significance in the pan-cancer were examined. RESULTS: A total of 10,106 DEGs were obtained from the two datasets. The top 266 differentially upregulated genes intersected with the top 1,497 overall survival-related genes, and 87 key genes were identified. High-expressed HMMR was associated with a poor prognosis of LUAD. Univariate and multifactorial Cox analysis showed that HMMR was an independent prognostic factor for LUAD patients. A high HMMR expression was strongly associated with the overall survival (OS) and disease-specific survival (DSS) in 11 cancer types and with poorer OS, DSS, and PFI in 10 cancer types. CONCLUSION: HMMR may be an independent prognostic indicator and an important biomarker in diagnosing and predicting the survival of LUAD patients. Also, HMMR may be a key predictor of a variety of cancers.

Identification of a Three-Gene Signature Based on Epithelial-Mesenchymal Transition of Lung Adenocarcinoma Through Construction and Validation of a Risk-Prediction Model.

Epithelial-mesenchymal transition (EMT) process, which is regulated by genes of inducible factors and transcription factor family of signaling pathways, transforms epithelial cells into mesenchymal cells and is involved in tumor invasion and progression and increases tumor tolerance to clinical interventions. This study constructed a multigene marker for lung predicting the prognosis of lung adenocarcinoma (LUAD) patients by bioinformatic analysis based on EMT-related genes. Gene sets associated with EMT were downloaded from the EMT-gene database, and RNA-seq of LUAD and clinical information of patients were downloaded from the TCGA database. Differentially expressed genes were screened by difference analysis. Survival analysis was performed to identify genes associated with LUAD prognosis, and overlapping genes were taken for all the three. Prognosis-related genes were further determined by combining LASSO regression analysis for establishing a prediction signature, and the risk score equation for the prognostic model was established using multifactorial COX regression analysis to construct a survival prognostic model. The model accuracy was evaluated using subject working characteristic curves. According to the median value of risk score, samples were divided into a high-risk group and low-risk group to observe the correlation with the clinicopathological characteristics of patients. Combined with the results of one-way COX regression analysis, HGF, PTX3, and S100P were considered as independent predictors of LUAD prognosis. In lung cancer tissues, HGF and PTX3 expression was downregulated and S100P expression was upregulated. Kaplan-Meier, COX regression analysis showed that HGF, PTX3, and S100P were prognostic independent predictors of LUAD, and high expressions of all the three were all significantly associated with immune cell infiltration. The present study provided potential prognostic predictive biological markers for LUAD patients, and confirmed EMT as a key mechanism in LUAD progression.

A large real-world cohort study of examined lymph node standards for adequate nodal staging in early non-small cell lung cancer.

BACKGROUND: The current National Comprehensive Cancer Network (NCCN) guidelines for non-small cell lung cancer (NSCLC) recommend that surgeons sample is not clear. We aimed to define a minimal number of examined lymph nodes for removal or sampling for optimized nodal staging recommendation, with a focus on T1-3N0M0 patients. METHODS: A total of 55,101 consecutive patients were selected, including 52,099 patients with US Surveillance, Epidemiology, and End Results (SEER) data and 3,002 patients in a Chinese multicenter database from 11 thoracic referral centers, who underwent complete resection plus lymph node dissection or sampling for stage T1-3N0M0 NSCLC. Propensity score-matching analysis was performed with R software, and a cut-off value was calculated using X-tile software. Survival was evaluated using the Kaplan-Meier method and Cox proportional hazard models. RESULTS: Five-year survival rates with respect to total examined lymph nodes numbers (examined lymph nodes <10 vs. examined lymph nodes ≥10) were 69% and 64% (group A), 66% and 63% (group B), 62% and 58% (group C), 81% and 75% (group D). There were significant differences between examined lymph nodes <10 and examined lymph nodes >10 in each group (P<0.001). CONCLUSIONS: A minimum of 10 examined lymph nodes would significantly improve T1-3N0M0 NSCLC prognosis and patients' survival rates if implemented as a minimum standard for lymphadenectomy. Therefore, we recommended a minimum of 10 examined lymph nodes for T1-3N0M0 patients.

A standard for hilar and intrapulmonary lymph node dissection and pathological examination in early non-small cell lung cancer.

BACKGROUND: There is considerable variation in the staging of lymph nodes (LNs) as part of tumor, node, metastasis (TNM) staging of non-small cell lung cancer (NSCLC). A new dissection and pathological examination standard for hilar and intrapulmonary LNs needs to be established for patients with early-stage T1-3N0M0 NSCLC. METHODS: This study involved 3,002 patients with T1-3N0M0 NSCLC who underwent radical lobectomy or total pneumonectomy in the thoracic departments of 11 Chinese institutions between January 1999 and October 2013. The Cox model was applied for univariate and multivariate analyses in the examination of station 10, 11 LN and station 12, 13, 14 LN. A hilar and intrapulmonary standard (HI standard) was then established based on univariate and multiple-factor analyses conducted using the Cox model. RESULTS: Among the 3,002 patients enrolled in the study, 2,609 underwent at least one examination of station 10, 11 LN (A1), while 393 did not undergo examination of station 10, 11 LN (A0). The A0 and A1 groups had 5-year survival rates of 76% and 80%, respectively (P=0.018). Further, 1,764 patients underwent at least one examination of station 12, 13, 14 LN (B1), while 1,238 patients did not (B0). The B0 and B1 groups had 5-year survival rates of 77% and 82%, respectively (P=0.008). In total, 1,269 patients attained the HI standard (C1), and 1,733 did not (C0). The C0 and C1 groups had 5-year survival rates of 77% and 83%, respectively (P<0.001). CONCLUSIONS: The HI standard can improve both the prognosis and survival rates of patients with T1-3N0M0 NSCLC. This will provide important guidance for pulmonary LN dissection and pathological examination in NSCLC cases.

Role of LASP-1, a novel SOX9 transcriptional target, in the progression of lung cancer.

Lung cancer accounts for most cancer-related deaths worldwide. However, the underlying mechanism by which it mediates the progression of lung cancer remains unclear. Expression of LASP-1 (LIM and SH3 protein 1) was evaluated in lung cancer tissues and tumor-adjacent normal tissues using immunohistochemistry and western blotting. Functional studies have shown that siRNA-mediated silencing of LASP-1 in human lung cancer cells and reduced cell proliferation, migration, and invasion. Flow cytometry and immunofluorescence staining also revealed that rate of cell apoptosis was increased after knockdown of expression of LASP-1, thereby suggesting that LASP-1 may function as an oncogene during lung cancer progression. SOX9 is an important transcription factor, which is involved in the development of several types of human cancer. Further analysis has showed the presence of a consensus-binding site of SOX9 in the promoter region of LASP-1. Mechanistic investigations showed that LASP-1 was transcriptionally activated by SOX9. Through luciferase reporter and ChIP assays, we demonstrated that LASP-1 was a direct target gene of sex determining region Y-box 9 (SOX9). Knockdown of SOX9 expression by RNA interference reduces cell proliferation and induces apoptosis of lung cancer cells, which was consistent with the results obtained from silencing the expression of LASP-1 in NCI­H1650 cells. Together, these findings indicated that LASP-1, as a downstream target of SOX9, may act as a novel biomarker for lung cancer and plays an important role in cell proliferation, migration, and invasion.

Interplay between chronic kidney disease (CKD) and upper tract urothelial carcinomas (UUC): foe or friend?

Although upper tract urothelial carcinomas (UUC) is curable through nephrectomy or nephroureterectomy, progression of chronic kidney disease (CKD) and CKD-related mortality have been highlighted as clinical challenges in recent years owing to the loss of a large number of nephrons. While CKD can promote the development of UUC, other risk factors such as hypertension, diabetes mellitus, advanced age, and anemia can facilitate the progression of CKD. Conversely, CKD is especially prevalent in UUC patients. However, the relationship between CKD and UUC, mechanisms for CKD causing UUC, and gender disparity of UUC of CKD patients have so far not been well-reviewed. As UUC gradually grows, the cancer can be a physical obstacle in the urinary tract. It will cause an increased tract pressure, subsequently resulting in the dysfunction of both nephrons and kidney. At the molecular level, reduced level of oxidative stress was observed in female UUC patients. Furthermore, radical nephrectomy therapy for UUC patients accelerates the progress of chronic kidney dysfunction. Incidentally, the remedies for CKD containing aristolochic acid (AA) are carcinogenic. Our present review offers a comprehensive look at the relationship between CKD and UUC from multiple perspectives. Early and precise identification of progression of CKD and UUC will benefit the patients at high-risk of CKD or UUC, which will also be instructive in directing timely and effective therapeutic interventions whenever necessary. It may also shed light on unveiling the underlying mechanisms of carcinogenesis of UUC, preventing CKD progression, and prolonging the patients' overall survival.

AFP (alpha fetoprotein): who are you in gastrology?

AFP-producing (hepatoid differentiation) gastric cancer (GC) initially reported in 1970 plays an important role in the field of gastrology, which should be distinguished from other solid-type GCs owing to their different biological behavior. This review article aims to summarize the literature related to the role of AFP in gastric cancer and to unveil the underlying mechanism by which AFP-production impacts prognosis of GC patients. The prima facie evidence demonstrated that AFP-producing GC is more aggressive and characterized by a high incidence of venous invasion, lymphatic invasion, and metachronous and synchronous liver metastasis compared with AFP-non producing GC. Furthermore, distant metastasis was frequently observed, leading to a poorer overall prognosis. The underlying molecular mechanism is still obscure and optimal regimen remains undefined well. Nevertheless, our present study advances the knowledge of AFP-producing GC in the field of gastrology. AFP-positivity should be highlighted and an a priori enhancive intervention is needed to improve prognosis in future clinical practice. Personalized medication is strongly suggested.

Tolerance induced by IL-6 deficient donor heart is significantly involved in myeloid-derived suppressor cells (MDSCs).

OBJECTIVES: Transplant tolerance induced by IL-6 deficient donor is supported by regulatory T cells (Tregs). However, it is unknown whether innate immunoregulatory cells such as myeloid-derived suppressor cells (MDSCs) are involved in the process. MATERIALS AND METHODS: In this study, we demonstrate the role of MDSCs by transplanting IL-6 deficient heart grafts into wild-type recipients in a murine allogeneic transplant model. RESULTS: Our data further revealed that utilization of IL-6 deficient heart grafts could cause a significant prolongation of allograft survival (Mantel-Cox Test, p = 0.001; Gehan-Breslow-Wilcoxon Test, p = 0.0016) and a remarkable increase of the frequency of CD11b + Gr1(-low) in the recipients' spleens (p = 0.0028). CONCLUSIONS: MDSCs rather than Th17 cells are closely involved in induced tolerance by IL-6 deficient donor heart. This unveiled mechanism of targeting IL-6 or its signaling pathway may provide a novel insight into preventing allograft rejection for non-sensitized transplant recipients.