Effect of Neoadjuvant Immunotherapy Combined with Chemotherapy on Pulmonary Function and Postoperative Pulmonary Complications in Esophageal Cancer: A Retrospective Study.

BACKGROUND: Neoadjuvant immunotherapy, targeting the PD-1 or PD-L1, combined with chemotherapy (NICT), can improve the radical resection and survival rates for locally advanced EC. However, it may impair pulmonary function, and the effect of NICT on pulmonary function and postoperative pulmonary complications in EC patients remains unknown. This study aimed to investigate whether NICT can affect pulmonary functions and postoperative pulmonary complications in EC patients. METHODS: The study retrospectively recruited 220 EC patients who received NICT at the Department of Esophageal Cancer in Tianjin Medical University Cancer Institute & Hospital from January 2021 to June 2022. Changes in pulmonary function before and after NICT were compared. Logistic regression analysis was performed to analyze the correlations of pulmonary functions and clinical characteristics with postoperative pulmonary complications, respectively. RESULTS: The FEV1% pred, FVC, FVC% pred, and FEV1/FVC% significantly increased after NICT, with a P-value of 0.018, 0.005, 0.001, and 0.036, respectively. In contrast, there was a significant decline in the DLCO (8.92 ± 2.34 L before NICT vs. 7.79 ± 2.30 L after NICT; P < 0.05) and DLCO% pred (102.97 ± 26.22% before NICT vs. 90.18 ± 25.04% after NICT; P < 0.05). High DLCO and DLCO% pred at baseline levels were risk factors for DLCO reduction in EC patients after NICT. Advanced age, smoking history, FEV1% pred after NICT, and FVC% pred baseline and after therapy were risk factors for postoperative pulmonary complications, with a P-value of 0.043, 0.038, 0.048, 0.034, and 0.004, respectively. Although the DLCO level decreased after NICT, it did not increase the incidence of postoperative pulmonary complications. CONCLUSION: NICT may improve pulmonary ventilation function but also lead to a decrease in DLCO and DLCO% pred in EC patients. Nevertheless, the decreased DLCO after NICT did not increase the risk of postoperative pulmonary complications.

USP4 promotes the proliferation, migration, and invasion of esophageal squamous cell carcinoma by targeting TAK1.

Ubiquitin-specific protease 4 (USP4) represents a potential oncogene involved in various human cancers. Nevertheless, the biological roles and precise mechanism of USP4 in esophageal squamous cell carcinoma (ESCC) progression are not understood. Here, USP4 expression was found to be markedly upregulated in ESCC tumor tissues and cells. Loss- and gain-of-function assays suggested that USP4 silencing inhibited ESCC cell proliferation, migration, and invasion, while USP4 overexpression promoted these behaviors. Consistently, USP4 silencing repressed tumor growth and metastasis in an ESCC nude mouse model in vivo. As a target molecule of USP4, transforming growth factor-ß-activated kinase 1 (TAK1) also showed high expression in ESCC. Moreover, we observed that USP4 specifically interacted with TAK1 and stabilized TAK1 protein levels via deubiquitination in ESCC cells. Importantly, USP4 promotes ESCC proliferation, migration, and invasion via the MEK/ERK signaling pathway and can be inhibited by U0126. Neutral red (NR), an inhibitor of USP4 can suppress ESCC progression in vitro and in vivo. Overall, this study revealed that USP4/TAK1 plays crucial roles in ESCC progression by modulating proliferation, migration, and invasion, and USP4 might be a potential therapeutic target in ESCC.

High expression of PPFIA1 in human esophageal squamous cell carcinoma correlates with tumor metastasis and poor prognosis.

BACKGROUND: PTPRF interacting protein alpha 1 (PPFIA1) is reportedly related to the occurrence and progression of several kinds of malignancies. However, its role in esophageal squamous cell carcinoma (ESCC) is unclear. This current study investigated the prognostic significance and biological functions of PPFIA1 in ESCC. METHODS: Oncomine, Gene Expression Profiling Interactive Analysis (GEPIA), and Gene Expression Omnibus (GEO) were used to investigate PPFIA1 expression in esophageal cancer. The relationship between PPFIA1 expression and clinicopathological characteristics and patient survival was evaluated in GSE53625 dataset, and verified in the cDNA array based on qRT-PCR and tissue microarray (TMA) dataset based on immunohistochemistry. The impact of PPFIA1 on the migration and invasion of cancer cells were investigated by wound-healing and transwell assays, respectively. RESULTS: The expression of PPFIA1 was obviously increased in ESCC tissues versus adjacent esophageal tissues according to online database analyses (all P < 0.05). High PPFIA1 expression was closely related to several clinicopathological characteristics, including tumor location, histological grade, tumor invasion depth, lymph node metastasis, and tumor-node-metastasis (TNM) stage. High PPFIA1 expression was related to worse outcomes and was identified as an independent prognostic factor of overall survival in ESCC patients (GSE53625 dataset, P = 0.019; cDNA array dataset, P < 0.001; TMA dataset, P = 0.039). Downregulation of PPFIA1 expression can significantly reduce the migration and invasion ability of ESCC cells. CONCLUSION: PPFIA1 is related to the migration and invasion of ESCC cells, and can be used as a potential biomarker to evaluate the prognosis of ESCC patients.

CXCR4 promotes the growth and metastasis of esophageal squamous cell carcinoma as a critical downstream mediator of HIF-1α.

C-X-C motif chemokine receptor 4 (CXCR4) belongs to the CXC chemokine receptor family, which mediates the metastasis of tumor cells and promotes the malignant development of cancers. However, its biological role and regulatory mechanism in esophageal squamous cell carcinoma (ESCC) remain unclear. Here, we found that CXCR4 expression was associated with lymph node metastasis and a poor prognosis. In vitro and in vivo studies demonstrated that CXCR4 overexpression promoted ESCC cell proliferation, migration, invasion, and survival, whereas silencing CXCR4 induced the opposite effects. Mechanically, HIF-1α transcriptionally regulates CXCR4 expression by binding to a hypoxia response element in its promoter. HIF-1α-induced ESCC cell migration and invasion were reversed by CXCR4 knockdown or treatment with MSX-122, a CXCR4 antagonist. Collectively, these data revealed that the HIF-1α/CXCR4 axis plays key roles in ESCC growth and metastasis and indicated CXCR4 as a potential target for ESCC treatment.

Preoperative increased systemic immune-inflammation index predicts poor prognosis in patients with operable non-small cell lung cancer.

BACKGROUND: A novel systemic immune-inflammation index (SII) has been recently reported to be associated with clinical outcome in several tumors. However, the prognostic value of SII has not been reported in operable non-small cell lung carcinoma (NSCLC). We aimed to investigate its clinical and prognostic value in patients with operable NSCLC underwent curative surgery. METHODS: Four hundred ten NSCLC patients staged I-IIIA were included in this retrospective study. The SII was calculated by the formula: neutrophil× platelet/lymphocyte. Receiver operating characteristic (ROC) curve was used to determine the optimal cut-off value for SII. Kaplan-Meier method and Cox proportional regression were used to analyze the prognostic value of SII. RESULTS: Patients were stratified into high low SII (≤395.4) and SII (>395.4) groups. High SII was significantly associated with advanced T stage and positive lymph node metastasis. Kaplan-Meier survival analysis showed that SII, PLR, NLR and LMR were all associated with OS. Multivariate analysis identified that SII was an independent predictor of OS. Furthermore, SII remained prognostic significance for NSCLC patients stratified by TNM subgroups. CONCLUSIONS: Preoperative SII was a powerful prognostic biomarker for predicting outcome in patients with operable NSCLC. Preoperative SII may assist clinicians treatment strategy making and individual treatment choice.

Analysis of the risk factors of postoperative cardiopulmonary complications and ability to predicate the risk in patients after lung cancer surgery.

BACKGROUND: Postoperative cardiopulmonary complications might be fatal for patients with lung cancer after surgery. The aim of this study was to identify the risk factors of postoperative cardiopulmonary complications in lung cancer patients and get a fitting formula for predicting incidences of cardiopulmonary complications. METHODS: We conducted a retrospective analysis of 653 patients with a diagnosis of lung cancer who underwent a surgery in the Tianjin Medical University Cancer Institute and Hospital (Tianjin, China) from January to December 2014. All patients received lung cancer surgeries. Clinical data was collected for the analysis of the influence factors of cardiopulmonary complication after lung cancer surgeries. The medical statistical analysis program R was used to calculate cardiopulmonary complication probability of classification of quantitative results. RESULTS: Our work showed that ages, lymphocyte count, smoking history, chronic bronchitis history, operation mode and extubation time were significantly associated with lung infection both in univariate and multivariate survival analysis. And ages, smoking history, arrhythmia of electrocardiogram and operation mode were significantly associated with postoperative arrhythmia both in univariate and multivariate survival analysis. Multiple linear regressions were generated with risk factors by program R software. Finally, we got a fitting formula for predicting cardiopulmonary complications. Risk score for each patient could be obtained by this formula. CONCLUSIONS: The incidences of pulmonary infection and arrhythmia were high for patients who underwent lung cancer surgery. It is important to discriminate risk factors for each patient for reducing the risk of heart and lung complications. Preoperative quantitative evaluation of cardiopulmonary complication after operation is beneficial to the risk control.

Preoperative pulmonary function correlates with systemic inflammatory response and prognosis in patients with non-small cell lung cancer: results of a single-institution retrospective study.

This study aimed at analyzing the relationship between preoperative pulmonary function and systemic inflammatory response (SIR) biomarkers, such as neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR) and lymphocyte-to-monocyte ratio (LMR) in patients with non-small cell lung cancer (NSCLC). Furthermore, the prognostic significance of these markers was also examined. The medical records of 358 NSCLC patients, who underwent curative lung resection, were retrospectively analyzed. Pulmonary function test values <80% of the predicted values were used to indicate impairment. A receiver operating characteristic curve was used to determine the thresholds of the SIR biomarkers. Univariate and multivariate survival analyses were then performed to identify the factors associated with the overall survival (OS). Furthermore, one prognostic model based on independent prognostic factors was established to classify the patients into low-, intermediate-, and high-risk groups. Results demonstrated that, preoperative forced vital capacity (FVC) was simultaneously associated with NLR, PLR, and LMR (P < 0.05). Multivariate analysis identified age, lymph node status, FVC, and NLR as independent prognostic factors for OS. A subgroup analysis showed that the prognostic value of FVC was independent of age, lymph node status, and NLR. The five-year OS rates for low-, intermediate-, and high-risk groups of prognostic model were 60.9%, 35.9%, and 15.3%, respectively (P < 0.05). Overall, preoperative FVC was an independent prognostic predictor of NSCLC. Significant correlations were observed among preoperative pulmonary function, SIR, and prognosis. Thus, the prognostic model may help us identify risk populations with NSCLC.

Metastatic lymph node ratio demonstrates better prognostic stratification than pN staging in patients with esophageal squamous cell carcinoma after esophagectomy.

This study aimed to evaluate the prognostic significance of lymph node ratio (LNR) by establishing a hypothetical tumor-ratio-metastasis (TRM) staging system in patients with esophageal squamous cell carcinoma (ESCC). The records of 387 ESCC patients receiving curative esophagectomy were retrospectively investigated. The optimal cut-point for LNR was assessed via the best cut-off approach. Potential prognostic parameters were identified through univariate and multivariate analyses. A novel LNR-based TRM stage was proposed. The prognostic discriminatory ability and prediction accuracy of each system were determined using hazard ratio (HR), Akaike information criterion (AIC), concordance index (C-index), and area under the receiver operating characteristic curve (AUC). The optimal cut-points of LNR were set at 0, 0~0.2, 0.2~0.4, and 0.4~1.0. Multivariate Cox analysis indicated that the LNR category was an independent risk factor of overall survival (P < 0.001). The calibration curves for the probability of 3- and 5-year survival showed good consistency between nomogram prediction and actual observation. The LNR category and TRM stage yielded a larger HR, a smaller AIC, a larger C-index, and a larger AUC than the N category and TNM stage did. In summary, the proposed LNR category was superior to the conventional N category in predicting the prognosis of ESCC patients.

Does tumor size improve the accuracy of prognostic prediction in patients with esophageal squamous cell carcinoma after surgical resection?

This study aimed to investigate whether the inclusion of tumor size could improve the prognostic accuracy in patients with esophageal squamous cell cancer (ESCC). A total of 387 patients with ESCC who underwent curative resection were enrolled in this analysis. The patients were categorized into small-sized tumors (SSTs) and large-sized tumors (LSTs) using an appropriate cut-off point for tumor size. Kaplan-Meier survival curve and log-rank test were used to evaluate the prognostic value of tumor size. A Cox regression model was adopted for multivariate analysis. Their accuracy was compared based on the presence or absence of tumor size. Using 3.5 cm as the optimal cut-off point, 228 and 159 patients presented with LSTs (≥ 3.5 cm) and SSTs (< 3.5 cm), respectively. The patients with LSTs had significantly worse prognoses than patients with SSTs (23.9% vs. 43.2%, P < 0.001). Multivariate analysis revealed that tumor size, histological type, invasion depth, and lymph node metastasis were independent predictors of overall survival. The addition of tumor size to the AJCC TNM staging improved the predictive accuracy of the 5-year survival rate by 3.9%. Further study showed that tumor size and T stage were independent predictors of the prognosis of node-negative patients, and the combination of tumor size and T stage improved the predictive accuracy by 3.7%. In conclusion, tumor size is indeed a simple and practical prognostic factor in patients with ESCC. It can be used to improve the prognostic accuracy of the current TNM staging, especially for patients with node-negative disease.

Lymph node ratio-based staging system as an alternative to the current TNM staging system to assess outcome in adenocarcinoma of the esophagogastric junction after surgical resection.

This study aimed to assess the prognostic value of the hypothetical tumor-N-ratio (rN)-metastasis (TrNM) staging system in adenocarcinoma of the esophagogastric junction (AEG). The clinical data of 387 AEG patients who received surgical resection were retrospectively reviewed. The optimal cut-off point of rN was calculated by the best cut-off approach using log-rank test. Kaplan-Meier plots and Cox regressions model were applied for univariate and multivariate survival analyses. A TrNM staging system based on rN was proposed. The discriminating ability of each staging was evaluated by using an adjusted hazard ratio (HR) and a -2log likelihood. The prediction accuracy of the model was assessed by using the area under the curve (AUC) and the Harrell's C-index. The number of examined lymph nodes (LNs) was correlated with metastatic LNs (r = 0.322, P < 0.001) but not with rN (r = 0.098, P > 0.05). The optimal cut-points of rN were calculated as 0, 0~0.3, 0.3~0.6, and 0.6~1.0. Univariate analysis revealed that pN and rN classifications significantly influenced patients' RFS and OS (P < 0.001). Multivariate analysis adjusted for significant factors revealed that rN was recognized as an independent risk factor. A larger HR, a smaller -2log likelihood and a larger prediction accuracy were obtained for rN and the modified TrNM staging system. Taken together, our study demonstrates that the proposed N-ratio-based TrNM staging system is more reliable than the TNM staging system in evaluating prognosis of AEG patients after curative resection.

Change of SPARC expression after chemotherapy in gastric cancer.

OBJECTIVE: The expression of tumor biomarkers may change after chemotherapy. However, whether secreted protein acidic and rich in cysteine (SPARC) expression changes after chemotherapy in gastric cancer (GC) is unclear. This study investigated the influence of chemotherapy on SPARC expression in GC. METHODS: Immunohistochemistry was used to analyze SPARC expression in 132 GC cases (including 54 cases with preoperative chemotherapy and 78 cases without preoperative chemotherapy). SPARC expression of postoperative specimens with and without preoperative chemotherapy was assessed to analyze the influence of chemotherapy on SPARC expression. RESULTS: SPARC was highly expressed in GC compared with the desmoplastic stroma surrounding tumor cells and noncancerous tissues. High SPARC expression was correlated with invasion depth, lymph node, and TNM stage. After chemotherapy, a lower proportion of high SPARC expression was observed in patients with preoperative chemotherapy than in the controls. For 54 patients with preoperative chemotherapy, gross type, histology, depth of invasion, lymph node, TNM stage, and SPARC expression were related to overall survival. Further multivariate analysis showed that lymph node, histology, and SPARC expression after chemotherapy were independent prognostic factors. CONCLUSION: SPARC expression may change after chemotherapy in GC. SPARC expression should be reassessed for patients with GC after chemotherapy.

The value of the systematic inflammation-based Glasgow Prognostic Score in patients with gastric cancer: a literature review.

The presence of a systemic inflammatory response (SIR) is recognized to occur in the presence of malignancy. And the SIR-Glasgow Prognostic Score (GPS)/modified GPS (mGPS) composed of the C-reactive protein (CRP) and albumin is a tumor stage- and treatment-independent, routinely available and well-standardized prognostic factor, reflects both an ongoing SIR (CRP) and a progressive nutritional decline (albumin) in patients with advanced cancer. Previous studies showed that GPS/mGPS appear to be a superior prognostic factor compared with other cellular components of the SIR and Eastern Cooperative Oncology Group performance status in some aspects. Besides, GPS/mGPS aids at deciding active or palliation treatment and selecting patients with gastric cancer who tolerate platinum-based chemotherapy. Therefore, GPS/mGPS may be incorporated or combined with other factors to improve assessment of prognosis and guide treatment of patients with gastric cancer in a routine clinical work. However, it remains to be determined whether the GPS and mGPS have different prognostic value in each stage of gastric cancer and the necessity of normalization of the GPS/mGPS by anti-inflammation and maintenance of performance status or nutritional status in clinical work.

Extranodal metastasis is a powerful prognostic factor in patients with adenocarcinoma of the esophagogastric junction.

BACKGROUND AND OBJECTIVES: The purpose of this study is to estimate the effect of extranodal metastasis (EM) on recurrence and survival in patients with adenocarcinoma of the esophagogastric junction (AEG) after curative resection. METHODS: Clinical data from 284 node-positive AEG patients who underwent curative resection were reviewed. Univariate and multivariate analyses were conducted to elucidate the effect of EM on recurrence-free survival (RFS) and overall survival (OS). RESULTS: EM was detected in 70 (24.6%) of the 284 cases. It had a significant correlation with tumor size, Lauren type, histopathological grading, depth of tumor invasion, number of metastatic nodes, lymph node ratio, and TNM stage. The 5-year RFS and OS rates were 22.2% and 24.3%, respectively. Patients with EM had a significantly decreased RFS (16 vs. 36 months, P < 0.001) and OS (23 vs. 41 months, P < 0.001) compared with those without EM. Multivariate analyses identified EM as an independent prognostic factor (P = 0.003 and 0.001, respectively). CONCLUSION: The presence of EM increases recurrence probability and reduces OS probability of AEG patients with lymph node metastasis. EM is a powerful prognostic factor reflecting a particularly aggressive biological behavior. Better understanding of EM status can help clinicians with regard to treatment decision and prognosis evaluation.