Evaluation of the efficacy and safety of immunotherapy in sarcoma: a two-center study.

Background: Sarcoma is a highly heterogeneous malignancy with a poor prognosis. Although chemotherapy and targeted therapy have improved the prognosis to some extent, the efficacy remains unsatisfactory in some patients. The efficacy and safety of immunotherapy in sarcoma need further evaluation. Methods: We conducted a two-center study of sarcoma patients receiving PD-1 immunotherapy at Tianjin Medical University Cancer Institute and Hospital and Henan Provincial Cancer Hospital. The treatment regimens included PD-1 inhibitor monotherapy and combination therapy based on PD-1 inhibitors. The observed primary endpoints were median progression-free survival (mPFS) and median overall survival (mOS). Survival curves were compared using the Kaplan-Meier method. Results: A total of 43 patients were included from the two centers. The median follow-up time for all patients was 13 months (range, 1-48 months). In the group of 37 patients with advanced or unresectable sarcoma, the mPFS was 6 months (95%CI: 5-12 months), and the mOS was 16 months (95%CI: 10-28 months). The ORR was 10.8% (4/37), and the DCR was 18.9% (7/37). Subgroup analysis showed no significant differences in mPFS (p=0.11) and mOS (p=0.88) between patients with PD-L1 negative/positive expression. There were also no significant differences in mPFS (p=0.13) or mOS (p=0.72) between PD-1 inhibitor monotherapy and combination therapy. Additionally, there were no significant differences in mPFS (p=0.52) or mOS (p=0.49) between osteogenic sarcoma and soft tissue sarcoma. Furthermore, the results showed no significant differences in mPFS (p=0.66) or mOS (p=0.96) between PD-1 inhibitors combined with targeted therapy and PD-1 inhibitors combined with AI chemotherapy. Among the 6 patients receiving adjuvant therapy after surgery, the mPFS was 15 months (95%CI: 6-NA months), and the mOS was not reached. In terms of safety, most adverse events were mild (grade 1-2) and manageable. The most severe grade 4 adverse events were bone marrow suppression, which occurred in 4 patients but resolved after treatment. There was also one case of a grade 4 adverse event related to hypertension. Conclusion: Immunotherapy is an effective treatment modality for sarcoma with manageable safety. Further inclusion of more patients or prospective clinical trials is needed to validate these findings.

Tumoral C2 Regulates the Tumor Microenvironment by Increasing the Ratio of M1/M2 Macrophages and Tertiary Lymphoid Structures to Improve Prognosis in Melanoma.

Immunotherapy is an essential therapy for individuals with advanced melanoma. However, not all patients respond to such treatment due to individual differences. We conducted a multidimensional analysis using transcriptome data from our center, as well as publicly available databases. We found that effective nivolumab treatment led to an upregulation of C2 levels, and higher levels following treatment are indicative of a good outcome. Through bioinformatics analyses and immunofluorescence, we identified a correlation between C2 and M1 macrophages. To further investigate the role of C2 in melanoma, we constructed subcutaneous tumorigenic models in C57BL/6 mice. The tumors in the C2 overexpression group exhibited significantly smaller sizes. Flow cytometric analysis of the mouse tumors demonstrated enhanced recruitment of macrophages, particularly of the M1 subtype, in the overexpression group. Moreover, single-cell RNA sequencing analysis revealed that C2-positive tumor cells exhibited enhanced communication with immune cells. We co-cultured tumor cell supernatants with macrophages in vitro and observed the induction of M1 subtype polarization. In addition, we discovered a close correlation between C2 and tertiary lymphoid structures. C2 has been demonstrated to exert a protective effect, mediated by its ability to modulate the tumor microenvironment. C2 serves as a prognostic marker for melanoma and can be employed to monitor the efficacy of immunotherapy.

The Efficacy and Underlying Pathway Mechanisms of ShiDuGao Treatment for Anus Eczema Based on GEO Datasets and Network Pharmacology.

Anus eczema is a chronic and recurrent inflammatory skin disease affecting the area around the anus. While the lesions primarily occur in the anal and perianal skin, they can also extend to the perineum or genitalia. ShiDuGao (SDG) has been found to possess significant reparative properties against anal pruritus, exudation control, moisture reduction, and skin repair. However, the genetic targets and pharmacological mechanisms of SDG on anal eczema have yet to be comprehensively elucidated and discussed. Consequently, this study employed a network pharmacological approach and utilized gene expression omnibus (GEO) datasets to investigate gene targets. Additionally, a protein-protein interaction network (PPI) was established, resulting in the identification of 149 targets, of which 59 were deemed hub genes, within the "drug-target-disease" interaction network. The gene function of SDG in the treatment of perianal eczema was assessed through the utilization of the Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) analysis. Subsequently, the anti-perianal eczema function and potential pathway of SDG, as identified in network pharmacological analysis, were validated using molecular docking methodology. The biological processes associated with SDG-targeted genes and proteins in the treatment of anus eczema primarily encompass cytokine-mediated responses, inflammatory responses, and responses to lipopolysaccharide, among others. The results of the pathway enrichment and functional annotation analyses suggest that SDG plays a crucial role in preventing and managing anal eczema by regulating the Shigellosis and herpes simplex virus 1 infection pathways. Network pharmacology and GEO database analysis confirms the multi-target nature of SDG in treating anal eczema, specifically by modulating TNF, MAPK14, and CASP3, which are crucial hub targets in the TNF and MAPK signaling pathways. These findings provide a clear direction for further investigation into SDG's therapeutic mechanism for anal eczema while highlighting its potential as an effective treatment approach for this debilitating condition.

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.

Establishment of a risk model by integrating hypoxia genes in predicting prognosis of esophageal squamous cell carcinoma.

BACKGROUND: Esophageal squamous cell carcinoma (ESCC) has a dismal prognosis, and hypoxia plays a key role in metastasis and proliferation of ESCC. Thus, we aimed to develop a hypoxia-based gene signature to assist in the treatment decisions and prognosis. METHODS: We performed consensus clustering analysis on samples from GSE53625 dataset from the Gene Expression Omnibus (GEO) database and used weighted gene co-expression network analysis to filter out candidate modules, which were then intersected with differentially expressed genes from clustered subgroups to obtain hypoxia-related genes (HRGs). After that, the aforementioned genes were used to construct risk score models and validated in The Cancer Genome Atlas (TCGA) database and Cox regression analysis were used to construct a nomogram. Immunohistochemical was used to detect protein expression levels of relevant genes. Moreover, the relationship between risk scores and tumor microenvironment was explored. RESULTS: A hypoxia risk model containing six genes (PNPLA1, CARD18, IL-18, SLC37A2, ADAMTS18, and FAM83C) was constructed by screening key HRGs. Poorer prognosis in the high-risk group than in the low-risk group. And Cox regression analysis showed that risk score was an independent prognostic factor. The nomogram based on risk scores could well predict 1-, 3-, and 5-year survival. P53, Wnt, and hypoxia signaling pathways may be some regulatory mechanisms of hypoxia associated with the tumor microenvironment. In addition, we confirmed the high expression of BGN and low expression of IL-18 in ESCC tissues. CONCLUSIONS: Our study determined the prognostic value of a 6-hypoxia gene signature and a prognostic model, providing potential prognostic predictors and therapeutic targets for ESCC.

The efficacy of probiotics on the prevention of pouchitis for patients after ileal pouch-anal anastomosis: A meta-analysis.

BACKGROUND: To date, a few studies indicated that probiotics are beneficial to pouchitis, but no meta-analyses summarized the outcomes of probiotics in pouchitis in detail. OBJECTIVE: This meta-analysis discusses probiotics in the prevention of pouchitis for patients after ileal pouch-anal anastomosis (IPAA) and the relationship between probiotics preventive effect and the duration of therapy and history. METHODS: PubMed, EMBASE and Cochrane Library databases were searched from inception until February 2022. Risk ratio (RR), mean difference (MD) and their 95% confidence interval (CI) were analyzed by Review Manager 5.3. The subgroup analysis was also performed to explore the agent for influencing outcomes. RESULTS: A total of 8 studies were included in this meta-analysis. The incidence of pouchitis in probiotics was significantly lower than that in the control (RR = 0.19, 95%CI [0.12, 0.32], P⁢ï⁢»â¢ 0.00001), and the PDAI (pouchitis disease activity index) in probiotics was also significantly lower (MD =-5.65, 95%CI [-9.48, -1.83]). After the subgroup analysis, we found that probiotics work better in the short-term (RR = 0.12, 95%CI [0.04, 0.40], P= 0.0004), but may not achieve the desired effect in the long-term (RR = 1.20, 95%CI [0.40, 3.60], P= 0.75). CONCLUSIONS: Probiotics are beneficial in the prevention of pouchitis after IPAA, especially in the short-term.

Intraindividual Tumor Heterogeneity of Mismatch Repair Status in Metastatic Colorectal Cancer.

Heterogeneous mismatch repair (MMR) status in metastatic colorectal cancer (mCRC) may associate with refractoriness to immunotherapy. We aimed here to study the concordance in MMR status between primary and paired metastasis in mCRC. Our study included 84 patients diagnosed with mCRC with primary and matched metastatic cancers. Immunohistochemistry was used to determine the MMR status of primary lesions and matched metastases. Pooled analysis of 913 cases was used to evaluate the prevalence and organ specificity of MMR status heterogeneity. The correlations between MMR pattern heterogeneity and clinical outcomes were analyzed. MMR status heterogeneity between primary and corresponding metastatic sites was exhibited by 10 (11.9%) patients. The prevalence of the heterogeneous MMR phenotype was significantly higher in primary tumors with deficient MMR (dMMR) than with proficient MMR (pMMR), which was verified in the pooled analysis ( P <0.001). Among patients with a dMMR primary tumor, the discrepancy was detected in liver, lung, ovary, peritoneum, and distant lymph node metastases. However, the discrepancy was confined to liver (26/440) or peritoneum (7/112) ( P =0.02) in patients with a pMMR primary tumor. Patients with or without MMR status heterogeneity experienced comparable overall survival ( P =0.452). Heterogeneous MMR patterns generally existed in a subset of patients with mCRC, particularly those with dMMR primary tumors. Testing the metastatic site may be valuable because the discordance of MMR status may potentially affect immune surveillance and immunotherapy.

Comparison of clinicopathological features and prognostic significance between synchronous multiple primary and solitary esophageal squamous cell carcinomas.

BACKGROUND: Synchronous multiple primary esophageal squamous cell carcinoma (S-MPESCC) refers to more than one primary esophageal carcinoma detected in a solitary patient at the time of initial presentation. The purpose of this study was to evaluate the clinicopathological features, appropriate surgical approaches and long-term survival in patients with S-MPESCC by comparing with those with solitary esophageal squamous cell carcinoma (SESCC). METHODS: In total, 567 patients with esophageal squamous cell carcinoma surgically resected in Tianjin Medical University Cancer Institute and Hospital from January 2012 to December 2018 were screened for retrospective analysis (50 in the S-MPESCC group and 516 in the SESCC group). RESULTS: No significant difference was observed in terms of other characteristics except total alcohol consumption (P = 0.029). S-MPESCC had higher lymph node rate than SESCC (62.0% and 44.1%, respectively; P = 0.015) especially in upper mediastinal (32.0% and 18.6%, respectively; P = 0.023) and abdominal (38.0% and 22.8%, respectively; P = 0.017) regions. The survival was not different between the two groups, and the 5-year survival rates of S-MPESCC and SESCC were 46.2% and 50.8%, respectively (P = 0.507). But for patients with pT3-4 cancers, the survival in S-MPESCC was worse than that in SESCC (P = 0.033). In the multivariate analysis, pT stage of primary cancer was an important independent predictor of prognosis in patients with S-MPESCC (hazard ratio [HR], 3.968; 95% confidence interval [CI], 1.031 to 15.268; P = 0.045). CONCLUSIONS: S-MPESCC was significantly different from SESCC in terms of clinicopathological characteristics include alcohol intake and pattern of lymphatic metastasis. Furthermore, S-MPESCC showed worse long-term survival than SESCC with increasing depth of primary cancer infiltration.

The prognostic performance of the log odds of positive lymph nodes in patients with esophageal squamous cell carcinoma: A population study of the US SEER database and a Chinese single-institution cohort.

BACKGROUND: The purpose of this study was to assess the prognostic performance of the log odds of positive lymph nodes (LODDS) value compared with the pathological N stage and lymph node ratio (LNR) in patients with esophageal squamous cell carcinoma (ESCC). METHOD: In total 1144 patients diagnosed with ESCC from the Surveillance, Epidemiology, and End Results (SEER) database and 930 patients from our validation cohort were eligible. Kaplan-Meier plotter and multivariate Cox proportional hazards models were conducted to investigate the prognostic value of the N stage, LNR stage, and LODDS stage. The homogeneity, discriminatory ability, and monotonicity of these variables were evaluated using the linear trend χ2 test, likelihood ratio χ2 test, Akaike information criterion (AIC), and consistency index (C-index) to determine the potential superiorities. RESULTS: The prognostic LODDS cutoff values were determined to be -1.49 and -0.55 (p < 0.001). Univariate analyses showed significant association among the N, LNR, and LODDS stages and overall survival of the patients (all p < 0.001). Multivariate analyses confirmed that the LODDS stage remained an independent prognostic indicator in both the SEER database and our validation cohort. Subgroup analyses identified the ability of LODDS stage to distinguish heterogeneous patients within various groups in both independent databases. Furthermore, the model with the highest C-index and smallest AIC value was the one incorporating the LODDS stage among the three investigated nodal classifications of both cohorts. CONCLUSION: The novel LODDS stage demonstrated better prognostic performance than the traditional N or LNR stages in ESCC patients. It can serve as an auxiliary factor to improve prognostic performance and can be applied to evaluate the lymph node status to increase the precision of staging and evaluation of survival.

Prognostic Significance of the Preoperative Albumin/Fibrinogen Ratio in Patients with Esophageal Squamous Cell Carcinoma after Surgical Resection.

Purpose: The purpose of the present study was to investigate the prognostic value of inflammatory and nutritional-based scores, including the albumin/fibrinogen ratio (AFR) and albumin/globulin ratio (AGR), in patients with esophageal squamous cell carcinoma (ESCC). Methods: The medical records of 641 patients with resectable ESCC from our institution were retrospectively analyzed. The preoperative AFR and AGR were investigated based on serum albumin, globulin and plasma fibrinogen levels. X-tile software, Kaplan-Meier survival curves and Cox proportional hazard models were performed to identify their prognostic value. The predictive accuracy was evaluated by the concordance index (C-index), calibration plots, and decision curve analysis (DCA). Results: The optimal cutoff values were 15.3 and 1.8 for AFR and AGR, respectively. Univariate survival analysis identified age, smoking history, tumor size, pT status, pN status, NLR, PLR, fibrinogen, albumin, AFR, and AGR as factors associated with overall survival. Multivariate analysis indicated that preoperative AFR (HR: 0.690, 95% CI = 0.495~0.960, P = 0.028), rather than other inflammation- and nutrition-based scores, was an independent predictor of overall survival. The C-index of the predicted nomogram containing AFR (C-index = 0.677) was higher than that of the nomogram without AFR (C-index = 0.656). The calibration curves showed that the predictive abilities were consistent with the actual observation results. Moreover, compared with the traditional staging system, the results of DCA showed that the nomogram had superior predictive ability and higher clinical utility. Conclusion: Our preliminary study suggested that a low preoperative AFR might be a novel and valuable predictor of poor prognosis in patients with ESCC, which may be helpful for prognosis assessment, patient counseling, and therapeutic modality selection.

Role of chemotherapy after curative esophagectomy in squamous cell carcinoma of the thoracic esophagus: A propensity score-matched analysis.

BACKGROUND: The efficacy of postoperative treatment of squamous cell carcinoma of the esophagus has not yet been determined. In this retrospective study, we investigated whether postoperative adjuvant chemotherapy (POCT) confers a survival benefit on patients who undergo curative esophagectomy. METHODS: A total of 782 patients were enrolled in our study. The patients were divided into surgery alone (S) and surgery plus postoperative chemotherapy (S + POCT) groups. Propensity score matching (PSM) was used to eliminate the differences in baseline characteristics. The primary endpoint was overall survival (OS), which was calculated by the Kaplan-Meier method and compared with the log-rank test. A Cox proportional hazards model was used to identify factors influencing the prognosis. RESULTS: Of 782 patients, 343 (43.9%) underwent S alone, and 439 (56.1%) underwent S + POCT before PSM. The five-year OS rates were 42.3% and 47.8% in the S and S + POCT groups (p = 0.080), respectively. After PSM (296 patients per group), the five-year OS rates were 48.7% and 56.2% in the S and S + POCT groups (p = 0.025), respectively. For different cycles of POCT, patients with more than three cycles had a better survival than those with less than three cycles. The significant predictive factors for OS were pN stage (HR = 1.861, 95% CI: 1.310-2.645, p = 0.001), number of dissected nodes (HR = 0.621, 95% CI: 0.494-0.781, p < 0.001) and POCT received (HR = 0.699, 95% CI: 0.559-0.875, p = 0.002), which were identified by multivariate Cox regression analyses in the matched samples. CONCLUSIONS: POCT appears to improve the OS rate of patients with ESCC after resection, and at least four chemotherapy cycles are necessary. These conclusions warrant further confirmation in large-scale multicenter randomized controlled trials.

Comparative study of treatment options and construction nomograms to predict survival for early-stage esophageal cancer: a population-based study.

BACKGROUND: The aim of this study was to investigate the impact of several common treatment options on the long-term survival of patients with early-stage esophageal cancer and to construct nomograms for survival prediction. METHOD: This study was performed using the Surveillance, Epidemiology and End Results (SEER) database (2004-2015) on patients with early-stage (pT1N0M0) esophageal cancer who underwent endoscopic local therapy (ET), radiotherapy (RT), esophagectomy (ES) or neoadjuvant therapy (NT). Multivariate Cox regression was used to explore which factors influenced patient survival, and these factors were then incorporated into propensity sore matching (PSM) and the construction of nomogram plots. Kaplan-Meier analysis was used to compare whether there was a difference in long-term survival between the other three treatments and esophagectomy. RESULT: Data from 4184 patients were included in this study. Multivariate Cox regression analysis showed that age, grade, marital status, and treatment method were independent factors affecting survival. After matching, Kaplan-Meier analysis showed that the ET group had better CSS than the ES group, but no difference in OS, while the NT and RT groups had worse OS and CSS than the ES group. In the nomogram prediction model, the c-indexes of the training and validation cohorts were 0.805 and 0.794, respectively. Additionally the ROC curve (5-year AUC = 0.877) and DCA curve showed that the model had a good predictive effect. CONCLUSION: For early-stage esophageal cancer, the results of this study showed that ET is not inferior to ES. Based on the independent factors affecting prognosis identified in the study, we constructed and validated a predictive model for predicting long-term survival in patients with early-stage esophageal cancer.

Ratio between negative and positive lymph nodes is a novel prognostic indicator for patients with esophageal cancer: A Surveillance, Epidemiology and End Results database analysis.

BACKGROUND: The aim of this study was to explore whether the ratio between negative and positive lymph nodes (RNP ) could predict the overall survival (OS) of esophageal cancer (EC) patients with lymph node metastasis following esophagectomy. METHODS: We utilized the Surveillance, Epidemiology and End Results (SEER) database to include the records of 2374 patients with lymph node metastases post-surgery. All patients were randomly assigned into the training cohort (n = 1424) and validation cohort (n = 950). Multivariate Cox regression analyses were performed to identify independent prognostic factors. A novel RNP -based TRNP M staging system was proposed. The prognostic value of N, RNP , TNM and TRNP M staging system was evaluated using the linear trend χ2 test, likelihood ratio χ2 test, and Akaike information criterion (AIC) to determine the potential superiorities. We constructed nomograms to predict survival in both cohorts, and the calibration curves confirmed the predictive ability. RESULTS: Univariate analyses showed that N and RNP stage significantly influenced the OS of patients. Multivariate analyses revealed that RNP was an independent prognostic predictor in both the training and validation cohorts. For the stratification analysis in the two cohorts, we found significant differences in the prognosis of patients in different RNP groups on the basis of the different N stages and the number of dissected lymph nodes. In addition, the lower AIC value of RNP stage and TRNP M staging system represented superior predictive accuracy for OS than the N stage and TNM staging system, respectively. Furthermore, the calibration curves for the probability of three- and five-year survival showed good consistency between nomogram predictive abilities and actual observation. CONCLUSIONS: We demonstrated that compared to the classical pathological lymph nodal staging system, the RNP stage showed superior predictive accuracy for OS and can serve as a more effective prognostic guidance for lymph node positive EC patients.