Targeting immune checkpoints on tumor-associated macrophages in tumor immunotherapy.

Unprecedented breakthroughs have been made in cancer immunotherapy in recent years. Particularly immune checkpoint inhibitors have fostered hope for patients with cancer. However, immunotherapy still exhibits certain limitations, such as a low response rate, limited efficacy in certain populations, and adverse events in certain tumors. Therefore, exploring strategies that can improve clinical response rates in patients is crucial. Tumor-associated macrophages (TAMs) are the predominant immune cells that infiltrate the tumor microenvironment and express a variety of immune checkpoints that impact immune functions. Mounting evidence indicates that immune checkpoints in TAMs are closely associated with the prognosis of patients with tumors receiving immunotherapy. This review centers on the regulatory mechanisms governing immune checkpoint expression in macrophages and strategies aimed at improving immune checkpoint therapies. Our review provides insights into potential therapeutic targets to improve the efficacy of immune checkpoint blockade and key clues to developing novel tumor immunotherapies.

Construction of a predictive model for immunotherapy efficacy in lung squamous cell carcinoma based on the degree of tumor-infiltrating immune cells and molecular typing.

BACKGROUND: To construct a predictive model of immunotherapy efficacy for patients with lung squamous cell carcinoma (LUSC) based on the degree of tumor-infiltrating immune cells (TIIC) in the tumor microenvironment (TME). METHODS: The data of 501 patients with LUSC in the TCGA database were used as a training set, and grouped using non-negative matrix factorization (NMF) based on the degree of TIIC assessed by single-sample gene set enrichment analysis (GSEA). Two data sets (GSE126044 and GSE135222) were used as validation sets. Genes screened for modeling by least absolute shrinkage and selection operator (LASSO) regression and used to construct a model based on immunophenotyping score (IPTS). RNA extraction and qPCR were performed to validate the prognostic value of IPTS in our independent LUSC cohort. The receiver operating characteristic (ROC) curve was constructed to determine the predictive value of the immune efficacy. Kaplan-Meier survival curve analysis was performed to evaluate the prognostic predictive ability. Correlation analysis and enrichment analysis were used to explore the potential mechanism of IPTS molecular typing involved in predicting the immunotherapy efficacy for patients with LUSC. RESULTS: The training set was divided into a low immune cell infiltration type (C1) and a high immune cell infiltration type (C2) by NMF typing, and the IPTS molecular typing based on the 17-gene model could replace the results of the NMF typing. The area under the ROC curve (AUC) was 0.82. In both validation sets, the IPTS of patients who responded to immunotherapy were significantly higher than those who did not respond to immunotherapy (P = 0.0032 and P = 0.0451), whereas the AUC was 0.95 (95% CI = 1.00-0.84) and 0.77 (95% CI = 0.58-0.96), respectively. In our independent cohort, we validated its ability to predict the response to cancer immunotherapy, for the AUC was 0.88 (95% CI = 1.00-0.66). GSEA suggested that the high IPTS group was mainly involved in immune-related signaling pathways. CONCLUSIONS: IPTS molecular typing based on the degree of TIIC in the TME could well predict the efficacy of immunotherapy in patients with LUSC with a certain prognostic value.

Identification of a Four-Gene Signature Associated with the Prognosis Prediction of Lung Adenocarcinoma Based on Integrated Bioinformatics Analysis.

Lung adenocarcinoma (LUAD) is often diagnosed at an advanced stage, so it is necessary to identify potential biomarkers for the early diagnosis and prognosis of LUAD. In our study, a gene co-expression network was constructed using weighted gene co-expression network analysis (WGCNA) in order to obtain the key modules and genes correlated with LUAD prognosis. Four hub genes (HLF, CHRDL1, SELENBP1, and TMEM163) were screened out using least absolute shrinkage and selection operator (LASSO)-Cox regression analysis; then, a prognostic model was established for predicting overall survival (OS) based on these four hub genes..Furthermore, the prognostic values of this four-gene signature were verified in four validation sets (GSE26939, GSE31210, GSE72094, and TCGA-LUAD) as well as in the GEPIA database. To assess the prognostic values of hub genes, receiver operating characteristic (ROC) curves were constructed and a nomogram was created. We found that a higher expression of four hub genes was associated with a lower risk of patient death. In a training set, it was demonstrated that this four-gene signature was a better prognostic factor than clinical factors such as age and stage of disease. Moreover, our results revealed that these four genes were suppressor factors of LUAD and that their high expression was associated with a lower risk of death. In summary, we demonstrated that this four-gene signature could be a potential prognostic factor for LUAD patients. These findings provide a theoretical basis for exploring potential biomarkers for LUAD prognosis prediction in the future.

Mefatinib as first-line treatment of patients with advanced EGFR-mutant non-small-cell lung cancer: a phase Ib/II efficacy and biomarker study.

EGFR inhibitors have revolutionized the treatment of advanced non-small-cell lung cancer (NSCLC). Mefatinib is a novel, bioavailable, second-generation, irreversible pan-EGFR inhibitor. This phase Ib/II open-label, single-arm, multi-center study investigated the efficacy, safety, biomarker, and resistance mechanisms of mefatinib in the first-line treatment of patients with advanced EGFR-mutant NSCLC. This study included 106 patients with EGFR-mutant stage IIIB-IV NSCLC who received first-line mefatinib at a daily dose of either 60 mg (n = 51) or 80 mg (n = 55). The primary endpoint was progression-free survival (PFS). Secondary endpoints were overall response rate (ORR), disease control rate (DCR), overall survival (OS), and safety. The cohort achieved an ORR of 84.9% and DCR of 97.2%. The median PFS was 15.4 months and the median OS was 31.6 months. Brain metastasis was detected in 29% of patients (n = 31) at diagnosis and demonstrated an ORR of 87.1%, PFS of 12.8 months, and OS of 25.2 months. Adverse events primarily involved skin and gastrointestinal toxicities, which were well-tolerated and manageable. Analyses of mutation profiles were performed using targeted sequencing of plasma samples at baseline, first follow-up 6 weeks from starting mefatinib therapy (F1), and at progression. Patients with concurrent TP53 mutations had comparable PFS as wild-type TP53 (14.0 vs 15.4 months; p = 0.315). Furthermore, circulating tumor DNA clearance was associated with longer PFS (p = 0.040) and OS (p = 0.002). EGFR T790M was the predominant molecular mechanism of mefatinib resistance (42.1%, 16/38). First-line mefatinib provides durable PFS and an acceptable toxicity profile in patients with advanced EGFR-mutant NSCLC.

CCNDBP1, a Prognostic Marker Regulated by DNA Methylation, Inhibits Aggressive Behavior in Dedifferentiated Liposarcoma via Repressing Epithelial Mesenchymal Transition.

The present study aimed to explore the prognostic value, function, and mechanism of CCNDBP1 in dedifferentiated liposarcoma (DDL). Immunohistochemistry staining was used to analyze the protein expression of CCNDBP1 in tissue specimens. After silencing CCNDBP1 in LPS853 and overexpressing CCNDBP1 in LPS510, CCK-8, clone formation, transwell migration, and invasion assays were used to detect cell proliferation, migration, and invasion ability. CCNDBP1-induced cell apoptosis was analyzed by flow cytometry. The altered expression of epithelial-mesenchymal transition (EMT)-related proteins were detected by Western blot. The methylation, gene expression, and clinical data of 58 samples with DDL were analyzed using the cancer genome atlas (TCGA) database. Low expression of CCNDBP1 was associated with a poor prognosis of patients with DDL and was considered an independent prognostic factor of the progression-free survival (PFS). CCNDBP1 significantly inhibited the clone formation, proliferation, migration, and invasion of cancer cells in vitro and promoted cancer cell apoptosis. CCNDBP1 could repress the pathological EMT, thereby inhibiting the malignant behaviors of DDL cells. The high degree of DNA methylation sites cg05194114 and cg22184989 could decrease the expression of CCNDBP1 and worsen the prognosis of DDL patients. This is the first study reporting that CCNDBP1 is a tumor suppressor gene of DDL and putative prognostic marker in DDL patients. CCNDBP1 might inhibit the ability of cell proliferation and invasion by repressing pathological EMT, and the expression of CCNDBP1 could be regulated by DNA methylation in DDL.

Identification and Validation of a Novel Six-lncRNA-Based Prognostic Model for Lung Adenocarcinoma.

OBJECTIVE: This study was conducted in order to establish a long non-coding RNA (lncRNA)-based model for predicting overall survival (OS) in patients with lung adenocarcinoma (LUAD). METHODS: Original RNA-seq data of LUAD samples were extracted from The Cancer Genome Atlas (TCGA) database. Univariate Cox survival analysis was performed to select lncRNAs associated with OS. The least absolute shrinkage and selection operator (LASSO) regression analysis and multivariate Cox analysis were performed for building an OS-associated lncRNA prognostic model. Moreover, receiver operating characteristic (ROC) curves were generated to assess predictive values of the hub lncRNAs. Consequently, qRT-PCR was conducted to validate its prognostic value. The potential roles of these lncRNAs in immunotherapy and anti-angiogenic therapy were also investigated. RESULTS: The lncRNA-associated risk score of OS (LARSO) was established based on the LASSO coefficient of six individual lncRNAs, including CTD-2124B20.2, CTD-2168K21.1, DEPDC1-AS1, RP1-290I10.3, RP11-454K7.3, and RP11-95M5.1. Kaplan-Meier analysis revealed that LUAD patients with higher LARSO values had a shorter OS. Furthermore, a new risk score (NRS), including LARSO, stage, and N stage, could better predict the prognosis of LUAD patients compared with LARSO alone. Evaluation of the prognostic model in our cohort demonstrated that patients with higher scores had a worse prognosis. In addition, correlation analysis between these six lncRNAs and immune checkpoints or anti-angiogenic targets suggested that LUAD patients with high LARSO might not be sensitive to immunotherapy or anti-angiogenic therapy. CONCLUSIONS: This robust six-lncRNA prognostic signature may be used as a novel and powerful prognostic biomarker for lung adenocarcinoma.

Fine Needle Aspiration Cytology (FNAC) for Chinese Patients With Acral and Cutaneous Melanoma: Accuracy and Safety Analysis From a Single Institution.

This study aimed to investigate the accuracy and safety of fine-needle aspiration cytology (FNAC) in Chinese patients with acral and cutaneous melanoma, and also to evaluate the influencing factors and their impact on prognosis. Data of 128 patients with stage 0-III acral and cutaneous melanoma treated in Fudan University Shanghai Cancer Center from 2009 to 2016 were collected from a prospective database. Further, 128 patients who did not undergo FNAC but had similar parameters were recruited as the matched group. Clinical features, FNAC status, and recurrence or metastasis status of patients were analyzed for overall survival (OS), melanoma-specific survival (MSS), recurrence-free survival (RFS), and metastasis-free survival (MFS). Of the 128 patients with FNAC, 5.5% (7/128) had a negative cytological diagnosis, 12.2% (5/41) had primary lesions, and 2.3% (2/87) had lesions in lymph nodes. Tumor thickness, status of ulceration, and subtype were not associated with accuracy for both primary and lymph node FNAC. With a median follow-up of 40 months in all patients, 55 had melanoma-specific death; the median OS and MSS were 95 months and 104 months, respectively. Patients with FNAC had significantly worse OS. Tumor progression occurred in 130 patients. The survival analysis revealed differences in OS and disease-free survival between the two groups. FNAC impacted patients' RFS and MFS; the difference in survival curves of RFS and MFS was also statistically significant. FNAC on primary or superficial lymphatic lesions was a good diagnostic tool for Chinese patients with acral and cutaneous melanoma, but it adversely impacted prognosis.

Outcome of patients with primary retroperitoneal solitary fibrous sarcoma.

BACKGROUND: To describe the clinicopathological features of primary retroperitoneal solitary fibrous tumor (RSFT) and define the prognostic factors. METHODS: The comprehensive data of 35 primary RSFT patients who got curative surgery at a tertiary cancer center from April 2004 to October 2018 were retrospectively analyzed. RESULTS: Male patients outnumbered female patients (19 vs. 16), with the age ranging from 19 to 73 years (median, 51 years). 7 (20%) patients had tumors located in special parts, including three in kidney, one in renal pelvis, one in bladder, one in prostate, and one in mesentery. Tumor sizes ranged from 2.5 to 25 cm (median, 9 cm). Microscopic negative margin was reached in 33 (94.3%) cases. 13 (37.1%) were classified as atypical/malignant, while 22 (62.9%) were benign. Concomitant organ excision was performed on 11 (31.4%) patients, with kidney (n = 5) being the most frequent organ. Multifocality was only found in 4 (11.4%) cases. The majority of the patients (31, 88.6%) did not get adjuvant treatment. The median follow-up time was 46 months (range 4-153 months). The 5-year DSS rate and DFS rate were 100% and 63.6%, respectively. In univariate analysis, tumor size ≥ 10 cm (P = 0.002) and atypical/malignant pathology (P = 0.024) were associated with decreased DFS. Multivariate analysis revealed that tumor size was the only independent prognostic factor for DFS (HR 6.03, 95% CI 1.18-30.77, P = 0.031). CONCLUSION: RSFT is uncommon, slow-growing, and recrudescent tumors. Large tumor size and malignant pathology are associated with decreased DFS. Tumor size ≥ 10 cm independently predicts shortened DFS.

Liposarcoma: Advances in Cellular and Molecular Genetics Alterations and Corresponding Clinical Treatment.

Liposarcoma is a malignant tumor of mesenchymal origin with significant tissue diversity. It is composed of adipocytes with different degrees of differentiation and different degrees of heteromorphosis. It is not sensitive to traditional radiotherapy and chemotherapy and has a poor prognosis. In recent years, with the rapid development of basic immunology, molecular genetics and tumor molecular biology, the histological classification of liposarcoma has become increasingly clear. More and more new methods and technologies, such as gene expression profile analysis, the whole genome sequencing, miRNA expression profile analysis and RNA sequencing, have been successfully applied to liposarcoma, bringing about a deeper understanding of gene expression changes and molecular pathogenic mechanisms in the occurrence and development of liposarcoma. This study reviews the present research status and progress of cellular and molecular alterations of liposarcoma and corresponding clinical treatment progress.

Undifferentiated Pleomorphic Sarcoma: Long-Term Follow-Up from a Large Institution.

PURPOSE: Our study aimed to describe the clinical features of undifferentiated pleomorphic sarcoma (UPS) and identify the predictors of poor outcomes. PATIENTS AND METHODS: The clinicopathological variables and treatment strategies of 100 UPS patients who underwent surgical resections at a single institution between November 2004 and July 2016 were reviewed. Kaplan-Meier and Cox regression method were conducted for survival analysis. RESULTS: The median follow-up time was 94 months (range, 1.5-154 months). R0 resection was applied for 72 cases, and the median tumor size was 5.75cm (range, 1-30cm). Tumor grades of 45 patients were intermediate grade (G2), and 54 patients were with advanced stage (stage III/IV). Twenty-seven patients presented with tumors involving important structures, in which the nerve was the most frequently invaded structure (n=12). During the follow-up, 40 patients suffered from postoperative local recurrence, and distant metastasis was observed in 25 patients which mainly metastasized to the lung (n=14). The 5-year OS rate, 5-year LRFS rate, and 5-year MFS rate was 53%, 55%, and 70%, respectively. Multivariate analysis revealed that tumor presentation, tumor size, and important structures involved (p=0.033, p=0.004, and p=0.033, respectively) were independent prognostic factors associated with OS. Meanwhile, age, resection quality and tumor grade were independent prognostic factors for LRFS (p=0.033, p=0.045, and p=0.007, respectively) and tumor depth was significantly associated with MFS (p=0.050) in multivariate analysis. CONCLUSION: Primary treatment of UPS should be conducted by experts in large sarcoma center. Wide surgical margin provides sufficient control of the disease recurrence.

Common Nevus and Skin Cutaneous Melanoma: Prognostic Genes Identified by Gene Co-Expression Network Analysis.

Skin cutaneous melanoma (SCM) is a common malignant tumor of the skin and its pathogenesis still needs to be studied. In this work, we constructed a co-expression network and screened for hub genes by weighted gene co-expression network analysis (WGCNA) using the GSE98394 dataset. The relationship between the mRNA expression of hub genes and the prognosis of patients with melanoma was validated by Gene Expression Profiling Interactive Analysis (GEPIA) database. Furthermore, immunohistochemistry in the Human Protein Atlas was used to validate hub genes and grayscale analysis was performed using ImageJ software. It was found that the yellow module was most significantly associated with the difference between common nevus and SCM, and 13 genes whose expression correlation >0.9 were candidate hub genes. The expression of three genes (STK26, KCNT2, CASP12) was correlated with the prognosis of SCM. STK26 (P = 0.0024) and KCNT2 (P < 0.0001) were significantly different between normal skin and SCM. These three hub genes have potential value as predictors for accurate diagnosis and prognosis of SCM in the future.

Prognostic analysis of surgically treated clear cell sarcoma: an analysis of a rare tumor from a single center.

BACKGROUND: The objective of this retrospective study was to evaluate the prognostic value of various factors in clear cell sarcoma patients after radical surgery. METHODS: Forty-two clear cell sarcoma patients from August 2006 to March 2018 were included in the study. Curves of disease-free survival and overall survival were calculated using the Kaplan-Meier method, and univariate and multivariate analyses of various prognostic factors were performed using a Cox proportional hazard regression model. Laboratory test of peripheral blood was recorded before surgery. The optimal cutoff value of systemic inflammatory markers was defined by receiver-operating curve analysis. RESULTS: The 5-year DFS and 5-year OS rate were 22% and 46%, respectively. The median DFS and OS times were 12 and 41.5 months, respectively. In univariate analysis, there was a significant association between shorter DFS and tumor size larger than 5 cm (p = 0.0043), positive surgical margin (p = 0.0233), and the neutrophil-to-lymphocyte ratio (NLR) higher than 2.73 (p = 0.0009). Furthermore, we observed a significant association between shorter OS and tumor size larger than 5 cm (p = 0.0075), positive surgical margin (p = 0.0101), NLR higher than 2.73 (p = 0.0126), the platelet-to-lymphocyte ratio (PLR) higher than 103.89 (p = 0.0147) and the lymphocyte-to-monocyte ratio (LMR) lower than 4.2 (p = 0.0445). A multivariate analysis demonstrated that the surgical margin (p = 0.013) and NLR (p = 0.001) were significantly associated with DFS. Tumor size (p = 0.010) and NLR (p = 0.013) were independent prognostic factors for OS. CONCLUSIONS: This study had the second largest sample around the world and preoperative NLR may be a useful prognostic factor in CCS patients after radical surgery.

Baseline platelet counts and derived inflammatory biomarkers: prognostic relevance in metastatic melanoma patients receiving Endostar plus dacarbazine and cisplatin.

Background: The clinical efficacy and safety of Endostar combined with chemotherapy in the treatment of metastatic malignant melanoma (MM) were analyzed and the indicators capable of predicting the efficacy of the regimen were identified to guide clinical practice. Patients and methods: The clinical data of 55 patients with metastatic MM without gene mutations who were treated with Endostar combined with dacarbazine and cisplatin were retrospectively analyzed. Efficacy was assessed using RECIST 1.1, and adverse events (AEs) were graded according to NCI-CTCAE 4.0. The log-rank test was used to compare the survival curves of patients in different subgroups, and stepwise multivariate Cox regression analysis was used to determine significant prognostic factors. Differences were considered statistically significant at P<0.05. Results: Of the 55 patients, seven showed a partial response, 20 showed stable disease, and 28 showed progressive disease. The median progression-free survival was 17.9 months. AEs were controllable. Univariate analysis identified biotherapy, clinical stage, clinical classification, low baseline platelet count, platelet to albumin ratio (PAR), and platelet to globulin ratio (PGR) as factors affecting drug efficacy. Multivariate Cox regression analysis identified clinical stage and PAR as independent factors predicting the efficacy of the regimen. Conclusions: Endostar combined with chemotherapy showed a curative effect on metastatic MM without gene mutations, and AEs were controllable. The baseline platelet count and derived PAR and PGR values were associated with the efficacy of the regimen. The potential value of efficacy prediction remains to be further verified by prospective random experiments.

Prognostic significance of pretreatment lymphocyte/monocyte ratio in retroperitoneal liposarcoma patients after radical resection.

BACKGROUND: The aim of this study was to evaluate the prognostic value of pretreatment inflammatory biomarkers in retroperitoneal liposarcoma (RPLS) patients after radical resection. PATIENTS AND METHODS: One hundred patients with RPLS who underwent radical resection between September 2004 and October 2010 at Fudan University Shanghai Cancer Center were included in this study. Laboratory tests of peripheral blood were sampled before surgery. The optimal cutoff values of systemic inflammatory markers were defined by receiver-operating curve analyses. Curves of disease-free survival (DFS) and overall survival (OS) were obtained by the Kaplan-Meier method. Cox proportional hazards regression modeling was used to perform univariate and multivariate analyses. RESULTS: The median follow-up time was 53 months. The median DFS and OS were 27 and 86 months, respectively. On the basis of the optimal cutoff value of 3, 24 patients were classified into low lymphocyte/monocyte ratio (LMR) group and 76 patients into high LMR group. In univariate analysis, low LMR group had significantly shorter DFS (P<0.001) and OS (P<0.001) compared to high LMR group. In multivariate analysis, low LMR was demonstrated as an independent negative prognostic factor for both DFS (HR=2.854, 95% CI=1.392-5.851, P=0.004) and OS (HR=3.897, 95% CI=1.681-9.033, P=0.002). CONCLUSION: Pretreatment LMR is a useful prognostic marker in RPLS patients after radical resection.

Retroperitoneal dedifferentiated liposarcoma: Analysis of 61 cases from a large institution.

Background: To describe the clinical features of retroperitoneal dedifferentiated liposarcoma (RP DDLS) and further evaluate the prognostic factors. Methods: The clinicopathological variables and treatment strategies of 61 RP DDLS patients who underwent surgical resections at a single institution between September 2005 and September 2016 were reviewed. Kaplan-Meier and Cox regression methods were conducted for survival analyses. Results: The average patients' age was 52 years (range, 27-81), and there was almost no gender predilection (30 males vs. 31 females). 51 (83.6%) patients got gross tumor resections (R0/R1 resection), and the median tumor size was 19 cm (range, 4.3-50 cm). 39(63.9%) patients were with intermediate-grade sarcoma and 22(36.1%) were with high-grade sarcoma. The median intraoperative blood loss was 400 ml (range, 50-2700ml). 19 (31.1%) patients presented multifocal diseases. Tumors were removed intactly in 42 (68.9%) patients. In order to obtain gross tumor resections, 33 (54.1%) of the patients underwent excisions of at least one adjacent organ, of which kidney (n=21, 63.6%) was the most common one. 6 (9.8%) patients developed distant metastases during follow-up. The overall 5-year progression-free survival (PFS) rate was 3.7%, with the median PFS of 19 months. The 5-year overall survival (OS) rate was 43.5%, with the median OS of 58 months. Updating to November 2017, 30 (49.2%) patients remained alive. The median follow-up time was 49 months. Multivariate analysis using Cox proportional hazards model revealed that tumor grade, blood loss, resection extent, and tumor integrity were independently associated with OS (p=0.032, p=0.018, p=0.020, p=0.005, respectively). Tumor grade, tumor integrity and multifocality were significant predictors for PFS (p=0.013, p=0.080, p=0.009, p=0.028, respectively). Conclusion: Intermediate-grade histology, intraoperative blood loss < 400 ml, complete tumor resection, and tumor integrity were independently associated with better OS. Intermediate-grade histology, tumor integrity and unifocal disease independently predicted favorable PFS.

Apatinib mesylate tablet in the treatment of advanced malignant melanoma.

BACKGROUND: Observing and studying clinical efficacy and safety of apatinib mesylate tablet in the treatment of advanced malignant melanoma (MM). METHODS: Retrospectively analyzing the clinical data of 22 patients with metastatic MM who had failed conventional chemotherapy from June 2016 to January 2018. All patients took 500 mg of apatinib mesylate tablets per day. The efficacy should be evaluated according to RECIST 1.1 criteria. Adverse events (AEs) should be graded according to NCI-CTCAE 4.0. RESULTS: There were two cases of partial remission (PR), 11 of stable disease (SD) and nine of progressive disease (PD) in the 22 patients with advanced MM, where the objective remission rate (ORR) was 9.1% and the disease control rate (DCR) was 59.1%. The median progression-free survival (PFS) was 7.5 months, and the 6-month progression-free survival rate (PFR) was 54.7%. Six patients died and the overall survival (OS) was not reached. AEs were controllable and all were in Grade 1-3. CONCLUSION: Apatinib mesylate tablets have a certain curative effect on patients with malignant melanomas of Stage IV who failed conventional chemotherapy. Apatinib mesylate tablets at a daily dose of 500 mg are well tolerated by most patients.