Direct comparisons of efficacy and safety between actinomycin-D and methotrexate in women with low-risk gestational trophoblastic neoplasia: a meta-analysis of randomized and high-quality non-randomized studies.

BACKGROUND: Actinomycin-D (Act-D) and Methotrexate (MTX) are both effective first-line agents for low-risk gestational trophoblastic neoplasia (LRGTN) with no consensus regarding which is more effective or less toxic. The primary objective of this meta-analysis is to compare Act-D with MTX in the treatment of LRGTN. METHODS: We systematically searched electronic databases, conferences abstracts and trial registries for randomized controlled trials (RCTs) and high-quality non-randamized controlled trials (non-RCTs), comparing Act-D with MTX for patients with LRGTN. Studies were full-text screened for quality assessment and data extraction. Eligible studies must have reported complete remission rate. A fixed-effects meta-analysis was conducted to quantify the efficacy and safety of Act-D and MTX on odds ratios (ORs) and 95% confidence intervals (95%CIs), respectively. RESULTS: A total of 8 RCTs and 9 non-RCTs (1674 patients) were included. In terms of efficacy, Act-D is superior to MTX in complete remission (80.2% [551/687] vs 65.1% [643/987]; OR 2.15, 95%CI 1.70 to 2.73). In the stratified analysis, patients from RCTs and non-RCTs both had a better complete remission from Act-D-based regimen (RCTs: 81.2% [259/319] vs 66.1% [199/301], OR 2.17, 95%CI 1.49 to 3.16; non-RCTs: 79.3% [292/368] vs 65.0% [444/686], OR 2.14, 95%CI 1.57 to 2.92). In terms of safety, patients receiving Act-D had higher risks of suffering nausea (OR 2.35, 95%CI 1.68 to 3.27), vomiting (OR 2.40, 95%CI 1.63 to 3.54), and alopecia (OR 2.76, 95%CI 1.60 to 4.75). Notably, liver toxicity (OR 0.38, 95%CI 0.19 to 0.76) was the only one that was conformed to have a higher risk for patients receiving MTX. In addition, the pooled results showed no significant difference of anaemia, leucocytopenia, neutropenia, thrombocytopnia, constipation, diarrhea, anorexia, and fatigue between Act-D and MTX. CONCLUSIONS: Our meta-analysis suggests that Act-D had better efficacy profile in general, and MTX had less toxicities in LRGTN. Future clinical trials should be better orchestrated to provide more valid data on efficacy and toxicity.

Abnormal vaginal flora correlates with pregnancy outcomes: A retrospective study from 737 pregnant women.

OBJECTIVE: Abnormal vaginal flora (AVF) is a common cause of vulvovaginal symptoms in women. This study aims to investigate the prevalence of AVF in pregnant women and assess associations between diverse AVF subtypes and pregnancy outcomes. METHODS: This study retrospectively collected clinical data of pregnant women who had vaginal flora tests (VFT) between January 2015 and December 2018 in the First Affiliated Hospital of Xi'an Jiaotong University. AVF were defined into different subtypes according to the results of VFT, including bacterial vaginosis (BV), vulvovaginal candidiasis (VVC), aerobic bacteria (AV), cytolytic vaginosis (CV), and trichomoniasis. Pregnancy outcomes included gestational age at delivery, preterm birth (PTB), premature rupture of membranes (PROM), and infant birth weight. Student's t-test and Fisher's exact test was used for analyses using SPSS 22.0. P < 0.05 was considered as statistical significance. RESULTS: A total of 737 pregnant women were included in this study. Pregnant women in AVF group suffered more PROM than women in normal vaginal flora (NVF) group (18.8% [33/176] vs 10.6% [32/302], P = 0.012); pregnant women with BV (31.3% [5/16] vs 10.6% [32/302], P = 0.018) and mixed vaginitis (55.6% [5/9] vs 10.6% [32/302], P = 0.001) had higher PROM rates than women in the NVF group. In addition, pregnant women in NVF and AVF groups had similar PTB rates (5.0% [15/302] vs 3.5% [32/302], P = 0.38). CONCLUSIONS: AVF, including BV and Mixed vaginitis, augments PROM risk in pregnant women, demonstrating the need for vaginal flora examination during pregnancy.

Women With Ovarian Cancer and With Fertility Preservation: A Survival Analysis Using the Surveillance, Epidemiology, and End Results Database and Construction of Nomograms to Predict Cancer-Specific Survival.

Objective: This study aimed to determine the risk and prognostic factors of ovarian cancer (OC) in women having fertility-sparing surgery, as well as survival outcomes of those with stage I epithelial ovarian cancer (EOC). We also determined the effect of chemotherapy in OC treatment and used multiple independent risk factors to establish a prognostic nomogram model for patients with stage I EOC. Patients and Methods: Individuals with OC and with fertility-sparing surgery (FSS) between 1998 and 2016 were identified in the SEER database. Univariate and multivariate logistic regression was performed to identify the distributions of patient characteristics according to chemotherapy. Cancer-specific survival (CSS) was assessed using Kaplan-Meier curves and log-rank tests. Univariate and multivariate Cox regression was conducted to determine the independent prognostic factors for CSS. Cox analysis was used to construct a nomogram model. The C-index and calibration plots showed the performance evaluation results. Results: A total of 1,839 women with OC with FSS were identified in the SEER database. Factors associated with significantly higher odds of undergoing chemotherapy included younger age, being unmarried, having grades 2-4, stages II-III, or clear cell and non-epithelial histologic type following a multivariate logistic regression analysis. Multivariate Cox regression analysis confirmed that age, marital status, chemotherapy, histologic type, grade, and the International Federation of Gynecology and Obstetrics (FIGO) stage were independent prognostic factors for CSS. In stage I EOC, the prognosis in patients with stage IA/IB-grade 3 (5-year CSS 85.3%) or stage IC (5-year CSS 80.6%) was worse than that in those with stage IA/IB-grade 1 (5-year CSS 95.2%), or stage IA/IB-grade 2 (5-year CSS 94.7%). However, chemotherapy improved the survival of patients with stage IA/IB-grade 3 (5-year CSS 78.1% vs. 94.6%, p = 0.024) or stage IC (5-year CSS 75.1% vs. 86.7%, p = 0.170). Discussion: The study provided population-based estimates of risk factors and prognoses in patients with OC and with FSS as well as the survival outcomes of patients with stage I EOC and the effect of chemotherapy. The constructed nomograms exhibited superior prognostic discrimination and survival prediction for patients with stage I EOC.

Effect of MAP3K8 on Prognosis and Tumor-Related Inflammation in Renal Clear Cell Carcinoma.

Background: MAPK kinase kinase 8 (MAP3K8) is involved in the regulation of MAPK cascades and immune responses. Differential expression of MAP3K8 is closely correlated with tumorigenesis. In this study, we used bioinformatics tools to explore expression level, prognostic values, and interactive networks of MAP3K8 in renal clear cell carcinoma (ccRCC). Methods: Differential expression of MAP3K8 was determined by TIMER2.0, UALCAN, and Oncomine Platform. For exploration of MAP3K8 mutation profile, TIMER2.0, DriverDBv3, and cBioPortal were used. The survival module of GEPIA, UALCAN, and DriverDBv3 was used to examine the prognostic value of MAP3K8. Immune infiltration was estimated by TIMER, TIDE, CIBERSORT, CIBERSORT-ABS, QUANTISEQ, XCELL, MCPCOUNTER, and EPIC algorithms. PPI networks and functional enrichment analysis were constructed using GeneMANIA, Cytoscape, and Metascape. The co-expression module in cBioPortal was used to find genes that are correlated with MAP3K8 in mRNA expression. Results: Compared to normal renal samples, ccRCC (3.08-fold change, P = 1.50E-7; 1.10-fold change, P = 3.00E-3), papillary RCC (2.24-fold change, P = 1.86E-4), and hereditary ccRCC (1.98-fold change, P = 1.69E-9) have significantly higher levels of MAP3K8 expression. Compared to Grade 1 ccRCC samples, Grade 2 (P = 1.28E-3) and Grade 3 (P = 7.41E-4) cases have higher levels of MAP3K8 methylation. Percentage of patients harboring MAP3K8 mutation is 0.3% from TIMER2.0 and 0.2 to 11.5% from cBioPortal. High levels of MAP3K8 expression were associated with poorer overall survival (OS) in ccRCC (GEPIA: Log-rank P = 0.60E-2, HR = 1.5; DriverDBv3: Log-rank P = 1.68E-7, HR = 2.21; UALCAN: P = 0.20E-2). MAP3K8 was positively correlated with the presence of T cell regulatory (Tregs) (QUANTISEQ: Rho = 0.33, P = 1.59E-13). PPI network and functional enrichment analyses revealed that MAP3K8 correlated with NFKBIZ, MIAT, PARP15, CHFR, MKNK1, and ERMN, which was mainly involved in I-kappaB kinase/NF-kappaB and toll-like receptor signaling pathways. Conclusion: MAP3K8 overexpression was correlated with damaged survival in ccRC and may play a crucial role in cancer-related inflammation via I-kappaB kinase/NF-kappaB and toll-like receptor signaling pathways.

Efficacy and safety of PARP inhibitors in the treatment of advanced ovarian cancer: An updated systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: Poly-ADP-ribose polymerase (PARP) inhibitors have emerged as a novel class of therapeutics for ovarian cancer (OC); however, PARP inhibitors present a class effect adverse-event profile. METHODS: A comprehensive literature review was performed for phase II or III randomized controlled trials (RCTs) published up to and including January 2020. We analyzed relevant clinical trials reporting the efficacy and toxicity profile of PARP inhibitors in patients with advanced OC. We estimated hazard ratios (HRs), incidences, risk ratios (RRs) and relative 95 % confidence intervals (95 % CI) for progression-free survival (PFS) and selected adverse events, using Stata 12.0 software package. RESULTS: The systematic review process yielded 10 eligible trials comprising 4,241 patients with advanced OC for survival analysis and 4553 patients for evaluation of toxicity profile. The pooled HR (PARP inhibitor vs control group) for PFS was 0.41 (95 % CI, 0.35-0.50) in overall patients, 0.51 (95 % CI, 0.40-0.64) in unselected setting, 0.32 (95 % CI, 0.26-0.39) in BRCA mutation setting, and 0.57 (95 % CI, 0.41-0.78) in wild-type setting. Patients treated with PARP inhibitors exhibited higher risks of all-grade and high-grade haematological toxicities, including anemia, leucopenia, neutropenia, thrombocytopenia (P < 0.05), and also presented higher risks of all-grade gastrointestinal side effects, including constipation, diarrhea, nausea, and vomiting as well as high-grade nausea and vomiting (P < 0.05). CONCLUSIONS: This study indicated that the use of PARP inhibitor provided substantial progression-free survival (PFS) benefits, irrespective of BRCA mutation status; however, treatment with PARP inhibitor was associated with increased risks of selected treatment-related adverse events.

Prognostic impact of tumor-infiltrating lymphocytes in high grade serous ovarian cancer: a systematic review and meta-analysis.

BACKGROUND: Tumor-infiltrating lymphocytes (TILs) are involved in the antitumor immune response. The association between prognosis in patients with TILs and high-grade serous ovarian cancer (HGSOC) remains obscure, with some studies reporting conflicting results. METHODS: We conducted an extensive literature search of electronic databases and retrieved prognostic data of each selected subtype of TILs, including CD3+, CD4+, CD8+, CD103+, and PD-1+ TILs. The fixed-effects model was applied to derive the pooled hazard ratio (HR) and 95% confidence interval (CI) of these markers. RESULTS: The systematic review process yielded 19 eligible studies comprising 6004 patients with HGSOC. We compared TIL-positive and TIL-negative patients, and the pooled HRs from the multivariate analysis revealed that intraepithelial CD8+ TILs were positively correlated with progression-free survival (PFS, HR 0.46, 95% CI 0.25-0.67) and overall survival (OS, HR 0.90, 95% CI 0.86-0.9); stromal CD8+ TILs were positively correlated with OS (HR 0.61, 95% CI 0.36-0.87). Furthermore, the pooled HRs from univariate analysis demonstrated that intraepithelial CD3+, CD4+, CD8+, and CD103+ TILs were positively associated with OS (HR 0.58, 95% CI 0.44-0.72; HR 0.37, 95% CI 0.16-0.59; HR 0.51, 95% CI 0.42-0.60, and HR 0.59, 95% CI 0.44-0.74, respectively); stromal CD4+ and CD8+ TILs were significantly associated with OS (HR 0.63, 95% CI 0.32-0.94 and HR 0.78, 95% CI 0.58-0.97, respectively). However, the pooled HR from the multivariate analysis revealed that PD-1+ TILs were not associated with the OS of patients with HGSOC (HR 0.97, 95% CI 0.90-1.04). CONCLUSION: This meta-analysis provided evidence of the association of CD3+, CD4+, CD8+, and CD103+ TILs with the survival benefits (OS and PFS) of patients with HGSOC.

Prognostic Value of Tumor-Infiltrating Lymphocytes Differs Depending on Lymphocyte Subsets in Esophageal Squamous Cell Carcinoma: An Updated Meta-Analysis.

Background: Tumor-infiltrating lymphocytes (TILs) play a role in the anti-tumor immune response, and are often found in esophageal squamous cell carcinoma (ESCC). Methods: We performed a systematic review and meta-analysis, aiming to establish pooled estimates for survival outcomes of TILs based on their abundance and infiltrating location. A literature search of PubMed/Medline, Embase, Web of Science and the Cochrane Library was conducted. Studies that investigated the prognostic significance of generalized, CD8+, CD4+, FoxP3+, CD3+, and CD45O+ TILs in ESCC patients were included. Results: In pooled analysis, generalized TILs infiltrating the entire tumor mass were positively associated with disease-free survival (DFS), with a univariate-related hazard ratio (HR) of 0.630 [95% confidence interval (CI) 0.415-0.955], and also positively associated with overall survival (OS), with a univariate-related HR of 0.586 (0.447-0.770) and a multivariate-related HR of 0.621 (0.439-0.878). The pan-tumor, intra-tumor and peri-tumor CD8+ TILs had a favorable effect on OS, with univariate-related HRs of 0.733 (0.555-0.968), 0.797 (0.660-0.962), and 0.776 (0.635-0.948), respectively. Similar results were observed in CD8+ TILs that infiltrated the whole tumor mass, with a multivariate-related HR of 0.705 (0.524-0.947). CD4+, FoxP3+, CD3+, and CD45O+ TILs were not linked to DFS or OS. Subtypes and spatial locations of TILs seemed to influence study outcomes. Conclusions: Experimental and analytical methods of future studies should be carefully designed to avoid overestimating the effect of TILs on prognosis. Our meta-analysis confirms the prognostic efficacy of generalized TILs and CD8+ TILs in esophageal squamous cell carcinoma (ESCC) patients.

Tumor Spread Through Air Spaces Is a Survival Predictor in Non-Small-Cell Lung Cancer.

BACKGROUND: Tumor spread through air spaces (STAS) is a newly recognized invasion pattern in non-small-cell lung cancer (NSCLC). However, the clinical application value of STAS in NSCLC remains to be clarified. We aimed to comprehensively explore the potential role of STAS as a prognostic indicator in NSCLC. PATIENTS AND METHODS: A systematic search was performed in PubMed, Embase, Cochrane Library, and Web of Science until April 15, 2018. A quantitative meta-analysis was conducted according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. RESULTS: A total of 3231 patients from 8 studies were included. STAS was observed in 1204 cases (37.3%). A significant association was found between STAS and poor progression-free survival (PFS) (hazard ratio [HR], 1.789; P < .001) and overall survival (OS; HR, 1.488; P < .001). STAS was also an independent prognostic factor for PFS (HR, 1.632; P < .001) and OS (HR, 1.475; P < .001) without obvious heterogeneity. Subgroup analyses and meta-regression showed histology type, tumor, node, metastases (TNM) stage, publication year, sample size, region, and quality score did not alter prognostic value of STAS. Tumor STAS was associated with male sex (P < .001), history of smoking (P < .001), tumor budding (P = .038), vascular invasion (P < .001), lymphatic invasion (P < .001), pleural invasion (P < .001), T stage (P < .001), N stage (P < .001), and TNM stage (P < .001). The publication bias was observed. After adjustment using a nonparametric "trim-and-fill" method, corrected HRs had no significant change. CONCLUSION: Tumor STAS is associated with clinicopathologically aggressive features and could be exploited as a novel prognostic predictor in NSCLC.

Efficacy and safety of immune checkpoint inhibitors in non-small cell lung cancer.

Immune checkpoint inhibitors (ICIs) are new therapeutic strategies for non-small cell lung cancer (NSCLC). We aimed to quantitatively evaluate the efficacy and safety of ICIs in NSCLC. Pubmed, Embase, Cochrane Library, and Web of Science were searched for randomized clinical trials comparing ICIs with control therapies in NSCLC. Data were pooled according to Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines. A total of 12 trails comprising 6,919 NSCLC patients were included in this meta-analysis. ICIs therapies significantly improved progression-free survival (PFS) (HR, 0.838; P < 0.001), overall survival (OS) (HR, 0.747; P < 0.001) and objective response rates (ORR) (RR, 1.311; P < 0.001) in NSCLC. Prognostic benefit was observed irrespective of age, sex, treatment line, performance status and histology. Survival improvement of ICIs was limited for NSCLC patients with non-smoker (PFS, P = 0.468; OS, P = 0.317) or central nervous system (CNS) metastasis (PFS, P = 0.209; OS, P = 0.090), or positive EGFR mutation (PFS, P = 0.083; OS, P = 0.522) or PD-L1 expression level less than 5% (PFS, P = 0.370; OS, P = 0.047). The relative risks of all-grade and high-grade (≥3) anemia, neutropenia, leukopenia, thrombocytopenia, stomatitis, nausea, pyrexia, asthenia and neuropathy were all decreased in patients received ICIs compared with control therapies. This meta-analysis provides clinical evidence that ICIs improve PFS, OS, and ORR in NSCLC with fewer adverse effects. Our data establish ICIs as a prefer treatment option for NSCLC patients with smoker, no CNS metastasis, wild type EGFR, and high PD-L1 expression.

Clinical values of Ku80 upregulation in superficial esophageal squamous cell carcinoma.

Ku80 is an important DNA repair protein. Here, this study sought to investigate clinical impacts of Ku80 expression for patients with superficial esophageal squamous cell carcinoma (ESCC). Immunohistochemical analysis of Ku80 expression was carried out in normal esophageal mucosa, squamous epithelial dysplasia, carcinoma in situ, and superficial ESCC. Its relationships with clinicopathological features and survival of superficial ESCC patients were further clarified. Lentivirus-mediated RNA interference was used to silence Ku80 gene in ECA109 and KYSE150 cells. Both quantitative real-time PCR and Western blot were employed to evaluate Ku80 levels. CCK-8 assay, clone formation assay, flow cytometry, and tumorigenesis experiment were performed to evaluate the malignant phenotype of ECA109 and KYSE150 cells. Increased Ku80 expression was observed in dysplastic esophageal mucosa and carcinoma in situ compared to normal esophageal mucosa (P < 0.001, P < 0.001). Ku80 expression was further increased in superficial ESCC in comparison with dysplastic esophageal mucosa and carcinoma in situ (P < 0.001, P = 0.034). In superficial ESCC, Ku80 overexpression was related to tumor differentiation (P = 0.017), T status (P = 0.011), nodal involvement (P = 0.005), TNM stage (P = 0.004), and postoperative recurrence (P = 0.008). Cox proportional hazards regression showed tumor differentiation, T status, nodal involvement, TNM stage, and Ku80 expression were both independent predictors of patients' overall survival and disease-free survival. Ku80 shRNA effectively reduced Ku80 expression, which significantly inhibited proliferation, clone formation, and induced apoptosis in ECA109 and KYSE150 cells. The tumor growth of xenografts was significantly reduced by Ku80 silencing in ECA109 and KYSE150 cells. Ku80 overexpression associates with unfavorable prognosis of superficial ESCC patients, and silencing of Ku80 could inhibit the malignant behavior of ESCC cells. We provide evidence that Ku80 has unrecognized roles in carcinogenesis and development of ESCC.