A meta-analysis of predictive value of blood biomarkers in gestational trophoblastic neoplasia.

Background: Neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) have been reported to play a diagnostic and predictive role in gestational trophoblastic disease. However, the conclusions are still ambiguous. This meta-analysis aimed to evaluate the combined predictive value of NLR and PLR in the malignant progression of gestational trophoblastic disease. Method: Electronic databases including PubMed, Embase, the Cochrane Library, Web of Science, Chinese National Knowledge Infrastructure, Wanfang and China Biomedical Literature Database were searched for the relevant literature published up to 1 October 2022. Study selection and data extraction were performed independently by two reviewers. All analyses were performed using Revman, MetaDisc and STATA software. Results: A total of 858 patients from five studies were included in this meta-analysis. The pooled sensitivity and specificity of NLR were 0.8 (95% CI: 0.71-0.88) and 0.73 (95% CI: 0.69-0.76), respectively, and the area under curve of the summary receiver operating curve was 0.81. The pooled sensitivity and specificity of PLR were 0.87 (95% CI: 0.75-0.95) and 0.49 (95% CI: 0.44-0.54), respectively, and the area under curve of the summary receiver operating curve was 0.88. I2 statistic and Deek's funnel plot showed no heterogeneity and publication bias. Conclusion: NLR can accurately predict the progression from hydatidiform mole to gestational trophoblastic neoplasia and is a promising biomarker in further follow-up.

Effect of lung metastasis on the treatment and prognosis of patients with gestational trophoblastic neoplasia: A systematic review and meta-analysis.

INTRODUCTION: Gestational trophoblastic neoplasia (GTN) is a highly invasive tumor, mainly spreading to the lungs. However, lung metastasis in GTN is usually not considered as an adverse prognostic factor. Therefore, the aim of this study was to summarize the results of previous studies and evaluate the effects of lung metastasis on the treatment and prognosis of GTN. MATERIAL AND METHODS: The study was prospectively registered in PROSPERO (CRD42023372371). Electronic databases including PubMed, Embase, the Cochrane Library, Chinese National Knowledge Infrastructure, Wanfang, and China Biomedical Literature Database were used for a systematical search of relevant studies published up to November 21, 2022. The observational studies reporting the clinical outcomes of GTN patients with and without lung metastasis were selected. The incidences of resistance, relapse, and mortality of GTN patients were extracted and successively grouped based on the presence of lung metastasis. The pooled relative risks (RRs) and 95% confidence interval (95% CI) of the eligible studies were calculated. The qualities of included studies were assessed with the Newcastle-Ottawa Scale and the certainty of evidence was graded based on the GRADE. The meta-analysis was performed using Stata 12.0 and GradePro software. RESULTS: Five publications with 3629 GTN patients were included. The meta-analysis revealed that the GTN with lung metastasis was strongly correlated with first-line chemoresistance (pooled RR = 1.40, 95% CI: 1.22 to 1.61, p < 0.001), recurrence (pooled RR = 3.03, 95% CI: 1.21 to 7.62, p = 0.018), and disease-specific death (pooled RR = 22.11, 95% CI: 3.37 to 145.08, p = 0.001). Ethnicity was also an important factor and Caucasian GTN patients with lung metastasis showed a higher risk of recurrence as revealed by the subgroup analysis (pooled RR = 5.10, 95% CI: 2.38 to 10.94, p < 0.001). CONCLUSIONS: GTN patients with lung metastasis exhibited a higher risk of chemoresistance, relapse, and disease-specific death. Patients with lung metastasis among the Caucasian population had a higher risk of recurrence than Asian populations. Therefore, the presence of lung metastases might be considered as a high-risk factor for prognosis of GTN and deserves more attention in the choice of first-line chemotherapy regimens and follow-up.

Cytocompatibility of pH-sensitive, chitosan-coated Fe3O4 nanoparticles in gynecological cells.

Nanoparticles that contact human cells without damaging basic human tissues are becoming more widely used in medicine. Efficient delivery to the intracellular target cell or compartment through the cell membrane must be achieved with minimal cytotoxicity to healthy cells. Fe3O4 nanoparticles have been widely used in biomedical research for their magnetic, non-toxic, and biocompatible properties. However, the effects of Fe3O4 nanoparticles coated with chitosan (CS) on gynecological cells are unclear. In this study, the Fe3O4 nanoparticles were coated with CS to enhance their cytocompatibility and dispersion in water. These CS-Fe3O4 nanoparticles were taken up by gynecological cells and did not affect cell viability in vitro. They have greater cytocompatibility in acidic environments than normal Fe3O4 nanoparticles and have the potential for drug delivery into gynecological cells.

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.

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.

Clinical characteristics and outcomes of extrauterine epithelioid trophoblastic tumors.

BACKGROUND: Epithelioid trophoblastic tumor (ETT) derived from intermediate trophoblasts is one type of gestational trophoblastic neoplasia (GTN), and it accounts for less than 2% of all gestational trophoblastic diseases (GTD). Extrauterine ETT is extremely rare, and there is currently no consistent strategy for its treatment and management. Therefore, the aim of the study is to analyze and summarize the clinicopathologic features of extrauterine ETT with or without metastasis. METHOD: The Web of Knowledge, Google Scholar, EMbase, congress of library, and PubMed were searched for extrauterine ETT without primary uterine lesions. All available data were extracted from published case reports or serial case reports, and then, the clinical and pathological characteristics were analyzed. RESULTS: Twenty-two clinical studies consisting of 27 patients diagnosed with extrauterine ETT, according to the given inclusion and exclusion criteria, were included in the study. A total of 27 cases of extrauterine ETT were identified. Of these cases, four (14.81%) were located in the lungs, three (11.11%) in the ovaries, two (7.41%) in the vagina, and eight (29.63%) patients had other primary lesions. The patients originated from different continents, with 59% located in Asia and 26% in North America. Among 23 patients, the antecedent pregnancy prior to the diagnosis was full-term in 12 cases, abortion in 6 cases, hydatidiform mole in 3 cases, and invasive mole in 1 case. From the available antecedent information on pregnancy, the median interval from pregnancy to diagnosis of extrauterine ETT was 4 years. Additionally, the median gravidity and para of the patients was three times and two times, respectively. The median hCG titer was 14,374 mIU/mL in 5 patients, and the mean ß-HCG titer was 3,724,805 mIU/mL in 14 patients. For all patients, the disease was confined to extrauterine ETT at diagnosis. From the available information, 20 cases were successfully treated by extraction of local lesions, and 12 cases received chemotherapy. Diagnosis was confirmed by histological tests. The Ki-67 staining ranged from 8.7 to 80%, and tumors were positive for hCG, PLAP, EMA, and p63. CONCLUSION: In this study, we observed that abnormal levels of serum hCG titers and the local presentation of lesions with varying intervals after antecedent term pregnancy were the most common presenting features of extrauterine ETT. In addition, we found that the extraction of extrauterine lesions was needed for the treatment of extrauterine ETT. Of course, the follow-up was also important.

Biocompatible carbon-doped MoSe2 nanoparticles as a highly efficient targeted agent for human renal cell carcinoma.

MoSe2 is a typical transition-metal dichalcogenide material, and many researches have been focused on using its property of near infrared strong absorption for laser mediated photothermal cancer treatment. However, the anti-canter effect of MoSe2 and its possible mechanism in renal cell carcinoma (RCC) is still unclear. RCC has high incidence of metastasis, which is known as one of the most lethal malignancies in the urological system. This study revealed that the carbon-doped MoSe2 particles can obviously inhibit proliferation for 786-O and ACHN cells. Meanwhile, the carbon-doped MoSe2 nanoparticles have little impact on the viability of KH-2 cells in vitro. The mechanism analysis revealed that the carbon-doped MoSe2 particles have hydrogen bond effect in aqueous solution, and the particle aggregation effect caused the KH-2 cells to have high viability. The carbon-doped MoSe2 nanoparticles with minimal toxicity may be a potential therapeutic candidate against RCC.

Secreted Frizzled Related Protein 2 Modulates Epithelial-Mesenchymal Transition and Stemness via Wnt/ß-Catenin Signaling in Choriocarcinoma.

BACKGROUND/AIMS: Choriocarcinoma (CC) is a highly aggressive gestational trophoblastic neoplasia; however, the underlying molecular mechanisms of its invasiveness and metastasis remain poorly understood. Human secreted frizzled-related protein 2 (SFRP2) could function as a tumor promoter or suppressor in different tumors, yet the role it plays in CC's invasion and metastasis is thoroughly unclear. The current study was aimed to explore the function and underlying mechanism of SFRP2 in CC. METHODS: The expression of SFRP2 in CC tissues was examined via immunohistochemistry. The methylation level and expression of SFRP2 in CC cell lines, JEG-3 and JAR were examined via bisulfite sequencing PCR (BSP), western blotting and quantitative RT-PCR. The biological role of increasing expressed SFRP2 through its promoter demethylation with 5-Aza-2'-deoxycytidine (5-Aza) was examined by a series of in vitro functional studies. Furthermore, lentivirus transfection technology was adopted to investigate the biological roles of SFRP2 knockdown in JEG-3 and JAR cells in vitro and in vivo. Moreover, its downstream signaling pathway was investigated. RESULTS: SFRP2 was downregulated in CC tissues, and its expression was inversely related to its promoter hypermethylation frequency in JEG-3 and JAR cells. Increased SFRP2 through its promoter demethylation inhibited cell migration, invasion and colony formation in JEG-3 and JAR cells, whereas decreased SFRP2 reversed the epithelial-mesenchymal transition (EMT) process and stemness in JEG-3 and JAR cells both in vitro and vivo. Mechanistically, SFRP2 regulated the EMT and stemness of CC cell lines via canonical Wnt/ß-catenin signaling, validated by the usage of a Wnt activator and inhibitor. CONCLUSION: The current study indicates that downregulated SFRP2 has potent tumor-promotive effects in CC through the modulation of cancer stemness and the EMT phenotype via activation of Wnt/ß-catenin signaling in vitro and in vivo.

Association between RAD51 135 G/C polymorphism and risk of 3 common gynecological cancers: A meta-analysis.

AIM: Available data concerning the association between RAD51 135G/C (rs1801320) polymorphism and the risk of 3 common gynecological cancers still could not reach a consensus. Thus, we conducted a meta-analysis to explore the relationship. METHODS: Several electronic databases and bibliographies of relevant articles were screened to identify the studies up to July 2017. Then a meta-analysis was performed to evaluate the connection between 3 common gynecological tumors' susceptibility and RAD51 135G/C polymorphism in different inheritance models. Simultaneously, we did subgroup analysis and sensitivity analysis if necessary. RESULTS: A total of 11 articles including 14 studies involving 4097 cases and 5890 controls were included in this meta-analysis. Overall, RAD51 135G/C polymorphism increased the risk of 3 common gynecological tumors. The subgroup analysis stratified by cancer types- endometrial carcinoma (EC) and ovarian cancer (OC)-showed that RAD51 135G/C polymorphism increased the risk of EC: allele model (C vs G: odds ratio [OR] = 4.32, 95% confidence interval [CI] = 2.63-7.10, P < .00001), dominant model (CC + GC vs GG: OR = 2.28, 95% CI = 1.44-3.60, P = .004), recessive model (CC vs GC + GG: OR = 10.27, 95% CI = 14.71-22.38, P < .00001), and homozygous model (CC vs GG: OR = 7.26, 95% CI = 3.59-14.68, P < .00001), but there was no significant association between RAD51 135G/C polymorphism and OC. In the subgroup analysis stratified by source of controls, a significantly increased risk was observed in hospital-based studies. Nevertheless, the data showed RAD51 135G/C polymorphism had no link in population-based studies. CONCLUSIONS: This meta-analysis suggested that RAD51 135G/C polymorphism was a risk factor for the three common gynecological tumors, especially for EC among hospital-based populations.

Association between XRCC1 polymorphisms and the risk of cervical cancer: a meta-analysis based on 4895 subjects.

The present meta-analysis was intended to explore the relationship between the X-ray repair cross complementing 1 (XRCC1) polymorphisms (Arg194Trp, Arg280His and Arg399Gln) and cervical cancer risk. Several electronic databases were searched systematically and bibliographies of relevant papers were identified carefully. Then, a meta-analysis was performed based on eligible studies in various genetic models. Pooled odds ratios (OR) with 95% confidence intervals (95% CI) were employed to evaluate the strength of associations between the XRCC1 polymorphisms and cervical cancer risk. Additionally, heterogeneity analysis and sensitivity analysis were done if necessary. Totally, 11 articles involving 2092 cases and 2803 controls were included. Taken together, there was no obvious association between the Arg194Trp or Arg280His polymorphism and cervical cancer risk. Considering the great heterogeneity, subgroup analysis was done, but the pooled result remained stable. Nevertheless, the association between the Arg399Gln polymorphism and cervical cancer risk showed distinct statistic significance in the allele model, dominant model, homozygous model and heterozygous model. In view of the exiting heterogeneity, we did subgroup analysis stratified by ethnicity, resulting in the fact that the Arg399Gln polymorphism was related to the decreased risk of cervical cancer. The Begg's test and Egger's test were used to find no publication bias. To conclude, the current meta-analysis indicated that the XRCC1 Arg399Gln polymorphism decreased the risk of cervical cancer, while the Arg194Trp and Arg280His polymorphisms were not associated with cervical caner risk. Certainly, a well-designed large-scale multicenter study is warranted to confirm the finding.