Hao Lin

Gut–Vaginal Microbiome Crosstalk in Ovarian Cancer: Implications for Early Diagnosis

Ovarian cancer remains a formidable global health burden, characterized by frequent late-stage diagnosis and elevated mortality rates attributable to its elusive pathogenesis and the critical lack of reliable early-detection biomarkers. Emerging investigations into the gut–vaginal microbiome axis have unveiled novel pathogenic mechanisms and potential diagnostic targets in ovarian carcinogenesis. This comprehensive review systematically examines the compositional alterations in and functional interplay between vaginal and intestinal microbial communities in ovarian cancer patients. We elucidate three principal mechanistic pathways through which microbial dysbiosis may drive oncogenesis: (1) estrogen-mediated metabolic reprogramming via β-glucuronidase activity; (2) chronic activation of pro-inflammatory cascades (particularly NF-κB and STAT3 signaling); (3) epigenetic silencing of tumor suppressor genes through DNA methyltransferase modulation. We propose an integrative diagnostic framework synthesizing multi-omics data—incorporating microbial profiles, metabolic signatures, pathway-specific molecular alterations, established clinical biomarkers, and imaging findings—within a multifactorial etiological paradigm. This innovative approach aims to enhance early-detection accuracy through machine learning-enabled multidimensional pattern recognition. By bridging microbial ecology with tumor biology, this review provides novel perspectives for understanding ovarian cancer etiology and advancing precision oncology strategies through microbiome-targeted diagnostic innovations.

Integration of pretreatment tumor markers in a nomogram model for prognostic prediction of FIGO stage I endometrial cancer: A multi‐institutional cohort study

AbstractObjectiveTraditionally, the prognosis of patients with FIGO stage I endometrial cancer is determined by clinicopathological risk factors. In this study, we assessed the potential contribution of pretreatment carcinoembryonic antigen (CEA) and carbohydrate antigen‐125 (CA‐125) levels to estimating the prognosis of these patients and aimed to develop and validate a prognostic nomogram.MethodsThis retrospective study included patients with FIGO stage I endometrial cancer who underwent treatment between January 2009 and December 2021 in the four institutes of Chang Gung Memorial Hospital. To identify optimal cutoff values of CEA and CA‐125 for predicting survival, receiver operating characteristic (ROC) curves were generated, the Kaplan–Meier method was used to estimate survival, and a Cox regression model was used to analyze the independent prognostic factors. Finally, a nomogram and calibration curve were constructed to predict patient survival probability.ResultsOf the 1559 patients evaluated, the optimal cutoff values of CEA and CA‐125 were 1.44 ng/mL (area under the ROC curve [AUC] 0.601) and 39.77 U/mL (AUC 0.503), respectively. Multivariate Cox regression analysis showed that pretreatment CEA (hazard ratio [HR] 2.11, 95% confidence interval [95% CI] 1.35–3.28), CA‐125 (HR 2.07, 95% CI 1.31–3.27), age >70 years (HR 12.54, 95% CI 5.05–31.11), myometrial invasion >50% (HR 1.69, 95% CI 1.03–2.73), non‐endometrioid histology (HR 1.83, 95% CI 1.14–2.95), high‐grade tumor (HR 2.41, 95% CI 1.46–3.97), and lymphovascular space invasion (HR 2.32, 95% CI 1.26–4.25) were significant variables associated with overall survival. These factors were used to construct the nomogram model, which showed good concordance and accuracy.ConclusionsIntegration of pretreatment CEA and CA‐125 in a prognostic nomogram is feasible. Our prediction model has the potential to assist clinicians in guiding appropriate clinical practice.

External validation of CEA and CA125 prediction model for lymph node metastasis in endometrial cancer: A multi-institute cohort study

Background We previously utilized pretreatment tumor markers Carcinoembryonic Antigen (CEA) and Cancer Antigen 125 (CA125) for predicting lymph node metastasis (LNM) in endometrioid endometrial cancer (EC). Objective The aim of this study was to externally validate a nomogram developed in our previous single-center retrospective study. Methods A multi-center validation study was conducted to recruit endometrioid EC patients from four branches of Chang Gung Memorial Hospital between 2009 and 2021, with patients participating in the original research being excluded. The previously established nomogram was applied with optimal cut-off values for CEA 1.4 ng/ml and CA125 40 U/mL identified through receiver operating characteristic (ROC) curves. The concordance index (C-index) was calculated to assess discrimination, and comparative negative predictive value (NPV) and negative likelihood ratio (NLR) were determined. Decision curve analysis (DCA) was plotted to evaluate our predictive model's clinical utility and net benefit. Results Overall, 1271 patients were included in this external validation study. The results demonstrated a C-index of 0.727, indicating moderate discrimination ability of the nomogram in predicting LNM in this independent cohort. Comparative analysis of NPV 97.2% and NLR 0.36 revealed performance metrics consistent with the original study, reinforcing the nomogram's potential clinical utility in ruling out the possibility of LNM if both pretreatment CEA and CA125 were less than 1.4 ng/ml and 40 U/mL, respectively. The DCA indicated that the nomogram provided clinical utility. Conclusion The reproducible performance metrics in the independent large sample cohort underscore the robustness and generalizability of utilizing CEA and CA125 as predictors of LNM in endometrioid EC, suggesting its potential as a simple tool for clinicians in preoperative decision-making regarding lymphadenectomy.

A comparative analysis of MMR immunohistochemistry panels: Evaluating the utility of four-protein versus two-protein panels in endometrial cancer patients

This study aimed to assess the accuracy of a two-protein panel for mismatch repair (MMR) immunohistochemistry (IHC) compared to a four-protein panel in a cohort of endometrial cancer patients. The study included patients diagnosed with endometrial cancer between January 2018 and December 2023 with patients underwent MMR IHC staining for the four-protein panel (MSH2, MSH6, MLH1, and PMS2) serving as the reference standard. Various combinations of two proteins were examined and evaluated for their accuracy against the four-protein panel. Sensitivity, negative predictive value (NPV), and negative likelihood ratio were calculated for each combination. McNemar's test was performed to assess discordance, and receiver operating characteristic (ROC) curves were generated to evaluate diagnostic accuracy. Of 593 patients, MMR deficiency defined as at least one protein loss was observed in 146 patients (24.62%). When compared with four-protein panel, the highest sensitivity was observed with the MSH6/PMS2 combination (99.32%), followed sequentially by MSH6/MLH1 (97.26%), MSH2/PMS2 (93.15%), MSH2/MLH1 (91.10%), MLH1/PMS2 (79.45%), and MSH2/MSH6 (21.92%). The MSH6/PMS2 combination also demonstrated the best NPV of 99.78% and negative likelihood ratio of 0.01, while MSH6/MLH1 showed satisfactory NPV of 99.11% and negative likelihood ratio of 0.03. McNemar's test revealed no statistical difference between the four-protein panel and the MSH6/PMS2 panel (p = 1.000), and the MSH6/MLH1 panel (p = 0.125). The two-protein panel, particularly MSH6/PMS2, offers high sensitivity and negative predictive value, suggesting its potential as a cost-effective alternative to the four-protein panel in MMR testing for endometrial cancer patients.

Elevated urinary phthalate levels in endometrial cancer patients: Evidence from a comparative study

Phthalates are common plasticizers with endocrine-disrupting properties. Although laboratory studies suggest links to estrogen-dependent cancers, their association with endometrial cancer (EC) in humans remains unclear. This study investigated urinary phthalate metabolite levels in relation to EC and explored potential lifestyle and dietary contributors to phthalate exposure. A total of 232 women, including 116 EC patients and 116 healthy controls, were enrolled. Urine samples were analyzed by UPLC-MS/MS to measure eight phthalate metabolites, adjusted for creatinine. Lifestyle and dietary information were collected via questionnaires. Logistic regression assessed associations between phthalate levels and EC, while Spearman's correlation examined inter-metabolite relationships. All eight metabolites were detected in over 90 % of participants, with significantly higher concentrations in the EC group. Among them, mono-benzyl phthalate (MBzP) was the only metabolite independently associated with EC (OR 3.712, 95 % CI 1.464-9.414, p = 0.006). Using a cutoff value of 0.145 µg/g Cr, EC remained the only independent predictor of elevated MBzP levels (OR 5.696, 95 % CI 2.572-12.615, p < 0.001). No significant associations were found between MBzP levels and lifestyle or dietary habits. Correlations among phthalate metabolites were generally consistent across groups, though MBzP showed weaker correlations, indicating potentially distinct exposure pathways. This study is the first to demonstrate an independent link between urinary MBzP levels and EC in humans. The lack of lifestyle or dietary influence highlights the complexity of exposure sources, emphasizing the need for further research to understand underlying mechanisms and environmental factors contributing to phthalate exposure.

Lifestyle factors and urine levels of organophosphorus flame retardants in endometrial cancer: insights from a case-control study

Organophosphate flame retardants (OPFRs) are commonly used in various consumer products to prevent fire hazards. However, OPFRs have been linked to several health problems, including cancer. This study aimed to investigate the association between urine levels of OPFRs and endometrial cancer (EC), and to explore the correlation between concentrations of parent OPFR compounds and their metabolites. Urine samples from 76 EC patients and 76 healthy controls were collected and analyzed for the levels of five common parent OPFRs and their respective metabolites. Propensity score matching was applied to account for differences in baseline characteristics between the two participant groups. Significantly higher levels of OPFRs in EC patients were identified, and logistic regression models were used to determine whether elevated OPFRs were associated with EC and to explore whether any lifestyle behaviors contributed to the increased OPFR levels. Spearman's rank correlation coefficients between the concentrations of the parent compounds and their metabolites were calculated. Out of the ten OPFRs studied, the median urine levels of bis(1,3-dichloro-2-propyl) phosphate (BDCPP), tris(2-butoxyethyl) phosphate (TBEP), and di-(2-butoxyethyl) phosphate (DBEP) were significantly higher in EC patients compared to healthy controls. After matching 41 patients with 41 controls, multiple logistic regression analysis revealed that only BDCPP (OR 4.274; 95% CI 1.172-15.592) was an independent factor associated with EC. A lifestyle questionnaire survey found that urine BDCPP levels were related to age (OR 4.294; 95% CI 1.015-18.164), meals eaten out (OR 4.238; 95% CI 1.454-12.354), and consumption of chilled-ready meals (OR 0.118; 95% CI 0.014-0.985). A positive correlation was only observed between the concentrations of TBEP and its metabolite DBEP; other correlations were not significant. We concluded that higher urine BDCPP level was an independent factor associated with EC, and higher BDCPP levels were related to aging, more meals eaten out, and fewer chilled-ready meals. These findings highlight the potential hazard of long-term OPFR exposure on the development of EC.

Molecular Interplay Between PTEN, ARID1A, PD-L1, and MMR in Asian Ovarian Clear Cell Carcinoma: Implications for Immunotherapy Response and Patient Stratification

Ovarian clear cell carcinoma (OCCC) represents a distinct histological subtype with a high prevalence in Asian populations and poor chemotherapy response. This study investigated molecular interactions between phosphatase and tensin homolog (PTEN), AT-rich interactive domain 1A (ARID1A), programmed death-ligand 1 (PD-L1), and mismatch repair (MMR) proteins in Asian patients with OCCC. Immunohistochemical analysis was performed on tissue microarrays from 69 OCCC cases. The expression of PTEN, ARID1A, PD-L1, and four MMR proteins was evaluated alongside clinical data. A high prevalence of PTEN loss (78.3%) and ARID1A deficiency (48.8%), with PD-L1 expression in 26.1% and MMR deficiency in 10.1% of cases, was observed. All PD-L1-positive tumors demonstrated concurrent PTEN loss (p = 0.007). MMR deficiency was significantly associated with ARID1A loss (p = 0.049). PTEN loss correlated with worse progression-free survival (PFS) in early-stage disease (p = 0.039). PTEN and ARID1A alterations represent early pathogenic events in Asian OCCC, with PTEN loss significantly impacting PFS in early-stage disease. The correlation between PTEN loss and PD-L1 expression, alongside ARID1A-MMR deficiency association, provides insights into OCCC’s immunological landscape and therapeutic vulnerabilities.

Effects of Icodextrin Solution (Adept®) on Ovarian Cancer Cell Proliferation in an In Vitro Model

Background and objective: Anti-adhesion barriers are currently used during ovarian cancer surgery to decrease adhesion-related morbidity. Adept® (4% icodextrin) solution, a liquid anti-adhesion material, has been widely used during gynecologic surgeries, though the risk of this barrier for oncologic surgery is controversial. The aim of this study was to determine the effect of Adept® solution on the proliferation of ovarian cancer cells. Materials and methods: We assessed the dose- and time-dependent effects of icodextrin on the growth and proliferation of OVCAR-3 and A2780 human ovarian tumor cell lines in vitro. Cell growth was determined by cell number counting. Expressions of cell cycle-regulation proteins (cyclin D1 and cyclin B1) were determined using Western blot analysis. Results: Adept® did not significantly increase ovarian cancer cell growth when tested at various concentrations (0, 1, 5, 10, 15, and 20%, equal to 0, 0.04, 0.2, 0.4, 0.6 and 0.8% icodextrin) and different time points (1–3 days) compared to control cells. Moreover, the protein levels of cyclin D1 and B1 were not overexpression-elevated in icodextrin-treated ovarian cancer cells, either with an increasing concentration or with an increasing treated time. These results demonstrated that Adept® does not activate the growth or proliferation of ovarian cancer cells in either a dose- or time-dependent manner. Conclusions: This study supports the use of Adept® solution as a safe anti-adhesion barrier for ovarian cancer surgery, though further in vivo studies are necessary.