Objective Ovarian cancer (OC) has the highest mortality among gynecologic malignancies. Angiopoietin-like protein 4 (ANGPTL4) is highly expressed in several solid tumors, but its role in OC metastasis remains unclear. This study aimed to investigate the regulatory mechanism of ANGPTL4 in OC progression. Methods We analyzed ANGPTL4 expression in OC tissues and cell lines using high-throughput sequencing, IHC, and bioinformatics, as well as its correlation with patient prognosis and tumor metastasis. Molecular biology experiments were conducted to investigate the underlying mechanisms by which ANGPTL4 promotes ovarian cancer metastasis, with a focus on its interactions with CDH5, ETV5, the AKT signaling pathway, and MMP2/9. Results ANGPTL4 was significantly upregulated in metastatic OC tissues and associated with worse OS, PFI, and DSS. Functionally, ANGPTL4 enhanced cell migration, invasion, and angiogenesis both in vitro and in vivo. Mechanistically, ANGPTL4 upregulated ETV5, which transcriptionally activated CDH5. Elevated CDH5 then triggered AKT phosphorylation and MMP2/9 expression, promoting metastasis. Conclusion This study is the first to untangle the molecular mechanism by which ANGPTL4 promotes ovarian cancer metastasis via activation of the ETV5/CDH5/p-AKT/MMP9 signaling axis, providing a theoretical foundation for novel therapeutic strategies targeting ANGPTL4 in ovarian cancer.

To distinguish and co-detect aneuploid CD31− tumor cells (TCs) and CD31+ tumor endothelial cells (TECs) may have significant diagnostic values for cervical cancer screening. However, there are very few relevant studies. In the present study, a novel “immunofluorescence staining integrated with fluorescence in situ hybridization (iFISH)” tumor tissue biopsy platform was applied to comprehensively investigate the clinical utilities of aneuploid TCs and TECs in all-stage cervical lesion smear specimens. A total of 196 patients were enrolled in this study. Immunofluorescence staining of p16 and Ki67 combined with FISH was applied to quantitatively co-detect and characterize subcategorized aneuploid CD31− TCs and CD31+ TECs in cervical cytological specimens. The Kruskal‒Wallis H test was used to compare the distributions of aneuploid TCs and TECs among all stages of cervical lesions and among the different high-risk HPV types (HPV16/18 and non-HPV16/18). The diagnostic value of detecting aneuploid TCs and TECs for high-grade squamous intraepithelial lesions (HSIL+) was investigated via receiver operating characteristic curve analysis. The number of total aneuploid CD31− TCs and their p16+ and/or Ki67+ (p16/Ki67+) subtypes increased markedly with the severity of cervical lesions, although a similar trend was not observed for aneuploid CD31+ TECs. The increase in aneuploid TCs resulted from HPV16/18 infection was mainly concentrated in low-grade squamous intraepithelial lesion(LSIL), whereas the increase caused by non-HPV16/18 infection was mainly concentrated in HSIL. To identify HSIL+, the area under the curve (AUC) of tetraploid TCs was the largest (0.739), followed by multiploid (≥ pentaploid) TCs (0.724) and triploid TCs (0.699). For the combined subtypes, the AUC of ≥ tetraploid TCs was 0.745, and their unique diagnostic value was clinically reflected by their high specificity. The quantity of CD31− aneuploid TCs was associated with the severity of cervical lesions. In HPV16/18 positive patients, aneuploid CD31− TCs were significantly increased in the LSIL. Moreover, aneuploid CD31− TCs exhibited remarkable specificity for detecting HSIL+. Further studies are required to expand the potential clinical utility of detecting CD31− aneuploid TCs.

Head and neck squamous cell carcinoma (HNSCC) is a highly aggressive malignancy characterized by a complex tumor microenvironment (TME) that plays a pivotal role in tumor initiation, progression, and immune evasion. Recent advancements have highlighted the intricate interplay between immune cell infiltration patterns, immune checkpoint dysregulation, and metabolic reprogramming in driving HNSCC immune escape. Despite these insights, significant challenges remain, including the incomplete understanding of specific immune evasion pathways and the lack of personalized therapeutic strategies. To address these gaps, this review introduces a novel “Trinity” regulatory network of immune evasion in HNSCC, encompassing: (1) metabolic reprogramming-mediated immune checkpoint modulation, (2) stromal cell-driven immune dysfunction, and (3) epigenetic remodeling fostering immune tolerance. This framework provides a theoretical foundation for the development of multi-targeted combination therapies and offers innovative strategies to overcome immune evasion. Additionally, this review systematically synthesizes the current understanding of the relationship between the HNSCC microenvironment and immune escape, with a focus on emerging immunotherapeutic approaches such as PD-1/PD-L1 inhibitors and CAR-T cell therapy. Leveraging cutting-edge single-cell sequencing and spatial transcriptomics, we elucidate the spatiotemporal heterogeneity of the HNSCC immune landscape and propose a new paradigm of “lineage plasticity-driven immune adaptation.” These insights not only advance our understanding of HNSCC biology but also pave the way for the development of precision immunotherapies aimed at improving patient survival and quality of life. By integrating multidisciplinary perspectives, this work underscores the importance of targeting the TME to achieve durable clinical responses and overcome immunotherapy resistance in HNSCC.

Abstract Background The prospective phase III multi-centre L-MOCA trial (NCT03534453) has demonstrated the encouraging efficacy and manageable safety profile of olaparib maintenance therapy in the Asian (mainly Chinese) patients with platinum-sensitive relapsed ovarian cancer (PSROC). In this study, we report the preplanned exploratory biomarker analysis of the L-MOCA trial, which investigated the effects of homologous recombination deficiency (HRD) and programmed cell death ligand 1 (PD-L1) expression on olaparib efficacy. Methods HRD status was determined using the ACTHRD assay, an enrichment-based targeted next-generation sequencing assay. PD-L1 expression was assessed by SP263 immunohistochemistry assay. PD-L1 expression positivity was defined by the PD-L1 expression on ≥ 1% of immune cells. Kaplan–Meier method was utilised to analyse progression-free survival (PFS). Results This exploratory biomarker analysis included 225 patients and tested HRD status [N = 190; positive, N = 125 (65.8%)], PD-L1 expression [N = 196; positive, N = 56 (28.6%)], and BRCA1/2 mutation status (N = 219). The HRD-positive patients displayed greater median PFS than the HRD-negative patients [17.9 months (95% CI: 14.5–22.1) versus 9.2 months (95% CI: 7.5–13.8)]. PD-L1 was predominantly expressed on immune cells. Positive PD-L1 expression on immune cells was associated with shortened median PFS in the patients with germline BRCA1/2 mutations [14.5 months (95% CI: 7.4–18.2) versus 22.2 months (95% CI: 18.3–NA)]. Conversely, positive PD-L1 expression on immune cells was associated with prolonged median PFS in the patients with wild-type BRCA1/2 [20.9 months (95% CI: 13.9–NA) versus 8.3 months (95% CI: 6.7–13.8)]. Conclusions HRD remained an effective biomarker for enhanced olaparib efficacy in the Asian patients with PSROC. Positive PD-L1 expression was associated with decreased olaparib efficacy in the patients with germline BRCA1/2 mutations but associated with improved olaparib efficacy in the patients with wild-type BRCA1/2. Trial registration NCT03534453. Registered at May 23, 2018.

This article has been retracted. Please see the Retraction Notice for more detail: https://doi.org/10.1186/s13048-022-01060-7.

This article has been retracted. Please see the Retraction Notice for more detail: https://doi.org/10.1186/s13048-022-01060-7.

根据目前对肿瘤的研究,人们认识到同一肿瘤在不同个体上的生物学特征和药物反应性都存在巨大的异质性,这是导致临床上对同一肿瘤采用相同治疗方法却产生不同效果的重要原因.因此,为了实现肿瘤个体化的精准治疗,人源性肿瘤组织异种移植(patient-derived xenografts,PDX)模型应运而生.PDX是一种可以保持原发肿瘤特征的良好模型,是通过将手术或活检获得的患者的肿瘤组织移植至免疫缺陷小鼠中而建立的,随后将小鼠数量扩增,然后给予不同的药物干预后进行药效学评价,再根据评估结果指导临床决策,从而实现肿瘤患者的个体化治疗[1].近年来,PDX模型由于可以较好地保留患者的组织病理学特征和遗传学特征,有望成为非临床和临床研究之间的桥梁[2].

Background Although global contraceptive coverage has increased significantly, high rates of unintended pregnancy remain the current global status quo. A comparative analysis of the differences and correlations of knowledge, attitude and practice (KAP) of sexual and reproductive health (SRH) of both partners will help guide public health work according to gender characteristics and needs, and reduce the occurrence of unintended pregnancy. Methods A questionnaire survey of people with unintended pregnancies including women and their male partners (n = 1,275 pairs) who sought help from the Shanghai General Hospital Affiliated to Shanghai Jiao Tong University School of Medicine from October 2017 to October 2021. Data were collected on sexual and reproductive health knowledge, attitudes, and practices in both partners who had unintended pregnancies. Chi-square test and Logistic regression were used to analyze the relationship between the occurrence of unintended pregnancy and KAP and its influencing factors. Paired odds ratio and McNemar's test were used to estimate the difference and concordance of KAP between partners. Results This study included 1,275 partners with a mean age of 30.0 years. The partner's overall level of KAP is good. Compared with women, men had better knowledge (χ2 = 3.93, p = 0.047) and more active contraceptive practices (χ2 = 19.44, p < 0.001). In the analysis of partner concordance, male contraceptive intention was found to be better than female [matched pairs odds ratio (ORMP) = 2.56, p < 0.001], and the concordance of positive contraceptive practice between partners increased with male education [adjusted odds ratio (aOR) = 1.556, 95% confidence interval (CI) = 1.185–2.044, p = 0.001]. In partner-paired regression analysis, compared with good contraceptive knowledge in both men and women in the partner, the risk of negative contraceptive practice was 1.7 times (aOR = 1.721, 95% CI = 1.234–2.400, p = 0.001) higher with good contraceptive knowledge in women but negative in men, while women with poor contraceptive knowledge but men with good knowledge are 1.3 times (aOR = 1.349, 95% CI = 1.000–1.819, p = 0.05) more likely to have negative contraceptive practices. In addition, compared with partners with positive contraceptive attitudes, women with positive attitudes but negative men and women with negative attitudes but positive men had 1.7 and 1.4 times the risk of negative contraceptive practices, respectively. Conclusion The study found that unintended pregnancy occurs mainly in young people, and the younger age of first sexual intercourse, the low education background and the lack of discussion of contraception between partners are risk factors for not taking contraceptive measures. Men's better knowledge and contraceptive practices compared with female partners, and poor male contraceptive knowledge and attitudes may lead to a higher risk of negative contraceptive practices, the results suggest that male KAP plays an important role in promoting contraceptive use and reducing unintended pregnancy.

PURPOSE This phase III trial aimed to explore the efficacy and safety of fuzuloparib (formerly fluzoparib) versus placebo as a maintenance treatment after response to second- or later-line platinum-based chemotherapy in patients with high-grade, platinum-sensitive, recurrent ovarian cancer. PATIENTS AND METHODS Patients with platinum-sensitive, recurrent ovarian cancer previously treated with at least two platinum-based regimens were assigned (2:1) to receive fuzuloparib (150 mg, twice daily) or matching placebo for 28-day cycles. The primary end points were progression-free survival (PFS) assessed by blinded independent review committee (BIRC) in the overall population and PFS by BIRC in the subpopulation with germline BRCA 1/2 mutation. RESULTS Between April 30, 2019, and January 10, 2020, 252 patients were randomly assigned to the fuzuloparib (n = 167) or placebo (n = 85). As of July 1, 2020, the median PFS per BIRC assessment in the overall population was significantly improved with fuzuloparib treatment (hazard ratio [HR], 0.25; 95% CI, 0.17 to 0.36; one-sided P < .0001) compared with that with placebo. The HR derived from a prespecified subgroup analysis showed a consistent trend of benefit in patients with germline BRCA 1/2 mutations (HR, 0.14; 95% CI, 0.07 to 0.28) or in those without mutations (HR, 0.46; 95% CI, 0.29 to 0.74). The most common grade ≥ 3 treatment-emergent adverse events reported in the fuzuloparib group were anemia (25.1%), decreased platelet count (16.8%), and decreased neutrophil count (12.6%). Only one patient (0.6%) discontinued fuzuloparib because of treatment-related toxicity (concurrent decreased white blood cell count and neutrophil count). CONCLUSION Fuzuloparib as maintenance therapy achieved a statistically significant and clinically meaningful improvement in PFS for patients with platinum-sensitive, recurrent ovarian cancer versus placebo, regardless of germline BRCA 1/2 mutation, and showed a manageable safety profile.

The lymph node status is one of the most critical prognostic factors used in determining adjuvant treatment in endometrial cancer (EC). Lymphadenectomy is associated significant surgical and postoperative risks. The use of sentinel lymph node mapping (SLNM) has emerged as an alternative method to complete lymphadenectomy in EC. However, there remains controversy surrounding the use of SLNM in high-risk disease and its false-negative rate (3%). The authors previously identified miR-204-5p as a tumor-suppressor miRNA associated with lymph node metastasis in EC tissues. The present study demonstrated that serum miR-204-5p in patients with EC has the potential for use as an early diagnostic biomarker combined with SLNM to assess the lymph node status prior to surgery. The present study also aimed to identify the optimal cut-off value of serum miR-204-5p. The relative expression levels of miR-204-5p were detected using reverse transcription-quantitative PCR in the serum of 52 patients with EC (total SLNM). A total of 20 patients diagnosed with ovarian cysts, 20 patients diagnosed with myoma, and 20 participants diagnosed with endometrial polyps or endometrial hyperplasia were included as the control group. miR-204-5p expression was also detected in lymph node tissues using in situ hybridization. The results revealed that serum miR-204-5p expression was downregulated in patients with EC compared with its expression in patients with benign ovarian cysts, myoma and endometrial hyperplasia/polyps (P<0.01). In accordance with the final pathological evaluation, patients with EC with a positive SLN status had a significantly lower level of miR-204-5p compared with those with a negative SLN status (P<0.01). The area under the ROC curve of miR-204-5p was 0.923, 95% CI (0.847-1.000), and the diagnostic value had a sensitivity of 87.2% and specificity of 80.0%, with an optimal cut-off value of 0.253. On the whole, it was demonstrated that a lower miR-204-5p expression is associated with lymph node metastasis in these SLN(+) EC tissues, indicating that the downregulation of serum miR-204-5p in patients with EC has potential for use as an early diagnostic biomarker combined with SLNM. In addition, with a cut-off value of 0.253, it appeared optimal for the prediction of lymph node metastasis in EC.

Background Angiopoietin-like 4 (ANGPTL4) is highly expressed in a variety of neoplasms and promotes cancer progression. Nevertheless, the mechanism of ANGPTL4 in ovarian cancer (OC) metastasis remains unclear. This study aimeds to explore whether ANGPTL4 regulates OC progression and elucidate the underlying mechanism. Methods ANGPTL4 expression in clinical patient tumor samples was determined by immunohistochemistry (IHC) and high-throughput sequencing. ANGPTL4 knockdown (KD) and the addition of exogeneous cANGPTL4 protein were used to investigate its function. An in vivo xenograft tumor experiment was performed by intraperitoneal injection of SKOV3 cells transfected with short hairpin RNAs (shRNAs) targeting ANGPTL4 in nude mice. Western blotting and qRT-PCR were used to detect the levels of ANGPTL4, CDH5, p-AKT, AKT, ETV5, MMP2 and MMP9 in SKOV3 and HO8910 cells transfected with sh-ANGPTL4 or shRNAs targeting ETV5. Results Increased levels of ANGPTL4 were associated with poor prognosis and metastasis in OC and induced the angiogenesis and metastasis of OC cells both in vivo and in vitro. This tumorigenic effect was dependent on CDH5, and the expression levels of ANGPTL4 and CDH5 in human OC werepositively correlated. In addition, CDH5 activated p-AKT, and upregulated the expression of MMP2 and MMP9. We also found that the expression of ETV5 was upregulated by ANGPTL4, which could bind the promoter region of CDH5, leading to increased CDH5 expression. Conclusion Our data indicated that an increase in the ANGPTL4 level results in increased ETV5 expression in OC, leading to metastasis via activation of the CDH5/AKT/MMP9 signaling pathway.

Abstract Background HPV16 and 18 are the most common high-risk human papillomavirus (HPV) types causing cervical lesions. Women with HPV16 and/or 18(HPV16/18) infections are the main targets for cervical screening. But the HPV16/18 infection status is complex, and clarifying the risk of different infection patterns for cervical lesions is essential for subsequent management options. Our study aimed to assess the risk of HPV16 or 18 combined with other high-risk(HR) and/or low-risk(LR) HPV types for cervical lesions and their clinical characteristics. Methods In this retrospective study, we analyzed the clinical data of 3,217 patients with HPV16/18 infection.We divided HPV16 or HPV18 multiple infections into 8 patterns: HPV16 + HR, HPV16 + LR, HPV16 + HR + LR, HPV18 + HR, HPV18 + LR, HPV18 + HR + LR, HPV16 + 18 and HPV16 + 18 + other-HPV. The analysis of data was performed by Chi-square test and multinational logistic regression. P < 0.05 was considered statistically significant. Results Among the HPV16/18 positive population, multiple infections accounted for 41.5% (1336/3217), and multiple infections were mainly associated with LSIL while single infection was more associated with HSIL+. And the risk of cervical lesions varied with different infection patterns. After adjusting co-factors, multiple logistic regression showed that compared with single HPV16 or 18 infection, HPV16 + HR and HPV18 + HR had a higher risk for LSIL(OR = 1.659, 95%=1.278–2.153; OR = 1.744,95%=1.046–2.907) while HPV16 + LR had a lower risk for HSIL+(OR = 0.477, 95%CI = 0.277–0.822). Conclusion Single HPV16 or 18 infection is more relevant to HSIL + with respect to multiple infections. Multiple infections may be transient that mainly lead to LSIL. Different infection patterns of multiple infections have different risks for cervical lesions, HPV16 or 18 combined with other HR-HPV are associated with a higher risk of LSIL, but HPV16 combined with LR-HPV decreases the risk of HSIL+. We propose that there is antagonistic relationship between HPV16 and some LR-HPV types.

Background We demonstrated that drinking hydrogen-rich water (HRW) inhibits endometrial tumor growth in our previous work. This research is to identify differentially expressed proteins (DEPs) between HRW and purified water groups in a xenograft mouse model of endometrial cancer (EC). Methods Samples were analyzed using tandem mass tags (TMTs) coupled with liquid chromatography-tandem mass spectrometry (LC-MS/MS). DEPs were identified using bioinformatics to determine potential molecular functions and immunohistochemical (IHC) staining. Results In total, 11 DEPs were identified in the HRW group relative to the control. The up-regulated proteins included Gatad1, Ttyh3, Nek4, Dyrk2, and Gimap1, while the down-regulated proteins included SP1, Msl1, Plekha7, Dtwd2, MSRA, and KRAS. Gene Ontology (GO) annotations and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways were associated with the binding region, biological regulation, endocrine resistance, estrogen signaling, choline metabolism in cancer and human cytomegalovirus infection. Furthermore, network analysis indicated that KRAS and MSRA interact with YWHAE. KRAS, YWHAE and SP1 were strongly expressed, while MSRA was weak expressed in atypical hyperplasia and EC tissue as well as in HRW group in xenograft tumor tissue. Conclusions KRAS, YWHAE, SP1 and MSRA might be regarded as focused biomarkers to assess the prognosis of EC.

全世界每年约新增 239000 例卵巢癌( ovarian cancer,OC)病例和152000 例OC死亡病例.OC在女性的恶性肿瘤中发病率排第七[1-2].据统计,2019 年美国OC新发病例约22530 例,死亡病例约13980 例[3].尽管大多数患者最初对常规治疗有反应,但超过70％的患者在诊断后的5 年内出现疾病复发或死亡.上皮性卵巢癌( epithelial ovarian cancer, EOC )是 OC 最常见的病理类型,占OC的50％ ～70％,极易复发,复发性EOC无法治愈,目前治疗目的主要是改善患者生存质量,延长患者无进展生存期( progression free survival,PFS)及总生存期(overall survival,OS).但可选的治疗方案有限,并且多以中老年患者居多,大部分患者不能耐受反复化疗所带来的不良反应.

Abstract Purpose: Fluzoparib (PARP inhibitor) showed promising antitumor activity for advanced ovarian cancer in a phase I study. This study aimed to assess the efficacy and safety of fluzoparib in patients with germline BRCA1/2-mutated recurrent ovarian cancer. Patients and Methods: This open-label, multicenter, single-arm, phase II study enrolled patients with platinum-sensitive recurrent ovarian cancer and germline BRCA1/2 mutation who had previously received two to four lines of platinum-based chemotherapy. Fluzoparib 150 mg was administered orally twice daily. The primary endpoint was independent review committee (IRC)-assessed objective response rate per RECIST v1.1. Results: A total of 113 patients were enrolled and received at least one dose of fluzoparib. As of data cutoff on March 21, 2020, the median follow-up period was 15.9 months (interquartile range, 13.5–18.5). The IRC- and investigator-assessed objective response rates were 69.9% [95% confidence interval (CI), 60.6–78.2] and 70.8% (95% CI, 61.5–79.0), respectively. The objective response rates were similar across all prespecified subgroups. The median IRC- and investigator-assessed progression-free survival was 12.0 months (95% CI, 9.3–13.9) and 10.3 months (95% CI, 9.2–12.0), respectively. The 12-month survival rate was 93.7% (95% CI, 87.2–96.9). Grade ≥3 adverse events occurred in 63.7% (72/113) of the patients, with the most common one being anemia/decreased hemoglobin. Adverse events that led to treatment interruption, dose reduction, and discontinuation occurred in 39.8%, 34.5%, and 0.9% of patients, respectively. One treatment-related death occurred. Conclusions: Fluzoparib demonstrated promising antitumor activity and acceptable safety profile in germline BRCA1/2-mutated, platinum-sensitive relapsed ovarian cancer. Thus, fluzoparib might be a novel treatment option for this population.

Abstract Background Lymph node status is one of the most important prognosis factors in determining adjuvant treatment in endometrial cancer (EC). However, lymphadenectomy bears significant surgical and postoperative risks. The use of the sentinel lymph node mapping (SLNM) has emerged as an alternative method to complete lymphadenectomy in EC. There remains controversy surrounding the SLNM in high-risk disease and its false negative rate (3%). We previously identified miR-204-5p is tumor suppressor miRNA associated with lymph node metastasis in endometrial cancer tissues. Here, we report serum miR-204-5p in EC patients have potential early diagnostic value combined with sentinel lymph node mapping. Methods The relative expression levels of miR-204-5p were detected by quantitative RT-PCR in the serum of 52 EC patients (total SLNM), 20 benign ovarian cyst patients and 20 myoma patients. The miR-204-5p expression was also detected in endometrial cancer tissues by in situ hybridization. Results Our results showed that serum miR-204-5p expression was down-regulated in EC patients than that in the benign ovarian cyst or myoma patients (p < 0.01).In accordance with final pathological evaluation, positive SLN EC patients have a significant lower level of miR-204-5p compared with negative SLN EC patients. The area under the ROC curve of miR-204-5p was 0.923, 95% CI(0.847, 1.000), and the diagnostic value with a sensitivity of 87.2% specificity of 80.0%. Conclusions Lower miR-204-5p expression is associated with lymph node metastasis in these SLN(+) EC tissues, indicate that down-regulation of serum miR-204-5p in EC patients have potential early diagnostic value combined with sentinel lymph node mapping.

Ovarian cancer (OC) is one of five leading causes of cancer related death among women worldwide. Although treatment has been improving, the survival rate has barely improved over the past 30 years. The fatality rate is due to asymptomatic early signs and the lack of long-term effective treatment strategies for advanced disease. Angiogenesis is an important process in tumour growth and metastasis and is the creation of new blood vessels from existing blood vessels. It is a dynamic and complex process involving various molecular regulatory pathways and multiple mechanisms. The inhibition of angiogenesis has become a recognized therapeutic strategy for many solid tumours. While benefits in progression-free survival have been observed, the OS is far from satisfactory for OC patients who receive antiangiogenic therapy. In this article, the present research status of angiogenesis in OC was reviewed and the reasons for poor antiangiogenic therapeutic effects was explored with the aim to identify potential therapeutic targets that may improve the effect of antiangiogenic therapies.