Overall survival associated with surgery, radiotherapy, and chemotherapy in metastatic vulvar cancer: A retrospective cohort study based on the SEER database.

Background: Large cancer registries help analyze the prognosis of rare malignancies, such as advanced vulvar cancer. This study aimed to compare the overall survival (OS) rates of patients with metastatic vulvar cancer who had undergone chemoradiotherapy and radiotherapy alone and identify prognostic factors using data from the Surveillance, Epidemiology, and End Results (SEER) registry. Methods: In this retrospective cohort study, we used the SEER database to identify patients with metastatic vulvar cancer diagnosed between 2000 and 2019. Propensity score matching was performed to balance the covariates. Kaplan-Meier curves and Cox models were used to analyze OS. Results: A total of 685 patients were included and divided into chemoradiotherapy and radiotherapy groups, and 400 patients were included after propensity score matching. The chemoradiotherapy group had higher OS in the matched cohort (hazard ratio [HR] = 0.7367; 95% confidence interval [CI]: 0.5906-0.9190; P = 0.0049) than the radiotherapy group, which was similar to that in the pre-matched cohort (P < 0.0001). Patients who had undergone surgery + radiotherapy with or without chemotherapy showed higher OS rates than those who had received radiotherapy with or without chemotherapy for patients aged <75 years and local tumor excision/destruction or surgical removal of the primary site was the recommended surgical choice (P < 0.05). Chemoradiotherapy is sufficient for patients ≥75 years of age. Conclusions: Patients with metastatic vulvar cancer should undergo surgery if they can tolerate it. Adjuvant chemoradiotherapy should be encouraged because this treatment modality was associated with higher OS than radiotherapy alone.

The remodeling of ovarian function: targeted delivery strategies for mesenchymal stem cells and their derived extracellular vesicles.

Premature ovarian insufficiency (POI) is an essential cause of reduced fertility and quality of life in young women. Mesenchymal stem cells (MSCs) and MSCs-derived extracellular vesicles (EVs) have the ability to migrate to damaged tissues and are considered as promising therapeutic approaches for POI. However, the homing ability and therapeutic efficacy of MSCs administered in vivo are still insufficient, and their potential tumorigenicity and multi-differentiation potential also bring many doubts about their safety. The targeting ability and migration efficiency of MSCs can be improved by genetic engineering and surface modification, thereby maximizing their therapeutic efficacy. However, the use of viral vectors also has increased safety concerns. In addition, EVs, which seem to be the current therapeutic alternative to MSCs, are still poorly targeted for distribution, although they have improved in terms of safety. This paper reviews the comparative therapeutic effects of MSCs and their derived EVs on POI, their biodistribution after in vivo administration, and the most important possible ovarian targeting strategies. Difficulties such as homogeneity and yield before clinical application are also discussed. This article will provide new insights into precision therapy and targeted drug delivery for female ovarian diseases.

Enhancing Oocyte Quality in Aging Mice: Insights from Mesenchymal Stem Cell Therapy and FOXO3a Signaling Pathway Activation.

Ovarian aging reduced the quality of oocytes, resulting in age-related female infertility. It is reported that mesenchymal stem cells (MSCs) therapy can improve age-related ovarian function decline and the success rate of in vitro maturation (IVM) in assisted reproductive therapy. In order to investigate the effectiveness and mechanisms of MSCs to enhance oocyte quality of cumulus oocyte complexes (COCs) in advanced age, this study focus on the respective functional improvement of oocytes and granulosa cells (GCs) from aging mice and further to explore and verify the possible mechanisms. Here, we studied a popular but significant protein of follicular development, Forkhead box O-3a (FOXO3a), which is a transcription factor that mediates a variety of cellular processes, but the functions of which in regulating oocyte quality in MSCs therapy still remain inconclusive. In this study, the RNA-seq data of metaphase II (MII) oocytes and GCs isolated from COCs confirmed that, GCs of immature follicles show the most potential to be the targeted cells of bone marrow mesenchymal stem cells (BMSCs) by FOXO3a signaling pathway. Furthermore, we demonstrated the effectiveness of BMSCs co-culture with aging COCs to enhance oocyte quality and found its mechanism to function via ameliorating the biological function of GCs by alleviating FOXO3a levels. These results provide significant fundamental research on MSCs therapy on ovarian aging, as well as offering guidance for raising the success rate of assisted reproductive technology such IVM in clinical and non-clinical settings.

Reversal of the immunosuppressive tumor microenvironment via platinum-based neoadjuvant chemotherapy in cervical cancer.

Background: Immunotherapy favors patients with tumors; however, only 3-26.3% of patients with cervical cancer benefit from single-agent immune checkpoint inhibitors. Combined immunotherapy and chemotherapy has been explored against tumor; however, the combination remains controversial. This study aimed to investigate the tumor immune microenvironment (TIME) and the effects of platinum-based neoadjuvant chemotherapy (NACT) in cervical cancer to identify the clinical value of combining chemotherapy with immunotherapy. Methods: Multiplex immunohistochemistry (IHC) with 11 markers (cluster of differentiation [CD]3, CD8, CD4, CD11c, CD68, forkhead box P3 [Foxp3], programmed cell death 1 [PD-1], programmed cell death 1 ligand 1 [PD-L1], indoleamine 2,3-dioxygenase [IDO], cyclin-dependent kinase inhibitor 2A [p16], and cytokeratin [CK]) was performed to evaluate TIME from 108 matched pre- and post-NACT cervical cancer samples. The mechanism of antitumor immunity triggered by NACT was explored using RNA sequencing (RNA-seq) from four paired samples and subsequently verified in 41 samples using IHC. Results: The infiltration rate of the CD8+ T cells in treatment-naive cervical cancer was 0.73%, and those of Foxp3+ regulatory T cells (Tregs) and IDO+ cells were 0.87% and 17.15%, respectively. Moreover, immunoreactive T cells, dendritic cells, and macrophages were more in the stromal than the intratumor region. NACT increased dendritic, CD3+ T, CD8+ T, and CD4+ T cells and decreased Tregs. The aforementioned alterations occurred predominantly in the stromal region and were primarily in responders. Non-responders primarily showed decreased Tregs and no increase in CD8+ T or dendritic cell infiltration. Furthermore, dendritic cells interacted more closely with CD3+ T cells after NACT, an effect primarily observed in responders. RNA-seq data revealed activation of the antigen receptor-mediated signaling pathway and upregulation of major histocompatibility complex (MHC) I and MHC II after chemotherapy, validated using IHC. Conclusions: NACT can reduce Tregs, and when tumor cells are effectively killed, antigen presentation is enhanced, subsequently activating antitumor immunity finitely. Our study provides the molecular characteristics and theoretical basis for the simultaneous or sequential combination of platinum-based NACT and immunotherapy for cervical cancer.

Mitochondria in Mesenchymal Stem Cells: Key to Fate Determination and Therapeutic Potential.

Mesenchymal stem cells (MSCs) have become popular tool cells in the field of transformation and regenerative medicine due to their function of cell rescue and cell replacement. The dynamically changing mitochondria serve as an energy metabolism factory and signal transduction platform, adapting to different cell states and maintaining normal cell activities. Therefore, a clear understanding of the regulatory mechanism of mitochondria in MSCs is profit for more efficient clinical transformation of stem cells. This review highlights the cutting-edge knowledge regarding mitochondrial biology from the following aspects: mitochondrial morphological dynamics, energy metabolism and signal transduction. The manuscript mainly focuses on mitochondrial mechanistic insights in the whole life course of MSCs, as well as the potential roles played by mitochondria in MSCs treatment of transplantation, for seeking pivotal targets of stem cell fate regulation and stem cell therapy.

Neoadjuvant chemotherapy plus camrelizumab for locally advanced cervical cancer (NACI study): a multicentre, single-arm, phase 2 trial.

BACKGROUND: Locally advanced cervical cancer constitutes around 37% of cervical cancer cases globally and has a poor prognosis due to limited therapeutic options. Immune checkpoint inhibitors in the neoadjuvant setting could address these challenges. We aimed to investigate the efficacy and safety of neoadjuvant chemo-immunotherapy for locally advanced cervical cancer. METHODS: In this single-arm, phase 2 trial, which was done across eight tertiary hospitals in China, we enrolled patients aged 18-70 years with untreated cervical cancer (IB3, IIA2, or IIB/IIIC1r with a tumour diameter ≥4 cm [International Federation of Gynecology and Obstetrics, 2018]) and an Eastern Cooperative Oncology Group performance status of 0 or 1. Eligible patients underwent one cycle of priming doublet chemotherapy (75-80 mg/m2 cisplatin, intravenously, plus 260 mg/m2 nab-paclitaxel, intravenously), followed by two cycles of a combination of chemotherapy (cisplatin plus nab-paclitaxel) on day 1 with camrelizumab (200 mg, intravenously) on day 2, with a 3-week interval between treatment cycles. Patients with stable disease or progressive disease received concurrent chemoradiotherapy, and patients with a complete response or partial response proceeded to radical surgery. The primary endpoint was the objective response rate, by independent central reviewer according to Response Evaluation Criteria in Solid Tumours, version 1.1. Activity and safety were analysed in patients who received at least one dose of camrelizumab. This study is registered with ClinicalTrials.gov, NCT04516616, and is ongoing. FINDINGS: Between Dec 1, 2020, and Feb 10, 2023, 85 patients were enrolled and all received at least one dose of camrelizumab. Median age was 51 years (IQR 46-57) and no data on race or ethnicity were collected. At data cutoff (April 30, 2023), median follow-up was 11·0 months (IQR 6·0-14·5). An objective response was noted in 83 (98% [95% CI 92-100]) patients, including 16 (19%) patients who had a complete response and 67 (79%) who had a partial response. The most common grade 3-4 treatment-related adverse events during neoadjuvant chemo-immunotherapy were lymphopenia (21 [25%] of 85), neutropenia (ten [12%]), and leukopenia (seven [8%]). No serious adverse events or treatment-related deaths occurred. INTERPRETATION: Neoadjuvant chemo-immunotherapy showed promising antitumour activity and a manageable adverse event profile in patients with locally advanced cervical cancer. The combination of neoadjuvant chemo-immunotherapy with radical surgery holds potential as a novel therapeutic approach for locally advanced cervical cancer. FUNDING: National Key Technology Research and Development Program of China and the National Clinical Research Center of Obstetrics and Gynecology.

The Dominant Mechanism of Cyclophosphamide-Induced Damage to Ovarian Reserve: Premature Activation or Apoptosis of Primordial Follicles?

Cyclophosphamide (CPM), a part of most cancer treatment regimens, has demonstrated high gonadal toxicity in females. Initially, CPM is believed to damage the ovarian reserve by premature activation of primordial follicles, for the fact that facing CPM damage, primordial oocytes show the activation of PTEN/PI3K/AKT pathways, accompanied by accelerated activation of follicle developmental waves. Meanwhile, primordial follicles are dormant and not considered the target of CPM. However, many researchers have found DNA DSBs and apoptosis within primordial oocytes under CPM-induced ovarian damage instead of premature accelerated activation. A stricter surveillance system of DNA damage is also thought to be in primordial oocytes. So far, the apoptotic death mechanism is considered well-proved, but the premature activation theory is controversial and unacceptable. The connection between the upregulation of PTEN/PI3K/AKT pathways and DNA DSBs and apoptosis within primordial oocytes is also unclear. This review aims to highlight the flaw and/or support of the disputed premature activation theory and the apoptosis mechanism to identify the underlying mechanism of CPM's injury on ovarian reserve, which is crucial to facilitate the discovery and development of effective ovarian protectants. Ultimately, this review finds no good evidence for follicle activation and strong consistent evidence for apoptosis.

Cut-off point of mature oocyte for routine clinical application of rescue IVM: a retrospective cohort study.

BACKGROUND: The rescue in vitro mature(Rescue IVM) technique allows the use of immature oocytes collected in conventional COH to obtain more mature oocytes for fertilization through in vitro maturation. Some studies have shown that Rescue IVM could improve clinical outcomes in patients undergoing IVF/ICSI, but the effectiveness and the indications for the clinical application of this technique remain controversial. It remains to be studied whether Rescue IVM should be universally applied in all conventional IVF/ICSI cycles. METHOD: This is a large retrospective cohort study that included a total of 22,135 female patients undergoing their first IVF treatment cycles. The effect of the number of mature oocytes(metaphaseII[MII]) on the cumulative live birth rate was investigated in a population with routine IVF/ICSI first. The receiver operating characteristic curve(ROC) analysis was used to explore the cut-off point of the number of MII affecting CLBR. Secondly, Patients undergoing ICSI with Rescue IVM were included in the analysis with those who underwent ICSI only during the same period, grouped according to the MII cut-off values. Multi-factor binary logistic regression and inverse probability weighting (IPW) were used to investigate whether Rescue IVM influenced the final cumulative live birth rate(CLBR). RESULTS: The CLBR increased with the number of MIIoocytes (P < 0.001). The ROC analysis showed the cut-off point for the number of MIIoocytes to have a significant effect on CLBR was 9 (sensitivity 0.715, specificity 0.656). Furthermore, 912 patients who underwent ICSI with Rescue IVM were included and compared to those who underwent ICSI only during the same period, and found Rescue IVM significantly increased the number of available MIIoocytes. For patients with MII numbers < 9, Rescue IVM significantly improves their clinical pregnancy rate(55.6% vs. 46.7%, P = 0.001) and CLBR(65.4% vs. 48.1%, P < 0.001), but not for those patients with MII numbers ≥ 9. CONCLUSION: This study further clarifies the candidates for the application of Rescue IVM technique: patients with an MII oocytes < 9 in a conventional IVF/ICSI cycle. In contrast, it is not necessary for patients who already have sufficient mature oocytes(≥ 9), to avoid over-medication.

Expectant treatment for angular pregnancy after assisted reproduction technology: a safe and patient-friendly treatment strategy.

Introduction: Currently, the treatment strategies for angular pregnancy in the first trimester after assisted reproduction technology (ART) are unclear. Improper treatment will cause unnecessary losses to patients, especially infertile patients, after ART. The purpose of this study was to clarify the pregnancy outcomes of expectant treatment for angular pregnancy post-ART and to provide a basis for the formulation of clinical treatment strategies. Method: This retrospective case series study was performed at the Reproductive Medicine Center of a university hospital. Maternal data and pregnancy outcomes were collected and analyzed for all patients diagnosed with angular pregnancies after ART between January 2016 and August 2021. The outcomes included live birth, term birth, premature birth, early pregnancy loss, fetal death, placental abruption, uterine rupture, maternal death, and hysterectomy. Results: A total of 78 patients were analyzed in this study, of whom 54 (69.2%) had live births, 44 (56.4%) had term births, 21 (26.9%) had an early pregnancy loss, 1 (1.3%) had mid-trimester missed abortion, 1 (1.3%) underwent mid-trimester labor induction due to fetal malformation, and 1 (1.3%) underwent uterine rupture. There were no cases of maternal death, placental abruption, or hysterectomies. Discussion: Angular pregnancy after ART is not as dangerous as that described in previous studies; most cases could be treated expectantly under close-interval follow-up and obtain live birth.

CAPA-IVM improves the cytoplasmic quality of in vitro-matured oocytes from unstimulated mice.

Ovarian tissue oocyte (OTO) in vitro maturation (IVM) is a strategy to improve fertility preservation efficiency. Here, the effects of capacitation IVM (CAPA-IVM) on OTO function were investigated. Immature cumulus-oocyte complexes (COCs) from unstimulated 28-day-old mouse ovaries (mimicking OTOs) underwent CAPA-IVM, standard IVM (S-IVM) or in vivo maturation following ovarian stimulation (OS; positive control), and oocyte meiotic maturation and cytoplasmic quality were assessed. CAPA-IVM resulted in improved oocyte meiotic maturation (P < 0.05) and cumulus expansion (P < 0.0001) compared to S-IVM, with expansion comparable to the OS group. MII OTO ROS was lower after CAPA-IVM than S-IVM (P < 0.0001) but not as low as in the OS group (P = 0.036). CAPA-IVM resulted in a better oocyte mitochondrial distribution than S-IVM (P < 0.05) and was similar to the OS group (P > 0.05). Mitochondrial membrane potential in MII OTOs was higher after CAPA-IVM than S-IVM and OS (P < 0.0001). Compared with S-IVM, CAPA-IVM resulted in lower rates of spindle/chromosome configuration and cortical granule distribution abnormalities (P < 0.05), which were similar to OS levels (P > 0.05). MII OTO intracellular Ca2+ levels were similar in the CAPA-IVM and OS groups (P > 0.05), while S-IVM decreased intracellular Ca2+ (P < 0.05). CAPA-IVM and S-IVM decreased mitochondrial Ca2+ levels (P < 0.05). CAPA-IVM increased expression of antioxidant genes (Sod2 and Sirt1) and Egfr (P < 0.05) but not apoptotic genes (Bcl2, Bax and Bcl2/Bax; P > 0.05). CAPA-IVM increased the OTO maturation rate and quality of oocytes from unstimulated mice to the extent that many features of oocyte cytoplasmic quality were comparable to superovulated in vivo matured oocytes.

Thin endometrium is associated with higher risks of preterm birth and low birth weight after frozen single blastocyst transfer.

Background: It has been demonstrated that a thin endometrium is associated with a lower chance of pregnancy, but there is a paucity of research into whether a thin endometrium adversely affects perinatal outcomes. Methods: This was a retrospective cohort study on 10098 frozen cycles with single blastocyst transfer, resulting in 5505 singleton clinical pregnancies, and 4314 singleton live births. Patients were divided into a thin endometrium group (<8 mm) and a normal endometrium group (≥8 mm). Multivariable logistic regression with restricted cubic splines, receiver operating characteristic curve, and multivariable linear model were used for statistical analysis. Results: The incidences of preterm birth (15.65 vs. 9.80%, aOR=1.69 [1.19-2.42]), low birth weight (8.40 vs. 4.10%, aOR=2.05 [1.27-3.30]) and gestational diabetes (6.87 vs. 4.17%, aOR=1.74 [1.05-2.90]) were all higher in the endometrial thickness (EMT) <8 mm group. The miscarriage rate was higher in the EMT <8 mm group than the EMT ≥8 mm group (27.91 vs. 20.39%, aOR=1.40 [1.10-1.79]). Conclusion: A thin endometrium may be associated with a higher incidence of preterm birth, low birth weight, and miscarriage. Therefore, embryo transfer should be performed with caution in these patients, and postponing to a later cycle with a thicker endometrium should be considered.

Aging conundrum: A perspective for ovarian aging.

Progressive loss of physiological integrity and accumulation of degenerative changes leading to functional impairment and increased susceptibility to diseases are the main features of aging. The ovary, the key organ that maintains female reproductive and endocrine function, enters aging earlier and faster than other organs and has attracted extensive attention from society. Ovarian aging is mainly characterized by the progressive decline in the number and quality of oocytes, the regulatory mechanisms of which have yet to be systematically elucidated. This review discusses the hallmarks of aging to further highlight the main characteristics of ovarian aging and attempt to explore its clinical symptoms and underlying mechanisms. Finally, the intervention strategies related to aging are elaborated, especially the potential role of stem cells and cryopreservation of embryos, oocytes, or ovarian tissue in the delay of ovarian aging.

Multi-biofunctional graphene oxide-enhanced poly-L-lactic acid composite nanofiber scaffolds for ovarian function recovery of transplanted-tissue.

In this study, we successfully constructed the new graphene oxide/poly-L-lactic acid (GO/PLLA) nanofiber scaffolds with a hydrophilic surface and porous network structure that were highly favorable for cell infiltration. When employed these new nanofiber scaffolds for a wide range of tissue engineering applications, it was expected to promote graft tissue survival and angiogenesis. The new GO/PLLA nanofiber scaffold with an appropriate concentration of 1.0 wt% was applied for the restoration of ovarian function and reserve in mice with primary ovarian insufficiency (POI). After co-transplanting the normal ovarian cortex loaded on these new nanomaterials into the in situ ovarian tissue of POI mice, the fusion of transplanted ovarian cortex with damaged ovarian tissue was improved, as well as the ovarian function and the follicle numbers. Moreover, angiogenesis was observed clearly and proved to exist in the transplanted tissue and nanomaterials, with the most conspicuous effect after co-transplantation with 1.0 wt% GO/PLLA nanofiber scaffold. In addition, nitric oxide (NO) production by phosphorylated endothelial nitric oxide synthase (p-eNOS) in vivo was proven to be involved in the effect of GO and PLLA on the improved survival rate of the transplanted ovarian cortex. This study provides a new method for the fertility preservation of ovarian tissue cryopreservation and transplantation, as well as a new strategy for the transplantation of other organs.

Identification of key genes and immune cell infiltration in recurrent implantation failure: A study based on integrated analysis of multiple microarray studies.

PROBLEM: Recurrent implantation failure (RIF) refers to a challenging topic in assisted reproductive technology (ART), the etiology of which may be attributed to impaired endometrial receptivity; however, the precise pathogenesis of RIF has not been thoroughly elucidated. METHOD OF STUDY: Four RIF microarray datasets were obtained from the Gene Expression Omnibus database and integrated by the "sva" R package. The differentially expressed genes (DEGs) were analyzed using the "limma" package and then GO, KEGG, GSEA, and GSVA were applied to perform functional and pathway enrichment analysis. The immune cell infiltration in the RIF process was evaluated by the CIBERSORT algorithm. Finally, the hub genes were identified through the CytoHubba and subsequently verified using two items of external endometrial data. RESULTS: 236 genes were differentially expressed in the endometrium of the RIF group. Functional enrichment analysis demonstrated that the biological functions of DEGs were mainly correlated to the immune-related pathways, including immune response, TNF signaling pathway, complement and coagulation cascades. Among the immune cells, γδ T cells decreased significantly in the endometrium of RIF patients. In addition, the key DEGs such as PTGS2, FGB, MUC1, SST, VCAM1, MMP7, ERBB4, FOLR1, and C3 were screened and identified as the hub genes involved in the pathogenesis of RIF. CONCLUSIONS: Abnormal immune response regulation of endometrium contributes to the occurrence of RIF, and γδ T cells may be the pivotal immune cells causing RIF. At the same time, the novel hub genes identified will provide effective targets for the prediction and therapy of RIF.

Body mass index is associated with miscarriage rate and perinatal outcomes in cycles with frozen-thawed single blastocyst transfer: a retrospective cohort study.

BACKGROUND: The association between body mass index (BMI) and IVF cycle outcomes remain inconclusive. In addition, the impact of BMI on perinatal outcomes has been less well-studied. The aim of this study was to assess the effects of BMI on pregnancy outcomes, as well as maternal and neonatal outcomes. METHODS: This was a retrospective cohort study on 10,252 frozen-thawed cycles with single blastocyst transfer between January 2016 and December 2019. Patients were divided into four groups: underweight (< 18.5 kg/m2), normal-weight (18.5-24 kg/m2), overweight (24-28 kg/m2), and obesity (≥ 28 kg/m2), according to the Chinese classification. Multivariate logistic regression and multivariate general linear model were used for statistical analysis. RESULTS: The rates of live birth and clinical pregnancy were comparable among groups. Miscarriage rate was higher in the obese women than that in the normal controls (27.51 vs. 20.91%, aOR = 1.453 (1.066-1.982)). Using the normal-weight women as reference, the underweight women had lower incidences of preterm birth (6.97 vs. 11.19%, aOR = 0.611 (0.422-0.884)), macrosomia (4.90 vs. 8.65%, aOR = 0.544 (0.353-0.837)) and large-for-gestational age (LGA, 11.18 vs. 16.54%, aOR = 0.643 (0.477-0.866)); the overweight women had higher prevalence of gestational diabetes (6.56 vs. 3.82%, aOR = 1.744 (1.232-2.468)), hypertension (4.42 vs. 2.32%, aOR = 1.822 (1.186-2.800)), macrosomia (12.93 vs. 8.65%, aOR = 1.596 (1.240-2.054)) and LGA (23.22 vs. 16.54%, aOR = 1.549 (1.270-1.890)); the obese women had higher incidences of preterm birth (16.87 vs. 11.19%, aOR = 1.646 (1.068-2.536)), cesarean delivery (93.98 vs. 87.91%, aOR = 2.078 (1.083-3.987)), gestational hypertension (4.82 vs. 2.32%, aOR = 2.138 (1.005-4.547)), macrosomia (14.88 vs. 8.65%, aOR = 1.880 (1.192-2.964)) and LGA (25.60 vs. 16.54%, aOR = 1.764 (1.218-2.555)). CONCLUSIONS: BMI has no significant effect on the chance of pregnancy or live birth, but obesity increases the risk of miscarriage. Underweight is associated with better maternal and neonatal outcomes, while overweight and obesity are associated with worse maternal and neonatal outcomes.

Clinical characteristics, pregnancy outcomes and ovarian function of pregnancy-associated breast cancer patients: a retrospective age-matched study.

BACKGROUND: Pregnancy-associated breast cancer (PABC) is a rare disease with increasing incidence. The prognosis, pregnancy outcomes and subsequent ovarian function of PABC patients are attracting attention. METHODS: Sixty-three PABC patients and 126 age-matched non-PABC patients were obtained in Tongji Hospital from January 2011 to September 2019. The clinical characteristics and ovarian function of PABC patients were compared with those of non-PABC patients. The pregnancy outcomes and neonatal outcomes of patients with breast cancer diagnosed during pregnancy (BCP) were described. Nonparametric tests, the χ2-test Kaplan-Meier, Cox regression and binomial logistic regression were used for analysis. RESULTS: PABC patients were diagnosed with a more advanced tumour stage (II: 47.6% vs. 45.2%, III: 33.3% vs. 19.8%, IV 3.2% vs. 0%, p = 0.003), which caused worse progression-free survival (PFS) (log-rank p = 0.0138) and breast cancer-specific survival (CSS) (log-rank p = 0.0076) than non-PABC patients. Tumour stage (III/IV vs. 0/I/II) (HR 16.017, 95% CI 5.830 ~ 44.006, p < 0.001) and endocrine therapy (HR 0.254, 95% CI 0.099 ~ 0.653, p = 0.004) were predictors of PFS. Tumour stage (III/IV vs. 0/I/II) (HR 30.875, 95% CI 7.232 ~ 131.820, p < 0.001), endocrine therapy (HR 0.200, 95% CI 0.049 ~ 0.818, p = 0.025) and targeted therapy (HR 0.143, 95% CI 0.028 ~ 0.743, p = 0.021) were predictors for breast CSS. Among the 15 BCP patients, 11 patients voluntarily continued their pregnancy, and the newborns had no obvious birth defects, either in 5 patients who received chemotherapy or in 6 patients who did not receive chemotherapy during pregnancy. Among the patients who received chemotherapy and did not receive endocrine therapy, 24 PABC patients and 48 non-PABC patients experienced chemotherapy-induced amenorrhea. There was no significant difference in resumption of menstruation between the two groups at 6 months and 12 months after the end of chemotherapy. No potential factors affecting resumption of menstruation were found. CONCLUSION: Pregnancy at diagnosis or within 1 year after delivery was not a risk factor for a worse prognosis in PABC patients. Compared with non-PABC patients, patients with PABC presented more aggressive tumour characteristics, which could mostly explain the worse prognosis observed in PABC patients. Receiving the appropriate regimen of chemotherapy in the second and third trimesters did not affect the maternal outcomes or neonatal outcomes of BCP patients. The special physiological state during pregnancy and lactation did not interfere with the damage of chemotherapy to ovarian function.

Application of Single-Cell RNA Sequencing in Ovarian Development.

The ovary is a female reproductive organ that plays a key role in fertility and the maintenance of endocrine homeostasis, which is of great importance to women's health. It is characterized by a high heterogeneity, with different cellular subpopulations primarily containing oocytes, granulosa cells, stromal cells, endothelial cells, vascular smooth muscle cells, and diverse immune cell types. Each has unique and important functions. From the fetal period to old age, the ovary experiences continuous structural and functional changes, with the gene expression of each cell type undergoing dramatic changes. In addition, ovarian development strongly relies on the communication between germ and somatic cells. Compared to traditional bulk RNA sequencing techniques, the single-cell RNA sequencing (scRNA-seq) approach has substantial advantages in analyzing individual cells within an ever-changing and complicated tissue, classifying them into cell types, characterizing single cells, delineating the cellular developmental trajectory, and studying cell-to-cell interactions. In this review, we present single-cell transcriptome mapping of the ovary, summarize the characteristics of the important constituent cells of the ovary and the critical cellular developmental processes, and describe key signaling pathways for cell-to-cell communication in the ovary, as revealed by scRNA-seq. This review will undoubtedly improve our understanding of the characteristics of ovarian cells and development, thus enabling the identification of novel therapeutic targets for ovarian-related diseases.

The Impact of Embryo Storage Time on Pregnancy and Perinatal Outcomes and the Time Limit of Vitrification: A Retrospective Cohort Study.

Background: The technique of embryo cryopreservation has been increasingly applied in clinical settings. However, there has been a concern about the safety and efficacy of long-term freezing of embryos. Therefore, the aim of this study was to evaluate whether storage time of vitrification had any effects on pregnancy as well as perinatal outcomes, further, to explore the appropriate time limit of vitrification. Methods: The study included women who underwent at least one frozen-thawed cycle with single embryo transfer between January 1st, 2016 and September 30th, 2019. Patients were assigned into 3 groups according to the storage time (<3 months, 3-12 months and >12 months) to evaluate the impact of embryo storage time on pregnancy and perinatal outcomes. To further investigate the time limit of vitrification, propensity score matching was used to compare the primary outcomes of patients with storage time of 1-3 years, 3-5 years, and >5 years to those stored for ≤1 year. Results: A total of 9806 frozen-thawed embryo transfer cycles were included in our study. After adjustment for confounding variables, no significant differences were found in pregnancy outcomes among groups. However, postponement of transfer increased the risks of large for gestational age and placenta previa. In addition, after propensity score matching, 171 cycles with storage time >5 years were matched with those ≤1 year, both the clinical pregnancy rate and live birth rate decreased significantly when the storage time exceeded 5 years. Conclusions: The duration of vitrification did not significantly affect the pregnancy outcomes within 5 years period. However, the clinical pregnancy rate and live birth rate both decreased significantly when the duration of vitrification exceeded 5 years. It is worth noting that the conclusion was drawn from a small sample study after propensity score matching and should be treated with caution. In addition, the cycles were from different time periods, which could have an impact on the results.

Differential immune responses in pregnant patients recovered from COVID-19.

Pregnant women are generally more susceptible to viral infection. Although the impact of SARS-CoV-2 in pregnancy remains to be determined, evidence indicates that the risk factors for severe COVID-19 are similar in pregnancy to the general population. Here we systemically analyzed the clinical characteristics of pregnant and non-pregnant female COVID-19 patients who were hospitalized during the same period and found that pregnant patients developed marked lymphopenia and higher inflammation evident by higher C-reactive protein and IL-6. To elucidate the pathways that might contribute to immunopathology or protective immunity against COVID-19 during pregnancy, we applied single-cell mRNA sequencing to profile peripheral blood mononuclear cells from four pregnant and six non-pregnant female patients after recovery along with four pregnant and three non-pregnant healthy donors. We found normal clonal expansion of T cells in the pregnant patients, heightened activation and chemotaxis in NK, NKT, and MAIT cells, and differential interferon responses in the monocyte compartment. Our data present a unique feature in both innate and adaptive immune responses in pregnant patients recovered from COVID-19.

Immune Response to COVID-19 During Pregnancy.

Pregnant women are generally more susceptible to viral infection. Although the impact of SARS-CoV-2 on pregnant women remains to be determined, evidence indicates that risks of adverse clinical outcomes are similar in pregnancy to the general population. Here we analyzed clinical symptoms and outcomes of 20 pregnant and 299 reproductive-aged non-pregnant female COVID-19 patients who were hospitalized during the same period. Laboratory measurements were compared among mild cases and healthy pregnant women. Our study found that pregnant patients showed enhanced innate immune response evident by higher neutrophils and C-reactive protein. Cytokines, chemokines, and growth factors (CCGFs) profiles from 11 pregnant and 4 non-pregnant COVID-19 patients and 10 healthy pregnant female patients, and lymphocyte subsets analysis of 7 pregnant patients and 19 non-pregnant patients, indicate suppressed cytokine storm and potential enhanced CD8+ T cell and NK cell activity in pregnant patients with COVID-19, which may be essential in contributing to the unique anti-SARS-CoV-2 response in pregnancy.