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.

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.

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.

Analysis of sex hormones and menstruation in COVID-19 women of child-bearing age.

RESEARCH QUESTION: Does SARS-CoV-2 infection have an effect on ovarian reserve, sex hormones and menstruation of women of child-bearing age? DESIGN: This is a retrospective, cross-sectional study in which clinical and laboratory data from 237 women of child-bearing age diagnosed with COVID-19 were retrospectively reviewed. Menstrual data from 177 patients were analysed. Blood samples from the early follicular phase were tested for sex hormones and anti-Müllerian hormone (AMH). RESULTS: Among 237 patients with confirmed COVID-19, severely ill patients had more comorbidities than mildly ill patients (34% versus 8%), particularly for patients with diabetes, hepatic disease and malignant tumours. Of 177 patients with menstrual records, 45 (25%) patients presented with menstrual volume changes, and 50 (28%) patients had menstrual cycle changes, mainly a decreased volume (20%) and a prolonged cycle (19%). The average sex hormone and AMH concentrations of women of child-bearing age with COVID-19 were not different from those of age-matched controls. CONCLUSIONS: Average sex hormone concentrations and ovarian reserve did not change significantly in COVID-19 women of child-bearing age. Nearly one-fifth of patients exhibited a menstrual volume decrease or cycle prolongation. The menstruation changes of these patients might be the consequence of transient sex hormone changes caused by suppression of ovarian function that quickly resume after recovery.

Distinct Clinical Characteristics and Risk Factors for Mortality in Female Inpatients With Coronavirus Disease 2019 (COVID-19): A Sex-stratified, Large-scale Cohort Study in Wuhan, China.

BACKGROUND: As the coronavirus disease 2019 (COVID-19) outbreak accelerates worldwide, it is important to evaluate sex-specific clinical characteristics and outcomes, which may affect public health policies. METHODS: Patients with COVID-19 admitted to Tongji Hospital between 18 January and 27 March 2020 were evaluated. Clinical features, laboratory data, complications, and outcomes were compared between females and males. Risk factors for mortality in the whole population, females, and males were determined respectively. RESULTS: There were 1667 (50.38%) females among the 3309 patients. The mortality rate was 5.9% in females but 12.7% in males. Compared with males, more females had no initial symptoms (11.1% vs 8.3%, P = .008). Complications including acute respiratory distress syndrome, acute kidney injury, septic shock, cardiac injury, and coagulation disorder were less common in females; critical illness was also significantly less common in females (31.1% vs 39.4%, P < .0001). Significantly fewer females received antibiotic treatment (P = .001), antiviral therapy (P = .025), glucocorticoids treatment (P < .0001), mechanical ventilation (P < .0001), and had intensive care unit admission (P < .0001). A lower risk of death was found in females (OR, .44; 95% CI, .34-.58) after adjusting for age and coexisting diseases. Among females, age, malignancy, chronic kidney disease, and days from onset to admission were significantly associated with mortality, while chronic kidney disease was not a risk factor in males. CONCLUSIONS: Significantly milder illness and fewer deaths were found in female COVID-19 inpatients and risk factors associated with mortality varied among males and females.

Do the Residual Lung Lesions Threaten Gestational Trophoblastic Neoplasia Patients?

OBJECTIVE: Although most gestational trophoblastic neoplasias (GTN) are sensitive to chemotherapy, the treatment strategy of patients who achieve normal ß-human chorionic gonadotropin (ß-hCG) after the completion of treatment but with residual lung lesions is undefined, let alone whether residual lung lesions threaten GTN patients with acceptable recurrent risk factors. METHODS: We observed 73 patients with stage III and stage IV GTN treated at the Department of Obstetrics and Gynecology, Tongji Hospital between September 2007 and August 2016. Among these patients, 46 women confirmed to have residual lung lesions with normalized ß-hCG titer levels at 6 weeks after the completion of treatment, and the other 27 were without residual lung lesions. Statistical analysis was used to compare the progression-free survival of these 73 patients. RESULTS: The follow-up period of all 73 patients ranged from 6 to 115 months. Six women relapsed with GTN. There were no significant statistical differences (P > 0.05) between the progression-free survival of the patients with residual lung lesions and those without, even in the subgroup of patients with GTN with recurrent risk factors. CONCLUSIONS: After the achievement of normalized ß-hCG by sufficient chemotherapy, residual lung lesions do not alter the prognosis of patients with GTN, even if the patients are with other recurrent risk factors.

Effects of cumulus cell removal time during in vitro fertilization on embryo quality and pregnancy outcomes: a prospective randomized sibling-oocyte study.

BACKGROUND: To investigate whether cumulus cell removal after a 3 h co-incubation of gametes can affect the outcomes of in vitro fertilization. METHODS: A prospective randomized sibling-oocyte study was performed in which sibling oocytes obtained from each patient were randomly assigned to either a 3 h or 20 h group (cumulus cells removed at 3 h or 20 h after insemination, respectively). Same origin embryos (either 3 h or 20 h) were transferred. The study participants were patients < 38 years old and with infertility due to tubal factors. The study outcomes included fertilization, embryo quality, and birth status. RESULTS: The study enrolled 172 patients, from whom 2275 oocytes were retrieved (1139 oocytes for the 3 h group and 1136 oocytes for the 20 h group). A total of 134 patients received embryo transfers (74 patients in the 3 h group and 60 patients in the 20 h group), and there were 54 live births (32 in the 3 h group and 22 in the 20 h group). When compared with patients in the 20 h group, patients in the 3 h group produced a larger number of optimal quality embryos, but had higher rates of polyspermy and low birth weight newborns. The two groups showed no differences in their rates of normal fertilization, pregnancy, and live birth. CONCLUSIONS: When compared with results obtained using a traditional cumulus cell removal protocol, early cumulus cell removal has both advantages and disadvantages. Further studies, and especially long-term outcome studies on newborns, need to be performed. TRIAL REGISTRATION: Current controlled trial ChiCTR-OOC-15006878.

The artificial cycle method improves the pregnancy outcome in frozen-thawed embryo transfer: a retrospective cohort study.

The aim of this retrospective cohort study was to investigate which preparation method is optimal for frozen-thawed embryo transfer (FET) treatment. Analyses were performed on 3160 FET cycles, including 654 cycles with a natural cycle (NC) protocol and 2506 cycles with an artificial cycle (AC) protocol. The primary outcome measures were the clinical pregnancy rate (CPR) and the live birth rate (LBR) per transfer. The Student's t-test, chi-square test and multiple logistic regression were used for statistical analysis. The CPR per transfer was 49.4% in the NC group and 58.6% in the AC group (OR = 1.270, 95% CI: 1.037-1.554). The LBR per transfer was 42.2% and 50.8% in the NC and AC groups, respectively (OR = 1.269, 95% CI: 1.037-1.552). Dividing the patients according to the type of transferred embryos, the CPR (67.3% versus 57.0%, p < 0.01) and LBR (58.8% versus 49.7%, p < 0.01) were higher after the AC protocol than after NC protocol in patients with blastocyst transfer. The NC and AC protocols yielded comparable CPR and LBR in the patients with cleavage embryo transfer. Our data indicate better pregnancy outcomes after the AC protocol than after the NC protocol. The AC protocol should be recommended in patients who were counseled before receiving FET treatment. Further studies are needed to confirm this finding.

The criteria for optimal down-regulation with gonadotropin-releasing hormone-agonist: a retrospective cohort study.

OBJECTIVE: The objective of this study is to investigate whether the degree of down-regulation using GnRH-agonists is associated with pregnancy outcomes. STUDY DESIGN: This retrospective analysis was performed on 2708 cycles from 2514 patients undergoing down-regulation with the luteal phase long protocol. The serum oestradiol (E2D) and luteinising hormone (LHD) levels, the diameter of the largest follicle (DLFD) and the endometrial-thickness (ENTD) after down-regulation were used to evaluate the degree of down-regulation. One-way analysis of variance with the Bonferroni adjustment, the chi-square test and multivariate logistic regression analyses were used for the statistical analysis. RESULTS: The cumulative clinical pregnancy rates (CCPR) and the cumulative live birth rates (CLBR) were higher in the cycles with E2D < 30 pg/ml (63.7%, OR = 1.405 (1.055-1.870) and 56.8%, OR = 1.372 (1.039-1.813)) and 30-55pg/ml (66.8%, OR = 1.439 (1.104-1.874) and 59.8%, OR = 1.397 (1.080-1.806)) than in those with E2D > 55 pg/ml (62.8% and 54.7%). There was a trend towards lower CCPRs and CLBRs in the cycles with DLFD > 10 mm or ENTD ≥ 6 mm; however, this difference was not significant. CONCLUSION: The degree of down-regulation is associated with ovarian response, pregnancy, and live birth. We propose the following criteria for optimal down-regulation: E2D 30-55 pg/ml, ENTD < 6 mm, and no apparent ovarian activity.

Regulation of endometrial receptivity by the highly expressed HOXA9, HOXA11 and HOXD10 HOX-class homeobox genes.

STUDY QUESTION: Are other HOX genes, in addition to HOXA10, involved in endometrial receptivity? SUMMARY ANSWER: The highly expressed HOXA9, HOXA11 and HOXD10 genes also appear to be involved in endometrial receptivity. WHAT IS KNOWN ALREADY: Within the HOX family of homeobox transcription factor genes are the leading candidates for the regulation of embryonic implantation. A crucial role of HOXA10 in endometrial receptivity has been well established. STUDY DESIGN, SIZE, DURATION: To identify HOX candidate genes, we performed data mining on all 39 human HOX genes in the 'Human body index' gene expression database of normal human tissue. The temporal and spatial expression pattern of four highly expressed HOX genes in the human endometrium was determined. To further investigate the function of these Hox genes, we used a robust in vivo mouse model in which we blocked maternal Hox gene expression. PARTICIPANTS/MATERIALS, SETTING AND METHODS: Analysis of a gene expression profile set in the public domain consisting of 504 samples representing 95 different normal human tissues, showed that in addition to HOXA10, also HOXA9, HOXA11, HOXB6 and HOXD10 mRNA showed increased expression in the human endometrium (16 samples). The temporal and spatial expression pattern of these four HOX genes throughout the menstrual cycle was determined in the endometrium from 27 female patients eligible for IVF-embryo transfer with a normal cycle by quantitative real-time PCR (qRT-PCR), western blot and immunohistochemistry. The role of maternal Hoxa9, Hoxa11 and Hoxd10 was assessed in a mouse implantation model by expression knockdown using RNA interference. Forty mice were transfected with Hoxa9-, Hoxa11- or Hoxd10-specific small hairpin RNA (shRNA) constructs or a vector control by injection into the uterine horn at Day 2 after vaginal plug detection (Day 1) (160 mice in total). The effects were examined by qRT-PCR and western blot at Day 4 and litter sizes counted at Day 9 of pregnancy. MAIN RESULTS AND THE ROLE OF CHANCE: HOXA10, HOXA9, HOXA11 and HOXD10 all showed increased expression during the mid-secretory phase of the menstrual cycle (P < 0.01). Knockdown of Hoxa9, Hoxa11 and Hoxd10 in the murine uterus resulted in significantly reduced average implantation rates (P < 0.01) and, with regard to four Hox target genes, also correlated with a significantly increased empty spiracles homolog 2 (Emx2) and insulin-like growth factor binding protein-1 (Igfbp1), and decreased integrin ß3 (Itgb3) and leukemia inhibitory factor (Lif), expression (P < 0.01). LIMITATIONS, REASONS FOR CAUTION: Menstrual cycle stage was not confirmed by serum hormone analysis. We verified the absence of significant differences in stage-specific expression of the reference genes used in our study (ACTB/Actb and GAPDH/Gapdh) and therefore possible limitations of this approach were minimized. In addition, the translatability of our data from a mouse model to patients needs to be investigated further. WIDER IMPLICATIONS OF THE FINDINGS: We provide evidence that three other HOX genes in addition to HOXA10 are involved in endometrial receptivity, and that part of their function is asserted through several known HOX target genes, suggesting the presence of a central HOX signal transduction pathway.

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.

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 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.

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.

Blastocyst culture and cryopreservation to optimize clinical outcomes of warming cycles.

Surplus embryos available for cryopreservation in fresh cycles are considered as having good potential for future use. However, the optimal stage of embryo cryopreservation remains unclear. In this study, 1190 patients with surplus embryos on day 3 were divided into two groups: cleavage-stage embryo cryopreservation (control group) and blastocyst cryopreservation (blastocyst group). The clinical outcomes of the subsequent warming cycles were evaluated. The proportion of cycles with blastocyst formation was 73.8% in the blastocyst group. Although in the blastocyst group, the cancellation rate of blastocyst transfer was increased due to lack of blastocysts available for cryopreservation, the blastocyst group achieved significantly higher rates of clinical pregnancy/cycle (43.2% versus 34.9%; P=0.003), pregnancy/transfer (59.5% versus 35.4%; P<0.001) and implantation (46.5% versus 22.2%; P<0.001) from the first warming cycle compared with the control group. In an embryo-number classified analysis, the clinical pregnancy rate was also higher in the blastocyst group. However, the cumulative pregnancy was similar between the two groups. Blastocyst culture as an embryo selection tool will not improve embryo viability but it will help patients to achieve pregnancy more quickly. Extended culture of surplus embryos to the blastocyst stage for cryopreservation optimizes the clinical outcomes.

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.

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.

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.