Fetal Hydrops Associated With 47,XXX: A Case Report and Literature Review.

This report aims to investigate the association between 47,XXX and fetal hydrops by examining a clinical case and performing a comprehensive review of the relevant literature. A 34-year-old Japanese woman, gravida 2, para 1, was diagnosed with fetal hydrops at 27 weeks' gestation. Prenatal testing revealed a 47,XXX karyotype. Interventions included thoracocentesis and a thoracoamniotic shunt. A cesarean delivery was performed at 34 weeks and the female neonate initially had respiratory challenges. After 69 days in the neonatal intensive care unit, the infant was discharged in stable condition, and the 47,XXX karyotype was confirmed. This case may add evidence suggesting an association between 47,XXX and fetal hydrops. Chromosomal abnormalities are causes of fetal hydrops, but its association with 47,XXX remains unclear. Providing comprehensive information on this condition to couples is crucial, and considering the inclusion of fetal hydrops in the list of associated conditions might be advisable.

Prognostic impact of the number of resected pelvic nodes in endometrial cancer: Japanese Gynecologic Oncology Group Study JGOG2043 post hoc analysis.

OBJECTIVE: This study aimed to determine whether the number of resected pelvic lymph nodes (PLNs) affects the prognosis of endometrial cancer (EC) patients at post-operative risk of recurrence. METHODS: JGOG2043 was a randomized controlled trial to assess the efficacy of three chemotherapeutic regimens as adjuvant therapy in EC patients with post-operative recurrent risk. A retrospective analysis was conducted on 250 patients who underwent pelvic lymphadenectomy alone in JGOG2043. The number of resected and positive nodes and other clinicopathologic risk factors for survival were retrieved. RESULTS: There were 83 patients in the group with less than 20 PLNs removed (group A), while 167 patients had 20 or more PLNs removed (group B). There was no significant difference in patients' backgrounds between the two groups, and the rate of lymph node metastasis was not significantly different. There was a trend toward fewer pelvic recurrences in group B compared with group A (3.5% vs. 9.6%; p=0.050). Although Kaplan-Meier analysis showed no statistically significant difference in survival rates between the two groups (5-year overall survival [OS]=90.3% vs. 84.3%; p=0.199), multivariate analysis revealed that resection of 20 or more nodes is one of the independent prognostic factors (hazard ratio=0.49; 95% confidence interval=0.24-0.99; p=0.048), as well as surgical stage, high-risk histology, and advanced age for OS. CONCLUSION: Resection of 20 or more PLNs was associated with improved pelvic control and better survival outcomes in EC patients at risk of recurrence who underwent pelvic lymphadenectomy alone and were treated with adjuvant chemotherapy.

Significance of definitive concurrent chemoradiotherapy for vulvar cancer: a Japanese Gynecologic Oncology Group nationwide survey study.

OBJECTIVE: This study aimed to show the results of radical radiation therapy (RT) and concurrent chemoradiotherapy (CCRT) for vulvar cancer (VC) based on data from a Japanese nationwide survey. MATERIALS AND METHODS: We collected data from 108 institutions on cases of VC diagnosed between January 2001 and December 2010. Patients with histologically proven squamous cell carcinoma and adenocarcinoma with curative intent were selected, and 172 patients with VC were included in this study. The collected data were analyzed for overall survival (OS) using the Kaplan-Meier method. Univariate and multivariate analyses were performed to examine the prognostic factors for patients with VC. RESULTS: The median follow-up period was 16.8 (range; 3.2-154.8) months. Fifty-five patients received CCRT, and 117 patients received RT alone. The 2-year OS rates (95% confidence interval [CI]) for stages I, II, III, and IV were 77.9% (55.8-100.0), 71.9% (53.8-89.9), 55.4% (42.5-68.3), and 41.5% (27.3-55.7) respectively. Univariate analyses showed that the FIGO stage (p = 0.001), tumor diameter (p = 0.005), and lymph node (LN) status (p = 0.001) were associated with OS. The concurrent use of chemotherapy resulted in a significantly longer OS in Stage III (p = 0.013). Multivariate analysis showed that the hazard ratios (95% CI) for tumor diameter, positivity for LN metastasis, and RT alone (no concurrent chemotherapy) were 1.502 (1.116-2.021), 1.801 (1.287-2.521), and 1.936 (1.187-3.159), respectively. CONCLUSIONS: Our analysis revealed that CCRT should be recommended, especially for Stage III VC patients. Further studies are warranted to determine who benefits from CCRT, considering primary tumor size and LN status. The study was registered at the University Hospital Medical Information Network (protocol number: UMIN000017080) on April 8th, 2015.

Targeting PDGF signaling of cancer-associated fibroblasts blocks feedback activation of HIF-1α and tumor progression of clear cell ovarian cancer.

Ovarian clear cell carcinoma (OCCC) is a gynecological cancer with a dismal prognosis; however, the mechanism underlying OCCC chemoresistance is not well understood. To explore the intracellular networks associated with the chemoresistance, we analyze surgical specimens by performing integrative analyses that combine single-cell analyses and spatial transcriptomics. We find that a chemoresistant OCCC subpopulation with elevated HIF activity localizes mainly in areas populated by cancer-associated fibroblasts (CAFs) with a myofibroblastic phenotype, which is corroborated by quantitative immunostaining. CAF-enhanced chemoresistance and HIF-1α induction are recapitulated in co-culture assays, which show that cancer-derived platelet-derived growth factor (PDGF) contributes to the chemoresistance and HIF-1α induction via PDGF receptor signaling in CAFs. Ripretinib is identified as an effective receptor tyrosine kinase inhibitor against CAF survival. In the co-culture system and xenograft tumors, ripretinib prevents CAF survival and suppresses OCCC proliferation in the presence of carboplatin, indicating that combination of conventional chemotherapy and CAF-targeted agents is effective against OCCC.

Clonal origin and genomic diversity in Lynch syndrome-associated endometrial cancer with multiple synchronous tumors: Identification of the pathogenicity of MLH1 p.L582H.

Lynch syndrome-associated endometrial cancer patients often present multiple synchronous tumors and this assessment can affect treatment strategies. We present a case of a 27-year-old woman with tumors in the uterine corpus, cervix, and ovaries who was diagnosed with endometrial cancer and exhibited cervical invasion and ovarian metastasis. Her family history suggested Lynch syndrome, and genetic testing identified a variant of uncertain significance, MLH1 p.L582H. We conducted immunohistochemical staining, microsatellite instability analysis, and Sanger sequencing for Lynch syndrome-associated cancers in three generations of the family and identified consistent MLH1 loss. Whole-exome sequencing for the corpus, cervical, and ovarian tumors of the proband identified a copy-neutral loss of heterozygosity (LOH) occurring at the MLH1 position in all tumors. This indicated that the germline variant and the copy-neutral LOH led to biallelic loss of MLH1 and was the cause of cancer initiation. All tumors shared a portion of somatic mutations with high mutant allele frequencies, suggesting a common clonal origin. There were no mutations shared only between the cervix and ovary samples. The profiles of mutant allele frequencies shared between the corpus and cervix or ovary indicated that two different subclones originating from the corpus independently metastasized to the cervix or ovary. Additionally, all tumors presented unique mutations in endometrial cancer-associated genes such as ARID1A and PIK3CA. In conclusion, we demonstrated clonal origin and genomic diversity in a Lynch syndrome-associated endometrial cancer, suggesting the importance of evaluating multiple sites in Lynch syndrome patients with synchronous tumors.

SLFN11 is a BRCA Independent Biomarker for the Response to Platinum-Based Chemotherapy in High-Grade Serous Ovarian Cancer and Clear Cell Ovarian Carcinoma.

BRCA1/2 mutations are robust biomarkers for platinum-based chemotherapy in epithelial ovarian cancers. However, BRCA1/2 mutations in clear cell ovarian carcinoma (CCC) are less frequent compared with high-grade serous ovarian cancer (HGSC). The discovery of biomarkers that can be applied to CCC is an unmet need in chemotherapy. Schlafen 11 (SLFN11) has attracted attention as a novel sensitizer for DNA-damaging agents including platinum. In this study, we investigated the utility of SLFN11 in HGSC and CCC for platinum-based chemotherapy. SLFN11 expression was analyzed retrospectively by IHC across 326 ovarian cancer samples. The clinicopathologic significance of SLFN11 expression was analyzed across 57 advanced HGSC as a discovery set, 96 advanced HGSC as a validation set, and 57 advanced CCC cases, all of whom received platinum-based chemotherapy. BRCA1/2 mutation was analyzed using targeted-gene sequencing. In the HGSC cohort, the SLFN11-positive and BRCA mutation group showed significantly longer whereas the SLFN11-negative and BRCA wild-type group showed significantly shorter progression-free survival and overall survival. Moreover, SLFN11-positive HGSC shrunk significantly better than SLFN11-negative HGSC after neoadjuvant chemotherapy. Comparable results were obtained with CCC but without consideration of BRCA1/2 mutation due to a small population. Multivariate analysis identified SLFN11 as an independent factor for better survival in HGSC and CCC. The SLFN11-dependent sensitivity to platinum and PARP inhibitors were validated with genetically modified non-HGSC ovarian cancer cell lines. Our study reveals that SLFN11 predicts platinum sensitivity in HGSC and CCC independently of BRCA1/2 mutation status, indicating that SLFN11 assessment can guide treatment selection in HGSC and CCC.

Endometrial Cancer with and without Endometriosis: Clinicopathological Differences.

Endometriosis is known to be associated with an increased risk of endometrioid and clear cell ovarian cancer. However, the association between endometriosis and endometrial cancer is controversial. Therefore, we retrospectively analyzed the medical records of women with endometrial cancer who had undergone surgery at our institution to evaluate the clinicopathological relationship between endometrial cancer and endometriosis. The study included 720 women pathologically diagnosed with endometrial cancer at our hospital between 2000 and 2020. The participants were allocated to two groups of patients with endometrial cancer: patients with endometriosis (n = 101) and patients without endometriosis (n = 619). Endometrial cancer patients with endometriosis were significantly younger (median age 54.0 vs. 58.0; p = 0.002). In addition, endometrial cancer patients with endometriosis had fewer pregnancies and deliveries (median pregnancy 1.58 vs. 1.99; p = 0.019, median delivery 1.25 vs. 1.56; p = 0.012). The percentage of patients classified as stage IA was significantly higher in those with endometrial cancer with endometriosis (68.3% vs. 56.4%; p = 0.029). In the analysis of synchronous ovarian cancer, the percentage of dual primary cancer was higher in patients with endometriosis (14.9% vs. 1.6%; p < 0.001). The association of young-onset early-stage endometrial cancer with endometriosis is an important finding that cannot be ignored clinically.

Incidence of Recurrent Uterine Rupture: A Systematic Review and Meta-analysis.

OBJECTIVE: We aimed to quantify the incidence of recurrent uterine rupture in pregnant women. DATA SOURCES: A literature search of PubMed, Web of Science, Cochrane Central, and ClinicalTrials.gov for observational studies was performed from 2000 to 2023. METHODS OF STUDY SELECTION: Of the 7,440 articles screened, 13 studies were included in the final review. We included studies of previous uterine ruptures that were complete uterine ruptures , defined as destruction of all uterine layers, including the serosa. The primary outcome was the pooled incidence of recurrent uterine rupture. Between-study heterogeneity was assessed with the I2 value. Subgroup analyses were conducted in terms of the country development status, year of publication, and study size (single center vs national study). The secondary outcomes comprised the following: 1) mean gestational age at which recurrent rupture occurred, 2) mean gestational age at which delivery occurred without recurrent rupture, and 3) perinatal complications (blood loss, transfusion, maternal mortality, and neonatal mortality). TABULATION, INTEGRATION, AND RESULTS: A random-effects model was used to pool the incidence or mean value and the corresponding 95% CI with R software. The pooled incidence of recurrent uterine rupture was 10% (95% CI 6-17%). Developed countries had a significantly lower uterine rupture recurrence rate than less developed countries (6% vs 15%, P =.04). Year of publication and study size were not significantly associated with recurrent uterine rupture. The mean number of gestational weeks at the time of recurrent uterine rupture was 32.49 (95% CI 29.90-35.08). The mean number of gestational weeks at the time of delivery without recurrent uterine rupture was 35.77 (95% CI 34.95-36.60). The maternal mortality rate was 5% (95% CI 2-11%), and the neonatal mortality rate was 5% (95% CI 3-10%). Morbidity from hemorrhage, such as bleeding and transfusion, was not reported in any study and could not be evaluated. CONCLUSION: This systematic review estimated a 10% incidence of recurrent uterine rupture. This finding will enable appropriate risk counseling in patients with prior uterine rupture. SYSTEMATIC REVIEW REGISTRATION: PROSPERO, CRD42023395010.

Comparison of maternal outcomes and clinical characteristics of prenatally vs nonprenatally diagnosed placenta accreta spectrum: a systematic review and meta-analysis.

OBJECTIVE: This study aimed to compare maternal outcomes of prenatally and nonprenatally diagnosed placenta accreta spectrum. DATA SOURCES: A systematic literature search was performed in PubMed, the Cochrane database, and Web of Science until November 28, 2022. STUDY ELIGIBILITY CRITERIA: Studies comparing the clinical presentation of prenatally and nonprenatally diagnosed placenta accreta spectrum were included. The primary outcomes were emergent cesarean delivery, hysterectomy, blood loss volume, number of transfused blood product units, urological injury, coagulopathy, reoperation, intensive care unit admission, and maternal death. In addition, the pooled mean values for blood loss volume and the number of transfused blood product units were calculated. The secondary outcomes included maternal age, gestational age at birth, nulliparity, previous cesarean delivery, previous uterine procedure, assisted reproductive technology, placenta increta and percreta, and placenta previa. METHODS: Study screening was performed after duplicates were identified and removed. The quality of each study and the publication bias were assessed. Forest plots and I2 statistics were calculated for each study outcome for each group. The main analysis was a random-effects analysis. RESULTS: Overall, 415 abstracts and 157 full-text studies were evaluated. Moreover, 31 studies were analyzed. Prenatally diagnosed placenta accreta spectrum was associated with a significantly lower rate of emergency cesarean delivery (odds ratio, 0.37; 95% confidence interval, 0.21-0.67), higher hysterectomy rate (odds ratio, 1.98; 95% confidence interval, 1.02-3.83), lower blood loss volume (mean difference, -0.65; 95% confidence interval, -1.17 to -0.13), and lower number of transfused red blood cell units (mean difference, -1.96; 95% confidence interval, -3.25 to -0.68) compared with nonprenatally diagnosed placenta accreta spectrum. The pooled mean values for blood loss volume and the number of transfused blood product units tended to be lower in the prenatally diagnosed placenta accreta spectrum groups than in the nonprenatally diagnosed placenta accreta spectrum groups. Nulliparity (odds ratio, 0.14; 95% confidence interval, 0.10-0.20), previous cesarean delivery (odds ratio, 6.81; 95% confidence interval, 4.12-11.25), assisted reproductive technology (odds ratio, 0.19; 95% confidence interval, 0.06-0.61), placenta increta and percreta (odds ratio, 3.97; 95% confidence interval, 2.24-7.03), and placenta previa (odds ratio, 6.81; 95% confidence interval, 4.12-11.25) showed statistical significance. No significant difference was found for the other outcomes. CONCLUSION: Despite its severity, the positive effect of prenatally diagnosed placenta accreta spectrum on outcomes underscores the necessity of a prenatal diagnosis. In addition, the pooled mean values provide a preoperative preparation guideline.

Uptake and Outcomes of Neoadjuvant Chemotherapy Among US Patients With Less Common Epithelial Ovarian Carcinomas.

Importance: Randomized clinical trials examining the effectiveness of neoadjuvant chemotherapy (NACT) for advanced ovarian cancer predominantly included patients with high-grade serous carcinomas. The use and outcomes of NACT in less common epithelial carcinomas are understudied. Objective: To investigate the uptake and survival outcomes in treatment with NACT for less common histologic subtypes of epithelial ovarian cancer. Design, Setting, and Participants: A retrospective cohort study and systematic literature review with meta-analysis was conducted using the National Cancer Database from 2006 to 2017 and the National Cancer Institute's Surveillance, Epidemiology, and End Results Program from 2006 to 2019. Data analysis was performed from July 2022 to April 2023. The evaluation included patients with stage III to IV ovarian cancer with clear cell, mucinous, or low-grade serous histologic subtypes who received multimodal treatment with surgery and chemotherapy. Exposures: Exposure assignment per the sequence of treatment: primary debulking surgery (PDS) followed by chemotherapy (PDS group) or NACT followed by interval surgery (NACT group). Main Outcomes and Measures: Temporal trends and characteristics of NACT use were assessed using multivariable analysis, and overall survival (OS) was assessed with the inverse probability of treatment weighting propensity score. Results: A total of 3880 patients were examined in the National Cancer Database including 1829 women (median age, 56 [IQR, 49-63] years) with clear cell, 1156 women (median age, 53 [IQR, 42-64] years) with low-grade serous, and 895 women (median age, 57 [IQR, 48-66] years) with mucinous carcinomas. NACT use increased in patients with clear cell (from 10.2% to 16.2%, 58.8% relative increase; P < .001 for trend) or low-grade serous (from 7.7% to 14.2%, 84.4% relative increase; P = .007 for trend) carcinoma during the study period. This association remained consistent in multivariable analysis. NACT use also increased, but nonsignificantly, in mucinous carcinomas (from 8.6% to 13.9%, 61.6% relative increase; P = .07 for trend). Across the 3 histologic subtypes, older age and stage IV disease were independently associated with NACT use. In a propensity score-weighted model, the NACT and PDS groups had comparable OS for clear cell (4-year rates, 31.4% vs 37.7%; hazard ratio [HR], 1.12; 95% CI, 0.95-1.33) and mucinous (27.0% vs 26.7%; HR, 0.90; 95% CI, 0.68-1.19) carcinomas. For patients with low-grade serous carcinoma, NACT was associated with decreased OS compared with PDS (4-year rates, 56.4% vs 81.0%; HR, 2.12; 95% CI, 1.55-2.90). Increasing NACT use and histologic subtype-specific survival association were also found in the Surveillance, Epidemiology, and End Results Program cohort (n = 1447). A meta-analysis of 4 studies, including the current study, observed similar OS associations for clear cell (HR, 1.13; 95% CI, 0.96-1.34; 2 studies), mucinous (HR, 0.93; 95% CI, 0.71-1.21; 2 studies), and low-grade serous (HR, 2.11; 95% CI, 1.63-2.74; 3 studies) carcinomas. Conclusions and Relevance: Despite the lack of data on outcomes of NACT among patients with less common carcinomas, this study noted that NACT use for advanced disease has gradually increased in the US. Primary chemotherapy for advanced-stage, low-grade serous ovarian cancer may be associated with worse survival compared with PDS.

Pathogenesis of endometrium-related diseases based on genomic alterations in normal uterine endometrium.

The human endometrium is a dynamically remodeling tissue that undergoes more than 400 cycles of regeneration, differentiation, shedding, and rapid healing during a woman's reproductive years. The endometrium is also the origin of various gynecologic diseases, such as endometriosis, adenomyosis, and uterine corpus cancer. Cancer-associated gene mutations are detected in endometriosis, adenomyosis, and normal endometrium. Some reports have demonstrated that the accumulation of genomic alterations is a critical carcinogenic mechanism in the progression from normal endometrium to ovarian clear cell carcinoma via endometriosis. In this review, we discuss the clinical importance of genomic alterations in the normal endometrium, contributing to the elucidation of the pathogenesis of endometrium-related diseases.

Pathologically diagnosed placenta accreta spectrum without placenta previa: a systematic review and meta-analysis.

OBJECTIVE: This systematic review and meta-analysis aimed to assess clinical characteristics related to pathologically proven placenta accreta spectrum without placenta previa. DATA SOURCES: A literature search of PubMed, the Cochrane database, and Web of Science was performed from inception to September 7, 2022. STUDY ELIGIBILITY CRITERIA: The primary outcomes were invasive placenta (including increta or percreta), blood loss, hysterectomy, and antenatal diagnosis. In addition, maternal age, assisted reproductive technology, previous cesarean delivery, and previous uterine procedures were investigated as potential risk factors. The inclusion criteria were studies evaluating the clinical presentation of pathologically diagnosed PAS without placenta previa. METHODS: Study screening was conducted after duplicates were identified and removed. The quality of each study and the publication bias were assessed. Forest plots and I2 statistics were calculated for each study outcome for each group. The main analysis was a random-effects analysis. RESULTS: Among 2598 studies that were initially retrieved, 5 were included in the review. With the exception of 1 study, 4 studies were included in the meta-analysis. This meta-analysis showed that placenta accreta spectrum without placenta previa was associated with less risk of invasive placenta (odds ratio, 0.24; 95% confidence interval, 0.16-0.37), blood loss (mean difference, -1.19; 95% confidence interval, -2.09 to -0.28) and hysterectomy (odds ratio, 0.11; 95% confidence interval, 0.02-0.53), and more difficult to diagnose prenatally (odds ratio, 0.13; 95% confidence interval, 0.04-0.45) than placenta accreta spectrum with placenta previa. In addition, assisted reproductive technology and a previous uterine procedure were strong risk factors for placenta accreta spectrum without placenta previa, whhereas previous cesarean delivery was a strong risk factor for placenta accreta spectrum with placenta previa. CONCLUSION: The differences in clinical aspects of placenta accreta spectrum with and without placenta previa need to be understood.

An attempt to establish real-world databases of poly(ADP-ribose) polymerase inhibitors for advanced or recurrent epithelial ovarian cancer: the Japanese Gynecologic Oncology Group.

The development of new treatments for gynecological malignancies has been conducted mainly through collaborative international phase III trials led by the United States and Europe. The survival outcomes of many gynecological malignancies have greatly improved as a result. Recent large-scale genome-wide association studies have revealed that drug efficacy and adverse event profiles are not always uniform. Thus, it is important to validate new treatment options in each country to safely and efficiently provide newly developed treatment options to patients with gynecological malignancies. The Japanese Gynecologic Oncology Group (JGOG) is conducting 5 cohort studies (JGOG 3026, 3027, 3028, 3030, and 3031) to establish real-world data (RWD) of poly(ADP-ribose) polymerase (PARP) inhibitor use in patients with advanced or recurrent epithelial ovarian cancer. The RWD constructed will be used to provide newly developed PARP inhibitors for women with advanced or recurrent ovarian cancer in a safer and more efficient manner as well as to develop further treatment options. In 2022, The JGOG, Korean Gynecologic Oncology Group, Chinese Gynecologic Cancer Society, and Taiwanese Gynecologic Oncology Group established the East Asian Gynecologic Oncology Trial Group to collaborate with East Asian countries in clinical research on gynecologic malignancies and disseminate new knowledge on gynecologic malignancies from Asia. The JGOG will conduct a collaborative integrated analysis of the RWD generated from Asian countries and disseminate real-world clinical knowledge regarding new treatment options that have been clinically implemented.

Obstetrical outcomes of pregnant women 50 years and older compared to those aged 45-49 years: A systematic review and meta-analysis.

AIM: In this review, We compared clinical characteristics of pregnant women aged 50 and older with those aged 45-49. Pregnant women ≥45 years are strongly associated with pregnancy-related complications, such as cesarean section rate, gestational hypertension, gestational diabetes mellitus, and preterm birth. Although pregnant women ≥50 years are considered more high-risk, differences in pregnancy outcomes between those over 45 and 50 years of age are unclear. METHODS: Our source strategy included using PubMed, the Cochrane Central Register of Controlled Trials, and Web of Science databases to include studies published between January 1, 2010 and September 30, 2022. The study population was pregnant women 50 years and older; the control group was pregnant women aged 45-49 years. Primary outcomes were cesarean section, gestational hypertension, gestational diabetes mellitus, and preterm birth. The secondary outcomes were small-for-gestational age, 5-min Apgar score < 7, neonatal intensive care unit admission (as neonatal outcomes), nulliparity, assisted reproductive technology (ART), and multifetal pregnancy (as maternal backgrounds). RESULTS: The incidence of cesarean section, gestational hypertension, and preterm delivery was significantly higher in those 50 years and older; however, significant differences disappeared when pooled analyses were limited to singleton pregnancies. ART was significantly more likely to be used for conception of pregnant women ≥50 years. Infants of women ≥50 years were more likely to be admitted to NICUs. CONCLUSIONS: The differences in outcomes between the two groups are obviously influenced by multiple pregnancies, therefore, reproductive medicine specialists should aim for singleton pregnancies in ART.

Prognostic Value of EMT Gene Signature in Malignant Mesothelioma.

Malignant mesothelioma (MESO) consists of epithelioid, biphasic, and sarcomatoid subtypes with different epithelial-mesenchymal transition (EMT) phenotypes. We previously identified a panel of four MESO EMT genes correlating with an immunosuppressive tumor microenvironment and poor survival. In this study, we investigated the correlation between these MESO EMT genes, the immune profile, and the genomic and epigenomic alterations to identify potential therapeutic targets to prevent or reverse the EMT process. Using multiomic analysis, we observed that the MESO EMT genes were positively correlated with hypermethylation of epigenetic genes and loss of CDKN2A/B expression. MESO EMT genes such as COL5A2, ITGAV, SERPINH1, CALD1, SPARC, and ACTA2 were associated with upregulation of TGF-ß signaling, hedgehog signaling, and IL-2-STAT5 signaling and downregulation of the IFN-α and IFN-γ response. Immune checkpoints such as CTLA4, CD274 (PD-L1), PDCD1LG2 (PD-L2), PDCD1 (PD-1), and TIGIT were upregulated, while LAG3, LGALS9, and VTCN1 were downregulated with the expression of MESO EMT genes. CD160, KIR2DL1, and KIR2DL3 were also broadly downregulated with the expression of MESO EMT genes. In conclusion, we observed that the expression of a panel of MESO EMT genes was associated with hypermethylation of epigenetic genes and loss of expression of CDKN2A and CDKN2B. Expression of MESO EMT genes was associated with downregulation of the type I and type II IFN response, loss of cytotoxicity and NK cell activity, and upregulation of specific immune checkpoints, as well as upregulation of the TGF-ß1/TGFBR1 pathway.

Homologous recombination inquiry through ovarian malignancy investigations: JGOG3025 Study.

The Cancer Genome Atlas (TCGA) network has clarified that ~50% of high-grade serous ovarian cancers show homologous recombination deficiency (HRD). However, the frequency of HRD in Japanese patients with ovarian cancer remains unclear. We aimed to identify the frequency of HR-associated gene mutations in Japanese patients with ovarian cancer. The JGOG3025 study is a multicenter collaborative prospective observational study involving 65 study sites throughout Japan. We recruited 996 patients who were clinically diagnosed with ovarian cancer before surgery from March 2017 to March 2019, and 701 patients were eligible according to the criteria. We used frozen tumor tissues to extract DNA and performed next-generation sequencing for 51 targeted genes (including 29 HR-associated genes) in 701 ovarian cancers (298 high-grade serous cases, 189 clear cell cases, 135 endometrioid cases, 12 mucinous cases, 3 low-grade serous cases, and 64 others). HRD was defined as positive when at least one HR-associated gene was mutated. The frequencies of HRD and tumor BRCA1/2 mutations were 45.2% (317/701) and 18.5% (130/701), respectively, in the full analysis set. Next, we performed multivariate Cox proportional hazards regression analysis for progression-free survival (PFS) and overall survival (OS). Advanced-stage ovarian cancer patients with HRD had adjusted hazard ratios of 0.72 (95% CI, 0.55-0.94) and 0.57 (95% CI, 0.38-0.86) for PFS and OS, respectively, compared with those without HRD (p = 0.016 and 0.007). Our study demonstrated that mutations in HR-associated genes were associated with prognosis. Further studies are needed to investigate the prognostic impact of each HR-associated gene in ovarian cancer.

Pregnancy outcomes at maternal age over 45 years: a systematic review and meta-analysis.

OBJECTIVE: This study aimed to identify trends in pregnancy outcomes, especially delivery mode, among pregnant patients older than 45 years. DATA SOURCES: A literature search was performed using PubMed, Web of Science, and the Cochrane Central Register of Controlled Trials for studies published between January 1, 2010, and June 30, 2022. STUDY ELIGIBILITY CRITERIA: The primary outcomes were cesarean delivery and assisted delivery. The secondary outcomes were preeclampsia, gestational diabetes mellitus, placenta previa, placental abruption, postpartum hemorrhage, and preterm birth. The inclusion criteria were studies examining the relationship between older age pregnancy and pregnancy outcomes, studies that compared pregnancy outcomes at maternal age ≥45 years and <45 years, and at least one of the primary and secondary pregnancy outcomes were included. METHODS: Study screening was performed after duplicates were identified and removed. The quality of each study and publication bias were assessed. Forest plots and I2 statistics were calculated for each study outcome for each group. The main analysis was a random-effects analysis. The inverse variance method was used to integrate the results if studies had an adjusted analysis. RESULTS: Among 4209 studies initially retrieved, 24 were included in this review. All studies were retrospective, observational studies. Pregnant patients aged ≥45 years had a significantly higher cesarean delivery rate (odds ratio, 2.87; 95% confidence interval, 2.50-3.30; I2=97%) than those aged <45 years. However, the emergency cesarean delivery rate was lower in older pregnant patients (odds ratio, 0.61; 95% confidence interval, 0.47-0.79; I2=79%). Pregnancy in older individuals was associated with a lower assisted delivery rate than pregnancy in younger individuals (odds ratio, 0.85; 95% confidence interval, 0.75-0.97; I2=48%). Preeclampsia, gestational diabetes mellitus, placenta previa, placental abruption, postpartum hemorrhage, and preterm birth were more likely to occur in pregnant patients aged ≥45 years than in those aged <45 years. Adjusted pooled analyses showed trends similar to those in the unadjusted pooled analyses. CONCLUSION: Adverse pregnancy outcomes, typically cesarean delivery, were more likely to occur in older (≥45 years) pregnant patients than in younger pregnant patients. However, the assisted delivery rate was lower in older pregnant patients.

Spatial genomic diversity associated with APOBEC mutagenesis in squamous cell carcinoma arising from ovarian teratoma.

Although the gross and microscopic features of squamous cell carcinoma arising from ovarian mature cystic teratoma (MCT-SCC) vary from case to case, the spatial spreading of genomic alterations within the tumor remains unclear. To clarify the spatial genomic diversity in MCT-SCCs, we performed whole-exome sequencing by collecting 16 samples from histologically different parts of two MCT-SCCs. Both cases showed histological diversity within the tumors (case 1: nonkeratinizing and keratinizing SCC and case 2: nonkeratinizing SCC and anaplastic carcinoma) and had different somatic mutation profiles by histological findings. Mutation signature analysis revealed a significantly enriched apolipoprotein B mRNA editing enzyme catalytic subunit (APOBEC) signature at all sites. Intriguingly, the spread of genomic alterations within the tumor and the clonal evolution patterns from nonmalignant epithelium to cancer sites differed between cases. TP53 mutation and copy number alterations were widespread at all sites, including the nonmalignant epithelium, in case 1. Keratinizing and nonkeratinizing SCCs were differentiated by the occurrence of unique somatic mutations from a common ancestral clone. In contrast, the nonmalignant epithelium showed almost no somatic mutations in case 2. TP53 mutation and the copy number alteration similarities were observed only in nonkeratinizing SCC samples. Nonkeratinizing SCC and anaplastic carcinoma shared almost no somatic mutations, suggesting that each locally and independently arose in the MCT. We demonstrated that two MCT-SCCs with different histologic findings were highly heterogeneous tumors with clearly different clones associated with APOBEC-mediated mutagenesis, suggesting the importance of evaluating intratumor histological and genetic heterogeneity among multiple sites of MCT-SCC.