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.

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.

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.

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.

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.