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Publication Metadata only Endometriosis and adenomyosis: shared pathophysiology(Elsevier Science Inc, 2023) Bulun, Serdar E.; Adli, Mazhar; Chakravarti, Debabrata; Parker, James Brandon; Milad, Magdy; Yang, Linda; Chaudhari, Angela; Tsai, Susan; Wei, Jian Jun; Yin, Ping; Yıldız, Şule; School of MedicineEndometriosis and adenomyosis are closely related disorders. Their pathophysiologies are extremely similar. Both tissues originate from the eutopically located intracavitary endometrium. Oligoclones of endometrial glandular epithelial cells with somatic mutations and attached stromal cells may give rise to endometriosis if they travel to peritoneal surfaces or the ovary via retrograde menstruation and/or may be entrapped in the myometrium to give rise to adenomyosis. In both instances, the endometrial cell populations possess survival and growth capabilities conferred by somatic epithelial mutations and epigenetic abnormalities in stromal cells. Activating mutations of KRAS are the most commonly found genetic variant in endometriotic epithelial cells, whereas the adenomyotic epithelial cells almost exclusively bear KRAS mutations. Epigenetic abnormalities in the stromal cells of endometriosis and adenomyosis are very similar and involve an abnormal expression pattern of nuclear receptors, including the steroid receptors. These epigenetic defects give rise to excessive local estrogen biosynthesis by aromatase and abnormal estrogen action via estrogen receptor-b. Deficient progesterone receptor expression results in progesterone resistance in both endometriosis and adenomyosis.Publication Metadata only Adenomyosis: single-cell transcriptomic analysis reveals a paracrine mesenchymal-epithelial interaction involving the WNT/SFRP pathway(Elsevier Science Inc, 2023) Kinali, Meric; Wei, Jian Jun; Milad, Magdy; Yin, Ping; Adli, Mazhar; Bulun, Serdar E.; Yıldız, Şule; School of MedicineObjective: To assess the cellular and molecular landscape of adenomyosis.Design: Single-cell analysis of genome-wide messenger RNA (mRNA) expression (single-cell RNA sequencing) of matched tissues of endometrium, adenomyosis, and myometrium using relatively large numbers of viable cells.Setting: Not applicable. Patient(s): Patients (n 1/4 3, age range 40-44 years) undergoing hysterectomy for diffuse adenomyosis. Main Outcome Measure(s): Definition of the molecular landscape of matched adenomyotic, endometrial and myometrial tissues from the same uterus using single-cell RNA sequencing and comparison of distinct cell types in these tissues to identify disease-specific cell populations, abnormal gene expression and pathway activation, and mesenchymal-epithelial interactions.Result(s): The largest cell population in the endometrium was composed of closely clustered fibroblast groups, which comprise 36% of all cells and seem to originate from pericyte progenitors differentiating to estrogen/progesterone receptor-expressing endometrial stromal-cells. In contrast, the entire fibroblast population in adenomyosis comprised a larger (50%) portion of all cells and was not linked to any pericyte progenitors. Adenomyotic fibroblasts eventually differentiate into extracellular matrix protein-expressing fibroblasts and smooth muscle cells. Hierarchical clustering of mRNA expression revealed a unique adenomyotic fibroblast population that clustered transcriptomically with endometrial fibroblasts, suggestive of an endometrial stromal cell population serving as progenitors of adenomyosis. Four other adenomyotic fibroblast clusters with disease-specific transcriptomes were distinct from those of endometrial or myometrial fibroblasts. The mRNA levels of the natural WNT inhibitors, named, secreted frizzled-related proteins 1, 2, and 4, were higher in these 4 adenomyotic fibroblast clusters than in endometrial fibroblast clusters. Moreover, we found that multiple WNTs, which originate from fibroblasts and target ciliated and unciliated epithelial cells and endothelial cells, constitute a critical paracrine signaling network in adenomyotic tissue. Compared with endometrial tissue, unciliated and ciliated epithelial cells in adenomyosis comprised a significantly smaller portion of this tissue and exhibited molecular evidence of progesterone resistance and diminished regulation of estrogen signaling.Conclusion(s): We found a high degree of heterogeneity in fibroblast-like cells in the adenomyotic uterus. The WNT signaling involving differential expression of secreted frizzled-related proteins, which act as decoy receptors for WNTs, in adenomyotic fibroblasts may have a key role in the pathophysiology of this disease.Publication Metadata only Role and effectiveness of progestins in pituitary suppression during ovarian stimulation for assisted reproductive technology: a systematic review and a meta-analysis(Edizioni Minerva Medica, 2023) Yıldız, Şule; Türkgeldi, Engin; Ata, Mustafa Barış; School of MedicineIntroduction: despite the many unknowns about its exact mechanism, progesterone and progestins are being successfully used to prevent luteinizing hormone (lH) surge during ovarian stimulation for assisted reproductive technology (art). We will review progestin primed ovarian stimulation (PPOs) protocols in comparison with gonadotropin releasing hormone (GnrH) analogues and each other. Evidence Acquisition: MedliNe via PubMed; cochrane central register of controlled trials (ceNtral); scopus; Web of science were screened with keywords related to assisted reproductive technology, ovarian stimulation progesterone, GnrH analogue and progesterone in several combinations. search period was from the date of inception of each database until 20 May 2022. Evidence Synthesis: live birth or ongoing pregnancy rate per embryo transfer (et) was similar in PPOs and GnrH antagonist cycles (rr=1.16, 95% ci: 0.93-1.44). clinical pregnancy rate per et was likewise similar (rr=1.12, 95% ci: 0.92-1.37). Miscarriage rate per pregnancy was similar with PPOs and GnrH antagonists in autologous cycles (rr=1.01, 95% ci: 0.65-1.55). Pooled analyses showed similar live birth rate between progestins and short GnrH agonist protocols (RR=1.01, 95% CI: 0.49-2.09), however, clinical pregnancy rates per ET were significantly higher with progestins (rr=1.31, 95% ci: 1.06-1.62). Miscarriage rate per pregnancy was similar with progestins (rr=0.82, 95% ci: 0.55-1.21). Conclusions: Progestins seem to be an efficient option for pituitary suppression during ovarian suppression, providing similar outcomes for stimulation and pregnancy. They can be especially beneficial for women for whom fresh ET is not considered.Publication Metadata only The effect of earthquake experience on pregnancy outcomes: a systematic review and meta-analysis(Elsevier, 2023) Aktoz, Fatih; Gunes, Ali Can; Yakın, Kayhan; School of MedicineObjectives: Pregnant women are vulnerable to the health consequences of earthquakes, experiencing stress and limited access to healthcare. Despite the widespread impact of these events, knowledge about their effects on pregnancy outcomes is scarce and inconsistent. This systematic review and meta-analysis aimed to evaluate the available evidence, estimate the overall effect, and identify key research gaps about earthquake on pregnant women. Study Design: A comprehensive search of English-language peer-reviewed articles was conducted using PubMed and Web of Science Core Collection. Various combinations of keywords related to earthquakes and pregnancy outcomes were used. Studies comparing quantitative data on pregnancy outcomes between earthquake-affected and unaffected pregnant women were included. Random and fixed-effects models were used to estimate the pooled effect size. Results: The meta-analysis revealed no significant difference in preterm delivery rates (OR: 1.18; 95 % CI: 0.94-1.47; I2 = 75 %; five studies, 26,365 women) and low birth weight (LBW) infant delivery rates (OR: 1.19; 95 % CI: 0.83-1.71; I2 = 72 %; three studies, 16,127 women) between the earthquake-affected and control groups. However, a statistically significant increase in small-for-gestational-age (SGA) infants was observed in the earthquake-affected group (OR: 1.25; 95 % CI: 1.08-1.43; I2 = 0 %; two studies, 10,238 women). Data on miscarriage and stillbirth rates were not suitable for meta-analysis. Conclusions: Limited evidence suggests that exposure to earthquakes may be associated with adverse pregnancy outcomes. Further studies are needed to confirm the increased risk of SGA in the affected population and to inform disaster management plans by enhancing our understanding of the adversities associated with earthquake exposure through more comprehensive epidemiologic research.Publication Metadata only Overall survival and patient-reported outcome results from the placebo-controlled randomized phase III IMagyn050/GOG 3015/ENGOT-OV39 trial of atezolizumab for newly diagnosed stage III/IV ovarian cancer(Academic Press Inc Elsevier Science, 2023) Pignata, Sandro; Bookman, Michael; Sehouli, Jalid; Miller, Austin; Penson, Richard T.; Anderson, Charles; Hietanen, Sakari; Myers, Tashanna; Madry, Radoslaw; Willmott, Lyndsay; Lortholary, Alain; Thomes-Pepin, Jessica; Aghajanian, Carol; Mccourt, Carolyn; Stuckey, Ashley; Wu, Xiaohua; Nishio, Shin; Copeland, Larry J.; He, Yvette; Molinero, Luciana; Patel, Sheetal; Lin, Yvonne G.; Khor, Victor K.; Moore, Kathleen N.; Taşkıran, Çağatay; School of MedicineObjective: To determine the impact on overall survival (OS) and patient-reported outcomes (PROs) of combining atezolizumab with standard therapy for newly diagnosed stage III/IV ovarian cancer. Methods: The placebo-controlled double-blind randomized phase III IMagyn050/GOG 3015/ENGOT-OV39 trial (NCT03038100) assigned eligible patients to 3-weekly atezolizumab 1200 mg or placebo for 22 cycles with platinum-based chemotherapy and bevacizumab. Coprimary endpoints were progression-free survival (already reported) and OS in the PD-L1-positive and intent-to-treat (ITT) populations, tested hierarchically. Prespecified PRO analyses focused on disease-related abdominal pain and bloating symptoms (European Organisation for Research and Treatment of Cancer QLQ-OV28), functioning, and health-related quality of life (HRQoL) (QLQ-C30). Results. After 38 months' median follow-up, the OS hazard ratio in the PD-L1-positive population was 0.83 (95% CI, 0.66-1.06; p= 0.13); median OSwas not estimablewith atezolizumab versus 49.2monthswith placebo. The hazard ratio for OS in the ITT population was 0.92 (95% CI, 0.78-1.09; median 50.5 versus 46.6 months, respectively). At week 9, similar proportions of patients in both arms of the neoadjuvant cohort showed >= 10-point improvement from baseline in abdominal pain and bloating, functioning, and HRQoL. In the primary surgery cohort, similar proportions of patients in each arm had improved, stable, or worsened physical and role function and HRQoL from baseline over time. Neither cohort showed differences between arms in treatment-related symptoms or overall side-effect bother. Conclusions: Incorporation of atezolizumab into standard therapy for newly diagnosed ovarian cancer does not significantly improve efficacy or impose additional treatment burden for patients.Publication Metadata only Prognostic value of isolated tumor cells in sentinel lymph nodes in low risk endometrial cancer: results from an international multi-institutional study(BMJ Publishing Group, 2023) Cucinella, Giuseppe; Schivardi, Gabriella; Zhou, Xun Clare; Alhilli, Mariam; Wallace, Sumer; Wohlmuth, Christoph; Baiocchi, Glauco; Tokgozoglu, Nedim; Raspagliesi, Francesco; Buda, Alessandro; Zanagnolo, Vanna; Zapardiel, Ignacio; Jagasia, Nisha; Giuntoli, Robert; Glickman, Ariel; Peiretti, Michele; Lanner, Maximilian; Chacon, Enrique; Di Guilmi, Julian; Pereira, Augusto; Laas-Faron, Enora; Fishman, Ami; Nitschmann, Caroline C.; Kurnit, Katherine; Moriarty, Kristen; Joehlin-Price, Amy; Lees, Brittany; Covens, Allan; De Brot, Louise; Bogani, Giorgio; Landoni, Fabio; Grassi, Tommaso; Paniga, Cristiana; Multinu, Francesco; De Vitis, Luigi Antonio; Hernández, Alicia; Mastroyannis, Spyridon; Ghoniem, Khaled; Chiantera, Vito; Shahi, Maryam; Fought, Angela J.; McGree, Michaela; Mariani, Andrea; Glaser, Gretchen; Taşkıran, Çağatay; School of MedicineObjective: The prognostic significance of isolated tumor cells (≤0.2 mm) in sentinel lymph nodes (SLNs) of endometrial cancer patients is still unclear. Our aim was to assess the prognostic value of isolated tumor cells in patients with low risk endometrial cancer who underwent SLN biopsy and did not receive adjuvant therapy. Outcomes were compared with node negative patients. Methods: Patients with SLNs-isolated tumor cells between 2013 and 2019 were identified from 15 centers worldwide, while SLN negative patients were identified from Mayo Clinic, Rochester, between 2013 and 2018. Only low risk patients (stage IA, endometrioid histology, grade 1 or 2) who did not receive any adjuvant therapy were included. Primary outcomes were recurrence free, non-vaginal recurrence free, and overall survival, evaluated with Kaplan-Meier methods. Results: 494 patients (42 isolated tumor cells and 452 node negative) were included. There were 21 (4.3%) recurrences (5 SLNs-isolated tumor cells, 16 node negative); recurrence was vaginal in six patients (1 isolated tumor cells, 5 node negative), and non-vaginal in 15 (4 isolated tumor cells, 11 node negative). Median follow-up among those without recurrence was 2.3 years (interquartile range (IQR) 1.1-3.0) and 2.6 years (IQR 0.6-4.2) in the SLN-isolated tumor cell and node negative patients, respectively. The presence of SLNs-isolated tumor cells, lymphovascular space invasion, and International Federation of Obstetrics and Gynecology (FIGO) grade 2 were significant risk factors for recurrence on univariate analysis. SLN-isolated tumor cell patients had worse recurrence free survival (p<0.01) and non-vaginal recurrence free survival (p<0.01) compared with node negative patients. Similar results were observed in the subgroup of patients without lymphovascular space invasion (n=480). There was no difference in overall survival between the two cohorts in the full sample and the subset excluding patients with lymphovascular space invasion. Conclusions: Patients with SLNs-isolated tumor cells and low risk profile, without adjuvant therapy, had a significantly worse recurrence free survival compared with node negative patients with similar risk factors, after adjusting for grade and excluding patients with lymphovascular space invasion. However, the presence of SLNs-isolated tumor cells was not associated with worse overall survival.Publication Metadata only Assessment of water, sanitation, and hygiene among women living in precarious households in a Turkish urban area(BMC, 2024) Oecek, Zeliha Asli; Turk, Meral; Unver, Aysegul; Şimşek, Sera; School of MedicineBackground: This study aimed to identify the determinants of water, sanitation, and hygiene (WASH) behaviors and conditions among women in poor neighborhoods in Izmir, Turkey, and to develop a scale for assessing WASH behaviors and conditions that is specifically designed for use in precarious urban areas. Methods: The study used a cross-sectional design, as well as a methodological feature for developing the scale. The sample size was calculated as 243 households out of 2667 households in the Basmane neighborhood, with a 95% confidence interval and a 6% margin of error, and a woman who was responsible for cleaning was invited to participate from each household. The scales for WASH behaviors and conditions, which served as dependent variables, were developed in a four-stage process, yielding two distinct scales. The WASH-Behaviors Scale had 14 items about hand, body, and home hygiene, whereas the WASH-Conditions in Households Scale included 16 items about variables like area per capita, physical structure, and cleaning tool availability. Age, ethnicity, number of children, education, work status, and income were among the independent variables. Data was collected through household visits. The scales' validity was evaluated using exploratory factor analysis. Linear logistic regression analysis was employed to assess the determinants of WASH behaviors. Results: The women, with an average age of 40.65 +/-; 14.35 years, faced economic challenges, as a substantial portion earned an income below the minimum wage. More than half of them were uninsured, and 72.6% were identified as migrants or refugees. Factor analysis confirmed the compatibility of both scales (KMO = 0.78-0.80, p < 0.05), elucidating 52-54% of the total variance. Factors such as ethnicity, number of children, husband's education level, income perception, and WASH conditions explained 48% of WASH behaviors. Conclusions: WASH-Behaviors and WASH-Conditions in Households scales met the validity criterion, and their scores were related to basic sociodemographic and economic characteristics like education, income, household size, and ethnicity. The scale development process emphasized the importance of considering both behaviors and household conditions, albeit using different techniques. The findings indicated that WASH conditions are more problematic than behaviors, and that behavioral interventions will not work unless the conditions are corrected.Publication Metadata only Do women with severely diminished ovarian reserve undergoing modified natural cycles benefit from earlier trigger at smaller follicle size?(Wiley, 2024) Lawrenz B; Melado L; Del Gallego R; Elkhatib I; Fatemi H.; N/A; Kalafat, Erkan; Ata, Mustafa Barış; School of MedicineObjective To evaluate whether trigger and oocyte collection at a smaller follicle size decreases the risk of premature ovulation while maintaining the reproductive potential of oocytes in women with a severely diminished ovarian reserve undergoing modified natural-cycle in-vitro fertilization. Methods This was a retrospective cohort study including women who had at least one unsuccessful cycle (due to no response) of conventional ovarian stimulation with a high dosage of gonadotropins and subsequently underwent a modified natural cycle with a solitary growing follicle (i.e. only one follicle > 10 mm at the time of trigger). The association between follicle size at trigger and various cycle outcomes was tested using regression analyses. Results A total of 160 ovarian stimulation cycles from 110 patients were included in the analysis. Oocyte pick-up (OPU) was performed in 153 cycles and 7 cycles were canceled due to premature ovulation. Patients who received their trigger at smaller follicle sizes (<= 15 mm) had significantly lower rates of premature ovulation and thus higher rates of OPU (98.9% vs 90.8%; odds ratio, 9.56 (95% CI, 1.58-182.9); P = 0.039) compared with those who received their trigger at larger follicle sizes (> 15 mm). On multivariable analysis, smaller follicle sizes at trigger (> 10 to 13 mm, > 13 to 15 mm, > 15 mm to 17 mm) were not associated significantly with a lower rate of cumulus-oocyte complex (COC) retrieval, metaphase-II (MII) oocytes or blastulation when compared to the > 17-mm group. On sensitivity analysis including only the first cycle of each couple, the maturity rate among those with COC retrieval was highest in follicle sizes > 15 to 17 mm (92.3%) and > 13 to 15 mm (91.7%), followed by > 10 to 13 mm (85.7%) and lowest in the > 17-mm group (58.8%). During the study period, five euploid blastocysts developed from 48 fertilized MII oocytes with follicle sizes of 12 mm (n = 3), 14 mm (n = 1) and 16 mm (n = 1) at trigger. Of those, four were transferred and resulted in two live births, both of which developed from follicles with a size at trigger of 12 mm. Conclusions The ideal follicle size for triggering oocyte maturation may be smaller in women with a severely diminished ovarian reserve managed on a modified natural cycle when compared to conventional cut-offs. The risk of OPU cancellation was significantly higher in women triggered at follicle size > 15 mm and the yield of mature oocytes was not adversely affected in women triggered at follicle size > 13 to 15 mm compared with > 15 to 17 mm. Waiting for follicles to reach sizes > 17mm may be detrimental to achieving optimal outcome.Publication Metadata only Neutralizing antibody levels and cellular immune response against Omicron variant in pregnant women vaccinated with mRNA and inactivated SARS-CoV-2 vaccines(Wiley, 2023) Demirci, O.; Ayaz, R.; N/A; Kalafat, Erkan; Talay, Zeynep Gülce; Can, Füsun; Çelik, Ebru; Koç University İşbank Center for Infectious Diseases (KU-IS CID); Graduate School of Health Sciences; School of MedicinePublication Metadata only Association of fetal growth restriction and stillbirth in twin compared with singleton pregnancies(Wiley, 2024) Martínez-Varea A.; Prasad, S.; Domenech, J.; Morales-Roselló, J.; Khalil, A.; N/A; Kalafat, Erkan; School of MedicineObjectives Twin pregnancies are at higher risk of stillbirth compared to singletons. Fetal growth restriction (FGR) is a major cause of perinatal mortality, but its impact on twins vs singletons remains unclear. The primary objective of this study was to investigate the association of FGR and small-for-gestational age (SGA) with stillbirth in twin compared with singleton pregnancies. A secondary objective was to assess these associations stratified by gestational age at delivery. Furthermore, we aimed to compare the associations of FGR and SGA with stillbirth in twin pregnancies using twin-specific vs singleton birth-weight charts, stratified by chorionicity. Methods This was a retrospective cross-sectional study of pregnancies receiving obstetric care and giving birth between 1999 and 2022 at St George's Hospital, London, UK. The exclusion criteria included triplet and higher-order pregnancies, those resulting in miscarriage or live birth at <= 23 + 6 weeks, termination of pregnancy and missing data regarding birth weight or gestational age at birth. Birth-weight data were collected and FGR and SGA were defined as birth weight <5th and <10th centiles, respectively. While standard logistic regression was used for singleton pregnancies, the association of FGR and SGA with stillbirth in twin pregnancies was investigated using mixed-effects logistic regression models. For twin pregnancies, intercepts were allowed to vary for twin pairs to account for intertwin dependency. Analyses were stratified by gestational age at delivery and chorionicity. Statistical significance was set at P <= 0.001. Results The study included 95 342 singleton and 3576 twin pregnancies. There were 494 (0.52%) stillbirths in singleton and 41 (1.15%) stillbirths in twin pregnancies (17 dichorionic and 24 monochorionic). SGA and FGR were associated significantly with stillbirth in singleton pregnancies across all gestational ages at delivery: the odds ratios (ORs) for SGA and FGR were 2.36 ((95% CI, 1.78-3.13), P < 0.001) and 2.67 ((95% CI, 2.02-3.55), P < 0.001), respectively, for delivery before 32 weeks; 2.70 ((95% CI, 1.71-4.31), P < 0.001) and 2.82 ((95% CI, 1.78-4.47), P < 0.001), respectively, for delivery between 32 and 36 weeks; and 3.85 ((95% CI, 2.83-5.21), P < 0.001) and 4.43 ((95% CI, 3.16-6.12), P < 0.001), respectively, for delivery after 36 weeks. In twin pregnancies, when stratified by gestational age at delivery, both SGA and FGR determined by twin-specific birth-weight charts were associated with increased odds of stillbirth for those delivered before 32 weeks (SGA: OR, 3.87 (95% CI, 1.56-9.50), P = 0.003 and FGR: OR, 5.26 (95% CI, 2.11-13.01), P = 0.001), those delivered between 32 and 36 weeks (SGA: OR, 6.67 (95% CI, 2.11-20.41), P = 0.001 and FGR: OR, 9.54 (95% CI, 3.01-29.40), P < 0.001) and those delivered beyond 36 weeks (SGA: OR, 12.68 (95% CI, 2.47-58.15), P = 0.001 and FGR: OR, 23.84 (95% CI, 4.62-110.25), P < 0.001). However, the association of stillbirth with SGA and FGR in twin pregnancies was non-significant when diagnosis was based on singleton charts (before 32 weeks: SGA, P = 0.014 and FGR, P = 0.005; 32-36 weeks: SGA, P = 0.036 and FGR, P = 0.008; after 36 weeks: SGA, P = 0.080 and FGR, P = 0.063). Conclusion Our study demonstrates that SGA and, especially, FGR are associated significantly with an increased risk of stillbirth across all gestational ages in singleton pregnancies, and in twin pregnancies when twin-specific birth-weight charts are used.