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Background: Preclinical studies in endometrial cancer (EC) show that metformin reduces cellular proliferation by PI3K-AKT-mTOR inhibition. We tested the hypothesis that short-term presurgical metformin reduces cellular proliferation in atypical endometrial hyperplasia (AEH) and endometrioid EC, and assessed the feasibility of using phosphorylated PI3K-AKT-mTOR proteins as tissue end points. Methods: Women with AEH or EC received metformin 850 mg twice a day or no drug in the presurgical window between diagnosis and hysterectomy. Before and after the window, tissue samples were obtained; serum markers of insulin resistance (e.g. homeostasis model of assessment of insulin resistance index) were determined; and anthropometrics measured (e.g. BMI). Cell proliferation (Ki-67) and PI3K-AKT-mTOR phosphostatus were assessed by immunohistochemistry and scored blinded to treatment. Results: Twenty-eight metformin-treated and 12 untreated patients, well matched for age and BMI, completed the study. Metformin treatment (median 20 days, range 7–34) was associated with a 17.2% reduction in tumour Ki-67 (95% CI −27.4, −7.0, P =0.002), in a dose-dependent manner. Tumour PI3K-AKT-mTOR protein phosphostatus varied but the effects were not significant after adjusting for changes in controls. Conclusions: Short-term metformin was associated with reduced Ki-67 expression in EC. Changes in tumour PI3K-AKT-mTOR protein phosphostatus were seen in both groups. Future studies should address the variability attributed to different sampling techniques including devascularisation of the uterus at hysterectomy.

Background Cesarean scar defects can lead to long-term complications, such as cesarean scar disorders, cesarean scar pregnancy, and the risk of uterine scar dehiscence and rupture in subsequent pregnancy. However, the optimal closure technique to prevent the development of cesarean scar defects (CSD) remains unclear. Therefore, this study aimed to explore whether two-layer interrupted versus two-layer continuous sutures could prevent the formation of CSD. Methods A randomized controlled trial was conducted in a single university hospital in Japan. We recruited pregnant women with ≥ 20 primary or previous cesarean sections. Participants were randomly assigned to either a two-layer interrupted or a two-layer continuous suture group. Residual myometrial thickness (RMT) and the depth of CSD were measured using sonohysterography, 6–8 months post-cesarean section. In addition, the rate of severe CSD, defined as a loss of over 50% of the myometrium, was examined. Results Of the 220 study participants, 43 dropped out; 89 in the interrupted group and 88 in the continuous group underwent sonohysterography. No significant difference in RMT was observed in the interrupted and continuous groups (median 8.1 [interquartile range, 6.2–9.9] mm and 7.9 [4.6–10.3] mm, respectively). However, the incidence of severe CSD in the interrupted group was significantly lower than that in the continuous group (2% versus 22%, p  < 0.0001). Multivariate logistic regression analysis revealed that the factors contributing to developing severe CSD were interrupted suture (odds ratio [OR]: 0.04, 95% confidence interval [95%CI]: 0.006–0.281, p  = 0.0011), the difference in myometrial thickness between the fundal and cervical sides at the center of the uterine wound before suturing (OR: 1.65, 95%CI: 1.144–2.367, p  = 0.0072), and retroversion of the uterus at 6–8 months after cesarean section (OR: 3.42, 95%CI: 1.074–10.946, p  = 0.0374). Conclusion This study suggested that two-layer interrupted sutures are superior to two-layer continuous sutures in preventing the development of severe CSD. Trial registration Clinical trial identification number: University Hospital Medical Information Network registration code, UMIN000040601. URL of the registration site: https://center6.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000046334 .

OBJECTIVELymphoceles are among the most common postoperative complications of pelvic lymphadenectomy (PL), with a reported incidence of 1% to 50%. Symptoms are pelvic pain, leg edema, gastrointestinal obstruction, obstructive uropathy, and deep vein thrombosis, and severe complications such as sepsis and lymphatic fistula formation. After laparoscopic PL, we tested the prevention of lymphoceles using collagen patch coated with the human coagulation factors (TachoSil, Nycomed International Management GmbH, Zurich, Switzerland) on 55 patients with endometrial cancer stages IB to II who had undergone laparoscopy. MATERIALS AND METHODSThe authors divided the patients into 2 laparoscopy groupsPL plus TachoSil (group 126 patients) and PL without TachoSil in a control group (group 229 patients), as historical cohort of patients who underwent PL between 2010 and 2012. We collected surgical parameters, and the patients underwent ultrasound examination on postoperative days 7, 14, and 28. The main outcome measures were the development of symptomatic or asymptomatic lymphoceles, the need for further surgical intervention, as adverse effect of surgery, and the drainage volume and duration. RESULTSThe same number of lymph nodes in both groups was removed; group 1 showed a lower drainage volume. Lymphoceles developed in 5 patients in group 1 and in 15 patients in group 2; of these, only 2 patients were symptomatic in group 1 and 5 patients were symptomatic in group 2, without statistical difference and no percutaneous drainage request. CONCLUSIONSIn this preliminary investigation, the intraoperative laparoscopy application of TachoSil seems to reduce the rate of postoperative lymphoceles after PL, providing a useful additional treatment option for reducing drainage volume and preventing lymphocele development after PL.

Uterine leiomyomas (fibroids) are a major source of gynecologic morbidity in reproductive age women and are characterized by the excessive deposition of a disorganized extracellular matrix, resulting in rigid benign tumors. Although down regulation of the transcription factor AP-1 is highly prevalent in leiomyomas, the functional consequence of AP-1 loss on gene transcription in uterine fibroids remains poorly understood. Using high-resolution ChIP-sequencing, promoter capture Hi-C, and RNA-sequencing of matched normal and leiomyoma tissues, here we show that modified enhancer architecture is a major driver of transcriptional dysregulation in MED12 mutant uterine leiomyomas. Furthermore, modifications in enhancer architecture are driven by the depletion of AP-1 occupancy on chromatin. Silencing of AP-1 subunits in primary myometrium cells leads to transcriptional dysregulation of extracellular matrix associated genes and partly recapitulates transcriptional and epigenetic changes observed in leiomyomas. These findings establish AP-1 driven aberrant enhancer regulation as an important mechanism of leiomyoma disease pathogenesis. Somatic mutations in MED12 have been implicated as the causal genetic lesion in the majority of uterine leiomyomas. Here, the authors profile the chromatin landscape of matched normal and leiomyoma tissues and find that changes in enhancer acetylation, enhancer-promoter interaction strength, differential enhancer usage and transcription factor AP-1 occupancy are significant drivers of transcriptional dysregulation in MED12 mutant leiomyomas.

Abstract Objectives The disruption or defect of the myometrium in the uterine scar of a cesarean section (CS) has been known by various names, such as uterine niche, isthmocele, deficient uterine scar, scar pouch, or diverticulum. Symptomatology, risk factors for niche development, and available treatment modalities have been recently studied. However, the histologic features of this disease remain unknown. Methods The histologic features of eight uterine niches are thoroughly described and a summary of the most important aspects of the uterine niche literature is provided. Five cases of CS scars without niche formation are comparatively examined. Results Most uterine niches harbor endocervical mucosa, often cystically dilated and/or an atrophic or disorganized endometrial mucosa of lower uterine segment origin. Regenerative epithelial atypia and fibroblastic stromal reaction are frequent features. No granulomatous reaction, important inflammation, or hemorrhage is seen. CS scars without niche formation do not harbor endocervical mucosa or inclusion cysts, fibroblastic stroma, or regenerative atypia. Conclusions As more prospective studies of uterine niche development and treatment will be conducted, a detailed pathologic report with the criteria proposed herein can be designed.

Uterine adenomyosis is a benign disorder that often co-occurs with endometriosis and/or leiomyoma, and impairs quality of life. The genomic features of adenomyosis are unknown. Here we apply next-generation sequencing to adenomyosis (70 individuals and 192 multi-regional samples), as well as co-occurring leiomyoma and endometriosis, and find recurring KRAS mutations in 26/70 (37.1%) of adenomyosis cases. Multi-regional sequencing reveals oligoclonality in adenomyosis, with some mutations also detected in normal endometrium and/or co-occurring endometriosis. KRAS mutations are more frequent in cases of adenomyosis with co-occurring endometriosis, low progesterone receptor (PR) expression, or progestin (dienogest; DNG) pretreatment. DNG’s anti-proliferative effect is diminished via epigenetic silencing of PR in immortalized cells with mutant KRAS . Our genomic analyses suggest that adenomyotic lesions frequently contain KRAS mutations that may reduce DNG efficacy, and that adenomyosis and endometriosis may share molecular etiology, explaining their co-occurrence. These findings could lead to genetically guided therapy and/or relapse risk assessment after uterine-sparing surgery. Uterine adenomyosis often co-occurs with endometriosis or leiomyoma, but little is known about its molecular underpinnings. Here, the authors show that KRAS mutations are frequent in this disease, which might reduce sensitivity to progestin treatment via epigenetic silencing of the progesterone receptor.

Uterine transplantation is currently the only solution that enables women with absolute uterine factor infertility to become pregnant and give birth to a child. In the preparatory phase of a human uterus transplantation, the sheep is the most recommended species. Cold ischaemia, i.e., a period of reduced or absent blood flow at cold conditions, can significantly impair the function of the transplanted organ. Cold ischaemia impairs smooth muscle function in general and reduces smooth muscle contractile activity. However, it seems to provide some protection against cold storage. Our main goal was to investigate the molecular mechanisms leading to reversible changes in myometrial myofilaments and to distinguish these from permanent changes, which was supported by histological imaging of uterine samples. Using fluorescence spectroscopy, we investigated important interactions between major components of smooth muscle such as actin and tissue-specific actin-binding proteins. We characterized functional changes by denaturation sensitivity and protein-protein interactions under low and high salt conditions by intrinsic tryptophan, Alexa488-phalloidin and eosin fluorescence emission spectroscopy assays. Our results suggest that short-term cold ischaemia causes minor disruption of muscle cells. The protein extracts of myometrium contained large amounts of actin, which was present in soluble complexes with actin-binding proteins after ischaemic stress. The results indicate that the contractile filament system underwent molecular stabilization and reassembly due to ischaemic stress and that the actin monomers were unable to form polymers due to increased heterologous protein-protein interactions. The content of necrotic proteins cannot be detected after brief ischaemia, but eosin selectively binds to large proteins (caldesmon, myosin chains, tropomyosin) and protein complexes. Based on these results, we can assume that short-term preservation of cold ischaemia in uterine transplantation reduces the risk of using it in clinical trials for complete myometrial recovery after reperfusion.

Adenomyosis is a poorly understood gynecological disorder lacking effective treatments. Controversy persists regarding \"invagination\" and \"metaplasia\" theories. The endometrial-myometrial junction (EMJ) connects the endometrium and myometrium and is important for diagnosing and classifying adenomyosis, but its in-depth study is just beginning. Using single-cell RNA sequencing and spatial profiling, we mapped transcriptional alterations across eutopic endometrium, lesions, and EMJ. Within lesions, we identified unique epithelial ( LGR5 +) and invasive stromal ( PKIB +) subpopulations, along with WFDC1 + progenitor cells, supporting a complex interplay between \"invagination\" and \"metaplasia\" theories of pathogenesis. Further, we observed endothelial cell heterogeneity and abnormal angiogenic signaling involving vascular endothelial growth factor and angiopoietin pathways. Cell-cell communication differed markedly between ectopic and eutopic endometrium, with aberrant signaling in lesions involving pleiotrophin, TWEAK, and WNT cascades. This study reveals unique stem cell-like and invasive cell subpopulations within adenomyosis lesions identified, dysfunctional signaling, and EMJ abnormalities critical to developing precise diagnostic and therapeutic strategies.

PurposeDespite the numerous studies on the factors involved in the genesis and growth of uterine leiomyomas, the pathogenesis of these tumors remains unknown. Intrinsic abnormalities of the myometrium, abnormal myometrial receptors for estrogen, and hormonal changes or altered responses to ischemic damage during the menstrual period may be responsible for the initiation of (epi)genetic changes found in these tumors. Considering these elements, we aimed to offer an overview about epigenetic and genetic landscape of uterine leiomyomas.MethodsNarrative overview, synthesizing the findings of literature retrieved from searches of computerized databases.ResultsSeveral studies showed that leiomyomas have a monoclonal origin. Accumulating evidence converges on the risk factors and mechanisms of tumorigenesis: the translocation t (12;14) and deletion of 7q were found in the highest percentages of recurrence; dysregulation of the HMGA2 gene has been mapped within the critical 12q14–q15 locus. Estrogen and progesterone are recognized as promoters of tumor growth, and the potential role of environmental estrogens has been poorly explored. The growth factors with mitogenic activity, such as transforming growth factor-β3, fibroblast growth factor, epidermal growth factor, and insulin-like growth factor-I are elevated in fibroids and may have a role as effectors of the tumor promotion.ConclusionThe new clues on genetics and epigenetics, as well as about the growth factors that control normal and pathological myometrial cellular biology may be of great help for the development of new effective and less invasive therapeutic strategies in the near future.

Uterine fibroids (UFs) are the most common benign gynecologic tumours affecting women of reproductive age. This study aims to deepen the understanding of UFs complex aetiology through harnessing the power of 3D organoid models derived from human myometrial stem cells to emulate the in vivo behaviour of these tumours. Isolated SCs were cultured over 7 days under a defined culture system. Immunohistochemistry, Immunofluorescence, organoid stiffness, RNA Sequencing was conducted, and differential gene expression was assessed using RT‐PCR. The derived organoids exhibited diverse populations of cells, including stem cells, smooth muscle, and fibroblasts. Excessive ECM deposition was shown via Collagen and Fibronectin expression. We confirmed that our organoids expressed oestrogen receptor in a pattern similar to that in their corresponding tissue, as well as responded to steroid hormone. Interestingly, we revealed significant racial disparities in ECM accumulation within organoids derived from different racial groups. This augmented ECM deposition is theorised to enhance tissue stiffness, as assessed using Young's modulus. Additionally, our research demonstrated significant decreases in fibrotic markers upon treatment with Vitamin D3 and Doxercalciferol. Furthermore, the pro‐fibroid effects of environmental phthalates further elucidate the potential factors contributing to UF pathology. The 3D organoid model can serve as a robust platform to study the underlying molecular mechanisms of UFs, besides offering invaluable insights for potential therapeutic interventions. Three‐dimensional stem cell‐derived organoid model can serve as a robust platform to study the underlying molecular mechanisms of UFs, UFs health disparity, environmental risk factors, besides offering invaluable insights for potential therapeutic interventions.