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- Clinical applications of levonorgestrel-releasing intrauterine system to gynecologic diseases. [REVIEW]
- Obstet Gynecol Sci 2013 Mar; 56(2):67-75.
The levonorgestrel-releasing intrauterine system (LNG-IUS), originally designed for contraception, has since been applied to various gynecologic diseases. This article summarizes the current status of clinical applications of LNG-IUS to the treatment of gynecologic diseases such as heavy menstrual bleeding, endometriosis, leiomyoma, adenomyosis, endometrial hyperplasia, and early-stage endometrial cancer.
- Differentiation of large (≥5cm) gastrointestinal stromal tumors from benign subepithelial tumors in the stomach: Radiologists' performance using CT. [JOURNAL ARTICLE]
- Eur J Radiol 2013 Nov 7.
To identify significant CT findings for the differentiation of large (≥5cm) gastric gastrointestinal stromal tumors (GIST) from benign subepithelial tumors and to assess whether radiologists' performance in differentiation is improved with knowledge of significant CT criteria.One-hundred twenty patients with pathologically proven large (≥5cm) GISTs (n=99), schwannomas (n=16), and leiomyomas (n=5) who underwent CT were enrolled. Two radiologists (A and B) retrospectively reviewed their CT images in consensus for the location, size, degree and pattern of enhancement, contour, growth pattern and the presence of calcification, necrosis, surface ulceration, or enlarged lymph nodes. CT findings considered significant for differentiation were determined using uni- and multivariate statistical analyses. Thereafter, two successive review sessions for the differentiation of GIST from non-GIST were independently performed by two other reviewers (C and D) with different expertise of 2 and 9 years using a 5-point confidence scale. At the first session, reviewers interpreted CT images without knowledge of significant CT findings. At the second session, the results of statistical analyses were provided to the reviewers. To assess improvement in radiologists' performance, a pairwise comparison of receiver operating curves (ROC) was performed.Heterogeneous enhancement, presence of necrosis, absence of lymph nodes, and mean size of ≥6cm were found to be significant for differentiating GIST from schwannoma (P<0.05). Non-cardial location, heterogeneous enhancement, and presence of necrosis were differential CT features of GIST from leiomyoma (P<0.05). Multivariate analyses indicated that absence of enlarged LNs was the only statistically significant variable for GIST differentiating from schwannoma. The area under the curve of both reviewers obtained using ROC significantly increased from 0.682 and 0.613 to 0.903 and 0.904, respectively, with information of the significant CT findings differentiating GISTs from non-GISTs (P<0.001).Non-cardial location, heterogeneous enhancement, presence of necrosis, larger lesion size, and absence of lymphadenopathy are highly suggestive CT findings for large GISTs in differentiation from schwannomas or leiomyomas. Regardless of radiologists' expertise, diagnostic performance in differentiation can be significantly improved with knowledge of these CT findings.
- GSTM1 Gene Expression Correlates to Leiomyoma Volume Regression in Response to Mifepristone Treatment. [Journal Article]
- PLoS One 2013; 8(12):e80114.
Progesterone receptor modulators, such as mifepristone are useful and well tolerated in reducing leiomyoma volume although with large individual variation. The objective of this study was to investigate the molecular basis for the observed leiomyoma volume reduction, in response to mifepristone treatment and explore a possible molecular marker for the selective usage of mifepristone in leiomyoma patients. Premenopausal women (N = 14) were treated with mifepristone 50 mg, every other day for 12 weeks prior to surgery. Women were arbitrarily sub-grouped as good (N = 4), poor (N = 4) responders to treatment or intermediate respondents (N = 3). Total RNA was extracted from leiomyoma tissue, after surgical removal of the tumour and the differential expression of genes were analysed by microarray. The results were analysed using Ingenuity Pathway Analysis software. The glutathione pathway was the most significantly altered canonical pathway in which the glutathione-s transferase mu 1 (GSTM1) gene was significantly over expressed (+8.03 folds) among the good responders compared to non responders. This was further confirmed by Real time PCR (p = 0.024). Correlation of immunoreactive scores (IRS) for GSTM1 accumulation in leiomyoma tissue was seen with base line volume change of leiomyoma R = -0.8 (p = 0.011). Furthermore the accumulation of protein GSTM1 analysed by Western Blot correlated significantly with the percentual leiomyoma volume change R = -0.82 (p = 0.004). Deletion of the GSTM1 gene in leiomyoma biopsies was found in 50% of the mifepristone treated cases, with lower presence of the GSTM1 protein. The findings support a significant role for GSTM1 in leiomyoma volume reduction induced by mifepristone and explain the observed individual variation in this response. Furthermore the finding could be useful to further explore GSTM1 as a biomarker for tailoring medical treatment of uterine leiomyomas for optimizing the response to treatment.www.clinicaltrials.gov: NCT00579475, Protocol date: November 2004. http://clinicaltrials.gov/ct2/show/NCT00579475.
- Uterine leiomyomata and cesarean birth risk: a prospective cohort with standardized imaging. [JOURNAL ARTICLE]
- Ann Epidemiol 2013 Nov 12.
To determine if women with leiomyomata detected using uniform ultrasound methods are at increased risk of cesarean birth, without regard to indication.Women were enrolled in Right from the Start (2000-2010), a prospective pregnancy cohort. Leiomyomata were counted, categorized, and measured during first trimester ultrasounds. Women provided information about demographics and reproductive history during first trimester interviews. Route of delivery was extracted from medical records or vital records, if the former were unavailable. Generalized estimating equations were used to calculate risk ratios (RR) and 95% confidence intervals (CIs) for the risk of cesarean birth by leiomyoma presence and characteristics.Among 2635 women, the prevalences of leiomyomata and cesarean birth were 11.2% and 29.8%, respectively. Women with leiomyomata, compared with those without, had a 27% increase in cesarean risk (RR, 1.27; CI, 1.17-1.37). The association was weaker following adjustment for maternal body mass index and age (adjusted risk ratio [ARR], 1.11; CI, 1.02-1.20). The adjusted risk was elevated for women with a single leiomyoma 3 cm or more in diameter (ARR, 1.22; CI, 1.14-1.32) and women with the largest total leiomyoma volumes (ARR, 1.59; CI, 1.44-1.76).Women with leiomyomata were at increased risk for cesarean birth particularly, those with larger tumor volumes.
- Extragonadal sclerosing stromal tumor: A rare case report. [JOURNAL ARTICLE]
- J Obstet Gynaecol Res 2013 Dec 10.
Sclerosing stromal tumor is a rare, benign, sex cord stromal tumor of the ovary. We report a case of extragonadal sclerosing stromal tumor in a 45-year-old woman who presented with menstrual irregularity and vague pelvic pain. Imaging studies showed a well-defined mass between the posterior wall of the bladder and uterus, suspected of being a pedunculated leiomyoma. The histopathological and immunohistochemical study was consistent with sclerosing stromal tumor. No ovarian tissue was found on representative sectioning. This is the first case of sclerosing stromal tumor in an extragonadal location.
- Role of single nucleotide polymorphisms in estrogen-metabolizing enzymes and susceptibility to uterine leiomyoma in Han Chinese: A case-control study. [JOURNAL ARTICLE]
- J Obstet Gynaecol Res 2013 Dec 10.
To explore the relationship between estrogen metabolism enzyme gene polymorphism and susceptibility to uterine fibroids, and to seek the screening molecular markers for genetic traits in uterine fibroid populations.A total of 300 female Han Chinese patients and 300 healthy female Han Chinese volunteers in Nanjing (age range, 30-50 years) were recruited from Zhongda Hospital, Southeast University from February 2011 to March 2012. The single nucleotide polymorphisms (SNP) of estrogen-metabolizing enzyme genes from the two groups of women were examined by polymerase chain reaction denaturing high-performance liquid chromatography, which were four COMT gene loci including rs3087869, rs165774, rs165599 and rs4680, three CYP1A1 gene loci including rs1048943, rs4646421 and rs4646422, and three CYP1B1 gene loci including rs1056827, rs1056836 and rs1056837. Genotype frequencies among cases and controls were calculated and analyzed by binary logistic regression.Regression analysis of SNP showed that COMT IVS1+2329C>T (odds ratio [OR], 2.872; 95% CI, 1.690-4.882) and Val158Met (OR, 2.593; 95% CI, 1.546-4.350), CYP1A1 Ile462Val (OR, 2.383; 95% CI, 1.418-4.005) and Gly45Asp (OR, 2.489; 95% CI, 1.49-4.159), and CYP1B1 Ala119Ser (OR, 3.361; 95% CI, 2.035-5.552) and Leu432Val (OR, 0.164; 95% CI, 0.061-0.441) influenced uterine fibroids significantly (P < 0.05). Allele and genotype frequencies among cases and control were calculated and examined to match the Hardy-Weinberg equilibrium with the χ(2) -test.The genetic polymorphisms of IVS1+2329C>T and Val158Met loci in COMT, Ile462Val and Gly45Asp loci in CYP1A1 and Ala119Ser loci in CYP1B1 were risk factors for uterine leiomyoma development, and Leu432Val locus in CYB1B1 may be a protective factor. The results provide a theoretical basis for genetic screening and early intervention for uterine leiomyoma-susceptible populations.
- Estrogen-mediated activation of fibroblasts and its effects on the fibroid cell proliferation. [JOURNAL ARTICLE]
- Transl Res 2013 Nov 20.
In this study, we explored the role of estrogen-mediated activation of stromal fibroblasts in the pathogenesis of uterine fibroid in patients. We isolated uterine fibroids and surrounding smooth muscle from patients and separated fibroblasts using immunomagnetic beads. We also measured the expression levels of estrogen receptors in fibroblasts and examined cell proliferation, expressions of fibroblast activation protein (FAP), extracellular matrix (ECM) (fibronectin, laminin, collagen I), growth factors (transforming growth factor-β, insulin-like growth factor-1), and cell proliferation pathway stimulated by estrogen. We also silenced the expression of FAP by RNA interference and analyzed the expression levels of these markers before and after E2 stimulation. Finally, we also investigated the effect of activated fibroblast supernatant on cell proliferation of fibroblasts, smooth muscle cells, and fibroid cells. We found that fibroblasts in uterine fibroid were activated, and the expression levels of estrogen receptors from fibroid cells were higher than those from smooth muscle cells. After estrogen stimulation, the proliferation activity of fibroblast was enhanced, and the expression of FAP, ECM, and growth factors was increased; the signaling pathway involved in cell proliferation was also activated. Interestingly, the activated fibroblast supernatant stimulation can promote cell proliferation. Silencing of FAP expression could inhibit the E2-mediated biological effects. In conclusion, estrogen promotes proliferation of uterine fibroids through the activation of fibroblasts, thus, activated fibroblasts may play an important role in the pathogenesis of uterine fibroids, which could be targeted in future for the treatment of uterine fibroid.
- Imaging for Uterine Myomas and Adenomyosis. [JOURNAL ARTICLE]
- J Minim Invasive Gynecol 2013 Dec 3.
Uterine myomas and adenomyosis are common findings, particularly in patients with symptoms of abdominal enlargement, pelvic pressure, abnormal uterine bleeding, dysmenorrhea and dyspareunia. The diagnosis and differentiation between both entities are critical in establishing treatment options and the operative approach for surgical management. This article reviews diagnostic options, their relative accuracy, and the impact accurate diagnosis has on treatment. A review was performed using PubMed, MdConsult, OVID and reviews, including cross-referenced articles, prospective and retrospective studies, published from 1980 to 2013. The article reviews the use of ultrasound, with its various modalities, magnetic resonance imaging (MRI), computerized tomography (CT), and positron emission tomography (PET) in the diagnosis, pretreatment evaluation, and differentiation of the myomas and adenomyosis.
- Ultrasound-guided percutaneous microwave ablation for submucosal uterine fibroids. [JOURNAL ARTICLE]
- J Minim Invasive Gynecol 2013 Dec 3.
To prospectively evaluate the efficiency and safety of ultrasound (US)-guided percutaneous microwave ablation (PMWA) in treating symptomatic submucosal uterine fibroids (SSUFs).Self-control study (Canadian Task Force classification II-1).A single centre (Department of Interventional Ultrasonics, General Hospital of Chinese PLA, Beijing, China).Twenty-two premenopausal women with 22 SSUFs.All of the patients underwent US-guided PMWA.PMWA was performed on 22 premenopausal women with 22 SSUFs. The mean patient age was 42.00±4.60 years (95% CI, 39.96-44.04). Five SSUFs were identified as type 0, 7 as type I and 10 as type II. Contrast-enhanced ultrasound and magnetic resonance imaging were performed pre- and post-operation. The volume of the fibroids, the patients' haemoglobin levels and scores on the Uterine Fibroid Symptom and Quality of Life (UFS-QOL) were recorded before and at 3 and 12 months after ablation. Complications were also recorded.All patients completed therapy with a single ablation. The baseline diameter of the SSUFs was 4.90±1.60 cm. The average fibroid volume reduction rate was 81.46±16.33% (95%CI, 73.06-89.86%) at 3 months (P<.001) and reached 90.00±9.79% (95%CI, 85.07-95.13%) at 12 months (P<.001). Three months after ablation, the patients' haemoglobin levels increased from 88.64±21.87 g/L (95%CI, 78.94-98.34) to 123.21±15.77 g/L (95%CI, 115.10-131.32) (P<.001) and remained stable at 12 months, with a value of 125.92±14.90 g/L (95%CI, 117.98-133.86). The scores on UFS-QOL were comparable, with normal levels observed at 1 year. No major complications were observed. Finally, 9 patients discharged necrotic masses.PMWA appears to be effective and safe for submucosal fibroids.
- Uterine smooth muscle tumors with features suggesting fumarate hydratase aberration: detailed morphologic analysis and correlation with S-(2-succino)-cysteine immunohistochemistry. [JOURNAL ARTICLE]
- Mod Pathol 2013 Dec 6.
Rare, sporadic uterine leiomyomas arise in the setting of severe metabolic aberration due to a somatic fumarate hydratase mutation. Germline mutations account for the hereditary leiomyomatosis and renal cell carcinoma syndrome, which predisposes for cutaneous and uterine leiomyomas and aggressive renal cell carcinomas. Altered fumarate hydratase leads to fumarate accumulation in affected cells with formation of S-(2-succino)-cysteine, which can be detected with the polyclonal antibody. High levels of these modified cysteine residues are found characteristically in fumarate hydratase-deficient cells but not in normal tissues or tumors unassociated with hereditary leiomyomatosis and renal cell carcinoma syndrome. We hypothesized that S-(2-succino)-cysteine-positive leiomyomas, indicating fumarate hydratase aberration, have morphologic features that differ from those without S-(2-succino)-cysteine positivity. Hematoxylin and eosin-stained slides of uterine smooth-muscle tumors were prospectively analyzed for features suggesting hereditary leiomyomatosis and renal cell carcinoma syndrome, such as prominent eosinophilic macronucleoli with perinucleolar halos, yielding nine cases. Germline genetic testing for fumarate hydratase mutations was performed in three cases. A detailed morphological analysis was undertaken, and S-(2-succino)-cysteine immunohistochemical analysis was performed with controls from a tissue microarray (leiomyomas (19), leiomyosarcomas (29), and endometrial stromal tumors (15)). Of the nine study cases, four had multiple uterine smooth muscle tumors. All cases had increased cellularity, staghorn vasculature, and fibrillary cytoplasm with pink globules. All cases had inclusion-like nucleoli with perinuclear halos (7 diffuse, 1 focal). All showed diffuse granular cytoplasmic labeling with the S-(2-succino)-cysteine antibody. Two of three tested patients had germline fumarate hydratase mutations. Only one leiomyoma from the tissue microarray controls was immunohistochemically positive, and it showed features similar to other immunohistochemically positive cases. Smooth-muscle tumors with fumarate hydratase aberration demonstrate morphological reproducibility across cases and S-(2-succino)-cysteine immuno-positivity. Although the features described are not specific for the germline fumarate hydratase mutation or the hereditary leiomyomatosis and renal cell carcinoma syndrome, their presence should suggest fumarate hydratase aberration. Identifying these cases is an important step in the diagnostic workup of patients with possible hereditary leiomyomatosis and renal cell carcinoma.Modern Pathology advance online publication, 6 December 2013; doi:10.1038/modpathol.2013.215.