Uterine Leiomyomas

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A rare coincidence of different types of driver mutations among uterine leiomyomas (UL)

A rare coincidence of different types of driver mutations among uterine leiomyomas (UL)

Mutations of mediator subcomplex 12 ( MED12 ) and of high mobility group protein AT-hook 2 ( HMGA2 ) are driver mutations in uterine leiomyomas (UL) that have not been observed to coexist in one tumor and even rarely coexist in different UL tumors of one patient. Here we describe a patient who underwent hysterectomy because of multiple leiomyomas which were studied by cytogenetics, MED12 hotspot sequencing, and copy number variation arrays. Two of the UL tumors had different HMGA2 rearrangements not detected by G-banding. Two UL tumors had deletions of the long arm of chromosome 3, in one case associated with a MED12 mutation. Both deletions lead to the loss of MED12L showing strong similarity with MED12 . It remains to be determined if this gene can play a role in leiomyomagenesis independent of MED12 . In summary, the patient presented exhibits an unusual coincidence of different driver mutations among her leiomyomas.
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GnRH analogs for the treatment of symptomatic uterine leiomyomas

GnRH analogs for the treatment of symptomatic uterine leiomyomas

Abstract Uterine leiomyomas are the most frequent be- nign disease of the female reproductive tract. To date, the standard treatment of uterine leiomyomas is lapar- otomic/laparoscopic excision in women who want to preserve their fertility, whereas the use of a more extensive surgery, such as hysterectomy, is reserved for disseminated uterine leiomyomatosis, usually in the perimenopausal period. Given the pathogenesis of uterine leiomyomas, it is clear that future treatments for leiomyomas may be medical. At present the only clini- cally relevant medical treatment of uterine leiomyoma is GnRH agonist administration in depot formulations. In this review, the use of GnRH agonists, with or without ‘‘add-back therapy,’’ and antagonists will be assessed. Keywords GnRH agonist Æ GnRH antagonist Æ GnRH analog Æ Add-back therapy Æ Uterine leiomyomas
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Impact of Genetic Variants in Estrogen Receptor-β Gene in the Etiology of Uterine Leiomyomas

Impact of Genetic Variants in Estrogen Receptor-β Gene in the Etiology of Uterine Leiomyomas

Estrogens exert their effects on target cells through the activation of estrogen receptors which are classified as nuclear estrogen receptors (ERs) and membrane bound receptors (mERs) (18). The pro- gression of cell proliferation in the G1 phase of the cell cycle is stimulated by estrogen in various target tissues, like uterus and breast. Evidence has shown that the concentration of estrogen in leio- myoma tissue is higher compared to the normal myometrium and the growth of tumor is influ- enced by both serum and tumor tissue estrogen le- vels indicating their sensitivity (19). ER-β mRNA was reported to be expressed at higher levels in leiomyomas when compared with matched my- ometrium (20). ER-β acts as a negative regulator of ER-α thereby exerting antiproliferative and apoptotic effect in different tissues as leiomyomas markedly regress in the postmenopausal state. Thus, it is tempting to speculate that ER-β could play a major role in the pathobiology of uterine leiomyomas.
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<p>Mifepristone inhibits IGF-1 signaling pathway in the treatment of uterine leiomyomas</p>

<p>Mifepristone inhibits IGF-1 signaling pathway in the treatment of uterine leiomyomas</p>

From October 2015 to January 2018, uterine leiomyoma tissues were obtained from 50 patients (the Han nation- ality) with age range 42±8.5 years, during the surgery of uterine myomectomy, subtotal or total hysterectomy. Tissues from surgery were identi fi ed by pathologist as uterine leiomyomas. The exclusion criteria were patients who used medicines or hormones within 3 months before surgery, or with other complications such as chronic diseases, infections, uterine malignancy and adenomyosis. This study followed the standards of the Declaration of Helsinki and was approved by the Research Ethical Committee of the Second Af fi liated Hospital of Wenzhou Medical University (No. KYKT2015-55). Written informed consent was obtained from all patients. The collected tissues from the central localization of uterine leiomyoma were used for isolation of primary uterine leiomyoma cells, and part of cells was then immortalized by ectopic expression of human telomerase reverse transcriptase via lentivirus transduction. Cells were grown in vitro using the methods as previously reported. 12
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Cytogenetically normal uterine leiomyomas without MED12-mutations – a source to identify unknown mechanisms of the development of uterine smooth muscle tumors

Cytogenetically normal uterine leiomyomas without MED12-mutations – a source to identify unknown mechanisms of the development of uterine smooth muscle tumors

However, as a typical sign of “firestorms” or “chro- mothripsis” the rearrangements are confined to well- circumscribed regions of chromosomes instead of being spread across the whole genome. In contrast, the remaining part of the genome appears to be rather “quiet”. While initially described in hematological malignancies [14,16] and some solid cancers as in particular sarcomas and carcinomas [14,15,17], in a recent study Mehine et al. [4] were able to show that chromothripsis-like rearrange- ments do also occur in uterine leiomyomas. Again a dras- tically reduced ability of some leiomyomas to proliferate in vitro may account for the lack of detection of these massive genomic rearrangements by classical cytogen- etics though highly complex genomic rearrangements in leiomyomas are occasionally found by conventional cytogenetics. However, the low resolution obtained has certainly hindered to recognize the ‘true complexity’ in these latter cases. As a rule, in chromothripsis the multiple rearrangements are correlated with multiple copy number alterations [18]. Typically, the characteristic changes ob- served reflect that the process causing this massive but localized breakage has been resolved in the absence of ongoing genomic instability. In the cases presented by Mehine et al. [4] no evidence for atypic or variant UL has been reported. Thus, chromothripsis is not likely to affect exclusively malignant cells and accordingly foot- prints of resolved chromothripsis do not necessarily ac- company malignant transformation. In line with this finding, the case described herein shows chromothrip- sis apparently in the absence of rearrangements of loci harboring known driver genes and the regions affected by massive rearrangements do not coincide with those shown to be frequently affected by firestorms in breast can- cer [15]. While, the tumor presented as a variant leiomyoma upon histological examination it clearly shows that
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Proteomics and uterine leiomyomas: a narrative review for better understanding of the disease

Proteomics and uterine leiomyomas: a narrative review for better understanding of the disease

Uterine Leiomyomas (also known as fibroids) are the monoclonal tumors originating from the smooth muscle cells of the myometrium and are generally benign in nature (Linder and Gartler, 1965). These are the most common benign pelvic tumor affecting nearly 70% of women in their reproductive age and despite 70% of women may have UL, 20-30% of women are symptomatic, that is, may have abnormal uterine bleeding or pelvic pain. These monoclonal fibroids are characterized by the excess of the extracellular matrix (Moroni et al., 2014). Since there are very few deaths associated with fibroids, hence these are generally associated with morbidity rather than mortality. Hysterectomy and Myomectomy are one of the leading gynecological surgical operations in the United States (Cardozo et al., 2012). Based on their location in the uterus, leiomyomas are classified into 4 primary types which include subserous, intramural, submucous and pedunculated type (McLucas, 2008). The size of the tumor may vary from 10mm to 20cm. It has been observed that in most of the cases there is generally more than one fibroid in the uterus (Walker and Stewart, 2005). The normal function of the uterus is disrupted leading to several complications like heavy menstrual bleeding, iron deficiency (anemia), pelvic discomfort and complications in pregnancy. There is generally no any visible symptom in
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Differential Expression of Receptor Tyrosine Kinases (RTKs) and IGF-I Pathway Activation in Human Uterine Leiomyomas

Differential Expression of Receptor Tyrosine Kinases (RTKs) and IGF-I Pathway Activation in Human Uterine Leiomyomas

Uterine leiomyomas (fibroids) are benign tumors that are prevalent in women of reproductive age. Research suggests that ac- tivated receptor tyrosine kinases (RTKs) play an important role in the enhanced proliferation observed in fibroids. In this study, a phospho-RTK array technique was used to detect RTK activity in leiomyomas compared with myometrial tissue. We found that fif- teen out of seventeen RTKs evaluated in this study were highly expressed (P < 0.02–0.03) in the leiomyomas, and included the IGF-I/IGF-IR, EGF/EGFR, FGF/FGF-R, HGF/HGF-R, and PDGF/PDGF-R gene families. Due to the higher protein levels of IGF-IR ob- served in leiomyomas by us in earlier studies, we decided to focus on the activation of the IGF-IR, its downstream effectors, and MAPKp44/42 to confirm our earlier findings; and validate the significance of the increased IGF-IR phosphorylation observed by RTK array analysis in this study. We used immunolocalization, western blot, or immunoprecipitation studies and confirmed that leiomyomas overexpressed IGF-IRβ and phosphorylated IGF-IRβ. Additionally, we showed that the downstream effectors, Shc, Grb2, and MAPKp44/42 (P < 0.02–0.001) were also overexpressed and involved in IGF-IR signaling in these tumors, while IRS-I, PI3K, and AKT were not. In vitro studies showed that IGF-I (100 ng/mL) increased the proliferation of uterine leiomyoma cells (UtLM) (P < 0.0001), and that phosphorylated IGF-IRβ, Shc, and MAPKp44/42 were also overexpressed in IGF-I-treated UtLM cells (P < 0.05), similar to the tissue findings. A neutralizing antibody against the IGF-IRβ blocked these effects. These data indicate that overex- pression of RTKs and, in particular, activation of the IGF-IR signaling pathway through Shc/Grb2/MAPK are important in mediating uterine leiomyoma growth. These data may provide new anti-tumor targets for noninvasive treatment of fibroids.
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Estradiol dependent uterine leiomyomas in transgenic mice

Estradiol dependent uterine leiomyomas in transgenic mice

Estradiol dependence of the uterine leiomyomas. The CaBP9K regulatory sequences directing the expression of SV40 Tag contain an estradiol responsive element (27). The fact that the uterine leiomyomas developed only after puberty in females suggested that they were hormone responsive, probably via this estradiol responsive element. Mice of several transgenic lines were ovariectomized at puberty and uterine tumor devel- opment was monitored. No uterine tumors developed up to 7 mo after ovariectomy (Table II), indicating that these trans- genic mice are good models of estrogen-dependent smooth muscle uterine tumors. The SV40 Tag expression analyzed by RT-PCR analysis was also hormone dependent (Fig. 6). SV40 Tag expression was not detected in the uterus of ovariecto- mized transgenic mice, but SV40 Tag expression was induced by estradiol treatment (Fig. 6). These results suggest that onco- gene expression is needed for the initiation of the uterine tu- mor. To determine if the oncogene was also necessary for maintenance of the tumor, transgenic mice which had already developed uterine tumors were ovariectomized and changes in the tumor were monitored by MRI (Fig. 7). The tumors had not developed 1 mo after ovariectomy, and a rather weak re- gression could be observed, while the tumor in the nonoper-
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Utility of a minimal skin incision laparotomy technique for removing uterine leiomyomas at a regional core hospital: a retrospective study

Utility of a minimal skin incision laparotomy technique for removing uterine leiomyomas at a regional core hospital: a retrospective study

All patients were operated on in the lithotomy position under general endotracheal anesthesia, and a Foley cath- eter was placed inside the bladder. Epidural anesthesia was also added. A skin incision less than approximately 5 cm in length was made longitudinally (4.3 ± 0.7 cm, 3–5. 5 cm, n = 76), and the adipose tissue and abdominal fascia were cut using a monopolar electric scalpel (Fig. 1a). After the rectus abdominis muscle was spread, the peritoneal membrane was opened with a scalpel and surgical scissors. In this procedure, the abdominal fascia and peritoneal membrane were cut longitudinally at a length of approxi- mately 6 cm. A Small or Medium Alexis® Wound Pro- tector/Retractor (Applied Medical Resources Corporation, Rancho Santa Margarita, CA, USA) was placed inside the wound to provide a wide operative view, making the uterus visible (Fig. 1b). Vasopressin solution was injected into the surrounding tissue to decrease bleeding after the locations of the leiomyomas were detected. The surface of the uterine trunk was cut with a monopolar electric scal- pel, and a part of the leiomyoma was grasped with a sharp
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A Case of Reed Syndrome with a Novel Mutation in the Fumarate Hydratase Gene

A Case of Reed Syndrome with a Novel Mutation in the Fumarate Hydratase Gene

A 37-year-old Fitzpatrick type II German female presented with a chief complaint of “painful bumps” on her extremities which started 15 years ago. She had seen several primary care physicians and dermatologists in the past and had one “bump” excised in Germany but had never been offered a diagnosis and was unable to access her records. Past med- ical history was pertinent for multiple uterine leiomyomas for which she underwent a total abdominal hysterectomy (TAH) that revealed a uterine smooth muscle tumor of uncertain malignant potential (STUMP). Family history was remarkable for a sister who also had similar “bumps” on her extremities which had never been biopsied. There was no family history of renal malignancies. Medications, allergies, and other review of systems were noncontributory. Physical exam revealed tender pink to erythematous 3–6 mm firm dermal papules on her bilateral calves and right anterior tibialis in the center of a 1 cm scar where one of her previous papules had been excised. Three 4 mm punch biopsies of
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Clinicopathological study of leiomyomas in hysterectomy specimens

Clinicopathological study of leiomyomas in hysterectomy specimens

Hysterectomy is a commonly performed procedure in the management of uterine leiomyomas. The ultimate diagnosis and prognosis depends on the histopathological examination; therefore, every operated specimen must be subjected to histopathology. The clinicopathological correlation is mandatory for optimal patient management. Funding: No funding sources

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The Value of Ultrasonography in the Diagnosis of Leiomyomas in Southeast Nigeria

The Value of Ultrasonography in the Diagnosis of Leiomyomas in Southeast Nigeria

Leiomyomas have been shown to increase in size during pregnancy likely due to pregnancy-related increase in estrogens (Baltarowith et al., 1988). However, according to Quyang (Quyang et al., 2006), the current literature on leiomyomas tends to underestimate the complications attributed to them. Over the years, several techniques have been employed in detecting these fibroid masses. One of the techniques is the use of bimanual pelvic examination which is a screening technique. This has the advantage of being cheap relative to other techniques. It can be carried out easily, and moreover does not require specialized equipments. But it has been shown from studies that it is neither sensitive nor specific enough to be used as a modality in screening.(Thomas, 1997) Ultrasound has been utilized as an invaluable imaging modality in evaluating and detecting uterine leiomyomas. An added advantage is that it is safe; non invasive and superior to other modalities of investigations like x-ray, computed tomography, pregnancy test which are non-specific and cannot be used to make accurate diagnosis.(Baltarowith et al., 1988) Ultrasound is regarded as the third arm of the gynecologist (Emuveyan, 2000), and its efficacy in the diagnosis and management of uterine leiomyomas has been acknowledged (Nzeh et al., 1988).
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Case Report Incidental finding of pre-peritoneal leiomyoma during laparoscopic hysterectomy: a case report and literature review

Case Report Incidental finding of pre-peritoneal leiomyoma during laparoscopic hysterectomy: a case report and literature review

rather the abdominal wall musculature (Figure 1C). The gynecologist then perform- ed the LH and removed both the uterus and pre-peritoneal ma-ss (Figure 1D) through the vagina. Histological examina- tion of the pelvic mass re- vealed leiomyoma with no fea- tures of malignancy; this was consistent with the findings in the uterine specimen. Thus, this patient had a solitary peri- toneal leiomyoma on the right pelvic wall coexisting with mul- tiple uterine leiomyomas and moderate anemia. She was discharged on the fourth po- stoperative day without any complications.
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Med12 gain of function mutation causes leiomyomas and genomic instability

Med12 gain of function mutation causes leiomyomas and genomic instability

MED12 is located on the X chromosome and encodes a 250- kDa protein that is a subunit of the large mediator complex and is involved in transcriptional regulation of the RNA polymerase II complex. The MED12 protein is highly conserved among eukaryotes (8) and plays an important role during embryogene- sis, as Med12-null mouse embryos arrest at E7.5 due to impaired mesoderm formation (9). Despite the high prevalence of MED12 mutations within human uterine leiomyomas, their causality and mode of action are not well understood. Here, we show that the common Med12 variant associated with human leiomyomas, Med12 c.131G>A, can drive tumor formation alone in a gain-of- function manner and causes genomic instability.
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Correlational Analysis of Interleukin 6, Adiponectin and Lipid Indices in Women with Uterine Fibroids

Correlational Analysis of Interleukin 6, Adiponectin and Lipid Indices in Women with Uterine Fibroids

Furthermore, the progressive adipocyte hypertrophy accentuates low grade chronic inflammation which is thought to play a major role in the progression of uterine fibroids. Adipocytes secrete proinflammatory cytokines like IL-6 and they also secrete anti-inflammatory mediators like adiponectin. In our study, we observed a significant increase in the levels of IL- 6 and a significant reduction in the levels of adiponectin, when women with uterine fibroids were compared with the controls. This observation is further supported by our observed significant inverse relationship between IL-6 and adiponectin in women with uterine fibroids. The observed elevated IL-6 could be attributed to excessive secretion of IL-6 by peritoneal macrophages which are abundantly present in enlarged adipocytes and are actively involved in their activities [28-30]. IL-6 and other proinflammatory factors produced due to excessive fat accumulation have a direct effect on the myometrium and this consequently enhances the growth of uterine leiomyomas [4,30].
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Leiomyoma with KAT6B-KANSL1 fusion: case report of a rapidly enlarging uterine mass in a postmenopausal woman

Leiomyoma with KAT6B-KANSL1 fusion: case report of a rapidly enlarging uterine mass in a postmenopausal woman

Monocytic leukemia zinc finger protein-related fac- tor (MORF) located at 10q22, now known as KAT6B, is involved in histone acetyltransferase and allows segments of DNA to be more accessible to transcrip- tion factors. Moore and colleagues [12] previously described rearrangement of MORF in four uterine leiomyomas. In three tumors, they also mapped a break involving 17q21 but did not identify a gene fu- sion partner. The fusion of KAT6B and KANSL1 (the latter positioned at 17q21) has been identified only once previously in a retroperitoneal leiomyoma [3]. It has been proposed that KAT6B-KANSL1 might function in regulation of transcription [3]. Although KAT6B rearrangements have been reported in leio- myomas, rare examples of uterine leiomyosarcoma [13] and acute myeloid leukemia [3, 12], fusions involving KANSL1 are rare. However, the three
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Dermoscopy as an adjuvant tool for detecting skin leiomyomas in patient with uterine fibroids and cerebral cavernomas

Dermoscopy as an adjuvant tool for detecting skin leiomyomas in patient with uterine fibroids and cerebral cavernomas

leiomyomatosis and renal cell cancer (HLRCC) [3]. Even though different gene mutations, missense, nonsense or whole gene deletions have been described in MCUL syndrome, a definite association between site or type of mutation and the risk of papillary renal-cell carcinoma has not been found yet [4]. Cutaneous leiomyomas - accounting for 75% of all extra-uterine leiomyomas - are uncommon benign smooth muscle tumours deriving ei- ther from the erector pili muscle of the pilosebaceous unit (piloleiomyomas), the cutaneous vascular smooth muscle fibers (angioleiomyomas) or from the dartos muscle (genital leiomyomas) [5]. Piloleiomyomas are the most common form and show firm, skin-colored or
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Unexpected pulmonary tumor: metastasis from a benign uterine leiomyoma in a post menopausal woman: a case report

Unexpected pulmonary tumor: metastasis from a benign uterine leiomyoma in a post menopausal woman: a case report

Extra-uterine locations of benign leiomyomas constitute a very rare phenomenon consisting of the occurrence of smooth muscle tumors with similar phenotype and genotype to those of benign uterine leiomyomas [1, 2]. These tumors are termed as benign metastasizing leio- myoma (BML), the term has been introduced in 1939 by Steiner [1, 3]. Since then, a few cases have been reported in the literature. Usually BML affects premenopausal women, very rarely menopausal patients, with a history of myomectomy or hysterectomy for uterine leiomyo- mas, and the tumors are discovered incidentally during a
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Novel missense mutation in the FH gene in familial renal cell cancer patients lacking cutaneous leiomyomas

Novel missense mutation in the FH gene in familial renal cell cancer patients lacking cutaneous leiomyomas

Smit et al. [21] advocated the proposed criteria for the clinical diagnosis of HLRCC as follows. Major criterion: multiple cutaneous pioleiomyomas confirmed histopatho- logically. Minor criteria: 1) surgical treatment for severely symptomatic uterine leiomyomas before age 40, 2) type 2 papillary renal cell carcinoma before age 40, and 3) a first- degree family member who meets one of the above- mentioned criteria. The diagnosis is likely when a proband meets the major criterion, and HLRCC may be suspected when a proband meets at least 2 minor criteria. However, in our cases, no cutaneous leiomyomas were found, but the first-degree family developed early onset papillary type 2 RCC with the same pathological features as the father, and this should be primarily considered as HLRCC.
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Somatic MED12 mutations are associated with poor prognosis markers in chronic lymphocytic leukemia

Somatic MED12 mutations are associated with poor prognosis markers in chronic lymphocytic leukemia

All MED12 mutations observed in exome or whole genome sequencing studies on CLL have resided in exons 1 and 2. Even though some mutations in other exons might be detectable by targeted sequencing with higher depth of coverage, results from these studies suggest that similarly to uterine leiomyomas, MED12 mutations in CLL are restricted to exons 1 and 2. In this study, mutation screening of exons 1 and 2 was done by direct sequencing using previously described primers [9, 12]. Samples were sequenced with Applied Biosystems 3730 DNA Analyzer (Life Technologies, Thermo Fischer Scientific Waltham, MA, USA) and analyzed manually and with Mutation Surveyor (Softgenetics, State College, PA, USA) or Lasergene SeqMan Pro (DNASTAR, Madison, WI, USA) softwares. See Supplemental Data for more details on the sample series and methods.
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