Anna Pesci

Diagnostic and prognostic significance of miRNA signatures in tissues and plasma of endometrioid endometrial carcinoma patients

The aim of our study was to define tissue and plasma miRNA signatures, which could potentially serve as diagnostic and prognostic markers in endometrioid endometrial cancer (EEC) and to investigate miRNA profiles in regard to clinicopathological characteristics. Tissue and plasma samples were collected from 122 women (77 EEC and 45 controls). Expression profiling of 866 human miRNAs and 89 human viral miRNAs was performed in 24 samples and was followed by qPCR validation in 104 patients. Expression of 16 miRNAs was analyzed in 48 plasma samples. Microarray study revealed regulation of 21 miRNAs in EEC tissues comparing to normal endometrium. Altered expression of 17 miRNAs was confirmed by qPCR performed in 104 tissue samples. Seven miRNAs were upregulated and two were downregulated in EEC plasma samples. Expression of a number of miRNAs was associated with International Federation of Gynecology and Obstetrics stage, grade, relapse and nodal metastases. Two miRNA signatures: miR‐92a/miR‐410 and miR‐92a/miR‐205/miR‐410 classified tumor tissues with higher accuracy in comparison to single miRNAs (AUC: 0.977, 95% CI: 0.927–0.996 and 0.984, 95% CI: 0.938–0.999, respectively). miRNA signature composed of miR‐205 and miR‐200a predicted relapse with AUC of 0.854 (95% CI: 0.691–0.951). Tissue miRNA signatures were independent prognostic markers of overall (miR‐1228/miR‐200c/miR‐429, HR: 2.98) and progression‐free survival (miR‐1228/miR‐429, HR: 2.453). Plasma miRNA signatures: miR‐9/miR‐1228 and miR‐9/miR‐92a, classified EEC plasma samples with high accuracy yielding AUCs of 0.909 (95% CI: 0.789–973) and 0.913 (95% CI: 0.794–0.976), respectively. We conclude that miRNA signatures hold a great promise to become noninvasive biomarkers for early EEC detection and prognosis.

Deregulation of miR-100, miR-99a and miR-199b in tissues and plasma coexists with increased expression of mTOR kinase in endometrioid endometrial carcinoma

BackgroundAlterations of mTOR gene expression have been implicated in the pathogenesis of endometrioid endometrial cancer however only few studies explored the cause of increased mTOR activation in this malignancy. miRNAs are small, noncoding RNAs, which were proven to regulated gene expression at the posttranscriptional level. The study aimed to explore deregulation of miRNAs targeting mTOR kinase (miR-99a, miR-100 and miR-199b) as a possible cause of its altered expression in EEC tissues. In addition expression of the three miRNAs was investigated in plasma of EEC patients and was assessed in terms of diagnostic and prognostic utility.MethodsWe investigated expression of mTOR kinase transcripts in 46 fresh tissue samples. Expression of miR-99a, miR-100 and miR-199b was investigated in the same group of fresh samples, and in additional 58 FFPE sections as well as in 48 plasma samples using qPCR. Relative quantification was performed using experimentally validated endogenous controls.ResultsmTOR kinase expression was increased in EEC tissues and was accompanied by decreased expression of all three miRNAs. Down-regulation of the investigated miRNAs was discovered in plasma of EEC patients and miRNA signatures classified EEC tissues (miR-99a/miR-100/miR-199b) and plasma (miR-99a/miR-199b) samples with higher accuracy in comparison to single miRNAs. We also revealed that miR-100 was an independent prognostic marker of overall survival.ConclusionsWe conclude that increased expression of mTOR kinase coexists with down-regulation of its targeting miRNAs, which could suggest a new mechanism of mTOR pathway alterations in EEC. In addition, our findings implicate that miRNA signatures can be considered promising biomarkers for early detection and prognosis of endometrioid endometrial carcinoma.

Highly increased maspin expression corresponds with up-regulation of miR-21 in endometrial cancer: a preliminary report.

Background: Maspin and programmed cell death 4 (Pdcd4) are tumor suppressor genes, and miR-21 is overexpressed in many solid tumors and was proven to negatively regulate a number of tumor suppressor genes including maspin and Pdcd4. The purpose of this study was to investigate the expression of maspin, Pdcd4, and miR-21 and their interrelations with clinicopathologic features in endometrial cancer using a quantitative approach. Methods: Maspin, Pdcd4, and miR-21 expressions were evaluated by a real-time polymerase chain reaction in 20 endometrial cancer and 10 normal endometrium samples. Results: Maspin showed a significantly increased expression in endometrial cancer samples compared with the control group and was up-regulated by a mean factor of 46.54 (SE range, 2.367-1160.26; 95% confidence interval, 0.515-15001, P < 0.0001). Expression of miR-21 was found significantly up-regulated in the sample group in comparison to control group by a mean factor of 2.312 (SE range, 0.741-7.778; 95% confidence interval 0.191-15.0, P = 0.028). No significant differences were present in the expression level of Pdcd4 between endometrial cancer and control groups. Comparison between IA and more advanced International Federation of Gynecology and Obstetrics stages of endometrial cancer in regard to expression levels of maspin, Pdcd4, and miR-21 did not reveal any significant differences. Similarly, no differences were encountered when histopathologic grading, myometrial invasion, age, body mass index, and parity were taken into consideration. Conclusions: Association between increased maspin expression and up-regulation of miR-21 in endometrial cancer suggests distinct and tissue-specific relationships of the 2 molecules in this type of malignancy and requires further studies that would reveal its clinical relevance.

Primary retroperitoneal acinar cell cystadenoma

In this report, we describe a case of hitherto unreported primary retroperitoneal acinar cell cystadenoma that morphologically and immunophenotypically resembled pancreatic acinar cell cystadenoma. Pancreatic acinar cell cystadenoma is a very uncommon benign lesion characterized by acinar cell differentiation, the evidence of pancreatic exocrine enzyme production, and the absence of cellular atypia. Our case occurred in a 55-year-old woman presenting a 10-cm multilocular cystic lesion in the retroperitoneum thought to be a mucinous cystic neoplasm. At laparotomy, the cystic mass, which showed no connection with any organ, was completely resected with a clinical diagnosis of cystic lymphangioma. The diagnosis of retroperitoneal acinar cell cystadenoma was based on the recognition of morphological acinar differentiation, the immunohistochemical demonstration of the acinar marker trypsin, and the absence of cellular atypia. These peculiar features can be used in the differential diagnosis with all the other cystic lesions of the retroperitoneum.

Cyclic sciatica in a patient with deep monolateral endometriosis infiltrating the right sciatic nerve.

Study Design Case report. Objective To show by case presentation, the potential for endometriosis to infiltrate the somatic nerves causing lower extremity neuropathic pain and to discuss possible surgical remedy and the effectiveness of laparoscopic neurolysis. Summary of Background Data Pelvic endometriosis may infiltrate the pelvic wall and somatic nerves causing severe neuropathic symptoms. Methods We report a case of a 41-year-old woman with a history of severe dysmenorrhea, dyspareunia, and chronic pelvic pain with concomitant monolateral right sciatica because of deep infiltrating pelvic endometriosis involving the sciatic nerve and pelvic wall. Results The patient was treated by laparoscopic neurolysis of the involved somatic nerves according to the Possover operation. Conclusions Endometriosis is a chronic inflammatory disease, potentially infiltrating the somatic nerves. Laparoscopic neurolysis is a therapeutic aetiological therapy, which can relieve neurological symptoms deriving from nerve infiltration/compression.

Total laparoscopic hysterectomy of very enlarged uterus (3030 g): case report and review of the literature

Fibromatosis is the most frequent benign uterine pathology of fertile women, rarely causing anomalous enlargement of the uterus. Traditionally the surgical treatment has been abdominal hysterectomy. However, development of minimally invasive techniques has led to major safeness of the laparoscopic route. We report a case of total laparoscopic hysterectomy performed on a uterus weighting more than 3,000 g and present a review of the literature about the laparoscopic approach to very enlarged uteri.

Pericardial, pleural and diaphragmatic endometriosis in association with pelvic peritoneal and bowel endometriosis: a case report and review of the literature.

Diaphragmatic endometriosis is a rare entity, often asymptomatic, which has been described only in small series. It is almost always associated with severe pelvic involvement. The most plausible theory about this condition is based on retrograde menstruation and subsequent transportation of viable cells in peritoneal fluid from the pelvis up the right gutter to the right hemidiaphragm, thus demonstrating its asymmetric distribution on the diaphragm. Pre-operative diagnosis is poorly supported by imaging techniques. In most cases, it is an incidental finding because the lesions may hide behind the right hepatic lobe. In that case it cannot be easily demonstrated with a laparoscope from an umbilical port. Symptomatic diaphragmatic endometriosis is associated with deep lesions which can involve the entire thickness of the diaphragm. In these cases, treatment is more difficult with possible incomplete pain relief and a considerable possibility of recurrence. In this subset, abdominal surgery is recommended. Surgical treatment must be individualized on the basis of the patients age, fertility desires, type and location of disease and symptoms. We report the surgical treatment of a patient with synchronous pericardial, pleural and diaphragmatic endometriosis associated with pelvic peritoneal and bowel involvement. A review of the literature regarding pericardial and diaphragmatic endometriosis focusing on anatomical and surgical aspects of its management is undertaken.

D-chiro-inositol phosphoglycan expression in human placenta at term in diabetes

We present a histological assessment of diabetic placenta for the localization of some insulin mediators that were reported to play a major role for lipid/glycogen metabolism in human placenta. Placental metabolism is fundamental to fetal wellbeing. In fact, all maternal metabolic alterations have a profound effect on placental development with a subsequent definite impact on pregnancy outcome and fetal growth [1]. We have previously reported abnormalities in expression and activation of specific insulin-like growth factor-I receptor signaling molecules and multiple members of the MAP kinase family in human placentas of fetuses with intra-uterine growth restriction [2]. Subsequent studies on placental metabolism have focused on a family of insulin mediators, namely inositol phosphoglycans that were found to be highly expressed in diabetic and preeclamptic placentas [3]. These molecules play a major role in the regulation of the disposal of glucose by oxidative and non-oxidative routes of storage by glycogen synthesis [4]. In fact, the complexity and specificity of insulin action are determined by an integrated signaling network of independent intracellular pathways with several downstream effectors that have been shown to modulate the signal amplitude and frequency for both shortand longterm effects. Specific acquired alterations in activation of proteins involved in insulin signaling in preeclamptic placenta were shown to be associated with the accumulation of D-chiro-inositol phosphoglycan and to play a role in the insulin-resistant state that occurs in preeclampsia [5]. A disturbed insulin signaling was demonstrated in these cases and associated to low activation of insulin receptor effectors through multiple serine phosphorylations in both IRS-1 and IRS-2 [5]. In this study, placental specimens from six healthy and diabetic women at term were assessed for chiro-inositol using antibodies (mouse anti-D-chiro-inositol phosphoglycan), kindly provided by Professor Eduardo Martinez (Pamplona, Spain). A standard procedure was used for the immunohistochemical staining. The primary anti-D-chiroinositol phosphoglycan antibody was diluted 1:100 in antibody diluent (Dako, USA) and incubated for 60 min at room temperature. The percentage of positive stained controls was used as a reference for comparison. In control cases (Fig. 1a), a clear immunostaining of the syncytiotrophoblast was found (p = 0.11) with a little activity within the villous stroma (p = 0.43). The endothelium of placental vessels shows a localization of D-chiro-inositol phosphoglycan in normal placenta while in diabetic samples is weakly stained (p \ 0.01, Fig. 1b). The extravillous trophoblast in the basal plate of diabetic cases reveals also staining (p = 0.23, Fig. 1c, d). In both cases, a weak staining was found in maternal plasma, while a strong staining was found in fetal plasma. According to these findings, we may hypothesize that the placenta uptakes D-chiro inositol phosphoglycan from M. Scioscia (&) Department of Obstetrics and Gynecology, Sacro Cuore Don Calabria General Hospital, Via Don A. Sempreboni, 5, 37024 Negrar, VR, Italy e-mail: marco.scioscia@sacrocuore.it

Symptomatic vaginal bleeding in a postmenopausal woman revealing colon adenocarcinoma metastasizing exclusively to the vagina.

Vaginal carcinomas are rare entities, accounting for 2% of all malignant cancers of the female genital tract, and the vast majority are metastatic. Adenocarcinoma of the colon metastasizing to the vagina is extremely rare, only 5 cases have been reported. We present the case of a woman who experienced vaginal bleeding as an isolated symptom of vaginal metastasis of colorectal adenocarcinoma. Vaginal localization of metastasis from colorectal cancer significantly worsens the survival prognosis, and a standard treatment has not yet been proposed. Potential mechanisms of spread of colorectal cancer to the vagina and therapeutic approaches are discussed. In this case, treatment included surgery and chemotherapy.

Survival in clinical stage I endometrial cancer with single vs. multiple positive pelvic nodes: results of a multi-institutional Italian study

Objective To investigate survival outcomes in endometrioid endometrial cancer (EEC) patients with single vs. multiple positive pelvic lymph nodes. Methods We performed a retrospective evaluation of all consecutive patients with histologically proven International Federation of Gynecology and Obstetrics (FIGO) stage IIIC1 EEC who underwent primary surgical treatment between 2004 and 2014 at seven Italian gynecologic oncology referral centers. Patients with pre- or intra-operative evidence of extra-uterine disease (including the presence of bulky nodes) and patients with stage IIIC2 disease were excluded, in order to obtain a homogeneous population. Results Overall 140 patients met the inclusion criteria. The presence of >1 metastatic pelvic node was significantly associated with an increased risk of recurrence and mortality, compared to only 1 metastatic node, at both univariate (recurrence: hazard ratio [HR]=2.19; 95% confidence interval [CI]=1.2–3.99; p=0.01; mortality: HR=2.8; 95% CI=1.24–6.29; p=0.01) and multivariable analysis (recurrence: HR=1.91; 95% CI=1.02–3.56; p=0.04; mortality: HR=2.62; 95% CI=1.13–6.05; p=0.02) and it was the only independent predictor of prognosis in this subset of patients. Disease-free survival (DFS) and disease-specific survival (DSS) were significantly longer in patients with only 1 metastatic node compared to those with more than 1 metastatic node (p=0.008 and 0.009, respectively). Conclusion The presence of multiple metastatic nodes in stage IIIC1 EEC represents an independent predictor of worse survival, compared to only one positive node. Our data suggest that EEC patients may be categorized according to the number of positive nodes.