Elisabetta Garavaglia

Continuous low‐dose oral contraceptive in the treatment of colorectal endometriosis evaluated by rectal endoscopic ultrasonography

Objective. Limited attention has been focused on the medical treatment of bowel endometriosis. This study evaluates the efficacy of administration of a continuous low‐dose oral contraceptive in treating pain and other symptoms associated with colorectal endometriotic nodules, as evaluated by rectal endoscopic ultrasonography. Design. Prospective observational study. Setting. Academic Department of San Raffaele Scientific Institute, Obstetrics and Gynecology Unit. Population. Symptomatic women of reproductive age (n=26) with colorectal nodules infiltrating at least the bowel muscularis propria and without a stenosis >50%. In 31% of the patients, endoscopic ultrasonography permitted diagnosis of nodules located more than 10 cm from the anal rim. Methods. Patients received a continuous low‐dose oral contraceptive containing 15 μg ethinylestradiol and 60 μg gestodene for 12 months. Subjective symptoms were prospectively evaluated, and nodule volumes were monitored using endoscopic ultrasonography. Main outcome measures. Nodule measurements were performed at baseline and after 12 months of treatment. Symptoms at the start and after 12 months were evaluated. Results. A significant improvement in the intensity of all the considered symptoms (dysmenorrhea, non‐menstrual pelvic pain, deep dyspareunia and painful defecation) was seen when evaluated by a visual analog scale. A reduction in terms of both diameter (mean reduction 26%) and volume of the nodules (mean reduction 62%) was observed after a 12 month period. Conclusions. A continuous low‐dose oral contraceptive therapy may reduce bowel endometriosis‐associated symptoms. In addition, this therapy induces a significant volumetric reduction of colorectal plaques when evaluated by endoscopic ultrasonography.

[18f]fluorodeoxyglucose positron emission tomography as a useful indicator of metastatic gestational trophoblastic tumor: preliminary results in three patients

OBJECTIVE The goal of this study was to evaluate the usefulness of positron emission tomography with [(18)F]fluorodeoxyglucose ([(18)F]FDG-PET) in detecting metastases in patients with gestational trophoblastic tumor (GTTs). METHODS A retrospective study was conducted on three patients with GTTs who had been studied with [(18)F]FDG-PET and computed tomography (CT) after an increase in human chorionic beta-gonadotropin (betahCG) serum levels. PET scans were performed with a multiring whole-body positron emission tomograph 45 min after an intravenous bolus injection of [(18)F]FDG ( approximately 5.2 MBq/kg). CT studies were obtained on a spiral scanner prior and after administration of intravenous iodinated contrast material. Within a week of CT and [(18)F]FDG-PET studies, the patients underwent surgical procedures for histological diagnosis. RESULTS In one patient, a lung lesion positive for neoplastic tissue with [(18)F]FDG-PET and negative with CT was confirmed to be a GTT metastasis at histology. In another patient, [(18)F]FDG-PET was negative, while CT was positive for the presence of lung metastasis; no viable tumor tissue was found at histological analysis. The remaining patient had a positive [(18)F]FDG-PET and CT study for lung metastasis; this was confirmed at histological analysis. In the same patient, both [(18)F]FDG-PET and CT depicted the presence of a liver lesion. Necrotic lesion regression after treatment was clearly documented with [(18)F]FDG-PET only. CONCLUSIONS Our preliminary results suggest that [(18)F]FDG-PET may be useful for the assessment of metastatic disease in patients with GTTs.

Human endometrial stromal cells are highly permissive to productive infection by zika virus

Zika virus (ZIKV) is a recently re-emerged flavivirus transmitted to humans by mosquito bites but also from mother to fetus and by sexual intercourse. We here show that primary human endometrial stromal cells (HESC) are highly permissive to ZIKV infection and support its in vitro replication. ZIKV envelope expression was detected in the endoplasmic reticulum whereas double-stranded viral RNA colocalized with vimentin filaments to the perinuclear region. ZIKV productive infection also occurred in the human T-HESC cell line together with the induction of interferon-β (IFN-β) and of IFN-stimulated genes. Notably, in vitro decidualization of T-HESC with cyclic AMP and progesterone upregulated the cell surface expression of the ZIKV entry co-receptor AXL and boosted ZIKV replication by ca. 100-fold. Thus, endometrial stromal cells, particularly if decidualized, likely represent a crucial cell target of ZIKV reaching them, either via the uterine vasculature in the viremic phase of the infection or by sexual viral transmission, and a potential source of virus spreading to placental trophoblasts during pregnancy.

Treatment of recurrent or metastatic low-grade endometrial stromal sarcoma: three case reports.

Background: The treatment of recurrent or metastatic low-grade endometrial stromal sarcoma (LG-ESS) is still controversial. Recurrent disease mainly develops in the lung or in the pelvis. When the evidence of extrauterine tumor extension exists, debulking is recommended. Responses to hormonal therapy have been reported, because of the presence of estrogen and progestin receptors. Also chemotherapy has been used, but the percentage of response is low. Cases: Three patients with lung and pelvic localization of LG-ESS are reported. The first patient showed lung relapse 22 months after pelvic surgery. The second patient developed pelvic and abdominal recurrences, managed by surgery, 33 months after primary treatment and a subsequent lung recurrence 11 years later. The third patient had lung metastases at the primary diagnosis. All these patients underwent hysterectomy, bilateral salpingo-oophorectomy, and exeresis of lung recurrences. Our 3 patients were all treated with medroxyprogesterone acetate for long periods. They all presented regression or stabilization of metastatic lesions. At present, they are alive and without any evidence of disease (39, 70, and 28 months). Conclusions: In LG-ESS, the combined treatment of surgery and progestin therapy is effective in achieving both local and distant disease control. Metastatic lesions, especially pulmonary lesions, seem to benefit from surgical removal, followed by progestin therapy. Hormonal therapy should be maintained for an indefinite period. On account of the long period existing between primary tumor and recurrent disease, a long-term follow-up is always recommended after the primary treatment.

Elevated Systemic Levels of Endocannabinoids and Related Mediators Across the Menstrual Cycle in Women With Endometriosis

Cannabinoids and modulators of the endocannabinoid system affect specific mechanisms that are critical to the establishment and development of endometriosis. The aim of this study was to measure the systemic levels of endocannabinoids and related mediators in women with and without endometriosis and to investigate whether such levels correlated with endometriosis-associated pain. Plasma and endometrial biopsies were obtained from women with a laparoscopic diagnosis of endometriosis (n = 27) and no endometrial pathology (n = 29). Plasma levels of endocannabinoids (N-arachidonoylethanolamine [AEA] and 2-arachidonoylglycerol [2-AG]) and related mediators (N-oleoylethanolamine [OEA] and N-palmitoylethanolamine [PEA]), messenger RNA expression of some of their receptors (cannabinoid receptor type 1 [CB1], CB2, transient receptor potential vanilloid type [TRPV1]), and the enzymes involved in the synthesis (N-acyl-phosphatidylethanolamine-hydrolyzing phospholipase D [NAPE-PLD]) and degradation (fatty acid amide hydrolase 1 [FAAH]) of AEA, OEA, and PEA were evaluated in endometrial stromal cells. The systemic levels of AEA, 2-AG, and OEA were elevated in endometriosis in the secretory phase compared to controls. The expression of CB1 was higher in secretory phase endometrial stromal cells of controls versus endometriosis. Similar expression levels of CB2, TRPV1, NAPE-PLD, and FAAH were detected in controls and endometriosis. Patients with moderate-to-severe dysmenorrhea and dyspareunia showed higher AEA and PEA levels than those with low-to-moderate pain symptoms, respectively. The association of increased circulating AEA and 2-AG with decreased local CB1 expression in endometriosis suggests a negative feedback loop regulation, which may impair the capability of these mediators to control pain. These preliminary data suggest that the pharmacological manipulation of the action or levels of these mediators may offer an alternative option for the management of endometriosis-associated pain.

External Validation of the Endometriosis Fertility Index (EFI) for Predicting Spontaneous Pregnancy after Surgery: Further Considerations on Its Validity

Background/Aims: The revised American Society for Reproductive Medicine classification of endometriosis has a limited predictive value for pregnancy after surgery. A tool for predicting spontaneous pregnancy or pregnancy following assisted reproduction technology (ART) represents a clinical need. This study aimed to (i) provide an external validation of the EFI score in predicting pregnancy in infertile Italian endometriosis women; (ii) evaluate the predictive value of EFI score on ART outcome for patients who previously attempted to spontaneously conceive after surgery. Methods: In 104 women with endometriosis, EFI score was calculated based on a prospective database data. Cumulative pregnancy rates curves were calculated using Kaplan-Meier (K-M) product limit estimate and log-rank test was used to evaluate differences between EFI groups. A receiver operating characteristic (ROC) curve was plotted for EFI as a predictor of ART outcome. Results: Differences in time to non-ART pregnancy for the six EFI groups were statistically significant (log-rank, p = 1.4 × 10-4). The area under the curve (AUC) for EFI as ART outcome predictor was 0.75 (95% CI 0.61-0.89, p = 6.2 × 10-3), while the best cut-point for pregnancy was 5.5. Conclusion: The EFI score is a reliable scoring system to predict non-ART and ART pregnancy outcome after surgery for endometriosis.

Ultrasound imaging after evacuation as an adjunct to β-hCG monitoring in posthydatidiform molar gestational trophoblastic neoplasia

OBJECTIVE The purpose of this study was to identify prognostic factors associated with development of gestational trophoblastic neoplasia (GTN) after hydatidiform mole (HM). STUDY DESIGN A retrospective analysis of 189 patients with HM was performed. We recorded features such as maternal age, HM history, blood group, gestational age, uterine volume at evacuation, presence of theca lutein cysts, vaginal bleeding, and transvaginal ultrasonography with color Doppler imaging. We considered risk predictors to be the presence of nodules and hypervascularization within the myometrium or endometrium (positive ultrasound imaging). An univariate and multivariate analysis, with the COX nominal logistic model, was performed. RESULTS Fourteen patients experienced GTN (7.4%). After univariate analysis, uterine size (P = .0139) and positive ultrasound results (P < .0001) were associated significantly with GTN development. At multivariate analysis, only positive ultrasound results maintained significance (likelihood ratio test: chi(2) = 0.0000). CONCLUSION The risk of GTN is increased in patients with uterine involvement that is assessed by ultrasound imaging. None of the other prognostic factors that were evaluated was predictive of GTN development.

Leisure and occupational physical activity at different ages and risk of endometriosis

OBJECTIVE Cohort and case-control studies have suggested that adult physical activity (PA) may lower endometriosis risk and improve symptoms, but evidence is still controversial. To add information on leisure and occupational PA impact, if any, on endometriosis risk, we have analyzed data from a small case-control study conducted in Milan (Italy). STUDY DESIGN Ninety cases and 90 controls (median age 35 years, range 18-76) were compared. Endometriosis was laparoscopically diagnosed within the year before interview. Information on demographic variables, menstrual and reproductive history, occupational and recreational physical activity was collected. RESULTS A consistent protective effect emerged between leisure PA and endometriosis risk. For <2-4 and ≥5h/week (reference no PA), the estimated odds ratios (ORs) were, respectively: 0.36 (95% CI 0.18-0.74) and 0.83 (95% CI 0.27-2.53) as regards PA in early adolescence; 0.31 (95% CI 0.15-0.63) and 0.78 (95% CI 0.25-2.38) as regards PA in teenage years; 0.34 (95% CI 0.12-0.94) and 0.33 (95% CI 0.08-1.28) for PA in adulthood. However, no significant trend was seen according to hours spent in leisure PA. Occupational PA did not show statistical significant differences among different types or across age classes. CONCLUSIONS These results suggest that leisure PA in early adolescence, teenage years and adulthood may, to some extent, decrease the risk of endometriosis. In the interpretation of these results, however, the role of potential biases cannot be totally ruled out.

Unravelling the ovarian endometrioma pathogenesis: “The long and winding road”* across the various theories

Controversy exists regarding the pathogenesis of endometriotic ovarian cysts. Different and complex theories have been proposed over the years since the description of chocolate cysts by Sampson in 1921. We have herein reviewed findings in support and against the most widely accepted theories. According to the theory of Hughesdson and Brosens, a prerequisite for endometrioma formation seems to be the inversion and progressive invagination of the ovarian cortex after the accumulation of menstrual debris derived from bleeding of superficial endometriotic implants, which are located on the ovarian surface and adherent to the peritoneum. Disproving the metaplasia hypothesis put forward by Donnez and coworkers and supporting the involvement of the ovulation process in the development of ovarian endometriosis, Vercellini and colleagues have recently demonstrated that a cystic corpus luteum may be a transitory step toward endometrioma formation. As these theories are not able to explain the various aspects of endometrioma formation fully, the possibility that the coelomic metaplasia of the ovarian mesothelium with changes into typical endometrial glands and stroma might be responsible for the endometrioma formation cannot be totally ruled out. Further research is needed to clearly elucidate the pathogenetic aspects of endometriotic ovarian cysts.

Transvaginal ultrasound predicts delayed response to chemotherapy and drug resistance in Stage I low-risk trophoblastic neoplasia

Methotrexate (MTX) resistance is defined on the basis of the human chorionic gonadotropin (hCG) curve. The aim of this study was to identify low‐risk non‐metastatic patients with gestational trophoblastic neoplasia (GTN) who can achieve resolution by continuing MTX treatment despite a transient hCG plateau.