Alice Bergamini

A systematic review on endometriosis during pregnancy: diagnosis, misdiagnosis, complications and outcomes

BACKGROUND Traditionally, pregnancy was considered to have a positive effect on endometriosis and its painful symptoms due not only to blockage of ovulation preventing bleeding of endometriotic tissue but also to different metabolic, hormonal, immune and angiogenesis changes related to pregnancy. However, a growing literature is emerging on the role of endometriosis in affecting the development of pregnancy and its outcomes and also on the impact of pregnancy on endometriosis. The present article aims to underline the difficulty in diagnosing endometriotic lesions during pregnancy and discuss the options for the treatment of decidualized endometriosis in relation to imaging and symptomatology; to describe all the possible acute complications of pregnancy caused by pre-existing endometriosis and evaluate potential treatments of these complications; to assess whether endometriosis affects pregnancy outcome and hypothesize mechanisms to explain the underlying relationships. METHODS This systematic review is based on material searched and obtained via Pubmed and Medline between January 1950 and March 2015. Peer-reviewed, English-language journal articles examining the impact of endometriosis on pregnancy and vice versa were included in this article. RESULTS Changes of the endometriotic lesions may occur during pregnancy caused by the modifications of the hormonal milieu, posing a clinical dilemma due to their atypical appearance. The management of these events is actually challenging as only few cases have been described and the review of available literature evidenced a lack of formal estimates of their incidence. Acute complications of endometriosis during pregnancy, such as spontaneous hemoperitoneum, bowel and ovarian complications, represent rare but life-threatening conditions that require, in most of the cases, surgical operations to be managed. Due to the unpredictability of these complications, no specific recommendation for additional interventions to the routinely monitoring of pregnancy of women with known history of endometriosis is advisable. Even if the results of the published studies are controversial, some evidence is suggestive of an association of endometriosis with spontaneous miscarriage, preterm birth and small for gestational age babies. A correlation of endometriosis with placenta previa (odds ratio from 1.67 to 15.1 according to various studies) has been demonstrated, possibly linked to the abnormal frequency and amplitude of uterine contractions observed in women affected. Finally, there is no evidence that prophylactic surgery would prevent the negative impact of endometriosis itself on pregnancy outcome. CONCLUSIONS Complications of endometriosis during pregnancy are rare and there is no evidence that the disease has a major detrimental effect on pregnancy outcome. Therefore, pregnant women with endometriosis can be reassured on the course of their pregnancies although the physicians should be aware of the potential increased risk of placenta previa. Current evidence does not support any modification of conventional monitoring of pregnancy in patients with endometriosis.

Unraveling the two entities of endometrioid ovarian cancer: A single center clinical experience

OBJECTIVE Due to the increasing prevalence of the benign condition, ovarian carcinoma arising from endometriosis is emerging as a relevant clinical entity with an unclear biological signature. We have investigated clinical and histologic features of endometriosis-associated endometrioid ovarian cancer using an institutional retrospective database. METHODS Patients diagnosed with endometrioid ovarian cancer at our institution were divided into two groups according to the fulfillment or not of Sampsons and Scotts criteria for the detection of endometriosis-associated ovarian cancer. Clinical and histological data were reported and compared. Survival analysis was obtained using the log-rank test in an unadjusted Kaplan-Meier method. Multivariate analysis was performed using the Cox proportional hazards regression model to establish independent factors associated with endometriosis-associated endometrioid ovarian cancer and to identify predictors of survival. The degree of concordance was evaluated by Cohens Kappa measures. RESULTS Patients with endometriosis-associated endometrioid ovarian cancer were significantly younger, had a lower disease stage (62% vs 23%; p=0.003), a less prevalent high grade tumor (38% vs 82%; p=0.002) and a higher prevalence of squamous and mucinous metaplasia. The rate of endometrial cancer diagnosis was significantly higher in women with endometriosis-associated endometrioid ovarian cancer (33%) than in other patients (11%) (p=0.04) with a 92% concordance between ovarian and endometrial histologic tumor grade. A significant difference in survival rate could not be demonstrated between patients with or without endometriosis. CONCLUSIONS The analysis of a retrospective endometrioid ovarian cancer database may allow to suggest a 40 molecular, morphological and clinical parallelism between endometrial and endometrioid ovarian cancers.

Morcellation worsens survival outcomes in patients with undiagnosed uterine leiomyosarcomas: A retrospective MITO group study

OBJECTIVE To investigate the impact of morcellation on survival outcomes of patients affected by undiagnosed uterine sarcoma. METHODS This is a retrospective study performed in 8 referral centers of MITO group. Data of women undergoing morcellation for apparent benign uterine myomas who were ultimately diagnosed with stage I uterine sarcoma on final pathology were compared with data of women who did not undergo morcellation. Uterine sarcoma included: leiomyosarcomas (LMS), smooth muscle tumors of uncertain malignant potential (STUMP), low-grade endometrial stromal sarcomas (LG-ESS) and undifferentiated uterine sarcomas (UUS). Two-year survival outcomes were evaluated using Kaplan-Meir and Cox models. RESULTS Overall 125 patients were identified: 31(24.8%), 21(16.8%) and 73(58.4%) patients had power morcellation during laparoscopy, non power morcellation during open surgery and non morcellation during open procedures, respectively. Considering patients affected by LMS, morcellation did not correlated with disease-free survival. However, patients undergoing either morcellation or power morcellation experienced a 3-fold increase risk of death in comparison to patients who had not morcellation (p=0.02). A trend towards an increase of recurrence was observed for patients undergoing morcellation for STUMP (HR 7.7, p=0.09); while no differences in survival outcomes were observed for patients with LG-ESS and UUS. CONCLUSIONS Our data suggest that morcellation increase the risk of death in patients affected by undiagnosed LMS. Further prospective studies are warranted in order to assess the risk to benefit ratio of power morcellator utilization in patients with apparent benign uterine myomas.

Hysteroscopic Resection in Fertility-Sparing Surgery for Atypical Hyperplasia and Endometrial Cancer: Safety and Efficacy

STUDY OBJECTIVES To evaluate the rate of intrauterine adhesions after hysteroscopic resection of hyperplastic and/or cancer areas and the efficacy of combined treatment. DESIGN Observational retrospective study. SETTING Patients affected by endometrial atypical hyperplasia of the endometrium or early stage endometrial carcinoma. PATIENTS Twenty-three patients, up to 45 years of age. INTERVENTION Conservative treatment based on hysteroscopic resection of hyperplastic and/or cancer areas and subsequent therapy with megestrol acetate 160 mg/day. METHODS AND MAIN RESULTS Approximately 5% of endometrial cancers (ECs) are diagnosed in women younger than 40 years old, usually with a good prognosis. From 2010 to 2014, 23 patients, up to age 45 years, who were affected by endometrial cancer (EC) grade 1 or atypical complex hyperplasia (ACH) and who wished to preserve fertility, underwent conservative treatment based on hysteroscopic resection of the hyperplastic and/or cancer areas and subsequent therapy with megestrol acetate 160 mg/day. Data with regard to age, body mass index, symptoms, history of infertility, and previous assisted reproductive technologies attempts, obstetrics history, previous diagnosis of intrauterine sinechiae, hysteroscopic findings, duration of therapy, follow-up reports, and reproductive outcomes were collected and analyzed. Of the 23 patients enrolled in the study, 3 patients (13%) presented with an endometrioid EC grade 1, and 20 patients (87%) had ACH. Twelve patients (52.2%) had complete remission after 3 months of progestin therapy, 9 patients (39.1%) had a complete remission after 6 months, and 2 (8.7%) patients had remission after 9 months. Six patients underwent a second hysteroscopic resection. The 3 patients with an initial diagnosis of EC had complete remission after a mean of 4 months of high-dose progestin therapy; in patients with ACH, remission occurred after a mean of 3 months. In all patients, intrauterine adhesions were not detected at any follow-up diagnostic hysteroscopy. After a median follow-up time of 25 months (range 8-37), we registered 1 (4.3%) relapse of disease. A total of 7 pregnancies in 6 patients were counted, after an average time of 7.4 months (range 3-13 months) after the end of progestin therapy. CONCLUSIONS Hysteroscopic resection of hyperplastic and/or cancer areas before high dosage progestin therapy seems to be a safe and effective approach in the management of ACH and in patients with early EC who wish to preserve fertility.

Perioperative Betamethasone Treatment Reduces Signs of Bladder Dysfunction in a Rat Model for Neurapraxia in Female Urogenital Surgery

BACKGROUND Information on autonomic neurapraxia in female urogenital surgery is scarce, and a model to study it is not available. OBJECTIVE To develop a model to study the impact of autonomic neurapraxia on bladder function in female rats, as well as to assess the effects of corticosteroid therapy on the recovery of bladder function in this model. DESIGN, SETTING, AND PARTICIPANTS Female Sprague-Dawley rats were subjected to bilateral pelvic nerve crush (PNC) and perioperatively treated with betamethasone or vehicle. Bladder function and morphology of bladder tissue were evaluated and compared with sham-operated rats. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS Western blot, immunohistochemistry, organ bath experiments, and cystometry. RESULTS AND LIMITATIONS Sham-operated rats exhibited regular micturitions without nonvoiding contractions (NVCs). Crush of all nerve branches of the pelvic plexus or PNC resulted in overflow incontinence and/or NVCs. Betamethasone treatment improved recovery of regular micturitions (87.5% compared with 27% for vehicle; p<0.05), reduced lowest bladder pressure (8 ± 2 cm H(2)O compared with 21 ± 5 cm H(2)O for vehicle; p<0.05), and reduced the amplitude of NVCs but had no effect on NVC frequency in PNC rats. Compared with vehicle, betamethasone-treated PNC rats had less CD68 (a macrophage marker) in the pelvic plexus and bladder tissue. Isolated bladder from betamethasone-treated PNC rats exhibited better nerve-induced contractions, contained more cholinergic and sensory nerves, and expressed lower amounts of collagen III than bladder tissue from vehicle-treated rats. CONCLUSIONS PNC causes autonomic neurapraxia and functional and morphologic changes of isolated bladder tissue that can be recorded as bladder dysfunction during awake cystometry in female rats. Perioperative systemic betamethasone treatment reduced macrophage contents of the pelvic plexus and bladder, partially counteracted changes in the bladder tissue, and had protective effects on micturition function.

Brain metastases in patients with EOC: Clinico-pathological and prognostic factors. A multicentric retrospective analysis from the MITO group (MITO 19)

BACKGROUND Brain metastases (BM) from epithelial ovarian cancer (EOC) are considered a rare and unfavourable event. There is no consensus regarding the best management of these patients. METHODS A multicenter retrospective analysis of patients with BM from EOC treated between 1997 and 2014 in 18 institutions of the MITO (Multicenter Italian Trials in Ovarian cancer) group was conducted. Univariate and multivariate analysis were performed. RESULTS A total of 174 women were identified as having BM from EOC. The median time interval between primary diagnosis of EOC and occurrence of BM was 26months (range 2-129months). The median overall survival from primary EOC diagnosis was 48months (95% CI 39.5-56.4months) and from diagnosis of BM was 12months (95% CI 9.6-14.3months). The majority of enrolled women (81.7%) were classified as sensitive to platinum-based chemotherapy. Four variables were significantly associated with poor overall survival in multivariate analysis: multiple BM [HR: 1.86 (95% CI: 1.22-2.84)], presence of extracranial disease [HR: 1.77 (95% CI: 1.11-2.83)] age [HR: 1.74 (95% CI: 1.17-2.59)], and monotherapy [HR: 2.57 (95% CI: 1.64-3.86)]. On the contrary, residual tumor at primary surgery, FIGO stage at primary diagnosis and platinum sensitivity were found to have no significant impact on survival from diagnosis of brain lesions. CONCLUSIONS Our results suggest that BM is a rare and late manifestation of EOC, with a 12-month life-span expectation. Multiple approach is a positive independent prognostic factor and should be proposed to carefully selected patients.

Randomized Controlled Trial Testing the Efficacy of Platinum-Free Interval Prolongation in Advanced Ovarian Cancer: The MITO-8, MaNGO, BGOG-Ov1, AGO-Ovar2.16, ENGOT-Ov1, GCIG Study.

Purpose Platinum-based chemotherapy (PBC) for patients with progressing ovarian cancer (OC) is more effective with a longer time interval from previous platinum treatment (platinum-free interval [PFI]). In 1999, it was hypothesized that prolonging PFI with single-agent non-PBC (NPBC) may offer a strategy to improve overall outcome. MITO-8 aimed to verify this hypothesis commonly used in clinical practice although it has not been prospectively tested. Methods MITO-8 is an open-label, prospective, randomized, superiority trial. Patients with OC who experienced disease progression 6 to 12 months after their last platinum treatment were randomly assigned 1:1 to the experimental sequence of NPBC followed by PBC at subsequent relapse or the standard reverse treatment sequence. Overall survival (OS) was the primary end point. Results Two hundred fifteen patients were enrolled (standard arm [n = 108]; experimental arm [n = 107]). The trial ended before planned because of slow enrollment. PFI was prolonged in the experimental arm (median, 7.8 v 0.01 months). There was no OS benefit in the experimental arm (median, 21.8 v 24.5 months; hazard ratio, 1.38; 95% CI, 0.99 to 1.94; P = .06). Progression-free survival after the sequence was significantly shorter in the experimental arm (median, 12.8 v 16.4 months; hazard ratio, 1.41; 95% CI, 1.04 to 1.92; P = .025). Global quality-of-life change after three cycles was worse in the experimental arm. Slight differences were observed in the incidence of adverse effects. Conclusion MITO-8 supports the recommendation that PBC not be delayed in favor of an NPBC in patients with partially platinum-sensitive OC. PBC should be used as a control arm in future trials of new drugs in this setting.

Feasibility and outcome of interval debulking surgery (IDS) after carboplatin-paclitaxel-bevacizumab (CPB): A subgroup analysis of the MITO-16A-MaNGO OV2A phase 4 trial

BACKGROUND Few data are available on the outcome of surgery after a bevacizumab-containing regimen. The MITO 16A- MaNGO OV2A phase 4 trial evaluates the outcomes of first-line CPB in a clinical-practice-like setting. Here we present the results of the subgroup of patients undergoing IDS after neoadjuvant treatment or suboptimal primary surgery. METHODS 400 chemonaïve epithelial ovarian cancer patients, age≥18, ECOG PS 0-2 were eligible to receive C (AUC 5 d1, q21) plus P (175mg/m2 d1, q21) and B (15mg/kg d1 q21) for 6cycles followed by B maintenance until cycle 22nd. RESULTS 79 patients (20%) underwent IDS. Overall, 74 patients received at least one administration of B before IDS. Median age was 61.2, 70% of the patients had FIGO IIIC disease. The median number of cycles before IDS was 3 both for chemotherapy and bevacizumab respectively. A residual disease ≤1cm was achieved in 64 patients (86.5%). Four percent of the patients experienced fever and 4% required blood transfusion after surgery. Surgical wound infection and/or dehiscence, pelvic abscess, intestinal sub-occlusion and fistula were experienced by one patient each. CONCLUSIONS In the MITO16A-MaNGO OV2A phase 4 trial, combined chemotherapy and bevacizumab did not hamper IDS and the rate of perioperative complications was similar to what expected without bevacizumab. These data support the hypothesis that adding bevacizumab to first line chemotherapy for ovarian cancer might not be denied to patients for whom IDS is planned.

Mental representations of illness in patients with gestational trophoblastic disease: How do patients perceive their condition?

Background Gestational Trophoblastic Disease comprises a group of benign and malignant disorders that derive from the placenta. Using Leventhal’s Common-Sense Model as a theoretical framework, this paper examines illness perception in women who have been diagnosed with this disease. Methods Thirty-one women diagnosed with Gestational Trophoblastic Disease in a hospital in Italy were asked to complete the Illness Perception Questionnaire-Revised to measure the following: illness Identity, illness opinions and causes of Gestational Trophoblastic Disease. Results High mean scores were observed in the Emotional representations and Treatment control subscales. A significant difference emerged between hydatidiform mole patients and those with gestational trophoblastic neoplasia on the Identity subscale. A significant correlation emerged between “time since diagnosis” and the Treatment control subscale. Discussion This study is the first to investigate illness perception in Gestational Trophoblastic Disease. From a clinical perspective the results highlight the need for multidisciplinary support programs to promote a more realistic illness perception.

Folate receptor alpha antagonists in preclinical and early stage clinical development for the treatment of epithelial ovarian cancer

ABSTRACT Introduction: The prognosis of patients affected by ovarian cancer has not substantially changed in the last decades and improving survival still remains a challenge. In the promising era of ‘personalized therapy’ several new biologic therapies are currently being investigated: in this setting, targeting the folate receptor (FR) has been considered a new potential strategy for biologic therapy. Areas covered: The aim of the current review is to summarize, giving a critical overview,promising folate receptor alpha antagonists under preclinical or early clinical development for ovarian cancer. Expert opinion: Two categories of therapeutics are included in this class: FRα targeted mAbs and FRα-binding-ADC (Antibody drug conjugates); both share the interesting possibility of selecting patients via a biomarker which is already available. In the first class, farletuzumab has reached the most advanced stage in clinical evaluation and results of a Phase II randomized trial are awaited to assess its efficacy in a specific patients’ setting. MOv18 IgE represents a novel strategy to target FRα expressing cells, which has shown encouraging results in preclinical studies: further evaluation is needed in the clinical setting. IMGN 853 is an innovative FRα-binding ADC under development, with only preliminary results of a Phase I trial available.