Publications

[How I do… Resection of the uterosacral ligament by laparoscopy with nerve sparing in 6 steps].

Identification of TP53 mutated group using a molecular and immunohistochemical classification of endometrial carcinoma to improve prognostic evaluation for adjuvant treatments.

INTRODUCTION: Molecular classification of endometrial carcinoma has been proposed to predict survival. However, its role in patient management remains to be determined. We aimed to identify whether a molecular and immunohistochemical classification of endometrial carcinoma could improve decision-making for adjuvant therapy. METHODS: All consecutive patients treated for endometrial carcinoma between 2010 and 2017 at Cochin University Hospital were included. Clinical risk of relapse was based on European Society for Medical Oncology-European Society of Gynaecological Oncology-European SocieTy for Radiotherapy & Oncology (ESMO-ESGO-ESTRO) consensus. The clinical event of interest was event-free survival. Formalin-fixed paraffin-embedded tissue samples were processed for histopathological analysis and DNA extraction. The nuclear expression of mismatch repair and TP53 proteins was analyzed by immunohistochemistry. Next-generation sequencing of a panel of 15 genes including TP53 and POLE was performed using Ampliseq panels on Ion Torrent PGM (ThermoFisher). Tumors were allocated into four molecular groups using a sequential method based on next-generation sequencing and immunohistochemistry data: (1) POLE/ultramutated-like; (2) MSI/hypermutated-like (mismatch repair-deficient); (3) TP53-mutated (without POLE mutations or mismatch repair deficiency); (4) not otherwise specified (the remaining tumors). RESULTS: 159 patients were included; 125 tumors were available for molecular characterization and distributed as follows: (1) POLE/ultramutated-like: n=4 (3%); (2) MSI/hypermutated-like: n=35 (30%); (3) TP53-mutated: n=30 (25%); and (4) not otherwise specified: n=49 (42%). Assessing the TP53 status by immunohistochemistry only rather than next-generation sequencing would have misclassified 6 tumors (5%). TP53-mutated tumors were associated with poor prognosis, independently of International Federation of Gynecology and Obstetrics (FIGO) stage and histological grade (Cox-based adjusted hazard ratio (aHR) 5.54, 95% CI 2.30 to 13.4), and independently of clinical risk of relapse (aHR 3.92, 95% CI 1.59 to 9.64). Among patients with FIGO stage I-II tumors, 6 (38%) TP53-mutated tumors had low/intermediate clinical risk of relapse and did not receive adjuvant chemotherapy or radiotherapy. CONCLUSION: Endometrial carcinoma molecular classification identified potentially under-treated patients with poor molecular prognosis despite being at low/intermediate clinical risk of relapse. Consideration of molecular classification in adjuvant therapeutic decisions should be evaluated in prospective trials.

Diagnosing adenomyosis: an integrated clinical and imaging approach.

BACKGROUND: Adenomyosis is a benign uterine disorder where endometrial glands and stroma are pathologically demonstrated within the uterine myometrium. The pathogenesis involves sex steroid hormone abnormalities, inflammation, fibrosis and neuroangiogenesis, even though the proposed mechanisms are not fully understood. For many years, adenomyosis has been considered a histopathological diagnosis made after hysterectomy, classically performed in perimenopausal women with abnormal uterine bleeding (AUB) or pelvic pain. Until recently, adenomyosis was a clinically neglected condition. Nowadays, adenomyosis may also be diagnosed by non-invasive techniques, because of imaging advancements. Thus, a new epidemiological scenario has developed with an increasing number of women of reproductive age with ultrasound (US) or magnetic resonance imaging (MRI) diagnosis of adenomyosis. This condition is associated with a wide variety of symptoms (pelvic pain, AUB and/or infertility), but it is also recognised that some women are asymptomatic. Furthermore, adenomyosis often coexists with other gynecological comorbidities, such as endometriosis and uterine fibroids, and the diagnostic criteria are still not universally agreed. Therefore, the diagnostic process for adenomyosis is challenging. OBJECTIVE AND RATIONALE: We present a comprehensive review on the diagnostic criteria of adenomyosis, including clinical signs and symptoms, ultrasound and MRI features and histopathological aspects of adenomyotic lesions. We also briefly summarise the relevant theories on adenomyosis pathogenesis, in order to provide the pathophysiological background to understand the different phenotypes and clinical presentation. The review highlights the controversies of multiple existing criteria, summarising all of the available evidences on adenomyosis diagnosis. The review aims also to underline the future perspective for diagnosis, stressing the importance of an integrated clinical and imaging approach, in order to identify this gynecological disease, so often underdiagnosed. SEARCH METHODS: PubMed and Google Scholar were searched for all original and review articles related to diagnosis of adenomyosis published in English until October 2018. OUTCOMES: The challenge in diagnosing adenomyosis starts with the controversies in the available pathogenic theories. The difficulties in understanding the way the disease arises and progresses have an impact also on the specific diagnostic criteria to use for a correct identification. Currently, the diagnosis of adenomyosis may be performed by non-invasive methods and the clinical signs and symptoms, despite their heterogeneity and poor specificity, may guide the clinician for a suspicion of the disease. Imaging techniques, including 2D and 3D US as well as MRI, allow the proper identification of the different phenotypes of adenomyosis (diffuse and/or focal). From a histological point of view, if the diagnosis of diffuse adenomyosis is straightforward, in more limited disease, the diagnosis has poor inter-observer reproducibility, leading to extreme variations in the prevalence of disease. Therefore, an integrated non-invasive diagnostic approach, considering risk factors profile, clinical symptoms, clinical examination and imaging, is proposed to adequately identify and characterise adenomyosis. WIDER IMPLICATIONS: The development of the diagnostic tools allows the physicians to make an accurate diagnosis of adenomyosis by means of non-invasive techniques, representing a major breakthrough, in the light of the clinical consequences of this disease. Furthermore, this technological improvement will open a new epidemiological scenario, identifying different groups of women, with a dissimilar clinical and/or imaging phenotypes of adenomyosis, and this should be object of future research.

Selective inhibition of TGFβ1 activation overcomes primary resistance to checkpoint blockade therapy by altering tumor immune landscape.

Despite breakthroughs achieved with cancer checkpoint blockade therapy (CBT), many patients do not respond to anti-programmed cell death-1 (PD-1) due to primary or acquired resistance. Human tumor profiling and preclinical studies in tumor models have recently uncovered transforming growth factor-β (TGFβ) signaling activity as a potential point of intervention to overcome primary resistance to CBT. However, the development of therapies targeting TGFβ signaling has been hindered by dose-limiting cardiotoxicities, possibly due to nonselective inhibition of multiple TGFβ isoforms. Analysis of mRNA expression data from The Cancer Genome Atlas revealed that TGFΒ1 is the most prevalent TGFβ isoform expressed in many types of human tumors, suggesting that TGFβ1 may be a key contributor to primary CBT resistance. To test whether selective TGFβ1 inhibition is sufficient to overcome CBT resistance, we generated a high-affinity, fully human antibody, SRK-181, that selectively binds to latent TGFβ1 and inhibits its activation. Coadministration of SRK-181-mIgG1 and an anti-PD-1 antibody in mice harboring syngeneic tumors refractory to anti-PD-1 treatment induced profound antitumor responses and survival benefit. Specific targeting of TGFβ1 was also effective in tumors expressing more than one TGFβ isoform. Combined SRK-181-mIgG1 and anti-PD-1 treatment resulted in increased intratumoral CD8+ T cells and decreased immunosuppressive myeloid cells. No cardiac valvulopathy was observed in a 4-week rat toxicology study with SRK-181, suggesting that selectively blocking TGFβ1 activation may avoid dose-limiting toxicities previously observed with pan-TGFβ inhibitors. These results establish a rationale for exploring selective TGFβ1 inhibition to overcome primary resistance to CBT.

Deep Infiltrating Endometriosis: a Previous History of Surgery for Endometriosis May Negatively Affect Assisted Reproductive Technology Outcomes.

For patients with endometriosis-related infertility, the impact of previous surgery for endometriosis before assisted reproductive technology (ART) remains controversial, particularly in cases of deep infiltrating endometriosis (DE). To study the impact of previous surgery for endometriosis on ART cumulative live-birth rates in DE patients, a retrospective cohort study included 222 DE patients who underwent ART. DE diagnosis was based on strict imaging criteria and histological confirmation of the disease for women with a previous history of surgery for endometriosis. ART outcomes were compared for patients with and without a previous history of surgery for endometriosis. The main outcome measures were cumulative live-birth rates (CLBR). Prognostic factors were identified by comparing women who became pregnant and those who did not, using an adjusted multiple logistic regression model. Two hundred twenty-two DE patients underwent a total of 440 ART cycles (including fresh and associated frozen-thawed embryo transfers). One hundred fifty-five women (69.8%) had a prior history of surgery for endometriosis. The CLBR was 26% after four ART cycles in the -'previous history of surgery for endometriosis-' group, while it reached 51.3% after four cycles (p < 0.001) in patients who had not previously undergone surgery for endometriosis. After multivariate analysis, a previous history of surgery for endometriosis (p = 0.001) and a past surgery for endometrioma (p = 0.005) were established as independent factors associated with lower pregnancy rates. Our preliminary results suggest that for DE patients, a previous history of surgery for endometriosis may be associated with negative ART outcomes.

High Levels of Anti-GM-CSF Antibodies in Deep Infiltrating Endometriosis.

Endometriosis is a chronic hormono-dependent inflammatory gynecological disease. Endometriosis can be subdivided into three forms: superficial peritoneal implants, endometrioma, and deep infiltrating endometriosis (DIE). Inflammation is a typical feature of endometriosis with overproduction of prostaglandins, chemokines, and cytokines, like granulocyte-macrophage colony-stimulating factor (GM-CSF). GM-CSF is a hematopoietic growth factor and immune modulator which belongs to the group of cytokines that actively participate in inflammatory reactions. GM-CSF autoantibodies (Ab) are described in inflammatory diseases such as Crohn disease and ulcerative colitis where high concentrations of anti-GM-CSF Ab are correlated with severity, complications, and relapses. We have evaluated the presence of anti-GM-CSF Ab in the serum of 106 patients with endometriosis and 92 controls using a home-made enzyme-linked immunosorbent assay (ELISA) and correlated the results with the form and severity of the disease. We found that anti-GM-CSF Ab level is significantly increased in the sera of patients with endometriosis compared to controls and is associated with the severity of the disease especially in patients with deep endometriosis (p < 0.0001) with the highest number of lesions (p = 0.0034), including digestive involvement (p = 0.0041). We also found a correlation between these levels of anti-GM-CSF Ab and the number of lesions in DIE patients (r = 0.913). In this way, searching anti-GM-CSF Ab in endometriosis patient sera could be of value for patient follow-up and put further insight into the role of inflammation and of GM-CSF in endometriosis pathogenesis.

Superficial Peritoneal Endometriosis: Clinical Characteristics of 203 Confirmed Cases and 1292 Endometriosis-Free Controls.

The aim of this study was to characterize a large sample of women with superficial peritoneal endometriosis (SUP) and no other types of endometriosis in order to test the association of SUP with gynecologic symptoms. We included 203 cases of histologically proven SUP and 1292 endometriosis-free controls diagnosed between January 2004 and July 2017. The participants were non-pregnant patients aged 18 to 42 years submitted to a laparoscopy or laparotomy for a benign gynecologic condition. We excluded all cases of ovarian endometrioma, deep infiltrating endometriosis, and women who had previously undergone an endometriosis surgery. All patients underwent face-to-face interviews, thorough preoperative physical examination, and transvaginal ultrasound. Pain severity was assessed preoperatively through an 11-point numerical rating scale. The association of SUP with gynecologic symptoms was adjusted for potential confounders using multivariable logistic regression. The presence of SUP was associated with lower body weight (59.8 vs. 63.5 kg) and body mass index (21.8 vs. 23.3 kg/m2), and a higher frequency of smoking habit (41.6% vs. 32.8%) and of positive familial history of endometriosis (7.0% vs. 2.3%). Moreover, SUP was associated with an increased risk of primary infertility (adjusted prevalence ratio [PR] 1.83, 95% confidence interval [CI] 1.46-2.24), moderate to intense dysmenorrhea (PR 1.43, 95% CI 1.31-1.52), and moderate to intense deep dyspareunia (PR 1.50, 95% CI 1.25-1.75). In conclusion, in this large surgical series, isolated SUP was independently associated to primary infertility and moderate to severe painful symptoms.

The Ovarian Response After Follicular Versus Luteal Phase Stimulation with a Double Stimulation Strategy.

The double-ovarian stimulation strategy has been proposed to optimize the number of oocytes retrieved within the shortest possible timeframe. The objective of this study is to explore the effectiveness of luteal phase (LP) ovarian stimulation as compared to the previous follicular phase (FP) stimulation in a double stimulation strategy. We conducted an observational cohort study of women scheduled for a double stimulation protocol between March 2014 and June 2017, who had completed the FP controlled ovarian stimulation (COS 1) and started the LP stimulation (COS 2) in the same cycle. Women received equivalent daily doses of gonadotropins in combination with GnRH-antagonist protocol for both the COS 1 and the COS 2 performed during the same cycle. Ovulation was triggered using GnRH-agonist in the two stimulations. The primary outcome was the number of oocytes retrieved. A total of 77 patients were included in the analysis. The number of oocytes retrieved after COS 1 was significantly higher than after the COS 2 (5.25 ± 3.38 for COS 1 versus 3.83 ± 3.14 for COS 2; p = 0.001). The duration of the stimulation was significantly shorter, the total dose of injected gonadotropins was significantly lower, and the estradiol level on the trigger day was significantly higher with COS 1 as compared to COS 2. Stimulation during the LP in a double-successive stimulation strategy results in a lower ovarian response as compared to the FP equivalent daily dose stimulation.

Associated ileocaecal location is a marker for greater severity of low rectal endometriosis.

OBJECTIVE: To determine whether ileocaecal endometriosis (ICE) is a marker for low rectal endometriosis (LRE) severity. DESIGN: Retrospective cohort study. SETTING: France. POPULATION AND SAMPLE: Analysis of 375 colorectal resections performed in women undergoing complete surgery for LRE from January 1995 to December 2015 in a university centre for endometriosis. METHODS: Univariate and multivariate analysis of anatomical, postoperative clinical, and long-term outcomes according to presence of ICE. MAIN OUTCOMES AND MEASURES: Mean number and type of deep infiltrating endometriosis (DIE) lesions, the existence of an associated endometrioma, and mean total American Society for Reproductive Medicine (ASRM) score. RESULTS: The prevalence of ICE was 25.6%. Primary end-point data showed that women with ICE had a significantly higher adjusted number of DIE lesions (OR = 1.43, 95% CI 1.02-3.03; P = 0.048), higher prevalence of endometriomas (OR = 1.91, 95% CI 1.04-3.51; P = 0.044), more associated DIE sigmoid lesions (OR = 2.12, 95% CI 1.07-3.91; P = 0.025), and a higher mean total ASRM score (OR = 2.07, 95% CI 1.12-4.14; P = 0.025). Women with ICE resected during the surgical procedure for LRE did not have more adverse postoperative clinical outcomes than ICE-negative patients. CONCLUSION: Ileocaecal endometriosis was significantly associated with greater LRE severity. In a complete surgical resection strategy, combining resection of ICE and LRE did not appear to increase postoperative rates of complications, morbidity or recurrence, nor did it seem to impair long-term clinical outcomes. TWEETABLE ABSTRACT: In women with low rectal endometriosis, 25% have an associated ileocaecal location that is a marker for severity.

Rethinking mechanisms, diagnosis and management of endometriosis.

Endometriosis is a chronic inflammatory disease defined as the presence of endometrial tissue outside the uterus, which causes pelvic pain and infertility. This disease should be viewed as a public health problem with a major effect on the quality of life of women as well as being a substantial economic burden. In light of the considerable progress with diagnostic imaging (for example, transvaginal ultrasound and MRI), exploratory laparoscopy should no longer be used to diagnose endometriotic lesions. Instead, diagnosis of endometriosis should be based on a structured process involving the combination of patient interviews, clinical examination and imaging. Notably, a diagnosis of endometriosis often leads to immediate surgery. Therefore, rethinking the diagnosis and management of endometriosis is warranted. Instead of assessing endometriosis on the day of the diagnosis, gynaecologists should consider the patient's 'endometriosis life'. Medical treatment is the first-line therapeutic option for patients with pelvic pain and no desire for immediate pregnancy. In women with infertility, careful consideration should be made regarding whether to provide assisted reproductive technologies prior to performing endometriosis surgery. Modern endometriosis management should be individualized with a patient-centred, multi-modal and interdisciplinary integrated approach.