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The Meigs syndrome is a rare but well known syndrome in which removal of the tumor results in cure. We report a case of a regressive Meigs syndrome after a definitive adnexal torsion which highlights the major role of the vascular phenomena in the physiopathology of this puzzling syndrome. [ABSTRACT FROM AUTHOR]

Objective: To describe the patterns of recurrence and the prognosis of patients with a recurrent TP53 mutated endometrial carcinoma treated initially by surgery., Methods: All patients with endometrial carcinoma, treated at hospital European Georges Pompidou between 2001 and 2021 were retrospectively included. Patients were separated into two groups: TP53-mutated and not TP53-mutated (POLE/ultramutated-like (POLEmut), dMMR (mismatch repair-deficient) and NSMP (No specific molecular profile)). We estimated survival using recurrence free survival, overall survival and overall survival from recurrence. The risk of recurrence according to TP53 status and the type of recurrence (locoregional recurrence, peritoneal recurrence, and metastasis) were also compared between the two groups., Results: Two hundred and ninety-one patients with endometrial carcinoma were included. Of these, 57 were TP53-mutated and 234 patients were not TP53-mutated. TP53 mutated patients had the worst recurrence free survival and overall survival (p < 0.001 for each). The hazard rate of recurrence was higher during the first three years for TP53 mutated endometrial carcinoma then tend to join the one of no TP53 mutated. There was a statistical difference between the two groups in terms of cumulative incidence of peritoneal recurrence (p = 0.002). There was, however, no statistical difference in overall survival from recurrence., Conclusions: TP53-mutated endometrial carcinoma were more likely to experience a recurrence during the first three years and most often peritoneal recurrence compared to not TP53-mutated. TP53 status in endometrial carcinoma could be useful to define follow-up. Further prospective studies are required to assess the predictive impact of TP53 mutation on chemotherapy benefit., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd, BASO ~ The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.)

French recommendations for clinical practice Nice-Saint-Paul de Vence 2022-2023: histomolecular diagnosis of endometrial carcinomas The characterisation of endometrial carcinomas has been recently modified and enriched by molecular classification, the integration of which now impacts therapeutic decisions on whether adjuvant therapy should be administered or not in localized tumors, and influences treatment selection in advanced disease. Mandatory information includes histological type according to WHO 2020 classification, histological grade, hormone receptors status and molecular classification, the main new elements to provide being analysis of MMR proteins, p53 status and POLE status in selected cases. Sampling and preparation of material must be performed adequately to allow complete analysis. Numerous markers can be used to better define histological type, distinguish between primary lesion or metastases, or provide prognostic information. Determination of MMR/MSI profile is complex but well defined by guidelines that precisely describe techniques to be used and interpretation rules. Knowledge of POLE status is useful to guide therapeutic strategy, especially to consider de-escalation in stages I and II, in particular in case of high grade and/or p53 mutated tumors. This is why indications of POLE determination must be well defined. Finally, oncogenetics consultation is recommended in dMMR tumors (except in case or MLH1 promoter methylation) and in patients with evocative familial history., (Copyright © 2023 Elsevier Masson SAS. Tous droits réservés. All rights reserved.)

Recommendations for clinical practice Nice/Saint-Paul-de-Vence 2022-2023 : Management of advanced/relapsing endometrial cancer Since the first recommendations in 2020 concerning metastatic and/or relapsed endometrial cancer, new treatment options have shown a benefit on patients' life expectancy, justifying their update. In first line, the choice will be made between chemotherapy with carboplatin/paclitaxel or hormone therapy with progestin, depending on tumor characteristics (histological type, grade, expression of hormone receptors, rate of progression). In case of a dMMR tumors, the use of immunotherapy within the framework of a therapeutic trial is an option. Beyond first-line chemotherapy, current standard treatment consists of the combination of pembrolizumab and lenvatinib, regardless of MMR status. Close clinical and biological monitoring is however necessary given the potential toxicity. Chemotherapy retains its place either as monotherapy (paclitaxel or doxorubicin) in the event of failure or contraindication to pembrolizumab-lenvatinib, or in combination with carboplatin in the event of a long free interval and pMMR tumor. The numerous ongoing clinical trials evaluating new therapeutic targets or strategies adapted to molecular or histological types should allow further improvements the prognosis of patients with metastatic endometrial cancer., (Copyright © 2023 Elsevier Masson SAS. Tous droits réservés. All rights reserved.)

Introduction: In early cervical cancer (EEC), 10 to 15% of patients without nodal metastasis (N-) will suffer from recurrences with further similar survival as N+ patients. However, no clinical, imaging or pathological risk-factor is today available to identify them. In the present study, we hypothesized that the N- histologically characterized patients who present a poor prognosis could be patients for whom metastasis are missed by classical procedure. Therefore, we propose to research HPV tumoral DNA (HPVtDNA) in pelvic Sentinel Lymph Nodes (SLN) biopsy using ultrasensitive droplet-based digital PCR (ddPCR) to detect eventual occult metastasis., Materials and Methods: Sixty HPV16, HPV18 or HPV33 positive EEC N- patients with available SLN were included. In SLN, HPV16 E6, HPV18 E7 and HPV33 E6 gene were respectively detected using ultrasensitive ddPCR technology. Survival data were analysed using Kaplan-Meier-curves and log-rank-test to compare progression-free survival (PFS) and disease-specific survival (DSS) in two groups according to their HPVtDNA status in SLN., Results: More than half (51.7%) of the patients finally showed HPVtDNA positivity in SLN initially diagnosed as negative by histology. Two patients with negative HPVtDNA SLN and 6 with positive HPVtDNA SLN group presented recurrence. Finally, all of the 4 deaths listed in our study occurred in the positive HPVtDNA SLN group., Conclusion: These observations hint that the use of ultrasensitive ddPCR to detect HPVtDNA in SLN could allow the identification of two subgroups of histologically N- patients that may have different prognosis and outcome. To our knowledge, our study is the first one to evaluate the detection of HPVtDNA in SLN in early cervical cancer using ddPCR highlighting its interest as a complementary tool for N- specific early cervical cancer diagnosis., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

The surgical specificities of advanced low-grade serous ovarian carcinoma (LGSOC) have been little investigated. Our objective was to describe surgical procedures/complications in primary (PDS) compared to interval debulking surgery (neoadjuvant chemotherapy and interval debulking surgery, NACT-IDS) and to assess the survival (progression-free (PFS) and overall survival (OS)) in patients with advanced LGSOC. We retrospectively analyzed advanced LGSOC from a nationwide registry (January 2000 to July 2017). A total of 127 patients were included (48% PDS and 35% NACT-IDS). Peritoneal carcinomatosis was more severe ( p = 0.01 to 0.0001, according to sites), surgery more complex ( p = 0.03) and late postoperative morbidity more frequent ( p = 0.03) and more severe in the NACT-IDS group. PFS and OS were similar in patients with CC0 and CC1 residual disease after PDS or IDS. Prognosis was poorest for NACT-IDS patients with CC2/CC3 resection (PFS: HR = 2.31, IC95% (1.3-4.58); p = 0.005; OS: HR = 4.98, IC95% (1.59-15.61); p = 0.006). NACT has no benefit in terms of surgical outputs in patients with advanced LGSOC. Patients with complete resection or minimal residual disease (CC0 and CC1) have similar prognoses. On the other hand, patients with CC2 and more residual disease have similar survival rates compared to nonoperated patients. Primary cytoreduction with complete or with minimal residuals should be preferred when feasible.

Background: Lymphadenectomy is debated in patients with ovarian cancer. The aim of our study was to evaluate the impact of lymphadenectomy in patients with high-grade serous ovarian cancer receiving neoadjuvant chemotherapy (NACT) followed by interval debulking surgery (IDS)., Methods: A retrospective, unicentric study including all patients undergoing NACT and IDS was carried out from 2005 to 2018. Patients with and without lymphadenectomy were compared in terms of recurrence free survival (RFS), overall survival (OS), and complication rates., Results: We included 203 patients. Of these, 133 had a lymphadenectomy (65.5%) and 77 had involved nodes (57.9%). Patients without a lymphadenectomy were older, had a more extensive disease and less complete CRS. No differences were noted between the lymphadenectomy and no lymphadenectomy group concerning 2-year RFS (47.4% and 48.6%, p = 0.87, respectively) and 5-year OS (63.2% versus 58.6%, p = 0.41, respectively). Post-operative complications tended to be more frequent in the lymphadenectomy group (18.57% versus 31.58%, p = 0.09). In patients with a lymphadenectomy, survival was significantly altered if the nodes were involved (positive nodes: 2-year RFS 42.5% and 5-year OS 49.4%, negative nodes: 2-year RFS 60.7% and 5-year OS 82.2%, p = 0.03 and p < 0.001, respectively)., Conclusion: Lymphadenectomy during IDS does not improve survival and increases post-operative complications., Competing Interests: Declaration of competing interest None., (Copyright © 2021 Elsevier Ltd, BASO ~ The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.)

New molecular therapeutic approaches have emerged in recent years for advanced gynaecological cancers, including targeted therapies such as poly-ADP-ribose polymerase inhibitors (PARPi). These have demonstrated efficacy in high-grade serous ovarian cancers in patients carrying a mutation in the BRCA gene, which predisposes them to breast and ovarian cancers. Clinical and pre-clinical data suggest that the activity of PARPi inhibitors may not be limited to BRCA mutated tumours and may involve the homologous recombination pathway. These data raise the question of the potential efficacy of PARPi in advanced endometrial and cervical cancers where treatment options are currently limited. At present, there are few data available on the activity of PARPi in endometrial and cervical cancers, but some results seem promising. In this review, we present a synthesis of the available studies concerning PARPi in endometrial and cervical cancer., (Copyright © 2021 Société Française du Cancer. Published by Elsevier Masson SAS. All rights reserved.)

Introduction: The benefit of a systematic lymphadenectomy is still debated in patients undergoing neoadjuvant chemotherapy (NACT) followed by interval debulking surgery (IDS) in ovarian cancer (OC). The objective of this study was to evaluate the predictive value of the pre-NACT and post-NACT CT in predicting definitive histological lymph node involvement. The prognostic value of a positive node on the CT was also assessed., Materiel and Methods: A retrospective, unicentric cohort study was performed including all patients with ovarian cancer who underwent NACT and IDS with a lymphadenectomy between 2005 and 2018. CT were analyzed blinded to pathology, and nodes with small axis ≥ 10 mm on CT were considered positive. Sensitivity (Se), specificity (Sp), and negative (NPV) and positive predictive values (PPV) and their CI95% were calculated. The 2-year recurrence free survival (RFS) and 5-year overall survival (OS) was compared., Results: 158 patients were included, among which 92 (58%) had histologically positive lymph nodes. CT had a Se, Sp, NPV and PPV of 35%, 82%, 47% and 73% before NACT and 20%, 97%, 47% and 91% after NACT, respectively. Patients with nodes considered positive had a non-significant lower 2-year RFS and 5-year OS on the pre-NACT and post-NACT CT. Patients at 'high risk' (nodes stayed positive on the CT or became positive after NACT) also had a non-significant lower 2-year RFS and 5-year OS., Conclusion: Presence of enlarged lymph nodes on CT is a weak indicator of lymph node involvement in patients with advanced ovarian cancer undergoing NACT. However, it could be used to assess prognosis., Competing Interests: Declaration of Competing Interest None., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Objectives: We aimed to assess the diagnostic value of frozen-section pathologic examination (FSE) of sentinel lymph nodes (SLN) in patients with early-stage cervical cancer., Methods: Two French prospective multicentric database on SLN biopsy for cervical cancer (SENTICOL I and II) were analysed. Patients with IA to IIA1 2018 FIGO stage, who underwent SLN biopsy with both FSE and ultrastaging examination were included., Results and Discussion: Between 2005 and 2012, 313 patients from 25 centers fulfilled the inclusion criteria. Metastatic involvement of SLN was diagnosed in 52 patients (16.6%). Macrometastases, micrometastases and isolated tumor cells (ITCs) were found in 27, 12 and 13 patients respectively. Among the 928 SLNs analysed, FSE identified 23 SLNs with macrometastases in 20 patients and 5 SLNs with micrometastases in 2 patients whereas no ITCs were identified. Ultrastaging of negative SLNs by FSE found macrometastases, micrometastases and ITCs in additional 7, 11 and 17 SLNs. Ultrastaging increased significantly the rate of patients with positive SLN from 7% to 16.6% (p < 0.0001). The sensitivity and the negative predictive value of FSE were 42.3% and 89.7% respectively or 56.4% and 94.1% if ITCs were excluded. False-negative cases were more frequent with tumor size ≥ 20 mm (OR = 4.46, 95%IC = [1.45-13.66], p = 0.01) and preoperative brachytherapy (OR = 4.47, 95%IC = [1.37-14.63], p = 0.01) and less frequent with patients included in higher volume center (>5 patients/year) (OR = 0.09, 95%IC = [0.02-0.51], p = 0.01)., Conclusions: FSE of SLN had a low sensitivity for detecting micrometastases and ITCs and a high negative predictive value for SLN status. Clinical impact of false-negative cases has to be assessed by further studies., Competing Interests: Declaration of competing interest None., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Patients who carry the BReast Cancer 1 or 2 (BRCA) gene mutations have an underlying hereditary predisposition for breast and ovarian cancers. These deleterious genetic mutations are the most common ones implicated in hereditary breast and ovarian cancers. Oncogenetic counselling plays a key role in identifying patient for BRCA testing and for mutation identification. BRCA1/2 carriers have to be followed up regularly and may justify breast and/or adnexal prophylactic surgery, according to the French National Cancer Institute guidelines (INCa). Poly- (DNA-riboses) polymerases inhibitors, notably olaparib, have a major role in the management of epithelial ovarian cancer in patients with BRCA mutation and many studies are ongoing to expand their indications in a near future., (Copyright © 2020 Elsevier Masson SAS. All rights reserved.)

Fumarate hydratase (FH)-deficient uterine leiomyomas represent 1% of all uterine leiomyomas. They show distinctive morphology, and are often associated with a loss of expression of FH protein, secondary to the inactivation of the FH gene. They can occur sporadically or in the hereditary setting of hereditary leiomyomatosis and renal cell carcinoma (HLRCC) syndrome associated with germline mutations of FH gene. So, it is relevant to consider this diagnosis in case of young women with numerous or bulky leiomyomas and evocative microscopic features, in particular at nuclear level. Genetic screening is essential to identify hereditary forms, which require appropriate surveillance and genetic screening of relatives. Here, we report the case of a 20cm uterine leiomyoma in a young 32-year-old woman, whose morphologic and immunohistochemical characteristics were suggestive of FH-deficient leiomyoma., (Copyright © 2020 Elsevier Masson SAS. All rights reserved.)

Objectives: Ovarian carcinomas represent a heterogeneous group of lesions with specific therapeutic management for each histological subtype. Thus, the correct histological diagnosis is mandatory., Material and Methods: References were searched by PubMed from January 2000 to January 2018 and original articles in French and English literature were selected., Results and Conclusions: In case of ovarian mass suspicious for cancer, a frozen section analysis may be proposed, if it could impact the surgical management. A positive histological diagnosis of ovarian carcinoma (type and grade) has to be rendered on histological (and not cytological) material before any chemotherapy with multiples and large sized biopsies. In case of needle biopsy, at least three fragments with needles>16G are needed. Histological biopsies need to be formalin-fixed (4% formaldehyde) less than 1h after resection and at least 6hours fixation is mandatory for small size biopsies. Tissue transfer to pathological labs up to 48hours under vacuum and at +4°C (in case of large surgical specimens) may be an alternative. Gross examination should include the description of all specimens and their integrity, the site of the tumor and the dimension of all specimens and nodules. Multiples sampling is needed, including the capsule, the solid areas, at least 1 to 2 blocks per cm of tumor for mucinous lesions, the Fallopian tube in toto, at least 3 blocks on grossly normal omentum and one block on the largest omental nodule. WHO classification should be used to classify the carcinoma (type and grade), with the use of a panel of immunohistochemical markers. High-grade ovarian carcinomas (serous and endometrioid) should be tested for BRCA mutation and in case of a detectable tumor mutation, the patient should be referred to an oncogenetic consultation., (Copyright © 2019 Elsevier Masson SAS. All rights reserved.)

Purpose of Investigation: The objective of this study was to evaluate the best pre- and intra-operative strategy to determine the European Society for Medical Oncology (ESMO) risk group., Materials and Methods: Retrospective study on patients supported for endometrial cancer between 2006 and 2011. Twelve algorithms, integrating endometrial biopsy for histological type and tumour grade, and ultrasound and/or magnetic resonance imaging (MRI)±intra-operative examination for determination of myometrial invasion, were built. The diagnostic values of each algorithm to predict high- and low-risk group were calculated., Results: During the study period, 159 patients were operated for endometrial cancer. On these 159 patients, 103 met the inclusion criteria. For the prediction of high-risk group, the best algorithm was endometrial biopsy and ultrasound, combined with MRI in case of myometrial invasion <50%±intra-operative examination in case of myometrial invasion <50% on MRI. For the prediction of low-risk group, the 2 best algorithms were endometrial biopsy and ultrasound or MRI, combined with MRI or ultrasound in case of myometrial invasion <50% and intra-operative examination in case of discrepancy between both exams. There was no internal or external validation., Conclusion: Our study suggests that the best strategy to predict actual ESMO risk group is endometrial biopsy and transvaginal ultrasound±MRI and intra-operative examination in case of myometrial invasion <50% on ultrasound., (Copyright © 2018 Elsevier Masson SAS. All rights reserved.)

Müllerian inhibiting substance, also called anti-Müllerian hormone (AMH), inhibits proliferation and induces apoptosis of AMH type II receptor-positive tumor cells, such as human ovarian cancers (OCs). On this basis, a humanized glyco-engineered monoclonal antibody (3C23K) has been developed. The aim of this study was therefore to experimentally confirm the therapeutic potential of 3C23K in human OCs. We first determined by immunofluorescence, immunohistochemistry and cytofluorometry analyses the expression of AMHRII in patient's tumors and found that a majority (60 to 80% depending on the detection technique) of OCs were positive for this marker. We then provided evidence that the tumor stroma of OC is enriched in tumor-associated macrophages and that these cells are responsible for 3C23K-induced killing of tumor cells through ADCP and ADCC mechanisms. In addition, we showed that 3C23K reduced macrophages induced-T cells immunosuppression. Finally, we evaluated the therapeutic efficacy of 3C23K alone and in combination with a carboplatin-paclitaxel chemotherapy in a panel of OC Patient-Derived Xenografts. In those experiments, we showed that 3C23K significantly increased the proportion and the quality of chemotherapy-based in vivo responses. Altogether, our data support the potential interest of AMHRII targeting in human ovarian cancers and the evaluation of 3C23K in further clinical trials., Competing Interests: CONFLICTS OF INTEREST This study was supported by grants from GamaMabs Pharma, in which belong two authors, Jean-Marc Barret and Jean-François Prost.

Our objective was to determine if supersonic shear wave elastography (SSWE) can detect changes in stiffness of a breast cancer model under therapy. A human invasive carcinoma was implanted in 22 mice. Eleven were treated with an anti-angiogenic therapy and 11 with glucose for 24 d. Tumor volume and stiffness were assessed during 2 wk before treatment and 0, 7, 12, 20 and 24 d after the start of therapy using SSWE. Pathology was assessed after 12 and 24 d of treatment. We found that response to therapy was associated with early softening of treated tumors only, resulting in a significant difference from non-treated tumors after 12 d of treatment (p = 0.03). On pathology, large areas of necrosis were observed at 12 d in treated tumors. Although treatment was still effective, treated tumors subsequently stiffened during a second phase of the treatment (days 12-24), with a small amount of necrosis observed on pathology on day 24. In conclusion, SSWE was able to measure changes in the stiffness of tumors in response to anti-cancer treatment. However, stiffness changes associated with good response to treatment may change over time, and increased stiffness may also reflect therapy efficacy., (Copyright © 2016 World Federation for Ultrasound in Medicine & Biology. Published by Elsevier Inc. All rights reserved.)

It is well known that several metals, such as lead, mercury, cadmium, and vanadium, can mimic the effects of estrogens (metallo-estrogens). Nevertheless, there are only a few studies that have assessed the effects of toxic metals on the female genital tract and, in particular, endometrial tissue. In this context, we measured the concentrations of several trace elements in human endometrial tissue samples from individuals with hyperplasia or adenocarcinoma and in normal tissues. Hyperplasic endometrial tissue has a 4-fold higher concentration of mercury than normal tissue. Mercury can affect both the AhR and ROS signaling pathways. Thus, we investigated the possible toxic effects of mercury by in vitro studies. We found that mercury increases oxidative stress (increased HO1 and NQO1 mRNA levels) and alters the cytoskeleton in the human endometrial Ishikawa cell line and to a lesser extent, in the "less-differentiated" human endometrial Hec-1b cells. The results might help to explain a potential link between this metal and the occurrence of endometrial hyperplasia.

T cells play a key role in the battle against cancer. To perform their antitumor activities, T cells need to adequately respond to tumor antigens by establishing contacts with either malignant cells or antigen-presenting cells. These latter functions rely on a series of migratory steps that go from entry of T cells into the tumor followed by their locomotion in the tumor stroma. Our knowledge of how T cells migrate within tumors mainly comes from experiments performed in mouse models. Whereas such systems have greatly advanced our understanding, they do not always faithfully recapitulate the disease observed in cancer patients. We previously described a technique based on tissue slices that enables to track with real-time imaging microscopy the motile behavior of fluorescent T cells plated onto fresh sections of human lung tumors. We have now refined this approach to monitor the locomotion of resident tumor-infiltrating CD8 T cells labeled with fluorescently coupled antibodies. Using this approach, our findings reveal that CD8 T cells accumulate in the stroma of ovarian and lung carcinomas but move slowly in this compartment. Conversely, even though less populated, tumors islets were found to be zones of faster migration for resident CD8 T cells. We also confirm the key role played by collagen fibers, which, by their orientation, spacing and density, control the distribution and migration of resident CD8 T cells within the tumor stroma. We have subsequently demonstrated that, under some physical tissue constraints, CD8 T cells exhibited a mode of migration characterized by alternate forward and backward movements. In sum, using an ex vivo assay to track CD8 T cells in fresh human tumor tissues, we have identified the extracellular matrix as a major stromal component in influencing T cell migration, thereby impacting the control of tumor growth. This approach will aid in the development and testing of novel immunotherapy strategies to promote T cell migration in tumors.

Introduction: Improved knowledge of recurrence sites after contemporary surgical management of ovarian cancer is needed., Material and Methods: We retrospectively reviewed consecutive patients managed for epithelial ovarian or tubal cancer with surgery and platinum-based chemotherapy between January 1, 2005, and December 31, 2009, in a tertiary teaching hospital. The site of first recurrence was recorded. Univariate analysis was performed to identify factors associated with site-specific recurrence. Overall survival and progression-free survival were computed using the Kaplan-Meier method, and log-rank tests were performed to assess the impact on survival of the variables of interest., Results: Recurrences were noted in 3 (20%) of 15 International Federation of Gynecologists and Obstetricians stage I to IIa patients and 36 (62.1%) of 58 International Federation of Gynecologists and Obstetricians IIb to IV patients, and the median progression-free survival was 21.6 (2.5-71) and 19.3 (1.8-67.6) months, respectively. In the advanced-disease group, 75% of recurrences involved the peritoneum and 40% were confined to the peritoneum; peritoneal recurrences developed at both treated and untreated sites. Peritoneal recurrence was associated with greater initial peritoneal involvement (Sugarbaker score, 12.1 ± 8.2 vs 7.1 ± 7.4; P = 0.01) and residual postoperative tumor. Nodal recurrences were noted in 38% of all recurrences, usually in combination with peritoneal recurrence and in the abdominal territories. Isolated distant metastasis was a rare mode of recurrence (8%)., Conclusions: The peritoneum is the main recurrence site in both early and advanced ovarian cancer. Initial disease spread and extent of surgery are associated with the recurrence risk. This article supports the view that more attention should be directed toward extensive treatment of the peritoneum.

Objective: To assess stiffness in a human breast cancer implanted in mice using shear wave elastography (SWE) during tumour growth and to correlate the results with pathology., Methods: Local ethics committee for animal research approval was obtained. A human invasive ductal carcinoma was implanted subcutaneously in 24 athymic nude female mice. Ultrasound was longitudinally performed in 22 tumours, every 1-2 weeks. Maximum diameter and mean stiffness were collected. Seven tumours were measured both in vivo and ex vivo. Tumours of different sizes were removed for pathological analysis on which the percentages of viable cellular tissue, fibrosis and necrosis were measured., Results: A total of 63 SWE measurements were performed. Stiffness increased during tumour growth with an excellent correlation with size (r = 0.94, P < 0.0001). No differences were found between the values of stiffness in vivo and ex vivo (P = 0.81). There was a significant correlation between elasticity and fibrosis (r = 0.83, P < 0.0001), a negative correlation with necrosis (r = -0.76, p = 0.0004) but no significant correlation with cellular tissue (r = 0.40, p = 0.1)., Conclusion: Fibrosis plays an important role in stiffness as measured by SWE, whereas necrosis is correlated with softness., Key Points: • In a breast cancer model, ultrasound tumour stiffness is correlated with size. • Stiffness changes with tumour growth are correlated with pathological changes. • Stiffness is very well correlated with proportion of tumour fibrosis. • Stiffness is inversely correlated with proportion of tumour necrosis. • Tumour stiffness measurements are similar in vivo and ex vivo.

Background: Sentinel lymph node (SLN) biopsy may improve nodal staging in cervical cancer. The aims of this study are to determine the rate of unusual patterns of cervical lymphatic drainage, to determine the rates of micrometastases and isolated tumor cells (ITCs) in SLNs, and to assess the clinical impact of SLN biopsy., Methods: Multicenter prospective study conducted between January 2005 and June 2007 in women undergoing laparoscopic surgery for early cervical cancer. Combined technetium/Patent Blue labeling was used. Lymphoscintigraphy was performed before surgery. SLN location was recorded, and factors associated with location were explored. SLNs underwent step sectioning ± immunohistochemistry., Results: 145 patients were enrolled and 139 included in a modified intention-to-diagnose analysis. Although 80.6 % of SLNs were in external iliac and interiliac areas, 38.2 % of patients had at least one SLN in an unexpected area and 5.1 % had SLNs only in unexpected areas. In unexpected areas, the number of SLNs per patient was not significantly different between lymphoscintigraphy and intraoperative detection (0.79 [0.62-1.02] versus 0.50 [0.37-0.68]; P = 0.096). In expected locations, there were significantly more blue and hot SLNs per patient than blue or hot SLNs (1.70 [1.45-1.99], 0.42 [0.30-0.57], 0.52 [0.39-0.69]). Of 28 metastatic SLNs, 17 contained micrometastases or ITCs. SLN involvement was found only by immunohistochemistry in 39.1 % of patients with positive nodes, and involved SLNs were located in unexpected areas in 17 % of those patients., Conclusions: Sentinel lymph node biopsy detects unusual drainage pathways and micrometastases in a substantial proportion of patients, thus improving nodal staging.

Objectives: Pelvic lymphadenectomy is associated with a significant risk of lower-limb lymphedema. In this proof-of-concept study, we evaluated the feasibility of identifying the lower-limb drainage nodes (LLDNs) during pelvic lymphadenectomy for endometrial cancer. Secondary objectives were to map lower-limb drainage and to assess the diagnostic value of our mapping technique., Methods: This prospective study included patients with endometrial cancer requiring pelvic lymphadenectomy, without neoadjuvant radiotherapy or chemotherapy and without history of lower-limb surgery. A radiopharmaceutical was injected into both feet on the day before surgery. LLDNs were identified using preoperative lymphoscintigraphy and intraoperative isotopic probe detection, then removed before complete pelvic lymphadenectomy. LLDNs and pelvic lymphadenectomy specimens underwent separate histological analysis., Results: Of the 12 patients with early-stage endometrial cancer, 10 underwent preoperative lymphoscintigraphy, which consistently identified inguinal, femoral, and pelvic LLDNs (detection rate: 100%). The intraoperative detection rate was 83% (10/12). Median number of hot nodes per patient was 5 nodes (range: 3-7) on the right and 3 nodes (range: 2-6) on the left. Of 107 LLDNs, 106 were in the external iliac area, including 38 in the lateral group and 45 in the intermediate and medial groups. None of the patients had node metastases at any site. No early complications related to the technique occurred., Conclusion: Our mapping technique appears feasible, safe, and associated with a high LLDN identification rate. LLDN mapping may allow the preservation of LLDNs, thereby decreasing the risk of lower-limb lymphedema and improving quality of life.

The purpose of this prospective multicenter study was to assess one-step nucleic acid amplification (OSNA) for intraoperative sentinel lymph node (SLN) metastasis detection in breast cancer patients, using final histology as the reference standard. OSNA results were also compared to intraoperative histology SLN evaluation and to standard clinicopathological risk markers. For this study, fresh SLNs were cut in four blocks, and alternate blocks were used for OSNA and histology. CK19 mRNA copy number was categorized as strongly positive, positive or negative. Positive histology was defined as presence of macrometastasis or micrometastasis. When discrepancies occurred, the entire SLNs were subjected to histological studies and the node lysates to additional molecular studies. Five hundred three SLN samples from 233 patients were studied. Mean time to evaluate two SLNs was 40 min. Sensitivity per patient was 91.4% (95% CI, 76.9-98.2%), specificity 93.3% (95% CI, 88.6-96.6%), positive likelihood ratio 13.7 and negative likelihood ratio 0.1. Sensitivity was 63.6% for frozen sections and 47.1% for touch imprint cytology. Both methods were 100% specific. Positive histology and positive OSNA were significantly associated with highest clinical stage, N1 status and vascular invasion; and OSNA results correlated with HER2/neu status and benefited patients with negative histology. These findings show that OSNA assay can allow detection of SLN metastasis in breast cancer patients intraoperatively with a good sensitivity, thus minimizing the need for second surgeries for axillary lymph node detection., (Copyright © 2011 UICC.)

Objectives: Screening for endometrial cancer is recommended in women at risk for hereditary nonpolyposis colorectal cancer/Lynch syndrome. No screening tool has been validated. The objective of this study was to assess the performance of ultrasonography used to screen for atypical hyperplasia and cancer in women at risk for hereditary nonpolyposis colorectal cancer/Lynch syndrome. Endometrial biopsy was the reference standard., Materials and Methods: Of 85 women with mismatch repair gene mutations or Amsterdam II criteria who were studied prospectively at our institution, 58 had 96 paired ultrasound-biopsy evaluations and were included in the study. Transvaginal or transabdominal ultrasonographic finding was considered normal if no polyps or intrauterine abnormalities were seen and if the maximum endometrial thickness was less than 4 mm in postmenopausal women not receiving hormonal replacement therapy or less than 6 mm in other women. Endometrial biopsy results were categorized as not interpretable, normal, or showing atypical hyperplasia or cancer. Sensitivity, specificity, positive predictive value, negative predictive value, and likelihood ratio of ultrasonography were computed., Results: The 58 patients had a mean age of 42.5 years and a median follow-up duration of 51.4 months (range, 17-106 months; 246 patient exposure years). Cancer was diagnosed in 2 patients. Ultrasonography had 100% sensitivity and 100% negative predictive value, 2.2 positive likelihood ratio, and 0 negative likelihood ratio. No interval cancers occurred., Conclusions: Ultrasonography had high sensitivity and an excellent negative likelihood ratio in this study. Further studies are needed, and ultrasonography should be compared with clinical follow-up, diagnostic hysteroscopy, or endometrial biopsy alone.

Granulosa cell tumours (GCTs) account for less than 3% of all ovarian malignancies but are among the most common sex cord-stromal tumours. They may develop at any age. Symptoms related to oestrogen production by the tumour may occur. Because GCTs are uncommon and cannot be diagnosed preoperatively, their management is challenging. Surgery with salpingo-oophorectomy and painstaking staging is mandatory. Adjuvant chemotherapy is required in some patients. We report two cases of adult GCTs that illustrate the usefulness of extensive abdominal exploration in every patient with a suspicious ovarian mass, to obviate the need for a second staging procedure. With this strategy, the prognosis is excellent, although the possibility of late recurrences requires prolonged follow-up.

Malignant nonepithelial ovarian tumours represent less than 20% of ovarian cancers in adults. Apart from haematological tumours, there are mainly germ cell tumours and sex cordstromal ovarian tumours. These tumours affect young women and are diagnosed in early stages associated with a good prognosis. The management of malignant nonepithelial ovarian tumours is difficult because they are rare and because we have to propose an appropriate oncological treatment, preserving fertility for these women of child-bearing age. We propose an update on recent data in the literature, focusing on management.

The objective of this study was to report the value of diagnostic hysteroscopy and endometrial biopsy for the detection of complex atypical hyperplasia or cancer in asymptomatic human non-polyposis colon cancer (HNPCC) patients. The secondary objective was to evaluate the accuracy of hysteroscopy, using endometrial biopsy as a gold standard. Consecutive patients at risk of HNPCC evaluated between January 1, 1999, and June 30, 2006 were included if they underwent diagnostic hysteroscopy at least once. Patients with a history of hysterectomy and those unwilling to undergo diagnostic hysteroscopy were not included. Yearly follow-up evaluations included diagnostic hysteroscopy, with endometrial biopsy. Hysteroscopic and histologic findings were recorded and compared. We included 62 patients, of whom 13 had mismatch repair gene mutations and 49 met Amsterdam II criteria. Of 125 attempted hysteroscopies, 11 (8%) failed. Hysteroscopy showed normally appearing mucosa in 46 cases, nonmalignant lesions in 65 cases, and possibly malignant lesions in 3 cases with abnormal uterine bleeding. Endometrial biopsy was attempted in 116 cases and failed in 12 (10%). Three cases each of simple hyperplasia and of cancer were diagnosed. No preinvasive or invasive lesions were found in asymptomatic women. When compared to endometrial biopsy, sensitivity of hysteroscopy was 100% for the detection of hyperplasia or cancer. No cases of cancer were diagnosed in asymptomatic patients in our study. However, diagnostic hysteroscopy ensured the diagnosis of endometrial adenocarcinoma in HNPCC women with bleeding. Nevertheless, usefulness and optimal modalities of screening remain to be determined.

The transcription factor CCAAT/enhancer binding protein-alpha (C/EBP alpha) is involved in the control of cell differentiation and proliferation, and has been suggested to act as a tumor suppressor in several cancers. By using microarray analysis, we have previously shown that hypoxia and estrogen down-regulate C/EBP alpha mRNA in T-47D breast cancer cells. Here, we have examined the mechanism by which the down-regulation by hypoxia takes place. Using the specific RNA polymerase II inhibitor 5,6-dichlorobenzimidazole-1-beta-D-ribofuranoside, the mRNA stability was analyzed under normoxia or hypoxia by quantitative reverse transcription-PCR. Hypoxia reduced the half-life of C/EBP alpha mRNA by approximately 30%. C/EBP alpha gene promoter studies indicated that hypoxia also repressed the transcription of the gene and identified a hypoxia-responsive element (-522; -527 bp), which binds to hypoxia-inducible factor (HIF)-1 alpha, as essential for down-regulation of C/EBP alpha transcription in hypoxia. Immunocytochemical analysis showed that C/EBP alpha was localized in the nucleus at 21% O(2), but was mostly cytoplasmic under 1% O(2). Knockdown of HIF-1 alpha by RNAi restored C/EBP alpha to normal levels under hypoxic conditions. Immunohistochemical studies of 10 tumor samples did not show any colocalization of C/EBP alpha and glucose transporter 1 (used as a marker for hypoxia). Taken together, these results show that hypoxia down-regulates C/EBP alpha expression in breast cancer cells by several mechanisms, including transcriptional and posttranscriptional effects. The down-regulation of C/EBP alpha in hypoxia is mediated by HIF-1.

Objectives: To map sentinel lymph nodes (SLNs) detected by intracervical injection in patients with endometrial cancer and to determine the prevalence of node micrometastases., Methods: Radionuclide and blue dye injections were used for SLN detection in 43 patients with clinical stage I endometrial cancer. Lymphoscintigraphy was done before surgery. Intraoperatively, the pelvic and para-aortic territories were examined for blue and/or radioactive nodes. Pelvic lymphadenectomy was performed with or without para-aortic lymphadenectomy. SLNs stained with hematoxylin-eosin-saffron were examined and, when negative, evaluated using step sectioning and immunohistochemistry., Results: Feasibility was 100%. No adverse effects occurred. SLNs were identified in 30 patients (69.8%), usually in an interiliac location (28/30 patients, 93.3%). SLNs were found only in the common iliac chain in 1 (3%) patient and in both the common iliac chain and promontory area in another (3%). No patients had para-aortic SLNs or SLNs confined to the promontory. Node metastases were identified in eight patients and were confined to SLNs in six. In 2 (2/30, 6%) patients, SLNs contained micrometastases. No false-negatives occurred., Conclusions: Intracervical injection of radionuclide and blue dye chiefly revealed pelvic SLNs. The prevalence of micrometastases was within the expected range. Comparisons with peritumoral injection are needed.

Objectives: To report the feasibility and results of diagnostic hysteroscopy in women at risk of HNPCC., Methods: Fifty-seven women with mismatch repair gene mutations (n = 11) or Amsterdam II criteria (n = 46) were followed-up prospectively from January 1999 to March 2005. Flexible hysteroscopy was performed once a year. The endometrium was sampled routinely., Results: Of 91 attempted hysteroscopies, 10 failed. The endometrial mucosa appeared normal in 34 cases. Polyps were seen in 12 cases, atrophy in 11, hypertrophy in 10, and fibroids in 7; two hysteroscopies suspected malignancy. A micropolypoid appearance was visualized during five hysteroscopies (5/81, 6%). Of the 86 endometrial biopsy attempts, 64 were successful and showed atrophy (n = 14), proliferation (n = 12), secretion (n = 27), polyps (n = 6), simple hyperplasia without atypia (n = 3), or cancer (n = 2). Micropolypoid appearance was not associated with a specific histological pattern. Operative hysteroscopy was done in 24 cases; in two patients with apparently benign focal lesions the results showed simple hyperplasia without atypias. Five patients underwent hysterectomy (simple hyperplasia without atypias, n = 2; endometrioid adenocarcinoma, n = 2; or secretory mucosa, n = 1). This study led to diagnosis of endometrial simple hyperplasia in 6% of cases and of cancer in 3%., Conclusions: In patients at risk of HNPCC, hysteroscopy appears feasible to screen endometrial pathology. Two cancers have been diagnosed over 91 patient-years at risk. Hysteroscopy should be compared to sonography as a screening tool in women at risk of HNPCC.

Background: Peroperative identification of malignancy is crucial to management planning for ovarian cysts. The aim of this study was to evaluate the performance of laparoscopy in identifying malignant ovarian cysts., Methods: Patients undergoing laparoscopy for ovarian cysts from 1998 to 2001 were enrolled prospectively. Physical findings, Doppler ultrasonography, and serum CA 125 served to compute two risk-of-malignancy indexes (RMI-1 and RMI-2), and laparoscopy findings served to categorize lesions as benign, possibly malignant, or malignant. Frozen sections were examined as needed. Final histology was the reference., Results: Of 313 patients, 294 had benign cysts, six borderline lesions, and 13 malignancies. Sensitivity and specificity were respectively 84 and 93% for RMI-1, 92 and 80% for RMI-2, 100 and 99% for laparoscopy, 91 and 100% for frozen sections, and 100 and 100% for laparoscopy plus frozen sections, which had 100% negative predictive value. Six (1.8%) adverse events occurred., Conclusions: Laparoscopy reliably identifies ovarian cancer and borderline disease. Morbidity is low compared to oncologic surgery.

Background: The sentinel lymph node (SLN) could improve the staging of endometrial cancer., Case: In a patient with endometrial cancer, preoperative lymphoscintigraphy showed a highly radioactive SLN in the left external iliac chain and a radioactive SLN in the right external iliac chain and at the promontory. Intraoperative lymphatic mapping using blue dye and a hand-held gamma probe showed the same nodes, as well as a blue node near the vena cava. Selective removal of these nodes allowed detection of a micrometastasis in the left external iliac node. Pelvic node dissection was performed, and a micrometastasis was found in a left non sentinel iliac node., Conclusion: The presence in our patient of micrometastases in a SLN and in a non-SLN belonging to the same chain confirms the value of SLN detection for diagnosing tumor spread.

The INK4a/ARF locus encodes 2 cell cycle regulatory proteins: p16 and p14(ARF). P16 inhibits the activities of cdks, which maintain the retinoblastoma protein (pRb) in its active hypophosphorylated state. P14(ARF) blocks MDM2-induced p53 degradation and transactivational silencing. In this study, we investigated the expression of p16 and p14(ARF) in reference human urothelium and in 51 urothelial carcinomas (UCs) of all stages and grades, by reverse transcription-polymerase chain reaction (RT-PCR). Patterns of p14(ARF) and p16 expression were compared with each other and then with patterns of p53 and pRb protein expression, respectively, as determined by immunohistochemistry. P14(ARF) and p16 mRNAs were present at low levels or were undetectable in reference urothelia and in most superficial tumors, whereas they were present at high levels in a subset of tumors of advanced stage and high grade. The expression profiles of these 2 mRNAs were correlated in all but 4 cases, indicating that the 2 INK4a products may have nonredundant functions. Forty-six of the 51 tumors (90%) presented changes to or a lack of activation of the p14(ARF)-p53 pathway and were p53 positive (n = 10), p14(ARF) negative (n = 23), or both p53 positive and p14(ARF) negative (n = 13), suggesting that these 2 components of the pathway may be altered or nonactivated. Markedly high levels of p16 mRNA (n = 5) were associated with the absence of pRb expression, with the exception of 1 case in which the p16 gene contained a deletion mutation. A lack of p16 mRNA or low levels of this mRNA were associated with pRb detection in all but 1 case. In invasive UCs, the p16-pRb pathway, the p14(ARF)-p53 pathway, or in many cases both pathways were altered or not activated, demonstrating the involvement of these pathways in invasive bladder tumorigenesis.

Objective: To examine the kinetics of growth, differentiation and senescence of normal human urothelium in an organoid-like culture model., Materials and Methods: Micro-dissected normal human urothelium explants were grown on porous membranes pretreated with various matrix components. Between 5 and 30 days of culture, cell proliferation was assessed by BrdU incorporation. Differentiation was evaluated on the basis of cytokeratin (Ck) and uroplakin (UP) expression. Epidermal growth factor family mRNA expression was monitored during explant outgrowth. Senescence was assessed by measuring endogenous beta-galactosidase activity and p16(INK4a) mRNA expression., Results: Collagen IV was the most efficient matrix component for urothelial cell expansion. BrdU incorporation by urothelial cells was 5% between 15 and 30 days, corresponding to steady-state urothelium in vivo. Heparin-binding EGF (HB-EGF), Amphiregulin (AR) and Transforming Growth Factor alpha (TGF alpha) expression correlated with increased cell proliferation. UPII expression was stable throughout culture. P16(INK4a) mRNA expression and beta-galactosidase activity increased on day 25, giving signs of senescence., Conclusions: This model retains many characteristics of the urothelium in vivo. It can be used for pharmacological studies between 15 to 25 days and to study mechanisms such as wound healing, proliferation and senescence.

The sentinel lymph node (SLN) biopsy has been proposed for the cancers of the uterus in order to optimize the diagnosis of lymphatic metastases and micrometastases in early stage tumors. Patients with early invasive cervical (n = 8) or endometrial (n = 15) cancers were enrolled. A lymphoscintigraphy was carried out before the intervention. Intraoperative SLN identification was performed with blue dye combined to a handheld gamma probe detection. Non-sentinel pelvic nodes were separately cleared out. SLNs were examined with frozen sections, permanent sections with hematoxylin-eosin staining and further serial sections with immunohistochemistry if negative. Six cervical cancer patients and 13 endometrial cancer patients had a positive lymphoscintigraphy, showing in 5 patients extra-iliac SLN(s). The intraoperative detection was successful in 6 cervical cancer patients and 14 endometrial cancer patients. The higher detection rate was obtained with the isotopic method. Most of the SLNs were ilio-obturator. Four endometrial cancer patients had a lymphatic spread, only involving the SLN in each case. No false negative SLN has been noted. SLN biopsy appears feasible in cervical and endometrial cancers. This procedure could improve the lymphatic evaluation of these cancers.

The interaction between FasL on tumor cells and Fas on lymphocytes may represent a tumor immune escape mechanism. We explored FasL expression and function in human urinary bladder transitional cell carcinomas (TCCs). FasL expression was observed in situ in 45% of TCCs (n = 45) and was absent in normal urothelium (n = 20). A correlation existed between FasL expression and high tumor grade (0% in G1, 14% in G2, and 75% in G3; P < 0.0001) and stage (13% in superficial Ta-T1 versus 81% in invasive T2-T4; P < 0.0001). FasL function was shown by the ability of two FasL-positive primary culture TCC cell lines (established from two FasL-positive invasive TCCs) to induce Fas-mediated killing not only of conventional Fas-sensitive targets (such as Jurkat cells or phytohemagglutinin-lymphoblasts), but also of autologous T lymphocytes generated in a mixed lymphocyte tumor-cell culture. In addition, an association between FasL expression by TCC cells and activated caspase-8, -9, and -3 expression by interferon-gamma-producing CD8-positive tumor-infiltrating lymphocytes was observed in situ. Our results show a functional expression of TCC-expressed FasL that correlates with tumor progression. These results suggest that TCC-expressed FasL may induce apoptosis of anti-tumor T lymphocytes in vivo, providing new insights on the mechanisms involved in bladder TCC progression.

The p15 gene which encodes a cyclin-dependent kinase inhibitor, is located in the 9p21 chromosomal region that is frequently deleted in human bladder transitional cell carcinomas (TCCs). The aim of the present paper is to study the potential involvement of the p15 gene in the evolution of TCCs. p15 mRNA expression was investigated by semi-quantitative RT-PCR in a series of 75 TCCs, 13 bladder cell lines and 6 normal bladder urothelia by semi-quantitative RT-PCR. p15 was expressed in the normal urothelium but p15 mRNA levels were significantly decreased in 66% of the superficial (Ta-T1) TCCs (P = 0.0015). In contrast, in muscle-invasive (T2-T4) TCCs, p15 expression differed widely between samples. p16 mRNA levels were also studied and there was no correlation between p15 and p16 mRNA levels, thus indicating that the two genes were regulated independently. Lower p15 expression in superficial tumours did not reflect a switch from quiescence to proliferative activity as normal proliferative urothelial controls did not present decreased p15 mRNA levels relative to quiescent normal urothelia. We further investigated the mechanisms underlying p15 down regulation. Homozygous deletions of the p15 gene, also involving the contiguous p16 gene, were observed in 42% of the TCCs with decreased p15 expression. No hypermethylation at multiple methylation-sensitive restriction sites in the 5;-CpG island of p15 was encountered in the remaining tumours. Our data suggest that decreased expression of p15 may be an important step in early neoplastic transformation of the urothelium and that a mechanism other than homozygous deletions or hypermethylation, may be involved in p15 down regulation.

Post-transplantation lymphoproliferative disorders (PTLDs) have been reported after bone marrow and solid-organ transplantation. It might be of interest to know the origin of PTLDs, because it has been suggested that a donor origin could be related to a better prognosis. We studied five cases of PTLD in sex-mismatched allografted recipients by in situ hybridization technique for chromosome Y on isolated cells as well as on frozen and on routinely fixed and paraffin-embedded material. Two proved to be of donor origin, including the only case of PTLD arising in the graft, and three of recipient origin. The best results were obtained on isolated cells, but it must be emphasized that hybridization on tissue sections from frozen material or from material fixed in formalin or in formalin-acetic acid-alcohol and then paraffin embedded also gave good results. Hybridization after fixation in Bouin's liquid was not reliable. These results suggest that evaluation of the origin of PTLDs can easily be performed on routinely processed cytologic and histologic material.