L'immunothérapie dans le cancer épithélial de l'ovaire : entre espoir et réalité [Immunotherapy in epithelial ovarian carcinoma: hope and reality]

National audienceLe cancer épithélial de l'ovaire (CEO) présente un pronostic sombre avec depuis deux décennies des progrès très modestes en terme de gain de survie. L'immunologie, longtemps négligée dans le CEO, apparait maintenant central dans l'histoire naturelle de cette maladie cancéreuse. L'objet de cette revue est une mise au point sur l'état des connaissances sur l'immunologie dans le CEO et la potentielle place de l'immunothérapie dans son traitement futur. Matériel et méthodes : Interrogation de la base de données MedLine en utilisant les mots clés : " Ovarian carinoma, immunotherapy, T lymphocyte, regulator T lymphocyte, dendritic cells, macrophage, antigen, chemotherapy, surgery, clinical trials ". Nous avons retenu les éléments pertinents pour la compréhension de l'immunologie du CEO, de la place des traitements conventionnels et des stratégies d'immunothérapie à partir des articles de langue anglaise et française. Résultats : L'infiltration intra-tumorale par des cellules immunitaires conditionnent de manière majeure le pronostic du CEO. Les traitements traditionnels du CEO que sont la chirurgie et la chimiothérapie diminuent l'immunosuppression de la patiente. L'immunologie est l'une des composantes de l'action thérapeutique de la chimiothérapie et de la chirurgie. L'immunothérapie après des résultats décevants est à l'aube d'une révolution thérapeutique en cancérologie par l'arrivée de drogue ciblant le microenvironnement tumoral tolérogène. Conclusion : L'immunologie conditionne l'histoire naturelle du CEO. La modulation de l'immunosuppression associée à une stimulation de l'immunité antitumorale est probablement l'une des prochaines révolutions thérapeutiques en cancérologie. Summary: Introduction: Epithelial ovarian carcinoma (EOC) has a worst prognosis with little progress in term of survival for the last two decades. Immunology received little interest in EOC in the past, but now appears very important in the natural history of this cancer. This review is an EOC immunology state of art and focuses on the place of immunotherapy in future. Material and methods: A systematic review of published studies was performed. Medline baseline interrogation was performed with the following keywords: " Ovarian carinoma, immunotherapy, T lymphocyte, regulator T lymphocyte, dendritic cells, macrophage, antigen, chemotherapy, surgery, clinical trials ". Identified publications (English or French) were assessed for the understanding of EOC immunology and the place of conventional treatment and immunotherapy strategy. Results: Intratumoral infiltration by immune cells is a strong prognosis factor in EOC. Surgery and chemotherapy in EOC decrease imunosuppression in patients. The antitumoral immunity is a part of the therapeutic action of surgery and chemotherapy. Until now, immunotherapy gave some disappointing results, but the new drugs that target the tolerogenic tumoral microenvironnement rise and give a new hope in the treatment of cancer. Conclusion: Immunology controls the EOC natural history. The modulation of immunosuppressive microenvironment associated with the stimulation of antitumoral immunity could be the next revolution in the treatment of cancer

A quantitative deficiency in peripheral blood Vγ9Vδ2 cells is a negative prognostic biomarker in ovarian cancer patients.

International audienceVγ9Vδ2 cells are cytotoxic T cells that are able to recognize epithelial ovarian carcinoma (EOC) cells. Therefore, Vγ9Vδ2 cell-based adoptive transfer is an attractive therapy for EOC. However, the inefficient ex vivo expansion after specific stimulation of Vγ9Vδ2 cells from some patients and the relationships between Vγ9Vδ2 cells and clinical course of EOC are issues that remain to be clarified. Herein, peripheral blood mononuclear cells (PBMCs) from 60 EOC patients were stimulated with bromohydrin pyrophosphate (BrHPP) or zoledronate, which are specific agonists of Vγ9Vδ2 cells. The compounds differed in their efficacies to induce ex vivo Vγ9Vδ2 PBMC expansion, but 16/60 samples remained inefficiently expanded with both stimuli. Interestingly, the Vγ9Vδ2 cells in these low-responding PBMCs displayed before expansion (ex vivo PBMCs) an altered production of the pro-inflammatory cytokines IFN-γ and TNF-α, a decreased naive fraction and a reduced frequency. No evidence of an involvement of CD4(+)CD25(+)Foxp3(+) regulatory cells was observed. Importantly, our data also demonstrate that a Vγ9Vδ2 cell frequency of 0.35% or less in EOC PBMCs could be used to predict low responses to both BrHPP and zoledronate. Moreover, our data highlight that such a deficiency is not correlated with advanced EOC stages but is associated with more refractory states to platinum-based chemotherapy and is an independent predictor of shorter disease-free survival after treatment. These results are the first to suggest a potential contribution of Vγ9Vδ2 cells to the anti-tumor effects of chemotherapeutic agents and they strengthen interest in strategies that might increase Vγ9Vδ2 cells in cancer patients

Application des recommandations dans la prise en charge du cancer de l’endomètre en pratique clinique. Étude rétrospective bretonne

National audienceObjective - To assess the use of French Cancer Institute recommendations for the diagnosis and treatment of endometrial cancer. Methods - Retrospective observational study involving 137 patients with endometrial cancer between 2011 and 2013. Results - Both MRI and pathological assessment with correct report as recommended were used for 66.4% of patients with endometrial cancer. For patients with correct preoperative assessment, 44.9% of patients were uncorrectly classified and upgraded on final pathological analysis of hysterectomy concerning lymph node involvement risk. These patients did not have confident surgical assessment, according this risk. Conclusion - To improve relevance of preoperative assessment in endometrial cancer, radiological and pathological expertise is required. However, even performed optimally, preoperative assessment does not allow correct risk stratification of lymph node involvement in endometrial cancer. This ineffective stratification leads to propose sentinel lymph node biopsy with hysterectomy in case of preoperative low risk endometrial cancer assessment

Risk Factors of Inadequate Colposcopy After Large Loop Excision of the Transformation Zone: A Prospective Cohort Study

International audienceObjective: The aim of the study was to identify the risk factors of post-large loop excision of the transformation zone (LLETZ) inadequate colposcopy. Materials and Methods: From December 2013 to July 2014, a total of 157 patients who had a LLETZ performed for the treatment of high-grade intraepithelial lesion with fully visible cervical squamocolumnar junction were included. All procedures were performed using semicircular loops. The use of colposcopy made during each procedure was systematically documented. Dimensions and volume of LLETZ specimens were measured at the time of procedure, before formaldehyde fixation. All participants were invited for a follow-up colposcopy 3 to 6 months after LLETZ. Primary end point was the diagnosis of post-LLETZ inadequate colposcopy, defined by a not fully visible cervical squamocolumnar junction and/or cervical stenosis. Results: Colposcopies were performed in a mean (SD) delay of 136 (88) days and were inadequate in 22 (14%) cases. Factors found to significantly increase the probability of post-LLETZ inadequate colposcopy were a history of previous excisional cervical therapy [adjusted odds ratio (aOR) = 4.29, 95% CI = 1.12-16.37, p = .033] and the thickness of the specimen (aOR = 3.12, 95% CI = 1.02-9.60, p = .047). The use of colpos-copy for the guidance of LLETZ was statistically associated with a decrease in the risk of post-LLETZ inadequate colposcopy (aOR = 0.19, 95% CI = 0.04-0.80, p = .024) as the achievement of negative endocervical margins (aOR = 0.26, 95% CI = 0.08-0.86, p = .027). Conclusions: Although the risk of post-LLETZ inadequate colpos-copy is increased in patients with history of excisional therapy and with the thickness of the excised specimen, it could be reduced with the use of colposcopic guidance and the achievement of negative endocervical margins. L arge loop excision of the transformation zone (LLETZ) is a routine procedure worldwide, because it is the first-line treatment of high-grade intraepithelial lesion (HSIL) of the cervix. Quality criteria for optimal LLETZ include the completeness of excision with the achievement of negative margins, while producing the minimal excised volume and depth of excision to minimize subsequent obstetrical and neonatal morbidity. 1,2 Obtaining negative margins is important, because incomplete excision exposes women to a significant risk of posttreatment residual and/or recurrent disease, particularly when the lesion involves the endo-cervical canal. 3,4 However, this risk remains higher to the general female population, even when negative margins are achieved. Women who had had a LLETZ remain therefore exposed to a 3-to 4-fold increased risk of developing subsequent cervical cancer at least for 20 years. 5-8 Thus, prolonged and careful post-LLETZ follow-up is mandatory, whatsoever the margins status. For the last decade, the value of human papillomavirus testing has been demonstrated in this indication. Although a negative human papillomavirus test has now been admitted as the best test of cure for patients, colposcopy remains needed when this test is found to be positive. 9-12 Although being the key examination in this indication, the accuracy of colposcopy performed after previous excisional therapy of HSIL is however questionable because the healing process might result in changes in the appearance of the transformation zone (TZ). However, the main limitation of post-LLETZ colposcopic examination is the possibility of inadequate colposcopy due to the inability to visualize the entire TZ. Known risk factors for inadequate colposcopy include age, severity of lesion, and estrogen status of the patient. 13 However, inadequate colposcopy is also one of the main adverse effects of excisional therapies of the cervix, including LLETZ. 13 However, data on the precise risk factors for inadequate colposcopy after LLETZ are limited because most studies have focused on the sole risk of cervical stenosis without considering the position and visibility of the squamocolumnar junction. 14-17 This point is however crucial because it is clinically essential to identify how post-LLETZ inadequate colposcopy could be avoided, thus preserving the possibility for the follow-up of these women

Cancer de l’endomètre au stade pécoce : ganglion sentinelle ou curage pelvien ?

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Un cas d’hyperplasie myointimale idiopathique des veines mésentériques du côlon [A case of idiopathic myointimal hyperplasia of mesenteric veins]

National audienceThe idiopathic myointimal hyperplasia of mesenteric veins is a rare pathology, affecting recto-sigmoid and mimicking clinically an inflammatory chronic disease of the bowel. Only about fifteen cases have been reported in the literature. This lesion is characterized by a myointimal thickening of the mesenteric veins, without inflammatory infiltrate of the vascular wall, differentiating it from vasculitis. We present here the case of a 48-year-old man, in whom the diagnosis of ulcerative colitis then digestive vasculitis had first been raised

Quality of life and female sexual function after skinning vulvectomy with split-thickness skin graft in women with vulvar intraepithelial neoplasia or vulvar Paget disease.

International audienceOBJECTIVE: Vulvar intraepithelial neoplasia (VIN) and vulvar Paget disease are managed with either vulvectomy, destructive treatments (laser, antimitotic drugs) or immunostimulants. All these options are associated with functional complications. The purpose of this study was to evaluate the surgical technique consisting of skinning vulvectomy with split-thickness skin graft, and its effect on overall quality of life and sexual function. METHODS: A retrospective study was conducted on thirteen patients who underwent skinning vulvectomy with split-thickness skin graft between 1999 and 2009. Overall quality of life and sexual function were assessed with the Medical Outcome Study Short Form 36 (MOS SF-36) and Female Sexual Function Index (FSFI), respectively. RESULTS: The median age of patients was 54 (range: 33-77) years. Three patients had Paget disease and 10 patients had VIN lesions. The excision margins were clear in 46% of cases. The incidence of occult cancer was 31%. The mean follow-up period was 77 (±35) months. Four patients experienced a relapse of their intraepithelial disease. The mean disease-free survival was 58 (±44) months. There was no significant difference in MOS SF-36 scores between the study population and the general population. The patients assessed with the FSFI regained normal sexual function after the surgical procedure. CONCLUSION: Skinning vulvectomy with split-thickness skin graft is a feasible technique yielding good results in terms of quality of life and sexual function. It enables occult cancer to be diagnosed in patients with VIN or Paget disease

Les nouveaux profils moléculaires dans le cancer de l’ovaire peuvent-ils modifier les stratégies thérapeutiques ?

National audienceEpithelial ovarian cancer (EOC) affects 4500 women a year in France, with a survival of 30% at 5 years. Treatment is based on extensive surgery and chemotherapy. Around 15% of EOCs are due to genetic mutation predisposition essentially with mutated BRCA1 and BRCA2 genes. Four histological subtypes are described (serous, endometrioid, and mucinous cells to clear), corresponding to different carcinogenesis and distinct molecular mutations. High-grade serous EOCs have a mutation of the BRCA genes in 20-30% of cases. This mutation causes a deficit of repair by homologous recombination of DNA in case of double strand break, allowing greater sensitivity to platinum salts and the use of PARP inhibitors, a protein involved in the repair of single-strand breaks of DNA. PARP inhibitors have shown efficacy in patients mutated BRCA but this effectiveness remains to be demonstrated in patients without congenital mutation, but with acquired BRCAness profile EOC. The BRCAness profile is defined by a tumor having a defect in DNA repair counterpart (not limited to BRCA mutation). Molecular definition of BRCAness is still not consensual but is necessary for the use of PARP inhibitors. Gene expression analyses have identified four subgroups of high-grade serous CEO: mesenchymal, proliferative, differentiated and immunoreactive. These four subtypes, not mutually exclusive, although correlated with prognosis, are not yet used in clinical routine

Are preoperative histology and MRI useful for classification of endometrial cancer risk?

International audienceBackground: The 2010 guidelines of the French National Cancer Institute (INCa) classify patients with endometrial cancer into three risk groups for lymph node invasion and recurrence on the basis of MRI and histological analysis of an endometrial specimen obtained preoperatively. The classification guides therapeutic choices, which may include pelvic and/or para-aortic lymphadenectomy. The purpose of this study was to evaluate the diagnostic performance of preoperative assessment to help identify intermediate- or high-risk patients requiring lymphadenectomy. Methods: The study included all patients who underwent surgery for endometrial cancer between January 2010 and December 2013 at either Rennes University Hospital or Vannes Regional Hospital. The criteria for eligibility included a preoperative assessment with MRI and histological examination of an endometrial sample. A histological comparison was made between the preoperative and surgical specimens. Results: Among the 91 patients who underwent a full preoperative assessment, the diagnosis of intermediate-or high-risk endometrial cancer was established by MRI and histology with a sensitivity of 70 %, specificity of 82 %, positive predictive value (PPV) of 87 %, negative predictive value (NPV) of 61 %, positive likelihood ratio (LR+) of 3.8 and negative likelihood ratio (LR-) of 0.3. The risk group was underestimated in 32 % of patients and overestimated in 7 % of patients. MRI underestimated endometrial cancer stage in 20 % of cases, while endometrial sampling underestimated the histological type in 4 % of cases and the grade in 9 % of cases. Conclusion: The preoperative assessment overestimated or underestimated the risk of recurrence in nearly 40 % of cases, with errors in lesion type, grade or stage. Erroneous preoperative risk assessment leads to suboptimal initial surgical management of patients with endometrial cancer