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6000 Background: The role of secondary cytoreductive surgery in recurrent ovarian cancer (ROC) has been under debate for decades. A recent trial in unselected patients (pts) failed to show an OS benefit. Methods: Pts with ROC and 1st relapse after 6+ months (mos) platinum-free interval (TFIp) were eligible if they presented with a positive AGO-score (PS ECOG 0, ascites ≤500 ml, and complete resection at initial surgery) and were prospectively randomized to second-line chemotherapy alone vs. cytoreductive surgery followed by the same chemotherapy; platinum combination therapy was recommended. OS was primary endpoint in this superiority trial. Results: 407pts were randomized 2010-2014. The TFIp exceeded 12 mos in 75% of pts. 206 pts were allocated to the surgery arm of whom finally 187 (91%) were operated. A complete resection was achieved in 75%; almost 90% in both arms received a platinum-containing second-line chemo. Primary endpoint analysis showed median OS of 53.7 mos with and 46.2 mos without surgery (HR 0.76, 95%CI 0.59-0.97, p=0.03); median PFS was 18.4 and 14 mos (HR: 0.66, 95%CI 0.54-0.82, p

The LACC (Laparoscopic Approach to Cervical Cancer Trial) study, released in 2018, described oncological findings in favour of open surgery compared to the minimally invasive pathway in the management of early stage cervical cancers. Our aim was to assess the impact of this study on surgical practices in France.Online questionnaire, consisting of 13 questions addressed to gynecology oncology french society (SFOG) surgeons.Forty questionnaires were collected. The median annual number of radical hysterectomy was 5 (0-20). Prior to the study, 92.5 % of cervical cancer patients had radical hysterectomy by minimally invasive surgery. In case of laparoscopy or robot, the uterine manipulator was used in 67.6 % and the colpotomy was performed intra-abdominally (78.4 %). After the LACC study, 60 % changed their practice. Open surgery was favored by 75 % of those who modified their practice. Among those continuing to perform minimally invasive surgeries, the manipulator and the intracorporeal colpotomy were discontinued. One-third of surgeons have changed their surgical practice for endometrial cancer in parallel.The results of the LACC study led to a change in surgical practices with an increase in open surgery and a stop in the use of the uterine manipulator and the laparoscopic/robotic intracorporeal colpotomy in the surgical management of early stage of cervical cancer.

Introduction. Lymph node metastasis is determinant in the prognosis and treatment of endometrioid endometrial cancer (EEC) but the risk–benefit balance of surgical lymph node staging remains controversial. Objective. Describe the pathways associated with lymph node metastases in EEC detected by whole RNA sequencing. Methods. RNA-sequencing was performed on a retrospective series of 30 non-metastatic EEC. N+ and N− patients were matched for tumoral size, tumoral grade and myometrial invasion. Results. Twenty-eight EECs were analyzable (16 N+ and 12 N−). Bioinformatics Unsupervised analysis revealed three patterns of expression, enriched in N+, mix of N+/N− and enriched in N−, respectively. The cluster with only N+ patient overexpressed extra cellular matrix, epithelial to mesenchymal and smooth muscle contraction pathways with respect to the N− profile. Differential expression analysis between N+ and N− was used to generate a 54-genes signature with an 87% accuracy. Conclusion. RNA-expression analysis provides a basis to develop a gene expression-based signature that could pre-operatively predict lymph node invasion.

Background Epithelioid peritoneal malignant mesothelioma (EPMM) is the most common subtype of this aggressive tumor. We compared two antibodies against PD-L1, a recent theranostic biomarker, and evaluated the prognostic value of PD-L1 expression by mesothelial and immune cells in EPMM. Methods Immunohistochemistry was performed on 45 EPMM. Clinical and pathological data were extracted from the RENAPE database. Using E1L3N and SP142 clones, inter-observer agreement, PD-L1 expression by mesothelial and immune cells and inter-antibody agreement were evaluated. The prognostic relevance of PD-L1 expression was evaluated in 39 EPMM by univariate and multivariate analysis of overall survival (OS) and progression-free survival (PFS). Results Inter-observer agreement on E1L3N immunostaining was moderate for mesothelial and immune cells, and fair for mesothelial and poor for immune cells using SP142. Using E1L3N, 31.1% of mesothelial and 15.6% of immune cells expressed PD-L1, and 22.2% of mesothelial and 26.7% of immune cells using SP142. Inter-antibody agreement was moderate. In most positive cases, 1–5% of tumor cells were positive. Using E1L3N, PD-L1 expression by lymphocytes was associated with better OS and PFS by both univariate and multivariate analysis. Cytoreductive surgery with hyperthermic intraperitoneal chemotherapy predicted better prognosis than other treatments. Solid subtype was an independent prognostic factor for worse OS. Conclusion E1L3N appeared easier to use than SP142 to evaluate PD-L1 expression. A minority of EPMM expressed PD-L1, and only a few cells were positive. PD-L1 expression by immune cells evaluated with E1L3N was an independent prognostic factor in EPMM.

Resume Le traitement du cancer epithelial avance de l’ovaire est multidisciplinaire faisant intervenir des equipes de chirurgie et d’oncologie medicale, experimentees dans la prise en charge de cette maladie, en suivant des criteres de qualite publies par les societes savantes. La strategie doit etre validee en reunion de concertation pluridisciplinaire (RCP) avant tout traitement. Le bilan pretherapeutique comporte le diagnostic histologique, l’evaluation de l’extension tumorale (bilan biologique, marqueurs, imagerie, cœlioscopie), l’evaluation de l’etat general (operabilite), dans le but de repondre a la question de la faisabilite d’une chirurgie d’exerese premiere. Le traitement standard suppose une exerese chirurgicale complete des lesions par laparotomie mediane, puis une chimiotherapie adjuvante a base de carboplatine et paclitaxel, six cycles avec la possibilite d’y associer du bevacizumab lors du traitement adjuvant et en entretien. Si une chirurgie complete d’emblee n’est pas envisageable a la suite du bilan initial, une chirurgie d’intervalle peut etre envisagee apres realisation de trois a quatre cures de chimiotherapie d’induction.

As the presence of second inferior vena cava may alter the extent of para‐aortic lymphadenectomy, early preoperative imaging diagnosis is of great significance to avoid intraoperative difficulties.

Lymph node metastasis is a principal prognostic factor for the treatment of endometrial cancer. Added value of para-aortic lymphadenectomy to only pelvic lymphadenectomy for intermediate/high-risk endometrial cancer patients remains controversial. A systematic review and meta-analysis was performed to assess the impact of combined pelvic and para-aortic lymph node dissection (PPALND) compared to only pelvic lymph node dissection (PLND) on survival outcomes of intermediate and/or high-risk patients. The systematic review and meta-analysis adhered to the PRISMA guidelines for meta-analyses of interventional studies. Pubmed, Scopus, EMBASE and Cochrane were searched up to April 20, 2018. Included studies were those comparing high-risk endometrial cancer patients that had performed pelvic and para-aortic lymph node dissection (PPALND) vs. only pelvic lymph node dissection (PLND) apart from standard procedure (total hysterectomy with bilateral salpingo-oophorectomy, TAHBSO). Primary outcomes of the study were overall survival and disease-free survival rates. Methodological quality of the included studies was assessed using the ROBINS-I tool. Overall quality of the evidence for the primary and secondary outcomes was evaluated as per GRADE guideline using the GRADE pro GD tool. There were 13 studies identified with 7349 patients included. All studies were retrospective observational as no RCTs or prospective studies adhering to inclusion criteria were retrieved. Combined pelvic and para-aortic lymphadenectomy was associated with 46% decreased risk for death (HR 0.54, 95% CI 0.35–0.83, I2 = 62.1%) and 49% decreased risk for recurrence (HR 0.51, 95% CI 0.28–0.93). It was also associated with increased 5-year OS rate (RR 1.13, 95% CI 1.04–0.24, I2 = 57.3%) and increased 5-year DFS rate (RR 1.23, 95% CI 1.14–1.31, I2 = 85.5) compared with only pelvic lymphadenectomy. Combined pelvic and para-aortic lymphadenectomy is associated with improved survival outcomes compared with only pelvic lymphadenectomy in women with intermediate/high-risk endometrial cancers. Further prospective studies should be performed.

SUCCOR study: an international European cohort observational study comparing minimally invasive surgery versus open abdominal radical hysterectomy in patients with stage IB1 cervical cancer FREE http://orcid.org/0000-0002-1908-3251Luis Chiva1, Vanna Zanagnolo2, Denis Querleu3, Nerea Martin- Calvo4, Juan Arévalo-Serrano5, Mihai Emil Căpîlna6, Anna Fagotti7, Ali Kucukmetin8, Constantijne Mom9, Galina Chakalova10, Shamistan Aliyev11, Mario Malzoni12, http://orcid.org/0000- 0001-5809-3535Fabrice Narducci13, Octavio Arencibia14, Francesco Raspagliesi15, Tayfun Toptas16, David Cibula17, Dilyara Kaidarova18, http://orcid.org/0000-0001-6763-9720Mehmet Mutlu Meydanli19, Mariana Tavares20, Dmytro Golub21, http://orcid.org/0000-0003-3140-4772Anna Myriam Perrone22, Robert Poka23, Dimitrios Tsolakidis24, Goran Vujić25, http://orcid.org/0000-0001-8935- 0311Marcin A Jedryka26, Petra L M Zusterzeel27, Jogchum Jan Beltman28, Frederic Goffin29, Dimitrios Haidopoulos30, Herman Haller31, Robert Jach32, Iryna Yezhova33, Igor Berlev34, Margarida Bernardino35, Rasiah Bharathan36, Maximilian Lanner37, Minna M Maenpaa38, http://orcid.org/0000-0002-4403-3707Vladyslav Sukhin39, Jean-Guillaume Feron40, Robert Fruscio41, 42, Kersti Kukk43, Jordi Ponce44, Jose Angel Minguez45, http://orcid.org/0000-0002-9618- 5606Daniel Vázquez-Vicente45, Teresa Castellanos45, Enrique Chacon46 and http://orcid.org/0000-0002-9700-0853Juan Luis Alcazar47 On behalf of the SUCCOR study Group Author affiliations Abstract Background Minimally invasive surgery in cervical cancer has demonstrated in recent publications worse outcomes than open surgery. The primary objective of the SUCCOR study, a European, multicenter, retrospective, observational cohort study was to evaluate disease-free survival in patients with stage IB1 (FIGO 2009) cervical cancer undergoing open vs minimally invasive radical hysterectomy. As a secondary objective, we aimed to investigate the association between protective surgical maneuvers and the risk of relapse. Methods We obtained data from 1272 patients that underwent a radical hysterectomy by open or minimally invasive surgery for stage IB1 cervical cancer (FIGO 2009) from January 2013 to December 2014. After applying all the inclusion-exclusion criteria, we used an inverse probability weighting to construct a weighted cohort of 693 patients to compare outcomes (minimally invasive surgery vs open). The first endpoint compared disease-free survival at 4.5 years in both groups. Secondary endpoints compared overall survival among groups and the impact of the use of a uterine manipulator and protective closure of the colpotomy over the tumor in the minimally invasive surgery group. Results Mean age was 48.3 years (range ; 23–83) while the mean BMI was 25.7 kg/m2 (range ; 15–49). The risk of recurrence for patients who underwent minimally invasive surgery was twice as high as that in the open surgery group (HR, 2.07 ; 95% CI, 1.35 to 3.15 ; P=0.001). Similarly, the risk of death was 2.42-times higher than in the open surgery group (HR, 2.45 ; 95% CI, 1.30 to 4.60, P=0.005). Patients that underwent minimally invasive surgery using a uterine manipulator had a 2.76-times higher hazard of relapse (HR, 2.76 ; 95% CI, 1.75 to 4.33 ; P

International audience; Purpose: Psammocarcinoma (PK) is a rare disease of unknown origin. We aimed to report the characteristics, management and survival of patients operated on for PK within the French Network for Rare Peritoneal Malignancies (RENAPE) expert centers.Patients and methods: All consecutive cases of PK operated within all 26 RENAPE centers between 1997 and 2018 were retrospectively analyzed.Results: Twenty-five patients were identified. The median age was 53 years [range 17–78]. None of the patients had extra peritoneal metastases at diagnosis. A median of 6 cycles of carboplatin-based systemic chemotherapy was delivered in 52% preoperatively (n = 13) and 56% postoperatively (n = 14); associated with placlitaxel for 12 patients. All patients were operated on. The median PCI was 23 [0–33]. Eighty-four percent had a complete cytoreductive surgery through digestive (n = 7), spleen (n = 3), pancreas (n = 1) resections and/or multiple peritonectomies (n = 11). Five patients (20%) had intraperitoneal chemotherapy. Morbidity (Dindo-Clavien ≥3) was 12%. No postoperative death occurred. After a median follow-up of 42 months (range [2–194]), the median overall (OS) and progression-free (DFS) survival times were respectively 128 months and 31 months. Eighteen patients recurred (72%), mainly in the peritoneum (n = 16). Four of them (22%) were reoperated. The 5 and 10-year DFS rates were both 20.3%. The 5 and 10-year OS rates were 62% and 51.7%, respectively. A complete cytoreductive surgery was associated with a better OS and DFS in a univariate analysis.Conclusion: Complete cytoreductive surgery is the cornerstone of the PK's management as a primary treatment. Recurrence remains common and new adjuvant strategies seem needed.

Purpose: Uterine leiomyosarcoma, which accounts for 7% of all soft-tissue sarcomas and 1%–3% of all uterine malignancies, is an aggressive tumor responsible for a significant proportion of uterine cancer–related deaths. While Federation Internationale des Gynaecologistes et Obstetristes (FIGO) stage is the most important prognostic factor, metastatic and relapse rates at stage I exceed 50% so it is currently impossible to predict the clinical outcome of stage I leiomyosarcomas. In 2010, our team published a transcriptomic signature composed of 67 genes related to chromosome biogenesis, mitosis control, and chromosome segregation. It has demonstrated its prognostic value in many cancer types and was recently successfully applied to formalin-fixed, paraffin-embedded sarcomas by NanoCind on NanoString technology, making another step forward toward its use in routine practice. Experimental Design: Sixty uterine leiomyosarcomas at any stage, including 40 localized in the uterus (stage I), were analyzed with the NanoCind (CINSARC with NanoString) signature. Its prognostic value was evaluated for overall survival and relapse-free survival and compared in multivariate analysis with other prognostic markers like FIGO staging and genomic index. Results: The NanoCind signature was able to split the heterogeneous group of uterine leiomyosarcomas of any stage including stage I into two distinct groups with different relapse-free survival and overall survival. These results were validated on an independent cohort of uterine leiomyosarcomas in The Cancer Genome Atlas consortium. Conclusions: The NanoCind signature is a powerful prognosticator that outperforms FIGO staging and the genomic index. The CINSARC signature is platform independent and “ready to use” and should now be used for randomization in future therapeutic trials.

BackgroundPelvic exenteration and its reconstructive techniques have been associated with high postoperative morbidity and a negative impact on patient quality of life. The aim of our study was to compare postoperative complications and quality of life in patients undergoing continent compared with non-continent urinary diversion after pelvic exenteration for gynecologic malignancies.MethodsWe designed a multicenter study of patients from 10 centers who underwent an anterior or total pelvic exenteration with urinary reconstruction for histologically confirmed persistent or recurrent gynecologic malignancy after previous treatment with radiotherapy. From January 2005 to September 2008, we included patients retrospectively, and from September 2008 to May 2009, patients were included prospectively which allowed collection of quality of life data. Demographic, surgical, and follow-up data were analyzed. Postoperative complications were classified according to the Clavien–Dindo classification. Quality of life was assessed using the European Organization for Research and Treatment of Cancer (EORTC)-QLQ-C30 (V.3.0) and EORTC-QLQ-OV28 quality of life questionnaires. We compared patients who underwent a continent urinary diversion with those who underwent a non-continent reconstruction.ResultsWe included 148 patients, 92 retrospectively and 56 prospectively. Among them, 77.4% had recurrent disease and 22.6% persistent disease after the primary treatment. In 70 patients, a urinary continent diversion was performed, and 78 patients underwent a non-continent diversion. Median age of the continent and incontinent groups was 53.5 (range 33–78) years and 57 (26-79) years, respectively. There were no significant differences between the continent and non-continent groups in median length of hospitalization (28.5 vs 26 days, P=0.19), postoperative grade III–IV complications (42.9% vs 42.3%, P=0.95), complications needing surgical (27.9% vs 34.6%, P=0.39) or radiological (14.7% vs 12.8%, P=0.74) intervention, and complication type (digestive (23.2% vs 16.7%, P=0.32) and urinary (15.9% vs 16.7%, P=0.91)). There were no significant differences between the groups in global health, global quality of life, and body image perception scores 1 year after surgery.ConclusionContinent and incontinent urinary reconstructions are equivalent in terms of postoperative complications and quality of life scores.

The large number of proteins found in the human body implies that a drug may interact with many proteins, called off-target proteins, besides its intended target. The PatchSearch web server provides an automated workflow that allows users to identify structurally conserved binding sites at the protein surfaces in a set of user-supplied protein structures. Thus, this web server may help to detect potential off-target protein. It takes as input a protein complexed with a ligand and identifies within user-defined or predefined collections of protein structures, those having a binding site compatible with this ligand in terms of geometry and physicochemical properties. It is based on a non-sequential local alignment of the patch over the entire protein surface. Then the PatchSearch web server proposes a ligand binding mode for the potential off-target, as well as an estimated affinity calculated by the Vinardo scoring function. This novel tool is able to efficiently detects potential interactions of ligands with distant off-target proteins. Furthermore, by facilitating the discovery of unexpected off-targets, PatchSearch could contribute to the repurposing of existing drugs. The server is freely available at http://bioserv.rpbs.univ-paris-diderot.fr/services/PatchSearch.

The European Society of Gynaecologic Oncology (ESGO) guidelines cover the whole field of common clinical situations in gynecologic oncology. Their elaboration follows a strict process including a systematic review of the literature, the setting up of a group of expert on the basis of scientific production, geographical balance, and multidisciplinarity, and an external review by users and patients. The recommendations for the management of vulvar cancer were elaborated in 2015 and published in 2017. They are available in open access on the ESGO website, and can be incorporated in clinical practice using the free ESGO guidelines smartphone application. This review is a selection of the sections addressing the diagnostic and strategical aspects of the management of lymph nodal disease in vulvar cancer. An additional review of the recent literature published since 2015 has been carried out. The management of nodal disease in vulvar cancer encompasses a diagnostic and a therapeutic component. Clinical and imaging assessment still play a major role, whilst the identification of the sentinel node is currently a mainstay of assessment of the nodal status in early vulvar cancer. The therapeutic component is based on the rational use of full lymph node dissection and (chemo)radiation.

1594 Background: Risk-reducing salpingo-oophorectomy (RRSO) is the gold standard in surgical prophylaxis of pelvic high-grade serous carcinoma (HGSC) for women at risk of breast/ovarian cancer. Due to significant adverse effects of early oophorectomy, 20-30% of women delay or deny performing this operation. Recent data highlight the fallopian origin of most pelvic HGSC, especially its fimbrial part. Thus, we suggested a new two-step risk-reducing procedure: the radical fimbriectomy (RF) with delayed oophorectomy (DO) (Leblanc et al Gyn Oncol 2011), leading to the current RF/DO Phase 2 study. We present the definitive results on primary and secondary objectives of this trial. Methods: BRCA1/2 carriers or any women with a documented familial risk of breast/ovarian cancer were first counseled to perform a classical laparoscopic RRSO. If they denied, they were offered to enter the RF/DO study. All specimens were submitted to the SEE-FIM pathological protocol. Pathological data along with all intra- and 30-day and beyond post-operative adverse events were prospectively recorded. Follow-up consisted in an annual clinical breast and gynecological examination, with tumor markers and hormonal status assessment. Primary endpoint was the rate of pelvic serous carcinoma. Secondary endpoints were procedure morbidity, rates of tubal abnormalities, breast cancer, secondary oophorectomy. Results: From January 2012 to October 2014, 121 RF were performed: 120 by laparoscopy, 1 laparotomy (concurrent myomectomy). An occult neoplasia was found in 3 cases with 1 invasive HGSC. Intraoperative complications were two grade1 bleedings without transfusion with no grade ≥3 early post-operative or delayed complication. With a median follow-up of 5.3 years (0.2 -7.6), no patient developed any pelvic HGSC, 21 patients developed a breast cancer (3 de novo, 18 recurrences/contralateral.). 1 cancer-free BRCA1-mutated lady delivered safe twins, after an uneventful post-RF pregnancy obtained with assisted reproductive technology (ART). Overall, 29 women underwent DO (by choice: 12 or menopause: 17) resulting in grade 3b complication in 1 case, but no pathological abnormality. Conclusions: RF/DO appears as a safe, well tolerated and effective procedure in terms of occult neoplasia detection. A successful pregnancy with ART was possible after radical fimbriectomy. Longer follow-up and larger cohort are necessary to confirm its efficacy in terms of ovarian cancer prophylaxis. Clinical trial information: NCT01608074.

Background: There is a lack of information as to which molecular processes, present at diagnosis, favor tumour escape from standard-of-care treatments in cervical cancer (CC). RAIDs consortium (www.raids-fp7.eu), conducted a prospectively monitored trial, [BioRAIDs (NCT02428842)] with the objectives to generate high quality samples and molecular assessments to stratify patient populations and to identify molecular patterns associated with poor outcome. Methods: Between 2013-2017, RAIDs collected a prospective CC sample and clinical dataset involving 419 participant patients from 18 centers in seven EU countries. Next Generation Sequencing has so far been carried out on a total of 182 samples from 377 evaluable (48%) patients, allowing to define dominant genetic alterations. Reverse phase protein expression arrays (RPPA) was applied to group patients into clusters. Activation of key genetic pathways and protein expression signatures were tested for associations with outcome. Findings: At a median FU of 22 months, progression-free survival rates of this FIGO stage IB1-IV population, treated predominantly (87%) by chemoradiation, were 65*4% [CI95%: 60*2-71.1]. Dominant oncogenic alterations were seen in PIK3CA (40%), while dominant suppressor gene alterations were seen in KMT2D (15%) and KMT2C (16%). Cumulative frequency of loss-of-function (LOF) mutations in any epigenetic modulatorgene alteration was 47% and it was associated with PIK3CA gene alterations in 32%. Patients with tumours harbouring alterations in both pathways had a significantly poorer PFS. A new finding was the detection of a high frequency of gains of TLR4 gene amplifications (10%), as well as amplifications, mutations, and non-frame-shift deletions of Androgen receptor (AR) gene in 7% of patients. Finally, RPPA protein expression analysis defined three expression clusters. Interpretation: Our data suggests that patient population may be stratified into four different treatment strategies based on molecular markers at the outset. Funding: European Union's Seventh Program grant agreement No 304810. Declaration of Interest: All authors declared: No conflict of interest. Ethical Approval: Ethical review was conducted according to national requirements and in accordance with the Declaration of Helsinki. All tumour and serum samples and clinical data were registered in a common database using a unique barcode system assuring data privacy.

Mesenchymal neoplasms of the uterus (corpus and cervix) encompass a heterogeneous group of tumors with differing morphologies, immunophenotypes and molecular alterations. With the advent of modern molecular techniques, such as next generation sequencing, newly defined genetic abnormalities are being reported in this group of neoplasms. Herein we report the clinicopathological and molecular features of a series of 13 spindle cell sarcomas of the uterus and vagina (10 cervix, 2 uterine corpus, 1 vagina) with morphology resembling fibrosarcoma. After targeted RNA-sequencing, dual FISH fusion and array-CGH analysis, 7 of 13 tumors exhibited NTRK rearrangements (6 TPM3-NTRK1 and 1 EML4-NTRK3) and 3 a COL1A1-PDGFB fusion; in the other 3 neoplasms, all of which were positive with S100 (2 diffuse, 1 focal), we identified no rearrangement. All the NTRK fusion-positive sarcomas were located in the cervix and exhibited diffuse staining with Trk while all the other neoplasms were negative. CD34 was diffusely positive in all 3 of the COL1A1-PDGFB fusion sarcomas. The latter molecular abnormality is identical to that commonly found in dermatofibrosarcoma protuberans and has not been reported previously in uterine mesenchymal neoplasms. We suggest that uterine sarcomas with a morphology resembling fibrosarcoma (and in which leiomyosarcoma and the known molecularly confirmed high-grade endometrial stromal sarcomas have been excluded) can be divided into 3 groups:- an NTRK fusion group, a COL1A1-PDGFB fusion group and a group containing neither of these molecular abnormalities which, on the basis of positive staining with S100, could be tentatively classified as malignant peripheral nerve sheath tumor, although additional molecular studies may identify specific genetic alterations necessitating a nomenclature change. We suggest a diagnostic algorithm when reporting such neoplasms. Identification of these newly described fusion-associated sarcomas is important given the potential for targeted treatments.

Despite efforts during the past decades, loop modeling remains a difficult part of protein structure modeling. Several approaches have been developed in the framework of crystal structures. However, for homology models, the modeling of loops is still far from being solved. We propose DaReUS-Loop, a data-based approach that identifies loop candidates mining the complete set of experimental structures available in the Protein Data Bank. Candidate filtering relies on local conformation profile-profile comparison, together with physico-chemical scoring. Applied to three different template-based test sets, DaReUS-Loop shows significant increase in the number of high-accuracy loops, and significant enhancement for modeling long loops. A special advantage is that our method proposes a prediction confidence score that correlates well with the expected accuracy of the loops. Strikingly, over 50% of successful loop models are derived from unrelated proteins, indicating that fragments under similar constraints tend to adopt similar structure, beyond mere homology.

International audience; BACKGROUND:Pelvic exenteration remains one of the most mutilating procedures, with important postoperative morbidity, an altered body image, and long-term physical and psychosocial concerns. This study aimed to assess quality of life (QOL) during the first year after pelvic exenteration for gynecologic malignancy performed with curative intent.METHODS:A French multicentric prospective study was performed by including patients who underwent pelvic exenteration. Quality of life by measurement of functional and symptom scales was assessed using the European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30 (version 3.0) and the EORTC QLQ-OV28 questionnaires before surgery, at baseline, and 1, 3, 6, and 12 months after the procedure.RESULTS:The study enrolled 97 patients. Quality of life including physical, personal, fatigue, and anorexia reported in the QLQ-C30 was significantly reduced 1 month postoperatively and improved at least to baseline level 1 year after the procedure. Body image also was significantly reduced 1 month postoperatively. Global health, emotional, dyspnea, and anorexia items were significantly improved 1 year after surgery compared with baseline values. Unlike younger patients, elderly patients did not regain physical and social activities after pelvic exenteration.CONCLUSIONS:Therapeutic decision on performing a pelvic exenteration can have a severe and permanent impact on all aspects of patients' QOL. Deterioration of QOL was most significant during the first 3 months after surgery. Elderly patients were the only group of patients with permanent decreased physical and social function. Preoperative evaluation and postoperative follow-up evaluation should include health-related QOL instruments, counseling by a multidisciplinary team to cover all aspects concerning stoma care, sexual function, and long-term concerns after surgery.

Ovarian small cell carcinoma of the hypercalcemic type (SCCOHT)/ovarian rhabdoid tumor is a rare and highly malignant tumor that typically occurs in young women. Up until now the diagnosis has been made on the basis of morphology without any specific immunohistochemical (IHC) markers. However, several authors have shown recently that SCCOHTs are characterized by inactivation of the SMARCA4 gene (encoding the BRG1 protein) resulting in a loss of BRG1 protein expression in IHC. We evaluated BRG1 and INI1 expression in 12 SCCOHTs and in a series of 122 tumors that could mimic SCCOHT morphologically: 9 juvenile granulosa cell tumors, 47 adult granulosa cell tumors, 33 high-grade ovarian serous carcinomas, 9 desmoplastic round cell tumors, 13 Ewing sarcomas (5 from the pelvis and 8 from soft tissues), 1 round cell sarcoma associated with CIC-DUX4 translocation from soft tissue (thigh), 1 case of high-grade endometrial stromal sarcoma of the ovary, and 9 melanomas. Forty-four adult granulosa cell tumors were interpretable by IHC. All 12 SCCOHTs were devoid of BRG1 expression and expressed INI1. All other interpretable 119 tumors showed BRG1 nuclear positivity, with variable staining proportions, ranging from 10% to 100% of positive cells (mean: 77%, median: 80%), variable intensities (weak: 5%, moderate: 37%, strong: 58%), and distributions: diffuse in 82 cases (70%) and heterogenous in 36 cases (30%). BRG1 positivity was heterogenous in desmoplastic round cell tumors and adult granulosa cell tumors. Overall, BRG1 is a useful diagnostic marker in SCCOHT, showing the absence of expression in SCCOHT. Nevertheless, the possible heterogeneity and the variable intensity of this staining warrant caution in the interpretation of BRG1 staining in biopsy specimens.

ObjectiveRobotic surgical techniques are known to be expensive, but they can decrease the cost of hospitalization and improve patients’ outcomes. The aim of this study was to compare the costs and clinical outcomes of conventional laparoscopy vs robotic-assisted laparoscopy in the gynecologic oncologic indications.MethodsBetween 2007 and 2010, 312 patients referred for gynecologic oncologic indications (endometrial and cervical cancer), including 226 who underwent conventional laparoscopy and 80 who underwent robot-assisted laparoscopy, were included in this prospective multicenter study. The direct costs, operating theater costs, and hospital costs were calculated for both surgical strategies using the microcosting method.ResultsBased on an average number of 165 surgical cases performed per year with the robot, the total extra cost of using the robot was €1456 per intervention. The robot-specific costs amounted to €2213 per intervention, and the cost of the robot-specific surgical supplies was €957 per intervention. The cost of the surgical supplies specifically required by conventional laparoscopy amounted to €1432, which is significantly higher than that of the robotic supplies (P < 0.001). Hospital costs were lower in the case of the robotic strategy (€2380 vs €2841, P < 0.001) because these patients spent less time in intensive care (0.38 vs 0.85 days). Operating theater costs were higher in the case of the robotic strategy (€1490 vs €1311, P = 0.0004) because the procedure takes longer to perform (4.98 hours vs 4.38 hours).ConclusionsThe main driver of additional costs is the fixed cost of the robot, which is not compensated by the lower hospital room costs. The robot would be more cost-effective if robotic interventions were performed on a larger number of patients per year or if the purchase price of the robot was reduced. A shorter learning curve would also no doubt decrease the operating theater costs, resulting in financial benefits to society.

Study Objective To describe the left lateral extraperitoneal approach to perform complete para-aortic and pelvic lymphadenectomy and transverse total hysterectomy from left to right as a novel approach to treat obese patients with endometrial cancer. Laparoscopic management of obese patients represents a challenge for the gynecologic surgeon. The extraperitoneal approach is technically easier in the obese patient because it naturally creates a bowel-free operative field. Design A prospective pilot bicentric and descriptive study (Canadian Task Force classification III) evaluating the feasibility and reproducibility of the transverse total hysterectomy and complete lymphadenectomy through left endoscopic extraperitoneal approach in obese patients with endometrial cancer. Setting A comprehensive cancer center in Toulouse and a teaching university hospital in Madrid. Patients Sixteen consecutive overweight or obese patients (body mass index > 25 kg/m 2 ) with high-risk endometrial cancer. Interventions Currently, the left extraperitoneal approach is routinely used to perform complete para-aortic and pelvic lymphadenectomy. It provides direct access to the left ureter and uterine pedicle. This access can be extended to the right side when performing a transverse extrafascial hysterectomy from left to right. The procedure starts from the left extraperitoneal space, where the left uterine artery is sectioned and the vesicovaginal and rectovaginal septa are developed, without opening the peritoneum. Colpotomy is performed from the left to the right side. Once the right ureter is identified, the right uterine artery can be safely transected. Alternatively, the right uterine artery can be sealed and sectioned during the right pelvic lymphadenectomy. At the end of the procedure the peritoneum is opened to complete the surgery. Measurements and Main Results Between May 2015 and February 2016, 16 consecutive obese patients were successfully treated using this technique. Median patient age was 62 years (range, 44–78), and median body mass index was 32.5 kg/m 2 (range, 26–42). In 3 cases the right uterine artery was sealed during the right pelvic lymphadenectomy, in 11 cases after completing vaginal opening, and in 2 cases after peritoneal opening. The median operative time was 137.5 minutes (range, 66–260). The median blood loss was 85 mL (range, 0–260), and no blood transfusion was required in any of our 16 patients. No significant complications occurred. Conclusion The full extraperitoneal approach represents an interesting alternative strategy for the surgical treatment of obese patients with high-risk endometrial cancer.

Steady progress in outcomes has been observed after standard treatment by surgery and chemotherapy in patients with advanced ovarian cancer (AOC), but little is known about outcomes after alternative neoadjuvant chemotherapy (NAC) proposed to primary inoperable patients. We assessed whether NAC offers comparable survival to standard treatment, whether survival rates have progressed over time, and what the optimal extent of surgery at late interval debulking surgery (IDS) should be. This was a retrospective data analysis of prospectively recorded patients with poor prognosis AOC treated by platinum/taxane NAC and late IDS (after six cycles). Independent prognostic factors for surgical morbidity and overall survival (OS) are determined and survival outcomes are compared to survival rates for a similar group of patients treated with platinum protocols. A total of 118 patients with stages IIIC-IV AOC (median age: 64 years, stage IV: 31 %) received IDS (46 % standard surgery and 54 % radical, with 68 % obtaining complete resection). Major morbidity was 18 %. OS was 42 months across all patients (95 % confidence interval 35.3–49.1) and 80 months in stage IIIC. This is higher by 15 months than after platinum-based treatment. Higher morbidity was associated with bowel resection. Longer OS was associated with ASA class I, stage IIIC, no bowel surgery, and no residual disease. The neoadjuvant approach with late IDS offers survival similar to that reported by standard treatment, with progress in outcomes compared with rates after platinum treatment. The goal of IDS surgery is complete resection, while sparing surrounding organs.

5501 Background: The role of secondary cytoreductive surgery in recurrent ovarian cancer (OC) has not been defined by level-1 evidence. Methods: Pts with OC and 1st relapse after 6+ mos platin-free interval (TFIp) were eligible if they presented with a positive AGO-score (PS ECOG 0, ascites ≤500 ml, and complete resection at initial surgery) and were randomized to 2nd-line chemotherapy alone vs cytoreductive surgery followed by chemo. Chemo regimens were selected according to the institutional standard. We report here results of the predetermined interim analysis. Results: 407pts were randomized 2010-2014. The TFIp exceeded 12 mos in 75% and 76% pts in both arms. 8.9% of 203 pts were operated despite of randomization to the no-surgery arm, whereas 6.9% of 204 pts in the surgery arm did not undergo operation. Complete resection was achieved in 67% of pts; 87% and 88% received a platinum-containing 2nd-line therapy. Median PFS was 14 mos without and 19.6 mos with surgery (HR: 0.66, 95%CI 0.52-0.83, pst and 2nd relapse equaled or even exceeded PFS-1 before 1strelapse in 26% after surgery and only 16% without-surgery. Analysis of the primary endpoint OS is kept blinded due to immaturity and will be evaluated after extended follow-up (the observed pooled unblinded 2-YSR was 83% instead of the initially in the protocol assumed 55-66%). 60d mortality rates were 0 and 0.5% in the surgery and no-surgery arm. Re-laparatomies were performed in 7 pts (3.5%) in the surgery arm.With the exception of myelosuppression which occurred more frequently in the no-surgery arm no further significant differences were observed with respect to grade 3+ acute adverse events. Conclusions: Surgery in pts with 1st relapse of OC after a TFIp of 6+ mos and selected by a positive AGO-Score resulted in a clinically meaningful increase of PFS and TFST with acceptable treatment burden. Until final OS data will definitively define the role of secondary cytoreductive surgery it should at least be considered as valuable option in pts with a positive AGO-Score. Clinical trial information: NCT01166737.

Image 1 Objective : Electrically neutral argon plasma (PlasmaJet™) technology is a surgical option that helps to get an aggressive cytoreduction in selected patients with ovarian cancer because it can be directly applied by the surgeon to treat the tissue surface [1,2]. Upper abdominal surgical procedures are an important part of the surgery in these patients [3], there is a 22% complications rate when they are performed [4]. We present a surgical approach to ovarian cancer debulking using PlasmaJet™. Methods: Case history and operative technique : 51 women supported for ovarian cancer Stage IIIC-IV were operated with systematic use of the PlasmaJet device at the Regional Institute Bergonie Cancer Center of Bordeaux, France between June 2012 and June 2014. 41.2% (n=21) patients underwent a Primary Debulking Surgery (PDS) and 58.8% (n=30) underwent an Interval Debulking Surgery. 78.4% (n=40) of the 51 patients studied had a complete cytoreduction. We present the case of a woman diagnosed with a mucinous ovarian carcinoma FIGO stage IVA, who underwent a PDS. Complete cytoreduction to no macroscopic disease was achieved, this included diaphragmatic and abdominal peritoneal stripping. Results : No post-operative complications were found in this case. 15.7% (n=8) of patients undergoing diaphragmatic stripping with the PlasmaJet required a pleural drain. It is a safe structured procedure, which could be performed to achieve optimal surgical results for patients with ovarian cancer. Conclusions : PlasmaJet™ helps the surgeon to perform a peritoneal stripping of the upper abdominal areas and appears to enable the surgeon to remove more disease without increased morbidity, pushing the cytoreduction/morbidity tradeoff.

International audience; Based on the importance of assessing the true extent of peritoneal disease, PeRitOneal MalIgnancy Stage Evaluation (PROMISE) internet application (www.e-promise.org) has been developed to facilitate tabulation and automatically calculate surgically validated peritoneal cancer index (PCI), and other surgically validated scores as Gilly score, simplified peritoneal cancer index (SPCI), Fagotti and Fagotti-modified scores. This application offers computer-assistance to produce simple, quick but precise and standardized pre, intra and postoperative reports of the extent of peritoneal metastases and may help specialized and non-specialized institutions in their current practice but also facilitate research and multicentre studies on peritoneal surface malignancies.

The gene cyclin-dependent kinase inhibitor 2A (CDKN2A) is frequently inactivated by deletion in bladder carcinoma. However, its role in bladder tumourigenesis remains unclear. We investigated the role of CDKN2A deletion in urothelial carcinogenesis, as a function of FGFR3 mutation status, a marker for one of the two pathways of bladder tumour progression, the Ta pathway. We studied 288 bladder carcinomas: 177 non-muscle-invasive (123 Ta, 54 T1) and 111 muscle-invasive (T2–4) tumours. CDKN2A copy number was determined by multiplex ligation-dependent probe amplification, and FGFR3 mutations by SNaPshot analysis. FGFR3 mutation was detected in 124 tumours (43.1%) and CDKN2A homozygous deletion in 56 tumours (19.4%). CDKN2A homozygous deletion was significantly more frequent in FGFR3-mutated tumours than in wild-type FGFR3 tumours (p = 0.0015). This event was associated with muscle-invasive tumours within the FGFR3-mutated subgroup (p < 0.0001) but not in wild-type FGFR3 tumours. Similar findings were obtained for an independent series of 101 bladder carcinomas. The impact of CDKN2A deletions on recurrence-free and progression-free survival was then analysed in 89 patients with non-muscle-invasive FGFR3-mutated tumours. Kaplan–Meier survival analysis showed that CDKN2A losses (hemizygous and homozygous) were associated with progression (p = 0.0002), but not with recurrence, in these tumours. Multivariate Cox regression analysis identified CDKN2A loss as a predictor of progression independent of stage and grade. These findings highlight the crucial role of CDKN2A loss in the progression of non-muscle-invasive FGFR3-mutated bladder carcinomas and provide a potentially useful clinical marker for adapting the treatment of such tumours, which account for about 50% of cases at initial clinical presentation. Copyright © 2012 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

5574Background: Risk-reducing salpingo-oophorectomy is the gold standard to prevent the development of a pelvic high grade serous carcinoma (HGSC) in women at risk of breast/ovarian cancer. However...

Objectives: To perform a cartography of lymph node metastases in epithelial ovarian cancer and to determine predictive factors of lymph node metastases. Method: The charts of 355 patients with epithelial ovarian cancer who underwent lymphadenectomy during a primary (n = 252) or secondary debulking surgery (n = 103) were analyzed. The topography of the lymph node metastases was notified for the whole group according to the stage of the disease, the histological type, and the moment of surgery. In patients who underwent a primary surgery before chemotherapy, independent prognostic variables for the risk of lymph node involvement were tested with a multivariate analysis. Independent prognostic factors were combined to determine risk profiles in individual patients. Results: The main area of the lymph node metastases was para-aortic. Isolated pelvic lymph node involvement was 10%. Three variables independently predicted lymph node invasion: advanced T stage, high-risk histological profile, and metastases. Conclusions: When lymphadenectomy is recommended, systematic lymph node dissections in the aortic and pelvic areas are warranted. An isolated pelvic lymph node assessment, particularly in the early stages, is inappropriate. By combining independent risk factors, a useful tool for individual risk assessment of lymph node involvement could be established, helping to decide whether to perform a lymph node dissection, especially at restaging surgery.

Minimally invasive surgery has demonstrated benefits that include improved pain control, decreased infection risk, and faster surgical recovery and return to work. Morcellation is an integral part of making laparoscopic surgery possible for the removal of large uterine leiomyomata, and the development of power morcellation has increased efficiency during these procedures. Morcellation may expose patients to increased morbidity in certain circumstances. This is particularly true in cases of unrecognized malignancy, where intra-abdominal dissemination of cancer may worsen the prognosis (overall survival and disease free survival). A critical review of published data supports that tissue morcellation can be performed safely in screened and selected patients.

International audience; Introduction: The direct relationship between surgical radicality to compensate biologic behavior and improvement of patient outcome at the time of primary or interval cytoreduction remains unclear.Objective: The aim of this study was to evaluate the impact of disease extension and surgical complexity on survival after complete macroscopic resection for stage IIIC-IV ovarian cancer.Materials and methods: Medical records from seven referral centers in France were reviewed to identify all patients who had complete cytoreductive surgery for stage IIIC-IV epithelial ovarian, fallopian, or primary peritoneal cancer. All patients had at least six cycles of carboplatin and paclitaxel combination therapy.Results: From the 374 consecutive patients with complete cytoreduction who were included in this study, stage, grade, upper abdominal disease, surgical complexity, and carcinomatosis extent were significantly associated with disease-free survival (DFS) at univariate analysis. Stage IV and the need for ultra-radical procedures were significantly associated with lower overall survival (OS). On multivariate analysis, radical surgery, including more than two visceral resections, was significantly associated with decreased DFS and OS.Conclusions: Patients who need complex surgical procedures involving two or more visceral resections in order to achieve successful complete cytoreduction have worse outcome than patients with less extensive procedures. The negative impact of surgical complexity was not significant in patients who underwent upfront procedures. Tumor volume and extension were associated with decreased DFS in patients undergoing a primary surgical approach. This adds to the evidence that, even though complete cytoreduction is currently the objective of surgery, tumor load remains an independent poor prognostic factor and probably reflects a more aggressive behavior.

Objective The aim of this study is to compare two-dimensional and three-dimensional ultrasound for the visualization and diagnosis of craniofacial dysmorphism. Methods In this prospective study, we performed three-dimensional (3D) ultrasound following good-quality two-dimensional (2D) ultrasound in an at-risk population. Findings from 2D and 3D examination were noted. Results Our series included 41 patients. In 20 cases, 3D performed better than 2D, and in two cases 2D was more informative. In 9 cases, there was no difference between the performance of the two, and in two cases both 2D and 3D gave inadequate results. However, in 7 cases 3D images could not be obtained. Conclusion Although it is rarely decisive, 3D ultrasound is of interest when it comes to the precise description of craniofacial dysmorphisms and the study of the fetal ears. Copyright © 2003 John Wiley & Sons, Ltd.

TPS5602 Background: Primary cytoreductive surgery (PDS) followed by chemotherapy has been considered as standard management for advanced ovarian cancer patients (pts) over decades. An alternative approach of interval debulking surgery (IDS) following neoadjuvant chemotherapy (NACT) was subsequently reported by two randomized phase III trials (EORTC‐GCG, CHORUS). Owing to important limitations of these studies, especially regarding surgical quality, optimal timing of surgical therapy in advanced ovarian cancer is still unclear. Methods: TRUST is an international open, randomized, controlled multicenter trial investigating overall survival (OS; primary endpoint) after PDS vs NACT and subsequent IDS in pts with FIGO stage IIIB‐IVB ovarian, tubal, and peritoneal carcinoma. Secondary objectives are safety of complete tumor resection, progression‐free survival and quality of life (QoL) as well as surgical morbidity. In order to guarantee adequate surgical quality, participating centers need to fulfill specific quality assurance criteria (e.g. ≥50% complete resection rate in upfront surgery for FIGO IIIB-IV pts, ≥36 debulking-surgeries/year) and agree to independent audits by TRUST Quality committee delegates. A 1:1 randomization to PDS or NACT followed by IDS stratified by center and age‐ECOG combination (ECOG 0 and age ≤65 years vs ECOG > 0 or age > 65 years) is performed. Pts in the PDS arm will undergo surgery followed by 6 cycles of platinum-based chemotherapy, whereas pts in the IDS arm will be treated with 3 cycles of NACT after histologic confirmation of the disease, followed by IDS and subsequently 3 cycles of platinum-based chemotherapy. Intention of surgery for both groups will be complete tumor resection as per guideline recommendations. Health related QoL will be assessed using the EORTC QLQ‐C30, QLQ‐OV28, and EQ‐5D‐3L questionnaires. For sample size planning, we considered a prolongation of median OS from 45 months in the IDS arm to 60 months in the PDS arm (HR 0.75) as clinically relevant. 380 events are needed to obtain a power of 80% in two‐sided log-rank test with significance level of 0.05. The primary analysis will be done in the ITT‐population of 686 randomized pts. By Feb 3 2017, 46 pts were randomized. Clinical trial information: NCT02828618.

Hereditary ovarian cancers account for 10% of all cases. Two major syndromes with dominant autosomal transmission are identified. The most common one is breast-ovarian cancer syndrome due to BRCA1 and BRCA2 genes mutations, and the Lynch syndrome with mutated MMR genes is the other. Alterations in homologous recombination specifically observed in ovarian cancer with BRCA defects associated to Parp inhibition create a synthetic lethality of special interest. Numerous studies are in progress to explore this promising new approach. Furthermore, it seems that carcinogenesis of these two syndromes are different, suggesting alternative therapeutic options in the near future in order to improve prognosis of ovarian carcinomas.

Objective: One of the concerns of prenatal diagnosis is to find sensitive markers to screen for chromosome abnormalities, such as serum assays or nuchal translucency (NT). This study reports our experience with NT measurement during the first trimester of pregnancy. Materials: The study was performed prospectively on 252 fetuses with either NT ≧3 mm or cystic hygroma. Results: We observed 50 abnormal karyotypes, i.e. 19.8%. The incidence of chromosome abnormalities increased with increasing maternal age and increasing NT thickness. For the 202 fetuses with normal karyotypes, outcome was unfavourable in 32 cases: 23 elective terminations of pregnancy, 8 spontaneous abortions and 1 neonatal death. Outcome was favourable in 141 cases. Twenty-nine pregnancies were lost to follow-up. Conclusion: Measurement of NT at 12 weeks’ gestation seems to be a good marker for chromosome abnormalities. When the karyotype is normal, the pregnancy outcome remains correlated with the degree of NT thickness. The finding of NT >3 mm between 10 and 14 weeks’ gestation dictates rigorous ultrasound monitoring and caution when predicting pregnancy outcome.

We report the results of our analyses of the GAW11 Problem 2 data set, using information from three different populations. In the first part of the paper, we used classical population genetic tests to compare affected individuals from the different populations, stratifying on the environmental factors. Thanks to existing linkage disequilibrium in one population, we found one of the disease susceptibility loci. In the second part of the paper, we used the marker association segregation chi 2 method to model the role of this disease susceptibility locus in the different populations and draw some inferences regarding the model used at that locus to generate the data.

International audience; BACKGROUND: Despite a high response rate to front-line therapy, prognosis of epithelial ovarian carcinoma (EOC) remains poor. Approaches that combine Cytoreductive Surgery (CRS) and Hyperthermic Intraperitoneal Chemotherapy (HIPEC) have been developed recently. The purpose of this study was to assess early and long-term survival in patients treated with this strategy. PATIENTS AND METHODS: A retrospective cohort multicentric study from French centres was performed. All consecutive patients with advanced and recurrent EOC treated with CRS and HIPEC were included. RESULTS: The study included 566 patients from 13 centres who underwent 607 procedures between 1991 and 2010. There were 92 patients with advanced EOC (first-line treatment), and 474 patients with recurrent EOC. A complete cytoreductive surgery was performed in 74.9% of patients. Mortality and grades 3 to 4 morbidity rates were 0.8% and 31.3%, respectively. The median overall survivals were 35.4 months and 45.7 months for advanced and recurrent EOC, respectively. There was no significant difference in overall survival between patients with chemosensitive and with chemoresistant recurrence. Peritoneal Cancer Index (PCI) that evaluated disease extent was the strongest independent prognostic factor for overall and disease-free survival in all groups. CONCLUSION: For advanced and recurrent EOC, curative therapeutic approach combining optimal CRS and HIPEC should be considered as it may achieve long-term survival in patients with a severe prognosis disease, even in patients with chemoresistant disease. PCI should be used for patient's selection.

Purpose To analyze the long-term results of pulsed-dose-rate (PDR) brachytherapy (BT) in cervical carcinoma patients treated at a single institution. Methods and Materials All patients with histopathologically proven Stages IB–IVA cervical carcinoma, treated at our institution with PDR intracavitary BT between April 1996 and November 2007, were included in this retrospective analysis. All patients underwent primary pelvic radiotherapy (45 Gy) with concomitant chemotherapy from 1999 and PDR intracavitary BT (16 Gy to the clinical target volume), followed by hysterectomy in 124 patients. Results Two hundred twenty-six patients received radiochemotherapy and BT. With a median followup of 81.7 months, the 5-year overall survival, disease-free survival, and local control (LC) were 67%, 65%, and 80%, respectively; seventy-seven relapses were observed including 38 local recurrences. Multivariate analysis showed earlier FIGO (International Federation of Gynecology and Obstetrics) stage and absence of nodal involvement to be associated with better overall and disease-free survivals. Use of three-dimensional image-guided BT planning and absence of nodal involvement were associated with better LC in the multivariate analysis. Late Grade ≥3 toxicity was experienced by 22 patients (9.7%), consisting of gastrointestinal toxicity for 6 patients, urinary tract for 10 patients, lymphatics for 3 patients, and vaginal toxicity for 3 patients. Conclusions This study demonstrates excellent LC rates with few late side effects with PDR BT for cervix carcinoma, similar to those reported in the literature with historical standard low-dose-rate BT.

The results of centromammary conservation in 37 patients with 20 mm-median-size breast cancer, located in the subareolar area (SAA), with an infiltration of the nipple-areolar-complex (NAC) in 12 patients and a retraction in 24, are reported. Breast conservative surgery was initially performed in 30 patients; five patients were first treated with chemotherapy; two patients received initial tamoxifen. Surgery comprised tumorectomy plus axillary dissection, with complete resection of the NAC (20 patients), or partial resection (nine patients), or without resection (eight patients). Post-operatively, all patients received 50 Gy external radiotherapy, with an additional external electron boost in 13 patients; 14 patients received adjuvant tamoxifen and two patients adjuvant chemotherapy. With a median follow-up of 49 months, one patient experienced a local failure and four a metastatic failure; 5-year overall actuarial survival and disease-free survival rates were 97%, and 75%. Cosmetic results were excellent in three patients, good in 25, and poor in seven. Breast conservation appears a satisfying treatment in small breast cancer located in SAA.

In the context of the renewed interest of peptides as therapeutics, it is important to have an on-line resource for 3D structure prediction of peptides with well-defined structures in aqueous solution. We present an updated version of PEP-FOLD allowing the treatment of both linear and disulphide bonded cyclic peptides with 9–36 amino acids. The server makes possible to define disulphide bonds and any residue–residue proximity under the guidance of the biologists. Using a benchmark of 34 cyclic peptides with one, two and three disulphide bonds, the best PEP-FOLD models deviate by an average RMS of 2.75 A u from the full NMR structures. Using a benchmark of 37 linear peptides, PEP-FOLD locates lowest-energy conformations deviating by 3 A u RMS from the NMR rigid cores. The evolution of PEP-FOLD comes as a new on-line service to supersede the previous server. The server is available at: http://bioserv .rpbs.univ-paris-diderot.fr/PEP-FOLD.

International audience; no abstract

Endometrial cancers with peritoneal spread are stage IVB of FIGO classification. Their pattern is similar to that of ovarian cancer. Optimal debulking surgery and chemotherapy are predictor of better overall and disease free survival. Despite the poor outcome, there is a need for new treatment options. Recommended management for this group of patients should consist of surgical cytoreduction followed by chemotherapy. There may be a role for neoadjuvant chemotherapy followed by interval surgery in selected subgroups of patients.

The gene cyclin-dependent kinase inhibitor 2A (CDKN2A) is frequently inactivated by deletion in bladder carcinoma. However, its role in bladder tumourigenesis remains unclear. We investigated the role of CDKN2A deletion in urothelial carcinogenesis, as a function of FGFR3 mutation status, a marker for one of the two pathways of bladder tumour progression, the Ta pathway. We studied 288 bladder carcinomas: 177 non-muscle-invasive (123 Ta, 54 T1) and 111 muscle-invasive (T2-4) tumours. CDKN2A copy number was determined by multiplex ligation-dependent probe amplification, and FGFR3 mutations by SNaPshot analysis. FGFR3 mutation was detected in 124 tumours (43.1%) and CDKN2A homozygous deletion in 56 tumours (19.4%). CDKN2A homozygous deletion was significantly more frequent in FGFR3-mutated tumours than in wild-type FGFR3 tumours (p = 0.0015). This event was associated with muscle-invasive tumours within the FGFR3-mutated subgroup (p0.0001) but not in wild-type FGFR3 tumours. Similar findings were obtained for an independent series of 101 bladder carcinomas. The impact of CDKN2A deletions on recurrence-free and progression-free survival was then analysed in 89 patients with non-muscle-invasive FGFR3-mutated tumours. Kaplan-Meier survival analysis showed that CDKN2A losses (hemizygous and homozygous) were associated with progression (p = 0.0002), but not with recurrence, in these tumours. Multivariate Cox regression analysis identified CDKN2A loss as a predictor of progression independent of stage and grade. These findings highlight the crucial role of CDKN2A loss in the progression of non-muscle-invasive FGFR3-mutated bladder carcinomas and provide a potentially useful clinical marker for adapting the treatment of such tumours, which account for about 50% of cases at initial clinical presentation.

Frédéric Guyon1, Pierre Tufféry1,21MTi, INSERM UMR-S973, Université Paris Diderot-Paris 7, Paris, France; 2RPBS, Université Paris Diderot-Paris 7, Paris, FranceAbstract: Quantifying the 3D similarity between two proteins is a difficult task that has motivated the assessment of several 3D scores. New developments in protein modeling and analysis have led to the emergence of new interest towards mining structures at the local level. We assess in the context of fragment mining several dissimilarity scores. We revisit the concept of mirror conformation previously introduced at the level of complete structures and extend it to the more local level. We also consider an explicit criterion measuring the fragment boundary discrepancies. Whereas classical criteria such as the root mean square deviation (RMSd) fail to identify similar shapes in a consistent way, we show that local mirror and boundary mismatch filtering greatly supplements classical scores to select significant matches. The geometrical conditions defined by such criteria can be considered as signatures of fragment similarity. Furthermore, it is possible to tune the degree of similarity depending on the size of the mirrors accepted. This results in a more intuitive perception of the concept of similarity, and opens new perspectives for the rapid mining of large collections of structures.Keywords: protein fragments, similarity, distance, mining

In this paper, we compare the accuracy of four string distances to recover correct phylogenies of complete genomes. These distances are based on common words shared by raw genomic sequences and do not require preliminary processing steps such as gene identification or sequence alignment. Moreover, they are computable in linear time. The first distance is based on Maximum Significant Matches. The second is computed from the frequencies of all the words of length k. The third one is based on the Average length of maximum Common Substrings at any position. The last one is based on the Ziv-Lempel compression algorithm. We describe a simulation process of evolution to generate a set of sequences having evolved according to a random tree topology T. This process allows both base substitutions and fragment insertion/deletion, including horizontal gene transfers. The distances between the generated sequences are computed using the four string formulas and the corresponding trees T′ are reconstructed using Neighbor-Joining. Trees T and T′ are compared using three topological criteria. These comparisons show that the MSM distance outperforms the others whatever the parameters used to generate sequences.