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Epithelioid mesothelioma is the most prevalent subtype of diffuse malignant peritoneal mesothelioma. The relationship between a strong adaptive immune response and a better prognosis in malignant solid tumors is widely known. Due to the low incidence of epithelioid malignant peritoneal mesothelioma (EMPM), very little is known about their immune micro-environment. We encountered several cases of tertiary lymphoid structures in EMPM in a previous study and aimed to investigate in the same series the prevalence, clinicopathological features, and the prognostic impact associated with tertiary lymphoid structures in EMPM (TLS-EMPM). Cases of EMPM, from 1995 to 2018, were retrieved from 7 French institutions from the RENAPE Network. The predictions in terms of overall survival (OS) and progression-free survival (PFS) of TLS-EMPM were analyzed. We report 52 cases of TLS-EMPM among a series of 138 cases of EMPM. TLS-EMPM was significantly associated with neoadjuvant chemotherapy, and was not a prognostic indicator for OS (p = 0.652) and PFS (p = 0.804) in our series. TLS is a component of the host immune response to EMPM significantly associated with neoadjuvant chemotherapy, but was not a predictor of prognosis for overall and progression-free survivals in this series. These findings provide another possible etiology for tertiary lymphoid structures., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Objective: To evaluate the concordance between preoperative European Society for Medical Oncology (ESMO)-European Society of Gynaecological Oncology (ESGO)-European SocieTy for Radiotherapy and Oncology (ESTRO) risk classification in early-stage endometrial cancer (EC) assessed by biopsy and magnetic resonance imaging (MRI) with this classification based on histology of surgical specimen., Methods: This bicentric retrospective study included women diagnosed with early-stage EC (≤stage II) who had a complete preoperative assessment and underwent a surgical management from January 2011 to December 2018. Patients were preoperatively classified into 3 degrees of risk of lymph node (LN) involvement based on biopsy and MRI. Based on final histological report, patients were re-classified using the preoperative classification. Concordance between the preoperative assessment and definitive histology was calculated with weighted Cohen's kappa coefficient., Results: A total of 333 women were included and kappa coefficient of preoperative risk classification was 0.49. The risk was underestimated and overestimated in 37% and 10% of cases, respectively. Twenty-nine percent of patients had an incomplete LN staging according to the degree of risk of re-classification. The observed discordance in the risk classification was attributed to MRI in 75% of cases, to biopsy in 18% and in 7% to both (p<0.001). Kappa coefficient for concordance was 0.25 for MRI and 0.73 for biopsy., Conclusion: Concordance between preoperative ESMO-ESGO-ESTRO risk classification and final histology is weak. Given that the risk was underestimated in the majority of patients wrongly classified, sentinel LN procedure instead of no LN dissection could be an option offered to preoperative low-risk patients to decrease the indication of second surgery for re-staging and/or to avoid toxicity of adjuvant radiotherapy., Competing Interests: No potential conflict of interest relevant to this article was reported., (Copyright © 2021. Asian Society of Gynecologic Oncology, Korean Society of Gynecologic Oncology, and Japan Society of Gynecologic Oncology.)

Introduction: Assisted reproductive technology including in vitro fertilization (IVF) and oocyte donation (OD) may increase risk for placenta-mediated diseases. Comprehensive analysis of histopathological placental lesions according to source of oocytes used in the IVF procedure - recipient derived (RD-IVF) vs oocyte donation (OD-IVF), has not been conducted in a population with a hypertensive disorder of pregnancy (HDP) and/or intrauterine growth restriction (IUGR)., Methods: A retrospective cohort study of archived placenta specimens from RD-IVF and OD-IVF pregnancies affected by HDP and/or IUGR was conducted with blinded histopathological placental examination. Three categories of lesions were differentiated and defined as main outcomes: maternal vascular malperfusion (MVM), chronic inflammation, and fetal vascular malperfusion (FVM). To determine the relationship between conception method and placental lesions, multivariable regressions were performed with maternal age, gestational age, HDP, birth and placental weight percentiles as model covariates., Results: 115 placentas were included 83 (72.2%) RD-IVF, 32 (27.8%) OD-IVF. Adjusted OR (aOR) for conception method was 5.05 (95%CI 0.58-43.90, p=0.142) for MVM, 1.87 (95%CI 0.68-5.15, p=0.228) for chronic inflammatory and 0.61 (95%CI 0.15-2.37, p=0.471) for FVM lesions. Multiple gestation demonstrated borderline association with MVM (aOR=0.24, 95%CI 0.04-1.51, p=0.129) and total pathology score (aRR=0.79, 95%CI 0.62-1.01, p=0.058). Subgroup analysis suggested greater odds of villitis of unknown etiology (VUE) for OD-IVF (aOR=2.98, 95%CI 1.12-7.93, p=0.029)., Discussion: Source of oocyte derivation demonstrated no evidence of association with main outcomes in cases of HDP and/or IUGR. Subgroup analysis demonstrated increased rates of inflammatory lesions for OD-IVF. Multiple gestation may be associated with decreased MVM and total lesions., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Purpose: The aim of our study was to assess concordance of staging laparoscopy and cytoreductive surgery (CRS) peritoneal cancer index (PCI) when applying a two-step surgical protocol. We also aimed to evaluate the accuracy of diagnostic laparoscopy to triage patients for complete cytoreduction, and to define optimal time between staging laparoscopy and CRS., Methods: We designed a retrospective review of prospectively collected data from patients with advanced ovarian cancer who underwent a diagnostic laparoscopy followed by a CRS a few weeks later (two-step surgical protocol), from January 2010 to April 2019. Only patients selected for complete cytoreduction, and with available PCI score from both surgeries were included. PCI concordance was assessed using intraclass correlation coefficient (ICC)., Results: During the study period 543 patients underwent a laparoscopic staging for ovarian carcinomatosis. Among them, 43 patients fulfilled inclusion criteria. ICC between laparoscopic and laparotomic PCI was 0.54. After applying the linear regression equation: laparoscopic PCI + 0.2 x [days between surgeries] + 2, ICC increased to 0.79. Completeness cytoreduction score and laparoscopic PCI were significantly associated (OR 1.27, 95% CI 1.03-1.57, p = 0.03). AUC of laparoscopic PCI to predict complete cytoreduction was 0.90., Conclusion: Concordance between laparoscopic PCI assessment and PCI score at the end of CRS is fair within a two-step surgical management. Laparoscopic assessment underestimates final PCI score by two points, and this difference increases with the delay between both surgeries. Diagnostic laparoscopy can adequately select patients for CRS, and optimal time to perform it is no more than 10 days after laparoscopy.

As sentinel lymph nodes (SLNs) are the first nodes receiving drainage from primary tumors, they provide important prognostic information about the nodal status of a tumor. SLN biopsy has modified the lymph node assessment by pathologists. This review highlights the different ways of histopathological and molecular SLN assessment according to the different gynecological cancers. Other than in breast cancer and melanoma, frozen section (FS) analysis of SLN in gynecological malignancies is still considered an important diagnostic tool. Intraoperative evaluation of the SLN allows to determine the need of completing lymph node dissection in case of metastasis. Intraoperative FS has a high negative predictive value (NPV) and is more sensitive than imprint cytology (IC) alone. If on intraoperative examination on FS the SLN is negative, subsequent analysis of the entire lymph node and histological ultrastadification has the potential to detect occult low volume metastases or to ascertain that a SLN is really negative. This reduces the morbidity compared to systematic pelvic and paraaortic lymph node dissection. Inclusion of the entire lymph node tissue in paraffin blocks after cutting it in 2 mm thick slices and histopathological ultrastaging with serial sections provides important prognostic information about the need of adjuvant treatment. Three sections at 200-250 µm seem to identify the majority of micrometastases. This review discusses different histopathological protocols and molecular [qRT-PCR and one-step nucleic acid amplification (OSNA®)] aspects of SLN evaluation in gynecological cancer.

Tumor antigen-specific CD4 T cells accumulate at tumor sites, evoking their involvement in antitumor effector functions in situ. Contrary to CD8 cytotoxic T lymphocyte exhaustion, that of CD4 T cells remains poorly appreciated. Here, using phenotypic, transcriptomic, and functional approaches, we characterized CD4 T cell exhaustion in patients with head and neck, cervical, and ovarian cancer. We identified a CD4 tumor-infiltrating lymphocyte (TIL) population, defined by high PD-1 and CD39 expression, which contained high proportions of cytokine-producing cells, although the quantity of cytokines produced by these cells was low, evoking an exhausted state. Terminal exhaustion of CD4 TILs was instated regardless of TIM-3 expression, suggesting divergence with CD8 T cell exhaustion. scRNA-Seq and further phenotypic analyses uncovered similarities with the CD8 T cell exhaustion program. In particular, PD-1hiCD39+ CD4 TILs expressed the exhaustion transcription factor TOX and the chemokine CXCL13 and were tumor antigen specific. In vitro, PD-1 blockade enhanced CD4 TIL activation, as evidenced by increased CD154 expression and cytokine secretion, leading to improved dendritic cell maturation and consequently higher tumor-specific CD8 T cell proliferation. Our data identify exhausted CD4 TILs as players in responsiveness to immune checkpoint blockade.

Objective: To assess the survival benefit of primary debulking surgery (PDS) compared to interval debulking surgery (IDS) after complete cytoreduction (CC-0) or cytoreduction to minimal residual disease (CC-1) in advanced ovarian cancer. Secondary objective was to evaluate the effect of tumor load and surgical complexity on patients' survival., Methods: A retrospective multicentric study was designed, including patients with IIIC-IV FIGO stage ovarian cancer who underwent PDS or IDS with CC-0 or CC-1 from January 2008 to December 2015 in four high-volume institutions. Patients were classified in three groups: PDS, IDS after 3-4 cycles of neoadjuvant chemotherapy (NACT), and IDS after 6 cycles. Disease-free survival (DFS) and overall survival (OS) were estimated. Univariable and multivariable analyses were conducted., Results: We included 549 patients, 175 (31.9%) underwent PDS, 224 (40.8%) had IDS after 3-4 cycles of NACT, and 150 (27.3%) underwent IDS after 6 cycles. Median DFS in PDS, IDS at 3-4 cycles and IDS at 6 cycles were 23.0 months (95%CI = [20.0-29.3]), 18.0 months (95%CI = [15.9-20.0]) and 17.1 months (95%CI = [15.0-20.9]), respectively; p < .001. Median OS were 84.0 months (95%CI = [68.3-111.0]), 50.7 months (95%CI = [44.6-59.5]) and 47.5 months (95%CI = [39.3-52.9]), respectively; p < .001. In multivariable analysis, high peritoneal cancer index score and NACT were negatively associated to DFS and OS. Surgical complexity and CC-1 were negatively associated to DFS., Conclusion: PDS offered a survival gain of almost three years compared to IDS in patients with minimal or no residual disease after surgery. PDS should remain the standard of care for advanced ovarian cancer., (Copyright © 2020. Published by Elsevier Inc.)

Although understanding of T-cell exhaustion is widely based on mouse models, its analysis in patients with cancer could provide clues indicating tumor sensitivity to immune checkpoint blockade (ICB). Data suggest a role for costimulatory pathways, particularly CD28, in exhausted T-cell responsiveness to PD-1/PD-L1 blockade. Here, we used single-cell transcriptomic, phenotypic, and functional approaches to dissect the relation between CD8 + T-cell exhaustion, CD28 costimulation, and tumor specificity in head and neck, cervical, and ovarian cancers. We found that memory tumor-specific CD8 + T cells, but not bystander cells, sequentially express immune checkpoints once they infiltrate tumors, leading, in situ , to a functionally exhausted population. Exhausted T cells were nonetheless endowed with effector and tumor residency potential but exhibited loss of the costimulatory receptor CD28 in comparison with their circulating memory counterparts. Accordingly, PD-1 inhibition improved proliferation of circulating tumor-specific CD8 + T cells and reversed functional exhaustion of specific T cells at tumor sites. In agreement with their tumor specificity, high infiltration of tumors by exhausted cells was predictive of response to therapy and survival in ICB-treated patients with head and neck cancer. Our results showed that PD-1 blockade-mediated proliferation/reinvigoration of circulating memory T cells and local reversion of exhaustion occur concurrently to control tumors., (©2020 American Association for Cancer Research.)

Brugada syndrome, also called Pokkuri Death Syndrome, is an autosomal dominant electrophysiological phenomenon that increases the risk of spontaneous ventricular tachyarrhythmia and sudden cardiac death. Due to sodium channel mutations in the cardiac membrane, most commonly SCN5A and SCN10A, the heart can be triggered into a fatal arrhythmia. Brugada syndrome can be triggered by fever, and medications including antiarrhythmics, psychotropics, and recreational drugs like cocaine and marijuana. We report a case that demonstrates the diagnosis of Brugada syndrome in an otherwise very healthy 22-year-old African-American male. He presented after a syncopal event and developed spontaneous ventricular tachycardia and torsades de pointes. Electrocardiogram (EKG) findings documented a type I Brugada pattern and, once stabilized, the patient underwent an internal cardioverter defibrillator (ICD) placement., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2020, Stockholm et al.)

Factors released by surrounding cells such as cancer-associated mesenchymal stromal cells (CA-MSCs) are involved in tumor progression and chemoresistance. In this study, we characterize the mechanisms by which naïve mesenchymal stromal cells (MSCs) can acquire a CA-MSCs phenotype. Ovarian tumor cells trigger the transformation of MSCs to CA-MSCs by expressing pro-tumoral genes implicated in the chemoresistance of cancer cells, resulting in the secretion of high levels of CXC chemokine receptors 1 and 2 (CXCR1/2) ligands such as chemokine (C-X-C motif) ligand 1 (CXCL1), CXCL2, and interleukin 8 (IL-8). CXCR1/2 ligands can also inhibit the immune response against ovarian tumor cells. Indeed, through their released factors, CA-MSCs promote the differentiation of monocytes towards M2 macrophages, which favors tumor progression. When CXCR1/2 receptors are inhibited, these CA-MSC-activated macrophages lose their M2 properties and acquire an anti-tumoral phenotype. Both ex vivo and in vivo, we used a CXCR1/2 inhibitor to sensitize ovarian tumor cells to carboplatin and circumvent the pro-tumoral effects of CA-MSCs. Since high concentrations of CXCR1/2 ligands in patients' blood are associated with chemoresistance, CXCR1/2 inhibition could be a potential therapeutic strategy to revert carboplatin resistance., (© The Author(s) (2019). Published by Oxford University Press on behalf of Journal of Molecular Cell Biology, IBCB, SIBS, CAS.)

Synaptic loss induced by soluble oligomeric forms of the amyloid β peptide (sAβos) is one of the earliest events in Alzheimer's disease (AD) and is thought to be the major cause of the cognitive deficits. These abnormalities rely on defects in synaptic plasticity, a series of events manifested as activity-dependent modifications in synaptic structure and function. It has been reported that pannexin 1 (Panx1), a nonselective channel implicated in cell communication and intracellular signaling, modulates the induction of excitatory synaptic plasticity under physiological contexts and contributes to neuronal death under inflammatory conditions. Here, we decided to study the involvement of Panx1 in functional and structural defects observed in excitatory synapses of the amyloid precursor protein (APP)/presenilin 1 (PS1) transgenic (Tg) mice, an animal model of AD. We found an age-dependent increase in the Panx1 expression that correlates with increased Aβ levels in hippocampal tissue from Tg mice. Congruently, we also observed an exacerbated Panx1 activity upon basal conditions and in response to glutamate receptor activation. The acute inhibition of Panx1 activity with the drug probenecid (PBN) did not change neurodegenerative parameters such as amyloid deposition or astrogliosis, but it significantly reduced excitatory synaptic defects in the AD model by normalizing long-term potentiation (LTP) and depression and improving dendritic arborization and spine density in hippocampal neurons of the Tg mice. These results suggest a major contribution of Panx1 in the early mechanisms leading to the synaptopathy in AD. Indeed, PBN induced a reduction in the activation of p38 mitogen-activated protein kinase (MAPK), a kinase widely implicated in the early neurotoxic signaling in AD. Our data strongly suggest that an enhanced expression and activation of Panx1 channels contribute to the Aβ-induced cascades leading to synaptic dysfunction in AD., (Copyright © 2020 Flores-Muñoz, Gómez, Mery, Mujica, Gajardo, Córdova, Lopez-Espíndola, Durán-Aniotz, Hetz, Muñoz, Gonzalez-Jamett and Ardiles.)

Introduction: Sentinel lymph node (SLN) detection has been shown to be accurate in detecting lymph node involvement in early-stage cervical cancer. The objective of this study was to evaluate the accuracy of frozen section examination in the assessment of SLN status, with the aim of adequately driving the intra-operative decision., Methods: We designed a retrospective study including patients from two comprehensive cancer centers between January 2001 and December 2018 with early-stage cervical cancer (IA1-IB2 according to International Federation of Gynecology and Obstetrics (FIGO) 2018) undergoing SLN dissection. The SLN procedure was performed using a cervical injection with technetium-99m combined with blue dye or indocyanine green in most cases., Results: A total of 176 patients fulfilled inclusion criteria. Bilateral mapping was detected in 153 (86.7%) of them. Nineteen of these patients (12.4%) had SLN involvement: 13 with macrometastases, three with micrometastases and three with isolated tumor cells (ITC). Macrometastatic disease was missed on frozen section in 3/13 FIGO 2018 stage IIIC patients. The three patients with ITC were also missed by frozen section examination.Considering only macrometastases as lymph node involvement, frozen section sensitivity was 76.9% (95% CI 49.7 to 91.8) and negative predictive value (NPV) was 97.9% (95% CI 94.0 to 99.3) in patients with bilateral detection. Including micrometastases, sensitivity was 81.2% (95% CI 57.0 to 93.4) and NPV remained at 97.9% (95% CI 93.9 to 99.3)., Conclusions: With a prevalence of final-stage IIIC in patients with pre-operative early-stage cervical cancer of the order of 10% in this series, the NPV of frozen section examination of SLN is very high, with an inferior limit of the CI superior to 94%. Diagnostic accuracy remains acceptable even if micrometastases are considered. The impact of missed ITC has not been established. Frozen section examination can be incorporated in the intra-operative decision algorithm., Competing Interests: Competing interests: None declared., (© IGCS and ESGO 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Proteus Syndrome is a rare complex overgrowth syndrome. We report a young female patient with Proteus Syndrome due to AKT1 mutation c.49G > A (p.Glu17Lys), presenting with a severe gynaecological involvement which necessitated a complete hysterectomy and a left adnexectomy. Cases of gynecological involvements in Proteus Syndrome are rare, not well known by physicians while they can be potentially severe., (Copyright © 2018. Published by Elsevier Masson SAS.)

Mutations of CTNNB1 have been implicated in tumorigenesis in many organs. However, tumors harboring a CTNNB1 translocation are extremely rare and this translocation has never been reported in a uterine mesenchymal neoplasm. We report a novel translocation t(2;3)(p25;p22) involving the GREB1 (intron 8) and CTNNB1 (exon 3) in a uterine tumor resembling ovarian sex cord tumor (UTROSCT), which exhibited extrauterine metastasis. The translocation detected by RNA-sequencing was validated by RT-PCR, and resulted in nuclear expression of β-catenin. Juxtapositioning with GREB1, which is overexpressed in response to estrogens, resulted in overexpression of a truncated and hypophosphorylated nuclear β-catenin in the primary and recurrent tumors. This accumulation of nuclear β-catenin results in a constitutive activation of the Wnt/β-catenin signaling pathway with a major oncogenic effect. The CTNNB1 gene fusion, promoted by an estrogen-responsive gene (GREB1), could be a potential driver of tumorigenesis in this case and a therapeutic target with adapted inhibitors. RT-PCR and immunohistochemistry performed on 11 additional UTROSCTs showed no CTNNB1 fusion transcript or nuclear β-catenin immunoreactivity., (© 2018 Wiley Periodicals, Inc.)

The poor prognosis of ovarian cancer (it is the leading cause of death from gynecological cancers) is mainly due to the acquisition of resistance to carboplatin. Among the possible resistance pathways, resistance to apoptosis and especially the overexpression of inhibitor of apoptosis proteins (IAP) cIAP1 and X-linked IAP (XIAP), have been implicated. DEBIO 1143, a SMAC (second mitochondria-derived activator of caspase) mimetic, belongs to a new class of targeted agents currently being evaluated in clinical trials, which activate apoptotic cell death and block pro-survival signaling in cancer cells. Here, we demonstrate that DEBIO 1143 in vitro inhibits the cell viability of two carboplatin-sensitive cell lines (IGROV-1 and A2780S) as well as three carboplatin-resistant cell lines (A2780R, SKOV-3 and EFO-21). Of note, DEBIO 1143 is able to reverse resistance to carboplatin by inducing cell death either by apoptosis or necroptosis depending on the cell lines. To identify a biomarker able to predict the sensitivity of the cell lines to DEBIO 1143 treatment we analyzed the expression of the DEBIO 1143 targets cIAP1 and XIAP, and one of their downstream targets, caspase 9. These proteins did not constitute a marker of DEBIO 1143 sensitivity/resistance. Importantly, we confirmed these findings in vivo in SKOV-3 xenograft models where DEBIO 1143 highly potentiated carboplatin treatment.

In order to help the clinician, mathematical models including several clinical and pathological variables are proposed in the literature with the aim to predict the occurrence of an event of interest. Nomograms allow individual prognosis for each patient. When they are developed, validated and correctly used, nomograms can provide important information for patients' care. But, despite the strong interest in nomograms in oncology, statistical methodologies used remain unknown from the medical community. This paper presents the major steps in the development, the validation and the clinical use of nomograms. Examples are given to illustrate these different points and the limits of this methodology. Finally, guidelines on the use of nomograms are proposed for clinicians., (Copyright © 2017 Société Française du Cancer. Published by Elsevier Masson SAS. All rights reserved.)

Surgery is often the first treatment option for patients with cancer. Patient survival essentially depends on the completeness of tumor resection. This is a major challenge, particularly in cases of peritoneal carcinomatosis, where tumors are widely disseminated in the large peritoneal cavity. Any development to help surgeons visualize these residual cells would improve the completeness of the surgery. For non-disseminated tumors, imaging could be used to ensure that the tumor margins and the draining lymph nodes are free of tumor deposits. Near-infrared fluorescence imaging has been shown to be one of the most convenient imaging modalities. Our aim was to evaluate the efficacy of a near-infrared fluorescent probe targeting the αvβ3 integrins (Angiostamp™) for intraoperative detection of tumors using the Fluobeam® device. We determined whether different human tumor nodules from various origins could be detected in xenograft mouse models using both cancer cell lines and patient-derived tumor cells. We found that xenografts could be imaged by fluorescent staining irrespective of their integrin expression levels. This suggests imaging of the associated angiogenesis of the tumor and a broader potential utilization of Angiostamp™. We therefore performed a veterinary clinical trial in cats and dogs with local tumors or with spontaneous disseminated peritoneal carcinomatosis. Our results demonstrate that the probe can specifically visualize both breast and ovarian nodules, and suggest that Angiostamp™ is a powerful fluorescent contrast agent that could be used in both human and veterinary clinical trials for intraoperative detection of tumors., Competing Interests: CONFLICTS OF INTEREST The authors have no conflicts of interest to disclose.

Background: Rare ovarian tumors represent >20% of all ovarian cancers. Given the rarity of these tumors, natural history, prognostic factors are not clearly identified. The extreme variability of patients (age, histological subtypes, stage) induces multiple and complex therapeutic strategies., Methods: Since 2011, a national network with a dedicated system for referral, up to 22 regional and three national reference centers (RC) has been supported by the French National Cancer Institute (INCa). The network aims to prospectively monitor the management of rare ovarian tumors and provide an equal access to medical expertise and innovative treatments to all French patients through a dedicated website, www.ovaire-rare.org., Results: Over a 5-year activity, 4612 patients have been included. Patients' inclusions increased from 553 in 2011 to 1202 in 2015. Expert pathology review and patients' files discussion in dedicated multidisciplinary tumor boards increased from 166 cases in 2011 (25%) to 538 (45%) in 2015. Pathology review consistently modified the medical strategy in 5-9% every year. The rate of patients' files discussed in RC similarly increased from 294 (53%) to 789 (66%). An increasing number (357 in 5 years) of gynecologic (non-ovarian) rare tumors were also registered by physicians seeking for pathological or medical advice from expert tumor boards., Conclusion: Such a nation-wide organization for rare gynecological tumors has invaluable benefits, not only for patients, but also for epidemiological, clinical and biological research., (© The Author 2017. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Microcystic stromal tumors (MCST), first described in 2009 by Irving et al., are rare ovarian neoplasms. The entity was introduced into the 2014 WHO classification of tumors of female reproductive organs in the group of sex cord-stromal tumors, which is rather heterogeneous. We studied three cases of ovarian tumor with the characteristic morphological features and immunohistochemical marker profiles of MCST. The three tumors showed micro, and macrocystic patterns with solid areas, and were composed of small round to spindle-shaped cells, without atypia. The tumors diffusely and strongly expressed CD10, FOXL2, and nuclear β-catenin, but without immmunoreactivity for hormone receptors, calretinin, or inhibin. Genome analyses showed no somatic mutation of exon 1 of the FOXL2 gene and of exons 24 and 25 of DICER1 gene, the latter not having been reported previously. The patients are well, without evidence of tumor progression 1 to 10 years after diagnosis.The absence of FOXL2 and DICER1 gene mutation, along with strong FOXL2 immunoreactivity provides additional evidence to place MCST within pure gonadal stromal rather than sex cord ovarian tumors.

Identifying genes where a variant allele is preferentially expressed in tumors could lead to a better understanding of cancer biology and optimization of targeted therapy. However, tumor sample heterogeneity complicates standard approaches for detecting preferential allele expression. We therefore developed a novel approach combining genome and transcriptome sequencing data from the same sample that corrects for sample heterogeneity and identifies significant preferentially expressed alleles. We applied this analysis to epithelial ovarian cancer samples consisting of matched primary ovary and peritoneum and lymph node metastasis. We find that preferentially expressed variant alleles include germline and somatic variants, are shared at a relatively high frequency between patients, and are in gene networks known to be involved in cancer processes. Analysis at a patient level identifies patient-specific preferentially expressed alleles in genes that are targets for known drugs. Analysis at a site level identifies patterns of site specific preferential allele expression with similar pathways being impacted in the primary and metastasis sites. We conclude that genes with preferentially expressed variant alleles can act as cancer drivers and that targeting those genes could lead to new therapeutic strategies.

Objective: Tubal lesions detected in specimen of risk reducing salpingo oophorectomy (RRSO) for mutation BRCA1/2 seems to play a role in ovarian carcinogenesis. The main objective of this study is to evaluate the prevalence of occult neoplasia, of Serous Tubal Intraepithelial Carcinoma (STIC), and signature P53 in a cohort of patients who underwent a risk reducing salpingo oophorectomy., Methods: From January 2010 to January 2014 unicentric, retrospective study on a consecutive cases cohort of RRSO for patients with a high risk of ovarian neoplasia (mutation BRCA 1/2 or family history). Pathological specimen should be analysed according to the SEE-FIM protocol., Results: Ninety-three RRSO were recorded. Among them, 44% of the patients had the germ line mutation BRCA1, 30.1% BRAC2 and 18.2% had no identified mutation. In all, 33.3% of the RRSO reveal a signature P53, in the fimbria for 93.9%, 7.9% of them were bilateral. 1,1‰ (n=1) of the patients presented a unilateral STIC. We obtained 4.3% of occult neplasia: 3 ovarian high-grade serous carcinomas and 1 tubal high-grade serous carcinoma. Only the tubal carcinoma coexists with STIC., Conclusion: 5,4% of the patients who underwent RRSO had a diagnostic of occult neoplasia. One percent of the patients had an isolated STIC. These results agree with recent data of the literature. Extensive examination of the Fallopian tube opens up a new way to understand ovarian carcinogenesis., (Copyright © 2015 Elsevier Masson SAS. All rights reserved.)

Vaginal reconstruction after pelvic exenteration (PE) represents a challenge for the oncologic surgeon. Since the introduction of perforator flaps, using pedicled vertical DIEP (deep inferior epigastric perforator) flap allows to reduce the donor site complication rate. From November 2012 to December 2014, 27 PEs were performed in our institution. 13 patients who underwent PE with vaginal reconstruction and programmed DIEP procedure for gynecologic malignancies were registered. Nine patients underwent PE for recurrent disease and four for primary treatment. Six of the 13 patients have a preoperative fistula. Anterior PE was performed in 10 patients, and total PE in 3 patients. A vertical DIEP flap was performed in 10 patients using one or two medial perforators. The reasons for abortion of vertical DIEP flap procedure were: failure to localizing perforator vessels in two cases, and unavailability of plastic surgeon in one case. A vertical fascia-sparring rectus abdominis myocutaneous flap was then harvested. Median length of surgery was 335min, and 60min for DIEP harvesting and vaginal reconstruction. No flap necrosis occurred. One patient in the VRAM (vertical rectus abdominis myocutaneous) group experienced a late incisional hernia and one patient in the DIEP flap group required revision for vaginal stenosis. In our experience, DIEP flap represents our preferred choice of flap for circumferential vaginal reconstruction after PE. To achieve a high reproducibility, the technically demanding pedicled vertical DIEP flap has to be harvested by a trained surgeon, after strict evaluation of the preoperative imaging with identification and localization of perforator vessels., (Copyright © 2015. Published by Elsevier Inc.)

The purpose of this study is to review the available evidence documenting the prognostic role of adherence to guidelines in gynecologic cancers. A systematic review of the PubMed database using "guideline," "adherence," and "cancer" was carried out on February 25, 2014. Two thousand one hundred twenty-three publications were identified. Only publications addressing the question of adherence to recommendations regarding surgical care and multidisciplinary management of gynecologic cancers were selected. Six studies were identified in endometrial cancer, 4 in ovarian cancer, and none in cervical cancer. Adoption of guidelines is an effective tool for disease control and must consequently be considered as a process measure of quality cancer care. It is urgent to develop reliable and reproducible tools to assess adherence to guidelines based on level 1 evidence in gynecologic cancer then to carry out investigations to document the prognostic impact of compliance with guidelines. The time has come to include adherence to guidelines in quality assurance programs.

Background: Hyaluronic acid is a prognostic factor in ovarian cancers. It is also a component of Hyaluronic Acid-Carboxymethyl Cellulose (HA-CMC) barrier, an anti-adhesion membrane widely used during abdominal surgeries in particular for ovarian carcinosis. 70% of patients who undergo ovarian surgery will relapse due to the persistence of cancer cells. This study's objective was to determine the oncological risk from use of this material, in the presence of residual disease, despite the benefit gained by it decreasing post-surgical adhesions in order to provide an unambiguous assessment of its appropriateness for use in ovarian surgical management., Methods: We assessed the effects of HA-CMC barrier on the in vitro proliferation of human ovarian tumor cell lines (OVCAR-3, IGROV-1 and SKOV-3). We next evaluated, in vivo in nude mice, the capacity of this biomaterial to regulate the tumor progression of subcutaneous and intraperitoneal models of ovarian tumor xenografts., Results: We showed that HA-CMC barrier does not increase in vitro proliferation of ovarian cancer cell lines compared to control. In vivo, HA-CMC barrier presence with subcutaneous xenografts induced neither an increase in tumor volume nor cell proliferation (Ki67 and mitotic index). With the exception of an increased murine carcinosis score in peritoneum, the presence of HA-CMC barrier with intraperitoneal xenografts modified neither macro nor microscopic tumor growth. Finally, protein analysis of survival (Akt), proliferation (ERK) and adhesion (FAK) pathways highlighted no activation on the xenografts imputable to HA-CMC barrier., Conclusions: For the most part, our results support the lack of tumor progression activation due to HA-CMC barrier. We conclude that the benefits gained from using HA-CMC barrier membrane during ovarian cancer surgeries seem to outweigh the potential oncological risks.

Purpose: Recent improvements in the detection of breast cancer at an early stage have resulted in a rising incidence of breast ductal carcinoma in situ with microinvasion. So far, there is no consensus regarding its optimal management. We hereby report on our 10-year single institutional experience in breast ductal carcinoma in situ with microinvasion including pathological reviewing., Patients and Methods: All consecutive patients treated for a ductal carcinoma in situ with microinvasion at the Institut Claudius-Regaud (Toulouse, France) over a 10-year period were included in this study. We reviewed all available histological materials., Results: Sixty-three patients were eligible for this study. Two patients presented with a lymph node invasion at diagnosis. Each patient benefited from initial surgical management, which consisted either in mastectomy (n=25) or conservative resection (n=37). Axillary exploration was performed in 52 patients (82%). After a median follow-up of 61.3 months [46.9;69], the 5-year overall survival and disease free survival were 98.2 (95% CI=[88.2;99.7]) and 89.5% (95% CI=[76.3;95.6]) respectively. Two delayed invasive relapses occurred leading to one specific death. The pathological review highlighted a trend towards a loss of HR and HER2 expression (9%) in the microinvasive component in comparison with its surrounded in situ carcinoma., Conclusion: The risk of initial lymph node involvement and delayed invasive local relapse deserve an optimal locoregional management including lymph node evaluation. The non-negligible discrepancy's rate between in situ and microinvasive components justifies HR status and HER2 expression assessment on the microinvasive component., (Copyright © 2014 Société française de radiothérapie oncologique (SFRO). Published by Elsevier SAS. All rights reserved.)

As part of the national 2009-2013 Cancer Plan, and with the support of the National cancer Institute and the French ministry of health, the National network for the treatment of rare peritoneal malignancies (RENAPE) has been organized. Its main objective is to optimize the framework for the healthcare management and treatment of rare peritoneal malignancies. This specific organization covers the whole national territory including clinical expert and specialized structures and should lead to an appropriate treatment based on expertise and proximity. Within the RENAPE network, the RENA-PATH group gathers the pathologists actively involved in the management of rare peritoneal malignancies. The actions of RENA-PATH are focused primarily on the harmonization of pathological diagnostic criteria, reporting of new cases in the RENAPE registry and histology reviewing., (Copyright © 2014. Published by Elsevier Masson SAS.)

Objective: The aim of the study was to report on the oncologic outcome of the disease spread to celiac lymph nodes (CLNs) in advanced-stage ovarian cancer patients., Methods: All patients who had CLN resection as part of their cytoreductive surgery for epithelial ovarian, fallopian, or primary peritoneal cancer were identified. Patient demographic data with particular emphasis on operative records to detail the extent and distribution of the disease spread, lymphadenectomy procedures, pathologic data, and follow-up data were included., Results: The median follow-up was 26.3 months. The median overall survival values in the group with positive CLNs and in the group with negative CLNs were 26.9 months and 40.04 months, respectively. The median progression-free survival values in the group with metastatic CLNs and in the group with negative CLNs were 8.8 months and 20.24 months, respectively (P = 0.053). Positive CLNs were associated with progression during or within 6 months after the completion of chemotherapy (P = 0.0044). Tumor burden and extensive disease distribution were significantly associated with poor progression-free survival, short-term progression, and overall survival. In multivariate analysis, only the CLN status was independently associated with short-term progression., Conclusions: Disease in the CLN is a marker of disease severity, which is associated to a high-risk group of patients with presumed adverse tumor biology, increased risk of lymph node progression, and worst oncologic outcome.

Objective: Early cervical cancer patients with pelvic lymph node metastasis do not benefit from radical hysterectomy. Assessment of the SLN status is thus crucial before deciding to perform a radical hysterectomy as opposed to aortic dissection only followed by definitive radiation therapy. Accuracy of frozen section of SLN has been questioned and deserves further investigation., Methods: Stage IA-IB1 cervical cancer patients who underwent SLN then full pelvic dissection at the Claudius Regaud Cancer Center in Toulouse, France, were included., Results: At least one SLN was identified in all 94 patients. Bilateral detection rate was 80.8%. Ectopic drainage area was found in 19 patients (20.2%). Sentinel lymph node involvement was found in 11 patients (11.7%). Sensitivity and NPV of frozen section pathological examination for the detection of macrometastatic disease was 100%, sensitivity for the detection of macro and micrometastatic disease, excluding ITC, was 88.9%, and NPV was 98.8%. Micrometastasis and isolated tumor cells (ITC) undetected at frozen section examination were found in 1 patient (1.06%) and 2 lymph nodes (1.24%), and in 2 patients (2.13%) and 2 lymph nodes (1.24%), respectively. Final pathology sensitivity of SLN was 100% for both macro and micrometastatic disease, including ITC., Conclusion: In our institution, intraoperative frozen examination of SLN accurately predicts the status of pelvic lymph nodes and is effective for selecting intraoperatively the group of patients who benefit from radical hysterectomy. In addition, our results suggest that patients with small tumors and bilateral detection of SLN can be spared full pelvic lymphadenectomy., (Copyright © 2013. Published by Elsevier Inc.)

Background: Intensive care unit (ICU) beds are a scarce resource, and admissions may require prioritization when demand exceeds supply. However, there are few empiric data on whether the availability of ICU beds influences triage and processes of care for hospitalized patients who develop sudden clinical deterioration., Methods Results: The cohort consisted of 3,494 patients. Reduced ICU bed availability was associated with a decreased likelihood of ICU admission within 2 hours of MET activation (P = 0.03) and with an increased likelihood of change in patient goals of care (P <0.01). Patients with sudden clinical deterioration when zero ICU beds were available were 33.0% (95% confidence interval (CI), -5.1% to 57.3%) less likely to be admitted to the ICU and were 89.6% (95% CI, 24.9% to 188.0%) more likely to have their goals of care changed compared with when more than two ICU beds were available. However, hospital mortality did not vary significantly by ICU bed availability (P = 0.82)., Conclusions: For hospitalized patients with sudden clinical deterioration, ICU bed scarcity decreases the probability of ICU admission and increases the probability of initiating comfort measures on the ward but does not influence hospital mortality.

The high rate of recurrence after apparently complete surgery and/or complete clinical response to chemotherapy implies that most patients have undetected minimal residual disease. Novel techniques such as laparoscopic or laparotomic fluorescence may prove to be crucial in reassessing the definition of primary outcome in ovarian cancer management. For this purpose, the importance of fluorescence in the peroperative detection of human ovarian adenocarcinoma cells has to be validated in animal models prior to be used in clinic by determining its efficiency in detecting infra-millimetric tumor metastases. In the preclinical data presented, a fluorescent RAFT-(cRGD)4 tracer molecule (AngioStamp(®)) with a very high affinity for the αvβ3 integrin was used. Infrared fluorescence was visualized with Fluobeam(®), an open fluorescent imaging system that could potentially be used in peroperative conditions in the future. We showed that this novel technique allowed the specific detection of residual tumor deposits and inframillimetric metastases in mice and dogs.

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.

Background: The early peritoneal invasion of epithelial ovarian cancer (EOC) by tumoral aggregates presents in ascites is a major concern. The role of the microenvironment seems to be important in this process but the lack of adequate models to study cellular interactions between cancer cells and stromal cells does not allow to uncover the molecular pathways involved. Our goal was to study the interactions between ovarian cancer cells (OCC) and mesenchymal stem cells (MSC) using a 3D model., Methods: We used millimetric pieces of amniochorionic membrane - referred to as amniotic membrane scaffold (AMS) - to create 3D peritoneal nodules mimicking EOC early invasion. We were able to measure the distribution and the depth of infiltration using confocal microsopy. We extracted MSC from the amniochorionic membrane using the markers CD34-, CD45-, CD73+, CD90+, CD105+ and CD29+ at the Fluorescence Activated Cell Sorting (FACS) analysis. We used transwell and wound healing tests to test OCC migration and invasion in vitro., Results: Here we show that OCC tumors were located in regions rich in MSC (70%). The tumors infiltrated deeper within AMS in regions rich in MSC (p<0.001). In vitro tests revealed that higher IL6 secretion in a context of MSC-OCC co-culture could enhance migration and invasion of OCC. After IL6 receptor antagonism, OCC infiltration was significantly decreased, mostly in regions rich in MSCs, indicating that recruitment and tridimensional invasion of OCC was dependent of IL6 secretion., Conclusions: The use of tridimensional models using AMS could be a useful tool to decipher early molecular events in ovarian cancer metastasis. Cytokine inhibitors interrupting the cross-talk between OCCs and MSCs such as IL6 should be investigated as a new therapeutic approach in ovarian cancer.

Within the microenvironment, Carcinoma-associated mesenchymal stem cells (Hospicells) are able to influence ovarian tumor development via, among others, the facilitation of angiogenesis in the tumor site allowing an accelerated tumor growth. We demonstrate the presence of a chemotactism between endothelial cells and Hospicells, and a cell line specific increased secretion of pro-angiogenic cytokines such as IL-6, IL-8 and VEGF from ovarian adenocarcinoma cells. Hospicells are also able to attract and activate macrophages to a M2 phenotype and allow them to secrete a huge quantity of pro-angiogenic cytokines, favorable to tumor progression of all the associated ovarian adenocarcinoma cells tested., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

Objective: To evaluate the sensitivity of sentinel node (SN) ultrastaging and to define parameters that may reduce the overall false-negative rate in women with early-stage cervical cancer., Methods: We analyzed data from a large retrospective multicenter cohort group with FIGO stages IA-IIB cervical cancer in whom at least one SN was identified and systematic pelvic lymphadenectomy was uniformly performed. All who were SN negative by initial evaluation were subjected to ultrastaging., Results: In all, 645 patients were evaluable. SN were detected bilaterally in 72% of cases and unilaterally in 28%. Patients with optimal bilateral SN detection were significantly more likely to have any metastasis detected (33.3% vs. 19.2%; P<0.001) as well as micrometastasis detected in their SN (39.6% vs. 11.4%). SN ultrastaging resulted in a low overall false-negative rate of 2.8% (whole group) and an even lower false-negative rate of 1.3% for patients with optimal bilateral mapping. Patients with false-negative SN after ultrastaging had a higher prevalence of LVSI and more frequent unilateral SN detection. Sensitivity of SN ultrastaging was 91% (95% CI: 86%-95%) for the whole group and 97% (95% CI: 91%-99%) in the subgroup with bilateral SN detection., Conclusion: These data confirm previous observations that optimal bilateral SN detection substantially decreases the false negative rate of SN ultrastaging and increases detection of micrometastasis. In patients with bilateral SN detection, the sensitivity of SN ultrastaging is not reduced in more advanced stages of the disease. SN mapping and ultrastaging should become standard practice in the surgical management of early-stage cervical cancer., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Coagulation disorders often accompany cancer onset and evolution, which, if not properly managed, could have grave consequences. Endothelial protein C is an important regulator of homeostasis and acts through its high affinity binding to its transmembrane receptor (EPCR). Soluble (sEPCR) which results from the proteolytic cleavage of the membrane bound form can trap activated endothelial protein C and deprive it of its anti-coagulant function. In this study, the expression of EPCR and its soluble form (sEPCR) released into plasma as a result of proteolytic cleavage were investigated in ovarian, breast, lung and colorectal cancer biopsies, as well as in ascitic cell clusters and peritoneal fluid from ovarian cancer samples. In parallel, breast, ovarian, lung and colorectal cancer cell lines were investigated for the expression of EPCR. The integrity of the EPCR gene sequence as well gene haplotypes were ascertained in the established cancer cell lines in order to understand their eventual regulatory functions. The results from the present study indicate that in cancer patients, the levels of sEPCR are significantly higher than the normal range compared to healthy volunteers. The increase in the levels of sEPCR parallels the increase in CA125, showing a close correlation. Therefore, the detection of sEPCR in cancer and during the post-treatment period could be taken into account as an additional marker that could re-inforce the one obtained using CA125 alone as a marker of cancer cell mass.

Background: Ovarian cancer is the most deadly gynecological cancer due to late diagnosis at advanced stage with major peritoneal involvement. To date most research has focused on primary tumor. However the prognosis is directly related to residual disease at the end of the treatment. Therefore it is mandatory to focus and study the biology of metastatic disease that is most frequently localized to the peritoneal cavity in ovarian cancer., Methods: We used high-density gene expression arrays to investigate gene expression changes between matched primary and metastatic (peritoneal) lesions., Results: Here we show that gene expression profiles in peritoneal metastasis are significantly different than their matched primary tumor and these changes are affected by underlying copy number variation differences among other causes. We show that differentially expressed genes are enriched in specific pathways including JAK/STAT pathway, cytokine signaling and other immune related pathways. We show that underlying copy number variations significantly affect gene expression. Indeed patients with important differences in copy number variation displayed greater gene expression differences between their primary and matched metastatic lesions., Conclusions: Our analysis shows a very specific targeting at both the genomic and transcriptomic level to upregulate certain pathways in the peritoneal metastasis of ovarian cancer. Moreover, while primary tumors use certain pathways we identify distinct differences with metastatic lesions. The variation between primary and metastatic lesions should be considered in personalized treatment of ovarian cancer.

Objective: Evaluate prognostic significance of low volume disease detected in sentinel nodes (SN) of patients with early stages cervical cancer. Although pathologic ultrastaging of SN allows for identification of low volume disease, including micro-metastasis and isolated tumor cells (ITC), in up to 15% of cases, prognostic significance of these findings is unknown., Methods: A total of 645 records from 8 centers were retrospectively reviewed. Enrolled in our study were patients with early-stage cervical cancer who had undergone surgical treatment including SN biopsy followed by pelvic lymphadenectomy and pathologic ultrastaging of SN., Results: Macrometastasis, micrometastasis, and ITC were detected by SN ultrastaging in 14.7%, 10.1%, and 4.5% patients respectively. False negativity of SN ultrastaging reached 2.8%. The presence of ITC was not associated with significant risk, both for recurrence free survival and overall survival. Overall survival was significantly reduced in patients with macrometastasis and micrometastasis; hazard ratio for overall survival reached 6.85 (95% CI, 2.59-18.05) and 6.86 (95% CI, 2.09-22.61) respectively. Presence of micrometastasis was an independent prognostic factor for overall survival in a multivariable model., Conclusion: Presence of micrometastasis in SN in patients with early stage cervical cancer was associated with significant reduction of overall survival, which was equivalent to patients with macrometastasis. No prognostic significance was found for ITC. These data highlight the importance of SN biopsy and pathologic ultrastaging for the management of cervical cancer., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Pseudomyxoma peritonei (PMP) arising from urachal tumors is extremely rare. To our knowledge, natural history, tumor biological behaviour, morbidity, treatment, and prognosis of PMP arising from the urachus are determined by the associated PMP. Management of urachal tumors with associated PMP should be based on aggressive locorregional therapy with cytoreductive surgery and hyperthermic intraperitoneal chemotherapy, similar to PMP arising from other origins., (Copyright © 2010. Published by Elsevier Ltd.)

Objective: Improvement of the management and outcome of ovarian cancers may require intraoperative detection and therapeutic intervention to treat minimal residual disease after complete surgery. The aim of this study was to validate the importance of fluorescence in the peroperative detection of human ovarian adenocarcinoma cells and to determine its efficiency in detecting infra millimetric tumor metastases., Methods: A fluorescent RAFT-(cRGD)₄ tracer molecule (AngioStamp®) was used. The tracer is based on a biomarker, which has a very high affinity for the α(v)β₃ integrin, which is overexpressed in a large ratio of cancer cells and neovessel endothelial cells during angiogenesis. Infrared fluorescence was visualized with Fluobeam®, an open fluorescent imaging system that could potentially be used in peroperative conditions in the future., Results: This novel technique allowed the specific detection of residual tumor deposits and inframillimetric metastases, smaller than 500μm, which were resected under fluorescent guidance. AngioStamp® was able to detect all types of cell lines, derived from human ovarian adenocarcinomas, before or after chemotherapy treatment in animals. The effectiveness of AngioStamp® for the detection of various human ovarian adenocarcinomas was assessed on 10 different fragments of tumor, implanted subcutaneously in nude mice. All implanted tumor fragments were visualized by AngioStamp®., Conclusions: The high rate of recurrence after apparently complete surgery and/or complete clinical response to chemotherapy implies that most patients have undetected minimal residual disease. Novel techniques such as laparoscopic or laparotomic fluorescence may prove to be crucial in reassessing the definition of primary outcome in ovarian cancer management., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Introduction: Prognostic value of complete macroscopic resection of primary disease has been reported and confirmed in several publications. Published data indicate that extensive upper abdominal disease involving the hepatic pedicle and celiac trunk is associated with an abortion of the surgical procedure or with suboptimal residual disease., Methods: All patients who had disease at the porta hepatis or celiac lymph node resection as part of cytoreductive surgery were included. Medical and operative records with particular emphasis on extent and distribution of disease spread, number of peritonectomy procedures, visceral resections, and lymphadenectomy procedures were examined., Results: A total of 28 patients who underwent some kind of celiac lymph node resection or resection of metastatic involvement of the porta hepatis were included. Median preoperative serum Ca-125 level was 78U/ml (range, 30-2950U/ml), and median ascites volume was 1900ml (range, 0-10,000ml). Of the 28 patients, 23 underwent supra-radical surgery for diffuse peritoneal carcinomatosis. Median operative time was 252minutes (range, 100-540minutes). Complete cytoreduction to CCO was achieved in all except one case, who was cytoreduced to millimetric residue. Fifteen patients had positive celiac nodes and nineteen patients had peritoneal disease in the porta hepatis region., Discussion: Resection of enlarged nodes and metastatic disease to the porta hepatis is feasible with an acceptable morbidity. The decision to undergo an aggressive cytoreductive surgery is based on appropriate patient selection depending on the extension of surgical procedure, on medical comorbidities, and on the potential to tolerate an extensive procedure, rather than on specific anatomic locations., (Copyright © 2010 Elsevier Inc. All rights reserved.)

Objective: Early stage primary carcinoma of the fallopian tube (PCFT) is an uncommon condition when strict criteria are applied. The aim of this study was to compare the outcome stage IA-IB PCFT to a matched group of ovarian cancer (OC)., Methods: Between 1990 and 2008, 32 patients with stage IA-IB of PCFT were recorded in the database of three French Institutions. A control group of patients with OC was constituted., Results: Eleven eligible PCFT cases and 29 OC controls fulfilled the stringent inclusion criteria. Median follow-up was 70.2 months. Five-year overall survival was 83.3% (95% confidence interval [CI], 27.3 to 97.5) for PCFT and 88.0% (95% CI, 66.9 to 96.0) for OC (p=0.93). In the subgroup of patients with grade 2-3, the outcome was similar in PCFT compared to OC patients (p=0.75). Five-year relapse-free survival was respectively 62.5% (95% CI, 22.9 to 86.1) and 85.0% (95% CI, 64.6 to 94.2) in the PCFT and OC groups (p=0.07). In the subgroup of patients (grade 2-3), there was no difference between PCFT and OC (p=0.65)., Conclusion: The findings did not reveal any difference in prognosis between early stage of PCFT and OC when grade is taken into account. Management of PCFT should mirror that of ovarian carcinoma.

Introduction: Pelvic exenteration (PE) remains one of the most mutilating surgical procedures with important postoperative morbidity. Laparoscopic approach has emerged in an attempt to reduce postoperative complications. The aim of the present study was to compare outcomes between laparoscopic pelvic exenteration combined with a vaginal or perineal approach, versus classical approach., Methods: A cohort study was performed by identifying patients who underwent laparoscopic pelvic exenteration, and retrospectively comparing data with open cases from the same period of time, from 2000 to 2008., Results: Fourteen patients underwent laparoscopic PE and 29 patients underwent an open exenterative procedure. All patients except one (97.6%) had received prior radiotherapy. Eighteen patients (41.9%) underwent total PE, 17 anterior PE (39.5%), and 8 posterior PE (18.6%). Urinary diversion (UD) technique consisted of 24 Miami pouch (68.6%), 9 Bricker diversion (25.7%), 1 Kock pouch (2.9%), and 1 ureterostomy (2.9%). Most frequent postoperative complications were related to the urinary diversion (45%) and bowel reconstruction (27.9%). Median estimated blood loss for the laparoscopy and laparotomy group was 400 ml (range 200-700 ml) and 875 ml (range 200-1600 ml), respectively. Transfusion rate was also significantly higher in the laparotomy group. Operative time, margin status, length of hospital stay, operative and postoperative morbidity, and disease and overall survival were not significantly different between both groups., Conclusions: Laparoscopic PE is feasible with curative intent to selected patients. Potential postoperative advantages of laparoscopic approach when compared to classical approach, oncological safety of the procedure, and QOL considerations need to be further investigated., (Copyright © 2010 Elsevier Inc. All rights reserved.)

Ovarian cancer is the most deadly gynecological cancer. The high rate of mortality is due to the large tumor burden with extensive metastatic lesion of the abdominal cavity. Despite initial chemosensitivity and improved surgical procedures, abdominal recurrence remains an issue and results in patients' poor prognosis. Transcriptomic and genetic studies have revealed significant genome pathologies in the primary tumors and yielded important information regarding carcinogenesis. There are, however, few studies on genetic alterations and their consequences in peritoneal metastatic tumors when compared to their matched ovarian primary tumors. We used high-density SNP arrays to investigate copy number variations in matched primary and metastatic ovarian cancer from 9 patients. Here we show that copy number variations acquired by ovarian tumors are significantly different between matched primary and metastatic tumors and these are likely due to different functional requirements. We show that these copy number variations clearly differentially affect specific pathways including the JAK/STAT and cytokine signaling pathways. While many have shown complex involvement of cytokines in the ovarian cancer environment we provide evidence that ovarian tumors have specific copy number variation differences in many of these genes.

Introduction: Conventional lymphoscintigraphy provides planar images with little spatial information on location of pelvic sentinel lymph nodes (SLN). SPECT has better spatial resolution and, in combination with anatomic accuracy provided by CT improves SLN preoperative localization. The aim of the study was to report on the results of hybrid imaging of SLN in early cervical cancer patients treated at Claudius Regaud Cancer Center., Methods: Stages IA-IB1 cervical cancer patients undergoing preoperative SPECT/CT for SLN detection were analysed., Results: Forty-one patients were included. A 100% SLN detection rate was achieved when a combined technique (radiotracer and blue dye) was used. At least one SLN was clearly visualized by SPECT/CT in 39 of 41 patients (95%) and full anatomic concordance with intraoperative anatomical location of SLN was found in 37 of the 39 patients with at least one SLN identified by SPECT/CT (95%). Location of removed SLN included the external and internal iliac area in 88% patients, the common iliac area in 10.5%, and the inframesenteric para-aortic area in 1.5%. No SLN was found in the infrarenal para-aortic region. Lymph node involvement was identified in 5 patients (12.1%). SLN correctly predicted lymph node involvement in all node-positive patients. However, SPECT/CT failed to identify 1 of the 5 metastatic SLN., Discussion: SPECT/CT accurately detected preoperative SLN topography and enhanced diagnostic sensitivity of SLN imaging, improving surgical approach to patients with cervical cancer staging. Diagnostic quality of anatomic landmarks of CT images of SPECT/CT could be further improved by the use of contrast injected CT., (Copyright © 2010 Elsevier Inc. All rights reserved.)

Objective: Aims of the study were to identify the incidence of micrometastases in negative para-aortic lymph nodes, and to assess the utility of ultrastaging in histologic evaluation of para-aortic lymph nodes., Material and Methods: Patients with advanced cervical cancer and negative para-aortic lymph nodes after routine histology examination were included. Paraffin-embedded tissue blocks were cut into 5-μm-thick slides at step serial sections at 200-μm intervals until there was no lymph node tissue left. 7 to 14 slides were obtained per lymph node and an immunohistochemistry staining with anti-cytokeratin antibody (EA1/EA3) was performed., Results: 581 histologically negative aortic nodes of 24 patients with advanced cervical cancer were assessed for para-aortic micrometastases (PAM). The incidence of micrometastases by the total number of studied lymph nodes was 0.003%. PAM were identified in 2 patients (8.3%), and additional submicrometastases were also found in one of them (4.1%). A single metastatic cluster of less than 0.2 mm was found in an afferent lymphatic vessel of another patient, not considered as a submicrometastases. PAM incidence was too low to allow for evaluation of associated risk factors, and for analysis of prognostic significance., Conclusion: Although examination of PAM with ultrastaging and IHC is expensive and time-consuming, and difficult to be routinely applied to all negative lymph nodes retrieved in a para-aortic lymphadenectomy, this study adds to current evidence that removal of aortic nodes may benefit a subgroup of advanced cervical cancer patients with PAM and negative aortic lymph node at imaging techniques including PET-scan., (Copyright © 2010. Published by Elsevier Inc.)

The microenvironment is known to play a dominant role in cancer progression. Cells closely associated with tumoral cells, named hospicells, have been recently isolated from the ascites of ovarian cancer patients. Whilst these cells present no specific markers from known cell lineages, they do share some homology with bone marrow-derived or adipose tissue-derived human mesenchymal stem cells (CD9, CD10, CD29, CD146, CD166, HLA-1). We studied the role of hospicells in ovarian carcinoma progression. In vitro, these cells had no effect on the growth of human ovarian carcinoma cell lines OVCAR-3, SKOV-1 and IGROV-1. In vivo, their co-injection with adenocarcinoma cells enhanced tumor growth whatever the tumor model used (subcutaneous and intraperitoneally established xenografts in athymic mice). In addition, their injection increased the development of ascites in tumor-bearing mice. Fluorescent macroscopy revealed an association between hospicells and ovarian adenocarcinoma cells within the tumor mass. Tumors obtained by coinjection of hospicells and human ovarian adenocarcinoma cells presented an increased microvascularization indicating that the hospicells could promote tumorigenicity of ovarian tumor cells in vivovia their action on angiogenesis. This effect on angiogenesis could be attributed to the increased HIF1alpha and VEGF expression associated with the presence of the hospicells. Collectively, these data indicate a role for these ascite-derived stromal cells in promoting tumor growth by increasing angiogenesis.

From March 2003 to April 2004, were prospectively collected in France 1,289 ductal carcinoma in situ (DCIS) with data on diagnosis, patient and tumour characteristics, and treatments. Median age was 56 years (range, 30-84). DCIS was diagnosed by mammography in 87.6% of patients. Mastectomy (M), conservative surgery alone (CS) and conservative surgery with radiotherapy (CS + RT) were performed in 30.5, 7.8 and 61.7% of patients, respectively. Sentinel node biopsy (SNB) and axillary dissection (AD) were performed in 21.3 and 10.4% of patients, respectively. Hormone therapy was administered to 13.4% of the patients. Nuclear grade was low in 21% of patients, intermediate in 38.5% and high in 40.5%. Excision was considered complete in 92% (CS) and 88.3% (CS + RT) of patients. Treatment modalities varied widely according to region: mastectomy rate, 20-37%; adjuvant RT, 84-96%; hormone treatment, 6-34%. Our survey on current DCIS management in France has highlighted correlations between pathological features (tumour size, margin, grade) and treatment options, with several similar variations to those observed in recent UK and US studies.

Hyperthermic intraperitoneal chemotherapy (HIPEC) represents a new treatment strategy aimed to improve outcome of patients with advanced ovarian cancer. Based on theoretical and experimental basis, HIPEC should stand as an effective treatment for ovarian cancer. Literature review reveals a number of different experiences on feasibility of this technique, but scientific evidence of current studies remains poor. Much more research is still required to elucidate unanswered questions. Before this technique can be routinely used, some controversial aspects have to be defined: which drug is the best to deliver and at what temperature, is it necessary to use mono- or poly-chemotherapy regimens, which is the time-point for HIPEC in the natural history of ovarian cancer: at front-line therapy, at interval debulking following initial neo-adjuvant chemotherapy, at consolidation following front-line therapy, or at the time of recurrence. Nevertheless, we must not forget that the most important issue in ovarian cancer prognosis is maximal cytoreductive surgery, with no residual disease at completion of initial surgery.

Aim: To determine the factors associated with the metastatic involvement of sentinel lymph node (SLN) biopsy in patients with early breast cancer., Study Design: This was a retrospective study of patients with T1 invasive breast cancer who underwent SLN biopsy at Claudius Regaud Institute between January 2001 and September 2008., Results: 1416 patients were recruited into this study. SLN metastases were detected in 368 patients (26%). Younger age, tumor size and location, histological type, nuclear grade, and lymphovascular invasion appear to be significant risk factors of SNL involvement. In multivariate analysis, tumor size, tumor location, histological type and lymphovascular invasion are significant factors. When the tumor size is >20 mm, the OR is 6.6 compared to a T1a tumor (3.145-14.175, p<0.001, confidence interval 95%). When the tumor is found in the inner quadrant, the risk of SLN involvement is reduced compared to external locations with an OR of 0.53 (0.409-0.709, p<0.001, confidence interval 95%). Non-ductal/lobular compared to infiltrative ductal cancer have a lower risk of SLN involvement with an OR of 0.423 (0.193-0.927, p<0.03, confidence interval 95%). Lymphovascular invasion increase the risk of positive SLN with an OR of 2.8 (1.9-4.1, p<0.001, confidence interval 95%)., Conclusion: It appears reasonable to avoid axillary lymph node dissection in older patients with T1a tumors of good histopathological type and in the absence of lymphovascular invasion.