Eliane Mery

Prognostic significance of low volume sentinel lymph node disease in early-stage cervical 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.

Oncologic Trogocytosis of an Original Stromal Cells Induces Chemoresistance of Ovarian Tumours

Background The microenvironment plays a major role in the onset and progression of metastasis. Epithelial ovarian cancer (EOC) tends to metastasize to the peritoneal cavity where interactions within the microenvironment might lead to chemoresistance. Mesothelial cells are important actors of the peritoneal homeostasis; we determined their role in the acquisition of chemoresistance of ovarian tumours. Methodology/Principal Findings We isolated an original type of stromal cells, referred to as “Hospicells” from ascitis of patients with ovarian carcinosis using limiting dilution. We studied their ability to confer chemoresistance through heterocellular interactions. These stromal cells displayed a new phenotype with positive immunostaining for CD9, CD10, CD29, CD146, CD166 and Multi drug resistance protein. They preferentially interacted with epithelial ovarian cancer cells. This interaction induced chemoresistance to platin and taxans with the implication of multi-drug resistance proteins. This contact enabled EOC cells to capture patches of the Hospicells membrane through oncologic trogocytosis, therefore acquiring their functional P-gp proteins and thus developing chemoresistance. Presence of Hospicells on ovarian cancer tissue micro-array from patients with neo-adjuvant chemotherapy was also significantly associated to chemoresistance. Conclusions/Significance This is the first report of trogocytosis occurring between a cancer cell and an original type of stromal cell. This interaction induced autonomous acquisition of chemoresistance. The presence of stromal cells within patients tumour might be predictive of chemoresistance. The specific interaction between cancer cells and stromal cells might be targeted during chemotherapy.

Hybrid imaging by SPECT/CT for sentinel lymph node detection in patients with cancer of the uterine cervix

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.

Bilateral ultrastaging of sentinel lymph node in cervical cancer: Lowering the false-negative rate and improving the detection of micrometastasis

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.

Loss of RhoB expression promotes migration and invasion of human bronchial cells via activation of AKT1.

Lung cancer is the leading cause of cancer-related death worldwide, mainly due to its highly metastatic properties. Previously, we reported an inverse correlation between RhoB expression and the progression of the lung cancer, occurring between preinvasive and invasive tumors. Herein, we mimicked the loss of RhoB observed throughout lung oncogenesis with RNA interference in nontumoral bronchial cell lines and analyzed the consequences on both cell transformation and invasion. Down-regulation of RhoB did not modify the cell growth properties but did promote migration and invasiveness. Furthermore, RhoB depletion was accompanied by modifications of actin and cell adhesion. The specific activation of the Akt1 isoform and Rac1 was found to be critical for this RhoB-mediated regulation of migration. Lastly, we showed that RhoB down-regulation consecutive to K-RasV12 cell transformation is critical for cell motility but not for cell proliferation. We propose that RhoB loss during lung cancer progression relates to the acquisition of invasiveness mediated by the phosphatidylinositol 3-kinase (PI3K)/AKT and Rac1 pathways rather than to tumor initiation.

Hospicells (ascites-derived stromal cells) promote tumorigenicity and angiogenesis

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 HIF1α 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.

Breast-conserving surgery with or without radiotherapy vs mastectomy for ductal carcinoma in situ: French Survey experience

From March 2003 to April 2004, 77 physicians throughout France prospectively recruited 1289 ductal carcinoma in situ (DCIS) patients and collected data on diagnosis, patient and tumour characteristics, and treatments. Median age was 56 years (range, 30–84). Ductal carcinoma in situ was diagnosed by mammography in 87.6% of patients. Mastectomy, conservative surgery alone (CS) and CS with radiotherapy (CS+RT) were performed in 30.5, 7.8 and 61.7% of patients, respectively. Thus, 89% of patients treated by CS received adjuvant RT. 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 (80% tamoxifen). Median tumour size was 14.5 mm (6, 11 and 35 mm for CS, CS+RT and mastectomy, respectively, P<0.0001). Nuclear grade was high in 21% of patients, intermediate in 38.5% and low in 40.5%. Excision was considered complete in 92% (CS) and 88.3% (CS+RT) of patients. Oestrogen receptors were positive in 69.8% of assessed cases (31%). 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 and grade) and treatment options, with several similar variations to those observed in recent UK and US studies.

Mesenchymal stem cells enhance ovarian cancer cell infiltration through IL6 secretion in an amniochorionic membrane based 3D model

BackgroundThe 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.MethodsWe 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.ResultsHere 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.ConclusionsThe 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.

Laparoscopic pelvic exenteration for gynaecological malignancy: Is there any advantage?

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.

Celiac lymph node resection and porta hepatis disease resection in advanced or recurrent epithelial ovarian, fallopian tube, and primary peritoneal cancer

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.