Eric Lambaudie

Comparison of models to predict nonsentinel lymph node status in breast cancer patients with metastatic sentinel lymph nodes: a prospective multicenter study.

PURPOSE Several models have been developed to predict nonsentinel lymph node (non-SN) status in patients with breast cancer with sentinel lymph node (SN) metastasis. The purpose of our investigation was to compare available models in a prospective, multicenter study. PATIENTS AND METHODS In a cohort of 561 positive-SN patients who underwent axillary lymph node dissection, we evaluated the areas under the receiver operating characteristic curves (AUCs), calibration, rates of false negatives (FN), and number of patients in the group at low risk for non-SN calculated from nine models. We also evaluated these parameters in the subgroup of patients with micrometastasis or isolated tumor cells (ITC) in the SN. RESULTS At least one non-SN was metastatic in 147 patients (26.2%). Only two of nine models had an AUC greater than 0.75. Three models were well calibrated. Two models yielded an FN rate less than 5%. Three models were able to assign more than a third of patients in the low-risk group. Overall, the Memorial Sloan-Kettering Cancer Center nomogram and Tenon score outperform other methods for all patients, including the subgroup of patients with only SN micrometastases or ITC. CONCLUSION Our study suggests that all models do not perform equally, especially for the subgroup of patients with only micrometastasis or ITC in the SN. We point out available evaluation methods to assess their performance and provide guidance for clinical practice.

ALDH1-Positive Cancer Stem Cells Predict Engraftment of Primary Breast Tumors and Are Governed by a Common Stem Cell Program

Cancer stem-like cells (CSC) have been widely studied, but their clinical relevance has yet to be established in breast cancer. Here, we report the establishment of primary breast tumor-derived xenografts (PDX) that encompass the main diversity of human breast cancer and retain the major clinicopathologic features of primary tumors. Successful engraftment was correlated with the presence of ALDH1-positive CSCs, which predicted prognosis in patients. The xenografts we developed showed a hierarchical cell organization of breast cancer with the ALDH1-positive CSCs constituting the tumorigenic cell population. Analysis of gene expression from functionally validated CSCs yielded a breast CSC signature and identified a core transcriptional program of 19 genes shared with murine embryonic, hematopoietic, and neural stem cells. This generalized stem cell program allowed the identification of potential CSC regulators, which were related mainly to metabolic processes. Using an siRNA genetic screen designed to target the 19 genes, we validated the functional role of this stem cell program in the regulation of breast CSC biology. Our work offers a proof of the functional importance of CSCs in breast cancer, and it establishes the reliability of PDXs for use in developing personalized CSC therapies for patients with breast cancer.

Role of robot-assisted laparoscopy in adjuvant surgery for locally advanced cervical cancer.

OBJECTIVE The aim of this study was to compare the feasibility and efficacy of robot-assisted laparoscopy with traditional laparotomy and conventional laparoscopy in a series of patients with locally advanced cervical cancer managed in our two institutions. METHODS Twenty-two patients who underwent robot-assisted laparoscopy were compared with 20 patients who underwent adjuvant surgery by laparotomy and 16 who underwent conventional laparoscopy, before the arrival of the Da Vinci surgical system. RESULTS There was no significant difference between the three groups in terms of body mass index, FIGO stage, or tumor histology. The complication rate was similar in the three groups of patients, although there was a trend towards more lymphatic complications in the robot-assisted subgroup managed medically. There was no significant difference in the recurrence rate between the robot-assisted laparoscopy, conventional laparoscopy and laparotomy groups (27.3%, 29.4% and 30%, respectively). CONCLUSION Robot-assisted laparoscopy is feasible after concurrent chemoradiation and brachytherapy in cases of locally advanced cervical cancer. This new surgical approach reduces hospital stay, and seems to result in less severe complications than conventional laparotomy without modifying the oncological outcome.

Kinome expression profiling and prognosis of basal breast cancers

BackgroundBasal breast cancers (BCs) represent ~15% of BCs. Although overall poor, prognosis is heterogeneous. Identification of good- versus poor-prognosis patients is difficult or impossible using the standard histoclinical features and the recently defined prognostic gene expression signatures (GES). Kinases are often activated or overexpressed in cancers, and constitute targets for successful therapies. We sought to define a prognostic model of basal BCs based on kinome expression profiling.MethodsDNA microarray-based gene expression and histoclinical data of 2515 early BCs from thirteen datasets were collected. We searched for a kinome-based GES associated with disease-free survival (DFS) in basal BCs of the learning set using a metagene-based approach. The signature was then tested in basal tumors of the independent validation set.ResultsA total of 591 samples were basal. We identified a 28-kinase metagene associated with DFS in the learning set (N = 73). This metagene was associated with immune response and particularly cytotoxic T-cell response. On multivariate analysis, a metagene-based predictor outperformed the classical prognostic factors, both in the learning and the validation (N = 518) sets, independently of the lymphocyte infiltrate. In the validation set, patients whose tumors overexpressed the metagene had a 78% 5-year DFS versus 54% for other patients (p = 1.62E-4, log-rank test).ConclusionsBased on kinome expression, we identified a predictor that separated basal BCs into two subgroups of different prognosis. Tumors associated with higher activation of cytotoxic tumor-infiltrative lymphocytes harbored a better prognosis. Such classification should help tailor the treatment and develop new therapies based on immune response manipulation.

Robotically-assisted laparoscopic anterior pelvic exenteration for recurrent cervical cancer: Report of three first cases

The first patient has been initially managed for a IB2 squamous cell carcinoma (SCC) with definitive concurrent pelvic chemoradiation and brachytherapy. A 2-cm urethral recurrence occurred 19 months after initial management. Biopsy confirmed a grade 2 squamous recurrence. Preoperative MRI and PET CT did not detect any extrapelvic spread. After tumor board, patient was suggested a RALPE with pelvic lymphadenectomy (10 pN0). Seven months later, she developed a fistula between the urinary stoma and skin, which was fixed after a surgical fistulectomy. After 9-month follow up, the patient is alive but with disease. Another central and lateropelvic recurrence has recently been diagnosed managed by chemotherapy.

Prospective Multicenter Comparison of Models to Predict Four or More Involved Axillary Lymph Nodes in Patients With Breast Cancer With One to Three Metastatic Sentinel Lymph Nodes

PURPOSE Three models have been developed to predict four or more involved axillary lymph nodes (ALNs) in patients with breast cancer with one to three involved sentinel lymph nodes (SLNs). Two scores were developed by Chagpar et al (Louisville scores excluding or including method of detection), and a nomogram was developed by Katz et al. The purpose of our investigation was to compare these models in a prospective, multicenter study. PATIENTS AND METHODS Our study involved a cohort of 536 patients having one to three involved SLNs who underwent ALN dissection. We evaluated the area under the receiver operating characteristic curve (AUC), calibration (for the Katz nomogram only), false-negative (FN) rate, and clinical utility of the three models. Results were compared with the optimal logistic regression (OLR) model that was developed from the validation cohort. RESULTS Among the 536 patients, 57 patients (10.6%) had > or = four involved ALNs. The AUC for the Katz nomogram was 0.84 (95% CI, 0.81 to 0.86). The Louisville score excluding method of detection was 0.75 (95% CI, 0.72 to 0.78). The Louisville score including method of detection was 0.77 (95% CI, 0.74 to 0.79). The FN rates were 2.5% (eight of 321 patients), 1.8% (two of 109 patients), and 0% (zero of 27 patients) for the Katz nomogram and the Louisville scores excluding and including method of detection, respectively. The Katz nomogram was well calibrated. Optimism-corrected bootstrap estimate AUC of the OLR model was 0.86. Using this result as a reasonable target for an external model, the performance of the Katz nomogram was remarkable. CONCLUSION We validated the three models for their use in clinical practice. The Katz nomogram outperformed the two other models.

Modified posterior pelvic exenteration for ovarian cancer.

Introduction: A modified posterior pelvic exenteration (MPE) might be needed to reach an optimal tumoral reduction. The issue of this study is to relate a multicentric experience of this kind of resection. Materials: Three hundred five patients who needed an MPE were analyzed from 9 French cancer centers. One hundred sixty-eight MPEs were performed during initial surgery (55.1%), 69 during interval surgery (22.6%), 36 after chemotherapy (11.8%), and 32 for recurrences (10.5%). Results: Three hundred two colorectal anastomoses were realized with a protective stoma in 59 (19.5%) of cases and a stoma closure in 76.5% (51). The rate of functional anastomosis was 96% (290/302). Complications occurred in 26.9% (82/305) of the patients, with a fistula in 25 (8.2%). The reintervention rate was 8.8% (27/305). The median length of hospitalization was 15 days. The absence of a macroscopic residual disease was obtained in 58% (173/303) of cases. A residual disease that was 1 cm or smaller was observed in 73 cases (24%) and 2 cm or smaller observed in 36 (11.9%). Postoperative chemotherapy was started with a median time of 32 days. Postoperative death occurred in 1 patient (0.33%). The survival rates were 62.7% and 27.6% at 2 and 5 years, respectively. With a multivariate analysis, the 2 significant prognostic factors were residual disease and time of surgery (P < 0.0001). Conclusions: A rectal invasion should not be an obstacle to reach the aim to obtain a macroscopic minimal residual disease or, if possible, the absence of one. An MPE is useful in those cases to reach optimal cytoreduction, with comparable results whatever the patients age is. A temporary protective stoma should be considered only exceptionally.

Robotically assisted para-aortic lymphadenectomy: Surgical results: A cohort study of 487 patients

Objectives The aim of this study was to evaluate perioperative outcomes of robotic-assisted laparoscopic para-aortic lymphadenectomy (PAL) in patients with gynecologic cancers during the learning phases of robotic surgery programs and to compare results of extraperitoneal versus transperitoneal approaches of PAL. Materials and Methods This study is a retrospective multicentric study of patients who underwent robotically assisted laparoscopic PAL (N = 487). Eleven European centers and 1 US center participated in the study. Abstracted data included age, body mass index, indication, type of surgical approach (transperitoneal or extraperitoneal), associated surgical procedures, operative time, estimated blood loss, lymph node count, hospital length of stay (LOS), and complications. Para-aortic lymphadenectomy was performed by an extraperitoneal approach in 58 cases (12%) and transperitoneal in 429 cases (88%). Results The mean (SD) para-aortic lymph node count was 12.6 (8.1), operative time was 217 (85) minutes, estimated blood loss was 105 (110) mL, and LOS was 2.8 (3.2) days. Four (0.8%) conversions to open and 2 (0.4%) conversions to laparoscopy were described. There were 32 lymphocysts (6.6%), 3 deep venous thromboses (0.6%), and 10 transfusions (2.1%). For transperitoneal approach, the average number of lymph nodes removed was higher in isolated PAL group than the hysterectomy combined group (report node counts 95% confidence interval, −7.29 to −3.52, P = 1.5 × 10−6). For isolated PAL, the LOS was shorter in the extraperitoneal group than in the transperitoneal group (report data 95% CI, −1.35 to −0.35, P = 0.001). Conclusions Robotic-assisted PAL seems safe and feasible. More lymph nodes were removed during an isolated transperitoneal PAL dissection compared with a combined procedure with hysterectomy. Extraperitoneal approach seems attractive relative to transperitoneal dissection, but the superiority of one or the other way is not demonstrated by our study.

Cost-Effectiveness of Conventional vs Robotic-Assisted Laparoscopy in Gynecologic Oncologic Indications.

Objective Robotic 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. Methods Between 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. Results Based 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). Conclusions The 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.

Morbidity of surgery after neoadjuvant chemotherapy including bevacizumab for advanced ovarian cancer.

Objective Neoadjuvant chemotherapy followed by interval debulking surgery is an alternative for the management of advanced ovarian cancer (AOC). Owing to unresectable disease at initial evaluation, some patients received bevacizumab in addition to neoadjuvant chemotherapy. The aim of this study was to evaluate the safety and postoperative course of patients who had received bevacizumab before debulking surgery for AOC. Methods In 2012, we identified all patients with AOC who had received neoadjuvant bevacizumab before debulking surgery. We recorded patients’ characteristics, surgical course, and postoperative complications. Results Five patients were identified, of whom 80% were International Federation of Gynecology and Obstetrics stage 4 at diagnosis. All patients underwent surgery after 6 courses of neoadjuvant chemotherapy with carboplatin, paclitaxel, and bevacizumab. The median number of bevacizumab injections was 3 (3–4), and the median time between the last injection of bevacizumab and surgery was 54 days (34–110 days). One patient had a grade 3 complication (lymphocyst with puncture under computed tomographic scans). Conclusion In this preliminary study, debulking surgery after neoadjuvant chemotherapy that included bevacizumab did not increase the rate of postoperative complications when there was a reasonable interval between the last bevacizumab injection and surgery. Larger studies are warranted to assess surgical safety after antiangiogenic treatment in the neoadjuvant setting for advanced ovarian cancer.