Mathieu Luyckx

Maximal cytoreduction in patients with FIGO stage IIIC to stage IV ovarian, fallopian, and peritoneal cancer in day-to-day practice: a Retrospective French Multicentric Study

Objectives To evaluate the outcome of maximal cytoreductive surgery in patients with stage IIIC to stage IV ovarian, tubal, and peritoneal cancer regarding overall survival (OS) and disease-free survival (DFS). Materials and Methods Five hundred twenty-seven patients with stage IIIC (peritoneal) and stage IV (pleural) ovarian, fallopian tube, and peritoneal carcinoma underwent surgery between January 2003 and December 2007 in 7 gynecologic oncology centers in France. Patients undergoing primary and interval debulking surgery were included, whichever the number of chemotherapy cycles. The extent of disease, type of surgical procedure, and amount of residual disease were recorded. A multivariate analysis of the outcome was performed, taking into account the stage, grade, and timing of surgery. Results Median DFS was 17.9 months, but median OS was not reached at the time of analysis. Complete cytoreductive surgery, without evident residual tumor at the end of the procedure, was obtained in 71% of all patients (primary surgery, 33%). After neoadjuvant therapy, the rate of complete debulking surgery was higher (74%) compared to primary cytoreductive surgery (65%). Twenty-three percent of patients needed “ultra radical surgery” to achieve this goal. The most significant predictive factor for DFS and OS was complete cytoreductive surgery compared to any amount, even minimal (1–10 mm), of residual disease. In the group of patients with complete cytoreductive surgery, the patients undergoing surgery before chemotherapy showed better DFS than those having first chemotherapy. Conclusion The findings confirm that complete cytoreduction is the criterion standard of surgery in the management of advanced ovarian, peritoneal, and fallopian tube cancer, whatever the timing of surgery. With experienced teams, surgery was completed, without evident residual tumor in 71% of the cases.

Efficacy of ovarian tissue cryopreservation for fertility preservation: lessons learned from 545 cases

STUDY QUESTION How effective is ovarian tissue cryopreservation (OTC)? SUMMARY ANSWER In our cohort of patients who underwent OTC, premature ovarian failure (POF) rates, return rates and pregnancy rates after autotransplantation were 31.5, 4.4 and 33%, respectively. WHAT IS KNOWN ALREADY OTC for fertility purposes has been performed for >20 years now. With over 86 live births reported worldwide and success rates of ~30% after autotransplantation of frozen-thawed ovarian cortex, the procedure should no longer be considered experimental. However, very few publications report the efficacy of this procedure. STUDY DESIGN, SIZE, DURATION Cases of ovarian tissue cryobanking for fertility preservation performed between 1997 and 2013 in a single institution were reviewed by analysis of the cryobank database and a prospective questionnaire sent out in March 2015. PARTICIPANTS/MATERIALS, SETTING, METHODS There were 545 patients who underwent OTC during this period. The analysis included indications for OTC, survival rates, ovarian function and spontaneous pregnancies after OTC, come-back rates for ovarian tissue transplantation, pregnancy rates after transplantation, and complication and satisfaction rates. MAIN RESULTS AND THE ROLE OF CHANCE OTC was performed in this cohort at a mean age of 22.3 ± 8.8 years for oncological indications (79%), benign gynecological pathologies (17.5%) and genetic risks of POF (3.5%). Of the 545 patients, 29% were under 18 years of age at the time of OTC and 15% were prepubertal. While 10% of patients died from their disease, 21 patients (3.9%) underwent autotransplantation, 7 of whom delivered a healthy baby, yielding a post-transplantation live birth rate of 33%. Of 451 patients who were sent the questionnaire, 143 agreed to respond (32%). Nevertheless, ovarian function could not be evaluated in 36% of those who answered. Of 92 evaluable patients, 31.5% were menopausal and 68.5% showed persistent ovarian function. Of 52 women who attempted to conceive naturally, 37 were successful (71%). Among 140 patients who answered the questionnaire, 96% were satisfied with the procedure and only 1 major complication (intra-abdominal hemorrhage) was encountered. Among all the patients, 12% have donated their ovarian cortex for research purposes or have had it destroyed. LIMITATIONS, REASONS FOR CAUTION The questionnaire participation rate (32%), limited follow-up (mean 7.6 ± 3.5 years) and use of only clinical criteria for evaluation of ovarian function made it difficult to accurately assess the risk of POF and efficiency of OTC. WIDER IMPLICATIONS OF THE FINDINGS Our findings confirm a 30% pregnancy rate after ovarian cortex autotransplantation but also stress the difficulties of evaluating the real efficacy of OTC. STUDY FUNDING/COMPETING INTEREST(S) No funding was sought for this study and none of the authors have any conflict of interest. TRIAL REGISTRATION NUMBER ClinicalTrials.gov Registration ID: CRYOFONOV01.

Characterization of patient-derived tumor xenograft models of endometrial cancer for preclinical evaluation of targeted therapies.

OBJECTIVE Endometrial carcinoma (EC) is the sixth most common cancer in women and therapies are limited for advanced and recurrent disease. Patient-derived tumor xenograft (PDTX) models are becoming popular tools in translational research because of their histological and genetic similarity to the original tumors and the ability to predict therapeutic response to treatments. Here, we established and characterized a panel of 24 EC PDTX models which includes the major histological and genetic subtypes observed in patients. METHODS Fresh tumor tissues collected from primary, metastatic and recurrent type I and type II EC patients were engrafted in immunocompromised mice. Histology, vimentin, and cytokeratin expression were evaluated, together with Microsatellite instability (MSI), mutation profiling by Whole Exome Sequencing and copy number profiling by Whole Genome Low Coverage Sequencing. The efficacy of both PI3K and MEK inhibitors was evaluated in a model of endometrioid carcinoma harboring PTEN, PIK3CA and KRAS mutations. RESULTS We observed good similarity between primary tumors and the corresponding xenografts, at histological and genetic level. Among the engrafted endometrioid models, we found a significant enrichment of MSI and POLE mutated tumors, compared to non-engrafted samples. Combination treatment with NVP-BEZ235 and AZD6244 showed the possibility to stabilize the tumor growth in one model originated from a patient who already received several lines of chemotherapy. CONCLUSION The established EC PDTX models, resembling the original human tumors, promise to be useful for preclinical evaluation of novel combination and targeted therapies in specific EC subgroups.

Secondary complete cytoreduction in recurrent ovarian cancer: benefit of optimal patient selection using scoring system

Objective Complete tumor cytoreduction seems to be beneficial for patients with recurrent epithelial ovarian cancer (REOC). The challenge is to identify patients eligible for such surgery. Several scores based on simple clinical parameters have attempted to predict resectability and help in patient selection for surgery in REOC. The aims of this study were to assess the performance of these models in an independent population and to evaluate the impact of complete resection. Materials and Methods A total of 194 patients with REOC between January 2000 and December 2010 were included in 2 French centers. Two scores were used: the AGO DESKTOP OVAR trial score and a score from Tian et al. The performance (sensitivity, specificity, and predictive values) of these scores was evaluated in our population. Survival curves were constructed to evaluate the survival impact of surgery on recurrence. Results Positive predictive values for complete resection were 80.6% and 74.0% for the DESKTOP trial score and the Tian score, respectively. The false-negative rate was high for both models (65.4% and 71.4%, respectively). We found a significantly higher survival in the patients with complete resection (59.4 vs 17.9 months, P < 0.01) even after adjustment for the confounding variables (hazard ratio [HR], 2.53; 95% confidence interval, 1.01–6.3; P = 0.04). Conclusions In REOC, surgery seems to have a positive impact on survival, if complete surgery can be achieved. However, factors predicting complete resection are not yet clearly defined. Recurrence-free interval and initial resection seem to be the most relevant factors. Laparoscopic evaluation could help to clarify the indications for surgery.

Are Early Relapses in Advanced-Stage Ovarian Cancer Doomed to a Poor Prognosis?

Objective Early recurrence (ER) after completion of therapeutic regimen in advanced-stage ovarian cancer is a challenging clinical situation. Patients are perceived as invariably having a poor prognosis. We investigated the possibility of defining different prognostic subgroups and the parameters implicated in prognosis of ER patients. Study Design We analyzed a multi-centric database of 527 FIGO stage IIIC and IV ovarian cancer patients. We defined patients relapsing within 12 months as ER and investigated using Cox logistic regression the prognostic factors in ER group. We subsequently divided ER patients into good and poor prognosis groups according to a lower or higher overall survival (OS) at 12 months after relapse and determined parameters associated to poor prognosis. Results The median follow up was 49 months. One hundred and thirty eight patients recurred within 12 months. OS and Disease Free Survival (DFS) were 24.6 and 8.6 months, respectively, in this group of patients. Among the ER patients, 73 had a poor prognosis with an OS after relapse below 12 months (mean OS = 5.2 months) and 65 survived after one year (mean OS = 26.9 months). Residual disease (RD) after debulking surgery and mucinous histological subtype negatively impacted prognosis (HR = 1.758, p = 0.017 and HR = 8.641, p = 0.001 respectively). The relative risk of death within 12 months following relapse in ER patients was 1.61 according to RD status. However, RD did not affect DFS (HR = 0.889, p = 0.5). Conclusion ER in advanced-stage ovarian cancer does not inevitably portend a short-term poor prognosis. RD status after initial cytoreduction strongly modulates OS, that gives additional support to the concept of maximum surgical effort even in patients who will experience early recurrence. The heterogeneity in outcomes within the ER group suggests a role for tumor biology in addition to classical clinical parameters.

Profile of vintafolide (EC145) and its use in the treatment of platinum-resistant ovarian cancer.

Objective Our aim was to review the profile of vintafolide (EC145) and its rationale for use in platinum-resistant ovarian cancer. First we investigated the folate receptors (FRs), folate’s pathway into cells, and its expression in normal and cancerous cells, before detailing the mechanism of action of vintafolide, its clinical applications, and the results of different study phases. Materials and methods A literature search was conducted through PubMed/Medline, Google, ClinicalTrials.gov and websites of pharmaceutical companies. Only articles in English were selected. All articles investigating folate receptor expression in ovarian cancer were selected first, than articles reviewing platinum resistance. Papers about vintafolide were collected, while those talking about synthesis and biochemistry concerns were excluded. The different Phase I and II studies were read, and an update on the website of pharmaceuticals companies were added. Results FR is a bundle-membrane receptor that is expressed normally in some normal tissues on the apical surface of cells, but highly expressed in ovarian cancer cells (>80%). It collects folate through endocytosis. Chemotherapy does not modify its expression in ovarian cancer cells, and its expression appears to be mostly associated with a poor prognosis and platinum resistance. Vintafolide is a folate-desacetylvinblastine monohydrazide conjugate, allowing a liberation of the drug into the cytoplasm of cancerous cells via the FR-α (FRα) and endocytosis, with high specificity. Phase I studies showed a 2.5 mg bolus dose to be nontoxic, with moderately adverse events. Phase II clinical trials for the first time demonstrated a statistically significant improvement in disease-free survival in patients with platinum-resistant ovarian cancer, and in those with a very poor prognosis who had already received three to four lines of systemic chemotherapy. The greater benefits were observed in patients with highly expressed FRα. Conclusion Vintafolide is a promising targeted agent for recurrent platinum-resistant ovarian cancer, first, thanks to its mechanism of action and the characteristics of FRα in ovarian cancer, and, second, because of the favorable results observed in the first clinical trials on platinum-resistant ovarian cancer. Phase III clinical trials are currently ongoing and are expected to confirm these results.

Differential expression of genes from the homeobox A cluster in deep endometriotic nodules and peritoneal lesions.

OBJECTIVE To compare expression of homeobox A (HOXA) genes involved in the differentiation of the female reproductive tract in deep endometriotic nodules and peritoneal lesions. DESIGN Prospective experimental study. SETTING Academic gynecology research unit. PATIENT(S) Thirty patients undergoing laparoscopy. INTERVENTION(S) During laparoscopy, deep endometriotic nodules (n=30) and peritoneal lesions (n=11) were recovered. Eutopic endometrium and vaginal tissue (n=30) were collected for control purposes. MAIN OUTCOME MEASURE(S) Quantification of HOXA-9, HOXA-10, HOXA-11, and HOXA-13 in deep nodules, peritoneal lesions, and control samples by real-time reverse-transcription polymerase chain reaction, and localization of HOXA-10 and HOXA-13 proteins by immunohistochemistry. RESULT(S) The HOXA-13 transcripts were detected in 29 out of 30 nodules, and their expression was significantly higher than in vaginal tissue, but they were barely detectable in endometrium and peritoneal lesions. Expression of HOXA-10 and HOXA-11 transcripts in deep nodules was similar to eutopic endometrium, and HOXA-10 expression was significantly lower in peritoneal endometriotic lesions. The HOXA-10 immunostaining was mainly localized in the stroma of deep endometriotic nodules, HOXA-13 in glandular structures and stroma, and neither of these proteins were detected in fibromuscular areas. CONCLUSION(S) Marked expression of HOXA-10 and HOXA-13 in the endometrium-like tissue of nodules but low expression in peritoneal endometriotic lesions supports the theory of differential origin of these two types of endometriosis.

Long-term nonsurgical control with ulipristal acetate of multiple uterine fibroids, enabling pregnancy.

MR images depict a marked response to Ulipristale Acetate in a woman with large uterine fibroids, and demonstrate no significant regrowth during pregnancy or 12 weeks postpartum

Matrix Metalloproteinase Activity Correlates With Uterine Myoma Volume Reduction After Ulipristal Acetate Treatment

Context Ulipristal acetate (UPA), a selective progesterone receptor modulator, clinically reduces uterine myoma size in 80% of cases. However, the molecular mechanism of action is still poorly understood, as is the reason why 20% of myomas do not respond to treatment. Objective To elucidate whether matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) are associated with myoma volume shrinkage after UPA therapy. Design Prospective study. Setting Academic research unit of a university hospital. Patients Uterine biopsies were obtained from 59 patients with symptomatic myomas undergoing myomectomy, 45 of whom were treated preoperatively with either one or greater than or equal to two, 3-month courses of UPA and 14 not given any hormone therapy to serve as controls. Myoma volume was individually monitored during UPA therapy to determine any substantial clinical response (defined as a reduction in volume of >25%). Three groups were established based on the response to treatment: responsive (R) after one course (n = 12); R after two to four courses (n = 15); and nonresponsive (NR; n = 18). Interventions UPA treatment given as preoperative management for symptomatic myomas. Main Outcome Measures MMP and TIMP expression assessed by zymography and immunohistochemistry. Results Compared with controls and NR myomas, responders showed significantly higher expression levels for MMP-1 (P < 0.0001) and MMP-2 (P = 0.009) and significantly lower expression levels for TIMP-1 (P = 0.040). Conclusions The correlation found between MMP expression and volume fold change supports the notion that MMPs play a key role in UPA-induced myoma shrinkage.

Progesterone Receptor Isoforms, Nuclear Corepressor-1 and Steroid Receptor Coactivator-1 and B-Cell Lymphoma 2 and Akt and Akt Phosphorylation Status in Uterine Myomas after Ulipristal Acetate Treatment: A Systematic Immunohistochemical Evaluation.

Objective: To investigate whether ulipristal acetate (UPA) treatment modifies the expression of progesterone receptor (PR), its nuclear cofactors steroid receptor coactivator-1 (SRC1) and nuclear corepressor-1 (NCoR1), prosurvival factor B-cell lymphoma 2 (Bcl-2), and Akt in uterine myomas. Patients: Prospective study of 59 women with symptomatic myomas undergoing myomectomy. Forty-two patients were treated preoperatively with UPA; the remaining 17 were not and they served as controls. Method: Tissue microarrays were obtained from surgical specimens and immunohistochemistry was performed. Blinded quantification of expression of PR (PR-A vs. PR-B), coactivator SRC1 and corepressor NCoR1, and prosurvival factor Bcl-2, and Akt and evaluation of Akt phosphorylation levels. Results: Compared with the control group, UPA does not alter PR protein levels or expression patterns in myomas, and the PR-A/PR-B ratio was similar, as well as cytoplasmic or nuclear expression of cofactors SRC1 and NCoR1. Bcl-2 was heterogeneously expressed throughout the samples and no significant modification in expression was evidenced. No significant difference was found in Akt expression and phosphorylation between treated and untreated myomas. Conclusion: This study did not find any significant change in the expression of the studied factors in myomas after UPA exposure. In conclusion, various theories on myomas cells proposed on the basis of in vitro studies are not supported in vivo.