Genomic profile analysis of leiomyomas with bizarre nuclei and fumarate hydratase deficient leiomyomas: Strengths, weaknesses, and limitations of array-CGH interpretation.

A close relationship has been demonstrated between genomic complexity and clinical outcome in uterine smooth muscle tumors. We studied the genomic profiles by array-CGH of 28 fumarate hydratase deficient leiomyomas and 37 leiomyomas with bizarre nuclei (LMBN) from 64 patients. Follow-up was available for 46 patients (from three to 249 months, mean 87.3 months). All patients were alive without evidence of disease. For 51 array-CGH interpretable tumors the mean Genomic Index (GI) was 16.4 (median: 9.8; from 1 to 57.8), significantly lower than the mean GI in LMS (mean GI 51.8, p < 0.001). We described three groups: (1) a group with FH deletion (24/58) with low GI (mean GI: 11 vs. 22,4, p = 0.02), (2) a group with TP53 deletion (17/58) with higher GI (22.4 vs. 11 p = 0.02), and (3) a group without genomic events on FH or TP53 genes (17/58) (mean GI:18.3; from 1 to 57.8). Because none of these tumors recurred and none showed morphological features of LMS we concluded that GI at the cut-off of 10 was not applicable in these subtypes of LM. By integration of all those findings, a GI <10 in LMBN remains a valuable argument for benignity. Conversely, in LMBN a GI >10 or alteration in tumor suppressor genes, should not alone warrant a diagnosis of malignancy. Nine tumors were tested with Nanocind CINSARC® signature and all were classified in low risk of recurrence. We propose, based on our observations, a diagnostic approach of these challenging lesions.

The OVAREX study: Establishment of ex vivo ovarian cancer models to validate innovative therapies and to identify predictive biomarkers.

BACKGROUND: Ovarian cancer is the first cause of death from gynecological malignancies mainly due to development of chemoresistance. Despite the emergence of PARP inhibitors, which have revolutionized the therapeutic management of some of these ovarian cancers, the 5-year overall survival rate remains around 45%. Therefore, it is crucial to develop new therapeutic strategies, to identify predictive biomarkers and to predict the response to treatments. In this context, functional assays based on patient-derived tumor models could constitute helpful and relevant tools for identifying efficient therapies or to guide clinical decision making. METHOD: The OVAREX study is a single-center non-interventional study which aims at investigating the feasibility of establishing in vivo and ex vivo models and testing ex vivo models to predict clinical response of ovarian cancer patients. Patient-Derived Xenografts (PDX) will be established from tumor fragments engrafted subcutaneously into immunocompromised mice. Explants will be generated by slicing tumor tissues and Ascites-Derived Spheroids (ADS) will be isolated following filtration of ascites. Patient-derived tumor organoids (PDTO) will be established after dissociation of tumor tissues or ADS, cell embedding into extracellular matrix and culture in specific medium. Molecular and histological characterizations will be performed to compare tumor of origin and paired models. Response of ex vivo tumor-derived models to conventional chemotherapy and PARP inhibitors will be assessed and compared to results of companion diagnostic test and/or to the patient's response to evaluate their predictive value. DISCUSSION: This clinical study aims at generating PDX and ex vivo models (PDTO, ADS, and explants) from tumors or ascites of ovarian cancer patients who will undergo surgical procedure or paracentesis. We aim at demonstrating the predictive value of ex vivo models for their potential use in routine clinical practice as part of precision medicine, as well as establishing a collection of relevant ovarian cancer models that will be useful for the evaluation of future innovative therapies. TRIAL REGISTRATION: The clinical trial has been validated by local research ethic committee on January 25th 2019 and registered at ClinicalTrials.gov with the identifier NCT03831230 on January 28th 2019, last amendment v4 accepted on July 18, 2023.

Outcomes of minimal residual disease at upfront debulking surgery compared with complete cytoreduction after neoadjuvant chemotherapy.

OBJECTIVE: The aim of this study was to compare surgical complexity, post-operative complications, and survival outcomes between patients with minimal residual disease (completeness of cytoreduction (CC) score) CC-1 at the time of primary debulking surgery and those with complete cytoreduction (CC-0) at the time of interval debulking surgery. METHODS: A retrospective multicenter study was conducted of patients with advanced ovarian cancer (International Federation of Gynecology and Obstetrics stage IIIC-IV) who underwent cytoreductive surgery achieving either minimal or no residual disease between January 2008 and December 2015. Patients underwent either primary or interval debulking surgery after receiving ≥3 cycles of neoadjuvant chemotherapy. The sub-group of patients with primary debulking surgery/CC-1 was compared with those with interval debulking surgery/CC-0. Overall survival and disease-free survival were estimated using the Kaplan-Meier method. RESULTS: A total of 549 patients were included, with upfront surgery performed in 175 patients (31.9%) and 374 patients (68.1%) undergoing interval debulking surgery. After primary debulking surgery, 157/175 (89.7%) had complete cytoreduction and 18/175 (10.3%) had minimal residual disease (primary debulking surgery/CC-1 group), while after interval debulking surgery, 324/374 (86.6%) had complete cytoreduction (interval debulking surgery/CC-0 group) and 50/374 (13.4%) had minimal residual disease. The rate of patients with peritoneal cancer index >10 was 14/17 (82.4%) for the primary debulking surgery/CC-1 group and 129/322 (40.1%) for the interval debulking surgery/CC-0 (p<0.001). The rate of patients with an Aletti score of ≥8 was 11/18 (61.1%) and 132/324 (40.7%), respectively (p=0.09) and the rate of major post-operative complications was 5/18 (27.8%) and 64/324 (19.8%), respectively (p=0.38). Overall median disease-free and overall survival were 19.4 months (95% CI 18.0 to 20.6) and 56.7 months (95%CI 50.2 to 65.8), respectively. Median disease-free survival for the primary debulking surgery/CC-1 group was 16.7 months (95% CI 13.6 to 20.0) versus 18.2 months (95% CI 16.4 to 20.0) for the interval debulking surgery/CC-0 group (p=0.56). Median overall survival for the primary debulking surgery/CC-1 group was 44.7 months (95% CI 34.3 to not reached) and 49.4 months (95% CI 46.2 to 57.3) for the interval debulking surgery/CC-0 group (p=0.97). CONCLUSIONS: Patients with primary debulking surgery with minimal residual disease and those with interval debulking surgery with no residual disease had similar survival outcomes. Interval surgery should be considered when achieving absence of residual disease is challenging at upfront surgery, given the lower tumor burden found during surgery.

Primary debulking surgery of the upper abdomen and the diaphragm, with a plasma device surgery system, for advanced ovarian cancer.

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

Total Infragastric Omentectomy Including the Vascular Perigastric Arcade in Patients With Advanced Serous Ovarian Tumors.

OBJECTIVE: The aim of this study was to document the need of including the perigastric area when performing omentectomy in patients with stage III to IV serous epithelial ovarian tumors. PATIENTS AND METHODS: Patients undergoing omentectomy in the setting of surgery for advanced epithelial serous ovarian cancer between February and September 2015 were included. Patients with macroscopic involvement of the perigastric area, nonepithelial serous tumors, and recurrences of ovarian cancer were excluded. The perigastric area was isolated and comprehensively processed for pathological examination. RESULTS: Twenty-four patients were included. Six patients underwent primary debulking surgery, and 18 patients underwent an interval debulking surgery. The mean number of pathologic blocks in the perigastric area was 24 (range, 8-41). Microscopic involvement of the perigastric omentum area was found in 62.5% of the cases. One patient had a low-grade serous carcinoma, with microscopic involvement of the perigastric area. Among the 23 patients with a high-grade serous carcinoma, 10 (83%) of 12 patients with a gross involvement of the rest of the omentum had a microscopic involvement of the perigastric area. The presence of microscopic disease in the perigastric arcade was found in 4 (36.3%) of 11 patients with a macroscopically normal omentum. CONCLUSIONS: In this study, evidence is given that total omentectomy including the perigastric area is a necessary component of complete cytoreductive surgery in advanced ovarian cancer, whatever the macroscopic appearance of the omentum.

Factors Limiting Ostomy Reversal After Cytoreductive Surgery for Ovarian Cancer: A Retrospective Study.

BACKGROUND/AIM: To investigate the factors related to non-reversal of ostomy after cytoreductive surgery in ovarian cancer. In many women with ovarian cancer, transitory ostomies are performed to limit the consequences of anastomotic leak. Although intended to be temporary, a proportion of these ostomies might never be reversed. PATIENTS AND METHODS: This was a retrospective study of patients with 2014 International Federation of Obstetrics and Gynecology stage IIB-IVB ovarian cancer requiring a transitory ostomy during primary or secondary cytoreductive surgery at the Bergonie Institute, France, and the University Hospital of Las Palmas, Spain, between January 2012 and December 2022. Rate of ostomy reversal, its timing (weeks) and postoperative complications were assessed. Multivariate logistic regression analysis was performed to identify limiting factors for ostomy reversal. RESULTS: During the study period, we reviewed data on 181 consecutive patients with ovarian cancer with transitory ostomy creation; 89 (49.2%) patients were not candidates for an ostomy reversal surgery because of disease progression (n=65), death (n=16), and patient's refusal of surgery (n=8). A total of 92 patients were candidates for reversal surgery and were therefore included in the final analysis. In total, 57 (62%) patients had their ostomy reversed. The mean time from ostomy creation to ostomy closure was 47.7 (standard deviation=33.1) weeks. Hartmann's procedure (leaving a rectal stump of 5-6 cm) was identified as an independent predictive factor for non-reversal of ostomy (odds ratio=6.42, 95% confidence interval=1.61-25.53; p=0.008). Complications after ostomy reversal occurred in 32 patients (34.8%). CONCLUSION: Hartmann's procedure is a limiting factor for ostomy reversal in patients with ovarian cancer. We recommend avoiding Hartmann's procedure during cytoreductive surgery, even after colorectal anastomotic leak.

Variability of treatment of locally advanced cervical cancer: How French multidisciplinary teams follow European guidelines?

INTRODUCTION: Cervical cancer is a global public health concern. Despite ESGO recommendations and FIGO classification changes, management of locally advanced cervical cancer (LACC) remains debated in France. Our study aimed to review LACC treatment practices and assess adherence to ESGO recommendations among different practitioners. METHODS: From February 2021 to August 2022, we conducted a survey among gynecologic oncology surgeons, radiation oncologists, and medical oncologists practicing in France and managing LACC (FIGO stages IB3-IVA) according to the 2018 FIGO classification. We analyzed responses against the 2018 ESGO recommendations as a "gold standard." RESULTS: Among 115 respondents (56% radiation oncologists, 30% surgeons, 13% medical oncologists), 48.6% of gynecologic surgeons didn't perform para-aortic lymphadenectomy (PAL) with significant radiologic pelvic involvement. PAL, when indicated by PET-CT, was more common in university hospitals (66.7% of surgeons). Surgeons in university hospitals also followed ESGO recommendations more closely. Overall, compliance with all ESGO recommendations was low: 5.7% of surgeons, 21.5% of radiation oncologists, and 60% of medical oncologists. Prophylactic para-aortic irradiation, per ESGO, was more frequent in comprehensive cancer centers (52% of radiation oncologists). CONCLUSION: Adherence to ESGO recommendations for LACC treatment appears low in France, particularly in surgery, with limited PAL in cases of lymph node negativity on PET-CT. However, these recommendations are more often followed by surgeons in university hospitals and radiation oncologists in cancer centers. Adherence to these recommendations may impact patient survival and warrants evaluation of care quality, justifying the organization of LACC management in expert centers.

Pelvic insufficiency fractures after intensity modulated radiation therapy combined with chemotherapy for cervix carcinoma: Incidence and impact of bone mineral density.

Background and Purpose: The aim of this study was to evaluate the incidence and predictive factors of Pelvic Insufficiency Fractures (PIFs) occurring after Intensity Modulated Radiation Therapy (IMRT) combined with chemotherapy for locally advanced cervical cancer (CC). Material and methods: Medical records of patients receiving radio-chemotherapy with IMRT between 2010 and 2020 for advanced CC were reviewed. PIFs were detected during follow-up on pelvic Magnetic Resonance Imaging (MRI) or Computed Tomography (CT). The cumulative incidence rate of PIFs and its confidence interval were calculated at 2 and 5 years of follow-up. Pre-therapeutic Bone Mineral Density (BMD) (g/cm3) was evaluated on CT simulation for sacrum and the fourth lumbar (L4) vertebrae. Sacrum dosimetric parameters (V30Gy, V40Gy, D50%, Dmean) were analyzed. Results: 136 patients were included. The median follow-up was 4.4 years. Median dose of D50% and V40Gy sacrum were 35.2 Gy (20.6-46.4) and 32.2% (7.2-73.4) respectively. The 2-year and 5-year cumulative incidence rates were 15.7% (95% CI: 9.88-22.71) and 22% (95% CI: 14.58-30.45) respectively. Median time interval between RT completion and PIFs' detection was 11.5 months (IQR: 7.4-22.3). Univariate analysis showed that older age (p < 0.01), postmenopausal status at baseline (p < 0.01), and lower sacral and spinal BMD at baseline (respectively p < 0.001 and p < 0.01) were significantly associated to all sites of PIFs, and lower sacral BMD with sacral fractures (p < 0.001). Conclusion: Post-IMRT PIFs were detected in 18.4% of patients with locally advanced CC. Individual predisposing factors as older age, postmenopausal status, decreased bone density on the CT simulation were mainly predictive.

[Treatments for rare ovarian tumors: What's new?] / Avancées thérapeutiques dans la prise en charge des tumeurs rares malignes ovariennes.

Even if each rare ovarian tumor (ROT) has a low incidence, the sum of all these entities represents almost the half of all ovarian neoplasms. Thus, development of dedicated clinical trial emerged as a prerequisite to improve their managements. Owing to the spreading of dedicated institutional networks and (supra)national collaborations, the number of clinical trials has increased the past few years, with different types of trials; while some focused on specific molecular features, others assessed innovative molecules. Furthermore, relevant randomized clinical trials were designed as a mean to position new treatment options. Currently, innovative molecular-driven trials, based on master protocol trials are emerging and may shed light towards the improvement of personalized medicine regarding ROT.

Comparative analysis of response to treatments and molecular features of tumor-derived organoids versus cell lines and PDX derived from the same ovarian clear cell carcinoma.

BACKGROUND: In the era of personalized medicine, the establishment of preclinical models of cancer that faithfully recapitulate original tumors is essential to potentially guide clinical decisions. METHODS: We established 7 models [4 cell lines, 2 Patient-Derived Tumor Organoids (PDTO) and 1 Patient-Derived Xenograft (PDX)], all derived from the same Ovarian Clear Cell Carcinoma (OCCC). To determine the relevance of each of these models, comprehensive characterization was performed based on morphological, histological, and transcriptomic analyses as well as on the evaluation of their response to the treatments received by the patient. These results were compared to the clinical data. RESULTS: Only the PDX and PDTO models derived from the patient tumor were able to recapitulate the patient tumor heterogeneity. The patient was refractory to carboplatin, doxorubicin and gemcitabine, while tumor cell lines were sensitive to these treatments. In contrast, PDX and PDTO models displayed resistance to the 3 drugs. The transcriptomic analysis was consistent with these results since the models recapitulating faithfully the clinical response grouped together away from the other classical 2D cell culture models. We next investigated the potential of drugs that have not been used in the patient clinical management and we identified the HDAC inhibitor belinostat as a potential effective treatment based on PDTO response. CONCLUSIONS: PDX and PDTO appear to be the most relevant models, but only PDTO seem to present all the necessary prerequisites for predictive purposes and could constitute relevant tools for therapeutic decision support in the context of these particularly aggressive cancers refractory to conventional treatments.

Biomarkers Associated with Lymph Nodal Metastasis in Endometrioid Endometrial Carcinoma.

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

The Anterior GRadient (AGR) family proteins in epithelial ovarian cancer.

Epithelial ovarian cancer (EOC) is the most common gynecologic disorder. Even with the recent progresses made towards the use of new therapeutics, it still represents the most lethal gynecologic malignancy in women from developed countries.The discovery of the anterior gradient proteins AGR2 and AGR3, which are highly related members belonging to the protein disulfide isomerase (PDI) family, attracted researchers' attention due to their putative involvement in adenocarcinoma development. This review compiles the current knowledge on the role of the AGR family and the expression of its members in EOC and discusses the potential clinical relevance of AGR2 and AGR3 for EOC diagnosis, prognosis, and therapeutics.A better understanding of the role of the AGR family may thus provide new handling avenues for EOC patients.

Bim, Puma and Noxa upregulation by Naftopidil sensitizes ovarian cancer to the BH3-mimetic ABT-737 and the MEK inhibitor Trametinib.

Ovarian cancer represents the first cause of mortality from gynecologic malignancies due to frequent chemoresistance occurrence. Increasing the [BH3-only Bim, Puma, Noxa proapoptotic]/[Bcl-xL, Mcl-1 antiapoptotic] proteins ratio was proven to efficiently kill ovarian carcinoma cells and development of new molecules to imbalance Bcl-2 member equilibrium are strongly required. Drug repurposing constitutes an innovative approach to rapidly develop therapeutic strategies through exploitation of established drugs already approved for the treatment of noncancerous diseases. This strategy allowed a renewed interest for Naftopidil, an α1-adrenergic receptor antagonist commercialized in Japan for benign prostatic hyperplasia. Naftopidil was reported to decrease the incidence of prostate cancer and its derivative was described to increase BH3-only protein expression in some cancer models. Based on these arguments, we evaluated the effects of Naftopidil on ovarian carcinoma and showed that Naftopidil reduced cell growth and increased the expression of the BH3-only proteins Bim, Puma and Noxa. This effect was independent of α1-adrenergic receptors blocking and involved ATF4 or JNK pathway depending on cellular context. Finally, Naftopidil-induced BH3-only members sensitized our models to ABT-737 and Trametinib treatments, in vitro as well as ex vivo, in patient-derived organoid models.

[Breast reconstruction in elderly patients: Studies of the practices at institut Bergonié during 2005-2015]. / Reconstruction mammaire chez les patientes âgées : études des pratiques de l'institut Bergonié 2005­2015.

INTRODUCTION: The objective of our study is to describe the practices of breast reconstruction in patients aged 70 years and over undergoing a radical mastectomy at institut Bergonié. MATERIAL AND METHODS: We performed a detailed single-site retrospective study from January 2005 to December 2015. Through a computerized review, we have identified and analyzed all patients aged 70 years and over who underwent a breast reconstruction. RESULTS: Five hundred and ninety patients underwent a radical mastectomy during the period. Twenty-eight patients (4.7%) benefited from a breast reconstruction. Nineteen patients (67.9%) had an immediate breast reconstruction and 9 patients (32.1%) had a delayed breast reconstruction, within an average time of 2 years. Sixteen patients (57.1%) benefited from the insertion of an expander replaced by a permanent implant. Five patients (17.9%) benefited from the immediate placement of an implant. Six patients (21.4%) had a reconstruction by autologous latissimus dorsi flap and 1 patient (3.6%) by exclusive lipofilling. Four patients (14.3%) presented postoperative complications without the need for removal of an implant or flap loss. Twenty patients (71.4%) were satisfied with their final reconstruction. CONCLUSIONS: Breast reconstruction in elderly patients is possible. Further studies are needed to better describe French practices.

[A critical assessment of morcellation in case of uterine malignancies and its impact on gynecologic surgery: From "precautionary principle" to "realism"]. / Impact pronostique de la morcellation chirurgicale en cas de cancers utérins: du « principe de précaution ¼ au « réalisme ¼.

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