Synergy of the microRNA Ratio as a Promising Diagnosis Biomarker for Mucinous Borderline and Malignant Ovarian Tumors.

Epithelial ovarian cancers (EOCs) are a heterogeneous collection of malignancies, each with their own developmental origin, clinical behavior and molecular profile. With less than 5% of EOC cases, mucinous ovarian carcinoma is a rare form with a poor prognosis and a 5-year survival of 11% for advanced stages (III/IV). At the early stages, these malignant forms are clinically difficult to distinguish from borderline (15%) and benign (80%) forms with a better prognosis due to the large size and heterogeneity of mucinous tumors. Improving their diagnosis is therefore a challenge with regard to the risk of under-treating a malignant form or of unnecessarily undertaking radical surgical excision. The involvement of microRNAs (miRNAs) in tumor progression and their potential as biomarkers of diagnosis are becoming increasingly recognized. In this study, the comparison of miRNA microarray expression profiles between malignant and borderline tumor FFPE samples identified 10 down-regulated and 5 up-regulated malignant miRNAs, which were validated by individual RT-qPCR. To overcome normalization issues and to improve the accuracy of the results, a ratio analysis combining paired up-regulated and down-regulated miRNAs was performed. Although 21/50 miRNA expression ratios were significantly different between malignant and borderline tumor samples, any ratio could perfectly discriminate the two groups. However, a combination of 14 pairs of miRNA ratios (double ratio) showed high discriminatory potential, with 100% of accuracy in distinguishing malignant and borderline ovarian tumors, which suggests that miRNAs may hold significant clinical potential as a diagnostic tool. In summary, these ratio miRNA-based signatures may help to improve the precision of histological diagnosis, likely to provide a preoperative diagnosis in order to adapt surgical procedures.

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.

The TRIPLEX study: use of patient-derived tumor organoids as an innovative tool for precision medicine in triple-negative breast cancer.

BACKGROUND: Triple negative breast cancers (TNBC) account for approximately 15% of all breast cancers and are associated with a shorter median survival mainly due to locally advanced tumor and high risk of metastasis. The current neoadjuvant treatment for TNBC consists of a regimen of immune checkpoint blocker and chemotherapy (chemo-ICB). Despite the frequent use of this combination for TNBC treatment, moderate results are observed and its clinical benefit in TNBC remains difficult to predict. Patient-derived tumor organoids (PDTO) are 3D in vitro cellular structures obtained from patient's tumor samples. More and more evidence suggest that these models could predict the response of the tumor from which they are derived. PDTO may thus be used as a tool to predict chemo-ICB efficacy in TNBC patients. METHOD: The TRIPLEX study is a single-center observational study conducted to investigate the feasibility of generating PDTO from TNBC and to evaluate their ability to predict clinical response. PDTO will be obtained after the dissociation of biopsies and embedding into extra cellular matrix. PDTO will be cultured in a medium supplemented with growth factors and signal pathway inhibitors. Molecular and histological analyses will be performed on established PDTO lines to validate their phenotypic proximity with the original tumor. Response of PDTO to chemo-ICB will be assessed using co-cultures with autologous immune cells collected from patient blood samples. PDTO response will finally be compared with the response of the patient to evaluate the predictive potential of the model. DISCUSSION: This study will allow to assess the feasibility of using PDTO as predictive tools for the evaluation of the response of TNBC patients to treatments. In the event that PDTO could faithfully predict patient response in clinically relevant time frames, a prospective clinical trial could be designed to use PDTO to guide clinical decision. This study will also permit the establishment of a living biobank of TNBC PDTO usable for future innovative strategies evaluation. TRIAL REGISTRATION: The clinical trial (version 1.2) has been validated by local research ethic committee on December 30th 2021 and registered at ClinicalTrials.gov with the identifier NCT05404321 on June 3rd 2022, version 1.2.

ACOSOG Z-0011 criteria impact on axillary surgery for early breast cancer in clinical practice: Evaluation in a retrospective cohort of 1900 patients.

BACKGROUND: There is a trend towards de-escalation in early breast cancer axillary surgery. In the American College of Surgeons Oncology Group (ACOSOG) Z-0011 trial, observation was shown to be non-inferior in terms of overall survival to complementary axillary lymph node dissection (cALND) in patients with up to two sentinel lymph node (SLN) metastases. The study included patients with T1-T2 invasive breast cancer, clinically node negative, undergoing breast-conserving surgery with SLN biopsy, followed by systemic therapy and radiotherapy. The aim of our study was to evaluate the impact of applying these ACOSOG Z-0011 inclusion criteria in routine practice. PATIENTS AND METHODS: This retrospective observational study was conducted in a French comprehensive cancer center where patients treated for breast cancer with primary surgery were prospectively included between 2010 and 2016. Patients meeting ACOSOG Z-0011 inclusion criteria were analyzed. RESULTS: Among the 1900 included patients, 1497 (79 %) met the ACOSOG Z-0011 criteria before surgery. Of these, 390 (20 %) had one or two metastatic SLN and could have avoided cALND. Out of these patients, 319 (81 %) presented cT1 tumors. During the study period, cALND was performed in 320 (82 %) patients and was free of metastases in 80 % of cases, having an impact on eligibility for adjuvant chemotherapy in only 3 (0.8 %) patients. CONCLUSIONS: In situations of primary breast cancer surgery, use of ACOSOG Z-0011 criteria could reduce the rate of cALND by 20 %. Further studies are needed to help select patients for whom abstention from any axillary surgery would be reasonable.

AMeTHYST (AMbulatory HYsterectomy surgery). Feasibility of minimally invasive outpatient hysterectomy, a preliminary study.

OBJECTIVES: Hysterectomy, one of the most frequent surgical procedures in women, is commonly performed by a minimally-invasive approach (laparoscopic or vaginal) as recommended by the French guidelines. The French authorities aim to have 66 % of all procedures performed as same-day surgery in 2020. The aim of this study was to evaluate the feasibility and identify factors associated with success or failure of same-day surgery for minimally-invasive hysterectomy. STUDY DESIGN: We conducted a prospective double-center observational study at the Caen and Amiens University Hospitals between September 2017 and May 2018 including hospitalized patients managed for a laparoscopic or vaginal hysterectomy. Patients were younger than 70 and have no major medical problems. The patients were placed into a "fit" or "unfit" group according to their Post Anaesthetic Discharge Scoring System (PADSS) score 6 h post-surgery. All the patients were asked to complete an assessment questionnaire during their hospitalization. RESULTS: Of the 50 included patients, half were placed in the "fit" group. A history of laparotomy was significantly predictive of failure of same-day discharge (p = 0.003) but not uterine size or Body Mass Index (BMI). The main barriers for discharge were pain (p<0.001) and postoperative nausea/vomiting (PONV) (p<0.001). Four patients, all in the "unfit" group, had Clavien-Dindo grade 1 postoperative complications. CONCLUSION: Same-day minimally invasive hysterectomy is a feasible and safe procedure. Factors associated with same-day hysterectomy failure were laparotomy, pain and postoperative nausea/vomiting.

A case-control study about foetal trauma during caesarean delivery.

OBJECTIVE: The caesarean section rate is gradually increasing in most countries. The frequency of occurrence of foetal injury per birth is estimated to 1%. The majority of these injuries presents a low functional impact, but remains responsible for a significant neonatal morbidity. Even though the foetal risk factors are well documented in cases of vaginal birth, they have not been accurately identified for caesarean section. The aim of this study is to identify the risk factors for neonatal fracture during caesarean section. METHODS: We conducted a retrospective case-control study comparing complicated caesarean sections foetal fracture with uncomplicated caesarean sections in a tertiary teaching hospital. We collected all the caesarean sections carried out between 1st January 2003 and 1st September 2015 and selected those the medical files of which presented a foetal fracture diagnosis. RESULTS: We identified 10 fractures during the study period, including four skull fractures, three long bone fractures, three clavicle fractures. In all these cases there were no complications with a median perspective of six years (median=6, IQR=4). The push method, which is performed during a caesarean section at the second stage of labour, is identified as a risk factor for foetal trauma in our study (OR: 20.2 [2.8-116.85], p<0.01). A significant correlation was found between transverse lie and foetal trauma (OR: 16.67, CI [1.39; 123.18], p=0.0137). CONCLUSION: Foetal trauma during caesarean delivery is a rare event for which the prognosis is most often favourable. Data in the literature on the subject are minimal. This study highlighted transverse lie and the push method as risks factors for foetal fractures during caesarean sections. This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.