Engineering ovarian tissue via biofabrication and 3D bioprinting: Challenges and emerging perspectives Chieh En Hsu, Mario Mazza, Giordano Perini, Antonio Minopoli, Valeria Ferrara, Caterina Perfili, Giulia Artemi, Alberto Augello, Valentina Palmieri, Claudia Marchetti, Raffaella Ergasti, Camilla Nero, Marco De Spirito, Massimiliano Papi Bioengineering and Translational Medicine, 2026 The development of bioprosthetic ovaries using advanced biofabrication and 3D bioprinting technologies has achieved significant attention in recent years. This work begins with an analysis of ovarian anatomy and physiology, emphasizing the critical structural and functional components that must be replicated for an effective engineered in vitro model. It further outlines the principles and capabilities of 3D bioprinting, with a focus on the customization of printing modalities and bioinks to closely mimic native ovarian tissue. Given the ovary's dual functions in gametogenesis and endocrine signaling, attention is given to how engineered constructs can be designed to restore hormonal homeostasis through the precise spatial arrangement and biological activity of embedded cells. Finally, the technical challenges and ethical considerations associated with translating bioprinted ovarian tissues into clinical applications are discussed.
Predictors of Successful Neoadjuvant Chemotherapy and Interval Cytoreductive Surgery in Management of Ovarian Cancer Claudia Marchetti, Gwenael Ferron, Olivier Colomban, Diana Giannarelli, Felix Blanc-Durand, Giovanni Scambia, Pierre-Alexandre Just, Domenica Lorusso, Eric Pujade-Lauraine, Raffaella Ergasti, Alain Lortholary, Carolina Maria Sassu, Isabelle Ray-Coquard, Filippo Maria Capomacchia, Pierre Combe, Adriana Ionelia Apostol, Gian Franco Zannoni, Aurore Carrot, Umberto Malapelle, Alexandra Leary, Anna Fagotti, Benoit You JCO Oncology Practice, 2025 PURPOSE In patients with ovarian cancer undergoing neoadjuvant chemotherapy (NACT) with the goal of achieving complete interval cytoreductive surgery (ICS), tools are needed to accurately assess NACT efficacy and predict the feasibility of complete ICS after 3-4 cycles. The GINECO group (France) and Gemelli Hospital (Italy) analyzed two independent data sets to evaluate the predictive values of three tools available in routine. METHODS Data from CHIVA randomized phase II trial (ClinicalTrials.gov identifier: NCT01583322 ) and Policlinico Gemelli real-world registry (ID5936-ProtN45) were used to construct the French (N = 185) and Italian data sets (N = 357). Logistic regression models were used to identify the significant predictors—among modeled CA-125 Elimination Rate Constant K (KELIM); radiologic response; and BRCA /homologous recombination deficiency (HRD) status—of the following key indicators of successful ICS after NACT: (1) a low peritoneal carcinomatosis burden (Peritoneal Carcinomatosis Index [PCI]/Predictive Index Value [PIV]); (2) a complete CC0-R0 ICS); and (3) a pathologic Chemotherapy Response Score of 3 (CRS3). RESULTS In both French and Italian data sets, a favorable KELIM score ≥1.0 was reproducibly a predictor of higher probability of low PCI/PIV (odds ratios [OR], 2.92-4.19); CC0-R0 ICS (OR, 3.66-4.24); and pathologic CRS3 (OR, 2.36-21.44). An objective radiologic response was inconsistently associated with a lower PCI/PIV (OR, 1.78-3.69) and a CC0-R0 ICS (OR, 1.78-5.20). The BRCA /HRD status was not predictive of NACT efficacy. The proportion of patients achieving a CRS3 response was similar regardless of BRCA /HRD status. CONCLUSION In two data sets, the tumor chemosensitivity assessed by the KELIM (online calculator) 29 was a consistent significant predictor of three critical outcomes associated with successful ICS after NACT. The radiologic response was inconsistently associated with lower disease bulk. The BRCA /HRD status was not predictive of NACT efficacy. These outcomes may inform decisions and future chemosensitizing innovative strategies.
Integrating clinical-molecular data to predict PARP inhibitors efficacy in advanced ovarian cancer patients after interval cytoreductive surgery Claudia Marchetti, Raffaella Ergasti, Filippo Maria Capomacchia, Diana Giannarelli, Luca Mastrantoni, Francesco Pepe, Adriana Ionelia Apostol, Carolina Maria Sassu, Camilla Nero, Alessia Piermattei, Gian Franco Zannoni, Giancarlo Troncone, Olivier Colomban, Gianluca Russo, Aurore Carrot, Umberto Malapelle, Benoit You, Domenica Lorusso, Giovanni Scambia, Anna Fagotti Gynecologic Oncology, 2025 OBJECTIVE: Selecting the maintenance strategy for advanced tubo-ovarian high-grade serous carcinoma (HGSC) is challenging. This study evaluates the correlation among chemotherapy response score (CRS), homologous recombination deficiency (HRD) status, and KELIM score; identifies predictors of Poly (ADP-ribose) polymerase (PARP) inhibitor (PARPi) efficacy and stratifies recurrence risk in PARPi-treated population. METHODS: Median Progression-free Survival (mPFS) and hazard ratios (HRs) were retrospectively calculated in HGSC patients after neoadjuvant chemotherapy (3/4 cycles), interval cytoreductive surgery, and adjuvant treatment. Variables included HRD status, disease stage, KELIM, radiological response, residual tumor, and CRS at surgery. A risk-stratification model predicting PARPi efficacy was developed. RESULTS: Among overall population (N = 373), 66.9 % of CRS3 patients reached favorable KELIM, 17.3 % had complete radiological response, and 97.8 % achieved complete surgery, with higher frequencies than CRS1/2 (p < 0.001). Univariate analysis of PFS on PARPi (N = 210) showed favorable covariates: CRS3 (HR 2.37, 95 % CI 1.39-4.04 and HR 1.59, 95 % CI 1.03-2.47 vs CRS1 and CRS2), BRCA mutation (HR 3.41 95 % CI 2.15-5.39 and HR 2.00 95 % CI 1.13-3.56 vs BRCAwt-HRDneg and -HRDpos) and continuum KELIM (HR 0.66, 95 % CI 0.45-0.96). At multivariate, CRS3 and BRCA mutation were confirmed significant. Combining HRD status, CRS, and KELIM four prognostic groups with different PARPi efficacy were identified (mPFS 38 vs 26 vs 18 vs 6 months for Low, Intermediate, High-Intermediate, and High-risk groups). CONCLUSIONS: CRS is a prognostic factor in PARPi-treated population as a PARPi efficacy surrogate. Integrating HRD status, CRS, and KELIM allows patients risk stratification and tailored maintenance. These results should be considered hypothesis-generating.
BRCA functional domains associated with high risk of multiple primary tumors and domain-related sensitivity to olaparib: the Prometheus Study L. Incorvaia, C. Marchetti, C. Brando, T.D. Bazan Russo, M. Bono, A. Perez, L. Congedo, R. Ergasti, L. Castellana, L. Insalaco, S. Contino, V. Gristina, A. Galvano, D. Fanale, G. Badalamenti, A. Russo, G. Scambia, V. Bazan ESMO Open, 2025 BACKGROUND: Germline pathogenic variants (gPVs) in the breast cancer susceptibility gene 1/2 (BRCA1/2) genes confer high-penetrance susceptibility to breast cancer (BC) and ovarian cancer (OC). Although most female BRCA carriers develop only a single BRCA-associated tumor in their lifetime, a smaller subpopulation is diagnosed with multiple primary tumors (MPTs). The genetic factors influencing this risk remain unclear. Further, in patients with BRCA-mutated tumors, there appears to be a variability in the effectiveness of olaparib treatment. PATIENTS AND METHODS: This real-world, multicenter, observational study aimed to determine whether the location of BRCA gPVs within functional domains (FDs) is associated with the development of MPTs and the magnitude of olaparib benefit. The study population comprised consecutive patients with OC who underwent hereditary cancer genetic testing between May 2015 and March 2023. MPT history was assessed based on mutated genes (BRCA1 or BRCA2) and the location of the PVs within the FDs. Clinical outcomes of olaparib first-line maintenance therapy were evaluated according to BRCA1/2 FD location. RESULTS: The frequency of MPT history in the overall population was 13.3% (118/882), and 20.4% in the BRCA-mutated subpopulation (68/333; P < 0.001). We observed a significant association between the DNA-binding domain (DBD) FD of BRCA2 and MPT. Specifically, 55.6% of BRCA2-mutated patients with PVs in the DBD had a history of BC as a second tumor. At a median follow-up of 48.5 months (95% confidence interval 10-70 months), the 48-month progression-free survival rates were 100.0% for patients with PVs in DBD, 91.7% for those with PVs in other FDs, and 36.4% for those with PVs in the RAD51-binding domain (RAD51-BD) of BRCA2 (P = 0.01). Results in the BRCA1 cohort were not statistically significant. CONCLUSIONS: The results suggest that the location of PVs within BRCA FDs may influence the onset of multiple tumors and the benefit of olaparib in patients with BRCA-mutated OC. These findings could be relevant for cancer prevention efforts, particularly given the increasing number of cancer survivors. However, further understanding is needed before these results can inform clinical decisions.
Focus on Trabectedin in Ovarian Cancer: What Do We Still Need to Know? Serena Maria Boccia, Carolina Maria Sassu, Raffaella Ergasti, Laura Vertechy, Adriana Ionelia Apostol, Eleonora Palluzzi, Anna Fagotti, Giovanni Scambia, Claudia Marchetti Drug Design Development and Therapy, 2024 In the era of single and combination maintenance therapies as well as platinum and Poly (ADP-ribose) polymerase inhibitors (PARPi) resistance, the choice of subsequent treatments following first-line platinum-based chemotherapy in recurrent ovarian cancer (ROC) patients has become increasingly complex. Within the ovarian cancer treatment algorithm, particularly in the emerging context of PARPi resistance, the role of trabectedin, in combination with pegylated liposomal doxorubicin (PLD) still preserves its significance. This paper offers valuable insights into the multifaceted role and mechanism of action of trabectedin in ROC. The main results of clinical trials and studies involving trabectedin/PLD, along with hints of Breast Cancer genes (BRCA)-mutated and BRCAness phenotype cases, are critically discussed. Moreover, this review provides and contextualizes potential scenarios of administering trabectedin in combination with PLD in ROC, according to established guidelines and beyond.
Consistent data about the predictive factors of the success of interval debulking surgery (CC0-IDS) in patients with advanced ovarian cancers in two large independent datasets Benoit You, Anna Fagotti, Olivier Colomban, Diana Giannarelli, Felix Blanc-Durand, Giovanni Scambia, Aurore Carrot, Domenica Lorusso, Eric Pujade-Lauraine, Raffaella Ergasti, Gaetan De Rauglaudre, Carolina Maria Sassu, Isabelle Laure Ray-Coquard, Filippo Maria Capomacchia, Pierre Combe, Adriana Ionela Apostol, Gwenael Ferron, Umberto Malapelle, Alexandra Leary, Claudia Marchetti Journal of Clinical Oncology, 2024 5560 Background: More than 50% of patients with FIGO stage III-IV epithelial ovarian cancers are treated with neoadjuvant chemotherapy (NACT) to achieve a complete interval debulking surgery (IDS), in the case of tumor response. Therefore, understanding the determinants of IDS success is crucial. The French GINECO and the Gemelli (Italy) groups analyzed 2 independent datasets to identify the predictive factors associated with low peritoneal carcinomatosis index (PCI) after 3or4 NACT cycles; complete IDS with no macroscopic residual lesion (CC0); high pathological chemotherapy response score (CRS3). Methods: The French dataset was built with the CHIVA (C) randomized phase II trial in 133 patients (NCT01583322). The Italian dataset was built with the Policlinico GEMELLI (G) real-life registry with 357 patients (ID5936–ProtN45). Univariate/multivariate logistic regression models were used to identify the clinical and biological covariates associated with: 1) low PCI after NACT (Sugarbaker PCI ≤ 10, or Fagotti score at IDS ≤ 2); 2) CC0 IDS; and 3) pathological CRS3. The tested predictors were the modeled CA-125 longitudinal kinetics parameter KELIM; the best radiological response according to RECIST 1.1; and BRCA mutation/ homologous recombination deficiency (HRD) status (C: ShallowHRD; G: Myriad&AmoyDx). The analyses were led independently in the 2 datasets. Results: Odds-ratios (OR) outcomes [95%CI] are presented in Table (*significant variables at multivariate). In both datasets, higher KELIM was the only predictor reproducibly associated with lower PCI after NACT (OR 4.08-4.44); higher probability of complete IDS (OR 4.66-7.29); and higher probability of pathology CRS3 (OR 2.97-12.43). The radiological response was inconsistently significant. The BRCA/HRD status was not predictive of IDS success elements. Conclusions: In 2 independent international datasets, the tumor primary chemosensitivity (assessed by CA-125 KELIM) was the only consistent predictor of IDS success after NACT in both datasets. Clinical trial information: NCT01583322 . [Table: see text]
Lymph node staging in grade 1–2 endometrioid ovarian carcinoma apparently confined to the ovary: Is it worth? Nicolò Bizzarri, Majdi Imterat, Robert Fruscio, Diana Giannarelli, Anna Myriam Perrone, Rosanna Mancari, Alexander Traut, Andrea Rosati, Andreas du Bois, Debora Ferrari, Pierandrea De Iaco, Raffaella Ergasti, Beyhan Ataseven, Tommaso Bianchi, Marco Di Stanislao, Maria Teresa Perri, Florian Heitz, Nicole Concin, Francesco Fanfani, Enrico Vizza, Giovanni Scambia, Philipp Harter, Anna Fagotti European Journal of Cancer, 2023 OBJECTIVE: The aim of this study was to assess the disease-free survival (DFS) and overall survival (OS) of patients with grade 1-2 endometrioid ovarian carcinoma apparently confined to the ovary, according to surgical staging. METHODS: Multicenter, retrospective, observational cohort study. Patients with endometrioid ovarian carcinoma, surgical procedure performed between May 1985 and December 2019, stage pT1 N0/N1/Nx, grade 1-2 were included. Patients were stratified according to lymphadenectomy (defined as removal of any lymph node versus no lymph node assessment), and subgroup analyses according to tumor grade were performed. Kaplan-Meier curves and cox regression analyses were used to perform survival analyses. RESULTS: 298 patients were included. 199 (66.8 %) patients underwent lymph node assessment. Of these, 166 (83.4 %) had unilateral/bilateral pelvic and para-aortic/caval lymphadenectomy. Eleven (5.5 %) patients of those who underwent lymph node assessment showed pathologic metastatic lymph nodes (FIGO stage IIIA1). Twenty-seven patients (9.1 %) had synchronous endometrioid endometrial cancer. After a median follow up of 45 months (95 %CI:37.5-52.5), 5-year DFS and OS of the entire cohort were 89.8 % and 96.2 %, respectively. Age ≤ 51 years (HR=0.24, 95 %CI:0.06-0.91; p = 0.036) and performance of lymphadenectomy (HR=0.25, 95 %CI: 0.07-0.82; p = 0.022) represented independent protective factors toward risk of death. Patients undergoing lymphadenectomy had better 5-year DFS and OS compared to those not receiving lymphadenectomy, 92.0 % versus 85.6 % (p = 0.016) and 97.7 % versus 92.8 % (p = 0.013), respectively. This result was confirmed after exclusion of node-positive patients. When stratifying according to tumor grade (node-positive excluded), patients with grade 2 who underwent lymphadenectomy had better 5-year DFS and OS than those without lymphadenectomy (93.0 % versus 83.1 %, p = 0.040 % and 96.5 % versus 90.6 %, p = 0.037, respectively). CONCLUSION: Staging lymphadenectomy in grade 2 endometrioid ovarian carcinoma patients was associated with improved DFS and OS. Grade 1 and grade 2 might be considered as two different entities, which could benefit from different approach in terms of surgical staging. Prospective studies, including molecular profiles are needed to confirm the survival drivers in this rare setting.
Impact of substage and histologic type in stage i ovarian carcinoma survival: A multicenter retrospective observational study Majdi Imterat, Nicolò Bizzarri, Robert Fruscio, Anna Myriam Perrone, Alexander Traut, Andreas du Bois, Andrea Rosati, Debora Ferrari, Pierandrea De Iaco, Beyhan Ataseven, Raffaella Ergasti, Silvia Volontè, Marco Tesei, Florian Heitz, Maria Teresa Perri, Nicole Concin, Francesco Fanfani, Giovanni Scambia, Anna Fagotti, Philipp Harter International Journal of Gynecological Cancer, 2022
Ectopic pregnancy in women with recurrent miscarriage Carlo Ticconi, Maria V. Capogna, Federica Martelli, Barbara Borelli, Valentina Bruno, Raffaella Ergasti, Roberto Sorge, Emilio Piccione, Adalgisa Pietropolli Journal of Obstetrics and Gynaecology Research, 2018