Background: Epithelial ovarian cancers (EOC) are usually diagnosed at an advanced stage and managed by complete macroscopic cytoreductive surgery (CRS) and systemic chemotherapy. Peritoneal recurrence occurs in 60% of patients and may be due to microscopic peritoneal metastases (mPM) which are neither eradicated by surgery nor controlled by systemic chemotherapy. The aim of this study was to assess and quantify the prevalence of residual mPM after complete macroscopic CRS in patients with advanced high-grade serous ovarian cancer (HGSOC). Methods: A prospective study conducted between 1 June 2018 and 10 July 2019 in a single referent center accredited by the European Society of Gynecological Oncology for advanced EOC management. Consecutive patients presenting with advanced HGSOC and eligible for complete macroscopic CRS were included. Up to 13 peritoneal biopsies were taken from macroscopically healthy peritoneum at the end of CRS and examined for the presence of mPM. A mathematical model was designed to determine the probability of presenting at least one mPM after CRS. Results: 26 patients were included and 26.9% presented mPM. There were no differences in characteristics between patients with or without identified mPM. After mathematical analysis, the probability that mPM remained after complete macroscopic CRS in patients with EOC was 98.14%. Conclusion: Microscopic PM is systematically present after complete macroscopic CRS for EOC and could be a relevant therapeutic target. Adjuvant locoregional strategies to conventional surgery may improve survival by achieving microscopic CRS.

Background and Aims: Cholangiocarcinoma (CCA) displays remarkable anatomical and histological heterogeneity. Besides diagnosis confirmation, histology currently does not have a major role in the management of CCA. We aimed to study the clinical relevance of histological heterogeneity of CCA and putative tissue biomarkers by creating a multicentric digitalized European CCA Histology Registry. Approach and Results: Nine referral centers, participating in the International Cholangiocarcinoma Clinical Registry, shared samples and data from 293 patients. Histological and immunohistochemistry stains (n=10) were performed. Computed tomography (CT) scans (n=112 cases) were analyzed by morphological and radiomics techniques. A selection of cases (n=18) was processed for spatial transcriptomics analysis. No significant differences in 5-year overall survival (OS) were found in perihilar CCA versus intrahepatic (i) CCA, and in small bile duct (SBD) versus large bile duct (LBD) iCCA. When cases were classified by Periodic acid of Schiff (PAS) positivity (mucin content), PAS ^HIGH LBD iCCA showed a significantly worse 5-year OS compared to PAS ^LOW iCCA. Multivariate Cox regression identified PAS ^HIGH LBD iCCA phenotype as an independent predictor of worse OS. PAS ^HIGH LBD iCCA subtype showed specific molecular characteristics at spatial transcriptomics and immunohistochemistry; CT scans and serology could distinguish PAS ^HIGH LBD iCCA phenotype with excellent accuracy. Conclusions: Our data underline the importance of identifying morphological subclasses with a significant prevalence in CCA as a tool for risk stratification and prognosis. The European CCA Histology Registry represents a valuable platform for integrating digital pathology with clinical, radiological, and molecular information as a framework for digital twin advancement.

Despite conventional treatment combining complete macroscopic cytoreductive surgery (CRS) and systemic chemotherapy, residual microscopic peritoneal metastases (mPM) may persist as the cause of peritoneal recurrence in 60% of patients. Therefore, there is a real need to specifically target these mPM to definitively eradicate any traces of the disease and improve patient survival. Therapeutic targeting method, such as photodynamic therapy, would be a promising method for such a purpose. Folate receptor alpha (FRα), as it is specifically overexpressed by cancer cells from various origins, including ovarian cancer cells, is a good target to address photosensitizing molecules. The aim of this study was to determine FRα expression by residual mPM after complete macroscopic CRS in patients with advanced high-grade serous ovarian cancer (HGSOC). A prospective study conducted between 1 June 2018 and 10 July 2019 in a single referent center accredited by the European Society of Gynecological Oncology for advanced EOC surgical management. Consecutive patients presenting with advanced HGSOC and eligible for complete macroscopic CRS were included. Up to 13 peritoneal biopsies were taken from macroscopically healthy peritoneum at the end of CRS and examined for the presence of mPM. In case of detection of mPM, a systematic search for RFα expression by immunohistochemistry was performed. Twenty-six patients were included and 26.9% presented mPM. In the subgroup of patients with mPM, FRα expression was positive on diagnostic biopsy before neoadjuvant chemotherapy for 67% of patients, on macroscopic peritoneal metastases for 86% of patients, and on mPM for 75% of patients. In the subgroup of patients with no mPM, FRα expression was found on diagnostic biopsy before neoadjuvant chemotherapy in 29% of patients and on macroscopic peritoneal metastases in 78% of patients. FRα is well expressed by patients with or without mPM after complete macroscopic CRS in patients with advanced HGSOC. In addition to conventional cytoreductive surgery, the use of a therapeutic targeting method, such as photodynamic therapy, by addressing photosensitizing molecules that specifically target FRα may be studied.