Tuula Anneli Salo

Histopathological risk assessment in multisite epithelial dysplasia: A meta‐analysis

Abstract Objective Histopathological grading of oral epithelial dysplasia (OED) is the current standard for stratifying cancer progression risk but is associated with subjectivity and variability. This problem is not commonly seen regarding the grading of epithelial dysplasia in other sites. This systematic review aims to compare grading systems for oral, anal, penile, and cervical epithelial dysplasia to determine their predictive accuracy for recurrence and malignant transformation (MT) outcomes. Methods The review protocol was registered in PROSPERO (CRD42023403035) and was reported according to the PRISMA checklist. A comprehensive search was performed in the main databases and gray literature. The risk of bias in individual studies was analyzed using the Joanna Briggs Institute checklist for each study design. Results Forty‐six studies were deemed eligible and included in this systematic review, of which 45 were included in the quantitative analysis. Meta‐analysis revealed that the binary system demonstrated a higher predictive ability for MT/recurrence of OED compared to multilevel systems. Higher predictive accuracy of MT was also observed for binary grading systems in anal intraepithelial neoplasia. Conclusions No significant difference was found between the current grading systems of epithelial dysplasia in different body parts. However, binary grading systems have shown better clinical outcomes.

Ex Vivo Immuno-Oncology Platform Reveals Spatial T-cell Infiltration Patterns Linked to ATR Inhibition Responses in High-Grade Serous Ovarian Cancer

Abstract Identifying new therapeutic approaches in high-grade serous ovarian cancer (HGSC) requires the development of more accurate preclinical models that replicate the patient-specific tumor and its microenvironment. To address this, we established immunocompetent patient-derived cultures (iPDC) for HGSC, cultured on a physiologically relevant human omentum gel matrix. We developed a high-throughput platform that combines drug testing, histologic analysis, genomic profiling, single-cell studies, and spatial biomarker discovery. Our results from 47 tumors showed that iPDCs recapitulated the tumor genomic and histologic characteristics while also retaining the intratumoral immune cells. The iPDC treatment responses correlated significantly with the patients’ clinical treatment responses. Using iPDCs and single-cell RNA sequencing, we identified potentially effective therapeutic options for patients with recurrent HGSC linked to distinct tumor cell states and mechanisms of resistance. High-throughput drug response profiling with single-cell imaging identified ataxia telangiectasia and Rad3-related inhibitor (ATRi) combined with an immunotherapy targeting autotaxin as a promising new combination treatment for HGSC. Using hyperplexed imaging and spatial analysis, we discovered that ATRi responses were associated with significant increases in both intra- and peritumoral T-cell infiltration, particularly in PD-1+ CD8+ T cells. Additionally, the ATRi-induced reactivation of CD8+ T cells was linked to spatial interactions with replication stress–positive tumor cells. Thus, our iPDC platform presents a representative high-throughput ex vivo model to advance precision oncology in HGSC, uncovering the ATRi-immunotherapy combination as a potentially effective therapeutic option for clinical translation.