Spatial and temporal intra-tumoral heterogeneity in advanced HGSOC: Implications for surgical and clinical outcomes.

Limited evidence exists on the impact of spatial and temporal heterogeneity of high-grade serous ovarian cancer (HGSOC) on tumor evolution, clinical outcomes, and surgical operability. We perform systematic multi-site tumor mapping at presentation and matched relapse from 49 high-tumor-burden patients, operated up front. From SNP array-derived copy-number data, we categorize dendrograms representing tumor clonal evolution as sympodial or dichotomous, noting most chemo-resistant patients favor simpler sympodial evolution. Three distinct tumor evolutionary patterns from primary to relapse are identified, demonstrating recurrent disease may emerge from pre-existing or newly detected clones. Crucially, we identify spatial heterogeneity for clinically actionable homologous recombination deficiency scores and for poor prognosis biomarkers CCNE1 and MYC. Copy-number signature, phenotypic, proteomic, and proliferative-index heterogeneity further highlight HGSOC complexity. This study explores HGSOC evolution and dissemination across space and time, its impact on optimal surgical cytoreductive effort and clinical outcomes, and its consequences for clinical decision-making.

Changes in Stem Cell Regulation and Epithelial Organisation during Carcinogenesis and Disease Progression in Gynaecological Malignancies.

Gynaecological malignancies represent a heterogeneous group of neoplasms with vastly different aetiology, risk factors, molecular drivers, and disease outcomes. From HPV-driven cervical cancer where early screening and molecular diagnostics efficiently reduced the number of advanced-stage diagnosis, prevalent and relatively well-treated endometrial cancers, to highly aggressive and mostly lethal high-grade serous ovarian cancer, malignancies of the female genital tract have unique presentations and distinct cell biology features. Recent discoveries of stem cell regulatory mechanisms, development of organoid cultures, and NGS analysis have provided valuable insights into the basic biology of these cancers that could help advance new-targeted therapeutic approaches. This review revisits new findings on stemness and differentiation, considering main challenges and open questions. We focus on the role of stem cell niche and tumour microenvironment in early and metastatic stages of the disease progression and highlight the potential of patient-derived organoid models to study key events in tumour evolution, the appearance of resistance mechanisms, and as screening tools to enable personalisation of drug treatments.

The Oxford Classic Links Epithelial-to-Mesenchymal Transition to Immunosuppression in Poor Prognosis Ovarian Cancers.

PURPOSE: Using RNA sequencing, we recently developed the 52-gene-based Oxford classifier of carcinoma of the ovary (Oxford Classic, OxC) for molecular stratification of serous ovarian cancers (SOCs) based on the molecular profiles of their cell of origin in the fallopian tube epithelium. Here, we developed a 52-gene NanoString panel for the OxC to test the robustness of the classifier. EXPERIMENTAL DESIGN: We measured the expression of the 52 genes in an independent cohort of prospectively collected SOC samples (n = 150) from a homogenous cohort who were treated with maximal debulking surgery and chemotherapy. We performed data mining of published expression profiles of SOCs and validated the classifier results on tissue arrays comprising 137 SOCs. RESULTS: We found evidence of profound nongenetic heterogeneity in SOCs. Approximately 20% of SOCs were classified as epithelial-to-mesenchymal transition-high (EMT-high) tumors, which were associated with poor survival. This was independent of established prognostic factors, such as tumor stage, tumor grade, and residual disease after surgery (HR, 3.3; P = 0.02). Mining expression data of 593 patients revealed a significant association between the EMT scores of tumors and the estimated fraction of alternatively activated macrophages (M2; P < 0.0001), suggesting a mechanistic link between immunosuppression and poor prognosis in EMT-high tumors. CONCLUSIONS: The OxC-defined EMT-high SOCs carry particularly poor prognosis independent of established clinical parameters. These tumors are associated with high frequency of immunosuppressive macrophages, suggesting a potential therapeutic target to improve clinical outcome.

Patients at the centre of care: debriefing patients after caesarean section.

Empowering patients and working collaboratively to improve healthcare is a focus for current healthcare development strategies. In obstetric practice, working in collaboration with women to discuss mode of delivery after caesarean section has been shown to impact women's choice. A preliminary survey in our tertiary maternity unit showed 20% of women gained 'full clarity' with the information they received after caesarean-section regarding indication, complications and impact on future delivery. Focus groups identified what information patients required about their surgery. General practitioners (GP) highlighted a lack of communication between secondary and primary care. Junior obstetricians surveyed felt uncertain about debriefing. The aim was to improve monthly 'full clarity' scores to 30% in 6 months. Our team introduced a debrief form, filled by the operator and kept in maternity notes. The operator verbally debriefed as part of their current standard practice. Junior doctors postoperatively debriefed the patient using the form. The triplicate form ensured both patients and primary care received a copy. It was anticipated that in the long term, this would provide consistent information and aid informed decision making in subsequent pregnancies. Review of the forms' use was undertaken weekly. Multidisciplinary input identified barriers to uptake. Plan, Do, Study, Act cycles promoted the project, disseminated results, evidenced growing participation and rewarded consistent form use. Patient groups critiqued the form layout. Teaching aimed to improve junior doctor confidence in debriefing discussions. Sustained participation resulted in effective form uptake. Patient 'full clarity' scores improved to 60% with minimal impact on workload. Teaching successfully improved junior doctor confidence as evidenced by increased documented debrief discussions. GP focus groups felt empowered to counsel women consistently about their surgery increasing clarity for everyone. This project highlights that patient satisfaction improves when we listen to their views and commit to change.