Ulla‐Maija Haltia

Health‐related quality of life in adult‐type ovarian granulosa cell tumor survivors

AbstractIntroductionAdult‐type granulosa cell tumor (AGCT) is a rare, slow‐growing ovarian neoplasm with a tendency for late relapses. Surgery is the cornerstone of the treatment, and chemotherapy and hormonal treatment are administered in advanced and recurrent disease. The objective of our study was to assess health‐related quality of life (HRQoL) in AGCT survivors.Material and Methods15D and European Organization for Research and Treatment of Cancer (EORTC‐QLQ‐C30) questionnaires were collected from our prospective AGCT patient cohort, consisting of 171 AGCT survivors. The age‐standardized general female population was used as a reference for 15D comparison. Clinical and sociodemographic variables and EORTC‐QLQ‐C30 symptom and function scales were used as independent variables in regression analysis explaining the variance in the 15D score.ResultsEighty‐six women (50.3%), with a mean age of 68 years, returned the questionnaires. The HRQoL of AGCT survivors was similar to the general female population. The mean 15D score in our patient group was 0.891 (reference population score 0.899, p = 0.454). The scores were slightly lower on the 15D dimensions of excretion and sexual activity, whereas mental function scores were higher compared with the reference population. A history of tumor recurrence, an increasing number of other chronic illnesses, and financial difficulties each diminished HRQoL in our patient cohort. Regressing the EORTC variables on 15D produced a high explanatory power and accurate predictions of 15D scores.ConclusionsHRQoL of AGCT survivors was equal to that of the controls. Mapping EORTC‐QLQ‐C30 to 15D validly predicted 15D scores in AGCT survivors, confirming the usefulness of generic 15D for estimating quality‐adjusted life years in cancer patient trials.

Clinicopathologic stratification demonstrates survival differences between endometrial carcinomas with mismatch repair deficiency and no specific molecular profile: a cohort study

Endometrial carcinomas with mismatch repair deficiency (MMRd) and no specific molecular profile (NSMP) are considered to have intermediate prognoses. However, potential prognostic differences between these molecular subgroups remain unclear due to the lack of standardized control for clinicopathologic factors. This study aims to evaluate outcomes of MMRd and NSMP endometrial carcinomas across guideline-based clinicopathologic risk groups. This study analyzed patients treated at a single tertiary center. Immunohistochemistry and polymerase-ϵ sequencing were performed for molecular classification. MLH1-deficient tumors underwent methylation-specific multiplex ligation-dependent probe amplification. Carcinomas were classified into clinicopathologic risk groups according to European guidelines. The analysis included 420 MMRd and 399 NSMP carcinomas. Among MMRd cases, 224 were subcategorized as MLH1-methylated or MLH1-non-methylated. Median follow-up was 71 months (range; 1-136). Survival differences were most notable in clinicopathologic medium-risk carcinomas, with the MMRd subgroup exhibiting poorer progression-free, disease-specific, and overall survival compared to NSMP. Adjusting for age and adjuvant therapy, MMRd still showed an association with progression-free survival. Both MLH1-methylated (n = 154) and MLH1-non-methylated tumors (n = 70) were associated with more aggressive clinicopathologic risk groups compared to NSMP, but only methylated tumors showed poorer outcomes. The distinct outcomes for MMRd and NSMP in the clinicopathologic medium-risk group suggest that uterine risk factors may worsen the prognosis for MMRd endometrial carcinomas. Advanced stage may be the primary factor contributing to poor outcomes in high-risk-advanced metastatic carcinomas. Clinicopathologic factors may particularly worsen the prognosis of MLH1-methylated carcinomas.

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.