Gitte Ørtoft

Sexual dysfunction is a frequent long-term complication following allogeneic hematopoietic stem cell transplantation (HSCT). This multicenter, prospective, randomized controlled trial evaluated the feasibility and efficacy of a multimodal intervention targeting sexual function and early detection of genital chronic graft-versus-host disease (cGVHD) in adult recipients of HSCT. Participants were randomized 1:1 to the intervention or usual care. The intervention included repeated questionnaires, genital assessments, and nurse-led consultations. Sexual function was assessed using the Female Sexual Function Index or the International Index of Erectile Function, with secondary outcomes including sexual health, sexual distress, and feasibility measures. Overall sexual function did not differ significantly between groups for women (difference (diff) 3.3, P = 0.391) or men (diff 0.9, P = 0.761). Significant improvements favoring the intervention group were observed in women’s sexual pain (diff −2.1, P = 0.019) and, for both sexes, in sexual pain (diff −13.6, P = 0.030), communication with professionals (diff −15.5, P = 0.017), and partnership quality (diff −22.8, P = 0.040). The incidence of genital cGVHD was 25.0% among male (n = 11) and 28.1% (n = 9) among females. We conclude that the multimodal intervention was feasible, led to improved sexual health, and facilitated earlier recognition of genital cGVHD, supporting the integration of interdisciplinary sexual health assessments into routine post-HSCT care.

POLE sequencing for somatic mutations ( POLE mut) guides adjuvant therapy in endometrial cancer (EC), but cost and infrastructural considerations lead to limited uptake. Omission of POLE testing leads to unnecessary exposure to radiotherapy and/or chemotherapy. We developed POLARIX, a multiple instance deep learning model with attention pooling, which predicts POLE mutation status from routine hematoxylin and eosin whole-slide images (WSIs). Trained on 2,238 cases from eleven EC cohorts, POLARIX showed clinical-grade discrimination across three external cohorts (Pooled: AUC=0.95, 95% CI: 0.91–0.98; n =68/481 POLE mut/ POLE wt). Attention maps highlight POLE morphologies. Clinical applicability is demonstrated using predefined thresholds based on three resource scenarios. The most sensitive threshold (“Low”) yields a test reduction of 77% (73%-81%) (sensitivity: 93% (85%-99%), specificity: 89% (87%-92%)). POLARIX is an interpretable and cost-efficient approach to reduce POLE testing in women with endometrial cancer, broadening access to precision oncology.

Objectives: To evaluate a scoring system using transvaginal ultrasound (TVS) to predict high‐risk endometrial cancer. Methods: Consecutive patients with endometrial cancer/atypical hyperplasia (n = 266) were preoperatively examined by residents using TVS. Clinical parameters, endometrial morphology and Doppler scores were recorded using a gray scale and Doppler TVS and related to final histopathology at hysterectomy. Multivariate logistic regression was used to correlate imaging and clinical parameters to the presence of high‐risk endometrial cancer (defined as FIGO stage Ib‐IV or high‐grade tumors [grade 3/non‐endometroid]) to develop the High‐Risk Endometrial Cancer (HIREC) score. Results: High‐risk endometrial cancer (n = 128) and lympho‐vascular space invasion (LVSI) (n = 43) were predicted by increased endometrial thickness (ET), age, and Doppler score. The HIREC scoring system, based on age, Doppler score, and ET performed well with an AUC of 78.5% (CI 95%: 73–84) to predict high‐risk cancer. By using a 2‐step strategy of (1) Preoperative identification of high‐grade tumors by biopsy, (2) Assessing the HIREC score, high‐risk endometrial cancer could be predicted at a HIREC score of ≥7 with sensitivity, specificity, and accuracy of 72.7, 88.4, and 80.8%. Low‐risk endometrial cancer was predicted at HIREC scores of <5 with sensitivity, specificity, and accuracy values of 91.4, 46.4 and 68.1%, respectively. Conclusions: Low and high HIREC scores effectively predicted low‐ and high‐risk endometrial cancer. The score is a simple point system suitable for the first ultrasound assessment. It may be used in preoperative work‐up to select treatment and additional imaging, but it needs to be validated in further studies.

Predicting distant recurrence of endometrial cancer (EC) is crucial for personalized adjuvant treatment. The current gold standard of combined pathological and molecular profiling is costly, hampering implementation. We developed HECTOR ( H istopathology-based E ndometrial C ancer T ailored O utcome R isk), a multimodal deep learning prognostic model using hematoxylin-and-eosin-stained whole-slide-images and tumor stage as input, on 1,912 patients from seven EC cohorts including the PORTEC-1/-2/-3 randomized trials. HECTOR demonstrated C-indices in internal ( n = 353) and external ( n = 151) test sets of 0.788 and 0.816 respectively, outperforming the current gold-standard, and identified patients with markedly different outcomes (10-year distant recurrence-free probabilities of 97.0%, 77.7% and 58.1% for HECTOR low, intermediate and high risk groups). HECTOR also predicted adjuvant chemotherapy benefit better than current methods. Morphological and genomic feature extraction identified correlates of HECTOR risk groups, some with therapeutic potential. HECTOR improves on the current gold-standard and may help delivery of personalized treatment in EC.

PURPOSE: Detection of 11 pathogenic variants in the POLE gene in endometrial cancer (EC) is critically important to identify women with a good prognosis and reduce overtreatment. Currently, POLE status is determined by DNA sequencing, which can be expensive, relatively time-consuming, and unavailable in hospitals without specialized equipment and personnel. This may hamper the implementation of POLE-testing in clinical practice. To overcome this, we developed and validated a rapid, low-cost POLE hotspot test by a quantitative polymerase chain reaction (qPCR) assay, QPOLE. MATERIALS AND METHODS: Primer and fluorescence-labeled 5′-nuclease probe sequences of the 11 established pathogenic POLE mutations were designed. Three assays, QPOLE-frequent for the most common mutations and QPOLE-rare-1 and QPOLE-rare-2 for the rare variants, were developed and optimized using DNA extracted from formalin-fixed paraffin-embedded tumor tissues. The simplicity of the design enables POLE status assessment within 4-6 hours after DNA isolation. An interlaboratory external validation study was performed to determine the practical feasibility of this assay. RESULTS: Cutoffs for POLE wild-type, POLE-mutant, equivocal, and failed results were predefined on the basis of a subset of POLE mutants and POLE wild-types for the internal and external validation. For equivocal cases, additional DNA sequencing is recommended. Performance in 282 EC cases, of which 99 were POLE-mutated, demonstrated an overall accuracy of 98.6% (95% CI, 97.2 to 99.9), a sensitivity of 95.2% (95% CI, 90.7 to 99.8), and a specificity of 100%. After DNA sequencing of 8.8% equivocal cases, the final sensitivity and specificity were 96.0% (95% CI, 92.1 to 99.8) and 100%. External validation confirmed feasibility and accuracy. CONCLUSION: QPOLE is a qPCR assay that is a quick, simple, and reliable alternative for DNA sequencing. QPOLE detects all pathogenic variants in the exonuclease domain of the POLE gene. QPOLE will make low-cost POLE-testing available for all women with EC around the globe.

Objective To compare the performance of the new ESGO-ESTRO-ESP (European Society of Gynecological Oncology-European Society for Radiotherapy & Oncology-European Society for Pathology) 2020 risk classification system with the previous 2016 risk classification in predicting survival and patterns of recurrence in the Danish endometrial cancer population. Methods This Danish national cohort study included 4516 patients with endometrial cancer treated between 2005 and 2012. Five-year Kaplan–Meier adjusted and unadjusted survival estimates and actuarial recurrence rates were calculated for the previous and the new classification systems. Results In the 2020 risk classification system, 81.0% of patients were allocated to low, intermediate, or high-intermediate risk compared with 69.1% in the 2016 risk classification system, mainly due to reclassification of 44.5% of patients previously classified as high risk to either intermediate or especially high-intermediate risk. The survival of the 2020 high-risk group was significantly lower, and the recurrence rate, especially the non-local recurrence rate, was significantly higher than in the 2016 high risk group (2020/2016, overall survival 59%/66%; disease specific 69%/76%; recurrence 40.5%/32.3%, non-local 34.5%/25.8%). Survival and recurrence rates in the other risk groups and the decline in overall and disease-specific survival rates from the low risk to the higher risk groups were similar in patients classified according to the 2016 and 2020 systems. Conclusion The new ESGO-ESTRO-ESP 2020 risk classification system allocated fewer patients to the high risk group than the previous risk classification system. The main differences were lower overall and disease-specific survival and a higher recurrence rate in the 2020 high risk group. The introduction of the new 2020 risk classification will potentially result in fewer patients at high risk and allocation to the new high risk group will predict lower survival, potentially allowing more specific selection for postoperative adjuvant therapy.