Search

Background Risk-assessment of endometrial cancer (EC) is based on clinicopathological factors and molecular subgroup. It is unclear whether adding hormone receptor expression, L1CAM expression or CTNNB1 status yields prognostic refinement. Methods Paraffin-embedded tumour samples of women with high-risk EC (HR-EC) from the PORTEC-3 trial (n = 424), and a Dutch prospective clinical cohort called MST (n = 256), were used. All cases were molecularly classified. Expression of L1CAM, ER and PR were analysed by whole-slide immunohistochemistry and CTNNB1 mutations were assessed with a next-generation sequencing. Kaplan–Meier method, log-rank tests and Cox’s proportional hazard models were used for survival analysis. Results In total, 648 HR-EC were included. No independent prognostic value of ER, PR, L1CAM, and CTNNB1 was found, while age, stage, and adjuvant chemotherapy had an independent impact on risk of recurrence. Subgroup-analysis showed that only in NSMP HR-EC, ER-positivity was independently associated with a reduced risk of recurrence (HR 0.33, 95%CI 0.15–0.75). Conclusions We confirmed the prognostic impact of the molecular classification, age, stage, and adjuvant CTRT in a large cohort of high-risk EC. ER-positivity is a strong favourable prognostic factor in NSMP HR-EC and identifies a homogeneous subgroup of NSMP tumours. Assessment of ER status in high-risk NSMP EC is feasible in clinical practice and could improve risk stratification and treatment.

BackgroundThe endometrial cancer molecular classification has been integrated into the 2020 World Health Organization (WHO) diagnostic classification and European treatment guidelines, and provides direction towards more effective and less toxic adjuvant treatment strategies for women with endometrial cancer.Primary Objective(s)The RAINBO program of clinical trials will investigate four molecular class-directed adjuvant treatment strategies following surgical resection to either increase cure rates through the addition of novel targeted therapies or safely reduce toxicity and improve quality of life through treatment de-escalation.Study HypothesisMolecular-directed adjuvant treatment strategies will improve clinical outcomes and reduce toxicity of unwarranted therapies in women with endometrial cancer. The overarching and translational research RAINBO program will advance knowledge of predictive and prognostic (bio)markers that will improve prognostication and treatment allocation.Trial DesignThe RAINBO program is a platform of four international clinical trials and an overarching research program. The randomized phase III p53abn-RED trial for women with invasive stage I–III p53abn endometrial cancer compares adjuvant chemoradiation followed by olaparib for 2 years with adjuvant chemoradiation alone. The randomized phase III MMRd-GREEN trial for women with stage II (with lymphovascular space invasion (LVSI)) or stage III mismatch repair-deficient (MMRd) endometrial cancer compares adjuvant radiotherapy with concurrent and adjuvant durvalumab for 1 year to radiotherapy alone. The randomized phase III NSMP-ORANGE trial is a treatment de-escalation trial for women with estrogen receptor positive stage II (with LVSI) or stage III no specific molecular profile (NSMP) endometrial cancer comparing radiotherapy followed by progestin for 2 years to adjuvant chemoradiation. ThePOLEmut-BLUE trial is a phase II trial in which the safety of de-escalation of adjuvant therapy is investigated for women with stage I–IIIPOLEmut endometrial cancer: no adjuvant therapy for lower-risk disease and no adjuvant therapy or radiotherapy alone for higher-risk disease. The overarching RAINBO program will combine data and tumor material of all participants to perform translational research and evaluate molecular class-based adjuvant therapy in terms of efficacy, toxicity, quality of life, and cost-utility.Major Inclusion/Exclusion CriteriaInclusion criteria include a histologically confirmed diagnosis of endometrial cancer treated by hysterectomy and bilateral salpingo-oophorectomy with or without lymphadenectomy or sentinel lymph node biopsy, with no macroscopic residual disease after surgery and no distant metastases, and molecular classification according to the WHO 2020 algorithm.Primary Endpoint(s)Recurrence-free survival at 3 years in the p53abn-RED, MMRd-GREEN, and NSMP-ORANGE trials and pelvic recurrence at 3 years in thePOLEmut-BLUE trial.Sample SizeThe p53abn-RED trial will include 554 patients, the MMRd-GREEN trial 316, the NSMP-ORANGE trial 600, and thePOLEmut-BLUE trial 145 (120 for lower-risk disease and approximately 25 for higher-risk disease). The overarching research program will pool the four sub-trials resulting in a total sample size of around 1600.Estimated Dates for Completing Accrual and Presenting ResultsThe four clinical trials will have different completion dates; main results are expected from 2028.Trial Registration NumberThe RAINBO program is registered at clinicaltrials.gov (NCT05255653).

Adjuvant radiotherapy is an important component of post-operative therapy for patients with early-stage endometrial cancer. In the past decades, many trials have been conducted to determine the optimal adjuvant treatment strategy, pelvic external beam radiotherapy or vaginal brachytherapy. As a result, vaginal brachytherapy became the treatment of choice for patients with early-stage endometrial cancer at high-intermediate risk, based on clinicopathological risk factors. Vaginal brachytherapy maximizes local control and has only mild side effects with limited impact on quality of life, in comparison with pelvic external beam radiotherapy. The most frequently used treatment schedule is the one which was used in the PORTEC-2 trial (21 Gy in three fractions specified at 5 mm depth) and, whenever available, image-guided brachytherapy should be used. However, the most convenient and effective treatment schedule remains to be established. More recently, the discovery and integration of four molecular classes in the risk assessment of endometrial cancer patients has created new opportunities to prevent over- and undertreatment. The 2021 endometrial cancer guideline of the European Society of Gynaecological Oncology (ESGO), European Society for Radiotherapy and Oncology (ESTRO), and the European Society of Pathology (ESP) now proposes an integrated risk stratification, in which both clinicopathologic and molecular factors are combined, to direct adjuvant therapy. This rationale is now investigated in multiple prospective trials. This review provides an overview of the rationale and currently recommended and new strategies for vaginal brachytherapy in patients with stage I and II endometrial cancer.

Introduction: The clinical role of the molecular endometrial cancer (EC) classification has not been fully explored in patients staged with lymphadenectomy or without adjuvant treatment, conditions that could potentially moderate the prognostic value of the classification. We aimed to evaluate the clinical outcome of the molecular subgroups in patients with high-grade EC staged by lymphadenectomy and those without adjuvant treatment.Methods: DNA-sequencing for the detection of pathogenic POLE-exonuclease domain mutations and immunohistochemistry for mismatch repair (MMR) proteins and p53 expression were performed on 412 high-grade EC from the Danish Gynaecological Cancer Database (2005-2012) to classify them as POLE-ultramutated (POLEmut), MMR-deficient (MMRd), p53-mutant (p53abn), or no specific molecular profile (NSMP). Patients with stage IV or residual disease after surgery were excluded. Kaplan-Meier method, log-rank test and Cox proportional hazard models were used for analysis.Results: Molecular analysis was successful in 367 EC; 251 patients had undergone lymphadenectomy. Five-year recurrence rates in this subgroup of patients was 36.7% for women with p53abn EC, 0.0% for POLEmut EC, 13.4% for MMRd EC and 42.9% for NSMP EC (p < 0.001). Similar results were observed among stage IA-IB patients. Among patients without adjuvant treatment (n = 264), none with POLEmut EC (n = 26) had a recurrence.Conclusion: The molecular EC classification has strong prognostic value, independent of clinicopathological factors, also among high-grade EC patients staged by lymphadenectomy and those without adjuvant treatment. The unfavourable prognosis of early-stage p53abn EC is not due to undetected lymph node metastasis, and the indolent behaviour of POLEmut EC is independent of adjuvant treatment.

Endometrial cancer (EC) diagnostics is evolving into a system in which molecular aspects are increasingly important. The traditional histological subtype-driven classification has shifted to a molecular-based classification that stratifies EC into DNA polymerase epsilon mutated (POLEmut), mismatch repair deficient (MMRd), and p53 abnormal (p53abn), and the remaining EC as no specific molecular profile (NSMP). The molecular EC classification has been implemented in the World Health Organization 2020 classification and the 2021 European treatment guidelines, as it serves as a better basis for patient management. As a result, the integration of the molecular class with histopathological variables has become a critical focus of recent EC research. Pathologists have observed and described several morphological characteristics in association with specific genomic alterations, but these appear insufficient to accurately classify patients according to molecular subgroups. This requires pathologists to rely on molecular ancillary tests in routine workup. In this new era, it has become increasingly challenging to assign clinically relevant weights to histological and molecular features on an individual patient basis. Deep learning (DL) technology opens new options for the integrative analysis of multi-modal image and molecular datasets with clinical outcomes. Proof-of-concept studies in other cancers showed promising accuracy in predicting molecular alterations from H&E-stained tumor slide images. This suggests that some morphological characteristics that are associated with molecular alterations could be identified in EC, too, expanding the current understanding of the molecular-driven EC classification. Here in this review, we report the morphological characteristics of the molecular EC classification currently identified in the literature. Given the new challenges in EC diagnostics, this review discusses, therefore, the potential supportive role that DL could have, by providing an outlook on all relevant studies using DL on histopathology images in various cancer types with a focus on EC. Finally, we touch upon how DL might shape the management of future EC patients.

Simple Summary This study aims to assess cancer control and preservation of the eye and visual acuity after proton therapy abroad for eye melanoma. For this, medical files were reviewed of Dutch uveal melanoma patients who were treated in Switzerland with proton therapy from 1987 to 2019. The tumours of these patients were too large and/or localised too close to the optic nerve to be treated with local plaque irradiation. There were 103 patients, of whom one had a uveal melanoma in both eyes. The tumours were relatively large and often localised around the central part of the retina. At five years after treatment, proton therapy had controlled the uveal melanomas of 94% of the patients and 81% had preserved their eye. Spread of the cancer beyond the eye was observed in 30% of the patients. Most patients (79%) became blind or had severe visual impairment after proton therapy; a small group of patients had mild or no visual impairment (17%). The size of the tumour, its localisation and the dose of proton therapy were important for the risk of decline in visual acuity. This study shows that proton therapy abroad for uveal melanoma is feasible and yields good results. Abstract Objective: To assess oncological and ophthalmological outcomes after international referral of uveal melanoma patients for proton therapy. Materials and Methods: This is a retrospective study among Dutch uveal melanoma patients who were treated in Switzerland with 60.0 CGE proton therapy (in 4 fractions) from 1987 to 2019. All patients were ineligible for brachytherapy due to tumour size and/or proximity to the optic nerve. Time-to-event analyses were performed using Kaplan–Meier’s methodology and Cox proportional hazards models. Results: There were 103 patients (104 eyes) with a median largest tumour diameter of 19 mm (range 6–26 mm). Tumours were localised centrally (11%), mid-peripherally (65%) or peripherally (34%). Median follow-up was 7 years. Five-year local control, distant metastasis-free survival and eye preservation rates were 94%, 70% and 81% respectively. At five years, severe, moderate and mild visual impairment was observed in respectively 79%, 4% and 6% of the patients. Larger tumour volumes and more central tumour localisation were associated with severe visual impairment. After correction for these factors, dose to the macula, optic disc and retina, but not optic nerve was significantly associated with severe visual impairment. Conclusion: International referral for proton therapy yielded good tumour control and eye preservation rates, but risk of distant metastasis and severe visual impairment were substantial, possibly due to the selection of advanced tumour stages and/or central localisation. Dose to the macula may be more relevant than dose to the optic nerve for preservation of visual acuity, which is relevant for the treatment planning of proton therapy.

External beam radiation therapy (EBRT) with concurrent chemotherapy followed by brachytherapy is a very effective treatment for locally advanced cervical cancer (LACC). However, treatment-related toxicity is common and reduces the patient’s quality of life (QoL) and ability to complete treatment or undergo adjuvant therapies. Intensity modulated proton therapy (IMPT) enables a significant dose reduction in organs at risk (OAR), when compared to that of standard intensity-modulated radiation therapy (IMRT) or volumetric-modulated arc therapy (VMAT). However, clinical studies evaluating whether IMPT consequently reduces side effects for LACC are lacking. The PROTECT trial is a nonrandomized prospective multicenter phase-II-trial comparing clinical outcomes after IMPT or IMRT/VMAT in LACC. Thirty women aged >18 years with a histological diagnosis of LACC will be included in either the IMPT or IMRT/VMAT group. Treatment includes EBRT (45 Gy in 25 fractions of 1.8 Gy), concurrent five weekly cisplatin (40 mg/m2), and 3D image (MRI)-guided adaptive brachytherapy. The primary endpoint is pelvic bones Dmean and mean bowel V15Gy. Secondary endpoints include dosimetric parameters, oncological outcomes, health-related QoL, immune response, safety, and tolerability. This study provides the first data on the potential of IMPT to reduce OAR dose in clinical practice and improve toxicity and QoL for patients with LACC

Purpose To evaluate and compare health-related quality of life (HRQL) of women with early-stage breast cancer (BC) treated with different radiotherapy (RT) regimens. Methods Data were collected from five prospective cohorts of BC patients treated with breast-conserving surgery and different RT regimens: intraoperative RT (IORT, 1 x 23.3 Gy; n = 267), external beam accelerated partial breast irradiation (EB-APBI, 10 x 3.85 Gy; n = 206), hypofractionated whole breast irradiation(hypo-WBI, 16 x 2.67 Gy; n = 375), hypo-WBI + boost(hypo-WBI-B, 21-26 x 2.67 Gy; n = 189), and simultaneous WBI + boost(WBI-B, 28 x 2.3 Gy; n = 475). Women >= 60 years with invasive/in situ carcinoma

Health care's institutional goals of abbreviating hospital stays and accelerating clinic visits are feeding professional loneliness, and meaningful advances in technology have levied a significant toll in the form of separation from patients and colleagues. The transition away from routine interaction with patients and colleagues toward more individual activities has contributed to loneliness and burnout. Addressing physicians' loneliness in the 21st century requires finding innovative ways to interact with each other. In recent years, health care leaders have increasingly turned to "nudges" to influence health-related behaviors. But harmful health and health care behaviors often arise in circumstances that give us . . .

Purpose: Patients with hematological malignancies (HM) have more unpredictable disease trajectories compared to patients with advanced solid tumors (STs) and miss opportunities for a palliative care approach. They often undergo intensive disease-directed treatments until the end of life with frequent emergency department (ED) visits and in-hospital deaths. Insight into end-of-life trajectories and quality of end-of-life care can support arranging appropriate care according to patients' wishes. Method: Mortality follow-back study to compare of end-of-life trajectories of HM and ST patients who died

Pulmonary nodules are frequently detected during diagnostic chest imaging and as a result of lung cancer screening. Current guidelines for their evaluation are largely based on low-quality evidence, and patients and clinicians could benefit from more research in this area.In this research statement from the American Thoracic Society, a multidisciplinary group of clinicians, researchers, and patient advocates reviewed available evidence for pulmonary nodule evaluation, characterized six focus areas to direct future research efforts, and identified fundamental gaps in knowledge and strategies to address them. We did not use formal mechanisms to prioritize one research area over another or to achieve consensus.There was widespread agreement that novel tests (including novel imaging tests and biopsy techniques, biomarkers, and prognostic models) may improve diagnostic accuracy for identifying cancerous nodules. Before they are used in clinical practice, however, better evidence is needed to show that they improve more distal outcomes of importance to patients. In addition, the pace of research and the quality of clinical care would be improved by the development of registries that link demographic and nodule characteristics with patient-level outcomes. Methods to share data from registries are also necessary.This statement may help researchers to develop impactful and innovative research projects and enable funders to better judge research proposals. We hope that it will accelerate the pace and increase the efficiency of discovery to improve the quality of care for patients with pulmonary nodules.