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Endometrial cancer is primarily treated with surgery. Adjuvant treatment strategies for endometrial cancer, such as external beam pelvic radiotherapy, vaginal brachytherapy, chemotherapy, and combined chemotherapy and radiotherapy, have been studied in several randomized trials. Adjuvant treatment is currently based on the presence of clinico-pathological risk factors. Low-risk disease is adequately managed with surgery alone. In high-intermediate risk endometrial cancer, adjuvant vaginal brachytherapy is recommended to maximize local control, with only mild side effects and without impact on quality of life. For high-risk endometrial cancer, recent large randomized trials support the use of pelvic radiotherapy, especially in stage I–II endometrial cancer with risk factors. For women with serous cancers and those with stage III disease, chemoradiation increased both recurrence-free and overall survival, while GOG-258 showed similar recurrence-free survival compared with six cycles of chemotherapy alone, but with better pelvic and para-aortic nodal control with combined chemotherapy and radiotherapy. Recent molecular studies, most notably the work from The Cancer Genome Atlas (TCGA) project, have shown that four endometrial cancer molecular classes can be distinguished; POLE ultra-mutated, microsatellite instable hypermutated, copy-number-low, and copy-number-high. Subsequent studies, using surrogate markers to identify groups analogous to TCGA sub-classes, showed that all four endometrial cancer sub-types are found across all stages, histological types, and grades. Moreover, the molecular sub-groups have proved to have a stronger prognostic impact than histo-pathological tumor characteristics. This introduces an new era of molecular classification based diagnostics and treatment approaches. Integration of the molecular factors and new therapeutic targets will lead to molecular-integrated adjuvant treatment including targeted treatments, which are the rationale of new and ongoing trials. This review presents an overview of current adjuvant treatment strategies in endometrial cancer, highlights the development and evaluation of a molecular-integrated risk profile, and briefly discusses ongoing developments in targeted treatment.

The main challenge in CT screening for lung cancer is the high prevalence of pulmonary nodules and the relatively low incidence of lung cancer. Management protocols use thresholds for nodule size and growth rate to determine which nodules require additional diagnostic procedures, but these should be based on individuals' probabilities of developing lung cancer. In this prespecified analysis, using data from the NELSON CT screening trial, we aimed to quantify how nodule diameter, volume, and volume doubling time affect the probability of developing lung cancer within 2 years of a CT scan, and to propose and evaluate thresholds for management protocols. Eligible participants in the NELSON trial were those aged 50–75 years, who have smoked 15 cigarettes or more per day for more than 25 years, or ten cigarettes or more for more than 30 years and were still smoking, or had stopped smoking less than 10 years ago. Participants were randomly assigned to low-dose CT screening at increasing intervals, or no screening. We included all participants assigned to the screening group who had attended at least one round of screening, and whose results were available from the national cancer registry database. We calculated lung cancer probabilities, stratified by nodule diameter, volume, and volume doubling time and did logistic regression analysis using diameter, volume, volume doubling time, and multinodularity as potential predictor variables. We assessed management strategies based on nodule threshold characteristics for specificity and sensitivity, and compared them to the American College of Chest Physicians (ACCP) guidelines. The NELSON trial is registered at www.trialregister.nl, number ISRCTN63545820. Volume, volume doubling time, and volumetry-based diameter of 9681 non-calcified nodules detected by CT screening in 7155 participants in the screening group of NELSON were used to quantify lung cancer probability. Lung cancer probability was low in participants with a nodule volume of 100 mm3 or smaller (0·6% [95% CI 0·4–0·8]) or maximum transverse diameter smaller than 5 mm (0·4% [0·2–0·7]), and not significantly different from participants without nodules (0·4% [0·3–0·6], p=0·17 and p=1·00, respectively). Lung cancer probability was intermediate (requiring follow-up CT) if nodules had a volume of 100–300 mm3 (2·4% [95% CI 1·7–3·5]) or a diameter 5–10 mm (1·3% [1·0–1·8]). Volume doubling time further stratified the probabilities: 0·8% (95% CI 0·4–1·7) for volume doubling times 600 days or more, 4·0% (1·8–8·3) for volume doubling times 400–600 days, and 9·9% (6·9–14·1) for volume doubling times of 400 days or fewer. Lung cancer probability was high for participants with nodule volumes 300 mm3 or bigger (16·9% [95% CI 14·1–20·0]) or diameters 10 mm or bigger (15·2% [12·7–18·1]). The simulated ACCP management protocol yielded a sensitivity and specificity of 90·9% (95% CI 81·2–96·1), and 87·2% (86·4–87·9), respectively. A diameter-based protocol with volumetry-based nodule diameter yielded a higher sensitivity (92·4% [95% CI 83·1–97·1]), and a higher specificity (90·0% [89·3–90·7). A volume-based protocol (with thresholds based on lung cancer probability) yielded the same sensitivity as the ACCP protocol (90·9% [95% CI 81·2–96·1]), and a higher specificity (94·9% [94·4–95·4]). Small nodules (those with a volume <100 mm3 or diameter <5 mm) are not predictive for lung cancer. Immediate diagnostic evaluation is necessary for large nodules (≥300 mm3 or ≥10 mm). Volume doubling time assessment is advocated only for intermediate-sized nodules (with a volume ranging between 100–300 mm3 or diameter of 5–10 mm). Nodule management protocols based on these thresholds performed better than the simulated ACCP nodule protocol. Zorgonderzoek Nederland Medische Wetenschappen and Koningin Wilhelmina Fonds.

B-cells play a key role in cancer suppression, particularly when aggregated in tertiary lymphoid structures (TLS). Here, we investigate the role of B-cells and TLS in endometrial cancer (EC). Single cell RNA-sequencing of B-cells shows presence of naïve B-cells, cycling/germinal center B-cells and antibody-secreting cells. Differential gene expression analysis shows association of TLS with L1CAM overexpression. Immunohistochemistry and co-immunofluorescence show L1CAM expression in mature TLS, independent of L1CAM expression in the tumor. Using L1CAM as a marker, 378 of the 411 molecularly classified ECs from the PORTEC-3 biobank are evaluated, TLS are found in 19%. L1CAM expressing TLS are most common in mismatch-repair deficient (29/127, 23%) and polymerase-epsilon mutant EC (24/47, 51%). Multivariable Cox regression analysis shows strong favorable prognostic impact of TLS, independent of clinicopathological and molecular factors. Our data suggests a pivotal role of TLS in outcome of EC patients, and establishes L1CAM as a simple biomarker. Tertiary lymphoid structures (TLS) are associated with a reduced risk of cancer recurrence and improved response to immune checkpoint blockade in several tumor types. Here the authors identify L1CAM as a marker for mature TLS and show that the presence of TLS is associated with favorable prognosis in patients with endometrial cancer from the PORTEC-3 trial.

Purpose Patients with advanced cancer commonly visit the emergency department (ED) during the last 3 months of life. Identification of these patients and their palliative care needs help initiating appropriate care according to patients’ wishes. Our objective was to provide insight into ED visits of advanced cancer patients at the end of life. Methods Adult palliative patients with solid tumours who died < 3 months after their ED visit were included (2011–2014). Patients, ED visits, and follow-up were described. Factors associated with approaching death were assessed using Cox proportional hazards models. Results Four hundred twenty patients were included, 54.5% was male, median age 63 years. A total of 54.6% was on systemic anti-cancer treatments and 10.5% received home care ≥ 1 per day. ED visits were initiated by patients and family in 34.0% and 51.9% occurred during out-of-office hours. Dyspnoea (21.0%) or pain (18.6%) were most reported symptoms. Before the ED visit, limitations on life-sustaining treatments were discussed in 33.8%, during or after the ED visit in 70.7%. Median stay at the ED was 3:29 h (range 00:12–18:01 h), and 319 (76.0%) were hospitalized. Median survival was 18 days (IQ range 7–41). One hundred four (24.8%) died within 7 days after the ED visit, of which 71.2% in-hospital. Factors associated with approaching death were lung cancer, neurologic deterioration, dyspnoea, hypercalcemia, and jaundice. Conclusion ED visits of advanced cancer patients often lead to hospitalization and in-hospital deaths. Timely recognition of patients with limited life expectancies and urgent palliative care needs, and awareness among ED staff of the potential of ED-initiated palliative care may improve the end-of-life trajectory of these patients.

Low-dose CT screening is recommended for individuals at high risk of developing lung cancer. However, CT screening does not detect all lung cancers: some might be missed at screening, and others can develop in the interval between screens. The NELSON trial is a randomised trial to assess the effect of screening with increasing screening intervals on lung cancer mortality. In this prespecified analysis, we aimed to assess screening test performance, and the epidemiological, radiological, and clinical characteristics of interval cancers in NELSON trial participants assigned to the screening group. Eligible participants in the NELSON trial were those aged 50–75 years, who had smoked 15 or more cigarettes per day for more than 25 years or ten or more cigarettes for more than 30 years, and were still smoking or had quit less than 10 years ago. We included all participants assigned to the screening group who had attended at least one round of screening. Screening test results were based on volumetry using a two-step approach. Initially, screening test results were classified as negative, indeterminate, or positive based on nodule presence and volume. Subsequently, participants with an initial indeterminate result underwent follow-up screening to classify their final screening test result as negative or positive, based on nodule volume doubling time. We obtained information about all lung cancer diagnoses made during the first three rounds of screening, plus an additional 2 years of follow-up from the national cancer registry. We determined epidemiological, radiological, participant, and tumour characteristics by reassessing medical files, screening CTs, and clinical CTs. The NELSON trial is registered at www.trialregister.nl, number ISRCTN63545820. 15 822 participants were enrolled in the NELSON trial, of whom 7915 were assigned to low-dose CT screening with increasing interval between screens, and 7907 to no screening. We included 7155 participants in our study, with median follow-up of 8·16 years (IQR 7·56–8·56). 187 (3%) of 7155 screened participants were diagnosed with 196 screen-detected lung cancers, and another 34 (<1%; 19 [56%] in the first year after screening, and 15 [44%] in the second year after screening) were diagnosed with 35 interval cancers. For the three screening rounds combined, with a 2-year follow-up, sensitivity was 84·6% (95% CI 79·6–89·2), specificity was 98·6% (95% CI 98·5–98·8), positive predictive value was 40·4% (95% CI 35·9–44·7), and negative predictive value was 99·8% (95% CI 99·8–99·9). Retrospective assessment of the last screening CT and clinical CT in 34 patients with interval cancer showed that interval cancers were not visible in 12 (35%) cases. In the remaining cases, cancers were visible when retrospectively assessed, but were not diagnosed because of radiological detection and interpretation errors (17 [50%]), misclassification by the protocol (two [6%]), participant non-compliance (two [6%]), and non-adherence to protocol (one [3%]). Compared with screen-detected cancers, interval cancers were diagnosed at more advanced stages (29 [83%] of 35 interval cancers vs 44 [22%] of 196 screen-detected cancers diagnosed in stage III or IV; p<0·0001), were more often small-cell carcinomas (seven [20%] vs eight [4%]; p=0·003) and less often adenocarcinomas (nine [26%] vs 102 [52%]; p=0·005). Lung cancer screening in the NELSON trial yielded high specificity and sensitivity, with only a small number of interval cancers. The results of this study could be used to improve screening algorithms, and reduce the number of missed cancers. Zorgonderzoek Nederland Medische Wetenschappen and Koningin Wilhelmina Fonds.

IntroductionThe role of cytoreductive surgery (CRS) in primary stage IV endometrial cancer (EC) remains debatable due to lack of evidence from large studies and heterogeneity of stage IV EC. To address this, we conducted a systematic review and meta-analysis to investigate the survival benefit of CRS in patients with primary stage IV EC.MethodsFive medical literature databases were systematically searched for original studies reporting survival data on primary stage IV EC by outcome of CRS (complete, optimal, or incomplete resection). Pooled hazard ratio’s (HR) were calculated using a random-effects model.ResultsTwelve studies, including 733 patients, were analysed. Of them, 187 (26%) had complete CRS and 146 patients (20%) optimal CRS. In five studies, including 79 patients (11%), complete and optimal CRS were combined. Ten studies reported a significant overall survival (OS) benefit after complete (18–48 months), and optimal CRS (13–34 months) compared to incomplete CRS (7–19 months). In patients with serous EC or extra-abdominal metastasis, a benefit of complete/optimal CRS was also observed. The pooled data showed improved OS from complete/optimal vs. incomplete CRS (HR=0.38, 95% CI 0.21–0.69, p=0.0016) (figure 1). Heterogeneity between studies was substantial.Conclusion/ImplicationsThis study indicates an OS benefit of complete/optimal CRS for patients with primary stage IV EC, including patients with serous EC or extra-abdominal metastasis. A superior survival benefit was seen after complete CRS compared to optimal CRS. Despite the considerable heterogeneity between studies, our findings suggest that CRS should be considered in the treatment of patients with primary stage IV EC.Abstract PR042/#442 Figure 1Forest plot of the meta-analysis comparing complete and optimal CRS vs incomplete CRS The p-value are the values mentioned by the authors

The NELSON (Nederlands Leuvens Longkanker Screenings Onderzoek) trial is, with 15,822 participants, the largest European lung cancer computer tomography screening trial. A volumetry-based screening strategy, stringent criteria for a positive screening, and an increasing length of screening interval are particular features of the NELSON trial. To determine the effect of stringent referral criteria and increasing screening interval on the characteristics of screen-detected lung cancers, and to compare this across screening rounds, between sexes, and with other screening trials. All NELSON participants with screen-detected lung cancer in the first three rounds were included. Lung cancer stage at diagnosis, histological subtype, and tumor localization were compared between the screening rounds, the sexes, and with other screening trials. In the first three screening rounds, 200 participants were diagnosed with 209 lung cancers. Of these lung cancers, 70.8% were diagnosed at stage I and 8.1% at stage IIIB-IV, and 51.2% were adenocarcinomas. There was no significant difference in cancer stage, histology, or tumor localization across the screening rounds. Women were diagnosed at a significantly more favorable cancer stage than men. Compared with other trials, the screen-detected lung cancers of the NELSON trial were relatively more often diagnosed at stage I and less often at stage IIIB-IV. Despite stringent criteria for a positive screening, an increasing length of screening interval, and few female participants, the screening strategy of the NELSON trial resulted in a favorable cancer stage distribution at diagnosis, which is essential for the effectiveness of our screening strategy. Clinical trial registered with www.trialregister.nl (ISRCTN63545820).

Numerous studies have shown that older women with endometrial cancer have a higher risk of recurrence and cancer-related death. However, it remains unclear whether older age is a causal prognostic factor, or whether other risk factors become increasingly common with age. We aimed to address this question with a unique multimethod study design using state-of-the-art statistical and causal inference techniques on datasets of three large, randomised trials. In this multimethod analysis, data from 1801 women participating in the randomised PORTEC-1, PORTEC-2, and PORTEC-3 trials were used for statistical analyses and causal inference. The cohort included 714 patients with intermediate-risk endometrial cancer, 427 patients with high-intermediate risk endometrial cancer, and 660 patients with high-risk endometrial cancer. Associations of age with clinicopathological and molecular features were analysed using non-parametric tests. Multivariable competing risk analyses were performed to determine the independent prognostic value of age. To analyse age as a causal prognostic variable, a deep learning causal inference model called AutoCI was used. Median follow-up as estimated using the reversed Kaplan-Meier method was 12·3 years (95% CI 11·9–12·6) for PORTEC-1, 10·5 years (10·2–10·7) for PORTEC-2, and 6·1 years (5·9–6·3) for PORTEC-3. Both overall recurrence and endometrial cancer-specific death significantly increased with age. Moreover, older women had a higher frequency of deep myometrial invasion, serous tumour histology, and p53-abnormal tumours. Age was an independent risk factor for both overall recurrence (hazard ratio [HR] 1·02 per year, 95% CI 1·01–1·04; p=0·0012) and endometrial cancer-specific death (HR 1·03 per year, 1·01–1·05; p=0·0012) and was identified as a significant causal variable. This study showed that advanced age was associated with more aggressive tumour features in women with endometrial cancer, and was independently and causally related to worse oncological outcomes. Therefore, our findings suggest that older women with endometrial cancer should not be excluded from diagnostic assessments, molecular testing, and adjuvant therapy based on their age alone. None.

Objectives To analyse computed tomography (CT) findings of interval and post-screen carcinomas in lung cancer screening. Methods Consecutive interval and post-screen carcinomas from the Dutch–Belgium lung cancer screening trial were included. The prior screening and the diagnostic chest CT were reviewed by two experienced radiologists in consensus with knowledge of the tumour location on the diagnostic CT. Results Sixty-one participants (53 men) were diagnosed with an interval or post-screen carcinoma. Twenty-two (36 %) were in retrospect visible on the prior screening CT. Detection error occurred in 20 cancers and interpretation error in two cancers. Errors involved intrabronchial tumour ( n  = 5), bulla with wall thickening ( n  = 5), lymphadenopathy ( n  = 3), pleural effusion ( n  = 1) and intraparenchymal solid nodules ( n  = 8). These were missed because of a broad pleural attachment ( n  = 4), extensive reticulation surrounding a nodule ( n  = 1) and extensive scarring ( n  = 1). No definite explanation other than human error was found in two cases. None of the interval or post-screen carcinomas involved a subsolid nodule. Conclusions Interval or post-screen carcinomas that were visible in retrospect were mostly due to detection errors of solid nodules, bulla wall thickening or endobronchial lesions. Interval or post-screen carcinomas without explanation other than human errors are rare. Key points • 22 % of missed carcinomas originally presented as bulla wall thickening on CT. • 22 % of missed carcinomas originally presented as endobronchial lesions on CT. • All malignant endobronchial lesions presented as interval carcinomas. • In the NELSON trial subsolid nodules were not a source of missed carcinomas.

ObjectivesMultiple studies have proven the prognostic value of molecular classification for stage I–III endometrial cancer patients. However, studies on the relevance of molecular classification for stage IV endometrial cancer patients are lacking. Hypothetically, poor prognostic molecular subtypes are more common in higher stages of endometrial cancer. Considering the poor prognosis of stage IV endometrial cancer patients, it is questionable whether molecular classification has additional prognostic value. Therefore, we determined which molecular subclasses are found in stage IV endometrial cancer and if there is a correlation with progression-free and overall survival.MethodsA retrospective multicenter cohort study was conducted using data from five Dutch hospitals. Patients with stage IV endometrial cancer at diagnosis who were treated with primary cytoreductive surgery or cytoreductive surgery after induction chemotherapy between January 2000 and December 2018 were included. Exclusion criteria were age <18 years or recurrent disease. The molecular classification was performed centrally on all tumor samples according to the World Health Organization 2020 classification (including POLE and estrogen receptor status). The Kaplan–Meier method was used to calculate progression free and overall survival in the molecular subclasses, for the different histological subtypes and for estrogen receptor positive versus estrogen receptor negative tumors. Groups were compared using the log-rank test.Results164 stage IV endometrial cancer patients were molecularly classified. Median age of the patients was 67 years (range 33–86). Most patients presented with a non-endometrioid histological subtype (58%). Intra-abdominal complete cytoreductive surgery was achieved in 60.4% of the patients. 101 tumors (61.6%) were classified as p53 abnormal, 35 (21.3%) as no specific molecular profile, 21 (12.8%) as mismatch repair deficient, and 6 (3%) as POLE mutated. Molecular classification had no significant impact on progression free (p=0.056) or overall survival (p=0.12) after cytoreductive surgery. Overall survival was affected by histologic subtype (p<0.0001) and estrogen receptor status (p=0.013).ConclusionThe distribution of the molecular subclasses in stage IV endometrial cancer patients differed substantially from the distribution in stage I–III endometrial cancer patients, with the unfavorable subclasses being more frequently present. Although the molecular classification was not prognostic in stage IV endometrial cancer, it could guide adjuvant treatment decisions.