Single-cell profiling of low-stage endometrial cancers identifies low epithelial vimentin expression as a marker of recurrent disease.

BACKGROUND: Identification of aggressive low-stage endometrial cancers is challenging. So far, studies have failed to pinpoint robust features or biomarkers associated with risk of recurrence for these patients. METHODS: Imaging mass cytometry was used to examine single-cell expression of 23 proteins in 36 primary FIGO IB endometrial cancers, of which 17 recurred. Single-cell information was extracted for each tumor and unsupervised clustering was used to identify cellular phenotypes. Distinct phenotypes and cellular neighborhoods were compared in relation to recurrence. Cellular differences were validated in a separate gene expression dataset and the TCGA EC dataset. Vimentin protein expression was evaluated by IHC in pre-operative samples from 518 patients to validate its robustness as a prognostic marker. FINDINGS: The abundance of epithelial, immune or stromal cell types did not associate with recurrence. Clustering of patients based on tumor single cell marker expression revealed distinct patient clusters associated with outcome. A cell population neighboring CD8+ T cells, defined by vimentin, ER, and PR expressing epithelial cells, was more prevalent in non-recurrent tumors. Importantly, lower epithelial vimentin expression and lower gene expression of VIM associated with worse recurrence-free survival. Loss and low expression of vimentin was validated by IHC as a robust marker for recurrence in FIGO I stage disease and predicted poor prognosis also when including all patients and in endometrioid patients only. INTERPRETATION: This study reveals distinct characteristics in low-stage tumors and points to vimentin as a clinically relevant marker that may aid in identifying a here to unidentified subgroup of high-risk patients. FUNDING: A full list of funding that contributed to this study can be found in the Acknowledgements section.

Preoperative pelvic MRI and 2-[18F]FDG PET/CT for lymph node staging and prognostication in endometrial cancer-time to revisit current imaging guidelines?

OBJECTIVE: This study presents the diagnostic performance of four different preoperative imaging workups (IWs) for prediction of lymph node metastases (LNMs) in endometrial cancer (EC): pelvic MRI alone (IW1), MRI and [18F]FDG-PET/CT in all patients (IW2), MRI with selective [18F]FDG-PET/CT if high-risk preoperative histology (IW3), and MRI with selective [18F]FDG-PET/CT if MRI indicates FIGO stage ≥ 1B (IW4). METHODS: In 361 EC patients, preoperative staging parameters from both pelvic MRI and [18F]FDG-PET/CT were recorded. Area under receiver operating characteristic curves (ROC AUC) compared the diagnostic performance for the different imaging parameters and workups for predicting surgicopathological FIGO stage. Survival data were assessed using Kaplan-Meier estimator with log-rank test. RESULTS: MRI and [18F]FDG-PET/CT staging parameters yielded similar AUCs for predicting corresponding FIGO staging parameters in low-risk versus high-risk histology groups (p ≥ 0.16). The sensitivities, specificities, and AUCs for LNM prediction were as follows: IW1-33% [9/27], 95% [185/193], and 0.64; IW2-56% [15/27], 90% [174/193], and 0.73 (p = 0.04 vs. IW1); IW3-44% [12/27], 94% [181/193], and 0.69 (p = 0.13 vs. IW1); and IW4-52% [14/27], 91% [176/193], and 0.72 (p = 0.06 vs. IW1). IW3 and IW4 selected 34% [121/361] and 54% [194/361] to [18F]FDG-PET/CT, respectively. Employing IW4 identified three distinct patient risk groups that exhibited increasing FIGO stage (p < 0.001) and stepwise reductions in survival (p ≤ 0.002). CONCLUSION: Selective [18F]FDG-PET/CT in patients with high-risk MRI findings yields better detection of LNM than MRI alone, and similar diagnostic performance to that of MRI and [18F]FDG-PET/CT in all. KEY POINTS: • Imaging by MRI and [18F]FDG PET/CT yields similar diagnostic performance in low- and high-risk histology groups for predicting central FIGO staging parameters. • Utilizing a stepwise imaging workup with MRI in all patients and [18F]FDG-PET/CT in selected patients based on MRI findings identifies preoperative risk groups exhibiting significantly different survival. • The proposed imaging workup selecting ~54% of the patients to [18F]FDG-PET/CT yield better detection of LNMs than MRI alone, and similar LNM detection to that of MRI and [18F]FDG-PET/CT in all.

Mismatch repair markers in preoperative and operative endometrial cancer samples; expression concordance and prognostic value.

BACKGROUND: The endometrial cancer mismatch repair (MMR) deficient subgroup is defined by loss of MSH6, MSH2, PMS2 or MLH1. We compare MMR status in paired preoperative and operative samples and investigate the prognostic impact of differential MMR protein expression levels. METHODS: Tumour lesions from 1058 endometrial cancer patients were immunohistochemically stained for MSH6, MSH2, PMS2 and MLH1. MMR protein expression was evaluated as loss or intact to determine MMR status, or by staining index to evaluate the prognostic potential of differential expression. Gene expression data from a local (n = 235) and the TCGA (n = 524) endometrial cancer cohorts was used for validation. RESULTS: We identified a substantial agreement in MMR status between paired curettage and hysterectomy samples. Individual high expression of all four MMR markers associated with non-endometrioid subtype, and high MSH6 or MSH2 strongly associated with several aggressive disease characteristics including high tumour grade and FIGO stage, and for MSH6, with lymph node metastasis. In multivariate Cox analysis, MSH6 remained an independent prognostic marker, also within the endometrioid low-grade subgroup (P < 0.001). CONCLUSION: We demonstrate that in addition to determine MMR status, MMR protein expression levels, particularly MSH6, may add prognostic information in endometrial cancer.

Antiemetic treatment of hyperemesis gravidarum in 1,064 Norwegian women and the impact of European warning on metoclopramide: a retrospective cohort study 2002-2019.

BACKGROUND: Women suffering from severe nausea and vomiting during pregnancy, hyperemesis gravidarum, have poor quality of life and increased risk of potentially fatal maternal and fetal complications. There is increasing and reassuring knowledge about safety of antiemetics in pregnancy. In 2013, the European Medical Agency (EMA) issued a warning on metoclopramide limiting treatment to maximum five days. Metoclopramide was the most used antiemetic in pregnancy at the time the warning was implemented in the Norwegian hyperemesis guidelines (2014). We aimed at describing changes in the treatment of hyperemesis over time, including changes associated with the EMA warning. METHODS: Retrospective chart review of all women hospitalized for hyperemesis gravidarum with metabolic disturbances between 01/Jan/2002 and 31/Dec/2019 at a university hospital serving nearly 10% of the pregnant population in Norway. Time-series analysis described changes over time and interrupted time series analysis quantified changes in treatment and clinical outcomes related to the EMA warning. RESULTS: In total, 1,064 women (1.2% of the birthing population) were included. The use of meclizine, prochlorperazine, and ondansetron increased during 2002-2019. This led to a yearly increase in the percentage of women using any antiemetic of 1.5% (95%CI 0.6; 2.4) pre-hospital, 0.6% (95%CI 0.2; 1.1) during hospitalization, and 2.6% (95%CI 1.3; 3.8) at discharge. Overall, only 50% of the women received antiemetics pre-hospital. Following the EMA warning, prehospital use of metoclopramide dropped by 30% (95%CI 25; 36), while use of any antiemetic pre-hospital dropped by 20% (95%CI 5.7; 34). In timely association, we observed a decrease in gestational age (-3.8 days, 98.75%CI 0.6; 7.1) at first admission, as well as indication of increased rate of termination of pregnancy with an absolute increase of 4.8% (98.75%CI 0.9; 8.7) in 2014. CONCLUSION: During 2002-2019, the overall use of antiemetics in treatment of hyperemesis increased. The EMA-warning on metoclopramide in 2013 temporarily limited pre-hospital antiemetic provision associated with hospitalization at lower gestational length and indication of an increase in termination of pregnancy.

What MRI-based tumor size measurement is best for predicting long-term survival in uterine cervical cancer?

BACKGROUND: Tumor size assessment by MRI is central for staging uterine cervical cancer. However, the optimal role of MRI-derived tumor measurements for prognostication is still unclear. MATERIAL AND METHODS: This retrospective cohort study included 416 women (median age: 43 years) diagnosed with cervical cancer during 2002-2017 who underwent pretreatment pelvic MRI. The MRIs were independently read by three radiologists, measuring maximum tumor diameters in three orthogonal planes and maximum diameter irrespective of plane (MAXimaging). Inter-reader agreement for tumor size measurements was assessed by intraclass correlation coefficients (ICCs). Size was analyzed in relation to age, International Federation of Gynecology and Obstetrics (FIGO) (2018) stage, histopathological markers, and disease-specific survival using Kaplan-Meier-, Cox regression-, and time-dependent receiver operating characteristics (tdROC) analyses. RESULTS: All MRI tumor size variables (cm) yielded high areas under the tdROC curves (AUCs) for predicting survival (AUC 0.81-0.84) at 5 years after diagnosis and predicted outcome (hazard ratios [HRs] of 1.42-1.76, p < 0.001 for all). Only MAXimaging independently predicted survival (HR = 1.51, p = 0.03) in the model including all size variables. The optimal cutoff for maximum tumor diameter (≥ 4.0 cm) yielded sensitivity (specificity) of 83% (73%) for predicting disease-specific death after 5 years. Inter-reader agreement for MRI-based primary tumor size measurements was excellent, with ICCs of 0.83-0.85. CONCLUSION: Among all MRI-derived tumor size measurements, MAXimaging was the only independent predictor of survival. MAXimaging ≥ 4.0 cm represents the optimal cutoff for predicting long-term disease-specific survival in cervical cancer. Inter-reader agreement for MRI-based tumor size measurements was excellent.

Interobserver agreement and prognostic impact for MRI-based 2018 FIGO staging parameters in uterine cervical cancer.

OBJECTIVES: To evaluate the interobserver agreement for MRI-based 2018 International Federation of Gynecology and Obstetrics (FIGO) staging parameters in patients with cervical cancer and assess the prognostic value of these MRI parameters in relation to other clinicopathological markers. METHODS: This retrospective study included 416 women with histologically confirmed cervical cancer who underwent pretreatment pelvic MRI from May 2002 to December 2017. Three radiologists independently recorded MRI-derived staging parameters incorporated in the 2018 FIGO staging system. Kappa coefficients (κ) for interobserver agreement were calculated. The predictive and prognostic values of the MRI parameters were explored using ROC analyses and Kaplan-Meier with log-rank tests, and analyzed in relation to clinicopathological patient characteristics. RESULTS: Overall agreement was substantial for the staging parameters: tumor size > 2 cm (κ = 0.80), tumor size > 4 cm (κ = 0.76), tumor size categories (≤ 2 cm; > 2 and ≤ 4 cm; > 4 cm) (κ = 0.78), parametrial invasion (κ = 0.63), vaginal invasion (κ = 0.61), and enlarged lymph nodes (κ = 0.63). Higher MRI-derived tumor size category (≤ 2 cm; > 2 and ≤ 4 cm; > 4 cm) was associated with a stepwise reduction in survival (p ≤ 0.001 for all). Tumor size > 4 cm and parametrial invasion at MRI were associated with aggressive clinicopathological features, and the incorporation of these MRI-based staging parameters improved risk stratification when compared to corresponding clinical assessments alone. CONCLUSION: The interobserver agreement for central MRI-derived 2018 FIGO staging parameters was substantial. MRI improved the identification of patients with aggressive clinicopathological features and poor survival, demonstrating the potential impact of MRI enabling better prognostication and treatment tailoring in cervical cancer. KEY POINTS: • The overall interobserver agreement was substantial (κ values 0.61-0.80) for central MRI staging parameters in the 2018 FIGO system. • Higher MRI-derived tumor size category was linked to a stepwise reduction in survival (p ≤ 0.001 for all). • MRI-derived tumor size > 4 cm and parametrial invasion were associated with aggressive clinicopathological features, and the incorporation of these MRI-derived staging parameters improved risk stratification when compared to clinical assessments alone.

MRI-assessed tumor-free distance to serosa predicts deep myometrial invasion and poor outcome in endometrial cancer.

OBJECTIVES: To explore the diagnostic accuracy of preoperative magnetic resonance imaging (MRI)-derived tumor measurements for the prediction of histopathological deep (≥ 50%) myometrial invasion (pDMI) and prognostication in endometrial cancer (EC). METHODS: Preoperative pelvic MRI of 357 included patients with histologically confirmed EC were read independently by three radiologists blinded to clinical information. The radiologists recorded imaging findings (T1 post-contrast sequence) suggesting deep (≥ 50%) myometrial invasion (iDMI) and measured anteroposterior tumor diameter (APD), depth of myometrial tumor invasion (DOI) and tumor-free distance to serosa (iTFD). Receiver operating characteristic (ROC) curves for the prediction of pDMI were plotted for the different MRI measurements. The predictive and prognostic value of the MRI measurements was analyzed using logistic regression and Cox proportional hazard model. RESULTS: iTFD yielded highest area under the ROC curve (AUC) for the prediction of pDMI with an AUC of 0.82, whereas DOI, APD and iDMI yielded AUCs of 0.74, 0.81 and 0.74, respectively. Multivariate analysis for predicting pDMI yielded highest predictive value of iTFD < 6 mm with OR of 5.8 (p < 0.001) and lower figures for DOI ≥ 5 mm (OR = 2.8, p = 0.01), APD ≥ 17 mm (OR = 2.8, p < 0.001) and iDMI (OR = 1.1, p = 0.82). Patients with iTFD < 6 mm also had significantly reduced progression-free survival with hazard ratio of 2.4 (p < 0.001). CONCLUSION: For predicting pDMI, iTFD yielded best diagnostic performance and iTFD < 6 mm outperformed other cutoff-based imaging markers and conventional subjective assessment of deep myometrial invasion (iDMI) for diagnosing pDMI. Thus, iTFD at MRI represents a promising preoperative imaging biomarker that may aid in predicting pDMI and high-risk disease in EC.

Longitudinal effects of adjuvant chemotherapy and lymph node staging on patient-reported outcomes in endometrial cancer survivors: a prospective cohort study.

BACKGROUND: Most patients with endometrial cancer with localized disease are effectively treated and survive for a long time. The primary treatment is hysterectomy, to which surgical staging procedures may be added to assess the need for adjuvant therapy. Longitudinal data on patient-reported outcomes comparing different levels of primary treatment are lacking, especially when adjuvant radiotherapy is omitted. OBJECTIVE: We assessed the impact of lymphadenectomy and adjuvant chemotherapy on patient-reported symptoms, function, and quality of life. We hypothesized that these treatment modalities would substantially affect patient-reported outcomes at follow-up. STUDY DESIGN: We prospectively included patients with endometrial cancer enrolled in the ongoing MoMaTEC2 study (ClinicalTrials.gov Identifier: NCT02543710). Patients were asked to complete the patient-reported outcome questionnaires European Organization for Research and Treatment of Cancer Quality of Life Questionnaire C30 and European Organization for Research and Treatment of Cancer Quality of Life Questionnaire EN24 preoperatively and at 1 and 2 years of follow-up. Functional domains and symptoms were analyzed for the whole cohort and by treatment received. To assess the effect of the individual treatment modifications, we used mixed regression models. RESULTS: Baseline data were available for 448 patients. Of these patients, 339 and 219 had reached 1-year follow-up and 2-year follow-up, respectively. Treatment included hysterectomy (plus bilateral salpingo-oophorectomy) alone (n=177), hysterectomy and lymph node staging without adjuvant therapy (n=133), or adjuvant chemotherapy irrespective of staging procedure (n=138). Overall, patients reported improved global health status and quality of life (+9 units; P<.001), increased emotional and social functioning, and increased sexual interest and activity (P<.001 for all) from baseline to year 1, and these outcomes remained stable at year 2. Means of functional scales and quality of life were similar to age- and sex-weighted reference cohorts. Mean tingling and numbness and lymphedema increased after treatment. The group who received adjuvant chemotherapy had a larger mean reduction in physical functioning (-6 vs +2; P=.002) at year 1, more neuropathy (+30 vs +5; P<.001; year 1) at years 1 and 2, and more lymphedema at year 1 (+11 vs +2; P=.007) than the group treated with hysterectomy and salpingo-oophorectomy only. In patients not receiving adjuvant chemotherapy, patient-reported outcomes were similar regardless of lymph node staging procedures. Adjuvant chemotherapy independently increased fatigue, lymphedema, and neuropathy in mixed regression models. CONCLUSION: Patients with endometrial cancer receiving adjuvant chemotherapy reported significantly reduced functioning and more symptoms up to 2 years after treatment. For patients treated by surgery alone, surgical staging did not seem to affect the quality of life or symptoms to a measurable degree at follow-up. Therefore, subjecting patients to lymph node removal to tailor adjuvant therapy seems justified from the patient's viewpoint; however, efforts should increase to find alternatives to traditional chemotherapy.

Salvage Radiation for Pelvic Relapse after Surgically Treated Endometrial Cancer.

(1) Background: This study evaluated the clinical outcome after salvage radiotherapy for first pelvic relapse after endometrial cancer (EC). (2) Methods: This multicenter retrospective study included EC patients with first central pelvic relapse without lymph node involvement treated with curative intent. Progression-free (PFS) and overall survival (OS) were calculated with the Kaplan-Meier method and possible predictive factors for risk of relapse and mortality were identified using the Cox model. (3) Results: We included 139 patients with median EQD2 (Equivalent Dose in 2 Gy fractions) to the clinical target volume of 70.0 Gy. During follow up of median 6.66 years, 39.6% patients developed a second relapse. Risk group classification at primary diagnosis based on histology, grading and FIGO stage and how the pelvic tumor boost was administered were independently associated with PFS and OS. Five-year OS was 68% (95% CI (59-75)) for the whole cohort. Five-year OS was 88% (95% CI (75-94)), 72% (95% CI (55-84)) and 38% (95% CI (15-60)) for the stage I low-, intermediate- and high-risk group, respectively. (4) Conclusions: The majority of central pelvic recurrences in RT-naive EC women can be successfully salvaged with radiotherapy. However, survival in patients with high-risk disease remains poor and warrants a more individualized approach to optimize outcome.

Handheld transabdominal ultrasound, after limited training, may confirm first trimester viable intrauterine pregnancy: a prospective cohort study.

OBJECTIVES: Handheld point-of-care abdominal ultrasound (POCUS) may be used by primary care physicians while vaginal ultrasound is limited to use in specialist care. We aimed to compare abdominal handheld ultrasound to vaginal ultrasound in determining first trimester viable intrauterine pregnancy and estimate gestational length. DESIGN: Prospective cohort study. SETTING: Gynaecologic outpatient clinic; women referred from GPs during early pregnancy. Handheld ultrasound using VscanExtend® was performed by fourth-year medical students with limited training. Transvaginal ultrasound using high-end devices was performed by ordinary hospital staff. SUBJECTS: Women in the first trimester of pregnancy referred for termination of pregnancy or with symptoms of early pregnancy complications. MAIN OUTCOME MEASURES: Rate of confirming vital intrauterine pregnancy (visualizing foetal heart beats) and measurement of crown-rump length (CRL) using handheld abdominal versus vaginal ultrasound. RESULTS: In all 100 women were included; 86 confirmed as viable intrauterine pregnancies and 14 pathological pregnancies (miscarriages/extrauterine pregnancies). Handheld abdominal ultrasound detected fetal heartbeats in 63/86 (73% sensitivity) of healthy pregnancies and confirmed lack of fetal heartbeats in all pathological pregnancies, total positive predictive value (PPV) 100% and total negative predictive value (NPV) 38%. From gestational week 7, handheld abdominal ultrasound confirmed vitality in 51/54 patients: PPV 100% and NPV 79%. CRL (n = 62) was median 1 mm shorter (95% confidence interval 1-2 mm) measured by handheld abdominal versus vaginal ultrasound. CONCLUSION: Handheld ultrasound has an excellent prediction confirming viable intrauterine pregnancy from gestational week 7. Validation studies are needed to confirm whether the method is suitable in primary care assessing early pregnancy complications.KEY POINTSWhen early pregnancy vitality needs to be confirmed, women will traditionally be referred to secondary care for transvaginal comprehensive ultrasonography performed with high-end devices by imaging specialists.In this study personnel with limited former training (fourth-year medical students) performed transabdominal POCUS using a handheld device, investigating 100 first trimester pregnancies for confirmation of viability.Using handheld ultrasound viable pregnancy was confirmed from gestational week 7 with 79% positive and 100% negative predictive value.If handheld ultrasound used in primary care confirms vital intrauterine pregnancy, the need for specialist referral could be reduced.

A 10-gene prognostic signature points to LIMCH1 and HLA-DQB1 as important players in aggressive cervical cancer disease.

BACKGROUND: Advanced cervical cancer carries a particularly poor prognosis, and few treatment options exist. Identification of effective molecular markers is vital to improve the individualisation of treatment. We investigated transcriptional data from cervical carcinomas related to patient survival and recurrence to identify potential molecular drivers for aggressive disease. METHODS: Primary tumour RNA-sequencing profiles from 20 patients with recurrence and 53 patients with cured disease were compared. Protein levels and prognostic impact for selected markers were identified by immunohistochemistry in a population-based patient cohort. RESULTS: Comparison of tumours relative to recurrence status revealed 121 differentially expressed genes. From this gene set, a 10-gene signature with high prognostic significance (p = 0.001) was identified and validated in an independent patient cohort (p = 0.004). Protein levels of two signature genes, HLA-DQB1 (n = 389) and LIMCH1 (LIM and calponin homology domain 1) (n = 410), were independent predictors of survival (hazard ratio 2.50, p = 0.007 for HLA-DQB1 and 3.19, p = 0.007 for LIMCH1) when adjusting for established prognostic markers. HLA-DQB1 protein expression associated with programmed death ligand 1 positivity (p < 0.001). In gene set enrichment analyses, HLA-DQB1high tumours associated with immune activation and response to interferon-γ (IFN-γ). CONCLUSIONS: This study revealed a 10-gene signature with high prognostic power in cervical cancer. HLA-DQB1 and LIMCH1 are potential biomarkers guiding cervical cancer treatment.

An MRI-Based Radiomic Prognostic Index Predicts Poor Outcome and Specific Genetic Alterations in Endometrial Cancer.

Integrative tumor characterization linking radiomic profiles to corresponding gene expression profiles has the potential to identify specific genetic alterations based on non-invasive radiomic profiling in cancer. The aim of this study was to develop and validate a radiomic prognostic index (RPI) based on preoperative magnetic resonance imaging (MRI) and assess possible associations between the RPI and gene expression profiles in endometrial cancer patients. Tumor texture features were extracted from preoperative 2D MRI in 177 endometrial cancer patients. The RPI was developed using least absolute shrinkage and selection operator (LASSO) Cox regression in a study cohort (n = 95) and validated in an MRI validation cohort (n = 82). Transcriptional alterations associated with the RPI were investigated in the study cohort. Potential prognostic markers were further explored for validation in an mRNA validation cohort (n = 161). The RPI included four tumor texture features, and a high RPI was significantly associated with poor disease-specific survival in both the study cohort (p < 0.001) and the MRI validation cohort (p = 0.030). The association between RPI and gene expression profiles revealed 46 significantly differentially expressed genes in patients with a high RPI versus a low RPI (p < 0.001). The most differentially expressed genes, COMP and DMBT1, were significantly associated with disease-specific survival in both the study cohort and the mRNA validation cohort. In conclusion, a high RPI score predicts poor outcome and is associated with specific gene expression profiles in endometrial cancer patients. The promising link between radiomic tumor profiles and molecular alterations may aid in developing refined prognostication and targeted treatment strategies in endometrial cancer.

A patient-clinician James Lind Alliance partnership to identify research priorities for hyperemesis gravidarum.

OBJECTIVE: There are many uncertainties surrounding the aetiology, treatment and sequelae of hyperemesis gravidarum (HG). Prioritising research questions could reduce research waste, helping researchers and funders direct attention to those questions which most urgently need addressing. The HG priority setting partnership (PSP) was established to identify and rank the top 25 priority research questions important to both patients and clinicians. METHODS: Following the James Lind Alliance (JLA) methodology, an HG PSP steering group was established. Stakeholders representing patients, carers and multidisciplinary professionals completed an online survey to gather uncertainties. Eligible uncertainties related to HG. Uncertainties on nausea and vomiting of pregnancy and those on complementary treatments were not eligible. Questions were verified against the evidence. Two rounds of prioritisation included an online ranking survey and a 1-hour consensus workshop. RESULTS: 1009 participants (938 patients/carers, 118 professionals with overlap between categories) submitted 2899 questions. Questions originated from participants in 26 different countries, and people from 32 countries took part in the first prioritisation stage. 66 unique questions emerged, which were evidence checked according to the agreed protocol. 65 true uncertainties were narrowed via an online ranking survey to 26 unranked uncertainties. The consensus workshop was attended by 19 international patients and clinicians who reached consensus on the top 10 questions for international researchers to address. More patients than professionals took part in the surveys but were equally distributed during the consensus workshop. Participants from low-income and middle-income countries noted that the priorities may be different in their settings. CONCLUSIONS: By following the JLA method, a prioritised list of uncertainties relevant to both HG patients and their clinicians has been identified which can inform the international HG research agenda, funders and policy-makers. While it is possible to conduct an international PSP, results from developed countries may not be as relevant in low-income and middle-income countries.

Patient-derived organoids reflect the genetic profile of endometrial tumors and predict patient prognosis.

Background: A major hurdle in translational endometrial cancer (EC) research is the lack of robust preclinical models that capture both inter- and intra-tumor heterogeneity. This has hampered the development of new treatment strategies for people with EC. Methods: EC organoids were derived from resected patient tumor tissue and expanded in a chemically defined medium. Established EC organoids were orthotopically implanted into female NSG mice. Patient tissue and corresponding models were characterized by morphological evaluation, biomarker and gene expression and by whole exome sequencing. A gene signature was defined and its prognostic value was assessed in multiple EC cohorts using Mantel-Cox (log-rank) test. Response to carboplatin and/or paclitaxel was measured in vitro and evaluated in vivo. Statistical difference between groups was calculated using paired t-test. Results: We report EC organoids established from EC patient tissue, and orthotopic organoid-based patient-derived xenograft models (O-PDXs). The EC organoids and O-PDX models mimic the tissue architecture, protein biomarker expression and genetic profile of the original tissue. Organoids show heterogenous sensitivity to conventional chemotherapy, and drug response is reproduced in vivo. The relevance of these models is further supported by the identification of an organoid-derived prognostic gene signature. This signature is validated as prognostic both in our local patient cohorts and in the TCGA endometrial cancer cohort. Conclusions: We establish robust model systems that capture both the diversity of endometrial tumors and intra-tumor heterogeneity. These models are highly relevant preclinical tools for the elucidation of the molecular pathogenesis of EC and identification of potential treatment strategies.

Erratum: Author Correction: Patient-derived organoids reflect the genetic profile of endometrial tumors and predict patient prognosis.

[This corrects the article DOI: 10.1038/s43856-021-00019-x.].

Cancer awareness in the general population varies with sex, age and media coverage: A population-based survey with focus on gynecologic cancers.

OBJECTIVES: There is a need for more knowledge about the public awareness and attitudes towards gynecologic cancers. We employed a research-purpose population-based citizen panel to assess how often people recall gynecologic cancers compared to other cancer types and to explore the relative importance of different information channels in relaying cancer information. STUDY DESIGN: We conducted an online survey using the Norwegian Citizen Panel (n = 1441 respondents), exploring associations between demographic factors and frequency of mentioning specific cancer types. We also searched The Norwegian Media Archive to assess the media coverage of different cancer types. Factors affecting likelihood of mentioning different cancers were assessed by multivariate regression. RESULTS: Only 41 % of respondents listed one or more cancers in female genital organs. Of the gynecological cancers, cervical cancer was most frequently mentioned (28 %), followed by ovarian (12 %) and endometrial cancer (11 %). Female responders were more likely to mention cervical (OR 2.47, 95 % CI 2.16-2.78) and ovarian cancer (OR 2.09, 95 % CI 1.60-2.58) than male responders, but not endometrial cancer. Family and friends who have had cancer (50 %) and different types of media coverage (41 %) were reported as the most common sources of cancer information. The three most frequently mentioned cancer types in our survey were breast (77 %), hematologic (76 %) and lung cancer (75 %), which also were the cancer types having most media coverage. CONCLUSIONS: Gynecological cancers are less frequently mentioned by Norwegian citizens when compared to several other cancer types such as breast-, hematologic- and lung cancer. Sex and age are important factors that affect awareness of cancer types. Media is likely to play an important role in what cancer types the public recalls.

Whole-Volume Tumor MRI Radiomics for Prognostic Modeling in Endometrial Cancer.

BACKGROUND: In endometrial cancer (EC), preoperative pelvic MRI is recommended for local staging, while final tumor stage and grade are established by surgery and pathology. MRI-based radiomic tumor profiling may aid in preoperative risk-stratification and support clinical treatment decisions in EC. PURPOSE: To develop MRI-based whole-volume tumor radiomic signatures for prediction of aggressive EC disease. STUDY TYPE: Retrospective. POPULATION: A total of 138 women with histologically confirmed EC, divided into training (nT = 108) and validation cohorts (nV = 30). FIELD STRENGTH/SEQUENCE: Axial oblique T1 -weighted gradient echo volumetric interpolated breath-hold examination (VIBE) at 1.5T (71/138 patients) and DIXON VIBE at 3T (67/138 patients) at 2 minutes postcontrast injection. ASSESSMENT: Primary tumors were manually segmented by two radiologists with 4 and 8 years' of experience. Radiomic tumor features were computed and used for prediction of surgicopathologically-verified deep (≥50%) myometrial invasion (DMI), lymph node metastases (LNM), advanced stage (FIGO III + IV), nonendometrioid (NE) histology, and high-grade endometrioid tumors (E3). Corresponding analyses were also conducted using radiomics extracted from the axial oblique image slice depicting the largest tumor area. STATISTICAL TESTS: Logistic least absolute shrinkage and selection operator (LASSO) was applied for radiomic modeling in the training cohort. The diagnostic performances of the radiomic signatures were evaluated by area under the receiver operating characteristic curve in the training (AUCT ) and validation (AUCV ) cohorts. Progression-free survival was assessed using the Kaplan-Meier and Cox proportional hazard model. RESULTS: The whole-tumor radiomic signatures yielded AUCT /AUCV of 0.84/0.76 for predicting DMI, 0.73/0.72 for LNM, 0.71/0.68 for FIGO III + IV, 0.68/0.74 for NE histology, and 0.79/0.63 for high-grade (E3) tumor. Single-slice radiomics yielded comparable AUCT but significantly lower AUCV for LNM and FIGO III + IV (both P < 0.05). Tumor volume yielded comparable AUCT to the whole-tumor radiomic signatures for prediction of DMI, LNM, FIGO III + IV, and NE, but significantly lower AUCT for E3 tumors (P < 0.05). All of the whole-tumor radiomic signatures significantly predicted poor progression-free survival with hazard ratios of 4.6-9.8 (P < 0.05 for all). DATA CONCLUSION: MRI-based whole-tumor radiomic signatures yield medium-to-high diagnostic performance for predicting aggressive EC disease. The signatures may aid in preoperative risk assessment and hence guide personalized treatment strategies in EC. LEVEL OF EVIDENCE: 4 TECHNICAL EFFICACY STAGE: 2.

Prognostic Value of the Diversity of Nuclear Chromatin Compartments in Gynaecological Carcinomas.

Statistical texture analysis of cancer cell nuclei stained for DNA has recently been used to develop a pan-cancer prognostic marker of chromatin heterogeneity. In this study, we instead analysed chromatin organisation by automatically quantifying the diversity of chromatin compartments in cancer cell nuclei. The aim was to investigate the prognostic value of such an assessment in relation to chromatin heterogeneity and as a potential supplement to pathological risk classifications in gynaecological carcinomas. The diversity was quantified by calculating the entropy of both chromatin compartment sizes and optical densities within compartments. We analysed a median of 281 nuclei (interquartile range (IQR), 273 to 289) from 246 ovarian carcinoma patients and a median of 997 nuclei (IQR, 502 to 1452) from 791 endometrial carcinoma patients. The prognostic value of the entropies and chromatin heterogeneity was moderately strongly correlated (r ranged from 0.68 to 0.73), but the novel marker was observed to provide additional prognostic information. In multivariable analysis with clinical and pathological markers, the hazard ratio associated with the novel marker was 2.1 (95% CI, 1.3 to 3.5) in ovarian carcinoma and 2.4 (95% CI, 1.5 to 3.9) in endometrial carcinoma. Integration with pathological risk classifications gave three risk groups with distinctly different prognoses. This suggests that the novel marker of diversity of chromatin compartments might possibly contribute to the selection of high-risk stage I ovarian carcinoma patients for adjuvant chemotherapy and low-risk endometrial carcinoma patients for less extensive surgery.

Gynaecological fistulae after surgery or radiotherapy. / Gynekologiske fistler etter kirurgi eller strålebehandling.

BACKGROUND: Gynaecological fistulae cause urinary and/or faecal incontinence. Haukeland University Hospital has systematically recorded treatments for gynaecological fistulae, since 2012 in its capacity as the Norwegian National Unit for Gynaecological Fistulae. This study describes characteristics of and therapeutic outcomes for gynaecological fistulae caused by surgery and/or radiotherapy. MATERIAL AND METHOD: We have conducted a retrospective cohort study of women who were treated at the Department of Gynaecology and Obstetrics, Haukeland University Hospital, in the period 1995-2019 for gynaecological fistulae due to surgery or radiotherapy. RESULTS: Surgery or radiotherapy was the cause of gynaecological fistulae in 182 of a total of 411 women. 163 of them consented to the study, 124/163 (76 %) with fistulae following surgery and 39/163 (24 %) with fistulae following radiotherapy. The post-surgical fistulae were mainly urogenital (91/124: 73 %) and most often caused by a hysterectomy (n = 71) or urinary incontinence procedure (n = 11). Post-radiotherapy fistulae were mainly enterogenital (34/39: 87 %), with rectal cancer (n = 22) and cervical cancer (n = 11) as the most frequent types of cancer. The main procedure was vaginal fistuloplasty, which was carried out on 100/124 (81 %) of women with post-surgical fistula and 7/39 (18 %) of those with post-radiotherapy fistula. Catheter drainage or stomy alone resulted in healing in 14/163 (9 %) of all patients. A total of 117/124 (94 %) of women with post-surgical fistula achieved healing, compared with 10/39 (26 %) with post-radiotherapy fistula. 28/39 (72 %) of the latter had a permanent urostomy or enterostomy. INTERPETATION: Gynaecological fistulae caused by surgery have a good healing rate, while post-radiotherapy fistulae are more often permanent.