Expression patterns of mismatch repair proteins in cervical cancer uncover independent prognostic value of MSH-2.

OBJECTIVE: Although early-detected cervical cancer is associated with good survival, the prognosis for late-stage disease is poor and treatment options are sparse. Mismatch repair deficiency (MMR-D) has surfaced as a predictor of prognosis and response to immune checkpoint inhibitor(s) in several cancer types, but its value in cervical cancer remains unclear. This study aimed to define the prevalence of MMR-D in cervical cancer and assess the prognostic value of MMR protein expression. METHODS: Expression of the MMR proteins MLH-1, PMS-2, MSH-2, and MSH-6 was investigated by immunohistochemical staining in a prospectively collected cervical cancer cohort (n=508) with corresponding clinicopathological and follow-up data. Sections were scored as either loss or intact expression to define MMR-D, and by a staining index, based on staining intensity and area, evaluating the prognostic potential. RNA and whole exome sequencing data were available for 72 and 75 of the patients and were used for gene set enrichment and mutational analyses, respectively. RESULTS: Five (1%) tumors were MMR-deficient, three of which were of neuroendocrine histology. MMR status did not predict survival (HR 1.93, p=0.17). MSH-2 low (n=48) was associated with poor survival (HR 1.94, p=0.02), also when adjusting for tumor stage, tumor type, and patient age (HR 2.06, p=0.013). MSH-2 low tumors had higher tumor mutational burden (p=0.003) and higher frequency of (frameshift) mutations in the double-strand break repair gene RAD50 (p<0.01). CONCLUSION: MMR-D is rare in cervical cancer, yet low MSH-2 expression is an independent predictor of poor survival.

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.

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.

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.

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.

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.

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.

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.

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.

Preoperative risk stratification in endometrial cancer (ENDORISK) by a Bayesian network model: A development and validation study.

BACKGROUND: Bayesian networks (BNs) are machine-learning-based computational models that visualize causal relationships and provide insight into the processes underlying disease progression, closely resembling clinical decision-making. Preoperative identification of patients at risk for lymph node metastasis (LNM) is challenging in endometrial cancer, and although several biomarkers are related to LNM, none of them are incorporated in clinical practice. The aim of this study was to develop and externally validate a preoperative BN to predict LNM and outcome in endometrial cancer patients. METHODS AND FINDINGS: Within the European Network for Individualized Treatment of Endometrial Cancer (ENITEC), we performed a retrospective multicenter cohort study including 763 patients, median age 65 years (interquartile range [IQR] 58-71), surgically treated for endometrial cancer between February 1995 and August 2013 at one of the 10 participating European hospitals. A BN was developed using score-based machine learning in addition to expert knowledge. Our main outcome measures were LNM and 5-year disease-specific survival (DSS). Preoperative clinical, histopathological, and molecular biomarkers were included in the network. External validation was performed using 2 prospective study cohorts: the Molecular Markers in Treatment in Endometrial Cancer (MoMaTEC) study cohort, including 446 Norwegian patients, median age 64 years (IQR 59-74), treated between May 2001 and 2010; and the PIpelle Prospective ENDOmetrial carcinoma (PIPENDO) study cohort, including 384 Dutch patients, median age 66 years (IQR 60-73), treated between September 2011 and December 2013. A BN called ENDORISK (preoperative risk stratification in endometrial cancer) was developed including the following predictors: preoperative tumor grade; immunohistochemical expression of estrogen receptor (ER), progesterone receptor (PR), p53, and L1 cell adhesion molecule (L1CAM); cancer antigen 125 serum level; thrombocyte count; imaging results on lymphadenopathy; and cervical cytology. In the MoMaTEC cohort, the area under the curve (AUC) was 0.82 (95% confidence interval [CI] 0.76-0.88) for LNM and 0.82 (95% CI 0.77-0.87) for 5-year DSS. In the PIPENDO cohort, the AUC for 5-year DSS was 0.84 (95% CI 0.78-0.90). The network was well-calibrated. In the MoMaTEC cohort, 249 patients (55.8%) were classified with <5% risk of LNM, with a false-negative rate of 1.6%. A limitation of the study is the use of imputation to correct for missing predictor variables in the development cohort and the retrospective study design. CONCLUSIONS: In this study, we illustrated how BNs can be used for individualizing clinical decision-making in oncology by incorporating easily accessible and multimodal biomarkers. The network shows the complex interactions underlying the carcinogenetic process of endometrial cancer by its graphical representation. A prospective feasibility study will be needed prior to implementation in the clinic.

Development of prediction models for lymph node metastasis in endometrioid endometrial carcinoma.

BACKGROUND: In endometrioid endometrial cancer (EEC), current clinical algorithms do not accurately predict patients with lymph node metastasis (LNM), leading to both under- and over-treatment. We aimed to develop models that integrate protein data with clinical information to identify patients requiring more aggressive surgery, including lymphadenectomy. METHODS: Protein expression profiles were generated for 399 patients using reverse-phase protein array. Three generalised linear models were built on proteins and clinical information (model 1), also with magnetic resonance imaging included (model 2), and on proteins only (model 3), using a training set, and tested in independent sets. Gene expression data from the tumours were used for confirmatory testing. RESULTS: LNM was predicted with area under the curve 0.72-0.89 and cyclin D1; fibronectin and grade were identified as important markers. High levels of fibronectin and cyclin D1 were associated with poor survival (p = 0.018), and with markers of tumour aggressiveness. Upregulation of both FN1 and CCND1 messenger RNA was related to cancer invasion and mesenchymal phenotype. CONCLUSIONS: We demonstrate that data-driven prediction models, adding protein markers to clinical information, have potential to significantly improve preoperative identification of patients with LNM in EEC.

High degree of heterogeneity of PD-L1 and PD-1 from primary to metastatic endometrial cancer.

OBJECTIVE: PD-L1 and PD-1 are predictive markers for immunotherapy and increasingly relevant in endometrial cancer. The reported fraction of positive primary tumors has been inconsistent. We investigated the expression of PD-L1 and PD-1 in primary tumors, also stratified by MSI. As immunotherapy is foremost relevant for metastatic disease, PD-L1 and PD-1 expression was also assessed in corresponding metastatic lesions. METHODS: PD-L1 and PD-1 was investigated in a prospective, population based endometrial cancer cohort of 700 patients with corresponding metastatic lesions from 68 and 74 patients respectively. Fresh tissue was used for gene expression analysis. RESULTS: In primary tumors, PD-L1 and PD-1 are expressed in 59% and 63%, respectively, but with no impact on survival, nor when stratified for MSS and MSI. Expression patterns of PD-L1 and PD-1 are similar in MSI and MSS tumors. Available metastatic lesions show heterogeneous expression of PD-L1 and PD-1. In gene expression analysis several genes related to immunological activity, including CD274 (encoding for PD-L1), were upregulated in PD-1 positive tumors. CONCLUSION: PD-L1 and PD-1 are frequently expressed in endometrial cancer and expression patterns are similar across MSS and MSI tumors. Expression in corresponding metastatic lesions is discordant compared to primary tumors. These findings are in particular relevant for treatment decisions in advanced and recurrent disease.

Preoperative 18F-FDG PET/CT tumor markers outperform MRI-based markers for the prediction of lymph node metastases in primary endometrial cancer.

OBJECTIVES: To compare the diagnostic accuracy of preoperative 18F-FDG PET/CT and MRI tumor markers for prediction of lymph node metastases (LNM) and aggressive disease in endometrial cancer (EC). METHODS: Preoperative whole-body 18F-FDG PET/CT and pelvic MRI were performed in 215 consecutive patients with histologically confirmed EC. PET/CT-based tumor standardized uptake value (SUVmax and SUVmean), metabolic tumor volume (MTV), and PET-positive lymph nodes (LNs) (SUVmax > 2.5) were analyzed together with the MRI-based tumor volume (VMRI), mean apparent diffusion coefficient (ADCmean), and MRI-positive LN (maximum short-axis diameter ≥ 10 mm). Imaging parameters were explored in relation to surgicopathological stage and tumor grade. Receiver operating characteristic (ROC) curves were generated yielding optimal cutoff values for imaging parameters, and regression analyses were used to assess their diagnostic performance for prediction of LNM and progression-free survival. RESULTS: For prediction of LNM, MTV yielded the largest area under the ROC curve (AUC) (AUC = 0.80), whereas VMRI had lower AUC (AUC = 0.72) (p = 0.03). Furthermore, MTV > 27 ml yielded significantly higher specificity (74%, p < 0.001) and accuracy (75%, p < 0.001) and also higher odds ratio (12.2) for predicting LNM, compared with VMRI > 10 ml (58%, 62%, and 9.7, respectively). MTV > 27 ml also tended to yield higher sensitivity than PET-positive LN (81% vs 50%, p = 0.13). Both VMRI > 10 ml and MTV > 27 ml were significantly associated with reduced progression-free survival. CONCLUSIONS: Tumor markers from 18F-FDG PET/CT outperform MRI markers for the prediction of LNM. MTV > 27 ml yields a high diagnostic performance for predicting aggressive disease and represents a promising supplement to conventional PET/CT reading in EC. KEY POINTS: • Metabolic tumor volume (MTV) outperforms other 18F-FDG PET/CT and MRI markers for preoperative prediction of lymph node metastases (LNM) in endometrial cancer patients. • Using cutoff values for tumor volume for prediction of LNM, MTV > 27 ml yielded higher specificity and accuracy than VMRI> 10 ml. • MTV represents a promising supplement to conventional PET/CT reading for predicting aggressive disease in EC.

Early maternal weight gain as a risk factor for SGA in pregnancies with hyperemesis gravidarum: a 15-year hospital cohort study.

BACKGROUND: Inadequate maternal weight gain increases the risk of small-for-gestational age (SGA) infants. Women with hyperemesis gravidarum (HG) are at risk of significant early pregnancy weight loss and insufficient total pregnancy weight gain. Recent studies have implied that weight gain during the first half of pregnancy is more crucial to pregnancy outcome than total weight gain. The aim of this study was to investigate whether not regaining prepregnancy weight by 13-18 weeks of gestation contributed to not reaching minimum body mass index (BMI)-specific total pregnancy weight gain and influenced the risk of SGA outcome in HG pregnancies. METHODS: In this retrospective 15-year cohort (2002-2016) of women hospitalized due to hyperemesis gravidarum, we reviewed individual patient hospital files and corresponding outpatient maternity records to collect prepregnancy BMI and weight, pregnancy weight gain (spanning 3-week intervals), delivery weight and foetal outcomes. BMI and total pregnancy weight gain goals were categorized according to the Institute of Medicine (IOM) 2009 guidelines: BMI < 18,5 kg/m2: 12.5-18 kg, 18.5-24.9 kg/m2: 11.5-16 kg, 25-29.9 kg/m2: 7-11.5 kg and > 30 kg/m2: 5-9 kg. Birth weight was categorized as SGA if less than the 10th percentile of sex- and gestational length-specific Norwegian neonatal weight charts. Nonparametric tests were used to compare weight categories, and logistic regression was used to predict the odds ratio (OR) of inadequate total pregnancy weight gain or SGA delivery. RESULTS: Out of 892 women hospitalized for HG during 2002-2016, 784 had a pregnancy lasting > 24 weeks, of which 746 were singleton pregnancies with follow-up until delivery. Among these women, 42 were classified as underweight, 514 as normal weight, 230 as overweight and 102 as obese before pregnancy. Not regaining prepregnancy weight by week 13-18 was an independent predictor of inadequate total gestational weight gain with an OR of 7.05 (95% CI 4.24-11.71) and an independent predictor for SGA outcome with an OR of 2.66 (95% CI 1.11-6.34), even when adjusted for total pregnancy weight gain, prepregnancy BMI, parity, age and smoking status. CONCLUSION: Inadequate total maternal weight gain and not regaining prepregnancy weight by week 13-18 may be considered independent risk factors for delivering a baby that is small for gestational age in pregnancies with hyperemesis gravidarum. Achieving adequate weight gain during the first trimester in HG pregnancies is important for the foetal outcome, underscoring the importance of nutritional treatment during this period.

Correction to: Early maternal weight gain as a risk factor for SGA in pregnancies with hyperemesis gravidarum: a 15-year hospital cohort study.

An amendment to this paper has been published and can be accessed via the original article.

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.

Poor outcome in hypoxic endometrial carcinoma is related to vascular density.

BACKGROUND: Identification of endometrial carcinoma (EC) patients at high risk of recurrence is lacking. In this study, the prognostic role of hypoxia and angiogenesis was investigated in EC patients. METHODS: Tumour slides from EC patients were stained by immunofluorescence for carbonic anhydrase IX (CAIX) as hypoxic marker and CD34 for assessment of microvessel density (MVD). CAIX expression was determined in epithelial tumour cells, with a cut-off of 1%. MVD was assessed according to the Weidner method. Correlations with disease-specific survival (DSS), disease-free survival (DFS) and distant disease-free survival (DDFS) were calculated using Kaplan-Meier curves and Cox regression analysis. RESULTS: Sixty-three (16.4%) of 385 ECs showed positive CAIX expression with high vascular density. These ECs had a reduced DSS compared to tumours with either hypoxia or high vascular density (log-rank p = 0.002). Multivariable analysis showed that hypoxic tumours with high vascular density had a reduced DSS (hazard ratio [HR] 3.71, p = 0.002), DDFS (HR 2.68, p = 0.009) and a trend for reduced DFS (HR 1.87, p = 0.054). CONCLUSIONS: This study has shown that adverse outcome in hypoxic ECs is seen in the presence of high vascular density, suggesting an important role of angiogenesis in the metastatic process of hypoxic EC. Differential adjuvant treatment might be indicated for these patients.

Blood steroids are associated with prognosis and fat distribution in endometrial cancer.

BACKGROUND: Despite being a hormone dependent cancer, there is limited knowledge regarding the relation between level of steroids in blood and prognosis for endometrial cancer (EC) patients. METHODS: In this study we investigated plasma levels of 19 steroids using liquid-chromatography tandem mass-spectrometry in 38 postmenopausal EC patients, 19 with long, and 19 with short survival. We explored if estradiol levels were associated with specific abdominal fat distribution patterns and if transcriptional alterations related to estradiol levels could be observed in tumor samples. RESULTS: The plasma steroid levels for DHEA, DHEAS, progesterone, 21 OH progesterone and E1S were significantly increased (all p < 0.05) in patients with long survival compared to short. Estradiol levels were significantly positively correlated with visceral fat percentage (p = 0.035), and an increased expression of genes involved in estrogen related signaling was observed in tumors from patients with high estradiol levels in plasma. CONCLUSION: Several of the identified plasma steroids represent promising biomarkers in EC patients. The association between increased estradiol levels and a high percentage of visceral fat indicates that visceral fat is a larger contributor to estradiol production compared to subcutaneous fat in this population.

Incidence of gynecological fistula and its surgical treatment: A national registry-based study.

INTRODUCTION: Gynecological fistula (affecting female genital organs) leads to involuntary loss of urine or feces. In industrialized societies, fistulas occur mostly as complications of surgery, radiation therapy or inflammatory bowel disease. We sought to determine the incidence of gynecological fistula and type of surgical treatment provided in Norway. MATERIAL AND METHODS: This was a retrospective national cohort study of women treated for gynecological fistula (International Classification of Disease-10 code N82) during 2008-2014, identified from the mandatory Norwegian Patient Registry. To compare groups, we utilized Chi-square or non-parametric tests. RESULTS: In all, 1627 women (.06% of the female Norwegian population) had 4475 hospital admissions with a diagnosis of gynecological fistula. In total, 1214/1627 (75%) had fistula as the main diagnosis: 346 (29%) a urogenital fistula, 672 (55%) an enterogenital, 38 (3%) a genitocutaneous and 22 (2%) both urinary and enteral fistula. Surgery for gynecological fistula was performed in 723 women, an incidence rate of 4.2 per 100 000 person-years (95% confidence interval [CI] 4.2-4.3); gynecological procedures (mostly vaginal/perineal) were performed in 163 women (23%), urological in 43 (6%), enteral in 267 (37%) and surgery involving multiple pelvic compartments in 250 (35%). Women undergoing fistula surgery had a median of three hospital contacts (95% CI 3-3), for 370 women (52%), the procedure was performed by a gynecologist, and 212 of these (29%) were also operated by urologists or gastroenterologists. CONCLUSIONS: Gynecological fistula is rare in Norway, with an overall incidence of 6/10 000 in the female population, whereas the incidence of surgically treated fistula is 4.2/100 000. However, the condition represents considerable morbidity for the individual patient.

Chromatin organisation and cancer prognosis: a pan-cancer study.

BACKGROUND: Chromatin organisation affects gene expression and regional mutation frequencies and contributes to carcinogenesis. Aberrant organisation of DNA has been correlated with cancer prognosis in analyses of the chromatin component of tumour cell nuclei using image texture analysis. As yet, the methodology has not been sufficiently validated to permit its clinical application. We aimed to define and validate a novel prognostic biomarker for the automatic detection of heterogeneous chromatin organisation. METHODS: Machine learning algorithms analysed the chromatin organisation in 461 000 images of tumour cell nuclei stained for DNA from 390 patients (discovery cohort) treated for stage I or II colorectal cancer at the Aker University Hospital (Oslo, Norway). The resulting marker of chromatin heterogeneity, termed Nucleotyping, was subsequently independently validated in six patient cohorts: 442 patients with stage I or II colorectal cancer in the Gloucester Colorectal Cancer Study (UK); 391 patients with stage II colorectal cancer in the QUASAR 2 trial; 246 patients with stage I ovarian carcinoma; 354 patients with uterine sarcoma; 307 patients with prostate carcinoma; and 791 patients with endometrial carcinoma. The primary outcome was cancer-specific survival. FINDINGS: In all patient cohorts, patients with chromatin heterogeneous tumours had worse cancer-specific survival than patients with chromatin homogeneous tumours (univariable analysis hazard ratio [HR] 1·7, 95% CI 1·2-2·5, in the discovery cohort; 1·8, 1·0-3·0, in the Gloucester validation cohort; 2·2, 1·1-4·5, in the QUASAR 2 validation cohort; 3·1, 1·9-5·0, in the ovarian carcinoma cohort; 2·5, 1·8-3·4, in the uterine sarcoma cohort; 2·3, 1·2-4·6, in the prostate carcinoma cohort; and 4·3, 2·8-6·8, in the endometrial carcinoma cohort). After adjusting for established prognostic patient characteristics in multivariable analyses, Nucleotyping was prognostic in all cohorts except for the prostate carcinoma cohort (HR 1·7, 95% CI 1·1-2·5, in the discovery cohort; 1·9, 1·1-3·2, in the Gloucester validation cohort; 2·6, 1·2-5·6, in the QUASAR 2 cohort; 1·8, 1·1-3·0, for ovarian carcinoma; 1·6, 1·0-2·4, for uterine sarcoma; 1·43, 0·68-2·99, for prostate carcinoma; and 1·9, 1·1-3·1, for endometrial carcinoma). Chromatin heterogeneity was a significant predictor of cancer-specific survival in microsatellite unstable (HR 2·9, 95% CI 1·0-8·4) and microsatellite stable (1·8, 1·2-2·7) stage II colorectal cancer, but microsatellite instability was not a significant predictor of outcome in chromatin homogeneous (1·3, 0·7-2·4) or chromatin heterogeneous (0·8, 0·3-2·0) stage II colorectal cancer. INTERPRETATION: The consistent prognostic prediction of Nucleotyping in different biological and technical circumstances suggests that the marker of chromatin heterogeneity can be reliably assessed in routine clinical practice and could be used to objectively assist decision making in a range of clinical settings. An immediate application would be to identify high-risk patients with stage II colorectal cancer who might have greater absolute benefit from adjuvant chemotherapy. Clinical trials are warranted to evaluate the survival benefit and cost-effectiveness of using Nucleotyping to guide treatment decisions in multiple clinical settings. FUNDING: The Research Council of Norway, the South-Eastern Norway Regional Health Authority, the National Institute for Health Research, and the Wellcome Trust.