Publications by authors named "Ingfrid S Haldorsen"

62 Publications

Two new mutations in the CEL gene causing diabetes and hereditary pancreatitis: How to correctly identify MODY8 cases.

J Clin Endocrinol Metab 2021 Nov 29. Epub 2021 Nov 29.

Gade Laboratory for Pathology, Department of Clinical Medicine, University of Bergen, Bergen, Norway.

Objective: Maturity-onset diabetes of the young, type 8 (MODY8) is associated with mutations in the CEL gene, which encodes the digestive enzyme carboxyl ester lipase. Several diabetes cases and families have in recent years been attributed to mutations in CEL without any functional or clinical evidence provided. To facilitate correct MODY8 diagnostics, we screened two cohorts of diabetes patients and delineated the phenotype.

Research Design: Young, lean Swedish and Finnish patients with a diagnosis of type 2 diabetes (352 cases, 406 controls) were screened for mutations in the CEL gene. We also screened 58 Czech MODY cases who had tested negative for common MODY genes. For CEL mutation-positive subjects, family history was recorded, and clinical investigations and pancreatic imaging performed.

Results: One Swedish and one Czech case with germline mutation in CEL were identified. Clinical and radiological investigations of these two probands and their families revealed dominantly inherited insulin-dependent diabetes, pancreatic exocrine dysfunction and atrophic pancreas with lipomatosis and cysts. Notably, hereditary pancreatitis was the predominant phenotype in one pedigree. Both families carried single-base pair deletions in the proximal part of the CEL variable number of tandem repeat (VNTR) region in exon 11. The mutations are predicted to lead to aberrant protein tails that make the CEL protein susceptible to aggregation.

Conclusions: The diagnosis of MODY8 requires a pancreatic exocrine phenotype and a deletion in the CEL VNTR in addition to dominantly inherited diabetes. CEL screening may be warranted also in families with hereditary pancreatitis of unknown genetic etiology.
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http://dx.doi.org/10.1210/clinem/dgab864DOI Listing
November 2021

A Gene Signature Identifying CIN3 Regression and Cervical Cancer Survival.

Cancers (Basel) 2021 Nov 16;13(22). Epub 2021 Nov 16.

Department of Pathology, Stavanger University Hospital, 4068 Stavanger, Norway.

The purpose of this study was to establish a gene signature that may predict CIN3 regression and that may aid in selecting patients who may safely refrain from conization. Oncomine mRNA data including 398 immune-related genes from 21 lesions with confirmed regression and 28 with persistent CIN3 were compared. L1000 mRNA data from a cervical cancer cohort was available for validation ( = 239). Transcriptomic analyses identified ( = 0.004), ( < 0.001), ( = 0.04), ( = 0.02), and ( = 0.005) as upregulated, and downregulated ( = 0.01) in CIN3 regression as compared to persistent CIN3 lesions. From these, a gene signature predicting CIN3 regression with a sensitivity of 91% (AUC = 0.85) was established. Transcriptomic analyses revealed proliferation as significantly linked to persistent CIN3. Within the cancer cohort, high regression signature score associated with immune activation by Gene Set enrichment Analyses (GSEA) and immune cell infiltration by histopathological evaluation ( < 0.001). Low signature score was associated with poor survival ( = 0.007) and large tumors ( = 0.01). In conclusion, the proposed six-gene signature predicts CIN regression and favorable cervical cancer prognosis and points to common drivers in precursors and cervical cancer lesions.
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http://dx.doi.org/10.3390/cancers13225737DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8616457PMC
November 2021

Feasibility and utility of MRI and dynamic F-FDG-PET in an orthotopic organoid-based patient-derived mouse model of endometrial cancer.

J Transl Med 2021 09 26;19(1):406. Epub 2021 Sep 26.

Department of Clinical Medicine, University of Bergen, 5021, Bergen, Norway.

Background: Pelvic magnetic resonance imaging (MRI) and whole-body positron emission tomography-computed tomography (PET-CT) play an important role at primary diagnostic work-up and in detecting recurrent disease in endometrial cancer (EC) patients, however the preclinical use of these imaging methods is currently limited. We demonstrate the feasibility and utility of MRI and dynamic F-fluorodeoxyglucose (FDG)-PET imaging for monitoring tumor progression and assessing chemotherapy response in an orthotopic organoid-based patient-derived xenograft (O-PDX) mouse model of EC.

Methods: 18 O-PDX mice (grade 3 endometrioid EC, stage IIIC1), selectively underwent weekly T2-weighted MRI (total scans = 32), diffusion-weighted MRI (DWI) (total scans = 9) and dynamic F-FDG-PET (total scans = 26) during tumor progression. MRI tumor volumes (vMRI), tumor apparent diffusion coefficient values (ADC) and metabolic tumor parameters from F-FDG-PET including maximum and mean standard uptake values (SUV/SUV), metabolic tumor volume (MTV), total lesion glycolysis (TLG) and metabolic rate of F-FDG (MR) were calculated. Further, nine mice were included in a chemotherapy treatment study (treatment; n = 5, controls; n = 4) and tumor ADC-values were compared to changes in vMRI and cellular density from histology at endpoint. A Mann-Whitney test was used to evaluate differences between groups.

Results: Tumors with large tumor volumes (vMRI) had higher metabolic activity (MTV and TLG) in a clear linear relationship (r = 0.92 and 0.89, respectively). Non-invasive calculation of MR from dynamic F-FDG-PET (mean MR = 0.39 μmol/min) was feasible using an image-derived input function. Treated mice had higher tumor ADC (p = 0.03), lower vMRI (p = 0.03) and tumor cellular density (p = 0.02) than non-treated mice, all indicating treatment response.

Conclusion: Preclinical imaging mirroring clinical imaging methods in EC is highly feasible for monitoring tumor progression and treatment response in the present orthotopic organoid mouse model.
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http://dx.doi.org/10.1186/s12967-021-03086-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8474962PMC
September 2021

Diagnostic Accuracy of Transabdominal Ultrasound and Computed Tomography in Chronic Pancreatitis: A Head-to-Head Comparison.

Ultrasound Int Open 2021 Apr 24;7(1):E35-E44. Epub 2021 Aug 24.

National Centre for Ultrasound in Gastroenterology, Department of Medicine, Helse Bergen HF, Haukeland University Hospital, Bergen, Norway.

Computed tomography (CT) is the most used imaging modality for diagnosing chronic pancreatitis (CP), but advances in transabdominal ultrasound (US) technology have given US a position as a viable alternative. We aimed to evaluate the diagnostic accuracy of abdominal CT and pancreatic US compared to the reference standard, a modified Mayo score. CT, US, and endoscopic ultrasound (EUS) were performed in patients referred due to suspected CP. The modified Mayo score included EUS results, clinical presentation, and results from exocrine and endocrine pancreatic function tests. We scored CT findings according to the modified Cambridge classification and US findings according to the Rosemont classification. In total, 73 patients were included. 53 patients (73%) were categorized as CP and 20 (27%) as non-CP. CT and US yielded similar sensitivities (68% and 64%, respectively) and specificities (75 and 85%, respectively) and similar areas under the receiver operating characteristic curves for diagnosing CP. We found no significant differences between the areas under the receiver operating characteristic curves (AUROCs) for CT (AUROC 0.75, 95% CI 0.63-0.87) and US (AUROC 0.81, 95% CI 0.71-0.91). We conclude that CT and US had comparable, moderate accuracy in diagnosing CP. Neither modality had high enough sensitivity to exclude the diagnosis as a standalone method.
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http://dx.doi.org/10.1055/a-1542-9146DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8384479PMC
April 2021

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

Am J Obstet Gynecol 2021 Aug 13. Epub 2021 Aug 13.

Centre for Cancer Biomarkers, Department of Clinical Science, University of Bergen, Bergen, Norway; Department of Obstetrics and Gynecology, Haukeland University Hospital, Bergen, Norway. Electronic address:

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.
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http://dx.doi.org/10.1016/j.ajog.2021.08.011DOI Listing
August 2021

Interval and Subsequent Round Breast Cancer in a Randomized Controlled Trial Comparing Digital Breast Tomosynthesis and Digital Mammography Screening.

Radiology 2021 07 11;300(1):66-76. Epub 2021 May 11.

From the Cancer Registry of Norway, PO 5313, Maiorstuen, 0304 Oslo, Norway (S.H., N.M., Å.S.H., A.S.D.); Faculty of Health Sciences, Oslo Metropolitan University, Oslo, Norway (S.H.); Department of Radiology, University of Washington School of Medicine, Seattle, Wash (C.I.L.); Department of Health Services, University of Washington School of Public Health, Seattle, Wash (C.I.L.); Sydney School of Public Health, Faculty of Medicine and Health, University of Sydney, Sydney, Australia (N.H.); Department of Radiology (H.S.A., I.S.H.), Department of Pathology (L.A.A.), and Mohn Medical Imaging and Visualization Centre (I.S.H.), Haukeland University Hospital, Bergen, Norway; and Department of Clinical Medicine (H.S.A., I.S.H.), Section for Pathology (L.A.A.), and Centre for Cancer Biomarkers CCBIO (L.A.A.), University of Bergen, Bergen, Norway.

Background Prevalent digital breast tomosynthesis (DBT) has shown higher cancer detection rates and lower recall rates compared with those of digital mammography (DM). However, data are limited on rates and histopathologic tumor characteristics of interval and subsequent round screen-detected cancers for DBT. Purpose To follow women randomized to screening with DBT or DM and to investigate rates and tumor characteristics of interval and subsequent round screen-detected cancers. Materials and Methods To-Be is a randomized controlled trial comparing the outcome of DBT and DM in organized breast cancer screening. The trial included 28 749 women, with 22 306 women returning for subsequent DBT screening 2 years later (11 201 and 11 105 originally screened with DBT and DM, respectively). Differences in rates, means, and distribution of histopathologic tumor characteristics between women prevalently screened with DBT versus DM were evaluated with Z tests, tests, and χ tests. Relative risk (RR) with 95% CIs was calculated for the cancer rates. Results Interval cancer rates were 1.4 per 1000 screens (20 of 14 380; 95% CI: 0.9, 2.1) for DBT versus 2.0 per 1000 screens (29 of 14 369; 95% CI: 1.4, 2.9; = .20) for DM. The rates of subsequent round screen-detected cancer were 8.1 per 1000 (95% CI: 6.6, 10.0) for women originally screened with DBT and 9.1 per 1000 (95% CI: 7.4, 11.0; = .43) for women screened with DM. The distribution of tumor characteristics did not differ between groups for either interval or subsequent screen-detected cancer. The RR of interval cancer was 0.69 (95% CI: 0.39, 1.22; = .20) for DBT versus DM, whereas RR of subsequent screen-detected cancer for women prevalently screened with DBT versus DM was 0.89 (95% CI: 0.67, 1.19; = .43). Conclusion Rates of interval or subsequent round screen-detected cancers and their tumor characteristics did not differ between women originally screened with digital breast tomosynthesis (DBT) versus digital mammography. The analysis suggests that the benefits of prevalent DBT screening did not come at the expense of worse downstream screening performance measures in a population-based screening program. © RSNA, 2021 See also the editorial by Taourel in this issue.
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http://dx.doi.org/10.1148/radiol.2021203936DOI Listing
July 2021

Diagnostic Accuracy of Computed Tomography Scores in Chronic Pancreatitis.

Pancreas 2021 04;50(4):549-555

Objectives: Computed tomography (CT) is the most commonly used imaging modality when diagnosing chronic pancreatitis (CP). We aimed to evaluate the diagnostic accuracy of CT scores for diagnosing CP.

Methods: One hundred eighteen patients were retrospectively included from an observational cohort study that comprised patients referred because of suspected CP. Patients were categorized as CP or non-CP using a modified Mayo score based on biochemistry, clinical presentation, and findings on endoscopic ultrasound and/or transabdominal ultrasound. The CT scans were scored according to the modified Cambridge classification and the unweighted CT score. Diagnostic performance indices were calculated using the modified Mayo score as reference standard.

Results: Seventy-six of the 118 patients fulfilled the CP diagnostic criteria (Mayo score ≥4). The modified Cambridge classification and the unweighted CT score yielded sensitivities of 63% and 67% and specificities of 91% and 91%, respectively, and similar areas under the receiver operating characteristic curves (95% confidence interval) of 0.79 (0.71-0.88)/0.81 (0.73-0.89), respectively (P, not significant).

Conclusions: Both CT scores had similar, moderate accuracies for diagnosing CP. The limitation in diagnostic accuracy makes CT ineligible as a single method to diagnose CP, supporting that the diagnostic process for CP needs to incorporate other imaging methods and/or markers for better diagnostics.
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http://dx.doi.org/10.1097/MPA.0000000000001803DOI Listing
April 2021

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

Br J Cancer 2021 05 15;124(10):1690-1698. Epub 2021 Mar 15.

Department of Obstetrics and Gynaecology, Haukeland University Hospital, Bergen, Norway.

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.
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http://dx.doi.org/10.1038/s41416-021-01305-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8110544PMC
May 2021

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

J Clin Med 2021 Feb 2;10(3). Epub 2021 Feb 2.

Section of Radiology, Department of Clinical Medicine, University of Bergen, 5020 Bergen, Norway.

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 ( < 0.001) and the MRI validation cohort ( = 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 ( < 0.001). The most differentially expressed genes, and , 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.
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http://dx.doi.org/10.3390/jcm10030538DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7867221PMC
February 2021

The role of sarcopenic obesity in high-grade endometrial cancer.

Int J Gynaecol Obstet 2021 Aug 26;154(2):248-255. Epub 2021 Feb 26.

Royal Cornwall Hospital NHS Trust, Truro, UK.

Objective: To investigate the relationship between obesity and sarcopenia in relation to overall survival (OS) and disease-specific survival (DSS) in high-grade endometrial cancer patients.

Methods: We conducted a retrospective study in women diagnosed with high-grade endometrial cancer (EC) between February 2006 and August 2017 in the Royal Cornwall Hospital who had abdominal computerized tomography (CT)-scan as part of routine staging work-up. Sarcopenia was assessed by measuring psoas-, paraspinal- and abdominal wall muscles on CT and defined by skeletal muscle index ≤41 cm /m . Sarcopenic obesity was defined as sarcopenia combined with body mass index (BMI) ≥30 kg/m .

Results: A total of 176 patients with median age of 70 years and median BMI of 29.4 kg/m were included in the study. The majority of patients (38%) had endometrioid type histology. Sarcopenia was not associated with OS (P = 0.951) or DSS (P = 0.545) However, in multivariate analysis, sarcopenic obesity was associated with reduced OS in endometrioid endometrial cancer (EEC) patients (P = 0.048).

Conclusion: Sarcopenic obesity is associated with OS in high-grade EEC patients, while sarcopenia without obesity is not related to OS or DSS in high-grade EC. In non-endometrioid endometrial cancer, there is no association between sarcopenic obesity and survival.
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http://dx.doi.org/10.1002/ijgo.13591DOI Listing
August 2021

Obesity and visceral fat: Survival impact in high-grade endometrial cancer.

Eur J Obstet Gynecol Reprod Biol 2021 Jan 21;256:425-432. Epub 2020 Nov 21.

Royal Cornwall Hospital NHS Trust, Truro, Cornwall, United Kingdom. Electronic address:

Background: Obesity is an important risk factor for the development of endometrial cancer (EC). Recent data showed that body fat distribution might be more relevant than Body Mass Index (BMI). High visceral fat percentage was shown to be an independent predictor for survival in EC, but mainly included grade 1-2 EC.

Objective: To evaluate body fat distribution and its relation to outcome in high-grade endometrial cancer.

Methods: Retrospective study in women diagnosed with high-grade EC between February 2006 and August 2017 at the Royal Cornwall Hospital who had abdominal CT-scan as part of routine diagnostic work-up. Subcutaneous abdominal fat volumes and visceral abdominal fat volumes were quantified based on CT-scan measurements, and visceral fat percentage calculated.

Results: A total of 176 patients with high-grade EC were included. The median age was 70 years and median BMI was 29.4 kg/m. The majority of patients had non-endometrioid endometrial cancer (NEEC; 62 %). High visceral fat percentage was associated with poor overall- and disease-specific survival (p = 0.006 and p = 0.026 respectively) in NEEC patients, but not in high-grade endometrioid EC (EEC). The most frequent obesity comorbidities hypertension and diabetes mellitus were significantly associated with high BMI and high visceral fat percentage.

Conclusion: In high-grade EC, high visceral fat percentage was an independent predictor of poor survival only in NEEC. The strong correlation between high visceral fat and obesity-related comorbidities might be reflective of an unhealthy macroenvironment.
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http://dx.doi.org/10.1016/j.ejogrb.2020.11.050DOI Listing
January 2021

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

Eur J Obstet Gynecol Reprod Biol 2021 Jan 1;256:25-31. Epub 2020 Nov 1.

Centre for Cancer Biomarkers, Department of Clinical Science, University of Bergen, Bergen, Norway; Department of Obstetrics and Gynecology, Haukeland University Hospital, Bergen, Norway. Electronic address:

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.
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http://dx.doi.org/10.1016/j.ejogrb.2020.10.051DOI Listing
January 2021

Comparing Screening Outcomes for Digital Breast Tomosynthesis and Digital Mammography by Automated Breast Density in a Randomized Controlled Trial: Results from the To-Be Trial.

Radiology 2020 12 15;297(3):522-531. Epub 2020 Sep 15.

From the Cancer Registry of Norway, PO Box 5313, Majorstuen, 0304 Oslo, Norway (N.M., A.S.D., S.H.); Department of Radiology, Haukeland University Hospital, Bergen, Norway (H.S.A., I.S.H.); Department of Clinical Medicine, University of Bergen, Bergen, Norway (H.S.A., I.S.H.); Department of Radiology, Seattle Cancer Care Alliance, University of Washington, Seattle, Wash (C.I.L.); Department of Translational Medicine, Diagnostic Radiology, Lund University Cancer Center, Malmö, Sweden (S.Z.); and Faculty of Health Sciences, Oslo Metropolitan University, Oslo, Norway (S.H.).

Background Digital breast tomosynthesis (DBT) is considered superior to digital mammography (DM) for women with dense breasts. Purpose To identify differences in screening outcomes, including rates of recall, false-positive (FP) findings, biopsy, cancer detection rate, positive predictive value of recalls and biopsies, and histopathologic tumor characteristics by density using DBT combined with two-dimensional synthetic mammography (SM) (hereafter, DBT+SM) versus DM. Materials and Methods This randomized controlled trial comparing DBT+SM and DM was performed in Bergen as part of BreastScreen Norway, 2016-2017. Automated software measured density (Volpara Density Grade [VDG], 1-4). The outcomes were compared for DBT+SM versus DM by VDG in descriptive analyses. A stratified log-binomial regression model was used to estimate relative risk of outcomes in subgroups by screening technique. Results Data included 28 749 women, 14 380 of whom were screened with DBT+SM and 14 369 of whom were screened with DM (both groups: median age, 59 years; interquartile range [IQR], 54-64 years). The recall rate was lower for women screened with DBT+SM versus those screened with DM for VDG 1 (2.1% [81 of 3929] vs 3.3% [106 of 3212]; = .001) and VDG 2 (3.2% [200 of 6216] vs 4.3% [267 of 6280]; = .002). For DBT+SM, adjusted relative risk of recall (VDG 2: 1.8; < .001; VDG 3: 2.4; < .001; VDG 4: 1.8; = .02) and screen-detected breast cancer (VDG 2: 2.4; = .004; VDG 3: 2.8; = .01; VDG 4: 2.8; = .05) increased with VDG, whereas no differences were observed for DM (relative risk of recall for VDG 2: 1.3; = .06; VDG 3: 1.1; = .41; VDG 4: 1.1; = .71; and relative risk of screen-detected breast cancer for VDG 2: 1.7; = .13; VDG 3: 2.1; = .06; VDG 4: 2.2; = .15). Conclusion Screening with digital breast tomosynthesis combined with synthetic two-dimensional mammograms (DBT+SM) versus digital mammography (DM) yielded lower recall rates for women with Volpara Density Grade (VDG) 1 and VDG 2. Adjusted relative risk of recall and screen-detected breast cancer increased with denser breasts for DBT+SM but not for DM. © RSNA, 2020 See also the editorial by Sechopoulos and Athanasiou in this issue.
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http://dx.doi.org/10.1148/radiol.2020201150DOI Listing
December 2020

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

PLoS Med 2020 05 15;17(5):e1003111. Epub 2020 May 15.

Department of Pathology, Canisius-Wilhelmina Hospital, Nijmegen, The Netherlands.

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.
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http://dx.doi.org/10.1371/journal.pmed.1003111DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7228042PMC
May 2020

Systematic approach for assessment of imaging features in chronic pancreatitis: a feasibility and validation study from the Scandinavian Baltic Pancreatic Club (SBPC) database.

Abdom Radiol (NY) 2020 05;45(5):1468-1480

Department of Radiology, Aalborg University Hospital, P.O. Box 365, 9100, Aalborg, Denmark.

Purpose: There is an unmet need for new systems with quantitative pancreatic imaging assessments to support better diagnosis and understand development of chronic pancreatitis (CP). The aims were to present such an approach for assessment of imaging features in CP, to apply this system in a multi-center cohort of CP patients (feasibility study), and to report inter-reader agreement between expert radiologists (validation study).

Methods: The feasibility study included pancreatic computed tomography (CT) or magnetic resonance imaging (MRI) from 496 patients with definitive CP in the Scandinavian Baltic Pancreatic Club (SBPC) database. Images were assessed according to the new SBPC imaging system (quantitative assessments of ductal and parenchymal features). Inter-reader agreement of reported imaging parameters was investigated for 80 CT and 80 MRI examinations by two expert radiologists.

Results: Reporting of the imaging features into the imaging system was deemed feasible for > 80% of CT and > 90% of MRI examinations. Quantitative assessments of main pancreatic duct diameters, presence/number/diameter of calcifications, and gland diameters had high levels of inter-reader agreement with κ-values of 0.75-0.87 and intraclass correlation coefficients of 0.74-0.97. The more subjective assessments, e.g., irregular main pancreatic duct and dilated side-ducts, had poor to moderate agreement with κ-values of 0.03-0.44.

Conclusion: The presented system provides a feasible mean for systematic assessment of CP imaging features. Imaging parameters based on quantitative assessment, as opposed to subjective assessments, have better reproducibility and should be preferred in the development of new grading systems for understanding pathophysiology and disease progression in CP.
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http://dx.doi.org/10.1007/s00261-020-02466-xDOI Listing
May 2020

Magnetic resonance radiomics for prediction of extraprostatic extension in non-favorable intermediate- and high-risk prostate cancer patients.

Acta Radiol 2020 Nov 28;61(11):1570-1579. Epub 2020 Feb 28.

Department of Clinical Medicine, University of Bergen, Norway.

Background: To investigate whether magnetic resonance (MR) radiomic features combined with machine learning may aid in predicting extraprostatic extension (EPE) in high- and non-favorable intermediate-risk patients with prostate cancer.

Purpose: To investigate the diagnostic performance of radiomics to detect EPE.

Material And Methods: MR radiomic features were extracted from 228 patients, of whom 86 were diagnosed with EPE, using prostate and lesion segmentations. Prediction models were built using Random Forest. Further, EPE was also predicted using a clinical nomogram and routine radiological interpretation and diagnostic performance was assessed for individual and combined models.

Results: The MR radiomic model with features extracted from the manually delineated lesions performed best among the radiomic models with an area under the curve (AUC) of 0.74. Radiology interpretation yielded an AUC of 0.75 and the clinical nomogram (MSKCC) an AUC of 0.67. A combination of the three prediction models gave the highest AUC of 0.79.

Conclusion: Radiomic analysis combined with radiology interpretation aid the MSKCC nomogram in predicting EPE in high- and non-favorable intermediate-risk patients.
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http://dx.doi.org/10.1177/0284185120905066DOI Listing
November 2020

Near-Infrared Fluorescent Imaging for Monitoring of Treatment Response in Endometrial Carcinoma Patient-Derived Xenograft Models.

Cancers (Basel) 2020 Feb 6;12(2). Epub 2020 Feb 6.

Centre for Cancer Biomarkers CCBIO, Department of Clinical Science, University of Bergen, 5021 Bergen, Norway.

Imaging of clinically relevant preclinical animal models is critical to the development of personalized therapeutic strategies for endometrial carcinoma. Although orthotopic patient-derived xenografts (PDXs) reflecting heterogeneous molecular subtypes are considered the most relevant preclinical models, their use in therapeutic development is limited by the lack of appropriate imaging modalities. Here, we describe molecular imaging of a near-infrared fluorescently labeled monoclonal antibody targeting epithelial cell adhesion molecule (EpCAM) as an in vivo imaging modality for visualization of orthotopic endometrial carcinoma PDX. Application of this near-infrared probe (EpCAM-AF680) enabled both spatio-temporal visualization of development and longitudinal therapy monitoring of orthotopic PDX. Notably, EpCAM-AF680 facilitated imaging of multiple PDX models representing different subtypes of the disease. Thus, the combined implementation of EpCAM-AF680 and orthotopic PDX models creates a state-of-the-art preclinical platform for identification and validation of new targeted therapies and corresponding response predicting markers for endometrial carcinoma.
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http://dx.doi.org/10.3390/cancers12020370DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7072497PMC
February 2020

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

Br J Cancer 2020 03 10;122(7):1014-1022. Epub 2020 Feb 10.

Centre for Cancer Biomarkers; Department of Clinical Science, University of Bergen, Bergen, Norway.

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.
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http://dx.doi.org/10.1038/s41416-020-0745-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7109044PMC
March 2020

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

Eur Radiol 2020 May 7;30(5):2443-2453. Epub 2020 Feb 7.

Mohn Medical Imaging and Visualization Centre (MMIV), Department of Radiology, Haukeland University Hospital, Jonas Liesvei 65, 5021, Bergen, Norway.

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 (SUV and SUV), metabolic tumor volume (MTV), and PET-positive lymph nodes (LNs) (SUV > 2.5) were analyzed together with the MRI-based tumor volume (V), mean apparent diffusion coefficient (ADC), 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 V 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 V > 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 V > 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 V> 10 ml. • MTV represents a promising supplement to conventional PET/CT reading for predicting aggressive disease in EC.
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http://dx.doi.org/10.1007/s00330-019-06622-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7160067PMC
May 2020

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

Gynecol Oncol 2020 04 21;157(1):260-267. Epub 2020 Jan 21.

Centre for Cancer Biomarkers CCBIO, Department of Clinical Science, University of Bergen, Bergen, Norway; Department of Obstetrics and Gynecology, Haukeland University Hospital, Bergen, Norway. Electronic address:

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.
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http://dx.doi.org/10.1016/j.ygyno.2020.01.020DOI Listing
April 2020

Blood Metabolites Associate with Prognosis in Endometrial Cancer.

Metabolites 2019 Dec 14;9(12). Epub 2019 Dec 14.

Centre for Cancer Biomarkers CCBIO, Department of Clinical Science, University of Bergen, N-5021 Bergen, Norway.

Endometrial cancer has a high prevalence among post-menopausal women in developed countries. We aimed to explore whether certain metabolic patterns could be related to the characteristics of aggressive disease and poorer survival among endometrial cancer patients in Western Norway. Patients with endometrial cancer with short survival ( = 20) were matched according to FIGO (International Federation of Gynecology and Obstetrics, 2009 criteria) stage, histology, and grade, with patients with long survival ( = 20). Plasma metabolites were measured on a multiplex system including 183 metabolites, which were subsequently determined using liquid chromatography-mass spectrometry. Partial least square discriminant analysis, together with hierarchical clustering, was used to identify patterns which distinguished short from long survival. A proposed signature of metabolites related to survival was suggested, and a multivariate receiver operating characteristic (ROC) analysis yielded an area under the curve (AUC) of 0.820-0.965 ( ≤ 0.001). Methionine sulfoxide seems to be particularly strongly associated with poor survival rates in these patients. In a subgroup with preoperative contrast-enhanced computed tomography data, selected metabolites correlated with the estimated abdominal fat distribution parameters. Metabolic signatures may predict prognosis and be promising supplements when evaluating phenotypes and exploring metabolic pathways related to the progression of endometrial cancer. In the future, this may serve as a useful tool in cancer management.
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http://dx.doi.org/10.3390/metabo9120302DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6949989PMC
December 2019

Imaging of Preclinical Endometrial Cancer Models for Monitoring Tumor Progression and Response to Targeted Therapy.

Cancers (Basel) 2019 Nov 27;11(12). Epub 2019 Nov 27.

Department of Clinical Medicine, University of Bergen, 5021 Bergen, Norway.

Endometrial cancer is the most common gynecologic malignancy in industrialized countries. Most patients are cured by surgery; however, about 15% of the patients develop recurrence with limited treatment options. Patient-derived tumor xenograft (PDX) mouse models represent useful tools for preclinical evaluation of new therapies and biomarker identification. Preclinical imaging by magnetic resonance imaging (MRI), positron emission tomography-computed tomography (PET-CT), single-photon emission computed tomography (SPECT) and optical imaging during disease progression enables visualization and quantification of functional tumor characteristics, which may serve as imaging biomarkers guiding targeted therapies. A critical question, however, is whether the in vivo model systems mimic the disease setting in patients to such an extent that the imaging biomarkers may be translatable to the clinic. The primary objective of this review is to give an overview of current and novel preclinical imaging methods relevant for endometrial cancer animal models. Furthermore, we highlight how these advanced imaging methods depict pathogenic mechanisms important for tumor progression that represent potential targets for treatment in endometrial cancer.
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http://dx.doi.org/10.3390/cancers11121885DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6966645PMC
November 2019

What Is the Role of Imaging at Primary Diagnostic Work-Up in Uterine Cervical Cancer?

Curr Oncol Rep 2019 07 29;21(9):77. Epub 2019 Jul 29.

Department of Obstetrics and Gynaecology, Maastricht University Medical Centre, Maastricht, The Netherlands.

Purpose Of Review: For uterine cervical cancer, the recently revised International Federation of Gynecology and Obstetrics (FIGO) staging system (2018) incorporates imaging and pathology assessments in its staging. In this review we summarize the reported staging performances of conventional and novel imaging methods and provide an overview of promising novel imaging methods relevant for cervical cancer patient care.

Recent Findings: Diagnostic imaging during the primary diagnostic work-up is recommended to better assess tumor extent and metastatic disease and is now reflected in the 2018 FIGO stages 3C1 and 3C2 (positive pelvic and/or paraaortic lymph nodes). For pretreatment local staging, imaging by transvaginal or transrectal ultrasound (TVS, TRS) and/or magnetic resonance imaging (MRI) is instrumental to define pelvic tumor extent, including a more accurate assessment of tumor size, stromal invasion depth, and parametrial invasion. In locally advanced cervical cancer, positron emission tomography-computed tomography (PET-CT) or computed tomography (CT) is recommended, since the identification of metastatic lymph nodes and distant metastases has therapeutic consequences. Furthermore, novel imaging techniques offer visualization of microstructural and functional tumor characteristics, reportedly linked to clinical phenotype, thus with a potential for further improving risk stratification and individualization of treatment. Diagnostic imaging by MRI/TVS/TRS and PET-CT/CT is instrumental for pretreatment staging in uterine cervical cancer and guides optimal treatment strategy. Novel imaging techniques may also provide functional biomarkers with potential relevance for developing more targeted treatment strategies in cervical cancer.
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http://dx.doi.org/10.1007/s11912-019-0824-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6663927PMC
July 2019

Diagnostic Accuracy of Clinical Biomarkers for Preoperative Prediction of Lymph Node Metastasis in Endometrial Carcinoma: A Systematic Review and Meta-Analysis.

Oncologist 2019 09 11;24(9):e880-e890. Epub 2019 Jun 11.

Department of Obstetrics and Gynaecology, Radboud University Medical Center, Nijmegen, The Netherlands.

Background: In endometrial carcinoma (EC), preoperative classification is based on histopathological criteria, with only moderate diagnostic performance for the risk of lymph node metastasis (LNM). So far, existing molecular classification systems have not been evaluated for prediction of LNM. Optimized use of clinical biomarkers as recommended by international guidelines might be a first step to improve tailored treatment, awaiting future molecular biomarkers.

Aim: To determine the diagnostic accuracy of preoperative clinical biomarkers for the prediction of LNM in endometrial cancer.

Methods: A systematic review was performed according to the Meta-analysis of Observational Studies in Epidemiology (MOOSE) guidelines. Studies identified in MEDLINE and EMBASE were selected by two independent reviewers. Included biomarkers were based on recommended guidelines (cancer antigen 125 [Ca-125], lymphadenopathy on magnetic resonance imaging, computed tomography, and F-fluorodeoxyglucose positron emission tomography/computed tomography [FDG PET-CT]) or obtained by physical examination (body mass index, cervical cytology, blood cell counts). Pooled sensitivity, specificity, area under the curve (AUC), and likelihood ratios were calculated with bivariate random-effects meta-analysis. Likelihood ratios were classified into (0.5-1.0 or 1-2.0), (0.2-0.5 or 2.0-5.0) or (0.1-0.2 or ≥ 5.0) impact.

Results: Eighty-three studies, comprising 18,205 patients, were included. Elevated Ca-125 and thrombocytosis were associated with a increase in risk of LNM; lymphadenopathy on imaging with a increase. Normal Ca-125, cytology, and no lymphadenopathy on FDG PET-CT were associated with a decrease. AUCs were above 0.75 for these biomarkers. Other biomarkers had an AUC <0.75 and incurred only impact.

Conclusion: Ca-125, thrombocytosis, and imaging had a and impact on risk of LNM and could improve preoperative risk stratification.

Implications For Practice: Routine lymphadenectomy in clinical early-stage endometrial carcinoma does not improve outcome and is associated with 15%-20% surgery-related morbidity, underlining the need for improved preoperative risk stratification. New molecular classification systems are emerging but have not yet been evaluated for the prediction of lymph node metastasis. This article provides a robust overview of diagnostic performance of all clinical biomarkers recommended by international guidelines. Based on these, at least measurement of cancer antigen 125 serum level, assessment of thrombocytosis, and imaging focused on lymphadenopathy should complement current preoperative risk stratification in order to better stratify these patients by risk.
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http://dx.doi.org/10.1634/theoncologist.2019-0117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6738307PMC
September 2019

Impact of body mass index and fat distribution on sex steroid levels in endometrial carcinoma: a retrospective study.

BMC Cancer 2019 Jun 7;19(1):547. Epub 2019 Jun 7.

Department of Obstetrics and Gynecology, Radboud University Medical Center, Geert Grooteplein 10, P.O. Box 9101, 6500, HB, Nijmegen, The Netherlands.

Background: Obesity is an important cause of multiple cancer types, amongst which endometrial cancer (EC). The relation between obesity and cancer is complicated and involves alterations in insulin metabolism, response to inflammation and alterations in estradiol metabolism. Visceral obesity is assumed to play the most important role in the first two mechanisms, but its role in estradiol metabolism is unclear. Therefore, this retrospective study explores the relationship of body mass index (BMI), visceral fat volume (VAV) and subcutaneous fat volume (SAV) and serum levels of sex steroids and lipids in patients with endometrial cancer.

Methods: Thirty-nine postmenopausal EC patients with available BMI, blood serum and Computed Tomography (CT) scans were included. Serum was analyzed for estradiol, dehydroepiandrosterone sulfate (DHEAS), androstenedione, testosterone, cholesterol, triglycerides and high (HDL), low (LDL) and non-high density (NHDL) lipoprotein. VAV and SAV were quantified on abdominal CT scan images. Findings were interpreted using pearson correlation coefficient and linear regression with commonality analysis.

Results: Serum estradiol is moderately correlated with BMI (r = 0.62) and VAV (r = 0.58) and strongly correlated with SAV (r = 0.74) (p < 0.001 for all). SAV contributes more to estradiol levels than VAV (10.3% for SAV, 1.4% for VAV, 35.9% for SAV and VAV, p = 0.01). Other sex steroids and lipids have weak and moderate correlations with VAV or SAV.

Conclusions: This study shows that serum estradiol is correlated with BMI and other fat-distribution measures in postmenopausal endometrial cancer patients. Subcutaneous fat tissue contributes more to the estradiol levels indicating that subcutaneous fat might be relevant in endometrial cancer carcinogenesis.
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http://dx.doi.org/10.1186/s12885-019-5770-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6555924PMC
June 2019

Two-view digital breast tomosynthesis versus digital mammography in a population-based breast cancer screening programme (To-Be): a randomised, controlled trial.

Lancet Oncol 2019 06 8;20(6):795-805. Epub 2019 May 8.

Department of Pathology, Haukeland University Hospital, Bergen, Norway; Centre for Cancer Biomarkers, Haukeland University Hospital, Bergen, Norway; Deparment of Clinical Medicine, University of Bergen, Bergen, Norway.

Background: Digital breast tomosynthesis is an advancement of mammography, and has the potential to overcome limitations of standard digital mammography. This study aimed to compare first-generation digital breast tomo-synthesis including two-dimensional (2D) synthetic mammograms versus digital mammography in a population-based screening programme.

Methods: BreastScreen Norway offers all women aged 50-69 years two-view (craniocaudal and mediolateral oblique) mammographic screening every 2 years and does independent double reading with consensus. We asked all 32 976 women who attended the programme in Bergen in 2016-17, to participate in this randomised, controlled trial with a parallel group design. A study-specific software was developed to allocate women to either digital breast tomosynthesis or digital mammography using a 1:1 simple randomisation method based on participants' unique national identity numbers. The interviewing radiographer did the randomisation by entering the number into the software. Randomisation was done after consent and was therefore concealed from both the women and the radiographer at the time of consent; the algorithm was not disclosed to radiographers during the recruitment period. All data needed for analyses were complete 12 months after the recruitment period ended. The primary outcome measure was screen-detected breast cancer, stratified by screening technique (ie, digital breast tomosynthesis and digital mammography). A log-binomial regression model was used to estimate the efficacy of digital breast tomosynthesis versus digital mammography, defined as the crude risk ratios (RRs) with 95% CIs for screen-detected breast cancer for women screened during the recruitment period. A per-protocol approach was used in the analyses. This trial is registered at ClinicalTrials.gov, number NCT02835625, and is closed to accrual.

Findings: Between, Jan 14, 2016, and Dec 31, 2017, 44 266 women were invited to the screening programme in Bergen, and 32 976 (74·5%) attended. After excluding women with breast implants and women who did not consent to participate, 29 453 (89·3%) were eligible for electronic randomisation. 14 734 women were allocated to digital breast tomosynthesis and 14 719 to digital mammography. After randomisation, women with a previous breast cancer were excluded (digital breast tomosynthesis group n=314, digital mammography group n=316), women with metastases from melanoma (digital breast tomosynthesis group n=1), and women who informed the radiographer about breast symptoms after providing consent (digital breast tomosynthesis group n=39, digital mammography group n=34). After exclusions, information from 28 749 women were included in the analyses (digital breast tomosynthesis group n=14 380, digital mammography group n=14 369). The proportion of screen-detected breast cancer among the screened women did not differ between the two groups (95 [0·66%, 0·53-0·79] of 14 380 vs 87 [0·61%, 0·48-0·73] of 14 369; RR 1·09, 95% CI 0·82-1·46; p=0·56).

Interpretation: This study indicated that digital breast tomosynthesis including synthetic 2D mammograms was not significantly different from standard digital mammography as a screening tool for the detection of breast cancer in a population-based screening programme. Economic analyses and follow-up studies on interval and consecutive round screen-detected breast cancers are needed to better understand the effect of digital breast tomosynthesis in population-based breast cancer screening.

Funding: Cancer Registry of Norway, Department of Radiology at Haukeland University Hospital, University of Oslo, and Research Council of Norway.
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http://dx.doi.org/10.1016/S1470-2045(19)30161-5DOI Listing
June 2019

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

Br J Cancer 2019 05 23;120(11):1037-1044. Epub 2019 Apr 23.

Department of Radiation Oncology, Radboud University Medical Center, Nijmegen, The Netherlands.

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.
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http://dx.doi.org/10.1038/s41416-019-0461-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6738053PMC
May 2019

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

Gynecol Oncol 2019 01 26;152(1):46-52. Epub 2018 Oct 26.

Department of Gynaecology and Obstetrics, GROW - School for Oncology & Developmental Biology, Maastricht University, Maastricht, the Netherlands.

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.
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http://dx.doi.org/10.1016/j.ygyno.2018.10.024DOI Listing
January 2019

Guidelines for the Diagnostic Cross Sectional Imaging and Severity Scoring of Chronic Pancreatitis.

Pancreatology 2018 Oct 28;18(7):764-773. Epub 2018 Aug 28.

Division of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh and UPMC, Pittsburgh, PA, USA.

The paper presents the international guidelines for imaging evaluation of chronic pancreatitis. The following consensus was obtained: Computed tomography (CT) is often the most appropriate initial imaging modality for evaluation of patients with suspected chronic pancreatitis (CP) depicting most changes in pancreatic morphology. CT is also indicated to exclude other potential intraabdominal pathologies presenting with symptoms similar to CP. However, CT cannot exclude a diagnosis of CP nor can it be used to exclusively diagnose early or mild disease. Here magnetic resonance imaging (MRI) and MR cholangiopancreatography (MRCP) is superior and is indicated especially in patients where no specific pathological changes are seen on CT. Secretin-stimulated MRCP is more accurate than standard MRCP in the depiction of subtle ductal changes. It should be performed after a negative MRCP, when there is still clinical suspicion of CP. Endoscopic ultrasound (EUS) can also be used to diagnose parenchymal and ductal changes mainly during the early stage of the disease. No validated radiological severity scoring systems for CP are available, although a modified Cambridge Classification has been used for MRCP. There is an unmet need for development of a new and validated radiological CP severity scoring system based on imaging criteria including glandular volume loss, ductal changes, parenchymal calcifications and parenchymal fibrosis based on CT and/or MRI. Secretin-stimulated MRCP in addition, can provide assessment of exocrine function and ductal compliance. An algorithm is presented, where these imaging parameters can be incorporated together with clinical findings in the classification and severity grading of CP.
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http://dx.doi.org/10.1016/j.pan.2018.08.012DOI Listing
October 2018

A randomized controlled trial of digital breast tomosynthesis versus digital mammography in population-based screening in Bergen: interim analysis of performance indicators from the To-Be trial.

Eur Radiol 2019 Mar 29;29(3):1175-1186. Epub 2018 Aug 29.

Cancer Registry of Norway, P.O. 5313, 0304, Majorstuen, Oslo, Norway.

Objectives: To describe a randomized controlled trial (RCT) of digital breast tomosynthesis including synthesized two-dimensional mammograms (DBT) versus digital mammography (DM) in a population-based screening program for breast cancer and to compare selected secondary screening outcomes for the two techniques.

Methods: This RCT, performed in Bergen as part of BreastScreen Norway, was approved by the Regional Committees for Medical Health Research Ethics. All screening attendees in Bergen were invited to participate, of which 89% (14,274/15,976) concented during the first year, and were randomized to DBT (n = 7155) or DM (n = 7119). Secondary screening outcomes were stratified by mammographic density and compared using two-sample t-tests, chi-square tests, ANOVA, negative binomial regression and tests of proportions (z tests).

Results: Mean reading time was 1 min 11 s for DBT and 41 s for DM (p < 0.01). Mean time spent at consensus was 3 min 12 s for DBT and 2 min 12 s for DM (p < 0.01), while the rate of cases discussed at consensus was 6.4% and 7.4%, respectively for DBT and DM (p = 0.03). The recall rate was 3.0% for DBT and 3.6% for DM (p = 0.03). For women with non-dense breasts, recall rate was 2.2% for DBT versus 3.4% for DM (p = 0.04). The rate did not differ for women with dense breasts (3.6% for both). Mean glandular dose per examination was 2.96 mGy for DBT and 2.95 mGy for DM (p = 0.433).

Conclusions: Interim analysis of a screening RCT showed that DBT took longer to read than DM, but had significantly lower recall rate than DM. We found no differences in radiation dose between the two techniques.

Key Points: • In this RCT, DBT was associated with longer interpretation time than DM • Recall rates were lower for DBT than for DM • Mean glandular radiation dose did not differ between DBT and DM.
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http://dx.doi.org/10.1007/s00330-018-5690-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6510877PMC
March 2019
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