Jonna Skov Madsen

Validation of the PHEEM instrument in a Danish hospital setting

The Postgraduate Hospital Educational Environment Measure (PHEEM) has been translated into Danish and then validated with good internal consistency by 342 Danish junior and senior hospital doctors. Four of the 40 items are culturally dependent in the Danish hospital setting. Factor analysis demonstrated that seven items are interconnected. This information can be used to shorten the instrument by perhaps another three items.

Utility of testing for monoclonal bands in serum of patients with suspected osteoporosis: retrospective, cross sectional study

Abstract Objective To determine whether measuring monoclonal bands (M component) in serum should be part of the investigation of patients referred to osteoporosis clinics. Design Retrospective, cross sectional, observational study. Setting Referral centre for osteoporosis in a university hospital, Denmark. Participants 799 people (685 women) aged 19 to 94 years newly referred with suspected osteoporosis. Main outcome measures Proportion of patients fulfilling the Nordic Myeloma Study Group definition for target condition and proportion of patients with other important haematological conditions. Results 4.9% (18 of 366) of patients with osteoporosis and 2.2% (9 of 408) of patients without osteoporosis had M component in serum (χ2 = 3.66, P = 0.04). Multiple myeloma was diagnosed in three patients with osteoporosis (absolute risk 0.8%, 95% confidence interval 0.11% to 1.7%). The relative risk of multiple myeloma in patients presenting with osteoporosis was 75 (10 to 160). As a diagnostic test for multiple myeloma in patients with osteoporosis, M component in serum had a specificity of 95.0% and a positive predictive value of 17.6%. 122 blood electrophoreses were carried out for each case of multiple myeloma diagnosed. All patients with multiple myeloma had a history of fragility fractures. If lymphoma was included as a target condition, the specificity increased to 95.3% and the positive predictive value increased to 23.5%. Monoclonal gammopathy of undetermined significance was diagnosed in 13 (3.6%) participants with osteoporosis and in eight (2.0%) participants with normal bone mineral density or osteopenia. Conclusions Patients presenting with osteoporosis should be tested for M component in serum, as 1 in 20 patients with newly diagnosed osteoporosis had multiple myeloma or monoclonal gammopathy of undetermined significance.

Sensitivity of CA 15-3, CEA and serum HER2 in the early detection of recurrence of breast cancer

Abstract Background: The aim of this project was to investigate the sensitivity of CA 15-3, CEA and HER2 in the early diagnosis of metastatic breast cancer. Methods: Serial serum values of CA 15-3, CEA and HER2 were determined in 107 patients with recurrence after breast cancer. Fifteen of the patients had primary disseminated disease, nine patients only developed local recurrence during the follow-up period and the remaining 83 developed distant metastases. Results: In the group of patients with distant metastatic disease (n=83), elevated serum levels of CA 15-3 (>32.4 U/mL), CEA (>2.5 µg/L for non-smokers and >10 µg/L for smokers) and HER2 (>15 µg/L) were found in 49.4%, 38.6% and 32.5%, respectively, at the time of diagnosis of recurrence. CA 15-3 was significantly better than HER2 (p=0.027). The most sensitive combination was obtained using CA 15-3/CEA (60.2%) or CA 15-3/HER2 (57.8%). Combining all three tumour markers raised the sensitivity to 63.9%. In the subgroup of patients with tissue HER2+ tumours, the sensitivity of HER2 increased to 55.6%. The best combination in this group was CEA/HER2 (66.7%). In the subgroup of patients with tissue HER2− tumours, CA 15-3 was significantly better. The best combination was CA 15-3/HER2 or CA 15-3/CEA with a sensitivity of 55.8% and 59.6%, respectively. Conclusions: The combination of several tumour markers enhances the sensitivity for detection of metastatic breast cancer. We recommend HER2 or the combination of CEA and HER2 in tissue HER2+ and CA 15-3 or the combination of CA 15-3 and CEA in tissue HER2−.

Home management of oral anticoagulation via telemedicine versus conventional hospital-based treatment

BACKGROUND AND OBJECTIVE We have developed an expert computer system for the control of oral anticoagulation therapy, accessible by the patients via their own computer. To investigate if the weekly measurement and dosing of international normalized ratio (INR) at home using the online Internet-based system was superior to conventional treatment, we performed a randomized, controlled trial. PATIENTS AND METHODS All 669 patients in our anticoagulation clinic were asked to participate in the trial, providing that they had Internet access and could use the CoaguChek XS system. A total of 140 patients were included and randomized to (A) once weekly measurement and report online, (B) twice weekly measurement and report online, and (C) continued conventional treatment with INR measurement in the lab every 4 weeks and dose adjustment by letter. RESULTS Group A had 79.7% (95% CI 79.0-80.3) of time in therapeutic range (TTR), group B 80.2% (95% CI 79.4-80.9) of TTR, and group C 72.7% (95% CI 71.9-73.4) TTR. Groups A and B perform statistically significantly better than the conventional group C, with a difference of TTR of 7% points (p < 2.2 × 10(-16)), whereas no difference was seen between A and B. CONCLUSION Home measurement of INR and the reporting and dosing of results online once a week increase TTR from 72% to 79% as compared to conventional computer-assisted monitoring in an anticoagulation clinic.

Serum HER-2 concentrations for monitoring women with breast cancer in a routine oncology setting

Abstract Background: The purpose of this study was to determine the positive predictive value (PPV) of positive serum human epidermal growth factor receptor-2 (HER-2) for monitoring women with breast cancer following diagnosis and treatment in a routine clinical setting. Methods: Serum HER-2 was measured in 1348 patients with breast cancer: 837 during routine oncology clinic visits and 511 following new diagnosis. All patients with positive serum HER-2, 1/5 of negative patients from the oncology clinic, and all the newly diagnosed were followed; a total of 862 patients. Serum HER-2 was measured using the Bayer ADVIA Centaur assay. Tissue HER-2 was determined using immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH). IHC +3 or IHC +2 and FISH>2.0 were positive. Patients were considered to have positive serum HER-2 when at least two values were >15 ng/mL. Recurrence, progression and regression were diagnosed according to usual clinical practice. Serum HER-2 concentrations did not contribute to diagnostic decision-making or selection of treatment. Results: From January 2004 to January 2009, 149 patients were found to have positive serum HER-2. Of these, 35 were tissue HER-2 positive at surgery, 69 tissue-negative and 45 were not determined. Fifty-five of 149 that were serum HER-2 positive (37%, 95% CI: 29–45) had metastases. Among the 35 tissue-positive patients, 25 had recurrence in the form of metastases and there was good correlation between recurrence/progression and increase in serum HER-2 (p<0.0003). There was also a high correlation between effect of treatment and decline in serum HER-2 (p<0.0003). Of the 69 tissue-negative patients, 29 had recurrence in the form of metastases, and there was good correlation with serum HER-2 levels (p<0.000004). In this routine application of serum HER-2, the PPV for metastases recurrence detection in both tissue-positive and tissue-negative was 54 of 104 (52%, 95% CI: 42%–62%), in tissue-positive 25 of 35 (71%, 95% CI: 54%–85%), in tissue-negative 29 of 69 (42%, 95% CI: 30%–54%). The lead time of increases in serum HER-2 before recurrence could be determined in ten tissue-positive patients was 3–24 months (mean 11.3 months), when compared to standard clinical imaging methods. Conclusions: Serum HER-2 is a useful marker for the detection of recurrence of breast cancer and for monitoring the effect of treatment, especially in tissue HER-2 positive patients. Clin Chem Lab Med 2009;47:1117–23.

Genetic variation in estrogen receptor, C-reactive protein and fibrinogen does not predict the plasma levels of inflammation markers after longterm hormone replacement therapy

Markers of inflammation, such as C-reactive protein (CRP) and fibrinogen, are associated with the risk of atherothrombosis. Plasma levels of these markers of inflammation are affected by hormone replacement therapy (HRT) and modulated by smoking. We studied whether genetic variation in the estrogen receptor- 1 (ESR1), CRP and fibrinogen-beta genes influences the plasma levels of inflammation markers after HRT. Plasma CRP and fibrinogen were measured after five years follow-up in healthy postmenopausal women (per-protocol group) who were randomised to hormone therapy (n=187) or no treatment (n=249). The effect of HRT, smoking and genetic variations in ESR1 (PvuII and XbaI), CRP (1444C/T) and fibrinogen-beta (FGB, -455G/A) were determined. The plasma concentration of CRP was higher in the HRT group than in the control group (2.03 mg/l and 1.41 mg/l, respectively; p < 0.001), while the concentration of fibrinogen was lower in the HRT group than in the control group (3.02 g/l and 3.20 g/l, respectively; p < 0.001), indicating that it is unlikely that inflammation is the common underlying pathway. There was a significant interaction between smoking and HRT on the fibrinogen (p=0.02), but not on the CRP concentration (n.s.). Genetic polymorphisms in ESR1, CRP and fibrinogen were not associated with an effect of HRT on the CRP and fibrinogen plasma levels, and no significant interaction with smoking was observed. In conclusion, higher plasma levels of CRP and lower plasma levels of fibrinogen were observed in women using HRT; however, genetic polymorphisms in ESR1, CRP and FGB were not associated with these effects of HRT.

A population-based prospective study of optic neuritis

Background: Optic neuritis (ON) is often associated with multiple sclerosis (MS). Early diagnosis is critical to optimal patient management. Objective: To estimate the incidence of acute ON and the rates of conversion to MS and antibody-mediated ON. Method: Population-based prospective study was performed in patients with ON from three ophthalmological departments and 44 practicing ophthalmologists from 2014 to 2016. Ophthalmological and neurological examination, magnetic resonance imaging (MRI), determination of aquaporin-4(AQP4)-IgG and myelin-oligodendrocyte glycoprotein (MOG)-IgG were investigated blindly. Results: In all, 63 patients were evaluated and 51 fulfilled the criteria for ON. All were Caucasian, with female:male ratio of 2.2:1 and a median age of 38 years (16–66); 44 (86%) had a single episode of ON (four bilateral), while 7/51 (14%) had recurrent ON. The overall age-specific incidence was 3.28 (2.44–4.31) per 100,000 person years, 2.02 for men and 4.57 for women. At follow-up, 20 patients met the diagnostic criteria for MS, MRI lesions disseminated in space and time in 17/20 patients. AQP4-IgG was detected in none, MOG-IgG was detected in two patients. Conclusion: The prospective incidence of ON was estimated. MRI enabled a diagnosis of MS in a subgroup of patients. Antibody-mediated ON with specificity for MOG was detected in 4% of cases.

Serum HER-2 predicts response and resistance to trastuzumab treatment in breast cancer.

Abstract Background: Serum HER2 (S-HER2) was approved in 2003 by the US Food and Drug Administration (FDA) for monitoring trastuzumab treatment in tissue HER2 positive breast cancer patients. Information of the value of S-HER2 is scarce. We hypothesised that S-HER2 would reflect the clinical effect of trastuzumab. Methods: We followed 48 patients eligible for trastuzumab treatment for up to 6 years or until death. S-HER2 was measured on an ADVIA Centaur System and S-Trastuzumab was measured by an in-house developed fluorescent enzyme immunoassay system on the ImmunoCap 100. Results: A decrease in S-HER2 of ≥20% was correlated to no progression in the disease in 20 out of 21 clinical courses (p<0.0001). An increase in S-HER2 of ≥20% was correlated to progression in the disease in 40 out of 44 clinical courses (p<0.0001). Patients with no recurrence after trastuzumab treatment (n=18) had a median S-HER2 concentration of 10.5 μg/L, whereas patients alive with recurrence (n=13) had a median S-HER2 of 20.1 μg/L (p=0.002). Patients who died prompted by recurrence (n=17) had a median S-HER2 of 232.4 μg/L at latest measurement before death (p=<0.0001) compared to patients without recurrence. In two patients with S-HER2 values above 1000 μg/L the concentrations of S-trastuzumab were measured below the target trough concentration in serum of 10 mg/L. Conclusions: Decreasing values of S-HER2 predicts response to treatment whereas increasing levels predict resistance. S-HER2 above 1000 μg/L warns that standard doses of trastuzumab may be insufficient as reflected by low concentrations of S-trastuzumab.

Circulating microRNAs as biomarkers of adult Crohn's disease.

Objective Previous studies have found a differential expression of microRNAs (miRNAs) in the blood of patients with Crohn’s disease (CD) compared with healthy controls. The aim of this study was to identify circulating miRNAs expressed in CD and assess their performance as biomarkers in patients with clinically suspected or known CD. Methods The study consisted of two parts: (a) miRNA profiling: The miRNA expression pattern was examined in six patients with CD and six controls using OpenArray miRNA profiling, and the best miRNAs were selected according to their P-value. (b) Validation cohort: In a well-characterized cohort of 102 patients with suspected or known CD, miRNAs identified by miRNA profiling or selected from previously published studies (hsa-miR-16, hsa-miR-21, hsa-miR-106a, and hsa-miR-140-3p) were measured in plasma using reverse transcription PCR. Results miRNA profiling: hsa-miR-369-3p, hsa-miR-376a, hsa-miR-376, hsa-miR-411#, hsa-miR-411, and mmu-miR-379 were downregulated in CD patients compared with the controls; hsa-miR-200c, hsa-miR-181-2#, and hsa-miR-125a-5p were upregulated (P<0.05). Validation cohort: Only hsa-miR-16 was significantly downregulated in patients with CD compared with patients without CD (fold change 0.83, P=0.02). Receiver operating characteristic analyses showed an area under the curve of 0.65. miRNAs could not discriminate inflammatory from stricturing CD or small bowel CD from CD involving the colon. Conclusion In a clinically relevant cohort of patients, miRNAs in plasma identified in the present and previous studies were inadequate biomarkers for the diagnosis of CD.

Venous thrombosis is not increased in younger women on genuine oestrogen postmenopausal hormonal replacement therapy: Results from the Danish Osteoporosis Prevention Study (DOPS)

Venous thrombosis is not increased in younger women on genuine oestrogen postmenopausal hormonal replacement therapy: Results from the Danish Osteoporosis Prevention Study (DOPS) -