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Hellberg, Dan
Publications (10 of 34) Show all publications
Pekar, G., Kasselaki, I., Pekar-Lukacs, A., Dekany, C., Hellberg, D. & Tot, T. (2019). Equivocal (HER2 IHC 2+) breast carcinomas: gene-protein assay testing reveals association between genetic heterogeneity, individual cell amplification status and potential treatment benefits. Histopathology, 74(2), 300-310
Open this publication in new window or tab >>Equivocal (HER2 IHC 2+) breast carcinomas: gene-protein assay testing reveals association between genetic heterogeneity, individual cell amplification status and potential treatment benefits
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2019 (English)In: Histopathology, ISSN 0309-0167, E-ISSN 1365-2559, Vol. 74, no 2, p. 300-310Article in journal (Refereed) Published
Abstract [en]

Aims: Genetic heterogeneity can pose a challenge to identifying eligible cases for targeted therapy in the human epidermal growth factor receptor 2 (HER2) immunohistochemistry (IHC) 2+ breast carcinoma group. In this study, we characterised this subset of tumours according to clinicopathological parameters.

Methods and results: We assessed 1000 tumour cells per case and recorded the number of HER2 and chromosome enumeration probe 17 (CEP17) copies using gene-protein assay slides. HER2 status was determined based on ASCO/CAP 2013 guidelines. Tumours with 5-50% of cancer cells with amplification were considered to be heterogeneous, whereas those with >50% were considered to be non-heterogeneous. In a study cohort of 110 HER2 IHC 2+ carcinomas, 93 (84.5%) were non-amplified, 12 (10.9%) were amplified and five (4.5%) were ISH-equivocal. All the HER2-amplified and two of ISH-equivocal cases (12.7%) corresponded to non-heterogeneous tumours, with highly significant differences evident in the average HER2/CEP17 ratio (P = 0.0002) and the proportion of cells with HER2 >6 copies (P < 0.0001) compared with heterogeneous lesions. NST grade 3 and HER2-amplified carcinomas average HER2/CEP17 ratio correlated with an increased number of cells with HER2/CEP17 >= 2.0 (P < 0.014). Triple-negative CEP17 polysomic carcinomas showed increased metastatic capacity (P = 0.003) compared with other tumour types.

Conclusion: Non-heterogeneous HER2 IHC 2+ tumours tend to be HER2-amplified. Adding the percentage of cells with HER2 >6 copies to the average HER2/CEP17 ratio may facilitate assessment of amplification status in ISH-equivocal cases. The proportion of cells with HER2/CEP17 >= 2.0 contributes information concerning the actual average HER2/CEP17 ratio, depending on tumour type.

Place, publisher, year, edition, pages
WILEY, 2019
Keywords
ASCO/CAP guidelines, breast cancer, gene-protein assay, HER2 IHC 2+, heterogeneity
National Category
Cancer and Oncology Cell and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-373315 (URN)10.1111/his.13733 (DOI)000453895100011 ()30113715 (PubMedID)
Available from: 2019-01-16 Created: 2019-01-16 Last updated: 2019-01-16Bibliographically approved
Ridefelt, P., Hilsted, L., Juul, A., Hellberg, D. & Rustad, P. (2018). Pediatric reference intervals for general clinical chemistry components: merging of studies from Denmark and Sweden. Scandinavian Journal of Clinical and Laboratory Investigation, 78(5), 365-372
Open this publication in new window or tab >>Pediatric reference intervals for general clinical chemistry components: merging of studies from Denmark and Sweden
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2018 (English)In: Scandinavian Journal of Clinical and Laboratory Investigation, ISSN 0036-5513, E-ISSN 1502-7686, Vol. 78, no 5, p. 365-372Article in journal (Refereed) Published
Abstract [en]

Background: Reference intervals are crucial tools aiding clinicians when making medical decisions. However, for children such values often are lacking or incomplete. The present study combines data from separate pediatric reference interval studies of Denmark and Sweden in order to increase sample size and to include also pre-school children who were lacking in the Danish study.

Methods: Results from two separate studies including 1988 healthy children and adolescents aged 6 months to 18 years of age were merged and recalculated. Eighteen general clinical chemistry components were measured on Abbott and Roche platforms. To facilitate commutability, the NFKK Reference Serum X was used.

Results: Age- and gender-specific pediatric reference intervals were defined by calculating 2.5 and 97.5 percentiles.

Conclusion: The data generated are primarily applicable to a Nordic population, but could be used by any laboratory if validated for the local patient population.

Keywords
Adolescents, biomarkers, children, clinical chemistry tests, reference values, reference standards
National Category
Pediatrics
Identifiers
urn:nbn:se:uu:diva-371065 (URN)10.1080/00365513.2018.1474493 (DOI)000449780700005 ()29806781 (PubMedID)
Available from: 2018-12-19 Created: 2018-12-19 Last updated: 2018-12-19Bibliographically approved
Pekar, G., Davies, H., Lukacs, A. P., Forsberg, L., Hellberg, D., Dumanski, J. & Tot, T. (2016). Biobanking multifocal breast carcinomas: sample adequacy with regard to histology and DNA content. Histopathology, 68(3), 411-421
Open this publication in new window or tab >>Biobanking multifocal breast carcinomas: sample adequacy with regard to histology and DNA content
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2016 (English)In: Histopathology, ISSN 0309-0167, E-ISSN 1365-2559, Vol. 68, no 3, p. 411-421Article in journal (Refereed) Published
Abstract [en]

AIMS: To determine the volume of tumoral and normal breast tissue containing sufficient DNA (>2 μg/sample) for genetic platforms and biobanking, with a focus on multifocality, tumoral heterogeneity, and factors that critically influence sample acceptability.

METHODS AND RESULTS: We examined 57 breast surgical specimens with multifocal (46/57) and unifocal (11/57) cancers. Punch biopsies were obtained from tissue slices under multimodal radiological guidance, and the colour-coded sampling sites were identified in large-format histology slides. The study comprised 415 DNA isolations from tumour (n = 105) and normal (n = 283) tissue, including skin (n = 27) samples. A single 2-mm core from invasive tumour contained sufficient DNA in 91.4% (96/105) of cases, depending on tumour type (3.8-108.2 μg/sample), number and size of additional foci in multifocal cases (P = 0.001), tumour consistency, and degree of necrosis. Three biopsies obtained with a 4-mm device were required from normal breast tissue, at least 10 mm from the tumour. Cold ischaemia for up to 82 min did not influence the yield of DNA.

CONCLUSIONS: Radiological disease mapping is useful for guiding optimal specimen slicing and for targeting breast lesions. A single 2-mm core from tumour and multiple 4-mm cores from normal breast tissue yield adequate DNA in the majority of samples.

Keywords
biobanking; breast cancer; DNA quality and quantity; heterogeneity; multifocality
National Category
Medical and Health Sciences Cancer and Oncology Cell and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-271418 (URN)10.1111/his.12758 (DOI)000367819400011 ()26083274 (PubMedID)
Available from: 2016-01-07 Created: 2016-01-07 Last updated: 2018-01-10Bibliographically approved
Hållmarker, U., Michaëlsson, K., Ärnlöv, J., Hellberg, D., Lagerqvist, B., Lindbäck, J. & James, S. K. (2016). Risk of recurrent ischaemic events after myocardial infarction in long-distance ski race participants. European Journal of Preventive Cardiology, 23(3), 282-290
Open this publication in new window or tab >>Risk of recurrent ischaemic events after myocardial infarction in long-distance ski race participants
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2016 (English)In: European Journal of Preventive Cardiology, ISSN 2047-4873, E-ISSN 2047-4881, Vol. 23, no 3, p. 282-290Article in journal (Refereed) Published
Abstract [en]

AIMS: To study whether a high level of physical activity prior to myocardial infarction (MI) also protects against recurrent MI (re-MI) or death.

METHODS AND RESULTS: A longitudinal study of a primary cohort consisting of 204,038 skiers with a proved substantially high level of physical activity in the world's largest long-distance ski race, Vasaloppet, and 499,543 non-skiers selected from the Swedish population. Individuals with severe diseases at baseline were excluded. In the nationwide clinical register, Swedeheart, we identified 7092 individuals with a first MI incident between 1989 and 2010. Of these, 1039 (0.5%) were skiers and 6053 (1.2%) were non-skiers. One hundred and sixty-three (15.7%) skiers and 1352 (22.3%) non-skiers suffered a re-MI or died during follow-up (median 4.44 years), corresponding to an incidence rate of 38.9 (95% confidence interval (CI) 33.2-45.4)/1000 person-years and 55.6 (95% CI 52.7-58.7)/1000 person-years, respectively. Severity of MI in both groups was the same. For skiers compared to non-skiers the unadjusted hazard ratio (HR) for re-MI was 0.66 (95% CI 0.52-0.82). For death or re-MI, HR was 0.70 (95% CI 0.59-0.82) with consistent results in subgroups based on race year, age, gender, education level, marital status. After adjustment for also smoking, diabetes, hypertension and cardiovascular medication, HR was 0.80 (95% CI 0.67-0.97).

CONCLUSIONS: This large cohort study supports the hypothesis that patients with MI and with prior physical activity and healthy lifestyle, as evidenced by their participation in a long-distance ski race, have a lower risk of subsequent re-MI or death.

Keywords
Myocardial infarction Cross-country skiing Vasaloppet Physical activity Sports Medicine
National Category
Public Health, Global Health, Social Medicine and Epidemiology Cardiac and Cardiovascular Systems
Research subject
Epidemiology
Identifiers
urn:nbn:se:uu:diva-260137 (URN)10.1177/2047487315578664 (DOI)000369526800007 ()25827685 (PubMedID)
Available from: 2015-08-17 Created: 2015-08-17 Last updated: 2017-12-04Bibliographically approved
Hållmarker, U., Åsberg, S., Michaëlsson, K., Ärnlöv, J., Hellberg, D., Lindbäck, J., . . . James, S. K. (2015). Risk of Recurrent Stroke and Death After First Stroke in Long‐Distance Ski Race Participants. Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease, 4(10), Article ID e002469.
Open this publication in new window or tab >>Risk of Recurrent Stroke and Death After First Stroke in Long‐Distance Ski Race Participants
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2015 (English)In: Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease, ISSN 2047-9980, E-ISSN 2047-9980, Vol. 4, no 10, article id e002469Article in journal (Refereed) Published
Abstract [en]

Background Physical activity is of benefit for primary prevention of cardiovascular diseases, but it appears to increase the risk for atrial fibrillation. We aimed to study a cohort of patients following a first stroke in individuals with previous high physical activity, compare them to the general population with respect to recurrent stroke and death, and relate these to atrial fibrillation.

Methods and Results From the participants of the Vasaloppet, the world's largest ski‐race, and matched individuals from the general population (n=708 604), we identified 5964 patients hospitalized with a first‐time stroke between 1994 and 2010. Individuals with severe diseases were excluded. One half percent of skiers and 1% of nonskiers were hospitalized due to stroke. The incidence rate was 8.3 per 100 person‐years among skiers and 11.1 among nonskiers. The hazard ratio (HR) for recurrent stroke or death between the 2 groups was 0.76 (95% CI 0.67 to 0.86). The result was consistent in subgroups. The HR for death was 0.66 (95% CI 0.56 to 0.78) and for recurrent stroke 0.82 (95% CI 0.70 to 0.96). After adjustment for smoking and socioeconomic factors, the HR for death was consistent at 0.70 (95% CI 0.56 to 0.87) while the HR for recurrent stroke was not statistically significant. Outcomes for skiers with atrial fibrillation tended to show a lower risk than for nonskiers.

Conclusions This large cohort study supports the hypothesis that patients with a stroke and with prior regular physical activity have a lower risk of death, while their risk for recurrent stroke is similar to that of nonskiers. The skiers had a higher incidence of atrial fibrillation, but still no increased risk of recurring stroke.

Keywords
atrial fibrillation; cerebrovascular disease; cross-country skiing; epidemiology; lifestyle; physical activity; prevention; recurrent stroke; sports medicine; Sweden; Vasaloppet
National Category
Public Health, Global Health, Social Medicine and Epidemiology
Research subject
Epidemiology
Identifiers
urn:nbn:se:uu:diva-260198 (URN)10.1161/JAHA.115.002469 (DOI)000364153000039 ()
Available from: 2015-08-17 Created: 2015-08-17 Last updated: 2019-03-11Bibliographically approved
Edman, K., Ohrn, K., Nordstrom, B., Holmlund, A. & Hellberg, D. (2015). Trends over 30years in the prevalence and severity of alveolar bone loss and the influence of smoking and socio-economic factors: based on epidemiological surveys in Sweden 1983-2013. International Journal of Dental Hygiene, 13(4), 283-291
Open this publication in new window or tab >>Trends over 30years in the prevalence and severity of alveolar bone loss and the influence of smoking and socio-economic factors: based on epidemiological surveys in Sweden 1983-2013
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2015 (English)In: International Journal of Dental Hygiene, ISSN 1601-5029, E-ISSN 1601-5037, Vol. 13, no 4, p. 283-291Article in journal (Refereed) Published
Abstract [en]

ObjectiveEpidemiological studies of the prevalence of periodontitis over an extended time using the same methodology to investigate and classify periodontitis are sparse in the literature. Smoking and socio-economic factors have been proven to increase the risk for periodontal disease. The objective of this study was to investigate 30-year time trends, using the same methodology to classify the prevalence and severity in alveolar bone loss (ABL) and to investigate the influence of tobacco and socio-economic factors. MethodsFour cross-sectional epidemiological studies in an adult population were performed in the county of Dalarna, Sweden, in 1983, 2003, 2008 and 2013. Random samples of 787-1133 individuals aged 35-85 who answered a questionnaire about tobacco use and socio-economic factors were radiographically and clinically examined. A number of teeth, ABL and calculus visible on radiographs were registered. The severity of ABL as detected on radiographs was classified into no bone loss, moderate or severe. ResultsThe prevalence of moderate ABL decreased from 45% in 1983 to 16% in 2008, but increased to 33% in 2013 (P<0.05). The prevalence of severe ABL remained the same from 1983 (7%) to 2013 (6%). Calculus visible on radiographs increased from 22% in 2008 to 32% in 2013 (P<0.05). Socio-economic factors had limited impact on the severity of ABL. ConclusionModerate ABL and calculus visible on radiographs significantly increased between 2008 and 2013. Smoking was the strongest factor associated with ABL overall.

Keywords
epidemiology, periodontal disease, smoking
National Category
Dentistry
Identifiers
urn:nbn:se:uu:diva-265798 (URN)10.1111/idh.12164 (DOI)000362736400009 ()26215672 (PubMedID)
Available from: 2015-11-03 Created: 2015-11-03 Last updated: 2017-12-01Bibliographically approved
Gremel, G., Bergman, J., Djureinovic, D., Edqvist, P.-H., Maindad, V., Bharambe, B. M., . . . Pontén, F. (2014). A systematic analysis of commonly used antibodies in cancer diagnostics. Histopathology, 64(2), 293-305
Open this publication in new window or tab >>A systematic analysis of commonly used antibodies in cancer diagnostics
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2014 (English)In: Histopathology, ISSN 0309-0167, E-ISSN 1365-2559, Vol. 64, no 2, p. 293-305Article in journal (Refereed) Published
Abstract [en]

AimsImmunohistochemistry plays a pivotal role in cancer differential diagnostics. To identify the primary tumour from a metastasis specimen remains a significant challenge, despite the availability of an increasing number of antibodies. The aim of the present study was to provide evidence-based data on the diagnostic power of antibodies used frequently for clinical differential diagnostics. Methods and resultsA tissue microarray cohort comprising 940 tumour samples, of which 502 were metastatic lesions, representing tumours from 18 different organs and four non-localized cancer types, was analysed using immunohistochemistry with 27 well-established antibodies used in clinical differential diagnostics. Few antibodies, e.g. prostate-specific antigen and thyroglobulin, showed a cancer type-related sensitivity and specificity of more than 95%. A majority of the antibodies showed a low degree of sensitivity and specificity for defined cancer types. Combinations of antibodies provided limited added value for differential diagnostics of cancer types. ConclusionsThe results from analysing 27 diagnostic antibodies on consecutive sections of 940 defined tumours provide a unique repository of data that can empower a more optimal use of clinical immunohistochemistry. Our results highlight the benefit of immunohistochemistry and the unmet need for novel markers to improve differential diagnostics of cancer.

Keywords
biological tumour markers, differential diagnosis, immunohistochemistry, surgical pathology, tissue microarray analysis
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-216054 (URN)10.1111/his.12255 (DOI)000328347800012 ()
Note

De två (2) första författarna delar förstaförfattarskapet.

Available from: 2014-01-20 Created: 2014-01-17 Last updated: 2018-02-01Bibliographically approved
Ridefelt, P., Gustafsson, J., Aldrimer, M. & Hellberg, D. (2014). Alkaline phosphatase in healthy children: reference intervals and prevalence of elevated levels.. Hormone Research in Paediatrics, 82(6), 399-404
Open this publication in new window or tab >>Alkaline phosphatase in healthy children: reference intervals and prevalence of elevated levels.
2014 (English)In: Hormone Research in Paediatrics, ISSN 1663-2818, E-ISSN 1663-2826, Vol. 82, no 6, p. 399-404Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: Transient hyperphosphatasemia (TH) is an often unnoticed benign entity, primarily affecting children below 5 years of age. However, the prevalence among healthy children is unknown. We used data from a Swedish pediatric reference interval project to estimate the prevalence of high alkaline phosphatase (ALP) among healthy children and to calculate pediatric reference intervals.

METHODS: Blood was collected from 699 subjectively healthy children aged 6 months to 18 years. After exclusion of subjects with high ALP, age- and gender-specific reference intervals were calculated.

RESULTS: Six children had ALP levels >16.7 µkat/l (>1,000 U/l), including 4 females and 2 males aged 7-22 months. The prevalence in the age group from 6 months to 2 years was 6.2% (6/97). None of the older children had levels of ALP >16.7 µkat/l. The study did not include the follow-up of these apparently healthy children. Consequently, conditions others than TH explaining the elevated ALP could not be excluded. However, general chemistry analyses, such as liver enzymes, calcium, intact PTH and vitamin D, were essentially normal in these children.

CONCLUSIONS: The prevalence of high ALP among subjectively healthy children was approximately 2.4% below 5 years of age and 6.2% below 2 years. Reference intervals vary with age and gender.  

National Category
Clinical Laboratory Medicine
Identifiers
urn:nbn:se:uu:diva-244228 (URN)10.1159/000369205 (DOI)000347918800008 ()25531333 (PubMedID)
Available from: 2015-02-12 Created: 2015-02-12 Last updated: 2017-12-04Bibliographically approved
Ridefelt, P., Hellberg, D., Aldrimer, M. & Gustafsson, J. (2014). Estimating reliable paediatric reference intervals in clinical chemistry and haematology. Acta Paediatrica, 103(1), 10-15
Open this publication in new window or tab >>Estimating reliable paediatric reference intervals in clinical chemistry and haematology
2014 (English)In: Acta Paediatrica, ISSN 0803-5253, E-ISSN 1651-2227, Vol. 103, no 1, p. 10-15Article, review/survey (Refereed) Published
Abstract [en]

Very few high-quality studies on paediatric reference intervals for general clinical chemistry and haematology analytes have been performed. Three recent prospective community-based projects utilising blood samples from healthy children in Sweden, Denmark and Canada have substantially improved the situation. ConclusionThe present review summarises current reference interval studies for common clinical chemistry and haematology analyses.

Keywords
Children, Clinical chemistry, Haematology, Paediatric, Reference interval
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-216242 (URN)10.1111/apa.12438 (DOI)000328736300006 ()
Available from: 2014-01-20 Created: 2014-01-20 Last updated: 2017-12-06Bibliographically approved
Lindström, A. K. & Hellberg, D. (2014). Immunohistochemical LRIG3 expression in cervical intraepithelial neoplasia and invasive squamous cell cervical cancer: association with expression of tumor markers, hormones, high-risk HPV-infection, smoking and patient outcome. European journal of histochemistry, 58(2), 83-87
Open this publication in new window or tab >>Immunohistochemical LRIG3 expression in cervical intraepithelial neoplasia and invasive squamous cell cervical cancer: association with expression of tumor markers, hormones, high-risk HPV-infection, smoking and patient outcome
2014 (English)In: European journal of histochemistry, ISSN 1121-760X, E-ISSN 2038-8306, Vol. 58, no 2, p. 83-87Article in journal (Refereed) Published
Abstract [en]

The novel biomarker LRIG3 is a member of the LRIG family (LRIG1-3). While LRIG1 has been associated with favorable prognosis and LRIG2 with poor prognosis in invasive cervical cancer, little is known about the role of LRIG3. The aim of this study was to investigate the expression of LRIG3 in invasive cancer and cervical intraepithelial neoplasia (CIN) for possible correlation with other tumor markers, to hormones and smoking, as a diagnostic adjunct in CIN, and prognostic value in invasive cancer. Cervical biopsies from 129 patients with invasive squamous cell carcinoma and 170 biopsies showing low grade and high grade CIN, or normal epithelium were stained for LRIG3 and 17 additional tumor markers. Among other variables the following were included: smoking habits, hormonal contraceptive use, serum progesterone, serum estradiol, high-risk HPV-infection, meno pausal status and ten-year survival. In CIN, high expression of the tumor suppressors retinoblastoma protein, p53, and p16, and Ecadherin (cell-cell interaction), or low expression of CK10, correlated to LRIG3 expression. In addition, progestogenic contraceptive use correlated to high expression of LRIG3. In invasive cancer there was a correlation between expression of the major tumor promoter c-myc and high LRIG3 expression. High LRIG3 expression correlated significantly to presence of high-risk HPV infection in patients with normal epithelium and CIN. There was no correlation between LRIG3 expression and 10-year survival in patients with invasive cell cervical cancer. LRIG3 expression is associated with a number of molecular events in CIN. Expression also correlates to hormonal contraceptive use. The results on expression of other tumor markers suggest that LRIG3 is influ-markers in cancer and precancerous cells. Further studies are needed to elucidate if LRIG3 expression might be clinically useful.

Keywords
LRIG3, cervical cancer, cervical intraepithelial neoplasia, biological markers, human papillomavirus, hormonal contraceptives, smoking
National Category
Cancer and Oncology Cell and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-229981 (URN)10.4081/ejh.2014.2227 (DOI)000338624700001 ()24998916 (PubMedID)
Available from: 2014-08-18 Created: 2014-08-18 Last updated: 2018-01-11Bibliographically approved
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