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Helenius, G., Lillsunde-Larsson, G. & Bergengren, L. (2023). Molecular triage of cervical screening samples in women 55-59 years of age: a pilot study. Infectious Agents and Cancer, 18(1), Article ID 31.
Open this publication in new window or tab >>Molecular triage of cervical screening samples in women 55-59 years of age: a pilot study
2023 (English)In: Infectious Agents and Cancer, ISSN 1750-9378, E-ISSN 1750-9378, Vol. 18, no 1, article id 31Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: With HPV screening the specificity of screening positives has decreased, even with a cytological triage test. Increases in colposcopies and detection of benign or low-grade dysplasia are reported, not least in older women. These results highlight the necessity to find other triage tests in HPV screening strategies, so that women can be more accurately selected for colposcopy, thus minimizing the clinically irrelevant findings.

METHODS: The study included 55- to 59-year-old women who exited the screening with normal cytology, but later in a follow-up test were positive for the HPV genotypes 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66 and 68 and had a cervical cone biopsy done. To model a screening situation with hrHPV-positive women, three different triage strategies, namely, cytology, genotyping and methylation, were performed. The study considered the effect of direct referral to colposcopy for HPV genotypes 16, 18, 31, 33, 45, 52 and 58, and methylation for FAM19A4 and hsa-mir124-2 and/or any form of abnormal cytology.

RESULTS: Seven out of 49 women aged 55-59 years with hrHPV had a cone biopsy with high-grade squamous intraepithelial lesion. No triage method found all cases, and when comparing positive and negative predictive value and false negative rate, cytology showed better results than genotyping and methylation.

CONCLUSION: This study does not support a switch in triage strategies from cytology to hrHPV genotyping and methylation for women above 55 years of age yet, but demonstrates the need for more evidence on molecular triage strategies.

Place, publisher, year, edition, pages
BioMed Central (BMC), 2023
Keywords
Cervical screening, Cytology, DNA methylation, Genotyping, Human papillomavirus
National Category
Obstetrics, Gynecology and Reproductive Medicine
Identifiers
urn:nbn:se:oru:diva-106026 (URN)10.1186/s13027-023-00510-1 (DOI)000992422800002 ()37221548 (PubMedID)2-s2.0-85160061876 (Scopus ID)
Available from: 2023-05-24 Created: 2023-05-24 Last updated: 2023-06-07Bibliographically approved
Thurfjell, V., Micke, P., Yu, H., Krupar, R., Svensson, M. A., Brunnström, H., . . . Mattsson, J. S. (2022). Comparison of ROS1-rearrangement detection methods in a cohort of surgically resected non-small cell lung carcinomas. Translational Lung Cancer Research (TLCR), 11(12), 2477-2494
Open this publication in new window or tab >>Comparison of ROS1-rearrangement detection methods in a cohort of surgically resected non-small cell lung carcinomas
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2022 (English)In: Translational Lung Cancer Research (TLCR), ISSN 2218-6751, Vol. 11, no 12, p. 2477-2494Article in journal (Refereed) Published
Abstract [en]

Background: Patients with non-small cell lung cancer (NSCLC) harboring a ROS proto-oncogene 1 (ROS1)-rearrangement respond to treatment with ROS1 inhibitors. To distinguish these rare cases, screening with immunohistochemistry (IHC) for ROS1 protein expression has been suggested. However, the reliability of such an assay and the comparability of the antibody clones has been debated. Therefore we evaluated the diagnostic performance of current detection strategies for ROS1-rearrangement in two NSCLC-patient cohorts.

Methods: Resected tissue samples, retrospectively collected from consecutive NSCLC-patients surgically treated at Uppsala University Hospital were incorporated into tissue microarrays [all n=676, adenocarcinomas (AC) n=40 1, squamous cell carcinomas (SCC) n=2 13, other NSCLC n=62]. ROS1rearrangements were detected using fluorescence in situ hybridization (FISH) (Abbott Molecular; ZytoVision). In parallel, ROS1 protein expression was detected using IHC with three antibody clones (D4D6, SP384, EPMGHR2) and accuracy, sensitivity, and specificity were determined. Gene expression microarray data (Affymetrix) and RNA-sequencing data were available for a subset of patients. NanoString analyses were performed for samples with positive or ambiguous results (n=21).

Results: Using FISH, 2/630 (0.3% all NSCLC; 0.5% non-squamous NSCLC) cases were positive for ROS1 fusion. Additionally, nine cases demonstrated ambiguous FISH results. Using IHC, ROS1 protein expression was detected in 24/665 (3.6% all NSCLC; 5.1% non-squamous NSCLC) cases with clone D4D6, in 18/639 (2.8% all NSCLC; 3.9% non-squamous NSCLC) cases with clone SP384, and in 1/593 (0.2% all NSCLC; 0.3% non-squamous NSCLC) case with clone EPMGHR2. Elevated RNA-levels were seen in 19/369 (5.1%) cases (Affymetrix and RNA-sequencing combined). The overlap of positive results between the assays was poor. Only one of the FISH-positive cases was positive with all antibodies and demonstrated high RNA-expression. This rearrangement was confirmed in the NanoString-assay and also in the RNA sequencing data. Other cases with high protein/RNA-expression or ambiguous FISH were negative in the NanoString-assay.

Conclusions: The occurrence of ROS1 fusions is low in our cohorts. The IHC assays detected the fusions, but the accuracy varied depending on the clone. The presumably false-positive and uncertain FISH results questions this method for detection of ROS1-rearrangements. Thus, when IHC is used for screening, transcript-based assays are preferable for validation in clinical diagnostics.

Place, publisher, year, edition, pages
AME Publishing, 2022
Keywords
Crizotinib, ROS proto-oncogene 1 (ROS1), fusion gene detection, molecular pathology, targeted therapy
National Category
Cancer and Oncology Respiratory Medicine and Allergy
Identifiers
urn:nbn:se:oru:diva-103003 (URN)10.21037/tlcr-22-504 (DOI)000894803800001 ()36636421 (PubMedID)2-s2.0-85147779135 (Scopus ID)
Funder
Swedish Cancer Society, CAN 2018/0716Swedish Research Council, 2021-02693Sjöberg Foundation
Note

Funding agencies:

Uppsala-Orebro Regional Research Council (Regionala forskningsrådet i Uppsala-Örebroregionen)

Selanders Stiftelse, Uppsala, Sweden

Lions Cancer Foundation, Uppsala, Sweden

Available from: 2023-01-10 Created: 2023-01-10 Last updated: 2023-12-08Bibliographically approved
Bergengren, L., Ryen, L., Flodström, C., Fadl, H., Udumyen, R., Karlsson, M. G. & Helenius, G. (2022). Effectiveness and costs of an implemented primary HPV cervical screening programme in Sweden: A population based cohort study. Preventive Medicine Reports, 25, Article ID 101675.
Open this publication in new window or tab >>Effectiveness and costs of an implemented primary HPV cervical screening programme in Sweden: A population based cohort study
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2022 (English)In: Preventive Medicine Reports, E-ISSN 2211-3355, Vol. 25, article id 101675Article in journal (Refereed) Published
Abstract [en]

Swedish guidelines recommend cervical screening with primary HPV for women ≥ 30 years of age. The aim of this study was to compare an implemented HPV cervical screening programme in the Region of Örebro County from September 1, 2016, with the former cytology-based screening programme.

The clinical effectiveness by means of number of high-grade squamous intraepithelial lesions (HSILs) and cervical cancer cases detected in histology within 12 months after the screening test, together with cost implications were the main outcomes. Data were retrieved from the Swedish National Cervical Screening Registry between the years 2014-2015 (cytology based screening) and 2017-2018(HPV based screening), including screening information such as invitations and cytology and histology diagnoses.

The detection rate of HSIL + among women ≥ 30 years of age was 1.2 times higher with HPV screening, but data revealed an increase in direct colposcopy referral rate by 54% and a higher percentage of irrelevant findings (≤LSIL). Screening based on HPV for women ≥ 30 has increased yearly cost from 1 to 1.3 million EUR, while increasing the number of HSIL + identified. Two thirds of the total costs are from visits for screening samples in the programme.

HPV screening detected more cases of HSIL + compared to cytology screening among women ≥ 30 although high colposcopy rate, high rate of clinical irrelevant findings and higher costs were shown in the HPV-based screening programme, which implies that alterations in the screening programme in the future are important to consider.

Place, publisher, year, edition, pages
Elsevier, 2022
Keywords
Cervical cancer, Health economy, Human papilloma virus (HPV), Screening
National Category
Cancer and Oncology Obstetrics, Gynecology and Reproductive Medicine
Identifiers
urn:nbn:se:oru:diva-97298 (URN)10.1016/j.pmedr.2021.101675 (DOI)000748438200026 ()35127354 (PubMedID)2-s2.0-85121919588 (Scopus ID)
Funder
Region Örebro County, OLL-841131
Available from: 2022-02-08 Created: 2022-02-08 Last updated: 2024-01-02Bibliographically approved
Koskela, A., Qvick, A., Jakobsen, I., Lindqvist, C. M., Farkas, S. A., Green, A., . . . Helenius, G. (2022). Evaluation of Microsatellite instability score from GMS560 DNA panel. In: : . Paper presented at Cutting-Edge Implementation of Precision Medicine in Europe, Stockholm, Sweden, September 22-23, 2022..
Open this publication in new window or tab >>Evaluation of Microsatellite instability score from GMS560 DNA panel
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2022 (English)Conference paper, Poster (with or without abstract) (Other academic)
Abstract [en]

Microsatellite instability is characterised by gains or losses of nucleotides in short tandem repeat sequences, microsatellites, dispersed throughout the human genome. Microsatellite instability status is a molecular fingerprint for DNA mismatch repair deficiency. Clinical detection of microsatellite instability status is important for identifying inherited disease in patients with colorectal and endometrial cancer but has also a prognostic value for survival and prediction of treatment response. Lately, microsatellite instability has been used as a tumor agnostic biomarker that predicts response to immune checkpoint inhibitors. To identify microsatellite instability status clinically, PCR and immunohistochemistry have been the gold standard. On the contrary, next generation sequencing provide simultaneous accession of large number of microsatellite loci and can be combined with detection of several other biomarkers. 

The national collaboration Genome Medicine Sweden have developed a solid tumour gene panel composed of 560 cancer associated genes with integrated microsatellite instability score. Our aim was to validate the microsatellite instability status based on microsatellite instability score from GMS560 DNA panel against the clinically used methods. Extracted DNA (100 ng) from formalin fixed paraffin embedded tissue sections with various tumour cell content >10% were analysed. During target enrichment sequencing analysis, allelic distribution from 5000 microsatellite markers were calculated by MSIsensor Pro to generate an instability score. 

The cohort consisted of microsatellite instable verified colorectal cancer samples (n=20), microsatellite stable solid tumour material (n=60). Preliminary results generated a microsatellite instability score for the colorectal cancer samples with a mean of 26.5 % (CI: 23.4-29.6, range: 16.9-32.3). Microsatellite stable tumour samples had a mean microsatellite instability score of 1.5 % (CI: 0.93-2.07, range: 1-4.45). 

In conclusion, we found the microsatellite instability score from GMS560 DNA panel to be both diagnostically sensitive and specific for determining MSI status due to obvious separation in instability. 

National Category
Cancer and Oncology
Identifiers
urn:nbn:se:oru:diva-108006 (URN)
Conference
Cutting-Edge Implementation of Precision Medicine in Europe, Stockholm, Sweden, September 22-23, 2022.
Available from: 2023-09-01 Created: 2023-09-01 Last updated: 2023-09-05Bibliographically approved
Kaliff, M., Lillsunde-Larsson, G., Helenius, G., Karlsson, M. & Bergengren, L. (2022). Full genotyping and FAM19A4/miR124-2 methylation analysis in high-risk human papillomavirus-positive samples from women over 30 years participating in cervical cancer screening in Örebro, Sweden. PLOS ONE, 17(9), Article ID e0274825.
Open this publication in new window or tab >>Full genotyping and FAM19A4/miR124-2 methylation analysis in high-risk human papillomavirus-positive samples from women over 30 years participating in cervical cancer screening in Örebro, Sweden
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2022 (English)In: PLOS ONE, E-ISSN 1932-6203, Vol. 17, no 9, article id e0274825Article in journal (Refereed) Published
Abstract [en]

Currently, cervical cancer prevention is undergoing comprehensive development regarding human papillomavirus (HPV) vaccination and cervical cancer screening. In Sweden and many other countries, high coverage vaccinated cohorts are entering screening within the next few years. This entails demands for baseline HPV genotype data across the screening age range for surveillance and a basis for screening program adjustment. In 2016, Örebro County, Sweden, changed to primary HPV screening using HPV mRNA testing followed by cytology triage. An alternative triage method to cytology could allow for a fully molecular screening algorithm and be implemented in a screening program where self-sampling is included. Hypermethylation analysis of the human genes FAM19A4/miR124-2 has been suggested as a promising triage method. HPV mRNA-positive screening samples (n = 529) were included and subjected to genotyping targeting a broad range of both low-risk and high-risk genotypes in addition to hypermethylation analysis of the two human genes FAM19A4/miR124-2. Data were connected to cytological and histological status and age. The most commonly detected genotypes were HPV31, 16, and 52. In addition, HPV18 was one of the most common genotypes in high-grade squamous intraepithelial lesions (HSILs) samples. In relation to available vaccines, 26% of the women with histological HSIL or cancer (≥HSIL) tested positive for only hrHPV included in the quadrivalent vaccine and 77% of the genotypes in the nonavalent vaccine. According to these figures, a relatively large proportion of the HSILs will probably remain, even after age cohorts vaccinated with the quadrivalent vaccine enter the screening program. Hypermethylation positivity was associated with increasing age, but no HPV-related independently predictive factors were found. Accordingly, age needs to be considered in development of future screening algorithms including triage with hypermethylation methodology.

Place, publisher, year, edition, pages
PLOS, 2022
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:oru:diva-101442 (URN)10.1371/journal.pone.0274825 (DOI)000892255200073 ()36137165 (PubMedID)2-s2.0-85138421382 (Scopus ID)
Funder
Region Örebro County, OLL-783961 OLL-929736
Available from: 2022-09-24 Created: 2022-09-24 Last updated: 2023-04-05Bibliographically approved
Fioretos, T., Wirta, V., Cavelier, L., Berglund, E., Friedman, M., Akhras, M., . . . Rosenquist, R. (2022). Implementing precision medicine in a regionally organized healthcare system in Sweden [Letter to the editor]. Nature Medicine, 28(10), 1980-1982
Open this publication in new window or tab >>Implementing precision medicine in a regionally organized healthcare system in Sweden
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2022 (English)In: Nature Medicine, ISSN 1078-8956, E-ISSN 1546-170X, Vol. 28, no 10, p. 1980-1982Article in journal, Letter (Refereed) Published
Place, publisher, year, edition, pages
Nature Publishing Group, 2022
National Category
Health Care Service and Management, Health Policy and Services and Health Economy
Identifiers
urn:nbn:se:oru:diva-101431 (URN)10.1038/s41591-022-01963-4 (DOI)000857867600001 ()36123428 (PubMedID)2-s2.0-85138201780 (Scopus ID)
Note

Funding agencies:

SciLifeLab 

Medical faculty at Gothenburg University

Medical faculty at Linköping University

Medical faculty at Lund University

Medical faculty at Karolinska Institutet 

Available from: 2022-09-23 Created: 2022-09-23 Last updated: 2022-10-26Bibliographically approved
Salomonsson, A., Jönsson, M., Behndig, A., Bergman, B., Botling, J., Brandén, E., . . . Planck, M. (2021). A Nationwide Population-Based Mapping of Mutations and Gene Fusions in Lung Cancer Among Never-Smokers. Paper presented at 2021 World Conference on Lung Cancer - 2021 World Conference on Lung Cancer Worldwide Virtual Event, September 8-14, 2021. Journal of Thoracic Oncology, 16(10 Suppl.), S974-S974
Open this publication in new window or tab >>A Nationwide Population-Based Mapping of Mutations and Gene Fusions in Lung Cancer Among Never-Smokers
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2021 (English)In: Journal of Thoracic Oncology, ISSN 1556-0864, E-ISSN 1556-1380, Vol. 16, no 10 Suppl., p. S974-S974Article in journal, Meeting abstract (Other academic) Published
Place, publisher, year, edition, pages
Elsevier, 2021
Keywords
Never-smoker, Gene fusion, Targetable alterations
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:oru:diva-95495 (URN)10.1016/j.jtho.2021.08.260 (DOI)000709606500260 ()
Conference
2021 World Conference on Lung Cancer - 2021 World Conference on Lung Cancer Worldwide Virtual Event, September 8-14, 2021
Available from: 2021-11-18 Created: 2021-11-18 Last updated: 2024-01-02Bibliographically approved
Berg von Linde, M., Johansson, K., Kruse, R., Helenius, G., Samano, N., Friberg, Ö., . . . Fröbert, O. (2021). Expression of Paracrine Effectors in Human Adipose-Derived Mesenchymal Stem Cells Treated With Plasma From Brown Bears (Ursus arctos). Clinical and Translational Science, 14(1), 317-325
Open this publication in new window or tab >>Expression of Paracrine Effectors in Human Adipose-Derived Mesenchymal Stem Cells Treated With Plasma From Brown Bears (Ursus arctos)
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2021 (English)In: Clinical and Translational Science, ISSN 1752-8054, E-ISSN 1752-8062, Vol. 14, no 1, p. 317-325Article in journal (Refereed) Published
Abstract [en]

Adipose-derived mesenchymal stem cells (ADSCs) are promising candidates for novel cell therapeutic applications. Hibernating brown bears sustain tissue integrity and function via unknown mechanisms, which might be plasma borne. We hypothesized that plasma from hibernating bears may increase the expression of favorable factors from human ADSCs. In an experimental study, ADSCs from patients with ischemic heart disease were treated with interventional media containing plasma from hibernating and active bears, respectively, and with control medium. Extracted RNA from the ADSCs was sequenced using next generation sequencing. Statistical analyses of differentially expressed genes were performed using fold change analysis, pathway analysis, and gene ontology. As a result, we found that genes associated with inflammation, such as IGF1, PGF, IL11, and TGFA, were downregulated by > 10-fold in ADSCs treated with winter plasma compared with control. Genes important for cardiovascular development, ADM, ANGPTL4, and APOL3, were upregulated in ADSCs when treated with winter plasma compared with summer plasma. ADSCs treated with bear plasma, regardless if it was from hibernating or active bears, showed downregulation of IGF1, PGF, IL11, INHBA, IER3, and HMOX1 compared with control, suggesting reduced cell growth and differentiation. This can be summarized in the conclusion that plasma from hibernating bears suppresses inflammatory genes and activates genes associated with cardiovascular development in human ADSCs. Identifying the involved regulator(s) holds therapeutic potential.

Place, publisher, year, edition, pages
Wiley-Blackwell Publishing Inc., 2021
National Category
Medical Genetics
Identifiers
urn:nbn:se:oru:diva-85881 (URN)10.1111/cts.12872 (DOI)000570678300001 ()32949228 (PubMedID)2-s2.0-85091017319 (Scopus ID)
Note

Funding Agencies:

Scandinavian Brown Bear Research Project  

Norwegian Institute for Nature Research  

Swedish University of Agricultural Sciences  

Uppsala Genome Center, Sweden  

National Bioinformatics Infrastructure Sweden 

Available from: 2020-09-24 Created: 2020-09-24 Last updated: 2024-01-16Bibliographically approved
Qvick, A., Stenmark, B., Carlsson, J., Isaksson, J., Karlsson, C. & Helenius, G. (2021). Liquid biopsy as an option for predictive testing and prognosis in patients with lung cancer. Molecular Medicine, 27(1), Article ID 68.
Open this publication in new window or tab >>Liquid biopsy as an option for predictive testing and prognosis in patients with lung cancer
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2021 (English)In: Molecular Medicine, ISSN 1076-1551, E-ISSN 1528-3658, Vol. 27, no 1, article id 68Article in journal (Refereed) Published
Abstract [en]

Background: The aim of this study was to investigate the clinical value of liquid biopsy as a primary source for variant analysis in lung cancer. In addition, we sought to characterize liquid biopsy variants and to correlate mutational load to clinical data.

Methods: Circulating cell-free DNA was extracted from plasma from patients with lung cancer (n = 60) and controls with benign lung disease (n = 16). Variant analysis was performed using the AVENIO ctDNA Surveillance kit and the results were correlated to clinical and variant analysis data from tumor tissue or cytology retrieved from clinical routine diagnostics.

Results: There were significantly more variants detected in lung cancer cases compared to controls (p = 0.011), but no difference between the histological subgroups of lung cancer was found (p = 0.465). Furthermore, significantly more variants were detected in patients with stage IIIb-IV disease compared to patients with stage I-IIIa (median 7 vs 4, p = 0.017). Plasma cfDNA mutational load was significantly associated with overall survival (p = 0.010). The association persisted when adjusted for stage and ECOG performance status (HR: 3.64, 95% CI 1.37-9.67, p = 0.009). Agreement between tumor and plasma samples significantly differed with stage; patients with stage IIIb-IV disease showed agreement in 88.2% of the cases with clinically relevant variants, compared to zero cases in stage I-IIIa (p = 0.004). Furthermore, one variant in EGFR, two in KRAS, and one in BRAF were detected in plasma but not in tumor samples.

Conclusion: This study concludes that in the vast majority of advanced NSCLC patients a reliable variant analysis can be performed using liquid biopsy from plasma. Furthermore, we found that the number of variants in plasma is associated with prognosis, possibly indicating a strategy for closer follow up on this crucial patient group.

Place, publisher, year, edition, pages
Springer, 2021
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:oru:diva-93189 (URN)10.1186/s10020-021-00331-1 (DOI)000669300200001 ()34217228 (PubMedID)2-s2.0-85110796418 (Scopus ID)
Note

Funding Agencies:

Örebro County Council Research committee  

Lions fund for cancer research Uppsala-Örebro  

Nyckelfonden-Örebro University Hospital Research Foundation  

Uppsala-Örebro Regional research council 

Available from: 2021-07-30 Created: 2021-07-30 Last updated: 2023-03-03Bibliographically approved
Edsjö, A., Palmqvist, R., Haglund, F., Helenius, G., Lindqvist, O., Fagman, H. & Botling, J. (2021). Molekylär patologi: nyckeln till målinriktad cancerbehandling [Molecular pathology - the key to precision oncology]. Läkartidningen, 118, Article ID 20209.
Open this publication in new window or tab >>Molekylär patologi: nyckeln till målinriktad cancerbehandling [Molecular pathology - the key to precision oncology]
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2021 (Swedish)In: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 118, article id 20209Article in journal (Refereed) Published
Abstract [sv]

Rapidly expanding knowledge of the molecular landscape of cancers has resulted in the implementation of an increasing number of specific therapies targeted at tumors with specific molecular aberrations. In response to this development, new tools for predictive testing for molecular targets need to be implemented in routine health care. To achieve robust future molecular diagnostic pathology, and equal opportunity for patients to qualify for targeted therapy, the national working group for Solid Tumors in the initiative Genomic Medicine Sweden (GMS) aims to implement regional and national platforms for comprehensive genomic tumor profiling and linked analysis pipelines. Novel IT-infrastrucutures and recruitment of bioinformaticians and molecular biologists to hospital labotatories are paramount. The infrastructure will allow wider inclusion into clinical trials and supplement the national cancer registries with molecular »real world data« for research and evaluation of implemented cancer therapies and diagnostic procedures.

Place, publisher, year, edition, pages
Läkartidningen Förlag AB, 2021
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:oru:diva-91813 (URN)33973224 (PubMedID)
Available from: 2021-05-17 Created: 2021-05-17 Last updated: 2021-05-17Bibliographically approved
Organisations
Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0003-2317-5738

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