Publications by authors named "M Westergaard"

109 Publications

Altered Antibody Response to Epstein-Barr Virus in Patients With Rheumatoid Arthritis and Healthy Subjects Predisposed to the Disease. A Twin Study.

Front Immunol 2021 11;12:650713. Epub 2021 Mar 11.

Department of Autoimmunity and Biomarkers, Statens Serum Institut, Copenhagen, Denmark.

To study Epstein-Barr virus (EBV) antibody patterns in twin individuals with rheumatoid arthritis (RA) and their healthy co-twins, and to determine the heritability of antibody responses against the EBV encoded EBNA1 protein. Isotypes of EBNA1 antibodies were measured in 137 RA affected- and 150 healthy twin pairs. We estimated the effect of RA and RA predisposition, anti-citrullinated antibodies (ACPA), IgM rheumatoid factor (RF), the shared epitope (SE) and the PTPN22-T allele (PTPN22) on the level of EBNA1 antibodies. We also determined the heritability of EBNA1 antibody levels. IgA-EBNA1 antibody levels were increased in twins from RA discordant twin pairs irrespective of RA, ACPA or IgM-RF status. The IgG-EBNA1 antibody level was elevated in healthy co-twins from RA discordant twin pairs but not in RA affected twins. The IgM-EBNA1 antibody level was elevated in both RA twins and their healthy co-twins. The effect of RA on the IgA-EBNA1 antibody level was reversed when SE was present and with no effect of PTPN22. The heritability of IgA-, IgG- and IgM-EBNA1 antibody level was 40.6, 65.5, and 54.3%, with no effect of environment shared by the twins. EBNA1 antibody levels are distinctively different between patients with RA and healthy subjects but also between relatives of RA strongly predisposed to RA and healthy subjects. The high level of IgA EBNA1 antibodies associated with RA and a family predisposition to RA is attributable to both genetics incl. the shared epitope and environmental variation.
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http://dx.doi.org/10.3389/fimmu.2021.650713DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7991571PMC
March 2021

Changes in the Tumor Immune Microenvironment during Disease Progression in Patients with Ovarian Cancer.

Cancers (Basel) 2020 Dec 18;12(12). Epub 2020 Dec 18.

National Center for Cancer Immune Therapy (CCIT-DK), Department of Oncology, Copenhagen University Hospital, 2730 Herlev, Denmark.

Anti-PD1/PDL1 therapy has proven efficacious against many cancers but only reached modest objective response rates against recurrent ovarian cancer. A deeper understanding of the tumor microenvironment (TME) may reveal other immunosuppressive mechanisms that warrant investigation as immunotherapeutic targets for this challenging disease. Matched primary and recurrent tumors from patients with high-grade serous ovarian carcinoma (HGSC) were analyzed by multicolor immunohistochemistry/immunofluorescence for the presence of T cells, B cells, macrophages, and for the expression of immunosuppressive and HLA molecules. Cancer- and immune-related gene expression was assessed by NanoString analysis. Recurrent tumors showed increased infiltration by immune cells, displayed higher expression of PDL1, IDO, and HLA molecules, and contained more stromal tissue. NanoString analysis demonstrated increased expression of gene signatures related to chemokines and T cell functions in recurrent tumors. The ovarian tumors showed high gene expression of and (TIM3) and enhanced levels of and in recurrent tumors compared to primary tumors. The majority of HGSC developed into a more inflamed phenotype during progression from primary to recurrent disease, including indications of adaptive immune resistance. This suggests that recurrent tumors may be particularly sensitive to inhibition of adaptive immune resistance mechanisms.
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http://dx.doi.org/10.3390/cancers12123828DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7767114PMC
December 2020

Dependence-like behaviour in patients treated for medication overuse headache: A prospective open-label randomized controlled trial.

Eur J Pain 2021 04 7;25(4):852-861. Epub 2021 Jan 7.

Danish Headache Centre, Rigshospitalet, Glostrup, Denmark.

Background: Dependence-like behaviour may complicate withdrawal and increase risk of relapse of medication overuse headache (MOH). The most effective treatment for reducing dependence-like behaviour is unknown.

Objectives: To compare patient-reported outcomes among three treatment strategies for MOH. The primary outcome was change in Severity of Dependence Scale (SDS) score from baseline to 6 months.

Methods: Patients with MOH were randomized to (1) withdrawal combined with preventive medication from start (W+P), (2) preventive medication without withdrawal (P), or (3) withdrawal with optional preventive medication 2 months after withdrawal (W). At baseline, 2, and 6 months, patients filled out SDS (used for measurements of dependence-like behaviour and treatment feasibility), Headache Under-Response of Treatment (HURT) and WHO Quality of Life BREF questionnaires.

Results: Out of 120 patients with MOH, 100 completed the 6-month follow-up and filled out questionnaires. The W+P arm was the most effective in treating MOH. After 6 months, the SDS score was reduced by 3.69 (95% CI 3.23-4.49) in the W+P arm, by 3.19 (95% CI 2.43-3.96) in the W arm, and by 1.65 (95% CI 0.96-2.33) in the P arm (p = 0.04). At baseline and after 2 months, the P arm was considered the most feasible treatment, but at 6-month follow-up, there was no difference in feasibility score, change in HURT score, or quality of life.

Conclusions: Dependence-like behaviour was reduced most in the two withdrawal arms. Withdrawal combined with preventive medication is recommended for the treatment of MOH.

Significance: Withdrawal combined with preventive medication from start is the treatment strategy that reduces dependence-like behaviour the most in MOH patients. Patients initially considered preventive treatment without withdrawal as the most feasible treatment. However, no difference in feasibility between the three arms was found at 6-month follow-up. Withdrawal combined with preventive medication is recommended for treatment of MOH.
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http://dx.doi.org/10.1002/ejp.1715DOI Listing
April 2021

Natural language processing and entrustable professional activity text feedback in surgery: A machine learning model of resident autonomy.

Am J Surg 2021 02 26;221(2):369-375. Epub 2020 Nov 26.

Department of Surgery, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA. Electronic address:

Background: Entrustable Professional Activities (EPAs) contain narrative 'entrustment roadmaps' designed to describe specific behaviors associated with different entrustment levels. However, these roadmaps were created using expert committee consensus, with little data available for guidance. Analysis of actual EPA assessment narrative comments using natural language processing may enhance our understanding of resident entrustment in actual practice.

Methods: All text comments associated with EPA microassessments at a single institution were combined. EPA-entrustment level pairs (e.g. Gallbladder Disease-Level 1) were identified as documents. Latent Dirichlet Allocation (LDA), a common machine learning algorithm, was used to identify latent topics in the documents associated with a single EPA. These topics were then reviewed for interpretability by human raters.

Results: Over 18 months, 1015 faculty EPA microassessments were collected from 64 faculty for 80 residents. LDA analysis identified topics that mapped 1:1 to EPA entrustment levels (Gammas >0.99). These LDA topics appeared to trend coherently with entrustment levels (words demonstrating high entrustment were consistently found in high entrustment topics, word demonstrating low entrustment were found in low entrustment topics).

Conclusions: LDA is capable of identifying topics relevant to progressive surgical entrustment and autonomy in EPA comments. These topics provide insight into key behaviors that drive different level of resident autonomy and may allow for data-driven revision of EPA entrustment maps.
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http://dx.doi.org/10.1016/j.amjsurg.2020.11.044DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7969407PMC
February 2021

Qualitative Analysis of Tumor-Infiltrating Lymphocytes across Human Tumor Types Reveals a Higher Proportion of Bystander CD8 T Cells in Non-Melanoma Cancers Compared to Melanoma.

Cancers (Basel) 2020 Nov 12;12(11). Epub 2020 Nov 12.

National Center for Cancer Immune Therapy (CCIT-DK), Department of Oncology, Copenhagen University Hospital, 2730 Herlev, Denmark.

Human intratumoral T cell infiltrates can be defined by quantitative or qualitative features, such as their ability to recognize autologous tumor antigens. In this study, we reproduced the tumor-T cell interactions of individual patients to determine and compared the qualitative characteristics of intratumoral T cell infiltrates across multiple tumor types. We employed 187 pairs of unselected tumor-infiltrating lymphocytes (TILs) and autologous tumor cells from patients with melanoma, renal-, ovarian-cancer or sarcoma, and single-cell RNA sequencing data from a pooled cohort of 93 patients with melanoma or epithelial cancers. Measures of TIL quality including the proportion of tumor-reactive CD8 and CD4 TILs, and TIL response polyfunctionality were determined. Tumor-specific CD8 and CD4 TIL responses were detected in over half of the patients in vitro, and greater CD8 TIL responses were observed in melanoma, regardless of previous anti-PD-1 treatment, compared to renal cancer, ovarian cancer and sarcoma. The proportion of tumor-reactive CD4 TILs was on average lower and the differences less pronounced across tumor types. Overall, the proportion of tumor-reactive TILs in vitro was remarkably low, implying a high fraction of TILs to be bystanders, and highly variable within the same tumor type. In situ analyses, based on eight single-cell RNA-sequencing datasets encompassing melanoma and five epithelial cancers types, corroborated the results obtained in vitro. Strikingly, no strong correlation between the proportion of CD8 and CD4 tumor-reactive TILs was detected, suggesting the accumulation of these responses in the tumor microenvironment to follow non-overlapping biological pathways. Additionally, no strong correlation between TIL responses and tumor mutational burden (TMB) in melanoma was observed, indicating that TMB was not a major driving force of response. No substantial differences in polyfunctionality across tumor types were observed. These analyses shed light on the functional features defining the quality of TIL infiltrates in cancer. A significant proportion of TILs across tumor types, especially non-melanoma, are bystander T cells. These results highlight the need to develop strategies focused on the tumor-reactive TIL subpopulation.
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http://dx.doi.org/10.3390/cancers12113344DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7696049PMC
November 2020