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Elfving, Hedvig
Publications (3 of 3) Show all publications
Elfving, H., Mattsson, J. S., Lindskog, C., Backman, M., Menzel, U. & Micke, P. (2019). Programmed Cell Death Ligand 1 Immunohistochemistry: A Concordance Study Between Surgical Specimen, Biopsy, and Tissue Microarray. Clinical Lung Cancer, 20(4), 258-262.e1
Open this publication in new window or tab >>Programmed Cell Death Ligand 1 Immunohistochemistry: A Concordance Study Between Surgical Specimen, Biopsy, and Tissue Microarray
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2019 (English)In: Clinical Lung Cancer, ISSN 1525-7304, E-ISSN 1938-0690, Vol. 20, no 4, p. 258-262.e1Article in journal (Refereed) Published
Abstract [en]

Programmed cell death ligand 1 (PD-L1) expression within the same lung cancer tissue is variable. In this study we evaluated if the PD-L1 expression on small biopsy specimens represent the PD-L1 status of the corresponding resection specimen. Our results indicate a relative good agreement between biopsy and surgical specimens, with a discordance in approximately 10% of the cases. Background: The immunohistochemical analysis of programmed cell death ligand 1 (PD-L1) expression in tumor tissue of non-small-cell lung cancer patients has now been integrated in the diagnostic workup. Analysis is commonly done on small tissue biopsy samples representing a minimal fraction of the whole tumor. The aim of the study was to evaluate the correlation of PD-L1 expression on biopsy specimens with corresponding resection specimens. Materials and Methods: In total, 58 consecutive cases with preoperative biopsy and resected tumor specimens were selected. From each resection specimen 2 tumor cores were compiled into a tissue microarray (TMA). Immunohistochemical staining with the antibody SP263 was performed on biopsy specimens, resection specimens (whole sections), as well as on the TMA. Results: The proportion of PD-L1-positive stainings were comparable between the resection specimens (48% and 19%), the biopsies (43% and 17%), and the TMAs (47% and 14%), using cutoffs of 1% and 50%, respectively (P > .39 all comparisons). When the resection specimens were considered as reference, PD-L1 status differed in 16%/5% for biopsies and in 9%/9% for TMAs (1%/50% cutoff). The sensitivity of the biopsy analysis was 79%/82% and the specificity was 90%/98% at the 1%/50% cutoff. The Cohens kappa value for the agreement between biopsy and tumor. was 0.70 at the 1% cutoff and 0.83 at the 50% cutoff. Conclusion: The results indicate a moderate concordance between the analysis of biopsy and whole tumor tissue, resulting in misclassification of samples in particular when the lower 1% cutoff was used. Clinicians should be aware of this uncertainty when interpreting PD-L1 reports for treatment decisions.

Keywords
Checkpoint inhibitors, Nivolumab, PD-1, PD-L1, Pembrolizumab
National Category
Cancer and Oncology Clinical Laboratory Medicine
Research subject
Pathology
Identifiers
urn:nbn:se:uu:diva-390976 (URN)10.1016/j.cllc.2019.02.012 (DOI)000475296800018 ()30926355 (PubMedID)
Funder
Swedish Cancer Society
Available from: 2019-08-16 Created: 2019-08-16 Last updated: 2020-01-03Bibliographically approved
Miyashita, N., Horie, M., Suzuki, H. I., Yoshihara, M., Djureinovic, D., Persson, J., . . . Nagase, T. (2018). An Integrative Analysis of Transcriptome and Epigenome Features of ASCL1-Positive Lung Adenocarcinomas. Journal of Thoracic Oncology, 13(11), 1676-1691
Open this publication in new window or tab >>An Integrative Analysis of Transcriptome and Epigenome Features of ASCL1-Positive Lung Adenocarcinomas
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2018 (English)In: Journal of Thoracic Oncology, ISSN 1556-0864, E-ISSN 1556-1380, Vol. 13, no 11, p. 1676-1691Article in journal (Refereed) Published
Abstract [en]

Introduction: A subgroup of lung adenocarcinoma shows neuroendocrine differentiation and expression of achaete-scute family bHLH transcription factor 1 (ASCL1), common to high-grade neuroendocrine tumors, small-cell lung cancer and large cell neuroendocrine carcinoma. Methods: The aim of this study was to characterize clinical and molecular features of ASCL1-positive lung adenocarcinoma by using recent transcriptome profiling in multiple patient cohorts and genome-wide epigenetic profiling including data from The Cancer Genome Atlas. Results: The ASCL1-positive subtype of lung adenocarcinoma developed preferentially in current or former smokers and usually did not harbor EGFR mutations. In transcriptome profiling, this subtype overlapped with the recently proposed proximal-proliferative molecular subtype. Gene expression profiling of ASCL1-positive cases suggested generally poor immune cell infiltration and none of the tumors were positive for programmed cell death ligand 1 protein expression. Genome-wide methylation analysis showed global DNA hypomethylation in ASCL1-positive cases. ASCL1 was associated with super-enhancers in ASCL1-positive lung adenocarcinoma cells, and ASCL1 silencing suppressed other super-enhancer-associated genes, suggesting thatASCL1 acts as a master transcriptional regulator. This was further reinforced by the essential roles of ASCL1 in cell proliferation, survival, and cell cycle control. Conclusions: These results suggest that ASCL1 defines a subgroup of lung adenocarcinoma with distinct molecular features by driving super-enhancer-mediated transcriptional programs.

Place, publisher, year, edition, pages
ELSEVIER SCIENCE INC, 2018
Keywords
Lung cancer, Adenocarcinoma, Neuroendocrine, ASCL1, NSCLC
National Category
Cancer and Oncology Clinical Laboratory Medicine
Research subject
Pathology
Identifiers
urn:nbn:se:uu:diva-371088 (URN)10.1016/j.jtho.2018.07.096 (DOI)000450088600020 ()30121393 (PubMedID)
Funder
Knut and Alice Wallenberg FoundationSwedish Cancer Society
Available from: 2018-12-19 Created: 2018-12-19 Last updated: 2019-03-29Bibliographically approved
Backman, M., La Fleur, L., Kurppa, P., Djureinovic, D., Elfving, H., Brunnström, H., . . . Micke, P.Extending the immune phenotypes of lung cancer: Oasis in the desert.
Open this publication in new window or tab >>Extending the immune phenotypes of lung cancer: Oasis in the desert
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(English)Manuscript (preprint) (Other academic)
Abstract [en]

Introduction: Tumor infiltrating immune cells are key elements of the tumor microenvironment and mediate the anti-tumor effects of immunotherapy. The aim of the study was to characterize patterns of immune cell infiltration in non-small cell lung cancer (NSCLC) in relation to tumor mutations and clinicopathological parameters. 

Methods: Lymphocytes (CD4+, CD8+, CD20+, FOXP3+, CD45RO+), macrophages (CD163+), plasma cells (CD138+), NK cells (NKp46+) and PD-L1+ were annotated on a tissue microarray including 357 operated NSCLC cases. Somatic mutations and tumor mutational burden were analyzed by targeted sequencing for 82 genes, and transcriptomic immune patterns were established in 197 patients based on RNAseq data. 

Results: We identified somatic mutations (TP53, NF1, KEAP1, CSMD3, LRP1B) that correlated with specific immune cell infiltrates. Hierarchical clustering revealed four immune classes: with (1) high immune cell infiltration (“inflamed”), (2) low immune cell infiltration (“desert”), (3) a mixed phenotype, and (4) a new phenotype with an overall muted inflammatory cell pattern but with an imprint of NK and plasma cells. This latter class exhibited low expression of immune response-related genes (e.g. CXCL9, GZMB, INFG, TGFB1), but was linked to better survival and therefore designated “oasis”. Otherwise, the four immune classes were not related to the presence of specific mutations (EGFR, KRAS, TP53) or histologic subtypes. 

Conclusion: We present a compartment-specific immune cell analysis in the context of the molecular and clinical background of NSCLC and identified the novel immune class “oasis”. The immune classification helps to better define the immunogenic potency of NSCLC in the era of immunotherapy. 

Keywords
Immune infiltration, PD-L1, checkpoint therapy, tumor microenvironment
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-390316 (URN)
Available from: 2019-08-08 Created: 2019-08-08 Last updated: 2019-08-20
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