Lorant Farkas

• Schandiz, Hossein Khalkhali; Farkas, Lorant; Park, Daehoon; Liu, Yan; Andersen, Solveig Norheim & Sauer, Torill [Show all 7 contributors for this article] (2025). High Ki67 expression, HER2 overexpression, and low progesterone receptor levels in high-grade DCIS: significant associations with clinical practice implications. Frontiers in Oncology. 15. doi: 10.3389/fonc.2025.1467664. Full text in Research Archive Show summary

  Simple summary: We investigated the role of Ki67, a ubiquitous marker in cancer, within the context of ductal carcinoma in situ (DCIS), a precursor of invasive breast cancer. Through rigorous analysis of histopathological and immunopathological samples from a substantial cohort, this study revealed robust correlations between heightened Ki67 expression, diminished progesterone (PR) levels, and HER2 overexpression, indicative of aggressive DCIS phenotypes. These findings offer novel insights into the surrogate immunomolecular subtyping landscape of DCIS, potentially refining risk stratification and therapeutic approaches. This elucidation underscores the translational significance of Ki67 as a prognostic and predictive biomarker in DCIS, with implications for personalized treatment paradigms and patient outcomes. Background: The Ki67 proliferation index is widely used in various tumors, including invasive breast carcinoma (IBC). However, its prognostic utility is often constrained by technical complexity. Its diagnostic and clinical significance in ductal carcinoma in situ (DCIS) remains uncertain. We studied Ki67 immunohistochemistry interobserver diagnostic agreement at different cutoff values in high-grade DCIS. Additionally, we investigated the associations between Ki67 expression, PR levels, and human epidermal growth factor receptor 2 (HER2) in high-grade DCIS among various subtypes (Luminal (Lum) A, LumB HER2-, LumB HER2+, HER2-enriched, and triple-negative)). Methods: Using histopathological specimens from 484 patients diagnosed with DCIS between 1996 and 2018, we implemented the 2013 St. Gallen recommendations for surrogate immunomolecular subtyping of IBC. Subtypes were classified, and the Ki67 interobserver diagnostic agreement between Counting Pathologist 1 (CP1) and CP2 was calculated using Cohen’s kappa coefficient at various cutoff values. Results: The Cohen’s kappa coefficient for interobserver agreement between CP1 and CP2 was κ = 0.586, indicating moderate agreement. Ki67 levels varied significantly among subtypes (p < 0.0001), with a median Ki67% being higher in cases with invasive components (p = 0.0351). Low PR combined with high Ki67% was significantly associated with HER2 overexpression (p = 0.0107). Conclusions: Interobserver agreement for the Ki67 count was moderate. Ki67 expression showed considerable variability in high-grade DCIS. Low PR levels combined with high Ki67 expression were linked to HER2 overexpression, showing possible clinical implications for identifying high-risk DCIS.

• Wang, Junbai; Yang, Mingyi; Ali, Omer; Dragland, Jenny Sofie; Bjørås, Magnar & Farkas, Lorant (2024). Predicting regulatory mutations and their target genes by new computational integrative analysis: A study of follicular lymphoma. Computers in Biology and Medicine. ISSN 0010-4825. 178, p. 1–15. doi: 10.1016/j.compbiomed.2024.108787. Full text in Research Archive Show summary

  Mutations in DNA regulatory regions are increasingly being recognized as important drivers of cancer and other complex diseases. These mutations can regulate gene expression by affecting DNA-protein binding and epigenetic profiles, such as DNA methylation in genome regulatory elements. However, identifying mutation hotspots associated with expression regulation and disease progression in non-coding DNA remains a challenge. Unlike most existing approaches that assign a mutation score to individual single nucleotide polymorphisms (SNP), a mutation block (MB)-based approach was introduced in this study to assess the collective impact of a cluster of SNPs on transcription factor-DNA binding affinity, differential gene expression (DEG), and nearby DNA methylation. Moreover, the long-distance target genes of functional MBs were identified using a new permutation-based algorithm that assessed the significance of correlations between DNA methylation at regulatory regions and target gene expression. Two new Python packages were developed. The Differential Methylation Region (DMR-analysis) analysis tool was used to detect DMR and map them to regulatory elements. The second tool, an integrated DMR, DEG, and SNP analysis tool (DDS-analysis), was used to combine the omics data to identify functional MBs and long-distance target genes. Both tools were validated in follicular lymphoma (FL) cohorts, where not only known functional MBs and their target genes (BCL2 and BCL6) were recovered, but also novel genes were found, including CDCA4 and JAG2, which may be associated with FL development. These genes are linked to target gene expression and are significantly correlated with the methylation of nearby DNA sequences in FL. The proposed computational integrative analysis of multiomics data holds promise for identifying regulatory mutations in cancer and other complex diseases.

• Schandiz, Hossein Khalkhali; Farkas, Lorant; Park, Daehoon; Liu, Yan; Andersen, Solveig Norheim & Geisler, Jürgen [Show all 7 contributors for this article] (2024). Low progesterone receptor levels in high-grade DCIS correlate with HER2 upregulation and the presence of invasive components. Frontiers in Oncology. 14:1347166, p. 1–10. doi: 10.3389/fonc.2024.1347166. Full text in Research Archive Show summary

  Objective In this study, we investigated pivotal molecular markers in human high-grade breast ductal carcinoma in situ (DCIS). Expression status of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth receptor 2 (HER2) was measured among various subtypes (Luminal (Lum) A, LumB HER2-, LumB HER2+, HER2-enriched and triple-negative). Methods In total, 357 DCIS cases were classified into respective subtypes, according to the 2013 St. Gallen guidelines. Each subtype was categorized into three subcategories: “Pure” (those without an invasive component), “W/invasive” (those with an invasive component), and “All” (the entire group of the given subtype). ER and PR expression were registered as intervals. Equivocal HER2 immunohistochemistry (IHC) cases (2+) were further investigated using dual-color in situ hybridization. Results The majority of patients (71%) were over the age of 50. We discovered no significant differences in the proportion of age between the “Pure” and “W/invasive” groups. There was no significant difference in ER/PR expression between “Pure” luminal subtypes of DCIS and “W/invasive” cases. We compared the HER2 IHC scores of “0”, “1+”, and “2+” among LumA and LumB HER2 subtypes and identified no statistically significant differences between “Pure” and “W/invasive” (p = 0.603). ER and PR expression ≥ 50% cutoff value was present in > 90% of all LumA cases. The incidences of cases with ER expression at cutoff values of < 10% and ≥ 50% in LumA were significantly different compared to other luminal subtypes (p < 0.0001). The proportion of cases with PR expression < 20% showed significant differences in the various luminal subtypes. In luminal B subtypes, low PR expression (< 20%) was significantly associated with both strong HER2 expression (3+) and the presence of an invasive component (p = 0.0001 and p = 0.0365, respectively). Conclusions ER and PR expression at ≥ 50% cutoff values were found in more than 90% of LumA cases. Samples with ER < 10% and ≥ 50% in LumA were significantly different compared to other luminal subtypes (p < 0.0001). Low PR expression in high-grade DCIS was strongly associated with HER2 overexpression (3+) and an invasive component (p = 0.0001 and p = 0.0365, respectively).

• Denholm, James; Schreiber, Benjamin A.; Jaeckle, Florian; Wicks, Mike N.; Benbow, Emyr W. & Bracey, Tim S. [Show all 23 contributors for this article] (2024). CD, or not CD, that is the question: a digital interobserver agreement study in coeliac disease. BMJ open gastroenterology. 11:e001252(1), p. 1–7. doi: 10.1136/bmjgast-2023-001252. Full text in Research Archive Show summary

  Objective Coeliac disease (CD) diagnosis generally depends on histological examination of duodenal biopsies. We present the first study analysing the concordance in examination of duodenal biopsies using digitised whole-slide images (WSIs). We further investigate whether the inclusion of immunoglobulin A tissue transglutaminase (IgA tTG) and haemoglobin (Hb) data improves the interobserver agreement of diagnosis. Design We undertook a large study of the concordance in histological examination of duodenal biopsies using digitised WSIs in an entirely virtual reporting setting. Our study was organised in two phases: in phase 1, 13 pathologists independently classified 100 duodenal biopsies (40 normal; 40 CD; 20 indeterminate enteropathy) in the absence of any clinical or laboratory data. In phase 2, the same pathologists examined the (re-anonymised) WSIs with the inclusion of IgA tTG and Hb data. Results We found the mean probability of two observers agreeing in the absence of additional data to be 0.73 (±0.08) with a corresponding Cohen’s kappa of 0.59 (±0.11). We further showed that the inclusion of additional data increased the concordance to 0.80 (±0.06) with a Cohen’s kappa coefficient of 0.67 (±0.09). Conclusion We showed that the addition of serological data significantly improves the quality of CD diagnosis. However, the limited interobserver agreement in CD diagnosis using digitised WSIs, even after the inclusion of IgA tTG and Hb data, indicates the importance of interpreting duodenal biopsy in the appropriate clinical context. It further highlights the unmet need for an objective means of reproducible duodenal biopsy diagnosis, such as the automated analysis of WSIs using artificial intelligence.

• Tahiri, Andliena; Puco, Katarina; Naji, Faris; Kristensen, Vessela N.; Alfsen, G. Cecilie & Farkas, Lorant [Show all 10 contributors for this article] (2022). Kinase activity profiling in renal cell carcinoma, benign renal tissue and in response to four different tyrosine kinase inhibitors. OncoTarget. 13(1), p. 970–981. doi: 10.18632/oncotarget.28257. Full text in Research Archive Show summary

  Kinase activity is frequently altered in renal cell carcinoma (RCC), and tyrosine kinase inhibitors (TKIs) are part of the standard treatment strategy in patients with metastatic disease. However, there are still no established biomarkers to predict clinical benefits of a specific TKI. Here, we performed protein tyrosine kinase (PTK) profiling using PamChip® technology. The aim of this study was to identify differences in PTK activity between normal and malignant kidney tissue obtained from the same patient, and to investigate the inhibitory effects of TKIs frequently used in the clinics: sunitinib, pazopanib, cabozantinib and tivozanib. Briefly, our results showed that 36 kinase substrates differs (FDR < 0.05) between normal and cancer kidney tissue, where members of the Src family kinases and the phosphoinositide-3-kinase (PI3K) pathway exhibit high activity in renal cancer. Furthermore, ex vivo treatment of clear cell RCC with TKIs revealed that pathways such as Rap1, Ras and PI3K pathways were strongly inhibited, whereas the neurotrophin pathway had increased activity upon TKI addition. In our assay, tivozanib and cabozantinib exhibited greater inhibitory effects on PTK activity compared to sunitinib and pazopanib, implying they might be better suitable as TKIs for selected RCC patients.

• Dobson, Rachel; Du, Peter Y.; Ráso-Barnett, Livia; Yao, Wen-Qing; Chen, Zi & Casa, Calogero [Show all 21 contributors for this article] (2022). Early detection of T-cell lymphoma with T follicular helper phenotype by RHOA mutation analysis. Haematologica. ISSN 0390-6078. 107(2), p. 489–499. doi: 10.3324/haematol.2020.265991. Full text in Research Archive
• Melum, Guro Reinholt; Farkas, Lorant; Scheel, Cecilie; Dieren, Brenda van; Gran, Einar & Liu, YJ [Show all 9 contributors for this article] (2014). A thymic stromal lymphopoietin-responsive dendriticcell subset mediates allergic responses in the upper airway mucosa. Journal of Allergy and Clinical Immunology. ISSN 0091-6749. 134(3), p. 613–621. doi: 10.1016/j.jaci.2014.05.010. Full text in Research Archive
• Skrindo, Ingebjørg; Farkas, Lorant; Kvale, Espen Østhagen; Johansen, Finn Eirik & Jahnsen, Frode Lars (2008). Depletion of CD4(+)CD25(+)CD127(lo) regulatory T cells does not increase allergen-driven T cell activation. Clinical and Experimental Allergy. ISSN 0954-7894. 38(11), p. 1752–1759. doi: 10.1111/j.1365-2222.2008.03081.x. Full text in Research Archive
• Kvale, Espen Østhagen; Fløisand, Yngvar; Lund-Johansen, Fridtjof; Rollag, Halvor; Farkas, Lorant & Ghanekar, Smita [Show all 9 contributors for this article] (2007). Plasmacytoid DCs regulate recall responses by rapid induction of IL-10 in memory T cells. Blood. ISSN 0006-4971. 109. doi: 10.1182/blood-2006-06-031484. Full text in Research Archive
• Farkas, Lorant; Kvale, Espen Østhagen; Lund-Johansen, Fridtjof & Jahnsen, Frode Lars (2006). Plasmacytoid dendritic cells induce a distinct cytokine pattern in virus-specific CD4(+) memory T cells that is modulated by CpG oligodeoxynucleotides. Scandinavian Journal of Immunology. ISSN 0300-9475. 64, p. 404–411. Full text in Research Archive
• Kvale, Espen Østhagen; Dalgaard, Jakob; Lund-Johansen, Fridtjof; Rollag, Halvor; Farkas, Lorant & Midtvedt, Karsten [Show all 9 contributors for this article] (2006). CD11c+ dendritic cells and plasmacytoid DCs are activated by human cytomegalovirus and retain efficient T cell–stimulatory capability upon infection. Blood. ISSN 0006-4971. 107(5), p. 2022–2029. doi: 10.1182/blood-2005-05-2016. Full text in Research Archive
• Haddeland, Unni; Karstensen, AB; Farkas, Lorant; Bø, Knut Olav; Pirhonen, Jouko & Karlsson, Malin [Show all 9 contributors for this article] (2005). Putative regulatory T cells are impaired in cord blood from neonates with hereditary allergy risk. Pediatric Allergy and Immunology. ISSN 0905-6157. 16, p. 104–112. Full text in Research Archive
• Farkas, Lorant; Kvale, Espen Østhagen; Johansen, Finn Eirik; Jahnsen, Frode Lars & Lund-Johansen, F (2004). Plasmacytoid dendritic cells activate allergen-specific Th2 memory cells: modulation by CpG oligodeoxynucleotides. Journal of Allergy and Clinical Immunology. ISSN 0091-6749. 114, p. 436–443. Full text in Research Archive

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• Farkas, Lorant; Schenck, Karl; Johansen, Finn-Eirik & Jahnsen, Frode L (2004). TSLP (thymic stromal lymphopoietin): a candidate target for treatment of allergy. Full text in Research Archive
• Farkas, Lorant (2004). Human plasmacytoid dendritic cells: involvement in allergy, autoimmunity and virus reactions. Universitetet i Oslo. ISSN 9788280721396. Full text in Research Archive

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