A new tool for technical standardization of the Ki67 immunohistochemical assay

Aung, Thazin Nwe; Ács, Balázs; Warrell, Jonathan; Bai, Yalai; Gaule, Patricia; Martinez-Morilla, Sandra; Vathiotis, Ioannis A.; Shafi, Saba; Moutafi, Myrto; Gerstein, Mark; Freiberg, Benjamin; Fulton, Regan; Rimm, David L.

doi:10.1038/s41379-021-00745-6

Cited by 35 publications

(24 citation statements)

References 23 publications

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“…However, several studies in the literature have attempted to refine this robust methodology, and the data suggest considerable/robust concordance between manual scoring and DIA. Klauschen et al describe promising results validating computer-assisted Ki-67 scoring in their analysis of over 1000 breast tumours [139], while Zhong et al observed 'almost perfect agreement between VA and DIA' in high cases of increased Ki-67 expression, as well as a significant degree of homogeneity in staining among their 155 cases [140]. DIA based on virtual double staining (VDS) with fused parallel cytokeratin and Ki-67 (MIB1) has been described to be greater than 85% congruent with VA by Roge et al in their evaluation of 140 core biopsies, further fuelling dispute as to the requirement for assessment of the whole tissue specimen [141].…”

Section: Digital Image Analysismentioning

confidence: 99%

Ki-67 as a Prognostic Biomarker in Invasive Breast Cancer

Davey

Hynes

Kerin

et al. 2021

Cancers

144

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The advent of molecular medicine has transformed breast cancer management. Breast cancer is now recognised as a heterogenous disease with varied morphology, molecular features, tumour behaviour, and response to therapeutic strategies. These parameters are underpinned by a combination of genomic and immunohistochemical tumour factors, with estrogen receptor (ER) status, progesterone receptor (PgR) status, human epidermal growth factor receptor-2 (HER2) status, Ki-67 proliferation indices, and multigene panels all playing a contributive role in the substratification, prognostication and personalization of treatment modalities for each case. The expression of Ki-67 is strongly linked to tumour cell proliferation and growth and is routinely evaluated as a proliferation marker. This review will discuss the clinical utility, current pitfalls, and promising strategies to augment Ki-67 proliferation indices in future breast oncology.

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Section: Digital Image Analysismentioning

confidence: 99%

Ki-67 as a Prognostic Biomarker in Invasive Breast Cancer

Davey

Hynes

Kerin

et al. 2021

Cancers

144

View full text Add to dashboard Cite

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“…However, future studies to formally evaluate the performance of this approach across laboratories are required given differences in slide generation protocols across different clinical centers (eg slide scanners, staining methods, tissue thickness). 25 , 26 Furthermore, we note that in some cases these alignments could occur even in the presence of tissue folds and tears in tissue provided that a sufficient number of good matches could be secured in other areas of the slide ( Supplementary Fig 2 ). It is likely that larger tissue sections with more distinctive tissue patterns may be more robust to tissue folds and artifacts when compared to smaller and less heterogeneous tissue fragments (eg uniform circular and rectangular tissue shapes).…”

Section: Discussionmentioning

confidence: 93%

Integrating morphologic and molecular histopathological features through whole slide image registration and deep learning

Faust

Lee

Dent

et al. 2022

Neuro-Oncology Advances

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Background Modern molecular pathology workflows in neuro-oncology heavily rely on the integration of morphologic and immunohistochemical patterns for analysis, classification, and prognostication. However, despite the recent emergence of digital pathology platforms and artificial intelligence-driven computational image analysis tools, automating the integration of histomorphologic information found across these multiple studies is challenged by large files sizes of whole slide images (WSIs) and shifts/rotations in tissue sections introduced during slide preparation. Methods To address this, we develop a workflow that couples different computer vision tools including scale-invariant feature transform (SIFT) and deep learning to efficiently align and integrate histopathological information found across multiple independent studies. We highlight the utility and automation potential of this workflow in the molecular subclassification and discovery of previously unappreciated spatial patterns in diffuse gliomas. Results First, we show how a SIFT-driven computer vision workflow was effective at automated WSI alignment in a cohort of 107 randomly selected surgical neuropathology cases (97/107 (91%) showing appropriate matches, AUC = 0.96). This alignment allows our AI-driven diagnostic workflow to not only differentiate different brain tumor types, but also integrate and carry out molecular subclassification of diffuse gliomas using relevant immunohistochemical biomarkers (IDH1-R132H, ATRX). To highlight the discovery potential of this workflow, we also examined spatial distributions of tumors showing heterogenous expression of the proliferation marker MIB1 and Olig2. This analysis helped uncovered an interesting and unappreciated association of Olig2 positive and proliferative areas in some gliomas (r = 0.62). Conclusion This efficient neuropathologist-inspired workflow provides a generalizable approach to help automate a variety of advanced immunohistochemically compatible diagnostic and discovery exercises in surgical neuropathology and neuro-oncology.

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“…S2 E – I ). The quantitation of signals, performed using Q-Path ( 42 ), ImageScope ( 43 ), or ImageJ ( 44 ), showed highly significant differences for Ki67, CD31, and CD71 in vehicle- and IT-treated tumors ( SI Appendix , Fig. S2 J – M ).…”

Section: Resultsmentioning

confidence: 99%

Intraductal administration of transferrin receptor-targeted immunotoxin clears ductal carcinoma in situ in mouse models of breast cancer—a preclinical study

Wang

Kumar

Ding

et al. 2022

Proc. Natl. Acad. Sci. U.S.A.

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The human transferrin receptor (TFR) is overexpressed in most breast cancers, including preneoplastic ductal carcinoma in situ (DCIS). HB21(Fv)-PE40 is a single-chain immunotoxin (IT) engineered by fusing the variable region of a monoclonal antibody (HB21) against a TFR with a 40 kDa fragment of Pseudomonas exotoxin (PE). In humans, the administration of other TFR-targeted immunotoxins intrathecally led to inflammation and vascular leakage. We proposed that for treatment of DCIS, intraductal (i.duc) injection of HB21(Fv)-PE40 could avoid systemic toxicity while retaining its potent antitumor effects on visible and occult tumors in the entire ductal tree. Pharmacokinetic studies in mice showed that, in contrast to intravenous injection, IT was undetectable by enzyme-linked immunosorbent assay in blood following i.duc injection of up to 3.0 μg HB21(Fv)-PE40. We demonstrated the antitumor efficacy of HB21(Fv)-PE40 in two mammary-in-duct (MIND) models, MCF7 and SUM225, grown in NOD/SCID/gamma mice. Tumors were undetectable by In Vivo Imaging System (IVIS) imaging in intraductally treated mice within 1 wk of initiation of the regimen (IT once weekly/3 wk, 1.5 μg/teat). MCF7 tumor–bearing mice remained tumor free for up to 60 d of observation with i.duc IT, whereas the HB21 antibody alone or intraperitoneal IT treatment had minimal/no antitumor effects. These and similar findings in the SUM225 MIND model were substantiated by analysis of mammary gland whole mounts, histology, and immunohistochemistry for the proteins Ki67, CD31, CD71 (TFR), and Ku80. This study provides a strong preclinical foundation for conducting feasibility and safety trials in patients with stage 0 breast cancer.

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A new tool for technical standardization of the Ki67 immunohistochemical assay

Cited by 35 publications

References 23 publications

Ki-67 as a Prognostic Biomarker in Invasive Breast Cancer

Ki-67 as a Prognostic Biomarker in Invasive Breast Cancer

Integrating morphologic and molecular histopathological features through whole slide image registration and deep learning

Intraductal administration of transferrin receptor-targeted immunotoxin clears ductal carcinoma in situ in mouse models of breast cancer—a preclinical study

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