Computerized image analysis of the Ki‐67 proliferation index in mantle cell lymphoma

Blaker, Yngvild Nuvin; Brodtkorb, Marianne; Maddison, John; Hveem, Tarjei S.; Nesheim, John Arne; Mohn, Hans Martin; Kolstad, Arne; Geisler, Christian H.; Liestøl, Knut; Smeland, Erlend B.; Holte, Harald; Delabie, Jan; Danielsen, Håvard E.

doi:10.1111/his.12624

Cited by 12 publications

(12 citation statements)

References 27 publications

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“…Usually, most of the neuropathologists select areas showing the highest proliferation. Here, in order to have a more reproducible counting method for both Ki-67 and MCM6, we adapted computerized color image analyses based on previous results for Ki-67 cell scoring (6,36). Consequently, a wide area was analyzed for each TMA spot.…”

Section: Discussionmentioning

confidence: 99%

Ki‐67 and MCM6 labeling indices are correlated with overall survival in anaplastic oligodendroglioma, IDH1‐mutant and 1p/19q‐codeleted: a multicenter study from the French POLA network

et al. 2019

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Anaplastic oligodendroglioma (AO), IDH-mutant and 1p/19q codeleted (IDHmut+/ 1p19qcodel), is a high-grade glioma with only limited prognostic markers. The primary objective of this study was to evaluate, by immunohistochemistry, the prognostic value of two proliferation markers, MCM6 and Ki-67, in a large series of IDHmut+/1p19qcodel AO included in the POLA ("Prise en charge des Oligodendrogliomes Anaplasiques") French national multicenter network. We additionally examined the transcriptome obtained from this series to understand the functional pathways dysregulated with the mRNA overexpression of these two markers. The labeling indices (LI) of MCM6 and Ki-67 were obtained via computer-assisted color image analyses on immunostained AO tissues of the cohort (n = 220). Furthermore, a subgroup of AO (n = 68/220) was used to perform transcriptomic analyses. A high LI of either MCM6 (≥50%) or Ki-67 (≥15%) correlated with shorter overall survival, both in univariate (P = 0.013 and P = 0.004, respectively) and multivariate analyses (P = 0.027; multivariate Cox model including age, mitotic index, MCM6 and Ki-67). MCM6 and Ki-67 LI also correlated with overall survival in an additional retrospective cohort of 30 grade II IDHmut+/1p19qcodel oligodendrogliomas. The prognostic value of MCM6 mRNA level was confirmed in The Cancer Genome Atlas (TCGA) IDHmut+/1p19qcodel gliomas. The transcriptomic approach revealed that high transcriptional expressions of MCM6 and MKI67 were both linked positively with cell cycle progression, DNA replication, mitosis, pro-neural phenotype as well as neurogenesis, and negatively with microglial cell activation, immune response, positive regulation of myelination, oligodendrocyte development, beta-amyloid binding and postsynaptic specialization. In conclusion, the overexpression of MCM6 and/or Ki-67 is independently associated to shorter overall survival in IDHmut+/1p19qcodel AO. These two easy-to-use and cost-effective markers could thus be used concurrently in routine pathology practice. Additionally, the transcriptomic analyses showed that AO with high proliferation index have down-regulated immune response and lower microglial cells activation, and bears pro-neural phenotype.

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Section: Discussionmentioning

confidence: 99%

Ki‐67 and MCM6 labeling indices are correlated with overall survival in anaplastic oligodendroglioma, IDH1‐mutant and 1p/19q‐codeleted: a multicenter study from the French POLA network

et al. 2019

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“…Collagen volume fraction in Masson trichrome stained cross-sections of the left ventricle was quantified by computerized image analyses as previously described in detail. 20 …”

Section: Methodsmentioning

confidence: 99%

Increased passive stiffness promotes diastolic dysfunction despite improved Ca2+ handling during left ventricular concentric hypertrophy

Røe

Aronsen

Skårdal

et al. 2017

Cardiovascular Research

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AimsConcentric hypertrophy following pressure-overload is linked to preserved systolic function but impaired diastolic function, and is an important substrate for heart failure with preserved ejection fraction. While increased passive stiffness of the myocardium is a suggested mechanism underlying diastolic dysfunction in these hearts, the contribution of active diastolic Ca2+ cycling in cardiomyocytes remains unclear. In this study, we sought to dissect contributions of passive and active mechanisms to diastolic dysfunction in the concentrically hypertrophied heart following pressure-overload.Methods and resultsRats were subjected to aortic banding (AB), and experiments were performed 6 weeks after surgery using sham-operated rats as controls. In vivo ejection fraction and fractional shortening were normal, confirming preservation of systolic function. Left ventricular concentric hypertrophy and diastolic dysfunction following AB were indicated by thickening of the ventricular wall, reduced peak early diastolic tissue velocity, and higher E/e’ values. Slowed relaxation was also observed in left ventricular muscle strips isolated from AB hearts, during both isometric and isotonic stimulation, and accompanied by increases in passive tension, viscosity, and extracellular collagen. An altered titin phosphorylation profile was observed with hypophosphorylation of the phosphosites S4080 and S3991 sites within the N2Bus, and S12884 within the PEVK region. Increased titin-based stiffness was confirmed by salt-extraction experiments. In contrast, isolated, unloaded cardiomyocytes exhibited accelerated relaxation in AB compared to sham, and less contracture at high pacing frequencies. Parallel enhancement of diastolic Ca2+ handling was observed, with augmented NCX and SERCA2 activity and lowered resting cytosolic [Ca2+].ConclusionIn the hypertrophied heart with preserved systolic function, in vivo diastolic dysfunction develops as cardiac fibrosis and alterations in titin phosphorylation compromise left ventricular compliance, and despite compensatory changes in cardiomyocyte Ca2+ homeostasis.

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“…The degree of fibrosis was quantified using Masson's trichrome‐stained sections from 7 to 11 individual mice per age and genotype. Blinded computerized image analyses were performed by ImmunoPath 1.3.9.0 (Room4, Crowborough, UK) as previously described in detail . In brief, analyses of annotated areas of the whole mouse hearts, PW and septum wall were performed separately.…”

Section: Methodsmentioning

confidence: 99%

Overexpression of integrin α11 induces cardiac fibrosis in mice

et al. 2017

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Computerized image analysis of the Ki‐67 proliferation index in mantle cell lymphoma

Abstract: Computerized image analysis of the Ki-67 index in MCL is an attractive alternative to semiquantitative estimation and can be introduced easily in a routine diagnostic setting for risk stratification in MCL.

Cited by 12 publications

References 27 publications

Ki‐67 and MCM6 labeling indices are correlated with overall survival in anaplastic oligodendroglioma, IDH1‐mutant and 1p/19q‐codeleted: a multicenter study from the French POLA network

Ki‐67 and MCM6 labeling indices are correlated with overall survival in anaplastic oligodendroglioma, IDH1‐mutant and 1p/19q‐codeleted: a multicenter study from the French POLA network

Increased passive stiffness promotes diastolic dysfunction despite improved Ca2+ handling during left ventricular concentric hypertrophy

Overexpression of integrin α11 induces cardiac fibrosis in mice

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