Minimal residual disease in high-risk neuroblastoma shows a dynamic and disease burden-dependent correlation between bone marrow and peripheral blood

Lin, Kyaw San; Uemura, Suguru; Thwin, Khin Kyae Mon; Nakatani, Naoko; Ishida, Toshiaki; Yamamoto, Nobuyuki; Tamura, Akihiro; Saito, Atsuro; Mori, Takeshi; Hasegawa, Daiichiro; Kosaka, Yoshiyuki; Nino, Nanako; Nagano, China; Takafuji, Satoru; Iijima, Kazumoto; Nishimura, Noriyuki

doi:10.1016/j.tranon.2021.101019

Cited by 6 publications

(7 citation statements)

References 45 publications

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“…Several MRD assays quantitating different NB-mRNAs by quantitative PCR (qPCR) or droplet digital PCR (ddPCR) have been shown to possess a significant prognostic value of MRD in BM samples (BM-MRD) for high-risk NB patients [ 14 , 15 , 16 , 17 , 18 ]. Although we and others have shown the significantly correlated MRD levels between BM and PB samples [ 17 , 18 , 19 ], the prognostic significance of MRD in PB and PBSC samples (PB-MRD and PBSC-MRD) is still unclear.…”

Section: Introductionmentioning

confidence: 81%

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Minimal residual disease detected by droplet digital PCR in peripheral blood stem cell grafts has a prognostic impact on high-risk neuroblastoma patients

Nino

Ishida

Nakatani

et al. 2022

Heliyon

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Section: Introductionmentioning

confidence: 81%

“…7NB-mRNAs ddPCR assay was carried out as described previously [ 18 , 19 , 31 ]. Briefly, total RNA was extracted from PBSC samples using a TRIzol Plus RNA purification kit (Life Technologies, Carlsbad, CA).…”

Section: Methodsmentioning

confidence: 99%

Minimal residual disease detected by droplet digital PCR in peripheral blood stem cell grafts has a prognostic impact on high-risk neuroblastoma patients

Nino

Ishida

Nakatani

et al. 2022

Heliyon

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“…These limit the clinical usefulness of these MRD measures as actionable prognostic biomarkers ( 44 , 47 ), and were also demonstrated in our findings. Instead, dysregulated mRNA expression of selected prognostic genes of neuroblastoma CTCs may represent more biologically-relevant markers of MRD ( 3 , 48 ) in the intact CTCs captured via our unbiased label-free system.…”

Section: Discussionmentioning

confidence: 99%

“…Indeed, MRD has also been identified in the bone marrow of children with low stage disease ( 64 ), supporting our proposed view that CTC gene expression may be more critical to overall disease phenotype than absolute cell numbers. Furthermore, significant gene expression changes have also been observed in CTCs and DTCs collected using density gradient methods corresponding to various states of clinical treatment failure and relapse ( 3 , 48 , 65 ), though these isolation approaches have not proven to be very efficient. Thus, the dysregulated genes identified in our study adds to the understanding of the altered gene expression landscape of neuroblastoma CTCs and DTCs.…”

Section: Discussionmentioning

confidence: 99%

Pro-metastatic and mesenchymal gene expression signatures characterize circulating tumor cells of neuroblastoma patients with bone marrow metastases and relapse

et al. 2022

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Existing marker-based methods of minimal residual disease (MRD) determination in neuroblastoma do not effectively enrich for the circulating disease cell population. Given the relative size differential of neuroblastoma tumor cells over normal hematogenous cells, we hypothesized that cell size-based separation could enrich circulating tumor cells (CTCs) from blood samples and disseminated tumor cells (DTCs) from bone marrow aspirates (BMA) of neuroblastoma patients, and that their gene expression profiles could vary dynamically with various disease states over the course of treatment. Using a spiral microfluidic chip, peripheral blood of 17 neuroblastoma patients at 3 serial treatment timepoints (diagnosis, n=17; post-chemotherapy, n=11; and relapse, n=3), and bone marrow samples at diagnosis were enriched for large intact circulating cells. Profiling the resulting enriched samples with immunohistochemistry and mRNA expression of 1490 cancer-related genes via NanoString, 13 of 17 samples contained CTCs displaying cytologic atypia, TH and PHOX2B expression and/or upregulation of cancer-associated genes. Gene signatures reflecting pro-metastatic processes and the neuroblastoma mesenchymal super-enhancer state were consistently upregulated in 7 of 13 samples, 6 of which also had metastatic high-risk disease. Expression of 8 genes associated with PI3K and GCPR signaling were significantly upregulated in CTCs of patients with bone marrow metastases versus patients without. Correspondingly, in patients with marrow metastases, differentially-expressed gene signatures reflected upregulation of immune regulation in bone marrow DTCs versus paired CTCs samples. In patients who later developed disease relapse, 5 genes involved in immune cell regulation, JAK/STAT signaling and the neuroblastoma mesenchymal super-enhancer state (OLFML2B, STAT1, ARHGDIB, STAB1, TLR2) were upregulated in serial CTC samples over their disease course, despite urinary catecholamines and bone marrow aspirates not indicating the disease recurrences. In summary, using a label-free cell size-based separation method, we enriched and characterized intact circulating cells in peripheral blood indicative of neuroblastoma CTCs, as well as their DTC counterparts in the bone marrow. Expression profiles of pro-metastatic genes in CTCs correlated with the presence of bone marrow metastases at diagnosis, while longitudinal profiling identified persistently elevated expression of genes in CTCs that may serve as novel predictive markers of hematogenous MRD in neuroblastoma patients that subsequently relapse.

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“…These blood components were selected because erythropoiesis, leukopoiesis, and thrombopoiesis take place during the last processes of hemopoiesis in the bone marrow environment. The strength of the examined correlations can be evaluated based on the values presented in Table 6 [36]. A correlation is negative when r < 0.…”

Section: Correlation Coefficientsmentioning

confidence: 99%

The Effect of Low Doses of Zearalenone (ZEN) on the Bone Marrow Microenvironment and Haematological Parameters of Blood Plasma in Pre-Pubertal Gilts

Mroz

Gajęcka

Przybyłowicz

et al. 2022

Toxins

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The aim of this study was to determine whether low doses of zearalenone (ZEN) influence the carry-over of ZEN and its metabolites to the bone marrow microenvironment and, consequently, haematological parameters. Pre-pubertal gilts (with a body weight of up to 14.5 kg) were exposed to daily ZEN doses of 5 μg/kg BW (group ZEN5, n = 15), 10 μg/kg BW (group ZEN10, n = 15), 15 μg/kg BW (group ZEN15, n = 15), or were administered a placebo (group C, n = 15) throughout the entire experiment. Bone marrow was sampled on three dates (exposure dates 7, 21, and 42—after slaughter) and blood for haematological analyses was sampled on 10 dates. Significant differences in the analysed haematological parameters (WBC White Blood Cells, MONO—Monocytes, NEUT—Neutrophils, LYMPH—Lymphocytes, LUC—Large Unstained Cells, RBC—Red Blood Cells, HGB—Haemoglobin, HCT—Haematocrit, MCH—Mean Corpuscular Volume, MCHC—Mean Corpuscular Haemoglobin Concentrations, PLT—Platelet Count and MPV—Mean Platelet Volume) were observed between groups. The results of the experiment suggest that exposure to low ZEN doses triggered compensatory and adaptive mechanisms, stimulated the local immune system, promoted eryptosis, intensified mycotoxin biotransformation processes in the liver, and produced negative correlations between mycotoxin concentrations and selected haematological parameters.

show abstract

Minimal residual disease in high-risk neuroblastoma shows a dynamic and disease burden-dependent correlation between bone marrow and peripheral blood

Cited by 6 publications

References 45 publications

Minimal residual disease detected by droplet digital PCR in peripheral blood stem cell grafts has a prognostic impact on high-risk neuroblastoma patients

Minimal residual disease detected by droplet digital PCR in peripheral blood stem cell grafts has a prognostic impact on high-risk neuroblastoma patients

Pro-metastatic and mesenchymal gene expression signatures characterize circulating tumor cells of neuroblastoma patients with bone marrow metastases and relapse

The Effect of Low Doses of Zearalenone (ZEN) on the Bone Marrow Microenvironment and Haematological Parameters of Blood Plasma in Pre-Pubertal Gilts

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