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A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Cancer Pathophysiology".

Deadline for manuscript submissions: closed (31 December 2020) | Viewed by 59866

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Special Issue Editor

Prof. Dr. Pierre A. Robe

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Guest Editor

Department of Neurology and Neurosurgery, University Hospital of Utrecht, Heidelberglaan, 100 3584 Cx Utrecht, The Netherlands
Interests: glioma; signaling pathway; radiation resistance; microenvironment; immune response

Special Issue Information

Dear colleagues,

The last few years have brought much needed knowledge on the biology, therapeutic resistance, and interaction with the immune system of malignant gliomas. However, progress in their treatment is still stagnant, and these primary brain tumors remain incurable. In addition, tumor cells alter the function of the surrounding brain, which greatly contributes to their morbidity and reduces the chances of patients to access treatment. The complex relationship between tumor cells and their environment is thus also a key to reach a cure. This Special Issue will focus on new advances in the pathophysiology of GBM, its relationship with the normal brain cells and the immune system, and novel approaches to tackle treatment resistance and eradicate this deadly brain cancer. We look forward to your contributions.

Prof. Dr. Pierre A. Robe
Guest Editor

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Keywords

glioma
signaling pathway
radiation resistance
microenvironment
immune response

Published Papers (14 papers)

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13 pages, 1194 KiB

Open AccessArticle

Glioblastomas within the Subventricular Zone Are Region-Specific Enriched for Mesenchymal Transition Markers: An Intratumoral Gene Expression Analysis

by Diana J. Z. Dalemans, Sharon Berendsen, Kaspar Draaisma, Pierre A. Robe and Tom J. Snijders

Cancers 2021, 13(15), 3764; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13153764 - 27 Jul 2021

Cited by 6 | Viewed by 1798

Abstract

Background: Involvement of the subventricular zone (SVZ) in glioblastoma is associated with poor prognosis and is associated with specific tumor-biological characteristics. The SVZ microenvironment can influence gene expression in glioblastoma cells in preclinical models. We aimed to investigate whether the SVZ microenvironment has any influence on intratumoral gene expression patterns in glioblastoma patients. Methods: The publicly available Ivy Glioblastoma database contains clinical, radiological and whole exome sequencing data from multiple regions from resected glioblastomas. SVZ involvement of the various tissue samples was evaluated on MRI scans. In tumors that contacted the SVZ, we performed gene expression analyses and gene set enrichment analyses to compare gene (set) expression in tumor regions within the SVZ to tumor regions outside the SVZ. We also compared these samples to glioblastomas that did not contact the SVZ. Results: Within glioblastomas that contacted the SVZ, tissue samples within the SVZ showed enrichment of gene sets involved in (epithelial-)mesenchymal transition, NF-κB and STAT3 signaling, angiogenesis and hypoxia, compared to the samples outside of the SVZ region from the same tumors (p < 0.05, FDR < 0.25). Comparison of glioblastoma samples within the SVZ region to samples from tumors that did not contact the SVZ yielded similar results. In contrast, we observed no differences when comparing the samples outside of the SVZ from SVZ-contacting glioblastomas with samples from glioblastomas that did not contact the SVZ at all. Conclusion: Glioblastoma samples in the SVZ region are enriched for increased (epithelial-)mesenchymal transition and angiogenesis/hypoxia signaling, possibly mediated by the SVZ microenvironment. Full article

(This article belongs to the Special Issue Recent Advances in Glioblastoma)

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14 pages, 3371 KiB

Open AccessArticle

Retrospective Validation of a 168-Gene Expression Signature for Glioma Classification on a Single Molecule Counting Platform

by Paul Minh Huy Tran, Lynn Kim Hoang Tran, Khaled bin Satter, Sharad Purohit, John Nechtman, Diane I. Hopkins, Bruno dos Santos, Roni Bollag, Ravindra Kolhe, Suash Sharma and Jin Xiong She

Cancers 2021, 13(3), 439; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13030439 - 25 Jan 2021

Cited by 3 | Viewed by 2103

Abstract

Gene expression profiling has been shown to be comparable to other molecular methods for glioma classification. We sought to validate a gene-expression based glioma classification method. Formalin-fixed paraffin embedded tissue and flash frozen tissue collected at the Augusta University (AU) Pathology Department between 2000–2019 were identified and 2 mm cores were taken. The RNA was extracted from these cores after deparaffinization and bead homogenization. One hundred sixty-eight genes were evaluated in the RNA samples on the nCounter instrument. Forty-eight gliomas were classified using a supervised learning algorithm trained by using data from The Cancer Genome Atlas. An ensemble of 1000 linear support vector models classified 30 glioma samples into TP1 with classification confidence of 0.99. Glioma patients in TP1 group have a poorer survival (HR (95% CI) = 4.5 (1.3–15.4), p = 0.005) with median survival time of 12.1 months, compared to non-TP1 groups. Network analysis revealed that cell cycle genes play an important role in distinguishing TP1 from non-TP1 cases and that these genes may play an important role in glioma survival. This could be a good clinical pipeline for molecular classification of gliomas. Full article

(This article belongs to the Special Issue Recent Advances in Glioblastoma)

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16 pages, 15207 KiB

Open AccessArticle

Orally Administered 5-aminolevulinic Acid for Isolation and Characterization of Circulating Tumor-Derived Extracellular Vesicles in Glioblastoma Patients

by Sybren L. N. Maas, Thomas S. van Solinge, Rosalie Schnoor, Anudeep Yekula, Joeky T. Senders, Jeroen de Vrij, Pierre Robe, Bob S. Carter, Leonora Balaj, Ger J. A. Arkesteijn, Esther N. M. Nolte-’t Hoen and Marike L. D. Broekman

Cancers 2020, 12(11), 3297; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12113297 - 07 Nov 2020

Cited by 10 | Viewed by 3008

Abstract

Background: In glioblastoma (GB), tissue is required for accurate diagnosis and subtyping. Tissue can be obtained through resection or (stereotactic) biopsy, but these invasive procedures provide risks for patients. Extracellular vesicles (EVs) are small, cell-derived vesicles that contain miRNAs, proteins, and lipids, and possible candidates for liquid biopsies. GB-derived EVs can be found in the blood of patients, but it is difficult to distinguish them from circulating non-tumor EVs. 5-aminolevulinic acid (5-ALA) is orally administered to GB patients to facilitate tumor visualization and maximal resection, as it is metabolized to fluorescent protoporphyrin IX (PpIX) that accumulates in glioma cells. In this study, we assessed whether PpIX accumulates in GB-derived EVs and whether these EVs could be isolated and characterized to enable a liquid biopsy in GB. Methods: EVs were isolated from the conditioned media of U87 cells treated with 5-ALA by differential ultracentrifugation. Blood samples were collected and processed from healthy controls and patients undergoing 5-ALA guided surgery for GB. High-resolution flow cytometry (hFC) enabled detection and sorting of PpIX-positive EVs, which were subsequently analyzed by digital droplet PCR (ddPCR). Results: PpIX-positive EVs could be detected in conditioned cell culture media as well as in patient samples after administration of 5-ALA. By using hFC, we could sort the PpIX-positive EVs for further analysis with ddPCR, which indicated the presence of EVs and GB-associated miRNAs. Conclusion: GB-derived EVs can be isolated from the plasma of GB patients by using 5-ALA induced fluorescence. Although many challenges remain, our findings show new possibilities for the development of blood-based liquid biopsies in GB patients. Full article

(This article belongs to the Special Issue Recent Advances in Glioblastoma)

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21 pages, 4598 KiB

Open AccessArticle

Epigenetic Targeting of Mcl-1 Is Synthetically Lethal with Bcl-xL/Bcl-2 Inhibition in Model Systems of Glioblastoma

by Enyuan Shang, Trang T. T. Nguyen, Chang Shu, Mike-Andrew Westhoff, Georg Karpel-Massler and Markus D. Siegelin

Cancers 2020, 12(8), 2137; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12082137 - 01 Aug 2020

Cited by 18 | Viewed by 3238

Abstract

Apoptotic resistance remains a hallmark of glioblastoma (GBM), the most common primary brain tumor in adults, and a better understanding of this process may result in more efficient treatments. By utilizing chromatin immunoprecipitation with next-generation sequencing (CHIP-seq), we discovered that GBMs harbor a super enhancer around the Mcl-1 locus, a gene that has been known to confer cell death resistance in GBM. We utilized THZ1, a known super-enhancer blocker, and BH3-mimetics, including ABT263, WEHI-539, and ABT199. Combined treatment with BH3-mimetics and THZ1 led to synergistic growth reduction in GBM models. Reduction in cellular viability was accompanied by significant cell death induction with features of apoptosis, including disruption of mitochondrial membrane potential followed by activation of caspases. Mechanistically, THZ1 elicited a profound disruption of the Mcl-1 enhancer region, leading to a sustained suppression of Mcl-1 transcript and protein levels, respectively. Mechanism experiments suggest involvement of Mcl-1 in the cell death elicited by the combination treatment. Finally, the combination treatment of ABT263 and THZ1 resulted in enhanced growth reduction of tumors without induction of detectable toxicity in two patient-derived xenograft models of GBM in vivo. Taken together, these findings suggest that combined epigenetic targeting of Mcl-1 along with Bcl-2/Bcl-xL is potentially therapeutically feasible. Full article

(This article belongs to the Special Issue Recent Advances in Glioblastoma)

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19 pages, 6168 KiB

Open AccessArticle

Ribosomal Protein S27/Metallopanstimulin-1 (RPS27) in Glioma—A New Disease Biomarker?

by Jonas Feldheim, Almuth F. Kessler, Dominik Schmitt, Ellaine Salvador, Camelia M. Monoranu, Julia J. Feldheim, Ralf-Ingo Ernestus, Mario Löhr and Carsten Hagemann

Cancers 2020, 12(5), 1085; https://doi.org/10.3390/cancers12051085 - 27 Apr 2020

Cited by 19 | Viewed by 2884

Abstract

Despite its significant overexpression in several malignant neoplasms, the expression of RPS27 in the central nervous system (CNS) is widely unknown. We identified the cell types expressing RPS27 in the CNS under normal and disease conditions. We acquired specimens of healthy brain (NB), adult pilocytic astrocytoma (PA) World Health Organization (WHO) grade I, anaplastic PA WHO grade III, gliomas WHO grade II/III with or without isocitrate dehydrogenase (IDH) mutation, and glioblastoma multiforme (GBM). RPS27 protein expression was examined by immunohistochemistry and double-fluorescence staining and its mRNA expression quantified by RT-PCR. Patients’ clinical and tumor characteristics were collected retrospectively. RPS27 protein was specifically expressed in tumor cells and neurons, but not in healthy astrocytes. In tumor tissue, most macrophages were positive, while this was rarely the case in inflamed tissue. Compared to NB, RPS27 mRNA was in mean 6.2- and 8.8-fold enhanced in gliomas WHO grade II/III with (p < 0.01) and without IDH mutation (p = 0.01), respectively. GBM displayed a 4.6-fold increased mean expression (p = 0.02). Although RPS27 expression levels did not affect the patients’ survival, their association with tumor cells and tumor-associated macrophages provides a rationale for a future investigation of a potential function during gliomagenesis and tumor immune response. Full article

(This article belongs to the Special Issue Recent Advances in Glioblastoma)

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29 pages, 1155 KiB

Open AccessEditor’s ChoiceArticle

Metformin as Potential Therapy for High-Grade Glioma

by Marek Mazurek, Jakub Litak, Piotr Kamieniak, Bartłomiej Kulesza, Katarzyna Jonak, Jacek Baj and Cezary Grochowski

Cancers 2020, 12(1), 210; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12010210 - 15 Jan 2020

Cited by 52 | Viewed by 8698

Abstract

Metformin (MET), 1,1-dimethylbiguanide hydrochloride, is a biguanide drug used as the first-line medication in the treatment of type 2 diabetes. The recent years have brought many observations showing metformin in its new role. The drug, commonly used in the therapy of diabetes, may also find application in the therapy of a vast variety of tumors. Its effectiveness has been demonstrated in colon, breast, prostate, pancreatic cancer, leukemia, melanoma, lung and endometrial carcinoma, as well as in gliomas. This is especially important in light of the poor options offered to patients in the case of high-grade gliomas, which include glioblastoma (GBM). A thorough understanding of the mechanism of action of metformin can make it possible to discover new drugs that could be used in neoplasm therapy. Full article

(This article belongs to the Special Issue Recent Advances in Glioblastoma)

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15 pages, 4968 KiB

Open AccessArticle

Genetic and Lineage Classification of Glioma-Initiating Cells Identifies a Clinically Relevant Glioblastoma Model

by Norihiko Saito, Nozomi Hirai, Kazuya Aoki, Sho Sato, Ryo Suzuki, Yu Hiramoto, Satoshi Fujita, Haruo Nakayama, Morito Hayashi, Takatoshi Sakurai and Satoshi Iwabuchi

Cancers 2019, 11(10), 1564; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers11101564 - 15 Oct 2019

Cited by 9 | Viewed by 3501

Abstract

The Cancer Genome Atlas (TCGA) project described a robust gene expression-based molecular classification of glioblastoma (GBM), but the functional and biological significance of the subclasses has not been determined. The present comprehensive analysis of 25 glioma-initiating cell (GIC) lines classifies GIC lines into four subtypes (classical, mesenchymal, proneural, and neural) that are closely related to the TCGA GBM subclasses and display distinct lineage characteristics and differentiation behavior that recapitulate neural development. More importantly, the GIC subtypes exhibit distinct biological phenotypes in relation to self-renewal capacity, proliferation, invasiveness, and angiogenic potential in vitro and in vivo. In addition, the GIC subtypes exhibit divergent patterns of signaling pathway activation and deactivation of the Wnt, Notch, and TGF-β pathways. These results will improve drug discovery targeting certain genetic mutation in glioblastoma and improve the development of precision medicine. Full article

(This article belongs to the Special Issue Recent Advances in Glioblastoma)

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Review

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25 pages, 2908 KiB

Open AccessReview

Recent Advances in Glioma Therapy: Combining Vascular Normalization and Immune Checkpoint Blockade

by Rachel L. Y. Ho and Ivy A. W. Ho

Cancers 2021, 13(15), 3686; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13153686 - 22 Jul 2021

Cited by 14 | Viewed by 3553

Abstract

Glioblastoma (GBM) accounts for more than 50% of all primary malignancies of the brain. Current standard treatment regimen for GBM includes maximal surgical resection followed by radiation and adjuvant chemotherapy. However, due to the heterogeneity of the tumor cells, tumor recurrence is often inevitable. The prognosis of patients with glioma is, thus, dismal. Glioma is a highly angiogenic tumor yet immunologically cold. As such, evolving studies have focused on designing strategies that specifically target the tyrosine kinase receptors of angiokines and encourage immune infiltration. Recent promising results from immunotherapies on other cancer types have prompted further investigations of this therapy in GBM. In this article, we reviewed the pathological angiogenesis and immune reactivity in glioma, as well as its target for drug development, and we discussed future directions in glioma therapy. Full article

(This article belongs to the Special Issue Recent Advances in Glioblastoma)

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23 pages, 1607 KiB

Open AccessFeature PaperReview

Long, Noncoding RNA Dysregulation in Glioblastoma

by Patrick A. DeSouza, Xuan Qu, Hao Chen, Bhuvic Patel, Christopher A. Maher and Albert H. Kim

Cancers 2021, 13(7), 1604; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13071604 - 31 Mar 2021

Cited by 18 | Viewed by 3454

Abstract

Transcription occurs across more than 70% of the human genome and more than half of currently annotated genes produce functional noncoding RNAs. Of these transcripts, the majority—long, noncoding RNAs (lncRNAs)—are greater than 200 nucleotides in length and are necessary for various roles in the cell. It is increasingly appreciated that these lncRNAs are relevant in both health and disease states, with the brain expressing the largest number of lncRNAs compared to other organs. Glioblastoma (GBM) is an aggressive, fatal brain tumor that demonstrates remarkable intratumoral heterogeneity, which has made the development of effective therapies challenging. The cooperation between genetic and epigenetic alterations drives rapid adaptation that allows therapeutic evasion and recurrence. Given the large repertoire of lncRNAs in normal brain tissue and the well-described roles of lncRNAs in molecular and cellular processes, these transcripts are important to consider in the context of GBM heterogeneity and treatment resistance. Herein, we review the general mechanisms and biological roles of lncRNAs, with a focus on GBM, as well as RNA-based therapeutics currently in development. Full article

(This article belongs to the Special Issue Recent Advances in Glioblastoma)

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19 pages, 13816 KiB

Open AccessReview

Residual Disease in Glioma Recurrence: A Dangerous Liaison with Senescence

by Diana A. Putavet and Peter L. J. de Keizer

Cancers 2021, 13(7), 1560; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13071560 - 29 Mar 2021

Cited by 14 | Viewed by 3874

Abstract

With a dismally low median survival of less than two years after diagnosis, Glioblastoma (GBM) is the most lethal type of brain cancer. The standard-of-care of surgical resection, followed by DNA-damaging chemo-/radiotherapy, is often non-curative. In part, this is because individual cells close to the resection border remain alive and eventually undergo renewed proliferation. These residual, therapy-resistant cells lead to rapid recurrence, against which no effective treatment exists to date. Thus, new experimental approaches need to be developed against residual disease to prevent GBM survival and recurrence. Cellular senescence is an attractive area for the development of such new approaches. Senescence can occur in healthy cells when they are irreparably damaged. Senescent cells develop a chronic secretory phenotype that is generally considered pro-tumorigenic and pro-migratory. Age is a negative prognostic factor for GBM stage, and, with age, senescence steadily increases. Moreover, chemo-/radiotherapy can provide an additional increase in senescence close to the tumor. In light of this, we will review the importance of senescence in the tumor-supportive brain parenchyma, focusing on the invasion and growth of GBM in residual disease. We will propose a future direction on the application of anti-senescence therapies against recurrent GBM. Full article

(This article belongs to the Special Issue Recent Advances in Glioblastoma)

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37 pages, 1688 KiB

Open AccessReview

Cellular and Molecular Mechanisms Underlying Glioblastoma and Zebrafish Models for the Discovery of New Treatments

by Pedro Reimunde, Alba Pensado-López, Martín Carreira Crende, Vanesa Lombao Iglesias, Laura Sánchez, Marta Torrecilla-Parra, Cristina M. Ramírez, Clément Anfray and Fernando Torres Andón

Cancers 2021, 13(5), 1087; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13051087 - 03 Mar 2021

Cited by 14 | Viewed by 5033

Abstract

Glioblastoma (GBM) is the most common of all brain malignant tumors; it displays a median survival of 14.6 months with current complete standard treatment. High heterogeneity, aggressive and invasive behavior, the impossibility of completing tumor resection, limitations for drug administration and therapeutic resistance to current treatments are the main problems presented by this pathology. In recent years, our knowledge of GBM physiopathology has advanced significantly, generating relevant information on the cellular heterogeneity of GBM tumors, including cancer and immune cells such as macrophages/microglia, genetic, epigenetic and metabolic alterations, comprising changes in miRNA expression. In this scenario, the zebrafish has arisen as a promising animal model to progress further due to its unique characteristics, such as transparency, ease of genetic manipulation, ethical and economic advantages and also conservation of the major brain regions and blood–brain–barrier (BBB) which are similar to a human structure. A few papers described in this review, using genetic and xenotransplantation zebrafish models have been used to study GBM as well as to test the anti-tumoral efficacy of new drugs, their ability to interact with target cells, modulate the tumor microenvironment, cross the BBB and/or their toxicity. Prospective studies following these lines of research may lead to a better diagnosis, prognosis and treatment of patients with GBM. Full article

(This article belongs to the Special Issue Recent Advances in Glioblastoma)

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25 pages, 7530 KiB

Open AccessReview

Tumor Heterogeneity in Glioblastomas: From Light Microscopy to Molecular Pathology

by Aline P. Becker, Blake E. Sells, S. Jaharul Haque and Arnab Chakravarti

Cancers 2021, 13(4), 761; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13040761 - 12 Feb 2021

Cited by 68 | Viewed by 6282

Abstract

One of the main reasons for the aggressive behavior of glioblastoma (GBM) is its intrinsic intra-tumor heterogeneity, characterized by the presence of clonal and subclonal differentiated tumor cell populations, glioma stem cells, and components of the tumor microenvironment, which affect multiple hallmark cellular functions in cancer. “Tumor Heterogeneity” usually encompasses both inter-tumor heterogeneity (population-level differences); and intra-tumor heterogeneity (differences within individual tumors). Tumor heterogeneity may be assessed in a single time point (spatial heterogeneity) or along the clinical evolution of GBM (longitudinal heterogeneity). Molecular methods may detect clonal and subclonal alterations to describe tumor evolution, even when samples from multiple areas are collected in the same time point (spatial-temporal heterogeneity). In GBM, although the inter-tumor mutational landscape is relatively homogeneous, intra-tumor heterogeneity is a striking feature of this tumor. In this review, we will address briefly the inter-tumor heterogeneity of the CNS tumors that yielded the current glioma classification. Next, we will take a deeper dive in the intra-tumor heterogeneity of GBMs, which directly affects prognosis and response to treatment. Our approach aims to follow technological developments, allowing for characterization of intra-tumor heterogeneity, beginning with differences on histomorphology of GBM and ending with molecular alterations observed at single-cell level. Full article

(This article belongs to the Special Issue Recent Advances in Glioblastoma)

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16 pages, 1087 KiB

Open AccessReview

The Current Status of Immune Checkpoint Inhibitors in Neuro-Oncology: A Systematic Review

by Cyrillo G. Brahm, Myra E. van Linde, Roelien H. Enting, Maaike Schuur, René H.J. Otten, Martijn W. Heymans, Henk M.W. Verheul and Annemiek M.E. Walenkamp

Cancers 2020, 12(3), 586; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12030586 - 04 Mar 2020

Cited by 42 | Viewed by 4817

Abstract

The introduction of immune checkpoint inhibitors (ICI), as a novel treatment modality, has transformed the field of oncology with unprecedented successes. However, the efficacy of ICI for patients with glioblastoma or brain metastases (BMs) from any tumor type is under debate. Therefore, we systematically reviewed current literature on the use of ICI in patients with glioblastoma and BMs. Prospective and retrospective studies evaluating the efficacy and survival outcomes of ICI in patients with glioblastoma or BMs, and published between 2006 and November 2019, were considered. A total of 88 studies were identified (n = 8 in glioblastoma and n = 80 in BMs). In glioblastoma, median progression-free (PFS) and overall survival (OS) of all studies were 2.1 and 7.3 months, respectively. In patients with BMs, intracranial responses have been reported in studies with melanoma and non-small-cell lung cancer (NSCLC). The median intracranial and total PFS in these studies were 2.7 and 3.0 months, respectively. The median OS in all studies for patients with brain BMs was 8.0 months. To date, ICI demonstrate limited efficacy in patients with glioblastoma or BMs. Future research should focus on increasing the local and systemic immunological responses in these patients. Full article

(This article belongs to the Special Issue Recent Advances in Glioblastoma)

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Other

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19 pages, 1579 KiB

Open AccessSystematic Review

TERT Promoter Alterations in Glioblastoma: A Systematic Review

by Nathalie Olympios, Vianney Gilard, Florent Marguet, Florian Clatot, Frédéric Di Fiore and Maxime Fontanilles

Cancers 2021, 13(5), 1147; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13051147 - 08 Mar 2021

Cited by 30 | Viewed by 6016

Abstract

Glioblastoma, the most frequent and aggressive primary malignant tumor, often presents with alterations in the telomerase reverse transcriptase promoter. Telomerase is responsible for the maintenance of telomere length to avoid cell death. Telomere lengthening is required for cancer cell survival and has led to the investigation of telomerase activity as a potential mechanism that enables cancer growth. The aim of this systematic review is to provide an overview of the available data concerning TERT alterations and glioblastoma in terms of incidence, physiopathological understanding, and potential therapeutic implications. Full article

(This article belongs to the Special Issue Recent Advances in Glioblastoma)

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