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3 pages, 195 KiB

Open AccessEditorial

Recurrent Glioblastoma: What Is the Route?

by Alberto Bosio and Giuseppe Lombardi

Cancers 2023, 15(7), 2028; https://doi.org/10.3390/cancers15072028 - 29 Mar 2023

Viewed by 986

Abstract

Glioblastoma (GBM) is the most frequent and aggressive malignant primary central nervous system tumor in adults [...] Full article

(This article belongs to the Special Issue Recurrent Glioblastoma)

4 pages, 204 KiB

Open AccessEditorial

A New Landscape for Systemic Pharmacotherapy of Recurrent Glioblastoma?

by Giuseppe Lombardi, Ahmed Idbaih, Emilie Le Rhun, Matthias Preusser, Vittorina Zagonel and Pim French

Cancers 2020, 12(12), 3775; https://doi.org/10.3390/cancers12123775 - 15 Dec 2020

Cited by 10 | Viewed by 1937

Abstract

Glioblastoma is the most common and aggressive primary malignant brain tumor in adult patients [...] Full article

(This article belongs to the Special Issue Recurrent Glioblastoma)

Research

Jump to: Editorial, Review

17 pages, 3021 KiB

Open AccessArticle

Whole Blood Transcriptional Fingerprints of High-Grade Glioma and Longitudinal Tumor Evolution under Carbon Ion Radiotherapy

by Maximilian Knoll, Maria Waltenberger, Jennifer Furkel, Ute Wirkner, Aoife Ward Gahlawat, Ivana Dokic, Christian Schwager, Sebastian Adeberg, Stefan Rieken, Tobias Kessler, Felix Sahm, Laila König, Christel Herold-Mende, Stephanie E. Combs, Jürgen Debus and Amir Abdollahi

Cancers 2022, 14(3), 684; https://doi.org/10.3390/cancers14030684 - 28 Jan 2022

Cited by 3 | Viewed by 2993

Abstract

Purpose: To assess the value of whole blood transcriptome data from liquid biopsy (lbx) in recurrent high-grade glioma (rHGG) patients for longitudinal molecular monitoring of tumor evolution under carbon ion irradiation (CIR). Methods: Whole blood transcriptome (WBT) analysis (Illumina HumanHT-12 Expression BeadChips) was [...] Read more.

Purpose: To assess the value of whole blood transcriptome data from liquid biopsy (lbx) in recurrent high-grade glioma (rHGG) patients for longitudinal molecular monitoring of tumor evolution under carbon ion irradiation (CIR). Methods: Whole blood transcriptome (WBT) analysis (Illumina HumanHT-12 Expression BeadChips) was performed in 14 patients with rHGG pre re-irradiation (reRT) with CIR and 3, 6 and 9 weeks post-CIR (reRT grade III:5, 36%, IV:9, 64%). Patients were irradiated with 30, 33, 36 GyRBE (n = 5, 6, 3) in 3GyRBE per fraction. Results: WTB analysis showed stable correlation with treatment characteristics and patients tumor grade, indicating a preserved tumor origin specific as well as dynamic transcriptional fingerprints of peripheral blood cells. Initial histopathologic tumor grade was indirectly associated with TMEM173 (STING), DNA-repair (ATM, POLD4) and hypoxia related genes. DNA-repair, chromatin remodeling (LIG1, SMARCD1) and immune response (FLT3LG) pathways were affected post-CIR. Longitudinal WTB fingerprints identified two distinct trajectories of rHGG evolution, characterized by differential and prognostic CRISPLD2 expression pre-CIR. Conclusions: Lbx based WTB analysis holds the potential for molecular stratification of rHGG patients and therapy monitoring. We demonstrate the feasibility of the peripheral blood transcriptome as a sentinel organ for identification of patient, tumor characteristics and CIR specific fingerprints in rHGG. Full article

(This article belongs to the Special Issue Recurrent Glioblastoma)

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12 pages, 4773 KiB

Open AccessArticle

Regorafenib in Recurrent Glioblastoma Patients: A Large and Monocentric Real-Life Study

by Giuseppe Lombardi, Mario Caccese, Marta Padovan, Giulia Cerretti, Giovanna Pintacuda, Renzo Manara, Francesca Di Sarra and Vittorina Zagonel

Cancers 2021, 13(18), 4731; https://doi.org/10.3390/cancers13184731 - 21 Sep 2021

Cited by 27 | Viewed by 3936

Abstract

Despite multimodal treatment with surgery and radiochemotherapy, the prognosis of glioblastoma remains poor, and practically all glioblastomas relapse. To date, no standard treatment exists for recurrent glioblastoma patients and traditional therapies have showed limited efficacy. Regorafenib is an oral multi-targeted tyrosine kinase inhibitor [...] Read more.

Despite multimodal treatment with surgery and radiochemotherapy, the prognosis of glioblastoma remains poor, and practically all glioblastomas relapse. To date, no standard treatment exists for recurrent glioblastoma patients and traditional therapies have showed limited efficacy. Regorafenib is an oral multi-targeted tyrosine kinase inhibitor showing encouraging benefits in recurrent GBM patients enrolled in the REGOMA trial. We performed a large study to investigate clinical outcomes and the safety of regorafenib in a real-life population of recurrent glioblastoma patients. Patients receiving regorafenib outside clinical trials at the Veneto Institute of Oncology were retrospectively reviewed. The major inclusion criteria were: histologically confirmed diagnosis of glioblastoma, prior first line therapy according to “Stupp protocol”, Eastern Cooperative Oncology Group (ECOG) performance status score ≤1. According to the original schedule, patients received regorafenib 160 mg once daily for the first 3 weeks of each 4-week cycle. The primary endpoints of the study were overall survival and safety. A total of 54 consecutive patients were enrolled. The median age was 56, MGMT methylated status was found in 28 out of 53 available patients (52.8%), IDH mutation in 5 (9.3%) and 22 patients were receiving steroids at baseline. The median overall survival was 10.2 months (95% CI, 6.4–13.9), the OS-12 was 43%. Age, MGMT methylation status and steroid use at baseline were not statistically significant on a multivariate analysis for OS. Patients reporting a disease control as best response to regorafenib demonstrated a significant longer survival (24.8 months vs. 6.2 months for patients with progressive disease, p = 0.0001). Grade 3 drug-related adverse events occurred in 10 patients (18%); 1 patient (2%) reported a grade 4 adverse event (rash maculo-papular). No death was considered to be drug-related. This study reported the first large “real-life” experience of regorafenib in recurrent glioblastoma. Overall, our results are close to the ones reported in the previous phase 2 study, despite the fact that we had a longer survival. We showed the encouraging activity and tolerability of this treatment in recurrent glioblastoma patients when used as a second-line treatment. Full article

(This article belongs to the Special Issue Recurrent Glioblastoma)

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17 pages, 3732 KiB

Open AccessFeature PaperArticle

Comparing Tumor Cell Invasion and Myeloid Cell Composition in Compatible Primary and Relapsing Glioblastoma

by Dongxu Zhao, Huabin Zhang, Ramazan Uyar, Jubayer A. Hossain, Hrvoje Miletic, Jörg-Christian Tonn, Rainer Glass and Roland E. Kälin

Cancers 2021, 13(14), 3636; https://doi.org/10.3390/cancers13143636 - 20 Jul 2021

Cited by 7 | Viewed by 3392

Abstract

Glioblastoma (GBM) recurrence after treatment is almost inevitable but addressing this issue with adequate preclinical models has remained challenging. Here, we introduce a GBM mouse model allowing non-invasive and scalable de-bulking of a tumor mass located deeply in the brain, which can be [...] Read more.

Glioblastoma (GBM) recurrence after treatment is almost inevitable but addressing this issue with adequate preclinical models has remained challenging. Here, we introduce a GBM mouse model allowing non-invasive and scalable de-bulking of a tumor mass located deeply in the brain, which can be combined with conventional therapeutic approaches. Strong reduction of the GBM volume is achieved after pharmacologically inducing a tumor-specific cell death mechanism. This is followed by GBM re-growth over a predictable timeframe. Pharmacological de-bulking followed by tumor relapse was accomplished with an orthotopic mouse glioma model. Relapsing experimental tumors recapitulated pathological features often observed in recurrent human GBM, like increased invasiveness or altered immune cell composition. Orthotopic implantation of GBM cells originating from biopsies of one patient at initial or follow-up treatment reproduced these findings. Interestingly, relapsing GBM of both models contained a much higher ratio of monocyte-derived macrophages (MDM) versus microglia than primary GBM. This was not altered when combining pharmacological de-bulking with invasive surgery. We interpret that factors released from viable primary GBM cells preferentially attract microglia whereas relapsing tumors preponderantly release chemoattractants for MDM. All in all, this relapse model has the capacity to provide novel insights into clinically highly relevant aspects of GBM treatment. Full article

(This article belongs to the Special Issue Recurrent Glioblastoma)

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16 pages, 3140 KiB

Open AccessArticle

A Phase Ib Clinical Trial of Metformin and Chloroquine in Patients with IDH1-Mutated Solid Tumors

by Mohammed Khurshed, Remco J. Molenaar, Myra E. van Linde, Ron A. Mathôt, Eduard A. Struys, Tom van Wezel, Cornelis J. F. van Noorden, Heinz-Josef Klümpen, Judith V. M. G. Bovée and Johanna W. Wilmink

Cancers 2021, 13(10), 2474; https://doi.org/10.3390/cancers13102474 - 19 May 2021

Cited by 14 | Viewed by 2370

Abstract

Background: Mutations in isocitrate dehydrogenase 1 (IDH1) occur in 60% of chondrosarcoma, 80% of WHO grade II-IV glioma and 20% of intrahepatic cholangiocarcinoma. These solid IDH1-mutated tumors produce the oncometabolite D-2-hydroxyglutarate (D-2HG) and are more vulnerable to [...] Read more.

Background: Mutations in isocitrate dehydrogenase 1 (IDH1) occur in 60% of chondrosarcoma, 80% of WHO grade II-IV glioma and 20% of intrahepatic cholangiocarcinoma. These solid IDH1-mutated tumors produce the oncometabolite D-2-hydroxyglutarate (D-2HG) and are more vulnerable to disruption of their metabolism. Methods: Patients with IDH1-mutated chondrosarcoma, glioma and intrahepatic cholangiocarcinoma received oral combinational treatment with the antidiabetic drug metformin and the antimalarial drug chloroquine. The primary objective was to determine the occurrence of dose-limiting toxicities (DLTs) and the maximum tolerated dose (MTD). Radiological and biochemical tumor responses to metformin and chloroquine were investigated using CT/MRI scans and magnetic resonance spectroscopy (MRS) measurements of D-2HG levels in serum. Results: Seventeen patients received study treatment for a median duration of 43 days (range: 7–74 days). Of twelve evaluable patients, 10 patients discontinued study medication because of progressive disease and two patients due to toxicity. None of the patients experienced a DLT. The MTD was determined to be 1500 mg of metformin two times a day and 200 mg of chloroquine once a day. A serum D/L-2HG ratio of ≥4.5 predicted the presence of an IDH1 mutation with a sensitivity of 90% and a specificity of 100%. By utilization of digital droplet PCR on plasma samples, we were able to detect tumor-specific IDH1 hotspot mutations in circulating tumor DNA (ctDNA) in investigated patients. Conclusion: Treatment of advanced IDH1-mutated solid tumors with metformin and chloroquine was well tolerated but did not induce a clinical response in this phase Ib clinical trial. Full article

(This article belongs to the Special Issue Recurrent Glioblastoma)

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16 pages, 1739 KiB

Open AccessArticle

Interstitial Photodynamic Therapy Using 5-ALA for Malignant Glioma Recurrences

by Stefanie Lietke, Michael Schmutzer, Christoph Schwartz, Jonathan Weller, Sebastian Siller, Maximilian Aumiller, Christian Heckl, Robert Forbrig, Maximilian Niyazi, Rupert Egensperger, Herbert Stepp, Ronald Sroka, Jörg-Christian Tonn, Adrian Rühm and Niklas Thon

Cancers 2021, 13(8), 1767; https://doi.org/10.3390/cancers13081767 - 07 Apr 2021

Cited by 28 | Viewed by 2974

Abstract

Interstitial photodynamic therapy (iPDT) using 5-aminolevulinic acid (5-ALA)-induced protoporphyrin IX (PpIX) as a cytotoxic photosensitizer could be a feasible treatment option for malignant gliomas. In a monocentric cohort of consecutive patients treated between 2006 and 2018, a risk profile analysis of salvage iPDT [...] Read more.

Interstitial photodynamic therapy (iPDT) using 5-aminolevulinic acid (5-ALA)-induced protoporphyrin IX (PpIX) as a cytotoxic photosensitizer could be a feasible treatment option for malignant gliomas. In a monocentric cohort of consecutive patients treated between 2006 and 2018, a risk profile analysis of salvage iPDT for local malignant glioma recurrences and associated outcome measures are presented here. It was considered indicated in patients with circumscribed biopsy-proven malignant glioma recurrences after standard therapy, if not deemed eligible for safe complete resection. A 3D treatment-planning software was used to determine the number and suitable positions of the cylindrical diffusing fibers placed stereotactically to ensure optimal interstitial irradiation of the target volume. Outcome measurements included the risk profile of the procedure, estimated time-to-treatment-failure (TTF), post-recurrence survival (PRS) and prognostic factors. Forty-seven patients were treated, of which 44 (median age, 49.4 years, range, 33.4–87.0 years, 27 males) could be retrospectively evaluated. Recurrent gliomas included 37 glioblastomas (WHO grade IV) and 7 anaplastic astrocytomas (WHO grade III). Thirty (68.2%) tumors were O-6-methylguanine-DNA methyltransferase (MGMT)-methylated, 29 (65.9%)—isocitrate dehydrogenase (IDH)-wildtype. Twenty-six (59.1%) patients were treated for their first, 9 (20.5%)—for their second, 9 (20.5%)—for the third or further recurrence. The median iPDT target volume was 3.34 cm³ (range, 0.50–22.8 cm³). Severe neurologic deterioration lasted for more than six weeks in one patient only. The median TTF was 7.1 (95% confidence interval (CI), 4.4–9.8) months and the median PRS was 13.0 (95% CI, 9.2–16.8) months. The 2- and 5-year PRS rates were 25.0% and 4.5%, respectively. The treatment response was heterogeneous and not significantly associated with patient characteristics, treatment-related factors or molecular markers. The promising outcome and acceptable risk profile deserve further prospective evaluation particularly to identify mechanisms and prognostic factors of favorable treatment response. Full article

(This article belongs to the Special Issue Recurrent Glioblastoma)

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21 pages, 4219 KiB

Open AccessArticle

The Tumor Suppressor MTUS1/ATIP1 Modulates Tumor Promotion in Glioma: Association with Epigenetics and DNA Repair

by Nikhil Ranjan, Vimal Pandey, Manas Kumar Panigrahi, Lukas Klumpp, Ulrike Naumann and Phanithi Prakash Babu

Cancers 2021, 13(6), 1245; https://doi.org/10.3390/cancers13061245 - 12 Mar 2021

Cited by 7 | Viewed by 2477

Abstract

Glioblastoma (GBM) is a highly aggressive brain tumor. Resistance mechanisms in GBM present an array of challenges to understand its biology and to develop novel therapeutic strategies. We investigated the role of a TSG, MTUS1/ATIP1 in glioma. Glioma specimen, cells and low [...] Read more.

Glioblastoma (GBM) is a highly aggressive brain tumor. Resistance mechanisms in GBM present an array of challenges to understand its biology and to develop novel therapeutic strategies. We investigated the role of a TSG, MTUS1/ATIP1 in glioma. Glioma specimen, cells and low passage GBM sphere cultures (GSC) were analyzed for MTUS1/ATIP1 expression at the RNA and protein level. Methylation analyses were done by bisulfite sequencing (BSS). The consequence of chemotherapy and irradiation on ATIP1 expression and the influence of different cellular ATIP1 levels on survival was examined in vitro and in vivo. MTUS1/ATIP1 was downregulated in high-grade glioma (HGG), GSC and GBM cells and hypermethylation at the ATIP1 promoter region seems to be at least partially responsible for this downregulation. ATIP1 overexpression significantly reduced glioma progression by mitigating cell motility, proliferation and facilitate cell death. In glioma-bearing mice, elevated MTUS1/ATIP1 expression prolonged their survival. Chemotherapy, as well as irradiation, recovered ATIP1 expression both in vitro and in vivo. Surprisingly, ATIP1 overexpression increased irradiation-induced DNA-damage repair, resulting in radio-resistance. Our findings indicate that MTUS1/ATIP1 serves as TSG-regulating gliomagenesis, progression and therapy resistance. In HGG, higher MTUS1/ATIP1 expression might interfere with tumor irradiation therapy. Full article

(This article belongs to the Special Issue Recurrent Glioblastoma)

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16 pages, 28149 KiB

Open AccessArticle

Intracellular Autofluorescence as a New Biomarker for Cancer Stem Cells in Glioblastoma

by Joana Vieira de Castro, Céline S. Gonçalves, Eduarda P. Martins, Irene Miranda-Lorenzo, Mariana T. Cerqueira, Adhemar Longatto-Filho, Afonso A. Pinto, Rui L. Reis, Nuno Sousa, Christopher Heeschen and Bruno M. Costa

Cancers 2021, 13(4), 828; https://doi.org/10.3390/cancers13040828 - 16 Feb 2021

Cited by 3 | Viewed by 2798

Abstract

The identification of cancer stem cells (CSCs), which are implicated in tumor initiation, progression, therapy resistance, and relapse, is of great biological and clinical relevance. In glioblastoma (GBM), this is still a challenge, as no single marker is able to universally identify populations [...] Read more.

The identification of cancer stem cells (CSCs), which are implicated in tumor initiation, progression, therapy resistance, and relapse, is of great biological and clinical relevance. In glioblastoma (GBM), this is still a challenge, as no single marker is able to universally identify populations of GBM cancer stem cells (GSCs). Indeed, there is still controversy on whether biomarker-expressing cells fulfill the functional criteria of bona fide GSCs, despite being widely used. Here, we describe a novel subpopulation of autofluorescent (Fluo⁺) cells in GBM that bear all the functional characteristics of GSCs, including higher capacity to grow as neurospheres, long-term self-renewal ability, increased expression of stem cell markers, and enhanced in vivo tumorigenicity. Mechanistically, the autofluorescent phenotype is largely due to the intracellular accumulation of riboflavin, mediated by the ABC transporter ABCG2. In summary, our work identifies an intrinsic cellular autofluorescent phenotype enriched in GBM cells with functional stem cells features that can be used as a novel, simple and reliable biomarker to target these highly malignant tumors, with implications for GBM biological and clinical research. Full article

(This article belongs to the Special Issue Recurrent Glioblastoma)

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17 pages, 3398 KiB

Open AccessArticle

TAK1 Inhibitor Enhances the Therapeutic Treatment for Glioblastoma

by Michela Campolo, Marika Lanza, Giovanna Casili, Irene Paterniti, Alessia Filippone, Maria Caffo, Salvatore M. Cardali, Ivana Puliafito, Cristina Colarossi, Gabriele Raciti, Salvatore Cuzzocrea and Emanuela Esposito

Cancers 2021, 13(1), 41; https://doi.org/10.3390/cancers13010041 - 25 Dec 2020

Cited by 7 | Viewed by 3050

Abstract

Glioblastoma (GBM) is a brain tumor characterized by poor therapeutic response and overall survival. Despite relevant progress in conventional treatments represented by the clinical use of temozolomide (TMZ), a combination of approaches might be a possible future direction for treating GBM. Transforming growth [...] Read more.

Glioblastoma (GBM) is a brain tumor characterized by poor therapeutic response and overall survival. Despite relevant progress in conventional treatments represented by the clinical use of temozolomide (TMZ), a combination of approaches might be a possible future direction for treating GBM. Transforming growth factor-beta-activated kinase-1 (TAK1) is an essential component in genotoxic stresses-induced NF-κB-activation and mitogen-activated protein kinase (MAPK)-pathways; however, the role of TAK1 in GBM-chemoresistance remains unknown. This study aimed to verify, in GBM human cell lines, in an in vivo U87-xenograft model and in TMZ-treated-patients, the effect of TAK1 inhibition on the sensitivity of GBM cells to chemotherapy. In vitro model, using GBM cell lines, showed that 5Z-7-oxozeaenol augmented the cytotoxic effects of TMZ, blocking TMZ-induced NF-κB-activation, reducing DNA-damage and enhancing TMZ-induced apoptosis in GMB cell lines. We showed a reduction in tumor burden as well as tumor volume in the xenograft model following the treatment with 5Z-7-oxozaenol associated with TMZ. Our results showed a significant up-regulation in TAK1, p-p38, p-JNK and NF-κB in glioblastoma TMZ-treated-patients and denoted the role of 5Z-7-oxozeaenol in increasing the sensitivity of GBM cells to chemotherapy, proving to be an effective coadjuvant to current GBM chemotherapeutic regimens, suggesting a new option for therapeutic treatment of GBM. Full article

(This article belongs to the Special Issue Recurrent Glioblastoma)

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27 pages, 6294 KiB

Open AccessArticle

Glioblastoma CUSA Fluid Protein Profiling: A Comparative Investigation of the Core and Peripheral Tumor Zones

by Giuseppe La Rocca, Giorgia Antonia Simboli, Federica Vincenzoni, Diana Valeria Rossetti, Andrea Urbani, Tamara Ius, Giuseppe Maria Della Pepa, Alessandro Olivi, Giovanni Sabatino and Claudia Desiderio

Cancers 2021, 13(1), 30; https://doi.org/10.3390/cancers13010030 - 23 Dec 2020

Cited by 6 | Viewed by 2513

Abstract

The present investigation aimed to characterize the protein profile of cavitating ultrasound aspirator fluid of newly diagnosed and recurrent glioblastoma comparing diverse zones of collection, i.e., tumor core and tumor periphery, with the aid of 5-aminolevulinic acid fluorescence. The samples were pooled and [...] Read more.

The present investigation aimed to characterize the protein profile of cavitating ultrasound aspirator fluid of newly diagnosed and recurrent glioblastoma comparing diverse zones of collection, i.e., tumor core and tumor periphery, with the aid of 5-aminolevulinic acid fluorescence. The samples were pooled and analyzed in triplicate by LC-MS following the shotgun proteomic approach. The identified proteins were then grouped to disclose elements exclusive and common to the tumor state or tumor zones and submitted to gene ontology classification and pathway overrepresentation analysis. The proteins common to the distinct zones were further investigated by relative quantitation, following a label free approach, to disclose possible differences of expression. Nine proteins, i.e., tubulin 2B chain, CD59, far upstream element-binding, CD44, histone H1.4, caldesmon, osteopontin, tropomyosin chain and metallothionein-2, marked the core of newly diagnosed glioblastoma with respect to tumor periphery. Considering the tumor zone, including the core and the fluorescence positive periphery, the serine glycine biosynthesis, pentose phosphate, 5-hydroxytryptamine degredation, de novo purine biosynthesis and huntington disease pathways resulted statistically significantly overrepresented with respect to the human genome of reference. The fluorescence negative zone shared several protein elements with the tumor zone, possibly indicating the presence of pathological aspects of glioblastoma rather than of normal brain parenchyma. On the other hand, its exclusive protein elements were considered to represent the healthy zone and, accordingly, exhibiting no pathways overrepresentation. On the contrary to newly diagnosed glioblastoma, pathway overrepresentation was recognized only in the healthy zone of recurrent glioblastoma. The TGFβ signaling pathway, exclusively classified in the fluorescence negative periphery in newly diagnosed glioblastoma, was instead the exclusive pathway classified in the tumor core of recurrent glioblastoma. These results, preliminary obtained on sample pools, demonstrated the potential of cavitron ultrasonic surgical aspirate fluid for proteomic profiling of glioblastoma able to distinguish molecular features specific of the diverse tumor zones and tumor states, possibly contributing to the understanding of the highly infiltrative capability and recurrent rate of this aggressive brain tumor and opening to potential clinical applications to be further investigated. Full article

(This article belongs to the Special Issue Recurrent Glioblastoma)

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16 pages, 1002 KiB

Open AccessArticle

FET PET Radiomics for Differentiating Pseudoprogression from Early Tumor Progression in Glioma Patients Post-Chemoradiation

by Philipp Lohmann, Mai A. Elahmadawy, Robin Gutsche, Jan-Michael Werner, Elena K. Bauer, Garry Ceccon, Martin Kocher, Christoph W. Lerche, Marion Rapp, Gereon R. Fink, Nadim J. Shah, Karl-Josef Langen and Norbert Galldiks

Cancers 2020, 12(12), 3835; https://doi.org/10.3390/cancers12123835 - 18 Dec 2020

Cited by 59 | Viewed by 4216

Abstract

Currently, a reliable diagnostic test for differentiating pseudoprogression from early tumor progression is lacking. We explored the potential of O-(2-[¹⁸F]fluoroethyl)-L-tyrosine (FET) positron emission tomography (PET) radiomics for this clinically important task. Thirty-four patients (isocitrate dehydrogenase (IDH)-wildtype glioblastoma, 94%) with progressive magnetic [...] Read more.

Currently, a reliable diagnostic test for differentiating pseudoprogression from early tumor progression is lacking. We explored the potential of O-(2-[¹⁸F]fluoroethyl)-L-tyrosine (FET) positron emission tomography (PET) radiomics for this clinically important task. Thirty-four patients (isocitrate dehydrogenase (IDH)-wildtype glioblastoma, 94%) with progressive magnetic resonance imaging (MRI) changes according to the Response Assessment in Neuro-Oncology (RANO) criteria within the first 12 weeks after completing temozolomide chemoradiation underwent a dynamic FET PET scan. Static and dynamic FET PET parameters were calculated. For radiomics analysis, the number of datasets was increased to 102 using data augmentation. After randomly assigning patients to a training and test dataset, 944 features were calculated on unfiltered and filtered images. The number of features for model generation was limited to four to avoid data overfitting. Eighteen patients were diagnosed with early tumor progression, and 16 patients had pseudoprogression. The FET PET radiomics model correctly diagnosed pseudoprogression in all test cohort patients (sensitivity, 100%; negative predictive value, 100%). In contrast, the diagnostic performance of the best FET PET parameter (TBR_max) was lower (sensitivity, 81%; negative predictive value, 80%). The results suggest that FET PET radiomics helps diagnose patients with pseudoprogression with a high diagnostic performance. Given the clinical significance, further studies are warranted. Full article

(This article belongs to the Special Issue Recurrent Glioblastoma)

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18 pages, 4296 KiB

Open AccessArticle

Enhanced Malignant Phenotypes of Glioblastoma Cells Surviving NPe6-Mediated Photodynamic Therapy are Regulated via ERK1/2 Activation

by Tatsuya Kobayashi, Makoto Miyazaki, Nobuyoshi Sasaki, Shun Yamamuro, Eita Uchida, Daisuke Kawauchi, Masamichi Takahashi, Yohei Otsuka, Kosuke Kumagai, Satoru Takeuchi, Terushige Toyooka, Naoki Otani, Kojiro Wada, Yoshitaka Narita, Hideki Yamaguchi, Yoshihiro Muragaki, Takakazu Kawamata, Kentaro Mori, Koichi Ichimura and Arata Tomiyama

Cancers 2020, 12(12), 3641; https://doi.org/10.3390/cancers12123641 - 04 Dec 2020

Cited by 10 | Viewed by 2690

Abstract

To manage refractory and invasive glioblastomas (GBM)s, photodynamic therapy (PDT) using talaporfin sodium (NPe6) (NPe6-PDT) was recently approved in clinical practice. However, the molecular machineries regulating resistance against NPe6-PDT in GBMs and mechanisms underlying the changes in GBM phenotypes following NPe6-PDT remain unknown. [...] Read more.

To manage refractory and invasive glioblastomas (GBM)s, photodynamic therapy (PDT) using talaporfin sodium (NPe6) (NPe6-PDT) was recently approved in clinical practice. However, the molecular machineries regulating resistance against NPe6-PDT in GBMs and mechanisms underlying the changes in GBM phenotypes following NPe6-PDT remain unknown. Herein, we established an in vitro NPe6-mediated PDT model using human GBM cell lines. NPe6-PDT induced GBM cell death in a NPe6 dose-dependent manner. However, this NPe6-PDT-induced GBM cell death was not completely blocked by the pan-caspase inhibitor, suggesting NPe6-PDT induces both caspase-dependent and -independent cell death. Moreover, treatment with poly (ADP-ribose) polymerase inhibitor blocked NPe6-PDT-triggered caspase-independent GBM cell death. Next, it was also revealed resistance to re-NPe6-PDT of GBM cells and GBM stem cells survived following NPe6-PDT (NPe6-PDT-R cells), as well as migration and invasion of NPe6-PDT-R cells were enhanced. Immunoblotting of NPe6-PDT-R cells to assess the behavior of the proteins that are known to be stress-induced revealed that only ERK1/2 activation exhibited the same trend as migration. Importantly, treatment with the MEK1/2 inhibitor trametinib reversed resistance against re-NPe6-PDT and suppressed the enhanced migration and invasion of NPe6-PDT-R cells. Overall, enhanced ERK1/2 activation is suggested as a key regulator of elevated malignant phenotypes of GBM cells surviving NPe6-PDT and is therefore considered as a potential therapeutic target against GBM. Full article

(This article belongs to the Special Issue Recurrent Glioblastoma)

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16 pages, 3258 KiB

Open AccessArticle

Immunohistochemically Characterized Intratumoral Heterogeneity Is a Prognostic Marker in Human Glioblastoma

by Friederike Liesche-Starnecker, Karoline Mayer, Florian Kofler, Sandra Baur, Friederike Schmidt-Graf, Johanna Kempter, Georg Prokop, Nicole Pfarr, Wu Wei, Jens Gempt, Stephanie E. Combs, Claus Zimmer, Bernhard Meyer, Benedikt Wiestler and Jürgen Schlegel

Cancers 2020, 12(10), 2964; https://doi.org/10.3390/cancers12102964 - 13 Oct 2020

Cited by 12 | Viewed by 2331

Abstract

Tumor heterogeneity is considered to be a hallmark of glioblastoma (GBM). Only more recently, it has become apparent that GBM is not only heterogeneous between patients (intertumoral heterogeneity) but more importantly, also within individual patients (intratumoral heterogeneity). In this study, we focused on [...] Read more.

Tumor heterogeneity is considered to be a hallmark of glioblastoma (GBM). Only more recently, it has become apparent that GBM is not only heterogeneous between patients (intertumoral heterogeneity) but more importantly, also within individual patients (intratumoral heterogeneity). In this study, we focused on assessing intratumoral heterogeneity. For this purpose, the heterogeneity of 38 treatment-naïve GBM was characterized by immunohistochemistry. Perceptible areas were rated for ALDH1A3, EGFR, GFAP, Iba1, Olig2, p53, and Mib1. By clustering methods, two distinct groups similar to subtypes described in literature were detected. The classical subtype featured a strong EGFR and Olig2 positivity, whereas the mesenchymal subtype displayed a strong ALDH1A3 expression and a high fraction of Iba1-positive microglia. 18 tumors exhibited both subtypes and were classified as “subtype-heterogeneous”, whereas the areas of the other tumors were all assigned to the same cluster and named “subtype-dominant”. Results of epigenomic analyses corroborated these findings. Strikingly, the subtype-heterogeneous tumors showed a clearly shorter overall survival compared to subtype-dominant tumors. Furthermore, 21 corresponding pairs of primary and recurrent GBM were compared, showing a dominance of the mesenchymal subtype in the recurrent tumors. Our study confirms the prognostic impact of intratumoral heterogeneity in GBM, and more importantly, makes this hallmark assessable by routine diagnostics. Full article

(This article belongs to the Special Issue Recurrent Glioblastoma)

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14 pages, 1935 KiB

Open AccessArticle

Pembrolizumab Activity in Recurrent High-Grade Gliomas with Partial or Complete Loss of Mismatch Repair Protein Expression: A Monocentric, Observational and Prospective Pilot Study

by Giuseppe Lombardi, Valeria Barresi, Stefano Indraccolo, Michele Simbolo, Matteo Fassan, Susanna Mandruzzato, Matteo Simonelli, Mario Caccese, Marco Pizzi, Arianna Fassina, Marta Padovan, Elena Masetto, Marina Paola Gardiman, Maria Giuseppina Bonavina, Maria Caffo, Pasquale Persico, Franco Chioffi, Luca Denaro, Angelo Paolo Dei Tos, Aldo Scarpa and Vittorina Zagonel Show full author list Hide full author list

Cancers 2020, 12(8), 2283; https://doi.org/10.3390/cancers12082283 - 14 Aug 2020

Cited by 41 | Viewed by 4254

Abstract

Introduction: Pembrolizumab demonstrated promising results in hypermutated tumors of diverse origin. Immunohistochemical loss of mismatch repair (MMR) proteins has been suggested as a surrogate of hypermutation in high-grade gliomas (HGG). We evaluated the efficacy and safety of pembrolizumab in relapsing HGGs with immunohistochemical [...] Read more.

Introduction: Pembrolizumab demonstrated promising results in hypermutated tumors of diverse origin. Immunohistochemical loss of mismatch repair (MMR) proteins has been suggested as a surrogate of hypermutation in high-grade gliomas (HGG). We evaluated the efficacy and safety of pembrolizumab in relapsing HGGs with immunohistochemical loss of at least 1 MMR protein. Molecular biomarkers of pembrolizumab activity were also analyzed. Methods: Consecutive patients with recurrent HGG and partial or complete loss of MMR protein expression were prospectively enrolled; they received pembrolizumab 200 mg once every 3 weeks until disease progression. The primary endpoint was disease control rate (DCR). Post hoc exploratory analyses included next-generation sequencing to assess tumor mutational burden (TMB), and immunostaining for CD8+ T-cells and CD68+ macrophages. Results: Among 310 HGG patients screened, 13 cases with MMR loss were enrolled: eight glioblastoma, four anaplastic astrocytoma, and one anaplastic oligodendroglioma. Median age was 43 years. DCR was 31%: four patients had stable disease and no patient had complete or partial response. TMB ranged between 6.8 and 23.4 mutations/megabase. Neither TMB nor gene mutations, nor CD8+ T-cell and CD68+ macrophage content, were associated with pembrolizumab activity. Conclusions: pembrolizumab showed no apparent benefit in these patients. No molecular biomarker was found to be associated with pembrolizumab activity. Full article

(This article belongs to the Special Issue Recurrent Glioblastoma)

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16 pages, 4451 KiB

Open AccessArticle

TP5, a Peptide Inhibitor of Aberrant and Hyperactive CDK5/p25: A Novel Therapeutic Approach against Glioblastoma

by Emeline Tabouret, Herui Wang, Niranjana Amin, Jinkyu Jung, Romain Appay, Jing Cui, Qi Song, Antonio Cardone, Deric M. Park, Mark R. Gilbert, Harish Pant and Zhengping Zhuang

Cancers 2020, 12(7), 1935; https://doi.org/10.3390/cancers12071935 - 17 Jul 2020

Cited by 8 | Viewed by 3590

Abstract

We examined the efficacy of selective inhibition of cyclin-dependent kinase 5 (CDK5) in glioblastoma by TP5. We analyzed its impact in vitro on CDK5 expression and activity, cell survival, apoptosis and cell cycle. DNA damage was analyzed using the expression of γH2A.X and [...] Read more.

We examined the efficacy of selective inhibition of cyclin-dependent kinase 5 (CDK5) in glioblastoma by TP5. We analyzed its impact in vitro on CDK5 expression and activity, cell survival, apoptosis and cell cycle. DNA damage was analyzed using the expression of γH2A.X and phosphorylated ATM. Its tolerance and efficacy were assessed on in vivo xenograft mouse models. We showed that TP5 decreased the activity but not the expression of CDK5 and p35. TP5 alone impaired cell viability and colony formation of glioblastoma cell lines and induced apoptosis. TP5 increased DNA damage by inhibiting the phosphorylation of ATM, leading to G1 arrest. Whereas CDK5 activity is increased by DNA-damaging agents such as temozolomide and irradiation, TP5 was synergistic with either temozolomide or irradiation due to an accumulation of DNA damage. Concomitant use of TP5 and either temozolomide or irradiation reduced the phosphorylation of ATM, increased DNA damage, and inhibited the G2/M arrest induced by temozolomide or irradiation. TP5 alone suppressed the tumor growth of orthotopic glioblastoma mouse model. The treatment was well tolerated. Finally, alone or in association with irradiation or temozolomide, TP5 prolonged mouse survival. TP5 alone or in association with temozolomide and radiotherapy is a promising therapeutic option for glioblastoma. Full article

(This article belongs to the Special Issue Recurrent Glioblastoma)

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Graphical abstract

18 pages, 2101 KiB

Open AccessArticle

Cognitive Functions in Repeated Glioma Surgery

by Gabriele Capo, Miran Skrap, Ilaria Guarracino, Miriam Isola, Claudio Battistella, Tamara Ius and Barbara Tomasino

Cancers 2020, 12(5), 1077; https://doi.org/10.3390/cancers12051077 - 26 Apr 2020

Cited by 14 | Viewed by 2356

Abstract

Low-grade gliomas (LGG) are slow-growing brain tumors infiltrating the central nervous system which tend to recur, often with malignant degeneration after primary treatment. Re-operations are not always recommended due to an assumed higher risk of neurological and cognitive deficits. However, this assumption is [...] Read more.

Low-grade gliomas (LGG) are slow-growing brain tumors infiltrating the central nervous system which tend to recur, often with malignant degeneration after primary treatment. Re-operations are not always recommended due to an assumed higher risk of neurological and cognitive deficits. However, this assumption is relatively ungrounded due to a lack of extensive neuropsychological testing. We retrospectively examined a series of 40 patients with recurrent glioma in eloquent areas of the left hemisphere, who all completed comprehensive pre- (T3) and post-surgical (T4) neuropsychological assessments after a second surgery (4-month follow up). The lesions were most frequent in the left insular cortex and the inferior frontal gyrus. Among this series, in 17 patients the cognitive outcomes were compared before the first surgery (T1), 4 months after the first surgery (T2), and at T3 and T4. There was no significant difference either in the number of patients scoring within the normal range between T3 and T4, or in their level of performance. Further addressing the T1–T4 evolution, there was no significant difference in the number of patients scoring within the normal range. As to their level of performance, the only significant change was in phonological fluency. This longitudinal follow-up study showed that repeated glioma surgery is possible without major damage to cognitive functions in the short-term period (4 months) after surgery. Full article

(This article belongs to the Special Issue Recurrent Glioblastoma)

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Review

Jump to: Editorial, Research

15 pages, 5502 KiB

Open AccessReview

Deciphering the Labyrinthine System of the Immune Microenvironment in Recurrent Glioblastoma: Recent Original Advances and Lessons from Clinical Immunotherapeutic Approaches

by Elena Anghileri, Monica Patanè, Natalia Di Ianni, Irene Sambruni, Martina Maffezzini, Micaela Milani, Luisa Maddaloni, Bianca Pollo, Marica Eoli and Serena Pellegatta

Cancers 2021, 13(24), 6156; https://doi.org/10.3390/cancers13246156 - 07 Dec 2021

Cited by 8 | Viewed by 2588

Abstract

The interpretation of the presence and function of immune infiltration in glioblastoma (GBM) is still debated. Over the years, GBM has been considered a cold tumor that is less infiltrated by effector cells and characterized by a high proportion of immunosuppressive innate immune [...] Read more.

The interpretation of the presence and function of immune infiltration in glioblastoma (GBM) is still debated. Over the years, GBM has been considered a cold tumor that is less infiltrated by effector cells and characterized by a high proportion of immunosuppressive innate immune cells, including GBM-associated microglia/macrophages (GAMs). In this context, the failure of checkpoint inhibitors, particularly in recurrent GBM (rGBM), caused us to look beyond the clinical results and consider the point of view of immune cells. The tumor microenvironment in rGBM can be particularly hostile, even when exposed to standard immunomodulatory therapies, and tumor-infiltrating lymphocytes (TILs), when present, are either dysfunctional or terminally exhausted. However, after checkpoint blockade therapy, it was possible to observe specific recruitment of adaptive immune cells and an efficient systemic immune response. In this review article, we attempt to address current knowledge regarding the tumor and immune microenvironment in rGBM. Furthermore, immunosuppression induced by GAMs and TIL dysfunction was revisited to account for genetic defects that can determine resistance to therapies and manipulate the immune microenvironment upon recurrence. Accordingly, we reevaluated the microenvironment of some of our rGBM patients treated with dendritic cell immunotherapy, with the goal of identifying predictive immune indicators of better treatment response. Full article

(This article belongs to the Special Issue Recurrent Glioblastoma)

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16 pages, 2062 KiB

Open AccessReview

Glioblastoma and MiRNAs

by Swalih P. Ahmed, Javier S. Castresana and Mehdi H. Shahi

Cancers 2021, 13(7), 1581; https://doi.org/10.3390/cancers13071581 - 30 Mar 2021

Cited by 24 | Viewed by 3412

Abstract

Glioblastoma (GB) is one of the most common types of lethal brain tumors. Although several treatment options are available including surgery, along with adjuvant chemo and radiotherapy, the disease has a poor prognosis and patients generally die within 14 months of diagnosis. GB [...] Read more.

Glioblastoma (GB) is one of the most common types of lethal brain tumors. Although several treatment options are available including surgery, along with adjuvant chemo and radiotherapy, the disease has a poor prognosis and patients generally die within 14 months of diagnosis. GB is chemo and radio resistant. Thus, there is a critical need for new insights into GB treatment to increase the chance of therapeutic success. This is why microRNA (miRNA) is being potentially considered in the diagnosis and treatment of glioblastoma. The objective of our review is to provide a holistic picture of GB up-regulated and down-regulated miRNA, in relationship with the expression of other genes, cell signaling pathways, and their role in GB diagnosis and treatment. MiRNA treatment is being considered to be used against GB together with radiotherapy and chemotherapy. Moreover, the use of miRNA as a diagnostic tool has also begun. Knowing that miRNAs are isolated in almost all human body fluids and that there are more than 3000 miRNAs in the human genome, plus the fact that each miRNA controls hundreds of different mRNAs, there is still much study needed to explore how miRNAs relate to GB for its proliferation, progression, and inhibition. Full article

(This article belongs to the Special Issue Recurrent Glioblastoma)

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22 pages, 5104 KiB

Open AccessReview

The Role of Network Science in Glioblastoma

by Marta B. Lopes, Eduarda P. Martins, Susana Vinga and Bruno M. Costa

Cancers 2021, 13(5), 1045; https://doi.org/10.3390/cancers13051045 - 02 Mar 2021

Cited by 6 | Viewed by 2800

Abstract

Network science has long been recognized as a well-established discipline across many biological domains. In the particular case of cancer genomics, network discovery is challenged by the multitude of available high-dimensional heterogeneous views of data. Glioblastoma (GBM) is an example of such a [...] Read more.

Network science has long been recognized as a well-established discipline across many biological domains. In the particular case of cancer genomics, network discovery is challenged by the multitude of available high-dimensional heterogeneous views of data. Glioblastoma (GBM) is an example of such a complex and heterogeneous disease that can be tackled by network science. Identifying the architecture of molecular GBM networks is essential to understanding the information flow and better informing drug development and pre-clinical studies. Here, we review network-based strategies that have been used in the study of GBM, along with the available software implementations for reproducibility and further testing on newly coming datasets. Promising results have been obtained from both bulk and single-cell GBM data, placing network discovery at the forefront of developing a molecularly-informed-based personalized medicine. Full article

(This article belongs to the Special Issue Recurrent Glioblastoma)

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29 pages, 466 KiB

Open AccessFeature PaperReview

Recurrent Glioblastoma: From Molecular Landscape to New Treatment Perspectives

by Cristina Birzu, Pim French, Mario Caccese, Giulia Cerretti, Ahmed Idbaih, Vittorina Zagonel and Giuseppe Lombardi

Cancers 2021, 13(1), 47; https://doi.org/10.3390/cancers13010047 - 26 Dec 2020

Cited by 100 | Viewed by 7683

Abstract

Glioblastoma is the most frequent and aggressive form among malignant central nervous system primary tumors in adults. Standard treatment for newly diagnosed glioblastoma consists in maximal safe resection, if feasible, followed by radiochemotherapy and adjuvant chemotherapy with temozolomide; despite this multimodal treatment, virtually [...] Read more.

Glioblastoma is the most frequent and aggressive form among malignant central nervous system primary tumors in adults. Standard treatment for newly diagnosed glioblastoma consists in maximal safe resection, if feasible, followed by radiochemotherapy and adjuvant chemotherapy with temozolomide; despite this multimodal treatment, virtually all glioblastomas relapse. Once tumors progress after first-line therapy, treatment options are limited and management of recurrent glioblastoma remains challenging. Loco-regional therapy with re-surgery or re-irradiation may be evaluated in selected cases, while traditional systemic therapy with nitrosoureas and temozolomide rechallenge showed limited efficacy. In recent years, new clinical trials using, for example, regorafenib or a combination of tyrosine kinase inhibitors and immunotherapy were performed with promising results. In particular, molecular targeted therapy could show efficacy in selected patients with specific gene mutations. Nonetheless, some molecular characteristics and genetic alterations could change during tumor progression, thus affecting the efficacy of precision medicine. We therefore reviewed the molecular and genomic landscape of recurrent glioblastoma, the strategy for clinical management and the major phase I-III clinical trials analyzing recent drugs and combination regimens in these patients. Full article

(This article belongs to the Special Issue Recurrent Glioblastoma)

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