Cancers

2024

Jump to: 2023, 2022, 2021, 2020

12 pages, 3307 KiB

Open AccessArticle

Predicting Isocitrate Dehydrogenase Status in Non-Contrast-Enhanced Adult-Type Astrocytic Tumors Using Diffusion Tensor Imaging and ¹¹C-Methionine, ¹¹C-Choline, and ¹⁸F-Fluorodeoxyglucose PET

by Shoji Yasuda, Hirohito Yano, Yuka Ikegame, Soko Ikuta, Takashi Maruyama, Morio Kumagai, Yoshihiro Muragaki, Toru Iwama, Jun Shinoda and Tsuyoshi Izumo

Cancers 2024, 16(8), 1543; https://doi.org/10.3390/cancers16081543 - 18 Apr 2024

Viewed by 994

Abstract

We aimed to differentiate the isocitrate dehydrogenase (IDH) status among non-enhanced astrocytic tumors using preoperative MRI and PET. We analyzed 82 patients with non-contrast-enhanced, diffuse, supratentorial astrocytic tumors (IDH mutant [IDH-mut], 55 patients; IDH-wildtype [IDH-wt], 27 patients) who underwent MRI and PET between [...] Read more.

We aimed to differentiate the isocitrate dehydrogenase (IDH) status among non-enhanced astrocytic tumors using preoperative MRI and PET. We analyzed 82 patients with non-contrast-enhanced, diffuse, supratentorial astrocytic tumors (IDH mutant [IDH-mut], 55 patients; IDH-wildtype [IDH-wt], 27 patients) who underwent MRI and PET between May 2012 and December 2022. We calculated the fractional anisotropy (FA) and mean diffusivity (MD) values using diffusion tensor imaging. We evaluated the tumor/normal brain uptake (T/N) ratios using ¹¹C-methionine, ¹¹C-choline, and ¹⁸F-fluorodeoxyglucose PET; extracted the parameters with significant differences in distinguishing the IDH status; and verified their diagnostic accuracy. Patients with astrocytomas were significantly younger than those with glioblastomas. The following MRI findings were significant predictors of IDH-wt instead of IDH-mut: thalamus invasion, contralateral cerebral hemisphere invasion, location adjacent to the ventricular walls, higher FA value, and lower MD value. The T/N ratio for all tracers was significantly higher for IDH-wt than for IDH-mut. In a composite diagnosis based on nine parameters, including age, 84.4% of cases with 0–4 points were of IDH-mut; conversely, 100% of cases with 6–9 points were of IDH-wt. Composite diagnosis using all parameters, including MRI and PET findings with significant differences, may help guide treatment decisions for early-stage gliomas. Full article

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2023

Jump to: 2024, 2022, 2021, 2020

19 pages, 13288 KiB

Open AccessArticle

Comprehensive Brain Tumour Characterisation with VERDICT-MRI: Evaluation of Cellular and Vascular Measures Validated by Histology

by Matteo Figini, Antonella Castellano, Michele Bailo, Marcella Callea, Marcello Cadioli, Samira Bouyagoub, Marco Palombo, Valentina Pieri, Pietro Mortini, Andrea Falini, Daniel C. Alexander, Mara Cercignani and Eleftheria Panagiotaki

Cancers 2023, 15(9), 2490; https://doi.org/10.3390/cancers15092490 - 27 Apr 2023

Cited by 3 | Viewed by 2509

Abstract

The aim of this work was to extend the VERDICT-MRI framework for modelling brain tumours, enabling comprehensive characterisation of both intra- and peritumoural areas with a particular focus on cellular and vascular features. Diffusion MRI data were acquired with multiple b-values (ranging from [...] Read more.

The aim of this work was to extend the VERDICT-MRI framework for modelling brain tumours, enabling comprehensive characterisation of both intra- and peritumoural areas with a particular focus on cellular and vascular features. Diffusion MRI data were acquired with multiple b-values (ranging from 50 to 3500 s/mm²), diffusion times, and echo times in 21 patients with brain tumours of different types and with a wide range of cellular and vascular features. We fitted a selection of diffusion models that resulted from the combination of different types of intracellular, extracellular, and vascular compartments to the signal. We compared the models using criteria for parsimony while aiming at good characterisation of all of the key histological brain tumour components. Finally, we evaluated the parameters of the best-performing model in the differentiation of tumour histotypes, using ADC (Apparent Diffusion Coefficient) as a clinical standard reference, and compared them to histopathology and relevant perfusion MRI metrics. The best-performing model for VERDICT in brain tumours was a three-compartment model accounting for anisotropically hindered and isotropically restricted diffusion and isotropic pseudo-diffusion. VERDICT metrics were compatible with the histological appearance of low-grade gliomas and metastases and reflected differences found by histopathology between multiple biopsy samples within tumours. The comparison between histotypes showed that both the intracellular and vascular fractions tended to be higher in tumours with high cellularity (glioblastoma and metastasis), and quantitative analysis showed a trend toward higher values of the intracellular fraction (fic) within the tumour core with increasing glioma grade. We also observed a trend towards a higher free water fraction in vasogenic oedemas around metastases compared to infiltrative oedemas around glioblastomas and WHO 3 gliomas as well as the periphery of low-grade gliomas. In conclusion, we developed and evaluated a multi-compartment diffusion MRI model for brain tumours based on the VERDICT framework, which showed agreement between non-invasive microstructural estimates and histology and encouraging trends for the differentiation of tumour types and sub-regions. Full article

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2022

Jump to: 2024, 2023, 2021, 2020

23 pages, 1729 KiB

Open AccessReview

Innovating Strategies and Tailored Approaches in Neuro-Oncology

by Alberto Picca, David Guyon, Orazio Santo Santonocito, Capucine Baldini, Ahmed Idbaih, Alexandre Carpentier, Antonio Giuseppe Naccarato, Mario Caccese, Giuseppe Lombardi and Anna Luisa Di Stefano

Cancers 2022, 14(5), 1124; https://doi.org/10.3390/cancers14051124 - 22 Feb 2022

Cited by 7 | Viewed by 3227

Abstract

Diffuse gliomas, the most frequent and aggressive primary central nervous system neoplasms, currently lack effective curative treatments, particularly for cases lacking the favorable prognostic marker IDH mutation. Nonetheless, advances in molecular biology allowed to identify several druggable alterations in a subset of IDH [...] Read more.

Diffuse gliomas, the most frequent and aggressive primary central nervous system neoplasms, currently lack effective curative treatments, particularly for cases lacking the favorable prognostic marker IDH mutation. Nonetheless, advances in molecular biology allowed to identify several druggable alterations in a subset of IDH wild-type gliomas, such as NTRK and FGFR-TACC fusions, and BRAF hotspot mutations. Multi-tyrosine kinase inhibitors, such as regorafenib, also showed efficacy in the setting of recurrent glioblastoma. IDH inhibitors are currently in the advanced phase of clinical evaluation for patients with IDH-mutant gliomas. Several immunotherapeutic approaches, such as tumor vaccines or checkpoint inhibitors, failed to improve patients’ outcomes. Even so, they may be still beneficial in a subset of them. New methods, such as using pulsed ultrasound to disrupt the blood–brain barrier, gene therapy, and oncolytic virotherapy, are well tolerated and may be included in the therapeutic armamentarium soon. Full article

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25 pages, 1728 KiB

Open AccessReview

Sociocognitive Functioning and Psychosocial Burden in Patients with Brain Tumors

by Milena Pertz, Uwe Schlegel and Patrizia Thoma

Cancers 2022, 14(3), 767; https://doi.org/10.3390/cancers14030767 - 1 Feb 2022

Cited by 12 | Viewed by 3168

Abstract

Brain tumors may represent devastating diseases and neuro-oncological research in the past solely focused on development of better treatments to achieve disease control. The efficacy of tumor-directed treatment was evaluated by progression-free and overall survival. However, as neuro-oncological treatment became more effective, preservation [...] Read more.

Brain tumors may represent devastating diseases and neuro-oncological research in the past solely focused on development of better treatments to achieve disease control. The efficacy of tumor-directed treatment was evaluated by progression-free and overall survival. However, as neuro-oncological treatment became more effective, preservation and improvement of quality of life (QoL) was noticed to represent an important additional outcome measure. The need to balance between aggressive tumor-directed treatment and preservation of QoL was increasingly acknowledged in brain tumor patients. QoL is comprised by many determinants; one of those may have been rather neglected so far: social cognition. Since diagnosis and treatment of brain tumors represent demanding life situations, patients may experience increased psychosocial burden and the negative consequences of illness on well-being may be buffered by intact social relationships. These skills to build and maintain supportive social relationships essentially depend on the ability to empathize with others and to recognize and appropriately address social conflicts, i.e., “sociocognitive functioning”. Therefore, sociocognitive functions may influence QoL and treatment outcome. In this article, we review the literature on psychosocial burden and sociocognitive functioning in adult brain tumor patients. Full article

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16 pages, 931 KiB

Open AccessReview

Effect of 5-Aminolevulinic Acid and Sodium Fluorescein on the Extent of Resection in High-Grade Gliomas and Brain Metastasis

by Lasse Cramer Ahrens, Mathias Green Krabbenhøft, Rasmus Würgler Hansen, Nikola Mikic, Christian Bonde Pedersen, Frantz Rom Poulsen and Anders Rosendal Korshoej

Cancers 2022, 14(3), 617; https://doi.org/10.3390/cancers14030617 - 26 Jan 2022

Cited by 28 | Viewed by 3792

Abstract

Surgery is essential in the treatment of high-grade gliomas (HGG) and gross total resection (GTR) is known to increase the overall survival and progression-free survival. Several studies have shown that fluorescence-guided surgery with 5-aminolevulinic acid (5-ALA) increases GTR considerably compared to white light [...] Read more.

Surgery is essential in the treatment of high-grade gliomas (HGG) and gross total resection (GTR) is known to increase the overall survival and progression-free survival. Several studies have shown that fluorescence-guided surgery with 5-aminolevulinic acid (5-ALA) increases GTR considerably compared to white light surgery (65% vs. 36%). In recent years, sodium fluorescein (SF) has become an increasingly popular agent for fluorescence-guided surgery due to numerous utility benefits compared to 5-ALA, including lower cost, non-toxicity, easy administration during surgery and a wide indication range covering all contrast-enhancing lesions with disruption of the blood–brain barrier in the CNS. However, currently, SF is an off-label agent and the level of evidence for use in HGG surgery is inferior compared to 5-ALA. Here, we give an update and review the latest literature on fluorescence-guided surgery with 5-ALA and SF for brain tumors with emphasis on fluorescence-guided surgery in HGG and brain metastases. Further, we assess the advantages and disadvantages of both fluorophores and discuss their future perspectives. Full article

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20 pages, 4654 KiB

Open AccessEditor’s ChoiceArticle

Metabolomic Phenotyping of Gliomas: What Can We Get with Simplified Protocol for Intact Tissue Analysis?

by Paulina Zofia Goryńska, Kamila Chmara, Bogumiła Kupcewicz, Krzysztof Goryński, Karol Jaroch, Dariusz Paczkowski, Jacek Furtak, Marek Harat and Barbara Bojko

Cancers 2022, 14(2), 312; https://doi.org/10.3390/cancers14020312 - 9 Jan 2022

Cited by 10 | Viewed by 2795

Abstract

Glioblastoma multiforme is one of the most malignant neoplasms among humans in their third and fourth decades of life, which is evidenced by short patient survival times and rapid tumor-cell proliferation after radiation and chemotherapy. At present, the diagnosis of gliomas and decisions [...] Read more.

Glioblastoma multiforme is one of the most malignant neoplasms among humans in their third and fourth decades of life, which is evidenced by short patient survival times and rapid tumor-cell proliferation after radiation and chemotherapy. At present, the diagnosis of gliomas and decisions related to therapeutic strategies are based on genetic testing and histological analysis of the tumor, with molecular biomarkers still being sought to complement the diagnostic panel. This work aims to enable the metabolomic characterization of cancer tissue and the discovery of potential biomarkers via high-resolution mass spectrometry coupled to liquid chromatography and a solvent-free sampling protocol that uses a microprobe to extract metabolites directly from intact tumors. The metabolomic analyses were performed independently from genetic and histological testing and at a later time. Despite the small cohort analyzed in this study, the results indicated that the proposed method is able to identify metabolites associated with different malignancy grades of glioma, as well as IDH and 1p19q codeletion mutations. A comparison of the constellation of identified metabolites and the results of standard tests indicated the validity of using the characterization of one comprehensive tumor phenotype as a reflection of all diagnostically meaningful information. Due to its simplicity, the proposed analytical approach was verified as being compatible with a surgical environment and applicable for large-scale studies. Full article

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2021

Jump to: 2024, 2023, 2022, 2020

9 pages, 2108 KiB

Open AccessArticle

Accumulation of Temozolomide-Induced Apoptosis, Senescence and DNA Damage by Metronomic Dose Schedule: A Proof-of-Principle Study with Glioblastoma Cells

by Lea Beltzig, Björn Stratenwerth and Bernd Kaina

Cancers 2021, 13(24), 6287; https://doi.org/10.3390/cancers13246287 - 14 Dec 2021

Cited by 11 | Viewed by 2811

Abstract

Temozolomide (TMZ), a first-line drug in glioma therapy, targets the tumor DNA at various sites. One of the DNA alkylation products is O⁶-methylguanine (O⁶MeG), which is, in the low dose range of TMZ, responsible for nearly all genotoxic [...] Read more.

Temozolomide (TMZ), a first-line drug in glioma therapy, targets the tumor DNA at various sites. One of the DNA alkylation products is O⁶-methylguanine (O⁶MeG), which is, in the low dose range of TMZ, responsible for nearly all genotoxic and cytotoxic effects relevant for cancer therapy. There is, however, a dispute regarding whether the TMZ concentration in the tumor tissue in patients is sufficient to elicit a significant cytotoxic or cytostatic response. Although treatment with TMZ occurs repeatedly with daily doses (metronomic dose schedule) and in view of the short half-life of the drug it is unclear whether doses are accumulating. Here, we addressed the question whether repeated low doses elicit similar effects in glioblastoma cells than a high cumulative dose. We show that repeated treatments with a low dose of TMZ (5 × 5 µM) caused an accumulation of cytotoxicity through apoptosis, cytostasis through cellular senescence, and DNA double-strand breaks, which was similar to the responses induced by a single cumulative dose of 25 µM TMZ. This finding, together with the previously reported linear dose–response curves, support the notion that TMZ is able to trigger a significant cytotoxic and cytostatic effect in vivo if the low-dose metronomic schedule is applied. Full article

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13 pages, 3305 KiB

Open AccessArticle

Sustained Accumulation of Blood-Derived Macrophages in the Immune Microenvironment of Patients with Recurrent Glioblastoma after Therapy

by Sara Magri, Beatrice Musca, Camilla Bonaudo, Ada Tushe, Maria Giovanna Russo, Elena Masetto, Vittorina Zagonel, Giuseppe Lombardi, Alessandro Della Puppa and Susanna Mandruzzato

Cancers 2021, 13(24), 6178; https://doi.org/10.3390/cancers13246178 - 7 Dec 2021

Cited by 14 | Viewed by 3903

Abstract

The cell composition of the glioblastoma (GBM) microenvironment depends on the recruitment of myeloid cells from the blood, promoting tumor progression by inducing immunosuppression. This phenomenon hampers immunotherapies and investigating its complexity may help to tailor new treatments. Peripheral blood and tissue specimens [...] Read more.

The cell composition of the glioblastoma (GBM) microenvironment depends on the recruitment of myeloid cells from the blood, promoting tumor progression by inducing immunosuppression. This phenomenon hampers immunotherapies and investigating its complexity may help to tailor new treatments. Peripheral blood and tissue specimens from the central and marginal tumor areas were collected from 44 primary and 19 recurrent GBM patients. Myeloid and lymphoid cell subsets and the levels of immunosuppressive markers were defined by multiparametric flow cytometry. Multiplexed immunohistochemistry was used to confirm the differences in the immune infiltrate and to analyze the cell spatial distribution. Relapsing GBM showed an increased presence of blood-derived macrophages in both tumor areas and a higher frequency of infiltrating lymphocytes, with a high level of exhaustion markers. The expansion of some myeloid-derived suppressor cell (MDSC) subsets in the blood was found in both primary and recurrent GBM patients. A significant inverse correlation between infiltrating T cells and an MDSC subset was also found. In patients with recurrent GBM after standard first-line therapy, the immune-hostile tumor microenvironment and the levels of some MDSC subsets in the blood persisted. Analysis of the immune landscape in GBM relapses aids in the definition of more appropriate stratification and treatment. Full article

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16 pages, 1431 KiB

Open AccessReview

An Overview of Intracranial Ependymomas in Adults

by Giuseppe Lombardi, Alessandro Della Puppa, Marco Pizzi, Giulia Cerretti, Camilla Bonaudo, Marina Paola Gardiman, Angelo Dipasquale, Fabiana Gregucci, Alice Esposito, Debora De Bartolo, Vittorina Zagonel, Matteo Simonelli, Alba Fiorentino and Francois Ducray

Cancers 2021, 13(23), 6128; https://doi.org/10.3390/cancers13236128 - 5 Dec 2021

Cited by 6 | Viewed by 4432

Abstract

Ependymomas are rare primary central nervous system tumors. They can form anywhere along the neuraxis, but in adults, these tumors predominantly occur in the spine and less frequently intracranially. Ependymal tumors represent a heterogenous group of gliomas, and the WHO 2016 classification is [...] Read more.

Ependymomas are rare primary central nervous system tumors. They can form anywhere along the neuraxis, but in adults, these tumors predominantly occur in the spine and less frequently intracranially. Ependymal tumors represent a heterogenous group of gliomas, and the WHO 2016 classification is based essentially on a grading system, with ependymomas classified as grade I, II (classic), or III (anaplastic). In adults, surgery is the primary initial treatment, while radiotherapy is employed as an adjuvant treatment in some cases of grade II and in all cases of anaplastic ependymoma; chemotherapy is reserved for recurrent cases. In recent years, important and interesting advances in the molecular characterization of ependymomas have been made, allowing for the identification of nine molecular subgroups of ependymal tumors and moving toward subgroup-specific patients with improved risk stratification for treatment-decisions and future prospective trials. New targeted agents or immunotherapies for ependymoma patients are being explored for recurrent disease. This review summarizes recent molecular advances in the diagnosis and treatment of intracranial ependymomas including surgery, radiation therapy and systemic therapies. Full article

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20 pages, 1338 KiB

Open AccessReview

The Emerging Role of Non-Coding RNAs in Pituitary Gland Tumors and Meningioma

by Soudeh Ghafouri-Fard, Atefe Abak, Bashdar Mahmud Hussen, Mohammad Taheri and Guive Sharifi

Cancers 2021, 13(23), 5987; https://doi.org/10.3390/cancers13235987 - 28 Nov 2021

Cited by 21 | Viewed by 3108

Abstract

Long non-coding RNAs (lncRNAs), microRNAs (miRNAs), and circular RNAs (circRNAs) are non-coding transcripts which are involved in the pathogenesis of pituitary gland tumors. LncRNAs that participate in the pathogenesis of pituitary gland tumors mainly serve as sponges for miRNAs. CLRN1-AS1/miR-217, XIST/miR-424-5p, H19/miR-93a, LINC00473/miR-502-3p, [...] Read more.

Long non-coding RNAs (lncRNAs), microRNAs (miRNAs), and circular RNAs (circRNAs) are non-coding transcripts which are involved in the pathogenesis of pituitary gland tumors. LncRNAs that participate in the pathogenesis of pituitary gland tumors mainly serve as sponges for miRNAs. CLRN1-AS1/miR-217, XIST/miR-424-5p, H19/miR-93a, LINC00473/miR-502-3p, SNHG7/miR-449a, MEG8/miR-454-3p, MEG3/miR-23b-3p, MEG3/miR-376B-3P, SNHG6/miR-944, PCAT6/miR-139-3p, lncRNA-m433s1/miR-433, TUG1/miR-187-3p, SNHG1/miR-187-3p, SNHG1/miR-302, SNHG1/miR-372, SNHG1/miR-373, and SNHG1/miR-520 are identified lncRNA/miRNA pairs that are involved in this process. Hsa_circ_0001368 and circOMA1 are two examples of circRNAs that contribute to the pathogenesis of pituitary gland tumors. Meanwhile, SNHG1, LINC00702, LINC00460, and MEG3 have been found to partake in the pathogenesis of meningioma. In the current review, we describe the role of non-coding RNAs in two types of brain tumors, i.e., pituitary tumors and meningioma. Full article

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15 pages, 1702 KiB

Open AccessArticle

Predicting Short-Term Survival after Gross Total or Near Total Resection in Glioblastomas by Machine Learning-Based Radiomic Analysis of Preoperative MRI

by Santiago Cepeda, Angel Pérez-Nuñez, Sergio García-García, Daniel García-Pérez, Ignacio Arrese, Luis Jiménez-Roldán, Manuel García-Galindo, Pedro González, María Velasco-Casares, Tomas Zamora and Rosario Sarabia

Cancers 2021, 13(20), 5047; https://doi.org/10.3390/cancers13205047 - 9 Oct 2021

Cited by 14 | Viewed by 2978

Abstract

Radiomics, in combination with artificial intelligence, has emerged as a powerful tool for the development of predictive models in neuro-oncology. Our study aims to find an answer to a clinically relevant question: is there a radiomic profile that can identify glioblastoma (GBM) patients [...] Read more.

Radiomics, in combination with artificial intelligence, has emerged as a powerful tool for the development of predictive models in neuro-oncology. Our study aims to find an answer to a clinically relevant question: is there a radiomic profile that can identify glioblastoma (GBM) patients with short-term survival after complete tumor resection? A retrospective study of GBM patients who underwent surgery was conducted in two institutions between January 2019 and January 2020, along with cases from public databases. Cases with gross total or near total tumor resection were included. Preoperative structural multiparametric magnetic resonance imaging (mpMRI) sequences were pre-processed, and a total of 15,720 radiomic features were extracted. After feature reduction, machine learning-based classifiers were used to predict early mortality (<6 months). Additionally, a survival analysis was performed using the random survival forest (RSF) algorithm. A total of 203 patients were enrolled in this study. In the classification task, the naive Bayes classifier obtained the best results in the test data set, with an area under the curve (AUC) of 0.769 and classification accuracy of 80%. The RSF model allowed the stratification of patients into low- and high-risk groups. In the test data set, this model obtained values of C-Index = 0.61, IBS = 0.123 and integrated AUC at six months of 0.761. In this study, we developed a reliable predictive model of short-term survival in GBM by applying open-source and user-friendly computational means. These new tools will assist clinicians in adapting our therapeutic approach considering individual patient characteristics. Full article

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11 pages, 1225 KiB

Open AccessArticle

Serum Exosomal microRNA-21, 222 and 124-3p as Noninvasive Predictive Biomarkers in Newly Diagnosed High-Grade Gliomas: A Prospective Study

by Debora Olioso, Mario Caccese, Alessandra Santangelo, Giuseppe Lippi, Vittorina Zagonel, Giulio Cabrini, Giuseppe Lombardi and Maria Cristina Dechecchi

Cancers 2021, 13(12), 3006; https://doi.org/10.3390/cancers13123006 - 15 Jun 2021

Cited by 30 | Viewed by 2848

Abstract

Background: High-grade gliomas (HGG) are malignant brain tumors associated with frequent recurrent disease. Clinical management of HGG patients is currently devoid of blood biomarkers for early diagnosis, monitoring therapeutic effects and predicting recurrence. Different circulating miRNAs, both free and associated with exosomes, are [...] Read more.

Background: High-grade gliomas (HGG) are malignant brain tumors associated with frequent recurrent disease. Clinical management of HGG patients is currently devoid of blood biomarkers for early diagnosis, monitoring therapeutic effects and predicting recurrence. Different circulating miRNAs, both free and associated with exosomes, are described in patients with HGG. We previously identified miR-21, miR-222 and miR-124-3p purified from serum exosomes as molecular signature to help pre-operative clinical diagnosis and grading of gliomas. The aim of the present study was to verify this signature as a tool to assess the effect of treatment and for the early identification of progression in newly diagnosed HGG patients. Material and Methods: Major inclusion criteria were newly diagnosed, histologically confirmed HGG patients, no prior chemotherapy, ECOG PS 0-2 and patients scheduled for radiochemotherapy with temozolomide as first-line treatment after surgery. RANO criteria were used for response assessment. Serum was collected at baseline and subsequently at each neuroradiological assessment. mir-21, -222 and -124-3p expression in serum exosomes was measured in all samples. Results: A total number of 57 patients were enrolled; 41 were male, 52 with glioblastoma and 5 with anaplastic astrocytoma; 18 received radical surgery. HGG patients with higher exosomal miRNA expression displayed a statistically significant lower progression-free survival and overall survival. Increased expression of miR-21, -222 and -124-3p during post-operative follow-up was associated with HGG progression. Conclusions: These data indicate that miR-21, -222 and -124-3p in serum exosomes may be useful molecular biomarkers for complementing clinical evaluation of early tumor progression during post-surgical therapy in patients with HGG. Full article

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10 pages, 432 KiB

Open AccessArticle

Depatuxizumab Mafodotin (Depatux-M) Plus Temozolomide in Recurrent Glioblastoma Patients: Real-World Experience from a Multicenter Study of Italian Association of Neuro-Oncology (AINO)

by Marta Padovan, Marica Eoli, Alessia Pellerino, Simona Rizzato, Claudia Caserta, Matteo Simonelli, Maria Michiara, Mario Caccese, Elena Anghileri, Giulia Cerretti, Roberta Rudà, Vittorina Zagonel and Giuseppe Lombardi

Cancers 2021, 13(11), 2773; https://doi.org/10.3390/cancers13112773 - 3 Jun 2021

Cited by 19 | Viewed by 3807

Abstract

Background: Depatuxizumab Mafodotin (Depatux-M; ABT-414) is an antibody-drug conjugate consisting of a specific antibody against activated EGFR and a cytotoxic agent with antimicrotubule activity. The INTELLANCE 2/EORTC 1410 phase 2 trial produced interesting results for the combination regimen of Depatux-M and temozolomide in [...] Read more.

Background: Depatuxizumab Mafodotin (Depatux-M; ABT-414) is an antibody-drug conjugate consisting of a specific antibody against activated EGFR and a cytotoxic agent with antimicrotubule activity. The INTELLANCE 2/EORTC 1410 phase 2 trial produced interesting results for the combination regimen of Depatux-M and temozolomide in EGFR-amplified glioblastoma patients at first recurrence. For the first time worldwide, our work investigated the clinical outcome and safety of this combination in a real-life population. Materials and Methods: Patients were enrolled from seven AINO (Italian Association of Neuro-Oncology) Institutions. The major inclusion criteria were: histologically confirmed diagnosis of glioblastoma, EGFR-amplified, one or more prior systemic therapies and ECOG PS ≤ 2. According to the original schedule, patients received Depatux-M 1.25 mg/kg every 2 weeks combined with temozolomide. The primary endpoints of the study were overall survival and safety. Results: A total of 36 patients were enrolled. The median age was 57 years, ECOG PS was 0–1 in 28 patients (88%), MGMT methylated status was found in 22 (64%), 15 patients (42%) received the combined treatment as second-line therapy. The median OS was 8.04 months (95% CI, 5.3–10.7), the 12 month-OS was 37%. On univariate and multivariate analyses, the MGMT methylation status was the only factor resulting significantly associated with survival. Grade 3 ocular toxicity occurred in 11% of patients; no grade 4 ocular toxicity was reported. No death was considered to be drug-related. Conclusions: The study reported the first “real world” experience of Depatux-M plus temozolomide in recurrent glioblastoma patients. Encouraging clinical benefits were demonstrated, even though most patients were treated beyond second-line therapy. Overall, the results are close to those reported in the previous phase 2 trial. Toxicity was moderate and manageable. Full article

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16 pages, 2727 KiB

Open AccessArticle

Inhibition of DNA Repair in Combination with Temozolomide or Dianhydrogalactiol Overcomes Temozolomide-Resistant Glioma Cells

by Shigeo Ohba, Kei Yamashiro and Yuichi Hirose

Cancers 2021, 13(11), 2570; https://doi.org/10.3390/cancers13112570 - 24 May 2021

Cited by 15 | Viewed by 2955

Abstract

Resistance to temozolomide and intratumoral heterogeneity contribute to the poor prognosis of glioma. The mechanisms of temozolomide resistance can vary within a heterogeneous tumor. Temozolomide adds a methyl group to DNA. The primary cytotoxic lesion, O6-methylguanine, mispairs with thymine, leading to a futile [...] Read more.

Resistance to temozolomide and intratumoral heterogeneity contribute to the poor prognosis of glioma. The mechanisms of temozolomide resistance can vary within a heterogeneous tumor. Temozolomide adds a methyl group to DNA. The primary cytotoxic lesion, O6-methylguanine, mispairs with thymine, leading to a futile DNA mismatch repair cycle, formation of double-strand breaks, and eventual cell death when O6-methylguanine DNA methyltransferase (MGMT) is absent. N7-methylguanine and N3-methyladenine are repaired by base excision repair (BER). The study aim was to elucidate temozolomide resistance mechanisms and identify methods to overcome temozolomide resistance in glioma. Several temozolomide-resistant clones were analyzed. Increased homologous recombination and mismatch repair system deficiencies contributed to temozolomide resistance. Inhibition of homologous recombination resensitized resistant cells with high homologous recombination efficiency. For the mismatch repair-deficient cells, inhibition of BER by PARP inhibitor potentiated temozolomide-induced cytotoxicity. Dianhydrogalactiol is a bifunctional DNA-targeting agent that forms N7-alkylguanine and inter-strand DNA crosslinks. Dianhydrogalactiol reduced the proliferation of cells independent of MGMT and mismatch repair, inducing DNA double-strand breaks and apoptosis in temozolomide-resistant cells. Further, inhibition of chk1 or homologous recombination enhanced dianhydrogalactiol-induced cytotoxicity in the cells. Selecting treatments most appropriate to the types of resistance mechanisms can potentially improve the prognosis of glioma. Full article

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17 pages, 2276 KiB

Open AccessArticle

Lesion-Function Analysis from Multimodal Imaging and Normative Brain Atlases for Prediction of Cognitive Deficits in Glioma Patients

by Martin Kocher, Christiane Jockwitz, Philipp Lohmann, Gabriele Stoffels, Christian Filss, Felix M. Mottaghy, Maximilian I. Ruge, Carolin Weiss Lucas, Roland Goldbrunner, Nadim J. Shah, Gereon R. Fink, Norbert Galldiks, Karl-Josef Langen and Svenja Caspers

Cancers 2021, 13(10), 2373; https://doi.org/10.3390/cancers13102373 - 14 May 2021

Cited by 7 | Viewed by 3340

Abstract

Cognitive deficits are common in glioma patients following multimodality therapy, but the relative impact of different types and locations of treatment-related brain damage and recurrent tumors on cognition is not well understood. In 121 WHO Grade III/IV glioma patients, structural MRI, O-(2-[18F]fluoroethyl)- [...] Read more.

Cognitive deficits are common in glioma patients following multimodality therapy, but the relative impact of different types and locations of treatment-related brain damage and recurrent tumors on cognition is not well understood. In 121 WHO Grade III/IV glioma patients, structural MRI, O-(2-[18F]fluoroethyl)-L-tyrosine FET-PET, and neuropsychological testing were performed at a median interval of 14 months (range, 1–214 months) after therapy initiation. Resection cavities, T1-enhancing lesions, T2/FLAIR hyperintensities, and FET-PET positive tumor sites were semi-automatically segmented and elastically registered to a normative, resting state (RS) fMRI-based functional cortical network atlas and to the JHU atlas of white matter (WM) tracts, and their influence on cognitive test scores relative to a cohort of matched healthy subjects was assessed. T2/FLAIR hyperintensities presumably caused by radiation therapy covered more extensive brain areas than the other lesion types and significantly impaired cognitive performance in many domains when affecting left-hemispheric RS-nodes and WM-tracts as opposed to brain tissue damage caused by resection or recurrent tumors. Verbal episodic memory proved to be especially vulnerable to T2/FLAIR abnormalities affecting the nodes and tracts of the left temporal lobe. In order to improve radiotherapy planning, publicly available brain atlases, in conjunction with elastic registration techniques, should be used, similar to neuronavigation in neurosurgery. Full article

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16 pages, 12906 KiB

Open AccessArticle

Pre-Surgery Cognitive Performance and Voxel-Based Lesion-Symptom Mapping in Patients with Left High-Grade Glioma

by Ilaria Guarracino, Tamara Ius, Cinzia Baiano, Serena D’Agostini, Miran Skrap and Barbara Tomasino

Cancers 2021, 13(6), 1467; https://doi.org/10.3390/cancers13061467 - 23 Mar 2021

Cited by 5 | Viewed by 2372

Abstract

(1) Background: The literature on the effects of high-grade glioma (HGG) growth on cognition is still scarce. (2) Method: A consecutive series of 85 patients with HGG involving the left hemisphere underwent an extended neuropsychological evaluation prior to surgery. Voxel-based lesion-symptom mapping (VLSM) [...] Read more.

(1) Background: The literature on the effects of high-grade glioma (HGG) growth on cognition is still scarce. (2) Method: A consecutive series of 85 patients with HGG involving the left hemisphere underwent an extended neuropsychological evaluation prior to surgery. Voxel-based lesion-symptom mapping (VLSM) was used to identify regions related to cognitive performance. (3) Results: The patients’ mean level of pre-surgery accuracy was overall high. They showed the greatest difficulties in language with tasks such as naming (42.1% of patients impaired on nouns and 61.4% on verbs), reading (36.3% on words and 32.7% on pseudo-words), auditory lexical decisions (43.9%) and writing (41.3%) being most frequently impaired. VLSM analysis revealed anatomically separated areas along the temporal cortex and the white matter related to impairments on the different tasks, with voxels commonly shared by all tasks restricted to a small region in the ventral superior and middle temporal gyrus. (4) Conclusions: High-grade glioma affects cognition; nonetheless, lesions do not cause diffuse deficits but selectively impact the different language sub-domains along the ventral stream and the dorsal stream for language processing. Full article

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16 pages, 6730 KiB

Open AccessArticle

Quality of Life in Brain Tumor Patients and Their Relatives Heavily Depends on Social Support Factors during the COVID-19 Pandemic

by Fabian M. Troschel, Franziska Ahndorf, Lisa-Marie Wille, Ralf Brandt, Johanna Jost, Sylvia Rekowski, Hans Theodor Eich, Walter Stummer, Rainer Wiewrodt, Kathleen Jetschke and Dorothee Wiewrodt

Cancers 2021, 13(6), 1276; https://doi.org/10.3390/cancers13061276 - 13 Mar 2021

Cited by 18 | Viewed by 3860

Abstract

The COVID-19 pandemic is associated with significant morbidity, mortality, and restrictions on everyday life worldwide. This may be especially challenging for brain tumor patients given increased vulnerability due to their pre-existing condition. Here, we aimed to investigate the quality of life (QoL) in [...] Read more.

The COVID-19 pandemic is associated with significant morbidity, mortality, and restrictions on everyday life worldwide. This may be especially challenging for brain tumor patients given increased vulnerability due to their pre-existing condition. Here, we aimed to investigate the quality of life (QoL) in brain tumor patients and relatives in this setting. Over twelve weeks during the first wave of the pandemic (04–07/2020), brain tumor patients and their families from two large German tertiary care centers were asked to complete weekly questionnaires for anxiety, depression, distress, and well-being. Information regarding social support and living conditions was also collected. One hundred participants (63 patients, 37 relatives) completed 729 questionnaires over the course of the study. Compared to relatives, patients showed more depressive symptoms (p < 0.001) and reduced well-being (p = 0.013). While acceptance of lockdown measures decreased over time, QoL remained stable. QoL measures between patients and their families were weakly or moderately correlated. The number of social contacts was strongly associated with QoL. Age, living conditions, ongoing therapy, employment, and physical activity were other predictors. QoL is correlated between patients and their families and heavily depends on social support factors, indicating the need to focus on the entire family and their social situation for QoL interventions during the pandemic. Full article

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13 pages, 1364 KiB

Open AccessArticle

The Frontal Aslant Tract and Supplementary Motor Area Syndrome: Moving towards a Connectomic Initiation Axis

by Robert G. Briggs, Parker G. Allan, Anujan Poologaindran, Nicholas B. Dadario, Isabella M. Young, Syed A. Ahsan, Charles Teo and Michael E. Sughrue

Cancers 2021, 13(5), 1116; https://doi.org/10.3390/cancers13051116 - 5 Mar 2021

Cited by 39 | Viewed by 4826

Abstract

Connectomics is the use of big data to map the brain’s neural infrastructure; employing such technology to improve surgical planning may improve neuro-oncological outcomes. Supplementary motor area (SMA) syndrome is a well-known complication of medial frontal lobe surgery. The ‘localizationist’ view posits that [...] Read more.

Connectomics is the use of big data to map the brain’s neural infrastructure; employing such technology to improve surgical planning may improve neuro-oncological outcomes. Supplementary motor area (SMA) syndrome is a well-known complication of medial frontal lobe surgery. The ‘localizationist’ view posits that damage to the posteromedial bank of the superior frontal gyrus (SFG) is the basis of SMA syndrome. However, surgical experience within the frontal lobe suggests that this is not entirely true. In a study on n = 45 patients undergoing frontal lobe glioma surgery, we sought to determine if a ‘connectomic’ or network-based approach can decrease the likelihood of SMA syndrome. The control group (n = 23) underwent surgery avoiding the posterior bank of the SFG while the treatment group (n = 22) underwent mapping of the SMA network and Frontal Aslant Tract (FAT) using network analysis and DTI tractography. Patient outcomes were assessed post operatively and in subsequent follow-ups. Fewer patients (8.3%) in the treatment group experienced transient SMA syndrome compared to the control group (47%) (p = 0.003). There was no statistically significant difference found between the occurrence of permanent SMA syndrome between control and treatment groups. We demonstrate how utilizing tractography and a network-based approach decreases the likelihood of transient SMA syndrome during medial frontal glioma surgery. We found that not transecting the FAT and the SMA system improved outcomes which may be important for functional outcomes and patient quality of life. Full article

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2020

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15 pages, 667 KiB

Open AccessReview

The Diagnostic and Therapeutic Role of Leptin and Its Receptor ObR in Glioblastoma Multiforme

by Thomas M. Kinfe, Andreas Stadlbauer, Yavor Bozhkov, Natalia Kremenevski, Sebastian Brandner, Michael Buchfelder and Shafqat R. Chaudhry

Cancers 2020, 12(12), 3691; https://doi.org/10.3390/cancers12123691 - 9 Dec 2020

Cited by 9 | Viewed by 3248

Abstract

Leptin has been recognized as a potential tumor growth promoter in various cancers including cranial tumor pathologies such as pituitary adenomas, meningiomas and gliomas. Despite recent advances in adjunctive therapy and the established surgical resection, chemo- and radiotherapy regimen, glioblastoma multiforme remains a [...] Read more.

Leptin has been recognized as a potential tumor growth promoter in various cancers including cranial tumor pathologies such as pituitary adenomas, meningiomas and gliomas. Despite recent advances in adjunctive therapy and the established surgical resection, chemo- and radiotherapy regimen, glioblastoma multiforme remains a particular diagnostic and therapeutic challenge among the intracranial tumor pathologies, with a poor long-term prognosis. Systemic inflammation and immune-metabolic signaling through diverse pathways are thought to impact the genesis and recurrence of brain tumors, and glioblastoma multiforme in particular. Among the various circulating mediators, leptin has gained especial diagnostic and therapeutic interest, although the precise relationship between leptin and glioblastoma biology remains largely unknown. In this narrative review (MEDLINE/OVID, SCOPUS, PubMed and manual searches of the bibliographies of known primary and review articles), we discuss the current literature using the following search terms: leptin, glioblastoma multiforme, carcinogenesis, immunometabolism, biomarkers, metformin, antidiabetic medication and metabolic disorders. An increasing body of experimental evidence implicates a relationship between the development and maintenance of gliomas (and brain tumors in general) with a dysregulated central and peripheral immune-metabolic network mediated by circulating adipokines, chemokines and cellular components, and in particular the leptin adipokine. In this review, we summarize the current evidence of the role of leptin in glioblastoma pathophysiology. In addition, we describe the status of alternative diagnostic tools and adjunctive therapeutics targeting leptin, leptin-receptors, antidiabetic drugs and associated pathways. Further experimental and clinical trials are needed to elucidate the mechanism of action and the value of immune-metabolism molecular phenotyping (central and peripheral) in order to develop novel adjunctive diagnostics and therapeutics for newly diagnosed and recurrent glioblastoma patients. Full article

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