2024

Jump to: 2023, 2022

13 pages, 1162 KiB

Open AccessArticle

Exploring Genetic Determinants: A Comprehensive Analysis of Serpin B Family SNPs and Prognosis in Glioblastoma Multiforme Patients

by Sohaib M. Al-Khatib, Ayah N. Al-Bzour, Mohammad N. Al-Majali, Laila M. Sa’d, Joud A. Alramadneh, Nour R. Othman, Abdel-Hameed Al-Mistarehi and Safwan Alomari

Cancers 2024, 16(6), 1112; https://doi.org/10.3390/cancers16061112 - 10 Mar 2024

Viewed by 737

Abstract

Serpins are serine proteinase inhibitors, with several serpins being overexpressed in cancer cells. Thus, we aim to analyze the single-nucleotide polymorphism (SNP) of Serpinb11 and its association with GBM survival. A cohort of 63 GBM patients recruited from King Abdullah University Hospital in [...] Read more.

Serpins are serine proteinase inhibitors, with several serpins being overexpressed in cancer cells. Thus, we aim to analyze the single-nucleotide polymorphism (SNP) of Serpinb11 and its association with GBM survival. A cohort of 63 GBM patients recruited from King Abdullah University Hospital in Jordan underwent polymorphism analysis and overall survival (OS) assessments. The Cancer Genome Atlas (GBM) cohort was useful for validation. We constructed a risk score using the principal component analysis for the following Serpin genes: Serpinb3, Serpinb5, Serpinb6, Serpinb11, and Serpinb12, and patients were grouped into high- vs. low-risk groups based on the median cutoff. Univariable Cox models were used to study the survival outcomes. We identified a significant association between rs4940595 and survival. In the TCGA cohort, Serpinb3 alterations showed worse OS. Univariable Cox showed worse PFS outcomes with higher SERPINB5 and SERPINB6 expression. A Serpin B 5-gene risk score showed a trend towards worse PFS in the high-risk group. Upregulated DEGs showed GO enrichment in cytokine regulation and production, positive regulation of leukocyte activation, and the MAPK cascade. The high-risk group showed a significantly higher infiltration of M2 macrophages and activated mast cells. Our findings showed a significant role of the Serpin B family in GBM survival in the Jordanian population. Full article

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19 pages, 5601 KiB

Open AccessArticle

Identification of Hypoxia Prognostic Signature in Glioblastoma Multiforme Based on Bulk and Single-Cell RNA-Seq

by Yaman B. Ahmed, Obada E. Ababneh, Anas A. Al-Khalili, Abdullah Serhan, Zaid Hatamleh, Owais Ghammaz, Mohammad Alkhaldi and Safwan Alomari

Cancers 2024, 16(3), 633; https://doi.org/10.3390/cancers16030633 - 01 Feb 2024

Viewed by 1201

Abstract

Glioblastoma (GBM) represents a profoundly aggressive and heterogeneous brain neoplasm linked to a bleak prognosis. Hypoxia, a common feature in GBM, has been linked to tumor progression and therapy resistance. In this study, we aimed to identify hypoxia-related differentially expressed genes (DEGs) and [...] Read more.

Glioblastoma (GBM) represents a profoundly aggressive and heterogeneous brain neoplasm linked to a bleak prognosis. Hypoxia, a common feature in GBM, has been linked to tumor progression and therapy resistance. In this study, we aimed to identify hypoxia-related differentially expressed genes (DEGs) and construct a prognostic signature for GBM patients using multi-omics analysis. Patient cohorts were collected from publicly available databases, including the Gene Expression Omnibus (GEO), the Chinese Glioma Genome Atlas (CGGA), and The Cancer Genome Atlas—Glioblastoma Multiforme (TCGA-GBM), to facilitate a comprehensive analysis. Hypoxia-related genes (HRGs) were obtained from the Molecular Signatures Database (MSigDB). Differential expression analysis revealed 41 hypoxia-related DEGs in GBM patients. A consensus clustering approach, utilizing these DEGs’ expression patterns, identified four distinct clusters, with cluster 1 showing significantly better overall survival. Machine learning techniques, including univariate Cox regression and LASSO regression, delineated a prognostic signature comprising six genes (ANXA1, CALD1, CP, IGFBP2, IGFBP5, and LOX). Multivariate Cox regression analysis substantiated the prognostic significance of a set of three optimal signature genes (CP, IGFBP2, and LOX). Using the hypoxia-related prognostic signature, patients were classified into high- and low-risk categories. Survival analysis demonstrated that the high-risk group exhibited inferior overall survival rates in comparison to the low-risk group. The prognostic signature showed good predictive performance, as indicated by the area under the curve (AUC) values for one-, three-, and five-year overall survival. Furthermore, functional enrichment analysis of the DEGs identified biological processes and pathways associated with hypoxia, providing insights into the underlying mechanisms of GBM. Delving into the tumor immune microenvironment, our analysis revealed correlations relating the hypoxia-related prognostic signature to the infiltration of immune cells in GBM. Overall, our study highlights the potential of a hypoxia-related prognostic signature as a valuable resource for forecasting the survival outcome of GBM patients. The multi-omics approach integrating bulk sequencing, single-cell analysis, and immune microenvironment assessment enhances our understanding of the intricate biology characterizing GBM, thereby potentially informing the tailored design of therapeutic interventions. Full article

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2023

Jump to: 2024, 2022

10 pages, 888 KiB

Open AccessArticle

Unplanned 30-Day Readmission in Glioblastoma Patients: Implications for the Extent of Resection and Adjuvant Therapy

by Johannes Kasper, Johannes Wach, Martin Vychopen, Felix Arlt, Erdem Güresir, Tim Wende and Florian Wilhelmy

Cancers 2023, 15(15), 3907; https://doi.org/10.3390/cancers15153907 - 01 Aug 2023

Cited by 1 | Viewed by 737

Abstract

Background: Unplanned early readmission (UER) within 30 days after hospital release is a negative prognostic marker for patients diagnosed with glioblastoma (GBM). This work analyzes the impact of UER on the effects of standard therapy modalities for GBM patients, including the extent of [...] Read more.

Background: Unplanned early readmission (UER) within 30 days after hospital release is a negative prognostic marker for patients diagnosed with glioblastoma (GBM). This work analyzes the impact of UER on the effects of standard therapy modalities for GBM patients, including the extent of resection (EOR) and adjuvant therapy regimen. Methods: Records were searched for patients with newly diagnosed GBM between 2014 and 2020 who were treated at our facility. Exclusion criteria were being aged below 18 years or missing data. An overall survival (OS) analysis (Kaplan–Meier estimate; Cox regression) was performed on various GBM patient sub-cohorts. Results: A total of 276 patients were included in the study. UER occurred in 13.4% (n = 37) of all cases, significantly reduced median OS (5.7 vs. 14.5 months, p < 0.001 by logrank), and was associated with an increased hazard of mortality (hazard ratio 3.875, p < 0.001) in multivariate Cox regression when other clinical parameters were applied as confounders. The Kaplan–Meier analysis also showed that patients experiencing UER still benefitted from adjuvant radio-chemotherapy when compared to radiotherapy or no adjuvant therapy (p < 0.001 by logrank). A higher EOR did not improve OS in GBM patients with UER (p = 0.659). Conclusion: UER is negatively associated with survival in GBM patients. In contrast to EOR, adjuvant radio-chemotherapy was beneficial, even after UER. Full article

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18 pages, 596 KiB

Open AccessReview

CAR T Cell Therapy in Glioblastoma: Overcoming Challenges Related to Antigen Expression

by Andrew S. Luksik, Eli Yazigi, Pavan Shah and Christopher M. Jackson

Cancers 2023, 15(5), 1414; https://doi.org/10.3390/cancers15051414 - 23 Feb 2023

Cited by 14 | Viewed by 4121

Abstract

Glioblastoma (GBM) is the most common primary brain tumor, yet prognosis remains dismal with current treatment. Immunotherapeutic strategies have had limited effectiveness to date in GBM, but recent advances hold promise. One such immunotherapeutic advance is chimeric antigen receptor (CAR) T cell therapy, [...] Read more.

Glioblastoma (GBM) is the most common primary brain tumor, yet prognosis remains dismal with current treatment. Immunotherapeutic strategies have had limited effectiveness to date in GBM, but recent advances hold promise. One such immunotherapeutic advance is chimeric antigen receptor (CAR) T cell therapy, where autologous T cells are extracted and engineered to express a specific receptor against a GBM antigen and are then infused back into the patient. There have been numerous preclinical studies showing promising results, and several of these CAR T cell therapies are being tested in clinical trials for GBM and other brain cancers. While results in tumors such as lymphomas and diffuse intrinsic pontine gliomas have been encouraging, early results in GBM have not shown clinical benefit. Potential reasons for this are the limited number of specific antigens in GBM, their heterogenous expression, and their loss after initiating antigen-specific therapy due to immunoediting. Here, we review the current preclinical and clinical experiences with CAR T cell therapy in GBM and potential strategies to develop more effective CAR T cells for this indication. Full article

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12 pages, 862 KiB

Open AccessEditor’s ChoiceReview

CAR-T Therapy in GBM: Current Challenges and Avenues for Improvement

by Ayush Pant and Michael Lim

Cancers 2023, 15(4), 1249; https://doi.org/10.3390/cancers15041249 - 16 Feb 2023

Cited by 8 | Viewed by 2697

Abstract

Completed clinical trials of CAR-T cells in glioblastoma (GBM) have revealed key challenges that limit their efficacy. These include incomplete antigen coverage, downregulation of target antigen in response to therapy, exposure to immunosuppressive cells and cytokines in the tumor microenvironment and exhaustion of [...] Read more.

Completed clinical trials of CAR-T cells in glioblastoma (GBM) have revealed key challenges that limit their efficacy. These include incomplete antigen coverage, downregulation of target antigen in response to therapy, exposure to immunosuppressive cells and cytokines in the tumor microenvironment and exhaustion of CAR-T cells. To overcome these challenges, CAR-T cells have been modified to maximize effector function and resist immunosuppression in the tumor while limiting toxicities to the host. Adoption of these novel CAR-T strategies in GBM can overcome the “cold tumor” phenotype of GBM and trigger an inflammatory cascade that maximizes tumor clearance and minimizes CAR-T dysfunction. To achieve this, understanding and harnessing the antigenic, metabolic and immunological composition of GBM is crucial. Here we review the findings from completed clinical trials of CAR-T cells in GBM as well as novel strategies that could improve CAR-T survival and function in the tumor. Full article

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26 pages, 1635 KiB

Open AccessReview

Dendrimer Technology in Glioma: Functional Design and Potential Applications

by Hallie Gaitsch, Andrew M. Hersh, Safwan Alomari and Betty M. Tyler

Cancers 2023, 15(4), 1075; https://doi.org/10.3390/cancers15041075 - 08 Feb 2023

Cited by 1 | Viewed by 2225

Abstract

Novel therapeutic and diagnostic methods are sorely needed for gliomas, which contribute yearly to hundreds of thousands of cancer deaths worldwide. Despite the outpouring of research efforts and funding aimed at improving clinical outcomes for patients with glioma, the prognosis for high-grade glioma, [...] Read more.

Novel therapeutic and diagnostic methods are sorely needed for gliomas, which contribute yearly to hundreds of thousands of cancer deaths worldwide. Despite the outpouring of research efforts and funding aimed at improving clinical outcomes for patients with glioma, the prognosis for high-grade glioma, and especially glioblastoma, remains dire. One of the greatest obstacles to improving treatment efficacy and destroying cancer cells is the safe delivery of chemotherapeutic drugs and biologics to the tumor site at a high enough dose to be effective. Over the past few decades, a burst of research has leveraged nanotechnology to overcome this obstacle. There has been a renewed interest in adapting previously understudied dendrimer nanocarriers for this task. Dendrimers are small, highly modifiable, branched structures featuring binding sites for a variety of drugs and ligands. Recent studies have demonstrated the potential for dendrimers and dendrimer conjugates to effectively shuttle therapeutic cargo to the correct tumor location, permeate the tumor, and promote apoptosis of tumor cells while minimizing systemic toxicity and damage to surrounding healthy brain tissue. This review provides a primer on the properties of dendrimers; outlines the mechanisms by which they can target delivery of substances to the site of brain pathology; and delves into current trends in the application of dendrimers to drug and gene delivery, and diagnostic imaging, in glioma. Finally, future directions for translating these in vitro and in vivo findings to the clinic are discussed. Full article

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19 pages, 4524 KiB

Open AccessReview

Tumor Microenvironment in Gliomas: A Treatment Hurdle or an Opportunity to Grab?

by Vincenzo Di Nunno, Marta Aprile, Lidia Gatto, Alicia Tosoni, Lucia Ranieri, Stefania Bartolini and Enrico Franceschi

Cancers 2023, 15(4), 1042; https://doi.org/10.3390/cancers15041042 - 07 Feb 2023

Cited by 4 | Viewed by 2823

Abstract

Gliomas are the most frequent central nervous system (CNS) primary tumors. The prognosis and clinical outcomes of these malignancies strongly diverge according to their molecular alterations and range from a few months to decades. The tumor-associated microenvironment involves all cells and connective tissues [...] Read more.

Gliomas are the most frequent central nervous system (CNS) primary tumors. The prognosis and clinical outcomes of these malignancies strongly diverge according to their molecular alterations and range from a few months to decades. The tumor-associated microenvironment involves all cells and connective tissues surrounding tumor cells. The composition of the microenvironment as well as the interactions with associated neoplastic mass, are both variables assuming an increasing interest in these last years. This is mainly because the microenvironment can mediate progression, invasion, dedifferentiation, resistance to treatment, and relapse of primary gliomas. In particular, the tumor microenvironment strongly diverges from isocitrate dehydrogenase (IDH) mutated and wild-type (wt) tumors. Indeed, IDH mutated gliomas often show a lower infiltration of immune cells with reduced angiogenesis as compared to IDH wt gliomas. On the other hand, IDH wt tumors exhibit a strong immune infiltration mediated by several cytokines and chemokines, including CCL2, CCL7, GDNF, CSF-1, GM-CSF, etc. The presence of several factors, including Sox2, Oct4, PD-L1, FAS-L, and TGF β2, also mediate an immune switch toward a regulatory inhibited immune system. Other important interactions are described between IDH wt glioblastoma cells and astrocytes, neurons, and stem cells, while these interactions are less elucidated in IDH-mutated tumors. The possibility of targeting the microenvironment is an intriguing perspective in terms of therapeutic drug development. In this review, we summarized available evidence related to the glioma microenvironment, focusing on differences within different glioma subtypes and on possible therapeutic development. Full article

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2022

Jump to: 2024, 2023

23 pages, 2139 KiB

Open AccessReview

Investigational Microbiological Therapy for Glioma

by Jing Wang, Yaxue Liu, Aohan Zhang, Wenxin Yu, Qian Lei, Bo Xiao and Zhaohui Luo

Cancers 2022, 14(23), 5977; https://doi.org/10.3390/cancers14235977 - 02 Dec 2022

Cited by 1 | Viewed by 2223

Abstract

Glioma is the most common primary malignancy of the central nervous system (CNS), and 50% of patients present with glioblastoma (GBM), which is the most aggressive type. Currently, the most popular therapies are progressive chemotherapy and treatment with temozolomide (TMZ), but the median [...] Read more.

Glioma is the most common primary malignancy of the central nervous system (CNS), and 50% of patients present with glioblastoma (GBM), which is the most aggressive type. Currently, the most popular therapies are progressive chemotherapy and treatment with temozolomide (TMZ), but the median survival of glioma patients is still low as a result of the emergence of drug resistance, so we urgently need to find new therapies. A growing number of studies have shown that the diversity, bioactivity, and manipulability of microorganisms make microbial therapy a promising approach for cancer treatment. However, the many studies on the research progress of microorganisms and their derivatives in the development and treatment of glioma are scattered, and nobody has yet provided a comprehensive summary of them. Therefore, in this paper, we review the research progress of microorganisms and their derivatives in the development and treatment of glioma and conclude that it is possible to treat glioma by exogenous microbial therapies and targeting the gut–brain axis. In this article, we discuss the prospects and pressing issues relating to these therapies with the aim of providing new ideas for the treatment of glioma. Full article

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22 pages, 661 KiB

Open AccessReview

Review of Intraoperative Adjuncts for Maximal Safe Resection of Gliomas and Its Impact on Outcomes

by Hani Chanbour and Silky Chotai

Cancers 2022, 14(22), 5705; https://doi.org/10.3390/cancers14225705 - 21 Nov 2022

Cited by 5 | Viewed by 1888

Abstract

Maximal safe resection is the mainstay of treatment in the neurosurgical management of gliomas, and preserving functional integrity is linked to favorable outcomes. How these modalities differ in their effectiveness on the extent of resection (EOR), survival, and complications remains unknown. A systematic [...] Read more.

Maximal safe resection is the mainstay of treatment in the neurosurgical management of gliomas, and preserving functional integrity is linked to favorable outcomes. How these modalities differ in their effectiveness on the extent of resection (EOR), survival, and complications remains unknown. A systematic literature search was performed with the following inclusion criteria: published between 2005 and 2022, involving brain glioma surgery, and including one or a combination of intraoperative modalities: intraoperative magnetic resonance imaging (iMRI), awake/general anesthesia craniotomy mapping (AC/GA), fluorescence-guided imaging, or combined modalities. Of 525 articles, 464 were excluded and 61 articles were included, involving 5221 glioma patients, 7(11.4%) articles used iMRI, 21(36.8%) used cortical mapping, 15(24.5%) used 5-aminolevulinic acid (5-ALA) or fluorescein sodium, and 18(29.5%) used combined modalities. The heterogeneity in reporting the amount of surgical resection prevented further analysis. Progression-free survival/overall survival (PFS/OS) were reported in 18/61(29.5%) articles, while complications and permanent disability were reported in 38/61(62.2%) articles. The reviewed studies demonstrate that intraoperative adjuncts such as iMRI, AC/GA mapping, fluorescence-guided imaging, and a combination of these modalities improve EOR. However, PFS/OS were underreported. Combining multiple intraoperative modalities seems to have the highest effect compared to each adjunct alone. Full article

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31 pages, 1178 KiB

Open AccessReview

Smart Nanoformulations for Brain Cancer Theranostics: Challenges and Promises

by Faraz Ahmad, Ressin Varghese, Subhrajita Panda, Siva Ramamoorthy, Mohammad Y. Areeshi, Sharmila Fagoonee and Shafiul Haque

Cancers 2022, 14(21), 5389; https://doi.org/10.3390/cancers14215389 - 01 Nov 2022

Cited by 7 | Viewed by 2708

Abstract

Despite their low prevalence, brain tumors are among the most lethal cancers. They are extremely difficult to diagnose, monitor and treat. Conventional anti-cancer strategies such as radio- and chemotherapy have largely failed, and to date, the development of even a single effective therapeutic [...] Read more.

Despite their low prevalence, brain tumors are among the most lethal cancers. They are extremely difficult to diagnose, monitor and treat. Conventional anti-cancer strategies such as radio- and chemotherapy have largely failed, and to date, the development of even a single effective therapeutic strategy against central nervous system (CNS) tumors has remained elusive. There are several factors responsible for this. Brain cancers are a heterogeneous group of diseases with variable origins, biochemical properties and degrees of invasiveness. High-grade gliomas are amongst the most metastatic and invasive cancers, which is another reason for therapeutic failure in their case. Moreover, crossing the blood brain and the blood brain tumor barriers has been a significant hindrance in the development of efficient CNS therapeutics. Cancer nanomedicine, which encompasses the application of nanotechnology for diagnosis, monitoring and therapy of cancers, is a rapidly evolving field of translational medicine. Nanoformulations, because of their extreme versatility and manipulative potential, are emerging candidates for tumor targeting, penetration and treatment in the brain. Moreover, suitable nanocarriers can be commissioned for theranostics, a combinatorial personalized approach for simultaneous imaging and therapy. This review first details the recent advances in novel bioengineering techniques that provide promising avenues for circumventing the hurdles of delivering the diagnostic/therapeutic agent to the CNS. The authors then describe in detail the tremendous potential of utilizing nanotechnology, particularly nano-theranostics for brain cancer imaging and therapy, and outline the different categories of recently developed next-generation smart nanoformulations that have exceptional potential for making a breakthrough in clinical neuro-oncology therapeutics. Full article

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26 pages, 1391 KiB

Open AccessFeature PaperReview

Applications of Focused Ultrasound for the Treatment of Glioblastoma: A New Frontier

by Andrew M. Hersh, Meghana Bhimreddy, Carly Weber-Levine, Kelly Jiang, Safwan Alomari, Nicholas Theodore, Amir Manbachi and Betty M. Tyler

Cancers 2022, 14(19), 4920; https://doi.org/10.3390/cancers14194920 - 08 Oct 2022

Cited by 20 | Viewed by 4453

Abstract

Glioblastoma (GBM) is an aggressive primary astrocytoma associated with short overall survival. Treatment for GBM primarily consists of maximal safe surgical resection, radiation therapy, and chemotherapy using temozolomide. Nonetheless, recurrence and tumor progression is the norm, driven by tumor stem cell activity and [...] Read more.

Glioblastoma (GBM) is an aggressive primary astrocytoma associated with short overall survival. Treatment for GBM primarily consists of maximal safe surgical resection, radiation therapy, and chemotherapy using temozolomide. Nonetheless, recurrence and tumor progression is the norm, driven by tumor stem cell activity and a high mutational burden. Focused ultrasound (FUS) has shown promising results in preclinical and clinical trials for treatment of GBM and has received regulatory approval for the treatment of other neoplasms. Here, we review the range of applications for FUS in the treatment of GBM, which depend on parameters, including frequency, power, pulse duration, and duty cycle. Low-intensity FUS can be used to transiently open the blood–brain barrier (BBB), which restricts diffusion of most macromolecules and therapeutic agents into the brain. Under guidance from magnetic resonance imaging, the BBB can be targeted in a precise location to permit diffusion of molecules only at the vicinity of the tumor, preventing side effects to healthy tissue. BBB opening can also be used to improve detection of cell-free tumor DNA with liquid biopsies, allowing non-invasive diagnosis and identification of molecular mutations. High-intensity FUS can cause tumor ablation via a hyperthermic effect. Additionally, FUS can stimulate immunological attack of tumor cells, can activate sonosensitizers to exert cytotoxic effects on tumor tissue, and can sensitize tumors to radiation therapy. Finally, another mechanism under investigation, known as histotripsy, produces tumor ablation via acoustic cavitation rather than thermal effects. Full article

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34 pages, 1712 KiB

Open AccessReview

Molecular Pathways and Genomic Landscape of Glioblastoma Stem Cells: Opportunities for Targeted Therapy

by Andrew M. Hersh, Hallie Gaitsch, Safwan Alomari, Daniel Lubelski and Betty M. Tyler

Cancers 2022, 14(15), 3743; https://doi.org/10.3390/cancers14153743 - 31 Jul 2022

Cited by 14 | Viewed by 4016

Abstract

Glioblastoma (GBM) is an aggressive tumor of the central nervous system categorized by the World Health Organization as a Grade 4 astrocytoma. Despite treatment with surgical resection, adjuvant chemotherapy, and radiation therapy, outcomes remain poor, with a median survival of only 14-16 months. [...] Read more.

Glioblastoma (GBM) is an aggressive tumor of the central nervous system categorized by the World Health Organization as a Grade 4 astrocytoma. Despite treatment with surgical resection, adjuvant chemotherapy, and radiation therapy, outcomes remain poor, with a median survival of only 14-16 months. Although tumor regression is often observed initially after treatment, long-term recurrence or progression invariably occurs. Tumor growth, invasion, and recurrence is mediated by a unique population of glioblastoma stem cells (GSCs). Their high mutation rate and dysregulated transcriptional landscape augment their resistance to conventional chemotherapy and radiation therapy, explaining the poor outcomes observed in patients. Consequently, GSCs have emerged as targets of interest in new treatment paradigms. Here, we review the unique properties of GSCs, including their interactions with the hypoxic microenvironment that drives their proliferation. We discuss vital signaling pathways in GSCs that mediate stemness, self-renewal, proliferation, and invasion, including the Notch, epidermal growth factor receptor, phosphatidylinositol 3-kinase/Akt, sonic hedgehog, transforming growth factor beta, Wnt, signal transducer and activator of transcription 3, and inhibitors of differentiation pathways. We also review epigenomic changes in GSCs that influence their transcriptional state, including DNA methylation, histone methylation and acetylation, and miRNA expression. The constituent molecular components of the signaling pathways and epigenomic regulators represent potential sites for targeted therapy, and representative examples of inhibitory molecules and pharmaceuticals are discussed. Continued investigation into the molecular pathways of GSCs and candidate therapeutics is needed to discover new effective treatments for GBM and improve survival. Full article

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14 pages, 1525 KiB

Open AccessFeature PaperArticle

Identification of a Prognostic Microenvironment-Related Gene Signature in Glioblastoma Patients Treated with Carmustine Wafers

by Ivana Manini, Emiliano Dalla, Vera Vendramin, Daniela Cesselli, Carla Di Loreto, Miran Skrap and Tamara Ius

Cancers 2022, 14(14), 3413; https://doi.org/10.3390/cancers14143413 - 14 Jul 2022

Cited by 1 | Viewed by 1646

Abstract

Despite the state-of-the-art treatment, patients diagnosed with glioblastoma (GBM) have a median overall survival (OS) of 14 months. The insertion of carmustine wafers (CWs) into the resection cavity as adjuvant treatment represents a promising option, although its use has been limited due to [...] Read more.

Despite the state-of-the-art treatment, patients diagnosed with glioblastoma (GBM) have a median overall survival (OS) of 14 months. The insertion of carmustine wafers (CWs) into the resection cavity as adjuvant treatment represents a promising option, although its use has been limited due to contrasting clinical results. Our retrospective evaluation of CW efficacy showed a significant improvement in terms of OS in a subgroup of patients. Given the crucial role of the tumor microenvironment (TME) in GBM progression and response to therapy, we hypothesized that the TME of patients who benefited from CW could have different properties compared to that of patients who did not show any advantage. Using an in vitro model of the glioma microenvironment, represented by glioma-associated-stem cells (GASC), we performed a transcriptomic analysis of GASC isolated from tumors of patients responsive and not responsive to CW to identify differentially expressed genes. We found different transcriptomic profiles, and we identified four genes, specifically down-regulated in GASC isolated from long-term survivors, correlated with clinical data deposited in the TCGA–GBM dataset. Our results highlight that studying the in vitro properties of patient-specific glioma microenvironments can help to identify molecular determinants potentially prognostic for patients treated with CW. Full article

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21 pages, 1242 KiB

Open AccessArticle

A Potential New Treatment for High-Grade Glioma: A Study Assessing Repurposed Drug Combinations against Patient-Derived High-Grade Glioma Cells

by Sarah Lastakchi, Mary Kanyinsola Olaloko and Christopher McConville

Cancers 2022, 14(11), 2602; https://doi.org/10.3390/cancers14112602 - 25 May 2022

Cited by 3 | Viewed by 2323

Abstract

Repurposed drugs have demonstrated in vitro success against high-grade gliomas; however, their clinical success has been limited due to the in vitro model not truly representing the clinical scenario. In this study, we used two distinct patient-derived tumour fragments (tumour core (TC) and [...] Read more.

Repurposed drugs have demonstrated in vitro success against high-grade gliomas; however, their clinical success has been limited due to the in vitro model not truly representing the clinical scenario. In this study, we used two distinct patient-derived tumour fragments (tumour core (TC) and tumour margin (TM)) to generate a heterogeneous, clinically relevant in vitro model to assess if a combination of repurposed drugs (irinotecan, pitavastatin, disulfiram, copper gluconate, captopril, celecoxib, itraconazole and ticlopidine), each targeting a different growth promoting pathway, could successfully treat high-grade gliomas. To ensure the clinical relevance of our data, TC and TM samples from 11 different patients were utilized. Our data demonstrate that, at a concentration of 100µm or lower, all drug combinations achieved lower LogIC₅₀ values than temozolomide, with one of the combinations almost eradicating the cancer by achieving cell viabilities below 4% in five of the TM samples 6 days after treatment. Temozolomide was unable to stop tumour growth over the 14-day assay, while combination 1 stopped tumour growth, with combinations 2, 3 and 4 slowing down tumour growth at higher doses. To validate the cytotoxicity data, we used two distinct assays, end point MTT and real-time IncuCyte life analysis, to evaluate the cytotoxicity of the combinations on the TC fragment from patient 3, with the cell viabilities comparable across both assays. The local administration of combinations of repurposed drugs that target different growth promoting pathways of high-grade gliomas have the potential to be translated into the clinic as a novel treatment strategy for high-grade gliomas. Full article

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15 pages, 912 KiB

Open AccessSystematic Review

Gliomas Infiltrating the Corpus Callosum: A Systematic Review of the Literature

by Paolo Palmisciano, Gianluca Ferini, Gina Watanabe, Christian Ogasawara, Emal Lesha, Othman Bin-Alamer, Giuseppe E. Umana, Kenny Yu, Aaron A. Cohen-Gadol, Tarek Y. El Ahmadieh and Ali S. Haider

Cancers 2022, 14(10), 2507; https://doi.org/10.3390/cancers14102507 - 19 May 2022

Cited by 6 | Viewed by 3385

Abstract

Background: Gliomas infiltrating the corpus callosum (G-I-CC) majorly impact patient quality-of-life, but maximally safe tumor resection is challenging. We systematically reviewed the literature on G-I-CC. Methods: PubMed, EMBASE, Scopus, Web of Science, and Cochrane were searched following the PRISMA guidelines to include studies [...] Read more.

Background: Gliomas infiltrating the corpus callosum (G-I-CC) majorly impact patient quality-of-life, but maximally safe tumor resection is challenging. We systematically reviewed the literature on G-I-CC. Methods: PubMed, EMBASE, Scopus, Web of Science, and Cochrane were searched following the PRISMA guidelines to include studies of patients with G-I-CC. Clinicopathological features, treatments, and outcomes were analyzed. Results: We included 52 studies comprising 683 patients. Most patients experienced headache (33%), cognitive decline (18.7%), and seizures (17.7%). Tumors mostly infiltrated the corpus callosum genu (44.2%) with bilateral extension (85.4%) into frontal (68.3%) or parietal (8.9%) lobes. Most G-I-CC were glioblastomas (84.5%) with IDH-wildtype (84.9%) and unmethylated MGMT promoter (53.5%). Resection (76.7%) was preferred over biopsy (23.3%), mostly gross-total (33.8%) and subtotal (32.5%). The tumor-infiltrated corpus callosum was resected in 57.8% of cases. Radiation was delivered in 65.8% of patients and temozolomide in 68.3%. Median follow-up was 12 months (range, 0.1–116). In total, 142 patients (31.8%) experienced post-surgical complications, including transient supplementary motor area syndrome (5.1%) and persistent motor deficits (4.3%) or abulia (2.5%). Post-treatment symptom improvement was reported in 42.9% of patients. No differences in rates of complications (p = 0.231) and symptom improvement (p = 0.375) were found in cases with resected versus preserved corpus callosum. Recurrences occurred in 40.9% of cases, with median progression-free survival of 9 months (0.1–72). Median overall survival was 10.7 months (range, 0.1–116), significantly longer in low-grade tumors (p = 0.013) and after resection (p < 0.001), especially gross-total (p = 0.041) in patients with high-grade tumors. Conclusions: G-I-CC show clinicopathological patterns comparable to other more frequent gliomas. Maximally safe resection significantly improves survival with low rates of persistent complications. Full article

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