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Walking the night road : coming of age in grief
\"Alexandra Butler--daughter of the Pulitzer-Price winning gerontologist Robert Butler and noted social worker and psychotherapist Myrna Lewis--writes of how she cared for her mother during her mother's sudden, brief, and terminal struggle with brain cancer. This memoir examines the strains of caregiving on both the caregiver and the one cared for. Alexandra was 24 when her mother was diagnosed with a glioblastoma, and spent the following months as her mother's primary caregiver, putting her own life on hold during that time. In addition to tracing the course of her mother's tragic illness, Alexandra also examines how the illness affected herself and everyone in her family. Ironically, both Myrna Lewis and Robert Butler were noted gerontologists who championed the concepts of healthy aging--they co-authored the classic work Love and Sex After 60, for example--yet both found their life's themes sorely tested by Lewis's condition. Butler in particular could not handle the illness and left much of the care to Alexandra. Thus the work also examines what happens when a social worker such as Lewis tragically transitions from professional to client\"-- Provided by publisher.
Book
Emerging treatment strategies for glioblastoma multiforme
Glioblastoma multiforme (GBM) is the deadliest form of brain tumor with a more than 90% 5‐year mortality. GBM has a paltry median survival of 12.6 months attributed to the unique treatment limitations such as the high average age of onset, tumor location, and poor current understandings of the tumor pathophysiology. The resection techniques, chemotherapic strategies, and radiation therapy currently used to treat GBM have slowly evolved, but the improvements have not translated to marked increases in patient survival. Here, we will discuss the recent progress in our understanding of GBM pathophysiology, and the diagnostic techniques and treatment options. The discussion will include biomarkers, tumor imaging, novel therapies such as monoclonal antibodies and small‐molecule inhibitors, and the heterogeneity resulting from the GBM cancer stem cell population.
Graphical Abstract
A comprehensive overview and discussion of our current understanding of glioblastoma multiforme (GBM) pathophysiology and heterogeneity, diagnostic techniques and treatment options, including novel therapies such as monoclonal antibodies and small‐molecule inhibitors.
Journal Article
Survival prediction of glioblastoma patients using machine learning and deep learning: a systematic review
Glioblastoma Multiforme (GBM), classified as a grade IV glioma by the World Health Organization (WHO), is a prevalent and notably aggressive form of brain tumor derived from glial cells. It stands as one of the most severe forms of primary brain cancer in humans. The median survival time of GBM patients is only 12–15 months, making it the most lethal type of brain tumor. Every year, about 200,000 people worldwide succumb to this disease. GBM is also highly heterogeneous, meaning that its characteristics and behavior vary widely among different patients. This leads to different outcomes and survival times for each individual. Predicting the survival of GBM patients accurately can have multiple benefits. It can enable optimal and personalized treatment planning based on the patient's condition and prognosis. It can also support the patients and their families to cope with the possible outcomes and make informed decisions about their care and quality of life. Furthermore, it can assist the researchers and scientists to discover the most relevant biomarkers, features, and mechanisms of the disease and to design more effective and personalized therapies. Artificial intelligence methods, such as machine learning and deep learning, have been widely applied to survival prediction in various fields, such as breast cancer, lung cancer, gastric cancer, cervical cancer, liver cancer, prostate cancer, and covid 19. This systematic review summarizes the current state-of-the-art methods for predicting glioblastoma survival using different types of input data, such as clinical features, molecular markers, imaging features, radiomics features, omics data or a combination of them. Following PRISMA guidelines, we searched databases from 2015 to 2024, reviewing 107 articles meeting our criteria. We analyzed the data sources, methods, performance metrics and outcomes of the studies. We found that random forest was the most popular method, and a combination of radiomics and clinical data was the most common input data.
Journal Article
Current Understanding of Hypoxia in Glioblastoma Multiforme and Its Response to Immunotherapy
Hypoxia is a hallmark of glioblastoma multiforme (GBM), the most aggressive cancer of the central nervous system, and is associated with multiple aspects of tumor pathogenesis. For example, hypoxia induces resistance to conventional cancer therapies and inhibits antitumor immune responses. Thus, targeting hypoxia is an attractive strategy for GBM therapy. However, traditional studies on hypoxia have largely excluded the immune system. Recently, the critical role of the immune system in the defense against multiple tumors has become apparent, leading to the development of effective immunotherapies targeting numerous cancer types. Critically, however, GBM is classified as a “cold tumor” due to poor immune responses. Thus, to improve GBM responsiveness against immunotherapies, an improved understanding of both immune function in GBM and the role of hypoxia in mediating immune responses within the GBM microenvironment is needed. In this review, we discuss the role of hypoxia in GBM from a clinical, pathological, and immunological perspective.
Journal Article
Limited recurrence distance of glioblastoma under modern radiotherapy era
Background
The optimal treatment volume for Glioblastoma multiforme (GBM) is still a subject of debate worldwide. The current study was aimed to determine the distances between recurring tumors and the edge of primary lesions, and thereby provide evidence for accurate target area delineation.
Methods
Between October 2007 and March 2019, 68 recurrent patients with GBM were included in our study. We measured the distance from the initial tumor to the recurrent lesion of GBM patients by expanding the initial gross tumor volume (GTV) to overlap the center of recurrent lesion, with the help of the Pinnacle Treatment Planning System.
Results
Recurrences were local in 47(69.1%) patients, distant in 12(17.7%) patients, and both in 9(13.2%) patients. Factors significantly influencing local recurrence were age (
P
= 0.049), sex (
P
= 0.049), and the size of peritumoral edema (
P
= 0.00). A total number of 91 recurrent tumors were analyzed. All local recurrences occurred within 2 cm and 94.8% (55/58) occurred within 1 cm of the original GTV based on T1 enhanced imaging. All local recurrences occurred within 1.5 cm and 98.3%(57/58) occurred within 0.5 cm of the original GTV based on T2-FLAIR imaging. 90.9% (30/33) and 81.8% (27/33) distant recurrences occurred >3 cm of T1 enhanced and T2-Flair primary tumor margins, respectively.
Conclusions
The 1 cm margin from T1 enhanced lesions and 0.5 cm margin from T2-Flair abnormal lesions could cover 94.8 and 98.3% local recurrences respectively, which deserves further prospective study as a limited but effective target area.
Journal Article
Analysis of the cancer genome atlas (TCGA) database identifies an inverse relationship between interleukin-13 receptor α1 and α2 gene expression and poor prognosis and drug resistance in subjects with glioblastoma multiforme
Glioblastoma multiforme (GBM) is the most common primary brain tumor in adults. A variety of targeted agents are being tested in the clinic including cancer vaccines, immunotoxins, antibodies and T cell immunotherapy for GBM. We have previously reported that IL-13 receptor subunits α1 and α2 of IL-13R complex are overexpressed in GBM. We are investigating the significance of IL-13Rα1 and α2 expression in GBM tumors. In order to elucidate a possible relationship between IL-13Rα1 and α2 expression with severity and prognoses of subjects with GBM, we analyzed gene expression (by microarray) and clinical data available at the public The Cancer Genome Atlas (TCGA) database (Currently known as Global Data Commons). More than 40% of GBM samples were highly positive for IL-13Rα2 mRNA (Log2 ≥ 2) while only less than 16% samples were highly positive for IL-13Rα1 mRNA. Subjects with high IL-13Rα1 and α2 mRNA expressing tumors were associated with a significantly lower survival rate irrespective of their treatment compared to subjects with IL-13Rα1 and α2 mRNA negative tumors. We further observed that IL-13Rα2 gene expression is associated with GBM resistance to temozolomide (TMZ) chemotherapy. The expression of IL-13Rα2 gene did not seem to correlate with the expression of genes for other chains involved in the formation of IL-13R complex (IL-13Rα1 or IL-4Rα) in GBM. However, a positive correlation was observed between IL-4Rα and IL-13Rα1 gene expression. The microarray data of IL-13Rα2 gene expression was verified by RNA-Seq data. In depth analysis of TCGA data revealed that immunosuppressive genes (such as FMOD, CCL2, OSM, etc.) were highly expressed in IL-13Rα2 positive tumors, but not in IL-13Rα2 negative tumors. These results indicate a direct correlation between high level of IL-13R mRNA expression and poor patient prognosis and that immunosuppressive genes associated with IL-13Rα2 may play a role in tumor progression. These findings have important implications in understanding the role of IL-13R in the pathogenesis of GBM and potentially other cancers.
Journal Article
Dexamethasone in Glioblastoma Multiforme Therapy: Mechanisms and Controversies
Glioblastoma multiforme (GBM) is the most common and malignant of the glial tumors. The world-wide estimates of new cases and deaths annually are remarkable, making GBM a crucial public health issue. Despite the combination of radical surgery, radio and chemotherapy prognosis is extremely poor (median survival is approximately 1 year). Thus, current therapeutic interventions are highly unsatisfactory. For many years, GBM-induced brain oedema and inflammation have been widely treated with dexamethasone (DEX), a synthetic glucocorticoid (GC). A number of studies have reported that DEX also inhibits GBM cell proliferation and migration. Nevertheless, recent controversial results provided by different laboratories have challenged the widely accepted dogma concerning DEX therapy for GBM. Here, we have reviewed the main clinical features and genetic and epigenetic abnormalities underlying GBM. Finally, we analyzed current notions and concerns related to DEX effects on cerebral oedema, cancer cell proliferation and migration and clinical outcome.
Journal Article
Temperature and Impedance Variations During Tumor Treating Fields (TTFields) Treatment
Tumor Treating Fields (TTFields) is an FDA-approved cancer treatment technique used for glioblastoma multiforme (GBM). It consists in the application of alternating (100–500 kHz) and low-intensity (1–3 V/cm) electric fields (EFs) to interfere with the mitotic process of tumoral cells. In patients, these fields are applied via transducer arrays strategically positioned on the scalp using the NovoTAL™ system. It is recommended that the patient stays under the application of these fields for as long as possible. Inevitably, the temperature of the scalp increases because of the Joule effect, and it will remain above basal values for the most part of the day. Furthermore, it is also known that the impedance of the head changes throughout treatment and that it might also play a role in the temperature variations. The goals of this work were to investigate how to realistically account for these increases and to quantify their impact on the choice of optimal arrays positions using a realistic head model with arrays positions obtained through NovoTAL™. We also studied the impedance variations based on the log files of patients who participated in the EF-14 clinical trial. Our computational results indicated that the layouts in which the arrays were very close to each other led to the appearance of a temperature hotspot that limited how much current could be injected which could consequently reduce treatment efficacy. Based on these data, we suggest that the arrays should be placed at least 1 cm apart from each other. The analysis of the impedance showed that the variations seen during treatment could be explained by three main factors: slow and long-term variations, array placement, and circadian rhythm. Our work indicates that both the temperature and impedance variations should be accounted for to improve the accuracy of computational results when investigating TTFields.
Journal Article
ADAM17 Confers Temozolomide Resistance in Human Glioblastoma Cells and miR-145 Regulates Its Expression
Glioblastoma (GBM) is a malignant brain tumor, commonly treated with temozolomide (TMZ). Upregulation of A disintegrin and metalloproteinases (ADAMs) is correlated to malignancy; however, whether ADAMs modulate TMZ sensitivity in GBM cells remains unclear. To explore the role of ADAMs in TMZ resistance, we analyzed changes in ADAM expression following TMZ treatment using RNA sequencing and noted that ADAM17 was markedly upregulated. Hence, we established TMZ-resistant cell lines to elucidate the role of ADAM17. Furthermore, we evaluated the impact of ADAM17 knockdown on TMZ sensitivity in vitro and in vivo. Moreover, we predicted microRNAs upstream of ADAM17 and transfected miRNA mimics into cells to verify their effects on TMZ sensitivity. Additionally, the clinical significance of ADAM17 and miRNAs in GBM was analyzed. ADAM17 was upregulated in GBM cells under serum starvation and TMZ treatment and was overexpressed in TMZ-resistant cells. In in vitro and in vivo models, ADAM17 knockdown conferred greater TMZ sensitivity. miR-145 overexpression suppressed ADAM17 and sensitized cells to TMZ. ADAM17 upregulation and miR-145 downregulation in clinical specimens are associated with disease progression and poor prognosis. Thus, miR-145 enhances TMZ sensitivity by inhibiting ADAM17. These findings offer insights into the development of therapeutic approaches to overcome TMZ resistance.
Journal Article