Initial cognitive impairment predicts shorter survival of patients with glioblastoma

Bruhn, Helena; Blystad, Ida; Milos, Peter; Malmström, Annika; Dahle, Charlotte; Vrethem, Magnus; Henriksson, Roger; Lind, Jonas

doi:10.1111/ane.13529

Cited by 10 publications

(12 citation statements)

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“…In addition, the top ten GO terms enriched by downregulated DEGs all had a strong link with synapse formation, stabilization, and signal transduction ( Figure 5(g) ). Clinically, patients with high-grade glioma tend to develop degenerative diseases such as memory loss and cognitive impairment, and it has been demonstrated that impaired cognitive function is associated with shorter survival in glioblastoma patients [ 42 ]. Furthermore, pyroptosis is strongly associated with Alzheimer's disease progression, and GSDMD serves as an important marker for AD [ 19 ].…”

Section: Resultsmentioning

confidence: 99%

“…ns: not significant. * * p < 0:01, * * * p < 0:001, and * * * * p < 0:0001. explain to some extent the clinical phenomenon of cognitive dysfunction associated with poor prognosis in glioblastoma patients [42]. Notably, the Riskscore was significantly positively correlated with BMDM infiltration, while the singlecell transcriptomics further demonstrated that NLRC4+ CASP1+ GSDMD+ and CASP4+ GSDMD+ cells were concentrated in a specific peripheral-derived BMDM cluster.…”

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confidence: 90%

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Bulk and Single-Cell Transcriptome Analyses Revealed That the Pyroptosis of Glioma-Associated Macrophages Participates in Tumor Progression and Immunosuppression

Yin

et al. 2022

Oxidative Medicine and Cellular Longevity

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Glioma is the most common of all central nervous system (CNS) malignancies and is associated with a poor prognosis. Pyroptosis has been proven to be associated with the progression of multiple tumors and CNS diseases. However, the relationships between pyroptosis and clinical prognosis and immune cell infiltration are unclear in glioma. In this study, we conducted a comprehensive exploration of pyroptosis in glioma. First, prognosis-related genes were screened at each key regulatory locus in the pyroptosis pathway, and the prognostic ability and coexpression relationships of GSDMD and its upstream pathway genes NLRC4/CASP1/CASP4 were identified and well validated in multiple datasets. Tissue microarray-based immunohistochemistry results showed higher levels of NLRC4 and N-terminal GSDMD in high-grade gliomas, providing conclusive evidence of pyroptosis in gliomas. The robustness of the prognostic model based on these four genes was well validated in TCGA and CGGA cohorts. Bulk RNA-seq-based analysis showed that the group defined as the high-risk group according to the model showed activation of multiple inflammatory response pathways and impaired synaptic gene expression and had a higher infiltration of bone marrow-derived macrophages (BMDMs) and a hypersuppressed immune microenvironment. More importantly, three independent single-cell RNA-seq (scRNA-seq) datasets demonstrated that tumor-infiltrating macrophages, particularly BMDMs but not tissue-resident microglia, showed significant coexpression of the GSDMD and CASP genes, and BMDMs from high-grade gliomas accounted for a higher proportion of immune infiltrating cells and had higher expression of pyroptosis genes. Finally, we revealed the activation of pathways in response to LPS/bacteria and oxidative stress during BMDM development toward the pyroptosis cell fate by pseudotime trajectory analysis, suggesting potential BMDM pyroptosis initiators. The above results provide not only novel insights into the pathological mechanisms of glioma but also novel therapeutic targets for glioma, suggesting the potential application of pyroptosis inhibitors (e.g., disulfiram).

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Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 90%

Bulk and Single-Cell Transcriptome Analyses Revealed That the Pyroptosis of Glioma-Associated Macrophages Participates in Tumor Progression and Immunosuppression

Yin

et al. 2022

Oxidative Medicine and Cellular Longevity

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“…Only some patients were referred to mental health services, with some only available through external providers, presenting an access barrier. Australian clinical practice guidelines and OCPs indicate early consistent psychosocial care of brain cancer patients and their carers is critical [ 10 , 18 , 24 , 25 ]. Most cognitive rehabilitation intervention programs reported improvements in patients' cognitive test-performance [ 26 ] and could be considered for inclusion in psychosocial care of HGG patients.…”

Section: Discussionmentioning

confidence: 99%

“…We identified low referrals to speech therapists, despite the frequent occurrence of speech aberrations (eg. expressive and receptive dysphasia) [ 18 ] and increasing communication deficits over time [ 28 ]. Occasionally issues relating to swallowing emerge, which can be addressed by speech pathologists [ 29 ].…”

Section: Discussionmentioning

confidence: 99%

Supportive care of patients diagnosed with high grade glioma and their carers in Australia

et al. 2022

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Purpose This study aimed to: determine the supportive care available for Australian patients with High Grade Glioma (HGG) and their carers; identify service gaps; and inform changes needed to implement guidelines and Optimal Care Pathways. Methods This cross-sectional online survey recruited multidisciplinary health professionals (HPs) who were members of the Cooperative Trials Group for Neuro-Oncology involved in management of patients diagnosed with HGG in Australian hospitals. Descriptive statistics were calculated. Fisher's exact test was used to explore differences between groups. Results 42 complete responses were received. A majority of MDT meetings were attended by a: neurosurgeon, radiation oncologist, medical oncologist, radiologist, and care coordinator. Less than 10% reported attendance by a palliative care nurse; physiotherapist; neuropsychologist; or speech therapist. Most could access referral pathways to a cancer care coordinator (76%), neuropsychologist (78%), radiation oncology nurse (77%), or psycho-oncologist (73%), palliative care (93–100%) and mental health professionals (60–85%). However, few routinely referred to an exercise physiologist (10%), rehabilitation physician (22%), dietitian (22%) or speech therapist (28%). Similarly, routine referrals to specialist mental health services were not standard practice. Nearly all HPs (94%) reported HGG patients were advised to present to their GP for pre-existing conditions/comorbidities; however, most HPs took responsibility (≤ 36% referred to GP) for social issues, mental health, symptoms, cancer complications, and treatment side-effects. Conclusions While certain services are accessible to HGG patients nationally, improvements are needed. Psychosocial support, specialist allied health, and primary care providers are not yet routinely integrated into the care of HGG patients and their carers despite these services being considered essential in clinical practice guidelines and optimal care pathways.

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“…In addition to emerging as possible side effects of ferroptosis pathway manipulation, cognitive impairment was also described as a glioblastoma symptom ( 75 ). Cognitive impairment often delays diagnosis and is associated with a reduced overall survival ( 75 ), which should be considered when assessing cognitive dysfunction as potential side effects of add–on drugs.…”

Section: Ferroptosis In Healthy Neurons and Potential Side–effects Of Ferroptosis Inductionmentioning

confidence: 99%

Genetic Profiles of Ferroptosis in Malignant Brain Tumors and Off-Target Effects of Ferroptosis Induction

Dahlmanns

Yakubov

Dahlmanns³

2021

Front. Oncol.

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Glioblastoma represents the most devastating form of human brain cancer, associated with a very poor survival rate of patients. Unfortunately, treatment options are currently limited and the gold standard pharmacological treatment with the chemotherapeutic drug temozolomide only slightly increases the survival rate. Experimental studies have shown that the efficiency of temozolomide can be improved by inducing ferroptosis – a recently discovered form of cell death, which is different from apoptosis, necrosis, or necroptosis and, which is characterized by lipid peroxidation and reactive oxygen species accumulation. Ferroptosis can also be activated to improve treatment of malignant stages of neuroblastoma, meningioma, and glioma. Due to their role in cancer treatment, ferroptosis-gene signatures have recently been evaluated for their ability to predict survival of patients. Despite positive effects during chemotherapy, the drugs used to induce ferroptosis – such as erastin and sorafenib – as well as genetic manipulation of key players in ferroptosis – such as the cystine-glutamate exchanger xCT and the glutathione peroxidase GPx4 – also impact neuronal function and cognitive capabilities. In this review, we give an update on ferroptosis in different brain tumors and summarize the impact of ferroptosis on healthy tissues.

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Initial cognitive impairment predicts shorter survival of patients with glioblastoma

Cited by 10 publications

References 70 publications

Bulk and Single-Cell Transcriptome Analyses Revealed That the Pyroptosis of Glioma-Associated Macrophages Participates in Tumor Progression and Immunosuppression

Bulk and Single-Cell Transcriptome Analyses Revealed That the Pyroptosis of Glioma-Associated Macrophages Participates in Tumor Progression and Immunosuppression

Supportive care of patients diagnosed with high grade glioma and their carers in Australia

Genetic Profiles of Ferroptosis in Malignant Brain Tumors and Off-Target Effects of Ferroptosis Induction

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