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16 pages, 3311 KiB

Open AccessArticle

Nomogram Model for Predicting the Prognosis of High-Grade Glioma in Adults Receiving Standard Treatment: A Retrospective Cohort Study

by Peng Du, Xionggang Yang, Li Shen, Jiawei Chen, Xiao Liu, Xuefan Wu, Aihong Cao and Daoying Geng

J. Clin. Med. 2023, 12(1), 196; https://doi.org/10.3390/jcm12010196 - 27 Dec 2022

Cited by 1 | Viewed by 1728

Abstract

Objectives: To identify the critical factors associated with the progression-free survival (PFS) and overall survival (OS) of high-grade glioma (HGG) in adults who have received standard treatment and establish a novel graphical nomogram and an online dynamic nomogram. Patients and Methods: This is [...] Read more.

Objectives: To identify the critical factors associated with the progression-free survival (PFS) and overall survival (OS) of high-grade glioma (HGG) in adults who have received standard treatment and establish a novel graphical nomogram and an online dynamic nomogram. Patients and Methods: This is a retrospective study of adult HGG patients receiving standard treatment (surgery, postoperative radiotherapy, and temozolomide (TMZ) chemotherapy) at Huashan Hospital, Fudan University between January 2017 and December 2019. We used uni- and multi-variable COX models to identify the significant prognostic factors for PFS and OS. Based on the significant predictors, graphical and online nomograms were established. Results: A total of 246 patients were enrolled in the study based on the inclusion criteria. The average PFS and OS were 22.99 ± 11.43 and 30.51 ± 13.73 months, respectively. According to the multi-variable COX model, age, extent of resection (EOR), and IDH mutation were associated with PFS and OS, while edema index (EI) was relevant to PFS. In addition, patients with IDH and TERT promoter co-mutations had longer PFSs and OSs, and no apparent survival benefit was found in the long-cycle TMZ adjuvant chemotherapy compared with the standard Stupp protocol. Based on these critical factors, a graphical nomogram and online nomogram were developed for predicting PFS and OS, respectively. The calibration curve showed favorable consistency between the predicted and actual survival rates. C-index and time-dependent AUC showed good discrimination abilities. Conclusions: We identified the significant predictors for the PFS and OS of HGG adults receiving standard treatment and established user-friendly nomogram models to assist neurosurgeons in optimizing clinical management and treatment strategies. Full article

(This article belongs to the Special Issue The Recent Updates in Glioblastoma Management)

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13 pages, 2958 KiB

Open AccessArticle

Glioma Shapes Blood–Brain Barrier Integrity and Remodels the Tumor Microenvironment: Links with Clinical Features and Prognosis

by Xiaokai Li, Lei Li, Ke Zhou, Huixiang Zhang, Ali Abdi Maalim, Xingyu Chen, Ximiao He, Xinmin Ding, Chuanrui Xu and Yonghong Wang

J. Clin. Med. 2022, 11(19), 5863; https://doi.org/10.3390/jcm11195863 - 04 Oct 2022

Cited by 3 | Viewed by 1545

Abstract

Background: The presence of the blood–brain barrier (BBB) uniquely distinguishes the brain from other organs, and various brain pathologies, including cancer, can disrupt or breach the BBB. The specific implications of BBB alterations in glioma have not been sufficiently clarified. Methods: In this [...] Read more.

Background: The presence of the blood–brain barrier (BBB) uniquely distinguishes the brain from other organs, and various brain pathologies, including cancer, can disrupt or breach the BBB. The specific implications of BBB alterations in glioma have not been sufficiently clarified. Methods: In this study, statistical analysis of the TCGA pan-glioma dataset and four other validation cohorts was used to investigate the infiltration of BBB constituent cells (endothelial cells, pericytes and astrocytes) in the glioma tumor microenvironment (TME). Results: We found that the infiltration proportions of the three BBB constituent cell types were highly collinear, which implied alteration of the BBB. Hence, we developed an index, the BBB score, which is calculated based on the infiltration proportion of BBB constituent cells. Furthermore, we observed that patients with higher BBB scores were more likely to be diagnosed with more malignant entities in the TCGA database according to significant molecular features, such as IDH mutation status and 1p/19q deletion. The BBB score was also strikingly positively correlated with WHO grade in other cohorts. More importantly, a higher BBB score correlated with shorter survival time and unfavorable prognosis in glioma patients. Finally, we showed that TME-related pathways may regulate BBB alterations and that coinhibitory immune checkpoints were enriched in samples with higher BBB scores. Conclusions: We showed that TME-related pathways may regulate BBB alterations and that coinhibitory immune checkpoints were enriched in samples with higher BBB scores. Assessing BBB alterations may help elucidate the complex role of the glioma TME and suggest new combination treatment strategies. Full article

(This article belongs to the Special Issue The Recent Updates in Glioblastoma Management)

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11 pages, 717 KiB

Open AccessArticle

Tumor Treating Fields Combine with Temozolomide for Newly Diagnosed Glioblastoma: A Retrospective Analysis of Chinese Patients in a Single Center

by Chunjui Chen, Hao Xu, Kun Song, Yi Zhang, Junyan Zhang, Yang Wang, Xiaofang Sheng, Lingchao Chen and Zhiyong Qin

J. Clin. Med. 2022, 11(19), 5855; https://doi.org/10.3390/jcm11195855 - 03 Oct 2022

Cited by 4 | Viewed by 2114

Abstract

Introduction: TTFields plus Temozolomide (TTFields/TMZ) extended survival versus TMZ alone in newly diagnosed glioblastoma (GBM) patients in the EF-14 trial. We have reported a retrospective analysis of newly diagnosed Chinese GBM patients who received TTFields/TMZ treatment and TMZ treatment from August 2018 to [...] Read more.

Introduction: TTFields plus Temozolomide (TTFields/TMZ) extended survival versus TMZ alone in newly diagnosed glioblastoma (GBM) patients in the EF-14 trial. We have reported a retrospective analysis of newly diagnosed Chinese GBM patients who received TTFields/TMZ treatment and TMZ treatment from August 2018 to May 2021 in Huashan hospital in Shanghai. Methods: Overall survival (OS) and progression-free survival (PFS) curves were constructed using the Kaplan–Meier method. A Cox proportional hazards regression model, propensity score matched data, and inverse probability of treatment weighting (IPTW) based on propensity score were used to assess the effect of TTFields and account for confounding factors. Results: In the preliminary analysis, the median PFS in TTFields/TMZ group was 16 months (95% CI, 9.6–24.6) versus 11 months (95% CI, 9–12) in TMZ group (p < 0.05). Median overall survival was 21.8 months (95% CI, 17.4-NA) with TTFields/TMZ versus 15 months (HR = 0.43; 95% CI, 13–18) with TMZ alone. The multivariate analysis identified surgery type, STUPP scheme, IDH status, and TTFields use as favorable prognostic factors. After PSM adjustment, the variate among the groups was similar, except that the methylation rate of MGMT promoter remained high in the TMZ group (12 v 32 months; p = 0.011). Upon IPTW Survival analysis, TTFields was associated with a significantly lower risk of death (HR = 0.19 in OS; 95% CI, 0.09–0.41) and progression (HR = 0.35; 95% CI 0.14–0.9) compared with TMZ group. Conclusion: In the final analysis of our single-center Chinese patients with glioblastoma, adding TTFields to temozolomide chemotherapy resulted in statistically significant improvement in PFS and OS. Full article

(This article belongs to the Special Issue The Recent Updates in Glioblastoma Management)

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13 pages, 4828 KiB

Open AccessArticle

APOL4, a Novel Immune-Related Prognostic Biomarker for Glioma

by Hua Zhu, Xinyao Hu, Shi Feng, Yuntao Li, Yonggang Zhang, Sheng Qiu, Ran Chen, Yingze Ye, Lijuan Gu, Zhihong Jian, Ximing Xu and Xiaoxing Xiong

J. Clin. Med. 2022, 11(19), 5765; https://doi.org/10.3390/jcm11195765 - 29 Sep 2022

Cited by 1 | Viewed by 1659

Abstract

Glioma is the common, most aggressive and poorest prognostic tumor type in the brain. More and more biomarkers associated with glioma treatment, prognosis, and immunity are being discovered. Here, we aimed to explore the underlying biological functions and prognostic predictive value of Apolipoprotein [...] Read more.

Glioma is the common, most aggressive and poorest prognostic tumor type in the brain. More and more biomarkers associated with glioma treatment, prognosis, and immunity are being discovered. Here, we aimed to explore the underlying biological functions and prognostic predictive value of Apolipoprotein L4 (APOL4) in glioma. We downloaded the expression data of APOL4 and clinical information from several databases and used R software for preprocessing. The clinical significance of APOL4 in a glioma outcome was explored by the Cox regression analysis and Kaplan–Meier survival analysis. In addition, immune infiltrates and microenvironmental indicators were assessed by CIBERSORT and TIMER. GO and KEGG analyses were used to analyze the potential functions of APOL4 in gliomas. APOL4 expression was increased in glioma specimens compared to normal tissues and correlated dramatically with the WHO grade. A survival analysis showed a shorter overall survival (OS) in glioma patients with APOL4 overexpression, and a Cox regression analysis showed that APOL4 was an independent prognostic factor for the OS of glioma patients. GSEA, GO, and KEGG enrichment analyses showed remarkable enrichment in immune-related pathways. APOL4 expression was positively correlated with immune infiltration (including DC cells, neutrophils, CD8+ T cells, B cells, macrophages, CD4+ T cells, etc.) and microenvironmental parameters (including immune, stromal, and ESTIMATE scores) in gliomas. Glioma patients with a higher expression of APOL4 may be more sensitive to immune checkpoint inhibitors (ICI). In conclusion, these findings suggest that APOL4 is associated with the tumor grade and immune infiltrates; APOL4 may be a new and potential biomarker for therapeutic and prognostic evaluations that may further suggest the therapeutic efficacy of immunotherapy. Full article

(This article belongs to the Special Issue The Recent Updates in Glioblastoma Management)

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17 pages, 5765 KiB

Open AccessArticle

SU4312 Represses Glioma Progression by Inhibiting YAP and Inducing Sensitization to the Effect of Temozolomide

by Xu Wang, Yi Zhou, Yan Wang, Xiang Wang, Yu Zhang, Yufei Mao, Long Zhang, Ji Qi, Yining Zhang, Feng Lyu, Linbo Gu, Rutong Yu and Xiuping Zhou

J. Clin. Med. 2022, 11(16), 4765; https://doi.org/10.3390/jcm11164765 - 16 Aug 2022

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Abstract

SU4312, initially designed as a multi-target tyrosine kinase inhibitor, is consequently reported to inhibit tumor angiogenesis by blocking VEGFR. However, although SU4312 can penetrate the brain–blood barrier, its potential to inhibit glioma growth is unknown. In this study, we report that SU4312 inhibited [...] Read more.

SU4312, initially designed as a multi-target tyrosine kinase inhibitor, is consequently reported to inhibit tumor angiogenesis by blocking VEGFR. However, although SU4312 can penetrate the brain–blood barrier, its potential to inhibit glioma growth is unknown. In this study, we report that SU4312 inhibited glioma cell proliferation and down-regulated yes-associated protein (YAP), the key effector of the hippo pathway. The exogenous over-expression of YAP partially restored the inhibitory effect of SU4312 on glioma progression. Interestingly, SU4312 sensitized the antitumor effect of temozolomide, both in vitro and in vivo. Moreover, SU4312 decreased the M2tumor-associated macrophages and enhanced anti-tumor immunity by down-regulating the YAP-CCL2 axis. In conclusion, our results suggest that SU4312 represses glioma progression by down-regulating YAP transcription and consequently CCL2 secretion. SU4312 may be synergistic with temozolomide for glioma treatment. Full article

(This article belongs to the Special Issue The Recent Updates in Glioblastoma Management)

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16 pages, 3713 KiB

Open AccessArticle

Morusin Enhances Temozolomide Efficiency in GBM by Inducing Cytoplasmic Vacuolization and Endoplasmic Reticulum Stress

by Rongchuan Zhao, Yuanshuai Zhou, Hong Zhang, Jinlin Pan, Fan Yang, Ruobing Zhang, Nafees Ahmad, Jiao Yang and Minxuan Sun

J. Clin. Med. 2022, 11(13), 3662; https://doi.org/10.3390/jcm11133662 - 24 Jun 2022

Cited by 1 | Viewed by 1803

Abstract

Glioblastoma multiforme (GBM) is an aggressive brain tumor with high risks of recurrence and mortality. Chemoradiotherapy resistance has been considered a major factor contributing to the extremely poor prognosis of GBM patients. Therefore, there is an urgent need to develop highly effective therapeutic [...] Read more.

Glioblastoma multiforme (GBM) is an aggressive brain tumor with high risks of recurrence and mortality. Chemoradiotherapy resistance has been considered a major factor contributing to the extremely poor prognosis of GBM patients. Therefore, there is an urgent need to develop highly effective therapeutic agents. Here, we demonstrate the anti-tumor effect of morusin, a typical prenylated flavonoid, in GBM through in vivo and in vitro models. Morusin showed selective cytotoxicity toward GBM cell lines without harming normal human astrocytes when the concentration was less than 20 µM. Morusin treatment significantly induced apoptosis of GBM cells, accompanied by the activation of endoplasmic reticulum (ER) stress, and the appearance of cytoplasmic vacuolation and autophagosomes in cells. Then, we found the ER stress activation and cytotoxicity of morusin were rescued by ER stress inhibitor 4-PBA. Furthermore, morusin arrested cell cycle at the G1 phase and inhibited cell proliferation of GBM cells through the Akt–mTOR–p70S6K pathway. Dysregulation of ERs and cell cycle in morusin exposed GBM cells were confirmed by RNA-seq analysis. Finally, we demonstrated the combination of morusin and TMZ remarkably enhanced ER stress and displayed a synergistic effect in GBM cells, and suppressed tumor progression in an orthotopic xenograft model. In conclusion, these findings reveal the toxicity of morusin to GBM cells and its ability to enhance drug sensitivity to TMZ, suggesting the potential application value of morusin in the development of therapeutic strategies for human GBM. Full article

(This article belongs to the Special Issue The Recent Updates in Glioblastoma Management)

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12 pages, 1185 KiB

Open AccessArticle

Prognostic Values of Combined Ratios of White Blood Cells in Glioblastoma: A Retrospective Study

by Pawel Jarmuzek, Marcin Kot, Piotr Defort, Jakub Stawicki, Julia Komorzycka, Karol Nowak, Anna Tylutka and Agnieszka Zembron-Lacny

J. Clin. Med. 2022, 11(12), 3397; https://doi.org/10.3390/jcm11123397 - 13 Jun 2022

Cited by 10 | Viewed by 1680

Abstract

In some malignant tumours, the changes in neutrophil counts in relation to other blood cells are connected with unfavourable prognosis. Nevertheless, the prognostic value of the combinations of the haematological components in glioblastoma (GBM) remains under dispute. The clinical significance of the neutrophil-to-lymphocyte [...] Read more.

In some malignant tumours, the changes in neutrophil counts in relation to other blood cells are connected with unfavourable prognosis. Nevertheless, the prognostic value of the combinations of the haematological components in glioblastoma (GBM) remains under dispute. The clinical significance of the neutrophil-to-lymphocyte ratio (NLR), systemic immune inflammation index (SII), and systemic inflammation response index (SIRI) was investigated in our study. We retrospectively studied 358 patients (males n = 195; females n = 163) aged 59.9 ± 13.5 yrs with newly diagnosed glioma and admitted to the Neurosurgery Centre. Routine blood tests and clinical characteristics were recorded within the first hour of hospital admission. The inflammatory variables: NLR, SII and SIRI exceeded the reference values and were significantly elevated in Grade 3 and Grade 4 tumour. The Cox model analysis showed that the age ≥ 63 years, NLR ≥ 4.56 × 10³/µL, SII ≥ 2003 × 10³/µL and SIRI ≥ 3.03 × 10³/µL significantly increased the risk of death in Grade 4 tumour patients. In the inflammatory variables, NLR demonstrated the highest impact on the survival time (HR 1.56; 95% CI 1.145–2.127; p = 0.005). In the first Polish study including GBM patients, the age in relation to simple parameters derived from complete blood cell count were found to have prognostic implications in the survival rate. Full article

(This article belongs to the Special Issue The Recent Updates in Glioblastoma Management)

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Review

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17 pages, 619 KiB

Open AccessReview

Depression and Quality of Life in Patients with Gliomas: A Narrative Review

by Yue Hu, Fang Deng, Lupeng Zhang, Keyue Hu, Shiqi Liu, Suye Zhong, Jun Yang, Xiaomin Zeng and Xiaoning Peng

J. Clin. Med. 2022, 11(16), 4811; https://doi.org/10.3390/jcm11164811 - 17 Aug 2022

Cited by 4 | Viewed by 1664

Abstract

In patients with gliomas, depression is a common complication that may cause severe psychological barriers and deteriorate the patient’s quality of life (QoL). Currently, the Hospital Anxiety and Depression Scale (HADS) is the most commonly used tool to diagnose depression in patients with [...] Read more.

In patients with gliomas, depression is a common complication that may cause severe psychological barriers and deteriorate the patient’s quality of life (QoL). Currently, the Hospital Anxiety and Depression Scale (HADS) is the most commonly used tool to diagnose depression in patients with gliomas. Female sex, unmarried status, low education level, high tumor grade, and a history of mental illness may increase the risks of depression and depressive symptoms in patients with gliomas. The QoL of patients with gliomas can be directly reduced by depression. Therefore, the evaluation and intervention of mood disorders could improve the overall QoL of patients with gliomas. Antidepressant use has become a treatment strategy for patients with gliomas and comorbid depression. This narrative review summarizes the current issues related to depression in patients with gliomas, including the prevalence, risk factors, and diagnostic criteria of depression as well as changes in QoL caused by comorbid depression and antidepressant use. The purpose of this review is to guide clinicians to assess the psychological status of patients with gliomas and to provide clinicians and oncologists with a new treatment strategy to improve the prognosis of such patients. Full article

(This article belongs to the Special Issue The Recent Updates in Glioblastoma Management)

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