scholarly journals Mindbomb Homolog-1 Index in the Prognosis of High-Grade Glioma and Its Clinicopathological Correlation

2019 ◽  
Vol 10 (02) ◽  
pp. 185-193
Author(s):  
Shyam Sundar Krishnan ◽  
Shanmugam Muthiah ◽  
Shilpa Rao ◽  
Suganthi Srinivasan Salem ◽  
Vasudevan Chakravarthy Madabhushi ◽  
...  
Keyword(s):  
Median Survival ◽  
High Grade Glioma ◽  
Tumor Grade ◽  
Bivariate Analysis ◽  
Karnofsky Performance Score ◽  
High Grade ◽  
Tissue Samples ◽  
Midline Crossing ◽  
Index Value ◽  
Mib 1

ABSTRACT Introduction: Gliomas are the most common brain tumors in adults originating from the glial cells. Glioblastoma multiforme is the most malignant and frequent among all gliomas. In recent years, the antibody Mindbomb Homolog-1 (MIB-1) has evolved as a measure of the proliferative nature of the glial tumors. This study aims to investigate the MIB-1 index value as an independent prognostic factor in high-grade gliomas and its correlation with outcome and survival. Materials and Methods: Mean MIB-1 index was determined in 51 high-grade glioma tissue samples in formalin. Its correlation with outcome by assessing the clinicoradiological parameters and median survival of patients in months were assessed. Survival analysis was studied by using the Kaplan–Meier bivariate analysis and Cox proportional ratio. Results: Preoperative Karnofsky Performance Score, WHO-PS, Neurological Performance Scale, and Mini–Mental Status Examination (MMSE) were statistically significant with respect to outcome and survival, whereas tumor factors such as size and perilesional edema were not. In particular, midline-crossing tumors and deep-seated tumors were significantly associated with high MIB-1 index and by correlation with outcome. There were significantly higher number (P < 0.0001) of patients with Grade IV tumors, with an MIB-1 index value above an arbitrary cutoff of 10% compared to Grade III tumors. In addition, median survival period of patients with low MIB-1 index was longer irrespective of tumor grade. Conclusion: Significant correlation between high-grade glioma and MIB-1 index suggests MIB-1 index to be a good prognostic tool, with MIB-1 index and midline-crossing variables being independent prognostic parameters.

scholarly journals Platelet-derived growth factor beta is a potent inflammatory driver in paediatric high-grade glioma

Brain ◽  
2020 ◽  
Author(s):  
James L Ross ◽  
Zhihong Chen ◽  
Cameron J Herting ◽  
Yura Grabovska ◽  
Frank Szulzewsky ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Median Survival ◽  
High Grade Glioma ◽  
Cell Types ◽  
Tumour Microenvironment ◽  
Pcr Analysis ◽  
High Grade ◽  
Tissue Samples ◽  
Inflammatory Microenvironment

Abstract Paediatric high-grade gliomas (HGGs) account for the most brain tumour-related deaths in children and have a median survival of 12–15 months. One promising avenue of research is the development of novel therapies targeting the properties of non-neoplastic cell-types within the tumour such as tumour associated macrophages (TAMs). TAMs are immunosuppressive and promote tumour malignancy in adult HGG; however, in paediatric medulloblastoma, TAMs exhibit anti-tumour properties. Much is known about TAMs in adult HGG, yet little is known about them in the paediatric setting. This raises the question of whether paediatric HGGs possess a distinct constituency of TAMs because of their unique genetic landscapes. Using human paediatric HGG tissue samples and murine models of paediatric HGG, we demonstrate diffuse midline gliomas possess a greater inflammatory gene expression profile compared to hemispheric paediatric HGGs. We also show despite possessing sparse T-cell infiltration, human paediatric HGGs possess high infiltration of IBA1+ TAMs. CD31, PDGFRβ, and PDGFB all strongly correlate with IBA1+ TAM infiltration. To investigate the TAM population, we used the RCAS/tv-a system to recapitulate paediatric HGG in newborn immunocompetent mice. Tumours are induced in Nestin-positive brain cells by PDGFA or PDGFB overexpression with Cdkn2a or Tp53 co-mutations. Tumours driven by PDGFB have a significantly lower median survival compared to PDGFA-driven tumours and have increased TAM infiltration. NanoString and quantitative PCR analysis indicates PDGFB-driven tumours have a highly inflammatory microenvironment characterized by high chemokine expression. In vitro bone marrow-derived monocyte and microglial cultures demonstrate bone marrow-derived monocytes are most responsible for the production of inflammatory signals in the tumour microenvironment in response to PDGFB stimulation. Lastly, using knockout mice deficient for individual chemokines, we demonstrate the feasibility of reducing TAM infiltration and prolonging survival in both PDGFA and PDGFB-driven tumours. We identify CCL3 as a potential key chemokine in these processes in both humans and mice. Together, these studies provide evidence for the potent inflammatory effects PDGFB has in paediatric HGGs.

scholarly journals How well do neurosurgeons predict survival in patients with high-grade glioma?

2021 ◽  
Author(s):  
Lisa Millgård Sagberg ◽  
Asgeir S. Jakola ◽  
Ingerid Reinertsen ◽  
Ole Solheim
Keyword(s):  
Median Survival ◽  
Survival Curve ◽  
Binary Logistic Regression ◽  
High Grade Glioma ◽  
Accurate Estimation ◽  
Binary Logistic Regression Analysis ◽  
High Grade ◽  
Clinical Prediction ◽  
Individual Level ◽  
Actual Survival

AbstractDue to the lack of reliable prognostic tools, prognostication and surgical decisions largely rely on the neurosurgeons’ clinical prediction skills. The aim of this study was to assess the accuracy of neurosurgeons’ prediction of survival in patients with high-grade glioma and explore factors possibly associated with accurate predictions. In a prospective single-center study, 199 patients who underwent surgery for high-grade glioma were included. After surgery, the operating surgeon predicted the patient’s survival using an ordinal prediction scale. A survival curve was used to visualize actual survival in groups based on this scale, and the accuracy of clinical prediction was assessed by comparing predicted and actual survival. To investigate factors possibly associated with accurate estimation, a binary logistic regression analysis was performed. The surgeons were able to differentiate between patients with different lengths of survival, and median survival fell within the predicted range in all groups with predicted survival < 24 months. In the group with predicted survival > 24 months, median survival was shorter than predicted. The overall accuracy of surgeons’ survival estimates was 41%, and over- and underestimations were done in 34% and 26%, respectively. Consultants were 3.4 times more likely to accurately predict survival compared to residents (p = 0.006). Our findings demonstrate that although especially experienced neurosurgeons have rather good predictive abilities when estimating survival in patients with high-grade glioma on the group level, they often miss on the individual level. Future prognostic tools should aim to beat the presented clinical prediction skills.

scholarly journals Classification and Treatment of Pediatric Gliomas in the Molecular Era

Children ◽  
2021 ◽  
Vol 8 (9) ◽  
pp. 739
Author(s):  
Peter Hauser
Keyword(s):  
Wide Spectrum ◽  
High Grade Glioma ◽  
Tumor Grade ◽  
Primary Treatment ◽  
Low Grade ◽  
High Grade ◽  
Therapeutic Approaches ◽  
Term Survival ◽  
Low Grade Gliomas ◽  
Leading Role

The overall survival of pediatric gliomas varies over a wide spectrum depending on the tumor grade. Low-grade gliomas have an excellent long-term survival, with a possible burden of surgery, irradiation, and chemotherapy; in contrast, high-grade gliomas generally have a short-term, devastating lethal outcome. Recent advances in understanding their molecular background will transform the classification and therapeutic approaches of pediatric gliomas. Molecularly targeted treatments may acquire a leading role in the primary treatment of low-grade gliomas and may provide alternative therapeutic strategies for high-grade glioma cases in the attempt to avoid the highly unsuccessful conventional therapeutic approaches. This review aims to overview this progress.

scholarly journals P10.02 Differentiating microglia and tumour associated macrophages in high grade glioma

2019 ◽  
Vol 21 (Supplement_3) ◽  
pp. iii40-iii41
Author(s):  
Z Woolf ◽  
M Swanson ◽  
T Park ◽  
A Brooks ◽  
M Dragunow
Keyword(s):  
High Grade Glioma ◽  
Cell Types ◽  
Immunofluorescent Staining ◽  
Immunocytochemical Staining ◽  
Rapid Progression ◽  
Low Grade ◽  
High Grade ◽  
Isolated Cells ◽  
Tissue Samples ◽  
Strong Basis

Abstract BACKGROUND Glioblastoma multiforme (GBM) is the most common primary brain tumour that affects adults. This aggressive tumour is invariably fatal, carrying a rapid progression and a dismal median survival period of only 15 months despite multimodal treatment approaches. Central to GBM pathogenesis is the immunosuppressive profile of these tumours. The two cell types that are highly abundant in these tumours and play critical roles in the immunosuppressive niche are the brain’s resident microglia and their peripheral counterparts - tumour associated macrophages (TAMs). Despite microglia and TAMs being ontogenetically distinct, these cells have largely been grouped together in research owing to the previous lack of cell-specific markers. Recent evidence has suggested that although TAMs may hold a predominantly pro-tumoral role, microglia may adopt a more anti-tumoral phenotype. Therefore, the differentiation of these two cell types is critical in elucidating the potentially characteristic roles of these two cell types in GBM pathogenesis. MATERIAL AND METHODS Tissue sections from resected low- and high-grade glioma tumours, along with epilepsy tissue (control), were used for immunohistochemistry (IHC) staining of macrophage pan-makers (Iba1, CD45, PU.1) and microglial-specific markers (TMEM119, P2RY12). Marker co-localisation was then used to differentiate microglia from TAMs. We further investigated a wider subset of cell-specific markers using multicolour flow cytometry and immunocytochemical staining of isolated cells from patient tissue samples. RESULTS Immunofluorescent staining of glioma and epilepsy tissue revealed two clear populations of cells; one population displayed long processes and co-labelling for both pan- and microglial-specific markers, whilst the other population displayed an amoeboid phenotype with only pan-maker staining. Preliminary analysis comparing microglia/TAM populations in low-grade, high-grade and epilepsy tissue suggests a clear difference in the proportions of these cells. CONCLUSION Our work complements RNA-Seq studies, showing that TMEM119 and P2RY12, alongside other markers, can indeed identify two distinct myeloid cell populations within glioma tissue. This provides a strong basis for further study where we aim to elucidate the respective roles of microglia and TAMs within tumours. Ultimately, this may hold the potential for differential targeting of these cells using immunotherapies.

scholarly journals Large volume re-irradiation with bevacizumab is a feasible salvage option for patients with refractory high-grade glioma

2014 ◽  
Vol 2 (1) ◽  
pp. 48-53 ◽  
Author(s):  
Michael Back ◽  
Cecelia E. Gzell ◽  
Marina Kastelan ◽  
Linxin Guo ◽  
Helen R. Wheeler
Keyword(s):  
Median Survival ◽  
Large Volume ◽  
Small Volume ◽  
Tumor Volume ◽  
High Grade Glioma ◽  
Target Volume ◽  
Tumor Diameter ◽  
High Grade ◽  
Kaplan Meier ◽  
Maximum Tumor Diameter

AbstractBackgroundClinical studies of re-irradiation (ReRT) for relapsed high-grade glioma (HGG) have generally reported the use of small volume ReRT techniques such as stereotactic radiosurgery in selected patients with isolated focal relapse. This study reports the outcome with large-volume ReRT to manage the more common mescenario of extensive diffuse relapse of HGG.MethodsAll HGG patients managed with an overlapping second course of radiation therapy (RT) for refractory progression of HGG between October 2009 and April 2013 were included. ReRT was initially used with bevacizumab (BEV), then used when disease was refractory to BEV, and finally used upfront with BEV-naïve patients. Tumor volume (GTV) and specific RT dosimetry factors, including the target volume treated (PTV), and cumulative RT dose maximum (Dmax), were analyzed. Median survival post ReRT was calculated using the Kaplan-Meier method and SPPS v19 software.ResultsEighteen HGG participants with refractory, bulky contrast-enhancing disease received ReRT. Thirteen participants had a maximum tumor diameter &gt;5 cm, and median GTV was 54 cm3. Seven participants had BEV-refractory disease, and 8 participants were BEV naïve. ReRT dose was 35–40 Gy in 15 fractions; median PTV was 133 cm3, and median Dmax was 98.2 Gy. Median survival post ReRT for all participants was 8 months (95%CI, 5.8–10.2 months); with 10 months and 3 months for the BEV-naïve and BEV-refractory participants, respectively (P = .024). Two early participants, who were managed without BEV, were later salvaged with BEV, including one who required craniotomy for radiation necrosis at 6 weeks post RT. No other significant morbidity was reported.ConclusionReRT combined with BEV is a feasible salvage treatment option for diffuse refractory HGG.

scholarly journals Functional Diffusion Map As an Early Imaging Biomarker for High-Grade Glioma: Correlation With Conventional Radiologic Response and Overall Survival

2008 ◽  
Vol 26 (20) ◽  
pp. 3387-3394 ◽  
Author(s):  
Daniel A. Hamstra ◽  
Craig J. Galbán ◽  
Charles R. Meyer ◽  
Timothy D. Johnson ◽  
Pia C. Sundgren ◽  
...  
Keyword(s):  
Overall Survival ◽  
Median Survival ◽  
Patient Survival ◽  
Characteristic Curve ◽  
High Grade Glioma ◽  
Cox Proportional Hazards ◽  
Response To Therapy ◽  
Imaging Biomarker ◽  
High Grade ◽  
Diffusion Map

PurposeAssessment of radiologic response (RR) for brain tumors utilizes the Macdonald criteria 8 to 10 weeks from the start of treatment. Diffusion magnetic resonance imaging (MRI) using a functional diffusion map (fDM) may provide an earlier measure to predict patient survival.Patients and MethodsSixty patients with high-grade glioma were enrolled onto a study of intratreatment MRI at 1, 3, and 10 weeks. Receiver operating characteristic curve analysis was used to evaluate imaging parameters as a function of patient survival at 1 year. Both log-rank and Cox proportional hazards models were utilized to assess overall survival.ResultsGreater increases in diffusion in response to therapy over time were observed in those patients alive at 1 year compared with those who died as a result of disease. The volume of tumor with increased diffusion by fDM at 3 weeks was the strongest predictor of patient survival at 1 year, with larger fDM predicting longer median survival (52.6 v 10.9 months; log-rank, P < .003; hazard ratio [HR] = 2.7; 95% CI, 1.5 to 5.9). Radiologic response at 10 weeks had similar prognostic value (median survival, 31.6 v 10.9 months; log-rank P < .0007; HR = 2.9; 95% CI, 1.7 to 7.2). Radiologic response and fDM differed in 25% of cases. A composite index of response including fDM and RR provided a robust predictor of patient survival and may identify patients in whom RR does not correlate with clinical outcome.ConclusionCompared with conventional neuroimaging, fDM provided an earlier assessment of equal predictive value, and the combination of fDM and RR provided a more accurate prediction of patient survival than either metric alone.

scholarly journals Homotopic functional connectivity disruptions in glioma patients are associated with tumor malignancy and overall survival

2021 ◽  
Author(s):  
Andy G S Daniel ◽  
Carl D Hacker ◽  
John J Lee ◽  
Donna Dierker ◽  
Joseph B Humphries ◽  
...  
Keyword(s):  
Overall Survival ◽  
Functional Connectivity ◽  
Healthy Subjects ◽  
High Grade Glioma ◽  
Tumor Grade ◽  
World Health ◽  
Low Grade ◽  
High Grade ◽  
Healthy Controls ◽  
Who Grade

Abstract Background Gliomas exhibit widespread bilateral functional connectivity (FC) alterations that may be associated with tumor grade. Limited studies have examined the connection-level mechanisms responsible for these effects. Given the typically strong FC observed between mirroring/homotopic brain regions in healthy subjects, we hypothesized that homotopic connectivity (HC) is altered in low-grade and high-grade glioma patients and the extent of disruption is associated with tumor grade and predictive of overall survival (OS) in a cohort of de novo high-grade glioma (World Health Organization [WHO] grade 4) patients. Methods We used a mirrored FC-derived cortical parcellation to extract blood-oxygen-level-dependent (BOLD) signals and to quantify FC differences between homotopic pairs in normal-appearing brain in a retrospective cohort of glioma patients and healthy controls. Results Fifty-nine glioma patients (WHO grade 2, n = 9; grade 4 = 50; mean age, 57.5 years) and thirty healthy subjects (mean age, 65.9 years) were analyzed. High-grade glioma patients showed lower HC compared to low-grade glioma patients and healthy controls across several cortical locations and resting-state networks. Connectivity disruptions were also strongly correlated with hemodynamic lags between homotopic regions. Finally, in high-grade glioma patients with known survival times (n = 42), HC in somatomotor and dorsal attention networks were significantly correlated with OS. Conclusions These findings demonstrate an association between tumor grade and HC alterations that may underlie global FC changes and provide prognostic information.

scholarly journals A New Mouse Model of Diffuse Midline Glioma to Test Targeted Immunotherapies

2021 ◽  
Author(s):  
Maggie D Seblani ◽  
Markella Zannikou ◽  
Joseph Duffy ◽  
Rebecca N Levine ◽  
Qianli Liu ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
Cell Lines ◽  
Median Survival ◽  
Delivery System ◽  
De Novo ◽  
High Grade Glioma ◽  
Cre Recombinase ◽  
High Grade ◽  
Diffuse Midline Glioma ◽  
De Novo Tumors

BACKGROUND: Diffuse midline gliomas remain incurable, with consistently poor outcomes in children despite radiotherapy. Immunotherapeutic approaches hold promise, with the integration of the host's immune system fundamental to their design. Here, we describe a new, genetically engineered immunocompetent model that incorporates interleukin 13 receptor alpha 2 (IL13Rα2), a tumor-associated antigen, which is suitable for further evaluation of the antitumor activity of IL13Rα2-targeted immunotherapeutics in preclinical studies. METHODS: The RCAS-Tv-a delivery system was used to induce gliomagenesis through overexpression of PDGFB and p53 deletion with and without human IL13Rα2 in Nestin-Tva; p53fl/fl mice. Neonatal pups were infected with Cre recombinase and PDGFB+IL13Rα2 or Cre recombinase and PDGFB in forth ventricle or right cortex of the brain to model diffuse midline glioma and pediatric high-grade glioma, respectively. Immunoblotting and flow cytometry was used to confirm target expression. Kaplan-Meier survival curves were established to compare tumor latency in both models. Tumor tissue was analyzed through immunohistochemistry and H&E staining. Cell lines generated from tumor-bearing mice were used for in vitro studies and orthotopic injections. RESULTS: The protein expression of PDGFB and IL13Rα2 was confirmed by flow cytometry and western blot. In both groups, de novo tumors developed without significant difference in median survival between PDGFB and p53 loss (n=25, 40 days) and PDGB, IL13Rα2, and p53 loss (n=33, 38 days, p=0.62). Tumors demonstrated characteristics of high-grade glioma such as infiltration, palisading necrosis, microvascular proliferation, high Ki-67 index, heterogeneous IL13Rα2 expression, and CD11b+ macrophages, along with a low proportion of CD3+ T cells. Orthotopic tumors developed from cell lines retained histopathological characteristics of de novo tumors. Mice orthotopically implanted with cells in the 4th ventricle or right cortex showed a median survival of 42 days and 41 (p=0.56) days, respectively. CONCLUSION: Generation of de novo tumors using the RCAS-Tv-a delivery system was successful, with tumors possessing histopathologic features common to pediatric diffuse gliomas. The development of these models opens the opportunity for preclinical assessment of IL13Rα2-directed immunotherapies with the potential for clinical translation.

Gamma Knife Radiosurgery for High-Grade Gliomas: Single-Center Experience of Six Years in China

2021 ◽  
Vol 99 (3) ◽  
pp. 181-186
Author(s):  
Ming Zhao ◽  
Xiangping Fu ◽  
Zhiwen Zhang ◽  
Liang Ma ◽  
Xiaopeng Wang ◽  
...  
Keyword(s):  
Gamma Knife ◽  
Cox Regression ◽  
Survival Rates ◽  
Gamma Knife Radiosurgery ◽  
Progression Free Survival ◽  
High Grade Glioma ◽  
Karnofsky Performance Score ◽  
High Grade ◽  
Alternative Treatment Option ◽  
The Mean

<b><i>Objective:</i></b> The aim of this study was to evaluate the efficacy of Gamma Knife radiosurgery (GKRS) as a salvage therapy for high-grade glioma in our center. <b><i>Methods:</i></b> A total of 167 patients with malignant glioma were treated with GKRS in our Gamma Knife Center between January 2013 and December 2017; 140 patients (85 males and 55 females) were followed up and enrolled in our study. A single lesion was found in 110 cases, and multiple lesions were found in 30 cases; 108 cases received a single therapy, and in 32 cases, at least 2 GKRSs were performed. The median tumor volume was 13.5 cm<sup>3</sup>. The mean radiation dosage was 14.35 Gy (range, 6–18 Gy). MRI was performed regularly. The RANO criteria and Cox analysis were used to evaluate the therapeutic efficiency. <b><i>Results:</i></b> Follow-up MRI showed the local control rate was 61.4% at 3 months after GKRS, 25.0% at 6 months, and 7.1% at 12 months. The mean and median progression-free survival (PFS) periods were 8.6 (95% CI, 6.3–11.0) and 4 (95% CI, 3.5–4.5) (range, 1–60) months, respectively. The overall survival (OS) after GKRS was 3–62 months, with a mean of 16.7 (95% CI, 14.6–18.9) months, and the median survival was 13 (95% CI, 12.1–13.9) months. The 1-, 2-, and 5-year survival rates were 51.4, 10.0, and 2.9%, respectively. No severe complications occurred. Cox regression showed that glioma pathology was closely related to prognosis (<i>p</i> &#x3c; 0.05). The Karnofsky Performance Score had little influence on PFS (<i>p</i> &#x3e; 0.05) but influenced OS significantly (<i>p</i> &#x3c; 0.05). <b><i>Conclusion:</i></b> GKRS can be used to effectively treat malignant brain glioma and can therefore be used as an alternative treatment option.

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