Astrocytic tumours: diffuse astrocytoma, anaplastic astrocytoma, glioblastoma, and gliomatosis cerebri

Astrocytic gliomas are primary brain tumours thought to originate from neural stem or progenitor cells. They are assigned grades II, III, or IV by the World Health Organization according to degree of malignancy as defined by histology. The following molecular markers are increasingly used for diagnostic subclassification or clinical decision-making: 1p/19q co-deletion status, O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation status, and isocitrate dehydrogenase 1 and 2 mutation status. Extent of resection is a favourable prognostic factor, but surgery is never curative. Radiotherapy prolongs progression-free survival across all astrocytic glioma entities. Alkylating agent chemotherapy is an active treatment in particular for patients with MGMT promoter-methylated tumours. Anti-angiogenic therapies have failed to improve survival, and the current focus of major clinical trials is on novel targeted agents or on immunotherapy.

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Do we really know who has an MGMT methylated glioma? Results of an international survey regarding use of MGMT analyses for glioma

Neuro-Oncology Practice ◽

10.1093/nop/npz039 ◽

2019 ◽

Vol 7 (1) ◽

pp. 68-76 ◽

Cited By ~ 4

Author(s):

Annika Malmström ◽

Małgorzata Łysiak ◽

Bjarne Winther Kristensen ◽

Elizabeth Hovey ◽

Roger Henriksson ◽

...

Keyword(s):

Dna Methyltransferase ◽

Clinical Decision Making ◽

Methylation Status ◽

Clinical Decision ◽

International Survey ◽

Mgmt Methylation ◽

International Consensus ◽

Methylguanine Dna Methyltransferase ◽

Cpg Sites ◽

International Consensus Guidelines

Abstract Background Glioma O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation status informs clinical decision making. Worldwide different methods and cutoff levels are used, which can lead to discordant methylation results. Methods We conducted an international survey to clarify which methods are regularly used and why. We also explored opinions regarding international consensus on methods and cutoff. Results The survey had 152 respondents from 25 countries. MGMT methylation status is determined for all glioblastomas in 37% of laboratories. The most common methods are methylation-specific polymerase chain reaction (msPCR) (37%) and pyrosequencing (34%). A method is selected for simplicity (56%), cost-effectiveness (50%), and reproducibility of results (52%). For sequencing, the number of CpG sites analyzed varies from 1–3 up to more than 16. For 50% of laboratories, the company producing the kit determines which CpG sites are examined, whereas 33% select the sites themselves. Selection of cutoff is equally distributed among a cutoff defined in the literature, by the local laboratory, or by the outside laboratory performing the analysis. This cutoff varies, reported from 1% to 30%, and in 1 laboratory tumor is determined as methylated in case of 1 methylated CpG site of 17 analyzed. Some report tumors as unmethylated or weakly vs highly methylated. An international consensus on MGMT methylation method and cutoff is warranted by 66% and 76% of respondents, respectively. The method preferred would be msPCR (45%) or pyrosequencing (42%), whereas 18% suggest next-generation sequencing. Conclusion Although analysis of MGMT methylation status is routine, there is controversy regarding laboratory methods and cutoff level. Most respondents favor development of international consensus guidelines.

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Methylation of MGMT promoter does not predict response to temozolomide in patients with glioblastoma in Donostia Hospital

Scientific Reports ◽

10.1038/s41598-020-75477-9 ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Larraitz Egaña ◽

Jaione Auzmendi-Iriarte ◽

Joaquin Andermatten ◽

Jorge Villanua ◽

Irune Ruiz ◽

...

Keyword(s):

Promoter Methylation ◽

Dna Methyltransferase ◽

Methylation Status ◽

Progression Free Survival ◽

Mgmt Promoter Methylation ◽

Mgmt Methylation ◽

Free Survival ◽

Methylguanine Dna Methyltransferase ◽

Mgmt Promoter ◽

Newly Diagnosed Glioblastoma

Abstract O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation status has been considered a prognostic factor in newly diagnosed glioblastoma (GBM). In this study, we evaluated the prognostic and predictive value of MGMT promoter methylation in patients with glioblastoma in Donostia Hospital. Surprisingly, methylation of MGMT promoter did not predict response to temozolomide in patients with glioblastoma in Donostia Hospital. Specifically, overall survival (OS) and progression-free survival (PFS) did not differ significantly by MGMT methylation status in our cohort. In contrast, both were longer in patients who received treatment, received more TMZ cycles, had a better general status and perform at least a partial resection. No association was detected between methylation of MGMT promoter and molecular markers such as ATRX, IDH, p53 and Ki67. These results indicate that MGMT methylation did not influence in patient survival in our cohort.

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Prognostic and Clinical Values of Chaperone Protein P4HB in Malignant Glioma

10.21203/rs.3.rs-808854/v1 ◽

2021 ◽

Author(s):

Stella Sun ◽

Karrie Mei-Yee Kiang ◽

Gilberto Ka-Kit Leung

Keyword(s):

Promoter Methylation ◽

Clinical Decision Making ◽

Methylation Status ◽

Progression Free Survival ◽

High Grade Glioma ◽

Mgmt Promoter Methylation ◽

Clinicopathological Parameters ◽

Who Grade ◽

Free Survival ◽

Mgmt Promoter

Abstract Introduction. Prolyl 4-hydroxylase, beta polypeptide (P4HB) has previously been identified by our group to play important roles in association with glioma malignancy and temozolomide (TMZ) resistance through the unfolded protein response (UPR). The present study focused on the prognostic value of P4HB in glioma. Methods. P4HB expression was assessed by immunohistochemical staining and semi-quantified by pathologist visual scoring in 73 WHO grade I-IV gliomas. Results were correlated with clinicopathological data. Results. Our results show that P4HB expression was significantly associated several clinicopathological parameters including age (p=0.035), tumour grade (p=0.002), and the number of TMZ treatment cycles received (p=0.043). Using Kaplan-Meier analysis, P4HB expression was positively correlated with mortality (p=0.014) and disease progression (p=0.026). In patients treated with TMZ, high P4HB expression level was significantly associated with poorer overall survival (OS) (p=0.014) and progression free survival (PFS) (p=0.027). The association between MGMT promoter methylation and P4HB expression was also interrogated. Patients with MGMTMethP4HBLow tumours had the most favourable progression free survival (48 months) than patients with other combination of MGMT methylation status and P4HB expression (log rank p=0.001). Multivariate analysis revealed that P4HB was an independent prognostic indicator for OS (p=0.048). Conclusions. P4HB could constitute an independent prognostic marker, especially for high grade glioma with the potential for informing a nuanced pathological stratification during clinical decision-making with respect to MGMT promoter methylation status and TMZ treatment.

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MGMT Promoter Methylation and Glioblastoma: A Comparison of Analytical Methods and of Tumor Specimens

The International Journal of Biological Markers ◽

10.5301/jbm.5000126 ◽

2015 ◽

Vol 30 (2) ◽

pp. 208-216 ◽

Cited By ~ 6

Author(s):

Laura Lattanzio ◽

Marzia Borgognone ◽

Cristina Mocellini ◽

Fabrizio Giordano ◽

Ermanno Favata ◽

...

Keyword(s):

Analytical Methods ◽

Dna Methyltransferase ◽

Tissue Sample ◽

Methylation Status ◽

Progression Free Survival ◽

High Sensitivity ◽

Predictive Biomarker ◽

Tissue Type ◽

Mgmt Methylation ◽

Mgmt Promoter

It is already well known that hypermethylation of the O6-methylguanine DNA methyltransferase (MGMT) gene promoter is a predictive biomarker of response to temozolomide treatment and of favorable outcomes in terms of overall survival (OS) and progression-free survival (PFS) in glioblastoma (GBM) patients. Nevertheless, MGMT methylation status has not currently been introduced into routine clinical practice, as the choice of the ideal technique and tissue sample specimen is still controversial. The aim of this study was to compare 2 analytical methods, methylation-specific polymerase chain reaction (MSP) and pyrosequencing (PSQ), and their use on 2 different tissue type samples, snap-frozen and formalin-fixed paraffin-embedded (FFPE), obtained from a single-center and uniformly treated cohort of 46 GBM patients. We obtained methylation data from all frozen tissues, while no results were obtained for 5 FFPE samples. The highest concordance for methylation was found on frozen tissues (88.5%, 23/26 samples), using PSQ (76.7%, 23/30 samples). Moreover, we confirmed that OS and PFS for patients carrying methylation of the MGMT promoter were longer than for patients with an unmethylated promoter. In conclusion, we considered MSP a limited technique for FFPE tissues due to the high risk of false-positive results; in contrast, our data indicated PSQ as the most powerful method to stratify methylated/unmethylated patients as it allows reaching quantitative results with high sensitivity and specificity. Furthermore, frozen tumor tissues were shown to be the best specimens for MGMT methylation analysis, due to the low DNA degradation and homogeneity in methylation throughout the tumor.

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Ethical use of off-label disease-modifying therapies for multiple sclerosis

Multiple Sclerosis Journal ◽

10.1177/13524585211030207 ◽

2021 ◽

pp. 135245852110302

Author(s):

Joanna Laurson-Doube ◽

Nick Rijke ◽

Anne Helme ◽

Peer Baneke ◽

Brenda Banwell ◽

...

Keyword(s):

Multiple Sclerosis ◽

Clinical Decision Making ◽

Clinical Decision ◽

World Health ◽

World Federation ◽

Off Label ◽

Disease Modifying Therapies ◽

The World ◽

Disease Modifying ◽

Health Organization

Background: Off-label disease-modifying therapies (DMTs) for multiple sclerosis (MS) are used in at least 89 countries. There is a need for structured and transparent evidence-based guidelines to support clinical decision-making, pharmaceutical policies and reimbursement decisions for off-label DMTs. Objectives/Results: The authors put forward general principles for the ethical use of off-label DMTs for treating MS and a process to assess existing evidence and develop recommendations for their use. Conclusion: The principles and process are endorsed by the World Federation of Neurology (WFN), American Academy of Neurology (AAN), European Academy of Neurology (EAN), Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS), European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS), Middle-East North Africa Committee for Treatment and Research in Multiple Sclerosis (MENACTRIMS) and Pan-Asian Committee for Treatment and Research in Multiple Sclerosis (PACTRIMS), and we have regularly consulted with the Brain Health Unit, Mental Health and Substance Use Department at the World Health Organization (WHO).

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Diagnostic accuracy of symptoms as a diagnostic tool for SARS-CoV 2 infection: a cross-sectional study in a cohort of 2,173 patients

BMC Infectious Diseases ◽

10.1186/s12879-021-05930-1 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Carlos Alfonso Romero-Gameros ◽

Tania Colin-Martínez ◽

Salomón Waizel-Haiat ◽

Guadalupe Vargas-Ortega ◽

Eduardo Ferat-Osorio ◽

...

Keyword(s):

Diagnostic Accuracy ◽

Diagnostic Tool ◽

Clinical Decision Making ◽

Multivariate Logistic Regression Analysis ◽

Clinical Decision ◽

Cross Sectional Study ◽

World Health ◽

Likelihood Ratios ◽

Cross Sectional ◽

Health Organization

Abstract Background The SARS-CoV-2 pandemic continues to be a priority health problem; According to the World Health Organization data from October 13, 2020, 37,704,153 confirmed COVID-19 cases have been reported, including 1,079,029 deaths, since the outbreak. The identification of potential symptoms has been reported to be a useful tool for clinical decision-making in emergency departments to avoid overload and improve the quality of care. The aim of this study was to evaluate the performances of symptoms as a diagnostic tool for SARS -CoV-2 infection. Methods An observational, cross-sectional, prospective and analytical study was carried out, during the period of time from April 14 to July 21, 2020. Data (demographic variables, medical history, respiratory and non-respiratory symptoms) were collected by emergency physicians. The diagnosis of COVID-19 was made using SARS-CoV-2 RT-PCR. The diagnostic accuracy of these characteristics for COVID-19 was evaluated by calculating the positive and negative likelihood ratios. A Mantel-Haenszel and multivariate logistic regression analysis was performed to assess the association of symptoms with COVID-19. Results A prevalence of 53.72% of SARS-CoV-2 infection was observed. The symptom with the highest sensitivity was cough 71%, and a specificity of 52.68%. The symptomatological scale, constructed from 6 symptoms, obtained a sensitivity of 83.45% and a specificity of 32.86%, taking ≥2 symptoms as a cut-off point. The symptoms with the greatest association with SARS-CoV-2 were: anosmia odds ratio (OR) 3.2 (95% CI; 2.52–4.17), fever OR 2.98 (95% CI; 2.47–3.58), dyspnea OR 2.9 (95% CI; 2.39–3.51]) and cough OR 2.73 (95% CI: 2.27–3.28). Conclusion The combination of ≥2 symptoms / signs (fever, cough, anosmia, dyspnea and oxygen saturation < 93%, and headache) results in a highly sensitivity model for a quick and accurate diagnosis of COVID-19, and should be used in the absence of ancillary diagnostic studies. Symptomatology, alone and in combination, may be an appropriate strategy to use in the emergency department to guide the behaviors to respond to the disease. Trial registration Institutional registration R-2020-3601-145, Federal Commission for the Protection against Sanitary Risks 17 CI-09-015-034, National Bioethics Commission: 09 CEI-023-2017082.

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Multimodal imaging patterns predict survival in recurrent glioblastoma patients treated with bevacizumab

Neuro-Oncology ◽

10.1093/neuonc/now086 ◽

2016 ◽

Vol 18 (12) ◽

pp. 1680-1687 ◽

Cited By ~ 46

Author(s):

Ken Chang ◽

Biqi Zhang ◽

Xiaotao Guo ◽

Min Zong ◽

Rifaquat Rahman ◽

...

Keyword(s):

Clinical Decision Making ◽

Progression Free Survival ◽

Clinical Decision ◽

Recurrent Glioblastoma ◽

Machine Learning Techniques ◽

Imaging Biomarkers ◽

Imaging Features ◽

Mri Features ◽

Fluid Attenuated Inversion Recovery ◽

Multimodal Mri

Abstract Background Bevacizumab is a humanized antibody against vascular endothelial growth factor approved for treatment of recurrent glioblastoma. There is a need to discover imaging biomarkers that can aid in the selection of patients who will likely derive the most survival benefit from bevacizumab. Methods The aim of the study was to examine if pre- and posttherapy multimodal MRI features could predict progression-free survival and overall survival (OS) for patients with recurrent glioblastoma treated with bevacizumab. The patient population included 84 patients in a training cohort and 42 patients in a testing cohort, separated based on pretherapy imaging date. Tumor volumes of interest were segmented from contrast-enhanced T1-weighted and fluid attenuated inversion recovery images and were used to derive volumetric, shape, texture, parametric, and histogram features. A total of 2293 pretherapy and 9811 posttherapy features were used to generate the model. Results Using standard radiographic assessment criteria, the hazard ratio for predicting OS was 3.38 (P < .001). The hazard ratios for pre- and posttherapy features predicting OS were 5.10 (P < .001) and 3.64 (P < .005) for the training and testing cohorts, respectively. Conclusion With the use of machine learning techniques to analyze imaging features derived from pre- and posttherapy multimodal MRI, we were able to develop a predictive model for patient OS that could potentially assist clinical decision making.

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Local Ablative Therapies in Oligometastatic NSCLC: New Data and New Directions

Seminars in Respiratory and Critical Care Medicine ◽

10.1055/s-0039-3400290 ◽

2020 ◽

Vol 41 (03) ◽

pp. 369-376

Author(s):

Pencilla Lang ◽

Daniel R. Gomez ◽

David A. Palma

Keyword(s):

Clinical Decision Making ◽

Treatment Phase ◽

Progression Free Survival ◽

Clinical Decision ◽

Stereotactic Ablative Radiotherapy ◽

Free Survival ◽

Fractionated Radiotherapy ◽

Disease States ◽

Ablative Therapies ◽

Clinical Scenarios

AbstractThe oligometastatic and oligoprogressive disease states have been recently recognized as common clinical scenarios in the management of non-small cell lung cancer (NSCLC). As a result, there has been increasing interest in treating these patients with locally ablative therapies including surgery, conventionally fractionated radiotherapy, stereotactic ablative radiotherapy, and radiofrequency ablation. This article provides an overview of oligometastatic and oligoprogressive disease in the setting of NSCLC and reviews the evidence supporting ablative treatment. Phase II randomized controlled trials and retrospective series suggest that ablative treatment of oligometastases may substantially improve progression-free survival and overall survival, and additional large randomized studies testing this hypothesis in a definitive context are ongoing. However, several challenges remain, including quantifying the possible benefits of ablative therapies for oligoprogressive disease and developing prognostic and predictive models to assist in clinical decision making.

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Clinical value of measurable residual disease testing for assessing depth, duration, and direction of response in multiple myeloma

Blood Advances ◽

10.1182/bloodadvances.2020002037 ◽

2020 ◽

Vol 4 (14) ◽

pp. 3295-3301

Author(s):

Joaquin Martinez-Lopez ◽

Sandy W. Wong ◽

Nina Shah ◽

Natasha Bahri ◽

Kaili Zhou ◽

...

Keyword(s):

Multiple Myeloma ◽

Clinical Decision Making ◽

Residual Disease ◽

Clinical Care ◽

Progression Free Survival ◽

Clinical Decision ◽

Routine Practice ◽

Clinical Value ◽

The Impact ◽

Measurable Residual Disease

Abstract Few clinical studies have reported results of measurable residual disease (MRD) assessments performed as part of routine practice. Herein we present our single-institution experience assessing MRD in 234 multiple myeloma (MM) patients (newly diagnosed [NDMM = 159] and relapsed [RRMM = 75]). We describe the impact of depth, duration, and direction of response on prognosis. MRD assessments were performed by next-generation sequencing of immunoglobulin genes with a sensitivity of 10−6. Those achieving MRD negativity at 10−6, as well as 10−5, had superior median progression-free survival (PFS). In the NDMM cohort, 40% of the patients achieved MRD negativity at 10−6 and 59% at 10−5. Median PFS in the NDMM cohort was superior in those achieving MRD at 10−5 vs <10−5 (PFS: 87 months vs 32 months; P < .001). In the RRMM cohort, 36% achieved MRD negativity at 10−6 and 47% at 10−5. Median PFS was superior for the RRMM achieving MRD at 10−5 vs <10−5 (PFS: 42 months vs 17 months; P < .01). Serial MRD monitoring identified 3 categories of NDMM patients: (A) patients with ≥3 MRD 10−6 negative samples, (B) patients with detectable but continuously declining clonal numbers, and (C) patients with stable or increasing clonal number (≥1 log). PFS was superior in groups A and B vs C (median PFS not reached [NR], NR, 55 respectively; P < .001). This retrospective evaluation of MRD used as part of clinical care validates MRD as an important prognostic marker in NDMM and RRMM and supports its use as an endpoint in future clinical trials as well as for clinical decision making.

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Survival benefits of hypofractionated radiotherapy combined with temozolomide or temozolomide plus bevacizumab in elderly patients with glioblastoma aged ≥ 75 years

Radiation Oncology ◽

10.1186/s13014-019-1389-7 ◽

2019 ◽

Vol 14 (1) ◽

Cited By ~ 6

Author(s):

Makoto Ohno ◽

Yasuji Miyakita ◽

Masamichi Takahashi ◽

Hiroshi Igaki ◽

Yuko Matsushita ◽

...

Keyword(s):

Elderly Patients ◽

Dna Methyltransferase ◽

Karnofsky Performance Status ◽

Performance Status ◽

Methylation Status ◽

Progression Free Survival ◽

Promoter Hypermethylation ◽

Hypofractionated Radiotherapy ◽

Methylguanine Dna Methyltransferase ◽

Grade 3

Abstract Background and purpose The purpose of this study was to evaluate the outcomes of elderly patients (aged ≥75 years) with newly diagnosed glioblastoma (GBM), who were treated with hypofractionated radiotherapy comprising 45 Gy in 15 fractions combined with temozolomide (TMZ) or TMZ and bevacizumab (TMZ/Bev). Materials and methods Between October 2007 and August 2018, 30 patients with GBM aged ≥75 years were treated with hypofractionated radiotherapy consisting of 45 Gy in 15 fractions. Twenty patients received TMZ and 10 received TMZ/Bev as upfront chemotherapy. O-6-methylguanine DNA methyltransferase (MGMT) promoter methylation status was analyzed by pyrosequencing. The cutoff value of the mean level of methylation at the 16 CpG sites was 16%. Results Median overall survival (OS) and progression-free survival (PFS) were 12.9 months and 9.9 months, respectively. The 1-year OS and PFS rates were 64.7 and 34.7%, respectively. Median OS and PFS did not differ significantly between patients with MGMT promoter hypermethylation (N = 11) and those with hypomethylation (N = 16) (17.4 vs. 11.8 months, p = 0.32; and 13.1 vs. 7.3 months, p = 0.11, respectively). The median OS and PFS were not significantly different between TMZ (N = 20) and TMZ/Bev (N = 10) chemotherapy (median OS: TMZ 12.9 months vs. TMZ/Bev 14.6 months, p = 0.93, median PFS: TMZ 8.5 months vs TMZ/Bev 10.0 months, p = 0.64, respectively). The median time until Karnofsky performance status (KPS) score decreasing below 60 points was 7.9 months. The best radiological responses included 11 patients with a partial response (36.7%). Grade 3/4 toxicities included leukopenia in 15 patients (50%), anorexia in 4 (13.3%), and hyponatremia during concomitant chemotherapy in 3 (10%). Conclusion Our hypofractionated radiotherapy regimen combined with TMZ or TMZ/Bev showed benefits in terms of OS, PFS, and KPS maintenance with acceptable toxicities in elderly patients with GBM aged ≥75 years.

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