High-grade Malignant Brain Tumors Research Articles

NIMG-82. FET PET SENSITIVITY IN PRIMARY BRAIN TUMORS ACCORDING TO CNS WHO 2021: VALUE AND PITFALLS IN PRESURGICAL IMPLEMENTATION

Abstract BACKGROUND FET-PET imaging has emerged as a valuable tool in the characterization of unclear brain lesions that cannot be clearly diagnosed with conventional diagnostic methods. In 2021, the Central Nervous System (CNS) World Health Organization (WHO) introduced significant changes in the classification of CNS tumors. Notably, under the new classification, certain cases of WHO grade II glioma may be reclassified as glioblastoma. Unfortunately, a subset of grade II gliomas, as defined by the 2016 WHO classification, may exhibit no detectable FET uptake and lack contrast enhancement on MRI, which can lead to underestimation of such tumors and potentially result in inappropriate treatment decisions, including avoiding surgery. Question: In how many cases did the diagnostics consisting of MRI and FET PET underestimate the malignancy in unclear brain lesions? METHODS In this study, we conducted a retrospective analysis of all patients who underwent FET PET imaging of the brain between 2017 and June 2021, prior to their first surgical brain intervention. We obtained the results from presurgical MRI-scans and categorized the lesions based on whether they exhibited contrast media enhancement or not, in addition to the postsurgical molecular-histopathologic diagnosis. Our analysis focused on identifying the number of cases in which the diagnosis of malignancy was underestimated in the context of the WHO 2016 classification. To further investigate these cases, we conducted NGS and 850k-analysis to reclassify the results in accordance with the new CNS WHO 2021 classification. RESULTS After enrolling 85 patients, our study found that according to the 2016 classification, preoperative imaging underestimated malignancy in 14 cases (16%) where histopathological analysis revealed high-grade malignant brain tumors. In 32 cases (27%), the preoperative imaging correctly suggested a malignant tumor, which was later confirmed by histopathological analysis after surgery. The final results of this reclassification after the CNS-WHO-2021 will be presented at SNO-meeting.

Machine Learning Assisted Methodology for Multiclass Classification of Malignant Brain Tumors

Analysis of malignant and non-malignant brain tumors is done using a computer-aided diagnosis system by practitioners worldwide. Radiologists refer computer-assisted techniques to draw conclusions using image modalities and inferences. Pedagogically, various machine learning approaches have been used, which usually focus on the classification of imaging modality into two categories, either normal and abnormal images or differentiating between benign and malignant tumors. Still, the work requirement is to classify these multi-class malignant tumors into their specific class with better precision. The proposed work focuses on distinguishing between the types of high-grade malignant brain tumors. This study is performed on real-life malignant brain tumor datasets having five classes. The proposed methodology uses the vast feature set from six domains to capture most of the hidden information in the extracted region of interest. Later, relevant features are extracted from the feature set pool using a new proposed feature selection algorithm named the Cumulative Variance method (CVM). Next, the selected features are used for model training and testing using K-Nearest Neighbour (KNN), multi-class Support Vector Machine (mSVM), and Neural Network (NN) for predicting multi-class classification accuracy. The experiments are performed using the proposed feature selection algorithm with three classifiers. The mean average classification accuracy achieved by using the proposed approach is88.43% (KNN), 92.5% (mSVM), and 95.86% (NN), respectively. The comparative analysis of the proposed approach with other existing algorithms like ICA, and GA suggest that the proposed approach gains an increase of accuracy around 2% (KNN), 3% (SVM), and 4% (NN).The experimentation results concluded that the proposed approach is found better with NN classifier with an accuracy of 95.86% using diversified features.

Metabolic and functional reprogramming of myeloid-derived suppressor cells and their therapeutic control in glioblastoma.

Glioblastoma, also known as glioblastoma multi-forme, is the most common and deadliest form of high-grade malignant brain tumors with limited available treatments. Within the glioblastoma tumor microenvironment (TME), tumor cells, stromal cells, and infiltrating immune cells continuously interact and exchange signals through various secreted factors including cytokines, chemokines, growth factors, and metabolites. Simultaneously, they dynamically reprogram their metabolism according to environmental energy demands such as hypoxia and neo-vascularization. Such metabolic re-programming can determine fates and functions of tumor cells as well as immune cells. Ultimately, glioma cells in the TME transform immune cells to suppress anti-tumor immune cells such as T, natural killer (NK) cells, and dendritic cells (DC), and evade immune surveillance, and even to promote angiogenesis and tumor metastasis. Glioma-associated microglia/macrophages (GAMM) and myeloid-derived suppressor cells (MDSC) are most abundantly recruited and expanded myeloid lineage cells in glioblastoma TME and mainly lead to immunosuppression. In this review, of myeloid cells we will focus on MDSC as an important driver to induce immunosuppression in glioblastoma. Here, we review current literature on immunosuppressive functions and metabolic reprogramming of MDSCs in glioblastoma and discuss their metabolic pathways as potential therapeutic targets to improve current incurable glioblastoma treatment.

Significant Association of Proline Allele in Tp53 Gene, Arg72pro Polymorphism in Brain Tumors and its Prognostic Value

Background: In TP53 gene, Arg72Pro polymorphism has been suggested to be associated with genetically determined susceptibility in various types of cancers including brain tumors. Our objective was to investigate the possible association between TP53 Arg72Pro polymorphism with brain tumor susceptibility and to examine its correlation with the clinico-pathologic variables of tumor cases for oncologic prognosis of patients. Materials and methods: The TP53 Arg72Pro genotypes were determined by Polymerase Chain Reaction- Based Restriction Fragment Length Polymorphism (PCR-RFLP) analysis in 90 age and gender matched brain tumor cases and 130 healthy controls. Results: We found significant difference in the frequency of Pro allele as 0.47 in cases versus 0.37 in controls (p 0.05). Proline related allele/genotype (GC) was significantly found associated in high grade malignant brain tumors, neuroepithelial tumors (p 0.05). Conclusion: Though overall distribution did not reveal significant association in TP53 Arg72Pro polymorphism among cases and controls but proline related genotype was found associated with susceptibility to the disease pathology.

Malignant focal brain lesions. Value of MRS tumour biomarkers in preoperative prediction of grades of malignancy

PurposeOur aim is to describe the spectrum of proton-MR spectroscopy in malignant focal brain lesions and to detect grade of malignancy using MRS tumor biomarkers. Materials and methods87 patients (63 males and 24 females) with focal brain lesion(s) are included in this study. All had a brain tumor recently diagnosed by MRI and had received no previous treatment. They were referred to MRS examination before surgical biopsy and/or resection or radiotherapy. ResultsIn malignant brain tumors, average Cho/NAA ratio was 3.3±0.22, Cho/Cr ratio was 2.95±0.21, MI/NAA ratio was 1.5±0.12, MI/Cr was 0.53±0.11 with lower MI levels and higher choline levels in more malignant tumours, lipid/lactate peak was detected in brain metastasis and high grade malignant brain tumors. ConclusionHigher Cho/NAA, Cho/Cr and MI/NAA ratios with lower MI/Cr, and high lipid/lactate peak, were most likely to be in high grade malignant brain tumors.

Invasion Precedes Tumor Mass Formation in a Malignant Brain Tumor Model of Genetically Modified Neural Stem Cells

Invasiveness, cellular atypia, and proliferation are hallmarks of malignant gliomas. To effectively target each of these characteristics, it is important to understand their sequence during tumorigenesis. However, because most gliomas are diagnosed at an advanced stage, the chronology of gliomagenesis milestones is not well understood. The aim of the present study was to determine the onset of these characteristics during tumor development. Brain tumor-initiating cells (BTICs) were established by overexpressing H-RasV12 in normal neural stem/progenitor cells isolated from the subventricular zone of adult mice harboring a homozygous deletion of the Ink4a/Arf locus. High-grade malignant brain tumors were then created by orthotopic implantation of 105 BTICs into the forebrain of 6-week-old wild-type mice. Micewere killed every week for 5 weeks, and tumors were assessed for cellular atypia, proliferation, hemorrhage, necrosis, and invasion. All mice developed highly invasive, hypervascular glioblastoma-like tumors. A 100% penetrance rate and a 4-week median survival were achieved. Tumor cell migration along fiber tracts started within days after implantation and was followed by perivascular infiltration of tumor cells with marked recruitment of reactive host cells. Next, cellular atypia became prominent. Finally, mass proliferation and necrosis were observed in the last stage of the disease. Video monitoring of BTICs in live brain slices confirmed the early onset of migration, as well as the main cell migration patterns. Our results showed that perivascular and intraparenchymal tumor cell migration precede tumor mass formation in the adult brain, suggesting the need for an early and sustained anti-invasion therapy.

Pegylated-liposomal doxorubicin and oral topotecan in eight children with relapsed high-grade malignant brain tumors

The combination of topoisomerase I and II chemotherapeutic agents has shown promising preclinical synergistic effects in the treatment of high-grade malignant brain tumors such as high-grade gliomas and choroid plexus carcinomas. To confirm the effectiveness of this treatment combination and determine its possible toxicity, we conducted a retrospective review of the charts of children who received the therapy. Patients with relapsed malignant brain tumors who were given an individualized treatment of pegylated (PEG)-liposomal doxorubicin and topotecan were included in our study. PEG-liposomal doxorubicin was given intravenously at a dosage of 30-40 mg/m(2) over 4 h once every 4 weeks. Additionally, an intravenous formulation of topotecan was given orally twice daily and was increased on an individual basis from a starting dosage of 0.3 mg/m(2) per application to a total daily dosage of 0.6 mg/m(2). Eight patients were included. The main toxicity (NCI-CTC) after three cycles of the combination therapy was grade IV hematotoxicity (n = 3); grade III hematotoxicity (n = 2), grade III stomatitis (n = 1), grade III infection (n = 2), grade III diarrhea (n = 1); and grade II dermatitis (n = 1). In four patients, stable disease was achieved for 9, 23, more than 24, and more than 48 weeks, respectively. The schedule of PEG-liposomal doxorubicin with 30-40 mg/m(2) every 4 weeks in combination with oral topotecan resulted in tumor response, but the toxicity was high. An individualized increasing dose of PEG-liposomal doxorubicin 10-20 mg/m(2) every two weeks is now recommended.

The 9L rat brain tumor model for pre-clinical investigation of radiation-chemotherapy interactions.

The rat 9L gliosarcoma brain tumor model has been used for more than thirty years to investigate a variety of potential therapeutic agents, combinations, schedules, and approaches that might be applicable to the management of high-grade malignant brain tumors in man. When tumor cells are implanted intracerebrally, a solid tumor grows until its mass results in the death of the animal, typically between 20 and 30 days postinoculation. Radiation therapy (either single or fractionated doses) is effective at prolonging survival in a dose-dependent manner. Numerous cancer chemotherapeutic agents, by a variety of doses, schedules, and routes of delivery, have demonstrated therapeutic efficacy in the 9L model. The combination of radiation and agents such as AZQ, BCNU, bleomycin, and cis-platinum has resulted in prolongation of survival that is significantly better than either agent used alone, without exceeding the tolerance of critical normal tissues. These pre-clinical data suggest that combining standard fractionated radiation therapy with appropriate concomitant cytotoxic chemotherapeutic agents might benefit patients with high-grade brain tumors.

Combination of aziridinylbenzoquinone and cis-platinum with radiation therapy in the 9L rat brain tumor model

Purpose : We evaluated the potentiating effects of aziridinylbenzoquinone (AZQ) and cis-platinum on the prolongation of survival by radiation therapy in a rat brain tumor model. Methods and Materials : On day 10 following intracranial inoculation of the 9L gliosarcoma, Fischer 344 rats were treated with radiation therapy (Cesium-137 source irradiator) and/or chemotherapy delivered either systemically (intraperitoneal or intravenous), or intracranially directly into the tumor in a volume of 5 μl. Increased life spans were calculated relative to the median survival time for the control (ILS-C) or to the median survival time for radiation therapy only (ILS-RT) group. Results : Median survival time for untreated rats was 22 ± 3 days for seven experiments. Radiation therapy (16 Gy) produced a significant ( p < 0.002) improvement in survival, with an average ILS-C of 75 ± 19%. Systemic AZQ (1 or 5 intravenous injections of 0.5 mg/kg) produced ILS's of 0 and 23%, the latter being significant ( p = 0.002). When added to radiation therapy, there were further improvements (ILS-RT's of 47 and 72%), but these were not significant. Intratumor AZQ (40 or 50 pg intracranially) produced significant ILS-C's of 30 and 33% ( p = 0.01 and 0.0002, respectively). Added to radiation therapy, intracranial AZQ produced improvements (ILS-RT's of 5 and 102%), with only the latter being significantly improved ( p = 0.009). Cis-platinum (3 μg intracranially) produced ILS-C's of 13 and 6%, neither significantly different from controls. Added to radiation therapy, cis-platinum caused improvements (ILS-RT's of 18 and 64%), with only the latter significant ( p = 0.049). Conclusion : These results demonstrate that AZQ delivered systemically, and AZQ and cis-platinum delivered intracranially, can produce statistically significant improvements in the survival of rats burdened with the 9L brain tumor. The agents delivered intracranially significantly potentiated the prolongation of survival obtained by radiation therapy. This preclinical evidence suggests that combining radiation therapy with these cytotoxic chemotherapeutic agents may benefit patients with high-grade malignant brain tumors.

INSULIN-LIKE GROWTH FACTOR BINDING PROTEIN 3 (IGFBP-3) CONCENTRATION IN CEREBROSPINAL FLUID (CSF) OF CHILDREN WITH BRAIN TUMORS OR LEUKEMIA

The major IGFBPs in CSF are IGFBP-2 and IGFBP-4. whereas IGFBP-3 is a minor component in CSF of healthy subjects. We investigated IGFBP-3 levels in CSF from patients with brain tumors, leukemia or meningitis. IGFBP-3 was measured by radioimmuno-assay with αIGFBP-3g I, a rabbit polyclonal antibody. Further, as proteolysis of IGFBP-3 is purt of the modulation of IGF activity IGFBP-3 fragmentation was quantified by densitometric analysis of [125I]IGFBP-3 protease assays. We examined CSFs of 24 children with malignant brain tumors. 18 children with leukemia and 13 children with meningitis. CSFs of 38 children, who received a lumbal puncture in order to exclude meningitis, were used to define a normalative range for IGFBP-3 concentration and IGFBP-3 protease activity in normal CSF. Elevated IGFBP-3 concentrations were found in CSF of 17 of all 24 (71%) brain tumor patients and 7 of 8 (87%) brain tumor patients who had microscopically detectable malignant cells in CSF. 13 of 14 (93%) patients with medulloblastoma or ependymoma and all 7 medulloblasioma/ependymoma patients with malignant cells in CSF had elevated IGFBP-3 concentrations in CSF. IGFBP-3 protease activity in CSF was elevated in 15 of 17 (88%) patients with histological high grade (WIIO III°/IV°) brain tumors. 5 of 6 (83%) patients with acute leukemia and microscopically detectable malignant cells in CSF at the time of diagnosis showed elevated IGFBP-3 concentrations in CSF that normalized under chemotherapy. leukemia patients without any detectable malignant cells in the CSF had normal IGFBP-3 concentrations in CSF. We conclude that in CSF of children with high grade malignant brain tumors or CNS leukemia. IGFBP-3 is elevated. We hypothesize that this phenomenon could be caused by local production of IGFBP-3 by the brain tumor tissue and secretion into CSF or by local secretion of IGFBP-3 by malignant cells that spread into CSF. This hypothesis is supported by the observation that only 2 of 13 (15%) meningitis patients had slightly elevated IGFBP-3 concentrations in CSF while high numbers of non malignant inflammatory cells were present in all cases. Further studies will analyse the origin of elevated IGFBP-3 levels in CSF of tumor patients and will show whether these findings are of diagnostic or prognostic value.

Lack of complications in long-term survivors after treatment with fluosol and oxygen as an adjuvant to radiation therapy for high-grade malignant brain tumors

Lack of complications in long-term survivors after treatment with fluosol and oxygen as an adjuvant to radiation therapy for high-grade malignant brain tumors

A phase I/II study of the use of Fluosol® as an adjuvant to radiation therapy in the treatment of primary high-grade brain tumors

The main objective of this study was to evaluate the safety and efficacy of a perfluorochemical emulsion, Fluosol®, with short-term high inspired oxygen tension as an adjuvant to radiation therapy in the treatment of high-grade tumors of the brain. Radiation was delivered to the whole brain at 1.8 Gy per daily treatment for 5 weeks to a total dose of 45 Gy. The radiation portals were then reduced in size to encompass the known volume of tumor, as determined by the presurgical contrast-enhancing ring on computed tomography (CT), plus a 3-cm margin. An additional 10 treatments of 2 Gy each were given to the smaller volume, to bring the total tumor dose to 65 Gy in 7 weeks. This report describes the experience of the first 18 patients treated at the University of Kansas Medical Center on this study, whose median follow-up time from the date of surgery is 77 weeks (62–115 w). Immediately following Fluosol® administration on a Monday, patients breathed 100% oxygen for at least 45 minutes prior to and throughout their radiation treatment. On each subsequent day of the weeks in which they received Fluosol®, patients breathed 100% oxygen. Hematology and blood chemistries were also drawn prior to Fluosol® treatment each Friday during treatment and at the 2-week, 3-month, and 6-month follow-up visits. The median age of the patients was 45 years (16–72); 13 patients were male and 15 carried the diagnosis of glioblastoma multiforme (3 had anaplastic astrocytoma). Two thirds of the patients had an initial allergic reaction to the Fluosol® consisting of back pain, shortness of breath, and flushing, but all responded to 50–100 mg of Benadryl. During radiation therapy, all patients developed scalp erythema and complete alopecia by the end of 3 weeks, but no patient required a treatment rest. The serum levels of SGOT, SGPT, and alkaline phosphatase were examined before and throughout the Fluosol® treatment and, by week 5, 11 18 of the patients had increased values of all three enzymes above the upper range of normal. These increases persisted through the end of treatment, but most values returned to essentially normal by the 3-month follow-up visit. We conclude that Fluosol®, given in the manner described above, appears to be associated with minimal significant side effects and no changes could be detected in the white matter of any of the patients at the time of their magnetic resonance imaging study at 6 months follow-up. The median survival time in these 18 patients is in excess of 64 weeks with 6 patients remaining alive at times ranging from 62 to 94 weeks from the time of surgery. If only those patients that survive greater than 1 year are compared to a historical group of long-term survivors treated similarly but without Fluosol®, then a statistically significant improvement in survival ( p < 0.005) is obtained. The lack of toxicity and the increased therapeutic benefit argue for continued study of Fluosol® and high inspired oxygen tension as an adjuvant to radiation therapy for the management of patients with high grade malignant brain tumors.