ABSTRACT
OBJECTIVE: Pediatric pilocytic astrocytoma (PPA) requires prolonged follow-up after initial resection. The landscape of transitional care for PPA patients is not well characterized. The authors sought to examine the clinical course and transition to adult care for these patients to better characterize opportunities for improvement in long-term care. METHODS: Pediatric patients (younger than 18 years at diagnosis) who underwent biopsy or resection for PPA between May 2000 and November 2022 at the authors' large academic center were retrospectively reviewed. Patient demographics, tumor characteristics, recurrence, adjuvant therapies, and follow-up data were extracted from the electronic medical record via chart review. Charts of patients who were 18 years or older as of January 1, 2024, were reviewed for adult follow-up notes. RESULTS: The authors identified 315 patients who underwent biopsy or resection for PPA between May 2000 and November 2022. The most common tumor location was posterior fossa (59.7%), and gross-total resection (GTR) was achieved in 187 patients (59.4%). In patients with GTR, progression/recurrence occurred less frequently (8.6% vs 41.4%, p < 0.01) compared to patients with non-GTR. Among 177 patients found to be age-eligible for transition to adult care, the authors found that 31 (17.5%) successfully transitioned. The average age at transition from pediatric to adult care was 21.7 years, and the average age at last known adult follow-up was 25.0 years. The authors found that patients who transitioned to adult care were followed longer (12.5 vs 7.0 years, p < 0.01) and were diagnosed at an older age (12.1 vs 9.6 years, p < 0.01) than their untransitioned counterparts. CONCLUSIONS: The authors found that there was a low rate of successful transition from pediatric to adult care for PPA; 17.5% of age-eligible patients are now cared for by adult providers, whereas an additional 18.6% completed appropriate follow-up during childhood and did not require transition to adult care. These findings underscore opportunities for improvement in the pediatric-to-adult transition process for patients with PPA, particularly for those with non-GTR who were not followed for at least 10 years, during which the risk of disease progression is thought to be highest.
Subject(s)
Astrocytoma , Brain Neoplasms , Transitional Care , Humans , Astrocytoma/surgery , Astrocytoma/therapy , Male , Female , Child , Adolescent , Brain Neoplasms/surgery , Brain Neoplasms/therapy , Retrospective Studies , Child, Preschool , Young Adult , Neoplasm Recurrence, Local/surgery , Adult , Transition to Adult Care , Infant , Follow-Up Studies , Neurosurgical Procedures/methodsABSTRACT
Alterations in miRNA levels have been observed in various types of cancer, impacting numerous cellular processes and increasing their potential usefulness in combination therapies also in brain tumors. Recent advances in understanding the genetics and epigenetics of brain tumours point to new aberrations and associations, making it essential to continually update knowledge and classification. Here we conducted molecular analysis of 123 samples of childhood brain tumors (pilocytic astrocytoma, medulloblastoma, ependymoma), focusing on identification of genes that could potentially be regulated by crucial representatives of OncomiR-1: miR-17-5p and miR-20a-5p. On the basis of microarray gene expression analysis and qRTPCR profiling, we selected six (WEE1, CCND1, VEGFA, PTPRO, TP53INP1, BCL2L11) the most promising target genes for further experiments. The WEE1, CCND1, PTPRO, TP53INP1 genes showed increased expression levels in all tested entities with the lowest increase in the pilocytic astrocytoma compared to the ependymoma and medulloblastoma. The obtained results indicate a correlation between gene expression and the WHO grade and subtype. Furthermore, our analysis showed that the integration between genomic and epigenetic pathways should now point the way to further molecular research.
Subject(s)
Brain Neoplasms , Gene Expression Profiling , Gene Expression Regulation, Neoplastic , Gene Regulatory Networks , MicroRNAs , Humans , MicroRNAs/genetics , Brain Neoplasms/genetics , Brain Neoplasms/pathology , Child , Male , Female , Adolescent , Child, Preschool , Medulloblastoma/genetics , Medulloblastoma/pathology , Astrocytoma/genetics , Astrocytoma/pathology , Ependymoma/genetics , InfantABSTRACT
INTRODUCTION: The WHO classification of central nervous system tumors (5th edition) classified astrocytoma, IDH-mutant accompanied with CDKN2A/B homozygous deletion as WHO grade 4. Loss of immunohistochemical (IHC) staining for methylthioadenosine phosphorylase (MTAP) was developed as a surrogate marker for CDKN2A-HD. Identification of imaging biomarkers for CDKN2A status is of immense clinical relevance. In this study, we explored the association between radiological characteristics of non-enhancing astrocytoma, IDH-mutant to the CDKN2A/B status. METHODS: Thirty-one cases of astrocytoma, IDH-mutant with MTAP results by IHC were included in this study. The status of CDKN2A was diagnosed by IHC staining for MTAP in all cases, which was further confirmed by comprehensive genomic analysis in 12 cases. The T2-FLAIR mismatch sign, cystic component, calcification, and intratumoral microbleeding were evaluated. The relationship between the radiological features and molecular pathological diagnosis was analyzed. RESULTS: Twenty-six cases were identified as CDKN2A-intact while 5 cases were CDKN2A-HD. The presence of > 33% and > 50% T2-FLAIR mismatch was observed in 23 cases (74.2%) and 14 cases (45.2%), respectively, and was associated with CDKN2A-intact astrocytoma (p = 0.0001, 0.0482). None of the astrocytoma, IDH-mutant with CDKN2A-HD showed T2-FLAIR mismatch sign. Cystic component, calcification, and intratumoral microbleeding were not associated with CDKN2A status. CONCLUSION: In patients with non-enhancing astrocytoma, IDH-mutant, the T2-FLAIR mismatch sign is a potential imaging biomarker for the CDKN2A-intact subtype. This imaging biomarker may enable preoperative prediction of CDKN2A status among astrocytoma, IDH-mutant.
Subject(s)
Astrocytoma , Brain Neoplasms , Cyclin-Dependent Kinase Inhibitor p16 , Isocitrate Dehydrogenase , Mutation , Humans , Astrocytoma/genetics , Astrocytoma/diagnostic imaging , Astrocytoma/pathology , Male , Female , Brain Neoplasms/genetics , Brain Neoplasms/diagnostic imaging , Brain Neoplasms/pathology , Isocitrate Dehydrogenase/genetics , Middle Aged , Adult , Cyclin-Dependent Kinase Inhibitor p16/genetics , Aged , Magnetic Resonance Imaging/methods , Purine-Nucleoside Phosphorylase/genetics , Biomarkers, Tumor/genetics , Young AdultABSTRACT
BACKGROUND: In the dynamic realm of modern medicine, the advent of virtual reality technology heralds a transformative era, reshaping the contours of diagnosis and surgical planning with its immersive prowess. This study delves into the groundbreaking application of virtual reality in the intricate dance of neurosurgery, particularly spotlighting its role in the management of astrocytoma grade III-a cerebral challenge of significant complexity. CASE PRESENTATION: A 30-year-old Middle Eastern man from Syria grappled with the invisible tendrils of pain, manifesting as persistent headaches and a numbing sensation that crept into his neck and extremities. For two relentless months, the morning sun brought not hope but an intensification of his agony, rendering him unable to partake in the daily dance of life. The usual sentinels of relief, analgesic drugs, stood defeated, offering no respite. The neurological examination was normal, there were no pathological findings on sensory and motor examination, and he exhibited normal reflexes and neither meningeal nor cerebellar signs. He showed a family history of breast cancer. The initial foray into the enigmatic depths of his brain via computed tomography and magnetic resonance imaging imaging unveiled a finding in the right temporal lobe, a lesion that suggested something more sinister. Previous medical interventions included analgesic medications prescribed for persistent headaches, but they offered no relief. No other therapeutic interventions were administered prior to the current diagnosis. It was here that virtual reality technology emerged not as a mere tool but as a beacon of precision, casting a three-dimensional light on the shadowy intruder. This technological marvel allowed for meticulous measurement 21.8 × 14.5 mm and localization within the temporal theater, setting the stage for what was to come. With the path laid clear, the patient embarked on a surgical odyssey, a quest to excise the unwelcome guest. The operation was a triumph, a testament to human ingenuity and the symbiotic relationship between flesh and machine. The postoperative verdict was delivered through the lens of histopathology, confirming the presence of an astrocytoma grade III, a cerebral interloper known for its rapid proliferation. The battle, however, was far from over. Complementary radiotherapy and chemotherapy were enlisted as allies in this ongoing war, their potent forces working in concert to stave off the cellular insurgence. The patient's journey through the healing arts was charted by periodic clinical and neurological examinations, with laboratory tests and the vigilant gaze of brain magnetic resonance imaging ensuring a watchful eye was kept on any potential resurgence. CONCLUSIONS: In this narrative of resilience and technological prowess, we witness the harmonious fusion of human touch and digital precision, a partnership that redefines the boundaries of medicine and the art of healing, by use of virtual reality technology in the diagnosis of astrocytoma and enhancing the accuracy, effectiveness, and safety of neurosurgical procedures, which can ultimately benefit patients with brain tumors.
Subject(s)
Astrocytoma , Brain Neoplasms , Magnetic Resonance Imaging , Virtual Reality , Humans , Adult , Male , Astrocytoma/surgery , Astrocytoma/diagnostic imaging , Astrocytoma/diagnosis , Brain Neoplasms/diagnostic imaging , Brain Neoplasms/surgery , Tomography, X-Ray Computed , Neurosurgical Procedures/methodsABSTRACT
OBJECTIVES: Seeking a noninvasive predictor for BRAF V600E mutation status of pleomorphic xanthoastrocytomas (PXAs) is essential for their prognoses and therapeutic use of BRAF inhibitors. We aimed to noninvasively diagnose BRAF V600E-mutated PXAs using MRI morphologic, DWI and clinical parameters. METHODS: The clinical findings, anatomical MRI characteristics, and diffusion parameters of 36 pathologically confirmed PXAs were retrospectively analyzed, and BRAF V600E-mutated (n = 16) and wild-type (n = 20) groups were compared. A binary logistic-regression analysis was performed, and a ROC curve was calculated to determine the independent predictors of BRAF V600E mutation status, diagnostic accuracy, and optimal cut-off value. RESULTS: A comparison of findings between groups showed that BRAF V600E-mutated PXAs were more frequent in children and young adults (≤ 35 years; P = 0.042) who often had histories of seizures (P = 0.004). Furthermore, BRAF V600E-mutated PXAs generally presented as solitary masses (P = 0.024), superficial locations with meningeal attachment (P < 0.001), predominantly cystic with mural nodules (P = 0.005), and had greater minimal ADC ratio (ADCratio) values of the tumor and peritumoral edema (P < 0.001). Binary logistic regression showed that age ≤ 35 years, solitary mass, superficial locations with meningeal attachment, and a greater minimal ADCratio of the tumor were independent predictors of BRAF V600E-mutated PXAs. The combination of all four independent predictors resulted in the highest sensitivity (100%) and specificity (90%), with AUC = 0.984. CONCLUSION: The BRAF V600E mutation status of PXAs could be noninvasively predicted using clinical and MRI characteristics. CRITICAL RELEVANCE STATEMENT: The noninvasive diagnostic criteria for BRAF V600E-mutated PXAs could offer guidance for the administration of BRAF V600E mutation inhibitors in the future.
Subject(s)
Astrocytoma , Brain Neoplasms , Diffusion Magnetic Resonance Imaging , Mutation , Proto-Oncogene Proteins B-raf , Humans , Proto-Oncogene Proteins B-raf/genetics , Female , Male , Astrocytoma/genetics , Astrocytoma/diagnostic imaging , Astrocytoma/pathology , Adult , Diffusion Magnetic Resonance Imaging/methods , Child , Adolescent , Retrospective Studies , Young Adult , Middle Aged , Brain Neoplasms/genetics , Brain Neoplasms/diagnostic imaging , Brain Neoplasms/pathology , Child, Preschool , Magnetic Resonance Imaging/methods , Prognosis , ROC CurveABSTRACT
The extracellular matrix (ECM) is a dynamic set of molecules produced by the cellular component of normal and pathological tissues of the embryo and adult. ECM acts as critical regulator in various biological processes such as differentiation, cell proliferation, angiogenesis, and immune control. The most frequent primary brain tumors are gliomas and by far the majority are adult astrocytic tumors (AATs). The prognosis for patients with these neoplasms is poor and the treatments modestly improves survival. In the literature, there is a fair number of studies concerning the composition of the ECM in AATs, while the number of studies relating the composition of the ECM with the immune regulation is smaller. Circulating ECM proteins have emerged as a promising biomarker that reflect the general immune landscape of tumor microenvironment and may represent a useful tool in assessing disease activity. Given the importance it can have for therapeutic and prognostic purposes, the aim of our study is to summarize the biological properties of ECM components and their effects on the tumor microenvironment and to provide an overview of the interactions between major ECM proteins and immune cells in AATs. As the field of immunotherapy in glioma is quickly expanding, we retain that current data together with future studies on ECM organization and functions in glioma will provide important insights into the tuning of immunotherapeutic approaches.
Subject(s)
Astrocytoma , Extracellular Matrix , Tumor Microenvironment , Humans , Extracellular Matrix/metabolism , Tumor Microenvironment/immunology , Astrocytoma/pathology , Astrocytoma/metabolism , Astrocytoma/immunology , Brain Neoplasms/pathology , Brain Neoplasms/immunology , Brain Neoplasms/metabolism , Adult , Animals , Extracellular Matrix Proteins/metabolismABSTRACT
BACKGROUND: The diagnosis of glioma has advanced since the release of the WHO 2021 classification with more molecular alterations involved in the integrated diagnostic pathways. Our study aimed to present our experience with the clinical features and management of astrocytoma, IDH mutant based on the latest WHO classification. METHODS: Patients diagnosed with astrocytoma, IDH-mutant based on the WHO 5th edition classification of CNS tumors at our center from January 2009 to January 2022 were included. Patients were divided into WHO 2-3 grade group and WHO 4 grade group. Integrate diagnoses were retrospectively confirmed according to WHO 2016 and 2021 classification. Clinical and MRI characteristics were reviewed, and survival analysis was performed. RESULTS: A total of 60 patients were enrolled. 21.67% (13/60) of all patients changed tumor grade from WHO 4th edition classification to WHO 5th edition. Of these, 21.43% (6/28) of grade II astrocytoma and 58.33% (7/12) of grade III astrocytoma according to WHO 4th edition classification changed to grade 4 according to WHO 5th edition classification. Sex (p = 0.042), recurrent glioma (p = 0.006), and Ki-67 index (p < 0.001) of pathological examination were statistically different in the WHO grade 2-3 group (n = 27) and WHO grade 4 group (n = 33). CDK6 (p = 0.004), FGFR2 (p = 0.003), and MYC (p = 0.004) alterations showed an enrichment in the WHO grade 4 group. Patients with higher grade showed shorter mOS (mOS = 75.9 m, 53.6 m, 26.4 m for grade 2, 3, and 4, respectively, p = 0.01). CONCLUSIONS: Patients diagnosed as WHO grade 4 according to the 5th edition WHO classification based on molecular alterations are more likely to have poorer prognosis. Therefore, treatment should be tailored to their individual needs. Further research is needed for the management of IDH-mutant astrocytoma is needed in the future.
Subject(s)
Astrocytoma , Magnetic Resonance Imaging , Mutation , Neoplasm Grading , World Health Organization , Humans , Astrocytoma/genetics , Astrocytoma/classification , Astrocytoma/pathology , Astrocytoma/diagnostic imaging , Male , Female , Retrospective Studies , Middle Aged , Adult , Magnetic Resonance Imaging/methods , Prognosis , Isocitrate Dehydrogenase/genetics , Central Nervous System Neoplasms/classification , Central Nervous System Neoplasms/genetics , Central Nervous System Neoplasms/pathology , Central Nervous System Neoplasms/diagnostic imaging , Aged , Young Adult , Brain Neoplasms/classification , Brain Neoplasms/genetics , Brain Neoplasms/diagnostic imaging , Brain Neoplasms/pathology , Brain Neoplasms/mortality , AdolescentSubject(s)
Astrocytoma , Brain Neoplasms , MAP Kinase Signaling System , Humans , Astrocytoma/genetics , Astrocytoma/pathology , Brain Neoplasms/genetics , Brain Neoplasms/pathology , MAP Kinase Signaling System/physiology , MAP Kinase Signaling System/genetics , Adult , Male , Female , Middle Aged , Mutation/geneticsABSTRACT
OBJECTIVES: To elucidate the relationship between DNA methylation profiling (DMP) and pathological diagnosis (PD) in pediatric glial and glioneuronal tumors with B-Raf proto-oncogene, serine/threonine kinase (BRAF) mutations, addressing their diagnostic challenges. METHODS: This retrospective study, conducted in Saudi Arabia, analyzed 47 cases from the Children's Brain Tumor Network online database using scanned images, next-generation sequencing data, and methylation profiles processed using the Heidelberg methylation brain tumor classifiers v12.5 and v12.8. The data was last access on 10 November 2023. RESULTS: The highest prevalence of BRAF mutations was observed in pilocytic astrocytoma and ganglioglioma. The DMP was consistent with PD in 23 cases, but discrepancies emerged in others, including diagnostic changes in diffuse leptomeningeal glioneuronal tumor and polymorphous low-grade neuroepithelial tumor of the young. A key inconsistency appeared between a pilocytic astrocytoma MC and a glioneuronal tumor PD. Two high-grade astrocytomas were misclassified as pleomorphic xanthoastrocytomas. Additionally, low variant allelic frequency in gangliogliomas likely contributed to misclassifications as control in 5 cases. CONCLUSION: This study emphasized the importance of integrating DMP with PD in diagnosing pediatric glial and glioneuronal tumors with BRAF mutations. Although DMP offers significant diagnostic insights, its limitations, particularly in cases with low tumor content, necessitate cautious interpretation, as well as its use as a complementary diagnostic tool, rather than a definitive method.
Subject(s)
Brain Neoplasms , DNA Methylation , Mutation , Proto-Oncogene Mas , Proto-Oncogene Proteins B-raf , Humans , Proto-Oncogene Proteins B-raf/genetics , Brain Neoplasms/genetics , Brain Neoplasms/pathology , Brain Neoplasms/diagnosis , Brain Neoplasms/diagnostic imaging , Child , Male , Female , DNA Methylation/genetics , Retrospective Studies , Child, Preschool , Ganglioglioma/genetics , Ganglioglioma/pathology , Ganglioglioma/diagnostic imaging , Adolescent , Glioma/genetics , Glioma/pathology , Glioma/diagnosis , Astrocytoma/genetics , Astrocytoma/pathology , Astrocytoma/diagnostic imaging , Astrocytoma/diagnosis , Infant , Saudi ArabiaABSTRACT
OBJECTIVE: Query the National Cancer Database (NCDB) to delineate epidemiologic frequency, care patterns, and survival outcomes of pediatric intramedullary spinal cord tumors (IMSCTs). METHODS: IMSCTs included ependymoma, astrocytoma, and hemangioblastoma. We examined data from the NCDB spanning 2004-2018, focusing on IMSCT in children aged 0-21 years. Our analysis included logistic and Poisson regression, Kaplan-Meier survival estimates, and Cox proportional hazards models. RESULTS: This study included 1066 patients aged 0-21 years. 59.4â¯% of patients were male, while 83.1â¯% were white. The most common tumor histology was ependymoma (57.5â¯%), followed by astrocytoma (36.1â¯%) and hemangioblastoma (6.4â¯%). 24.9â¯% of patients received radiotherapy, with radiotherapy utilization being highest among patients aged 6-10 years. Chemotherapy utilization was highest in patients aged 0-5 years. 87.2â¯% of patients underwent surgical resection, with higher rates in patients aged 16-21 years. Overall survival did not differ significantly between resected and non-resected patients (p = 0.315). Patients in rural areas had worse OS than those in metro areas (HR = 4.42, p = 0.048). Patients with astrocytoma had worse OS compared to other histologies (HR = 2.21, p = 0.003). Astrocytoma patients were over twice as likely to have prolonged LOS compared to ependymoma patients (OR = 2.204, p < 0.001). CONCLUSIONS: In summary, our analysis utilizing the NCDB database provides a comprehensive overview of demographics, care patterns, and outcomes for the largest cohort of pediatric IMSCTs to date. These insights underscore the complexity of managing IMSCTs and emphasize the need for tailored approaches to improve patient outcomes.
Subject(s)
Astrocytoma , Databases, Factual , Ependymoma , Spinal Cord Neoplasms , Humans , Adolescent , Male , Child , Female , Spinal Cord Neoplasms/therapy , Spinal Cord Neoplasms/epidemiology , Spinal Cord Neoplasms/mortality , Infant , Child, Preschool , Young Adult , Astrocytoma/therapy , Astrocytoma/mortality , Astrocytoma/epidemiology , Ependymoma/therapy , Ependymoma/mortality , Ependymoma/epidemiology , Infant, Newborn , United States/epidemiology , Hemangioblastoma/therapy , Hemangioblastoma/epidemiology , Survival RateABSTRACT
BACKGROUND: Subependymal giant cell astrocytoma is a benign brain tumor that occurs in patients with tuberous sclerosis complex. Surgical removal is the traditional treatment, and expert opinion is strongly against the use of radiotherapy. Recently, success has been reported with the mTor inhibitor everolimus in reducing tumor volume, but regrowth has been observed after dose reduction or cessation. CASE REPORT: We present the case of a 40-year-old Asian female patient treated successfully for growing bilateral subependymal giant cell astrocytoma with fractionated stereotactic radiotherapy before everolimus became available. After a follow-up of 8 years, everolimus was administered for renal angiomyolipoma and the patient was followed up until 13 years after radiotherapy. Successive magnetic resonance imaging demonstrated an 80% volume reduction after radiotherapy that increased to 90% with everolimus. A review of the literature was done leveraging Medline via PubMed, and we assembled a database of 1298 article references and 780 full-text articles in search of evidence for contraindicating radiotherapy in subependymal giant cell astrocytoma. Varying results of single-fraction radiosurgery were described in a total of 13 cases. Only in two published cases was the radiation dose of fractionated radiotherapy mentioned. One single publication mentions an induced secondary brain tumor 8 years after whole-brain radiotherapy. CONCLUSION: There is no evidence of contraindication and exclusion of fractionated radiotherapy in treating subependymal giant cell astrocytoma. Our experience demonstrates that subependymal giant cell astrocytoma, as other benign intracranial tumors, responds slowly but progressively to radiotherapy and suggests that fractionated stereotactic radiotherapy holds promise to consolidate responses obtained with mTor inhibitors avoiding regrowth after cessation.
Subject(s)
Astrocytoma , Brain Neoplasms , Everolimus , Radiosurgery , Humans , Female , Astrocytoma/radiotherapy , Astrocytoma/surgery , Adult , Brain Neoplasms/radiotherapy , Everolimus/therapeutic use , Magnetic Resonance Imaging , Antineoplastic Agents/therapeutic use , Treatment Outcome , Kidney Neoplasms/radiotherapy , Kidney Neoplasms/pathology , Tuberous Sclerosis/complicationsABSTRACT
BACKGROUND AND PURPOSE: Radiological features on magnetic resonance imaging (MRI) were attributed to oligodendroglioma, although the diagnostic accuracy in a real-world clinical setting remains partially elusive. This study investigated the accuracy and robustness of tumor heterogeneity and tumor border delineation on T2-weighted MRI to distinguish oligodendroglioma from astrocytoma. MATERIALS AND METHODS: Eight readers from three different specialties (radiology, neurology, neurosurgery) with varying levels of experience blindly rated 79 T2-weighted MR images of patients with either oligodendroglioma or astrocytoma. After the first reading session, all readers were re-invited for a second reading session within three weeks. Diagnostic accuracy, including area under the receiver operator characteristics curve (AUC), and intra-observer variability and inter-observer variability were used as outcome measures. RESULTS: Pooled sensitivity and specificity to distinguish oligodendroglioma from astrocytoma for the use of tumor heterogeneity were 59.9 % respectively 74.5 %, and 85.7 % respectively 40.1 % for tumor border. A second reading session did not result in a significant change in sensitivity or specificity for tumor heterogeneity (P = 0.752 and P = 0.733, respectively) or tumor border (P = 0.309 and P = 0.271, respectively). An AUC of 0.825 was achieved with regard to predicting oligodendroglial origin of gliomas. Intra-observer agreement ranged from moderate to very good for tumor heterogeneity (kappa-value 0.43-0.87) and tumor border (0.40-0.84). A moderate inter-oberserver agreement was achieved for tumor heterogeneity and tumor border (kappa-value of 0.50 and 0.45, respectively). CONCLUSION: This study demonstrates that tumor heterogeneity and tumor borders on T2-weighted MRI could be used with moderate Finter-observer agreement to non-invasively distinguish oligodendroglioma from astrocytoma.
Subject(s)
Astrocytoma , Brain Neoplasms , Magnetic Resonance Imaging , Oligodendroglioma , Sensitivity and Specificity , Humans , Brain Neoplasms/diagnostic imaging , Brain Neoplasms/pathology , Oligodendroglioma/diagnostic imaging , Oligodendroglioma/pathology , Astrocytoma/diagnostic imaging , Astrocytoma/pathology , Diagnosis, Differential , Magnetic Resonance Imaging/methods , Female , Male , Middle Aged , Adult , Reproducibility of Results , Observer Variation , AgedABSTRACT
RATIONALE AND OBJECTIVES: Various methods exist to perform and post-process perfusion weighted MR imaging in the post-treatment imaging of glioma patients to differentiate tumor progression from tumor-related abnormalities. One of these post-processing methods produces 'fractional tumor burden' maps. This multi-reader study investigated the clinical feasibility of fractional tumor burden maps on real world data from radiological follow-up of high-grade astrocytoma patients. METHODS: Five readers with background in radiology and varying levels of experience were tasked with assessing 30 astrocytoma and glioblastoma patients during one reader session. First, they were provided with a dataset of conventional MRI sequences, including perfusion MRI with regional cerebral blood volume maps. Then the dataset was expanded with a corresponding fractional tumor burden maps. Diagnostic accuracy, duration of post-processing, duration of the assessment of the fractional tumor burden maps, the diagnostic confidence reported by the readers and their diagnoses were recorded. Final diagnosis was determined by clinical and radiological follow-up and/or histopathological data used as gold standard. RESULTS: A mean sensitivity of 83.3 % and mean specificity of 55.1 % was obtained without the use of fractional tumor burden maps, whereas their additional of fractional tumor burden maps resulted in a mean sensitivity and specificity of 79.5 % and 54.2 %, respectively. Diagnostic accuracies with and without fractional tumor burden maps were not significantly different (Z = 0.76, p = 0.450). The median time spent post-processing was 313 s, while the median duration of the assessment of the FTB maps was 19 s. Interestingly, reader confidence increased significantly after adding the fractional tumor burden-maps to the assessment (Z = 454, p < 0.01). CONCLUSIONS: While the use of fractional tumor burden maps does not carry additional value in the radiological follow-up of post-operative high-grade astrocytoma and glioblastoma patients, it does give readers more confidence in their diagnosis.
Subject(s)
Brain Neoplasms , Sensitivity and Specificity , Tumor Burden , Humans , Brain Neoplasms/diagnostic imaging , Female , Male , Middle Aged , Adult , Aged , Magnetic Resonance Angiography/methods , Astrocytoma/diagnostic imaging , Reproducibility of Results , Image Interpretation, Computer-Assisted/methods , Glioblastoma/diagnostic imagingABSTRACT
In recent years, the classification of adult-type diffuse gliomas has undergone a revolution, wherein specific molecular features now represent defining diagnostic criteria of IDH-wild-type glioblastomas, IDH-mutant astrocytomas, and IDH-mutant 1p/19q-codeleted oligodendrogliomas. With the introduction of the 2021 WHO CNS classification, additional molecular alterations are now integrated into the grading of these tumors, given equal weight to traditional histologic features. However, there remains a great deal of heterogeneity in patient outcome even within these established tumor subclassifications that is unexplained by currently codified molecular alterations, particularly in the IDH-mutant astrocytoma category. There is also significant intercellular genetic and epigenetic heterogeneity and plasticity with resulting phenotypic heterogeneity, making these tumors remarkably adaptable and robust, and presenting a significant barrier to the design of effective therapeutics. Herein, we review the mechanisms and consequences of genetic and epigenetic instability, including chromosomal instability (CIN), microsatellite instability (MSI)/mismatch repair (MMR) deficits, and epigenetic instability, in the underlying biology, tumorigenesis, and progression of IDH-mutant astrocytomas. We also discuss the contribution of recent high-resolution transcriptomics studies toward defining tumor heterogeneity with single-cell resolution. While intratumoral heterogeneity is a well-known feature of diffuse gliomas, the contribution of these various processes has only recently been considered as a potential driver of tumor aggressiveness. CIN has an independent, adverse effect on patient survival, similar to the effect of histologic grade and homozygous CDKN2A deletion, while MMR mutation is only associated with poor overall survival in univariate analysis but is highly correlated with higher histologic/molecular grade and other aggressive features. These forms of genomic instability, which may significantly affect the natural progression of these tumors, response to therapy, and ultimately clinical outcome for patients, are potentially measurable features which could aid in diagnosis, grading, prognosis, and development of personalized therapeutics.
Subject(s)
Astrocytoma , Brain Neoplasms , Disease Progression , Epigenesis, Genetic , Isocitrate Dehydrogenase , Mutation , Humans , Brain Neoplasms/genetics , Brain Neoplasms/pathology , Astrocytoma/genetics , Astrocytoma/pathology , Isocitrate Dehydrogenase/genetics , Mutation/genetics , Epigenesis, Genetic/geneticsABSTRACT
PURPOSE: SGLT2, the sodium glucose cotransporter two, is expressed in human pancreatic, prostate and brain tumors, and in a mouse cancer model SGLT2 inhibitors reduce tumor glucose uptake and growth. In this study we have measured the effect of a specific SGLT2 inhibitor, Jardiance® (Empagliflozin), on glucose uptake into astrocytomas in patients. METHODS: We have used a specific SGLT glucose tracer, α-methyl-4-[18F]fluoro-4-deoxy-α-D-glucopyranoside (Me4FDG), and Positron Emission Tomography (PET) to measure glucose uptake. Four of five patients enrolled had WHO grade IV glioblastomas, and one had a low grade WHO Grade II astrocytoma. Two dynamic brain PET scans were conducted on each patient, one before and one after treatment with a single oral dose of Jardiance, a specific SGLT2 inhibitor. As a control, we also determined the effect of oral Jardiance on renal SGLT2 activity. RESULTS: In all five patients an oral dose (25 or 100 mg) of Jardiance reduced Me4FDG tumor accumulation, highly significant inhibition in four, and inhibited SGLT2 activity in the kidney. CONCLUSIONS: These initial experiments show that SGLT2 is a functional glucose transporter in astocytomas, and Jardiance inhibited glucose uptake, a drug approved by the FDA to treat type 2 diabetes mellitus (T2DM), heart failure, and renal failure. We suggest that clinical trials be initiated to determine whether Jardiance reduces astrocytoma growth in patients.
Subject(s)
Astrocytoma , Brain Neoplasms , Glucose , Positron-Emission Tomography , Sodium-Glucose Transporter 2 Inhibitors , Sodium-Glucose Transporter 2 , Humans , Astrocytoma/metabolism , Astrocytoma/drug therapy , Astrocytoma/diagnostic imaging , Astrocytoma/pathology , Brain Neoplasms/metabolism , Brain Neoplasms/drug therapy , Brain Neoplasms/diagnostic imaging , Brain Neoplasms/pathology , Glucose/metabolism , Sodium-Glucose Transporter 2 Inhibitors/therapeutic use , Sodium-Glucose Transporter 2 Inhibitors/pharmacology , Male , Sodium-Glucose Transporter 2/metabolism , Glucosides/pharmacology , Female , Middle Aged , Fluorodeoxyglucose F18 , AgedABSTRACT
PURPOSE: The T2-FLAIR mismatch sign is a highly specific diagnostic imaging biomarker for astrocytoma, IDH-mutant. However, a definitive prognostic imaging biomarker has yet to be identified. This study investigated imaging prognostic markers, specifically analyzing T2-weighted and FLAIR images of this tumor. METHODS: We retrospectively analyzed 31 cases of non-enhancing astrocytoma, IDH-mutant treated at our institution, and 30 cases from The Cancer Genome Atlas (TCGA)/The Cancer Imaging Archive (TCIA). We defined "super T2-FLAIR mismatch sign" as having a significantly strong low signal comparable to cerebrospinal fluid at non-cystic lesions rather than just a pale FLAIR low-signal tumor lesion as in conventional T2-FLAIR mismatch sign. Cysts were defined as having a round or oval shape and were excluded from the criteria for the super T2-FLAIR mismatch sign. We evaluated the presence or absence of the T2-FLAIR mismatch sign and super T2-FLAIR mismatch sign using preoperative MRI and analyzed the progression-free survival (PFS) and overall survival (OS) by log-rank test. RESULTS: The T2-FLAIR mismatch sign was present in 17 cases (55%) in our institution and 9 cases (30%) within the TCGA-LGG dataset without any correlation with PFS or OS. However, the super T2-FLAIR mismatch sign was detected in 8 cases (26%) at our institution and 13 cases (43%) in the TCGA-LGG dataset. At our institution, patients displaying the super T2-FLAIR mismatch sign showed significantly extended PFS (122.7 vs. 35.9 months, p = 0.0491) and OS (not reached vs. 116.7 months, p = 0.0232). Similarly, in the TCGA-LGG dataset, those with the super T2-FLAIR mismatch sign exhibited notably longer OS (not reached vs. 44.0 months, p = 0.0177). CONCLUSION: The super T2-FLAIR mismatch is a promising prognostic imaging biomarker for non-enhancing astrocytoma, IDH-mutant.
Subject(s)
Astrocytoma , Brain Neoplasms , Isocitrate Dehydrogenase , Magnetic Resonance Imaging , Mutation , Humans , Isocitrate Dehydrogenase/genetics , Male , Female , Astrocytoma/diagnostic imaging , Astrocytoma/genetics , Astrocytoma/pathology , Retrospective Studies , Brain Neoplasms/genetics , Brain Neoplasms/diagnostic imaging , Brain Neoplasms/pathology , Prognosis , Middle Aged , Adult , Aged , Biomarkers, Tumor/genetics , Young Adult , Follow-Up Studies , Survival RateABSTRACT
In order to obtain models of gliomas of varying degrees of malignancy, we performed morphological and molecular genetic study of a tissue strain of glioma 10-17-2 (Astrid-17) obtained by intracranial passaging of tumor fragments of chemically induced rat brain tumor, and a cell strain isolated from it. More or less pronounced changes in the expression levels of Mki67, Trp53, Vegfa, and Gfap genes in the tissue and cell strain of glioma 10-17-2 (Astrid-17) compared with intact brain tissue were shown. The tissue model of glioma 10-17-2 (Astrid-17) according to the studied characteristics shows features of grade 3-4 astrocytoma and the cellular model - grade 2-3 astrocytoma.
Subject(s)
Brain Neoplasms , Glial Fibrillary Acidic Protein , Glioma , Vascular Endothelial Growth Factor A , Animals , Rats , Brain Neoplasms/genetics , Brain Neoplasms/pathology , Brain Neoplasms/metabolism , Glioma/genetics , Glioma/pathology , Glioma/metabolism , Glial Fibrillary Acidic Protein/genetics , Glial Fibrillary Acidic Protein/metabolism , Vascular Endothelial Growth Factor A/genetics , Vascular Endothelial Growth Factor A/metabolism , Tumor Suppressor Protein p53/genetics , Tumor Suppressor Protein p53/metabolism , Ki-67 Antigen/metabolism , Ki-67 Antigen/genetics , Male , Astrocytoma/genetics , Astrocytoma/pathology , Astrocytoma/metabolism , Gene Expression Regulation, Neoplastic , Cell Line, Tumor , Brain/pathology , Brain/metabolismABSTRACT
Spinal cord astrocytoma (SCA) is a rare subtype of astrocytoma, posing challenges in diagnosis and treatment. Low-grade SCA can achieve long-term survival solely through surgery, while high-grade has a disappointing prognosis even with comprehensive treatment. Diagnostic criteria and standard treatment of intracranial astrocytoma have shown obvious limitations in SCA. Research on the molecular mechanism in SCA is lagging far behind that on intracranial astrocytoma. In recent years, huge breakthroughs have been made in molecular pathology of astrocytoma, and novel techniques have emerged, including DNA methylation analysis and radiomics. These advances are now making it possible to provide a precise diagnosis and develop corresponding treatment strategies in SCA. Our aim is to review the current status of diagnosis and treatment of SCA, and summarize the latest research advancement, including tumor subtype, molecular characteristics, diagnostic technology, and potential therapy strategies, thus deepening our understanding of this uncommon tumor type and providing guidance for accurate diagnosis and treatment.
Subject(s)
Astrocytoma , Spinal Cord Neoplasms , Humans , Astrocytoma/genetics , Astrocytoma/therapy , Astrocytoma/diagnosis , Astrocytoma/pathology , Spinal Cord Neoplasms/therapy , Spinal Cord Neoplasms/genetics , Spinal Cord Neoplasms/diagnosis , Spinal Cord Neoplasms/pathology , Biomarkers, Tumor/genetics , Pathology, Molecular , DNA Methylation , Disease Management , Prognosis , Neoplasm GradingABSTRACT
INTRODUCTION: High grade astrocytic glioma (HGG) is a lethal solid malignancy with high recurrence rates and limited survival. While several cytotoxic agents have demonstrated efficacy against HGG, drug sensitivity testing platforms to aid in therapy selection are lacking. Patient-derived organoids (PDOs) have been shown to faithfully preserve the biological characteristics of several cancer types including HGG, and coupled with the experimental-analytical hybrid platform Quadratic Phenotypic Optimization Platform (QPOP) which evaluates therapeutic sensitivity at a patient-specific level, may aid as a tool for personalized medical decisions to improve treatment outcomes for HGG patients. METHODS: This is an interventional, non-randomized, open-label study, which aims to enroll 10 patients who will receive QPOP-guided chemotherapy at the time of first HGG recurrence following progression on standard first-line therapy. At the initial presentation of HGG, tumor will be harvested for primary PDO generation during the first biopsy/surgery. At the point of tumor recurrence, patients will be enrolled onto the main study to receive systemic therapy as second-line treatment. Subjects who undergo surgery at the time of recurrence will have a second harvest of tissue for PDO generation. Established PDOs will be subject to QPOP analyses to determine their therapeutic sensitivities to specific panels of drugs. A QPOP-guided treatment selection algorithm will then be used to select the most appropriate drug combination. The primary endpoint of the study is six-month progression-free survival. The secondary endpoints include twelve-month overall survival, RANO criteria and toxicities. In our radiological biomarker sub-study, we plan to evaluate novel radiopharmaceutical-based neuroimaging in determining blood-brain barrier permeability and to assess in vivo drug effects on tumor vasculature over time. TRIAL REGISTRATION: This trial was registered on 8th September 2022 with ClinicalTrials.gov Identifier: NCT05532397.
Subject(s)
Brain Neoplasms , Neoplasm Recurrence, Local , Humans , Neoplasm Recurrence, Local/drug therapy , Neoplasm Recurrence, Local/pathology , Brain Neoplasms/drug therapy , Brain Neoplasms/pathology , Brain Neoplasms/diagnostic imaging , Astrocytoma/drug therapy , Astrocytoma/pathology , Astrocytoma/diagnostic imaging , Organoids/drug effects , Organoids/pathology , Organoids/diagnostic imaging , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Neoplasm GradingABSTRACT
Azoospermia is a form of male infertility characterized by a complete lack of spermatozoa in the ejaculate. Sertoli cell-only syndrome (SCOS) is the most severe form of azoospermia, where no germ cells are found in the tubules. Recently, FANCM gene variants were reported as novel genetic causes of spermatogenic failure. At the same time, FANCM variants are known to be associated with cancer predisposition. We performed whole-exome sequencing on a male patient diagnosed with SCOS and a healthy father. Two compound heterozygous missense mutations in the FANCM gene were found in the patient, both being inherited from his parents. After the infertility assessment, the patient was diagnosed with diffuse astrocytoma. Immunohistochemical analyses in the testicular and tumor tissues of the patient and adequate controls showed, for the first time, not only the existence of a cytoplasmic and not nuclear pattern of FANCM in astrocytoma but also in non-mitotic neurons. In the testicular tissue of the SCOS patient, cytoplasmic anti-FANCM staining intensity appeared lower than in the control. Our case report raises a novel possibility that the infertile carriers of FANCM gene missense variants could also be prone to cancer development.