Lower-grade gliomas (WHO grade II/III) have been classified into clinically relevant molecular subtypes based on
and 1p/19q mutation status. The purpose was to investigate whether T2/FLAIR MRI ...features could distinguish between lower-grade glioma molecular subtypes.
MRI scans from the TCGA/TCIA lower grade glioma database (
= 125) were evaluated by two independent neuroradiologists to assess (i) presence/absence of homogenous signal on T2WI; (ii) presence/absence of "T2-FLAIR mismatch" sign; (iii) sharp or indistinct lesion margins; and (iv) presence/absence of peritumoral edema. Metrics with moderate-substantial agreement underwent consensus review and were correlated with glioma molecular subtypes. Somatic mutation, DNA copy number, DNA methylation, gene expression, and protein array data from the TCGA lower-grade glioma database were analyzed for molecular-radiographic associations. A separate institutional cohort (
= 82) was analyzed to validate the T2-FLAIR mismatch sign.
Among TCGA/TCIA cases, interreader agreement was calculated for lesion homogeneity
= 0.234 (0.111-0.358), T2-FLAIR mismatch sign
= 0.728 (0.538-0.918), lesion margins
= 0.292 (0.135-0.449), and peritumoral edema
= 0.173 (0.096-0.250). All 15 cases that were positive for the T2-FLAIR mismatch sign were
-mutant, 1p/19q non-codeleted tumors (
< 0.0001; PPV = 100%, NPV = 54%). Analysis of the validation cohort demonstrated substantial interreader agreement for the T2-FLAIR mismatch sign
= 0.747 (0.536-0.958); all 10 cases positive for the T2-FLAIR mismatch sign were
-mutant, 1p/19q non-codeleted tumors (
< 0.00001; PPV = 100%, NPV = 76%).
Among lower-grade gliomas, T2-FLAIR mismatch sign represents a highly specific imaging biomarker for the
-mutant, 1p/19q non-codeleted molecular subtype.
.
Abstract
Pleomorphic xanthoastrocytoma (PXA) is a rare type of brain tumor that affects children and young adults. Molecular prognostic markers of PXAs remain poorly established. Similar to ...gangliogliomas, PXAs show prominent immune cell infiltrate, but its composition also remains unknown. In this study, we correlated DNA methylation and BRAF status with clinical outcome and explored the tumor microenvironment. We performed DNA methylation in 21 tumor samples from 18 subjects with a histological diagnosis of PXA. MethylCIBERSORT was used to deconvolute the PXA microenvironment by analyzing the associated immune cell-types. Median age at diagnosis was 16 years (range 7–32). At median follow-up of 30 months, 3-year and 5-year overall survival was 73% and 71%, respectively. Overall survival ranged from 1 to 139 months. Eleven out of 18 subjects (61%) showed disease progression. Progression-free survival ranged from 1 to 89 months. Trisomy 7 and CDKN2A/B (p16) homozygous deletion did not show any association with overall survival (p = 0.67 and p = 0.74, respectively). Decreased overall survival was observed for subjects with tumors lacking the BRAF V600E mutation (p = 0.02). PXAs had significantly increased CD8 T-cell epigenetic signatures compared with previously profiled gangliogliomas (p = 0.0019). The characterization of immune cell-types in PXAs may have implications for future development of immunotherapy.
Abstract
Diffuse spinal cord gliomas (SCGs) are rare tumors associated with a high morbidity and mortality that affect both pediatric and adult populations. In this retrospective study, we sought to ...characterize the clinical, pathological, and molecular features of diffuse SCG in 22 patients with histological and molecular analyses. The median age of our cohort was 23.64 years (range 1–82) and the overall median survival was 397 days. K27M mutation was significantly more prevalent in males compared to females. Gross total resection and chemotherapy were associated with improved survival, compared to biopsy and no chemotherapy. While there was no association between tumor grade, K27M status (p = 0.366) or radiation (p = 0.772), and survival, males showed a trend toward shorter survival. K27M mutant tumors showed increased chromosomal instability and a distinct DNA methylation signature.
Sudden unexpected death in epilepsy (SUDEP) is the leading cause of epilepsy-related mortality in young adults. The exact mechanisms are unknown but death often follows a generalized tonic-clonic ...seizure. Proposed mechanisms include seizure-related respiratory, cardiac, autonomic, and arousal dysfunction. Genetic drivers underlying SUDEP risk are largely unknown. To identify potential SUDEP risk genes, we compared whole-exome sequences (WES) derived from formalin-fixed paraffin embedded surgical brain specimens of eight epilepsy patients who died from SUDEP with seven living controls matched for age at surgery, sex, year of surgery and lobe of resection. We compared identified variants from both groups filtering known polymorphisms from publicly available data as well as scanned for epilepsy and candidate SUDEP genes. In the SUDEP cohort, we identified mutually exclusive variants in genes involved in µ-opiod signaling, gamma-aminobutyric acid (GABA) and glutamate-mediated synaptic signaling, including
,
,
,
,
,
,
,
and
. In SUDEP patients we also identified variants in genes associated with cardiac arrhythmia, including
,
,
,
,
, and
, which were not present in living epilepsy controls. Our data shows that genomic analysis of brain tissue resected for seizure control can identify potential genetic biomarkers of SUDEP risk.
Liposarcoma is a malignant soft tissue tumor that rarely involves the gastrointestinal tract. The dedifferentiated type typically carries the worst prognosis. Here, we describe a rare case of ...dedifferentiated liposarcoma of the rectum in a young male patient who was treated with surgical excision. Treatment is often difficult and there is no clear consensus on the benefits of radiotherapy or chemotherapy.
We present a unique case of a patient simultaneously diagnosed with solitary fibrous tumor (SFT) and unrelated adenocarcinoma of the lung, both proven with separate pathology. It was subsequently ...found that the SFT had metastasized to the brain by additional pathology, and not the predicted adenocarcinoma. SFTs are a rare mesenchymal neoplasm that accounts for less than 2% of all reported soft tissue tumors. SFTs most commonly arise in the thoracic cavity, but are frequently found in various locations throughout the body, and rarely metastasize to the brain. This case highlights that rare neoplasms, such as SFT, should not be ruled out as a potential cause of metastasis. Due to the rarity of this clinical situation, we also provide a review and discussion of previously reported SFT cases and the use of postoperative radiation therapy. The optimal treatment for individual patients remains unclear in this unique situation. Surgical resection followed by adjuvant Gamma Knife radiation therapy to the surgical bed appears to be a safe option for local treatment of SFT in select patients. Further studies are needed of this rare clinical situation in order to better understand and optimize future treatments for patients with SFT and metastasis to the brain.
Epithelioid sarcoma is a rare high-grade malignancy identified by Enzinger in 1970. It accounts for 1% of all reported soft tissue sarcomas and presents most commonly in distal upper extremities in ...young adults with a male predominance. At this time, there are only 5 previously reported cases of primary epithelioid sarcoma of the orbit. We present a primary orbital epithelioid sarcoma case of a patient who underwent orbital exenteration followed by external beam radiation treatment. Because the literature is limited, this is to our knowledge the largest descriptive analysis of cases of orbital epithelioid sarcoma. We also provide a detailed review of all the previously reported primary orbital epithelioid sarcoma cases, as well as a discussion on the use of postoperative radiation therapy for patients with epithelioid sarcoma. Surgical resection followed by adjuvant radiation therapy appears to be a safe option for local treatment of this rare malignancy, but further future studies are needed of this rare clinical situation in order to better understand and optimize treatment for patients with orbital epithelioid sarcoma.
Background. Extraosseous Ewing’s sarcoma in the spinal epidural space is a rare malignancy, especially in adults. Case Presentation. A 40-year-old male presented with back pain and urinary hesitancy. ...MRI revealed a thoracic extradural mass with no osseous involvement. He underwent surgery for gross total resection of the mass, which was diagnosed as Ewing’s sarcoma. He was subsequently treated with chemoradiotherapy. He remains disease-free 1 year after surgery. Review of the literature indicated only 45 previously reported cases of spinal epidural extraosseous Ewing’s sarcoma in adults. Conclusions. Extraosseous Ewing’s sarcoma in the spinal epidural space is a rare clinical entity that should be included in the differential for spinal epidural masses. Its treatment is multidisciplinary but frequently requires surgical intervention due to compressive neurologic symptoms. Gross total resection appears to correlate with improved outcomes.
OBJECTIVE:Because the D-2-hydroxyglutarate (D2HG) product of mutant isocitrate dehydrogenase 1 (IDH1) is released by tumor cells into the microenvironment and is structurally similar to the ...excitatory neurotransmitter glutamate, we sought to determine whether IDH1 increases the risk of seizures in patients with glioma, and whether D2HG increases the electrical activity of neurons.
METHODS:Three WHO grade II-IV glioma cohorts from separate institutions (total N = 712) were retrospectively assessed for the presence of preoperative seizures and tumor location, WHO grade, 1p/19q codeletion, and IDH1 status. Rat cortical neurons were grown on microelectrode arrays, and their electrical activity was measured before and after treatment with exogenous D2HG, in the presence or absence of the selective NMDA antagonist, AP5.
RESULTS:Preoperative seizures were observed in 18%–34% of IDH1 wild-type (IDH1) patients and in 59%–74% of IDH1 patients (p < 0.001). Multivariable analysis, including WHO grade, 1p/19q codeletion, and temporal lobe location, showed that IDH1 was an independent correlate with seizures (odds ratio 2.5, 95% confidence interval 1.6–3.9, p < 0.001). Exogenous D2HG increased the firing rate of cultured rat cortical neurons 4- to 6-fold, but was completely blocked by AP5.
CONCLUSIONS:The D2HG product of IDH1 may increase neuronal activity by mimicking the activity of glutamate on the NMDA receptor, and IDH1 gliomas are more likely to cause seizures in patients. This has rapid translational implications for the personalized management of tumor-associated epilepsy, as targeted IDH1 inhibitors may improve antiepileptic therapy in patients with IDH1 gliomas.
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