Intracranial Leptomeninges Research Articles

Abstract 6735: Identifying the role of novel driver TREX subcomplex in medulloblastoma growth and progression

Abstract Background: Medulloblastoma (MB) is the most common malignant brain cancer in children. Despite the progress made in treating MB, the 5-year survival rate for high-risk tumors remains poor and risk of recurrence within 2 years of treatment is still high. Almost all MB deaths are attributed to leptomeningeal dissemination (LMD) as MB spreads exclusively through cerebrospinal fluid (CSF) to spinal and intracranial leptomeninges. Unfortunately, patients who do survive have reduced quality of life because of the highly toxic side effects of radiation and chemotherapy. Those facts underline the importance of identifying new drivers of medulloblastoma and understanding the mechanism by which those drivers may promote medulloblastoma. Towards that goal, I aim to identify novel drivers of MB and characterize novel therapies for treating (LMD-MB). Using an unbiased genome-wide screen, we discovered THO complex as one of the highly differentially expressed genes that may provide survival advantage to MB cells. THO is a subcomplex of the TREX complex, is known to couple mRNA transcription, processing and nuclear export associated with spliced mRNA. Methods: Recent work in our lab utilizing various genomes and proteomics identified THO complex as a possible target. Transfection agents were used to knockdown part of the TREX subcomplex expression in several MB cells. Western blot and qPCR verified the knockdown. The cell viability was measured using Cell Titer Glo, and cell proliferation was evaluated with an IncuCyte. Cells were seeded at a low density and cultured until colonies formed then were fixed and stained with crystal violet. In addition, cells were seeded in a serum-free medium and allowed to migrate to complete media before being fixed and stained. Flow cytometry was used to examine cells for apoptosis and cell cycle. For apoptosis, cells were stained with propidium iodide (PI) and Annexin FTIC, and for the cell cycle, cells were stained and followed by PI. Results: The Cancer Dependency Map (Dep-Map) meta-analysis revealed that MB strongly depends on The TREX subcomplex. Significantly, increased THO complex expression was associated with a worse overall survival rate in MB patients. Our findings indicated that part of the TREX subcomplex depletion decreased MB cell survival in the short- and long-term proliferation, migration, and invasion. Furthermore, part of TREX subcomplex depletion promoted apoptosis in MB cells. I propose that THO complex may be a new driver of MB and that strategies aiming to reduce part of TREX subcomplex levels and activity might benefit MB patients. Conclusion: TREX subcomplex parts depletion has been demonstrated to reduce MB cells in vitro in various experiments. Future research, including CRISPR-CAS9-based knockout models, single-cell sequencing, and metabolomics, will further elucidate the mechanism(s) and utility of the TREX subcomplex axis in LMD-MB. Citation Format: Shahad M. Abdulsahib, Santosh Timilsina, Manjeet Rao. Identifying the role of novel driver TREX subcomplex in medulloblastoma growth and progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6735.

Leptomeningeal dissemination: a sinister pattern of medulloblastoma growth.

Leptomeningeal dissemination (LMD) is the defining pattern of metastasis for medulloblastoma. Although LMD is responsible for virtually 100% of medulloblastoma deaths, it remains the least well-understood part of medulloblastoma pathogenesis. The fact that medulloblastomas rarely metastasize outside the CNS but rather spread almost exclusively to the spinal and intracranial leptomeninges has fostered the long-held belief that medulloblastoma cells spread directly through the CSF, not the bloodstream. In this paper the authors discuss selected molecules for which experimental evidence explains how the effects of each molecule on cell physiology contribute mechanistically to LMD. A model of medulloblastoma LMD is described, analogous to the invasion-metastasis cascade of hematogenous metastasis of carcinomas. The LMD cascade is based on the molecular themes that 1) transcription factors launch cell programs that mediate cell motility and invasiveness and maintain tumor cells in a stem-like state; 2) disseminating medulloblastoma cells escape multiple death threats by subverting apoptosis; and 3) inflammatory chemokine signaling promotes LMD by creating an oncogenic microenvironment. The authors also review recent experimental evidence that challenges the belief that CSF spread is the sole mechanism of LMD and reveal an alternative scheme in which medulloblastoma cells can enter the bloodstream and subsequently home to the leptomeninges.

A Case Report of Atypical Teratoid/Rhabdoid Tumor with Diffuse Leptomeningeal Carcinomatosis and Review of Current Literature

We present a rare case of craniospinal atypical teratoid/rhabdoid tumor (ATRT) with leptomeningeal carcinomatosis in young adult. A previously healthy 25 year old man presented to the hospital after a one week history of intermittent confusion, intractable headache and a single new onset seizure. Two lumbar punctures were completed and both revealed elevated RBC, elevated protein and predominantly lymphocytic pleocytosis. Both lumbar punctures were unrevealing with normal cytology and flow cytometry. Contrasted magnetic resonance imaging (MRI) of the brain revealed extensive intracranial leptomeningeal and cranial nerve enhancement. Contrasted MRI of the spinal cord revealed extensive leptomeningeal and dural enhancement with multifocal areas of nodular mass-like enhancement along the entire spinal cord. Spinal biopsies were performed and a pathological diagnosis of ATRT was made. Aggressive radiotherapy and chemotherapy treatment were started. Unfortunately, the patient expired within 12 months of the initial diagnosis.

Intracranial spreading of a spinal anaplastic astrocytoma

A 63-year-old man was admitted with bilateral sensory loss up to thoracic level TH 8, progressive spastic paraparesis of legs, urinary incontinence, and fecal obstipation. Symptoms had begun 3 weeks earlier. Spinal MRI showed a contrast-enhancing mass with perifocal edema in the spinal cord at TH 6–7, and brain MRT was unsuspicious (Fig. 1a). Cerebral spinal fluid (CSF) revealed leukocytosis (19 cells/ll), elevated lactate (4.9 mmol/l), and protein (65.8 mg/dl) without neoplastic cells. Suspecting an autonomic inflammatory disease, steroids were applied, leading only to temporary improvement. Plasma separation brought no improvement. MRI then demonstrated an enlargement of the intramedullary mass with subtotal compression of the spinal cord. A biopsy showed astrocytic cells with GFAP (glial fibrillary acidic protein) and MAP2-positive tumor cells. The Ki67-proliferation index was beyond 5%. Diagnosis of an anaplastic astrocytoma WHO grade III was made. Since gross total resection was impossible, combined radiochemotherapy with temozolomide [1] was undertaken. Symptoms and MRI scans remained stable, but 14 months after the first symptoms, a progressive complete internal and external paresis of the left oculomotor nerve occurred. The other symptoms remained stable. Brain MRI revealed enlargement of the left oculomotor nerve in its prepontine course to the cavernous sinus with contrast enhancement as a sign of cortical infiltration of the adjacent temporomesial parenchyma (Fig. 1b). Spinal MRI showed cervical and thoracic leptomeningeal enhancement (Fig. 1c, d), the primary intramedullary tumor remained stable. CSF revealed elevated lactate (5.3 mmol/l) and lympho-monocytic pleocytosis (14 cells/ll) with atypic cells suspicious for meningeosis neoplastica. A biopsy of the swollen oculomotor nerve showed tumor cells with many mitoses, areas of necrosis, focal GFAP-positive cell accumulation (Online resource 1), and nuclear accumulation of p53 in a few cells. The Ki67 proliferation index was above 30%, therefore the histological evaluation was glioblastoma. Only a few days after the biopsy, the patient developed dysphagia, dysarthria, and dyspnea, which was most likely due to basal infiltration of the leptomeninges, and died within 2 weeks. In summary, the patient presented first with a spinal anaplastic astrocytoma WHO grade III. Later leptomeningeal and cerebral dissemination occurred. Histology revealed a growing malignancy consistent with glioblastoma. This case is of special interest because of the very rare circumstance of a malignant spinal anaplastic astrocytoma spreading to spinal and intracranial leptomeninges and even supratentorial parenchyma. The second biopsy revealed a different—higher—grade than before, therefore a multifocal glioma cannot be ruled out completely, but Electronic supplementary material The online version of this article (doi:10.1007/s00415-011-6253-0) contains supplementary material, which is available to authorized users.

Primary Central Nervous System Lymphoma Causing Multiple Spinal Cord Compression and Carcinomatous Meningitis in a 6-year-old

Primary central nervous system lymphoma (PCNSL) is an uncommon form of non-Hodgkin lymphoma affecting the brain, spinal cord, and leptomeninges. Carcinomatous meningitis (CM) and spinal cord compression in PCNSL are very rare and usually present in advanced stages of the disease. The average survival time of a CM patient is about 4 to 6 weeks, which may be extended to about 4 to 6 months with treatment. Here we present a case of CM and spinal cord compression by multiple PCNSL in a 6-year-old girl, who has survived 2 years and 9 months posttreatment with no recurrence. To the best of our knowledge this is the very first case reporting survival after CM. The patient presented with weakness of her right arm, right leg, and left side of the face. Examination revealed mild facial asymmetry with left facial lower motor neuron palsy and lateral gaze restriction of left eye. Magnetic resonance imaging of her spinal cord showed postcontrast enhancement of the intradural structures on the spinal canal at levels C3-C6 and L1-L5 and along with the intracranial leptomeninges. Histopathological examination of the neoplastic tissue from cauda equina revealed B-cell non-Hodgkin lymphoma. After chemotherapy her disease regressed and magnetic resonance imaging showed no evidence of recurrence or residual disease. In our experience the response to chemotherapy was remarkable and recommend that aggressive tumor resection strategies should be reserved for cases with severe signs of spinal compression.

Neurosarcoidosis involving optic nerves and leptomeninges: computed tomography findings

A case of neurosarcoidosis with extensive involvement of both optic nerves and intracranial leptomeninges is reported. Computed tomography demonstrates diffuse enlargement of the optic nerves and extensive nodular contrast medium enhancement of the leptomeninges of the anterior and middle cranial fossae extending into the frontal convexity. Only one such case has been previously reported in the computed tomography literature. Marked therapeutic response was obtained clinically and demonstrated on a follow-up computed tomography after therapy with corticosteroids. Differential diagnosis of computed tomography findings is discussed.