Investigating the effects of arginine methylation inhibitors on microdissected brain tumour biopsies maintained in a miniaturised perfusion system.

Arginine methylation is a post-translational modification that consists of the transfer of one or two methyl (CH3) groups to arginine residues in proteins. Several types of arginine methylation occur, namely monomethylation, symmetric dimethylation and asymmetric dimethylation, which are catalysed by different protein arginine methyltransferases (PRMTs). Inhibitors of PRMTs have recently entered clinical trials to target several types of cancer, including gliomas (NCT04089449). People with glioblastoma (GBM), the most aggressive form of brain tumour, are among those with the poorest quality of life and likelihood of survival of anyone diagnosed with cancer. There is currently a lack of (pre)clinical research on the possible application of PRMT inhibitors to target brain tumours. Here, we set out to investigate the effects of clinically-relevant PRMT inhibitors on GBM biopsies. We present a new, low-cost, easy to fabricate perfusion device that can maintain GBM tissue in a viable condition for at least eight days post-surgical resection. The miniaturised perfusion device enables the treatment of GBM tissue with PRMT inhibitors ex vivo, and we observed a two-fold increase in apoptosis in treated samples compared to parallel control experiments. Mechanistically, we show thousands of differentially expressed genes after treatment, and changes in the type of arginine methylation of the RNA binding protein FUS that are consistent with hundreds of differential gene splicing events. This is the first time that cross-talk between different types of arginine methylation has been observed in clinical samples after treatment with PRMT inhibitors.

The oldest presenting neurenteric cyst of the spinal cord.

We describe an 81-year-old gentleman presenting with mild myelopathic symptoms in the upper limbs. Imaging showed a C1-3 intradural extramedullary lesion initially thought to be an arachnoid cyst. A C1 + 2 hemilaminectomy and partial excision was performed with histology revealing a neurenteric cyst (NC). NCs are congenital tumours that usually present within the third decade of life, they account for 1% of all spinal tumours. A literature search was conducted and we found that the age of presentation might actually be earlier than previously described. We also found that there has never before been a case described in the eighth decade of life, making this the oldest known symptomatic presentation of this rare condition.

Posterior Cranial Fossa Meningioma Causing Tonsillar Herniation and Giant Cervicothoracic Syringomyelia: Case Report and Review of Literature.

Syringomyelia is a fluid-filled cyst within the spinal cord and is usually associated with conditions that obstruct the cerebrospinal fluid (CSF) (flow at the foramen magnum or spinal levels such as Chiari malformations, arachnoiditis, and basilar invaginations). Very rarely, posterior cranial fossa tumors can lead to tonsillar herniation and secondary syringomyelia. There are only nine reported cases in the literature. We report a rare case of a 56-year-old female with posterior cranial meningioma and secondary syringomyelia, admitted with headache, nausea, vomiting, and ataxic gait. Magnetic resonance imaging (MRI) demonstrated a large posterior fossa lesion causing early ventriculomegaly and a giant cervicothoracic syrinx within the upper spinal cord extending from the hindbrain inferiorly to the level of T8. She underwent a posterior fossa craniectomy with left C1 hemilaminectomy and complete excision of the tumor. In 6 months following her procedure, an MRI scan showed a significant reduction in the caliber of the syringomyelia throughout its length, and there was a significant improvement in symptoms. Although the pathophysiology of syrinx formation is still poorly understood, the alteration of CSF dynamic flow has been implicated. A common unifying cause appears to be increased transcranial difference in intracranial pressure across the foramen magnum causing tonsillar herniation, irrespective of location in the posterior fossa. With high syrinx pressure, mechanical stress-induced structural change of the spinal cord occurs, allowing the persistence and progression of the syrinx in the spinal cord. Syringomyelia appears to be resolved partially or completely after craniotomy and excision of the posterior fossa lesion.

Lumbar Fixation Using the Cortical Bone Trajectory Fixation: A Single Surgeon's Experience With 3-Year Follow-up.

BACKGROUND: Pedicle screw fixation with a cortical bone trajectory (CBT) has emerged as an effective alternative to traditional techniques of lumbar fusion, especially in osteoporotic patients. The proposed benefits of CBT screws include a stronger grip in the elderly and osteoporotic population and low surgical morbidity. We present a prospective study with a 3-yr follow-up of 80 patients operated on by the same surgeon. OBJECTIVE: To assess the outcomes of the CBT technique in patients with at least 3-yr follow-up. METHODS: Eighty patients who underwent lumbar fusion using the CBT fixation by the same surgeon were included in the study. The outcomes, Oswestry Disability Index (ODI), back pain visual analog scale (VAS), leg pain VAS, walking distance, opioid use, nonopioid analgesia use, and EuroQol 5D-5L index were measured preoperatively and during the 1- and 3-yr postoperative follow-up visits. Time from surgery, indication for surgery, intervertebral cage insertion, body mass index (BMI), and their interactions were analyzed as predictors in a separate mixed-effects model for each outcome. We assessed all outcomes as 1 group of patients, but we also elaborated on a classification scheme based on a combination of radiological and dynamical assessment of microinstability, macroinstability, and spondylolisthesis. RESULTS: The relationship between the outcomes and time showed considerable interpatient heterogeneity because all intercepts (all P < .001) and the linear trend temporal slopes for walking distance (P = .019) and nonopioid analgesics use (P < .001) varied across patients. The intercepts and the linear trend slopes for nonopioid use were significantly correlated (P = .039). Time from surgery significantly predicted all outcomes (P < .001). Intervertebral cage insertion was associated with significantly less opioid use (P = .017). The indication for surgery significantly modified the effect of time on the ODI (P = .042) and the VAS for leg pain (P = .025). Moreover, higher BMI was also associated with a significantly steeper linear trend in the VAS for leg pain (P = .028). Among patients with microinstability, the linear trend for the EuroQol 5D-5L index was significantly steeper with, rather than without, spondylolisthesis (P = .024). CONCLUSION: In all patients who underwent CBT-based lumbar fusion, there was a steep trend toward improvement in ODI, VAS score for leg pain, and opioid use at 1 yr after surgery. Patients with normal BMI and microinstability alone had a decline in the rate of improvement at 3 yr, whereas the rest continued to show improvement at 3 yr postprocedure. Spinal fixation and fusion using CBT shows satisfactory outcomes. Larger series and a double-blind randomized trial would be helpful for further identifying the pros and cons of this technique.

Primary pituitary granulomatosis with polyangiitis and the role of pituitary biopsy, case report and literature review.

BACKGROUND: Pituitary dysfunction (PD) in granulomatosis with polyangiitis (GPA) is a rare manifestation of the disease with an incidence of 2% and tends to occur as the disease progresses. On very rare occasions, PD can be the initial presentation of GPA. From our literature review, only 6 such cases were documented. CASE PRESENTATION: We present a rare case of GPA in a 57-year-old female who primarily presented with PD and visual disturbance without any other systemic features of GPA. Her initial ANCA screen was negative and her MRI scan showed an enlarged pituitary gland with cystic changes. A pituitary biopsy confirmed the diagnosis and she was started on immunosuppressants. After completing her immunotherapy, her diabetic insipidus subsided and her vision markedly improved. LITERATURE REVIEW: A literature search on Pubmed, Cochrane, Open Grey, and SciELO with keywords 'granulomatosis', 'polyangiitis', and 'pituitary' was performed. A total of 72 articles were reviewed. 6 articles were identified where PD was the presenting complaint of GPA without other systemic involvement. DISCUSSION: Secondary hypophysitis in GPA indicates pituitary inflammation resulting from systemic disease or pituitary near-lying lesions. PD in GPA tends to occur with concomitant active disease at other sites. Headache seemed to be a common presenting feature with diabetic insipidus being the most common type of PD. Tissue biopsy is essential to confirm diagnosis. Pituitary biopsy is rarely required as other organ involvement is available for safer tissue sampling. However, in our case, pituitary biopsy had a role in confirming diagnosis and avoiding treatment delay. CONCLUSION: PD as a primary manifestation in GPA without systemic involvement is very rare and poses a diagnostic challenge. Pituitary biopsy can aid in diagnosis, allowing prompt treatment and prevention of long-term complications of untreated GPA such as permanent pituitary dysfunction. Nevertheless, the risk and benefit of pituitary surgery in each case should be weighted.

Inhibiting Arginine Methylation as a Tool to Investigate Cross-Talk with Methylation and Acetylation Post-Translational Modifications in a Glioblastoma Cell Line.

Glioblastomas (GBM) are the most common grade 4 brain tumours; patients have very poor prognosis with an average survival of 15 months after diagnosis. Novel research lines have begun to explore aberrant protein arginine methylation (ArgMe) as a possible therapeutic target in GBM and ArgMe inhibitors are currently in clinical trials. Enzymes known as protein arginine methyltransferases (PRMT1-9) can lead to mono- or di-ArgMe, and in the latter case symmetric or asymmetric dimethylation (SDMA and ADMA, respectively). Using the most common GBM cell line, we have profiled the expression of PRMTs, used ArgMe inhibitors as tools to investigate post-translational modifications cross-talk and measured the effect of ArgMe inhibitors on cell viability. We have identified novel SDMA events upon inhibition of ADMA in GBM cells and spheroids. We have observed cross-talk between ADMA and lysine acetylation in GBM cells and platelets. Treatment of GBM cells with furamidine, a PRMT1 inhibitor, reduces cell viability in 2D and 3D models. These data provide new molecular understanding of a disease with unmet clinical needs.