Current Management of Brain Metastases: Overview and Teaching Cases

Over the past two decades, increased global incidence of malignancy, improved systemic disease treatment with prolonged survival, and increased central nervous system (CNS) surveillance in cancer patients have all contributed to a rise in cerebral metastatic disease. As many patients retain good neurologic function, the approach to their management has shifted markedly; a pre-terminal prognosis and palliative treatment have been replaced by individualized care plans to prolong functional survival. However, the rapid shifts in disease characteristics, treatment options and emerging evidence can be challenging to navigate, and a rational approach to brain metastases is needed. We discuss the changing epidemiology of brain metastases and consider approaches to prognostic classification. We review current treatment modalities and discuss the significant studies pertaining to each, with emphasis on Level 1 evidence when available and cooperative group trials, as well as studies on adverse effects. To integrate the information presented, we offer case scenarios that highlight pertinent decision-making factors. The shift in care goal for cerebral metastases from symptom palliation to prolongation of survival is not only feasible, but in many cases indicated. The appropriate application of various treatment modalities must be considered in the context of individual patients and their primary cancer

DNA methylation profiling to predict recurrence risk in meningioma: development and validation of a nomogram to optimize clinical management

Abstract Background Variability in standard-of-care classifications precludes accurate predictions of early tumor recurrence for individual patients with meningioma, limiting the appropriate selection of patients who would benefit from adjuvant radiotherapy to delay recurrence. We aimed to develop an individualized prediction model of early recurrence risk combining clinical and molecular factors in meningioma. Methods DNA methylation profiles of clinically annotated tumor samples across multiple institutions were used to develop a methylome model of 5-year recurrence-free survival (RFS). Subsequently, a 5-year meningioma recurrence score was generated using a nomogram that integrated the methylome model with established prognostic clinical factors. Performance of both models was evaluated and compared with standard-of-care models using multiple independent cohorts. Results The methylome-based predictor of 5-year RFS performed favorably compared with a grade-based predictor when tested using the 3 validation cohorts (ΔAUC = 0.10, 95% CI: 0.03–0.018) and was independently associated with RFS after adjusting for histopathologic grade, extent of resection, and burden of copy number alterations (hazard ratio 3.6, 95% CI: 1.8–7.2, P &lt; 0.001). A nomogram combining the methylome predictor with clinical factors demonstrated greater discrimination than a nomogram using clinical factors alone in 2 independent validation cohorts (ΔAUC = 0.25, 95% CI: 0.22–0.27) and resulted in 2 groups with distinct recurrence patterns (hazard ratio 7.7, 95% CI: 5.3–11.1, P &lt; 0.001) with clinical implications. Conclusions The models developed and validated in this study provide important prognostic information not captured by previously established clinical and molecular factors which could be used to individualize decisions regarding postoperative therapeutic interventions, in particular whether to treat patients with adjuvant radiotherapy versus observation alone. </jats:sec

Investigations of the Expression, Activation and Functional Significance of Platelet-derived Growth Factor Receptor in Pediatric Glioblastoma

Solid tumours arising from malignant transformation of glial cells are one of the leading causes of central nervous system tumour-related death in children. Recurrence in spite of rigorous surgical and chemoradiation therapies remains a major hurdle in management of these tumours. Here, we investigate the efficacy of the second-generation receptor tyrosine kinase (RTK) inhibitor nilotinib as a therapeutic option for the management of pediatric glioblastoma. We have utilised two independent pediatric glioblastoma cell lines with either high expression of platelet-derived growth factor receptor alpha (PDGFRα) or PDGFRβ expression in in vitro assays to investigate the specific downstream effects of nilotinib treatment. We show that nilotinib inhibits ligand-dependent activation of PDGFRα and suppresses AKT signalling. Nilotinib furthermore decreases cell proliferation and colony formation, as well as in vivo growth of xenograft tumours. Our results suggest that nilotinib may be effective for management of a PDGFRα-dependent group of pediatric high-grade gliomas.M.Sc

Intracranial Complications of Orbital Cellulitis

Due to the close association of the anterior skull base with the orbit and sinuses, intracranial complications of orbital cellulitis can be a significant cause of morbidity and mortality. Intracranial involvement can include cavernous sinus thrombosis, epidural abscess, subdural empyema, meningitis, and brain abscess. Long-term sequelae may include visual deficit, neurological impairment, and seizure. A high clinical suspicion and prompt diagnosis and management are necessary for the optimal prognosis

Investigation of the in vitro therapeutic efficacy of nilotinib in immortalized human NF2-null vestibular schwannoma cells.

Vestibular schwannomas (VS) are a common posterior fossa brain tumor, and though benign can cause significant morbidity, particularly loss of hearing, tinnitus, vertigo and facial paralysis. The current treatment options for VS include microsurgical resection, stereotactic radiosurgery or close surveillance monitoring, with each treatment option carrying associated complications and morbidities. Most importantly, none of these options can definitively reverse hearing loss or tinnitus. Identification of a novel medical therapy, through the use of targeted molecular inhibition, is therefore a highly desirable treatment strategy that may minimize complications arising from both tumor and treatment and more importantly be suitable for patients whose options are limited with respect to surgical or radiosurgical interventions. In this study we chose to examine the effect of Nilotinib on VS. Nilotinib (Tasigna®) is a second-generation receptor tyrosine kinase (RTK) inhibitor with a target profile similar to that of imatinib (Gleevec®), but increased potency, decreased toxicity and greater cellular and tissue penetration. Nilotinib targets not only the BCR-ABL oncoprotein, but also platelet-derived growth factor (PDGF) receptor signalling. In this preclinical study, the human NF2-null schwannoma cell line HEI-193 subjected to nilotinib inhibition demonstrated decreased viability, proliferation and anchorage-independent growth, and increased apoptosis. A daily dose of nilotinib for 5 days inhibited HEI-I93 proliferation at a clinically-relevant concentration in a dose-dependent manner (IC(50) 3-5 µmol/L) in PDGF-stimulated cells. These anti-tumorigenic effects of nilotinib were correlated to inhibited activation of PDGFR-α and PDGFR-β and major downstream signalling pathways. These experiments support a therapeutic potential for Nilotinib in VS

The molecular structure of Rv2074, a probable pyridoxine 5′-phosphate oxidase from Mycobacterium tuberculosis, at 1.6 Å resolution

The crystal structure of a probable pyridoxine 5′-phosphate oxidase, Rv2074 from M. tuberculosis, has been solved by the two-wavelength anomalous dispersion method and has been refined at 1.6 Å resolution. Two citric acid molecules are bound fortuitously to the possible active site of Rv2074

Nilotinib inhibition of HEI-193 cells decreases activation of PDGFR-α and PDGFR-β.

<p>HEI-193 cells inhibited with nilotinib and stimulated with PDGF-BB or GM were lysed and analyzed by Western immunoblot using phophorylation-specific antibodies. Comparison was made to total protein expression, as determined by immunoblotting using non-activation specific antibodies. Densitometry was used to evaluate fold-change in phosphorylation, with values normalized to activation in the presence of vehicle control. **denotes significant (<i>p</i><0.05) difference compared to phosphorylation in vehicle control. (A) PDGF-BB activation of both PDGFR-α and PDGFR-β is abrogated in the presence of ≥3 µM nilotinib. (B) GM-stimulated activation of PDGFR-β is inhibited by ≥3 µM nilotinib.</p

Nilotinib decreases the <i>in vitro</i> tumorigenicity of HEI-193 cells.

<p>Anchorage-independent growth in soft agar was inhibited in the presence of nilotinib. (A) Visual assessment of agar plates shows qualitative decrease of colony formation by nilotinib. (B) The number of colonies was reduced at ≥3 µM nilotinib in media containing PDGF-BB, and at ≥5 µM in GM. *denotes significant value (<i>p</i><0.05). (C) The mean maximal colony diameter was decreased by nilotinib at ≥3 µM in PDGF-BB media, and at ≥5 µM in GM. *denotes significant value (<i>p</i><0.05).</p