Katharine J. Drummond

KRAS Mutation Is Associated with Lung Metastasis in Patients with Curatively Resected Colorectal Cancer

Purpose: Oncogene mutations contribute to colorectal cancer development. We searched for differences in oncogene mutation profiles between colorectal cancer metastases from different sites and evaluated these as markers for site of relapse. Experimental Design: One hundred colorectal cancer metastases were screened for mutations in 19 oncogenes, and further 61 metastases and 87 matched primary cancers were analyzed for genes with identified mutations. Mutation prevalence was compared between (a) metastases from liver (n = 65), lung (n = 50), and brain (n = 46), (b) metastases and matched primary cancers, and (c) metastases and an independent cohort of primary cancers (n = 604). Mutations differing between metastasis sites were evaluated as markers for site of relapse in 859 patients from the VICTOR trial. Results: In colorectal cancer metastases, mutations were detected in 4 of 19 oncogenes: BRAF (3.1%), KRAS (48.4%), NRAS (6.2%), and PIK3CA (16.1%). KRAS mutation prevalence was significantly higher in lung (62.0%) and brain (56.5%) than in liver metastases (32.3%; P = 0.003). Mutation status was highly concordant between primary cancer and metastasis from the same individual. Compared with independent primary cancers, KRAS mutations were more common in lung and brain metastases (P < 0.005), but similar in liver metastases. Correspondingly, KRAS mutation was associated with lung relapse (HR = 2.1; 95% CI, 1.2 to 3.5, P = 0.007) but not liver relapse in patients from the VICTOR trial. Conclusions: KRAS mutation seems to be associated with metastasis in specific sites, lung and brain, in colorectal cancer patients. Our data highlight the potential of somatic mutations for informing surveillance strategies. Clin Cancer Res; 17(5); 1122–30. ©2011 AACR.

Primary melanocytic neoplasms of the central nervous system

Primary melanocytic neoplasms of the central nervous system (CNS) are rare lesions arising from melanocytes of the leptomeninges. They include diffuse leptomeningeal melanocytosis or melanomatosis, melanocytoma and primary malignant melanoma. We have reviewed the English literature regarding these lesions, which consists of case reports and a small number of larger case series. The presenting features, radiological, surgical and histological findings are reviewed, as are current management options and prognosis. We also present illustrative case reports of diffuse leptomeningeal melanocytosis and primary melanoma of the CNS.

The incidence of medulloblastomas and primitive neurectodermal tumours in adults and children

Medulloblastomas (MB) and primitive neurectodermal tumours (PNET) are known to affect children more than adults. To estimate the magnitude of the differences between the incidence of adults and children, the incidence rates, ratios and time trends of MB and PNET in children and adults are measured using data from the Surveillance, Epidemiology and End-Results (SEER) database. Between 1973 and 2007 in the SEER 9 registries, 1372 people were diagnosed with a MB and 530 with a PNET. The overall incidence rate of MB and PNET is approximately 1.5 and 0.62 per million population in the USA. Children (1-9 years of age) with MB had an incidence rate of 6.0, compared to 0.6 in adults, and therefore children are 10 times more likely to be affected by an MB than adults. Children are 4.6 times as likely to be afflicted by a PNET than adults. The difference in incidence rates based on sex existed only in children. Our study confirmed that the incidence rates of MB has not changed over time.

Meningiomas: Updating basic science, management, and outcome

Background:Meningiomas are biologically complex and clinically and surgically challenging. These features, combined with the rewarding potential for cure, make them of great interest to neurologists, neurosurgeons, and neuroscientists alike. Review Summary:Initially, we review the clinical context of meningiomas, particularly recent changes in histopathological classification, diagnosis, and neuroimaging. Secondly, the underlying basic science as it has evolved over the last decades is summarized. The status of areas recently of intense interest, such as steroid hormone receptors and oncogenic viruses is described. Additionally, emerging areas of great promise, such as cytogenetics and molecular biology are presented. Lastly, we describe recent advances in management. In particular, skull-base surgery, image-guided surgery, and advances in radiotherapy are emphasized. The possible impact of basic research on management and outcome is also outlined. Conclusions:Although usually benign and amenable to cure, meningiomas still present significant diagnostic and treatment challenges. Advances in basic science, surgery, and adjuvant therapy are widening the potential for safe, effective, evidence-based management leading to even better outcomes.

Comparative PET study using F-18 FET and F-18 FDG for the evaluation of patients with suspected brain tumour

The aim of this prospective pilot study in patients with suspected or known brain tumour was to establish the diagnostic value of O-(2-[(18)F]-fluoroethyl)-L-tyrosine (FET) positron emission tomography (PET) when compared to fluorine-18 fluorodeoxyglucose (FDG) PET. Twenty-five FET PET and FDG PET scans were performed on 21 consecutive patients within 24 months. Final malignant pathology included 11 glioma (eight low-grade, three high grade), two lymphoma, one olfactory ganglioneuroblastoma, one anaplastic meningioma. Benign pathology included two encephalitis and one cortical dysplasia. Definitive pathology was not available in three patients. The accuracy of PET was determined by subsequent surgical histopathology in 12 and clinical/imaging course in nine patients. Median follow-up period was 20 months. FET sensitivity was 93%, specificity 100%, accuracy 96%, positive predictive value (PPV) 100% and negative predictive value (NPV) 91%. FDG sensitivity was 27%, specificity 90%, accuracy 52%, PPV 80% and NPV 45%. FET PET is more accurate than FDG PET for detecting malignant brain lesions, especially low-grade gliomas.

MRI safety; nephrogenic systemic fibrosis and other risks

Magnetic resonance imaging (MRI) is now a commonly used imaging modality in many neurosurgical and neurological conditions. Although generally regarded as safe, there are a number of important safety considerations. These include a recently recognised, rare condition termed nephrogenic systemic fibrosis (NSF) that occurs in patients with significant renal impairment who receive gadolinium based contrast. Currently, NSF remains poorly understood and there is no universally effective treatment beyond the avoidance of contrast in patients with significant renal impairment. Other safety considerations include MRI contraindicated devices and the role of MRI in pregnancy.

A systematic review of types and efficacy of online interventions for cancer patients.

OBJECTIVE This review examines the evidence-based literature surrounding the use of online resources for adult cancer patients. The focus is online resources that connect patients with their healthcare clinician and with supportive and educational resources, their efficacy and the outcome measures used to assess them. METHODS The following databases were systematically searched for relevant literature: MEDLINE, PsychINFO, Cochrane Central Register of Controlled Trials, CINAHL, Inspec and Computers and Applied Science. Included were studies conducted in an outpatient setting, and reporting a measurable, clinically relevant outcome. Fourteen studies satisfied the inclusion criteria. RESULTS The efficacy of online interventions was varied, with some demonstrating positive effects on quality of life and related measures, and two demonstrating poorer outcomes for intervention participants. The majority of interventions reported mixed results. Included interventions were too heterogeneous for meta-analysis. CONCLUSIONS The overall benefit of online interventions for cancer patients is unclear. Although there is a plethora of interventions reported without analysis, current interventions demonstrate mixed efficacy of limited duration when rigorously evaluated. PRACTICE IMPLICATIONS The efficacy of on-line interventions for cancer patients is unclear. All on-line interventions should be developed using the available evidence-base and rigorously evaluated to expand our understanding of this area.

Metastatic atypical meningioma: case report and review of the literature.

Extracranial metastasis of an intracranial meningioma is rare. We discuss the clinical, radiological and histopathological presentation of an elderly man with pulmonary metastases from a recurrent meningioma of atypical histology, and review the literature pertaining to this phenomenon.

Regulation of glycogen synthase kinase-3 beta (GSK-3β) by the Akt pathway in gliomas

Gliomas are aggressive brain tumours that, despite advances in multimodal therapies, continue to portend a dismal prognosis. Glioblastoma multiforme (GBM) represents the most aggressive glioma and patients have a median survival of 14 months, even with the best available treatments. The phosphoinositide 3-kinase/Akt/glycogen synthase kinase-3 beta (GSK-3β) and Wnt/β-catenin pathways are dysregulated in a number of cancers, and these two pathways share a common node protein, GSK-3β. This protein is responsible for the regulation/degradation of β-catenin, which reduces β-catenins translocation to the nucleus and influences the subsequent transcription of oncogenes. The non-specific small-molecule GSK-3β inhibitor, lithium chloride (LiCl), and the specific Akt inhibitor, AktX, were used to treat U87MG and U87MG.Δ2-7 human glioma cell lines. LiCl treatment significantly affected cell morphology of U87MG and U87MG.Δ2-7 cells, while also increasing levels of phospho-GSK-3β in a dose-dependent manner. Increased cell proliferation was observed at low-to-mid LiCl concentrations as determined by MTT cell growth assays. Treatment of U87MG and U87MG.Δ2-7 cells with AktX resulted in reduced levels of phospho-GSK-3β through its inhibition of Akt, in addition to decreased levels of phosphorylated (active) Akt in a dose-dependent fashion. We have shown in this study that GSK-3β regulation by phosphorylation is important for cell morphology and growth, and that LiCl enhances growth of U87MG and U87MG.Δ2-7 cells by inhibiting GSK-3β through its phosphorylation, whereas AktX reduces growth via activation of GSK-3β by inhibiting Akts kinase activity.

IDH1 mutation is associated with seizures and protoplasmic subtype in patients with low‐grade gliomas

The isocitrate dehydrogenase 1 (IDH1) R132H mutation is the most common mutation in World Health Organization (WHO) grade II gliomas, reported to be expressed in 70–80%, but only 5–10% of high grade gliomas. Low grade tumors, especially the protoplasmic subtype, have the highest incidence of tumor associated epilepsy (TAE). The IDH1 mutation leads to the accumulation of 2‐hydroxyglutarate (2HG), a metabolite that bears a close structural similarity to glutamate, an excitatory neurotransmitter that has been implicated in the pathogenesis of TAE. We hypothesized that expression of mutated IDH1 may play a role in the pathogenesis of TAE in low grade gliomas.