Lipids, Mitochondria and Cell Death: Implications in Neuro-oncology

Polyunsaturated fatty acids (PUFAs) are known to inhibit cell proliferation of many tumour types both in vitro and in vivo. Their capacity to interfere with cell proliferation has been linked to their induction of reactive oxygen species (ROS) production in tumour tissues leading to cell death through apoptosis. However, the exact mechanisms of action of PUFAs are far from clear, particularly in brain tumours. The loss of bound hexokinase from the mitochondrial voltage-dependent anion channel has been directly related to loss of protection from apoptosis, and PUFAs can induce this loss of bound hexokinase in tumour cells. Tumour cells overexpressing Akt activity, including gliomas, are sensitised to ROS damage by the Akt protein and may be good targets for chemotherapeutic agents, which produce ROS, such as PUFAs. Cardiolipin peroxidation may be an initial event in the release of cytochrome c from the mitochondria, and enriching cardiolipin with PUFA acyl chains may lead to increased peroxidation and therefore an increase in apoptosis. A better understanding of the metabolism of fatty acids and eicosanoids in primary brain tumours such as gliomas and their influence on energy balance will be fundamental to the possible targeting of mitochondria in tumour treatment.

Updated response assessment criteria for high-grade gliomas: response assessment in neuro-oncology working group.

Currently, the most widely used criteria for assessing response to therapy in high-grade gliomas are based on two-dimensional tumor measurements on computed tomography (CT) or magnetic resonance imaging (MRI), in conjunction with clinical assessment and corticosteroid dose (the Macdonald Criteria). It is increasingly apparent that there are significant limitations to these criteria, which only address the contrast-enhancing component of the tumor. For example, chemoradiotherapy for newly diagnosed glioblastomas results in transient increase in tumor enhancement (pseudoprogression) in 20% to 30% of patients, which is difficult to differentiate from true tumor progression. Antiangiogenic agents produce high radiographic response rates, as defined by a rapid decrease in contrast enhancement on CT/MRI that occurs within days of initiation of treatment and that is partly a result of reduced vascular permeability to contrast agents rather than a true antitumor effect. In addition, a subset of patients treated with antiangiogenic agents develop tumor recurrence characterized by an increase in the nonenhancing component depicted on T2-weighted/fluid-attenuated inversion recovery sequences. The recognition that contrast enhancement is nonspecific and may not always be a true surrogate of tumor response and the need to account for the nonenhancing component of the tumor mandate that new criteria be developed and validated to permit accurate assessment of the efficacy of novel therapies. The Response Assessment in Neuro-Oncology Working Group is an international effort to develop new standardized response criteria for clinical trials in brain tumors. In this proposal, we present the recommendations for updated response criteria for high-grade gliomas.

Molecular neuro-oncology in clinical practice: a new horizon.

Primary brain tumours are heterogeneous in histology, genetics, and outcome. Although WHO's classification of tumours of the CNS has greatly helped to standardise diagnostic criteria worldwide, it does not consider the substantial progress that has been made in the molecular classification of many brain tumours. Recent practice-changing clinical trials have defined a role for routine assessment of MGMT promoter methylation in glioblastomas in elderly people, and 1p and 19q codeletions in anaplastic oligodendroglial tumours. Moreover, large-scale molecular profiling approaches have identified new mutations in gliomas, affecting IDH1, IDH2, H3F3, ATRX, and CIC, which has allowed subclassification of gliomas into distinct molecular subgroups with characteristic features of age, localisation, and outcome. However, these molecular approaches cannot yet predict patients' benefit from therapeutic interventions. Similarly, transcriptome-based classification of medulloblastoma has delineated four variants that might now be candidate diseases in which to explore novel targeted agents.

Temozolomide: a milestone in neuro-oncology and beyond?

Temozolomide (Temodal, Temodar), an imidazol derivative, is a second-generation alkylating agent. The orally available prodrug with the capacity of crossing the blood-brain barrier received accelerated US FDA approval in 1999. Three pivotal Phase II trials showed modest activity in the treatment of recurrent anaplastic astrocytoma glioblastoma. In 2005, the FDA and the European Agency for the Evaluation of Medicinal Products approved temozolomide for use in newly diagnosed glioblastoma, in conjunction with radiotherapy, based on an European Organisation for Research and Treatment of Cancer/National Cancer Institute of Canada Phase III trial. The adverse events associated with temozolomide are mild-to-moderate and generally predictable; the most serious are noncumulative and reversible myelosuppression and, in particular, thrombocytopenia, which occurs in less than 5% of patients. Continuous temozolomide administration is associated with profound CD4-selective lymphocytopenia. Molecular studies have suggested that the benefit of temozolomide chemotherapy is restricted to patients whose tumors have a methylated methylguanine methyltransferase gene promotor and are thus unable to repair some of the chemotherapy-induced DNA damage. Temozolomide is under investigation for other disease entities, in particular lower-grade glioma, brain metastases and melanoma.

Correlative studies in neuro-oncology trials: should they influence treatment?

Recent molecular correlative studies accompanying clinical trials in glioma have provided strong evidence for prognostic markers and predictive factors for treatment response. However, to what extent can these markers influence the limited choice of therapeutic options? Do we further validate the markers in the next trials or move on, incorporate the markers for patient selection or stratification, aim at improving the modestly effective treatments by adding new drugs, and develop alternative therapy strategies for patients selected for their bad predictor?

Personalized care in neuro-oncology coming of age: why we need MGMT and 1p/19q testing for malignant glioma patients in clinical practice.

Histological subtyping and grading by malignancy are the cornerstones of the World Health Organization (WHO) classification of tumors of the central nervous system. They shall provide clinicians with guidance as to the course of disease to be expected and the choices of treatment to be made. Nonetheless, patients with histologically identical tumors may have very different outcomes, notably in patients with astrocytic and oligodendroglial gliomas of WHO grades II and III. In gliomas of adulthood, 3 molecular markers have undergone extensive studies in recent years: 1p/19q chromosomal codeletion, O(6)-methylguanine methyltransferase (MGMT) promoter methylation, and mutations of isocitrate dehydrogenase (IDH) 1 and 2. However, the assessment of these molecular markers has so far not been implemented in clinical routine because of the lack of therapeutic implications. In fact, these markers were considered to be prognostic irrespective of whether patients were receiving radiotherapy (RT), chemotherapy, or both (1p/19q, IDH1/2), or of limited value because testing is too complex and no chemotherapy alternative to temozolomide was available (MGMT). In 2012, this situation has changed: long-term follow-up of the Radiation Therapy Oncology Group 9402 and European Organisation for Research and Treatment of Cancer 26951 trials demonstrated an overall survival benefit from the addition to RT of chemotherapy with procarbazine/CCNU/vincristine confined to patients with anaplastic oligodendroglial tumors with (vs without) 1p/19q codeletion. Furthermore, in elderly glioblastoma patients, the NOA-08 and the Nordic trial of RT alone versus temozolomide alone demonstrated a profound impact of MGMT promoter methylation on outcome by therapy and thus established MGMT as a predictive biomarker in this patient population. These recent results call for the routine implementation of 1p/19q and MGMT testing at least in subpopulations of malignant glioma patients and represent an encouraging step toward the development of personalized therapeutic approaches in neuro-oncology.

Diagnosis and treatment of primary CNS lymphoma in immunocompetent patients: guidelines from the European Association for Neuro-Oncology.

The management of primary CNS lymphoma is one of the most controversial topics in neuro-oncology because of the complexity of the disease and the very few controlled studies available. In 2013, the European Association of Neuro-Oncology created a multidisciplinary task force to establish evidence-based guidelines for immunocompetent adults with primary CNS lymphoma. In this Review, we present these guidelines, which provide consensus considerations and recommendations for diagnosis, assessment, staging, and treatment of primary CNS lymphoma. Specifically, we address aspects of care related to surgery, systemic and intrathecal chemotherapy, intensive chemotherapy with autologous stem-cell transplantation, radiotherapy, intraocular manifestations, and management of elderly patients. The guidelines should aid clinicians in their daily practice and decision making, and serve as a basis for future investigations in neuro-oncology.

Extremely late development of pituitary carcinoma after surgery and radiotherapy

Introduction Pituitary carcinomas account for 0.1 or 0.2% of pituitary tumors. The authors report a rare case of a pituitary carcinoma mimicking a radio-induced meningioma. Case report Fifty-five years-old male presents a previous history of transcranial surgery in 1983 for invasive pituitary adenoma followed by whole-brain radiotherapy (5100 cGy). After three years he presented worsening of visual deficits and MRI evidenced recurrence of the lesion. In 1992, he underwent a transcranial approach to treat recurrent supraselar disease, followed by stereoctatic radiotherapy. In 2006, clinical condition was stable; however three right frontal extra-axial lesions were diagnosed by MRI, compatible with meningioma. The histological examination revealed pituitary adenoma. No lesions were found in craniospinal axis. Further treatment was not recommended by radiotherapists due previous actinic treatments. Two years radiological follow-up revealed no recurrence. Conclusion In these high risk cases, active and constant surveillance must be pertained, regardless the time of follow-up.

Meningeal carcinomatosis in breast cancer: prognostic factors and outcome

Meningeal carcinomatosis (MC) occurs in up to 5% of breast cancer patients. Few studies have evaluated prognostic markers in breast cancer patients with MC. Our aim was to describe the treatment of breast cancer patients with MC, and identify prognostic factors related to survival. Sixty breast cancer patients that had a diagnosis of MC between January 2003 and December 2009 were included. The median age was 46 years (range 27-76). Most patients had invasive ductal carcinoma (78.3%) and high histological/nuclear grade (61.7/53.3%). Estrogen and progesterone receptors were positive in 51.7 and 43.3% of patients, respectively, and 15% were HER-2-positive. Symptoms at presentation were headache, cranial nerve dysfunction, seizures, and intracranial hypertension signals. Diagnosis was made by CSF cytology in 66.7% of cases and by MRI in 71.7%. Intrathecal (IT) chemotherapy was used in 68.3% of patients, and 21.6% received a new systemic treatment (chemo- or hormone therapy). Median survival was 3.3 months (range 0.03-90.4). There was no survival difference according to age, nuclear grade, hormonal and HER-2 status, CSF features, sites of metastasis, systemic and IT chemotherapy, or radiotherapy. However, histological grade and performance status had a significant impact on survival in the multivariate analysis. Only four papers have addressed prognostic factors in breast cancer patients with MC in the last two decades. The results of those reports are discussed here. High histological grade and poor performance status seem to impact survival of breast cancer patients with MC. Prospective studies are necessary to clarify the role of IT and systemic treatment in the treatment of those patients.