Molecularly based management of gliomas in clinical practice.

Histological subtyping and grading of malignancy are the cornerstone of the present World Health Organization (WHO) Classification of CNS tumors. However, among diffuse gliomas of the adult, patients with histologically identical tumors may have different outcomes. As the genomic analysis of these tumors has progressed, it has become clear that specific molecular features transcend histologically defined variants, and may become markers of prognostic and/or predictive value. At the present time, the number of molecular biomarkers with confirmed clinical relevance (MGMT promoter methylation, 1p/19q codeletion, IDH1/2 mutations) remains limited, but new technologies will hopefully provide new candidates requiring rigorous validation in well-designed clinical trials.

MGMT promoter methylation in plasma of glioma patients receiving temozolomide.

Promoter methylation of the O6-methylguanine-DNA methyltransferase (MGMT) gene plays a role in cellular response to alkylating agents. In the present study aimed to: (i) evaluate the concordance between MGMT promoter methylation status in tumor tissue and plasma; (ii) monitor MGMT promoter methylation status in plasma taken before and during temozolomide treatment; (iii) explore the value of MGMT promoter methylation status in plasma as a prognostic/predictive biomarker in glioma patients. We enrolled 58 patients with histologically confirmed glioma at different grades of malignancy. All patients underwent surgical resection and temozolomide treatment. Paraffin-embedded tumor tissue was available for 48 patients. Blood samples were collected from all patients before temozolomide treatment (baseline) and at each MRI examination for a 12-month period. MGMT promoter methylation status was assessed in both sample types by real time PCR with a specific probe. The frequency of MGMT promoter methylation was 60.4 % in tumor tissue and 41.38 % in plasma. MGMT promoter methylation status was concordant in the two sample types (Kappa = 0.75, 95 % confidence interval (CI) 0.57-0.93; p value <0.001). Overall and progression-free survival were longer in patients with methylated MGMT promoter. Mortality was higher in patients with unmethylated MGMT promoter, whether in tumor tissue [hazard ratio (HR) 2.21; 95 % CI 0.99-4.95] or plasma (HR 2.19; 95 % CI 1.02-4.68). Progression-free survival was shorter in patients with unmethylated MGMT promoter, whether in tissue (HR 2.30; 95 % CI 1.19-4.45) or plasma (HR 1.77; 95 % CI 0.95-3.30). The cumulative incidence of unmethylated MGMT promoter in plasma at baseline was 58 %, and reached virtually 100 % at 12 months. In conclusion MGMT promoter methylation status in tumor tissue and plasma was highly concordant, and both were associated with longer survival, supporting the role of the detection of methylated MGMT promoter in predicting treatment response. However we suggest caution in using plasma as a surrogate of tumor tissue due to possible false-negative results.

Antiangiogenic therapy of brain tumors: the role of bevacizumab.

Angiogenesis is one of the hallmarks of cancer, including brain tumors. Malignant gliomas have the highest degree of vascular proliferation among solid tumors; thus, angiogenic pathways represent an attractive target to interfere with tumor growth. Up to date VEGF pathway targeting with specific drugs has yielded interesting therapeutics results. In particular bevacizumab, a monoclonal antibody against VEGF-A, has shown clinical activity in malignant gliomas, especially glioblastomas, in terms of a high response rate on MRI and a significant increase in progression-free survival.

Perspectives of Personalized Chemotherapy of Gliomas Based on Molecular Tumor Profiling.

Histopathological typing and grading are the cornerstones of the World Health Organization classification of the central nervous system tumors. It provides clinicians with information on the natural course of the disease and thus guides therapeutic choices. Nonetheless, patients with histologically identical tumors may have different outcomes and response to therapy. In recent years, extensive research has been done on three molecular markers in adult gliomas, namely MGMT promoter methylation, 1p/19q co-deletion, and IDH1/IDH2 mutations. These markers may have either a prognostic or a predictive value, differentiation of which is often difficult as both can coexist. At present, MGMT promoter methylation is considered as a predictive marker for response of glioblastoma to chemotherapy with temozolomide, particularly in elderly patients, 1p/19q co-deletion is a molecular signature of oligodendroglial tumors and predictive marker for response of anaplastic gliomas to PCV chemotherapy, and IDH1/IDH2 mutations have a strong favorable prognostic value across all glioma histopathological grades.

Temozolomide as salvage treatment for recurrent intracranial ependymomas of the adult: a retrospective study.

BACKGROUND: Few data are available on temozolomide (TMZ) in ependymomas.We investigated the response, survival, and correlation with MGMT promoter methylation in a cohort of patients with adult intracranial ependymoma receiving TMZ as salvage therapy after failure of surgery and radiotherapy. PATIENTS AND METHODS: We retrieved clinical information from the institutional database and follow-up visits, and response to TMZ on MRI was evaluated according to the MacDonald criteria. RESULTS: Eighteen patients (median age, 42 y), with either WHO grade III (10) or grade II (8) ependymoma were evaluable. Tumor location at diagnosis was supratentorial in 11 patients and infratentorial in 7. Progression before TMZ was local in 11 patients, local and spinal in 6 patients, and spinal only in one patient. A median of 8 cycles of TMZ (1-24) was administered. Response to TMZ consisted of complete response (CR) in one (5%) patient, partial response (PR) in 3 (17%) patients, stable disease (SD) in 7 (39%) patients, and progressive disease (PD) in 7 (39%) patients. Maximum response occurred after 3, 10, 14, and 15 cycles, respectively, with neurological improvement in 2 patients. All 4 responding patients were chemotherapy naïve. Both anaplastic (2) and grade II (2) tumors responded. Median progression-free survival and overall survival were 9.69 months (95% CI, 3.22-30.98) and 30.55 months (95% CI, 12.85-52.17), respectively. MGMT methylation was available in 11 patients and was not correlated with response or outcome. CONCLUSION: TMZ has a role in recurrent chemo-naïve adult patients with intracranial ependymoma, regardless of tumor grade and MGMT methylation. We suggest that, after failure of surgery and radiotherapy, TMZ should be considered as a possible first-line treatment for recurrent ependymoma.

Is there a Role for Bevacizumab in Non-Glial Tumors?

Angiogenesis is one of the hallmarks of cancer, including brain tumors. The vascular endothelial growth factor (VEGF) family and their receptors are of utmost importance in the complex interaction between pro- and anti-angiogenic factors, and have a crucial role in tumor angiogenesis. Up to date, targeting the VEGF pathway with specific drugs has yielded interesting results in oncology. In particular bevacizumab (Bev), a humanized monoclonal antibody against VEGF-A, has been approved by the Food and Drug Administration (FDA) for use in recurrent glioblastomas failing standard radiochemotherapy. Bevacizumab is now being extensively investigated in several non-glial brain tumors, such as vestibular schwannomas, meningiomas, ependymomas, medulloblastomas and miscellaneous histotypes. The aim of this review is to reevaluate the literature on the use of Bev in non-glial brain tumors.

Risk of cancer in patients with Guillain-Barré syndrome (GBS). A population-based study.

The possible relationship between Guillain-Barré syndrome (GBS) and cancer is still controversial and the existence of a paraneoplastic GBS remains unconfirmed. To better define whether there is a relationship between GBS and malignancy, we compared the observed and the expected number of patients with tumours in a population-based cohort of subjects with GBS. Clinical differences between GBS patients with or without malignancies were analysed. Data were obtained from the Piemonte and Valle d'Aosta Register for GBS (PARGBS) (years 1990-1998). GBS was diagnosed according to NINCDS criteria. The number of expected cases of malignancy in the PARGBS population was calculated using the incidence rate of all types of cancer (ICD codes 140-208) in Piemonte [1985-1987], and in the most important town of this region, that is Turin (years 1993-1997). In the nine-year period, 435 incident patients with GBS were found. Nine of them developed cancer in the six months preceding or following GBS; in seven of them, the diagnosis of cancer and GBS was concomitant. The expected number of malignant tumours was 3.7 (using the incidence in Piemonte) and 3.8 (using the incidence in Turin); therefore, the odds ratios were 2.43 (95 % CI, 1.11-4.62) and 2.37 (95% CI, 1.09-4.50), respectively (p<0.01). Although the cases with malignancies were clinically similar to the other cases of GBS observed through the Register, the mortality in GBS patients with cancer was higher and was the final cause of death in two patients affected by severe cancer. These results suggest a possible correlation between some cases of GBS and cancer. However, GBS in cancer patients does not meet all the criteria for paraneoplastic diseases.

Neuropathology of olfactory ensheathing cell transplantation into the brain of two amyotrophic lateral sclerosis (ALS) patients.

Although a large number of amyotrophic lateral sclerosis (ALS) patients have undergone transplantation procedures with olfactory ensheathing cells (OECs) in the Bejing Hospital, to our knowledge, no post-mortem neuropathologic analyses have been performed. We examined the post-mortem brain of two Italian patients affected by ALS who underwent cellular transplantation in Beijing with their consent. Our aim was to assess the events following the graft procedure to possibly support the rationale of the treatment strategy. The neuropathologic findings were analyzed on the basis of the limited awareness of the experimental conditions and discussed in relation to the safety, efficacy and long-term outcome of the transplanted cells. Islands of quiescent, undifferentiated cells within the delivery track persisting for up to 12 months-24 months were found. Prominent glial and inflammatory reaction around the delivery track strongly supports the encasement of the graft. Evidence of axonal regeneration, neuronal differentiation and myelination was not seen. The surgical procedure of implantation was not compatible with a neurotrophic effect. The OEC transplantation did not modify the neuropathology of ALS in the two patients. In conclusion, the present neuropathologic analysis does not support a beneficial effect of fetal OEC implantation into the frontal lobes of ALS patients.

TDP-43 redistribution is an early event in sporadic amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder consisting of progressive loss of motor neurons. TDP-43 has been identified as a component of ubiquitin-immunoreactive inclusions of motor neurons in ALS. We focused on the diffuse cytoplasmic TDP-43 immunoreactivity in ALS neurons, and quantitatively assessed it in comparison with skein/round TDP-43 and ubiquitin immunostaining in motor neurons of 30 sporadic ALS cases. The percentage of spinal motor neurons with cytoplasmic TDP-43 immunoreactivity was higher than that of ubiquitin-immunoreactive ones. The percentage of TDP-43-positive motor neurons was independent of neuron counts in anterior horns, while the percentage of ubiquitinated neurons was inversely correlated. Aiming to define the cytosolic localization of TDP-43, the immunoblot analysis of spinal cord and frontal cortex showed that full-length TDP-43, the 45 kDa form and ubiquitinated TDP-43 are found in the soluble inclusion-free fraction. The present data suggest that delocalization, accumulation and ubiquitination of TDP-43 in the cytoplasm of motor neurons are early dysfunctions in the cascade of the events leading to motor neuron degeneration in ALS, preceding the formation of insoluble inclusion bodies. Being cytoplasmic accumulation an ongoing event during the course of the illness, a therapeutic approach to this incurable disease can be envisaged.