Review: Peering through a keyhole: liquid biopsy in primary and metastatic central nervous system tumours.

Tumour molecular profiling by liquid biopsy is being investigated for a wide range of research and clinical purposes. The possibility of repeatedly interrogating the tumour profile using minimally invasive procedures is helping to understand spatial and temporal tumour heterogeneity, and to shed a light on mechanisms of resistance to targeted therapies. Moreover, this approach has been already implemented in clinical practice to address specific decisions regarding patients' follow-up and therapeutic management. For central nervous system (CNS) tumours, molecular profiling is particularly relevant for the proper characterization of primary neoplasms, while CNS metastases can significantly diverge from primary disease or extra-CNS metastases, thus compelling a dedicated assessment. Based on these considerations, effective liquid biopsy tools for CNS tumours are highly warranted and a significant amount of data have been accrued over the last few years. These results have shown that liquid biopsy can provide clinically meaningful information about both primary and metastatic CNS tumours, but specific considerations must be taken into account, for example, when choosing the source of liquid biopsy. Nevertheless, this approach is especially attractive for CNS tumours, as repeated tumour sampling is not feasible. The aim of our review was to thoroughly report the state-of-the-art regarding the opportunities and challenges posed by liquid biopsy in both primary and secondary CNS tumours.

Safe transportation of formalin-fixed liquid-free pathology specimens.

Diagnostic pathology activities are largely based on fixation of tissues in 4% formaldehyde, which has recently been re-classified as a carcinogenic compound and banned in several countries. Hospitals that do not have in-house pathology services need to send surgical and biopsy specimens to referral centers. These are generally transferred in liquid containers, under suboptimal safety conditions, as accidental spillage of potentially dangerous substances may occur. A safe, innovative, two-step procedure for pathology sample transportation is presented. Formalin-fixed material from ten surgical cases was dissected (including surrogate biopsies) and preserved in liquid-free plastic bags under vacuum for up to 30 days and subsequently processed for conventional histology, several immunohistochemical markers, and molecular tests (e.g., RAS mutation). The data were compared with the corresponding routine analyses. Formalin-fixed specimens after up to 30 days under vacuum storage gave equivalent results compared to standard histopathological slides and molecular tests, regarding both hematoxylin-eosin, immuno-stained slides and also nucleic acid extracted for molecular tests. The proposal of under-vacuum sealing pathology specimens that were previously formalin fixed can be adopted to transfer liquid-free biopsy and surgical specimens to referral pathology services. In fact, it is easy to perform, less expensive (both plastic bags and domestic-type vacuum chamber machines are at affordable costs), and above all is fully safe and adequate in the pre-analytical processing of pathology specimens.

The post-surgical era of GBM: How molecular biology has impacted on our clinical management. A review.

Glioblastoma (GBM) is the most common glioma in adults, with incidence increasing by 3% per year. According to the World Health Organization Classification of Central Nervous System Tumors, GBM is considered a grade IV tumor due to its malignant behavior. The aim of this review is to summarize the main biological aspects of GBM. In particular, we focused our attention on those alterations which have been proven to have an impact on patients' outcome, mainly in terms of overall survival (OS), or on the tumor response to therapies. We have also analyzed the cellular biology and the interactions between GBM and the surrounding environment.

Safety of bevacizumab in patients with malignant gliomas: a systematic review.

Angiogenesis has recently become a major target for the development of new antineoplastic drugs. The most serious adverse events linked to angiogenesis inhibitors are venous or arterial thromboembolism and haemorrhage. Thus, there is need to define with more certainty the impact of these new drugs in terms of adverse effects in neurological patients. The aim of the study is to assess the risk of venous thromboembolism (VTE) and bleeding in patients with malignant gliomas treated with bevacizumab with or without concomitant anticoagulant therapy. A review of published literature was performed in Medline, from which 476 records were identified. A total of 27 full-text articles, including retrospective analyses, retrospective reviews, and open label trials, were assessed for eligibility. The investigated drugs included bevacizumab alone, bevacizumab plus chemotherapy with/without concomitant radiation therapy; only two articles dealt with bevacizumab in association with anticoagulant treatment. A total of 2,208 patients with malignant gliomas, were identified and included in the analysis. From data it appears that patients receiving bevacizumab had a major risk of developing VTE that increased when bevacizumab is associated with radio-chemotherapy (4.27 vs 7.46 %). Regarding bleeding, data showed that patients treated with anticoagulant had a significantly increased risk of severe central nervous system (CNS) bleeding compared to patients not receiving anticoagulant therapy (0.6 vs 8.2 %). The use of bevacizumab combined with chemo-radiotherapy seems to be associated with a higher risk for VTE compared to patients receiving antiangiogenic therapy alone. The associated use of anticoagulants and bevacizumab far increases the risk of developing CNS and non-CNS bleeding higher than grade 3, compared to patients receiving bevacizumab alone.

Anti-angiogenic approaches to malignant gliomas.

Despite advances in multidisciplinary approaches, the prognosis for most patients with malignant gliomas is poor. Malignant gliomas are highly vascularized tumors with elevated expression of vascular endothelial growth factor (VEGF), an important mediator of angiogenesis. Recent studies of bevacizumab, an anti-VEGF monoclonal antibody, alone or associated with chemotherapy, have demonstrated high response rates and prolongation of median and 6-month progression-free survival. Clinical evaluation of several multitarget small molecule tyrosine kinase inhibitors is ongoing. Other promising antiangiogenic compounds are cilengitide and continuous temozolomide. Toxicity is acceptable. Open issues are represented by patterns of tumor progression, resistance mechanisms and biomarkers.