Domenico La Torre

miR-21 and 221 upregulation and miR-181b downregulation in human grade II–IV astrocytic tumors

MicroRNAs (miRNAs) are small noncoding regulatory RNAs that reduce stability and/or translation of fully or partially sequence-complementary target mRNAs. Recent evidence indicates that miRNAs can function both as tumor suppressors and as oncogenes. It has been demonstrated that in glioblastoma multiforme miR-21 and 221 are upregulated whereas miR-128 and 181 are downregulated. Expression of miR-21, 221, 128a, 128b, 128c, 181a, 181b, 181c was studied using real-time quantitative reverse transcriptase polymerase chain reaction and northern blotting for human astrocytic tumors with different grade of malignancy. miR-21 and 221 were overexpressed in glioma samples, whereas miRNA 181b was downregulated compared with normal brain tissue. miRNA-21 was hyperexpressed in all tumor samples whereas higher levels of miRNA-221 were found in high-grade gliomas. This study is the first analysis of miRNAs in astrocytic tumor at different stages of malignancy. The different expression pattern observed in tumors at different stages of malignancy is probably dependent on the cell-specific repertoire of target genes of tumors sharing different molecular pathways activity and suggests miRNAs may have also a place in diagnosis and staging of brain tumors.

Nuclear factor‐κB activation and differential expression of survivin and Bcl‐2 in human grade 2–4 astrocytomas

Antiapoptotis resulting from hyperactivation of the transcription factor NF‐κB has been described in several cancer types. It is triggered by the interaction of the tumor necrosis factor (TNF) with its receptors and recruitment of the intermediate factor TNF‐receptor associated factor (TRAF) 2. The NF‐κB transcriptional activity could amplify the expression of antiapoptotic genes. The authors investigated the activity of NF‐κB, and the mRNA expression of TNFα, TNFα receptor, TRAF1, TRAF2, and TRAF‐associated NF‐κB activator (TANK), and the antiapoptotic genes Bcl‐2, c‐IAP 1 and 2, and Survivin in human astrocytic tumors.

Microsurgical Anatomic Features of the Olfactory Nerve: Relevance to Olfaction Preservation in the Pterional Approach

OBJECTIVE: The pterional approach represents the standard approach for most lesions of the anterior and middle cranial fossa. It requires some degree of frontal lobe retraction, which may result in temporary or permanent damage of olfaction because of nerve avulsion or mechanical compression. The purpose of this study, based on microanatomic dissection of human cadaveric specimens, was to review the microsurgical anatomic features of the nerve and suggest operative nuances that may contribute to reducing the rate of postoperative olfactory dysfunction. METHODS: Twenty olfactory nerves and tracts were examined in 10 human cadaveric heads obtained from three fresh and seven formalin-fixed adult cadavers. A standard pterional craniotomy was performed. The olfactory nerve was dissected from its arachnoidal envelopes and then mobilized for an average length of 30 mm (range, 25–35 mm). RESULTS: The possible retraction of the frontal lobe was 10 to 15 mm. More retraction invariably resulted in nerve disruption. CONCLUSION: The standard sylvian and basal cistern opening may be insufficient to guarantee preservation of olfactory function. Early identification and arachnoidal dissection of the nerve may reduce the rate of olfaction compromise. The opening of the subarachnoidal space should be performed in a proximal-to-distal manner to allow early visualization of the olfactory bulb and its dissection. The arachnoidal dissection should be performed with sharp instruments, avoiding any traction on the posterior portion of the olfactory tract. Any direct retractor compression should also be avoided to spare the microvasculature lying on the dorsal surface of the nerve.

Drugs of anaesthesia and cancer

Anaesthesia represents one of the most important medical advances in history, and, nowadays, can widely be considered safe, thanks to the discovery of new drugs and the adoption of modern technologies. Nevertheless, anaesthetic practices still represent cause for concern regarding the consequences they produce. Various anaesthetics are frequently used without knowing their effects on specific diseases: despite having been reported that invasion or metastasis of cancer cells easily occurs during surgical procedures, numerous anaesthetics are used for cancer resection even if their effect on the behaviour of cancer cells is unclear. Guidelines for a proper use of anaesthetics in cancer surgery are not available, therefore, the aim of the present review is to survey available up-to-date information on the effects of the most used drugs in anaesthesia (volatile and intravenous anaesthetics, nitrous oxide, opioids, local anaesthetics and neuromuscular blocking drugs) in correlation to cancer. This kind of knowledge could be a basic valuable support to improve anaesthesia performance and patient safety.

Transcranial Doppler Ultrasonography in the Assessment of Cerebral Circulation Arrest: Improving Sensitivity by Trancervical and Transorbital Carotid Insonation and Serial Examinations

IntroductionTranscranial Doppler (TCD) can detect the cerebral circulation arrest (CCA) in brain death. TCD is highly specific, but less sensitive because of false-negatives accounting for up to 10%. The aim of the study was to explore the diagnostic accuracy of TCD and to determine whether it can be augmented by strategies such as the insonation of the extracranial internal carotid artery (ICA) and sequential examinations.MethodsData of 184 patients, who met clinical criteria of brain death, observed from 1998 through 2006, were retrospectively reviewed. The study of cerebral arteries was performed through the transtemporal approach, suboccipital insonation of the vertebro-basilar system, transorbital insonation of the ICA and ophthalmic artery, and transcervical insonation of the extracranial ICA. Repeated exams were performed in cases of persistent diastolic flow.ResultsThe specificity of the testing was 100%, no false-positive cases were recorded. The sensitivity of conventional TCD examination was 82.1%. The insonation of the extracranial ICA increased sensitivity to 88% allowing the detection of CCA in those patients lacking temporal windows; serial examinations further increased sensitivity to 95.6%.ConclusionsThe addition of insonation of the cervical ICA and of the siphon increased sensitivity of TCD. Nevertheless, a CCA flow patterns may appear later on those segments. Serial examinations, may be needed in those cases.

Role of Inflammation and Oxidative Stress Mediators in Gliomas

Gliomas are the most common primary brain tumors of the central nervous system. Despite relevant progress in conventional treatments, the prognosis of such tumors remains almost invariably dismal. The genesis of gliomas is a complex, multistep process that includes cellular neoplastic transformation, resistance to apoptosis, loss of control of the cell cycle, angiogenesis, and the acquisition of invasive properties. Among a number of different biomolecular events, the existence of molecular connections between inflammation and oxidative stress pathways and the development of this cancer has been demonstrated. In particular, the tumor microenvironment, which is largely orchestrated by inflammatory molecules, is an indispensable participant in the neoplastic process, promoting proliferation, survival and migration of such tumors. Proinflammatory cytokines, such as tumor necrosis factor-alpha, interleukin-1beta, and interferon-gamma, as well as chemokines and prostaglandins, are synthesized by resident brain cells and lymphocytes invading the affected brain tissue. Key mediators of cancer progression include nuclear factor-kappaB, reactive oxygen and nitrogen species, and specific microRNAs. The collective activity of these mediators is largely responsible for a pro-tumorigenic response through changes in cell proliferation, cell death, cellular senescence, DNA mutation rates, DNA methylation and angiogenesis. We provide a general overview of the connection between specific inflammation and oxidative stress pathway molecules and gliomas. The elucidation of specific effects and interactions of these factors may provide the opportunity for the identification of new target molecules leading to improved diagnosis and treatment.

Protecting venous structures during radiosurgery for parasagittal meningiomas

Symptomatic edema is a potential complication of meningioma radiosurgery. Parasagittal meningiomas are at a particular risk for symptomatic edema, suggesting a role for a venous occlusive complication. The authors sought to develop a strategy to optimize CyberKnife stereotactic radiosurgical treatment parameters to reduce the irradiation of the peritumoral venous system. Multislice CT venography with 3D reconstructions was performed and coregistered with thin-section, contrast-enhanced, volumetric MR images. The tumor and critical volumes were contoured on the MR images. Venous anatomical details obtained from the CT venographic study were then exported onto the MR imaging and fused MR imaging-CT study. Target and critical structure volumes and dosimetric parameters obtained with this method were analyzed. The authors found that reducing the irradiation of veins that course along the surface of the meningioma, which may be at risk for radiation-induced occlusion, is feasible in parasagittal meningioma radiosurgery without compromising other treatment parameters including conformality, homogeneity, and target coverage. Long-term follow-up is needed to assess the clinical validity of this treatment strategy.

Anesthetic Techniques and Cancer Recurrence after Surgery

Many of the most common anesthetics are used in surgical oncology, yet effects on cancer cells are still not known. Anesthesia technique could differentially affect cancer recurrence in oncologic patients undergoing surgery, due to immunosuppression, stimulation of angiogenesis, and dissemination of residual cancer cells. Data support the use of intravenous anesthetics, such as propofol anesthesia, thanks to antitumoral protective effects inhibiting cyclooxygenase 2 and prostaglandins E2 in cancer cells, and stimulation of immunity response; a restriction in the use of volatile anesthetics; restriction in the use of opioids as they suppress humoral and cellular immunity, and their chronic use favors angiogenesis and development of metastases; use of locoregional anesthesia compared with general anesthesia, as locoregional appears to reduce cancer recurrence after surgery. However, these findings must be interpreted cautiously as there is no evidence that simple changes in the practice of anesthesia can have a positive impact on postsurgical survival of cancer patients.

HUMAN LEUKOCYTE ANTIGEN FREQUENCY IN HUMAN HIGH-GRADE GLIOMAS: A CASE-CONTROL STUDY IN SICILY

OBJECTIVEHuman leukocyte antigens (HLAs) are widely expressed cell surface molecules that present antigenic peptides to T lymphocytes and modulate immune response against inflammatory and malignant diseases. The aim of this study was to compare HLA distribution in patients with newly diagnosed high-grade gliomas (HGGs) and 2 control groups from a restricted geographic area (eastern Sicily). METHODSHLA allele frequency, as determined from peripheral blood of 56 adult patients with HGGs, was compared with that of 2 different control groups: 140 healthy bone marrow donors (group A) and 69 virtually brain tumor–free patients (group B). HLA expression was evaluated using a reverse transcriptase polymerase chain reaction–sequence-specific oligonucleotide probe. RESULTSThere was significant expression of HLA-A*11 in patients with HGGs compared with control groups A and B (P < 0.003 and P < 0.018, respectively). Significant expression of HLA genotypes in patients with HGGs was also identified for HLA-DQB1*06 (P = 0.005), HLA-DRB1*14 (P = 0.001), and HLA-DRB3*01 (P = 0.007) compared with control group B. In HGG patients, there was statistically significantly decreased expression, compared with control groups A and B, of HLA-B*07 (P = 0.002 and P = 0.03, respectively) and HLA-C*04 (P = 0.007 and P = 0.016, respectively). There was statistically significant lower expression of HLA-C*05 in the HGG group compared with group B (P < 0.03). CONCLUSIONThis is the first study to describe the frequency of distribution of HLAs in a population from a restricted geographic area. The findings suggest a possible correlation between HLA allele distribution and the occurrence of newly diagnosed malignant astroglial brain tumors.

Telomere Length Modulation in Human Astroglial Brain Tumors

Background Telomeres alteration during carcinogenesis and tumor progression has been described in several cancer types. Telomeres length is stabilized by telomerase (h-TERT) and controlled by several proteins that protect telomere integrity, such as the Telomere Repeat-binding Factor (TRF) 1 and 2 and the tankyrase-poli-ADP-ribose polymerase (TANKs-PARP) complex. Objective To investigate telomere dysfunction in astroglial brain tumors we analyzed telomeres length, telomerase activity and the expression of a panel of genes controlling the length and structure of telomeres in tissue samples obtained in vivo from astroglial brain tumors with different grade of malignancy. Materials and Methods Eight Low Grade Astrocytomas (LGA), 11 Anaplastic Astrocytomas (AA) and 11 Glioblastoma Multiforme (GBM) samples were analyzed. Three samples of normal brain tissue (NBT) were used as controls. Telomeres length was assessed through Southern Blotting. Telomerase activity was evaluated by a telomere repeat amplification protocol (TRAP) assay. The expression levels of TRF1, TRF2, h-TERT and TANKs-PARP complex were determined through Immunoblotting and RT-PCR. Results LGA were featured by an up-regulation of TRF1 and 2 and by shorter telomeres. Conversely, AA and GBM were featured by a down-regulation of TRF1 and 2 and an up-regulation of both telomerase and TANKs-PARP complex. Conclusions In human astroglial brain tumours, up-regulation of TRF1 and TRF2 occurs in the early stages of carcinogenesis determining telomeres shortening and genomic instability. In a later stage, up-regulation of PARP-TANKs and telomerase activation may occur together with an ADP-ribosylation of TRF1, causing a reduced ability to bind telomeric DNA, telomeres elongation and tumor malignant progression.