Avoiding the Blinded Funnel: A Combined Single Piece Fronto-Temporo-Orbito-Zygomatic Craniotomy Endoscopic-Assisted Approach with Multimodal Assistance for an Epidermoid Tumor of Meckel's Cave-Case Report.

A Meckel's cave tumor poses a great challenge because of the peculiar neurovascular structure of the area and the deep location. Multiple surgical approaches have been designed for this area. In this report, we describe a case treated with a combined one step single piece fronto-temporo-orbito-zygomatic craniotomy (FTOZ) endoscopic-assisted approach for the treatment of an epidermoid tumor of Meckel's cave. A 51-year-old woman presented with a clinical history of left trigeminal neuralgia and paresthesia. CT imaging revealed a left basal temporal tumor. MR showed a tumor located in Meckel's cave near the cavernous sinus, with a good enhancement after gadolinium administration. The tumor was resected through a lateral basal subtemporal extradural approach followed by an intradural approach using intraoperative neuronavigation, endoscopic assistance, neurophysiological monitoring, and an intraoperative ultrasound probe. The lesion was completely removed. No new onset neurological damage has occurred. The symptoms improved following surgery. The aesthetic appearance of the patient was respected. The combined approach with a single piece fronto-temporo-orbito-zygomatic craniotomy has enabled us to work on a wider operating field to completely remove the lesion avoiding blind spots.

MicroRNAs expression in pituitary tumors: differences related to functional status, pathological features, and clinical behavior.

BACKGROUND: MicroRNAs (miRNAs) are small non-coding RNA molecules that regulate gene expression at post-transcriptional level, having a role in many biological processes, such as control of cell proliferation, cell cycle, and cell death. Altered miRNA expression has been reported in many neoplasms, including pituitary adenomas (PAs). PURPOSE: In this study, we aimed to evaluate the expression of 20 miRNAs involved in pathways relevant to pituitary pathophysiology, in PAs and normal pituitary tissue and to correlate their expression profile with clinical and pathological features. METHODS: Pituitary tumor samples were obtained during transphenoidal surgery from patients with non-functioning (NFPA, n = 12) and functioning (n = 11, 5 GH-, 3 ACTH-, 3 PRL-omas) PAs. The expression of selected miRNAs in PAs and in normal pituitary was analyzed by RT-qPCR. miRNAs expression was correlated with demographic, clinical, and neuroradiological data and with histopathological features including pituitary hormones immunostaining, Ki-67 proliferation index, and p53 immunohistochemistry evaluation. RESULTS: All evaluated miRNAs except miR-711 were expressed in both normal and tumor pituitary tissue. Seventeen miRNAs were significantly down-regulated in pituitary tumors compared to normal pituitary. miRNAs were differentially expressed in functioning PAs or in NFPAs, as in the latter group miR-149-3p (p = 0.036), miR-130a-3p (p = 0.014), and miR-370-3p (p = 0.026) were significantly under expressed as compared to functioning tumors. Point-biserial correlation analysis demonstrated a negative correlation between miR-26b-5p and Ki-67 (p = 0.031) and between miR-30a-5p and 'atypical' morphological features (p = 0.038) or cavernous sinus invasion (p = 0.049), while 508-5p was inversely correlated with clinical aggressiveness (p = 0.043). CONCLUSIONS: In this study, we found a significant down-regulation of 17 miRNAs in PAs vs normal pituitary, with differential expression profile related to functional status and tumor aggressiveness.

Peptide receptor radionuclide therapy for aggressive pituitary tumors: a monocentric experience.

In aggressive pituitary tumors (PT) showing local invasion or growth/recurrence despite multimodal conventional treatment, temozolomide (TMZ) is considered a further therapeutic option, while little data are available on peptide receptor radionuclide therapy (PRRT). We analyzed PRRT effectiveness, safety and long-term outcome in three patients with aggressive PT, also reviewing the current literature. Patient #1 (F, giant prolactinoma) received five cycles (total dose 37 GBq) of 111In-DTPA-octreotide over 23 months, after unsuccessful surgery and long-term dopamine-agonist treatment. Patient #2 (M, giant prolactinoma) underwent two cycles (12.6 GBq) of 177Lu-DOTATOC after multiple surgeries, radiosurgery and TMZ. In patient #3 (F, non-functioning PT), five cycles (29.8 GBq) of 177Lu-DOTATOC followed five surgeries, radiotherapy and TMZ. Eleven more cases of PRRT-treated aggressive PT emerged from literature. Patient #1 showed tumor shrinkage and visual/neurological amelioration over 8-year follow-up, while the other PTs continued to grow causing blindness and neuro-cognitive disorders (patient #2) or monolateral amaurosis (patient #3). No adverse effects were reported. Including the patients from literature, 4/13 presented tumor shrinkage and clinical/biochemical improvement after PRRT. Response did not correlate with patients' gender or age, neither with used radionuclide/peptide, but PRRT failure was significantly associated with previous TMZ treatment. Overall, adverse effects occurred only in two patients. PRRT was successful in 1/3 of patients with aggressive PT, and in 4/5 of those not previously treated with TMZ, representing a safe option after unsuccessful multimodal treatment. However, at present, considering the few data, PRRT should be considered only in an experimental setting.

Potential clinical role of telomere length in human glioblastoma.

Glioblastoma Multiforme (GBM) is the most common and lethal of human primary central nervous system (CNS) tumors. Due to the tumour's intrinsic clinical and molecular heterogeneity, choice of initial treatment, prediction of survival, stratification of patients, prediction and monitoring of response to therapy, represent some of the greatest challenges in the management of GBM patients. Patients, despite optimal surgery, radiation and chemotherapy, still have a median survival of 14-16 months. A reason for this dismal prognosis is because of the relative inaccuracy of current prognostic markers, so far based on clinical or pathological variables. Molecular markers that effectively predict response to therapy and survival outcomes are limited. Consequently, there is a strong need to develop novel and independent markers of prognosis. Ideal biomarkers for solid tumors would serve one or more important functions. Telomeres, guanine-rich tandem DNA repeats of the chromosomal end, provide chromosomal stability, regulates important cellular processes, and seem to be implicated in human carcinogenesis. Recently, telomeres have been shown either to be associated with clinical markers of disease progression or to be independent markers of cancer prognosis in solid tumours, including GBM. Nevertheless, a corresponding comprehensive discussion of these promising developments in brain tumours has not yet been available in the literature. Therefore, here we reviewed studies focused on the assessment of telomeric length in brain tumours with the aim to emphasized those findings indicating a potential clinical role of telomeres in GBM. With the aim to enhance the awareness of the potential clinical role of telomeres' length information in GBM, using a southern blot analysis, telomeric length in excised tumour samples was analyzed. Moreover, an attempt to correlated telomere length with patients' overall survival, was also performed. The findings here reviewed shows some contradictory results, due to different tissues used as controls, but mainly to cellular and molecular heterogeneity in GBMs that drive molecular mechanisms controlling telomere length, included telomerase and Alternative Lengthening of Telomeres (ALT), through multiple mechanisms. However, overall these studies, including our own, are consistent with the hypothesis that GBMs' telomeres were always shorter when compared with Normal Brain Tissue (NBT), and together with higher telomerase activity seem to be associated with malignancy and poor outcome; while tumours with ALT phenotype have longer telomeres, "less malignant" behaviour and better prognosis. We conclude that, although not entirely consistent in the type of telomere alteration, i.e., attrition vs. elongation, and unclear on the underlying mechanisms, multiple studies in brain tumours have shown that telomere dysfunctions are associated with parameters of clinical outcome in patients with GBMs and therefore will be part of novel risk assessment and prognostic modalities for patients with these still dismal disease.

Different methods for anatomical targeting.

AIM: Several procedures are used in the different neurosurgical centers in order to perform stereotactic surgery for movement disorders. At the moment no procedure can really be considered superior to the other. We contribute with our experience of targeting method. METHODS: Ten patients were selected, in accordance to the guidelines for the treatment of Parkinson disease, and operated by several methods including pallidotomy, bilateral insertion of chronic deep brain electrodes within the internal pallidum and in the subthalamic nucleus (18 procedures). INTERVENTIONS: in each patient an MR scan was performed the day before surgery. Scans were performed axially parallel to the intercommissural line. The operating day a contrast CT scan was performed under stereotactic conditions. MEASURES: after digitalization of the MRI images, it was possible to visualize the surgical target and to relate it to parenchimal and vascular anatomic structures readable at the CT examination. The CT scan obtained was confronted with the MR previously performed, the geometrical relation between the different parenchimal and vascular structures and the selected targets were obtained. Stereotactic coordinates were obtained on the CT examination. RESULTS: It was possible to calculate the position of the subthalamic nucleus and of the internal pallidum on the CT scan, not only relating to the intercommissural line, but considering also the neurovascular structures displayed both on the MRI and the CT scans. CONCLUSION: The technique that our group presents consist in an integration between information derived from the CT and the MR techniques, so that we can benefit from the advantages of both methods and overcome the disadvantages.

Large sphenocavernous meningiomas: is there still a role for the intradural approach via the pterional-transsylvian route?

BACKGROUND: Large-sized sphenocavernous meningiomas represent a surgical challenge. Although the role of skull base techniques with combined extra- and intradural steps has been recently emphasized, pure intradural resection tactics via the pterional route constitute the traditional microsurgical approach for resection of such tumours. METHOD: We report the application of the pterional-transsylvian approach in 13 patients with sphenocavernous meningiomas. This series is unique because it includes only patients with tumours exceeding 5 cm in their greatest dimension. FINDINGS: A gross total resection was accomplished in 10 patients (77%). Eight patients had a good outcome, one had a persistent mild hemiparesis, and one died. No recurrences occurred in this group. Three patients (23%) had subtotal resections owing to invasion of the cavernous sinus in one instance and encasement of the middle cerebral artery in the others. Two had a good outcome and one died. In these patients minimal asymptomatic tumour progression was seen 3 and 6 years after surgery. The overall surgical outcome was good in 10 patients (77%), fair in one, and death in two. INTERPRETATION: In our experience, large sphenocavernous meningiomas may be operated on adopting pure intradural resection tactics via the pterional-transsylvian route with rates of gross total removal and surgical complications related to brain retraction or vascular manipulation comparable to those of extensive skull base approaches. The traditional intradural pterional transsylvian approach continues to have a place in the treatment of these lesions.

Systemic administration of a calpain inhibitor reduces behavioral deficits and blood-brain barrier permeability changes after experimental subarachnoid hemorrhage in the rat.

Increases in intracellular calcium and subsequent activation of calcium-activated proteases (e.g., calpains) may play a critical role in central nervous system injury. Several studies have implicated calpain activation following subarachnoid hemorrhage (SAH). This study evaluated the effect of a calpain inhibitor administration following SAH in the rat on behavioral deficits (postinjury days 1-5, employing a battery of well-characterized assessment tasks), and blood-brain barrier permeability changes (48 h post-SAH, quantifying the microvascular alterations according to the extravasation of protein-bound Evans Blue using a spectrophotofluorimetric technique). Rats were injected with 400 microl of autologous blood into the cisterna magna to induce SAH. Within 5 min after the surgical procedure, Calpain Inhibitor II or vehicle was continuously administered intravenously for 2 days. Results indicated that Calpain Inhibitor II treatment after SAH significantly improved (a) beam balance time (day 1, p < 0.05), but not beam balance score, (b) latency to traverse the beam on days 1-4 (day 1-3, p < 0.001; day 4, p < 0.01), and (c) loss in body weight on days 4-5 (p < 0.05). Evans Blue dye extravasation was significantly less in SAH Calpain Inhibitor II-treated rats compared to SAH vehicle-treated rats in seven out of the eight brain regions studied (p < 0.001, 0.01, and 0.05). These results suggest that pharmacological inhibition of a relatively selective, membrane-permeant calpain inhibitor can significantly reduce some pathophysiological SAH consequences, and indicate that the inhibition of calpain may be a beneficial therapeutic approach to reduce post-SAH global brain dysfunction.

Traumatic intracerebellar hemorrhagic contusions and hematomas.

BACKGROUND: Traumatic intracerebellar hemorrhagic contusions and hematomas (TIHC) are unusual lesions and their surgical management remains controversial. METHODS: From January 1990 to July, 1998, 3290 patients underwent computed tomography for acute head trauma at our Institution. Eighteen patients (0.54%) were retrospectively identified as harboring TIHC. Patients were divided into two groups. In Group I (n=78) GCS at admission was > or = 9. Seven patients presented with isolated TIHC and one with an associated supratentorial lesion. Three patients exhibited an evolving clinico-radiological course. In Group II patients (n=10) GCS at admission was < or = 7. All but one presented with severe supratentorial lesions and associated brainstem signs. RESULTS: In group I six patients had their TIHC managed conservatively, and two were operated on, and all recovered completely. In group II, two patients were operated on. The outcome was poor in 90% of cases. CONCLUSIONS: TIHC constitute a protean clinico-pathological entity. Non-comatose patients with intracerebellar clots less than 3 cm in diameter should be treated conservatively and expected to make a good recovery. Surgery is indicated for larger hematomas causing cisternal and IV ventricle compression ab initio or as a result of their secondary evolution. In severely ill patients admitted comatose, it is generally the primary brain stem damage and the concomitant severe supratentorial lesions to dictate the prognosis. In these cases obliteration of the posterior fossa cisterns is the most reliable indicator of poor outcome.

Radiation-induced blood-brain barrier changes: pathophysiological mechanisms and clinical implications.

The pathophysiology of whole-brain radiation (WBR) toxicity remains incompletely understood. The possibility of a primary change in blood-brain barrier (BBB) associated with microvascular damage was investigated. Rats were exposed to conventional fractionation in radiation (200 +/- cGy/d, 5d/wk; total dose, 4,000 cGy). BBB changes were assessed by means of the quantitative 14C-alpha-aminoisobutyric acid (AIB) technique coupled with standard electron microscopy (EM) and morphometric techniques as well as studies of the transcapillary passage of horseradish peroxidase (HRP). At 15 days after WBR, AIB transport across BBB increased significantly in cerebral cortex. EM disclosed vesicular transport of HRP across the intact endothelium without opening of the tight junctions. Ninety days after WBR, well-defined alterations of the microvasculature were observed. The main feature of cortical microvessels was their collapsed aspect, associated with perivascular edema containing cell debris. Data suggest a possible association between damage of the microvascular/glial unit of tissue injury and development of radiation-induced brain cerebral dysfunction. We hypothesize the following sequence of pathophysiological events: WBR causes an early increase in BBB permeability, which produces perivascular edema and microvascular collapse. The interference with microcirculation affects blood flow and energy supply to the tissue, resulting in structural damage on an ischemic/dysmetabolic basis.

Microsurgical excision of a primary isolated hypothalamic eosinophilic granuloma. Case report.

Solitary focal eosinophilic granuloma (EG) is one element in the spectrum of diseases associated with Langerhans' cell histiocytosis (LCH). This report documents the occurrence of a primary isolated hypothalamic EG in a man who presented with diabetes insipidus and panhypopituitarism. His treatment consisted of complete microsurgical excision of the lesion. After a 13-month follow-up period, no residual tumor was evident on magnetic resonance imaging and no other lesions were present in peripheral tissues. This case is unique in several respects: 1) it is the third documented case of a primary isolated hypothalamic LCH granuloma diagnosed in a living patient; 2) it is the only known example of complete microsurgical excision of such a lesion in the hypothalamic region; and 3) it demonstrates the efficacy of direct surgery in this scenario, as compared with other treatment modalities such as biopsy and irradiation, suggesting that complete surgical excision may represent the treatment of choice for isolated intracerebral LCH granulomas, being curative in most instances. Also, the literature is reviewed for information about the diagnosis and treatment of this particular type of unifocal brain lesion.

Time-related ultrastructural changes in an experimental model of whole brain irradiation.

To stimulate therapeutic irradiation, we exposed rats to conventional fractionation (200 +/- 4 cGy/d, 5 d/wk; total dose, 4000 cGy). The effects of this regimen were assessed by electron microscopic examinations of brain microvascular and parenchymal cells 15 and 90 days after irradiation. Studies of the transendothelial passage of horseradish peroxidase provided information about the functional status of the blood-brain barrier. At 15 days after irradiation, there was an increased vesicular transport of horseradish peroxidase across the intact endothelium without opening of the tight junctions, and without evidence of structural alterations of neuropil, neuronal bodies, and astrocytes. Ninety days after irradiation, well-defined ultrastructural alterations were observed, involving the microvasculature, the neuropil, the neuronal bodies, and astrocytes. The main ultrastructural feature of cortical microvessels was their collapsed aspect, associated with perivascular edema containing cell debris. Altered neurons and reactive activated astrocytes were also noticeable. These data suggest a possible association, not necessarily causal, between damage of the microvascular/glial unit of tissue injury and development of radiation-induced brain toxicity.

Brain energy metabolism in the acute stage of experimental subarachnoid haemorrhage: local changes in cerebral glucose utilization.

An experimental model was used to investigate acute alterations of cerebral metabolic activity in rats subjected to subarachnoid haemorrhage (SAH). Haemorrhages were produced in anaesthetized animals by injecting 0.3 ml of autologous, arterial nonheparinized blood into the cisterna magna. Control rats received subarachnoid injections of mock-cerebrospinal fluid to study the effect of sudden raised intracranial pressure, or underwent sham operation. Three hours after SAH rats were given an intravenous injection of [14C]-2-deoxyglucose. Experiments were terminated by decapitation, and the brains were removed and frozen. Regional brain metabolic activity was studied by quantitative autoradiography. In comparison with sham-operated controls, cerebral metabolic activity was diffusely decreased after SAH. Statistically significant decreases in metabolic rate were observed in 23 of 27 brain regions studied. Subarachnoid injections of mock-cerebrospinal fluid also produced depression of cerebral metabolic activity, but quantitatively these changes were not as pronounced and diffuse as in SAH rats. The present study shows that a widespread depression of brain metabolism occurs in the acute stage after experimental SAH and is probably secondary to the subarachnoid presence of blood itself and/or blood products.