Molecular biology of gliomas: present and future challenges.

Malignant brain tumours are one of the most relevant causes of morbidity and mortality across a wide range of individuals. Malignant glioma is the most common intra axial tumor in the adult. Many researches on this theme brought advances in the knowledge of gliomas biology and pathogenesis and to the development of new agents for targeted molecular therapy. Recent studies focused on either tumor metabolism analysis or epigenetic regulation in the pathogenesis or maintenance of brain tumors. This Review summarizes these developments analyzing molecular pathology and possible further developments for targeted therapies.

Are acute subdural hematomas possible without head trauma?

Acute subdural hematomas (ASDHs) are rarely reported in the literature. In general, it is due to head trauma, but if the traumatic event is very mild, it is inadequate to explain the ASDH occurrence. Risk factors for the development of spontaneous ASDH include hypertension, vascular abnormalities and deficit of coagulation. We present two cases of ASDH in patients with the coagulation deficit and review of the literature to understand the coagulation factors role and platelet role in the management of ASDHs.

Sentinel lymph node biopsy in squamous cell carcinoma of the head and neck: 10 years of experience.

Sentinel node (SN) biopsy of head and neck cancer is still considered investigational, and agreement on the width of the surgical sampling has not yet been reached. From May 1999 to Dec 2009, 209 consecutive patients entered a prospective study: 61.7% had primary tumour of the oral cavity and 23.9% of the oropharynx. SN was not found in 26 patients. Based on these data and definitive histopathological analysis, we proposed six hypothetic scenarios to understand the percentage of neck recurrences following different treatments Among patients with identified SN, 54 cases were pN+: 47 in SN and 7 in a different node. Considering the six hypothetic scenarios: "only SN removal", "SN level dissection", "neck dissection from the tumour site to SN level", "selective neck dissection of three levels (SND)", "dissection from level I to IV" and "comprehensive I-V dissection", neck recurrences could be expected in 6.5%, 3.8%, 2.18%, 2.73%, 1.09% and 1.09% of cases, respectively. SN biopsy can be considered a useful tool to personalize the surgical approach to a N0 carcinoma. The minimum treatment of the neck is probably dissection of the levels between the primary tumour and the level containing the SN(s). Outside the framework of a clinical study, the best treatment can still be considered SND.

An extended use of the sentinel node in head and neck squamous cell carcinoma: results of a prospective study of 100 patients.

Most studies concerning the use of the sentinel node technique in head and neck cancers have included clinically N0 patients with primary early stage tumours of the oral cavity or upper part of oropharynx; furthermore, node sampling has been performed during the same session, but separately from the tumour. The perspective of avoiding unnecessary neck dissection, without increasing the risk of delayed diagnosis of lymph node metastasis, is rewarding, not only for early stage tumours of the oral cavity but also for tumours in advanced stages and/or at different anatomic sites. In the attempt to establish the reliability of extended use of the sentinel node technique, 100 consecutive untreated patients (from 1999 to 2002) with tumours located in the oral cavity, oropharynx, hypopharynx and larynx, at any T stage, entered the study. N+ patients with paramedian tumours and contralateral clinically negative nodes were also enrolled. After injection of the 99mTc albumin microcolloid, pre- and intra-operative evaluations with a gamma-probe were done. N0 patients (59) were submitted to mono- or bilateral selective neck dissection; the N+ patients (41) received homolateral dissection of all levels and contralateral selective dissection. An en bloc resection of the tumour was performed both in N0 and N+ patients. In the N0 group, histological examination showed no evidence of metastases in "hot" nodes in 34 patients and also the remaining nodes were negative. Metastases were found in one or more of the gamma-probe positive nodes (14 cases), or in a closely located node at the same level (2 cases) or in a node close to a "hot" area of the submandibular salivary gland (1 case). In 8 patients, lymphoscintigraphy did not identify any sentinel node and histology of all lymph nodes was negative for metastases. In the N+ group, no metastases were found in the sentinel nodes of 21 patients and also the remaining nodes were negative; in 4 patients, metastases were found in sentinel nodes. In 16 patients, lymphoscintigraphy did not identify any sentinel node and histology of all lymph nodes was negative for metastases. In no patients were metastases found outside the level containing the lymph node identified as sentinel by the gamma-probe. In conclusion, the strategy of the sentinel node is reliable, but, to be confirmed as a standard approach, it requires trials with a larger number of patients. The technique requires a multidisciplinary and well "amalgamated" team. It may likely be used also in T3 and T4 oro-hypopharyngeal and laryngeal primary tumours and to determine surgical treatment of the contralateral neck in patients with N2a, N2b, N3 on T close to the midline.

An unusual case of lipoblastic meningioma of the falx cerebri.

The clinicopathological features of a lipomatous meningioma of the falx cerebri with an unusual histological pattern are presented.

Cabergoline modulation of alpha-subunits and FSH secretion in a gonadotroph adenoma.

Most non-functioning pituitary adenomas respond poorly to medical therapy. We describe the case of a 62-year-old man who presented with clinical features of an invasive macroadenoma. Baseline hormonal evaluation revealed increased FSH and alpha-subunit (alpha-SU) levels. Transsphenoidal exeresis followed by radiotherapy (RT) was performed. Almost all neoplastic cells were intensely immunoreactive for alpha-SU. On PCR analysis, specific amplification products were observed for somatostatin 2, 3 and 5 receptors as well as for both short and long isoforms of the dopamine D2 receptor. In vitro, alpha-SU and FSH were released into the medium by adenoma cells and increased after TRH stimulation. After surgery, alpha-SU and FSH levels were still elevated. Short-term slow-release lanreotide treatment did not modify either alpha-SU or FSH levels. Cabergoline was started and a fast and long-lasting decrease in alpha-SU and, to a lesser extent, in FSH was observed. The tumor remnant was unmodified on magnetic resonance imaging 3 years after surgery and RT. This case report shows that the in vitro expression of somatostatin receptors may not be directly associated to the in vivo response of alpha-SU and FSH to lanreotide, probably because of a functional uncoupling of the receptors. Cabergoline should be considered as an effective therapy for hormonal, and perhaps proliferative, control of gonadotroph adenoma remnants before the effects of RT are fully effective.

Gonadotropin-releasing hormone-induced partial empty sella clinically mimicking pituitary apoplexy in a woman with a suspected non-secreting macroadenoma.

Pituitary apoplexy has been reported as a rare complication of dynamic testing used for the study of pituitary functional reserve. In 1993, a diagnosis of non-secreting macroadenoma with moderate functional hyperprolactinaemia was made in a 43-year-old woman. Soon after the start of therapy with bromocriptine up to 5 mg/die, the patient complained of nausea and postural hypotension. As the symptoms persisted even when the dose was reduced to 2.5 mg/die, the patient was transferred to therapy with quinagolide at the dosage of 37.5 microg/die. PRL levels quickly normalized (range 1.4-5.7 ng/ml) as well as menstrual cycles, and no side-effect was reported. In 1995 a sellar magnetic resonance imaging (MRI) showed no shrinkage of the known macroadenoma. In 1996, few hours after a gonadotropin-releasing-hormone (GnRH) test, which showed normal LH and FSH response and with baseline PRL levels in the normal range, the patient started complaining of severe frontal headache, nausea and vomiting. No gross visual defects were present. An emergency computed tomography (CT) showed no evident hemorrhagic infarction in the macroadenoma. The symptoms completely resolved in few days with steroidal and antiemetic therapy. A new MRI performed in 1998 showed a partial empty sella and PRL levels were in the normal range under dopaminergic treatment. The pituitary functional reserve proved normal on dynamic testing. The temporal association between the onset of symptoms and the GnRH test strongly suggests an association between the two events. No evident signs of pituitary apoplexy (either on emergency CT or hormonal evaluation) were detected. The authors suggest that GnRH can cause severe side-effects that mimic pituitary apoplexy without related morphological evidence and that, in our particular case, it can have caused the gradual disappearance of the non-secreting macroadenoma. Moreover, a causal role of the chronic dopaminergic treatment cannot be completely ruled out.

Nitric oxide biphasically modulates GH secretion in cultured cells of GH-secreting human pituitary adenomas.

BACKGROUND: Nitric oxide (NO) biphasically modulates osteoclast function, sperm motility and testosterone production by exerting a positive effect at low concentrations and a negative effect at high concentrations. In this study the effect due to administration of four NO-donors, each releasing an individual amount of NO, was studied on GH secretion from human adenomatous GH-secreting cells. METHODS: Sodium nitroprusside (SNP), diethylenetriamine NO adduct (DETA/NO), diethylamine/NO complex sodium salt (DEA/NO), and S-nitroso-N-acetylpenicillamine (SNAP) were administered at a concentration of 10-4 M to cells isolated after transsphenoidal adenomectomy from five acromegalic patients. RESULTS: SNP significantly (p < 0.01) increased GH secretion, while the other NO donors inhibited GH secretion in comparision with the amount of GH spontaneously released by unstimulated cells. Each drug showed an individual degree of inhibitory potency: DEA/NO > DETA/NO > SNAP. Nitrite accumulation in the media was measured as a marker of NO released by each individual drug and was found to be different for each drug (DEA/NO > DETA/NO > SNAP > SNP). A negative correlation (R = -0.93; p < 0.05) was found between nitrite release and GH secretion induced by each drug. CONCLUSIONS: These data show that low and quasi-physiological levels of NO, such as those released by SNP, stimulate GH secretion, while high NO levels, such as those released by the other NO-donors, inhibit GH secretion. Thus, NO is shown to be able to modulate GH secretion in a dose-dependent manner in GH adenomatous cells from human pituitary adenomas.

Recovery of third nerve palsy after endovascular packing of internal carotid-posterior communicating artery aneurysms.

SUMMARY: Endovascular packing of intracranial aneurysm with preservation of the parent vessel has become in many cases a valid alternative to surgical clipping. Regression of oculomotor disorders after clipping of internal carotid-posterior communicating artery (ICA-PCoA) aneurysms has been well assessed. This report focuses on the reversal of third nerve palsy after endovascular packing of ICA-PCoA aneurysms. To this end, clinical appearances, neuroradiological features, and endovascular interventional procedures of six treated patient are reported and discussed in the light of the very few previous case observations found in the literature. Results indicate that endovascular packing of ICA-PCoA aneurysms may produce effective recovery of correlated third nerve dysfunction.

Somatostatin and its analog lanreotide inhibit the proliferation of dispersed human non-functioning pituitary adenoma cells in vitro.

OBJECTIVE: Somatostatin is a powerful inhibitor of hormone secretion and cell proliferation. Treatment with somatostatin analogs in humans causes a reduction in size and secretory activity of some endocrine tumors, including somatotropic pituitary adenomas. Less studied are the effects of somatostatin agonists on non-functioning pituitary adenomas (NFPAs). In this study we characterized the effects of somatostatin and its analog lanreotide on the proliferation of NFPAs in vitro and the intracellular mechanisms involved. DESIGN: Twenty-three NFPA post-surgical specimens were analyzed for somatostatin receptor (SSTR) expression and 12 of them were cultured in vitro to study somatostatin's effects on cell proliferation, assessed by means of [(3)H]thymidine uptake, and the intracellular signaling. RESULTS: One or more SSTR subtypes were expressed in 90% of the adenomas tested. Somatostatin and lanreotide treatment inhibited phorbol myristate acetate (PMA)-induced cell proliferation. Vanadate pretreatment reversed somatostatin and lanreotide inhibition of PMA-induced DNA synthesis suggesting an involvement of tyrosine phosphatase in this effect. In the only adenoma tested, somatostatin directly induced a tyrosine phosphatase activity. Somatostatin and lanreotide caused also a significant inhibition of voltage-sensitive calcium channel activity induced by 40mmol/l K(+) depolarization in microfluorimetric analysis. CONCLUSIONS: These data show that somatostatin and lanreotide inhibit human NFPA cell proliferation in vitro, and suggest that activation of tyrosine phosphatases and inhibition of the activity of voltage-dependent calcium channels may represent intracellular signals mediating this effect.

[New strategies for treatment of intracranial aneurysm]. / Nuove strategie per il trattamento degli aneurismi intracranici.

Prevision for the next future in a dramatic advances era we are living now has to be based upon fields consistently correlated to significative and immediately employable developments. Technical improvements in the next future, at the beginning of the third millennium, may schematically identified into two basic domains: the former, concerning surgical techniques; the latter, dealing with endovascular and neuroendoscopic techniques.

Nitric oxide modulates in vivo and in vitro growth hormone release in acromegaly.

Nitric oxide (NO) has recently been shown to modulate pituitary secretion both in vivo and in vitro. The aim of this study was to investigate the effects of this chemical transmitter on spontaneous and growth-hormone-releasing hormone (GHRH)-induced growth hormone (GH) secretion in acromegalic patients, as well as from GH-secreting tumors maintained in vitro. The study was carried out in 7 acromegalic patients (46.2 +/- 2 years) and in 5 normal subjects (40.1 +/- 1.5 years). GH and prolactin (PRL) secretion were assayed during the administration of isosorbide dinitrate (ID, 5 mg, orally), an NO donor, GHRH, and ID plus GHRH. During ID, a significant (p < 0.05) increase (37%) over basal GH levels was only observed in acromegalics. There was no change in GH levels in response to GHRH or ID plus GHRH in either group. No significant change in PRL levels was observed in either group during ID, while GHRH, with or without ID, induced a slight increase in PRL levels in acromegalics only. Tumor specimens were obtained by selective transsphenoidal adenomectomy, and the cells were plated and incubated for 1, 2 and 24 h in the presence of sodium nitroprusside, a releaser of NO (SNP, 0.3 or 0.6 mM), of GHRH (10-8 M) or of both. SNP significantly (p < 0.001) increased GH levels in a dose-dependent manner (R = 0.99, p = 0.02), but was unable to modify the GH response to GHRH. In acromegalics, a significant correlation (R = 0.822, p < 0.045) and a correlation near the limit of significance (R = 0.73, NS) were observed respectively between the in vivo GH response to ID and the in vitro response to SNP at 24 h. No significant effect was observed on PRL secretion during SNP incubations, while GHRH produced a significant increase in PRL after 2 and 24 h incubation in acromegalics. These observations indicate that NO plays a stimulatory role in vivo and in vitro on GH secretion in acromegalic patients.

Intradiploic arachnoid cyst: case report.

Because of the extreme rarity of intradiploic arachnoid cysts, their pathogenesis is unknown; congenital or traumatic origins are suggested. We report an intradiploic arachnoid cyst in a 57-year-old woman, without a history of trauma, in whom a forgotten injury might play a significant role.

Hemangioma of the temporal muscle.

BACKGROUND: Hemangiomas are benign vascular tumors. Because less than 1% of all hemangiomas are intramuscular, only 8 cases of temporal muscle hemangioma have been described to date. This is a case study of a 13-year-old girl who was referred to our institution because of a soft swelling located in the left temple that has enlarged progressively since birth. METHODS: CT scan, angiography and MRI showed a tumor mass lying in the temporal muscle, with homogeneous contrast enhancement. No tumor blush or feeding arteries were detected. At surgical exploration, the tumor appeared to be well demarcated. It was totally excised, sparing the surrounding temporal muscle, which did not present any sign of infiltration. Histopathologic examination showed the lesion to be a cavernous hemangioma. RESULTS: The cosmetic result was excellent, and MRI after 1 month and 2 years showed complete absence of the lesion and no evidence of recurrence. CONCLUSIONS: Although this type of tumor may be treated by various methods surgical excision yields the best results in the short and the long term. The surrounding tissue is spared as much as possible when no signs of infiltration are noted at operation, especially when involving small and functionally important muscles, as in our case.

Multicentrical growth of meningiomas: "spatial" or "temporal" phenomenon.

Small nodules of neoplastic cells protruding from the arachnoidal layer surrounding an intracranial meningioma, completely independent from the tumor mass, have been observed in three patients who underwent primary surgery. The high rate of recurrence for meningiomas after a seemingly total excision has been many times reported, and related to histological subtypes, tumor site, and hormonal influence. In the past meningotheliomatous cell aggregates protruding from the inner surface of the dura mater at a distance of 3 cm from the insertion of globoid meningiomas have been described, and the concept of "localized dural multifocality" emphasized. Probably this concept has to be enlarged to consider meningioma as a "neoplastic disease" with different grade of expression. The presence of unidentified macroscopic or microscopic clusters of neoplastic cells, lying around, more or less close to, the line of insertion of lesion, could render any attempt to gain a "radical" excision useless.

Luigi Rolando and his pioneering efforts to relate structure to function in the nervous system.

The fissure separating the motor from the sensory cortex and the substantia gelatinosa capping the posterior horn of the spinal cord are still known by the name of the Italian anatomist Rolando, Luigi Rolando was born in Turin, Italy, in 1773 and died in 1831. His life was not easy, the first of his problems being the death of his father when Rolando was still very young. Three people were to be influential in his life and career: Father Maffei, his maternal uncle who raised him; Dr. Cigna, the anatomy professor who discovered his talent; and Dr. Anformi, a general practitioner who introduced him to the practice of medicine and to the best circles of the city. Forced to leave Turin by the Napoleonic invasion of the country, Rolando first stopped in Florence, where he learned about anatomical dissection, drawing, and engraving and studied the appearance of nervous tissue under the microscope. Later he went to Sardinia where, although cut off from European cultural circles, he developed his major theories. Rolando pioneered the idea that brain functions could be differentiated and located in specific areas and discovered the fixed pattern of cerebral convolutions, highlighting motor and sensory gyri. He demonstrated the complexity of the central gray matter of the spinal cord, describing the "substantia gelatinosa," and he deduced that nervous structures are connected in a network of nervous fibers linked by electrical impulses. Rolando had to struggle for recognition, however, as the priority of his discoveries was challenged by the almost contemporaneous work of Gall and Spurzheim on cerebral localization and of Flourens on cerebellar function. Nevertheless, his efforts contributed greatly to the clarification of brain function. His observations on nervous anatomy have been especially accurate, as shown by the nomenclature "fissure of Rolando."