GLYOXALASE I A111E, PARAOXONASE 1 Q192R AND L55M POLYMORPHISMS IN ITALIAN PATIENTS WITH SPORADIC CEREBRAL CAVERNOUS MALFORMATIONS: A PILOT STUDY.

It is already known that the conditions of increased oxidative stress are associated to a greater susceptibility to vascular malformations including cerebral cavernous malformations (CCMs). These are vascular lesions of the CNS characterized by abnormally enlarged capillary cavities that can occur sporadically or as a familial autosomal dominant condition with incomplete penetrance and variable clinical expression attributable to mutations in three different genes: CCM1(Krit1), CCM2 (MGC4607) and CCM3 (PDCD10). Polymorphisms in the genes encoding for enzymes involved in the antioxidant systems such as glyoxalase I (GLO I) and paraoxonase I (PON I) could influence individual susceptibility to the vascular malformations. A single nucleotide polymorphism was identified in the exon 4 of GLO 1 gene that causes an amino acid substitution of Ala for Glu (Ala111Glu). Two common polymorphisms have been described in the coding region of PON1, which lead to glutamine → arginine substitution at 192 (Q192R) and a leucine → methionine substitution at 55 (L55M). The polymorphisms were characterized in 59 patients without mutations in the CCM genes versus 213 healthy controls by PCR/RFLP methods using DNA from lymphocytes. We found that the frequency of patients carrying the GLO1 A/E genotype among the case group (56%) was four-fold higher than among the controls (14.1%). In the cohort of CCM patients, an increase in the frequency of PON192 Q/R genotype was observed (39% in the CCM group versus 3.7% in the healthy controls). Similarly, an increase was observed in the proportion of individuals with the genotype R/R in the disease group (5%) in respect to the normal healthy cohort (0.5%). Finally, the frequency of the PON55 heterozygotes L/M genotype was 29% in patients with CCMs and 4% in the healthy controls. The same trend was observed in PON55 homozygous M/M genotype frequency (CCMs 20% vs controls 10%). The present study aimed to investigate the possible association of GLO1 A111E, PON1 Q192R and L55M polymorphisms with the risk of CCMs. We found that individuals with the GLO1 A /E genotype, PON192/QR-RR genotypes and PON55/LM-MM genotypes had a significantly higher risk of CCMs compared with the other genotypes. However, because CCM is a heterogeneous disease, other additional factors might be involved in the initiation and progression of CCM disease.

First demonstration of the effectiveness of peptide receptor radionuclide therapy (PRRT) with 111In-DTPA-octreotide in a giant PRL-secreting pituitary adenoma resistant to conventional treatment.

In prolactin-secreting giant adenomas, cabergoline treatment is the first line approach. Surgery and/or radiotherapy are indicated when the tumour is resistant to medical treatment and continues growing, causing visual field impairment. Data concerning other therapeutic approach are scanty. Although PRL-secreting tumours may express somatostatin receptors type 2, 3 and 5, somatostatin analogs treatment is generally ineffective and peptide receptor radionuclide therapy (PRRT) has never been reported. A 58 year-old woman complaining of severe neurological symptoms caused by a giant prolactinoma, relapsing after surgery and not-responding to dopamine-agonists and octreotide LAR treatment, underwent four cycles of PRRT with 111-Indium-DTPA-octreotide with remarkable tumour shrinkage and a significant improvement in clinical conditions. No side effects were reported. This is the first report on the effectiveness and safety of PRRT with radio-labelled somatostatin analogs in a patient with aggressive giant prolactinoma resistant to conventional treatment.

Osteoblastic meningiomas: clinico-pathological and immunohistochemical features of an uncommon variant.

Osteoblastic meningioma is a rare variant of meningioma characterized by the presence of a variable number of bone spicules within the tumor parenchyma. Its histogenesis has not been yet fully clarified. Herein we report clinical and histological findings and expression of bone matrix proteins (osteocalcin and ostepontin) observed in seven osteoblastic meningiomas. None of the cases displayed recurrences or significant re-growth after partial resection. In 5/7 cases the osseous component occurred in association with psammoma bodies and dystrophic calcification. Interestingly, foci composed of immature bone trabeculae, mineralized chondroid matrix, and osteoclasts were found in one of the two cases with no psammoma bodies or calcification, suggesting enchondral ossification. Positive staining for osteocalcin, which is a marker of terminal osteoblastic differentiation, was observed within the bone spicules in all meningiomas, but not in the chondroid mineralized matrix. On the other hand, immuno-expression of osteopontin, an early osteogenic marker, was observed in the osteoclasts and in mature and immature bone spiculae, calcification, and psammoma bodies. Even more, osteopontin was extensively expressed by the neoplastic cells of cases without calcification or psammoma bodies, suggesting acquisition of osteoblastic phenotype in these meningiomas. In conclusion, osteoblastic meningioma seems to be an indolent variant of meningiomas characterized by a slow growth and good prognosis. Our histological and immunohistochemical findings suggest that bone formation may occur through two different pathways, i.e., as the final step of calcification or through a metaplastic mechanism in cases with absent calcification or psammoma bodies.

Sstr2A immunohistochemical expression in human meningiomas: is there a correlation with the histological grade, proliferation or microvessel density?

Somatostatin anti-proliferative and anti-angiogenic activities, together with the expression of somatostatin receptors (sstrs), account for the use of somatostatin analogues in the treatment of human tumours. In the present study, sstr2A immunohistochemical expression was analyzed in grade II and III meningiomas and was compared with that revealed in grade I meningiomas. Thirty-five formalin-fixed paraffin-embedded meningiomas, comprising 13 grade I, 19 grade II and 3 grade III tumours, according to the WHO 2007 classification, were submitted to immunohistochemical assays for sstr2A. Moreover, in the same cohort of tumours, the immunoexpression of CD105, a specific marker for neo-angiogenesis, as well as the Ki-67 labelling index (LI), reflecting the proliferative activity of the meningiomas, were recorded. Sstr2A immunoreaction was evidenced in 26/35 cases and was localized at the cytoplasm and the plasma membrane in 12 and in 14 cases, respectively. Specifically, a positive staining was found in 7/13 grade I, in 16/19 grade II and in 3/3 grade III tumours, thus demonstrating that sstr2A is frequently expressed in high grade meningiomas. A significantly higher microvessel density (MVD), assessed by CD105 immunostaining and Ki-67 LI were evidenced in high grade meningiomas. A significant correlation was recorded between sstr2A expression and a high MVD of the meningiomas. The existence of a correlation between sstr2A expression and the entity of neo-angiogenesis provides the basis for the use of somatostatin analogue-based therapies in the treatment of meningiomas.

Five-level one-piece laminoplasty for extensive tumors of the lumbar spine.

The authors describe the surgical method and results of nonexpansive one-piece multivel laminoplasty of the whole lumbar spine, for microsurgical resection of extensive spinal tumors. This technique allows a very comfortable approach to the dura and intradural content, as well as a perfect replacement of the posterior spinal arch with supporting elements and an optimal reconstruction of the spinal anatomy. A nonexpansive whole lumbar one-piece laminoplasty was performed for resection of extensive multilevel lumbar tumors. The authors report an illustrative case of a patient who initially presented with a three-year history of numbness on both legs and progressive difficulty in walking. Two months before admission, he complained of bilateral sciatica and rectourinary dysfunction. A spinal magnetic resonance imaging (MRI) documented an intradural tumor extending from L2 to S1. The patient underwent a nonexpansive whole lumbar one-piece laminoplasty and microsurgical removal of the intradural lesion. The postoperative course was uneventful, the sensory disturbances and bilateral sciatica early recovered while rectourinary disturbance gradually improved up to a complete resolution at one year follow-up. The authors believe that multilevel laminoplasty rather than laminectomy is the technique of choice as a posterior procedure for extensive lumbar spinal tumors. With this technique, it is possible to obtain a very confortable approach to the dura and intradural content, as well as a perfect replacement of the posterior spinal arch with supporting elements and an optimal reconstruction of the normal spine. Moreover, this method prevents postoperative instability and deformity and avoids the so called post-laminectomy epidural membrane.

Malignant teratoma in Klippel-Feil syndrome: a case report and review of the literature.

INTRODUCTION: Klippel-Feil syndrome is characterized by a congenital fusion of cervical vertebrae. Intracranial teratomas are nongerminomatous germ cell tumors and they account for 0.3 to 0.9% of all intracranial tumors. Teratomas with malignant transformation refer to lesions which give rise to malignant cancer of somatic type. The association between tumors of dermoid origin and Klippel-Feil malformation is extremely rare. Only 23 other cases have so far been reported, and only one case of dermoid tumor with areas of dedifferentiation on squamous cell carcinoma has been described. CASE PRESENTATION: We report the case of a 72-year-old white man with a 2-year history of gait and balance disturbances. A brain magnetic resonance imaging revealed a fourth ventricle neoplastic process with infiltrative features. He was operated through a suboccipital craniectomy with a C1 laminotomy and bilateral vertebral artery transposition. At 6-months follow-up, magnetic resonance imaging showed an early regrowth of the fourth ventricle tumor, with the same radiological features. CONCLUSIONS: Patients with Klippel-Feil malformation could develop posterior fossa dermoid tumors. The malignant potential of such tumors must be considered and surgery is recommended. Particular attention must be focused on the histopathological analysis in order to identify possible foci of malignant transformation.

MRI Tractography of Corticospinal Tract and Arcuate Fasciculus in High-Grade Gliomas Performed by Constrained Spherical Deconvolution: Qualitative and Quantitative Analysis.

BACKGROUND AND PURPOSE: MR imaging tractography is increasingly used to perform noninvasive presurgical planning for brain gliomas. Recently, constrained spherical deconvolution tractography was shown to overcome several limitations of commonly used DTI tractography. The purpose of our study was to evaluate WM tract alterations of both the corticospinal tract and arcuate fasciculus in patients with high-grade gliomas, through qualitative and quantitative analysis of probabilistic constrained spherical deconvolution tractography, to perform reliable presurgical planning. MATERIALS AND METHODS: Twenty patients with frontoparietal high-grade gliomas were recruited and evaluated by using a 3T MR imaging scanner with both morphologic and diffusion sequences (60 diffusion directions). We performed probabilistic constrained spherical deconvolution tractography and tract quantification following diffusion tensor parameters: fractional anisotropy; mean diffusivity; linear, planar, and spherical coefficients. RESULTS: In all patients, we obtained tractographic reconstructions of the medial and lateral portions of the corticospinal tract and arcuate fasciculus, both on the glioma-affected and nonaffected sides of the brain. The affected lateral corticospinal tract and the arcuate fasciculus showed decreased fractional anisotropy (z = 2.51, n = 20, P = .006; z = 2.52, n = 20, P = .006) and linear coefficient (z = 2.51, n = 20, P = .006; z = 2.52, n = 20, P = .006) along with increased spherical coefficient (z = -2.51, n = 20, P = .006; z = -2.52, n = 20, P = .006). Mean diffusivity values were increased only in the lateral corticospinal tract (z = -2.53, n = 20, P = .006). CONCLUSIONS: In this study, we demonstrated that probabilistic constrained spherical deconvolution can provide essential qualitative and quantitative information in presurgical planning, which was not otherwise achievable with DTI. These findings can have important implications for the surgical approach and postoperative outcome in patients with glioma.

Tachykinins (substance P, neurokinin A, neuropeptide K, and neurokinin B) in the cerebral circulation: vasomotor responses in vitro and in situ.

The vasomotor responses of tachykinins have been studied in the cerebral vasculature of human, pig, cat, and guinea pig. Substance P (SP), neurokinin A (NKA), neurokinin B (NKB), and neuropeptide K (NPK) induced concentration-dependent relaxations of precontracted cerebral arteries in all species when examined by a sensitive in vitro technique. In addition, the relaxant responses to SP, NKA, and NKB were studied in cat pial arterioles by peptide microapplication in situ. In human pial vessels, the order of relaxant potency was SP greater than NKB greater than NKA greater than NPK; in the pig middle cerebral artery, there was no difference in potency between the tachykinins; in the cat middle cerebral artery, SP = NKB greater than NKA = NPK; and in the guinea pig basilar artery, SP much greater than NPK = NKA greater than NKB. Responses induced by SP, NKA, and NKB in the cat were comparable in vitro and in situ. Removal of the endothelium abolished relaxation induced by all four tachykinins. The relaxant responses of guinea pig basilar arteries to SP, NKA, and NPK were competitively antagonized by the SP antagonist Spantide. However, Spantide lowered the Imax of the NKB concentration-response curve without any rightward shift, suggesting action at a different site than the other tachykinins. In the guinea pig basilar artery, the relaxation seems to be exerted via a NK-1 receptor subtype while the receptor subtype is more unclear in cerebral arteries from human, cat, and pig.(ABSTRACT TRUNCATED AT 250 WORDS)

Evidence that calcitonin gene-related peptide contributes to the capsaicin-induced relaxation of guinea pig cerebral arteries.

Pretreatment with capsaicin caused a depletion of substance P (SP)-, neurokinin A (NKA)- and calcitonin gene-related peptide (CGRP)-like immunoreactivity (-LI) from the trigeminal ganglion, dura mater and cerebral arteries. The effect of capsaicin on isolated basilar arteries of guinea pig resulted in a biphasic relaxant response of histamine precontracted vessels. The first phase of the capsaicin-induced relaxation was absent in capsaicin-treated guinea pigs. Furthermore, repeated administration of capsaicin decreased the first but not the second phase of relaxation, supporting the view that a stored agent was released, while the second phase probably was due to a direct effect of capsaicin per se. The biphasic effect was not modified by the SP antagonist Spantide in a concentration that blocks tachykinin response (3.10(-6) M), nor by removal of the endothelium. There was no significant difference in pD2 values (-log concentration eliciting half maximum relaxation) between relaxations induced by SP, NKA, neurokinin B, neuropeptide K or CGRP in capsaicin pretreated as compared to vehicle-treated animals. These results are in support of the assumption that CGRP is involved in the capsaicin-induced relaxation caused by release of vasoactive agents from sensory afferent nerves.

5-HT-containing nerves to major cerebral arteries of the gerbil originate in the superior cervical ganglia.

This study has shown that over 95% of the 5-hydroxytryptamine (5-HT)-containing nerves to major cerebral arteries in the gerbil share a common origin with noradrenergic cerebrovascular nerves in the superior cervical ganglia. A small group of 5-HT-containing and noradrenergic nerves to the vessels of the posterior brain circulation had a different origin, which may be either central or peripheral. The pial blood vessels of the gerbil appeared to have no 5-HT-containing nerve supply. The effects of unilateral superior cervical ganglionectomy on 5-HT-containing and noradrenergic nerves to the arteries of the circle of Willis were different. Our results showed total loss of 5-HT-containing nerves on the vessels ipsilateral to the ganglionectomy combined with ca. 50% reductions of nerve density on the vessels of the contralateral side. There were no contralateral reductions of noradrenergic nerve density in parallel experiments although again the ipsilateral side was totally denervated. We suggest that 5-HT-containing cerebrovascular nerves are differently distributed as well as being in some way more sensitive to nerve damage compared to noradrenergic cerebrovascular nerves. The relationship between a combined serotonergic and noradrenergic vasoconstrictor control of large cerebral blood vessels and serotonergic vasodilation of small pial blood vessels is discussed.

Effect of recombinant human erythropoietin on cerebral ischemia following experimental subarachnoid hemorrhage.

Erythropoietin exerts a neuroprotective effect during cerebral ischemia. We investigated the effect of systemic administration of recombinant human erythropoietin in a rabbit model of subarachnoid hemorrhage-induced acute cerebral ischemia. The animals were divided into three groups: group 1, subarachnoid hemorrhage; group 2, subarachnoid hemorrhage plus placebo; group 3, subarachnoid hemorrhage plus recombinant human erythropoietin (each group, n=8). Experimental subarachnoid hemorrhage was produced by injecting autologous blood into the cisterna magna. Treatment with recombinant human erythropoietin and placebo was started 5 min after subarachnoid hemorrhage and was continued every 8 h for 24 h. Before the animals were killed, erythropoietin concentration was measured in the cerebrospinal fluid. The rabbits were killed 24 h after subarachnoid hemorrhage and ischemic brain injury was histologically evaluated. In group 3, the concentration of erythropoietin in the cerebrospinal fluid was significantly increased and a significant reduction in cortical necrotic neuron count was also observed. These findings may encourage the use of erythropoietin in the treatment of cerebral ischemia that often occurs in the early stage of subarachnoid hemorrhage.

In vivo evidence that erythropoietin has a neuroprotective effect during subarachnoid hemorrhage.

To ascertain in vivo whether recombinant human erythropoietin has a neuroprotective effect on the cortex during subarachnoid hemorrhage, 56 rabbits were divided into the following groups: Group 1 control sham operated plus placebo (n=14; saline solution - NaCl 0.9%); Group 2 control sham operated plus recombinant human erythropoietin (n=14); Group 3 subarachnoid hemorrhage plus placebo (n=14); Group 4 subarachnoid hemorrhage plus recombinant human erythropoietin (n=14; intraperitoneal administration of recombinant human erythropoietin immediately after inducing subarachnoid hemorrhage). In none of the Groups 1 and 2 animals was subarachnoid hemorrhage induced. In Group 3 rabbits, an increase in locomotor activity (open field apparatus) was observed 24, 48 and 72 h after surgery, and the mortality rate was 42.9% within 72 h after surgery, and, no increase in locomotor activity was observed in Group 4 rabbits, which survived for at least 72 h. Our findings suggest that recombinant human erythropoietin may be of benefit in the treatment of subarachnoid hemorrhage.

Origin and postnatal development of nerves showing 5-hydroxytryptamine-like immunoreactivity supplying major cerebral arteries of the rat.

Nerve plexuses showing 5-hydroxytryptamine (5-HT)-like immunoreactivity (5-HTLI) have been demonstrated in all the major cerebral arteries of the rat using fluorescence immunohistochemistry on whole-mount stretch preparations. Following bilateral superior cervical ganglionectomy, nerves disappeared from all the vessels studied with the exception of the vertebral and basilar arteries where fibres remained. Using image analysis, the density of nerves containing 5-HTLI showed little change between vessels from 3 to 4-week-old and 6 to 7-week-old animals, in contrast to another study which has shown marked reductions in 5-HT-immunoreactive neuronal cell bodies in the superior cervical ganglion over the same period of early development. It was concluded that while the terminals of cerebrovascular nerves retain the capacity to synthesise and/or store 5-HT throughout life, their cell bodies may lose this function soon after birth.

Cerebral perivascular serotonergic fibres have a peripheral origin in the gerbil.

The origin of serotonergic nerves supplying the large cerebral vessels of the gerbil has been investigated after bilateral superior cervical ganglionectomy. Immunohistochemical techniques were applied to whole-mount stretch preparations of the cerebral vessels. Removal of both ganglia resulted in the complete loss of immunoreactive fibres in the vessels supplied by the internal carotid artery and in a marked reduction of fibres innervating vessels of the vertebro-basilar system, indicating that most of the cerebrovascular serotonergic nerves have a peripheral sympathetic origin in the gerbil. The contrast with the central origin of serotonergic perivascular nerves claimed in the rat is discussed.

Spasmodic torticollis due to neurovascular compression of the spinal accessory nerve by the anteroinferior cerebellar artery: case report.

OBJECTIVE AND IMPORTANCE: Spasmodic torticollis is a neuromuscular disorder characterized by uncontrollable clonic and intermittently tonic spasm of the neck muscles. We report a case of spasmodic torticollis attributable to neurovascular compression of the right XIth cranial nerve by the right anteroinferior cerebellar artery (AICA). CLINICAL PRESENTATION: A 72-year-old man with a 2-year history of right spasmodic torticollis underwent magnetic resonance imaging, which demonstrated compression of the right XIth cranial nerve by an abnormal descending loop of the right AICA. INTERVENTION: The patient underwent microvascular decompression surgery. During surgery, it was confirmed that an abnormal loop of the right AICA was compressing the right accessory nerve. Compression was released by the interposition of muscle between the artery and the nerve. CONCLUSION: The patient's postoperative course was uneventful, and his symptoms were fully relieved at the 2-year follow-up examination. This is the first reported case of spasmodic torticollis attributable to compression by the AICA; usually, the blood vessels involved are the vertebral artery and the posteroinferior cerebellar artery.

Peritumoral edema in meningiomas: microsurgical observations of different brain tumor interfaces related to computed tomography.

Although generally benign tumors, meningiomas may be associated with extensive peritumoral brain edema as seen on computed tomographic scans. Fifty-two patients with intracranial meningiomas were studied, and the hypodense areas on computed tomographic scans were related to the intraoperative microsurgical findings and to the sizes of the tumors. We have identified three kinds of tumor-brain interfaces characterized by different difficulties in microsurgical dissection: smooth type, transitional type, and invasive type. These different microsurgical interfaces seem to correlate very precisely with computed tomographic images of halo-like and finger-like hypodense areas, allowing prediction of the microsurgical effort to be made in the surgery of meningiomas. The size of the tumor seems to be important in our subjects in determining the amount of edema produced. Indeed, a positive correlation (P < 0.001) was found between the sizes of the tumors and the extent of peritumoral hypodensity. A positive correlation (P < 0.002) also has been found between grade of edema and cortical penetration. Cerebral cortex disruption was systematically observed by us in invasive-type meningiomas and in 3 of 21 cases (14.3%) in transitional-type meningiomas. No penetration was observed in smooth-type meningiomas.

Do spinal meningiomas penetrate the pial layer? Correlation between magnetic resonance imaging and microsurgical findings and intracranial tumor interfaces.

OBJECTIVE: To study the relationships between spinal dura-arachnoid and tumor-cord interfaces in spinal meningiomas and to investigate whether a disruption of the pial layer and penetration of the tumor in the spinal cord occurs. METHODS: Fifteen patients with histologically proven meningiomas underwent magnetic resonance imaging (MRI) preoperatively. All patients underwent microsurgery. The histological characteristics of the tumors were compared with MRI and microsurgical findings. RESULTS: At surgery, the peritumoral hypointense rim revealed by MRI in 10 of 15 patients corresponded to a well-defined cerebrospinal fluid-containing space confined between the outer arachnoidal layer and the inner leptomeningeal layer. In those patients in whom the hypointense peritumoral rim was absent, the inner layer was either difficult to identify or clearly absent, and the blood vessels were extremely adherent to the tumor, requiring a more cautious dissection. Penetration of the tumors through disruption of the pial surface was not documented. CONCLUSION: Previous anatomic and electron microscopy studies demonstrated, in human spinal meninges, the presence of an intermediate layer attached to the inner aspect of the arachnoid, extending laterally over the dorsal surface of the spinal cord and arborizing over the nerve roots and blood vessels. The intermediate layer is not present in human cerebral leptomeninges. The presence/absence of this layer might explain the hypointense rim detected by MRI and might also explain why no penetration and no peritumoral edema is observed in spinal meningiomas as compared with intracranial meningiomas.

Primary cervical melanoma with brain metastases. Case report and review of the literature.

Primary intramedullary melanoma is a very rare tumor that occurs most frequently in the middle or lower thoracic spinal cord. The authors present a case of primary cervical cord melanoma that developed in a 62-year-old man who was surgically treated and subsequently underwent radiation therapy. Clinical and histogenetic features of this neoplasm and results of chemo-. radio-, and immunotherapy are reported. Both "dysembryogenetic" and "mesodermal" hypotheses on the origin of primary spinal melanoma are discussed.

Cerebellopontine angle lipoma. Case report.

A cerebellopontine angle (CPA) lipoma in a 17 year-old woman is reported. The patient was admitted for evaluation of episodic vertigo, preauricolar pain and progressive hearing loss on the right ear. Auditory brain stem evoked potentials revealed an interwave latency increase on the right ear. Computerized Tomography and Magnetic Resonance Imaging showed a low density lesion and high intensity signal, respectively, in the right CPA. Reports of surgically treated lipomas of the CPA are extremely rare. Our patient underwent a right lateral suboccipital craniotomy and a subtotal resection of the lesion. Histological examination revealed a richely vascularized lipomatous tissue traversed by nerve fibers. The surgical indication for such rare lesion is discussed.