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SUMMARY The authors report their experience with the use of ventriculo-peritoneal shunts with Pudenz valves in the treatment of 47 cases of hydrocephalus of various pathogeneses. A definite improvement was attained in two-thirds of the cases, and the causes and treatment of complications in the remaining one-third are discussed. RESUME Les auteurs presentent leur experience dans l'application de la derivation ventriculoperitoneale avec valve de Pudenz-Raimondi utilisee dans 47 cas d'hydrocephalie de differente origine. Le controle a distance revele une remarquable amelioration de 2/3 des malades operes. Les auteurs concluent avec une analyse des causes de complication. ZUSAMMENFASSUNG Die Autoren beschreibsn Ihre Erfahrung in der Anwendung der ventriculo-peritonealen Derivationen mit Pudenz-Raimondi-Ventil auf 47 Patienten mit Hydrocephalus von verschiedener Pathogenesis. Nachkontrollen beweisen die Verbesserung in 2/3 der Patienten. Schliesslich untersuchen die Autoren die Grunde von Komplikationen. RESUMEN Los Autores refieren la experiencia de 47 casos de hidrocefalo de diversa patogenesis tratados con una derivacion ventriculo-peritoneal con la valvula de Pudenz-Raimondi. En los sucesivos controles a distancia los 2/3 de los pacientes han obtenido ventaja con dicha derivacion. Son ademas discutidas las causas de las complicaciones.

SUMMARY A total of 76 shunt-treated hydrocephalic children were examined at least once between two and 12 years after surgery to determine what skull changes had occurred and to assess the children's intellectual status. The high incidence of skull changes in shunt-treated, non-tumoral, hydrocephalic children was confirmed. A strict relationship existed between skull changes and low intracranial pressure. The results indicate that impairment of mental development parallels the degree of skull changes, suggesting a close relationship between impaired mental development and cerebrospinal fluid hypotension. RESUME Modifications crâniennes et niveau intellectuel chez les enfants hydrocephales traites par shunt 76 enfants hydrocephales traites par shunt ont ete examines au moins une fois de deux a 12 ans, apres une intervention pour determiner les modifications crâniennes survenues et apprecier le niveau intellectuel des enfants. La grande frequence des modifications crâniennes chez les enfants porteurs d'une hydrocephalic non tumorale, traitee par shunt a ete confirmee. Une stricte liaison existe entre les malformations crâniennes et la basse pression intracrânienne. Les resultats indiquent un parallelisme entre l'alteration du developpement mental et le degre des modifications crâniennes suggerant une relation etroite entre l'alteration du developpement mental et l'hypotension du LCR. ZUSAMMENFASSUNG Schadelveranderungen und intellektueller Befund bei Kindern mit Hydrocephalus nach Ventilimplantation Insgesamt 76 Kinder mit Hydrocephalus, die ein Ventil bekommen hatten, wurden mindestens zweimal in dem Zeitraum von zwei bis 12 Jahren nach der Operation nachuntersucht, um festzustellen welche Schadelveranderungen sich ausgebildet hatten und um den intellektuellen Befund der Kinder festzuhalten. Es wurde bestatigt, das bei Hydrocephalus-kindern ohne Tumor nach der Ventilimplantation haufig Schadelveranderungen auftreten. Eine direkte Beziehung fand sich zwischen Schadelveranderungen und niedrigem Schadelinnendruck. Die Befunde sprechen dafur, das eine Beeintrachtigung der geistigen Entwicklung mit dem Grad der Schadelveranderungen korreliert, wobei eine enge Beziehung zwischen beeintrachtigter geistiger Entwicklung und herabgesetztem Liquordruck anzunehmen ist. RESUMEN Cambios craneales y estado intelectual en ninos hidrocefalicos tratados con derivation Un total de 76 ninos hidrocefalicos tratados con derivacion fueron examinados por lo menos una vez entre los dos y doce anos despues de la intervention quirurgica, para determinar que cambios craneales habian ocurrido y evaluar el estado intelectual de los ninos. Se confirmo la alta incidencia de los cambios craneales en ninos con hidrocefalias no tumorales tratadas con derivacion. Existia una estricta relacion entre los cambios craneales y la baja presion intracraneal. Los resultados indican que la alteration del desarrollo mental es paralela al grado de cambios craneales, sugiriendo una relacion proxima entre el desarrollo mental afectado y la hipotension del liquido cerebroespinal.

OBJECTIVEThe biological features of malignant gliomas include high cell proliferation, extensive local infiltration of tumor cells into normal brain, and marked neovascularization. αvβ3 integrin is highly expressed in malignant gliomas and plays a role in glioma growth. This article investigates the

The typical, well recognized childhood epilepsy syndrome caused by hypothalamic hamartoma is characterized by early-onset, stereotyped attacks of uncontrollable laughter, frequent refractory seizures with progressive cognitive deterioration and severe behavioral problems. Here, we report a 17-year-old patient with gelastic phenomenon started in the neonatal period, later on associated with drug resistant polymorphic seizures, intellectual deficit and behavioral disorders, who improved by partial resection of an expected hypothalamic hamartoma that, in turn, resulted to be a hypothalamic low-grade astrocytoma.

Summary: Purpose: To determine the potential effectiveness of phenytoin (PHT) in preventing early postoperative seizures in patients undergoing craniotomy for supratentorial brain tumors. Methods: Two hundred patients requiring elective craniotomy for supratentorial brain tumors were randomized to two groups of equal size, with a prospective, open-label, controlled design. One group received PHT (18 mg/kg as an intravenous intraoperative load, followed by additional daily doses aimed at maintaining serum PHT concentrations within the 10- to 20-aeg/ml range) for 7 consecutive days. In the other group, PHT was not administered. More than 90% of patients in both groups continued to take preexisting anticonvulsant medication (AEDs) with carbamazepine or phenobarbital throughout the study. The primary efficacy end point was the number of patients remaining free from seizures during the 7-day period after the operation. Results: Of 100 patients allocated to PHT, 13 experienced seizures during the 7-day observation period, compared with 11 of 100 patients in the placebo group (p > 0.05). Most seizures occurred in the first day after surgery in both groups. There were no differences between groups in the proportion of patients experiencing more than one seizure, but there was a trend for generalized seizures to be more common in PHT-treated patients than in controls (11 vs. five patients, respectively). Status epilepticus occurred in one patient in the PHT group and in two patients in the control group. Of the 13 PHT-treated seizure patients, 11 had serum PHT concentrations within the target range, and only two had concentrations below range on the days their seizures occurred. Conclusions: PHT, given at dosages producing serum concentrations within the target range, failed to prevent early postoperative seizures in patients treated with concomitant AEDs. Prophylactic administration of PHT cannot be recommended in these patients.

OBJECTIVEThis study analyzed the expression of integrins αvβ3 and αvβ5 in glioma tissue and focused on the periphery of high-grade gliomas.METHODSThe analysis was performed with Western blot, immunohistochemistry, and immunofluorescence, by use of two monoclonal antibodies able to recognize the functional integrin heterodimer. The expression of integrin-related ligands and growth factors also was studied. Sections from the tumor periphery were classified as either tumor periphery (light tumor infiltrate or scant visible cells) or peritumor (heavy tumor infiltration).RESULTSOur data on glioma tissues demonstrated that both integrins were expressed in glioma cells and vasculature and their expression correlated with the histological grade. αvβ3 expression was prominent in astrocytic tumors. Both integrins were markers of tumor vasculature, particularly of endothelial proliferation. A high-grade glioma periphery demonstrated a prominent expression of integrin αvβ3. Cells demonstrating αvβ3 positivity were identified as tumor astrocytes and endothelial cells by double imaging. The same cells were surrounded by some αvβ3 ligands and co-localized fibroblast growth factor 2. Matrix metalloproteinase 2 also was found to be co-localized with αvβ3 in the same cells. αvβ3 expression was more relevant in tumor astrocytes. αvβ3 integrin and vascular endothelial growth factor expression increased from the periphery to the tumor center.CONCLUSIONOur data support the role of integrins αvβ3 and αvβ5 in glioma-associated angiogenesis. In addition, they suggest a role for integrin αvβ3 in neoangiogenesis and cell migration in high-grade glioma periphery.

OBJECTIVEIntegrins are emerging as alternative receptors capable of mediating several biological functions, such as cell-matrix and cell-cell adhesion, cell migration, signal transduction, and angiogenesis. Two αv integrins, i.e., αvβ3 and αvβ5, play critical roles in mediating these activities, particularly in tumors. No data are available on the expression of these integrins in meningiomas.METHODSUsing Western blot and immunohistochemical analyses with LM609 and PG32, two monoclonal antibodies capable of recognizing the functional integrin heterodimer, we evaluated the expression of αvβ3 and αvβ5 integrins in a series of 34 meningiomas of different histological subtypes and grades. We studied their expression in tumor cells and vasculature, as well as the expression of their related angiogenic factors (fibroblast growth factor 2 and vascular endothelial growth factor) and the αvβ3 ligand vitronectin.RESULTSαvβ3 and αvβ5 integrins were expressed by neoplastic vasculature and cells. αvβ3 and αvβ5 expression was associated and correlated with that of their respective growth factors (fibroblast growth factor 2 and vascular endothelial growth factor) and microvessel counts and densities. αvβ3 was more strongly expressed than αvβ5 in two cases of histologically benign meningiomas with aggressive clinical behavior. αvβ3 expression was associated with that of its related ligand vitronectin and was also evident in small vessels of brain tissue closely surrounding meningiomas.CONCLUSIONOur data demonstrate the expression of αvβ3 and αvβ5 integrins in meningioma cells and vasculature. Our findings suggest a role for both of these integrins, and particularly αvβ3, in meningioma angiogenesis.

BACKGROUND This study investigated the relevance of prognostic factors and the impact of histological features in posterior fossa ependymoma. METHODS The charts of 26 patients (aged 1–59 years, mean 20.6 years; 11 adults) with posterior fossa ependymoma operated on between January 1983 and December 1994 were reviewed and patients followed up (mean: 93 months). RESULTS Gross total resection was performed in 18 patients (69%), subtotal in seven patients (27%), biopsy in one patient (4%). One patient (3.8%) developed respiratory complications and died. All patients underwent posterior fossa radiotherapy (5000 cGy) after surgery. Four children first received chemotherapy and then radiotherapy only when at least 3 years old. Eleven patients (42%) received radiotherapy and subsequently chemotherapy. The 5-year survival rate was 90% for adults and 40% for children (≤ 6 years). CONCLUSIONS This review suggests that a) younger patients (≤ 6 years), despite multimodality treatment, have a poor prognosis; b) the microanatomical location of the tumor (lateral recess, roof, and floor) influences the extent of tumor removal (p < 0.05); c) longer survivals are associated with complete removal (p < 0.05); d) the histological feature most often related to a poor prognosis is a high mitotic index (p < 0.05), whereas vascular proliferation (p = 0.149), necrosis (p = 0.215), nuclear atypia (p = 0.384) and high cellularity (p = 0.786) do not affect survival; e) histological classification (WHO) does not reflect different survival rates between ependymomas and anaplastic ependymomas (p = 0.082).

Thirteen patients with tumors in the pineal region were submitted to pre- and post-operative blood sampling (08:00, 14:00, 20:00, and 02:00 hr) for three or four consecutive days. A single cerebrospinal fluid (CSF) sample was collected at surgery, and melatonin levels determined. In all patients, serum and CSF beta subunit of human chorionic gonadotrophin (betaHCG), carcino embryonic antigen (CEA), and alpha-fetoprotein (AFP) levels were measured. Histology revealed four pineocytomas, one pineoblastoma, four germinomas, one immature teratoma, one pilocytic astrocytoma, one lymphoma, and one meningioma. Serum and CSF levels of serological biomarkers were normal, except for one of the germinoma cases. In most patients, alteration either in the circadian rhythm or in the melatonin concentration was observed before surgery. In benign neoplasms the circadian rhythm was conserved. In pineoblastoma, lymphoma, and three out of four germinomas, melatonin concentrations were undetectable. In one case of germinoma, melatonin levels were high, with the circadian rhythm being abolished. According to conventional histology, all germinomas were similar. Therefore, in a rare case of pineal germinoma with high melatonin levels, the tissue was subjected to an in depth investigation (immunohistochemical and ultrastructural) in order to determine the pathology and the possible differences from the other typical germinomas. Results were compared to those provided from other pineal neoplasms. Electron microscopy examination detected the presence of clusters of intermediate filaments and numerous electrondense granules only in the case of a germinoma producing melatonin.

Cavernous haemangiomas rarely occur in the pineal region, only eight histologically verified cases have been reported to date. Clinically and radiographically, they are often confused with other tumours of the pineal region, particularly germ cell tumours. When radiotherapy is performed without the benefit of biopsy, cavernous haemangiomas as well as other radioresistant neoplasms may be unnecessarily treated. We report two surgically treated cases of cavernous haemangioma of the pineal region, and comment upon one treated by shunt placement alone. Two cases were associated with an adjacent venous malformation. In all instances, magnetic resonance imaging (MRI) permitted a correct pre-operative diagnosis. We conclude that surgical exploration and total resection is the treatment of choice when the diagnosis of cavernous haemangioma is suspected on the basis of neuro-imaging. A conservative attitude is justifiable in the case of elderly patients with a higher surgical risk.

The incidence, magnitude, and duration of acute pain experienced by neurosurgical patients after various brain operations are not precisely known, because of a lack of well-designed clinical and epidemiological studies. We assessed these important pain variables in 37 consecutive patients who underwent various brain neurosurgical procedures. Postoperative pain was more common than generally assumed (60%). In two-thirds of the patients with postoperative pain, the intensity was moderate to severe. Pain most frequently occurred within the first 48 hours after surgery, but a significant number of patients endured pain for longer periods. Pain was predominantly superficial (86%), suggesting somatic rather than visceral origin and possibly involving pericranial muscles and soft tissues. Subtemporal and suboccipital surgical routes yielded the highest incidence of postoperative pain. Age and sex were significantly associated with the onset of pain, with female and younger patients reporting higher percentages of postoperative pain. Psychological Minnesota Multiphasic Personality Inventory profiles of patients with and without pain significantly differed on the Hypochondriasis scale, with patients without pain scoring unexpectedly higher than patients with pain. It is possible that hypochondriasis serves as a defense mechanism against pain, at least in some patients. Results of this pilot study indicate that postoperative pain after brain surgery is an important, although neglected, clinical problem, that deserves greater attention by surgical teams, to provide better and more appropriate treatment.

La Risonanza Magnetica Funzionale (RMF) ha dimostrato di poter localizzare la sede di aree corticali funzionali in numerosi protocolli su volontari sani. La identificazione prechirurgica di aree corticali eloquenti è molto importante al fine della realizzazione di un intervento il meno lesivo possibile per la funzione. Il sowertimento più o meno grossolano della regione anatomica da parte di un processo espansivo rende spesso difficile la identificazione di determinati reperi anatomici. Ci siamo proposti di studiare con RMF, su tomografo convenzionale, pazienti affetti da neoplasie intra ed extrassiali che interessavano il lobo frontale posteriore o quello parietale. Sono stati studiati quindici pazienti, tutti destrimani, di età compresa tra i 15 ed i 64 anni. Sono state ottenute mappe di attivazione, che hanno evidenziato aree di significativo aumento del segnale in regione parieto-frontale posteriore. La morfologia delle aree di significativo aumento di segnale era il più delle volte di tipo serpiginoso. Quando l'effetto massa era netto, l'area attivata nell'emisfero patologico appariva dislocata rispetto a quella nell'emisfero controlaterale. Sino ad ora sono stati ripetuti gli esami di RMF dopo l'intervento chirurgico in tre pazienti che non presentavano deficit motori significativi all'arto superiore. Neoplasms compressing or infiltrating cerebral cortex often alter the normal anatomy in such a way that the neurosurgeon can not easily localize and spare functional areas. Moreover, the results of mass effect on brain functional anatomy have not been extensively investigated in vivo yet.

In this study, 78 patients with aqueductal stenosis were submitted to detailed neurodevelopmental assessment with a follow-up of 5-25 years. Sixty-eight percent of patients were categorized as normal; they either attended normal school courses or had regular jobs. Among these, 34% had some motor abnormalities (ataxia, mild hemiparesis, visual disturbances). Twenty-four percent (19 cases) were moderately disabled (trainable retardation) and 8% (6 cases) were severely handicapped. Epilepsy was observed in 13% of the cases. Incidence of recurrent and generalized seizures paralleled neurodevelopmental outcome (5% in normal, 16% in moderately disabled and 50% in severely disabled patients). Endocrine dysfunctions were evident in 28% of the cases and were characterized by precocious or delayed puberty, amenorrhea and somatic underdevelopment. No patient with ventricular enlargement and a cortical mantle width below 20 mm showed a good outcome. Large ventricles were compatible with normal mental development when compensated with a corresponding cranial vault enlargement. In patients with normal mental status and motor abnormalities, long-term CT scan findings revealed the presence of focal brain abnormalities (poroencephaly, brain atrophy, calcifications, extracerebral collections).

Infections due to Gemella morbillorum are unusual and not associated with preferential anatomical sites, although bacteremia and infective endocarditis predominate [1]. Reported here are two cases of cerebral abscess due to Gemella morbillorum. To the best of our knowledge, this pathogen has never been previously isolated from suppurative cerebral lesions. Case 1 involved a 47-year-old male patient who had been treated for 1 week with amoxicillin (40 mg/kg/day) for a dental abscess. Two weeks later, he developed fever and became progressively confused. Intense headache and vomiting were also present. He was referred to our neurosurgical unit from the emergency ward of a hospital in southeastern Milan. On admission, neurological evaluation revealed mild hemiparesis without clinical signs of meningitis. Laboratory analysis showed a peripheral leukocyte count of 9800 cells/ml and an increased erythrocyte sedimentation rate of 60 mm/h. Liver and kidney function tests were normal. Chest radiographs showed normal findings. A contrast computed tomography (CT) scan revealed a frontoparietal lesion (diameter, 2.8 cm) with central hypodensity and a thin layer of peripheral contrast enhancement, surrounded by moderate edema. A cerebral abscess was suspected, and the patient was treated initially with ceftriaxone (50 mg/kg/day). Twentyfour hours later progressive neurological impairment occurred with worsening of the hemiparesis. The patient’s body temperature was always below 37 C. Needle aspiration was performed on the cerebral abscess through a frontal burr hole, and a catheter was left in the abscess cavity and tunnelized under the skin. Daily vancomycin (5 mg/10 ml saline solution) and saline solution irrigation were administered from day 1 to day 3 after surgery in accordance with our institution’s treatment protocol for cerebral abscess. Aerobic and anaerobic cultures were performed, revealing Gemella morbillorum as a sole pathogen. The organism was isolated on Schaedler agar base supplemented with 5% sheep blood and vitamin K under anaerobic conditions and identified using API 20 A (bioM rieux, France). The strains were characterized as gram-positive cocci arranged in pairs and short chains; they were catalase negative, pyrrolidonyl aminopeptidase positive and esculin hydrolysis negative. Antibiotic susceptibility testing revealed susceptibility to penicillin, amoxicillin, cephalosporin (ceftriaxone was not tested), piperacillin and imipenem, but not to tetracycline, metronidazole and erythromycin. The antibiotic regimen was subsequently changed to amoxicillin and clavulanic acid (80 mg/kg/day). Progressive neurological recovery was observed. Serial CT scans documented a decrease in the volume of the lesion delimiting the inflammatory region. An echocardiograph ruled out infective endocarditis. The patient was discharged in good neurological condition on day 12 of hospitalization, and antibiotic therapy was continued with orally administered amoxicillin and clavulanic acid (50 mg/kg/day) for 3 weeks. Case 2 involved a 40-year-old, previously healthy, male patient who presented with a 4-day history of fever, severe headache, progressive ideo-motor impairment, speech and gait disturbances. A single generalized seizure was reported, but no clinical signs of meningitis were present. He was referred to our neurosurgical unit 1 month after the patient in case 1 from the emergency ward of the same hospital. D. Spagnoli ()) · L. Innocenti · R. M. Villani Department of Neuroscience, Unit of Neurosurgery, University of Milano—Ospedale Maggiore of Milano, IRCCS, Via Francesco Sforza 35, 20122 Milan, Italy e-mail: dspagnoli@libero.it Tel.: +39-025-5035502 Fax: +39-025-5013853

Rapid virological response (RVR) is now considered the strongest predictor of sustained virological response (SVR) in patients with HCV undergoing antiviral treatment, and thus, shorter antiviral treatment for these patients has been suggested. However, no data exist on the predictive value of RVR in HCV carriers with normal ALT values. A total of 137 patients with persistently normal ALT treated with peginterferon alfa 2a and ribavirin were studied. Fifteen patients dropped out early because of side effects, and in 10 patients with HCV-1 treatment was discontinued because of lack of early virological response (EVR). RVR was observed in 68% of the patients (42% patients with HCV-1, 90% HCV-2 and 64% HCV-3). An end-of-treatment response was observed in 86% of the patients (68% HCV-1, 100% HCV-2 and 91% HCV-3). SVR was maintained in 91 patients (46% HCV-1, 97% HCV-2 and 82% HCV-3). Overall, 92% patients with rapid response did obtain HCV eradication vs only 38% of those without rapid response. HCV-1 patients with baseline HCV RNA400×10(3) IU/mL were more likely to achieve RVR and SVR than those with higher HCV RNA levels. We conclude that patients with genotype 1 and normal ALT who achieve HCV RNA negativity at week 4 may have a higher probability of eradicating their infection. Because of the concomitant favourable demographic and virological features often found in this particular subset of patients, the duration of therapy in these people might be shortened in the case of RVR. Persistently normal alanine aminotransferase levels patients with genotype 2 or 3 have a high chance of achieving SVR, so retesting of HCV RNA during treatment may have no additional practical value in these subjects.

Objective: A challenging issue is to create a heart valve with growth and remodeling potential, which would be of great interest for congenital heart valve surgery. This study was performed to evaluate the growth and remodeling potentials of a decellularized heart valve. Methods: In 4 juvenile sheep (age 12 ± 1 weeks) with a weight of 24.3 ± 4.4 kg, a 17-mm diameter decellularized porcine valve was implanted as pulmonary valve replacement. Valve growth was evaluated by transthoracic echocardiography. At explantation, valves were evaluated by gross examination, light microscopy (hematoxylin and eosin, von Kossa, Sirius red, Weigert and Gomori staining), electron microscopy and immunohistochemistry. Atomic absorption spectrometry was performed to evaluate calcium content. Results: All animals showed fast recovery. The mean follow-up was 9.0 ± 1.8 months. All sheep at least doubled their weight (54.3 ± 9.2 kg). Echocardiography showed no regurgitation and a flow velocity of 0.7 ± 0.1 m/s at the latest follow-up. The valve diameter increased from 17.6 ± 0.5 to 27.5 ± 2.1 mm (p < 0.018). Gross examination showed a similar wall thickness of the implanted valve and native pulmonary wall, with smooth and pliable leaflets. Histology showed a monolayer of endothelial cells, fibroblast ingrowth and production of new collagen. No calcification was seen at von Kossa staining, confirmed by low calcium content levels of the valve wall and leaflets at atomic absorption spectrometry. Conclusions: This glutaraldehyde-free heart valve showed not only the absence of calcification, but also remodeling and growth potential.

The subthalamic nucleus (STN) has a key role in the pathophysiology of Parkinson's disease and is the primary target for high-frequency deep brain stimulation (DBS). The STN rest electrical activity in Parkinson's disease, however, is still unclear. Here we tested the hypothesis that pharmacological modulation of STN activity has rhythm-specific effects in the classical range of EEG frequencies, below 50 Hz. We recorded local field potentials (LFPs) through electrodes implanted in the STN of patients with Parkinson's disease (20 nuclei from 13 patients). After overnight withdrawal of antiparkinsonian therapy, LFPs were recorded at rest both before (off) and after (on) acute administration of different antiparkinsonian drugs: levodopa, apomorphine, or orphenadrine. In the off-state, STN LFPs showed clearly defined peaks of oscillatory activity below 50 Hz: at low frequencies (2–7 Hz), in the alpha (7–13 Hz), low-beta (13–20 Hz), and high-beta range (20–30 Hz). In the on-state after levodopa and apomorphine administration, low-beta activity significantly decreased and low-frequency activity increased. In contrast, orphenadrine increased beta activity. Power changes elicited by levodopa and apomorphine at low frequencies and in the beta range were not correlated, whereas changes in the alpha band, which were globally not significant, correlated with the beta rhythm (namely, low beta: 13–20 Hz). In conclusion, in the human STN, there are at least two rhythms below 50 Hz that are separately modulated by antiparkinsonian medication: one at low frequencies and one in the beta range. Multiple rhythms are consistent with the hypothesis of multiple oscillating systems, each possibly correlating with specific aspects of human STN function and dysfunction.

The construction of the Hospital for the Poor was begun in Milan in 1451 at the instigation of Francesco Sforza, Duke of Milan. In contrast to what had happened during the Dark Ages of the Medieval period, the new hospital was extraordinary both in construction and in medical organization. Wards for the patients were separated according to diseases, infective and noninfective, and according to sex. Each patient had his or her own bed and was fed adequately and kept warm. Patients were no longer treated by astrologers or monks but rather by doctors who had studied medicine at the University of Pavia. Each ward had its own doctor and surgeon, and from 1558 on, there was a doctor on duty in the hospital 24 hours a day. The hospital had its own pharmacy and drug reference book. The Hospital for the Poor, or Cà Granda (Big House), or the Ospedale Maggiore, as it was variously called from the 15th to the 19th centuries, became a training ground for anatomic and clinical studies. It was only in 1929 that a Faculty of Medicine was set up at Ospedale Maggiore.

OBJECTIVE: The biological features of malignant gliomas include high cell proliferation, extensive local infiltration of tumor cells into normal brain, and marked neovascularization. alphavbeta3 integrin is highly expressed in malignant gliomas and plays a role in glioma growth. This article investigates, the in vitro and in vivo effects of a synthetic alphavbeta3 integrin inhibitor called IS201 on human malignant gliomas. METHODS: The in vitro effects of IS201. were studied by performing adhesion assays, competition studies, semi-in vivo angiogenic assays, and migration and proliferation assays. For the in vivo experiments, IS201 was administered systemically in nude mouse intracranial and subcutaneous malignant glioma models. RESULTS: IS201 reacted selectively to alphavbeta3 integrin in glioma cells and tissues. In vitro, IS201 strongly inhibited angiogenesis and simultaneously exhibited potent antimitotic and antimigratory effects on numerous tumor and endothelial cell lines. In addition, at high concentrations, IS201 induced endothelial and tumor cell apoptosis. In vivo, when IS201 was administered intraperitoneally in subcutaneous and intracranial nude mouse glioma models, it potently reduced malignant glioma growth. Inhibition levels of 76 and 82% were observed at concentrations of 1 and 5 mg/kg, respectively, in the U87 intracranial model. The suppression of tumor growth is associated with a decrease in tumor vascularity, an increase in apoptosis, and a decrease in tumor cell proliferation. CONCLUSION: This work expands the understanding of the effects of anti-alphavbeta3 integrin inhibitors on malignant gliomas. In addition to direct proapoptotic and antiangiogenic effects, IS201 inhibits tumor and endothelial cell proliferation and migration, resulting in a potent inhibition of glioma growth in vivo

The systemic administration of endogenous inhibitors significantly reduced the growth of human glioma in vivo, but required the production of a large amount of biologically active protein. In this study we reduced the amount of protein needed and optimized the therapeutical response by delivering the endogenous inhibitors locally into the brain by osmotic minipumps. Human hemopexin fragment of MMP-2 or COOH-terminal fragment of platelet factor-4 were delivered locally and continuously into the brain of mice implanted intracranially with glioma cells, by osmotic minipumps connected to an intracranial catheter. Local delivery of human hemopexin fragment of MMP-2 and COOH-terminal fragment of platelet factor-4 significantly inhibited the growth of well-established malignant glioma in nude and BALB/C mice. When the inhibitors were given at the same concentration, the efficacy of the local delivery was much higher than that reached with the systemic administration, both when the inhibitor was administered daily or continuously by s.c. minipumps. Moreover, the local delivery reduced the amount of protein needed to reach a significant therapeutic response. Intracerebral delivery maintained a long-term control of glioma growth and inhibited glioma recurrence in a surgical resection model. Treatment showed no side effects. Histochemical analysis of tumors showed that the tumor growth inhibition was the result of a decrease in tumor vasculature and a change in tumor vessel morphology. Our data demonstrate that local intracerebral delivery of endogenous inhibitors effectively inhibits malignant glioma growth and reduces the amount of protein needed to reach a therapeutical response.

Ceramide represents an important sphingoid mediator involved in the signaling pathways that control cell proliferation, differentiation, and death. To determine whether ceramide levels correlate with the malignant progression of human astrocytomas, we investigated these levels in surgical specimens of glial tumors of low-grade and high-grade malignancy. Tumor samples obtained from 52 patients who underwent therapeutic removal of primary brain tumors were used. The tumors were classified according to standard morphologic criteria and were grouped into tumors of low-grade and high-grade malignancy. Sections of normal brain tissue adjacent to the tumor were also analyzed in 11 of the 52 patients. After extraction and partial purification, ceramide was measured by quantitative derivatization to ceramide-1-phosphate using diacylglycerol kinase and [γ-32P]ATP. Ceramide levels were significantly lower in the combined high-grade tumors compared with low-grade tumors and in both tumor groups compared with peritumoral tissue. The results indicate an inverse correlation between the amount of ceramide and tumor malignancy as assessed by both the histological grading and ganglioside pattern. Moreover, overall survival analysis of 38 patients indicates that ceramide levels are significantly associated with patient survival. The present findings indicate that ceramide is inversely associated with malignant progression of human astrocytomas and poor prognosis. The downregulation of ceramide levels in human astrocytomas emerges as a novel alteration that may contribute to glial neoplastic transformation. The low ceramide levels in high-grade tumors may provide an advantage for their rapid growth and apoptotic resistant features. This study appears to support the rationale for the potential benefits of a ceramide-based chemotherapy. GLIA 39:105–113, 2002. © 2002 Wiley-Liss, Inc.

Results of the treatment of 27 children with craniopharyngioma are reported. A subfrontal pterional approach was used in 55.6% of cases, a transsphenoidal and a transcallosal or transcortical approach in 25.9% and 18.5% of cases, respectively. Radical removal was the goal of surgery and was achieved in 70.8% of cases treated as primary surgery. The operative mortality was 3.7% and was due to hypothalamic failure. Most (81.4%) patients were followed up, for a mean of 7 years. Patients were evaluated according to a functional evaluation scale and outcome categories proposed by us. The scale takes account of tumor (recurrences and their eventual evolution); visual functions; endocrine functions (mainly hypothalamic), attainment of endocrine balance and drug regimen; headache; and psychosocial function. Recurrences were observed in 17.6% of patients treated with radical surgery and in 42.8% of those treated with limited surgery plus radiotherapy. A progressive amelioration of visual, endocrine and neuropsychosocial functions from the intervention to follow-up was observed in the majority of patients. Complete tumor excision was associated in 85% of cases with a low score on the functional scale, reflecting a high functional performance. Adequate substitution therapy maintained endocrine balance in 81% of patients. Since the intervention a progressive decrease in the number and dosages of medications has been observed. The majority of patients were again able to lead a normal social life. Small stature, obesity, headache, and emotional and sexual disturbances were frequent cause of long-term disability even despite adequate drug regimens. The functional evaluation scale we propose is a simple and effective tool that can be easily used during routine evaluation of patients with craniopharyngioma.

Purpose : Our goal was (a) to test the ability of functional MRI (fMRI) to localize the hand primary motor cortex in patients with brain neoplasms using a conventional scanner and (b) to compare within the same subject the location and morphology of the activated motor areas in the affected hemisphere with the contralateral ones. Method : Seventeen right-handed patients with frontoparietal intra- and extraaxial tumors were studied. Hand motor performance ranged from normal to slight impairment of finger dexterity. The fMRI study was based on a series of FLASH images. Two or three contiguous slices parallel to the bicommissural plane were acquired through the level of frontoparietal cortex. Each patient was requested to perform with each hand a finger-tapping task or a simpler repetitive flexion-extension of the last four fingers. Pseudo-color activation maps were then calculated by a Z-score method and superimposed on high resolution images. Results : Five patients were excluded because of gross motion artifacts. In all other patients, areas of significant signal increase were detected on the precentral gyrus. They had a spot-like appearance, and no substantial side-to-side differences in shape or extension could be observed. In the presence of severe compression of the gyri, a displacement of the activated areas in the affected hemisphere with respect to the contralateral ones was noticeable. Conclusion : fMRI localization of the primary motor area using a conventional scanner can be obtained also in patients with brain tumors, although with a lower success rate than in normal volunteer studies, mainly because of subject compliance problems. Areas of significantly increased signal are detectable even in cortex where normal anatomical patterns are lost.

Functional magnetic resonance imaging (fMRI), which uses BOLD (blood oxygenation level dependent contrast) technique, allows the identification of physiologically activated brain areas by means of a local and transient magnetic resonance (MR) signal increase [l]. The physical and physiological bases of the observed signal changes are not totally understood. The most accepted theory associates a local decrease in deoxyhemoglobin concentration within the venous microcirculation with the MR signal increase detected during brain activation [2].

Although Northfield’s opinion of 1957 that: “the treatment of these (craniopharyngioma) patients is fraught with difficulty and disappointment to a degree probably not offered by any other intracranial tumor with exception of glioblastoma” nowadays sounds unacceptably pessimistic, craniopharyngioma surgery is still a major challenge, even for experienced neurosurgeons, and many consider it one of the most delicate intracranial procedures (Baskin and Wilson 1986; Cushing 1932; Hoffman et al. 1992; Katz 1975; Manaka et al. 1985).

Uniaxial stretch of the optic nerve of the albino guinea pig can reproduce the axonal damage as demonstrated in prolonged traumatic coma in humans and primates. By morphological and neurophysiological approaches we have demonstrated that in the acute phase (24 hrs after injury) axonal lesions are characterized by terminal clubs and focal axonal enlargements along with an elongation of visual evoked potentials (VEPs). In this model, in which the lesion is distributed along the entire nerve, the velocity of the fast phase of axoplasmic transport in injured nerves was increased (218 mm/day vs. 176 mm/day in controls) and so was the amount of transported proteins. There was no accumulation and a block of protein uptake at the site of the lesion as demonstrated in other biological models. One week after injury, axonal lesions observed in the acute phase and alterations of VEPs disappeared, whereas the rate of axonal transport and the amount of protein uptake were persistently increased. Therefore in this model, an increase of anterograde fast transport was demonstrated both in acute and chronic phases. Since regeneration of optic axons was never evident on morphological study, the restoration of axonal function and the persistence of active axonal transport one week after injury support that spontaneous reparative processes occurred in lesioned axons.

During the period 1950–1990, 67 cases of anterior optic pathways gliomas have been observed in our Institute (48 were in the paediatric age). During the last decade, CT and MRI have greatly improved the diagnostic capabilities allowing a more precise definition of the tumor size and site and involvement of the contiguous structures. Options in the treatment should vary according to the different anatomical situations. Surgical resection is indicated for tumors involving a single optic nerve when visual functions are completely compromised. In these cases long-term results are excellent. In optic nerve cases with preserved visual functions, a clinical, neuroradiological and neurophysiological (PEV) monitoring is mandatory and no therapy should be adopted. When involvement of both optic nerve and chiasm is demonstrated, surgery is indicated only in the presence of particular conditions:well delimited cystic lesions or exophitic growths. When the tumor infiltrates the hypothalamic region and in the cases in which only a biopsy is possible, radiotherapy should be adopted.

The neurosurgeon often finds himself in the position to having to decide whether or not to operate on an elderly patient suffering from intracranial meningioma. The decision is rarely easy and the results often disappointing. We studied 46 cases of intracranial meningioma in patients over 70 years of age, 34 patients were operated on while 12 patients were not, although both groups were subjected to long term follow-up. The operative mortality rate was 12%, a rate which increased to 20% at 3 months follow-up. Various unfavourable prognostic factors were taken into consideration, the most significant of which were: poor overall clinical condition, peritumoral oedema, the presence of diabetes mellitus and the duration of surgery. A scored grading system was created to standardize surgical indications in elderly patients with cerebral meningioma. An analysis of the grading system, when applied to patients submitted to surgery, showed that the decreased patients within 3 months of surgery had a score which varied from 7 to 12, with a mean score of 10. The surviving patients had a score averaging from 10 to 16 with a mean of 13. The patients with the lowest scores (7-9) had a 100% mortality rate while those in the upper ranges (13-16) demonstrated a mortality rate of 0%. Among the conservatively treated patients the worst outcome was seen in patients with a grading equal to or less than 12.

A new model of focal axonal injury was reproduced by rapid and controlled elongation (uniaxial stretch) of the guinea pig optic nerve. Light microscopy study of optic nerve specimens after horseradish peroxidase injection into the vitreous of the animal's eye showed that axonal lesions were identical to those seen in human and primate post-traumatic diffuse axonal injury (DAI). The lesions were characterized by the formation of terminal clubs in severed axons and focal axonal enlargements in those axons that were lesioned-in-continuity. Visual-evoked potentials upon flash stimulation were recorded before and after injury. Mean amplitude and mean latency of occipital peaks were significantly elongated in the acute post-traumatic phase. Electron microscopy examination showed that the main axonal changes observed in this model were cytoskeleton disorganization, accumulation of axoplasm membrane-bound bodies at the site of terminal balls and dilatations-in-continuity and detachment of the axolemma from the myelin sheath. Such axonal alterations were similar to those found in many other biological models of central and peripheral axonal injuries in which the lesion was produced by invasive methods. This model is unique since it reproduces the same mechanism of injury and the identical lesions that have been demonstrated in humans and primates with post-traumatic (DAI).

In a series of 180 patients affected by brain stem tumors, 70 cases of children up to 16 years are analyzed. Diagnosis was made with clinical examinations, neuroradiological tests and, in 20 cases, with surgical explorations. A description is made concerning the clinical status with regard to site, extension and features of the tumor. Then the authors analyze statistically the survival of such patients in connection with clinical symptomatology, the radiological picture, medical treatment, radiation and/or surgical therapy either in the few cases of subtotal removal of the tumors, or in the more numerous cases of palliative procedures such as intra- and extrathecal CSF shunting.

Of 600 patients submitted to radioisotope cisternography carried out with radioiodinated human serum albumin (I131-HSA) a group of 140 had head injuries. Our investigation was intended to study the modifications of CSF circulation and absorption which accompany cranio-cerebral trauma. Of 88 head injured patients who did not undergo operation 44 had transient loss of consciouness, and 44 were in prolonged coma. Fifty-two patients underwent operation. Of these 5 had skull fractures with dural lesions, 7 had extradural haematomas, 19 had subdural haematomas, and 21 had brain contusions. Cisternograms were performed at different time intervals after trauma, and in some instances the test was repeated in order to study the possible long tern alterations of CSF circulation and absorption. Abnormalities of cisternographic pictures are classified into the following groups: 1 degree asymmetric diffusion; 2 degree operative cavity stagnation; 3 degree ventricular reflux; 4 degree associated abnormalities. Cisternographic features are analysed in relation to the corresponding clinical and pneumoencephalographic patterns in the patients examined. These investigations may enable us to recognise possible indications for shunt procedures in the management of CSF absorption defects, which are so frequently apparent after head injury.

Forty-one children with severe head injuries and diffuse brain lesions were selected from a consecutive series of 62 children in traumatic coma (21 focal mass lesions) and studied. According to the CT pattern, two main types of intracranial lesions were considered: diffuse axonal injury (DAI) and diffuse brain swelling (DBS). High mortality, due to secondary increases of intracranial pressure (ICP), correlated well with the patterns of severe DBS, absence of perimesencephalic cisterns, and obliteration of the ventricles. However, children with normal CTs, and/or obvious shearing injuries indicative of DAI, had favorable outcomes; there was no mortality if increased ICP was not present. We conclude that although there does not seem to be any routine indications for ICP monitoring in children with pure DAI, early ICP monitoring and aggressive management of increasing ICP should be considered in comatose children with DBS, especially when associated with subarachnoid hemorrhage and respiratory or circulatory failure.

The pathogenesis of brain dysfunction in phenylketonuria (PKU) is still under investigation. Hyperphenylalaninaemia results in increased turnover of myelin. In order to demonstrate the derangement of myelinization in PKU we studied the visual evoked potentials (VEP) in 14 PKU patients and in 20 normal subjects. VEP findings were correlated with the metabolic control of the disease and with the electroencephalographic findings. VEP were more sensitive than the EEG in detecting a neurological dysfunction. VEP are influenced by dietary control and are normal only in children with good metabolic control.

Primary intracranial rhabdomyosarcoma (RMS) is a rare tumor in infancy and childhood that is found in various locations in the central nervous system. The clinical course worsens rapidly, and the final outcome is poor, with a median survival time of 8–10 months. Invasion of the meninges, spontaneous intratumoral bleeding, spinal leptomeningeal CSF spreading of tumor cells, and early recurrence of the mass are the distinctive features of RMS. Diagnosis of RMS may be missed: immunohistochemical staining using specific markers (myoglobin, myosin, desmin, vimentin, enolase), along with ultrastructural studies, provide the basis for making the final diagnosis. Treatment of RMS includes surgical excision, craniospinal radiation therapy, and chemiotherapy. We report two cases of primary RMS in the CNS located in the posterior fossa and frontotemporal area. Both children underwent total surgical removal of the mass. Early recurrence of the tumor mass was noticed in both patients 2 months after surgery. Both children died shortly thereafter.

The AA. discuss the usefulness of brain scans in the diagnosis of head injuries. Brain scans have been carried out on 91 patients, 51 scans with Neohydrin-Hg203 and 40 with Technetium 99m. The method is very useful for head injuries with subacute or chronic brain damage, but the minimal time for the examination (1 hour after the injection of Technetium 99m) is often too long for the diagnosis of acute lesions. 13 subdural haematomas out of 14, one intracerebral haematoma and 12 brain contusions out of 13 were correctly localized. Subdural haematomas are so clearly recognisable, that in a large percentage of cases it is possible to operate on without further neuroradiological investigations.

The follow up of brain scans in 530 consecutive patients is presented. Positive results have been obtained using Hg 203-Neohydrin in 170 out of 203 (84%), intracranial tumours in 24 out of 61 (40%) cerebrovascular disorders and in 7 out of 23 (30%) head injuries.

Gli autori studiano il passaggio del Na24 dal sangue al liquor ventricolare e lombare in soggetti normali e con blocco ventricolare, per un periodo di tempo protratto sino a 52 h. In tutti i soggetti osservano, nel liquor ventricolare come nel lombare, che i livelli di radioattivita, dopo aver raggiunto l'equilibrio con il sangue, aumentano cosi da creare un gradiente positivo di Na24 nel liquor. Questa osservazione documenta la esistenza di una selettivita di membrana e verosimilmente di un lavoro attivo realizzato della barriera emato-liquorale.

The passage of tritiated water, some electrolytes and iodinated serum albumin from the plasma into the ventricular and lumbar cerebrospinal fluid has been studied in normal humans during a period of time from between 50–70 hours.

Since the effects of cyclic nucleotides are mediated via protein kinases activation, we have studied the properties and regulation of these enzymes in cytosol and particulate fraction of normal cerebral tissues and of some human brain tumors. We found that distribution and activity of cyclic nucleotide-dependent protein kinases are regulated differently among various brain tumors and in comparison to normal gray and white matter. Pathological tissues show an higher cGMP-dependent protein kinase and this biochemical pattern is particularly evident in tumors with more pronounced malignancy. These data further confirm the hypothesis of a correlation between the increase of cGMP function and cellular growth and malignancy.