Temozolomide and thalidomide in the treatment of glioblastoma multiforme.

OBJECTIVE: The aim of this study was to assess efficacy and toxicity of temozolomide given alone or in combination with thalidomide, an anti-angiogenetic drug, in patients with newly diagnosed glioblastoma multiforme (GBM). PATIENTS AND METHODS: 46 patients with histologically proven GBM were eligible for inclusion. Twenty-three patients (15 males and 8 females) received temozolomide on a conventional schedule; 23 patients (12 males and 11 females) received temozolomide on the same schedule and thalidomide was dose-adjusted in each individual patient based on their tolerance. RESULTS: The median survival time was 12 months for temozolomide and 13 months for temozolomide + thalidomide. CONCLUSION: The administration of temozolomide in association with thalidomide after radiotherapy (RT) does not offer an advantage over temozolomide alone in adults with newly diagnosed GBM. The two therapeutic strategies produce similar results for survival, but the latter regimen shows a moderate increase in toxicity.

Primary leptomeningeal gliomatosis: case report and review of the literature.

A 62-year-old woman developed dysphasia, signs of intracranial hypertension and seizures. An MRI scan evidenced extra-axial contrast enhancement in the absence of mass lesions. CSF analysis was negative for malignant cytology and viral or bacterial microbiology. In the absence of other evidence, considering the acute clinical onset and MRI picture, a viral encephalitis was suspected and antiviral therapy was started, however, with no effect. Death occurred three weeks after presentation because of acute brain swelling. Autopsy revealed leptomeningeal gliomatosis and diffuse parenchymal infiltration at the cerebellar and left temporal lobe. Primary leptomeningeal gliomatosis (PLMG) is a rare event. The reported case and the reviewed literature evidence that clinical signs at presentation are non-specific, CSF negative findings are common, the diagnosis is always delayed and the prognosis dismal.

Surgery for intracerebral hemorrhage.

The surgical treatment of intracerebral hemorrhage (ICH) is one of the most controversial areas of neurosurgery. Randomized trials are inconclusive due to the small number of patients enrolled or because performed in pre CT era. We analyze the 232 patients admitted to the Niguarda Hospital of Milano, Italy, for ICH during the period January 2001-December 2002. Sixty patients were operated: 29 had secondary haemorrhage, and 30 a primary one. The strategy followed in these patients is presented. The series suggests that indication to surgery is a complex process including several factors that have to be all considered in each patient.

Adult brain low-grade astrocytomas: survival after surgery and radiotherapy.

In order to identify prognostic factors of survival, twelve elements of disease and treatment have been evaluated for a population of 49 patients with diffuse low-grade astrocytoma treated with surgical resection and radiotherapy. The survival values were inversely correlated with age and major residual portion. On the other hand, KPS, lobar site, grade II Daumas-Duport lesions, protoplasmatic variant, early epilepsy, hyperfractionated radiotherapy and extent of exeresis were prognostic factors correlated with survival. Tumor extent and radiation total dose were not correlated in a meaningful way. Only KPS was statistically significant when compared to all the prognostic factors. We believe that patient selection according to age, lesion site and histological features are not sufficient to generate a homogeneous tumoral population. The most appropriate therapy for treating low-grade astrocytomas is still an open subject. However, recent studies have shown that the prognostic value of a group of factors is useful to plan controlled studies that compare differentiated treatment protocols.

Pathophysiology, clinical manifestations and supportive care of metastatic brain cancer.

Brain metastases (BrM) are tumours that originate in tissues outside the central nervous system and spread secondarily to involve mainly the brain. The management of patients with cerebral metastases is complex, costly, and in some instances controversial. Furthermore, even in patients with widespread systemic cancer, the symptoms of the disease are often controllable while the symptoms of the BrM may be disabling. The treatment of BrM is one of the few areas of neuro-oncology where real progress has been made in the last twenty years. Moreover, the costs of managing this disease are rising, as therapies become more intensive and the number of patients with BrM increases. Modern neuroradiological imaging techniques, which are able to discover BrM earlier in the course of systemic cancer, and the greater efficacy of specific treatments, which lengthens survival, have increased the prevalence. The aggressive treatment of BrM may add some benefits to the patient, but its excessive cost leads to the necessity for accurate cost-effectiveness analysis. The latter begins with a complete understanding of the disease: its diagnosis, natural history and results of various modalities of treatment. While the development of BrM usually indicates a poor prognosis for the patient, advances in supportive care have made it possible to reverse most of the neurological symptoms and to give patients a meaningful extension of useful life.

Surgical treatment of intracranial dural arteriovenous fistulae: role of venous drainage.

OBJECTIVE: This report focuses on the surgical management of aggressive intracranial dural arteriovenous fistulae (d-AVFs), which are defined as fistulae with arterialized leptomeningeal veins (red veins). Particular attention is paid to the accurate identification of the venous drainage pattern and to the choice of the proper treatment strategy. METHODS: Thirty-four consecutive patients with aggressive intracranial d-AVFs were treated between 1994 and 1998. Angiographic studies allowed the identification of two main types of aggressive lesions, i.e., d-AVFs with sinus drainage and reflow into leptomeningeal veins (12 patients), which we designated sinus fistulae, and d-AVFs drained exclusively by leptomeningeal veins without sinus interposition (22 patients), which we designated nonsinus fistulae. All patients underwent surgical treatment, which consisted of resection of the fistulous sinus tract in 12 cases of sinus fistulae and interruption of the draining veins at their dural origin in 22 cases of nonsinus fistulae. Surgical preparation via multistage transarterial embolization was required in all 12 cases of sinus fistulae and in 4 of 22 cases of nonsinus fistulae. RESULTS: The mortality rate was 0%, and there were no instances of lasting morbidity. Radioanatomic cures were achieved in all cases. There was no case of venous hypertension or venous infarction after resection of the affected sinus or interruption of the draining veins. No arteriovenous shunts recurred during the follow-up period. CONCLUSION: Careful preoperative identification of the venous drainage pattern seems critical for planning of the correct surgical strategy to treat aggressive intracranial d-AVFs. If the fistula exhibits sinus drainage with reflow into leptomeningeal veins, surgical excision of the fistulous sinus segment represents a safe and definitive treatment option. In these cases, the affected sinus may be safely removed, provided that preoperative angiograms demonstrate participation of the sinus in drainage of the lesion, indicating that the sinus is nonfunctional. Conversely, if the fistula exhibits pure leptomeningeal drainage, the sinus does not participate in drainage of the lesion and cannot be excised. In these cases, the best treatment involves interruption of the draining veins at the point at which they exit the dural wall of the sinus. This simple easy treatment has been proven to be safe and highly effective in permanently eliminating arteriovenous shunts.

Surgical treatment of poor-grade aneurysm patients.

Patients who are severely struck by subarachnoid hemorrhage (the so called poor-grades) have been usually considered almost hopeless. Conversely, it is now becoming apparent that a significant number of poor grades could be perhaps salvageable during the first hours after the hemorrhage. In this paper we are reporting the results of an aggressive management protocol including immediate intensive care management and early surgery. Early surgery was offered to all patients without vital brain destructions on CT-scan, with treatable intracranial hypertension and stabilization of vital parameters. By this attitude, among 32 initial unselected consecutive poor grades, we could manage by early surgery 15 patients (47%), obtaining 11 favourable outcomes (35%). These encouraging results in the treatment of patients otherwise destined to ominous consequences are now to be compared with the presently available less invasive endovascular techniques.

Transbasal approaches to aneurysms of the vertebro-basilar junction.

The most difficult aneurysms to be surgically treated are those of the vertebro-basilar junction area. This is due to their deep location and the proximity of brain stem and cranial nerves. Recently, new transbasal surgical approaches have been developed in order to realize a shorter and more direct access. Clival lesions, such as neoplasms, angiomas, and aneurysms, can now be safely faced through these routes. In this paper, we report our recent experience in transbasal approaches for the management of six consecutive patients, with aneurysms in this area. In four of these patients, the initial treatment consisted of an attempt at endovascular aneurysm obliteration using the Guglielmi Detachable Coil system, whereas, in the other two patients (basing on age, aneurysm size and neurological conditions), surgery was considered as the treatment of choice. Unfortunately, the endovascular treatment failed in all cases, and all patients had to be eventually operated on. In all cases, surgical clipping was performed through the combination of a transmastoid (asterional) approach with the suboccipital lateral approach. By this route, in all cases, parent arteries proved well delineated, the aneurysms could always be correctly clipped. Good long-term results were achieved in all cases but one. When surgery is to be performed, the importance of a thorough wide exposure of the whole vertebro-basilar junction area, as well as the importance of having multiple accesses to the lesion, cannot be overemphasized.

Multidisciplinary (surgical and endovascular) approach to intracranial aneurysms.

In spite of the availability of the new endovascular technique (GDC) to manage cerebral aneurysms, to date, the crucial question "which is the proper treatment in a given patient?" still remains unsettled. In order to check whether an answer is possible, we retrospectively reviewed a personal series of 192 consecutive patients with cerebral aneurysms (1993-1995). We found 164 patients who had been considered eligible for active aneurysm treatment. Treatment modality has been chosen case by case on the basis of patient conditions, and aneurysm size and location. Four groups of patients were identified: Group 1: 104 patients (63.4%) with subarachnoid hemorrhage (SAH) in whom the treatment of choice was surgery; Group 2: 27 SAH patients (16.4%) in whom the first choice was GDC; Group 3: 7 SAH patients (4.2%) who died before the scheduled treatment; Group 4: 26 patients (15%) with not ruptured aneurysm who had either surgery or GDC. Based on the results of this series (improvement of the overall results through the multidisciplinary approach), we have developed the guidelines to prospectively manage future cases of cerebral aneurysms with the purpose to rationalize the management, thus further improving the overall results.

[Subarachnoid hemorrhage from ruptured aneurysms in elderly patients]. / L'emorragia subaracnoidea da rottura di aneurisma nel paziente anziano.

Advanced age is a recognized risk factor in patients with SAH. A strong correlation has been found between advanced age and impairment of consciousness at admission, presence of thick subarachnoid clot, intraventricular hemorrhage and acute hydrocephalus. Thus suggesting a more severe disease in elderly. Moreover the incidence of rebleeding increases with advancing age. As to the results of surgery a linear correlation between age and outcome has been found in most of series and it is difficult to identify a critical age. However the rate of patients with a poor outcome is significantly higher when an age cut off 60-65 years is considered. Significant improvements have been obtained in the last 30 years in elderly but mortality rate still remains at high level: in the order of 20% in the patients 60-70 years old. For patients over 70 years only results from single series are available and these suggest favourable results in very selected cases. The introduction of GDC coil in the treatment of cerebral aneurysms has changed the management of most SAH patients and particularly of the older ones. The guidelines of current management of such patients followed at the Niguarda Hospital of Milan are presented. Age is one of the four "factors" taken into consideration for a selection of treatment (surgery or coil).

Aneurysms of the vertebro-basilar junction area: preliminary experience in endovascular and surgical management.

Aneurysms of the vertebro-basilar junction area have been considered the most difficult to be surgically treated because of their deep location, the proximity of the brain stem and the cranial nerves. However, at present, new endovascular techniques and new transbasal surgical approaches offer valuable management strategies. This paper concerns six consecutive patients whom we managed either endovascularly or surgically during a period of eighteen months. Direct surgical treatment was offered to two young patients with relatively small aneurysms in good neurological condition, whereas the other four patients initially underwent an endovascular attempt at aneurysm obliteration using the Guglielmi detachable coil system. Unfortunately, interventional neuroradiology failed in three cases, and surgery had to be re-considered. Accordingly, a total of five patients underwent surgical clipping through the combination of a transmastoid retrolabyrinthine approach with the suboccipital lateral approach. This combination of approaches provided a good control of both vertebral arteries and basilar artery, and allowed the aneurysm to be correctly clipped in all cases. Good long-term results were achieved in all cases but one. Based on this preliminary experience, we would stress the importance of multidisciplinary approach with a treatment calibrated for each single case. Furthermore, if surgery is to be performed, the combination of transmastoid-retrolabyrinthine and suboccipital lateral approaches provides a wide exposure of the whole vertebro-basilar junction area and allows good access to the lesion.

Comparison of pediatric and adult cerebral arteriovenous malformations.

The authors report 19 consecutive children with cerebral arteriovenous malformations over the period 1978-1992. These patients are compared with a series of 120 consecutive adult patients with the same pathology, managed during the same period. The main clinical and angiographic features, as well as the treatment modalities and outcome are reviewed and compared. Children seem to harbour smaller and simpler lesions than adults. Furthermore, despite a more severe clinical presentation, children appears to fare better than adults. The possibility of evolution of brain arteriovenous malformations is discussed.

Complex arteriovenous fistula of the brain in an infant. Case report.

A rare case of complex cerebral arteriovenous fistula in an infant is reported. An 8-month-old boy first presented with a syndrome of increased intracranial pressure. Neuroradiological assessment showed a direct intracerebral arteriovenous shunt with marked venous engorgement. No hemorrhage was evident. Direct surgical treatment was decided. Clinical and radioanatomical cure was achieved. The main angiographic and pathophysiologic features of this unusual entity, as well as the available therapeutic options, are reviewed and discussed.

Cavernous hemangioma of the skull. Case report and review of the literature.

Osseous hemangiomas are rare skeletal tumors that constitute 0.7% of all osseous neoplasms. The most common site is the vertebral column while involvement of the calvarium is extremely rare accounting for 0.2% of all bone neoplasm. The authors present a case of a 35-years-old man who was admitted with right parietal swelling and review the gross appearance, pathogenesis, histopathology, radiological features and treatment of this neoplasm.

Surgical interruption of leptomeningeal drainage as treatment for intracranial dural arteriovenous fistulas without dural sinus drainage.

Intracranial dural arteriovenous fistulas (AVFs) have been recognized as acquired lesions that can behave aggressively depending on the pattern of venous drainage. Based on the type of venous drainage, they can be classified as fistulas drained only by venous sinuses, those drained by venous sinuses with retrograde flow in arterialized leptomeningeal veins, and fistulas drained solely by arterialized leptomeningeal veins. Serious symptoms, including hemorrhage and focal deficit, are related to the presence of arterialized leptomeningeal veins. In this paper, the authors report a consecutive series treated between 1988 and 1993 of 20 cases of intracranial dural AVFs with "pure leptomeningeal drainage." All patients underwent surgical interruption of the leptomeningeal draining veins. Based on the arterial supply, nine patients were managed by direct surgery, whereas 11 patients were prepared for surgery by means of preoperative arterial embolization. Radioanatomical cure of the fistula and good neurological recovery were achieved in 18 cases. Complete obliteration of the fistula was documented angiographically in two cases, but fatal hemorrhage occurred, probably due to partial thrombosis of the venous drainage. Based on this experience, the authors believe that surgical interruption of the draining veins is the best treatment option for intracranial dural AVFs. However, surgical results may be affected by the extension of postoperative thrombosis, which in turn may be related to the degree of preoperative venous engorgement.

"High risk" anterior basal skull fractures. Surgical treatment of 64 consecutive cases.

Anterior Basal Skull Fractures (ABSFs) may be complicated by Cerebrospinal Fluid (CSF) fistulae and intracranial infections. An initially non-operative management is usually suggested since most fistulae spontaneously stop within a few days thus requiring no surgical repair. However, if the fistula fails to stop or recurs, surgical treatment is to be considered. Furthermore, if the fracture is complicated by meningitis, there is a relative risk of recurring infections and surgical repair may be also considered. Finally, surgical repair may be suggested in cases of compound, comminuted, depressed, largely extended cranio-facial fractures (the so-called "fracas craniofaciaux") where spontaneous healing is considered unlikely and risk of infection is high. Accordingly we termed "high risk" fractures those associated with active (persistent or recurring) cerebrospinal fluid fistula, those with meningitis and the so-called "fracas craniofaciaux". In this paper, we report our personal experience in surgical treatment of 64 consecutive "high risk" anterior basal skull fractures. Thirty-seven patients had persistent or recurring fistulae, ten had intracranial infections and seventeen had severe bone derangement of the anterior skull base. The osteodural repairs were performed through bilateral or unilateral subfrontal approach. In 59 cases the initial procedure was successful whereas 4 patient needed additional surgery but were ultimately successfully treated. One patient died. No major permanent neurologic or neuropsychologic impairments were reported. On the basis of our experience, we think that intracranial repair is a very suitable treatment modality in facing "high risk" anterior basal skull fractures.

Delayed complications of ethmoid fractures: a "growing fracture" phenomenon.

Delayed complications of ethmoid fractures are considered relatively rare. However, meningitis, recurrence of previously ceased cerebrospinal fluid rhinorrhea and delayed onset of cerebrospinal fluid rhinorrhea are possible even years after trauma. We report 10 consecutive patients with delayed complications of ethmoid fractures, whom we treated over the past 11 years. All patients had previously sustained a closed head injury and had remained anosmic. Variously after trauma (ranging from 2 months to 31 years), these patients were re-admitted because of meningitis (6 cases), recurrence of previously ceased cerebrospinal fluid rhinorrhea (3 cases), and delayed onset of cerebrospinal fluid rhinorrhea (1 case). In all cases the delayed complications were associated with relatively large defects of the ethmoid bone. These bone lesions were now evident even in those patients whose radiological assessments had been normal after trauma. All patients underwent a successful surgical repair and remained well during the follow-up. We discuss the possibility that delayed complications of ethmoid fractures are due to a mechanism like that of "growing fractures" in children.

Intramedullary spinal cord metastasis. Case report.

The authors report a case of intramedullary spinal cord tumor in a 52-years old woman operated, 5 years before the beginning of medullary syndrome, for mammary carcinoma. Intramedullary metastasis was associated to another secondary localization in the pituitary stalk. The importance of magnetic resonance image and aggressive treatment is stressed.