Expression of vascular endothelial growth factor receptor-1/-2 and nitric oxide in unruptured intracranial aneurysms.

The biological mechanisms associated with the development and rupture of intracranial aneurysms are not fully understood. To clarify the role of VEGF and the related receptors in the pathophysiology of aneurysm, immunostaining for VEGF, VEGFR1 and VEGFR2 was performed on specimens from six unruptured aneurysms and on two specimens of normal arteries wall as a control. The results were correlated with NO concentration of CSF collected during surgery from 8 patients affected by unruptured aneurysms and in 11 control patients. The immunohistochemical data showed a different pattern of VEGF/VEGFR1/VEGFR2 in aneurysms when compared with control. The results of this preliminary study suggest an imbalance of VEGF, VEGFR1 and VEGFR2, and the interaction of VEGF and NO in the pathophysiology of unruptured aneurysms. Our data support the hypothesis of aneurysm formation associated with a loss of expression of VEGFR1, moderate expression of VEGFR2 and high concentration of nitrate.

Craniotomies without burr holes using an oscillating saw.

OBJECTIVE: The object of this study is to describe a new method for performing craniotomies which obviates the need for burr holes, improves bony reconstruction, and reduces post-operative cosmetic deformities. Moreover, this technique provides excellent exposure of skull base structures and dural venous sinuses. METHODS: Craniotomies in varied locations are created with the use of a micro-oscillating saw and chisel. No burr holes are used and reconstruction with plates and screws is unnecessary. RESULTS: We initially applied our technique to approaches to the anterior skull base with combined craniofacial tumour resections. We have since performed over 2000 craniotomies of any size and shape in all supratentorial locations using the oscillating saw. CONCLUSIONS: We have found that our method creates better cosmetic results than standard techniques and is safer for craniotomies spanning dural venous sinuses. With experience, operating time was significantly reduced and costs were lowered because reconstruction with fixation devices was not needed.

Primary chemotherapy followed by anterior craniofacial resection and radiotherapy for paranasal cancer.

BACKGROUND: To study prospectively the activity of primary chemotherapy with cisplatin, fluorouracil and leucovorin (PFL) in patients with paranasal cancer receiving surgery and postoperative radiotherapy. PATIENTS AND METHODS: Forty-nine patients, previously untreated, with resectable paranasal carcinoma were enrolled. PFL (leucovorin 250 mg/m2/day for 5 days as a 120 h continuous infusion (c.i.), 5-fluorouracil 800 mg/m2/day from day 2 as a 96 h c.i. and cisplatin 100 mg/m2 day 2 q 3 weeks) was planned for five courses. RESULTS: Thirty-two patients (65%) completed three or more chemotherapy courses. Two deaths from thrombotic events were observed after the first cycle. Eight cardiac toxicities were recorded during chemotherapy causing treatment discontinuation. Objective response to PFL was observed in 21 patients [43%; 95% confidence interval (CI) 29% to 58%], including four complete responses (CRs) (8%; 95% CI 2% to 20%) and 17 partial responses (PRs) (35%). Pathological complete remission (pCR) was achieved in eight of 49 patients (16%). At 3 years, overall survival was 69% and event-free survival 57%. Overall and event-free survival in patients achieving pCR is 100%. CONCLUSIONS: PFL is active in paranasal cancer. Patients who attain a pathological complete remission have a favorable prognosis. Cardiovascular complications represent the limiting toxicity. Primary chemotherapy combined with surgery-sparing treatment approaches deserves further investigation.

Combined anterior craniofacial resection for tumors involving the cribriform plate: early postoperative complications and technical considerations.

OBJECTIVE: Combined craniofacial resection has become the standard approach for malignant tumors involving the cribriform plate and anterior cranial fossa. Despite its widespread application, however, many surgeons agree that the procedure carries a risk of significant morbidity and even mortality. The purpose of this study was to analyze the experience at a single institution to determine the incidence of early postoperative complications encountered after combined craniofacial resection of tumors involving the cribriform plate and to provide information to improve management. METHODS: Between 1987 and 1997, 168 patients underwent combined craniofacial resection at the National Cancer Institute of Milan for tumors involving the cribriform plate. Patient charts, operative notes, follow-up clinic notes, radiographic studies, and pathology reports were analyzed. Morbidity encountered in the first 30 cases was compared with that encountered in the subsequent 138 cases. RESULTS: The most frequently encountered pathological findings were adenocarcinoma (53.6%), squamous cell carcinoma (17%), and esthesioneuroblastoma (9.8%). Eight patients (4.7%) died, 6 of whom were among the first 30 patients to undergo resection. Among patients with fatal complications were three with meningoencephalitis, three with intracranial hemorrhage, and one with myocardial infarction. Fifty patients (29.7%) had nonfatal morbidity; 16 of these patients were among the first 30 patients operated. Transient cerebrospinal fluid leakage was the most frequent adverse effect (9.5%); 12 patients (7.1%) had pneumocephalus, 3 (1.8%) had meningitis, 4 (2.4%) had wound infections, 3 (1.8%) experienced transient impairment of mental status, 3 (1.8%) had transient diplopia, 2 (1.2%) had diabetes insipidus, and 1 (0.6%) had bone flap necrosis. CONCLUSION: We observed a dramatic decrease in mortality and morbidity in patients who underwent combined craniofacial resection after the first 30 cases in our series. Improvement of specific aspects of surgical technique, such as more refined reconstructive methods and improved prophylactic antibiotic therapy, is at least partly responsible for this favorable trend.

[Malignant maxillary tumors involving the pterygo-maxillary and infratemporal fossae: a series of 200 cases]. / Resezione cranio-facciale anteriore per tumori maligni: esperienza di 200 casi.

At the Cranio-Maxillo-Facial Surgery Unit of the Istituto Nazionale per lo Studio e la Cura dei Tumori in Milan, Italy between 1987 and 1999 200 anterior cranio-facial resections were performed on malignant ethmoid tumors involving the anterior cranial base and extending to the nasal fossae and, at times to the orbit and maxillary and sphenoid sinuses. In the second portion of this case study the authors simplified their surgical technique. The frontal craniotomy was made rectangular and low, performed with an oscillating saw and scalpel, without drilling holes. The osteotomy of the cranial base was modulated according to tumor extension. Typically a paralateronasal facial incision was performed without opening the upper lip. Whenever the maxillary sinus and/or orbit were involved, the skin incision and osteotomy was consequently modified. Repair of the cranial base was performed with a pedicled pericranial flap. In this case study there were 6 post-operative deaths in the first 30 patients and only 2 in the remaining 170. The male/female ratio was 145/55, mean age 55 years (12-80) and average follow-up 38 months (2-117). There were 120 primary tumors while the remaining 80 patients presented recurrences from prior treatments. There were 96 adenocarcinomas, 42 spinocellular carcinomas, 21 esthesioneuroblastoma 15 adenoid-cystic carcinomas, 9 melanomas and 17 rare tumors. Our classification identified the following stages: 69 T2, 54 T3 and 77 T4 while the UICC-AJCC staging system indicated: 25 T1, 16 T2, 68 T3 and 91 T4. The NED survival according to tumor stage (INT classification) was: T262.3%, T3 44.4% and T4 29.9%. The NED survival for patients who had not previously undergone treatment was: T2 71.7%, T3 58.8% and T4 42.5%. On the other hand the NED survival for the cases of recurrence was: T2 43.5%, T3 20% and T4 16.2%. These results lead to the conclusion that the surgical technique currently used is valid and that the anterior cranio-facial resection should always be performed in patients with ethmoid tumors coming into contact with, or eroding, the cribriform plate. For all staging classes, the prognosis for those patients undergoing surgery for recurrence from prior, inadequate treatment was significantly worse than that for the primary tumors.

High-dose methylprednisolone reduces cytokine-induced adhesion molecules on human brain endothelium.

OBJECTIVE: We investigated the in vitro effects of low- and high-dose methylprednisolone (MP) on the cytokine-induced expression of HLA-DR, ICAM-1 and VCAM-1 on human brain microvessel endothelial cells (HBMECs). METHODS: Brain endothelium was obtained from microvessels included in the apparently normal white matter of surgical specimens of nine patients. Cells were stained with monoclonal antibodies anti-HLA-DR, anti-ICAM-1 and anti-VCAM-1 and analysed by flow cytometry as fluorescence histograms. The mean fluorescence intensity (MFI) of HBMECs treated with different stimuli was calculated. RESULTS: gamma-IFN-induced HLA-DR was down-regulated in a dose-dependent manner by MP. High-dose MP reduced the TNF-alpha-induced ICAM-1 and VCAM-1 expression. CONCLUSIONS: The down-regulation of adhesion molecules on cerebral endothelial cells could decrease mononuclear cell transmigration through the blood brain barrier and consequently the perivascular infiltrates. The results add support to the rationale for high-dose MP treatment in multiple sclerosis relapses.

Isolation and characterization of neural stem cells from the adult human olfactory bulb.

We have recently isolated stem cells deriving from the olfactory bulbs of adult patients undergoing particularly invasive neurosurgery. After improving our experimental conditions, we have now obtained neural stem cells according to clonal analysis. The cells can be expanded, established in continuous cell lines and differentiated into the three classical neuronal phenotypes (neurons, astrocytes, and oligodendrocytes). Also, after exposition to leukemia inhibitory factor, we are able to improve the number of neurons, an ideal biological source for transplantation in various neurodegenerative disorders.

A new classification for malignant tumors involving the anterior skull base.

OBJECTIVES: To propose our clinical classification of malignant ethmoid tumors and to compare it with the last American Joint Committee on Cancer (AJCC)-Union Internationale Contre le Cancer (UICC) classification, published in 1997. DESIGN: Retrospective review. SETTING: Tertiary cancer facility. PATIENTS: We evaluated 123 consecutive patients undergoing craniofacial resection for malignant ethmoid tumors involving the anterior skull base. The mean follow-up was 60 months. Fifty-nine patients (48%) presented with recurrent disease after prior therapy. We classified them with a new classification system (Istituto Nazionale per lo Studio e la Cura dei Tumori) based on the most commonly accepted unfavorable prognostic factors (involvement of dura mater; intradural extension; involvement of the orbit and, in particular, of its apex; invasion of maxillary, frontal, and/or sphenoid sinuses; and invasion of the infratemporal fossa and skin. We also classified patients with the AJCC classification published in 1997. MAIN OUTCOME MEASURES: Disease-free status and overall survival rate. To study a possible association with tumor stage, the Cox regression model was adopted. RESULTS: According to our classification, patient distribution by tumor type was T2, n = 46; T3, n = 29; and T4, n = 48 (no T1 tumors were present in the series). For previously untreated patients, 5-year disease-free survival estimates were T2, 57%; T3, 50%; and T4, 13%. For relapses, corresponding figures were T2, 31%; T3, 23%; and T4, 1%. The prognostic difference among stages was statistically significant (P<.001). Similar results were obtained for overall survival. In contrast, patient distribution among different AJCC stages was less balanced, and we failed to detect a significant association with the clinical outcome using this classification. CONCLUSION: We propose the use of our staging system by all those specialists in the field willing to validate the classification and possibly apply it for clinical and investigational purposes.

Anterior craniofacial resection for malignant ethmoid tumors--a series of 91 patients.

BACKGROUND: Anterior craniofacial resection is now recognized as the best treatment for ethmoid tumors involving the cribriform plate with or without invasion of anterior cranial fossa. METHODS: Ninety-one patients underwent an anterior craniofacial resection for ethmoid malignant tumors at the Milan Cancer Institute between 1987 and 1994. The patient population was divided into two sections (30 and 61 patients) based upon some important variants (type of craniotomy, antibiotic treatment, postoperative care). RESULTS: The mean age was 53.4 years (range, 24 to 78 years). There were 62 men and 29 women. Forty-nine patients had a recurrence after previous treatments (surgery and/or radiotherapy). The subdivision by histology was as follows: 50 cases of adenocarcinoma, 16 cases of epidermoid and undifferentiated carcinoma, 8 cases of esthesioneuroblastoma, 5 cases of adenoid cystic carcinoma, 5 cases of melanoma, and 6 rare tumors. The stages (according to our new staging) were as follows: 37 cases with T2, 27 cases with T3, and 27 cases with T4. The mean follow-up was 47 months. Seven patients died after surgery (6 in the first series). The survival at 3 and 5 years was, respectively, 52% and 47%, and the disease-free survival (DFS) was 30% and 24%, with a statistically significant difference at multivariate analysis in favor of patients without prior treatment (p = .033) or T2 versus T3 and T4 (p<.007). CONCLUSIONS: An anterior craniofacial resection should be performed in cases of ethmoid tumors reaching or eroding the cribriform plate. A scrupulous intra- and postoperative approach is necessary to avoid severe complications. The patients often survive for a long time with recurrence ongoing. Our new staging identifies the critical extensions of ethmoid tumors.

Skull base reconstruction after anterior craniofacial resection.

Anterior craniofacial resection has become a popular operation for nasoethmoid tumours involving the skull base. Many papers have been published since the first by Ketcham et al. in 1963. However, there is still controversy about the method for reconstruction of an anterior skull base defect after resection. The simple reconstruction of Ketcham has been followed by more sophisticated procedures using galeal-pericranial flaps, free flaps with microvascular anastomosis and bony or alloplastic augmentation. The main purposes of the reconstructions are to prevent brain herniation, to avoid intracranial infections, to diminish the risk of CSF leakage and to avoid pneumocephalus. From the relevant literature and our own experience of 168 anterior craniofacial resections, we conclude that a pedicled pericranial flap is the best choice for closing a cranial base defect.

[Classification of ethmoid malignancies]. / Classificazione dei tumori maligni dell'etmoide.

The UICC and AJCC never classified ethmoid malignancies prior to the latest edition (1997). Most classifications in the literature refer to a single histological type (estensioneuroblastoma or carcinoma) while others basically consider the intracranial extension, without distinguishing between intra or extradural. Still others consider invasion of the orbit. There is as yet no classification which considers all the prognostic factors associated with the extension of this neoplasm. The authors reviewed 84 patients with ethmoid malignancy who had undergone anterior cranio-facial resection between 1987 and 1994 and had been followed up for a minimum of 36 months. Of these patients, 43 were recurrences of previous treatment while 42 had not previously been treated. The breakdown was as follows: 45 adenocarcinoma, 14 squamous cell carcinoma (more or less differentiated), 8 etesioneuroblastoma, 6 adenoidocistic carcinoma, 5 melanoma and 6 rare forms. These cases were staged according to a new classification identifying the worst prognostic factors: invasion into the dura and, above all, intradural extension; invasion of the sphenoid sinus, orbit, and in particular the orbit apex, the frontal sinus, the maxillary sinus, the pterygoid, infratemporal fossa and the skin. Until 1994 we used this classification which is similar to the one proposed by the UICC in 1997. On the basis of this classification our case breakdown is as follows: T2 35, T3 24, T4 25 (there were no cases of T1). Since a patient can live as much as 4-5 years with a recurrence but the recurrences all appeared within 2 years after surgery, we used a NED survival at 36 months as index of healing. The NED survival at 36 months was: T2 54%, T3 41%, T4 8%. In patients which had not received prior treatment the NED survival was: T2 63%, T3 45%, T4 9%. The progressive worsening of prognosis from T2 to T4, particularly in patients which had not been pretreated, leads us to assume that the true prognostic factors for malignant ethmoid tumors have been identified.

Analyses of prognostic factors in a retrospective review of 92 children with ependymoma: Italian Pediatric Neuro-oncology Group.

The principal aim of this report is to present the results of multivariate analyses conducted to identify clinical prognostic factors in 92 children aged < 16 years with ependymoma (EPD) retrospectively collected in seven Italian centres. They were treated over a 16-year period (1977-1993). Treatment modalities varied. Surgery and radiotherapy (RT) was the "gold standard" management method for the majority of these children. Only in the late 1980s did some of them receive chemotherapy (CT), mainly with vincristine, lomustine (CCNU) and prednisone. The median follow-up of the entire study population is 36 months (average 43 months; range 12 to 214 months). The 10-year overall (OS) and the progression-free survival (PFS) of the study population were 55.5% (CI 41.4-69.4%) and 34.7% (CI 21.4-47.8%), respectively. Age (< 5 years; > 5 years), sex, site (infratentorial vs. supratentorial), histology (anaplastic/malignant vs. non-anaplastic/non-malignant), type of resection (complete vs. incomplete); use and fields of RT, and of CT employed were entered in a multivariate regression model to test their impact on OS and PFS. On univariate analysis, radical surgery, the use of RT and age more than 5 years at the time of diagnosis achieved statistically significant values for predicting long-term OS and PFS. Histology reached marginal statistical significance but only for PFS. When those variables were entered in a multivariate analysis only radical resection (P = 0.00142 and 0.0001) resulted a significant factor for predicting long-term OS and PFS, while the use of RT reached a marginal statistical significance, but only for PFS (P = 0.05). Children who had the tumour completely resected did significantly better than all the others who had less than a complete resection, with a 10-year OS and PFS for the two groups of patients of 69.8% (CI 53-86.5%) and 57.2% (CI 40.3-75%) and of 32.5% (CI 8.5-57.6%) and 11.1% (0-24.4%), respectively. These findings suggest that, for childhood EPD, radical resection should be pursued as much as reasonably possible. Thus, it seems justified proposing for future trials, patient stratification by entity of surgical resection.

Gene transfer of suicide genes for the treatment of malignant gliomas: efficacy, limitations, and perspectives for a combined immunotherapy.

The potential of gene therapy strategies for malignant gliomas that are based on retroviral-mediated transfer of a "suicide gene" such as Herpes Simplex Virus-thymidine kinase HSV-tk and subsequent treatment by a prodrug (ganciclovir, for example), has been emphasized by the promising results obtained by several groups. However, further experimental data as well as preliminary clinical results indicate that the low efficiency of retroviral-mediated gene transfer in vivo as well as difficulties for the diffusion of the prodrug inside the tumour mass can limit the efficacy of this form of gene therapy. To achieve a more effective limitation of tumour growth other approaches may be combined with the "suicide gene" strategy and the enhancement of the immunological response to the tumour by cytokine gene transfer is prominent among these approaches. The authors' experiments in nude mice confirm the antineoplastic role of IL-4 and encourage testing the effects of the simultaneous transfer of IL-4 and HSV-tk genes in immunocompetent animals.

[Anterior cranio-facial resection for malignant tumors: report of 91 cases]. / Resezione cranio-facciale anteriore per tumori maligni: esperienza di 91 casi.

Between 1987 and 1994 we performed 103 anterior cranio-facial resections in patients affected by tumors involving the ethmoid, the nasal cavities and, sometimes, the orbit, the maxillary and sphenoid sinuses. The cibriform plate was always involved. The tumor invaded the frontal dura in 20 patients without intradural neoplastic vegetations. These were present in 6 cases. Ninety-one of these patients had a malignant tumor; from the histologic point of view we had 50 adenocarcinomas, 16 epidermoid carcinomas, 8 estesioneuroblastomas, 6 adenoid cystic carcinomas, 5 melanomas and 6 infrequent types. The surgical technique became simplier in the second half of our patients. Now we perform a coronal skin incision and prepare a pericranial flap without the galea and use it to reconstruct the cranial base defect without bone or alloplastic material. The frontal craniotomy is rectangular, low and made by an oscillating saw without trephine holes. The posterior section of the skull base for a typical ethmoid tumor is always on the sphenoid roof and the lateral ones on the medial third of the orbital roof, al least in the more interested side. The anterior section is on the frontal sinus floor. The osteotomies may be enlarged according to tumor extension. Our facial incision is paranasal without splitting of the upper lip, but sometimes we used wider skin incisions and osteotomies for tumors involving the maxillary sinus and palate. We had many important complications in the first half of out patients with 7 postoperative deaths but none in the second half. Fifty-five percent of the adenocarcinomas, 7% of the epidermoid carcinomas, 75% of the estesioneuroblastomas, 100% of the adenoid cystic carcinomas and 0% of the melanomas are alive and well. Forty-six patients were previously treated elsewhere and 45 were untreated. The cure rate of these two groups of patients is very different: 38.1% of the first versus 61.9% of the second ones are alive and free of disease. Our experience proves that every transfacial or transnasal resection of an ethmoidal tumor involving the cribriform plate must be avoided.

Triventricular hydrocephalus: review of 71 cases evaluated at the Istituto Neurologico "C. Besta" Milan over the last 10 years.

The authors review 71 patients with triventricular hydrocephalus in whom a contrast-enhanced CT scan did not show any tumoral or vascular lesion that could have caused the hydrocephalus. The patients were subdivided into three age groups. The results of the neuroradiological examination, the surgical treatment, and the complications of the shunt procedure are analyzed, with special reference to the high number (13) of periaqueductal alterations of signal pattern found on MRI (interpreted as a "slow growing" neoplasm) and to the incidence and causes of shunt malfunction.

Cerebral germ cell tumor and XXY karyotype.

Metaphases from a cultured cerebral germ cell tumor (CGCT) in a boy with a 46,XY constitutional karyotype had 47 chromosomes with an additional X chromosome and a translocation (1;21)(q11;p11). CGCT appear to be nonrandomly associated with Klinefelter syndrome, and a supernumerary X chromosome and trisomy of the 1q21-->1qter region may be clonal abnormalities in these tumors. The predisposition of Klinefelter patients to develop CGCT may be due to the pathogenetic relevance of the extra X chromosome both as an acquired and a constitutional abnormality.

Clinical features and MR imaging in children with repaired myelomeningocele.

The aim of the study is to define the role of associated malformations in the clinical evolution of children affected by myelomeningocele. MRI investigation of the spinal cord was carried out on 25 patients between the age of 7.3 and 18.10 with MMC repaired and followed up for at least 7 years. The relation between associated malformations demonstrated by MRI and clinical trend was analysed. The results are the following: 1) presence of asymptomatic tethered cord in all cases; 2) high frequency (92%) of Chiari malformation; 3) presence of syringomyelia in 20% of patients, symptomatic in 1; 4) presence of ventricular enlargement in 72% of cases without increased intracranial pressure syndrome. For a better therapeutic approach prospective MRI studies are needed in order to follow up associated malformations.

Neoadjuvant chemotherapy in the treatment of recurrent glioblastomas (GBM).

We wondered whether second line chemotherapy in recurrent GBM patients might be useful for debulking the tumor mass and improving patient performance status to prepare the way for second surgical intervention. We have treated 18 recurrent glioma patients with high dose methotrexate (HDMTX) plus 5-fluorouracil (5FU). 5 Patients were responders, 6 had stable disease, and 7 disease progression. 5 patients, 3 PRs and 2 SDs, underwent a second operation after two chemotherapy cycles. Disease progression resumed at 11.5 +/- 7 weeks in the non reoperated patients, and at 32.6 +/- 9.3 weeks in the reoperated group from initiation of neoadjuvant treatment. Survival time in reoperated patients was 82.6 weeks. Although our experience with this policy is still limited, we believe that reoperation in selected recurrent GBM patients can be worthwhile.

Cisplatin and etoposide combination therapy for primary glial tumors: preliminary results.

In this preliminary trial we studied 29 patients with primary malignant glial tumors to investigate the effectiveness of cisplatin combined with etoposide on these tumors. Hyperfractionated radiation therapy was given in the course of chemotherapy. The time to tumor progression in these glioblastoma multiforme (GBM) patients encouraged us to continue this treatment in a phase III study.