Prospective study of carmustine wafers in combination with 6-month metronomic temozolomide and radiation therapy in newly diagnosed glioblastoma: preliminary results.

OBJECT: Locoregional chemotherapy with carmustine wafers, positioned at surgery and followed by radiation therapy, has been shown to prolong survival in patients with newly diagnosed glioblastoma, as has concomitant radiochemotherapy with temozolomide. A combination of carmustine wafers with the Stupp treatment regimen has only been investigated in retrospective studies. METHODS: In a single-institution prospective study, the authors assessed 12-month progression-free survival (PFS), toxicity, and overall survival in patients with glioblastoma treated with surgery, carmustine wafers, radiotherapy, and 6-month metronomic temozolomide chemotherapy. Thirty-five patients with de novo glioblastoma, between the ages of 18 and 70 years, and with Karnofsky Performance Scale scores of at least 70, were included in the study. Patients were followed monthly and assessed using MRI every 2 months. RESULTS: After a median follow-up of 15 months, the median time to tumor progression was 12.5 months and median survival was 17.8 months. Due to toxicity (mostly hematological), 7 patients had to prematurely stop temozolomide treatment. Twenty-two patients developed Grade 3 CD4(+) lymphocytopenia. Three patients developed oral-esophageal candidiasis, 2 developed pneumonia, and 1 developed a dorsolumbar zoster. Early intracranial hypertension was observed in 1 patient, and 1 was treated empirically for suspected brain abscess. One patient died of Legionella pneumonia soon after repeat surgery. CONCLUSIONS: Overall, this treatment schedule produced promising results in terms of PFS without a marked increase in toxicities as compared with the Stupp regimen. However, the gain in median survival using this schedule was less clear. Only prospective comparative trials will determine whether these preliminary results will translate into a long-term survival advantage with an acceptable toxicity profile.

Expression profile of frizzled receptors in human medulloblastomas.

Secreted WNT proteins signal through ten receptors of the frizzled (FZD) family. Because of the relevance of the WNT/ß-catenin (CTNNB1) signaling pathway in medulloblastomas (MBs), we investigated the expression of all ten members of the FZD gene family (FZD1-10) in 17 human MBs, four MB cell lines and in normal human cerebellum, using real-time PCR. We found that FZD2 transcript was over-expressed in all MBs and MB cell lines. Western blot analysis confirmed the expression of FZD2 at the protein level. Moreover, the levels of FZD2 transcript were found to correlate with those of ASPM transcript, a marker of mitosis essential for mitotic spindle function. Accordingly, ASPM mRNA was expressed at a very low level in the adult, post-mitotic, human cerebellum, at higher levels in fetal cerebellum and at highest levels in MB tissues and cell lines. Unlike FZD2, the other FZDs were overexpressed (e.g., FZD1, FZD3 and FZD8) or underexpressed (e.g., FZD7, FZD9 and FZD10) in a case-restricted manner. Interestingly, we did not find any nuclear immuno-reactivity to CTNNB1 in four MBs over-expressing both FZD2 and other FZD receptors, confirming the lack of nuclear CTNNB1 staining in the presence of increased FZD expression, as in other tumor types. Overall, our results indicate that altered expression of FZD2 might be associated with a proliferative status, thus playing a role in the biology of human MBs, and possibly of cerebellar progenitors from which these malignancies arise.

The neurophysiological balance in Chiari type 1 malformation (CM1), tethered cord and related syndromes.

The Chiari malformation (CM) is a syndrome embodied in heterogeneous groups of malformations, spanning from the more benign and known, the CM1, to more complex syndromes such as the rare association with the tethered cord, as spinal lipomas, and the CM2, associated to open spina bifida. The clinical picture may be well expressed and detected at birth or even during intrauterine life, as for CM2, but in the other cases they may run a rather subtle clinical course. The diagnosis of these syndromes is driven by clinical examination and MRI, and it usually requires a multidisciplinary approach in order to plan the therapeutic strategies, such as surgery. Among the diagnostic investigations, the imaging techniques represent the most useful, for their capabilities to detect subclinical lesions, such as syringomyielia and lipoma; the urological investigation is useful to evaluate the urogenital dysfunctions. The neurophysiological investigations represent a non invasive diagnostic procedure to investigate the peripheral nerve, the spinal cord, the brainstem functionalities and more higher brain functions; the nerve conduction studies and the cranial reflexes, the brainstem (BAEP) and the somatosensory (SEPs) evoked potentials (EPs), alone or in combination, can be used for the diagnosis, follow-up and intraoperative monitoring. The most useful diagnostic tools in CM1 are likely represented by the brainstem auditory evoked potentials (BAEPs) and the blink-reflex (BR), while the usefulness of SEPs is still doubtful and debated; in CM2 and tethered cord the neurophysiological techniques can be combined in different ways in order to make a functional balance and to answer specific questions. BAEPs and BR can be useful to investigate the brain stem functionality and SEP to evaluate whether the ascending sensory pathway to the cortex can be hampered at some level; the visual EPs are particularly useful to evaluate the integrity of posterior visual pathway and visual cortex in the case of associated hydrocephalus. In the tethered cord, both nerve conduction study and somatosensory evoked potentials (SEPs) are useful to evaluate motor and sensory dysfunction of the lombosacral roots and nerves and spinal cord for their capability to detect subclinical impairment of conduction along the sensory and motor pathway. Finally, last but not the least, the neurophysiological techniques are remarkably useful during surgery; the intraoperative monitoring (IOM) by means of electromyography and direct nerve stimulation and recordings are able to detect early nerve damage, minimize nerve lesions and optimise the surgical techniques. In the operated children with incomplete removal of lipoma and/or persistent tethering, the recordings of SEP and BAEP are useful to demonstrate a conduction deterioration along the ascending sensory pathway due to increasing tethering of the spinal cord due to somatic growth.

Tethered cord: natural history, surgical outcome and risk for Chiari malformation 1 (CM1): a review of 110 detethering.

The surgical results of this series of occult spina bifida seem better than the natural history registered in the long pre-operative period in terms of neurological deterioration. The major contribution to this result is attributed to neurophysiological monitoring that lowers the risks of permanent damage and increases the percentage of effective detethering. The present series of TCS, due to conus and filar lipoma, documents that CM1 is a really rare association occurring in less than 6% of the patients, despite the low position of conus. The detethering procedure did not influence the tonsillar position, thus excluding the correlation between the tethering and the tonsillar descent. The genetic alteration documented in a girl reinforces the hypothesis of a rare complex polymaformative picture deserving multiple procedures according to the prevailing clinical symptoms.

Second-look surgery for ependymoma: the Italian experience.

OBJECT: Complete ependymoma resection ensures a better prognosis for children with this tumor, but the complete excision of infratentorial ependymomas involves serious risks. Second-look surgery for tumor remnants may be less harmful and enable complete removal. There is a potential, although still unclear, role for neoadjuvant chemotherapy in preparation for further surgery. METHODS: Since 1994, the authors have adopted two successive protocols for intracranial ependymoma, both including a phase of adjuvant chemotherapy for children with surgical tumor remnants with a plan for potential second-look surgery before radiotherapy. RESULTS: In the first protocol, 9 of 63 children underwent further surgery, and 6 became tumor free with no additional sequelae. Their prognosis for progression-free survival and freedom from local relapse was comparable to that of children who were operated on only once. In the second protocol, efforts were made to achieve complete resection and 29 of 110 patients underwent reoperations: 9 after the first surgery, 17 after chemotherapy, and 3 soon after radiotherapy. Fourteen of the 29 patients became tumor free, 1 of them with worsening neurological symptoms. The outcome of the 66 patients who became tumor free after 1 operation was compared with that of the 14 who became tumor free after reoperation. The 3-year progression-free survival of the 66 patients compared with the 14 other patients was 71.4% ± 6.9% and 90% ± 9.5%, respectively; the 3-year freedom from local relapse was 84.7% ± 5.9% and 90% ± 9.5%, respectively; and the 3-year overall survival was 85.9% ± 5.4% and 87.5% ± 11.7%, respectively. CONCLUSIONS: Second-look surgery proved feasible with no major morbidity, and results improved with time. Local tumor control was comparable in patients undergoing 1 or more resections.

Treatment for Chiari 1 malformation (CIM): analysis of a pediatric surgical series.

Children may present a peculiar picture of CIM, as syncopes and acute paraparesis. In a series of 99 children operated for CIM at FINCB there were no major surgical morbidity nor mortality. The preoperative symptoms improved more in this pediatric series than in the adult cases treated at the same institution in the same period; a reason could be the shorter duration of symptoms and another the children plasticity. An untreated nonsyndromic craniosynostosis was present in 10 cases. In our hands, the results of the limited extradural decompression were poor. In some CIM associated with psychiatric symptoms an unexpected improvement was observed after tonsilar resection. The associated Syringomyelia reduced in more than 80% of children and disappeared in a significant number. The rare associated tethered cord (5%) needed a double treatment, detethering by itself being insufficient to treat also tonsillar descent. The clinical symptoms are often more serious in children than in the adults, but the results of surgery, especially on the syrinx, are better.

Neuroradiological diagnosis of Chiari malformations.

Chiari malformations 1, 2, 3 represent different degrees of herniation of posterior fossa content into the cervical canal (Chiari 1 and 2), or through an upper-cervical meningocele (Chiari 3), whereas Chiari 4 anomaly consists of hypoplasia of the cerebellum. Chiari 1 malformation (CM1) is the commonest anomaly; it is probably related to a mesodermal defect that create a congenitally small posterior fossa, subsequent overcrowding of its contents and herniation through the foramen magnum. The diagnosis of CM1 is based on the demonstration of the downward displacement and particular shape of the cerebellar tonsils into the upper cervical spinal canal associated with obliteration of the subarachnoid spaces at the level of the foramen magnum. MRI has a fundamental role in the correct identification of the anatomical aspects of this malformation and associated anomalies and represents the imaging modality of choice.

Angiographically proven cervical venous engorgement: a possible concurrent cause in the pathophysiology of Hirayama's myelopathy.

The objective of this study is to discuss the possible role of cervical posterior epidural plexus engorgement during cervical flexion in the pathogenesis of Hirayama myelopathy. In Hirayama disease, MRI during neck flexion often shows that the posterior dura detaches from the posterior arches compressing the spinal cord. Autopsies demonstrated asymmetric changes in the anterior horns consistent with chronic ischemic damage, attributed to arterial insufficiency during flexion or to microcirculatory changes due to compression by the tight dura. In a 15-year-old patient with 5-year history of distal upper limbs weakness, MRI demonstrated marked venous engorgement of the posterior epidural plexus in cervical flexion, confirmed by angiography. Laminectomy from C3 to C6 with duraplasty was performed. At one-year follow-up, the clinical condition of the patient remained stable. In Hirayama myelopathy, compression of the spinal cord by the tight dura is probably the most important pathogenetic factor. However, venous congestion in flexion might play an additional role in determining spinal cord ischemic changes.

Brainstem cavernomas: long-term results of microsurgical resection in 52 patients.

OBJECTIVE: To review the natural history and the long-term results of microsurgical resection of brainstem cavernous angiomas operated on in one institution. METHODS: A retrospective analysis was conducted of the preoperative and postoperative course in 52 consecutive patients who underwent microsurgical resection of a brainstem cavernoma between 1990 and 2002. The role of sex, age, cavernoma location, size, multiple bleedings, relationships to the pial-ependymal surface, surgical approach, and preoperative magnetic resonance imaging appearance were evaluated as prognostic factors possibly influencing outcome. Discrete data were compared by use of the chi2 test and Fisher's exact test as appropriate. RESULTS: The risk of hemorrhage was 3.8% per patient per year. The rebleeding rate was 34.7%. Nineteen of 29 patients who experienced new neurological deficits after surgery improved over time to their preoperative condition or better. Permanent morbidity was observed in 10 (19%) of 52 patients (follow-up: 1.5-10.5 yr; mean, 4.7 yr; median, 4.3 yr; standard deviation, 0.2 yr). The final Karnofsky Performance Scale score for these 10 patients was 90 in 2 patients, 80 in 2, 70 in 2, 60 in 2, 50 in 1, and 30 in 1. The mortality rate was 1.9%. The incidence of permanent new neurological deficits was lower in the 20 patients whose lesion could be removed through an anterolateral pontine approach (5 versus 29%; P = 0.035). CONCLUSION: Surgical resection is recommended for superficial lesions and for lesions that can be reached through the anterolateral pontine surface. Surgery is also recommended for symptomatic cavernomas with a satellite subacute hematoma.

Combined chemotherapy and radiotherapy for intracranial germinomas in adult patients: a single-institution study.

We report on our experience in the treatment of intracranial germinomas (18 pure germinomas and two germinomas with syncytiotrophoblastic giant cells) according to a strategy of radiotherapy doses and fields reduction after a neoadjuvant chemotherapy (Cisplatin-vinblastine and bleomycin combination). Radiation therapy was delivered after the completion of the third and last course of chemotherapy. For the solitary germinoma the target volume was the gross tumour volume. In the five multifocal germinoma patients the whole ventricle volume was irradiated. For the single disseminated germinoma patient we treated the whole central nervous system. The cumulative doses were 30 Gy for the pure germinomas. For the STGCs, a cumulative dose of 35 Gy was used. The median follow-up was 55 months (range 12-120). 18 patients were alive without recurrence of disease. In the two patients with STGCs the death took place 16 and 35 months after diagnosis.

Association of chromosome 10 losses and negative prognosis in oligoastrocytomas.

Oligoastrocytomas are mixed gliomas harboring different genetic alterations and with heterogeneous clinical evolution. We have looked for correlations between genetic losses and clinical evolution in 34 oligoastrocytomas. Loss of heterozygosity (LOH) with different microsatellite markers was studied on chromosomes 1p, 10q, 17p, and 19q. LOH on 1p was found in 44% of the tumors, on 10q in 24%, on 17p in 18%, and on 19q in 38%. LOH on 1p and 19q was combined in 29% of the patients. LOH on 1p was associated with significantly longer overall survival (p = 0.0092) and LOH on 10q with shorter overall survival (p = 0.0206). The observation that LOH on 10q predicts a short survival in oligoastrocytomas is novel and provides further evidence that genetic analysis may help to predict the clinical evolution of different gliomas, giving a more rationale basis to therapeutic options.