Targeting adrenomedullin receptors with systemic delivery of neutralizing antibodies inhibits tumor angiogenesis and suppresses growth of human tumor xenografts in mice.

Adrenomedullin (AM) is a multifunctional peptide vasodilator that transduces its effects through calcitonin receptor-like receptor/receptor activity modifying protein-2 and -3 (CLR/RAMP2 and CLR/RAMP3). Previously, we reported on the development of an anti-AM antibody that potently inhibits tumor cell proliferation in vitro and tumor growth in vivo. Here, we report the effect of anti-AM receptor antibodies (alphaAMRs) on angiogenesis and tumor growth. We demonstrate that alphaAMRs decrease in a dose-dependent manner the growth of U87 glioblastoma cells and HT-29 colorectal cancer cells, but not A549 lung cancer cells, in vitro. In vivo, AM in Matrigel plugs induces angiogenesis by promoting recruitment of endothelial cells, pericytes, myeloid precursor cells, and macrophages and by promoting channel formation. Remarkably, systemic administration of alphaAMRs every 3 d markedly reduced neovascularization of Matrigel plugs in a dose-dependent fashion, as demonstrated by reduced numbers of the recruited cells and vessel structures. Several human tumor xenografts in athymic mice were used to examine the effect of alphaAMR treatment on tumor angiogenesis and growth. AlphaAMR treatment significantly suppressed the growth of glioblastoma, lung, and colon tumors. Histological examination of alphaAMR-treated tumors showed evidence of disruption of tumor vascularity with decreased microvessel density, depletion of endothelial and pericyte cells, and increased tumor cell apoptosis. These findings support the conclusion that alphaAMR treatment inhibits tumor growth by suppression of angiogenesis and tumor growth and suggest that AMRs may be useful therapeutic targets.

Successful treatment of a giant isolated cerebral mucormycotic (zygomycotic) abscess using endoscopic debridement: case report and therapeutic considerations.

BACKGROUND: Cerebral mucormycosis without rhino-orbital or systemic involvement is an extremely rare condition mostly associated with parenteral drug abuse. CASE DESCRIPTION: We report the case of a 42-year-old woman who presented with hemiparesis of the left side and altered mental status. Neuroradiologic workup demonstrated an inflammatory lesion involving the right basal ganglia. Proton magnetic resonance spectroscopy demonstrated features consistent with a pyogenic abscess. Computed tomography-guided stereotactic biopsy led to the diagnosis of cerebral mucormycosis. Parenteral AMB-L treatment was conducted, but the patient worsened clinically, presenting with a complete hemiplegia, and cerebral magnetic resonance imaging (MRI) scans demonstrated a voluminous abscess formation. Then, under stereotactic guidance, a surgical endoscopic debridement of the abscess cavity associated with the placement of an Ommaya reservoir was performed. Systemic and intralesional treatment with AmB associated with an adjunctive immune therapy was conducted. At 3-year follow-up, the patient had recovered partially from her left hemiplegia, allowing her to walk without help, and cerebral MRI scans showed complete resorption of the abscess. CONCLUSION: Our good results suggest that surgical endoscopic debridement associated with intravenous and intracavitary antifungal therapy might be valuable in treating voluminous deep-seated mucormycotic lesions.

Open kyphoplasty for management of metastatic and severe osteoporotic spinal fracture. Technical note.

OBJECT: Elderly patients in poor general health frequently suffer vertebral body (VB) fractures due to osteoporosis or vertebral metastatic lesions. Kyphoplasty and vertebroplasty have become the standard treatment for these types of fractures. In certain conditions that cause local kyphosis, such as spinal cord compression due to a metastatic epidural tumor or the shortening of the spinal canal secondary to vertebral compression, the surgical treatment should provide decompression and stabilization during a short intervention. In this study the authors evaluated a surgical technique that frequently combines a same-session surgical decompression, such as a laminectomy, and posterior instrumentation-assisted stabilization during the same open intervention in which the VB is stabilized by kyphoplasty. METHODS: During an 18-month period, the authors treated 18 patients with VB fractures according to this protocol: 14 patients with vertebral metastatic lesions and four with osteoporosis. The patients' mean age was 60 years. All suffered severe pain preoperatively (mean visual analog scale [VAS] score of 7). Fourteen of the 18 patients suffered a neurological deficit. Twenty-three vertebral levels were treated; in 15 patients it was necessary to place posterior instrumentation. The mean duration of the intervention was 90 minutes. Pain in all patients improved 3 days after the intervention, and the mean VAS score decreased to 2. Patients with a neurological dysfunction improved. The mean quantity of injected cement for the kyphoplasty procedure was 7 ml. The mean duration of hospitalization was 7 days. Neuroimaging revealed cement leaks in two cases: one into the disc interspace and one anteriorly into the fractured part of the vertebra. After the intervention, most patients with metastatic lesions underwent radiotherapy. No procedure-related complications occurred. CONCLUSIONS: This procedure allows decompression of the spinal cord, consolidation of the VB and thus a stabilization of the vertebral column, and may provide an alternative treatment to invasive VB excision in patients in poor general health.

Use of a self-expanding stent with balloon angioplasty in the treatment of dural arteriovenous fistulas involving the transverse and/or sigmoid sinus: functional and neuroimaging-based outcome in 10 patients.

OBJECT: The goal of this study was to evaluate the clinical and angiography results in 10 patients with transverse-sigmoid dural arteriovenous fistulas (DAVFs) treated using sinus angioplasty and dural sinus stent insertion. METHODS: Between 2001 and 2003, 10 consecutive patients (six men and four women, age range 54-79 years) who had presented with transverse and/or sigmoid sinus DAVFs with or without sinus thrombosis underwent self-expanding stent placement and balloon angioplasty. Eight fistulas involved the transverse sinus, three the sigmoid sinus, and one the torcular and occipital sinuses. According to the Djindjian-Merland grading system, there were two Type I, five Type Ila, one Type Ilb, and two Type IV DAVFs. The mean clinical follow-up period was 21.1 months. At the last follow-up examination, seven patients were asymptomatic and three were dramatically improved. The mean angiography follow-up period was 7.5 months for the available population: four patients had complete DAVF occlusion, four had significant flow reduction, and two who experienced clinical improvement refused conventional angiography control studies. Delayed computerized tomography angiography scans were obtained to evaluate stent permeability in nine of the 10 patients. Stent permeability was demonstrated in eight of the nine patients with available control studies at a mean follow up of 20.8 months. There were two transient neurological deficits but no severe and permanent complications. CONCLUSIONS: In this series, sinus stent insertion resulted in a cure or significant clinical improvement in all patients harboring a DAVF, with no severe or permanent complication. Stent placement for transverse and/or sigmoid sinus DAVFs is a promising technique whose viability should be confirmed in larger series with longer follow-up periods.

Differential regulation of proopiomelanocortin and pituitary-restricted transcription factor (TPIT), a new marker of normal and adenomatous human corticotrophs.

Since the identification of the pituitary-restricted transcription factor Tpit, a novel T-box factor that is only present in mouse in the two pituitary proopiomelanocortin (POMC)-expressing lineages, no information was available on its pattern of expression in human pituitary. We investigated by immunohistochemistry and in situ hybridization the expression of TPIT in normal human anterior pituitary tissue and in several types of human pituitary adenomas (n = 52). TPIT expression was restricted to the nucleus of normal or adenomatous human corticotroph cells. No specific TPIT immunostaining was detectable in all prolactin (PRL)-, GH-, or gonadotropin-secreting adenomas. In situ hybridization studies demonstrated that TPIT transcripts were coexpressed with POMC mRNA in both secreting and silent corticotroph adenomas, and in normal corticotrophs, whereas TPIT mRNA was not detectable in other types of pituitary adenomas. Unlike POMC, TPIT was not up-regulated by adrenalectomy in rats and did not seem down-regulated in the normal pituitary adjacent to human corticotroph microadenomas. TPIT is the only currently known transcription factor selectively expressed in human normal and adenomatous corticotrophs. In human and experimental models, TPIT and its target gene POMC were thus differentially regulated by glucocorticoids. Moreover, TPIT represents a new marker of POMC-expressing pituitary cells.

PAI-1 and EGFR expression in adult glioma tumors: toward a molecular prognostic classification.

PURPOSE: Molecular classification of gliomas is a major challenge in the effort to improve therapeutic decisions. The plasminogen activator system, including plasminogen activator inhibitor type 1 (PAI-1), plays a key role in tumor invasion and neoangiogenesis. Epidermal growth factor receptor (EGFR) is involved in the control of proliferation. The contribution of PAI-1 and EGFR to the survival of gliomas was retrospectively investigated. METHODS AND MATERIALS: Fifty-nine adult gliomas treated by neurosurgery and conventional irradiation were analyzed, including 9 low-grade (2) and 50 high-grade (3-4) tumors (WHO classification). PAI-1 was measured on cytosols and EGFR on solubilized membranes using ELISA methods. RESULTS: High PAI-1 levels were strongly associated with high histologic grade (p < 0.001) and histologic necrosis (p < 0.001). PAI-1 also correlated positively with patient age (p = 0.05) and negatively with Karnofsky index (p = 0.01). By univariate analysis of the high-grade population, higher PAI-1 (p < 0.0001) and EGFR values (p = 0.02) were associated with shorter overall survival. Only PAI-1 was an independent factor in multivariate analysis. Grade 3 tumors with low PAI-1 (100% 3-year overall survival rate) presented the same clinical outcome as the low-grade tumors. CONCLUSIONS: In this prognostic study, PAI-1 and EGFR expression revealed similarities and differences between high-grade gliomas that were not apparent by traditional clinical criteria. These data strongly support that biologic factors should be included in glioma classification and the design of clinical trials to treat more homogeneous populations.

Endoscopic third ventriculostomy for treatment of noncommunicating syringomyelia associated with a Chiari I malformation and hydrocephalus: case report and pathophysiological considerations.

OBJECTIVE AND IMPORTANCE: A Chiari I malformation associated with syringomyelia and hydrocephalus is a rare condition. We report the successful use of endoscopic third ventriculostomy for the treatment of this pathological entity. The successful use of this technique in such a case has not been previously described, and the results allow us to speculate on the pathophysiological mechanism involved. CLINICAL PRESENTATION: A 34-year-old woman presented with headaches, a motor deficit of the right upper limb, and gait dyspraxia. Magnetic resonance imaging scans demonstrated dilation of all ventricles, compression of the retrocerebellar cerebrospinal fluid space, downward displacement of the tonsils, and syringomyelia. Syringomyelia involved the cervicodorsal cord below C3, with a syrinx-free segment between C1 and C3 and no enlargement of the rostral part of the central canal. INTERVENTION: Endoscopic third ventriculostomy resulted in prompt improvement of the clinical symptoms. Postoperative magnetic resonance imaging scans demonstrated shrinkage of the syrinx and return of the cerebellar tonsils to their physiological positions. CONCLUSION: This experience demonstrates that endoscopic third ventriculostomy, which is a simple, safe technique, may be the treatment of choice for associated Chiari I malformations, hydrocephalus, and syringomyelia (even the noncommunicating type).

Intracranial meningeal melanocytoma associated with ipsilateral nevus of Ota. Case report.

In this report, the authors review the case of a man with a neurocutaneous syndrome. He presented with an intracerebral melanocytoma associated with a blue nevus of the scalp; its location and its appearance during childhood supported the diagnosis of a nevus of Ota. Meningeal melanocytomas are increasingly being diagnosed, but remain rare. Primary meningeal malignant melanoma is the first differential diagnosis to eliminate. Despite their common embryonic origin. the association of a melanocytoma with a nevus of Ota is rare. A nevus of Ota exhibits the same melanocytic proliferation and affects the trigeminal nerve territory. An ocular effect is not always observed. In contrast to an ocular lesion, a nevus of Ota rarely transforms into a malignant melanoma. It is found only among caucasians. During 4 years of follow-up review after surgery, the patient remained asymptomatic. Other than antiepileptic therapy, he received no complementary treatment and cerebral imaging revealed no evidence of recurrence.

Cervicosternotomy as an anterior approach to the upper thoracic and cervicothoracic spinal junction.

OBJECT: The cervicothoracic junction is always a difficult area to approach. When operating on this specific area (for tumor or trauma), the aim is generally to decompress and stabilize the spine. The authors describe an improved median sternotomy method for reaching the anterior aspect of the spine down to T-5. METHODS: Seven patients with a mean age of 40 years (range 17-68 years) were included in this study. The vertebral lesion was due to trauma in 4 cases and tumor in the other 3. A single vertebral body was involved in 2 cases, 2 in 3 cases, and 3 in 2 cases. The vertebra most often involved was T-3 (6 cases), although T-4 was involved in 2 cases, T-5 in 2 cases, and T-1 and T-2 in 1 case each. All patients underwent the same preoperative workup: CT scanning, MR imaging, and CT angiography of the aortic arch. RESULTS: The median sternotomy made it possible to effectively decompress and stabilize the spinal cord. An anterior screw plate was used in 5 cases. The plate extended from T-2 to T-5 in 3 cases, from T-2 to T-4 in 2 cases, and from C-7 to T-4 in 1 case. The mean duration of surgery was 195 minutes (range 180-240 minutes). No neurological deterioration occurred. The mean hospital stay was 8 days (range 6-15 days). In 2 cases (28.6%), recurrent left nerve palsy was observed postoperatively; the palsy was transient in both of these cases, and full recovery occurred within 3 months. The mean follow-up among this series of patients was 29 months (range 22-38 months). CONCLUSIONS: The median sternotomy provided a good means of reaching the upper thoracic spine (T2-5) and cervicothoracic junction. It enables surgeons to decompress the spinal cord and stabilize the spine.

Brown-Sequard-type myelopathy due to cervical disc herniation associated with severe carotid stenosis prompting rapid combined corpectomy and carotid endarterectomy under deep anticoagulant therapy.

BACKGROUND CONTEXT: The risk of stroke because of carotid retraction during an anterior cervical spine surgery as well as the risk of bleeding complications after an anterior cervical corpectomy under deep anticoagulation and antiplatelet therapy is a surgical issue poorly addressed in the literature. PURPOSE: To describe the feasibility and safety of a simultaneous carotid endarterectomy and anterior corpectomy and fusion under deep anticoagulation in a patient with a cervical spinal cord compression and a severe carotid artery stenosis. STUDY DESIGN: Case report. METHODS: The authors describe the case of a 79-year-old man who had a 1-month history of progressive pain in the neck and left arm, associated with progressive weakness in the left arm and leg. He also presented a history of coronaropathy and bilateral severe carotid stenosis for which he was receiving a regimen of antiplatelet therapy. RESULTS: The cervical magnetic resonance imaging demonstrated a C4-C5 disc herniation migrating down to C5. His condition worsened rapidly during hospitalization prompting a rapid decompression. Given the necessity of a C5 corpectomy and the risk of stroke during anterior cervical spine surgery, it was therefore decided to undertake the surgical procedure under efficient anticoagulant and antiplatelet therapy. A combined endarterectomy and spinal decompression and fusion were then performed. The postoperative course was uneventful, and the patient recovered neurologically. CONCLUSIONS: This case suggests that such a combined carotid endarterectomy and cervical corpectomy with fusion under anticoagulant and antiplatelet therapy is feasible. However, even if the unique clinical presentation of our patient led us to undertake such a surgical strategy, therapeutic decision in patients presenting with both severe carotid stenosis and cervical spinal cord compression should rely on a case-by-case analysis.

Management of large vestibular schwannomas by combined surgical resection and gamma knife radiosurgery.

In this report, we evaluated the treatment results of a combination of surgery and radiosurgery for large vestibular schwannomas. The series of 8 patients included in this study underwent surgery followed by radiosurgical treatment between January 2000 and January 2006. The patients included 5 males and 3 females aged 24-78 years (mean age: 53 years). The average maximum diameter of the tumor was 40 (35-45) mm. At the time of radiosurgery, the treatment size became 18 (9-20) mm. The mean peripheral dose administered was 11.8 (range 11-13) Gy, and the mean dose administered in the centre of the tumor was 23.75 (22-26) Gy. The mean follow-up period was 46 months after radiosurgery. Excellent facial nerve function (House-Brackmann grade 1 or 2) was preserved in 7/8 patients (87.5%). In the case of large vestibular schwannomas, the combined management is one option for maintaining cranial nerve function and tumor growth control.

Solitary fibrous tumors of the central nervous system: clinicopathological and therapeutic considerations of 18 cases.

OBJECTIVE: This is a retrospective study of 18 patients harboring a solitary fibrous tumor of the central nervous system. Therapeutic management and outcome were analyzed. METHODS: Between 1999 and 2004, 18 patients harboring central nervous system solitary fibrous tumors were surgically treated at our two institutions. There were nine men and nine women. The patient ages ranged from 33 to 75 years, with a median age of 56.1 years. The locations were spinal in six cases (33.3%), the posterior fossa in six cases (33.3%), supratentorial in four cases (22.2%), and orbital in two cases (11.2%). RESULTS: The median follow-up period was 45.3 months. Gross total resection was achieved in 10 cases (55.6%); tumor recurrence or progression occurred in nine cases (50%). Incomplete surgical resection was significantly associated with recurrence (P = 0.018). On univariate analysis, extent of surgery was also associated with a longer progression-free survival (P = 0.05). No statistically significant correlation can be found between histological features and recurrence. CONCLUSION: Prognosis of solitary fibrous tumors of the central nervous system remains unclear; consequently, careful and close monitoring of patients and long-term follow-up are mandatory. Radical surgical excision seems to be a significant and reliable prognosis factor, although pathological prognostic features must be defined. In other respects, the role of postoperative radiotherapy in atypical or incompletely resected solitary fibrous tumors of the central nervous system remains to be determined and, therefore, warrants larger series with longer follow-up periods.

Brainstem metastases: management using gamma knife radiosurgery.

OBJECTIVE: Brainstem metastasis is an uncommon complication of systemic cancer, generally considered to have a highly unfavorable prognosis. Surgical risks are high and standard radiation or chemotherapy have little effect. The purpose of this study is to evaluate our experience using Gamma Knife radiosurgery (GKRS) for the management of brainstem metastasis. METHODS: Between July 1992 and March 2001, we treated 28 patients with brainstem metastasis using GKRS. Lesions were located in the pons in 17 patients, midbrain in nine, and medulla oblongata in two. At time of the radiosurgery, eight patients presented with another supratentorial metastasis. The most frequent primary tumor site was the lung (13 cases) followed by the melanoma in four cases, the kidney in two, and other locations in six. Only six patients underwent fractionated whole-brain radiation therapy. Mean marginal radiation dose for GKRS was 19.6 Gy (range, 11-30). Mean maximum diameter was 17.2 mm (range, 10-30). RESULTS: No GKRS-related morbidity was observed. Local tumor control was achieved in 92% of patients. Twenty-six patients have died. Death was related to the progression of the brainstem lesion in two cases. Mean and median survival after GKRS were 10.2 and 12 months, respectively. Follow-up periods in the two surviving patients were 12 and 13 months. CONCLUSION: The results of this small series demonstrate that GKRS can be a valuable modality for safe and effective management of brain stem metastasis. Owing to the high risk of surgical resection and low efficacy of medical treatment, radiosurgery can be proposed upfront.

Evaluation of fractionated radiotherapy and gamma knife radiosurgery in cavernous sinus meningiomas: treatment strategy.

OBJECTIVE: To investigate the respective role of fractionated radiotherapy (FR) and gamma knife stereotactic (GKS) radiosurgery in cavernous sinus meningioma (CSM) treatment. METHODS: The authors report the long-term follow-up of two populations of patients harboring CSMs treated either by FR (Group I, 38 patients) or GKS radiosurgery (Group II, 36 patients). There were 31 females with a mean age of 53 years in Group I and 29 females with a mean age of 51.2 years in Group II. In 20 patients (Group I) and 13 patients (Group II), FR and GKS radiosurgery were performed as an adjuvant treatment. In 18 patients (Group I) and in 23 patients (Group II), FR and GKS radiosurgery were performed as first line treatment. In our early experience with GKS radiosurgery (1992, date of gamma knife availability in the department), patients with tumors greater than 3 cm, showing close relationship with the optic apparatus (<3 mm) or skull base dural spreading, were treated by FR. Secondarily, with the advent of new devices and our growing experience, these criteria have evolved. RESULTS: The median follow-up period was 88.6 months (range, 42-168 mo) for Group I and 63.6 months (range, 48-92 mo) for Group II. According to Sekhar's classification, 26 (68.4%) patients were Grade III to IV in Group I and 10 (27.8%) patients in Group II (P < 0.05); 23 (60.5%) patients had extensive lesions in Group I and 7 (19.4%) patients in Group II (P < 0.05). Mean tumor volume was 13.5 cm in Group I and 5.2 cm in Group II (P < 0.05). Actuarial progression-free survival was 94.7% and 94.4% in Group I and II, respectively. Clinically, improvement was seen for 24 (63.2%) patients in Group I and for 21 (53.8%) patients in Group II (P > 0.05). Radiologically, 11 (29%, Group I) patients and 19 (Group II, 52.7%) patients showed tumor shrinkage (P = 0.04). Transient morbidity was 10.5% in Group I and 2.8% in Group II. Permanent morbidity was 2.6% in Group I and 0% in Group II. CONCLUSION: FR and GKS radiosurgery are safe and efficient techniques in treatment of CSMs, affording comparable satisfactory long-term tumor control. However, GKS radiosurgery provides better radiological response, is far more convenient, and fits into most patients lives much better than FR. Therefore, in the authors' opinion, GKS radiosurgery should be advocated in first intention for patients with CSMs, whereas conventional radiotherapy should be reserved for cases that are not amenable to this technique, thus making these two therapeutic modalities not alternative but complementary tools in CS meningioma treatment strategy.

An unusual presentation of a lumbar synovial cyst: case report.

STUDY DESIGN: A case of intraforaminal synovial cyst is reported. OBJECTIVES: To stress the importance of the way intraforaminal synovial cyst, a very rare condition, causes a peculiar position of the nerve root in the foramen and to describe the required surgical approach. SUMMARY OF BACKGROUND DATA: Intraforaminal synovial cyst is a highly unusual finding. The existence of this rare entity raises the problem of differential diagnosis with other space-occupying lesions of the neural foramen, such as herniated disc, neurinoma, neurofibroma, and metastatic lesions METHODS AND RESULTS: A 64-year-old woman suffered a right L4 radiculopathy with motor deficit. Computed tomography showed a space-occupying lesion in the L4-L5 foramen isodense with the disc. Magnetic resonance images showed a right intraforaminal cystic lesion at the L4-L5 level with no enhancement after intravenous infusion of gadolinium. A 3-cm cystic lesion, which appeared to arise from the L4-L5 facet joint without direct communication, was excised from the L4-L5 foramen. In contrast with intraforaminal disc herniation, downward displacement of the L4 nerve root was observed. Two months after surgery, the patient was pain-free and neurologic examination revealed no motor deficit. CONCLUSIONS: An unusual intraforaminal presentation of a lumbar synovial cyst demonstrates the importance of considering this entity and of adapting the surgical technique to avoid injury to the nerve root.

Effects of adrenomedullin on endothelial cells in the multistep process of angiogenesis: involvement of CRLR/RAMP2 and CRLR/RAMP3 receptors.

Recently, we demonstrated that U87 glioblastoma xenograft tumors treated with anti-adrenomedullin (AM) antibody were less vascularized than control tumors, suggesting that AM might be involved in neovascularization and/or vessel stabilization. Angiogenesis, the sprouting of new capillaries from preexisting blood vessels, is a multistep process that involves migration and proliferation of endothelial cells, remodeling of the extracellular matrix and functional maturation of the newly assembled vessels. In our study, we analyzed the role of AM on human umbilical vein endothelial cell (HUVEC) phenotype related to different stages of angiogenesis. Here we report evidence that AM promoted HUVEC migration and invasion in a dose-dependent manner. The action of AM is specific and is mediated by the calcitonin receptor-like receptor/receptor activity-modifying protein-2 and -3 (CRLR/RAMP2; CRLR/RAMP3) receptors. Furthermore, AM was able to induce HUVEC differentiation into cord-like structures on Matrigel. Suboptimal concentrations of vascular endothelial growth factor (VEGF) and AM acted synergistically to induce angiogenic-related effects on endothelial cells in vitro. Blocking antibodies to VEGF did not significantly inhibit AM-induced capillary tube formation by human endothelial cells, indicating that AM does not function indirectly through upregulation of VEGF. These findings suggest that the proangiogenic action of AM on cultured endothelial cells via CRLR/RAMP2 and CRLR/RAMP3 receptors may translate in vivo into enhanced neovascularization and therefore identify AM and its receptors acting as potential new targets for antiangiogenic therapies.

Histological and MR correlations in Gliomatosis cerebri.

The diagnosis of Gliomatosis cerebri (GC) is known to be difficult and is still a matter of debate. In order to better define this entity, we studied clinical, neuroradiological, pathological and follow-up data of 9 patients affected with GC. MRI were done with T1 before and after gadolinium injection, and with T2-weighted images and Flair in 3 cases. Histological confirmation of glial proliferation was obtained in all patients by craniotomy or stereotactic biopsies. Patients were treated and followed-up in our center. The histological analyses highlighted a heterogeneous glial proliferation with various degrees of anaplasia in all the cases including 2 cases of oligodendroglioma, 1 case of anaplastic oligodendroglioma, 2 cases of anaplastic mixed oligoastrocytoma, 1 case of anaplastic astrocytoma, 2 cases of glioblastoma and 1 case of astrocytic proliferation typical of GC. The topography of the tumoral infiltration was characteristic involving mainly the white matter, basal ganglia and thalamus, brainstem and less often hypothalamus. More than two cerebral lobes were involved. Contrast enhancement, mass effect and necrosis were minimal compared to the extent of tumoral infiltration. Patients were treated with various schemes of treatment all including nitrosourea. Survival from diagnosis was under one year except for 2 patients (17 and 14 months). This study shows that the diagnosis of GC needs to be based not on pathological data alone, but on pathological, clinical and, above all, on radiological criteria. Response to therapy could not clearly be observed in GC, despite oligodendroglial component in 6/9 cases. Prognosis of GC was constantly poor.

Neutralization of adrenomedullin inhibits the growth of human glioblastoma cell lines in vitro and suppresses tumor xenograft growth in vivo.

Presently, there is no effective treatment for glioblastoma, the most malignant and common brain tumor. Growth factors are potential targets for therapeutic strategies because they are essential for tumor growth and progression. Peptidylglycine alpha-amidating monooxygenase is the enzyme producing alpha-amidated bioactive peptides from their inactive glycine-extended precursors. The high expression of peptidylglycine alpha-amidating monooxygenase mRNA in glioblastoma and glioma cell lines points to the involvement of alpha-amidated peptides in tumorigenic growth processes in the brain. After screening of amidated peptides, it was found that human glioblastoma cell lines express high levels of adrenomedullin (AM) mRNA, and that immunoreactive AM is released into the culture medium. AM is a multifunctional regulatory peptide with mitogenic and angiogenic capabilities among others. Real-time quantitative reverse transcriptase-polymerase chain reaction analysis showed that AM mRNA was correlated to the tumor type and grade, with high expression in all glioblastomas analyzed, whereas a low expression was found in anaplastic astrocytomas and barely detectable levels in low-grade astrocytomas and oligodendrogliomas. In the present study we also demonstrate the presence of mRNA encoding the putative AM receptors, calcitonin receptor-like receptor/receptor activity-modifying protein-2 and -3 (CRLR/RAMP2; CRLR/RAMP3) in both glioma tissues and glioblastoma cell lines and further show that exogenously added AM can stimulate the growth of these glioblastoma cells in vitro. These findings suggest that AM may function as an autocrine growth factor for glioblastoma cells. One way to test the autocrine hypothesis is to interrupt the function of the endogenously produced AM. Herein, we demonstrate that a polyclonal antibody specific to AM, blocks the binding of the hormone to its cellular receptors and decreases by 33% (P < 0.001) the growth of U87 glioblastoma cells in vitro. Intratumoral administration of the anti-AM antibody resulted in a 70% (P < 0.001) reduction in subcutaneous U87 xenograft weight 21 days after treatment. Furthermore, the density of vessels was decreased in the antibody-treated tumors. These findings support that AM may function as a potent autocrine/paracrine growth factor for human glioblastomas and demonstrate that inhibition of the action of AM (produced by tumor cells) may suppress tumor growth in vivo.

Phase II study of temozolomide without radiotherapy in newly diagnosed glioblastoma multiforme in an elderly populations.

BACKGROUND: Currently, the survival of patients age > 70 years with glioblastoma multiforme (GBM) ranges from 4 months to 6 months, although radiotherapy and/or chemotherapy may prolong survival in certain subgroups. Temozolomide is an oral chemotherapeutic agent with efficacy against malignant gliomas and a favorable safety profile. This open-label, single-center, Phase II study was designed to evaluate the efficacy and safety of temozolomide as first-line chemotherapy and exclusive treatment in elderly patients with newly diagnosed GBM. METHODS: Chemotherapy-naïve patients (age > 70 years) were treated with temozolomide at a dose of 150-200 mg/m(2) per day for 5 consecutive days of a 28-day cycle until they developed disease progression. No radiation therapy was administered. The primary endpoint was median overall survival (OS); secondary endpoints included progression-free survival (PFS) and toxicity. RESULTS: Thirty-two patients (median age, 75 years; median Karnofsky performance status, 70) experienced a median OS of 6.4 months and a median PFS of 5.0 months. Of 29 patients who were assessed for response, 9 patients (31%) achieved a partial response, 12 patients (41%) maintained stable disease, and 8 patients (28%) developed progressive disease. Adverse events primarily were mild, with NCI CTC Grade 3-4 thrombocytopenia and neutropenia reported to occur in 6% and 9% of patients, respectively. No neurotoxicity was observed. Treatment delays and dose reductions occurred in 13% and 14% of cycles, respectively. CONCLUSIONS: Temozolomide represents a safe, easily administered, and effective therapeutic approach for elderly patients with newly diagnosed GBM.