New clinical, pathological and molecular prognostic models and calculators in patients with locally diagnosed anaplastic oligodendroglioma or oligoastrocytoma. A prognostic factor analysis of European Organisation for Research and Treatment of Cancer Brain Tumour Group Study 26951.

BACKGROUND: The prognosis of patients with anaplastic oligodendrogliomas (AOD) and oligoastrocytomas (AOA) is variable. Biomarkers might be helpful to identify more homogeneous disease subtypes and improve therapeutic index. The aim of this study is to develop new clinical, pathological and molecular prognostic models for locally diagnosed anaplastic gliomas with oligodendroglial features (AOD or AOA). METHODS: Data from 368 patients with AOD or AOA recruited in The European Organisation for Research and Treatment of Cancer (EORTC) trial 26951 on adjuvant PCV (Procarbazine, CCNU, Vincristine) chemotherapy in anaplastic oligodendroglial tumours were used to develop multifactor models to predict progression free survival (PFS) and overall survival (OS). Different models were compared by their percentage of explained variation (PEV). Prognostic calculators were derived from these new models. RESULTS: Treatment (for PFS only), younger age, confirmed absence of residual tumour on imaging, frontal location, good World Health Organisation (WHO) performance status, absence of endothelial abnormalities and/or necrosis, 1p/19q codeletion and Isocitrate dehydrogenase 1 (IDH1) mutation were independent factors that predicted better PFS and OS. CONCLUSIONS: We identified important prognostic factors for AOD and AOA and showed that molecular markers added a major contribution to clinical and pathological factors in explaining PFS and OS. With a positive predictive value of 92% for PFS and 94% for OS, our models allow physicians to precisely identify high risk patients and aid in making therapeutic decisions.

Carpal tunnel syndrome diagnosed by general practitioners: an observational study.

The aim of this study was to investigate the results of both clinical testing and standardised nerve conduction studies performed on patients with Carpal tunnel syndrome (CTS) complaints, who had been referred to the neurologist by their general practitioners. Analysis of the data of neurological examination and electrodiagnostic tests (EDX) were performed on patients that had been referred by general practitioners. A total of 232 patients with clinically defined CTS, who had been referred by general practitioners, were seen by a neurologist and subsequently underwent electrodiagnostic testing. The diagnosis of CTS made by general practitioners was clinically confirmed by the neurologist in 187 of 232 (81%) patients. In these 187 patients, EDX confirmed CTS clinical diagnosis in 180. In 40 (17%), the neurologists disagreed with the clinical diagnosis of CTS because signs and symptoms were not those of clinical CTS. We showed that general practitioners are very well capable of making a clinical diagnosis of CTS. Therefore, direct referral of patients by general practitioners for nerve conduction studies to have their diagnosis of CTS confirmed is a desirable and time-saving procedure.

Rupture of an intracerebral aneurysm after carotid endarterectomy: a case report.

Coincidental intracerebral aneurysm and internal carotid artery stenosis is a rare combination. This case report describes the development of an intracerebral aneurysm in the presence of an internal carotid artery stenosis in an 58-year old women. Furthermore, the management of intracerebral aneurysm in combination with an internal carotid artery stenosis is discussed as well as the role of potential important hemodynamic factors involved in the development and rupture of these aneurysms.

Metastatic medulloblastoma in an adult; treatment with temozolomide.

Medulloblastoma is a malignant brain tumour most frequently seen in children. Treatment of this tumour type usually consists of surgery followed by radiotherapy. Relapses of medulloblastoma are sensitive to chemotherapy and treatment with chemotherapeutics in children has increased the survival rates. A medulloblastoma at adult age is extremely rare, and there is no overall accepted treatment, especially not in the case of a relapse. Recently improvement of survival was reported in patients with glioblastoma treated with a combination of radiotherapy and concomitant temozolomide. This observation encouraged us to decide to treat an adult patient with a recurrent medulloblastoma with temozolomide. This female patient showed a recurrence of a medulloblastoma 7 years after the initial presentation with metastatic spread along the neuraxis and progressive neurological deterioration. Treatment with temozolomide resulted in relief of clinical symptoms and stabilization of tumour growth for 8 months.

Characterization of oligodendrogliomas using short echo time 1H MR spectroscopic imaging.

Oligodendroglial tumors may not be distinguished easily from other brain tumors based on clinical presentation and magnetic resonance imaging (MRI) alone. Identification of these tumors however may have therapeutic consequences. The purpose of this study was to characterize and identify oligodendrogliomas by their metabolic profile as measured by (1)H MR spectroscopic imaging (MRSI). Fifteen patients with oligodendroglial tumors (eight high-grade oligodendrogliomas, seven low-grade oligodendrogliomas) underwent MRI and short echo time (1)H MRSI examinations. Five main metabolites found in brain MR spectra were quantified and expressed as ratios of tumor to contralateral white matter tissue. The level of lipids plus lactate was also assessed in the tumor. For comparison six patients with a low grade astrocytoma were also included in the study. The metabolic profile of oligodendrogliomas showed a decreased level of N-acetylaspartate and increased levels of choline-containing compounds and glutamine plus glutamate compared with white matter. The level of glutamine plus glutamate was significantly higher in low-grade oligodendrogliomas than in low-grade astrocytomas and may serve as a metabolic marker in diagnosis and treatment planning. In high-grade oligodendrogliomas large resonances of lipids plus lactate were observed in contrast to low-grade tumors.

Primary non-Hodgkin's lymphoma in multiple vertebrae presenting as a lumbar radicular syndrome: A case report.

STUDY DESIGN: A case report is presented. OBJECTIVE: To report and discuss a case of primary non-Hodgkin's lymphoma in 10 different vertebrae in the spine of a 25-year-old woman. SUMMARY OF BACKGROUND DATA: To the authors' knowledge, a case of primary bone lymphoma in several vertebrae has not been reported previously. METHODS: Primary bone lymphoma was diagnosed using magnetic resonance images and biopsy of one spine lesion. There was no other localization of the lymphoma. RESULTS: With chemotherapeutic treatment, the lymphoma was in remission for 16 months. The patient then died of complications associated with acute lymphatic B-cell leukemia. CONCLUSIONS: The incidence of primary bone lymphoma in a population with non-Hodgkin's lymphoma is less than 1%. A case with multiple localizations of lymphoma in the spine has never been reported before.

Microhemorrhages in the central nervous system: report of a patient with microhemorrhages in brain and spinal cord.

A 53-year-old, woman with microhemorrhages in the brain and spinal cord is described. This patient was initially seen with a reversible oculomotor paresis and hypertension, a year later she developed spinal cord symptoms. T2-weighted magnetic resonance imaging showed characteristic hypointense lesions in the brain and spinal cord consistent with microhemorrhages. Although the occurrence of microhemorrhages in the brain has been described before, the combination of brain and spinal cord microhemorrhages has not been reported yet. The observations in our patient suggest that microvascular changes related to hypertension are a common cause for these microhemorrhages.

Spatial relationship between hypoxia and the (perfused) vascular network in a human glioma xenograft: a quantitative multi-parameter analysis.

PURPOSE: To quantitatively study the spatial distribution of tumor hypoxia in relation to the perfused vasculature. METHODS AND MATERIALS: Using a human glioma xenograft model, nude mice were administered two different hypoxia markers (NITP or pimonidazole) and the perfusion marker Hoechst 33342. Frozen tumor sections were sequentially scanned for perfusion, hypoxia, and vasculature, respectively, to quantitate perfusion, vasculature, and hypoxia parameters in the same section. RESULTS: All tumors showed incomplete perfusion. Both NITP and pimonidazole stained the same hypoxic tumor areas. No statistically significant differences between the two markers were observed. The density of the perfused vessels was inversely related to the hypoxic fraction. At critical distances from perfused vessels, hypoxia occurred. These data suggest that predominantly diffusion-limited hypoxia was detected, based on the spatial distribution of nearby vessels. Also, the proportion of hypoxia distributed over arbitrary zones of 50 microm around perfused vessels was calculated. The largest proportion of hypoxia was found at distances beyond 100 microm from perfused vessels. CONCLUSION: With the multiple staining and functional microscopic imaging technique described here, the spatial relationship between perfused vessels and hypoxia was quantified in whole tumor cross-sections. The usefulness of this histologically-based method to quantitate morphological and physiological aspects of the tumor microenvironment was evaluated.

Hypoxia in a human intracerebral glioma model.

OBJECT: The development of hypoxia in human gliomas is closely related to functional vasculature and the presence of hypoxia has important biological and therapeutic consequences. Assessment of hypoxia is necessary to understand its role in treatment response and to evaluate treatment strategies to improve tumor oxygenation. In this study, the authors report findings of their analysis of the degree of hypoxia in relation to other vascular parameters in a human intracerebral glioma xenograft. METHODS: In sections of tumor, hypoxic regions were identified immunohistochemically by using the hypoxic marker pimonidazole. The S-phase marker bromodeoxyuridine was used to detect cell proliferation, and the perfusion marker Hoechst 33342 was used to delineate perfused vessels. Vascular structures were stained with an endothelial marker. Hypoxic tumor regions were clearly present in this human intracerebral glioma model. Hypoxic areas were usually found in nonperfused regions, whereas tumor cell proliferation was especially marked in perfused tumor areas. Furthermore, by using in situ hybridization the authors identified infiltrating tumor cells in the normal brain. This feature is often observed in gliomas in patients. CONCLUSIONS: This model is a representative human glioma model that provides the researcher with the opportunity to analyze the relationship between the degree of hypoxia and vascular parameters, as well as to examine the effects of treatments aimed at modification of the oxygenation status of a tumor.

Neuropraxia of the cervical spinal cord following cervical spinal cord trauma: a report of five patients.

Neuropraxia of the cervical spinal cord is a rare condition which is almost exclusively reported in American football players following cervical hyperextension or hyperflexion trauma. In this entity-neurological symptoms of both arms and legs for a period of up to 15 minutes are observed with complete recovery. We report the characteristics of five patients not involved in contact sport activities with a neuropraxia of the spinal cord following cervical trauma. In four of the five patients, this syndrome was associated with a cervical canal stenosis. Surgical decompression was performed in two patients with progressive neurological symptoms after an initial period of recovery. The cases illustrates that although neuropraxia of the spinal cord is usually seen in athletes, also other persons may be at risk for developing this condition, especially when a preexisting spinal stenosis is present. Patients who experienced neuropraxia of the spinal cord should thus be evaluated carefully for the presence of cervical spinal cord abnormalities.

Genetic reflection of glioblastoma biopsy material in xenografts: characterization of 11 glioblastoma xenograft lines by comparative genomic hybridization.

OBJECT: Human tumors implanted as subcutaneous xenografts in nude mice are widely used for the study of tumor biology and therapy. Validation of these models requires knowledge of the genetic makeup of the xenografts. The aim of this study was to establish whether chromosomal imbalances in 11 xenograft lines derived from human glioblastomas multiforme (x-GBMs) are similar to those found in GBM biopsy samples. The authors also studied genetic stability during serial passaging of three xenograft lines. METHODS: Chromosomal imbalances in x-GBMs were detected using comparative genomic hybridization (CGH). The authors compared the CGH results in x-GBMs with those in the original GBMs (o-GBMs) that were used to establish three of the xenograft lines and with the GBM biopsy results reported in the literature (1-GBMs). In three xenograft lines two different passages were analyzed. CONCLUSIONS: The results show that the chromosomal imbalances in x-GBMs are similar to those in o-GBMs and 1-GBMs, indicating that the GBM xenograft lines used were valid models from a genetic point of view. The CGH analysis of two different passages of three xenograft lines indicates that x-GBMs (like 1-GBMs) show intratumoral genetic heterogeneity and do not acquire chromosomal imbalances as a result of serial passaging.

Improvement of central pontine myelinolysis as demonstrated by repeated magnetic resonance imaging in a patient without evidence of hyponatremia.

Central pontine myelinolysis is usually associated with hyponatremia or rapid correction of this condition. In general, this neurological disorder has a fatal prognosis. We observed a 30-year-old woman with a history of chronic alcohol abuse but without evidence of hyponatremia, who developed severe pontine central myelinolysis. The initial magnetic resonance (MR)-imaging showed a marked lesion in the central pontine area, sequential MR-imaging revealed progressive reduction of this defect over the following months. This reduction was accompanied by excellent clinical recovery. This case report demonstrates that central pontine myelinolysis is not always associated with hyponatremia and illustrates that, although in general the prognosis is bad, some patients may recover with improvement of the abnormalities on the MR-images.

A quantitative analysis of vascularization and perfusion of human glioma xenografts at different implantation sites.

The effect of tissue site of implantation of four different human gliomas on tumor vascularity and perfusion was examined. Vascular parameters of gliomas implanted subcutaneously in the nude mouse and intracerebrally in the nude rat were analyzed. Tumor vessels were stained with an antibody to collagen type IV and perfusion was investigated with the perfusion marker Hoechst 33342. Characteristic vascular patterns were observed in both intracerebral and subcutaneous xenografts belonging to the same tumor line. Major differences in vascular architecture and in the degree of vascularization were noted in comparisons of the two implantation sites for the same tumor line. Tumor perfusion was highly variable for both locations of tumor growth. Distinct differences between the implantation sites of similar tumor lines in vascular perfusion, intervascular distance, and vascular density were present. Incomplete perfusion of vascular structures, as seen in this study, may result in reduced delivery of oxygen to tumor areas. Therefore, measurements of vascular density and intervascular distance alone, without knowledge of the perfusion status, may not be sufficient to estimate the degree of tumor oxygenation. Furthermore, differences in vascular parameters may have important consequences for treatment modalities such as radiotherapy and chemotherapy. Thus, the findings in our study suggest that care has to be taken in extrapolating therapy results obtained with subcutaneous glioma tumor models to the original growth location of gliomas, the brain, due to major differences in vasculature.

Antiangiogenic therapy in brain tumor models.

The prognosis of patients with malignant brain tumors remains poor despite new developments in neurosurgery, chemotherapy and radiotherapy. Malignant gliomas are highly vascularized, and there is ample evidence that their growth is angiogenesis-dependent. Therefore, new therapeutic approaches often include the inhibition of angiogenesis. In this review, experimental studies of antiangiogenic agents in brain tumor models are summarized. The results of these experiments as well as potential pitfalls in extrapolation to the clinic are discussed.

Suramin treatment of human glioma xenografts; effects on tumor vasculature and oxygenation status.

In this study the effect of suramin on tumor growth, vascularity and oxygenation of a human glioma xenografted in the nude mouse was examined. Vascular parameters and oxygenation status of the xenografts were determined immunohistochemically in frozen sections of the tumors, using the hypoxia marker pimonidazole-hydrochloride to detect hypoxic areas. Tumor vessels in these sections were stained by an endothelial cell marker and perfusion of vessels was visualized by administration of the perfusion marker Hoechst 333342 before harvesting the tumors. The vascular parameters were quantified with an image analysis system. The results show that tumor growth was reduced considerably after suramin treatment. This growth suppression was accompanied by marked changes in vascular architecture. Although the total vascular area and perfused fraction of tumor vessels remained unchanged after suramin treatment, vascular density increased, indicating that more but smaller vessel structures had developed during therapy. These vessel structures were also more homogeneously spread over the tumor area. Control tumors showed extensive areas of hypoxia while in treated tumors hypoxic areas had mostly disappeared. This effect was probably due to the higher density of homogeneously distributed perfused vessel structures in the treated tumors, contributing to an increased oxygenation of the tumor. These observations suggest that suramin therapy can result in marked changes not only in tumor vascularity but also in tumor oxygenation status which may have important consequences for sensitivity of these tumors to other therapies such as radiation treatment.

Delayed vascular changes after antiangiogenic therapy with antivascular endothelial growth factor antibodies in human glioma xenografts in nude mice.

OBJECTIVE: The purpose of this study was to examine the delayed effects of antivascular endothelial growth factor treatment on tumor growth and vascularity in a subcutaneous mouse tumor model of human glioblastoma. METHODS: Antivascular endothelial growth factor antibody treatment was administered for a period of 6 weeks, to suppress tumor growth. To detect late vascular effects, tumor vascular parameters for treated tumors and control tumors were analyzed 4 weeks thereafter. By that time, tumors had grown to adequate sizes (diameter, 8-10 mm) for comparison with untreated control tumors. Vascular parameters were quantified by using an image-analysis system. RESULTS: Vascular density was significantly lower in antivascular endothelial growth factor antibody-treated tumors, compared with control tumors of similar size. The vascular architecture of treated tumors was also distinctly different, compared with control tumors, showing larger but sparser vessel structures. CONCLUSION: These findings suggest that antiangiogenic therapy may have a prolonged effect on the vascular architecture of certain tumors, resulting in enduring changes in the tumor vessels. Because tumor vasculature plays an important role in the sensitivity to various treatment modalities, these changes are likely to influence the responses of these tumors to further therapy.

The effect of the anti-angiogenic agent TNP-470 on tumor growth and vascularity in low passaged xenografts of human gliomas in nude mice.

The effect of the anti-angiogenic agent TNP-470 on tumor growth, vascular area, vascular density and tumor perfusion of two different subcutaneously implanted human glioma xenografts (E98 and E106) in nude mice was evaluated. Vascular parameters were investigated with an image analysis system. For both tumor lines a small but significant tumor growth suppression was observed. However, no differences in vascular parameters between TNP-470 treated tumors and controls could be found after 6 weeks of treatment. It is concluded that although TNP-470 is a promising anti-angiogenic agent in many tumor types, at least 2 glioma lines seem to be partly resistant to its anti-angiogenic effects. Further evaluation of the effects of combination of TNP-470 and cytostatic agents or radiotherapy in human glioma xenografts are required to determine the place of anti-angiogenic therapy in general and treatment with the anti-angiogenic agent TNP-470 more specifically in the treatment of human gliomas.

[Vascularization and perfusion of tumors as target in cancer therapy]. / Vascularisatie en doorbloeding van tumoren als doelwit voor kankertherapie.

Many tumours depend on the formation of an own vascular system to support progressive tumour growth. This is accomplished through induction of vessel growth from pre-existing vessels, a process called neo-angiogenesis. Therefore, inhibiting neo-angiogenesis and modulating tumour perfusion constitute attractive possibilities for tumour therapy, combined, of course, with treatment aimed at the tumour cells themselves. By now many angiogenesis inhibitors have been developed, but their use is mostly still experimental. They inhibit endothelial proliferation and migration (fumagillin derivates, angiostatin, suramin) or prevent proteolytic degeneration of the extracellular matrix by products of the tumour (metalloproteinase inhibitors). Improving tumour oxygenation and perfusion by carbogen inhalation and nicotinamide or vasoactive agents (flunarizine, verapamil, nicotinamide) enhances the effects of radiotherapy and improves delivery of chemotherapeutic agents to the tumour. Research is currently in progress into the efficacy of accelerated radiotherapy in combination with carbogen inhalation and administration of nicotinamide in tumours of the head and neck, bladder, bronchi and brain.

In vivo (31)P magnetic resonance spectroscopy and morphometric analysis of the perfused vascular architecture of human glioma xenografts in nude mice.

The relationship between the bioenergetic status of human glioma xenografts in nude mice and morphometric parameters of the perfused vascular architecture was studied using (31)P magnetic resonance spectroscopy (MRS), fluorescence microscopy and two-dimensional digital image analysis. Two tumour lines with a different vascular architecture were used for this study. Intervascular distances and non-perfused area fractions varied greatly between tumours of the same line and tumours of different lines. The inorganic phosphate-nucleoside triphosphate (P(i)/NTP) ratio increased rapidly as mean intervascular distances increased from 100 microm to 300 microm. Two morphometric parameters - the percentage of intervascular distances larger than 200 microm (ivd200) and the non-perfused area fraction at a distance larger than 100 microm from a nearest perfused vessel (area100), - were deduced from these experiments and related to the P(i)/NTP ratio of the whole tumour. It is assumed that an aerobic to anaerobic transition influences the bioenergetic status, i.e. the P(i)/NTP ratio increased linearly with the percentage of ivd200 and the area100.