Central nervous system hemangioblastomas, endolymphatic sac tumors, and von Hippel-Lindau disease.

Von Hippel-Lindau disease (VHL) is a hereditary cancer syndrome caused by germline mutations of the VHL tumor suppressor gene. Major progress has been made in the last decade in both clinical and fundamental aspects of VHL. The VHL gene product, pVHL, has major and multiple functions: pVHL regulates not only first angiogenesis but also extracellular matrix formation and the cell cycle. A molecular diagnosis of VHL is now available, leading to a transformation in clinical management of patients and their families. Diagnosis of VHL has to be suspected in patients with a VHL-related tumor without familial history and especially in case of hemangioblastoma or endolymphatic sac tumors. Such patients should be systematically investigated for clinical and molecular evidence of VHL disease. Treatment of symptomatic hemangioblastomas remains mainly neurosurgical, often in emergency, but stereotactic radiosurgery is emerging as an alternative therapeutic procedure. In the future, antiangiogenic drugs could represent a potential medical treatment of CNS hemangioblastomas in view of their highly vascular structure. Lastly, visceral manifestations of VHL disease are also of critical importance and require early detection for effective treatment.

Germline mutation profile of the VHL gene in von Hippel-Lindau disease and in sporadic hemangioblastoma.

von Hippel-Lindau (VHL) disease is a dominantly inherited disorder predisposing those afflicted to hemangioblastomas of the central nervous system and the retina, renal cell carcinomas, pheochromocytomas, and pancreatic tumors. The disease has been associated with mutations of the VHL gene. The screening of 92 unrelated patients with VHL disease for point mutations in this gene revealed 61 DNA variants. In addition, a search for EcoR1 rearrangements revealed germline anomalies in 5 patients. The 61 variants could be subdivided in 20 mutations predicted to alter the open reading frame (8 nonsense mutations, 8 frame shift mutations, and 4 mutations in consensus splicing sites) and 43 DNA sequence variants of a priori unknown biological consequence (4 in-frame insertions or deletions, 36 missense mutations, and 3 apparently silent variations). The 3' end of the coding sequence of the VHL gene, which encodes the Elongin binding domain was the site of 5 of 20 truncating mutations (25%) and of 18 of 41 DNA variants (44%) causing uncertain functional impairment. A similar screening in 18 patients with sporadic hemangioblastoma revealed 2 missense DNA variants. In order to corroborate this latter observation, a systematic screening for germline alteration of the VHL gene might be performed in a larger series of sporadic hemangioblastoma. If this preliminary result is confirmed, more than 10% of sporadic hemangioblastoma might be related to a mild VHL disease, thus a follow-up program similar to that recommended in cases of VHL disease should probably be discussed in the corresponding families.

Haemangioblastoma of the central nervous system in von Hippel-Lindau disease. French VHL Study Group.

Haemangioblastoma of the central nervous system (CNS) is the most characteristic lesion and the most common presenting manifestation of von Hippel-Lindau (VHL) disease and has a striking tendency to multiple occurrence. Its sites of predilection are the posterior fossa (cerebellum++), and the spinal cord. Haemangioblastoma may cause increased intracranial pressure and/or neurological deficits and remains the main cause of morbidity and mortality in VHL. Treatment of symptomatic haemangioblastoma remains neurosurgical and is often in emergency. Haemangioblastoma appears to be more commonly associated with VHL than previously reported and suggests that all patients with 'sporadic' haemangioblastoma should be investigated for evidence of VHL disease. From a fundamental point of view, haemangioblastoma is a benign neoplastic entity with a double, vascular and cellular differentiation. Mutational inactivation of both copies of the VHL gene plays a major role in the pathogenesis of haemangioblastoma. Over-expression of vascular endothelial growth factor (VEGF) and VEGF-receptors has been recently demonstrated in these tumours, raising the possibility of angioblastic origin, and is of very great interest in view of the direct implication of the VHL gene in negative regulation of VEGF.

Somatic inactivation of the VHL gene in Von Hippel-Lindau disease tumors.

Von Hippel-Lindau (VHL) disease is a dominantly inherited disorder predisposing to retinal and CNS hemangioblastomas, renal cell carcinoma (RCC), pheochromocytoma, and pancreatic tumors. Interfamilial differences in predisposition to pheochromocytoma reflect allelic heterogeneity such that there is a strong association between missense mutations and risk of pheochromocytoma. We investigated the mechanism of tumorigenesis in VHL disease tumors to determine whether there were differences between tumor types or classes of germ-line mutations. Fifty-three tumors (30 RCCs, 15 hemangioblastomas, 5 pheochromocytomas, and 3 pancreatic tumors) from 33 patients (27 kindreds) with VHL disease were analyzed. Overall, 51% of 45 informative tumors showed loss of heterozygosity (LOH) at the VHL locus. In 11 cases it was possible to distinguish between loss of the wild-type and mutant alleles, and in each case the wild-type allele was lost. LOH was detected in all tumor types and occurred in the presence of both germ-line missense mutations and other types of germline mutation associated with a low risk of pheochromocytoma. Intragenic somatic mutations were detected in three tumors (all hemangioblastomas) and in two of these could be shown to occur in the wild-type allele. This provides the first example of homozygous inactivation of the VHL by small intragenic mutations in this type of tumor. Hypermethylation of the VHL gene was detected in 33% (6/18) of tumors without LOH, including 2 RCCs and 4 hemangioblastomas. Although hypermethylation of the VHL gene has been reported previously in nonfamilial RCC and although methylation of tumor-suppressor genes has been implicated in the pathogenesis of other sporadic cancers, this is the first report of somatic methylation in a familial cancer syndrome.

[Variety of pancreatic lesions observed in von Hippel-Lindau disease. Apropos of 8 cases]. / Variété des lésions pancréatiques observées au cours de la maladie de von Hippel-Lindau. Présentation de 8 cas.

Von Hippel-Lindau's disease is a rare genetic disease, with an autosomal dominant mode of inheritance, characterised by the development of several tumours, such as haemangioblastoma of the central nervous system and retina, renal cysts or carcinoma and pheochromocytoma. Several pancreatic lesions, mainly represented by multiple cysts, are also encountered. We report here 8 cases of pancreatic involvement in patients affected with von Hippel-Lindau's disease. It consisted of multiple cysts (3 cases), serous cystadenoma (2 cases), endocrine tumour (1 case), haemangioblastoma (1 case) and ductal adenocarcinoma (1 case). Diagnosis of a rare lesion of the pancreas (multiple cysts, serous cystadenoma or vascularized tumour) in a young patient may lead to search the other lesions of von Hippel-Lindau's disease and to undergo a familial inquiry in order to propose a multidisciplinary approach for patients affected by the disease.

Predominant occurrence of somatic mutations of the NF2 gene in meningiomas and schwannomas.

The NF2 gene is a putative tumor-suppressor gene that, when it is altered in the germline, causes neurofibromatosis type 2, a tumor-susceptibility disease that mainly predisposes to schwannomas and meningiomas. The recent isolation of the NF2 gene on chromosome 22 allows the identification of somatic mutations in human tumors. We have searched for mutations of the NF2 gene in 331 primary human tumors using a screening method based on denaturing gradient gel electrophoresis, which allows the detection of mutations in 95% of the coding sequence. Mutations were observed in 17 of 57 meningiomas and in 30 of 89 schwannomas. No mutations were observed for 17 ependymomas, 70 gliomas, 23 primary melanomas, 24 pheochromocytomas, 15 neuroblastomas, 6 medulloblastomas, 15 colon cancers, and 15 breast cancers. All meningiomas and one-half of the schwannomas with identified NF2 mutations demonstrated chromosome 22 allelic losses. We conclude that the involvement of the NF2 gene in human tumorigenesis may be restricted to schwannomas and meningiomas, where it is frequently inactivated by a two-hit process.

DNA-based presymptomatic diagnosis for the von Hippel-Lindau disease by linkage analysis.

Von Hippel-Lindau (VHL) disease is an autosomal dominantly inherited condition characterized by a predisposition to the development of haemangioblastoma, renal cell carcinoma and phaeochromocytoma. The gene which, when altered, causes the disease was cloned in 1993, and maps within a series of known polymorphic loci in the 3p25-p26 region. To optimize a DNA-based presymptomatic diagnosis, we have selected six highly informative microsatellite loci, closely linked to the VHL gene. Genotyping using a multiplex-PCR approach was performed in 26 affected families including 99 asymptomatic relatives born from an affected parent. Ninety-six subjects were informative with one or more markers, 76 being informative with markers on both sides of the gene. Combination of age-related and DNA-based risk information improved the accuracy of risk assessment for 90 at-risk patients (91%) and allowed attribution of risk with a confidence limit higher than 0.98 in 79 cases (88%).

Pheochromocytoma as the first manifestation of von Hippel-Lindau disease.

BACKGROUND: von Hippel-Lindau disease is an autosomal dominant disorder characterized by the development of hemangioblastomas in the cerebellum, spinal cord, and retina, renal cell carcinoma and cysts, pancreatic cysts, and pheochromocytoma. METHODS: We have studied a series of 36 French patients affected with von Hippel-Lindau disease pheochromocytoma. Thirty (83%) of them were diagnosed as having von Hippel-Lindau disease because the disease occurred in a familial von Hippel-Lindau disease setting; six (17%) were diagnosed as having von Hippel-Lindau disease because they displayed another characteristic manifestation of that disease. RESULTS: The mean age at pheochromocytoma diagnosis was 29 +/- 14 years (5 to 62 years). Bilateral tumors were documented in 15 (42%) cases, paraganglioma was associated with adrenal pheochromocytoma in four cases, and malignant pheochromocytoma occurred in three cases. Prevalence of pheochromocytoma revealing von Hippel-Lindau disease was 20 (53%) out of 36. In six cases pheochromocytoma was the only manifestation of the disease. CONCLUSIONS: In the interest of the patients themselves and of family members who are at risk, search for von Hippel-Lindau disease must be systematic in the presence of pheochromocytoma. Basic checkup may be completed with familial inquiry, ophthalmoscopy, cerebral magnetic resonance imaging, abdominal ultrasonography, and computed tomography-scan for detection of latent lesions. In the future, after characterization of von Hippel-Lindau disease gene mutations, molecular diagnosis is going to be possible in individual patients.

Characterization of several DNA polymorphic markers in the LIF gene region.

We describe seven restriction fragment length polymorphisms (RFLPs) in the Leukemia Inhibitory Factor (LIF) gene region. These new markers, found using a cosmid contig, have been used to map precisely the chromosome 22 long arm.

[The value of magnetic resonance imaging in the diagnosis of spinal cord hemangioblastoma. Apropos of 12 cases]. / Intérêt de l'imagerie par résonance magnétique dans le diagnostic des hémangioblastomes médullaires. A propos de 12 observations.

This study concerned a series of 12 patients, 4 of whom had Von Hippel-Lindau disease. Six of these patients were explored by myelography, 6 by spinal cord angiography, 8 by CT scan with contrast injection and 12 by MRI, with gadolinium injection in 8. MRI proved to be the choice examination for the diagnosis of spinal cord tumor, but gadolinium injection was necessary since it made it possible to detect the tumoral bud and its intense enhancement. The absence of gadolinium injection led us to an erroneous initial diagnosis of syringomyelia in two patients and glioma in one. Sagittal sections made it easier to evaluate the tumoral extension in patients with evidence or suspicion of Von Hippel-Lindau disease. Arteriography was indicated, as it provided a preoperative map and diagnosed punctiform lesions.

Integrated imaging system for stereotactic neurosurgery.

Talairach's method remains the most universal of all stereotactic methods. It makes it possible to go back to an examination left interrupted, but above all, it provides multiple lateral and coronal approaches in matters of epilepsy, radio-isotopes or photobiology. The advances achieved in modern imaging methods, notably CT and MRI, and the performance of modern computers have enabled us to devise an integrated imaging system meant to accelerate and make feasible calculations of penetrating trajectories, according to the position of the target as previously defined by CT and MRI sections, and taking into account the position of vessels given by angiography. The principal options we selected were: transfer onto video tapes of teleangiographic films and introduction of CT and MRI images obtained either from films or directly in digits on cartridges or networks. The system includes an advanced PC-type microcomputer with 8 memories of 1,024/1,024 images: 4 mega octets random access memories and a hard disc of 150 mega octets; 2 high-resolution screens to present the images, dialogue tools (alphanumeric screen, keyboard, trackball) and the usual peripherals. Our system performs three main functions: it acquires images to create or complete the patient's records; it exploits the images by calculating the parameters required for operations; it handles the records through the various peripherals of the system. Our system can retrace the proportional 3D squaring according to the CA-CP distance calculated from ventriculography or MRI, and calculates the position of the SEEG electrodes. The stereoscopic effect is obtained by means of glasses with liquid crystal obturator from two angiographic series: one orthogonal, the other 6 degrees out of phase. The daily use of this system on more than 50 patients has shown that it is accurate and reliable, irrespective of the makes of CT and MRI machines.

Role of Gd-DOTA in the evaluation and imaging of experimental blood-brain barrier disruption in brain edemas and their improvement after anti-inflammatory drugs treatment.

This study was carried out to evaluate the effect of new anti-inflammatory drugs in the treatment of brain edema in new models. Experimental brain edema was induced in rats by stereotaxic injection of phospholipase A2 into one hemisphere. Concentrations of intravenously injected gadolinium-DOTA in the lesioned hemisphere were three times as high as in normal rat hemisphere. Edema was reduced by treatment with anti-inflammatory drugs such as dexamethasone (P < 0.01) or an experimental benzamide drug (P < 0.02). Magnetic resonance imaging (MRI) was then used to evaluate edema reduction after administration of contrast medium. We observed weighted scans for control lesioned rats, a reduction of signal intensity after dexamethasone and no significant regression after the benzamide drug. For purposes of experimental brain edema research in rats, the MRI technique facilitates detection and evaluation of the anti-inflammatory activity of molecules crossing the blood-brain barrier.

[Pheochromocytoma, first manifestation of Von Hippel-Lindau disease: a possibility to be considered]. / Phéochromocytome, première manifestation de la maladie de von Hippel-Lindau: une éventualité à connaître.

Von Hippel-Lindau (VHL) disorder is an autosomal dominant disease characterized by the almost constant development of hemangioblastomas in the central nervous system (cerebellum, spinal cord and retina). In addition, various types of tumors including renal cell carcinomas, pancreatic cysts and pheochromocytomas are frequently observed in VHL gene carriers. Linkage of the VHL locus to the RAF-1 oncogene on the short arm of chromosome 3 (3p25-26) has been recently reported. Pheochromocytoma is of particular interest because of the risk of inaugural malignant hypertensive crisis but especially because of a great degree of interfamily variability (from 0 to 92% of affected members in previously reported large kindreds). We have studied a French series of 25 pheochromocytoma (11 males, 14 females) in VHL affected patients. Twenty pheochromocytoma (80%) occurred in a familial context, whereas 5 (20%) were consistent with "apparent sporadic cases". The mean age at pheochromocytoma diagnosis was 27 years (5-55 years). Bilateral tumours have been documented in 13 cases (52%). The prevalence of pheochromocytoma revealing VHL was 14 out 25 (56%). In these cases, VHL diagnosis was considered up to 25 years later. In 6 cases (2 deceased) pheochromocytoma was the only manifestation of VHL. Thus, search for VHL must be systematic in the presence of pheochromocytoma, in the interest of the patients themselves and of potential at-risk family members (prevention of hypertensive crisis linked to latent tumours). Basic check-up (neurological and somatic examination, ophthalmoscopy, familial inquiry) may be completed with cerebral CT scan or MRI and abdominal ultrasonography followed, if positive or doubtful, by abdominal MRI or selective angiography.

Photodynamic treatment of normal endothelial cells or glioma cells in vitro.

Photodynamic therapy is based on the interaction of a sensitizer (hematoporphyrin derivative) selectively retained by tumor cells, which becomes toxic after light exposure. We studied the influence of exogenous prostaglandins and indomethacin on photodynamic therapy of normal human endothelial cells and glioma cells. Although differing in origin and kinetic properties, endothelial cells exhibited photodynamic therapy sensitivity quite comparable to that of C6 cells. However, in contrast to studies performed using radiotherapy, exogenous prostaglandins decreased rather than protected the surviving fraction of both cell types treated by photodynamic therapy. Indomethacin, a potent inhibitor of endogenous prostaglandin synthesis, increased the surviving fraction of C6 glioma cells but not that of endothelial cells. Exogenous or endogenous prostaglandins seem to influence in vitro photodynamic therapy in a different way than does radiotherapy.

[Intracerebral morphine therapy in cancer patients]. / Morphinothérapie par voie intracérébrale chez le cancéreux.

An overview of recent studies concerning opioids and their pharmacokinetics is presented. In the light of these findings it is shown that intracerebral administration may be justified. The authors experience with 63 cases is detailed: all cancer patients in the final stage. Initial dosage by the intraventricular route was 500 to 700 microgram-day but in one case twice daily injections of 1.200 microgram were needed. The dosage needed doubled over the observation period of 2 to 3 months. The mean length of survival was 75 days. Among complications nausea and vomiting were observed in 15 to 35% of the cases, sweating and pruritus in 15%, urinary retention in 15 to 20%. In some cases euphoria, motor excitement and hallucinations occurred. Chronic constipation was present in all cases. Two cases of meningitis were successfully treated by antibiotics. Pain relief was judged excellent or good in 75% of the cases. In 20% other analgesics had to be added to the treatment. In 5% the method failed.

[Bone integration within calcium phosphate ceramic by creation of posterior inter-articular lumbar spine fusions in dogs]. / Etude de l'intégration osseuse d'une céramique de phosphate de calcium par réalisation d'arthrodèses lombaires inter-articulaires postérieures chez le chien.

Following earlier experiments in which several calcium phosphate ceramics were tested, the aim of this study was to evaluate bone integration within a macroporous biphasic calcium ceramic (M.B.C.P.) in comparison to autologous bone grafts, by producing posterior lumbar spine fusions in dogs. Five dogs were used. 40 posterior lumbar joints were exposed; 38 articular surfaces were removed, 27 M.B.C.P. and 5 autologous bone grafts were implanted; 6 joints were kept free of implant for control purposes. Fixation with a metal rod was performed using Luque's method. Tetracycline was used for a double marking of bone growth. Joints were removed at 4 weeks in 1 dog, 8 weeks in two and 13 weeks in the remaining 2 dogs. Demineralized and non demineralized sections were examined. After 1 month, sections with M.B.C.P. showed early signs of mineralization of the scar tissue between the biomaterial and one of the facets of the joint. Fluoroscopy revealed an absence of bone growth in the pores at the center of the ceramic implant. After 3 months, a number of M.B.C.P. blocks had become integrated into both sides of the joint; however some microfractures in the biomaterial with discontinuity between the mineralized areas was seen. Macroporous calcium phosphate ceramic leads to revascularization allowing bone reconstruction. Similarities in the kinetics and mechanisms of bone integration between the ceramic and autologous bone grafts are demonstrated.

[Hemodynamic monitoring in microneurosurgical excision by sub- and retro-sinus approach in seated position in acoustic neurinoma]. / Surveillance hémodynamique au cours de l'exérèse micro-neurochirurgicale par voie sous- et rétrosinusienne en position assise du neurinome de l'acoustique.

Haemodynamic data (thermodilution Swan-Ganz catheter and radial artery cannula) were collected in 17 patients (52.4 +/- 8 yr) during retrosigmoid approach for removal of an acoustic tumour in the seated position. Measurements were made before stimulation of posterior fossa structures (period 1) and during tumour dissection along the brain stem (period 2). Significant increases in systolic, diastolic and mean blood pressures, in pulmonary capillary wedge pressure, in cardiac index and in stroke index were observed during period 2, whereas heart rate, right atrial pressure and systemic vascular resistances were unaffected. The greater the size of the tumour and the difficulties in dissection, the greater were these intraoperative haemodynamic changes. In addition, the pulmonary arterial blood temperature and the noradrenaline plasma concentrations (double isotope enzymatic assay) increased significantly during period 2. In conclusion, the prolonged microsurgical technique of acoustic tumour dissection through the retrosigmoid approach may modify left ventricular loading conditions and may lead to pulmonary oedema, even if intravascular volume expansion was minimal and ventricular function was near normal.