Juha Jääskeläinen

Debulking or biopsy of malignant glioma in elderly people - a randomised study.

Summary.Background: Patients with radiologically (MRI and/or CT images) suspected malignant glioma is referred to radiotherapy after craniotomy and resection of the tumour or after diagnostic biopsy. Patients with poor preoperative status and elderly patients are diagnosed more often by biopsy and treated by radiotherapy rather than by craniotomy and tumour resection. However, based on previous retrospective studies it is not possible to conclude which procedure is better for elderly patients. Thus a prospective study comparing these two procedures with elderly patients was planned. Methods: 30 patients older than 65 years with radiologically (CT and/or MRI) obvious malignant glioma were randomised into two groups: I) stereotactic biopsy and II) open craniotomy and resection of the tumour. Nineteen patients were diagnosed to have grade IV glioma and four patients grade III glioma. Seven out of 30 (23%) were followed in the “intention-to-treat” group with diagnosis of stroke (n=3), metastasis (n=2), malignant lymphoma (n=1) and one with out histological diagnosis. Patients with histologically verified malignant glioma (grade III–IV) were diagnosed by stereotactic biopsy (n=13) or by open craniotomy and resection (n=10) and all the patients were referred to radiotherapy. Survival and time of deterioration were followed. Findings: The overall median survival time was 146 (95% CI 89–175) days after the procedure. The estimated median survival time was 171 (95% CI 146–278) days after the craniotomy versus 85 (95% CI 55–157) days after the biopsy (p=0.035). The estimated survival time was 2.757 times longer (95% CI 1.004–7.568, p=0.049) after craniotomy. However, there was no significant difference in the time of deterioration between these two treatments (p=0.057). Amount of radiotherapy given had a significant effect on survival (p=0.001). Interpretation: Longer survival time is achieved after open craniotomy and resection of tumour. However, overall benefit of open surgery to patient seems to be modest, while time of deterioration did not differ between two treatment groups. Our results support previous studies on the benefit of radiotherapy in the treatment of malignant glioma.

Factors Affecting Operative and Excess Long-term Mortality in 935 Patients with Intracranial Meningioma

Between 1953 and 1980, a total of 935 patients underwent surgery for intracranial meningioma in the Department of Neurosurgery of the Helsinki University Hospital. The patients were followed up until death or the end of the year 1987. The cumulative observed survival rate was 91% at 3 months, 89% at 1 year, and 63% at 15 years. The relative survival rate, that is, the ratio of the the observed and the expected rates, was 91% at 3 months, 89% at 1 year, and 78% at 15 years. Significant risk factors for operative mortality (7%) for the 652 patients operated on from 1966 to 1980 were poor preoperative clinical condition, absence of epilepsy, old age, incomplete tumor removal, pulmonary embolism, and an intracranial hematoma requiring evacuation. For those 828 patients who survived the first postoperative year, the factors predicting an excess risk of death for up to 15 years were incomplete tumor removal, poor pre- and postoperative clinical condition, anaplasia of the tumor, and hyperostosis. Patients whose tumors were not completely removed had a 4.2-fold relative excess risk of death as compared with patients whose tumors were completely removed, and patients who had malignant tumors had a 4.6-fold risk as compared with those who had benign tumors.

The ezrin protein family: membrane-cytoskeleton interactions and disease associations

Ezrin, radixin, moesin and merlin form a subfamily of conserved proteins in the band 4.1 superfamily. Ezrin protein subfamily members act as linkers between the plasma membrane and the cytoskeleton. Members of the subfamily have been shown to interact with each other, with cell adhesion molecules such as CD44 and with F-actin. Recent data indicate that intercellular adhesion molecules 1 and 2 also interact with ezrin. The proteins are also involved in the redistribution of intercellular adhesion molecules and the organization of cell membrane structures. Merlin is a tumor suppressor that is involved in tumorigenesis of schwannomas and meningiomas. Merlin has the same overall protein structure as the other proteins in the subfamily but may have partially distinct functions.

Tie Endothelial Cell-specific Receptor Tyrosine Kinase Is Upregulated in the Vasculature of Arteriovenous Malformations

Arteriovenous malformations (AVMs) are congenital lesions composed of abnormal vasculature, with no capillary component, and are clinically significant due to their tendency to spontaneously hemorrhage. The mechanisms regulating the genesis and progression of these lesions are unknown. In order to study the role of angiogenesis in AVMs, we have analyzed the expression of the endothelial cell mitogen vascular endothelial growth factor (VEGF) and a novel endothelial cell-specific receptor tyrosine kinase, Tie, by in situ hybridization and immunohistochemistry in these malformations and surrounding brain tissue. We have previously shown upregulation of Tie accompanying wound healing and tumor progression. In this study, we demonstrate significantly elevated levels of Tie mRNA and protein in AVM and surrounding brain vasculature. Upregulation of VEGF mRNA was observed in the cells of brain parenchyma adjacent to the AVM, and VEGF protein was detected in this tissue as well as in AVM endothelia. Normal brain, in comparison, expressed little or no Tie or VEGF. The significant upregulation of VEGF and Tie in AVMs may indicate some ongoing angiogenesis, possibly contributing to the slow growth and maintenance of the AVM, and could be of potential use in the therapeutic targeting of these lesions.

Long-term survival of 1986 patients with intracranial meningioma diagnosed from 1953 to 1984 in Finland. Comparison of the observed and expected survival rates in a population-based series

Intracranial meningioma was diagnosed and histologically verified in 1986 patients, 597 men and 1389 women, between 1953 and 1984 in Finland. The closing date of this survival study was December 31, 1987, and the follow‐up was complete. Meningiomas, usually slowly growing and surgically curable benign tumors, caused considerable short‐term mortality, with a relative survival rate (RSR) of 83% at 1 year, and slight but continual long‐term mortality, with RSR of 71% at 15 years. From 1979 to 1984, when computed tomography (CT) was available, the mortality at 3 months for the patients who had surgical procedures was 2% in those younger than 45 years and 10% in those older than 64 years; patients who did not have operations had 1‐year mortality of 61%. The short‐term and long‐term excess mortalities are associated significantly with old age, no surgical procedure, and the period of diagnosis; the long‐term excess mortality also is associated with male gender.

Long-Term Prognosis of Haemangioblastoma of the CNS: Impact of von Hippel-Lindau Disease

Summary¶ The aim was to assess the frequency of von Hippel-Lindau disease (VHL) and the long-term prognosis of VHL and non-VHL patients among 110 consecutive patients with haemangioblastoma (HB) of the CNS treated between 1953 and 1993 at one neurosurgical unit. To reveal VHL manifestations we performed a detailed clinical and radiological examination (neuraxis and abdomen) (61/110), VHL-gene mutation analysis (40/110), and collection of all available clinical, imaging, operative and autopsy data from the hospitals involved. All patients were followed-up with a median of 14 years (excluding 14 operative deaths), and no patient was lost to follow-up. Altogether 49 patients died during the follow-up. In the 14 VHL patients (13%), HB(s) of the CNS were detected at a median age of 33 years, retinal HB(s) at 39 years, and renal cell carcinoma (RCC) at 43 years. The frequency of VHL in patients operated on for HB(s) was 29% before the age of 25 years, 19% between 25 and 45 years, and only 2% after 45 years. HB patients not meeting the VHL criteria had internal organ cysts in 14%. One non-VHL patient (4%) had two adjacent HBs in the same cyst wall. The growth rates of non-VHL and VHL-related HBs were similar as indicated by the median time to recurrence and the proliferation indices (MIB-1). Recurrence of the HB in patients whose primary operation was considered radical developed in four of the 10 VHL patients at a median of 19 years, and in nine of the 74 non-VHL patients at a median of 11 years. The median length of life of all VHL and non-VHL patients was 46 and 63 years, respectively. In VHL, RCC and HBs were equal causes of death.

Outcome of 31 intracranial haemangiopericytomas: Poor predictive value of cell proliferation indices

SummaryCell proliferation indices of 31 primary intracranial haemangiopericytomas (HPC) and their recurrences and metastases were correlated with the long-term recurrence, metastasis and survival rates. Paraffin-embedded specimens were used for K-67, PCNA and p53 immunostainings and for estimation of S-phase fraction (S-PF) in flow cytometry. The median Ki-67 and PCNA indices and S-PFs were 10.4, 3.2, and 4.0 for primary HPCs and 14.1, 14.1, and 5.5 for recurrences, respectively. High indices were associated with higher recurrence, metastasis and death rates, but not at the p ≤ 0.5 level. Consequently, these indices do not seem useful in planning of treatment and follow-up of meningeal HPCs. Meningeal HPCs, in contrast to meningiomas, recur almost always despite seemingly complete removal and often metastasize elsewhere in the body. This difference between two sharply demarcated tumours must reflect particularly adhesive and infiltrative properties of HPC cells and not just higher proliferation potential.

Structure-function relationships in the ezrin family and the effect of tumor-associated point mutations in neurofibromatosis 2 protein

Ezrin, radixin and moesin (ERM proteins) link cell adhesion molecules to the cytoskeleton, modulate cell morphology and cell growth and are involved in Rho-mediated signal transduction. Merlin, the tumor suppressor in neurofibromatosis 2, is a diverged member of the ezrin family, but its function is at least partially similar to the ERM proteins. In the N-domain, the ezrin family belongs to the band 4.1 superfamily. Secondary structure predictions made separately for the ezrin and band 4.1-tyrosine phosphatase families give a similar pattern for the homologous N-domains, indicating that both families have a similar binding site for the integral membrane proteins. The alpha-domain shows a strong coiled-coil prediction, that can be involved in the protein dimerization. The C-terminal actin-binding site in the ERM proteins and the actin-binding helix in the villin headpiece have a common amino acid motif. In merlin, the published tumor-associated single amino acid mutations in the N-domain are located in the conserved sites, and they affect mainly the predicted helices and strands, indicating that these mutations cause the disease primarily by disturbing the protein structure. In the alpha- and C-domains, some of the mutations break the helical structures. Some known mutations are observed at a site potentially interacting with cell adhesion molecules. We will also discuss the implications of the evolutionary information and the actin-binding models in the ezrin family.

A population‐based study on the incidence and survival rates of 3857 glioma patients diagnosed from 1953 to 1984

Intracranial glioma was diagnosed during the patients life and histologically verified in 3857 patients between 1953 and 1984 in Finland. Their survival up to the end of 1987 was analyzed, the follow‐up being complete. The treatment was by operation in 1193 cases, radiation in 459 cases, both operation and radiation in 1486 cases, and neither operation nor radiation in 719 cases. The 1‐year, 5‐year, 10‐year, and 15‐year cumulative relative survival rates were 0.53, 0.29, 0.20, and 0.18, respectively. The newborn to 14‐year‐olds lost 56% of their life expectancy; the 15‐year‐olds to 44‐year‐olds, 71%; the 45‐year‐olds to 64‐year‐olds, 88%; and the 65‐year‐olds to 99‐year‐olds, 91%. According to the model with the best fit in regression analysis the prognosis was significantly better among young, recently diagnosed patients who had undergone both operation and radiation.

Genetic aberrations in sporadic and neurofibromatosis 2 (NF2)-associated schwannomas studied by comparative genomic hybridization (CGH).

Summary¶ Background. Schwannomas occur sporadically or in association with neurofibromatosis 2 (NF2), an autosomal dominant disorder, which predisposes to multiple schwannomas, meningiomas and spinal ependymomas, with bilateral vestibular schwannomas as the classic hallmark. As NF2 and sporadic schwannomas differ in some respect in their clinical and biological behavior we evaluated whether there are any differences in the distribution of genetic aberrations between NF2 and sporadic schwannomas. Our interest was also to verify whether secondary genetic alterations besides the loss of 22q could be detected in schwannomas. Methods. We investigated DNA copy number changes in 25 schwannomas (12 NF2 and 13 sporadic schwannomas) using the comparative genomic hybridization (CGH) technique. Some chromosomal regions were further studied by LOH or FISH analysis. Findings. CGH detected genomic abnormalities in 15 of 25 schwannomas (60%). The most common alteration was loss on 22q, found in 32% (8/25) of schwannomas. No consistent changes were detected in other chromosomal regions. The overall number of genetic aberrations was similar in NF2 and in sporadic schwannomas. Interpretation. Our results support the present view that loss of chromosome 22q harboring the NF2 gene plays a universal role in the pathogenesis of schwannomas without consistent involvement of other chromosomal regions.