Long-term survival and transmission of INI1-mutation via nonpenetrant males in a family with rhabdoid tumour predisposition syndrome.

Rhabdoid tumour predisposition syndrome (RTPS) is a rare syndrome caused by inheritance of a mutated INI1 gene for which only two multigeneration families have been reported. To further characterise the genotype and phenotype of RTPS, we present a third family in which at least three cousins developed an atypical teratoid/rhabdoid tumour (AT/RT) at a young age. Two of these patients showed unusual long survival, and one of these developed an intracranial meningioma and a myoepithelioma of the lip in adulthood. Mutation analysis of INI1 revealed a germline G>A mutation in the donor splice site of exon 4 (c.500+1G>A) in the patients and in their unaffected fathers. This mutation prevents normal splicing and concomitantly generates a stop codon, resulting in nonsense-mediated mRNA decay. Biallelic inactivation of INI1 in the tumours, except for the meningioma, was confirmed by absence of nuclear INI1-protein staining. The myoepithelioma of one of the patients carried an identical somatic rearrangement in the NF2 gene as the AT/RT, indicating that both tumours originated from a common precursor cell. In conclusion, this study demonstrates for the first time transmission of a germline INI1-mutation in a RTPS family via nonpenetrant males, long-term survival of two members of this family with an AT/RT, and involvement of INI1 in the pathogenesis of myoepithelioma.

Giant Brunner's hamartomas of the duodenum and obstructive jaundice. An overview of the literature and suspicion of malignancy in a case.

BACKGROUND/AIMS: 150 cases of Brunner's gland hamartoma (BGH) have been reported in the literature. BGHs are benign and are thought not to cause bile obstruction. METHODS: In this case report, a 60-year-old male is presented with unexplained obstructive jaundice who was also known for over 17 years with diffuse adenomatous hyperplasia of Brunner's glands in the duodenum. Despite the benign preoperative diagnosis, the choice of treatment was Whipple's procedure due to suspicion of a coexisting malignancy. RESULTS: Pathological analysis of the resection specimen revealed multiple BGHs and an adenocarcinoma of the papilla of Vater (PoV). Molecular pathology using loss of heterogeneity analysis was used to confirm that both were different entities. CONCLUSION: It is likely that previous reports of malignant degeneration of BGHs may actually have been cases involving the coexistence of a PoV adenocarcinoma. Physicians need to be alert when a patient presents with BGH accompanied with obstructive jaundice for simultaneously occurring PoV adenocarcinoma.

[Guideline 'Leptomeningeal metastases of solid tumours']. / Richtlijn 'Leptomeningeale metastasen van solide tumoren'.

In view of recent progressive insight in the diagnosis and treatment of leptomeningeal metastases of solid tumours, a new guideline has been designed on the initiative of the Dutch Association of NeuroOncology and the Netherlands Society of Neurology, with methodological support from the Dutch Institute for Healthcare Improvement (CBO). - There are no neurological symptoms or signs, nor MRI characteristics that are unique to leptomeningeal metastasis. However, clinical suspicion of leptomeningeal metastasis in a patient known to have cancer, in combination with specific MRI characteristics is sufficient to make the diagnosis. If MRI or CT results are negative or inconclusive cerebrospinal-fluid assessment should be conducted. - Management of care of patients with leptomeningeal metastasis without brain metastases can be based on a series of categories that have been developed using prognostic factors such as Karnofsky performance status, serious encephalopathy or neurological dysfunction, systemic disease, sensitivity of the tumour for chemotherapy or hormonal treatment - In the context of meaningful palliation, systemic treatment, if necessary in combination with radiotherapy to clinically relevant sites, is preferable to intrathecal chemotherapy. - Intrathecal chemotherapy combined with local radiotherapy is recommended if effective systemic treatment is not available, and if the tumour is potentially sensitive to methotrexate, cytarabine or thiotepa. The combination of intrathecal methotrexate and whole-brain radiotherapy should be avoided.

Stable incidence of childhood and adult glioma in The Netherlands, 1989-2003.

Time trends in the incidence of glioma may reflect changes in the prevalence of environmental risk factors for glioma. We therefore investigated trends in the incidence of childhood and adult glioma in The Netherlands from 1989 to 2003. We used population-based incidence data from the Netherlands Cancer Registry. We calculated European standardised incidence rates for glioma, and stratified for age, gender and glioma subgroups. Changes in the incidence were estimated by calculating the Estimated Annual Percentage Change. Similar to other countries, the overall incidence of glioma was fairly stable in The Netherlands during the period 1989 to 2003, for both children and adults. In adult astrocytic glioma, a significantly increasing incidence of high-grade astrocytoma was balanced by simultaneous decreases of low-grade astrocytoma, astrocytoma with unknown malignancy grade and glioma of uncertain histology. Most of these time trends can be explained by improving detection and diagnostic precision. Stable incidence rates of adult and childhood glioma suggest that no major changes in environmental risk factors have occurred, which influenced the incidence of glioma in the studied period.

Hypertension as a risk factor for glioma? Evidence from a population-based study of comorbidity in glioma patients.

BACKGROUND: Little is known about the aetiology of glioma. Research is often hampered by the low incidence and high mortality of the disease. Concomitant diseases in glioma patients may indicate possible aetiological pathways. We therefore studied comorbidity in glioma patients. PATIENTS AND METHODS: We performed a case-control study using population-based data from the Eindhoven Cancer Registry. We compared prevalences of concomitant diseases in 510 glioma patients with two reference cancer populations from the same registry. RESULTS: Compared with all other cancer patients, a significantly higher prevalence of hypertension was found in glioma patients for age categories 60-74 years [odds ratio (OR) 1.37; 95% confidence interval (CI) 1.02-1.84] and 75+ years (OR 2.37; 95% CI 1.34-4.21). The association was most pronounced in elderly men and in astrocytic glioma, with a maximum in age category 75+ years (OR 5.86; 95% CI 2.20-15.7). The prevalence of cerebrovascular disease was higher in glioma patients >45 years old (OR 1.67; 95% CI 1.12-2.47), whereas the prevalence of other cancers was lower (OR 0.64; 95% CI 0.48-0.87). No consistent associations were detected for several other concomitant diseases. CONCLUSIONS: Our data suggest an association between hypertension and glioma, although questions remain about causality and the possible mechanisms. We hypothesise that this association is mediated through potentially neurocarcinogenic effects of antihypertensive medication.

Inverse correlation between genetic aberrations and malignancy grade in ependymal tumors: a paradox?

OBJECTIVE: The goal of our study was to investigate the inverse correlation between number of genetic aberrations and malignancy grade in ependymal tumors at the ploidy level. METHODS: we examined seven myxopapillary ependymomas (mpEs) (WHO grade I), 28 spinal and cerebral ependymomas (Es) (WHO grade II), and 18 cerebral anaplastic ependymomas (aEs) (WHO grade III) using image DNA cytometry. The ploidy status was correlated with clinicopathological characteristics and with the results obtained by comparative genomic hybridization (CGH) analysis that we performed in about half of these tumors. RESULTS: mpEs were exclusively located in the spinal cord and aEs in the cerebrum only, whereas Es were located in both the spinal cord and brain. We found aneuploidy or tetraploidy to be common in the group of mpEs (6 out of 7) and much less frequent in Es (6 out of 28) and aEs (4 out of 18). Three-year postoperative survival was 100% for mpEs, 100% for spinal Es, 92% for cerebral Es, and 33% for aEs. Our CGH results in a selection of these tumors revealed the highest number of genetic aberrations in the mpEs (average 16; n = 2), a lower number in Es (average 12; n = 11) and the lowest number in aEs (average 5; n = 6). Interestingly, in the group of Es and aEs, a high number of genetic aberrations as detected by CGH was not correlated with aneuploidy or tetraploidy. Three patients, all with mpEs had local seeding. CONCLUSION: These results underline that mpEs are distinctly different from Es and aEs at the genetic level and that extensive genomic alterations and aneuploidy in ependymal tumors are not in itself an indicator of malignant behavior.

Contrast enhancement in Lhermitte-Duclos disease of the cerebellum: correlation of imaging with neuropathology in two cases.

Lhermitte-Duclos disease (LDD), also known as dysplastic gangliocytoma, is a rare cerebellar lesion. It has long been regarded as avascular. We report two patients with surgically proven LDD in whom contrast enhancement was observed on MRI. Neuropathological examination revealed proliferation of veins. We suggest that peripheral enhancement of LDD probably reflects vascular proliferation of the cerebellar venous draining system, and should be considered part of the imaging features of LDD.

Critical illness polyneuropathy and myopathy (CIPNM): evidence for local immune activation by cytokine-expression in the muscle tissue.

In a longitudinal prospective study a muscle biopsy was taken from 30/32 (33%) of the 98 patients who developed critical illness polyneuropathy and myopathy (CIPNM). Neuropathic changes were found in 37%, myopathic in 40%, and a combination in 23% of the biopsies. The immunohistopathology showed macrophages and Th-cells in 40% and 60% of the muscle biopsies respectively. Small mainly perivascular infiltrates contained macrophages and Th-cells. ICAM-1, VCAM and MAC were found on the vascular endothelium in 58%, 53% and 79% respectively. In all biopsies there was an upregulation of both HLA-I and HLA-DR. Proinflammatory cytokines and TNFalphaR75 were also produced locally (IL-1beta in 71%, IFN-gamma in 40%, IL-12 in 73%, TNFalphaR75 in 90%). The anti-inflammatory cytokine IL-10 was simultaneously expressed in 96% of the biopsies. HLA-DR, TNFalphaR75 and IL-10 differed significantly when compared with control muscle biopsies. Our data provide evidence that small numbers of activated leukocytes producing both pro- and anti-inflammatory cytokines infiltrate skeletal muscle of CIPNM patients. We propose that the local balance of leukocyte activities is of importance in the pathophysiology of muscle weakness in CIPNM.

[The indispensable anamnesis: in-vitro fertilization in a woman under treatment for melanoma]. / De onmisbare anamnese; in-vitro fertilisatie bij een vrouw onder behandeling wegens melanoom.

A couple consulted the gynaecologist repeatedly because of a primary fertility disorder. When they had desired children for 8 years, no pregnancy had yet occurred. In-vitro fertilization (IVF) treatment was started. A few days after the beginning of the hormonal treatment that precedes the IVF procedure, the woman noted a swelling in the right inguinal area for which she consulted the surgeon. This swelling was found to be a metastasis of a melanoma that had been removed from her leg 6 months previously. The gynaecologist was not aware of this case history and the surgeon was not informed of the started IVF treatment. As was found later, this was in accordance with the couple's wishes. The first IVF treatment resulted in a pregnancy that ended with the birth of a healthy boy. The placenta showed melanomatous metastases and the mother died 2 months after the birth of her son.

Chemical analysis of an epidermoid cyst with unusual CT and MR characteristics.

Chemical analysis of the contents of a so-called bright epidermoid of the posterior fossa with unusual CT and MR imaging characteristics suggested that a combination of high protein content and high viscosity were responsible for the atypical imaging findings.

Thrombosis of the deep cerebral veins: CT and MRI findings with pathologic correlation.

Deep cerebral vein thrombosis can present with acute, severe neurological symptoms and may be rapidly fatal as in the 20-year-old woman reported here. Although MRI is superior for establishing the diagnosis, CT is usually the first examination performed in the clinical setting. It is therefore important to recognise certain indicators such as extensive bithalamic low density. These and certain other less specific signs are correlated with the MRI and autopsy findings.

Giant chondroma of the falx. Case report and review of the literature.

The authors describe the radiological and pathological features in a patient with an intracranial chondroma originating in the falx cerebri. Diagnostic procedures and management in treatment are discussed, and a review of the literature is presented.

[Apolipoprotein E polymorphism and Alzheimer disease]. / Apolipoproteïne E polymorfisme en de ziekte van Alzheimer.

At present a reliable and specific diagnostic test of Alzheimer's disease is not available. Thus far, diagnosis is based on clinical criteria despite their occasional inadequacy. Post mortem search for neuropathological hallmarks can establish the diagnosis with certainty. In the present case control study we performed an apoE genotyping for 21 patients, divided into an Alzheimer-positive and an Alzheimer-negative group after neuropathological search. As described in the literature, the apoE-epsilon 4 allele was overrepresented in the Alzheimer-positive group, while in the Alzheimer-negative group the apoE-epsilon 3 allele dominated. The epsilon 4 allele of the apoE gene may be considered as a biological risk factor for the development of Alzheimer's disease. Especially in geriatric patients with cognitive impairment, apoE genotyping seems to be a supplementary tool for risk assessment.

[Acute myopathy during treatment of status asthmaticus]. / Acute myopathie tijdens behandeling wegens status asthmaticus.

Two patients with chronic pulmonary disease, a woman of 38 and a man of 54 years old, who had developed a status asthmaticus, had difficulties being weaned from artificial ventilation. They suffered from an acute myopathy caused by a combination of high-dose corticosteroids and muscle relaxants (pancuronium, vecuronium). This acute myopathy is characterised by generalised flaccid quadriplegia with muscle atrophy and areflexia, difficulties being weaned from artificial ventilation, myoglobinuria and high levels of creatine kinase activity in serum. The prognosis is good; almost complete recovery occurs. Muscle biopsy may reveal necrotising myopathy and occasionally, selective loss of thick myofilaments.

Primary leiomyosarcoma of the spine.

We present a 39-year-old man with tumour of the eighth thoracic vertebra, causing compression of the spinal cord. The tumour proved to be a primary leiomyosarcoma (LMS) of bone, an uncommon neoplasm; to our knowledge this is the first report of primary LMS in the spine. The lesion was documented by plain radiography, myelography, CT, MRI and digital subtraction angiography. These investigations did help to focus on the differential diagnosis and demonstrated the extent of the bony lesion, the findings were nonspecific, and the correct diagnosis was established by pathological examination.

The enigmatic origin of olfactory schwannoma.

We present a case of so-called olfactory schwannoma in a 17-year-old male. The diagnostic procedures included computed tomography and digital subtraction angiography. Histological examination with tumor markers, S100, Leu-7 (CD57) and EM showed the tumor tissue to be a schwannoma. Arguments are raised that olfactory schwannomas are comparable to or even occur as intracerebral schwannomas with frontal localisation.

A miniaturized cuff electrode for electrical stimulation of peripheral nerves in the freely moving rat.

A bipolar cuff electrode for electrical stimulation of small diameter peripheral nerves is described. The cuff is made of a highly flexible rubber-impression material, and the electrode assembly is suited for chronic implantation. Its manual construction is easy and reliable, utilizing only simple tools. The cuff completely envelopes nerves of varying diameter and requires a minimal amount of manipulations of the nerve, thereby reducing the chance of surgical trauma. The snug envelope prevents the nerve from drying, and minimizes shunting between the two leads by extracellular fluids. Small outer dimensions were achieved: 1.4 x 1.1 x 2.3 mm (width x height x length) when used with nerves of 1 mm diameter, which minimizes pressure and damage to surrounding tissues. Morphometric analysis of nerves enclosed in cuffs for 28-30 h revealed a small decrease in the number of large-diameter fibers. Stimulation thresholds remained, however, constant throughout the experiments.