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Brain tumours.

Brain tumours are uncommon but not rare. They occur particularly in the young and the middle aged. Rather more than 50 per cent are malignant with poor prognosis in spite of surgery, radiotherapy, and chemotherapy. However, benign brain tumours can in general be cured. Early diagnosis and treatment are important in diminishing the morbidity and mortality rates in the latter group and in providing better palliative management in the former. Advances in neuroradiology, particularly the development of CT, have made early diagnosis possible, given clinical awareness of the syndromes of brain tumour on the part of the physician. New methods of accurate CT-controlled surgery for glioma have also been introduced. Advances in adjuvant methods of radiotherapy, with radiation sensitizers or interstitial implantation, and of chemotherapy by tailoring the drug regimen to an individual patient and by targeting agents specifically to brain tumour, are being sought while the feasibility of fresh modes of immunotherapy has been tested. These developments hold some hope that results for malignant glioma may improve in the forseeable future.

Adenoma↗

Current and future developments in the use of temozolomide for the treatment of brain tumours.

Brain tumours comprise only 2% of all adult cancers, but they are among the most debilitating malignant diseases. Temozolomide, an alkylating agent that can be administered orally, has been approved for the treatment of recurrent malignant glioma on a daily schedule for 5-day cycles. Continuous administration schedules with a higher dose intensity are being explored, but an improvement in efficiency remains to be shown. The benefit from temozolomide given as a single agent in recurrent disease will be several weeks at best. This drug is therefore now undergoing clinical testing as neoadjuvant chemotherapy or with concomitant radiotherapy in patients with newly diagnosed glioma. Several phase I trials are investigating the combination of temozolomide with other agents active against brain tumours. This review briefly summarises the pharmacological background and clinical development of temozolomide and focuses on current and future clinical exploration of this drug for the treatment of brain tumours.

Antineoplastic Agents, Alkylating↗

Polymers to treat brain tumours.

Brain tumours are difficult to treat by conventional methods. A biodegradable polymer, poly-[bis(p-carboxyphenoxy)propane sebacic acid] with a nitrosourea, carmustine, has been demonstrated to be biocompatible in the brains of experimental animals and to release drugs in a predictable sustained manner. Carmustine impregnated in polymers appears to be more effective than when delivered by standard methods. A Phase I clinical study has demonstrated the safety of this approach in treating brain tumours and a Phase III placebo-controlled study is currently underway. Other applications of the polymer in the treatment of brain diseases are discussed.

Animals↗

Iodine-125 interstitial irradiation of virally induced dog brain tumours.

Brain tumours were induced by intracerebral inoculation of beagle puppies with Avian sarcoma virus (ASV) suspension. The inoculation produced solitary or multiple sarcomas in three dogs and intraventricular anaplastic gliomas in four dogs. At the time of the first tumour positive CT-control Iodine-125 seeds (activity 8.5-10.5 mCi) were placed into the lesion. The radioactive Iodine-125 implants produced sharply delineated calcifying necroses with vital unaffected tumour outside the necrosis. The necrotizing and calcifying effect was apparent after 18 days and complete after 97 days when a transitional zone was no longer detectable. The response of neoplastic tissue to low dose rate interstitial irradiation was distinctly different in terms of the volume of necrosis when compared with Iodine-125 radionecroses in healthy brain tissue.

Animals↗

Differential CD44 expression patterns in primary brain tumours and brain metastases.

Splicing variants of CD44 (CD44v) are increasingly recognised as metastasis-promoting factors in rodent and some human cancers. However, the frequency for CD44v expression in human cancers and their metastases and the status of CD44v expression in low or non-metastatic tumours is still uncertain. To address this issue, we investigated CD44 expression patterns in brain metastases (BMTs) spread from more than ten organs and five types of primary brain tumours (PBTs) by Northern blot, reverse transcription-polymerase chain reaction (RT-PCR) and immunocytochemical analysis. The results demonstrated that all of the 56 PBTs examined express standard form of CD44 (CD44s) but none of them express CD44v. In contrast, 22 of 26 BMTs studied were found with CD44v expression. Our data thus present direct evidence of a general distribution of CD44 in BMTs but suggest that such expression is an extremely rare event in PBTs. Therefore, the presence or absence of CD44v expression may be related to high or low metastatic potential of human malignancies.

Adult↗

Peri-tumoural hypoxia in human brain: peroperative measurement of the tissue oxygen tension around malignant brain tumours.

Malignant brain tumours contain focal hypoxic areas that may increase their resistance to chemotherapy and radiotherapy. Following surgical excision, the peri-tumoural area will contain residual viable tumour cells, and this area is therefore the logical site for subsequent therapy. The new bioreductive agents are metabolized under hypoxic conditions to produce a cytotoxic species. Peroperative peri-tumoural micro-polarographic measurements have been made to establish the oxygen environment of this region and to determine whether the hypoxic conditions might allow for bioreductive drug activation. The micro-polarographic method is described and results are presented for "normal" white matter (8 patients) to allow comparison with peri-tumoural brain (8 patients) before and after removal of the tumour. The results suggest that peri-tumoural brain (median pO2 10.8 mmHg, 18% pO2 < 2.5 mmHg) is markedly hypoxic in comparison with the "normal" brain (median pO2 15.3 mmHg, less than 2% < 2.5 mmHg), and that surgery improves peri-tumoural oxygenation towards that of the "normal" white matter. It is concluded that the hypoxic peri-tumoural area can provide the conditions under which bioreductive agents may be activated.

Adult↗

Proton magnetic resonance spectroscopy ((1)H MRS) of human brain tumours: assessment of differences between tumour types and its applicability in brain tumour categorization.

Our objective was to evaluate the usefulness of proton magnetic resonance spectroscopy ((1)H MRS) in categorizing brain tumours. In vivo single-voxel (1)H MRS at an echo time of 136 ms was performed in 108 patients with brain neoplasms that included 29 meningiomas (MEN), 15 low-grade astrocytomas (LGA), 12 anaplastic astrocytomas (AA), 25 glioblastomas (GBM) and 27 metastases (MET). Time-domain fitted areas of nine resonances were evaluated in all spectra. Twenty-five additional tumours were prospectively included as independent test set. Differences in at least two resonances were found in all pairwise comparisons of tumour groups except in GBM vs MET. Large lipid resonance at 1.30 ppm was found to be characteristic of GBM and MET, and alanine was characteristic of MEN. Significant differences were found between LGA and AA in choline-containing compounds and total creatine resonances. When implemented in a stepwise algorithm, these findings correctly classified 84% (21 of 25) tumours in the independent test set. Some additional utility was found in glycine/myo-inositol at 3.55 ppm for bilateral differentiation between GBM and MET (9 of 11, 82% correct classification in the test set). (1)H MRS provides useful information to categorize the most common brain tumours that can be implemented in clinical practice with satisfactory results.

Adolescent↗

Role of medical history in brain tumour development. Results from the international adult brain tumour study.

In an international population-based case-control study carried out in 8 centres in 6 countries, we investigated the role of specific medical conditions in the aetiology of brain tumours in adults. Recruited were 1,178 glioma and 331 meningioma cases and 2,493 age- and gender-matched population controls. Only medical conditions occurring at least 2 years before brain tumour diagnosis were considered. Relative risks (RRs) and 95% confidence intervals (CIs) were estimated using a conditional logistic regression model. Heterogeneity between centres was tested. No association between meningioma and previous medical conditions was observed. For glioma, there was an increased risk associated with epilepsy (RR = 6.55, 95% CI 3.40-12.63), but this was considerably weaker for epilepsy of more than 20 years duration. The risk remained elevated after adjustment for use of anti-epileptic drugs. There was a statistically significant inverse association between glioma and all allergic diseases combined (RR = 0.59, 95% CI 0.49-0.71); this was also observed for specific allergic conditions, namely, asthma and eczema. Subjects who reported a history of infectious diseases (e.g., colds, flu) showed a 30% reduction in risk (RR = 0.72, 95% CI 0.61-0.85). The decreased risks for glioma in subjects reporting a history of allergic conditions or infectious diseases may indicate an influence of immunological factors on the development of glioma. The association between glioma and epilepsy has to be interpreted cautiously and needs further investigation.

Adult↗

Brain tumours in man.

Brain tumours occur at all ages but they differ in type depending upon the age of the patient. In adults, probably more than 50% of tumours in the brain are metastatic carcinomas or melanomas. The pathological classification of primary brain tumours depends largely upon the cell type involved. Recently, immunocytochemical identification of cell-specific proteins by the use of polyclonal or monoclonal antibodies has greatly enhanced the accuracy of cell identification within tumours. Primary brain tumours in children arise mainly in the brain stem and cerebellum and are astrocytomas, primitive neuroectodermal tumours (medulloblastomas) and ependymomas. Gliomas form the largest group of primary brain tumours in adults, with an annual incidence of 3.94/100,000 in Southern England. In young adults, well differentiated astrocytomas and oligodendrogliomas arise in the cerebral hemispheres. Poorly differentiated, malignant glial tumours include anaplastic astrocytomas and glioblastoma multiforme; these tumours are most common in older adults with a peak annual incidence of 7.3/100,000 in the sixth decade. The major complication of brain tumours is due to their mass effect from tumour growth and from peritumoral oedema. Surgical excision of gliomas is difficult and usually incomplete due to the infiltrative nature of the tumour. As yet these tumours respond poorly to irradiation and chemotherapy.

Adult↗

'Pseudo-Alzheimer's' and primary brain tumour.

Primary brain tumour may present in the elderly purely as a dementing illness before the onset or detection of sensorimotor neurological symptoms or signs. Although neurological examination may indicate no definite signs, close attention to accepted DSM-IIIR and NINCDS-ADRDA diagnostic criteria for primary degenerative dementia and 'probable' Alzheimer's disease respectively will suggest a process other than a degenerative one. This was the case in two patients with primary brain tumour presenting clinically with dementing illness similar to but distinct from Alzheimer's disease.

Aged↗

Farm-related exposures and childhood brain tumours in seven countries: results from the SEARCH International Brain Tumour Study.

A total of 1218 cases of childhood brain tumours (CBT) and 2223 control subjects from the general population were included in a population-based case-control study conducted in nine centres in seven countries. Mothers were asked about farm- or agriculture-related exposures. Significantly elevated odds ratios (OR) for CBT were associated with children's personal and maternal prenatal exposure while living on a farm with pigs (child OR = 1.7, mother OR = 2.3), horses (child OR = 1.6, mother OR = 1.8), dogs (child OR = 1.5, mother OR = 1.5) and cats (child OR = 1.5, mother OR = 1.7). Children who were exposed to pigs, horses and cats combined, while living on a farm, had a threefold elevated OR for CBT. Increased ORs for primitive neuroectodermal tumours (PNET) were associated with children's farm exposure to dogs (OR = 1.9) and cats (OR = 2.2), and maternal farm exposure to pigs (OR = 4.2). The OR for CBT was elevated (OR = 2.3) for children of mothers who had preconception/prenatal farm- or agriculture-related employment involving potential contact with animals, relative to no farm- or agriculture-related employment. In particular, increased ORs for CBT were observed for children of mothers who were employed as general farmers (OR = 4.1) or general farm workers (OR = 3.8). During the 5 years preceding the index child's birth, maternal exposures were related to CBT, relative to no maternal exposure to agricultural chemicals or animal products: fertilisers (OR = 1.8), pesticides (OR = 2.0), animal manure (OR = 2.0) and unprocessed wool (OR = 3.0). Our findings suggest that various farm-related exposures are positively associated with CBT and warrant further investigation into the public health importance of these associations.

Adolescent↗

Evolving role of myeloablative chemotherapy in the treatment of childhood brain tumours.

Primary brain tumours, a heterogeneous group of cancer that constitute the second most common cancer in childhood, were historically treated with neurosurgical resection and radiation therapy. Chemotherapy has proven to be beneficial for some histological types, which has since led to exploration of the role of high-dose chemotherapy and haematopoietic stem cell rescue. Patients with high-grade glial tumours, primitive neuroectodermal tumours and high-risk medulloblastoma usually fare poorly. The indicators of bad prognosis are metastatic status, extent of resection and age. Children <3 years at diagnosis carry worse prognosis. Rare cancers such as ependymoblastoma, atypical teratoid rhabdoid tumour and choroid plexus carcinoma have a dismal prognosis regardless of the above-mentioned indicators. The use of myeloablative therapy (MAT) has been investigated to improve the rate of long-term DFS, as well as to reduce and delay in the youngest children the use of the craniospinal irradiation associated with unacceptable late effects. We will overview the literature regarding patients with 'good and uncertain indications' to MAT. Ependymoma and brain stem tumours, for which the available data discourage the use of MAT, are excluded. Finally, we will summarize a single Institution experience (Giannina Gaslini Children's Hospital, Genoa) with MAT in the period 1997-2003.

Antineoplastic Agents↗

'Do I have a brain tumour, doctor'?

Brain tumours cause symptoms through raised intracranial pressure, epilepsy and local effects. The progressive worsening of these symptoms and signs is the most important clue to the presence of a tumour.

Brain↗

Calculation of radiation dose enhancement factors for dose enhancement therapy of brain tumours.

When brain tumours are loaded with iodinated contrast media (CM) and exposed to x-rays, the photoelectrons, Auger electrons and fluorescent x-rays from the iodine enhance the radiation dose absorbed by the tumour. A modified CT scanner, the CTX, can be used to localize the tumour and to deliver the dose enhancement therapy. Monte Carlo calculations are presented here of the central-axis radiation depth dose in a brain containing a tumour loaded with an iodine concentration of 5 mg ml-1 and irradiated with the CTX operated at various kV settings. The dose enhancement factor (DEF) is also calculated for various field sizes and for 5 mg ml-1 of gadolinium in the tumour when the CTX is operated at 140 kV. The calculated values of the DEF are close to published experimental results.

Animals↗

N-ras mutation in chemically induced rat brain tumour.

Rat brain tumour was induced by treatment with N-ethyl-nitrosourea. Using Southern blot analysis, restriction fragment length polymorphism of N-ras gene was identified. Comparative studies showed that new restriction site did not occur in the DNA of DMN induced renal and liver tumours. The data suggest that the mutation occurring may be specific to the "target" cell or to the structure of carcinogens.

Animals↗

Lactate dehydrogenase and aspartete transaminase of the cerebrospinal fluid in patients with brain tumours, congenital hydrocephalus, and brain abscess.

The diagnostic value of CSF lactate dehydrogenase and aspartate transaminase in cases of brain tumours (except for CSF AST in the benign tumours), congenital hydrocephalus, and brain abscess is established. Tumour cyst fluids show a higher enzymatic activity than does the CSF. The two enzyme estimations do not help in differentiating the supratentorial from the infratentorial tumours. CSF AST is superior to CSF LD in discriminating the malignant and benign tumours, in so far as the AST is increases selectively in malignancy. Estimates of CSF LD are slightly superior to those of CSF AST, both in incidence of abnormality and the degree of their rise.

Aspartate Aminotransferases↗