Promoter hypermethylation-mediated down-regulation of RUNX3 gene in human brain tumors.

BACKGROUND: The Runx family proteins, including RUNX3, are tissue-restricted transcription factors and play role in neuronal development and tumorigenesis. RUNX3 has an important role in glioblastoma (GBM) tumorigenesis because of its promoter hypermethylation. AIM: We aimed to evaluate the methylation-mediated expression regulation of RUNX3 gene in brain tumors. PATIENTS AND METHODS: Cases of meningiomas WHO grade III (3), anaplastic astrocytomas (3), diffuse astrocytoma (3), and GBM (12) were recruited into this study. Real-time quantitative PCR was performed for analyses of DNA promoter methylation and analyses of methylation-mediated expression status of RUNX3 gene was performed by real-time quantitative RT-PCR. RESULTS: There was no significant difference between methylated and unmethylated quantitative ratio of RUNX3 gene promoter region and also no significant difference in relative ratio of RUNX3 gene expression in brain tumor groups. Methylated and unmethylated ratio in anaplastic astrocytoma, diffuse astrocytoma, GBM, meningioma (WHO grade III) and in all groups were; 1.44, 1.09, 1.51, 1.52 and 1.43, respectively. One allele was found methylated necessarily. No methylation was detected in one case of GBM group and one case of anaplastic astrocytoma group. There was no unmethylated promoter in one of the GBM cases. There were significant differences between relative ratio of RUNX3 gene expression and methylated/unmethylated ratio rates for all cases (p = 0.001) and GBM groups (p = 0.041). CONCLUSION: This study overemphasized the RUNX3 gene importance in brain tumors, due to the existence of at least one methylated allele.

Langerhans' cell histiocytosis of the temporal lobe and pons.

Intracerebral Langerhans' cell histiocytosis (LCH) is rare and tends to involve the hypothalamus. The authors report a rare case of LCH in the temporal lobe that subsequently was followed by a brainstem lesion. This appears to be the first case of temporal lobe and brainstem LCH that has been treated successfully and published. A 24-year-old man complained of cacosmia and nausea with a slight headache. He had a left temporal LCH, which was removed completely, but developed a brainstem lesion a year later. The pontine LCH was treated with radiosurgery. The follow-up period was 4 years without any neurological or radiological symptoms or signs. The 12 cases of solitary intracranial non-hypothalamic LCH reported previously are reviewed. Gamma knife radiosurgery effectively controlled the local growth of the pontine LCH without adverse effect.

Failure to detect Chlamydia pneumoniae DNA in cerebral aneurysmal sac tissue with two different polymerase chain reaction methods.

OBJECTIVE: Chlamydia pneumoniae (C pneumoniae) is a common cause of a usually mild, community acquired pneumonia. This organism, however, can spread from the respiratory tract into other parts of the body and has been detected in up to 70% of atheromatous lesions in blood vessels. Although the exact mechanism of the C Pneumoniae contribution to the pathogenesis of atherosclerosis remains unknown, prophylactic antibiotic trials are planned for people at high risk for coronary disease. METHOD: In this study the authors aimed to investigate C pneumoniae DNA content in the cerebral aneurysmal sac tissue with the aid of polymerase chain reaction (PCR) method. C pneumoniae DNA was searched in 15 surgically clipped and removed aneurysmal sac tissue and in two tumour (an ependymoma of the fourth ventricle and a craniofaringoma) samples by touchdown enzyme time release PCR (TETR PCR) targeting 16S rRNA gene and by nested PCR targeting ompA gene. RESULTS: Both PCR methods were sensitive to detect in C pneumoniae 4x10(-2) genomes. C pneumoniae DNA was not detected in any of the 17 sample tissues of these patients. CONCLUSION: The contribution of C pneumoniae in the development of intracranial aneurysms cannot be excluded despite the results of this study. Further studies on the possible role of C pneumoniae or any other micro-organisms in the pathogenesis of aneurysms should be performed.

Efficacy of controlled-release papaverine pellets in preventing symptomatic cerebral vasospasm.

OBJECT: Vasospasm as a complication of subarachnoid hemorrhage is a major concern in clinical practice. The systemic drugs in current use are of limited value. Topical, intrathecal, or intraarterial papaverine administered during surgical or angiographic procedures is a potent vasodilating drug; however, hypotension limits its systemic application. Local application of papaverine in a biodegradable controlled- or sustained-release matrix is proposed for vasospasm prophylaxis to be used in patients scheduled for aneurysm surgery. METHODS: Controlled-release papaverine (PapaCR) drug pellets were prepared using the biodegradable aliphatic polyester poly(DL-lactide-co-glycolide) as the carrier matrix. In vitro tests were performed to determine drug kinetics. One hundred seventeen patients, 73 assigned to the control group and 44 assigned to the PapaCR-treated group, participated in this study. Patients who were deemed to be at high risk for the development of vasospasm were selected to participate in the study. During aneurysm surgery, drug pellets were placed in cisterns over arterial segments. In two patients, cerebrospinal fluid was sampled every 6 hours for the first 5 days through a lumbar catheter that had been inserted at the beginning of aneurysm surgery. The incidence of clinical vasospasm and Glasgow Outcome Scale scores in the patients were evaluated statistically. The results of in vitro studies showed that effective local concentrations of papaverine could be maintained for more than 10 days. The first-degree drug-release profile was demonstrated using this design. In clinical studies no adverse effects due to the drug were seen. The PapaCR effectively prevented development of clinical vasospasm. and outcome scores were significantly better in patients in the treated group. CONCLUSIONS: Local application of controlled- or sustained-release papaverine can be safely used in preventing vasospasm.

Spinal hydatid disease.

Vertebral hydatid cysts are rare and found in less than 1% of all the cases of hydatidosis. Neural compression is common in vertebral hydatidosis. The prognosis is generally regarded as very poor. This paper examines the natural history and complications which may arise during the treatment of vertebral hydatid cyst, and discusses their treatment. Thirteen cases of hydatid disease affecting the vertebrae are presented. The patients were admitted with symptoms of spinal cord compression. Twelve were treated by laminectomy and one by costotransversectomy. Low back pain radiating to the legs and lower extremity weakness were the predominant symptoms. Different degrees of pareses were present in 12 patients. Nine patients had impaired sensation in lower extremities. In 13 patients, 27 operations were performed. The major complication of surgery was the death of one patient due to the formaline irrigation. The surgical goal should be an extensive removal of the cysts and affected bone. The surgical area needs to be irrigated with hypertonic saline. Mebendazole or albendazole therapy seems to retard the recurrences and control the disease.

Surgery of intramedullary spinal cord tumors.

The diagnosis and management of intramedullary spinal cord tumors have been significantly influenced by new diagnostic and surgical tools such as MRI, ultrasonic aspiration, intraoperative ultrasound, and evoked potential monitoring. In this study we compared the surgical results of our earlier cases using conventional methods with more recent cases using these new methods. We report our experience based on 44 adult cases. Histologic diagnosis revealed ependymoma (20 cases), astrocytoma (15 cases), glioblastoma multiforme (1 case), and other histologic diagnoses (8 cases). We performed 20 gross total resections, 19 partial resections, and 5 biopsies. The mean follow-up period was 25.8 months (3 months-10 years). Surgical results were improvement in 11 patients (25%), stabilization in 24 (54%), and deterioration in 9 (20%). The first 28 cases (group A) were diagnosed using conventional myelography and CT myelography. The more recent 16 cases (group B) were diagnosed with MRI and operated on using techniques such as ultrasonic aspiration, intraoperative monitoring and ultrasound imaging. Radical surgery (total excision) was performed in 36% (n = 10) of group A, while it was possible in 62% (n = 10) of group B. Deterioration after operation was noted in 28% (n = 8) of group A, but only 6.2% (n = 1) of group B. These results stress the importance of a preoperative MRI scan and the positive effects of intraoperative ultrasound imaging, ultrasonic aspiration, and evoked potential monitoring on surgical results. With the help of these tools, most intramedullary spinal cord tumors may be diagnosed and treated surgically with significantly decreased risk. Radical surgery was possible in as many as 62% of our more recent patients. Partial resection with radiotherapy should be confined to patients with high-grade astrocytomas.

An experimental trial of cyclic nucleotides on multicellular spheroids derived from human brain tumours.

The effects of cyclic nucleotides, dibutyryl cyclic adenosine monophosphate and dibutyryl cyclic guanosine monophosphate (db-cAMP and db-cGMP), on the growth rate of multicellular tumour spheroids were evaluated by comparing the growth delay and colony forming efficiency in vitro. Multicellular tumour spheroids were derived directly from human brain tumours. To compare the chemotherapeutic effect of cyclic nucleotides, CCNU was used as a known effective cytotoxic drug on malignant gliomas. Significant growth delay was obtained by db-cAMP (p less than 0.001) while CCNU was tumouricidal rather then producing a delay in growth of the tumour spheroids. Db-cGMP found not to be effective in decreasing the growth rate of the tumour spheroids in vitro (p greater than 0.2). The role of cyclic nucleotides in brain tumours is discussed on a review basis.

The failure of human leukocyte interferon to influence the growth of human glioma cell populations: in vitro and in vivo studies.

Five high-grade (3 grade III and 2 grade IV) astrocytoma tumour cell populations were treated with a preparation of Human Leukocyte Interferon either in monolayer cell culture or as multicellular spheroids in vitro or as xenografts growing in immune-deprived mice in vivo. A moderate and transient sensitivity was seen in one grade III tumour when tested in both of the in vitro assays, but no inhibition of growth was seen in vivo. Two tumours which were apparently resistant to Interferon treatment responded to orthodox chemotherapy. When used in conjunction with BCNU, Interferon was not effective in prolonging delay in tumour growth. It is concluded that Interferon is unlikely to be an effective agent in the treatment of malignant brain tumours.

Multicellular tumour spheroids derived from human brain tumours.

Multicellular tumour spheroids were prepared from a total of 46 human brain tumour biopsies by collagenase digestion and plating into agar coated flasks. Both primary malignant and secondary tumours formed spheroids with some correlation between the malignancy of tumour and the ability to undergo spheroid formation. The spheroids were capable of progressive growth, the rate of which was dependent, to some extent, on environmental conditions and was reflected by an increase in cell number within the spheroids. Spheroids prepared in this way may prove to be useful models for in vitro chemosensitivity and the general biology of brain tumours.