FDG-PET on irradiated brain tumor: ten years' summary.

PURPOSE: To evaluate FDG-PET in post-radiotherapy differentiation of tumor recurrence/malignant degeneration and radiation reaction, and to assess the role of PET in terms of survival. MATERIAL AND METHODS: 117 consecutive patients with a total of 156 FDG-PET examinations with positive but non-diagnostic MRI and/or CT were included. Final diagnosis was based on histopathology or correlated with radiologic and clinical follow-up. Brain metastases from lung carcinomas were further studied separately. Survival time was analysed using the Kaplan-Meier method. RESULTS: There were 61 true-positive, 2 false-positive, 15 false-negative, and 51 true-negative PET examinations; 5 positive and 22 negative PET examinations were indeterminate. The positive predictive value of a PET examination was 96% in all and 100% in brain metastases from lung carcinoma. The negative predictive value based on the histopathologic results was 55.6%. Survival time was significantly longer in patients with negative PET. CONCLUSION: FDG-PET is a valuable tool in the detection of tumor recurrence, especially lung carcinoma metastasis. FDG uptake is a prognostic marker.

Gamma knife radiosurgery for patients with multiple cerebral metastases.

Although efficacy of gamma knife radiosurgery has been demonstrated in numerous studies, the policies in patients with multiple metastases seem to be unequivocal. The maintained quality of life, the possibility of short hospitalization and the continuation of a systemic chemotherapy are increasingly important arguments in favor of a minimally invasive radiosurgical approach. These factors are particularly emphasized in patients with a dismal prognosis. The current retrospective analysis was undertaken to summarize the clinical results of radiosurgery in patients with multiple cerebral metastases of various primary cancer. Fractionated whole brain radiotherapy (WBRT) was omitted as prophylactic treatment and applied only in cases with general tumor spread. Clinical data of all consecutive patients (n = 215) who received gamma knife radiosurgery for cerebral metastases between January 2001 and January 2003 at the gamma knife Centers of the Karolinska Hospital and H.M. Queen Sophia Hospital (Sophiahemmet) Stockholm were analyzed retrospectively. 172 patients were treated for multiple metastases (198 treatments). The median prescription dose was 22 Gy (range 14-34 Gy). The Kaplan Meier plot shows a median survival (MST) of 7.8 months for patients with multiple cerebral metastases and 13.7 months for patients with single metastases. There was no relation between survival and number of metastases in patients with multiple metastases. Within this group 11.6% (20/172 patients) developed adverse radiation reactions. Tumor recurrences were documented by FDG-PET in 7 patients (out of 172 patients: 4.1%) after a median latency of 10 months after radiosurgery. In summary, gamma knife radiosurgery provides a highly effective and minimally invasive method to treat patients with multiple cerebral metastases even without prophylactic WBRT. Local control and patient survival in the present series of patients is in accordance with other retrospective series of patients with single and multiple metastases.

Inhibition of DNA synthesis in human gliomas by roscovitine.

The early effect of 1-100 microM roscovitine, a purine analogue and cyclin-dependent kinase inhibitor, was studied on tissue specimens from eight human malignant gliomas. The tissue was incubated immediately after resection with DMEM containing [3H]methylthymidine plus vehicle alone or the proper concentration of roscovitine for 30-90 min. The DNA synthesis rate was assessed by measurement of [3H]methylthymidine incorporation into trichloroacetic acid insoluble material/mg protein/min. In all gliomas, 100 microM roscovitine inhibited DNA synthesis by 71-97% (average 89 +/- 8%, p<0.0001). This inhibitory effect of roscovitine appeared within 30 min of incubation and was concentration dependent.

Induction of a T- and B-cell response against a unique amino acid sequence of the mouse IgG2A hinge region in a MAb-treated patient.

A patient with malignant glioblastoma was treated with intratumoral infusions of the murine MAb425 (IgG2A) directed against the epidermal growth factor receptor. At the 10th infusion, the patient developed somnolence, fever and headache. The symptoms increased during the subsequent 48 hr but then gradually disappeared within a week. The cerebrospinal fluid (CSF) contained increased concentrations of interleukin-2. The main CSF cell subset was CD4 T-cells. A marked blood lymphocyte proliferative response against mouse IgG2A was noted. The reactive T-cell epitope(s) could be localized to a 14 amino acid (RGPTIKPCPPCKCP) long peptide of the hinge region. A B-cell response (IgG antibodies) against this peptide was also induced.

Intratumoral infusion of the monoclonal antibody, mAb 425, against the epidermal-growth-factor receptor in patients with advanced malignant glioma.

Malignant glioblastoma may over-express the epidermal-growth-factor receptor (EGF-R). Normal brain cells show a low or no expression of EGF-R. A mouse monoclonal antibody (IgG2A) (mAb 425) (EMD55900) (Merck KGaA, Bernstadt, Germany) directed against EGF-R was produced for therapeutic use. Eight patients with primary or recurrent, EGF-R-positive glioblastomas entered the study, which was designed to evaluate the clinical effect of the mAb. In order to achieve a high tumor cell saturation, the mAb was injected intratumorally twice weekly through an implantable catheter. The total administered dose varied between 4 mg and 120 mg. In 3 patients with solid tumors, a massive tumor necrosis was noted, with infiltration of macrophages, granulocytes and T cells. A further 3 patients developed clinical and radiological signs of an intense, local, inflammatory reaction. There may be a relation between the mAb dosage and the antitumor effect, insofar as higher doses seemed to cause a more pronounced, inflammatory reaction. Of the 8 patients, 6 developed human, anti-(mouse Ig) antibodies. This anti-EGF-R mAb may induce an intense, inflammatory reaction and a considerable necrosis in glioblastoma. However, the planned schedule could not be completed, even after the dose level was re-adjusted, owing to inflammatory reactions, which were severe without prior tumor debulking.

Polymeric controlled-release amsacrine chemotherapy in an experimental glioma model.

The purpose of this study was to fabricate and investigate amsacrine containing polymeric rods for use in interstitial chemotherapy of malignant glioma. Ethylene vinyl acetate copolymer (EVAc) rods containing 40% amsacrine (AMSA) were fabricated successfully with an extrusion method. In vitro kinetic studies revealed a high level of reproducibility of the production process. The release of AMSA showed a biphasic pattern consistent with a matrix-type controlled-release system with an initial more rapid release rate followed by a slower and more linear release phase. Release of AMSA was observed for over 6 months and the rods continue to release in a stable fashion. In vitro studies using rat glioma (RG2) in cell culture showed that cells treated with AMSA released from the rods were killed in a dose dependent manner indicating that AMSA incorporated into the polymer remained biologically active. In vivo studies of rats with single AMSA rods implanted five days after RG2 tumour implantation revealed histological evidence of an anti-tumour effect as well as an increased survival (p < 0.0003). The mean survival of the amsacrine treated rats was 78 days with 50% still remaining alive > 5 months after implantation. All control animals developed tumours and died within 15-19 days after tumour implantation (mean = 17 days). Amsacrine implanted animals showed no significant histological or clinical evidence of toxicity. We conclude that amsacrine containing EVAc rods can be safely and efficaciously use against the RG2 experimental glioma in a rat model and warrant further investigation.

Loss of heterozygosity in malignant gliomas involves at least three distinct regions on chromosome 10.

A panel of glial tumors consisting of 11 low grade gliomas, 9 anaplastic gliomas, and 29 glioblastomas were analyzed for loss of heterozygosity by examining at least one locus for each chromosome. The frequency of allele loss was highest among the glioblastomas, suggesting that genetic alterations accumulate during glial tumor development. The most common genetic alteration detected involved allele losses of chromosome 10 loci; these losses were observed in all glioblastomas and in three of the anaplastic gliomas. In order to delineate which chromosome 10 region or regions were deleted in association with glial tumor development, a deletion mapping analysis was performed, and this revealed the partial loss of chromosome 10 in eight glioblastomas and two of the anaplastic gliomas. Among these cases, three distinct regions of chromosome 10 were indicated as being targeted for deletion: one telomeric region on 10p and both telomeric and centromeric locations on 10q. These data suggest the existence of multiple chromosome 10 tumor suppressor gene loci whose inactivation is involved in the malignant progression of glioma.

Evidence of a local immune activation in cystic brain tumors.

The fluid of cystic brain tumors was characterized with regard to the protein content. In most malignant tumors, the concentrations of immunoglobulins G and M (IgG and IgM) were higher relative to other proteins in the cyst fluid than in the serum of the same patient. A markedly elevated ratio of monomeric to pentameric IgM was detected in the cyst fluid of two patients with glioblastomas. The results indicate a local immunoglobulin synthesis in malignant cystic brain tumors. It is hypothesized that higher-than-expected concentrations of IgG and IgM in cyst fluid as compared to plasma are a sign of an ongoing immune response triggered by the tumor.

A new method for characterization of low grade gliomas using ultra low field magnetic resonance imaging.

Low grade gliomas were studied with ultra low field magnetic resonance imaging (ULF MRI). The tumors exhibited high tissue contrast in both T1 and T2-weighted images as compared to normal brain tissue. Moreover they were sharply delineated towards the surrounding brain tissue. When compared with X-ray computed tomography the tumors were more readily detected and delineated by using ultra-low field magnetic imaging. A computer-assisted classification procedure was used to define new regions of interest for relaxation time estimations. By using this procedure more accurate estimations of the T1 and T2 values were obtained.

Does successful interferon treatment of tumor patients require life-long treatment?

Case histories of 5 tumor patients treated with natural leukocyte interferon-alpha (IFN-alpha) are presented. One patient with juvenile laryngeal papillomatosis responded well to interferon treatment, but the disease recurred when therapy was withdrawn. Upon reinstitution of treatment, the patient once again responded well. Another patient with myelomatosis also responded well to interferon therapy and in this case, too, the tumor recurred when interferon treatment was withdrawn. Reinstitution of interferon therapy was, however, unsuccessful. One patient with generalized giant cell tumor of bone responded with regression after more than 5 years of interferon treatment. Another patient with pulmonary osteosarcoma metastases, having received irradiation and interferon combination therapy followed by sole interferon treatment, responded well with a lasting stationary radiogram after 6 years of interferon treatment. One patient with malignant glioma, showing signs of tumor growth during the first few months of interferon therapy, eventually responded, and became disease-free after 6 years. The latter 3 patients are continuously receiving interferon therapy although more than 5 years have elapsed since their interferon therapy was initiated. It is suggested that interferon therapy for malignant tumors be given for life (or to progression of disease) in responding patients. Such a concept entails biological implications for interferon therapy in general and for antitumor action of interferons in particular. Other possible clinical schedules should only be constructed within the framework of controlled clinical trials.

Somatomedins in tumour cyst fluid, cerebrospinal fluid, and tumour cytosol in patients with glial tumours.

In the present study, the levels of the growth-promoting hormones, somatomedins, were analysed in tumour cyst fluid, CSF, and tumour cytosol, collected from 22 unselected patients with intracranial tumours. All samples contained somatomedin activity. 5/7 CSF samples, taken from patients with tumour mass visible on CT, showed elevated concentrations. 6/9 cyst fluid samples, taken from patients with glioma were elevated compared with normal serum somatomedin levels. Tumour cytosol, taken from 7 patients with malignant glioma contained somatomedins in an elevated level compared with values previously analysed from normal adult brains. These preliminary findings demonstrate for the first time the presence of somatomedins in brain tumours and suggest the use of somatomedins as a possible brain tumour marker.

Enhancement of insulin-like growth factor 2 receptors in glioblastoma.

The somatomedins (IGF-1/IGF-2) are a family of growth-promoting hormones which have been identified in the human central nervous system where their specific receptors are distributed. The present study identified somatomedin receptors in glioblastoma and compared them with those found in normal brain. A significant enhancement in the binding of 125I-IGF-2 but not 125I-IGF-1 to glioblastoma membranes was found. A fourfold increase in IGF-2 receptor concentration was observed. These findings indicate enhanced expression of the IGF-2 receptor in glioblastoma.

Stereotactic radiation therapy of intracranial lesions. Methodologic aspects.

A technique for stereotactic radiation therapy of cerebral tumours and arteriovenous malformations using a linear accelerator (6 MV photons) is proposed. Treatment relies on a fixation system that permits a precise use of the coordinates estimated at stereotactic angiography or stereotactic computed tomography. The field of treatment can be exactly outlined in the CT images during repeat examinations, thus facilitating the recognition of changes induced by radiation. The system also allows the extent of the arteriovenous malformation, as seen at angiography, to be accurately traced in the CT sections thus enabling evaluation of possible radiation damage to surrounding brain structures. The precision of the method as well as its hypothetical merits and disadvantages are discussed. The number of patients treated is still small and the follow-up time is too short in the majority of cases to allow definite conclusions. Examples of preliminary results are given.

Congenital constriction of the foramen of Monro.

We report two cases of hydrocephalus in adults. The radiological investigations and direct inspection during surgery in one of the cases indicate that the hydrocephalus is caused in both cases by a benign stricture in the region of the foramen of Monro and that this constriction is congenital. This origin of hydrocephalus has not been reported previously in adults.

Thymidine kinase in brain-tumor cysts.

A recently developed method for deoxythymidine kinase (TK) determination was applied to brain-tumor cyst fluid and fluid from a non-neoplastic intracerebral cyst. The fluid from all tumors tested positive for TK whereas the non-neoplastic cyst lacked TK. Cyst fluid was also analyzed for TK before and after intracystic instillation of BCNU. It is suggested that TK activity in the fluid in cystic brain lesions could prove useful in deciding whether an intracerebral lesion is neoplastic. Also, TK activity can be used to evaluate the effect of topical therapy.

The effect of systemic human interferon-alpha administration to patients with glioblastoma multiforme.

This report presents the results of a phase I trial of the value of human leucocyte interferon-alpha in the treatment of glioblastoma. Twelve patients entered the trial. In one case we believe that the patient benefitted from the interferon treatment. CT scans of patients on interferon did not reveal the true extent of the tumorous tissue.