Long-term survival of patients suffering from glioblastoma multiforme treated with tumor-treating fields.

Glioblastoma multiforme (GBM) is the most common and malignant primary intracranial tumor, and has a median survival of only 10 to 14 months with only 3 to 5% of patients surviving more than three years. Recurrence (RGBM) is nearly universal, and further decreases the median survival to only five to seven months with optimal therapy. Tumor-treating fields (TTField) therapy is a novel treatment technique that has recently received CE and FDA approval for the treatment of RGBM, and is based on the principle that low intensity, intermediate frequency electric fields (100 to 300 kHz) may induce apoptosis in specific cell types. Our center was the first to apply TTField treatment to histologically proven GBM in a small pilot study of 20 individuals in 2004 and 2005, and four of those original 20 patients are still alive today. We report two cases of GBM and two cases of RGBM treated by TTField therapy, all in good health and no longer receiving any treatment more than seven years after initiating TTField therapy, with no clinical or radiological evidence of recurrence.

[Temporal lobe epilepsy in adults and possibilities of neurosurgical treatment: the role of magnetic resonance]. / Temporální epilepsie dospelých a moznosti neurochirurgické lécby: úloha magnetické rezonance.

Temporal lobe epilepsy is the most common type of focal epilepsy diagnosed in adult patients. According to the location of seizure generation it is classified as mesial temporal lobe epilepsy and neocortical lateral lobe epilepsy. Diagnosis of temporal lobe epilepsy can be proved by the combination of the clinical manifestation of partial complex seizures, scalp-video EEG monitoring, results of magnetic resonance imaging (MRI) and imaging of interictal fluoro-deoxy-glucose positron emission tomography. Mesial temporal sclerosis is the most common finding on MRI. Temporal lobe epilepsy is the most surgically amenable diagnosis and results of surgery treatments are clearly superior to the prolonged medical therapy; surgical treatment of the mesial temporal epilepsy with mesial temporal sclerosis has the best clinical results. Except for standard microsurgical approaches such as anterior temporal resection and selective amygdalo-hippocampectomy, stereotactic thermocoagulation amygdalo-hippocampectomy is provided in our epilepsy centre. This alternative approach has comparable clinical outcome to the standard surgery approaches in 2 years clinical follow-ups. MRI is important not only in diagnostic procedures, but also in neuronavigation of surgery approaches, per operation control of the extent of resections and postoperative follow-ups, especially in failed epilepsy surgery.

Microsurgical and stereotactic radiofrequency amygdalohippocampectomy for the treatment of mesial temporal lobe epilepsy: different volume reduction, similar clinical seizure control.

We compared stereotactic radiofrequency amygdalohippocampectomy (SAHE) with microsurgical amygdalohippocampectomy (AHE) in a group of 33 patients with mesial temporal lobe epilepsy in terms of hippocampal and amygdalar volume reductions and clinical outcome. In 23 subjects treated by SAHE, the hippocampal volume decreased by 58.0% (20.0; median, quartile range), with p = 10(-4), and the amygdalar volume decreased by 55.2% (23.8), with p = 10(-4). Two years after SAHE, 74% of patients were classified as class I, 22% as class II and 4% as class III. In 10 subjects treated by AHE, 83.5% (11.2) of the hippocampal and 53.1% (53.9) of the amygdalar volumes were removed (p = 0.05 and p = 0.005, respectively). Two years after the operation, 50% of the subjects were classified as class I, 30% as class II and 10% as class III and IV. To conclude, SAHE leads to a similar reduction of the amygdalar volume but to a significantly lower reduction of the hippocampal volume than AHE. The clinical outcome of SAHE is comparable with that of AHE.

Expression and enzymatic activity of dipeptidyl peptidase-IV in human astrocytic tumours are associated with tumour grade.

Alterations in dipeptidyl peptidase-IV (DPP-IV) enzymatic activity are characteristic of malignant transformation. Through its well-characterized functionality in regulating the activity of bioactive peptides by removal of the N-terminal dipeptide, DPP-IV activity may have profound effects upon metastatic potential and cell growth. Although DPP-IV/CD26 (EC 3.4.14.5) is the canonical representative of the group, a number of other proteins including DPP-7, 8, 9, and seprase/fibroblast activation protein-alpha (FAP-alpha) have been shown to have similar enzymatic activity. This study was set up to address the relative representation and enzymatic activity of plasma membrane localized DPP-IV/CD26 and FAP-alpha in human brain and astrocytic tumours. In parallel, expression of CXCR4, receptor for glioma cell growth stimulator chemokine SDF-1alpha known to be a DPP-IV substrate, was investigated. This is the first report showing that non-malignant brain tissue contains a DPP-IV-like enzymatic activity attributable mostly to DPP-8/9, while the substantial part of the activity in glioma is due to increased DPP-IV/CD26, localized in both the vascular and parenchymal compartments. DPP-IV enzymatic activity increased dramatically with tumour grade severity. A grade-related increase in CXCR4 receptor paralleled the rise in DPP-IV expression and activity. These data might support a role for DPP-IV regulation of the CXCR4-SDF-1alpha axis in glioma development.

The diagnostics of recurrent gliomas using FDG-PET: still questionable?

BACKGROUND: For a number of years, FDG-PET was considered as a gold standard for the differential diagnosis of recurrent glioma and radionecrosis. Recently published papers have introduced a wealth of scepticism into this area. The aim of this work is to specify the added value of FDG PET, as compared to MRI, in terms of diagnostics of recurrent gliomas in the clinical setting of the PET Centre Prague. MATERIAL AND METHODS: MRI and FDG-PET were used to examine 29 patients for suspicious glioma recurrence, after 30 open neurosurgical operations or re-operations combined with chemo- and/or radiotherapy. The sensitivity, specificity and accuracy of both examinations were calculated with respect to their micromorphological findings (n = 28) or the clinical and radiological follow-up (n = 2). RESULTS: MRI detected 23/24 tumour recurrences (sensitivity = 95.8%) and FDG PET only 15 of these (sensitivity = 62.5%). MRI specified only 3/6 radionecrotic lesions (specificity = 50.0%), while FDG PET identified 5/6 (specificity = 83.3%). Overall accuracy was 26/30 (86.7%) for MRI and 20/30 (66.7%) for FDG PET. In the subgroup of MRI positive or equivocal findings (n = 29) FDG PET was clearly positive in 15 cases. High-grade glioma recurrence was subsequently confirmed in all of them. On the other hand negative or equivocal FDG PET was associated in 5/14 cases (35.7%) with radionecrosis, in 3/14 (21.4%) with low-grade glioma and in 6/14 (42.9%) with high-grade glioma. CONCLUSIONS: MRI is the method of choice for the detection of glioma recurrence but it is associated with a high rate of false positive results. FDG PET has significantly lower sensitivity; nevertheless it does help to specify MRI positive lesions. FDG PET positive lesions give a very high probability of high-grade glioma, but its equivocal and negative findings are of no clinical value.

NovoTTF-100A versus physician's choice chemotherapy in recurrent glioblastoma: a randomised phase III trial of a novel treatment modality.

PURPOSE: NovoTTF-100A is a portable device delivering low-intensity, intermediate frequency electric fields via non-invasive, transducer arrays. Tumour Treatment Fields (TTF), a completely new therapeutic modality in cancer treatment, physically interfere with cell division. METHODS: Phase III trial of chemotherapy-free treatment of NovoTTF (20-24h/day) versus active chemotherapy in the treatment of patients with recurrent glioblastoma. Primary end-point was improvement of overall survival. RESULTS: Patients (median age 54 years (range 23-80), Karnofsky performance status 80% (range 50-100) were randomised to TTF alone (n=120) or active chemotherapy control (n=117). Number of prior treatments was two (range 1-6). Median survival was 6.6 versus 6.0 months (hazard ratio 0.86 [95% CI 0.66-1.12]; p=0.27), 1-year survival rate was 20% and 20%, progression-free survival rate at 6 months was 21.4% and 15.1% (p=0.13), respectively in TTF and active control patients. Responses were more common in the TTF arm (14% versus 9.6%, p=0.19). The TTF-related adverse events were mild (14%) to moderate (2%) skin rash beneath the transducer arrays. Severe adverse events occurred in 6% and 16% (p=0.022) of patients treated with TTF and chemotherapy, respectively. Quality of life analyses favoured TTF therapy in most domains. CONCLUSIONS: This is the first controlled trial evaluating an entirely novel cancer treatment modality delivering electric fields rather than chemotherapy. No improvement in overall survival was demonstrated, however efficacy and activity with this chemotherapy-free treatment device appears comparable to chemotherapy regimens that are commonly used for recurrent glioblastoma. Toxicity and quality of life clearly favoured TTF.

Chemotherapeutic treatment efficacy and sensitivity are increased by adjuvant alternating electric fields (TTFields).

BACKGROUND: The present study explores the efficacy and toxicity of combining a new, non-toxic, cancer treatment modality, termed Tumor Treating Fields (TTFields), with chemotherapeutic treatment in-vitro, in-vivo and in a pilot clinical trial. METHODS: Cell proliferation in culture was studied in human breast carcinoma (MDA-MB-231) and human glioma (U-118) cell lines, exposed to TTFields, paclitaxel, doxorubicin, cyclophosphamide and dacarbazine (DTIC) separately and in combinations. In addition, we studied the effects of combining chemotherapy with TTFields in an animal tumor model and in a pilot clinical trial in recurrent and newly diagnosed GBM patients. RESULTS: The efficacy of TTFields-chemotherapy combination in-vitro was found to be additive with a tendency towards synergism for all drugs and cell lines tested (combination index

Alternating electric fields arrest cell proliferation in animal tumor models and human brain tumors.

We have recently shown that low intensity, intermediate frequency, electric fields inhibit by an anti-microtubule mechanism of action, cancerous cell growth in vitro. Using implanted electrodes, these fields were also shown to inhibit the growth of dermal tumors in mice. The present study extends these findings to additional cell lines [human breast carcinoma; MDA-MB-231, and human non-small-cell lung carcinoma (H1299)] and to animal tumor models (intradermal B16F1 melanoma and intracranial F-98 glioma) using external insulated electrodes. These findings led to the initiation of a pilot clinical trial of the effects of TTFields in 10 patients with recurrent glioblastoma (GBM). Median time to disease progression in these patients was 26.1 weeks and median overall survival was 62.2 weeks. These time to disease progression and OS values are more than double the reported medians of historical control patients. No device-related serious adverse events were seen after >70 months of cumulative treatment in all of the patients. The only device-related side effect seen was a mild to moderate contact dermatitis beneath the field delivering electrodes. We conclude that TTFields are a safe and effective new treatment modality which effectively slows down tumor growth in vitro, in vivo and, as demonstrated here, in human cancer patients.