Therapeutic vaccination against autologous cancer stem cells with mRNA-transfected dendritic cells in patients with glioblastoma.

BACKGROUND: The growth and recurrence of several cancers appear to be driven by a population of cancer stem cells (CSCs). Glioblastoma, the most common primary brain tumor, is invariably fatal, with a median survival of approximately 1 year. Although experimental data have suggested the importance of CSCs, few data exist regarding the potential relevance and importance of these cells in a clinical setting. METHODS: We here present the first seven patients treated with a dendritic cell (DC)-based vaccine targeting CSCs in a solid tumor. Brain tumor biopsies were dissociated into single-cell suspensions, and autologous CSCs were expanded in vitro as tumorspheres. From these, CSC-mRNA was amplified and transfected into monocyte-derived autologous DCs. The DCs were aliquoted to 9-18 vaccines containing 10(7) cells each. These vaccines were injected intradermally at specified intervals after the patients had received a standard 6-week course of post-operative radio-chemotherapy. The study was registered with the ClinicalTrials.gov identifier NCT00846456. RESULTS: Autologous CSC cultures were established from ten out of eleven tumors. High-quality RNA was isolated, and mRNA was amplified in all cases. Seven patients were able to be weaned from corticosteroids to receive DC immunotherapy. An immune response induced by vaccination was identified in all seven patients. No patients developed adverse autoimmune events or other side effects. Compared to matched controls, progression-free survival was 2.9 times longer in vaccinated patients (median 694 vs. 236 days, p = 0.0018, log-rank test). CONCLUSION: These findings suggest that vaccination against glioblastoma stem cells is safe, well-tolerated, and may prolong progression-free survival.

Prognostic variables in oligodendroglial tumors: a single-institution study of 95 cases.

We analyzed the relationships among clinical variables, histology, 1p/19q status, and outcome in 95 patients with oligodendroglial tumors. The study enrolled adult patients who underwent first-time surgery for a supratentorial oligodendroglial tumor at Oslo University Hospital, Rikshospitalet. Tumors were: 27 oligodendrogliomas, WHO grade II; 32 oligoastrocytomas, WHO grade II; 16 anaplastic oligodendrogliomas, WHO grade III; 14 anaplastic oligoastrocytomas, WHO grade III; and 6 glioblastomas with a major oligodendroglial component, WHO grade IV. The clinical files were reviewed. Three neuropathologists evaluated the histological slides independently. Loss-of-heterozygosity analysis for 1p and 19q was performed by PCR. Favorable prognostic factors from univariate analyses included seizures as presenting symptom, female sex, location in the frontal lobe, low WHO grade, classic histology, absence of gemistocytic cells, and combined 1p/19q loss. Solitary 19q loss was a negative prognostic marker. 1p/19q status was of prognostic significance in both tumors with classic and nonclassic oligodendroglial histology. In the multivariate analysis, WHO grade II (P< .001), frontal tumor location (P= .002), and combined 1p/19q loss (P< .001) remained favorable prognostic variables. Our results suggest that tumor location, WHO grade, and 1p/19q status are important independent variables associated with survival in oligodendroglial tumors. The study suggests that solitary 19q loss is a negative prognostic variable and that 1p/19q loss is associated with prolonged survival also in oligodendroglial tumors without classic histology.

Radiological and clinical assessment of long-term brain tumour survivors after radiotherapy.

BACKGROUND AND PURPOSE: Late adverse effects of therapeutic brain radiotherapy (RT) may develop after long latency periods and our objective was to assess long-term brain tumour survivors following RT to large partial brain volumes. MATERIALS AND METHODS: Assessment of MRI, SOMA/LENT score, quality of life and neuroendocrine function was performed in 33 adult brain tumour patients 6-25 years following RT. Fraction dose was 1.8 Gy to a median total dose of 54 Gy (range: 45.0-59.4 Gy). Ten patients had been given two opposing portals including one whole hemisphere, while 23 patients had in addition received an ipsilateral field. In 25 patients the hypothalamic and pituitary area had been included in the RT field. Results were compared within the study group and towards the general population matched for age and gender. RESULTS: All patients had white matter changes with increased signal intensity on T2 and FLAIR images. Discrete lesions (grade 1), beginning confluence of lesions (grade 2), and large confluent areas (grade 3) were present in 8, 8 and 17 patients, respectively. Patients treated with intra-arterial chemotherapy and patients at higher age at follow-up had significantly more grade 3 changes. Atrophy, lacunar lesions and contrast enhancement was found in 17, 18 and 23 patients, respectively. Significantly worse clinical status and quality of life was found in patients with white matter changes grade 3 or atrophy. Patients given full-dose RT to less volume did not have significantly less toxicity. Two cases of meningioma were found at 16 and 22 years after RT. Nineteen neuroendocrine abnormalities were observed in 16/25 patients. CONCLUSIONS: External radiotherapy to the brain at a standard fractionation regime will cause varying degrees of late neurotoxicity and/or neuroendocrine disturbances in most patients. Life-long follow-up is recommended.

Progress in long-term survival in adult patients with supratentorial low-grade gliomas: a population-based study of 993 patients in whom tumors were diagnosed between 1970 and 1993.

OBJECT: The goal of this study was to document and compare long-term survival during the periods 1970 through 1981 and 1982 through 1993 in all adult patients in Norway with histologically verified supratentorial low-grade gliomas (LGGs). METHODS: Nine hundred ninety-three patients 15 to 69 years of age were found to have a primary supratentorial diffuse astrocytoma, oligodendroglioma, oligoastrocytoma, or pilocytic astrocytoma. Survival time was analyzed in all patients and, in a subset of 451 patients, the influence of new imaging methods on the time from symptom onset to imaging diagnosis was estimated. Overall median survival was 6.4 years (95% confidence interval [CI] 5.7-7.1 years). Survival times for patients in whom a diagnosis was made between 1970 and 1981 (397 patients) and between 1982 and 1993 (596 patients) were 4.1 years (95% CI 3.3-4.9 years) and 9.2 years (95% CI 7.9-10.6 years), respectively (p < 0.0001). Survival also improved in the later period within each histological subgroup. In patients in whom a biopsy was performed the median length of survival was 6.4 years (95% CI 3.1-9.7 years); in patients treated with subtotal tumor resection it was 6.8 years (95% CI 5.8-7.7 years); and in those treated with gross-total tumor resection it was 7.6 years (95% CI 5.5-9.7 years), a nonsignificant difference (p = 0.59). A considerable age-dependent variation in overall survival was demonstrated. The availability of computerized tomography (CT) scanning and/or magnetic resonance (MR) imaging as a diagnostic tool reduced the median period of symptoms prior to diagnosis by 6 months. CONCLUSIONS: Long-term overall survival significantly improved, but age-related differences in prognosis persisted. The increased sensitivity of the diagnostic method due to the availability of CT scanning and/or MR imaging may partly, but not entirely, account for the observed magnitude of improvement in overall survival. Thus local tumor treatment improved during the study period.

Late radiation effects on hearing, vestibular function, and taste in brain tumor patients.

PURPOSE: To investigate late radiation effects on hearing, vestibular function, and taste after conventional radiotherapy in brain tumor patients. METHODS AND MATERIALS: Hearing, vestibular function, and taste were assessed in 33 brain tumor patients irradiated unilaterally to the tumor-bearing hemisphere and the temporal bone. Median observation time after completion of radiotherapy was 13 years; the fraction dose was 1.8 Gy, and mean radiation dose was 53.1 Gy. RESULTS: Deep ulceration in the external ear canal and osteoradionecrosis on the irradiated side was seen in three patients. Reduced hearing was found for air and bone conduction of the irradiated side compared to the opposite side (0.25-2 kHz: 6.1 dB, 4 kHz: 10.3 dB, 6 kHz: 15.6 dB, and 8 kHz: 16.5 dB). For bone conduction, the corresponding figures were 0.25-2 kHz: 5.5 dB and 4 kHz: 8.2 dB. Three patients had a canal paresis of the irradiated side, and three patients had affection of the chorda tympani. CONCLUSION: Irradiation of the temporal bone with doses usually given in the treatment of patients with brain tumors may cause osteoradionecrosis, sensorineural hearing loss, dysfunction of the vestibular inner ear, and loss of taste. Head-and-neck examination should be included in the follow-up of long-term survivors.

A cost-minimising analysis of standard radiotherapy and two experimental therapies in glioblastoma.

BACKGROUND AND PURPOSE: Accelerated radiotherapy (ART) and intracavity brachytherapy (ICBT) have been introduced in the primary treatment of glioblastoma. Our objective was to determine total treatment costs, hospitalisation time, and treatment outcome in these two experimental therapies compared to standard treatment. MATERIALS AND METHODS: In the time period 1985 to 1st May 1999, a total of 174 patients with histologically confirmed glioblastoma multiforme were given postoperative radiotherapy according to three different treatment schedules at three different time intervals. A conventional regime of external radiotherapy (54Gy/30 fractions) was given to 58 patients (group I), 75 patients were treated with ART (48Gy/twice daily 30 fractions) (group II), and 41 patients were given ICBT (60Gy/ten fractions) (group III). Treatment costs including surgery, hospital stay, hospital hotel stay, and radiotherapy were calculated. RESULTS: The total mean costs employing the three treatment alternatives were calculated to $25,618 (group I), $23,442 (group II), and $14,534 (group III). Total mean stay in hospital for the whole primary treatment was 48.8, 41.6, and 19 days for groups I, II, and III respectively. Median survival figures were 16, 14, and 13 months for groups I, II, and III, respectively. CONCLUSIONS: The total cost of postoperative radiotherapy in glioblastoma is comparable to other health care services. ART did not improve the total treatment cost or influence the need for hospitalisation compared to standard treatment. ICBT seemed to have economic benefits with less need for hospitalisation.