Very-low-carbohydrate diet enhances human T-cell immunity through immunometabolic reprogramming.

Very-low-carbohydrate diet triggers the endogenous production of ketone bodies as alternative energy substrates. There are as yet unproven assumptions that ketone bodies positively affect human immunity. We have investigated this topic in an in vitro model using primary human T cells and in an immuno-nutritional intervention study enrolling healthy volunteers. We show that ketone bodies profoundly impact human T-cell responses. CD4+ , CD8+ , and regulatory T-cell capacity were markedly enhanced, and T memory cell formation was augmented. RNAseq and functional metabolic analyses revealed a fundamental immunometabolic reprogramming in response to ketones favoring mitochondrial oxidative metabolism. This confers superior respiratory reserve, cellular energy supply, and reactive oxygen species signaling. Our data suggest a very-low-carbohydrate diet as a clinical tool to improve human T-cell immunity. Rethinking the value of nutrition and dietary interventions in modern medicine is required.

Resting-state fMRI detects alterations in whole brain connectivity related to tumor biology in glioma patients.

BACKGROUND: Systemic infiltration of the brain by tumor cells is a hallmark of glioma pathogenesis which may cause disturbances in functional connectivity. We hypothesized that aggressive high-grade tumors cause more damage to functional connectivity than low-grade tumors. METHODS: We designed an imaging tool based on resting-state functional (f)MRI to individually quantify abnormality of functional connectivity and tested it in a prospective cohort of patients with newly diagnosed glioma. RESULTS: Thirty-four patients were analyzed (World Health Organization [WHO] grade II, n = 13; grade III, n = 6; grade IV, n = 15; mean age, 48.7 y). Connectivity abnormality could be observed not only in the lesioned brain area but also in the contralateral hemisphere with a close correlation between connectivity abnormality and aggressiveness of the tumor as indicated by WHO grade. Isocitrate dehydrogenase 1 (IDH1) mutation status was also associated with abnormal connectivity, with more alterations in IDH1 wildtype tumors independent of tumor size. Finally, deficits in neuropsychological performance were correlated with connectivity abnormality. CONCLUSION: Here, we suggested an individually applicable resting-state fMRI marker in glioma patients. Analysis of the functional connectome using this marker revealed that abnormalities of functional connectivity could be detected not only adjacent to the visible lesion but also in distant brain tissue, even in the contralesional hemisphere. These changes were associated with tumor biology and cognitive function. The ability of our novel method to capture tumor effects in nonlesional brain suggests a potential clinical value for both individualizing and monitoring glioma therapy.

Biological tumor volume in 18FET-PET before radiochemotherapy correlates with survival in GBM.

OBJECTIVE: The aim of this prospective longitudinal study was to identify static and dynamic O-(2-[(18)F]fluoroethyl)-L-tyrosine PET ((18)FET-PET)-derived imaging biomarkers in patients with glioblastoma (GBM). METHODS: Seventy-nine patients with newly diagnosed GBM were included; 42 patients underwent stereotactic biopsy (unresectable tumors) and 37 patients microsurgical tumor resection. All patients were scheduled to receive radiotherapy plus concomitant and adjuvant temozolomide (RCx/TMZ). (18)FET-PET evaluation using static and dynamic analysis was done before biopsy/resection, after resection, 4 to 6 weeks following RCx, and after 3 cycles of TMZ. Endpoints were survival and progression-free-survival. Prognostic factors were obtained from proportional hazards models. RESULTS: Biological tumor volume before RCx (BTV(preRCx)) was the most important (18)FET-PET-derived imaging biomarker and was independent of MGMT promoter methylation and clinical prognostic factors: patients with smaller BTV(preRCx) had significantly longer progression-free and overall survival (OS). (18)FET time-activity curves (TACs) before treatment and their changes after RCx were also related to outcome; patients with initially increasing TACs experienced longer OS. CONCLUSION: BTV(preRCx) and TAC represent important (18)FET-PET-derived imaging biomarkers in GBM. Increasing TACs are associated with prolonged OS. The BTV(preRCx) is a strong prognostic factor for progression-free survival and OS independent of the mode of surgery. Our data furthermore suggest that patients harboring resectable GBM might benefit from maximal PET-guided tumor resection.

Molecular stereotactic biopsy technique improves diagnostic accuracy and enables personalized treatment strategies in glioma patients.

BACKGROUND: In gliomas molecular biomarkers are increasingly gaining diagnostic, prognostic and predictive significance. Determination of biomarker status after biopsy is important as not all patients are eligible for open tumor resection. We developed and validated prospectively (6/10-12/11) a protocol allowing for both reliable determination of multiple biomarkers and representative histological diagnoses from small-sized biopsies. METHODS: All molecular stereotactic biopsies were performed according to a detailed workflow. The selection of specimens best suited for molecular analyses was intra-operatively guided by the attending neuropathologist. Postoperative screening was done by methylation specific PCR using two distinct cryopreserved specimens to test for reproducibility of the findings and to rule out contamination. The DNA of a single best-suited specimen (1 mm(3)) was subjected to detailed molecular analysis (MGMT promoter methylation, IDH1/2 mutational status, LOH 1p and/or 19q). RESULTS: 159 consecutively enrolled untreated gliomas were analyzed (94 glioblastomas, 2 gliosarcomas, 24 anaplastic astrocytomas, 10 oligo-tumors grade II/III, 20 grade II astrocytomas and 9 pilocytic astrocytomas). Transient morbidity was 2 %. Overall, the drop-out rate due to tissue contamination was 0.4 %. Median time from biopsy to histological and molecular genetic analyses was 3 and 5 days, respectively. Distributions of the respective biomarker status for tumor subgroups were consistent with the literature. The final histological diagnosis was changed/modified in 5/159 patients according to molecular findings. Treatment after molecular biopsy was highly personalized. CONCLUSIONS: Molecular stereotactic biopsy is feasible and safe, can be implemented in daily clinical practice, improves diagnostic precision and enables personalized treatment.

Epigenetics in human gliomas.

Aberrant epigenetic landscapes and their involvement in genesis and progression of tumors, as well as in treatment responses and prognosis, indicate one of the most emerging fields in cancer research. In gliomas, the most common human primary brain tumors, and in particular in glioblastoma, the most malignant and devastating brain tumor entity in adults, the elucidation of distinct patterns of aberrant DNA methylation, histone modification, and miRNA expression and their interrelationship has fundamentally changed our point of view on these highly heterogeneous tumors. In the current review article, we address the basic principles of epigenetic control in gliomas, their current and putative future role in prognostic and predictive models and possible interactions within the epigenetic network. We discuss diagnostic and therapeutic opportunities appearing at horizon of epigenetic research. Moreover, we present current and propose future clinical workflow models for molecular characterization of malignant gliomas.

[18F]fluoroethyltyrosine-positron emission tomography-based therapy monitoring after stereotactic iodine-125 brachytherapy in patients with recurrent high-grade glioma.

Therapy monitoring of glioma after stereotactic iodine-125 brachytherapy (SBT) remains challenging because posttherapeutic changes in magnetic resonance imaging can mimic tumor progression. We evaluated the prognostic value of serial [18F]fluoroethyltyrosine (FET)-positron emission tomographic (PET) scans for therapy monitoring of high-grade glioma (HGG) after SBT. Thirty-three patients with recurrent HGG were included. Serial FET-PET scans were performed prior to therapeutic intervention and at 3-month intervals during the first year after SBT. FET-PET evaluation was performed by both conventional data analysis and kinetic analysis. Prognostic factors were obtained from proportional hazard models. Median local progression-free survival (LPFS) was 11.1 months. Maximal standardized background uptake value (SUVmax/BG) and biologic tumor volume (BTV) differentiated accurately between therapeutic effects and local tumor progression at the 6-month and subsequent examinations. Increasing uptake kinetics at baseline (p < .05) and during follow-up (p < .01) were stringently associated with a longer LPFS. Early increase in FET uptake after SBT is not unequivocally associated with tumor progression; it might be induced by reactive changes and could easily lead to a misclassification of the tumor status (pseudoprogression). Six months after SBT (or later), however, increased SUVmax/BG and BTV values are associated with a worse prognosis. Multivariate analysis stresses the prognostic importance of dynamic studies.

In human glioblastomas transcript elongation by alternative polyadenylation and miRNA targeting is a potent mechanism of MGMT silencing.

Favorable outcome after chemotherapy of glioblastomas cannot unequivocally be linked to promoter hypermethylation of the O6-methylguanine-DNA methyltransferase (MGMT) gene encoding a DNA repair enzyme associated with resistance to alkylating agents. This indicates that molecular mechanisms determining MGMT expression have not yet been fully elucidated. We here show that glioblastomas are capable to downregulate MGMT expression independently of promoter methylation by elongation of the 3'-UTR of the mRNA, rendering the alternatively polyadenylated transcript susceptible to miRNA-mediated suppression. While the elongated transcript is poorly expressed in normal brain, its abundance in human glioblastoma specimens is inversely correlated with MGMT mRNA expression. Using a bioinformatically guided experimental approach, we identified miR-181d, miR-767-3p, and miR-648 as significant post-transcriptional regulators of MGMT in glioblastomas; the first two miRNAs induce MGMT mRNA degradation, the latter affects MGMT protein translation. A regression model including the two miRNAs influencing MGMT mRNA expression and the MGMT methylation status reliably predicts The Cancer Genome Atlas MGMT expression data. Responsivity of MGMT expressing T98G glioma cells to temozolomide was significantly enhanced after transfection of miR-181d, miR-767-3p, and miR-648. Taken together, our results uncovered alternative polyadenylation of the MGMT 3'-UTR and miRNA targeting as new mechanisms of MGMT silencing.

O-methylguanine-DNA methyltransferase (MGMT) mRNA expression predicts outcome in malignant glioma independent of MGMT promoter methylation.

BACKGROUND: We analyzed prospectively whether MGMT (O(6)-methylguanine-DNA methyltransferase) mRNA expression gains prognostic/predictive impact independent of MGMT promoter methylation in malignant glioma patients undergoing radiotherapy with concomitant and adjuvant temozolomide or temozolomide alone. As DNA-methyltransferases (DNMTs) are the enzymes responsible for setting up and maintaining DNA methylation patterns in eukaryotic cells, we analyzed further, whether MGMT promoter methylation is associated with upregulation of DNMT expression. METHODOLOGY/PRINCIPAL FINDINGS: ADULT PATIENTS WITH A HISTOLOGICALLY PROVEN MALIGNANT ASTROCYTOMA (GLIOBLASTOMA: N = 53, anaplastic astrocytoma: N = 10) were included. MGMT promoter methylation was determined by methylation-specific PCR (MSP) and sequencing analysis. Expression of MGMT and DNMTs mRNA were analysed by real-time qPCR. Prognostic factors were obtained from proportional hazards models. Correlation between MGMT mRNA expression and MGMT methylation status was validated using data from the Cancer Genome Atlas (TCGA) database (N = 229 glioblastomas). Low MGMT mRNA expression was strongly predictive for prolonged time to progression, treatment response, and length of survival in univariate and multivariate models (p<0.0001); the degree of MGMT mRNA expression was highly correlated with the MGMT promoter methylation status (p<0.0001); however, discordant findings were seen in 12 glioblastoma patients: Patients with methylated tumors with high MGMT mRNA expression (N = 6) did significantly worse than those with low transcriptional activity (p<0.01). Conversely, unmethylated tumors with low MGMT mRNA expression (N = 6) did better than their counterparts. A nearly identical frequency of concordant and discordant findings was obtained by analyzing the TCGA database (p<0.0001). Expression of DNMT1 and DNMT3b was strongly upregulated in tumor tissue, but not correlated with MGMT promoter methylation and MGMT mRNA expression. CONCLUSIONS/SIGNIFICANCE: MGMT mRNA expression plays a direct role for mediating tumor sensitivity to alkylating agents. Discordant findings indicate methylation-independent pathways of MGMT expression regulation. DNMT1 and DNMT3b are likely to be involved in CGI methylation. However, their exact role yet has to be defined.

Predominant influence of MGMT methylation in non-resectable glioblastoma after radiotherapy plus temozolomide.

BACKGROUND: Patients with non-resectable glioblastoma generally exhibit a poor prognosis, even after radiotherapy plus concomitant and adjuvant temozolomide (XRT/TMZ→TMZ). Unfortunately, no data are available concerning the predictive value of O(6)-methylguanine-DNA methyltransferase (MGMT) promoter methylation for this important subpopulation. For clarification, a prospective study was conducted. METHODS: Adult patients with a non-resectable glioblastoma were included. A molecular stereotactic biopsy technique was used for tumour characterisation combining histopathological diagnosis with small sample size adjusted methylation-specific PCR (MSP) and sodium bisulfite sequencing. Treatment included XRT (60 Gy in 30 fractions)/TMZ (daily dose of 75 mg/m(2))→TMZ (150-200 mg/m(2) per day for 5 days of every 28-day cycle). The primary end point was progression-free survival (PFS). Secondary endpoints were overall survival (OS) and treatment response (TR). Patients were categorised in the Radiation Therapy Oncology Group (RTOG)-recursive partitioning analysis (RPA) Classes III (N=4), IV (N=12), V (N=28) and VI (N=12). RESULTS AND DISCUSSION: The success rates of MSP and sequence analyses were 100%. The MGMT promoter was methylated in 30/56 tumours, which was associated with an increased PFS (median 56 versus 20 weeks; hazard ratio 0.15; range 0.07 to 0.33; p<0.0001), higher frequency of TR (93.3% vs 46.2%; p=0.0008) and increased OS (median 104 vs 28 weeks; hazard ratio 0.18; range 0.08 to 0.38; p<0.0001). The transient perioperative morbidity was 1.8%. CONCLUSION: MGMT promoter methylation has a predominant favourable influence even for the important subpopulation with non-resectable glioblastoma. The molecular stereotactic biopsy technique is safe and effective for predictive evaluation and helps to avoid both over- and undertreatment.

Identification of valid endogenous control genes for determining gene expression in human glioma.

In human glioma, quantitative real-time reverse-transcription PCR (qPCR) is a frequently used research tool. However, no systematic analysis of suitable reference genes for reliable gene expression analysis has been performed so far. In the current study, we tested 19 commonly used reference genes for their expression stability in human astrocytoma WHO Grade II, astrocytoma WHO Grade III, and glioblastoma (WHO Grade IV) both alone and compared with normal brain. First, equivalence tests for equal expression of candidate genes were applied, and those genes showing differential expression were ruled out from further analyses. Second, expression stability of the remaining candidate genes was determined by the NormFinder software. Generally, glioblastoma exhibited the highest expression levels and largest variability of candidate genes, whereas the opposite was true for normal brain. Even though Normfinder analyses revealed a large number of genes suitable for normalization in each of the tumor subgroups and across these groups, this number was drastically reduced after inclusion of normal brain into the analyses: Only GAPDH, IPO8, RPL13A, SDHA, and TBP were expected not to be differentially expressed; NormFinder analysis indicated favorable stability values for all of these genes, with TBP and IPO8 being the most stable ones. These 5 genes represent different physiological pathways and may be regarded as universal reference genes applicable for accurate normalization of gene expression in human astrocytomas of different grades (WHO Grades II-IV) alone and compared with normal brain, thereby enabling longitudinally designed studies (eg, in astrocytoma before and after malignant transformation).

Novel molecular stereotactic biopsy procedures reveal intratumoral homogeneity of loss of heterozygosity of 1p/19q and TP53 mutations in World Health Organization grade II gliomas.

We report a molecular stereotactic biopsy technique that combines histopathologic diagnosis with small sample size-adjusted molecular genetic analysis of low-grade gliomas that are ineligible for tumor resection. Loss of heterozygosity (LOH) of 1p/19q and TP53 mutations were analyzed in 1-mm tissue samples from 42 World Health Organization grade II gliomas (30 astrocytomas, 8 oligoastrocytomas, 4 oligodendrogliomas) using polymerase chain reaction-based microsatellite and sequence analysis. Alternating histological and molecular genetic evaluation within 1-mm steps at different sites within each tumor was performed to determine reproducibility of the results and the intratumoral distribution of the biomarkers. Multiple serial biopsies (range, 2-5 per tumor) taken from distinct intratumoral areas revealed concordant molecular genetic findings and homogeneous distribution of both biomarkers throughout 41 tumors. Contamination by nonneoplastic tissue could be recognized by corresponding histological evaluation and resulted in discordant LOH findings in 1 tumor. The frequency of LOH 1p/19q and TP53 mutations was consistent with the literature; these genetic alterations were found to be mutually exclusive. There was no biopsy-related morbidity. We conclude that determination of the LOH 1p/19q and TP53 status using this molecular stereotactic biopsy technique is safe and reliable in cases of unresectable gliomas.

Microsurgery plus whole brain irradiation versus Gamma Knife surgery alone for treatment of single metastases to the brain: a randomized controlled multicentre phase III trial.

BACKGROUND: Is Gamma Knife surgery alone as effective as surgery plus whole brain irradiation (WBRT) for patients with a single, small-sized brain metastasis? METHODS: Patients aged between 18 and 80 years harboring a single, resectable metastasis < or =3 cm in diameter, a Karnofsky performance score (KPS) > or =70, and a stable systemic disease were randomly assigned to microsurgery plus WBRT or Gamma Knife surgery alone. The primary end point was length of survival, secondary end points were recurrence of tumor in the brain, health related quality of life, and treatment related toxicity. RESULTS: Due to poor patient accrual, the study was stopped prematurely. The final analysis was based on 33 patients in the surgery and 31 patients in the radiosurgery group. Treatment results did not differ in terms of survival (P = 0.8), neurological death rates (P = 0.3), and freedom from local recurrence (P = 0.06). Patients of the radiosurgery group experienced more often distant recurrences (P = 0.04); after adjustment for the effects of salvage radiosurgery this difference was lost (P = 0.4). Radiosurgery was associated with a shorter hospital stay, less frequent and shorter timed steroid application (P < or = 0.001), and lower frequency of grade 1/2 toxicities (according to the RTOG/EORTC CNS toxicity criteria, P < or = 0.01). Improved scores for role functioning and quality of life were seen 6 weeks after radiosurgery (P < 0.05); this difference was lost 6 months after treatment. CONCLUSIONS: In patients harboring a single, small-sized metastasis, Gamma Knife surgery alone is less invasive; local tumor control seems to be as high as after surgery plus WBRT. Distant tumor control, however, is significantly less frequently achieved (after radiosurgery alone). The role of radiosurgical salvage therapy (alternatively to WBRT) for distant tumor control deserves further prospective evaluation.

FET PET for the evaluation of untreated gliomas: correlation of FET uptake and uptake kinetics with tumour grading.

PURPOSE: Treatment and prognosis of gliomas depend on their histological tumour grade. The aim of the study was to evaluate the potential of [(18)F]fluoroethyltyrosine (FET) PET for non-invasive tumour grading in untreated patients. METHODS: Dynamic FET PET studies were performed in 54 patients who, based on MRI, were estimated to have low grade (LG; n = 20), intermediate (WHO II-III; n = 4) or high grade (HG; n = 30) tumours. For standard evaluation, tumour SUV(max) and the ratio to background (SUV(max)/BG) were calculated (sum image: 20-40 min). For dynamic evaluation, mean SUV values within a 90% isocontour ROI (SUV90) and the SUV90/BG ratios were determined for each time frame to evaluate the course of FET uptake. Results were correlated with histopathological findings from PET-guided stereotactic biopsies. RESULTS: Histology revealed gliomas in all patients. Using the standard method a statistically significant difference (p = 0.001) was found between LG (n = 20; SUV(max)/BG: 2.16 +/- 0.98) and HG (n = 34; SUV(max)/BG: 3.29 +/- 1.06) gliomas (opt. threshold 2.58: SN71%/SP85%/area under ROC curve [AUC]:0.798), however, with a marked overlap between WHO II to IV tumours. Time activity curves showed slight increase in LG, whereas HG tumours presented with an early peak (10-20 min) followed by a decrease. Dynamic evaluation successfully separated LG from HG gliomas with higher diagnostic accuracy (SN94%/SP100%/AUC:0.967). CONCLUSIONS: Based on the ratio-based method, a statistically significant difference was found between LG and HG gliomas. Due to the interindividual variability, however, no reliable individual grading was possible. In contrast, dynamic evaluation allowed LG and HG gliomas to be differentiated with high diagnostic power and, thus, should supplement the conventional method.

Interstitial photodynamic therapy of nonresectable malignant glioma recurrences using 5-aminolevulinic acid induced protoporphyrin IX.

BACKGROUND AND OBJECTIVE: Limited knowledge of the light and temperature distribution within the target volume in combination with non-selective accumulation of the applied photosensitizers (PS) has hampered the clinical relevance of interstitial photodynamic therapy (iPDT) for treatment of malignant glioma patients. The current pilot study focused on the development and the clinical implementation of an accurate and reproducible irradiation scheme for iPDT using 5-aminolevulinic acid (5-ALA) induced protoporphyrin IX (PPIX) as a selectively working PS. STUDY DESIGN/MATERIALS AND METHODS: Monte Carlo simulations of fluence rate and heat transport simulations were performed using the optical properties of normal brain tissue infiltrated by tumor cells (absorption coefficient micro(a) = 0.2 cm(-1), reduced scattering coefficient: micro'(s) = 20 cm(-1)). A modified 3-D treatment-planning software was used to calculate both, the treatment-volume and the exact position of the light diffusers within the lesion. The feasibility and the risk of iPDT were tested in 10 patients with small and circumscribed recurrent malignant gliomas. RESULTS: The optimum distance between the implanted light diffusers was determined to be 9 mm with regard to both fluence rate and temperature distribution. For this distance a temperature increase above 42 degrees C was not expected to occur. Up to six cylindrical light diffusers were stereotactically implanted to achieve a complete irradiation of the tumor volume, which was possible in every single patient (mean tumor volume: 5.9 cm3). The total applied light fluence was between 4,320 J and 11,520 J. Side effects of iPDT were not observed. Median survival was 15 months. CONCLUSION: 5-ALA iPDT in combination with a 3-D treatment-planning (which was based on optical and thermal simulations) is a safe and feasible treatment modality. The clinical impact of these findings deserves further prospective evaluation.

Analysis of 18F-FET PET for grading of recurrent gliomas: is evaluation of uptake kinetics superior to standard methods?

UNLABELLED: The aim of the present study was to evaluate whether extended analyses of O-(2-18F-fluoroethyl)-L-tyrosine (FET) uptake kinetics provide results superior to those of standard tumor-to-background ratios in predicting tumor grade in patients with pretreated gliomas. METHODS: Dynamic 18F-FET PET studies (0-40 min after injection of 180 MBq of 18F-FET) were performed on 45 glioma patients with suspected tumor recurrence after multimodal treatment. For the standard method, tumoral maximal standardized uptake value (SUVmax) and the ratio to the background were derived from a summed image 20-40 min after injection. Dynamic data evaluation comprised several approaches: first, SUV within a 90% isocontour threshold (SUV90) and the respective ratio to the background calculated for each time frame between 5 and 40 min after injection; second, the time to peak analysis; and third, various parameters accounting for the individual time course of 18F-FET uptake. Results were correlated with the histopathologic findings of MRI/PET-guided stereotactic biopsies and were evaluated with respect to their discriminatory power to separate low- from high-grade tumors using receiver-operating characteristic (ROC) analyses. RESULTS: The parameters taking into account the individual time course of 18F-FET uptake were able to differentiate low-grade from high-grade recurrent astrocytomas with high diagnostic accuracy, reaching the best differentiation with a sensitivity and specificity of 92% and an area under the ROC curve (AUC) of 0.94. For the other parameters, the respective values were considerably lower (time to peak: 85% sensitivity and 88% specificity; SUV90-to-background ratio for single-frame evaluation of the early-uptake phase: 100% sensitivity, 62% specificity, and 0.81 AUC). The lowest performance was provided by the standard method (SUVmax: 73% sensitivity, 54% specificity, and 0.60 AUC; SUVmax-to-background ratio: 62% sensitivity, 62% specificity, and 0.59 AUC). Time-activity curves (5-40 min after injection) slightly and steadily increased in tumor-free patients and in low-grade tumors, whereas high-grade tumors showed an early peak around 10-15 min after injection followed by a decrease. CONCLUSION: This study has shown differences in the dynamics of 18F-FET uptake between recurrent low- and high-grade gliomas. Therefore, parameters addressing the different kinetic behaviors allow discrimination with high diagnostic power between these 2 prognostically different groups. Thus, the techniques introduced here are clearly superior to the yet most widely used standard method.

Interstitial 125I radiosurgery of supratentorial de novo WHO Grade 2 astrocytoma and oligoastrocytoma in adults: long-term results and prognostic factors.

BACKGROUND: Detailed long-term outcome data are not available for adult patients with World Health Organization (WHO) Grade 2 astrocytoma or oligoastrocytoma. METHODS: A previously published short-term data set of 239 adult patients with circumscribed de novo supratentorial astrocytoma (187 patients) and oligoastrocytoma (52 patients) treated with interstitial iodine-125 ((125)I) radiosurgery as primary treatment (1979-1992) was revisited. Survival, progression-free survival, functionally independent survival, postrecurrence survival, and time to malignant transformation were estimated with the Kaplan-Meier method. Prognostic factors were obtained from the Cox multivariate proportional hazards model. RESULTS: Five-, 10-, and 15-year survival was 56%, 37%, and 26%, respectively (median follow-up, 10.3 yrs). Progression-free survival was 45%, 21%, and 14%, respectively. The corresponding malignant transformation rates were 33%, 54%, and 67%. No leveling off of the Kaplan-Meier curves could be observed for any of the chosen endpoints. Age > 50 years, a tumor volume > 20 mL, and/or a Karnofsky score < or = 80 were associated with decreased survival or progression-free survival. Age > 35 years and/or a tumor volume > 20 mL increased risk of malignant transformation. Prognostic factors determined subsets of patients with 10-year survival ranging from as low as 6% to as high as 55% and progression-free survival ranging 1-31%. CONCLUSIONS: Long-term tumor stabilization is rare. As outcome is mainly determined by treatment-independent factors, minimization of any treatment-related risk must be considered essential.

Prognostic impact of TP53 mutation status for adult patients with supratentorial World Health Organization Grade II astrocytoma or oligoastrocytoma: a long-term analysis.

BACKGROUND: The goal of the current study was to retrospectively assess the prognostic impact of TP53 mutation status and P53 expression/accumulation on long-term outcome for adult patients with supratentorial World Health Organization (WHO) Grade II astrocytoma or oligoastrocytoma. METHODS: The authors revisited a previously published short-term data set containing information on 159 consecutive patients who were treated between 1991 and 1998. Each patient was screened for TP53 mutations and P53 overexpression/accumulation. The reference point for all analyses was the date of surgical treatment, and the date of last follow-up examination was August 2002. Overall survival, progression-free survival, postrecurrence survival, and time to malignant transformation were estimated using the Kaplan-Meier method, and potential prognostic factors were evaluated using the multivariate proportional hazards model. RESULTS: The median follow-up duration for survivors was 80.4 months (standard deviation, 33.0 months). TP53 mutations, which were present in 49.1% of all tumors, occurred preferentially in gemistocytic tumors (P < 0.05). In addition, the TP53 status of the primary tumor was predictive of the TP53 status of the recurrent tumor in all cases of disease recurrence. The 5-year overall and progression-free survival rates were 77.5% and 43.2%, respectively, and the risk of malignant transformation at 5 years postsurgery was 32.7%. Unfavorable prognostic factors with respect to survival duration included older age (> or = 50 years; P < 0.002), gemistocytic subtype (P < 0.01), and positive TP53 mutation status (P < 0.05), all of which were also negatively associated with progression-free survival (P < 0.05, P < 0.001, and P < 0.003, respectively). In contrast, positive TP53 mutation status was the only significant predictor of a reduction in time to malignant transformation (P < 0.03). P53 overexpression/accumulation did not exhibit prognostic relevance in any of the multivariate models constructed in the current study. CONCLUSIONS: TP53 mutations are common early events in the pathogenesis of WHO Grade II astrocytoma or oligoastrocytoma. In the current study, positive TP53 mutation status (but not P53 overexpression/accumulation) was found to be an independent unfavorable predictor of survival, progression-free survival, and time to malignant transformation. The therapeutic implications of these findings have yet to be determined.

Stereotactic radiosurgery for multiple brain metastases from breast carcinoma.

BACKGROUND: The current study analyzed the feasibility and outcome of stereotactic radiosurgery (SRS) for treatment of brain metastases from breast carcinoma. METHODS: During an 8-year period, 151 patients with a combined total of 620 brain metastases from breast carcinoma underwent 197 outpatient SRS procedures. Sixty-three percent of all patients had multiple brain metastases. The median tumor volume was 2.2 cm(3) (range, 0.1-20.9 cm(3)). The mean prescribed tumor dose was 19 +/- 4 grays. Local/distant tumor recurrences were treated with additional radiosurgical therapy for patients with stable systemic disease. All patients were categorized according to the Radiation Therapy Oncology Group classification. Survival time and freedom from local tumor recurrence were analyzed using the Kaplan-Meier method. Prognostic factors were identified using the Cox proportional hazards model. RESULTS: The overall median survival duration was 10 months after SRS. Ninety-four percent of patients did not experience local brain tumor recurrence after radiosurgery. In addition, 70.2% of patients did not have disease recurrence in the brain. Most patients died of systemically progressing malignancy. A Karnofsky performance score > 70 and recursive partitioning analysis Class I were related to prolonged survival in the univariate and multivariate analyses. Age, whole-brain radiotherapy, surgery, number of metastases, chemotherapy, and latency period from diagnosis of the primary tumor to the development of brain metastases did not reach prognostic relevance in the multivariate model. Patients with RPA I, II, and III survived 34.9, 9.1, and 7.9 months, respectively. There was no treatment related permanent morbidity and mortality. The transient morbidity rate was 17%. Sixteen patients exhibited symptomatic transient complications related to treatment. CONCLUSIONS: The results of the current study indicate that SRS is a feasible treatment concept for selected patients with multiple brain metastases from breast carcinoma.

Long term course of WHO grade II astrocytomas of the Insula of Reil after I-125 interstitial irradiation.

OBJECTIVE: To present long-term results after interstitial iodine-125 irradiation of adult patients with de-novo World Health Organization (WHO) Grade II astrocytomas and oligoastrocytomas of the insula of Reil with special respect to the treatment-related risk. METHODS: 55 consecutively treated patients (from 1979 to 1992) with circumscribed tumors with a diameter < 5 cm (astrocytomas: 46 patients, oligoastrocytomas: 9 patients) were included. The reference dose-calculated to the outer boundary of the tumor-was in the range of 60-100 Gy and the dose rate was low (< 10 cGy/h). Progression-free survival, risk of malignant transformation, survival, and the incidence of radiogenic complications were estimated by the Kaplan-Meier method. Prognostic factors were obtained from the Cox-model. RESULTS: Median follow up for the survivors was > 10 years. 5-year (10-year) progression-free survival was 40.7 % (20.2 %), and 5-year (10-year) survival 54.6 % (28.4 %). Malignant transformation occurred in 42.4 % after 5 years. Neither of the Kaplan-Meier curves showed a leveling off over time. Transient (progressive) radiogenic complications were observed in 13 [4] patients (one-year overall complication rate: 18%), and were significantly associated with a tumor diameter >3.5 cm (p<0.001). No long term side-effects were detected and delayed external beam irradiation (in case of tumor progression) did not enhance the risk. Tumor enhancement on CT was the only unfavorable predictor for survival. CONCLUSION: A limited overall prognosis for adult patients with insular WHO grade II astrocytomas and oligoastrocytomas was detected. Interstitial I-125 irradiation offers a minimal-invasive and low-risk treatment option for circumscribed tumors with a diameter < 3.5 cm. Larger tumors require further evaluation for optimal treatment.