Correction to: Biological tumour volumes of gliomas in early and standard 20-40 min 18F-FET PET images differ according to IDH mutation status.

The name of M. Unterrainer was inadvertently presented as M. Unterrrainer in the original article.

Biological tumour volumes of gliomas in early and standard 20-40 min 18F-FET PET images differ according to IDH mutation status.

PURPOSE: For the clinical evaluation of O-(2-18F-fluoroethyl)-L-tyrosine (18F-FET) PET images, the use of standard summation images obtained 20-40 min after injection is recommended. However, early summation images obtained 5-15 min after injection have been reported to allow better differentiation between low-grade glioma (LGG) and high-grade glioma (HGG) by capturing the early 18F-FET uptake peak specific for HGG. We compared early and standard summation images with regard to delineation of the PET-derived biological tumour volume (BTV) in correlation with the molecular genetic profile according the updated 2016 WHO classification. METHODS: The analysis included 245 patients with newly diagnosed, histologically verified glioma and a positive 18F-FET PET scan prior to any further treatment. BTVs were delineated during the early 5-15 min and standard 20-40 min time frames using a threshold of 1.6 × background activity and were compared intraindividually. Volume differences between early and late summation images of >20% were considered significant and were correlated with WHO grade and the molecular genetic profile (IDH mutation and 1p/19q codeletion status). RESULTS: In 52.2% of the patients (128/245), a significant difference in BTV of >20% between early and standard summation images was found. While 44.3% of WHO grade II gliomas (31 of 70) showed a significantly smaller BTV in the early summation images, 35.0% of WHO grade III gliomas (28/80) and 37.9% of WHO grade IV gliomas (36/95) had a significantly larger BTVs. Among IDH-wildtype gliomas, an even higher portion (44.4%, 67/151) showed significantly larger BTVs in the early summation images, which was observed in 5.3% (5/94) of IDH-mutant gliomas only: most of the latter had significantly smaller BTVs in the early summation images, i.e. 51.2% of IDH-mutant gliomas without 1p/19q codeletion (21/41) and 39.6% with 1p/19q codeletion (21/53). CONCLUSION: BTVs delineated in early and standard summation images differed significantly in more than half of gliomas. While the standard summation images seem appropriate for delineation of LGG as well as IDH-mutant gliomas, a remarkably high percentage of HGG and, particularly, IDH-wildtype gliomas were depicted with significantly larger volumes in early summation images. This finding might be of interest for optimization of treatment planning (e.g. radiotherapy) in accordance with the individual IDH mutation status.

Gross total but not incomplete resection of glioblastoma prolongs survival in the era of radiochemotherapy.

BACKGROUND: This prospective multicenter study assessed the prognostic influence of the extent of resection when compared with biopsy only in a contemporary patient population with newly diagnosed glioblastoma. PATIENTS AND METHODS: Histology, O(6)-methylguanine-DNA methyltransferase (MGMT) promoter methylation status, and clinical data were centrally analyzed. Survival analyses were carried out with the Kaplan-Meier method. Prognostic factors were assessed with proportional hazard models. RESULTS: Of 345 patients, 273 underwent open tumor resection and 72 biopsies; 125 patients had gross total resections (GTRs) and 148, incomplete resections. Surgery-related morbidity was lower after biopsy (1.4% versus 12.1%, P = 0.007). 64.3% of patients received radiotherapy and chemotherapy (RT plus CT), 20.0% RT alone, 4.3% CT alone, and 11.3% best supportive care as an initial treatment. Patients ≤60 years with a Karnofsky performance score (KPS) of ≥90 were more likely to receive RT plus CT (P < 0.01). Median overall survival (OS) (progression free survival; PFS) ranged from 33.2 months (15 months) for patients with MGMT-methylated tumors after GTR and RT plus CT to 3.0 months (2.4 months) for biopsied patients receiving supportive care only. Favorable prognostic factors in multivariate analyses for OS were age ≤60 years [hazard ratio (HR) = 0.52; P < 0.001], preoperative KPS of ≥80 (HR = 0.55; P < 0.001), GTR (HR = 0.60; P = 0.003), MGMT promoter methylation (HR = 0.44; P < 0.001), and RT plus CT (HR = 0.18, P < 0.001); patients undergoing incomplete resection did not better than those receiving biopsy only (HR = 0.85; P = 0.31). CONCLUSIONS: The value of incomplete resection remains questionable. If GTR cannot be safely achieved, biopsy only might be used as an alternative surgical strategy.

Personalized surgical therapy.

Gliomas are more or less diffuse tumours with the ability to infiltrate surrounding functional brain tissue. Thus, curative surgical treatment generally cannot be achieved. Despite these limitations, open tumour resection represents one of the mainstays in glioma treatment settings. Beyond tissue sampling for accurate histological and molecular genetic evaluation, decompressive effects in the case of space occupying tumours and oncologically relevant cytoreductive effects of microsurgery have been reported in selected patients with glioma of different grades. This paper provides practical considerations in order to integrate the concept of a personalized surgical therapy into the prognostic network of low- and high-grade gliomas, covering both microsurgery and stereotactic biopsy techniques.

Hot spots in dynamic (18)FET-PET delineate malignant tumor parts within suspected WHO grade II gliomas.

Molecular imaging studies have recently found inter- and intratumoral heterogeneity in World Health Organization (WHO) grade II gliomas. A correlative analysis with tumor histology, however, is still lacking. For elucidation we conducted the current prospective study. Fifty-five adult patients with an MRI-based suspicion of a WHO grade II glioma were included. [F-18]Fluoroethyltyrosine ((18)FET) uptake kinetic studies were combined with frame-based stereotactic localization techniques and used as a guide for stepwise (1-mm steps) histopathological evaluation throughout the tumor space. In tumors with heterogeneous PET findings, the O(6)-methylguanine-DNA methyltransferase (MGMT) promoter methylation status and expression of mutated protein isocitrate dehydrogenase variant R132H (IDH1) were determined inside and outside of hot spot volumes. Metabolic imaging revealed 3 subgroups: the homogeneous WHO grade II glioma group (30 patients), the homogeneous malignant glioma group (10 patients), and the heterogeneous group exhibiting both low- and high-grade characteristics at different sites (15 patients). Stepwise evaluation of 373 biopsy samples indicated a strong correlation with analyses of uptake kinetics (p < 0.0001). A homogeneous pattern of uptake kinetics was linked to homogeneous histopathological findings, whereas a heterogeneous pattern was associated with histopathological heterogeneity; hot spots exhibiting malignant glioma characteristics covered 4-44% of the entire tumor volumes. Both MGMT and IDH1 status were identical at different tumor sites and not influenced by heterogeneity. Maps of (18)FET uptake kinetics strongly correlated with histopathology in suspected grade II gliomas. Anaplastic foci can be accurately identified, and this finding has implications for prognostic evaluation and treatment planning.

The place of interstitial brachytherapy and radiosurgery for low-grade gliomas.

Even though stereotactic brachytherapy has been used for treatment of complex located low-grade glioma for many years, its place within modern treatment concepts is still debated and only a few centers have gained experience with this complex treatment modality. The current article reviews selection criteria, treatment protocols, radiobiology, treatment effects, risk models and side effects of stereotactic brachytherapy. Potentially alternative techniques such as radiosurgery were also reviewed under consideration of radiobiological similarities and differences.

Serial stereotactic biopsy of brainstem lesions in adults improves diagnostic accuracy compared with MRI only.

OBJECTIVE: The aim of the current prospective study was to analyse the validity of MRI based diagnosis of brainstem gliomas which was verified by stereotactic biopsy and follow-up evaluation as well as to assess prognostic factors and risk profile. METHODS: Between 1998 and 2007, all consecutive adult patients with radiologically suspected brainstem glioma were included. The MRI based diagnosis of the lesions was made independently by an experienced neuroradiologist. Histopathological evaluation was performed in all patients from paraffin embedded specimens obtained by multimodal image guided stereotactic serial biopsy technique. Histopathological results were compared with prior radiological assessment. Length of survival was estimated with the Kaplan-Meier method and prognostic factors were calculated using the Cox model. RESULTS: 46 adult patients were included. Histological evaluation revealed pilocytic astrocytoma (n = 2), WHO grade II glioma (n = 14), malignant glioma (n = 12), metastasis (n = 7), lymphoma (n = 5), cavernoma (n = 1), inflammatory disease (n = 2) or no tumour/gliosis (n = 3). Perioperative morbidity was 2.5% (n = 1). There was no permanent morbidity and no mortality. All patients with "no tumour" or "inflammatory disease" survived. Patients with low grade glioma and malignant glioma showed a 1 year survival rate of 75% and 25%, respectively; the 1 year survival rate for patients with lymphoma or metastasis was 30%. In the subgroup with a verified brainstem glioma, negative predictors for length of survival were higher tumour grade (p = 0.002) and Karnofsky performance score < or =70 (p = 0.004). CONCLUSION: Intra-axial brainstem lesions with a radiological pattern of glioma represent a very heterogeneous tumour group with completely different outcomes. Radiological features alone are not reliable for diagnostic classification. Stereotactic biopsy is a safe method to obtain a valid tissue diagnosis, which is indispensible for treatment decision.

Surgical resection plus stereotactic 125I brachytherapy in adult patients with eloquently located supratentorial WHO grade II glioma - feasibility and outcome of a combined local treatment concept.

OBJECTIVE: The current pilot study analyzed feasibility, risk and effectiveness of 1) microsurgery plus stereotactic iodine-125 ((125)I) brachytherapy (SBT) for large (diameter > 4 cm), circumscribed, and complex located WHO grade II glioma and 2) SBT alone for small (diameter < 4 cm), and complex located recurrences. METHODS: Lowactivity temporary (125)I seeds were used. The applied reference dose was 54 Gy and the dose rate was low (median, 10 cGy/h). Time to progression and time to additional external beam radiation (EBR) and/or chemotherapy were estimated with the Kaplan-Meier method. Any adverse sequel potentially attributable to treatment was classified as morbidity. Treatment effects of SBT were estimated according to the modified MacDonald criteria. RESULTS: Thirtyone patients (de novo group: n = 18, recurrence group: n = 13) were included. The median tumor volume before surgery was 66 ml. A planned partial tumor resection achieved eligibility for SBT in all patients. Transient morbidity of microsurgery and SBT was 27.8 % and 6.4 %, respectively. There was no permanent morbidity. Radiogenic complications did not occur. Complete response, partial response, and stable disease were seen in 8, 9, and 14 patients, respectively. Ten patients exhibited tumor progression (overall 5-year progression- free survival > 60 %). The 5-year probability to receive chemotherapy and/or EBR was 18 %. CONCLUSION: A planned partial tumor resection of large and complex located WHO grade II glioma is safe. SBT of small and complex located residual of recurrent tumors is safe and minimally invasive. Combined treatment may provide the possibility to withhold EBR and/or chemotherapy for a considerable number of patients and deserves further prospective evaluation.

The positive predictive value of O-(2-[18F]fluoroethyl)-L-tyrosine (FET) PET in the diagnosis of a glioma recurrence after multimodal treatment.

OBJECTIVE: To explore prospectively the positive predictive value of O-(2-[(18)F]fluoroethyl)-L-tyrosine (FET)-PET in selected patients with a magnetic resonance imaging (MRI)-based suspicion of a glioma recurrence or progression. Methods Patients with a supratentorial glioma (initial World Health Organization (WHO) grade II, III or IV) were considered eligible if they had both an MRI-(new/progressive contrast-enhancing lesion) and FET-PET-based diagnosis of a recurrence/progression after various forms and combinations of irradiation and chemotherapy. Criterion for tumour recurrence/progression in FET-PET was a standardized uptake value (SUVmax)/Background (BG) ratio of >2.0 in the late uptake phase. All patients underwent multimodal (MRI, FET-PET) imaging-guided stereotactic biopsy. The positive predictive value was defined as the proportion of MRI and FET-PET findings indicating glioma recurrence/progression that also tested positive for tumour recurrence/progression after stereotactic biopsy. RESULTS: Thirty-one patients with initially WHO grade II (17), WHO grade III (6), and grade IV glioma (8) were included. In 26 patients FET-PET results indicating tumour recurrence/progression were concordant with the biopsy results. In five patients histopathologic evaluation failed to reveal a "vital" tumour. FET-PET findings were also discordant with the radiographic and clinical follow-up in these five patients. The positive predictive value of FET-PET was 84%. CONCLUSION: The positive predictive value of FET-PET using the standard ratio method is high, but not high enough to replace stereotactic biopsy in this highly selected study cohort. Whether the calculation of FET uptake in the early phase and/or the evaluation of uptake kinetics will improve the positive predictive value of FET-PET deserves prospective evaluation.

Interstitial iodine-125 radiosurgery alone or in combination with microsurgery for pediatric patients with eloquently located low-grade glioma: a pilot study.

PURPOSE: The optimal therapeutic management of children with World Health Organization grade I and II gliomas not accessible to complete resection is poorly defined. Radical surgical resection is the first-line treatment for large hemispheric tumors, whereas interstitial iodine-125 radiosurgery (IRS) might be an attractive treatment concept for selected patients with small (tumor diameter in the range of 4 cm) and circumscribed tumors in any location of the brain. Precise high-dose application, maximal sparing of surrounding normal tissue, and the absence of long-term complications have been reported to be the hallmark of IRS. Therefore, the therapeutic impact and the risk of IRS alone or in combination with microsurgery (in case of larger tumor volumes) were prospectively examined. METHODS: Seven boys and four girls were included (mean age, 6.8 years; range, 11 months to 16 years). IRS (after stereotactic biopsy) was considered to be indicated for circumscribed tumors with a diameter in the range of 4 cm (four cases). For larger tumors, a combined microsurgical/radiosurgical approach was preferred (seven patients). Temporary iodine-125 seeds were used exclusively (tumor dose calculated to the boundary, 54 Gy; dose rate, 10 cGy/h). Tumor location was hypothalamic/suprasellar in four, lobar in three, deep (thalamus and pineal gland) in two, and within the brain stem in two children. Treatment effects of IRS were estimated according to the MacDonald criteria. RESULTS: A complete response after IRS was seen in four patients, and a partial response was seen in seven patients (median follow-up, 31.5 months). There was no perioperative morbidity after microsurgery and/or IRS, and no radiogenic complications occurred during the follow-up period. Five patients experienced an improvement in their deficits, and no deterioration in neurological/endocrine function was seen in any of the patients at the time of last follow-up evaluation. CONCLUSION: IRS alone or in combination with microsurgery (in the case of larger tumors) is a safe, effective, and minimally invasive treatment strategy for eloquently located pediatric low-grade gliomas and deserves further prospective evaluation.

O-(2-[18F]fluoroethyl)-L-tyrosine PET for monitoring the effects of convection-enhanced delivery of paclitaxel in patients with recurrent glioblastoma.

PURPOSE: Convection-enhanced delivery (CED) of paclitaxel is a new locoregional approach for patients with recurrent glioblastoma. The aim of this study was to evaluate O-(2-[(18)F]fluoroethyl)-L-tyrosine (FET) positron emission tomography (PET) in monitoring the effects of this type of direct drug delivery. METHODS: Eight patients with recurrent glioblastoma underwent CED of paclitaxel, which was infused over stereotactically placed catheters into the tumour. FET PET and MRI were performed before and 4 weeks after therapy and then at 3-month intervals to document follow-up. For quantitative evaluation, SUV(max)(tumour)/SUV(mean)(background) ratios were calculated. RESULTS: At baseline all tumours showed gadolinium enhancement and high FET uptake (SUV(max)/BG 3.2+/-0.8). Four weeks after CED, a statistically significant decrease in FET uptake was seen (SUV(max)/BG-17%; p<0.01). During follow-up, no recurrence was observed within the CED area. Two out of eight patients with extended tumours died 4 and 5 months after treatment, most probably from local complications. Temporarily stable disease with stable FET uptake was observed in six of eight patients; this was followed by progression and increasing FET uptake ratios (+46%) distant from the CED area in five of the six patients 3-13 months after CED. One patient still presents stable FET uptake 10 months after CED. MRI showed unchanged/increasing contrast enhancement and oedema without ability to reliably assess disease progression. CONCLUSION: FET PET is a valuable tool in monitoring the effects of CED of paclitaxel. In long-term follow-up, stable or decreasing FET uptake, even in contrast-enhancing lesions, is suggestive of reactive changes, whereas increasing ratios appear always to be indicative of recurrence. Therefore, FET PET is more reliable than MRI in differentiating stable disease from tumour regrowth.

Image guided interstitial laser thermotherapy: a canine model evaluated by magnetic resonance imaging and quantitative autoradiography.

OBJECTIVE: To determine the applicability and safety of a new canine model suitable for correlative magnetic resonance imaging (MRI) studies and morphological/pathophysiological examination over time after interstitial laser thermotherapy (ILTT) in brain tissue. MATERIAL AND METHODS: A laser fibre (Diode Laser 830 nm) with an integrated temperature feedback system was inserted into the right frontal white matter in 18 dogs using frameless navigation technique. MRI thermometry (phase mapping i.e. chemical shift of the proton resonance frequency) during interstitial heating was compared to simultaneously recorded interstitial fiberoptic temperature readings on the border of the lesion. To study brain capillary function in response to ILTT over time quantitative autoradiography was performed investigating the unidirectional blood-to-tissue transport of carbon-14-labelled alpha amino-isobutyric acid (transfer constant K of AIB) 12, 36 hours, 7, 14 days, 4 weeks and 3 months after ILTT. RESULTS: All laser procedures were well tolerated, laser and temperature fibres could be adequately placed in the right frontal lobe in all animals. In 5 animals MRI-based temperature quantification correlated strongly to invasive temperature measurements. In the remaining animals the temperature fibre was located in the area of susceptibility artifacts, therefore, no temperature correlation was possible. The laser lesions consisted of a central area of calcified necrosis which was surrounded by an area of reactive brain tissue with increased permeability. Quantitative autoradiography indicated a thin and spherical blood brain barrier lesion. The magnitude of K of AIB increased from 12 hours to 14 days after ILTT and decreased thereafter. The mean value of K of AIB was 19 times (2 times) that of normal white matter (cortex), respectively. CONCLUSION: ILTT causes transient, highly localised areas of increased capillary permeability surrounding the laser lesion. Phase contrast imaging for MRI thermomonitoring can currently not be used for reliable temperature readings in vivo. The suggested new canine model proved to be safe, accurate, easy to use, and provides clinical, radiographic, pathological and physiological correlations.

Stereotactic radiosurgery without radiation therapy providing high local tumor control of multiple brain metastases from renal cell carcinoma.

The aim of this study was to analyse treatment effects after stereotactic radiosurgery (SRS) without whole brain radiation therapy (WBRT) as primary treatment for patients harboring brain metastases of renal cell carcinoma (RCC). During an 8-year period, 85 patients with 376 brain metastases from RCC underwent 134 outpatient SRS procedures. 65 % of all patients had multiple brain metastases. The median tumor volume was 1.2 cm (3) (range: 0.1 - 14.2 cm (3)). Mean prescribed tumor dose was 21.2 (+/- 3.2) Gy. Local/distant tumor recurrences were treated by additional SRS in cases of stable systemic disease. Overall median survival was 11.1 months after SRS. The local tumor control rate after SRS was 94 %. Most patients (78 %) died because of systemically progressing cancer. A KPS > 70 and RTOG class I were related to prolonged survival time. Patients of the RTOG groups I, II and III survived for 24.2 months, 9.2 months and 7.5 months, respectively. There was no permanent morbidity after SRS. 11 patients (12.9 %) showed transient radiogenic complications and 3 patients (3.5 %) died because of intratumoral bleedings after SRS. Stereotactic radiosurgery alone achieves excellent local tumor control rates for patients with small brain metastases from renal cell carcinoma.

Outcome and prognostic factors of hemicraniectomy for space occupying cerebral infarction.

OBJECTIVE: To determine long term functional outcome and length of survival of patients undergoing decompressive craniectomy for space occupying infarction of the middle cerebral artery (MCA), and to identify risk factors associated with death and unfavourable outcomes METHODS: Databases of patients undergoing decompressive craniectomy for space occupying MCA infarction compiled at eight neurosurgical departments (1996-2001) were merged, and 188 patients were evaluated. Mortality was calculated by the Kaplan-Meier method. Clinical outcome was rated using the Glasgow outcome scale (GOS). The prognostic impact of patient related covariates on length of survival and the GOS was analysed multivariately. RESULTS: The unadjusted 3, 6, and 12 month mortality rates were 7.9%, 37.6%, and 43.8%, respectively (median follow up, 26 weeks). In the "best" multivariate model, age >50 years (p<0.02) and the involvement of two or more additional vascular territories (p<0.01) had an unfavourable impact on length of survival. The adjusted six month mortality was as low as 20.0% (no risk factor) and as high as 59.7% (two risk factors). A GOS score of 50 years (p<0.0003): 34.9% of the patients 3, as compared with 12.0% of the elderly subpopulation. The side of the infarct did not have prognostic relevance. CONCLUSIONS: Results of surgical treatment in patients <50 years of age undergoing decompressive craniectomy are encouraging. The effectiveness of decompressive craniectomy for patients >50 years remains questionable and should be analysed in the framework of a prospective randomised study.

[Significance of stereotactic biopsy for the management of WHO grade II supratentorial glioma]. / Der Stellenwert der stereotaktischen Hirnbiopsie für das Management von Patienten mit supratentoriellen Gliomen WHO-Grad-II.

OBJECTIVE: The aim of this prospective study was to compare the diagnostic value of magnetic resonance imaging (MRI) and stereotactic biopsy in patients harboring WHO grade II gliomas. METHODS: Stereotactic biopsy was performed in 62 adult patients with low-signal, nonenhancing, space-occupying lesions on T1 MR imaging between 1998 and 2001. The results of histological analysis were compared to the preoperative imaging diagnoses. Any adverse perioperative sequel was considered as morbidity. Applied treatment strategies are described. RESULTS: Transient perioperative morbidity for the stereotactic approach was 4.8% (three patients), and there was no mortality or permanent morbidity. In four patients, neoplastic lesions could be excluded (gliosis: three patients, encephalitis: one), and WHO grade III gliomas were seen in five patients (14.8.% false positive rate of neurodiagnostic imaging). The diagnostic reliability of stereotactic biopsy was 96.8%. The following treatment strategies were initiated: microsurgery (17 patients), interstitial radiosurgery (12 patients), combination of microsurgery and interstitial radiosurgery (21 patients), external beam irradiation (six patients),and chemotherapy (two patients). Four patients were initially not treated. CONCLUSIONS: Diagnostic neuroimaging is not sufficient for the planning of rational treatment strategies in patients harboring WHO grade II gliomas. Frame-based stereotactic biopsy is a prerequisite for individualized treatment strategies.