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.

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.

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.

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 risk of interstitial radiotherapy of low-grade gliomas.

BACKGROUND AND PURPOSE: The risk of side effects of low activity (i.e. <20 mCi) Iodine-125I (125I) interstitial radiotherapy was analyzed in patients with low-grade gliomas. MATERIALS AND METHODS: Permanent (247 patients) or temporary 125I-implants (268 patients) were used with a median reference dose of 60 Gy and 100 Gy, respectively, which was calculated to the outer rim of the tumour. The mean dose rate for temporary implants was low (median, 10 cGy/h). Risk factors were obtained from the multivariate proportional-hazards model. RESULTS: Radiogenic complications occurred in 39/515 patients (28 patients with transient symptoms and 11 patients with progressive symptoms). The most important risk factor was the volume of the intratumoural 200 Gy isodose. Available experimental data have associated a high dose zone in this range with the size of the treatment induced radionecrosis. Rapid tumour shrinkage (decrease of the tumour volume > or =50%) within the first 6 months with subsequent centripetal movement of non-pathologic tissue into the high dose zone and a reimplantation were additional risk factors. Radiation injury after rapid tumour shrinkage could be better avoided with temporary implants. A 200 Gy isodose volume <4.5 ml corresponded to an estimated risk of radiogenic complications <3%. There was a steep increase of the risk beyond this limit. Translation of the 200 Gy isodose volume in terms of the treatment volume and the reference dose allows rational treatment planning. The estimated risk of a temporary implant with an applied reference dose of 60 Gy and a treatment volume <23 ml was <3%. CONCLUSIONS: The intratumoural necrotizing effect of a low activity 125I implant limits its application to small treatment volumes. Radiation injury outside the treatment volume can be better avoided with temporary implants in the case of rapid tumour shrinkage.

Stereotactic management of lesions of the pineal region.

OBJECTIVE: The relevance of the computed tomography-guided stereotactic approach for the management of lesions of the pineal region is analyzed. METHODS: In a retrospective analysis conducted between 1985 and 1993, the risk profile, the diagnostic accuracy, and the therapeutic relevance of the stereotactic approach in 106 patients was studied. Survival analysis was used to assess the reliability of the stereotactically obtained diagnosis in terms of follow-up observation. RESULTS: A histological diagnosis was obtained in 103 of the 106 patients. In three patients, a conclusive diagnosis could not be established because of intraoperative complications. One lesion was misdiagnosed as a pineocytoma instead of a pineoblastoma. Two of the 106 patients died; 9 patients experienced perioperative morbidity. In 38 patients, the stereotactic approach was also useful for therapy. Cyst aspiration and/or internal drainage was performed in 18 patients with symptomatic cystic lesions, and radiosurgical treatment with use of interstitial 125iodine was performed in 16 patients with low-grade tumors and in 4 patients with solitary metastases. In 12 patients, the obtained tissue diagnosis was the basis for deferring additional therapy. In 43 patients with germ-cell tumors, pineoblastomas, or malignant gliomas, a stereotactic biopsy was the starting point for additional radiotherapy/chemotherapy. Open tumor resection played a minor role (five patients). CONCLUSION: The stereotactic approach to the pineal region is a relatively safe procedure in experienced hands. The diagnosis obtained by computed tomography-guided stereotactic biopsy is a valid basis for treatment decisions. Long-term follow-up observation of the benign lesions is necessary for a definite confirmation of diagnostic accuracy.

Surgical resection and radiation therapy versus biopsy and radiation therapy in the treatment of glioblastoma multiforme.

There has been considerable controversy over the concept of treating glioblastoma multiforme with cytoreductive surgery. Therefore, a retrospective study of cases treated between 1986 and 1991 was conducted to analyze and compare the results of stereotactic biopsy followed by radiation therapy performed in 58 patients with those of surgical resection plus radiation therapy in 57 patients. In both groups, conventionally fractionated radiation (1.7 to 2.0 Gy/day) was delivered, with a total dose of 50 to 60 Gy. Biopsy was performed only in patients with tumors judged to be inoperable. These patients carried a higher surgical risk and were in worse neurological condition than the patients in the resection group. The median survival time for the resection group was 39.5 weeks, as compared with 32 weeks for the biopsy group. This difference was not significant. The most important prognostic factor was the patient's age. The treatment variable biopsy versus resection did not reach prognostic relevance. In patients with midline shift who underwent biopsy, the Karnofsky Performance Scale score decreased in more patients during radiation therapy. The clinical status 6 weeks after surgery, however, showed no significant differences between the two groups. The comparable survival times for the two groups place doubt on the concept of treating glioblastoma multiforme with cytoreductive surgery. Presently, radiation therapy is the most effective treatment for patients with glioblastoma. There is no question that decompressive surgery followed by radiation therapy should be performed whenever necessary for sever space-occupying lesions and when it will not cause new neurological deficits.

Interstitial radiosurgery of low-grade gliomas.

The treatment of patients with low-grade gliomas remains a subject of controversy, especially with respect to new treatment modalities such as interstitial radiosurgery (brachytherapy), radiosurgery, and stereotactic radiotherapy. In a retrospective analysis conducted between 1979 and 1991, the authors studied the results of interstitial radiosurgery in 455 patients with low-grade gliomas (World Health Organization (WHO) Grade I+WHO Grade II) with regard to survival time, quality of life, the risk of malignant transformation, and the risk profile of the treatment concept. Interstitial radiosurgery with iodine-125 was performed using permanent (1979-1985) or temporary implants (after 1985) with low-dose rates (< or = 10 cGy/hr) and a reference dose of 60 to 100 Gy calculated to the outer rim of the tumor. The 5- and 10-year survival rates in patients with pilocytic astrocytomas (97 patients) were 84.9% and 83%, and in patients with WHO Grade II astrocytomas (250 patients) 61% and 51%, respectively. Five-year survival rates for patients with oligoastrocytomas (60 patients), oligodendrogliomas (27 patients), and gemistocytic astrocytomas (21 patients) were 49%, 50%, and 32%, respectively. In the group with WHO Grade II gliomas, young age and a good performance status were associated with a better prognosis. Unfavorable factors were midline shift, enhancement on computerized tomography (CT) scan, and tumor recurrence after previous radiotherapy or surgery. Tumor location had no influence on the prognosis (247 patients in this series had deep-seated tumors). Malignant transformation was the major cause of death. Important risk factors for malignancy were the patient's age, tumor enhancement in CT scan, and tumor recurrence after previous surgery or radiotherapy. Perioperative mortality was 0.9% and perioperative morbidity was 1.7%. Radiogenic complications were observed in 2.7% of all patients, most often in larger tumors and after using permanent implants. The authors conclude that interstitial radiosurgery represents a specific treatment modality for selected patients with unifocal circumscribed low-grade gliomas with a diameter of less than 4 cm in any location. The efficacy of this treatment lies in the same range as the best results after surgery and radiotherapy.

Surgery and radiotherapy compared with gamma knife radiosurgery in the treatment of solitary cerebral metastases of small diameter.

OBJECT: The aim of this retrospective study was to compare treatment results of surgery plus whole-brain radiation therapy (WBRT) with gamma knife radiosurgery alone as the primary treatment for solitary cerebral metastases suitable for radiosurgical treatment. METHODS: Patients who had a single circumscribed tumor that was 3.5 cm or smaller in diameter were included. Treatment results were compared between microsurgery plus WBRT (52 patients, median tumor dose 50 Gy) and radiosurgery alone (56 patients, median prescribed tumor dose 22 Gy). In case of local/distant tumor recurrence in the radiosurgery group, additional radiosurgical treatment was administered in patients with stable systemic disease. Survival time was analyzed using the Kaplan-Meier method, and prognostic factors were obtained from the Cox model. The patient groups did not differ in terms of age, gender, pretreatment Karnofsky Performance Scale (KPS) score, duration of symptoms, tumor location, histological findings, status of the primary tumor, time to metastasis, and cause of death. Patients who suffered from larger lesions underwent surgery (p < 0.01). The 1-year survival rate (median survival) was 53% (68 weeks) in the surgical group and 43% (35 weeks) in the radiosurgical group (p = 0.19). The 1-year local tumor control rates after surgery and radiosurgery were 75% and 83%, respectively (p = 0.49), and the 1-year neurological death rates in these groups were 37% and 39% (p = 0.8). Shorter overall survival time in the radiosurgery group was related to higher systemic death rates. A pretreatment KPS score of less than 70 was a predictor of unfavorable survival. Perioperative morbidity and mortality rates were 7.7% and 1.6% in the resection group, and 8.9% and 1.2% in the radiosurgery group, respectively. Four patients presented with transient radiogenic complications after radiosurgery. CONCLUSIONS: Radiosurgery alone can result in local tumor control rates as good as those for surgery plus WBRT in selected patients. Radiosurgery should not be routinely combined with radiotherapy.

[Brain protective interstitial laser thermotherapy. Therapy of brain tumors without secondary damage]. / Gehirn schonende interstitielle Laserthermotherapie. Therapie von Hirntumoren ohne Umgebungsschäden.

The purpose of interstitial radiosurgery is to deliver a necrotizing dose of heat to an accurately defined focal area without damaging adjacent healthy brain tissue. To achieve this, heat at a temperature of 60-100 degrees C is applied via a laser fiber placed stereotactically in the center of the tumor. With the aid of thermosensitive magnetic resonance imaging (MRI), not only can the heat distribution within and around the tumor be measured during treatment, but also the extent of the lesion produced assessed. Interstitial laser thermotherapy (ILTT) performed under MRI monitoring, could become an important interdisciplinary minimally invasive treatment option for patients with brain tumors. Experimental data on the biological effects of interstitial laser therapy on normal brain tissue are not yet available, and only preliminary clinical studies investigating the effects of laser energy on brain tumors have so far been carried out. This overview presents a description of our own initial results, discusses the present state of our knowledge and current possibilities and limitations of this new treatment modality.

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.