Technical report: surgical preparation of human brain tissue for clinical and basic research.

BACKGROUND: The study of the distinct structure and function of the human central nervous system, both in healthy and diseased states, is becoming increasingly significant in the field of neuroscience. Typically, cortical and subcortical tissue is discarded during surgeries for tumors and epilepsy. Yet, there is a strong encouragement to utilize this tissue for clinical and basic research in humans. Here, we describe the technical aspects of the microdissection and immediate handling of viable human cortical access tissue for basic and clinical research, highlighting the measures needed to be taken in the operating room to ensure standardized procedures and optimal experimental results. METHODS: In multiple rounds of experiments (n = 36), we developed and refined surgical principles for the removal of cortical access tissue. The specimens were immediately immersed in cold carbogenated N-methyl-D-glucamine-based artificial cerebrospinal fluid for electrophysiology and electron microscopy experiments or specialized hibernation medium for organotypic slice cultures. RESULTS: The surgical principles of brain tissue microdissection were (1) rapid preparation (<1 min), (2) maintenance of the cortical axis, (3) minimization of mechanical trauma to sample, (4) use of pointed scalpel blade, (5) avoidance of cauterization and blunt preparation, (6) constant irrigation, and (7) retrieval of the sample without the use of forceps or suction. After a single round of introduction to these principles, multiple surgeons adopted the technique for samples with a minimal dimension of 5 mm spanning all cortical layers and subcortical white matter. Small samples (5-7 mm) were ideal for acute slice preparation and electrophysiology. No adverse events from sample resection were observed. CONCLUSION: The microdissection technique of human cortical access tissue is safe and easily adoptable into the routine of neurosurgical procedures. The standardized and reliable surgical extraction of human brain tissue lays the foundation for human-to-human translational research on human brain tissue.

Patterns, predictors and prognostic relevance of high-grade hematotoxicity after temozolomide or temozolomide-lomustine in the CeTeG/NOA-09 trial.

PURPOSE: In the randomized phase III trial CeTeG/NOA-09, temozolomide (TMZ)/lomustine (CCNU) combination therapy was superior to TMZ in newly diagnosed MGMT methylated glioblastoma, albeit reporting more frequent hematotoxicity. Here, we analyze high grade hematotoxicity and its prognostic relevance in the trial population. METHODS: Descriptive and comparative analysis of hematotoxicity adverse events ≥ grade 3 (HAE) according to the Common Terminology of Clinical Adverse Events, version 4.0 was performed. The association of HAE with survival was assessed in a landmark analysis. Logistic regression analysis was performed to predict HAE during the concomitant phase of chemotherapy. RESULTS: HAE occurred in 36.4% and 28.6% of patients under CCNU/TMZ and TMZ treatment, respectively. The median onset of the first HAE was during concomitant chemotherapy (i.e. first CCNU/TMZ course or daily TMZ therapy), and 42.9% of patients with HAE receiving further courses experienced repeat HAE. Median HAE duration was similar between treatment arms (CCNU/TMZ 11.5; TMZ 13 days). Chemotherapy was more often discontinued due to HAE in CCNU/TMZ than in TMZ (19.7 vs. 6.3%, p = 0.036). The occurrence of HAE was not associated with survival differences (p = 0.76). Regression analysis confirmed older age (OR 1.08) and female sex (OR 2.47), but not treatment arm, as predictors of HAE. CONCLUSION: Older age and female sex are associated with higher incidence of HAE. Although occurrence of HAE was not associated with shorter survival, reliable prediction of patients at risk might be beneficial to allow optimal management of therapy and allocation of supportive measures. TRIAL REGISTRATION: NCT01149109.

[Traumatology-an interdisciplinary task: exclusively for educational purposes?] / Traumatologie ­ eine interdisziplinäre Aufgabe: nur in der Lehre?

BACKGROUND: Traumatology of the head and neck region is not only a part of otorhinolaryngology, but also has a large overlap with neighboring disciplines of the head and neck region. In Freiburg, an interdisciplinary lecture on "ENT emergencies" was implemented in the 21/22 winter semester. The aim was to provide an even more realistic view on interdisciplinary patient care and to make evident the areas of intersection of four of the major head disciplines (otorhinolaryngology, neurosurgery, ophthalmology, and maxillofacial surgery). MATERIALS AND METHODS: A new, special lecture in otorhinolaryngology was implemented as part of the regular online lecture series accompanying the semester. With reference to the clinical care of ENT emergencies, possible overlaps with neighboring disciplines were identified and explained by the discipline representatives or discussed in front of and with the auditorium. At the end of the semester, all participating students (n = 173) were invited to evaluate the seminar using the survey tool "EvaSys" (EvaSys GmbH, Lüneburg, Germany). In total, 78 students participated in the evaluation process. RESULTS: The new lecture concept was very well accepted and immediately ranked top among the interdisciplinary lecture titles within the ENT lecture series. The clear communication of the term "interdisciplinarity" in the sense of a complementary clinical cooperation was also very successful and was appreciated accordingly by students during the evaluation process. CONCLUSION: Pragmatic presentation of ideal clinical patient care using an interdisciplinary approach is possible within the regular ENT lecture series. This realistic portrayal, beyond any technical and/or professional differences, is of great interest to students and is considered clinically relevant. Thus, interdisciplinary lectures provide a valuable tool to teach the fundamental values of clinical interdisciplinary management for the best possible patient care.

Longitudinal stability of molecular alterations and drug response profiles in tumor spheroid cell lines enables reproducible analyses.

The utility of patient-derived tumor cell lines as experimental models for glioblastoma has been challenged by limited representation of the in vivo tumor biology and low clinical translatability. Here, we report on longitudinal epigenetic and transcriptional profiling of seven glioblastoma spheroid cell line models cultured over an extended period. Molecular profiles were associated with drug response data obtained for 231 clinically used drugs. We show that the glioblastoma spheroid models remained molecularly stable and displayed reproducible drug responses over prolonged culture times of 30 in vitro passages. Integration of gene expression and drug response data identified predictive gene signatures linked to sensitivity to specific drugs, indicating the potential of gene expression-based prediction of glioblastoma therapy response. Our data thus empowers glioblastoma spheroid disease modeling as a useful preclinical assay that may uncover novel therapeutic vulnerabilities and associated molecular alterations.

Risk and management of pre-diabetes.

Type 2 diabetes mellitus (T2DM) is associated with a two- to four-fold increased risk of developing cardiovascular disease (CVD) and microvascular complications, which may already be present before diagnosis. It is, therefore, important to detect people with an increased risk of T2DM at an early stage. In order to identify individuals with so-called 'pre-diabetes', comprising impaired fasting glucose (IFG) and impaired glucose tolerance (IGT), current guidelines have developed definitions based on fasting plasma glucose, two-hour glucose concentrations and haemoglobin A1c. Subjects with pre-diabetes are at an increased risk of developing T2DM and CVD. This elevated risk seems similar according to the different criteria used to define pre-diabetes. The risk of progression to T2DM or CVD does, however, depend on other risk factors such as sex, body mass index and ethnicity. Based on the risk factors to develop T2DM, many risk assessment models have been developed to identify those at highest risk. These models perform well to identify those at risk and could be used to initiate preventive interventions. Many studies have shown that lifestyle modification and metformin are effective in preventing the development of T2DM, although lifestyle modification seems to have a more sustainable effect. In addition, lifestyle modification seems more effective in those with IGT than those with IFG. In this review, we will describe the different definitions used to define pre-diabetes, progression from pre-diabetes to T2DM or other vascular complications, risk factors associated with progressions and the management of progression to T2DM, ending with clinical recommendations.

Acarbose improves glycemic control and reduces body weight: Subanalysis data of South Asia region.

Alpha-glucosidase inhibitors (AGIs) are widely used especially in Asian countries as a treatment option for type 2 diabetes patients with high postprandial glycaemia. However, data from South Asia region is very limited. In order to examine the effect of AGI in real-life setting, 10 PMS/NIS from all over the world from the launch of acarbose to date were pooled in one database and exploratory analysis was performed for glycemic parameters and weight. In total 62,905 patients were pooled from 21 countries and regions. Mean follow up (± SD) was 12.2 ± 4.8 weeks (range 0.1-108.9). From South Asia region (India and Pakistan), 8,738 Asian patients were enrolled. Mean PPG decreased from 240.0 and 261.1 mg/dl at baseline by 70.26 ± 65.10 and 82.96 ± 56.59 mg/dl at the last visit in total and South Asian populations, respectively (n = 53,883; n = 7,991, P < 0.0001 for both). Mean FPG decreased from 171.6 and 176.5 mg/dl at baseline by 38.48 ± 47.83 and 49.59 ± 41.41 mg/dl at the last visit in total and South Asian populations, respectively (n = 56,672; n = 7,837, P < 0.0001 for both). Mean HbA1c decreased from 8.4 and 8.4% at baseline by 1.11 ± 1.31% and 0.91 ± 0.93% at the last visit in total and South Asian populations, respectively (n = 38,843; n = 2,343, P < 0.0001 for both). Mean relative reduction of body weight (BW) was 1.40 ± 3.28% and 1.10 ± 3.39% at the last visit for mean baseline BW 73.6 and 74.2 kg in total and South Asian populations, respectively (n = 54,760; n = 7,718, P < 0.0001 for both). Consistent with RCT meta-analyses, post-hoc analysis of real-life data showed acarbose treatment improved glycaemic control and reduced the BW. Acarbose treatment in real life setting showed significant reductions in all glycemic parameters and BW in Asian patients from South Asia region.

Alpha-glucosidase inhibitor, acarbose, improves glycamic control and reduces body weight in type 2 diabetes: Findings on indian patients from the pooled data analysis.

Alpha-glucosidase inhibitors are widely used especially in Asian countries as a treatment option for type 2 diabetes patients with high postprandial glycemia (PPG). The higher carbohydrate in the Indian diets lead to greater prandial glycemic excursion, increased glucosidase, and incretin activity in the gut and may need special therapeutic strategies to tackle these glucose peaks. This is the subgroup analysis of Indian subjects who participated in the GlucoVIP study that investigated the effectiveness and tolerability of acarbose as add-on or monotherapy in a range of patients with type 2 diabetes mellitus. A total of 1996 Indian patients were included in the effectiveness analysis. After 12.5 weeks (mean), the mean change in 2-hour PPG from baseline was -74.4 mg/dl, mean HbA1c decreased by -1.0%, and mean fasting blood glucose decreased by -37.9 mg/dl. The efficacy of acarbose was rated "very good" or "good" in 91.1% of patients, and tolerability as "very good" or "good" in 88.0% of patients. The results of this observational study suggest that acarbose was effective and well tolerated in the Indian patients with T2DM.

[PET-MR in patients with glioblastoma multiforme]. / PET-MR bei Patienten mit Glioblastoma multiforme.

Glioblastoma multiforme (GBM) is the most common and most aggressive primary tumor of the brain. In recent years newer therapeutic approaches have been developed. To allow for an optimized treatment planning it is important to precisely delineate necrotic tissue, edema and vital tumor tissue and to identify the most aggressive parts of the GBM. The magnetic resonance (MR) portion of an MR-positron emission tomography (PET) examination in patients with GBM should consist of both structural and functional sequences including diffusion-weighted and perfusion sequences. The use of (18)F-fluorodeoxyglucose ((18)F-FDG) is limited in patients with gliomas as glucose metabolism is already physiologically high in parts of the brain but (18)F-FDG is nevertheless a commonly used radiopharmaceutical for neuro-oncological questions. (18)F-fluorothymidine reflects the cellular activity of thymidine kinase 1 and correlates with the expression of KI-67 as an index of mitotic activity. The nitroimidazole derivatives (18)F-fluoromisonidazole and (18)F-fluoroazomycin arabinoside ((18)F-FAZA) allow the detection of hypoxic areas within the tumor. In recent years amino acid tracers, such as (18)F-fluoroethyltyrosine are increasingly being used in the diagnosis of gliomas. The simultaneous PET-MR image acquisition allows new approaches, e.g. motion correction by the simultaneous acquisition of MR data with a high temporal resolution and an improved quantification of the PET signal by integrating the results of functional MR sequences. Moreover, the simultaneous acquisition of these two time-consuming methods leads to reduced imaging times for this, often severely ill patient group.

Insulin and atherosclerosis: how are they related?

The relationship between insulin and atherosclerosis is complex. People with type 2 diabetes are affected by three main glycaemic disorders: chronic hyperglycaemia; glycaemic variability; and iatrogenic hypoglycaemia. In addition to this triumvirate, the diabetic condition is characterized by lipid disorders, chronic low-grade inflammation and activation of oxidative stress. All these associated disorders reflect the insulin-resistant nature of type 2 diabetes and contribute to the development and progression of cardiovascular (CV) diseases. By both lowering plasma glucose and improving the lipid profile, insulin exerts beneficial effects on CV outcomes. In addition, insulin has several pleiotropic effects such as anti-inflammatory, antithrombotic and antioxidant properties. Insulin per se exerts an inhibitory effect on the activation of oxidative stress and seems able to counteract the pro-oxidant effects of ambient hyperglycaemia and glycaemic variability. However, insulin actions remain a subject of debate with respect to the risk of adverse CV events, which can increase in individuals exposed to high insulin doses. Evidence from the large-scale, long-term ORIGIN trial suggests that early implementation of insulin supplementation therapy in the course of glycaemic disorders, including type 2 diabetes, has a neutral impact on CV outcomes compared with standard management. Thus, the answer to the question "What impact does insulin have on atherosclerosis?" remains unclear, even though it is logical to deduce that insulin should be initiated as soon as possible and that small doses of insulin early on are better than higher doses later in the disease process.

A comprehensive analysis of vascular complications in 3,889 glioma patients from the German Glioma Network.

Ischemic strokes, intracranial hemorrhages (ICH) and deep venous thromboembolism (DVT) are clinically important events in patients with gliomas. In this multicentre, noninterventional observational study, current data pertaining to frequency, contributing factors and outcomes of vascular events during times of anti-angiogenic therapy with the antibody against vascular endothelial growth factor, bevacizumab (BEV) was collected from the German Glioma Network. Among 3,889 glioma patients, 70 ischemic strokes (1.8 %) and 123 ICH (3.2 %) were recorded. 143 DVT (5.0 %) were recorded in 2,855 patients. Rates of DVT and ICH, but not of ischemic strokes, increased with the World Health Organization (WHO) grade of glioma. In 81 BEV-treated patients, five ischemic strokes (6.2 %), one ICH (1.2 %) and six DVT (7.4 %) were documented. Compared to patients that were not treated with BEV, ischemic stroke rate was significantly higher during treatment with BEV (p < 0.001). The rates of DVT (p = 0.123) or ICH (p = 0.571) in BEV-treated patients did not differ. On cerebral magnetic resonance imaging (MRI), BEV-related ischemic strokes appeared as diffusion-restricted sites next to contrast-enhancing tumor. 67 % of ICH, 61 % of ischemic strokes and 18 % of DVT occurred postoperatively (within 30 days after tumor resection). Outcome after postoperative ICH was significantly worse than after spontaneous ICH (p = 0.008). Ischemic stroke outcomes did not differ between postoperative and spontaneous occurrence (p = 0.401). Rate of pulmonary embolism did not differ significantly between postoperative and spontaneous DVT (p = 0.133). Relatively low rates of ICH and DVT might be partially due to a high proportion of low-grade gliomas in this patient cohort. The finding of a relevant number of symptomatic, therapy-associated intracerebral diffusion restrictions should be controlled in ongoing phase III studies.

A simple new non-invasive sweat indicator test for the diagnosis of diabetic neuropathy.

A simple non-invasive indicator test (Neuropad(®)) has been developed for the assessment of sweating and, hence, cholinergic innervation in the diabetic foot. The present review summarizes current knowledge on this diagnostic test. The diagnostic ability of this test is based on a colour change from blue to pink at 10 min, with excellent reproducibility, which lends itself to patient self-examination. It has a high sensitivity (65.1-100%) and negative predictive value (63-100%), with moderate specificity (32-78.5%) and positive predictive value (23.3-93.2%) for the diagnosis of diabetic peripheral neuropathy. It also has moderate to high sensitivity (59.1-89%) and negative predictive value (64.7-91%), but low to moderate specificity (27-78%) and positive predictive value (24-48.6%) for the diagnosis of diabetic cardiac autonomic neuropathy. There are some data to suggest that Neuropad can detect early diabetic neuropathy, but this needs further evaluation. It remains to be established whether this test can predict foot ulceration and amputation, thereby contributing to the identification of high-risk patients.

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.

[Prevalence of undetected diabetes mellitus in invasive and interventional cardiology. Silent diabetes in the catheterization laboratory]. / Prävalenz unentdeckter Glukosestoffwechselstörungen in der invasiven und interventionellen Kardiologie. "Silent diabetes" im Herzkatheterlabor.

In most randomized controlled trials on revascularization therapy for patients with ischemic coronary artery disease (CAD), the diabetes prevalence ranges between 15% and 35%. However, the true prevalence of diabetes is probably considerably underestimated in these trials. The European heart survey diabetes and the heart published in 2004 supplied strong evidence that there are many additional cases of undetected prediabetics and diabetics in any cardiology patient cohort. The long-term outcome of newly detected diabetics was found to be comparable to patients with already known diabetes mellitus. With this in mind, the Dresden silent diabetes study investigated the prevalence of undetected diabetes mellitus by oral glucose tolerance testing (OGTT) and comparative HbA1c sampling in 1,015 patients admitted for coronary angiography. Patients with known diabetes were excluded from the study.According to the OGTT only 513 patients (51%) were classified with normal glucose tolerance (NGT), 10 (1%) with isolated impaired fasting glucose (IFG), 349 (34%) with impaired glucose tolerance (IGT) and 143 (14%) were diagnosed with newly detected diabetes mellitus (DM). According to the HbA1c measurements 588 patients (58%) were classified as normal, 385 (38%) as borderline and only 42 (4%) were diagnosed with diabetes (DM). There was a significant correlation between the extent of CAD and glycemic status as defined by the OGTT. The number of patients with IGT and diabetes increased with the extent of CAD (IGT group p<0.001, diabetes group p=0.01). However, no such correlation was observed when glycemic status was defined by HbA1c testing.Based on these results an OGTT should be routinely performed in patients with known or suspected coronary artery disease undergoing coronary angiography for diagnosis of diabetes, as HbA1c measurements alone appear to miss a substantial proportion of patients. These findings are of high clinical relevance with regard to optimal coronary revascularization procedure chosen in catheterization laboratories, preferably drug-eluting stents in cases of diabetes mellitus or newly detected diabetes mellitus and preferably coronary bypass surgery in diabetics with multi-vessel disease and high SYNTAX scores.

Oral glucose tolerance test and HbA1c for diagnosis of diabetes in patients undergoing coronary angiography: [corrected] the Silent Diabetes Study.

AIMS/HYPOTHESIS: The primary aim of this study was to compare the results of HbA(1c) measurements with those of an OGTT for early diagnosis of 'silent diabetes' in patients with coronary artery disease (CAD) undergoing angiography without prediagnosed diabetes. A secondary aim was to investigate the correlation between the extent of CAD and the glycaemic status of the patient. METHODS: Data from 1,015 patients admitted for acute (n = 149) or elective (n = 866) coronary angiography were analysed. Patients with known diabetes were excluded from the study. Using the OGTT results, patients were classified as having normal glucose tolerance (NGT), impaired fasting glucose (IFG), impaired glucose tolerance (IGT) or diabetes. According to the results of the HbA(1c) measurements, patients were classified into three groups: normal (HbA(1c) <5.7% [<39 mmol/mol]), borderline (HbA(1c) 5.7-6.4% [39-47 mmol/mol]) and diabetes (HbA(1c) ≥6.5% [≥48 mmol/mol]). RESULTS: Based on the OGTT, 513 patients (51%) were classified with NGT, 10 (1%) with IFG, 349 (34%) with IGT and 149 (14%) were diagnosed with diabetes. According to HbA(1c) measurements, 588 patients (58%) were classified as normal, 385 (38%) as borderline and 42 (4%) were diagnosed with diabetes. The proportion of patients with IGT and diabetes increased with the extent of CAD (IGT ρ = 0.14, p < 0.001, diabetes ρ = 0.09, p = 0.01). No differences in HbA(1c) were seen among the groups with different extents of CAD (p = 0.652). CONCLUSIONS/INTERPRETATION: An OGTT should be performed routinely for diagnosis of diabetes in patients with CAD undergoing coronary angiography, since HbA(1c) measurement alone appears to miss a substantial proportion of patients with silent diabetes. A limitation of the study is that the OGTT was not performed before the angiography.

Intraoperative computed tomography.

Intraoperative computed tomography (iCT) has gained increasing impact among modern neurosurgical techniques. Multislice CT with a sliding gantry in the OR provides excellent diagnostic image quality in the visualization of vascular lesions as well as bony structures including skull base and spine. Due to short acquisition times and a high spatial and temporal resolution, various modalities such as iCT-angiography, iCT-cerebral perfusion and the integration of intraoperative navigation with automatic re-registration after scanning can be performed. This allows a variety of applications, e.g. intraoperative angiography, intraoperative cerebral perfusion studies, update of cerebral and spinal navigation, stereotactic procedures as well as resection control in tumour surgery. Its versatility promotes its use in a multidisciplinary setting. Radiation exposure is comparable to standard CT systems outside the OR. For neurosurgical purposes, however, new hardware components (e.g. a radiolucent headholder system) had to be developed. Having a different range of applications compared to intraoperative MRI, it is an attractive modality for intraoperative imaging being comparatively easy to install and cost efficient.

[Challenge in diabetes therapy: effects of glitazones beyond blood glucose control]. / Herausforderung Diabetestherapie: Effekte der Glitazone jenseits der Blutzuckerkontrolle.

Not just since the results of ACCORD, ADVANCE and VADT were published, it is clear that lowering blood glucose alone does not reduce the cardiovascular risk of patients with type 2 diabetes. In fact, many studies also indicate that some treatment strategies may even have adverse effects. To treat type 2 diabetes appropriately, the co-morbidities such as diabetic dyslipidaemia, hypertension or nephropathy must also be taken into account. Thiazolidinediones reduce insulin resistance thus allowing to direct the treatment of type 2 diabetes towards its pathophysiologic origin. Due to their mechanism of action, thiazolidinediones not only lower blood glucose but have also beneficial effects on inflammatory and atherogenic parameters, blood pressure and microalbuminuria. Furthermore pioglitazone improves dyslipidaemia and reduces mortality, myocardial infarction and stroke in high risk patients. Effects of rosiglitazone on the cardiovascular risk are yet unclear. Numerous studies document the efficacy and safety of thiazolidinediones and provide a basis for an evidence-based therapeutic approach beyond blood glucose control.

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.