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Background: Surgical decompression (SD) followed by radiotherapy (RT) is superior to RT alone in patients with metastatic spinal disease with epidural spinal cord compression (ESCC) and neurological deficit. For patients without neurological deficit and low- to intermediate-grade intraspinal tumor burden, data on whether SD is beneficial are scarce. This study aims to investigate the neurological outcome of patients without neurological deficit, with a low- to intermediate-ESCC, who were treated with or without SD. Methods: This single-center, multidepartment retrospective analysis includes patients treated for spinal epidural metastases from 2011 to 2021. Neurological status was assessed by Frankel grade, and intraspinal tumor burden was categorized according to the ESCC scale. Spinal instrumentation surgery was only considered as SD if targeted decompression was performed. Results: ESCC scale was determined in 519 patients. Of these, 190 (36.6%) presented with no neurological deficit and a low- to intermediate-grade ESCC (1b, 1c, or 2). Of these, 147 (77.4% were treated with decompression and 43 (22.65%) without. At last follow-up, there was no difference in neurological outcome between the two groups. Conclusions: Indication for decompressive surgery in neurologically intact patients with low-grade ESCC needs to be set cautiously. So far, it is unclear which patients benefit from additional decompressive surgery, warranting further prospective, randomized trials for this significant cohort of patients.

Background Percutaneous pedicle screw fixation in obese patients remains a surgical challenge. We aimed to compare patient-reported outcomes and complication rates between obese and nonobese patients who were treated by minimally invasive transforaminal lumbar interbody fusion (MIS-TLIF). Methods The authors retrospectively reviewed patients who underwent MIS-TLIF at a single institution between 2011 and 2014. Patients were classified as obese (body mass index [BMI] ≥30 kg/m2) or nonobese (BMI Results The final study group consisted of 71 patients, 24 obese (33.8%, 34.8 ± 3.8 kg/m2) and 47 nonobese (66.2%, 25.4 ± 2.9 kg/m2). Instrumentation failures (13.6 vs. 17.0%), dural tears (17.2 vs. 4.0%), and revision rates (16.7 vs. 19.1%) were similar between both groups (p > 0.05). Perioperative improvements in back pain (4.3 vs. 5.4, p = 0.07), leg pain (3.8 vs. 4.2, p = 0.6), and ODI (13.3 vs. 22.5, p = 0.5) were comparable among the groups and persisted at long-term follow-up. Obese patients had worse postoperative physical component SF-36 scores than nonobese patients (36.4 vs. 42.7, p = 0.03), while the mental component scores were not statistically different (p = 0.09). Conclusion Obese patients can achieve similar improvement of the pain intensity and functional status even at long-term follow-up. In patients with appropriate surgical indications, obesity should not be considered a contraindication for MIS-TLIF surgery.

Background: Adequate assessment of spinal instability using the spinal instability neoplastic score (SINS) frequently guides surgical therapy in spinal epidural osseous metastases and subsequently influences neurological outcome. However, how to surgically manage ‘impending instability’ at SINS 7–12 most appropriately remains uncertain. This study aimed to evaluate the necessity of spinal instrumentation in patients with SINS 7–12 with regards to neurological outcome. Methods: We screened 683 patients with spinal epidural metastases treated at our interdisciplinary spine center. The preoperative SINS was assessed to determine spinal instability and neurological status was defined using the Frankel score. Patients were dichotomized according to being treated by instrumentation surgery and neurological outcomes were compared. Additionally, a subgroup analysis of groups with SINS of 7–9 and 10–12 was performed. Results: Of 331 patients with a SINS of 7–12, 76.1% underwent spinal instrumentation. Neurological outcome did not differ significantly between instrumented and non-instrumented patients (p = 0.612). Spinal instrumentation was performed more frequently in SINS 10–12 than in SINS 7–9 (p < 0.001). The subgroup analysis showed no significant differences in neurological outcome between instrumented and non-instrumented patients in either SINS 7–9 (p = 0.278) or SINS 10–12 (p = 0.577). Complications occurred more frequently in instrumented than in non-instrumented patients (p = 0.016). Conclusions: Our data suggest that a SINS of 7–12 alone might not warrant the increased surgical risks of additional spinal instrumentation.

To date, diagnosis of IDH1 mutation is based on DNA sequencing and immunohistochemistry, methods limited in terms of sensitivity and ease of use. Recently, the diagnosis of IDH1 mutation by real-time polymerase chain reaction was introduced as an alternative method. In this study, real-time polymerase chain reaction was validated as a tool for detection of IDH1 mutation, and expression levels were analyzed for correlation with course of the disease. A total of 113 tumor samples were obtained intraoperatively from 84 patients with glioma having a diagnosis of diffuse glioma (World Health Organization II), anaplastic glioma (World Health Organization III), secondary glioblastoma ± chemotherapy, primary glioblastoma ± chemotherapy (World Health Organization IV). Tumor samples were snap frozen and processed for sectioning and RNA and protein isolation. Presence of IDH1 mutation was determined by DNA sequencing. Hereafter, quantitative expression of IDH1 messenger RNA was assessed using real-time polymerase chain reaction with specific primers for IDH1 mutation and –wt; protein expression was verified by Western Blot analysis and immunohistochemistry. Additionally, 19 samples of low-grade glioma and their consecutive high-grade glioma were analyzed at different time points of the disease. IDH1 mutation was identified in 63% of samples by DNA sequencing. In correlation with the real-time polymerase chain reaction results, a cutoff value was determined. Above this threshold, sensitivity and specificity of real-time polymerase chain reaction in detecting IDH1 mutation were 98% and 94%, respectively. Quantitative analysis revealed that IDH1 mutation expression is upregulated in secondary glioblastoma (mean ± standard error of mean: 3.52 ± 0.55) compared to lower grade glioma (II = 1.54 ± 0.22; III = 1.67 ± 0.23). In contrast, IDH1 wt expression is upregulated in all glioma grades (concentration >0.1) compared to control brain tissue (0.007 ± 0.0016). Western Blot analysis showed a high concordance to both sequencing and real-time polymerase chain reaction results in qualitative analysis of IDH1 mutation status (specificity 100% and sensitivity 100%). Moreover, semiquantitative protein expression analysis also showed higher expression levels of mutated IDH1 in secondary glioblastoma. In our study, real-time polymerase chain reaction and Western Blot analysis were found to be highly efficient methods in detecting IDH1 mutation in glioma samples. As cost-effective and time-saving methods, real-time polymerase chain reaction and Western Blot analysis may therefore play an important role in IDH1 mutation analysis in the future. IDH1 mutation expression level was found to correlate with the course of disease to a certain extent. Yet, clinical factors as recurrent disease or prior radiochemotherapy did not alter IDH1 mutation expression level.

Background To evaluate the long-term functional recovery and health-related quality of life (HRQOL) in patients after surgically treated putaminal hemorrhages. Surgery for putaminal hemorrhages remains a controversial issue. Although numerous reports describe conflictive results regarding short-term outcome of surgically treated patients, very little is known about their long-term recovery and their HRQOL. Methods In this monocentric, retrospective study we analyzed mortality, long-term functional outcome, activity of daily life status, and HRQOL undergoing craniotomy for hematoma evacuation between December 2004 and January 2011. Results Forty-nine consecutive patients were identified with 8 (16.3%) patients dying during acute care. Forty-one patients surviving acute phase were transferred to neurologic rehabilitation hospitals. One patient was lost to follow-up. Median follow-up was 52.9 (17-101) months. At follow-up, 24 of 40 (60%) patients still were alive with 16 of 40 (40%) patients living with major disability (modified Rankin Scale [mRS], 4 or 5). Seven patients (17.5%) showed a mRS lesser than or equal to 3 with only 3 (7.5%) of those living functionally independent (mRS, 0-2). HRQOL in survivors was reduced with a median DEMQOL/DEMQOL (a patient/caregiver reported outcome measure designed to assess health-related quality of life of people with dementia) proxy score of 92 and 93, respectively. All patients showed severe impairment in activities of daily life. Conclusions This is the first long-term follow-up analysis for patients with surgically treated putaminal hemorrhages. Survivors show only marginal recovery despite intensive neurologic rehabilitation; most remain dependent with a reduced HRQOL and significantly impaired activities of daily life status.

Background Leakage of cerebrospinal fluid (CSF) because of large prolactinomas represents a complex issue. Because of limited anatomic space, multiple leakage sites, and scarce locally available tissue for repair, surgical possibilities are limited. We report an initial case of using a radial fasciocutaneous flap applied subfrontally to cover a large skull base defect, supported by preoperative three-dimensional (3D) printing for surgical planning. Case Description A 29-year-old woman developed severe nuchal pain that was caused by destruction of large parts of her skull base by a prolactinoma. After occipitocervical fusion, medical treatment showed good tumor response but led to CSF leakage after 12 months. An endoscopic approach and ventriculoperitoneal shunt implantation failed to stop the leakage. A 3D model of the skull improved the understanding of the expanded osseous destruction and multiple CSF leakage sites and supported surgical planning. For an extensive coverage of the former clivus and sella region, an intracranially applied radial flap was planned. Dopamine-agonist medication was increased before the operation. Intraoperatively, the flap was brought into position subchiasmatically and wound around the pituitary stalk. CSF leakage was not observed on follow-up (10 weeks). Long-term follow-up will determine the effectiveness of this method.

This is a retrospective single-center study.The aim of the study was to evaluate the impact of cage characteristics and position toward clinical and radiographic outcome measures in patients undergoing extreme lateral interbody fusion (ELIF).ELIF is utilized for indirect decompression and minimally invasive surgical treatment for various degenerative spinal disorders. However, evidence regarding the influence of cage characteristics in patient outcome is minimal.Patients undergoing ELIF between 2007 and 2011 were included in a retrospective study. Demographic and perioperative data, as well as cage characteristics and side of approach were extracted. Radiographic parameters including lumbar lordosis, foraminal height, and disc height as well as clinical outcome parameters (Oswestry Disability Index and Visual Analog Scale) were measured preoperatively, postoperatively, and at the latest follow-up examination. Cage dimensions, in situ position, and type were correlated with radiographic and clinical outcome parameters.In total, 84 patients with a total of 145 functional spinal units were analyzed. At the last follow-up of 17.7 months, radiographic and clinical outcome measures revealed significant improvement compared with before surgery with both, 18 and 22 mm cage anterior-posterior diameter subgroups (P≤0.05). Among cage characteristics, 22 mm cages presented superior restoration of foraminal and disc heights compared with 18 mm cages (P≤0.05). Neither position of the cage (anterior vs. posterior), nor the type (parallel vs. lordotic) had a significant impact on restoration of foraminal height and lumbar lordosis. Moreover, the side of surgical approach did not influence the amount of foraminal height increase.Cage anterior-posterior diameter is the determining factor in restoration of foraminal height in ELIF. Cage height, type, positioning, and side of approach do not have a determining role in radiographic outcome in the present study. Sustainable foraminal height restoration is achieved by implantation of wider cages.Level 3.

Background Extreme lateral interbody fusion (ELIF) is a powerful tool for interbody fusion and coronal deformity correction. However, evidence regarding the success of ELIF in decompressing foraminal, lateral recess, and central canal stenosis is lacking. We performed a systematic review of current literature on the potential and limitations of ELIF to indirectly decompress neural elements. Methods A literature search using PubMed, Cochrane, and ScienceDirect databases was performed according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses criteria. Information on study design, sample size, population, procedure, number and location of involved levels, follow-up time, and complications as well as information on conflict of interest was extracted and evaluated. Results We selected 20 publications including 1080 patients for review. Most publications (90%) were retrospective case series. Most frequent indications for ELIF included degenerative disc disease, spinal stenosis, spondylolisthesis, and degenerative scoliosis. Most studies revealed significant improvement in radiographic and clinical outcome after ELIF. Mean foraminal area, central canal area, and subarticular diameter increased by 31.6 mm 2 , 28.5 mm 2 , and 0.85 mm. ELIF successfully improved foraminal stenosis. Contradictory results were found for indirect decompression of central canal stenosis. Data on lateral recess stenosis were scarce. Conclusions Current data suggest ELIF to be an efficient technique in decompression of foraminal stenosis. Evidence on decompression of central canal or lateral recess stenosis via ELIF is low, and results are inconsistent. Most studies are limited by study design, sample size, and potential conflicts of interest.

Mitochondrial dysfunction has been implicated in the pathogenesis of Huntington disease (HD), a primarily neurodegenerative disorder that results from an expansion in the polymorphic trinucleotide CAG tract in the HD gene. In order to evaluate whether mitochondrial DNA (mtDNA) variation contributes to HD phenotype we genotyped 13 single nucleotide polymorphisms (SNPs) that define the major European mtDNA haplogroups in 404 HD patients. Genotype-dependent functional effects on intracellular ATP concentrations were assessed in peripheral leukocytes. In patients carrying the most common haplogroup H (48.3%), we demonstrate a significantly lower age at onset (AO). In combination with PGC-1 alpha genotypes, 3.8% additional residual variance in HD AO can be explained. Intracellular ATP concentrations in HD patients carrying the cytochrome c oxidase subunit I (CO1) 7028C allele defining haplogroup H were significantly higher in comparison to non-H individuals (mean +/- SEM, 599 +/- 51.8 ng/ml, n = 14 vs. 457.5 +/- 40.4 ng/ml, p = 0.03, n = 9). In contrast, ATP concentrations in cells of HD patients independent from mtDNA haplogroup showed no significant differences in comparison to matched healthy controls. Our data suggest that an evolutionarily advantageous mitochondrial haplogroup is associated with functional mitochondrial alterations and may modify disease phenotype in the context of neurodegenerative conditions such as HD.

OBJECTIVE: Following the concept of glioma stem-like cells being the crucial reservoir for self-renewal, differentiation and proliferation of malignant brain tumors and escaping from adjuvant therapy numerous efforts have been made to exactly characterize them. However, several functional assays and analysis of surface markers to clearly identify this subgroup have led to insufficient and controversial results so far. Therefore we analyzed the expression levels of a bunch of potential markers of glioma stem-like cells in human glioma samples of different WHO grades and different treatment. We aimed not only to identify an adequate specific marker for stemness in human gliomas but also to gain insight into expression changes with increasing tumor grade and effects of chemotherapy on cancer stem cell activity. METHODS: cDNA was synthesized from mRNA of 80 snap frozen tumor samples from patients with gliomas of different tumor grades and pre-treatment (WHO grade II, III, secondary glioblastoma ± chemotherapy, primary glioblastoma ± chemotherapy, peritumoral tissue) and from 5 cell lines (U87, Gl36, HES2 (human embryonic stem cells), NPC (neuronal progenitor cells), hDF (human dermal fibroblasts)). Using quantitative real-time PCR relative expression levels of cMyc, Klf4, Nanog, Nestin, Oct4, and Sox2 were analyzed. Quantitative data were normalized in relation to the housekeeping gene SDHA. Results are depicted in mean ± SEM. RESULTS: The expression of Sox2 in all tested tumor groups was higher than in the control peritumoral tissue (2.10 ± 0.72). Interestingly highest expression levels were seen in WHO grade II (8.37 ± 1.60) and grade III (9.80 ± 2.20) tumor groups. cMyc, Nanog and Nestin expression were generally low compared to other tested genes in all tumor samples including control tissue, without any significant differences between the tumor grades and pre-treatment. Oct4 expression was high in all tested tumor groups (mean ranging from 7.5-57.77) compared to other genes. Remarkably Klf4 was lower expressed in two of the tested tumor groups compared to control tissue. CONCLUSIONS: We here provide expression profiles of different stemness genes in human tumors of different grades and treatment on genetic level. Interestingly, the transcription factor Sox2 seems to play a role especially in gliomagenesis as it is overexpressed in lower grade gliomas. At present we are completing our findings with biochemical methods (Western blot analysis).

INTRODUCTION: Besides standard evaluation of histology, immunology and molecular markers as MGNT, IDH etc. an additional screening for biomarkers, genetic alterations and epigenetic features deriving from tissue from primary or recurrent brain tumors may harbor potential as prognostic and predictive information. With this pilot study we intended to examine in how far tissue obtained by stereotactic biopsy can be utilized for extended evaluation. METHODS: Stereotactically guided serial tissue samples (1mm diameter) from 16 patients were analyzed. Besides clinically obligatory routine histo-pathological, immunological and molecular evaluation (e.g. GFAP, S100, Vimentin, MAP2, EGFR, IDH1, p53 and MIB-1) probes were also utilized for analysis for further immunohistochemistry, for genomic DNA extraction, for RNA and protein extraction: The biochemical analysis was done by Western blot using various antibodies (e.g. ALDH1, AHR, GFAP, beta-actin). Furthermore, molecular techniques were applied including the methylation status of the MGMT promoter by bi-sulfit conversion of the DNA and following PCR and the IDH1/2 mutation status verification by pyro-sequencing. RESULTS: In most of the 16 patients the clinical routine diagnostic could be evaluated including MGMT promotor- and IDH1/2 mutation status (two diffuse astrocytomas, two anaplastic astrocytomas, nine glioblastomas, three other tumors). Genomic DNA could be extracted from stereotactic probes. RNA extraction was also possible, but the amount of cDNA obtained from the RNA from stereotactic samples was significant lower in 14/16 patient samples than the amount of cDNA normally used for quantitative RT-PCR from open resection. Besides, there was no biopsy-related morbidity. CONCLUSION: Tissue provided by stereotactically guided serial biopsies in patients with primary and recurrent brain tumors is safe and feasible. Besides clinical routine diagnostic the tissue can also sufficiently be used for of a variety of additional immunohistochemical, biochemical, and molecular analyses. This information may provide valuable and potential treatment relevant factors.

Diagnostic of the IDH1 mutation (IDH1mut) is so far based on DNA sequencing and immunohistochemistry (IHC), methods limited in terms of sensitivity and ease of use. Recently, measuring the IDH1mut level by real time PCR was introduced as alternative method. Therefore, we aimed to (i) validate this new technique in a larger patient cohort, compare it to control tissue, and (ii) investigate if the expression of both, IDH1mut and IDH1 wildtype (IDH1wt) correlates with the course of disease and different treatment regimens. A total of 113 tumor samples were obtained intraoperatively from 84 glioma patients with diagnosis of diffuse glioma (WHO°II), anaplastic glioma (WHO°III), secondary glioblastoma +/- chemotherapy (CTx), primary glioblastoma +/- CTx (WHO°IV). Tumor samples were snap frozen and processed for sectioning, RNA and protein isolation. The quantitative expression of IDH1 mRNA was assessed using real-time PCR with specific primers for IDH1mut and -wt; protein expression was verified by Western Blot analysis and IHC. Additionally, 19 samples of LGG and their consecutive HGG were analyzed at different time points of disease. Allele-specific quantitative RT-PCR does work in larger patient cohorts and seems to be an easy and ∼10 times more sensitive method for quantitative IDH1mut evaluation compared to the ones used so far. Our results with this new method confirmed previous data showing that most astrocytomas and secondary GBM bear the mutation (conc. 0.13 to 0.2) whereas most primary GBM do not (conc. ∼0.025). Quantitative analysis revealed that IDH1mut expression is upregulated in sGBM (mean±SEM: 3.52±0.55) compared to lower grade glioma (II° = 1.54±0.22; III° = 1.67±0.23). By contrast, IDH1wt expression is upregulated in all glioma grades (con. >0.1) compared to control brain tissue (0.007± 0.0016). Western Blot analysis showed a high concordance to both, sequencing and RT-PCR results in qualitative analysis of IDH1mut status (specificity 100% and sensitivity 100%). Moreover, semiquantitative protein expression analysis also showed higher expression levels of mutated IDH1 in sGBM. Taken together, recurrent disease and radiochemotherapy do not alter the general IDH1 status. Moreover, we found an increase of IDH1mut gene expression in sec. GBM compared to lower grade glioma indicating a pivotal role of IDH1mut not only in gliomagenesis but also in glioma progression. Citation Format: Marco Timmer, Moritz Perrech, Gabriele Röhn, Lena Dreher, Roland Goldbrunner. Qualitative and quantitative analysis of IDH1 mutation in progressive gliomas by allele-specific quantitative RT-PCR and Western blot analysis. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2218. doi:10.1158/1538-7445.AM2015-2218

e17085 Background: Diagnostic of the IDH1 mutation (IDH1mut) is so far based on DNA sequencing and immunohistochemistry (IHC), methods limited in terms of sensitivity and ease of use. Recently, mea...

Biomarkers, genetic alterations and epigenetic marks gain in importance as prognostic and predictive markers both, after primary diagnosis and in the recurrent disease situation. However, tissue samples are needed throughout the longitudinal course of the disease in order to adjust therapy to changing conditions. A remaining question is whether an open tumor resection is superior for pathological and molecular analysis compared to a small stereotactic biopsy. We compared the diagnostic potential of stereotactic biopsies to tissue samples from gross total resections. 16 stereotactic 1-mm tissue samples (2 diffuse astrocytomas, 2 anaplastic astrocytomas, 9 glioblastomas, 3 other tumors) were analyzed with an approach combining histopathologic diagnosis with small sample size-adjusted moleculargenetic analysis. Serial biopsies were taken throughout the tumor. Single probes were taken for single analysis (e.g. 1 probe for immunohistochemistry, 1 probe for genomic DNA extraction, 1 probe for RNA and protein extraction etc.). This procedure is eligible as the literature reports homogeneous distribution of biomarkers throughout tumors. We report that for each single patient a microscopic analysis, different immunhistochemical stainings (e.g. GFAP, S100, Vimentin, MAP2, EGFR, IDH1, p53, and MIB-1) as well as biochemical and molecular analysis could be performed with material obtained from a single stereotactic biopsy. The biochemical analysis was done by Western blot using various antibodies (e.g. ALDH1, AHR, GFAP, beta-actin). Furthermore, molecular techniques were applied including the methylation status of the MGMT promoter by bisulfit conversion of the DNA and following PCR and the IDH1/2 mutation status verification by pyro-sequencing. Genomic DNA could be extracted from all stereotactic probes. RNA extraction was also possible, but the amount of cDNA which could be obtained from the RNA of stereotactic samples was significant lower in 14 (out of the 16) samples than the amount of cDNA normally used for quantitative RT-PCR from open operations. There was no biopsy-related morbidity. We conclude that determination of many different immunohistochemical, biochemical, and molecular parameters are possible using the stereotactic biopsy technique. Moreover, the procedure is safe and reliable. The stereotactic biopsy enables decision making for optimizing the treatment of brain tumors without the necessity of an open resection. This finding has even more clinical impact in elderly patients or in patients with eloquent tumor localizations.