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Purpose: Preclinical data indicate anti-invasive activity of APG101, a CD95 ligand (CD95L)–binding fusion protein, in glioblastoma.Experimental Design: Patients (N = 91) with glioblastoma at first or second progression were randomized 1:2 between second radiotherapy (rRT; 36 Gy; five times 2 Gy per week) or rRT+APG101 (400 mg weekly i.v.). Patient characteristics [N = 84 (26 patients rRT, 58 patients rRT+APG101)] were balanced.Results: Progression-free survival at 6 months (PFS-6) rates were 3.8% [95% confidence interval (CI), 0.1–19.6] for rRT and 20.7% (95% CI, 11.2–33.4) for rRT+APG101 (P = 0.048). Median PFS was 2.5 (95% CI, 2.3–3.8) months and 4.5 (95% CI, 3.7–5.4) months with a hazard ratio (HR) of 0.49 (95% CI, 0.27–0.88; P = 0.0162) adjusted for tumor size. Cox regression analysis adjusted for tumor size revealed a HR of 0.60 (95% CI, 0.36–1.01; P = 0.0559) for rRT+APG101 for death of any cause. Lower methylation levels at CpG2 in the CD95L promoter in the tumor conferred a stronger risk reduction (HR, 0.19; 95% CI, 0.06–0.58) for treatment with APG101, suggesting a potential biomarker.Conclusions: CD95 pathway inhibition in combination with rRT is an innovative concept with clinical efficacy. It warrants further clinical development. CD95L promoter methylation in the tumor may be developed as a biomarker. Clin Cancer Res; 20(24); 6304–13. ©2014 AACR.

Acknowledgement. List of investigators and other study stuff at the individual sites.

CONSORT Statement

Suppl Figures S1-S4. S1: Genomic Localization of the CpG2 in the CD95 L promoter. S2: Survival probability according to CpG2 methylation status. S3: Survival probability according to CD95L expression as detected by IHC. S4 a and b: Cox regression data for CpG1 and 2 in the CD95L promoter.

Background Little is known about delivery of neurosurgical care, complication rate and outcome of patients with high-grade glioma (HGG) during the coronavirus disease 2019 (Covid-19) pandemic. Methods This observational, retrospective cohort study analyzed routine administrative data of all patients admitted for neurosurgical treatment of an HGG within the Helios Hospital network in Germany. Data of the Covid-19 pandemic (March 1, 2020—May 31, 2022) were compared to the pre-pandemic period (January 1, 2016—February 29, 2020). Frequency of treatment and outcome (in-hospital mortality, length of hospital stay [LOHS], time in intensive care unit [TICU] and ventilation outside the operating room [OR]) were separately analyzed for patients with microsurgical resection (MR) or stereotactic biopsy (STBx). Results A total of 1763 patients underwent MR of an HGG (648 patients during the Covid-19 pandemic; 1115 patients in the pre-pandemic period). 513 patients underwent STBx (182 [pandemic]; 331 patients [pre-pandemic]). No significant differences were found for treatment frequency (MR: 2.95 patients/week [Covid-19 pandemic] vs. 3.04 patients/week [pre-pandemic], IRR 0.98, 95% CI: 0.89–1.07; STBx (1.82 [Covid-19 pandemic] vs. 1.86 [pre-pandemic], IRR 0.96, 95% CI: 0.80–1.16, P > .05). Rates of in-hospital mortality, infection, postoperative hemorrhage, cerebral ischemia and ventilation outside the OR were similar in both periods. Overall LOHS was significantly shorter for patients with MR and STBx during the Covid-19 pandemic. Conclusions The Covid-19 pandemic did not affect the frequency of neurosurgical treatment of patients with an HGG based on data of a large nationwide hospital network in Germany. LOHS was significantly shorter but quality of neurosurgical care and outcome was not altered during the Covid-19 pandemic.

Ronald Seidel,1 Marc Tietke,2 Oliver Heese,3 Uwe Walter4 1Asklepios Medical Center, Department of Anesthesiology and Intensive Care, Schwedt, Germany; 2Helios Medical Center, Department of Neuroradiology, Schwerin, Germany; 3Helios Medical Center, Department of Neurosurgery, Schwerin, Germany; 4University Medical Center Rostock, Department of Neurology, Rostock, GermanyCorrespondence: Ronald SeidelAsklepios Medical Center, Department of Anesthesiology and Intensive Care, Am Klinikum 1, Schwedt, 16303, GermanyTel +49 3332 534521Email ronald-seidel@t-online.deAbstract: Thoracic epidural analgesia (TEA) is a standard procedure in multimodal analgesia applied in major thoracic and abdominal surgeries. Two cases are presented with serious complications related to TEA. In both cases, earlier reaction of the treating physicians to patient-reported sensory symptoms could have prevented the complicated course. The first case was a 73-year-old patient with bronchial carcinoma who underwent right lower lobe resection. In this case, dabigatran 150 mg/d (indication: permanent atrial fibrillation) had been discontinued 72 hours before surgery, and enoxaparin 80 mg (every 12 hours) had been started 11 hours after surgery. An epidural hematoma developed postoperatively. Magnetic resonance imaging (MRI) was performed only after paraplegia had developed the next day. Unfortunately, delayed hematoma evacuation could not prevent persistent paraplegia in this case, which was complicated by hospital-acquired pneumonia with sepsis and acute renal failure. The second case was a 39-year-old patient with ulcerative colitis and an initially undetected malposition of the epidural catheter. Immediately after test bolus injection, the patient reported paresthesia and overall discomfort, which however could not be safely attributed to either the test dose or the already started general anesthesia. The patient could only be extubated after stopping the epidural infusion. Accidental re-start of epidural infusion led to coma, conjugate eye deviation, and respiratory arrest, necessitating re-intubation. Computed tomography (CT) ruled out intracerebral pathology and showed a catheter position centrally in the spinal canal. Fortunately, no neurological deficits were detected after catheter removal.Keywords: epidural analgesia, dabigatran, paraplegia, perioperative complications

Objective To validate with a prospective study a decision-supporting coding system for the surgical approach for multilevel degenerative cervical myelopathy. Methods Ten cases were presented on an internet platform, including clinical and imaging data. A single-approach (G1), a choice between 2 (G2), or 3 approaches (G3) were options. Senior and junior spine surgeons analyzed 7 parameters: location and extension of the compression of the spinal cord, C-spine alignment and instability, general morbidity and bone diseases, and K-line and multilevel corpectomy. For each parameter, an anterior, posterior, or combined approach was suggested. The most frequent letter or the last letter (if C) of the resulting 7-letter code (7LC) suggested the surgical approach. Each surgeon performed 2 reads per case within 8 weeks. Results G1: Interrater reliability between junior surgeons improved from the first read (κ = 0.40) to the second (κ = 0.76, p < 0.001) but did not change between senior surgeons (κ = 0.85). The intrarater reliability was similar for junior (κ = 0.78) and senior (κ = 0.71) surgeons. G2: Junior/senior surgeons agreed completely (58%/62%), partially (24%/23%), or did not agree (18%/15%) with the 7LC choice. G3: junior/senior surgeons agreed completely (50%/50%) or partially (50%/50%) with the 7LC choice. Conclusion The 7LC showed good overall reliability. Junior surgeons went through a learning curve and converged to senior surgeons in the second read. The 7LC helps less experienced surgeons to analyze, in a structured manner, the relevant clinical and imaging parameters influencing the choice of the surgical approach, rather than simply pointing out the only correct one.

Purpose As an essential part of the health care system, the requirements for specialist training are subject to a continuous process of change. The aim of the present study was to evaluate the current specialist training situation of all departments in a tertiary care hospital in Germany. Differences between assistant and chief physicians should be pointed out. Materials and methods The analysis of the current training situation was carried out on the basis of an individually created questionnaire. The questionnaire content included career goal and specialism. The characteristic values initial training (IT), training structure (TS) and training content were measured on a numeric scale from 1 to 5. In addition, an overall assessment of the trainers’ competences was performed. The questionnaire was sent to 208 assistant physicians (AP) and 34 chief physicians (CP). Results Totally 92 APs (44.2%) and 22 CPs (64.7%) participated. Senior physician was the most common career goal (34.1%), followed by the branch (28.6%). The importance of the topics initial training (IT) and training structure (TS) were evaluated as mean value: ITCP=1.5, ITAP=1.6; p=0.701 and TSCP=1.4, TSAP=1.5; p=0.669. The results concerning the implementation of the topics IT and TS in the daily routine show significant differences between APs and CPs (ITCP=2.0, ITAP=3.2; p=0.002; TSCP=1.9, TSAP=3.0; p Conclusion Our data underline the importance of specialist training subjects. These are partly perceived very differently by APs and CPs. Innovative concepts for the induction phase, well-structured training curricula, providing management skills, the overall use of skills labs and digital documentation might support the satisfaction and the outcome of specialist training. This could also improve quality in patient care.

Catheter-tip-associated granulomas (CTG) are a rare but serious complication of intrathecal analgesic delivery pumps (IADP), which interfere with pain modulation and can cause irreversible neurologic deficits. The treatment of symptomatic CTG generally involves surgical resection and catheter removal. We present a case of an unresectable CTG, which we managed using progressive lowering of the intrathecal morphine sulfate (ITMS) dosage as well as spinal cord stimulation (SCS). A 55-year-old female with failed back surgery syndrome (FBSS) presented with new-onset left-sided lumbar radiculopathy after five years of moderately successful ITMS therapy. An MRI study suggested an unknown mass associated with the tip of the catheter. The tumor’s adherence to nerve roots of the conus terminalis prevented a complete resection and only allowed for a biopsy. After the SCS implantation, we progressively lowered the ITMS dose. In a follow-up consultation, the patient reported the regression of the radiculopathy as well as satisfactory pain levels without oral opiates. In this case of CTG, cessation of intrathecal morphine prevented the further growth of the granuloma. SCS effectively addressed both the chronic lumbar back pain as well as the new-onset radicular pain caused by the CTG.

Background Antimicrobial stewardship (AMS) strategies worldwide focus on optimising the use of antibiotics. Selective susceptibility reporting is recommended as an effective AMS tool although there is a lack of representative studies investigating the impact of selective susceptibility reporting on antibiotic use. The aim of this study was to investigate the impact of selective susceptibility reporting of Staphylococcus aureus (S. aureus) on antibiotic consumption. Enhancing the use of narrow-spectrum beta-lactam antibiotics such as flucloxacillin/cefazolin/cefalexin is one of the main goals in optimising antibiotic therapy of S. aureus infections. Methods This interventional study with control group was conducted at a tertiary care hospital in Germany. During the one-year interventional period susceptibility reports for all methicillin-sensitive S. aureus (MSSA) were restricted to flucloxacillin/cefazolin/cefalexin, trimethoprim-sulfamethoxazole, clindamycin, gentamicin and rifampin/fosfomycin, instead of reporting all tested antibiotics. The impact of implementing selective reporting was analysed by monitoring total monthly antibiotic consumption in our hospital and in a reference hospital (recommended daily dose/100 occupied bed days: RDD/100 BD), as well as on an individual patient level by analysing days of therapy adjusted for bed days (DOT/ 100 BD) for patients with S. aureus bacteremia (SAB) and respectively skin and soft tissue infections (SSTI). Results MSSA-antibiograms were acquired for 2836 patients. The total use of narrow-spectrum beta-lactams more than doubled after implementing selective reporting (from 1.2 to 2.8 RDD/100 BD, P Conclusions As narrow-spectrum beta-lactams are not widely used for other infections, their increase in the overall consumption of the entire hospital was a strong indicator that selective reporting guided clinicians to an optimised antibiotic therapy of S. aureus infections. On a patient level, this assumption was verified by a significant improved treatment of S. aureus infections in the subgroups of SAB and SSTI. As useful AMS tool, we recommend implementing selective reporting rules into the national/international standards for susceptibility reporting.

Background During the course of disease, most glioma patients learn that there is no cure for their tumor. It is therefore not uncommon for patients or caregivers to seek complementary and alternative medicine (CAM) treatments. Patterns of CAM use vary across the globe, but little is known about the type of, and motivation for, CAM use in most countries. Methods Here we conducted a cross-sectional survey of CAM use in patients harboring gliomas of World Health Organization (WHO) grades II to IV at 3 specialized neuro-oncology centers in Switzerland. Results Of 208 patients who returned the survey, approximately half reported having used or using CAM. CAM use was associated with younger age. Patients suffering from WHO grade II gliomas were less likely to indicate CAM use. The leading motivation for CAM use was to contribute actively to the treatment of the disease. CAM use was commonly not counseled or supervised by a health care professional. Cost and issues of reimbursement were not an important factor in the decision against or for CAM use. Conclusions Physicians caring for glioma patients should be aware of and explore CAM use to better understand patients’ attitudes toward their disease, to provide counseling, and to identify potential interactions of CAM with standard treatments for gliomas.

SummaryObjective Selective amygdalohippocampectomy (sAHE) is a well-established treatment for temporal lobe epilepsy, commonly with favorable neuropsychological outcome. Yet, it is still unknown if subsequent resection of the anteromesial temporal lobe (AMTLR), when necessary, deteriorates neuropsychological performance in this selected group of patients. Thus, we evaluated the clinical and neuropsychological data of patients who, due to insufficient seizure control after sAHE, received a subsequent ipsilateral AMTLR and compared these findings with patients who did not receive a second resection (control group). Methods Patients’ characteristics and neuropsychological data were assessed and analyzed in the reoperated as well as in the control group at each step of treatment. Experienced neuropsychologists conducted the standardized examination focusing on verbal, figural and working memory, speech fluency and attention. Preoperative diagnostics included further continuous video-electroencephalography monitoring, high-resolution magnetic resonance imaging and functional transcranial Doppler sonography. Results Eighty patients having received sAHE in our center from 11/2007 to 02/2013 were included in this study. Seventeen of these patients underwent subsequent AMTLR. Thirteen of these were available for follow-up after the second surgery and twelve had a comprehensive neuropsychological testing at all three steps. Analyzing the neuropsychological data revealed no significant differences compared with controls. On the individual level, the data demonstrated that improvement in a subdomain was more frequent than decline, if the performance had already deteriorated after the first procedure. Seizure control improved significantly (p < 0.001) in all patients after subsequent AMTLR resulting in seven patients being seizure-free at follow-up. Significance Subsequent AMTLR following sAHE can be a safe procedure to improve seizure outcome in selected patients. In our series the risk for further neuropsychological deterioration after the second procedure was low. The neuropsychological performance after the sAHE can be a valuable criterion to advise patients who are eligible for a second surgery on their risk of further cognitive decline.

BACKGROUND: Patients suffering from brain tumors, as other cancer patients, may rely on additional support of complementary and alternative medicine (CAM) treatment during the course of disease. However, the assessment and documentation of CAM is not necessarily part of the clinical routine in oncological consultations. Moreover, CAM comprises different agents and treatments that may vary depending on the country the patient lives. Overall, there is a lack of information on type and motivation for CAM use in glioma patients in Switzerland. MATERIAL AND METHODS: A multi-center cross-sectional survey analysis of CAM use in glioma patients was conducted in 3 specialized Neuro-Oncology Centers in Switzerland from 2012–2015. On the occasion of a regular consultation, a questionnaire including multiple choice questions as well as open response questions was provided to patients suffering from a glioma WHO II-IV. RESULTS: Overall, 208 patients completed the survey. Approximately half of the patients (n=101 patients, 49 %) reported the use of CAM during the course of the disease. Patients reported the wish to contribute actively to the cancer treatment as the most important motivation for CAM use. CAM user were most likely younger patients, usually using CAM without medical supervision and without necessarily being reimbursed by the insurance company. CAM use was distributed amongst WHO grades and both genders. CONCLUSIONS: In this multi-center survey analysis conducted in Switzerland, almost half of the glioma patients reported to have used CAM during the course of the disease. This demand should be addressed by the treating physicians. An accurate documentation and counseling could improve patient care, by avoiding potential interactions with the standard treatment and by incorporation of patients’ needs into therapy. Funded by the Swiss Brain Tumor Foundation

The prognosis for glioma remains dismal, and little is known about the final disease phase. To obtain information about this period, we surveyed caregivers of patients who were registered in the German Glioma Network and who died from the disease.A questionnaire with 15 items, focusing on medical, logistic, and mental health support and symptom control during the final 4 weeks, was sent to caregivers. For some of the questions, a scale from 1 (inadequate) to 10 (excellent) was used.Of 1655 questionnaires, 605 were returned (36.6%) and evaluated. We found that 67.9% of the patients were taken care of at home for the last 4 weeks; 47.7% died at home, 22.6% died in hospitals, and 19.3% died in hospice facilities. Medical support was provided by general practitioners in 72.3% of cases, by physicians affiliated with a nursing home or hospice in 29.9%, and by general oncologists in 17%. Specialized neuro-oncologists were involved in 6%. The caregivers ranked the medical support with a mean of 7.2 (using a 10-point scale), nursing service with 8.1, and mental health support with 5.5. In 22.9% of cases, no support for the caregivers themselves was offered by medical institutions.Although these data reflect the caregivers' subjective views, they are useful in understanding and improving current patterns of care. While patients and their caregivers are supported mainly by neuro-oncologists for most of the disease phase, the end-of-life phase is managed predominantly by general practitioners and specialists in palliative care. Close cooperation between these specialties is necessary to meet the specific needs of glioma patients.

The median survival of glioblastoma patients is approximately 12 months. However, 3-5% of the patients survives for more than 3 years and are referred to as long-term survivors. The clinical and molecular factors that contribute to long-term survival are still unknown. To identify specific parameters that might be associated with this phenomenon, we performed a detailed clinical and molecular analysis of 55 primary glioblastoma long-term survivors recruited at the six clinical centres of the German Glioma Network and one associated centre. An evaluation form was developed and used to document demographic, clinical and treatment-associated parameters. In addition, environmental risk factors, associated diseases and occupational risks were assessed. These patients were characterized by young age at diagnosis and a good initial Karnofsky performance score (KPS). None of the evaluated socioeconomic, environmental and occupational factors were associated with long-term survival. Molecular analyses revealed MGMT hypermethylation in 28 of 36 tumours (74%) investigated. TP53 mutations were found in 9 of 31 tumours (29%) and EGFR amplification in 10 of 38 tumours (26%). Only 2 of 32 tumours (6%) carried combined 1p and 19q deletions. Comparison of these data with results from an independent series of 141 consecutive unselected glioblastoma patients registered in the German Glioma Network revealed significantly more frequent MGMT hypermethylation in the long-term survivor group. Taken together, our findings underline the association of glioblastoma long-term survival with prognostically favourable clinical factors, in particular young age and good initial performance score, as well as MGMT promoter hypermethylation.

Early postoperative dysphagia after anterior cervical surgery is a well-known phenomenon with so far unknown etiology. We hypothesised that direct pressure induced by the medial retractor blade on pharynx/esophagus mucosal wall leads to local ischemia. Subsequently postoperative hyperemia and swelling of the pharynx/esophagus may result in swallowing disturbance. To prove the hypothesis local blood flow inside the pharynx/esophagus wall during anterior cervical surgery was measured using a laser Doppler (LD) perfusion monitor unit. Fifteen patients underwent standard anterior cervical discectomy and fusion (ACDF). The LD probe was placed underneath the medial retractor blade in order to gain information at the maximum point of pressure applied onto the pharynx/esophagus wall. Local perfusion was measured prior to retractor opening (5 min), during spreading of the retractor and after its closure (5 min). Perfusion was measured semiquantitatively in perfusion units (PU). Local perfusion ranged from 30 to 210 PU (mean 107) prior to retractor opening, from 7 to 60 PU (mean 30) with open retractor and from 15 to 280 PU (mean 117) after retractor closure. In all 15 patients the open retractor led to hypoperfusion ranging from 21 to 93% compared to the baseline level. In seven patients a reactive hyperemia at the end of the procedure was detected (32-89% compared to baseline level). In four patients after hypoperfusion during spreading of the retractor the baseline levels were reached again and in four patients perfusion remained diminished even after retractor closure. To best of our knowledge, this is the first report on intraoperative measurement of local perfusion of the pharynx/esophagus wall during anterior cervical surgery. Diminished local perfusion was observed in all patients during spreading of the retractor and post-procedure hyperemia was recorded in 46% of the patients. The local ischemia of the pharynx/esophagus wall may be a crucial step in the development of postoperative dysphagia.

Purpose: Preclinical data indicate anti-invasive activity of APG101, a CD95 ligand (CD95L)–binding fusion protein, in glioblastoma. Experimental Design: Patients (N = 91) with glioblastoma at first or second progression were randomized 1:2 between second radiotherapy (rRT; 36 Gy; five times 2 Gy per week) or rRT+APG101 (400 mg weekly i.v.). Patient characteristics [N = 84 (26 patients rRT, 58 patients rRT+APG101)] were balanced. Results: Progression-free survival at 6 months (PFS-6) rates were 3.8% [95% confidence interval (CI), 0.1–19.6] for rRT and 20.7% (95% CI, 11.2–33.4) for rRT+APG101 (P = 0.048). Median PFS was 2.5 (95% CI, 2.3–3.8) months and 4.5 (95% CI, 3.7–5.4) months with a hazard ratio (HR) of 0.49 (95% CI, 0.27–0.88; P = 0.0162) adjusted for tumor size. Cox regression analysis adjusted for tumor size revealed a HR of 0.60 (95% CI, 0.36–1.01; P = 0.0559) for rRT+APG101 for death of any cause. Lower methylation levels at CpG2 in the CD95L promoter in the tumor conferred a stronger risk reduction (HR, 0.19; 95% CI, 0.06–0.58) for treatment with APG101, suggesting a potential biomarker. Conclusions: CD95 pathway inhibition in combination with rRT is an innovative concept with clinical efficacy. It warrants further clinical development. CD95L promoter methylation in the tumor may be developed as a biomarker. Clin Cancer Res; 20(24); 6304–13. ©2014 AACR.

Summary Objective Epilepsy surgery is a standard treatment option for medically intractable temporal lobe epilepsy. Selective amygdalohippocampectomy (SAH) and anterior temporal lobectomy (ATL) are two of the standard surgical procedures in these cases. We conducted a retrospective analysis of patients treated with SAH via a modified transsylvian approach in our epilepsy center between 2008 and 2011, and we analyzed the impact of adjacent procedure-related infarctions on seizure outcome in these patients. Methods Infarctions were detected by magnetic resonance imaging (MRI) within the first week postoperatively and by a second MRI 9 months after surgical intervention. Neuropsychological testing was performed preoperatively. Evaluation of seizure outcome and postoperative neuropsychological testing were conducted approximately 1 year after epilepsy surgery. Correlative clinical data were analyzed by retrospective chart review. Results The postoperative MRI revealed temporal infarctions in 47.9% (n = 23/48) and frontal infarctions in 10.4% (n = 5/48) of the patients. These vascular events were asymptomatic in terms of focal neurologic deficits. Of the patients, 68.5% (n = 37/54) were free of disabling seizures (Engel class I) 1 year after the procedure. Patients with temporal infarctions were significantly more often free of disabling seizures (Engel class I, p = 0.046) than patients without temporal infarctions. Neuropsychological testing indicated a deterioration in verbal memory after SAH in patients with infarctions on the language-lateralized hemisphere compared to patients without infarction (p = 0.011). All other tested neuropsychological categories showed no significant differences between patients with or without infarctions. Significance Our results indicate a surprisingly high number of procedure-related temporal infarctions after transsylvian SAH. Hence, the volume of nonfunctional “eliminated” tissue is enlarged unintentionally, which is a possible explanation for better seizure outcome in these patients. This result supports the notion that ATL is the favorable procedure for temporal lobe epilepsy compared to SAH in the nondominant hemisphere, as neuropsychological deficits are rarely to be expected. A PowerPoint slide summarizing this article is available for download in the Supporting Information section here.

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

The overall survival of patients with BM-MM primarily depends on the number of metastases and pretreatment level of LDH. In the case of a single brain metastasis, stereotactic radiotherapy or neurosurgical metastasectomy is by far the most important factor for improving survival.

Purpose The prognostic value of genetic alterations characteristic of glioblastoma in patients treated according to present standards of care is unclear. Patients and Methods Three hundred one patients with glioblastoma were prospectively recruited between October 2004 and December 2006 at the clinical centers of the German Glioma Network. Two hundred fifty-eight patients had radiotherapy, 199 patients had temozolomide, 189 had both, and seven had another chemotherapy as the initial treatment. The tumors were investigated for TP53 mutation, p53 immunoreactivity, epidermal growth factor receptor, cyclin-dependent kinase CDK 4 or murine double minute 2 amplification, CDKN2A homozygous deletion, allelic losses on chromosome arms 1p, 9p, 10q, and 19q, O6-methylguanine methyltransferase (MGMT) promoter methylation, and isocitrate dehydrogenase 1 (IDH1) mutations. Results Median progression-free (PFS) and overall survival (OS) were 6.8 and 12.5 months. Multivariate analysis revealed younger age, higher performance score, MGMT promoter methylation, and temozolomide radiochemotherapy as independent factors associated with longer OS. MGMT promoter methylation was associated with longer PFS (relative risk [RR], 0.5; 95% CI, 0.38 to 0.68; P < .001) and OS (RR, 0.39; 95% CI, 0.28 to 0.54; P < .001) in patients receiving temozolomide. IDH1 mutations were associated with prolonged PFS (RR, 0.42; 95% CI, 0.19 to 0.91; P = .028) and a trend for prolonged OS (RR, 0.43; 95% CI, 0.15 to 1.19; P = .10). No other molecular factor was associated with outcome. Conclusion Molecular changes associated with gliomagenesis do not predict response to therapy in glioblastoma patients managed according to current standards of care. MGMT promoter methylation and IDH1 mutational status allow for stratification into prognostically distinct subgroups.

Various in vivo studies demonstrated a migration tendency of neural stem cells (NSCs) toward gliomas, making these cells a potential carrier for delivery of therapeutic genes to disseminated glioma cells. We analyzed which factors determine NSC migration and invasion in vitro. Conditioned media prepared from 10 different human glioma cell lines, as well as 13 different tumor-associated growth factors, were analyzed for their chemotactic effects on murine C17.2 NSCs. The growth factor receptor status was analyzed by reverse transcriptase–polymerase chain reaction. Invasion of NSCs into multicellular tumor spheroids generated from 10 glioma cell lines was quantified. NSCs displayed a heterogeneous migration pattern toward glioma spheroids as well as toward glioma-cell-conditioned medium. Chemotactic migration was stimulated up to fivefold by conditioned medium as compared to controls. In coculture assays, NSC invasion varied from single cell invasion into glioma spheroids to complete dissemination of NSCs into glioma spheroids of different cell lines. Among 13 different growth factors, scatter factor/hepatocyte growth factor (SF/HGF) was the most powerful chemoattractant for NSCs, inducing a 2.5-fold migration stimulation. An antibody against SF/HGF inhibited migratory stimulation induced by conditioned media. NSC migration can be stimulated by various growth factors, similar to glioma cell migration. The extent to which NSCs infiltrate three-dimensional glioma cell aggregates appears to depend on additional factors, which are likely to include cell-to-cell contacts and interaction with extracellular matrix proteins.

Within a short time from diagnosis glioma patients usually become aware that the tumor is incurable and that conventional therapies have only limited success. Therefore it is not uncommon that these patients seek second opinions or contact patient self-help groups. Moreover, it is common that patients seek for other treatments themselves, as an adjunct or alternative to conventional therapies. We here describe complementary therapy (CT) use in a cohort of glioma patients treated at three neuro-oncology centers in Switzerland. A previously developed questionnaire from the German Glioma Network was adapted for Swiss conditions and distributed consecutively in the outpatient clinics. We retrieved questionnaires from 139 patients with gliomas of WHO grades II to IV. Fifty-one percent of the participants reported the use of CT. The main motivation for the use of CT was to actively participate in the fight against the disease. However, only a minority of patients using CT was counselled and accompanied by a physician for this treatment. Regarding reimbursement, health insurances in Switzerland are obliged to cover the costs of some defined CT. However, reimbursement was crucial for only 30 percent of the patients in the decision for CT use. CT usage in glioma patients is more frequent in this Swiss cohort (51 %) compared to a cohort from the German Glioma Network (40 %) and probably heavily underestimated in general. Patients often use sources for information and therapeutics outside neuro-oncology centers and outside medical competence. Physicians involved in the treatment of glioma patients should be aware of self-treatments in addition to standard of care.

Parathyroid hormone-related protein (PTHrP) is the major mediator of the humoral hypercalcemia of malignancy and of malignant osteolysis associated with skeletal metastases of common epithelial cancers. PTHrP secretion is regulated by the extracellular calcium concentration ([Ca2+]o) in several types of normal and malignant cells. Because the [Ca2+]o-sensing receptor (CaR) is a key mediator of [Ca2+]o-regulated hormone secretion [e.g., of parathyroid hormone (PTH) by parathyroid chief cells], we investigated the expression of the CaR and PTHrP in normal and neoplastic glial cells and studied the effects of [Ca2+]oon PTHrP secretion. Our results show that primary embryonic human astrocytes (HPA) express CaR mRNA and protein as detected by RT-PCR and Western analysis, respectively. Furthermore, astrocytomas and meningiomas also express the CaR at similar levels as assessed by RT-PCR and Northern and Western blot analyses. HPA and astrocytomas express transcripts encoding all three known isoforms of PTHrP [PTHrP(139), PTHrP(141), and PTHrP(173), comprising 139, 141, and 173 predicted amino acid residues, respectively] as assessed by RT-PCR, whereas meningiomas express only the first two of these. Finally, elevated levels of [Ca2+]oand other polycationic CaR agonists dose dependently stimulate PTHrP secretion from HPA, astrocytomas, and meningiomas, although both basal and high [Ca2+]o-stimulated rates of PTHrP secretion are ∼2.5-fold higher in HPA than in the glial tumors studied here. Therefore, our results show that HPA, astrocytomas, and meningiomas express both the CaR and PTHrP and that CaR agonists stimulate PTHrP secretion.