Oliver Heese

Molecular predictors of progression-free and overall survival in patients with newly diagnosed glioblastoma: A prospective translational study of the German Glioma Network

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, O(6)-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.

Number of metastases, serum lactate dehydrogenase level, and type of treatment are prognostic factors in patients with brain metastases of malignant melanoma

This multicenter study aimed to identify prognostic factors in patients with brain metastases from malignant melanoma (BM‐MM).

Neural stem cell migration toward gliomas in vitro

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.

A randomised, open label phase III trial with nimotuzumab, an anti-epidermal growth factor receptor monoclonal antibody in the treatment of newly diagnosed adult glioblastoma

PURPOSE A randomised, open label phase III trial was conducted to evaluate efficacy of nimotuzumab, a monoclonal antibody against epidermal growth factor receptor (EGF-R) added to standard therapy for newly diagnosed glioblastoma. PATIENTS AND METHODS 149 glioblastoma patients stratified as with or without residual tumour were randomly assigned to receive either intravenous nimotuzumab 400mg weekly added to standard radiochemotherapy followed by 400mg biweekly after twelve weeks or standard radiochemotherapy. Progression status after 52 weeks (12moPFS) and progression-free survival (PFS) based on Macdonald criteria were co-primary and overall survival (OS), toxicity and quality of life secondary end-points. RESULTS 142 patients were evaluated for efficacy (per protocol cohort). 12 moPFS was 25.6% in the experimental arm and 20.3% in the control group. In residual tumour patients (n=81) median PFS was 5.6 versus 4.0 months, (hazard ratio (HR), 0.87; 95% confidence interval (CI), 0.55-1.37), for patients without residual tumour (n=61) it was 10.6 versus 9.9 months, (HR, 1.01; 95% CI, 0.57-1.77). Median OS in patients with residual tumour was 19.5 versus 16.7 months, (HR, 0.90; 95% CI, 0.52-1.57; P=0.7061), for patients without 23.3 versus 21.0 months (HR, 0.77; 95% CI, 0.41-1.44; P=0.4068). A small cohort of MGMT non-methylated patients with residual tumour showed PFS of 6.2 versus 4.0 months (HR, 0.77; 95% CI, 0.35-1.67; P=0.4997) and OS of 19.0 versus 13.8 months (HR, 0.66; 95% CI, 0.27-1.64; P=0.3648). EGF-R amplification did not correlate with clinical efficacy of nimotuzumab. Nimotuzumab was well tolerated. CONCLUSION This study, albeit negative, contains hypothesis generating signals supporting evaluation of correlative, efficacy-predicting tumour parameters for nimotuzumab in the treatment of glioblastoma.

A Phase II, Randomized, Study of Weekly APG101+Reirradiation versus Reirradiation in Progressive Glioblastoma

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.

The Impact of Esophagus Retraction on Early Dysphagia After Anterior Cervical Surgery: Does a Correlation Exist?

Study Design. Prospective study of 92 patients who underwent anterior cervical surgery. Intraoperative esophagus retraction and postoperative dysphagia were recorded and evaluated. Objective. Early dysphagia after anterior cervical discectomy and fusion is an underestimated side effect. The aim of this study was to investigate whether postoperative swallowing disturbances correlate with the amount of intraoperative retraction of the pharynx/esophagus wall measured during the procedure. Summary of Background Data. The anterior approach to the cervical spine is a routinely used and, in general, safe procedure. A recent prospective study focused on the underreported side effect of postoperative dysphagia, with an incidence of up to 50% at 1 month and 12.5% at 12 months. The etiology of postoperative dysphagia is not known in detail. Methods. An online pressure transducer between the retractor and pharynx/esophagus recorded the epi-esophageal pressure in 92 patients. In 31 patients, a transducer was additionally inserted into the pharynx/esophagus in order to measure the endo-esophageal pressure. The patients rated swallowing difficulty during the first postoperative 5 days using a 10-point score. A control group of 32 lumbar surgery patients was also evaluated for swallowing disturbances. Results. Mean epi-esophageal pressure after retractor opening was 76.3 mm Hg, and mean endo-esophageal pressure was 16.3 mm Hg. An adjustment to 75% and 76%, respectively, of the initial value occurred within the first hour. Of patients, 49.3% complained of swallowing disturbances. There was a significant prevalence of the female gender. No correlation between the amount of retraction and postoperative dysphagia was observed. Conclusions. A correlation between intraoperative pharynx/esophagus retraction and postoperative swallowing disturbances could not be confirmed. The cause of the prevalence of the female gender is unknown. However, the absence of impaired deglutition in the control group suggests that a local phenomenon must be causative of swallowing disturbances following anterior cervical discectomy and fusion.

Angiogenesis-related Growth Factors in Brain Tumors

Numerous growth factors have been implicated in glioma angiogenesis. This chapter focuses on the role of scatter factor/hepatocyte growth factor, fibroblast growth factor, platelet-derived growth factor and transforming growth factor beta. We review the expression pattern of these factors in gliomas, their functional contribution to tumor angiogenesis - also in relation to vascular endothelial growth factor, and the effects resulting from their inhibition or overexpression in gliomas in vivo.

Secretory meningiomas: a benign subgroup causing life-threatening complications.

While meningiomas are known as slow-growing extracerebral neoplasms, the subgroup of secretory meningiomas with histologically benign characteristics tend to cause disproportional peritumoral edema, frequently leading to severe medical and neurological complications in postoperative management. Among 1,484 meningiomas that were resected at our institution between 1990 and 2007, 44 (3%) patients were found to have the histological diagnosis of a secretory meningioma. The clinical course, radiological appearance, and histopathological features were retrospectively analyzed to examine the specifics of these benign lesions. Meningiomas were located at the convexity (n = 14), the cranial base (18), and the sphenoid ridge (12). A severe, nearly hemispheric perifocal edema disproportional to tumor size was seen on preoperative MR imaging in 18 (41%) patients. Following surgical resection, the postoperative course was uneventful in 29 patients. In 15 patients, severe peritumoral edema continued or even increased on postoperative CT imaging. Six patients showed midline shift and clinical worsening necessitating respirator-assisted ventilation and intracranial pressure monitoring. An association between the extent of brain edema and number of periodic acid Schiff-positive pseudopsammomas was found (p < 0.02). Further, the size of the edema correlated with the number of immunohistochemically detected cells expressing carcinoembryonic antigen (CEA) and cytokeratin (CK) (p < 0.01). Mean MIB-1 (Ki-67 antigen) proliferation index was 3.0% (range, 0%-17%) and did not correlate with edema or tumor recurrence. Secretory meningiomas are frequently associated with severe peritumoral edema. The extent of edema correlates with immunohistochemically detected expression of CEA and CK. Extended perifocal edema in meningiomas is an unusual finding and should alert the neurosurgeon that surgery may aggravate edema excessively, leading to a life-threatening postoperative situation.

Vascular events after transsylvian selective amygdalohippocampectomy and impact on epilepsy outcome

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.

Hydrocephalus therapy: reduction of shunt occlusions using a peel-away sheath

In order to avoid shunt occlusions through particles of brain parenchyma a new procedure was used. Conventionally during ventricle puncture brain tissue may intrude into perforating holes of the ventricular catheter and subsequently shunt dysfunction may occur. By using a peel-away sheath the ventricular catheter can be protected during puncture. The conventional technique (n=90) was compared with the peel-away sheath technique (n=20) in a retrospective analyses in regard to shunt revisions during a 1-year period. Shunt revision was done in 18% (16/90) within 1 year using the conventional technique, respectively, 5% (1/20) using the peel-away sheath technique. Although criteria for statistical significance were not reached these data are worth to be mentioned. A randomised prospective study is initiated and the key features are presented.