Simon Bayerl

High-Resolution Mechanical Imaging of Glioblastoma by Multifrequency Magnetic Resonance Elastography

Objective To generate high-resolution maps of the viscoelastic properties of human brain parenchyma for presurgical quantitative assessment in glioblastoma (GB). Methods Twenty-two GB patients underwent routine presurgical work-up supplemented by additional multifrequency magnetic resonance elastography. Two three-dimensional viscoelastic parameter maps, magnitude |G*|, and phase angle φ of the complex shear modulus were reconstructed by inversion of full wave field data in 2-mm isotropic resolution at seven harmonic drive frequencies ranging from 30 to 60 Hz. Results Mechanical brain maps confirmed that GB are composed of stiff and soft compartments, resulting in high intratumor heterogeneity. GB could be easily differentiated from healthy reference tissue by their reduced viscous behavior quantified by φ (0.37±0.08 vs. 0.58±0.07). |G*|, which in solids more relates to the materials stiffness, was significantly reduced in GB with a mean value of 1.32±0.26 kPa compared to 1.54±0.27 kPa in healthy tissue (P = 0.001). However, some GB (5 of 22) showed increased stiffness. Conclusion GB are generally less viscous and softer than healthy brain parenchyma. Unrelated to the morphology-based contrast of standard magnetic resonance imaging, elastography provides an entirely new neuroradiological marker and contrast related to the biomechanical properties of tumors.

Time lapse in vivo microscopy reveals distinct dynamics of microglia-tumor environment interactions – a new role for the tumor perivascular space as highway for trafficking microglia

Microglial cells are critical for glioma growth and progression. However, only little is known about intratumoral microglial behavior and the dynamic interaction with the tumor. Currently the scarce understanding of microglial appearance in malignant gliomas merely originates from histological studies and in vitro investigations. In order to understand the pattern of microglia activity, motility and migration we designed an intravital study in an orthotopic murine glioma model using CX3CR1‐eGFPGFP/wt mice. We analysed the dynamics of intratumoral microglia accumulation and activity, as well as microglia/tumor blood vessel interaction by epi‐illumination and 2‐photon laser scanning microscopy. We further investigated cellular and tissue function, including the enzyme activity of intratumoral and microglial NADPH oxidase measured by in vivo fluorescence lifetime imaging. We identified three morphological phenotypes of tumor‐associated microglia cells with entirely different motility patterns. We found that NADPH oxidase activation is highly divergent in these microglia subtypes leading to different production levels of reactive oxygen species (ROS). We observed that microglia motility is highest within the perivascular niche, suggesting relevance of microglia/tumor blood vessel interactions. In line, reduction of tumor blood vessels by antivascular therapy confirmed the relevance of the tumor vessel compartment on microglia biology in brain tumors. In summary, we provide new insights into in vivo microglial behavior, regarding both morphology and function, in malignant gliomas. GLIA 2016;64:1210–1226

The Sagittal Balance Does not Influence the 1 Year Clinical Outcome of Patients With Lumbar Spinal Stenosis Without Obvious Instability After Microsurgical Decompression.

Study Design. A retrospective study with retrospective and prospective inclusion of 100 patients. Objective. To determine whether the sagittal balance (SB) influences the clinical outcome of patients with degenerative lumbar spinal stenosis, who underwent microsurgical decompression. Summary of Background Data. The SB has become a critical factor for clinical decision making in the surgical treatment of spinal degenerative diseases. However, a frequently recommended sagittal realignment of elderly, multimorbid patients is accompanied by a significant rate of complications. The influence of SB on the clinical outcome of patients with degenerative spinal stenosis, who undergo decompressive surgery is not well understood. The aim of this study was to explore whether the clinical outcome of these patients is related to the SB and whether patients with spinal stenosis and degenerative sagittal imbalance necessitate restoration of the SB in addition to microsurgical decompression. Methods. One hundred patients with lumbar spinal stenosis, who received microsurgical decompression, were retrospectively identified and classified according to the severity of sagittal imbalance: (1) normal balance group, (2) minor loss of balance group, and (3) major loss of balance group. Sagittal parameters were determined from preoperative lateral spinal radiographs. As outcome parameters, we analyzed pre- and postoperative visual analogue scales for leg and back pain, walking distance, Oswestry disability index, Roland and Morris disability questionnaire, Odoms criteria, and the SF-36 score. Results. All groups significantly benefited from surgery concerning leg pain, back pain, and disability in every days life. There was no difference in patients with decompensated sagittal imbalance compared to patients with normal SB regarding life quality 6 to 24 months after microsurgical decompression. Conclusions. Patients with symptomatic degenerative spinal stenosis and excluded major instability significantly benefit from microsurgical decompression regardless of their sagittal spinal balance. Thus, restoration of the SB for patients with symptomatic degenerative spinal stenosis cannot be recommended in addition to microsurgical decompression. Level of Evidence: 3

Combined temozolomide and sunitinib treatment leads to better tumour control but increased vascular resistance in O6-methylguanine methyltransferase-methylated gliomas

INTRODUCTION Combined antiangiogenic and cytotoxic treatment represents an appealing treatment approach for malignant glioma. In this study we characterised the antitumoural and microvascular consequences of sunitinib (Su) and temozolomide (TMZ) therapy and verified the ideal treatment protocol, with special focus on a potential therapeutic window for combined scheduling. MATERIALS AND METHODS O(6)-Methylguanine methyltransferase (MGMT) status was analysed by pyrosequencing. Tumour growth of subcutaneous xenografts was assessed under different treatment protocols (TMZ, SU, SU followed by TMZ, TMZ followed by SU, combined TMZ/SU). Intravital microscopy (dorsal skinfold chamber model) assessed microvascular consequences. Immunohistochemistry included tumour and endothelial cell proliferation, apoptosis and vascular pericyte coverage. Real-time polymerase chain reaction (RT-PCR) analysed the expression of angiogenesis-related pathways in response to therapy. RESULTS Combined TMZ/SU resulted in significantly reduced tumour growth compared to either monotreatment (TMZ: 106 ± 13 mm(3); SU: 114 ± 53 mm(3); TMZ/SU: 34 ± 7 mm(3)) by additional antiangiogenic effects and synergistic induction of apoptosis versus TMZ monotreatment. Sequential treatment protocols did not show additive antitumour responses. TMZ/SU aggravated vascular resistance mechanisms characterised by significantly higher blood flow rate (TMZ: 74 ± 34 μl/s; SU: 164 ± 36 μl/s; TMZ/SU: 254 ± 95 μl/s), reduced permeability (TMZ: 1.05 ± 0.02; SU: 0.99 ± 0.07; TMZ/SU: 0.89 ± 0.05) and recovery of pericyte-endothelial interactions (TMZ: 89 ± 7%; SU: 67 ± 9%, TMZ/SU:80 ± 10%) versus either monotreatment. Vascular resistance was paralleled by an increase in Ang-1 and Tie-2 and by the downregulation of Dll4. CONCLUSION Sequential application of TMZ and SU in the angiogenic window does not add antitumour efficacy to monotherapy. Simultaneous application yields beneficial tumour control due to additive antiangiogenic and proapoptotic effects. Combined treatment may aggravate pericyte-mediated vascular resistance mechanisms by altering Ang-1-Tie-2 and Dll4/Notch pathways.

Microvascular biodistribution of L19-SIP in angiogenesis targeting strategies

INTRODUCTION Various strategies using L19-mediated fibronectin targeting have become useful clinical tools in anti-tumour therapy and diagnostics. The aim of our study was to characterise the microvascular biodistribution and binding process during tumour angiogenesis and after anti-angiogenic therapy. MATERIALS AND METHODS SF126 glioma and F9 teratocarcinoma cells were implanted into dorsal skin fold chambers (SF126: n = 4; F9: n = 6). Using fluorescence and confocal intravital microscopy the biodistribution process was assessed at t = 0 h, t = 4 h and t = 24 h after intravenous application of Cy3-L19-SIP. Sunitinib treatment was applied for six days and microscopy was performed 2 and 6 days after treatment initiation. Analysed parameters included: vascular and interstitial binding, preferential binding sites of L19-SIP, microvascular blood flow rate, microvascular permeability. Histological analysis included CD31 and DAPI. RESULTS L19-SIP showed a specific and time-dependent neovascular binding with a secondary extravasation process reaching optimal vascular/interstitial binding ratio 4 hours after iv administration (F9: L19-SIP: vascular binding: 74.6 ± 14.5; interstitial binding: 46.8 ± 12.1; control vascular: 22,2 ± 16.6). Angiogenic sprouts were preferred binding sites (F9: L19-SIP: 188 ± 15.5; RTV: 90.6 ± 13.5). Anti-angiogenic therapy increased microvascular hemodynamics (SF126: Su: 106.6 ± 13.3 μl/sec; Untreated: 19.7 ± 9.1 μl/sec) and induced increased L19-SIP accumulation (SF 126: t24; Su: 92.6 ± 2.7; Untreated: 71.9 ± 5.9) in therapy resistant tumour vessels. CONCLUSION L19-SIP shows a time and blood-flow dependent microvascular biodistribution process with angiogenic sprouts as preferential binding sites followed by secondary extravasation of the antibody. Microvascular biodistribution is enhanced in anti-angiogenic-therapy resistant tumour vessels.

The sagittal spinal profile type: a principal precondition for surgical decision making in patients with lumbar spinal stenosis

OBJECTIVE Microsurgical decompression (MD) in patients with lumbar spinal stenosis (LSS) shows good clinical results. Nevertheless, 30%-40% of patients do not have a significant benefit after surgery-probably due to different anatomical preconditions. The sagittal profile types (SPTs 1-4) defined by Roussouly based on different spinopelvic parameters have been shown to influence spinal degeneration and surgical results. The aim of this study was to investigate the influence of the SPT on the clinical outcome in patients with LSS who were treated with MD. METHODS The authors retrospectively investigated 100 patients with LSS who received MD. The patients were subdivided into 4 groups depending on their SPT, which was determined from preoperative lateral spinal radiographs. The authors analyzed pre- and postoperative outcome scales, including the visual analog scale (VAS), walking distance, Oswestry Disability Index, Roland-Morris Disability Questionnaire, Odoms criteria, and the 36-Item Short Form Health Survey score. RESULTS Patients with SPT 1 showed a significantly worse clinical outcome concerning their postoperative back pain (VASback-SPT 1 = 5.4 ± 2.8; VASback-SPT 2 = 2.6 ± 1.9; VASback-SPT 3 = 2.9 ± 2.6; VASback-SPT 4 = 1.5 ± 2.5) and back pain-related disability. Only 43% were satisfied with their surgical results, compared with 70%-80% in the other groups. CONCLUSIONS A small pelvic incidence with reduced compensation mechanisms, a distinct lordosis in the lower lumbar spine with a high load on dorsal structures, and a long thoracolumbar kyphosis with a high axial load might lead to worse back pain after MD. Therefore, the indication for MD should be provided carefully, fusion can be considered, and other possible reasons for back pain should be thoroughly evaluated and treated.

Single- and multi-level anterior decompression and fusion for cervical spondylotic myelopathy - A long term follow-up with a minimum of 5 years

OBJECTIVE Cervical spondylotic myelopathy (CSM) is a common disease leading to significant neurological disability. We compared patients suffering from a single- and a multi-level pathology to analyze the influence of the natural course of the disease on the long-term outcome after surgery. METHODS We analyzed the records of 52 patients with CSM after surgery. The neurological status of the patients was assessed by the modified Japanese Orthopaedic Association Scale (mJOAS). X-rays were conducted before and after surgery. RESULTS 52 patients were treated by a single-level (n=27) or a multi-level approach (n=25) more than 5 years ago. A significant improvement of the neurological status could be seen even 5 years or more after surgery in both groups without differences. After one year no further improvement could be observed. In the single-level group a trend to a subsequent loss of lordotic correction could be seen. Anterior plates were only used in the multi-level group. CONCLUSION The anterior approach is an effective procedure to improve the symptoms of a CSM for many years. The risk of a multi-level pathology does not appear to exceed the risks of a single-level pathology concerning clinical long-term outcome after surgery. The clinical success is not hindered by a loss of correction in this specific setting.

Impact of timing of cranioplasty on hydrocephalus after decompressive hemicraniectomy in malignant middle cerebral artery infarction

OBJECTIVE Patients with malignant middle cerebral artery infarction frequently develop hydrocephalus after decompressive hemicraniectomy. Hydrocephalus itself and known shunt related complications after ventriculo-peritoneal shunt implantation may negatively impact patientś outcome. Here, we aimed to identify factors associated with the development of hydrocephalus after decompressive hemicraniectomy in malignant middle cerebral artery infarction. PATIENTS AND METHODS A total of 99 consecutive patients with the diagnosis of large hemispheric infarctions and the indication for decompressive hemicraniectomy were included. We retrospectively evaluated patient characteristics (gender, age and selected preoperative risk factors), stroke characteristics (side, stroke volume and existing mass effect) and surgical characteristics (size of the bone flap, initial complication rate, time to cranioplasty, complication rate following cranioplasty, type of implant, number of revision surgeries and mortality). RESULTS Frequency of hydrocephalus development was 10% in our cohort. Patients who developed a hydrocephalus had an earlier time point of bone flap reimplantation compared to the control group (no hydrocephalus=164±104days, hydrocephalus=108±52days, p<0.05). Additionally, numbers of revision surgeries after cranioplasty was associated with hydrocephalus with a trend towards significance (p=0.08). CONCLUSION Communicating hydrocephalus is frequent in patients with malignant middle cerebral artery infarction after decompressive hemicraniectomy. A later time point of cranioplasty might lead to a lower incidence of required shunting procedures in general as we could show in our patient cohort.

Two-level cervical corpectomy—long-term follow-up reveals the high rate of material failure in patients, who received an anterior approach only

In contrast to a one-level cervical corpectomy, a multilevel corpectomy without posterior fusion is accompanied by a high material failure rate. So far, the adequate surgical technique for patients, who receive a two-level corpectomy, remains to be elucidated. The aim of this study was to determine the long-term clinical outcome of patients with cervical myelopathy, who underwent a two-level corpectomy. Outcome parameters of 21 patients, who received a two-level cervical corpectomy, were retrospectively analyzed concerning reoperations and outcome scores (VAS, Neck Disability Index (NDI), Nurick scale, modified Japanese Orthopaedic Association score (mJOAS), Short Form 36-item Health Survey Questionnaire (SF-36)). The failure rate was determined using postoperative radiographs. The choice over the surgical procedures was exercised by every surgeon individually. Therefore, a distinction between two groups was possible: (1) anterior group (ANT group) with a two-level corpectomy and a cervical plate, (2) anterior/posterior group (A/P group) with two-level corpectomy, cervical plate, and additional posterior fusion. Both groups benefitted from surgery concerning pain, disability, and myelopathy. While all patients of the A/P group showed no postoperative instability, one third of the patients of the ANT group exhibited instability and clinical deterioration. Thus, a revision surgery with secondary posterior fusion was needed. Furthermore, the ANT group had worse myelopathy scores (mJOASANT group = 13.5 ± 2.5, mJOASA/P group = 15.7 ± 2.2). Patients with myelopathy, who receive a two-level cervical corpectomy, benefitted from surgical decompression. However, patients with a sole anterior approach demonstrated a very high rate of instability (33%) and clinical deterioration in a long-term follow-up. Therefore, we recommend to routinely perform an additional posterior fusion after two-level cervical corpectomy.

Revision surgery for cervical artificial disc: Surgical technique and clinical results

OBJECTIVE Cervical artificial disc replacement (C-ADR) was developed with the goal of preserving mobility of the cervical segment in patients with degenerative disc disease. So far, little is known about experiences with revision surgery and explantation of C-ADRs. Here, we report our experience with revision the third generation, Galileo-type disc prosthesis from a retrospective study of two institutions. PATIENTS AND METHODS Between November 2008 and July 2016, 16 patients with prior implantation of C-ADR underwent removal of the Galileo-type disc prosthesis (Signus, Medizintechnik, Germany) due to a call back by industry. In 10 patients C-ADR was replaced with an alternative prosthesis, 6 patients received an ACDF. Duration of surgery, time to revision, surgical procedure, complication rate, neurological status, histological findings and outcome were examined in two institutions. RESULTS The C-ADR was successfully revised in all patients. Surgery was performed through the same anterior approach as the initial access. Duration of the procedure varied between 43 and 80min. Access-related complications included irritation of the recurrent nerve in one patient and mal-positioning of the C-ADR in another patient. Follow up revealed two patients with permanent mild/moderate neurologic deficits, NDI (neck disability index) ranged between 10 and 42%. CONCLUSIONS Anterior exposure of the cervical spine for explantation and revision of C-ADR performed through the initial approach has an overall complication rate of 18.75%. Replacements of the Galileo-type disc prosthesis with an alternative prosthesis or conversion to ACDF are both suitable surgical options without significant difference in outcome.