Intracranial Germinomas: Diagnosis, Pathogenesis, Clinical Presentation, and Management.

PURPOSE OF REVIEW: Intracranial germinomas constitute a rare brain tumor entity of unknown etiology, characterized by unique histopathology and molecular biology. In this manuscript, we review the literature focusing on the epidemiology, histopathology with molecular biology, clinical presentation with emphasis on tumor location, diagnostic workup, and current treatment strategies with related clinical outcomes of intracranial germinomas. RECENT FINDINGS: Although the optimal treatment strategy remains a matter of debate, intracranial germinomas respond well to radiotherapy, chemotherapy, or a combination of both and are characterized by very high cure and survival rates. It is well-known that early discrimination of germinomas from other intracranial neoplasms facilitates the timely initiation of appropriate treatment, thereby contributing to the reduction of morbidity as well as mortality. Ongoing research will need to be directed towards discovering and refining reliable parameters for early diagnosis and evaluation of prognosis in patients with intracranial germinomas.

Prediction of the Topography of the Corticospinal Tract on T1-Weighted MR Images Using Deep-Learning-Based Segmentation.

INTRODUCTION: Tractography is an invaluable tool in the planning of tumor surgery in the vicinity of functionally eloquent areas of the brain as well as in the research of normal development or of various diseases. The aim of our study was to compare the performance of a deep-learning-based image segmentation for the prediction of the topography of white matter tracts on T1-weighted MR images to the performance of a manual segmentation. METHODS: T1-weighted MR images of 190 healthy subjects from 6 different datasets were utilized in this study. Using deterministic diffusion tensor imaging, we first reconstructed the corticospinal tract on both sides. After training a segmentation model on 90 subjects of the PIOP2 dataset using the nnU-Net in a cloud-based environment with graphical processing unit (Google Colab), we evaluated its performance using 100 subjects from 6 different datasets. RESULTS: Our algorithm created a segmentation model that predicted the topography of the corticospinal pathway on T1-weighted images in healthy subjects. The average dice score was 0.5479 (0.3513-0.7184) on the validation dataset. CONCLUSIONS: Deep-learning-based segmentation could be applicable in the future to predict the location of white matter pathways in T1-weighted scans.

Assessment of conformity of actual thoraco-lumbar pedicle screw dimensions to manufacturers' specifications.

Although correct selection of pedicle screw dimensions is indispensable to achieving optimum results, manufacturer-specified or intended dimensions may differ from actual dimensions. Here we analyzed the reliability of specifications made by various manufacturers by comparing them to the actual lengths and diameters of pedicle screws in a standardized experimental setup. We analyzed the actual length and diameter of pedicle screws of five different manufacturers. Four different screw lengths and for each length two different diameters were measured. Measurements were performed with the pedicle screws attached to a rod, with the length determined from the bottom of the tulip to the tip of the screw and the diameters determined at the proximal and distal threads. Differences in length of > 1 mm were found between the manufacturers' specifications and our actual measurements in 24 different pedicle screws. The highest deviation of the measured length from the manufacturers' specification was 3.2 mm. The difference in length between the shortest and longest screw with identical specifications was 3.4 mm. The highest deviation of the measured proximal thread diameters and the manufacturer's specifications was 0.5 mm. The diameter of the distal thread depends on the shape of the pedicle screw and hence varies between manufacturers in conical screws. We found clear differences in the length of pedicle screws with identical manufacturer specifications. Since differences between the actual dimensions and the dimensions indicated by the manufacturer may vary, this needs to be taken into account during the planning of spine instrumentation.

Physiological MRI Biomarkers in the Differentiation Between Glioblastomas and Solitary Brain Metastases.

PURPOSE: Glioblastomas (GB) and solitary brain metastases (BM) are the most common brain tumors in adults. GB and BM may appear similar in conventional magnetic resonance imaging (cMRI). Their management strategies, however, are quite different with significant consequences on clinical outcome. The aim of this study was to evaluate the usefulness of a previously presented physiological MRI approach scoping to obtain quantitative information about microvascular architecture and perfusion, neovascularization activity, and oxygen metabolism to differentiate GB from BM. PROCEDURES: Thirty-three consecutive patients with newly diagnosed, untreated, and histopathologically confirmed GB or BM were preoperatively examined with our physiological MRI approach as part of the cMRI protocol. RESULTS: Physiological MRI biomarker maps revealed several significant differences in the pathophysiology of GB and BM: Central necrosis was more hypoxic in GB than in BM (30 %; P = 0.036), which was associated with higher neovascularization activity (65 %; P = 0.043) and metabolic rate of oxygen (48 %; P = 0.004) in the adjacent contrast-enhancing viable tumor parts of GB. In peritumoral edema, GB infiltration caused neovascularization activity (93 %; P = 0.018) and higher microvascular perfusion (30 %; P = 0.022) associated with higher tissue oxygen tension (33 %; P = 0.020) and lower oxygen extraction from vasculature (32 %; P = 0.040). CONCLUSION: Our physiological MRI approach, which requires only 7 min of extra data acquisition time, might be helpful to noninvasively distinguish GB and BM based on pathophysiological differences. However, further studies including more patients are required.

Pedicle Screw Instrumentation of the Cervicothoracic Junction in the Sitting Position using CT-guided Navigation: Application and Technical Aspects.

BACKGROUND: We evaluate the feasibility and potential advantages of spinal CT navigation in the placement of pedicle screws at the cervicothoracic junction in the sitting position to counteract the anatomy-related limitations of 2D fluoroscopy. METHODS: We retrospectively analyze the data from 15 patients who underwent CT-based navigation-guided placement of a total of 36 pedicle screws at the cervicothoracic junction in the sitting position. RESULTS: CT-based spinal navigation is a useful method in increasing accuracy of pedicle screw instrumentation in the sitting position, successfully counteracting the anatomy-related limitations of 2D fluoroscopy at the cervicothoracic junction. CONCLUSION: CT-based navigation-guided placement of pedicle screws at the cervicothoracic junction in the sitting position proved to be an accurate, safe, and user-friendly method.

Neurological outcome and frequency of overdrainage in normal pressure hydrocephalus directly correlates with implanted ventriculo-peritoneal shunt valve type.

BACKGROUND: The correlation between neurological outcome and frequency of overdrainage in the management of idiopathic normal pressure hydrocephalus (iNPH) using different ventriculoperitoneal shunt valve types is under investigation. Thus, we retrospectively compared one group of iNPH patients implanted with a programmable differential pressure valve (DPV) with another group treated by implantation of a DPV in combination with a flow-regulated anti-siphon device valve (ASD). METHODS: A retrospective evaluation of clinical outcome and frequency of overdrainage of 40 consecutive iNPH patients following surgical management between 08/2010 and 08/2014 was performed. Within the first 2 years of the study, a programmable DPV was implanted in 21 patients (DPV-group, 14 males, 7 females, mean age 74.0 ± 6.0 years). In the following two years, a programmable DPV with a flow-regulated ASD was implanted in 19 patients (ASD- group, 12 males, 7 females, mean age 73.3 ± 4.2 years). Neurological outcome was assessed by employing the NPH recovery rate (comparison of pre- and postoperative Kiefer-score). Mean follow-up period was 12.4 ± 9.8 months. RESULTS: In the DPV-group, three patients (14.3%) experienced severe overdrainage needing surgical intervention despite initial higher valve opening pressures (175 ± 11 mmH2O), compared to one non surgical overdrainage in the ASD-group despite significant lower valve opening pressure (144 ± 22 mmH2O). Excellent/good clinical outcome was found in 78.9% of the patients implanted with ASD compared to 44.4% of patients in the DPV group (p < 0.05). CONCLUSION: Our results clearly demonstrate reduction in surgical over-drainage frequency and resulting complications in iNPH patients, with significantly better clinical outcome following insertion of a flow regulated ASD VP shunt compared to a DPV VP shunt, despite both systems comprised a programmable opening pressure mechanism.

Supra-complete surgery via dual intraoperative visualization approach (DiVA) prolongs patient survival in glioblastoma.

Safe and complete resection represents the first step in the treatment of glioblastomas and is mandatory in increasing the effectiveness of adjuvant therapy to prolong overall survival. With gross total resection currently limited in extent to MRI contrast enhancing areas, the extent to which supra-complete resection beyond obvious contrast enhancement could have impact on overall survival remains unclear. DiVA (dual intraoperative visualization approach) redefines gross total resection as currently accepted by enabling for the first time supra-complete surgery without compromising patient safety. This approach exploits the advantages of two already accepted surgical techniques combining intraoperative MRI with integrated functional neuronavigation and 5-ALA by integrating them into a single surgical approach. We investigated whether this technique has impact on overall outcome in GBM patients. 105 patients with GBM were included. We achieved complete resection with intraoperative MRI alone according to current best-practice in glioma surgery in 75 patients. 30 patients received surgery with supra-complete resection. The control arm showed a median life expectancy of 14 months, reflecting current standards-of-care and outcome. In contrast, patients receiving supra-complete surgery displayed significant increase in median survival time to 18.5 months with overall survival time correlating directly with extent of supra-complete resection. This extension of overall survival did not come at the cost of neurological deterioration. We show for the first time that supra-complete glioma surgery leads to significant prolongation of overall survival time in GBM patients.

Early CSF and Serum S100B Concentrations for Outcome Prediction in Traumatic Brain Injury and Subarachnoid Hemorrhage.

OBJECTIVES: S100B has been proposed as a putative biochemical marker in determining the extent of brain injury and corresponding prognosis in neurotrauma. The aim of this study was to evaluate the prognostic value of S100B early concentrations in serum and cerebrospinal fluid (CSF) in traumatic brain injury (TBI) and subarachnoid hemorrhage (SAH), to determine prognostically relevant threshold values and to evaluate fluctuation following EVD placement. PATIENTS AND METHODS: In 102 patients (45 SAH and 57 TBI) under intensive care unit (ICU) treated between January 2011 and December 2012 with external ventricular drain (EVD) S100B measurements were performed simultaneously in serum and CSF during the first 5 days and before and after EVD exchange. Glasgow coma scale (GCS) was assessed on admission and Glasgow outcome scale (GOS) 6 months later. RESULTS: Peak S100B levels in CSF and serum were measured on the first day after admission and concentrations decreased during the ensuing days post injury gradually. CSF and serum S100B concentrations in TBI patients were significantly higher than in SAH (p<0.005). Both in TBI and SAH patients S100B concentrations in CSF and serum were significantly higher in patients with an unfavorable outcome (GOS 1-3) in comparison to patients with a good outcome (GOS 4-5). Correlation of S100B concentrations in serum and GOS score at 6 months was significant both in TBI and SAH (p<0.05). Serum S100B concentrations >0.7µg/l correlated with 100% mortality. Correlation between S100B in CSF and GOS was significant in SAH (p<0.05), whereas it was not significant in TBI. After EVD exchange (n=53) we found a significant increase of S100B concentration in CSF (p<0.005). CONCLUSION: Initial S100B levels have a limited prognostic value in neurotrauma with CSF concentrations being highly sensitive to smallest influences like EVD placement. However, high initial S100B levels of >0.7µg/dl in serum are associated with 100% mortality, which might help to guide therapy strategies in severe neurotrauma.

A new functional classification system (FGA/B) with prognostic value for glioma patients.

Despite advances in multimodal treatments, malignant gliomas remain characterized by a short survival time. Surgical treatment is accepted to be the first line of therapy, with recent studies revealing that maximal possible tumor reduction exerts significant impact on patient outcome. Consideration of tumor localization in relation to functionally eloquent brain areas has been gaining increasing importance. Despite existing assessment methods, the availability of a simple but reliable preoperative grading based on functional data would therefore prove to be indispensable for the prediction of postoperative outcome and hence for overall survival in glioma patients. We performed a clinical investigation comprising 322 patients with gliomas and developed a novel classification system of preoperative tumor status, which considers tumor operability based on two graduations (Friedlein Grading - FG): FGA with lesions at safe distance to eloquent regions which can be completely resected, and FGB referring to tumors which can only be partially resected or biopsied. Investigation of outcome revealed that FGA were characterized by a significantly longer overall survival time compared to FGB. We offer the opportunity to classify brain tumors in a dependable and reproducible manner. The FGA/B grading method provides high prognostic value with respect to overall survival time in relation to the extent of location-dependent tumor resection.

Intraoperative vascular DIVA surgery reveals angiogenic hotspots in tumor zones of malignant gliomas.

Malignant gliomas belong to the most threatening tumor entities and are hallmarked by rapid proliferation, hypervascularization and an invasive growth pattern. The primary obstacle in surgical treatment lies in differentiation between healthy and pathological tissue at the tumor margins, where current visualization methods reach their limits. Here, we report on a novel technique (vascular dual intraoperative visualization approach - vDIVA) enabling visualization of different tumor zones (TZ I-III) on the basis of angiogenic hotspots. We investigated glioblastoma patients who underwent 5-ALA fluorescence-guided surgery with simultaneous intraoperative ICG fluorescence angiography. This vDIVA technique revealed hypervascularized areas which were further histologically investigated. Neuropathological assessments revealed tissue areas at the resection margins corresponding to TZ II, and postoperative CD34- and Map2 immunostaining confirmed these angiogenic hotspots to be occupied by glioma cells. Hence, the vascular architecture in this transitional zone could be well differentiated from both primary tumor bulk and healthy brain parenchyma. These data demonstrate that ICG fluorescence angiography improves state-of-the-art glioma surgery techniques and facilitates the future characterization of polyclonal attributes of malignant gliomas.

Clinical Course Score (CCS): a new clinical score to evaluate efficacy of neurotrauma treatment in traumatic brain injury and subarachnoid hemorrhage.

BACKGROUND: Neurotrauma continues to represent a challenging public health issue requiring continual improvement in therapeutic approaches. As no such current system exists, we present in this study the Clinical Course Score (CCS) as a new clinical score to evaluate the efficacy of neurotrauma treatment. METHODS: The CCS was calculated in neurotrauma patients to be the difference between the grade of the Glasgow Outcome Scale 6 months after discharge from our department and the grade of a 1 to 5 point reduced Glasgow Coma Scale on admission. We assessed the CCS in a total of 248 patients (196 traumatic brain injury [TBI] patients and 52 subarachnoid hemorrhage [SAH] patients) who were treated in our Department of Neurosurgery between January 2011 and December 2012. RESULTS: We found negative CCS grades both in mild TBI and in mild SAH patients. In patients with severe TBI or SAH, we found positive CCS grades. In SAH patients, we found higher CCS scores in younger patients compared with elderly subjects in both mild and severe cases. CONCLUSIONS: The CCS can be useful in evaluating different therapeutic approaches during neurotrauma therapy. This new score might improve assessment of beneficial effects of therapeutic procedures.

Histone deacetylases inhibition by SAHA/Vorinostat normalizes the glioma microenvironment via xCT equilibration.

Malignant gliomas are characterized by neurodegenerative actions leading to the destruction of surrounding brain parenchyma. The disturbance in glutamate homeostasis caused by increased expression of the glutamate transporter xCT plays a key role in glioma progression. We demonstrate that the HDAC-inhibitor SAHA specifically inhibits the xCT-transporter expression. Thereby, tumor cell stress is engendered, marked by increase in ROS. Moreover, SAHA dependent xCT-reduction correlates with the inhibition of ATF4-expression, a factor known to foster xCT expression. Since xCT/system Xc- is pivotal for the brain tumor microenvironment, normalization of this system is a key in the management of malignant gliomas. To date, the problem lay in the inability to specifically target xCT due to the ubiquitous expression of the xCT-transporter--i.e. in non-cancerously transformed cells too--as well as its essential role in physiological CNS processes. Here, we show xCT-transporter equilibration through SAHA is specific for malignant brain tumors whereas SAHA does not affect the physiological xCT levels in healthy brain parenchyma. Our data indicate that SAHA operates on gliomas specifically via normalizing xCT expression which in consequence leads to reduced extracellular glutamate levels. This in turn causes a marked reduction in neuronal cell death and normalized tumor microenvironment.

The impact of dietary isoflavonoids on malignant brain tumors.

Poor prognosis and limited therapeutic options render malignant brain tumors one of the most devastating diseases in clinical medicine. Current treatment strategies attempt to expand the therapeutic repertoire through the use of multimodal treatment regimens. It is here that dietary fibers have been recently recognized as a supportive natural therapy in augmenting the body's response to tumor growth. Here, we investigated the impact of isoflavonoids on primary brain tumor cells. First, we treated glioma cell lines and primary astrocytes with various isoflavonoids and phytoestrogens. Cell viability in a dose-dependent manner was measured for biochanin A (BCA), genistein (GST), and secoisolariciresinol diglucoside (SDG). Dose-response action for the different isoflavonoids showed that BCA is highly effective on glioma cells and nontoxic for normal differentiated brain tissues. We further investigated BCA in ex vivo and in vivo experimentations. Organotypic brain slice cultures were performed and treated with BCA. For in vivo experiments, BCA was intraperitoneal injected in tumor-implanted Fisher rats. Tumor size and edema were measured and quantified by magnetic resonance imaging (MRI) scans. In vascular organotypic glioma brain slice cultures (VOGIM) we found that BCA operates antiangiogenic and neuroprotective. In vivo MRI scans demonstrated that administered BCA as a monotherapy was effective in reducing significantly tumor-induced brain edema and showed a trend for prolonged survival. Our results revealed that dietary isoflavonoids, in particular BCA, execute toxicity toward glioma cells, antiangiogenic, and coevally neuroprotective properties, and therefore augment the range of state-of-the-art multimodal treatment approach.

Improving the extent of malignant glioma resection by dual intraoperative visualization approach.

Despite continuing debates around cytoreductive surgery in malignant gliomas, there is broad consensus that increased extent of tumor reduction improves overall survival. However, maximization of the extent of tumor resection is hampered by difficulty in intraoperative discrimination between normal and pathological tissue. In this context, two established methods for tumor visualization, fluorescence guided surgery with 5-ALA and intraoperative MRI (iMRI) with integrated functional neuronavigation were investigated as a dual intraoperative visualization (DIV) approach. Thirty seven patients presumably suffering from malignant gliomas (WHO grade III or IV) according to radiological appearance were included. Twenty-one experimental sequences showing complete resection according to the 5-ALA technique were confirmed by iMRI. Fourteen sequences showing complete resection according to the 5-ALA technique could not be confirmed by iMRI, which detected residual tumor. Further analysis revealed that these sequences could be classified as functional grade II tumors (adjacent to eloquent brain areas). The combination of fluorescence guided resection and intraoperative evaluation by high field MRI significantly increased the extent of tumor resection in this subgroup of malignant gliomas located adjacent to eloquent areas from 61.7% to 100%; 5-ALA alone proved to be insufficient in attaining gross total resection without the danger of incurring postoperative neurological deterioration. Furthermore, in the case of functional grade III gliomas, iMRI in combination with functional neuronavigation was significantly superior to the 5-ALA resection technique. The extent of resection could be increased from 57.1% to 71.2% without incurring postoperative neurological deficits.

Hydrocephalus associated with vestibular schwannomas: management options and factors predicting the outcome.

OBJECT: The current, generally accepted optimal management for hydrocephalus related to vestibular schwannomas (VSs) is primary tumor removal, with further treatment reserved only for patients who remain symptomatic. Previous studies have shown, however, that this management can lead to an increase in surgery-related complications. In this study, the authors evaluated their experience with the treatment of such patients, with the aim of identifying the following: 1) the parameters correlating to the need for specific hydrocephalus treatment following VS surgery; and 2) patients at risk for developing hydrocephalus-related complications. METHODS: This was a retrospective study of a 400-patient series. The complication rates and outcomes following primary hydrocephalus treatment versus primary VS removal were compared. Patients undergoing primary tumor removal were further subdivided on the basis of the need for subsequent hydrocephalus treatment. The 3 categories of parameters tested for correlation with the need for such subsequent treatment as well as with heightened risk for developing complications were patient-, tumor-, and hydrocephalus-related. RESULTS: Of the entire series, 53 patients presented with hydrocephalus. Forty-eight of 53 patients underwent primary VS surgery, of whom 42 (87.5%) did not require additional hydrocephalus treatment. Of the 6 patients who did require additional hydrocephalus treatment, only 3 ultimately required a VP shunt. Factors correlating to the need of hydrocephalus treatment after VS removal were large tumor size, irregular tumor surface, and severe preoperative hydrocephalus. Patients with a longer symptom duration prior to surgery, those with polycyclic tumors, or with inhomogeneous VS, were at heightened risk for the development of CSF leaks. The general and functional outcome of surgery showed no correlation to the presence of preoperative hydrocephalus. CONCLUSIONS: Primary tumor removal is the optimum management of disease in patients with VS with associated hydrocephalus; it leads to resolution of the hydrocephalus in the majority of cases, and the outcome is similar to that of patients without hydrocephalus. Certain factors may aid in identifying patients at risk for developing persistent hydrocephalus as well as those at risk for CSF leaks.

Bilateral malignant melanoma metastases to the internal auditory canal/cerebellopontine angle: surgical management and preservation of function.

Although intracranial metastases of malignant melanomas are common, localization at the cerebellopontine angle (CPA) or in the internal auditory canal (IAC) is rare, and bilateral presentation especially so. We present the case of a 46-year-old Caucasian woman with bilateral IAC/CPA lesions and a prior history of malignant melanoma on the right leg. During preoperative investigations, the presence of the bilateral IAC/CPA lesions along with several radiologically identified lesions along the neural axis led to the suspicion that she had neurofibromatosis Type 2 despite her history of malignant melanoma and the lack of characteristic skin lesions and family history. Histopathological analysis of the resected lesion confirmed the intraoperative diagnosis of bilateral CPA malignant melanoma metastases. Surgical removal of the tumors via the retrosigmoid approach with preservation of normal bilateral facial nerve function and unilateral serviceable hearing, combined with control of the systemic disease, provided this patient with a near-normal quality of life for at least 42 months after the initial diagnosis of melanoma.