The role of molecular tumor boards in neuro-oncology: a nationwide survey.

BACKGROUND: In neuro-oncology, the inclusion of tumor patients in the molecular tumor board has only become increasingly widespread in recent years, but so far there are no standards for indication, procedure, evaluation, therapy recommendations and therapy implementation of neuro-oncological patients. The present work examines the current handling of neuro-oncological patients included in molecular tumor boards in Germany. METHODS: We created an online based survey with questions covering the handling of neuro-oncologic patient inclusion, annotation of genetic analyses, management of target therapies and the general role of molecular tumor boards in neuro-oncology in Germany. We contacted all members of the Neuro-Oncology working group (NOA) of the German Cancer Society (DKG) by e-mail. RESULTS: 38 responses were collected. The majority of those who responded were specialists in neurosurgery or neurology with more than 10 years of professional experience working at a university hospital. Molecular tumor boards (MTB) regularly take place once a week and all treatment disciplines of neuro-oncology patients take part. The inclusions to the MTB are according to distinct tumors and predominantly in case of tumor recurrence. An independently MTB member mostly create the recommendations, which are regularly implemented in the tumor treatment. Recommendations are given for alteration classes 4 and 5. Problems exist mostly within the cost takeover of experimental therapies. The experimental therapies are mostly given in the department of medical oncology. CONCLUSIONS: Molecular tumor boards for neuro-oncological patients, by now, are not standardized in Germany. Similarities exists for patient inclusion and interpretation of molecular alterations; the time point of inclusion and implementation during the patient treatment differ between the various hospitals. Further studies for standardization and harmonisation are needed. In summary, most of the interviewees envision great opportunities and possibilities for molecular-based neuro-oncological therapy in the future.

Clinical, radiological and pathological features of temporomesial tumors in the adult. A single center experience from 15 years.

Introduction: The mesial temporal lobe plays a distinct role in epileptogenesis, and tumors in this part of the brain potentially have specific clinical and radiological features. Differentiating high-grade from lower-grade tumors or non-neoplastic lesions can be challenging, preventing the decision for early resection that can be critical in high-grade tumors. Methods: A brain tumor database was analyzed retrospectively to identify patients with temporomesial tumors. We determined clinical features (age, sex, symptoms leading to clinical presentation) as well as neuroradiological (tumor location and the presence of contrast enhancement on initial magnetic resonance imaging (MRI)) and neuropathological findings. Results: We identified 324 temporal tumors. 39 involved the mesial temporal lobe. 77% of temporomesial tumors occured in males, and 77% presented with seizures, regardless of tumor type or grade. In patients 50 years or older, 90% were male and 80% had glioblastoma (GBM); there was no GBM in patients younger than 50 years. 50% of GBMs lacked contrast enhancement. Male sex was significantly associated with GBM. In both contrast-enhancing and non-enhancing tumors, age of 50 years or older was also significantly associated with GBM. Conclusion: In middle-aged and older patients with a mesial temporal lobe tumor, GBM is the most likely diagnosis even when there is no MRI contrast enhancement. Prolonged diagnostic workup or surveillance strategies should be avoided and early resection may be justified in these patients.

Postoperative Communicating Hydrocephalus Following Grade 2/3 Glioma Resection: Incidence, Timing and Risk Factors.

BACKGROUND: In diffusely infiltrating gliomas, the maximum extent of tumor resection is an important predictor of overall survival, irrespective of histological or molecular subtype or tumor grade. For glioblastoma WHO grade 4 (GBM), it has been shown that resection-related events, such as ventricular opening and ventriculitis, increase the risk for development of communicating hydrocephalus (CH) requiring cerebrospinal fluid (CSF) diversion surgery. Risk factors for the development and the incidence of hydrocephalus following resection of other types of infiltrating gliomas are less well established. In this study, we evaluated the incidence and timing of occurrence of different types of hydrocephalus and potential risk factors for the development of CH following resection of grade 2 and 3 gliomas. METHODS: 346 patients who underwent tumor resection (WHO grade 2: 42.2%; 3: 57.8%) at our department between 2006 and 2019 were analyzed retrospectively. For each patient, age, sex, WHO grade, histological type, IDH mutation and 1p/19q codeletion status, tumor localization, number of resections, rebleeding, ventriculitis, ventricular opening during resection and postoperative CSF leak were determined. Uni- as well as multivariate analyses were performed to identify associations with CH and independent risk factors. RESULTS: 24 out of 346 (6.9%) patients needed CSF diversion surgery (implantation of a ventriculoperitoneal or ventriculoatrial shunt) following resection. Nineteen patients (5.5%) had CH, on median, 44 days after the last resection (interquartile range: 18-89 days). Two patients had obstructive hydrocephalus (OH), and three patients had other CSF circulation disorders. CH was more frequent in grade 3 compared to grade 2 gliomas (8.5 vs. 1.4%). WHO grade 3 (odds ratio (OR) 7.5, p = 0.00468), rebleeding (OR 5.0, p = 0.00984), ventriculitis (OR 4.1, p = 0.00463) and infratentorial tumor localization (OR 6.6, p = 0.00300) were identified as significant independent risk factors for the development of post-resection CH. Ventricular opening was significantly associated with CH, but it was not an independent risk factor. CONCLUSION: Physicians treating brain tumor patients should be aware that postoperative CH requiring CSF shunting occurs not only in GBM but also after resection of lower-grade gliomas, especially in grade 3 tumors. It usually occurs several weeks after resection. Rebleeding and postoperative ventriculitis are independent risk factors.

A unified classification approach rating clinical utility of protein biomarkers across neurologic diseases.

A major evolution from purely clinical diagnoses to biomarker supported clinical diagnosing has been occurring over the past years in neurology. High-throughput methods, such as next-generation sequencing and mass spectrometry-based proteomics along with improved neuroimaging methods, are accelerating this development. This calls for a consensus framework that is broadly applicable and provides a spot-on overview of the clinical validity of novel biomarkers. We propose a harmonized terminology and a uniform concept that stratifies biomarkers according to clinical context of use and evidence levels, adapted from existing frameworks in oncology with a strong focus on (epi)genetic markers and treatment context. We demonstrate that this framework allows for a consistent assessment of clinical validity across disease entities and that sufficient evidence for many clinical applications of protein biomarkers is lacking. Our framework may help to identify promising biomarker candidates and classify their applications by clinical context, aiming for routine clinical use of (protein) biomarkers in neurology.

Postoperative communicating hydrocephalus following glioblastoma resection: Incidence, timing and risk factors.

Introduction: Glioblastoma (GBM) is the most common malignant primary brain tumor. Treatment includes maximally safe surgical resection followed by radiation and/or chemotherapy. However, resection can lead to ventricular opening, potentially increasing the risk for development of communicating hydrocephalus (CH). Complications such as rebleeding and infection may also lead to CH and, eventually, the need for cerebrospinal fluid (CSF) diversion surgery. In this study, we evaluated the incidence of different types of hydrocephalus and potential risk factors for the development of CH following glioblastoma resection. Methods: 726 GBM patients who underwent tumor resection at our department between 2006 and 2019 were analyzed retrospectively. Potential risk factors that were determined for each patient were age, sex, tumor location, the number of resection surgeries, ventricular opening during resection, postoperative CSF leak, ventriculitis, and rebleeding. Uni- as well as multivariate analyses were performed to identify associations with CH and independent risk factors. Results: 55 patients (7.6%) needed CSF diversion surgery (implantation of a ventriculoperitoneal or ventriculoatrial shunt) following resection surgery. 47 patients (6.5%) had CH, on median, 24 days after the last resection (interquartile range: 17-52 days). 3 patients had obstructive hydrocephalus (OH) and 5 patients had other CSF circulation disorders. Ventricular opening (odds ratio (OR): 7.9; p=0.000807), ventriculitis (OR 3.3; p=0.000754), and CSF leak (OR 2.3; p=0.028938) were identified as significant independent risk factors for the development of post-resection CH. Having more than one resection surgery was associated with CH as well (OR 2.1; p=0.0128), and frontal tumors were more likely to develop CH (OR 2.4; p=0.00275), while temporal tumors were less likely (OR 0.41; p=0.0158); However, none of those were independent risk factors. Age, sex, or rebleeding were not associated with postoperative CH. Conclusion: Postoperative CH requiring CSF shunting is not infrequent following GBM resection and is influenced by surgery-related factors. It typically occurs several weeks after resection. If multiple risk factors are present, one should discuss the possibility of postoperative CH with the patient and maybe even consider pre-emptive shunt implantation to avoid interruption of adjuvant tumor therapy. The incidence of CH requiring shunting in GBM patients could rise in the future.

High expression of estrogen receptor alpha and aromatase in glial tumor cells is associated with gender-independent survival benefits in glioblastoma patients.

INTRODUCTION: Glioblastoma multiforme (GBM) is a highly malignant glial tumor, affecting men more often than women. The reason for this gender-specific predominance remains unclear, raising the question whether these effects are subject to hormonal control. The purpose of this study was to examine the expression of estrogen receptor alpha (ERα) and aromatase in human GBM tissue samples in relation to patient survival and furthermore to investigate the effect of standard chemotherapy in combination with estradiol treatment on glioblastoma tumor cell lines in vitro. METHODS: 60 tissue samples (31 male, 29 female) of GBM patients were analysed with immunohistochemistry for ERα and aromatase for survival analyses. The cell lines LN18 and LN229 were treated with 17ß-estradiol (E2) in different dosing regimens and the cell viability was measured with MTT assay. After estradiol pre-treatment Temozolomide was added and tested again. RESULTS: High expression of ERα and aromatase in the GBM tissue samples was associated with significantly longer survival times of GBM patients, regardless of gender and body-mass-index. The treatment with high concentrations of estradiol resulted in lower tumor cell viability, compared to control. The cells significantly showed a stronger sensitivity against Temozolomid (TMZ) after estradiol pre-treatment. CONCLUSION: ERα-expression of glial tumour cells seems to play an important prognostic role as a biomarker in GBM, as well as the expression of the enzyme Aromatase. The combined treatment of GBM with standard chemotherapy and estradiol may be beneficial to patient's survival.