Tarlov cysts are a rare condition. While they appear asymptomatic mostly, some patients develop severe clinical symptoms. Tarlov cysts can grow over time and may result from disturbances within the spinal CSF system. Due to the rare character, the disease can be a burden for both patients and physicians. Treat or not to treat, and if yes, how to treat is a relevant question. Here, a retrospective, observational study on 49 patients suffering from symptomatic Tarlov cysts treated with a combined endoscopic-microsurgical approach was performed. The microsurgical resection was combined with thecaloscopy inside the lower lumbosacral subarachnoidal space to improve the CSF flow and pressure regulation capability. The purpose was to prove that the surgical method was able to prevent recurrence and gives a major relief of symptoms. Our data suggest that combined interventional treatment of symptomatic Tarlov Cysts is helpful to treat the long-standing symptoms. In all patients we found signs for inflammatory processes at the level of the lumbar leptomeningeal sheets, involving the pia mater and the arachnoid. We found evidence that patients suffering from a slow inflammatory process within the leptomeninges might have increase risk of developing Tarlov cysts. We hypothesized that local CSF flow and pressure regulation mechanism become invalid by the morphological changes at the arachnoid and lose the capability to regulate CSF pressure down by pressing minimal volumes of CSF out of the dural sac at the nerve root exits.

Sacral Tarlov cysts (TCs), often asymptomatic, can cause significant pain and severe neurological dysfunction. Conventional treatments are generally associated with high recurrence and complication rates. Specifically, the substantial recurrence rates, which can reach as high as 50%, significantly impact long-term outcomes. Recent evidence increasingly supports the hypothesis that the formation of Tarlov cysts (TCs) may be associated with inflammatory processes within the nerve root sheath, further exacerbated by elevated cerebrospinal fluid (CSF) pressure. This retrospective study explores thecaloscopy, combined with surgical techniques, as a more effective alternative. We observed a total of 78 patients, 48 of whom underwent endoscopic fenestration of the arachnoid sheath in addition to microsurgical resection of the TC. We found that the fenestration of the arachnoid sheath at the level of lumbosacral spinal nerve root entry led to a significantly decreased risk of developing recurrent TCs (5/48 vs. 9/30). Only one of the patients suffered from a persistent new bladder dysfunction after microsurgical resection. This presented technique provides a promising treatment path for the future management of TCs, offering a safe and more effective treatment option compared to previous methods. Additionally, the advantages of the thecaloscopy provide pathophysiological implications regarding the development of perineural cysts.

Colloid cysts are histologically well defined and consist of three main components, a capsule, with an underlying epithelial layer, and a mucinous heart. In our case, we present a 35-year-old female with acute deterioration of level of consciousness. An emergent CT scan showed a cystic lesion occluding the intraventricular foramen. The lesion was endoscopically excised through a transfrontal approach. Microscopic examination of the resected specimen revealed hyphal-like structures (HLS). This rare finding was first described by Dodds and Powers in 1977 and, in its microscopic nature, it mimics actinomyces of the third ventricle.

Supplementary Figure 2 - PDF file 128K, Cell cycle analyses under cilengitide treatment. Meningioma cell lines treated with cilengitide and analysed for cell cycle changes

Supplementary Figure 1 - PDF file 57K, integrin mRNA expression in meningiomas

Supplementary Figure 3 - PDF file 43K, Overall survival of mice treated with cilengitide and control animals

Meningiomas are the most frequent primary intracranial tumors. The considerable variety of histological subtypes has been expanded by the definition of molecular alterations, which can improve both diagnostic accuracy and determination of individual patient's outcome. According to the upcoming WHO classification of brain tumors, the in‐time analysis of frequent molecular events in meningiomas may become mandatory to define meningioma subtypes. We have compiled a custom‐made amplicon‐based next generation sequencing (NGS) meningioma panel covering the most frequent known recurrent mutations in 15 different genes. In an unselected consecutive meningioma cohort (109 patients) analyzed over a period of 12 months, we detected mutations in 11 different genes, with most frequent alterations in NF2 (43%), AKT1 E17K (15%), and TRAF7 (13%). In 39 tumors (36%), two different mutations were detected, with NF2 and SUFU ( n = 5) and KLF4 and TRAF7 ( n = 5) being the most frequent combinations. No alterations were found in POLR2A, CDKN2A, CDKN2B, and BAP1 , and no homozygous CDKN2A/B deletion was detected. NF2 mutations were found in tumors of all WHO grades, whereas mutations in KLF4, TRAF7, and SMO were restricted to WHO grade I meningiomas. In contrast, SMARCE1 and TERT mutations were associated with WHO grade II meningiomas (according to the WHO classification 2016). The distribution of mutations across histological subtypes or tumor localization was in line with the existing literature, with typical combinations like KLF4 K 409Q / TRAF7 for secretory meningiomas and preferential skull base localization of meningiomas harboring SMO and AKT1 E17K mutations. Thus, we present a custom‐made NGS meningioma panel providing a time and cost‐efficient reliable detection of relevant somatic molecular alterations in meningiomas suitable for daily routine.

Brain metastases frequently occur during the course of disease in patients suffering from lung cancer. Occasionally, neurological symptoms caused by brain metastases (BM) might represent the first sign of systemic tumor disease (so called precocious metastases), leading to the detection of the primary lung tumor. The biological basis of precocious BM is largely unknown, and treatment options are not well established for this subgroup of patients. Therefore, we retrospectively analyzed 33 patients (24 non-small cell lung cancer (NSCLC)), 9 small cell lung cancer (SCLC)) presenting with precocious BM focusing on molecular alterations potentially relevant for the tumor's biology and treatment. We found five FGFR1 amplifications (4 adenocarcinoma, 1 SCLC) among 31 analyzed patients (16.1%), eight MET amplifications among 30 analyzed tumors (7 NSCLC, 1 SCLC; 26.7%), three EGFR mutations within 33 patients (all adenocarcinomas, 9.1%), and five KRAS mutations among 32 patients (all adenocarcinomas; 15.6%). No ALK, ROS1 or RET gene rearrangements were detected. Our findings suggest that patients with precocious BM of lung cancer harbor EGFR mutations, MET amplifications or FGFR1 amplifications as potential targeted treatment options.

Tumor cells tend to metabolize glucose through aerobic glycolysis instead of oxidative phosphorylation in mitochondria. One of the rate limiting enzymes of glycolysis is 6-phosphofructo-1-kinase, which is allosterically activated by fructose 2,6-bisphosphate which in turn is produced by 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (PFK-2/FBPase-2 or PFKFB). Mounting evidence suggests that cancerous tissues overexpress the PFKFB isoenzyme, PFKFB3, being causing enhanced proliferation of cancer cells. Initially, six PFKFB3 splice variants with different C-termini have been documented in humans. More recently, additional splice variants with varying N-termini were discovered the functions of which are to be uncovered. Glioblastoma is one of the deadliest forms of brain tumors. Up to now, the role of PFKFB3 splice variants in the progression and prognosis of glioblastomas is only partially understood. In this study, we first re-categorized the PFKFB3 splice variant repertoire to simplify the denomination. We investigated the impact of increased and decreased levels of PFKFB3-4 (former UBI2K4) and PFKFB3-5 (former variant 5) on the viability and proliferation rate of glioblastoma U87 and HEK-293 cells. The simultaneous knock-down of PFKFB3-4 and PFKFB3-5 led to a decrease in viability and proliferation of U87 and HEK-293 cells as well as a reduction in HEK-293 cell colony formation. Overexpression of PFKFB3-4 but not PFKFB3-5 resulted in increased cell viability and proliferation. This finding contrasts with the common notion that overexpression of PFKFB3 enhances tumor growth, but instead suggests splice variant-specific effects of PFKFB3, apparently with opposing effects on cell behaviour. Strikingly, in line with this result, we found that in human IDH-wildtype glioblastomas, the PFKFB3-4 to PFKFB3-5 ratio was significantly shifted towards PFKFB3-4 when compared to control brain samples. Our findings indicate that the expression level of distinct PFKFB3 splice variants impinges on tumorigenic properties of glioblastomas and that splice pattern may be of important diagnostic value for glioblastoma.

A hallmark of glioblastoma is the high level of aerobic glycolysis. PFKFB3 and PFKFB4 are regulatory glycolytic enzymes, which are overexpressed in glioblastomas. Selective inhibition of these enzymes has emerged as a new approach in tumor therapy. We investigated the ratios of PFKFB3 to PFKFB4 mRNA expression in 66 astrocytic tumors of different malignancy grades. PFKFB3 mRNA levels were considerably higher than those of PFKFB4 in all analyzed tumors. IDH-wildtype glioblastomas showed lower PFKFB3 to PFKFB4 mRNA ratios (7.7:1) than IDH-mutant lowgrade astrocytomas (36.5:1), indicating a dependency of the ratio on malignancy grade. In IDH-wildtype glioblastomas exhibiting loss of heterozygosity (LOH) of the PFKFB3 gene locus, the decrease of PFKFB3 mRNA levels was accompanied by lower PFKFB4 mRNA levels, but the PFKFB3 to PFKFB4 mRNA ratio did not differ between tumors with or without PFKFB3 LOH. IDH-wildtype primary glioblastoma patients with high PFKFB3 to PFKFB4 mRNA ratios above the average of 7.7:1 had a significantly longer overall survival time (14 months) than patients with lower ratios (9 months). Our results indicate that low PFKFB3 to PFKFB4 expression ratio is a poor prognostic factor in patients with IDH-wildtype primary glioblastoma and that PFKFB3 and PFKFB4 might represent promising targets for astrocytoma and glioblastoma treatment.

Mesenchymal stem cells (MSC) have been found in various cancers and were discussed to influence tumor biology. Cells fulfilling the complete MSC criteria, including surface marker expression (CD73, CD90, CD105) and tri-lineage differentiation, have been isolated solely from a low percentage of high-grade meningiomas. In contrast, pure co-expression of the surface-markers was relatively frequent, raising the question for an additional role of these membrane proteins in meningiomas. Therefore, here we analyzed the expression of CD73, CD90 and CD105 in a series of meningiomas of all grades. Although no significant association of any marker with meningeal tumor growth per se or with tumor-grade was observed, we detected a positive Pearson correlation (r = 0.55, p ≤ 0.05) in low-grade tumors between CD73 and the most relevant tumor suppressor NF2/Merlin, supported by a tendency of lower CD73 expression in cases with allelic losses at the NF2-locus, which express significantly lower NF2/Merlin-mRNA (p ≤ 0.05). In two pairs of syngenous meningeal or meningioma cell lines with or without shRNA-mediated knockdown of NF2/Merlin a nearly complete loss of CD73 mRNA expression was observed after the knockdown (p ≤ 0.001). This suggested that the correlation observed in tumors may result from a direct functional link between Merlin and CD73. Since CD73 is a 5′-exonucleotidase (termed NT5E), we discuss a potential role of NT5E-mediated purinergic signaling to modulate actin-cytoskeleton and cell contacts, which may be a functional link to NF2/Merlin.

E-Cadherin has been suggested to be involved in meningioma progression but is also known as a key player of epithelial to mesenchymal transition (EMT). We wondered whether the adherens junction protein E-Cadherin, the tight junction protein Zo-1, and transcription factors suppressing E-Cadherin expression (Slug, Snail, Twist, Zeb-1) are differentially expressed between histopathological subtypes of meningioma, and if the expression of these factors is related to biological features of meningiomas. Analyzing 85 meningiomas of various histopathological subtypes and grades of malignancy by immunohistochemistry and 50 of them in addition by real-Time-PCR, we observed significantly reduced expression of Zeb-1, Twist and Slug, together with slightly increased expression levels for E-Cadherin and Zo- 1 in fibroblastic WHO-grade I tumors compared to meningothelial WHO grade I tumors, contradicting the hypothesis of EMT in the fibroblastic meningiomas characterized by mesenchymal appearance. However, comparing aggressive WHO grade II or III meningiomas with WHO-grade I tumors, we observed altered expression levels (loss of E-Cadherin and Zo-1, increased expression of Zeb-1 and Slug) indicating molecular features of EMT in aggressive meningiomas. This was supported by reduced E-Cadherin and increased Slug levels in recurrent compared to non-recurrent meningiomas. The expression levels of E-cadherin and Zo-1 were positively correlated with expression of NF2 mRNA. In primary meningioma cultures and IOMM-Lee meningioma cells, EMT induction by TGF-ß resulted in altered morphology and increased expression of EMT associated transcription factors. Meningioma cells with allelic losses of NF2 showed generally higher levels of various EMT relevant proteins, but were unresponsive to TGF-ß treatment. Our data indicate that aggressive meningiomas of WHO grade II/III are characterized by molecular alterations indicating partial EMT. This might contribute to the aggressive biology of these tumors.

Primary pineal melanoma is exceedingly rare, and sufficient treatment options have not been established. Here we describe a 57-year-old male patient who presented with short-term memory disturbance and ataxia. Magnetic resonance imaging of the brain showed a tumor mass in the pineal gland. Biopsy revealed a malignant melanocytic tumor. No primary malignant melanoma was known, and extensive imaging studies including PET-CT excluded other sites affected by a malignant melanoma. The demonstration of the BRAF V600E mutation in the pineal tumor made the patient eligible for intrathecal treatment with vemurafenib. Unfortunately, the patient died 26 days after surgery due to tumor hemorrhage. This is the first report of V600E in primary pineal melanoma, suggesting that a fraction of these rare tumors might additionally benefit from vemurafenib treatment.

Brain metastases due to endometrial cancer are rare and usually occur in the context of widespread disease. We present a rare case of a 74-year-old woman with recurrent endometrial cancer in terms of a solitary brain lesion two years after initial diagnosis. She was treated with local resection of the brain metastasis and subsequent whole-brain radiotherapy. She then experienced relapse twice, presenting two solitary metastases at two different time points at the same location as at initial diagnosis, but never showed any signs of extracranial widespread disease. The patient has been alive for 13 months after detection of her initial brain metastasis. Despite the identification of some risk factors, there is still very limited knowledge why some patients develop brain metastases as the only sign of distant spread. Our review of the literature revealed that the combination of two treatment modalities yields higher survival rates than single treatment-alone, as was the case in the presented patient. Further case reports, as well as large and prospective studies, may contribute to a better understanding of the etiology and dynamics of this disease and allow better evaluation of treatment options.

Abstract Purpose: Meningiomas are frequent intracranial or spinal neoplasms, which recur frequently and can show aggressive clinical behaviour. We elucidated the impact of the integrin inhibitor cilengitide on migration, proliferation, and radiosensitization of meningioma cells. Experimental Design: We analyzed integrin expression in tissue microarrays of human meningiomas and the antimeningioma properties of cilengitide in cell cultures, subcutaneous and intracranial nude mouse models by measuring tumor volumes and survival times. Results: αvβ5 was the predominantly expressed integrin heterodimer in meningiomas, whereas αvβ3 was mainly detected in tumor blood vessels. Application of up to 100 μg/mL cilengitide resulted in only mildly reduced proliferation/survival of meningioma cell lines. Effects on cell survival could be enhanced by irradiation. One μg/mL cilengitide was sufficient to significantly inhibit meningioma cell migration and invasion in vitro. A daily dosage of 75 mg/kg did neither affect tumor volumes nor overall survival (P = 0.813, log-rank test), but suppressed brain invasion in a significant fraction of treated animals. A combination of 75 mg/kg cilengitide daily and irradiation (2 × 5 Gy) led to a 67% reduction of MRI-estimated tumor volumes in the intracranial model (P < 0.01), whereas the corresponding reduction reached by irradiation alone was only 55% (P < 0.05). Conclusions: These data show that a monotherapy with cilengitide is not likely to achieve major responses in rapidly growing malignant meningiomas, although brain invasion may be reduced because of the strong antimigratory properties of the drug. The combination with radiotherapy warrants further attention. Clin Cancer Res; 19(19); 5402–12. ©2013 AACR.

Background/Aims: Minimally invasive neurosurgery is a growing field, more so in recent decades. The modernization of tools, especially the endoscope, has allowed for critical improvements and crucial advancements in minimally invasive neurosurgery. The current classification scheme for endoscopic procedures needs to be updated to reflect these advancements. Methods: Although the field of neuroendoscopy is continually evolving, the terminologies utilized to describe endoscopic procedures reflect and favor its use as mostly an assisting device complementing the microscope. Even though the classification was adequate for its time, it has become inexact and therefore confusing. We therefore propose a new classification scheme that encompasses the growing independence of endoscopic minimally invasive neurosurgery (EMIN) as well as the changing landscape within EMIN procedures. Results: We have classified our EMIN procedures, since 2002, as either ‘intraendoscopic’ (IEN) or ‘extraendoscopic’ (XEN) in relation to the endoscope’s axis. Exemplary cases of IEN and a review of the literature are presented as well. Conclusion: Our proposed classification scheme for solely endoscopic procedures is presented. The role of the endoscope as an independent tool is clarified.

Loss of heterozygosity (LOH) on chromosome arm 10p is very common in high‐grade gliomas and is, among others, concentrated on the region 10p14‐p15. Presence of multiple tumor suppressor genes is assumed, but until now only Krüpple‐like transcription factor 6 ( KLF6 ) has been suggested as possible target of LOH in this region. On the basis of the fact that the splice variant 4 ( UBI2K4 ) of the PFKFB3 gene, located in 10p15.1, inhibits the anchorage‐independent growth of U87 glioblastoma cells, we hypothesized that PFKFB3 is a target gene of LOH in glioblastomas. In this study, we analyzed 40 glioblastomas for LOH in 10p15, including the PFKFB3 and KLF6 loci, by PCR‐based microsatellite analysis. We detected LOH of PFKFB3 in 55% (22/40) of glioblastomas. LOH of KLF6 , mapped 2.5 cM telomerically to the PFKFB3 locus, was not stringently correlated to the PFKFB3 LOH. The allelic deletion of PFKFB3 resulted in a decrease of PFKFB3 mRNA level accompanied by a lower PFKFB3 protein level. The expression of growth‐inhibiting splice variant UBI2K4 was effectively reduced in glioblastomas with PFKFB3 LOH and a positive correlation with overall PFKFFB3 expression was observed. The PFKFB3 LOH as well as the resulting low UBI2K4 expression level was associated with a poor prognosis of glioblastoma patients. We conclude that LOH on 10p14‐p15 in glioblastomas targets PFKFB3 and in particular splice variant UBI2K4 , a putative tumor suppressor protein in glioblastomas. © 2011 Wiley Periodicals, Inc.

The bifunctional enzyme 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (PFK-2/FBPase-2) controls the glycolytic flux via the allosteric activator fructose 2,6-bisphosphate. Because of its proto-oncogenic character, the PFK-2/FBPase-2 of the PFKFB3 gene is assumed to play a critical role in tumorigenesis. We investigated the PFKFB3 expression in 40 human astrocytic gliomas and 20 non-neoplastic brain tissue specimens. The PFKFB3 protein levels were markedly elevated in high-grade astrocytomas relative to low-grade astrocytomas and corresponding non-neoplastic brain tissue, whereas no significant increase of PFKFB3 mRNA was observed in high-grade astrocytomas when compared with control tissue. In the group of glioblastomas the PFKFB3 protein inversely correlates with EGFR expression. The findings demonstrate that PFKFB3 up-regulation is a hallmark of high-grade astrocytomas offering an explanation for high glycolytic flux and lactate production in these tumors.