Spontaneous involution of a large pineal cyst: Case report and narrative review.

OBJECTIVE: To illustrate the possibility of spontaneous involution of a pineal cyst, justifying an initial observation strategy in patients without evident mass effect. BACKGROUND: Pineal cysts are frequent radiological findings, with a reported overall prevalence from 0.6% to 40%. Historically, surgery has been reserved for patients with symptoms attributable to a mass effect of the cyst. Despite the high prevalence of pineal cysts, the clinical approach to patients with non-specific symptoms remains controversial. METHODS: We report on the spontaneous involution of a large pineal cyst in a 26-year-old female who presented in our outpatient clinic with transient symptoms of headache and nausea. PubMed and Web of Science databases were scrutinized using a predefined search strategy in accordance with the Population, Intervention, Comparison and Outcome (PICO) set-up using "pineal cyst" and "surgery" as search terms. Only peer-reviewed publications were considered eligible. Titles and abstracts of 1513 manuscripts were screened for relevance. After excluding 1420 publications evaluating non-relevant pathology, the eligibility of the remaining 93 full-text records was further assessed and included if they reported patients with pineal cysts presenting with intractable symptoms without hydrocephalus or Parinaud syndrome, and if they documented on their symptomatology and clinical management. CONCLUSION: Recent case series and reviews report favorable results of surgery in patients with pineal cysts but also a potentially high complication rate. However, the evidence offered by these reports is limited and a placebo effect cannot be ruled out. Therefore, surgery cannot be unequivocally advocated in these patients. Instead, an initial surveillance strategy is advocated. We concur with a previously propounded surveillance strategy of a single follow-up magnetic resonance imaging at 12 months. This case report demonstrates the importance of an initial observation strategy since pineal cysts may also show a spontaneous involution.

Single-arm, open-label, multicentre first in human study to evaluate the safety and performance of dural sealant patch in reducing CSF leakage following elective cranial surgery: the ENCASE trial.

OBJECTIVE: The dural sealant patch (DSP) is designed for watertight dural closure after cranial surgery. The goal of this study is to assess, for the first time, safety and performance of the DSP as a means of reducing cerebrospinal fluid (CSF) leakage in patients undergoing elective cranial intradural surgery with a dural closure procedure. DESIGN: First in human, open-label, single-arm, multicentre study with 360-day (12 months) follow-up. SETTING: Three large tertiary reference neurosurgical centres, two in the Netherlands and one in Switzerland. PARTICIPANTS: Forty patients undergoing elective cranial neurosurgical procedures, stratified into 34 supratentorial and six infratentorial trepanations. INTERVENTION: Each patient received one DSP after cranial surgery and closure of the dura mater with sutures. OUTCOME MEASURES: Primary composite endpoint was occurrence of one of the following events: postoperative percutaneous CSF leakage, intraoperative leakage at 20 cm H2O positive end-expiratory pressure or postoperative wound infection. Overall success was defined as achieving the primary endpoint in no more than two patients. Secondary endpoints were device-related serious adverse events or adverse events (AEs), pseudomeningocele and thickness of dura+DSP. Additional endpoints were reoperation in 30 days and user satisfaction. RESULTS: No patients met the primary endpoint. No device-related (serious) AEs were observed. There were two incidences of self-limiting pseudomeningocele as confirmed on MRI. Thickness of dura and DSP were (mean±SD) 3.5 mm±2.0 at day 7 and 2.1 mm±1.2 at day 90. No patients were reoperated within 30 days. Users reported a satisfactory design and intuitive application. CONCLUSIONS: DSP, later officially named Liqoseal, is a safe and potentially efficacious device for reducing CSF leakage after intracranial surgery, with favourable clinical handling characteristics. A randomised controlled trial is needed to assess Liqoseal efficacy against the best current practice for reducing postoperative CSF leakage. TRIAL REGISTRATION NUMBER: NCT03566602.

Single-Arm, Open-Label, Multicenter Study to Evaluate the Safety and Performance of Dura Sealant Patch in Reducing Cerebrospinal Fluid Leakage Following Elective Cranial Surgery: The ENCASE Trial Study Protocol.

BACKGROUND: Cerebrospinal fluid (CSF) leakage is one of the most common neurosurgical complications, occurring in 4% to 32% of surgical cases, with a higher incidence in complicated skull base surgery, intradural spine surgery, and the surgery of the posterior fossa. Our group developed a Dural Sealant Patch (DSP) for watertight dural closure after cranial surgery. OBJECTIVE: To clinically study for the first time the safety and performance of the DSP as a means of reducing CSF leakage in patients undergoing elective cranial intradural surgery with a dural closure procedure. METHODS: We will conduct an open-label, single-arm, multicenter study with a 360 d (12 mo) follow-up. A total of 40 patients will be enrolled at 3 sites. The primary endpoint is a combination of occurrences of one of the following events: postoperative percutaneous CSF leakage, intraoperative leakage at 20 cm H2O, or postoperative wound infection. The secondary endpoints are pseudomeningocele and thickness of dura + DSP. EXPECTED OUTCOMES: Not more than 3 patients will meet the primary endpoint suggesting safety and efficacy. DISCUSSION: As a next step, a randomized controlled trial against the best current practice will follow to evaluate if DSP reduces CSF leakage while its safety is noninferior.

Growth-factor-driven rescue to receptor tyrosine kinase (RTK) inhibitors through Akt and Erk phosphorylation in pediatric low grade astrocytoma and ependymoma.

Up to now, several clinical studies have been started investigating the relevance of receptor tyrosine kinase (RTK) inhibitors upon progression free survival in various pediatric brain tumors. However, single targeted kinase inhibition failed, possibly due to tumor resistance mechanisms. The present study will extend our previous observations that vascular endothelial growth factor receptor (VEGFR)-2, platelet derived growth factor receptor (PDGFR)ß, Src, the epidermal growth factor receptor (ErbB) family, and hepatocyte growth factor receptor (HGFR/cMet) are potentially drugable targets in pediatric low grade astrocytoma and ependymoma with investigations concerning growth-factor-driven rescue. This was investigated in pediatric low grade astrocytoma and ependymoma cell lines treated with receptor tyrosine kinase (RTK) inhibitors e.g. sorafenib, dasatinib, canertinib and crizotinib. Flow cytometry analyses showed high percentage of cells expressing VEGFR-1, fibroblast growth factor receptor (FGFR)-1, ErbB1/EGFR, HGFR and recepteur d'origine nantais (RON) (respectively 52-77%, 34-51%, 63-90%, 83-98%, 65-95%). Their respective inhibitors induced decrease of cell viability, measured with WST-1 cell viability assays. At least this was partially due to increased apoptotic levels measured by Annexin V/Propidium Iodide apoptosis assays. EGF, HGF and FGF, which are normally expressed in brain (tumor) tissue, showed to be effective rescue inducing growth factors resulting in increased cell survival especially during treatment with dasatinib (complete rescue) or sorafenib (partial rescue). Growth-factor-driven rescue was less prominent when canertinib or crizotinib were used. Rescue was underscored by significantly activating downstream Akt and/or Erk phosphorylation and increased tumor cell migration. Combination treatment showed to be able to overcome the growth-factor-driven rescue. In conclusion, our study highlights the extensive importance of environmentally present growth factors in developing tumor escape towards RTK inhibitors in pediatric low grade astrocytoma and ependymoma. It is of great interest to anticipate upon these results for the design of new therapeutic trials with RTK inhibitors in these pediatric brain tumors.

Anti-angiogenic therapy in pediatric brain tumors: an effective strategy?

Brain tumors are still the leading cause of cancer morbidity and mortality among children, despite different therapeutic options including neurosurgery, chemotherapy and radiation. As angiogenesis is highly crucial in brain tumor growth and progression, numerous clinical trials evaluating diverse anti-angiogenic agents have been described. In the present review, we aimed to answer the question if anti-angiogenic therapy is an effective strategy in the treatment of children with brain tumors. Although some encouraging results have been published of anti-angiogenic therapy targeting vascular endothelial growth factor (VEGF)/VEGF receptor signaling or epidermal growth factor receptor (EGFR), still more insight is warranted to be highly conclusive about the efficacy of anti-angiogenic therapy with currently potential upcoming anti-angiogenic agents in pediatric brain tumors. However, given the need for new therapeutic strategies, multi targeted therapy with anti-angiogenic agents anticipating on possible tumor escape mechanisms could be effective in the future treatment of pediatric brain tumors.

Tumor vessel biology in pediatric intracranial ependymoma.

OBJECT: This study aimed to characterize the pediatric intracranial ependymoma vasculature in terms of angiogenic activity and maturation status so as to provide indications for the applicability of vessel-targeted therapy in cases of pediatric intracranial ependymoma. METHODS: Tumor samples obtained in patients with ependymomas were immunohistochemically (double) stained for Ki 67/CD34, caspase 3a/CD34, vascular endothelial growth factor (VEGF)-A, -B, -C, -D, collagen Type IV, and smooth muscle actin to determine microvessel density, tumor and endothelial cell proliferation and apoptotic fraction, the relative expression of VEGF family members, and the coverage of the tumor endothelial cells by basal membrane and pericytes. Messenger RNA expression of angiopoietin-1 and -2 was analyzed by real-time reverse transcriptase polymerase chain reaction. These data were compared with those obtained in a glioblastoma series. RESULTS: Despite a low endothelial cell turnover, the microvessel density of ependymomas was similar to that of glioblastomas. In ependymomas the expression of VEGF-A was within the range of the variable expression in glioblastomas. The staining intensities of VEGF-B, -C, and -D in ependymomas were significantly lower (p < 0.001). The expression of angiopoietin-1 was higher in ependymomas than in glioblastomas (p = 0.03), whereas angiopoietin-2 expression was similar. The coverage of tumor endothelial cells with basal membrane and pericytes was more complete in ependymomas (p = 0.009 and p = 0.022, respectively). CONCLUSIONS: The ependymoma vasculature is relatively mature and has little angiogenic activity compared with malignant gliomas. Therefore, the window for vessel normalization as a therapeutic aim might be considered small. However, the status of the tumor vasculature may not be a reliable predictor of treatment effect. Therefore, possible benefits of antiangiogenic treatment cannot be excluded beforehand in patients with ependymomas.

The angiopoietin 1/angiopoietin 2 balance as a prognostic marker in primary glioblastoma multiforme.

OBJECT: In the present study, the authors analyzed the ANGPT1/ANGPT2 balance in the context of therapeutic outcome in 62 patients with primary glioblastomas multiforme (GBMs). METHODS: The tumor tissue used was obtained in adult patients who underwent neurosurgical debulking. Microvessel density was assessed by morphometric analysis. Double immunostaining for Ki 67/CD34 and cleaved caspase-3/CD34 was used to investigate the proliferation and apoptotic fraction of both endothelial and tumor cells. The expression of VEGFs (A-D) was evaluated on immunohistochemistry. To measure tumor vascular stabilization, the ANGPT1/ANGPT2 mRNA balance was determined using real-time reverse transcriptase polymerase chain reaction. RESULTS: Within the hypoxic perinecrotic tumor area, the apoptotic fraction of endothelial cells was positively correlated with VEGFA expression (p < 0.001). Higher levels of VEGFA correlated with greater proliferation of endothelial cells in the intermediate tumor area (p = 0.031). Vascular endothelial growth factor D was significantly more highly expressed within the perinecrotic tumor area compared with the intermediate tumor area (p < 0.001). Multivariate analysis showed a significant association between the ANGPT1/ANGPT2 balance and the survival time of patients with GBMs (p = 0.035). CONCLUSIONS: The results of the present study suggest that the ANGPT1/ANGPT2 balance has prognostic value in patients with primary GBMs. The authors' findings support the need for further studies of the feasibility of antiangiogenic therapy in primary GBMs, with a special focus on the normalization of tumor vasculature.