MET receptor serves as a promising target in melanoma brain metastases.

The development of brain metastases hallmarks disease progression in 20-40% of melanoma patients and is a serious obstacle to therapy. Understanding the processes involved in the development and maintenance of melanoma brain metastases (MBM) is critical for the discovery of novel therapeutic strategies. Here, we generated transcriptome and methylome profiles of MBM showing high or low abundance of infiltrated Iba1high tumor-associated microglia and macrophages (TAMs). Our survey identified potential prognostic markers of favorable disease course and response to immune checkpoint inhibitor (ICi) therapy, among them APBB1IP and the interferon-responsive gene ITGB7. In MBM with high ITGB7/APBB1IP levels, the accumulation of TAMs correlated significantly with the immune score. Signature-based deconvolution of MBM via single sample GSEA revealed enrichment of interferon-response and immune signatures and revealed inflammation, stress and MET receptor signaling. MET receptor phosphorylation/activation maybe elicited by inflammatory processes in brain metastatic melanoma cells via stroma cell-released HGF. We found phospho-METY1234/1235 in a subset of MBM and observed a marked response of brain metastasis-derived cell lines (BMCs) that lacked druggable BRAF mutations or developed resistance to BRAF inhibitors (BRAFi) in vivo to MET inhibitors PHA-665752 and ARQ197 (tivantinib). In summary, the activation of MET receptor in brain colonizing melanoma cells by stromal cell-released HGF may promote tumor self-maintenance and expansion and might counteract ICi therapy. Therefore, therapeutic targeting of MET possibly serves as a promising strategy to control intracranial progressive disease and improve patient survival.

Endoscopic transaqueductal stent placement for tumor-related aqueductal compression in pediatric patients: surgical consideration, technique, and results.

PURPOSE: Endoscopic transaqueductal stenting has become a well-accepted treatment option for a selected small subset of aqueductal stenosis-related obstructive hydrocephalus. However, transaqueductal stenting poses unique challenges and risks which requires critical consideration. This report discusses the clinical experiences with transaqueductal stenting for periaqueductal tumor-related aqueductal stenosis focusing on pediatric patients. METHODS: A retrospective analysis of all patients undergoing endoscopic TAS from 01/1993 to 01/2022 in the author's departments was performed. Demographic, clinical, radiological, and intraoperative endoscopic data were evaluated. All patients with AS-related occlusive hydrocephalus that was treated with TAS were analyzed and prospectively followed. Special attention has been given to providing insights into indications, surgical technique, and limitations. RESULTS: Out of 28 endoscopic transaqueductal endoscopis stenting procedures, five procedures were performed on periaqueductal tumor-related obstructive hydrocephalus, two children and three adult patients. CSF pathway was obstructed by tumor located in the aqueduct in 2, by tumor in the thalamus/mesencephalon in 1, by a tumor within the third ventricle in 1, and by a tumor of the lamina tecti in 1. Simultaneously with transaqueductal stenting, 2 endoscopic third ventriculostomies (ETV), 3 tumor biopsies, and 1 tumor resection were performed. Postoperative complications included the following: CSF fistula (1 case), and asymptomatic fornix contusion (1 case). A working aqueductal stent was achieved in all cases based on clinical follow-up evaluation. Postoperatively, all patients showed improvement or resolution of their symptoms. The mean follow-up period was 25.2 months (range, 1-108 months). One patient died due to tumor progression during early follow-up. No stent migration was seen. CONCLUSION: Endoscopic third ventriculostomy remains the gold standard for treatment of CSF circulation obstructions with lesions in the posterior third ventricle and aqueduct. Transaqueductal stenting for periaqueductal tumor-related aqueductal compression is technically feasible. However, because of the potential high risks and subtle advantages compared with ETV transaqueductal stenting, it might be indicated in a small subset of well-selected patients if alternative treatment options are not at hand.

Stented endoscopic third ventriculostomy: technique, safety, and indications-a multicenter multinational study.

PURPOSE: Endoscopic third ventriculostomy (ETV) is an effective treatment for obstructive hydrocephalus. Secondary stoma closure may be life threatening and is the most common reason for late ETV failure, mostly secondary to local scarring. Local stents intended to maintain patency are rarely used. In this study, we summarize our experience using stented ETV (sETV), efficacy, and safety. MATERIAL AND METHODS: Data was retrospectively collected from all consecutive patients who underwent ETV with stenting at four centers. Collected data included indications for using sETV, hydrocephalic history, surgical technique, outcomes, and complications. RESULTS: Sixty-seven cases were included. Forty had a primary sETV, and 27 had a secondary sETV (following a prior shunt, ETV, or both). The average age during surgery was 22 years. Main indications for sETV included an adjacent tumor (n = 15), thick or redundant tuber cinereum (n = 24), and prior ETV failure (n = 16). Fifty-nine patients (88%) had a successful sETV. Eight patients failed 11 ± 8 months following surgery. Reasons for failure included obstruction of the stent, reabsorption insufficiency, and CSF leak (n = 2 each), and massive hygroma and tumor spread (n = 1 each). Complications included subdural hygroma (n = 4), CSF leak (n = 2), and stent malposition (n = 1). There were no complications associated with two stent removals. CONCLUSION: Stented ETV appears to be feasible and safe. It may be indicated in selected cases such as patients with prior ETV failure, or as a primary treatment in cases with anatomical alterations caused by tumors or thickened tuber cinereum. Future investigations are needed to further elucidate its role in non-communicating hydrocephalus.

Endoscope-assisted microvascular decompression in hemifacial spasm with a teflon bridge.

BACKGROUND: Microvascular conflicts in hemifacial spasm typically occur at the facial nerve's root exit zone. While a pure microsurgical approach offers only limited orientation, added endoscopy enhances visibility of the relevant structures without the necessity of cerebellar retraction. METHODS: After a retrosigmoid craniotomy, a microsurgical decompression of the facial nerve is performed with a Teflon bridge. Endoscopic inspection prior and after decompression facilitates optimal Teflon bridge positioning. CONCLUSIONS: Endoscope-assisted microsurgery allows a clear visualization and safe manipulation on the facial nerve at its root exit zone.

Neuroendoscopy: history, endoscopes, and instrumentation.

INTRODUCTION: Endoscopy was first employed in the surgical treatment of neurosurgical diseases early in the twentieth century, but did not become an established practice for a long time, mainly because of poor technology and clinical results. After a slow re-appearance in the 1980s, the 1990s saw an explosion of techniques and instrumentation. Continuing technological improvement has led to further expansion of surgical techniques and indications for use of neuroendoscopy. DISCUSSION: The expansion of ventricular endoscopy has led to significant understanding of CSF disorders. Aqueduct stenosis as cause of hydrocephalus and arachnoid cysts are an example of pathologies, the concept and understanding of which now is considerably enhanced, due to the application of neuroendoscopy in their treatment. Management of loculated hydrocephalus has been facilitated considerably with the use of the endoscope. The concepts of aqueductoplasty, septostomy, and foraminoplasty of the foramina of Monro and Magendie emerged, which were previously unknown. Skull base surgery, especially surgery for craniopharyngioma, has seen dramatic improvement in results with the use of the endoscope. Coupling of the endoscope with neuronavigation has expanded technical capabilities even further. Overall, we can do a lot more with the endoscope now in comparison to 30 years ago. CONCLUSION: We should always remember that the endoscope is only a tool. Its use has indications and limitations related to its design and our ability to extract the maximum, in the context of its shortcomings. Further technological advances will push surgical frontiers even more in years to come.

Endoscope-assisted microsurgical resection of a third ventricular immature teratoma.

BACKGROUND: Reaching a tumor within the third ventricle is challenging, and planning an accessible trajectory is crucial without injuring the surrounding structures. We report a 5-year-old boy presented with headache and a seizure where sequential MRI brain studies in a short time period revealed a rapid growing immature teratoma within the third ventricle with hydrocephalic changes. Several management procedures were performed for CSF diversion and medical treatment of the tumor with chemotherapy and stem cell therapy. The tumor was rapidly growing, and surgical excision was decided. Total resection was achieved via endoscope-assisted microsurgical transcallosal approach. Seven years after surgery, the patient experienced no recurrence of the tumor with a favorable clinical condition. CONCLUSION: We report a rare case of posterior third ventricular immature teratoma where the endoscope-assisted microsurgical technique was implemented with favorable long-term postoperative outcome.

The value of intraoperative indocyanine green angiography in microvascular decompression for hemifacial spasm to avoid brainstem ischemia.

PURPOSE: Despite being rarely reported, ischemic insults resulting from compromising small brainstem perforators following microvascular decompression (MVD) remain a potential devastating complication. To avoid this complication, we have been using indocyanine green (ICG) angiography intraoperatively to check the flow within the small brainstem perforators. We aim to evaluate the safety and usefulness of ICG videoangiography in MVD. METHODS: We extracted retrospective data of patients who received ICG videoangiography from our prospectively maintained database for microvascular decompression. We noted relevant data including demographics, offending vessels, operative technique, outcome, and complications. RESULTS: Out of the 438 patients, 15 patients with a mean age (SD) of 53 ± 10.5 years underwent intraoperative ICG angiography. Male:female was 1:1.14. The mean disease duration prior to surgery was 7.7 ± 5.3 years. The mean follow-up (SD) was 50.7 ± 42.0 months. In 14 patients, the offending vessel was an artery, and in one patient, a vein. Intraoperative readjustment of the Teflon pledget or sling was required in 20% (3/15) of the cases. No patient had any sort of brainstem ischemia. Eighty percent of the patients (12/15) experienced complete resolution of the spasms. 86.7% (13/15) of the patients reported a satisfactory outcome with marked improvement of the spasms. Three patients experienced slight hearing affection after surgery, which improved in two patients later. There was no facial or lower cranial nerve affection. CONCLUSION: Intraoperative ICG is a safe tool for evaluating the flow within the brain stem perforators and avoiding brainstem ischemia in MVD for hemifacial spasm.

Serum Biomarkers of a Pro-Neuroinflammatory State May Define the Pre-Operative Risk for Postoperative Delirium in Spine Surgery.

Advances in spine surgery enable technically safe interventions in older patients with disabling spine disease, yet postoperative delirium (POD) poses a serious risk for postoperative recovery. This study investigates biomarkers of pro-neuroinflammatory states that may help objectively define the pre-operative risk for POD. This study enrolled patients aged ≥60 scheduled for elective spine surgery under general anesthesia. Biomarkers for a pro-neuroinflammatory state included S100 calcium-binding protein ß (S100ß), brain-derived neurotrophic factor (BDNF), Gasdermin D, and the soluble ectodomain of the triggering receptor expressed on myeloid cells 2 (sTREM2). Postoperative changes of Interleukin-6 (IL-6), Interleukin-1ß (IL-1ß), and C-reactive protein (CRP) were assessed as markers of systemic inflammation preoperatively, intraoperatively, and early postoperatively (up to 48 h). Patients with POD (n = 19, 75.7 ± 5.8 years) had higher pre-operative levels of sTREM2 (128.2 ± 69.4 pg/mL vs. 97.2 ± 52.0 pg/mL, p = 0.049) and Gasdermin D (2.9 ± 1.6 pg/mL vs. 2.1 ± 1.4 pg/mL, p = 0.29) than those without POD (n = 25, 75.6 ± 5.1 years). STREM2 was additionally a predictor for POD (OR = 1.01/(pg/mL) [1.00-1.03], p = 0.05), moderated by IL-6 (Wald-χ2 = 4.06, p = 0.04). Patients with POD additionally showed a significant increase in IL-6, IL-1ß, and S100ß levels on the first postoperative day. This study identified higher levels of sTREM2 and Gasdermin D as potential markers of a pro-neuroinflammatory state that predisposes to the development of POD. Future studies should confirm these results in a larger cohort and determine their potential as an objective biomarker to inform delirium prevention strategies.

Long-term outcome and quality of life after CNS cavernoma resection: eloquent vs. non-eloquent areas.

The aim of this study is to analyze the long-term quality of life after surgery of cavernoma. A monocentric retrospective study was conducted on 69 patients with cavernoma treated microsurgically between 2000 and 2016. The eloquence was adopted from Spetzler-Martin definition. A most recent follow-up was elicited between 2017 and 2019, in which the quality of life (QoL) was evaluated with the Short Form-12 questionnaire (SF12). Forty-one lesions were in eloquent group (EG), 22 in non-eloquent group (NEG), 3 in orbit, and 3 in the spinal cord. Postoperative worsening of the modified Rankin scale (mRS) occurred in 19.5% of cases in EG versus 4.5% in NEG. After a mean follow-up of 6.5 years (SD 4.6), the neurological status was better or unchanged compared to baseline in 85.4% of EG and 100% of NEG. Regarding QoL assessment of 44 patients (EG n = 27, NEG n = 14) attended the last follow-up. Patients after eloquent cavernoma resection reported a non-inferior QoL in most SF12 domains (except for physical role) compared to NEG. However, they reported general health perception inferior to norms, which was affected by the limited physical and emotional roles. At a late follow-up, the surgical morbidity was transient in the NEG and mostly recovered in the EG. The QoL comparison between eloquent and non-eloquent cavernomas created interesting and new data after prolonged follow-up. These results add value for decision-making as well as patient counseling for future encountered cases. Preoperative evaluation of QoL is recommended for future studies to assess QoL dynamics.

Pineal cysts without hydrocephalus: microsurgical resection via an infratentorial-supracerebellar approach-surgical strategies, complications, and their avoidance.

Indications for surgery of pineal cysts without ventriculomegaly are still under debate. In view of the limited data for pineal cyst resection in the absence of hydrocephalus, and the potential risk of this approach, we have analyzed our patient cohort focusing on strategies to avoid complications according to our experience in a series of 73 pineal cyst patients. From 2003 to 2015, we reviewed our database retrospectively for all patients operated on a pineal cyst. Furthermore, we prospectively collected patients from 2016 to 2020. In summary, 73 patients with a pineal cyst were treated surgically between 2003 and 2020. All patients were operated on via a microscopic supracerebellar-infratentorial (SCIT) approach. The mean follow-up period was 26.6 months (range: 6-139 months). Seventy-three patients underwent surgery for a pineal cyst. An absence of enlarged ventricles was documented in 62 patients (51 female, 11 male, mean age 28.1 (range 4-59) years). Main presenting symptoms included headache, visual disturbances, dizziness/vertigo, nausea/emesis, and sleep disturbances. Complete cyst resection was achieved in 59/62 patients. Fifty-five of 62 (89%) patients improved after surgery with good or even excellent results according to the Chicago Chiari Outcome Scale, with complete or partial resolution of the leading symptoms. Pineal cysts resection might be an indication in certain patients for surgery even in the absence of ventriculomegaly. The high percentage of postoperative resolution of quality-of-life impairing symptoms in our series seems to justify surgery. Preoperatively, other causes of the leading symptoms have to be excluded.

Purely venous compression in trigeminal neuralgia-can we predict the outcome of surgery.

PURPOSE: Controversies regarding venous compression and trigeminal neuralgia (TN) still exist. The study demonstrates our experience for microvascular decompression (MVD) in TN caused by purely venous compression. The goal was to identify prognostic anatomical or surgical factors that may influence the outcome. METHODS: Between 2004 and 2020, 49 patients were operated with purely venous compression. Average age was 58.4 years. Mean history of TN was 7.8 years. Microsurgical procedures included transposition or separation of the vein, coagulation, and division. Several features have been analyzed with respect to BNI scores. RESULTS: Evaluation on discharge revealed a complete pain relief in 39 (80%), partial improvement in 7 (14%), and no benefit in 3 (6%) patients. Facial hypesthesia was reported by 14 (28.6%) patients. Mean follow-up (FU) was 42.1 months. BNI pain intensity score on FU revealed 71.4% excellent to very good scores (score 1: 32 (65.3%); 2: 3 (6.1%)). BNI facial numbness score 2 could be detected in 13 patients (26.5%) during FU. There was no statistical relationship between immediate pain improvement or BNI pain intensity score on FU with respect to surgical procedure, size of trigeminal cistern, type of venous compression, venous caliber, trigeminal nerve indentation, or neurovascular adherence. BNI facial numbness score was dependent on type of venous compression (p < 0.05). CONCLUSION: We did not find typical anatomical features that could either predict or influence the outcome regarding pain improvement or resolution in any form. Neither classic microvascular decompression (interposition/transposition) nor sacrificing the offending vein made any difference in outcome.

A multivariable prediction model for recovery patterns and time course of symptoms improvement in hemifacial spasm following microvascular decompression.

BACKGROUND: Microvascular decompression (MVD) success rates exceed 90% in hemifacial spasm (HFS). However, postoperative recovery patterns and durations are variable. OBJECTIVE: We aim to study factors that might influence the postoperative patterns and duration needed until final recovery. METHOD: Only patients following de-novo MVD with a minimum follow-up of 6 months were included. Overall trend of recovery was modeled. Patients were grouped according to recognizable clinical recovery patterns. Uni- and multivariable analyses were used to identify the factors affecting allocation to the identified patterns and time needed to final recovery. RESULTS: A total of 323 (92.6%) patients had > 90% symptom improvement, and 269 (77.1%) patients had complete resolution at the last follow-up. The overall trend of recovery showed steep remission within the first 6 months, followed by relapse peaking around 8 months with a second remission ~ 16 months. Five main recovery patterns were identified. Pattern analysis showed that evident proximal indentation of the facial nerve at root exit zone (REZ), males and facial palsy are associated with earlier recovery at multivariable and univariable levels. anterior inferior cerebellar artery (AICA), AICA/vertebral artery compressions and shorter disease durations are related to immediate resolution of the symptoms only on the univariable level. Time analysis showed that proximal indentation (vs. distal indentation), males and facial palsy witnessed significantly earlier recoveries. CONCLUSION: Our main finding is that in contrast to peripheral indentation, proximal indentation of the facial nerve at REZ is associated with earlier recovery. Postoperative facial palsy and AICA compressions are associated with earlier recoveries. We recommend a minimum of 1 year before evaluating the final outcome of MVD for HFS.

Management of non-vestibular schwannomas in adult patients: a systematic review and consensus statement on behalf of the EANS skull base section Part II: Trigeminal and facial nerve schwannomas (CN V, VII).

BACKGROUND: Non-vestibular schwannomas are relatively rare, with trigeminal and jugular foramen schwannomas being the most common. This is a heterogenous group which requires detailed investigation and careful consideration to management strategy. The optimal management for these tumours remains unclear and there are several controversies. The aim of this paper is to provide insight into the main principles defining management and surgical strategy, in order to formulate a series of recommendations. METHODS: A task force was created by the EANS skull base section committee along with its members and other renowned experts in the field to generate recommendations for the surgical management of these tumours on a European perspective. To achieve this, the task force performed an extensive systematic review in this field and had discussions within the group. This article is the second of a three-part series describing non-vestibular schwannomas (V, VII). RESULTS: A summary of literature evidence was proposed after discussion within the EANS skull base section. The constituted task force dealt with the practice patterns that exist with respect to pre-operative radiological investigations, ophthalmological assessments, optimal surgical and radiotherapy strategies, and follow-up management. CONCLUSION: This article represents the consensually derived opinion of the task force with respect to the treatment of trigeminal and facial schwannoma. The aim of treatment is maximal safe resection with preservation of function. Careful thought is required to select the appropriate surgical approach. Most middle fossa trigeminal schwannoma tumours can be safely accessed by a subtemporal extradural middle fossa approach. The treatment of facial nerve schwannoma remains controversial.

Management of non-vestibular schwannomas in adult patients: a systematic review and consensus statement on behalf of the EANS skull base section. Part I: oculomotor and other rare non-vestibular schwannomas (I, II, III, IV, VI).

BACKGROUND: Non-vestibular schwannomas are relatively rare, with trigeminal and jugular foramen schwannomas being the most common. This is a heterogeneous group which requires detailed investigation and careful consideration to management strategy. The optimal management for these tumours remains unclear, and there are several controversies. The aim of this paper is to provide insight into the main principles defining management and surgical strategy, in order to formulate a series of recommendations. METHODS: A task force was created by the EANS skull base section along with its members and other renowned experts in the field to generate recommendations for the surgical management of these tumours on a European perspective. To achieve this, the task force performed an extensive systematic review in this field and had discussions within the group. This article is the first of a three-part series describing non-vestibular schwannomas (I, II, III, IV, VI). RESULTS: A summary of literature evidence was proposed after discussion within the EANS skull base section. The constituted task force dealt with the practice patterns that exist with respect to pre-operative radiological investigations, ophthalmological assessments, optimal surgical and radiotherapy strategies and follow-up management. CONCLUSION: This article represents the consensually derived opinion of the task force with respect to the treatment of non-vestibular schwannomas. For each of these tumours, the management of these patients is complex, and for those which are symptomatic tumours, the paradigm is shifting towards the compromise between function preservation and progression-free survival.

Quality of life and olfactory function after suprasellar craniopharyngioma surgery-a single-center experience comparing transcranial and endoscopic endonasal approaches.

The endoscopic endonasal approach to suprasellar craniopharyngiomas has become popular as alternative to transcranial approaches. However, the literature lacks data regarding quality of life and olfactory function. The assessment of the long-term quality of life and olfactory function of all patients harboring a suprasellar craniopharyngioma who underwent surgery in our department has been done. Patient characteristics and perioperative data were gathered in a prospectively maintained database. At the last follow-up visit, the olfactory function and the quality of life (ASBQ, SNOT-22) as well as visual and pituitary function were assessed. Thirteen and 17 patients underwent surgery via a transcranial (T) and endonasal (E) route, respectively. No differences were seen in ASBQ, SNOT-22, and olfactory function between T and E, but in E were more full-time worker and less obesity. CSF leaks occurred in 15% of T and 29% of E (p = 0.43). Patients from group E had a superior visual outcome which was most pronounced in the visual field. The degree of new anterior and posterior pituitary gland deficiency after surgery and in the follow-up was lower in group E. The general and sinonasal quality of life and the olfactory function are equal in E and T. E is associated with a superior visual outcome, lower rates of diabetes insipidus, and lower rates of obesity, but has a higher risk for postoperative CSF leaks.

Tear-drop technique in iliac screw placement: a technical analysis.

BACKGROUND: Instrumentation of the lumbosacral region is one of the more challenging regions due to the complex anatomical structures and biomechanical forces. Screw insertion can be done both navigated and based on X-ray verification. In this study, we demonstrate a fast and reliable open, low exposure X-ray-guided technique of iliac screw placement. METHODS: Between October 2016 and August 2019, 48 patients underwent sacropelvic fixation in tear-drop technique. Screw insertion was performed in open technique by using an X-ray converter angulated 25-30° in coronal and sagittal view. The anatomical insertion point was the posterior superior iliac spine. Verification of correct screw placement was done by intraoperative 3D scan. RESULTS: In total, 95 iliac screws were placed in tear-drop technique with a correct placement in 98.1%. CONCLUSIONS: The tear-drop technique showed a proper screw position in the intraoperative 3D scan and therefore may be considered an alternative technique to the navigated screw placement.

Aggressive pituitary neuroendocrine tumors: current practices, controversies, and perspectives, on behalf of the EANS skull base section.

Aggressive pituitary neuroendocrine tumors (APT) account for 10% of pituitary tumors. Their management is a rapidly evolving field of clinical research and has led pituitary teams to shift toward a neuro-oncological-like approach. The new terminology "Pituitary neuroendocrine tumors" (PitNet) that was recently proposed to replace "pituitary adenomas" reflects this change of paradigm. In this narrative review, we aim to provide a state of the art of actual knowledge, controversies, and recommendations in the management of APT. We propose an overview of current prognostic markers, including the recent five-tiered clinicopathological classification. We further establish and discuss the following recommendations from a neurosurgical perspective: (i) surgery and multi-staged surgeries (without or with parasellar resection in symptomatic patients) should be discussed at each stage of the disease, because it may potentialize adjuvant medical therapies; (ii) temozolomide is effective in most patients, although 30% of patients are non-responders and the optimal timeline to initiate and interrupt this treatment remains questionable; (iii) some patients with selected clinicopathological profiles may benefit from an earlier local radiotherapy and/or chemotherapy; (iv) novel therapies such as VEGF-targeted therapies and anti-CTLA-4/anti-PD1 immunotherapies are promising and should be discussed as 2nd or 3rd line of treatment. Finally, whether neurosurgeons have to operate on "pituitary adenomas" or "PitNets," their role and expertise remain crucial at each stage of the disease, prompting our community to deal with evolving concepts and therapeutic resources.

PIM1 Inhibition Affects Glioblastoma Stem Cell Behavior and Kills Glioblastoma Stem-like Cells.

Despite comprehensive therapy and extensive research, glioblastoma (GBM) still represents the most aggressive brain tumor in adults. Glioma stem cells (GSCs) are thought to play a major role in tumor progression and resistance of GBM cells to radiochemotherapy. The PIM1 kinase has become a focus in cancer research. We have previously demonstrated that PIM1 is involved in survival of GBM cells and in GBM growth in a mouse model. However, little is known about the importance of PIM1 in cancer stem cells. Here, we report on the role of PIM1 in GBM stem cell behavior and killing. PIM1 inhibition negatively regulates the protein expression of the stem cell markers CD133 and Nestin in GBM cells (LN-18, U-87 MG). In contrast, CD44 and the astrocytic differentiation marker GFAP were up-regulated. Furthermore, PIM1 expression was increased in neurospheres as a model of GBM stem-like cells. Treatment of neurospheres with PIM1 inhibitors (TCS PIM1-1, Quercetagetin, and LY294002) diminished the cell viability associated with reduced DNA synthesis rate, increased caspase 3 activity, decreased PCNA protein expression, and reduced neurosphere formation. Our results indicate that PIM1 affects the glioblastoma stem cell behavior, and its inhibition kills glioblastoma stem-like cells, pointing to PIM1 targeting as a potential anti-glioblastoma therapy.

GD2 targeting by dinutuximab beta is a promising immunotherapeutic approach against malignant glioma.

PURPOSE: Disialoganglioside GD2 is expressed by glioblastoma multiforme (GBM) cells representing a promising target for anti-GD2 immunotherapeutic approaches. The aim of the present study was to investigate anti-tumor efficacy of the chimeric anti-GD2 antibody (Ab) dinutuximab beta against GBM. METHODS: Expression levels of GD2 and complement regulatory proteins (CRP; CD46, CD55 and CD59) on well-known and newly established primary tumor originated GBM cell lines were analyzed by flow cytometry. Ab-dependent cellular (ADCC) and complement-dependent cytotoxicity (CDC) mediated by dinutuximab beta against GBM cells were determined by a non-radioactive calcein-AM-based assay. RESULTS: Analysis of primary GBM cells revealed a heterogeneous GD2 expression that varied between the cell lines analyzed with higher expression levels in the tumor surface compared to the core originated cells. Both GD2-positive and -negative tumor cells were detected in every cell line analyzed. In contrast to CDC, ADCC mediated by dinutuximab beta was observed against the majority of GBM cells. Importantly, CDC-resistant cells showed high expression of the CRP CD46, CD55 and CD59. CONCLUSION: Our present data show anti-tumor effects mediated by dinutuximab beta against GBM cells providing a rationale for a GD2-directed immunotherapy against GBM. Due to high CRP expression, a combining of GD2-targeting with CRP blockade might be a further treatment option for GBM.

ETV in infancy and childhood below 2 years of age for treatment of hydrocephalus.

PURPOSE: Age and etiology play a crucial role in success of endoscopic third ventriculostomy (ETV) as a treatment of obstructive hydrocephalus. Outcome is worse in infants, and controversies still exist whether ETV is superior to shunt placement. We retrospectively analyzed 70 patients below 2 years from 4 different centers treated with ETV and assessed success. METHODS: Children < 2 years who received an ETV within 1994-2018 were included. Patients were classified according to age and etiology; < 3, 4-12, and 13-24 months, etiologically; aqueductal stenosis, post-hemorrhagic-hydrocephalus (PHH), tumor-related, fourth ventricle outflow obstruction, with Chiari-type II and following CSF infection. We investigated statistically the predictors for ETV success through computing Kaplan-Meier estimates using patient's follow-up time and time to ETV failure. RESULTS: We collected 70 patients. ETV success rate was 41.4%. The highest rate was in tumor-related hydrocephalus and fourth ventricle outlet obstruction (62.5%, 60%) and the lowest rate was in Chiari-type II and following infection (16.7%, 0%). The below 3 months age group showed relatively lower success rate (33.3%) in comparison to older groups which showed similar results (46.4%, 46.6%). Statistically, a previous VP shunt was a predictor for failure (p value < 0.05). CONCLUSION: Factors suggesting a high possibility of failure were age < 3 months and etiology such as Chiari-type II or following infection. Altered CSF dynamics in patients with PHH and under-developed arachnoid villi may play a role in ETV failure. We do not recommend ETV as first line in children < 3 months of age or in case of Chiari II or following infection.