Natural history of spinal cord metastasis from brain glioblastomas.

BACKGROUND AND OBJECTIVES: Spinal cord metastasis arising from an intracranial glioblastoma is a rare and late event during the natural course of the disease. These pathological entities remain poorly characterized. This study aimed to identify and investigate the timeline, clinical and imaging findings, and prognostic factors of spinal cord metastasis from a glioblastoma. METHODS: Consecutive histopathological cases of spinal cord metastasis from glioblastomas in adults entered in the French nationwide database between January 2004 and 2016 were screened. RESULTS: Overall, 14 adult patients with a brain glioblastoma (median age 55.2 years) and harboring a spinal cord metastasis were included. The median overall survival as 16.0 months (range, 9.8-22.2). The median spinal cord Metastasis Free Survival (time interval between the glioblastoma diagnosis and the spinal cord metastasis diagnosis) was 13.6 months (range, 0.0-27.9). The occurrence of a spinal cord metastasis diagnosis greatly impacted neurological status: 57.2% of patients were not ambulatory, which contributed to dramatically decreased Karnofsky Performance Status (KPS) scores (12/14, 85.7% with a KPS score ≤ 70). The median overall survival following spinal cord metastasis was 3.3 months (range, 1.3-5.3). Patients with a cerebral ventricle effraction during the initial brain surgery had a shorter spinal cord Metastasis Free Survival (6.6 vs 18.3 months, p = 0.023). Out of the 14 patients, eleven (78.6%) had a brain IDH-wildtype glioblastoma. CONCLUSIONS: Spinal cord metastasis from a brain IDH-wildtype glioblastoma has a poor prognosis. Spinal MRI can be proposed during the follow-up of glioblastoma patients especially those who have benefited from cerebral surgical resection with opening of the cerebral ventricles.

Retrospective and integrative analyses of molecular characteristics and their specific imaging parameters in pediatric grade 1 gliomas.

BACKGROUND: Pediatric low-grade gliomas (PLGG) are the most common brain tumors diagnosed during childhood and represent a heterogeneous group associating variable molecular abnormalities. To go further and develop specific statistical patterns between tumor molecular background, imaging features, and patient outcome, a retrospective study was performed in a group of non-neurofibromatosis type 1 (non-NF1) grade 1 PLGGs. PATIENTS AND METHODS: Seventy-eight children, followed from 2004 to 2017, were retrospectively reported. In this population, we analyzed radiological and molecular parameters. Their therapeutic management comprised surgery or surgery plus chemotherapies. RESULTS: Considering all 78 patients, 59 had only a surgical removal and 19 patients were treated with postoperative chemotherapy. Twelve progressions were reported in the partially resected and chemotherapeutic groups, whereas four deaths occurred only in the highly treated patients. As expected, in the global cohort, PLGG with BRAF p.V600E and/or CDKN2A loss exhibited poor outcomes and we evidenced significant associations between those molecular characteristics and their imaging presentation. In the chemo-treated patients, when associating initial and 6-month magnetic resonance imaging (MRI) parameters to the molecular features, the good risk situations were significantly linked to the presence of a large tumor cyst at diagnosis and the appearance during treatment of a higher cystic proportion that we called cystic conversion. CONCLUSION: So, additionally to the presence of BRAF p.V600E or CDKN2A deletion in grade 1 PLGGs, the absence on diagnostic MRI of cystic parts and/or cystic conversion at 6-month chemotherapy were significantly linked to a worst prognosis and response to treatment. These imaging features should be considered as prognostic markers in future PLGG studies.

Endoscopic-enhanced supra-cerebellar trans-tentorial (SCTT) approach to temporo-mesial region: a multicenter study.

Surgical access to the temporo-mesial area may be achieved by several routes such as the sub-temporal, the temporal trans-ventricular, the pterional/trans-sylvian, and the occipital interhemispheric approaches; nonetheless, none of them has shown to be superior to the others. The supra-cerebellar trans-tentorial approach allows a great exposure of the middle and posterior temporo-mesial region, while avoiding temporal lobe retraction. A prospective multicenter study was designed to collect data on patients undergoing endoscopic-enhanced SCTT approach to excise left temporo-mesial lesions. The study involved 5 different neurosurgical European centers and ran from 2015 to 2020. All patients had preoperative as well as postoperative brain MRI and ophthalmology evaluation. A total of 30 patients were included in this study, the mean follow-up was 44 months (range 18 to 84 months), male/female ratio was 16/14, and mean age was 39 years. A gross total resection was achieved in 29/30 (96.7%) cases. All surgical procedures were uneventful, without transient or permanent neurological deficits thanks to the preservation of the posterior cerebral artery. The endoscopic-enhanced SCTT approach provides satisfactory exposure to the left temporo-mesial region. Its minimally invasive nature helps minimize the surgical risks related to vascular and white tract manipulation, which represent known limitations of open microsurgical as well as other approaches.

All pineal tumors expressing germ cell tumor markers are not necessarily germ cell tumors: histopathological and molecular study of a midline primary intracranial sarcoma DICER1-mutant.

Primary intracranial sarcoma DICER1-mutant is a rare and newly recognized tumor type introduced in the 2021 WHO Classification of Central Nervous System Tumors. It is defined as a spindle cell sarcoma dysplaying eosinophilic intracytoplasmic globules, myogenic differentiation, and DICER1 gene mutation, either somatic or germline. Most reported cases were hemispheric except one, recently described in the pineal region. Here, we report the case of a 12 year-old boy with a pineally located tumor. Despite midline location, poorly differenciated morphology and germ cell marker expression, the association of DICER1 and NF1 hotspot mutations and a specific DNA methylation signature finally lead to the diagnosis of primary intracranial sarcoma DICER1-mutant instead of germ cell tumor. Furthermore, our molecular exploratory results involved a pathway, which was not previously evidenced in those DICER1 mutated cerebral sarcoma that is the canonical Wnt signaling driving likely a part of oncogenesis in this newly described pineal entity.

Effect of an intraoperative periradicular application of platelet-rich fibrin (PRF) on residual post-surgical neuropathic pain after disc herniation surgery: study protocol for NeuroPRF, a randomized controlled trial.

BACKGROUND: The prevalence of post-surgical lumbar neuropathic radiculopathy is approximately 30%. Poor response to the recommended treatments for neuropathic pain, namely antidepressants and/or gabapentinoids, requires the development of new techniques to prevent chronic pain. One such well-tolerated technique is the administration of autologous plasma enriched in platelets and fibrin (PRF). This approach is largely used in regenerative medicine owing to the anti-inflammatory and analgesic properties of PRF. It could also be an interesting adjuvant to surgery, as it reduces neurogenic inflammation and promotes nerve recovery, thereby reducing the incidence of residual postoperative chronic pain. The aim of the present study is to evaluate the benefit of periradicular intraoperative application of PRF on the residual postsurgical neuropathic pain after disc herniation surgery. METHODS: A randomized, prospective, interventional, controlled, single-blind study with evaluation by a blind outcome assessor will be performed in Strasbourg University Hospital. We will compare a control group undergoing conventional surgery to an experimental group undergoing surgery and periradicular administration of PRF (30 patients in each arm). The primary outcome is the intensity of postoperative neuropathic radicular pain, measured by a visual analog scale (VAS) at 6 months post-surgery. The secondary outcomes are the characteristics of neuropathic pain (NPSI), the quality of life (SF-12 and PGIC), the presence of anxiety/depression symptoms (HAD), and the consumption of analgesics. We will also carry out transcriptomic analysis of a panel of pro- and anti-inflammatory cytokines in blood samples, before surgery and at 6 months follow-up. These gene expression results will be correlated with clinical data, in particular, with the apparition of postoperative neuropathic pain. DISCUSSION: This study is the first randomized controlled trial to assess the efficacy of PRF in the prevention of neuropathic pain following surgery for herniated disc. This study addresses not only a clinical question but will also provide information on the physiopathological mechanisms of neuropathic pain. TRIAL REGISTRATION: This study is registered at ClinicalTrials.gov: NCT05196503 , February 24, 2022.

Molecular Heterogeneity in BRAF-Mutant Gliomas: Diagnostic, Prognostic, and Therapeutic Implications.

Over the last few decades, deciphering the alteration of molecular pathways in brain tumors has led to impressive changes in diagnostic refinement. Among the molecular abnormalities triggering and/or driving gliomas, alterations in the MAPK pathway reign supreme in the pediatric population, as it is encountered in almost all low-grade pediatric gliomas. Activating abnormalities in the MAPK pathway are also present in both pediatric and adult high-grade gliomas. Across those alterations, BRAF p.V600E mutations seem to define homogeneous groups of tumors in terms of prognosis. The recent development of small molecules inhibiting this pathway retains the attention of neurooncologists on BRAF-altered tumors, as conventional therapies showed no significant effect, nor prolonged efficiency on the high-grade or low-grade unresectable forms. Nevertheless, tumoral heterogeneity and especially molecular alteration(s) associated with MAPK-pathway abnormalities are not fully understood with respect to how they might lead to the specific dismal prognosis of those gliomas and/or affect their response to targeted therapies. This review is an attempt to provide comprehensive information regarding molecular alterations related to the aggressiveness modulation in BRAF-mutated gliomas and the current knowledge on how to use those targeted therapies in such situations.

Pushing the boundaries of accuracy and reliability during stereotactic procedures: A prospective study on 526 biopsies comparing the frameless robotic and Image-Guided Surgery systems.

INTRODUCTION: A 12-year long, prospective, single center study was conducted, comparing two frameless systems for brain biopsies: ROSA robotic-assisted stereotaxy and BrainLab Varioguide image-guided stereotaxy (Image Guided Surgery, IGS). METHOD: All consecutive adult and pediatric patients undergoing frameless brain biopsies were included. Successfully achieving diagnosis was the primary endpoint, analysis of all periprocedural complications was the secondary endpoint, and the tertiary endpoint was the length of the procedure, with the aim of assessing of the learning curve for each operator over time. The results for the ROSA robot and the Varioguide system were compared and benchmarked to data from the literature. RESULTS: We performed 526 on 516 patients, 314 with the ROSA robot (Group A) and 212 with the IGS Varioguide (Group B). Histological diagnosis was achieved in 97.4% of cases in Group A, versus 93.3% in Group B (p < 0.05). No statistically significant difference was found for secondary and tertiary endpoints. The complication rate appeared similar between the 2 frameless systems, with a hemorrhagic complications rate of 3.5% in Group A and 4.7% in Group B. Permanent neurological deterioration was only recorded in 0.8% of cases from Group B. Mortality was recorded in 0.3% in Group A and 0.4% in Group B. CONCLUSION: This study provides evidence to confirm that robotic surgery lives up to its promises of increased safety, accuracy, and reliability.

A Laboratory Investigation on a Tailored Skin and Muscle Flap Variant for the Retrosigmoid Approach.

Introduction An anatomical study was conducted to test a modified C-shaped flap designed for patients undergoing a keyhole approach and/or minicraniotomy for retrosigmoid approach (KRSA). Materials and Methods Ten heads specimens were used. The surgical technique investigated was based on a 4-cm C-shaped skin incision with medial convexity (placed 8 cm laterally to the external occipital protuberance, with the lower edge terminating 1.5 to 2 cm above the mastoid tip), which followed by careful subperiosteal dissection and completed by reflecting and securing the skin flap layer anteriorly and the muscle flaps superiorly and inferiorly by stitches. Anatomical findings, including depth of surgical corridor till to the cerebellopontine cistern (CPC) as well as the sparing of neurovascular structures, were evaluated in every specimen. Results Twenty surgical approaches to CPC were conducted, resulting in a short working distance to the target (32 mm) without any need for a self-retaining retractor. In every specimen, the integrity of occipital muscles and cutaneous nerves was maintained, and a solid multilayer closure was always achieved. These data suggest that landmarks-based design of this C-shaped incision could be helpful in avoiding damages to the soft tissues encountered during KRSA. Conclusion This modified approach provides a wide surgical corridor to access the CPC while ensuring the minimal invasiveness of the standard S-shaped incision. Compared with the latter, it preserves better the integrity of the surrounding soft tissues and appears less likely to cause any iatrogenic injury to occipital muscles and cutaneous nerves.

Characterizing chaotic melodies in automatic music composition.

In this paper, we initially present an algorithm for automatic composition of melodies using chaotic dynamical systems. Afterward, we characterize chaotic music in a comprehensive way as comprising three perspectives: musical discrimination, dynamical influence on musical features, and musical perception. With respect to the first perspective, the coherence between generated chaotic melodies (continuous as well as discrete chaotic melodies) and a set of classical reference melodies is characterized by statistical descriptors and melodic measures. The significant differences among the three types of melodies are determined by discriminant analysis. Regarding the second perspective, the influence of dynamical features of chaotic attractors, e.g., Lyapunov exponent, Hurst coefficient, and correlation dimension, on melodic features is determined by canonical correlation analysis. The last perspective is related to perception of originality, complexity, and degree of melodiousness (Euler's gradus suavitatis) of chaotic and classical melodies by nonparametric statistical tests.

Hypoxia Inducible Factors' Signaling in Pediatric High-Grade Gliomas: Role, Modelization and Innovative Targeted Approaches.

The brain tumor microenvironment has recently become a major challenge in all pediatric cancers, but especially in brain tumors like high-grade gliomas. Hypoxia is one of the extrinsic tumor features that interacts with tumor cells, but also with the blood-brain barrier and all normal brain cells. It is the result of a dramatic proliferation and expansion of tumor cells that deprive the tissues of oxygen inflow. However, cancer cells, especially tumor stem cells, can endure extreme hypoxic conditions by rescheduling various genes' expression involved in cell proliferation, metabolism and angiogenesis and thus, promote tumor expansion, therapeutic resistance and metabolic adaptation. This cellular adaptation implies Hypoxia-Inducible Factors (HIF), namely HIF-1α and HIF-2α. In pediatric high-grade gliomas (pHGGs), several questions remained open on hypoxia-specific role in normal brain during gliomagenesis and pHGG progression, as well how to model it in preclinical studies and how it might be counteracted with targeted therapies. Therefore, this review aims to gather various data about this key extrinsic tumor factor in pHGGs.

Surgical preference regarding different materials for custom-made allograft cranioplasty in patients with calvarial defects: Results from an internal audit covering the last 20 years.

BACKGROUND: Secondary cranioplasty (CP) plays a key role in restoring cranial vault anatomy and normal brain function following decompressive craniectomy (DC). The scientific literature provides only fragmentary information regarding the best timing and material for CP, making a direct comparison of different materials difficult. OBJECT: To identify and report according to STROBE guidelines local trends in choice of materials for CP, complications rate and surgical outcomes. METHODS: We conducted an audit on secondary CP covering the last 20 years of surgical practice at our Institution. Custom-made CP used over the years were made of: porous hydroxyapatite (PHA), polymetylmethacrylate (PMMA), polyetheretherketone (PEEK), acrylic and titanium. The primary endpoint of this study was the incidence of postoperative complications, such as: implant infection, fracture and dislocation. Secondary endpoints were the followings: patients satisfaction with cosmetic result, rate of implant integration, and long-term neurological outcome. RESULTS: A total of 218 patients were included, given the predominance of PHA (Group A) or PMMA (Group B) CP, a direct comparison was made only between those two groups. Overall reoperation rate was 6.5% versus 28%; implants' osseointegration rate was of 69% versus 24%; satisfaction rate was 66% versus 44%, in Group A and B respectively. CONCLUSIONS: This single-centre study provides Level 3 evidence that PHA yields better outcomes than PMMA CP. Designing a management algorithm for planning and executing CP is difficult for clinical and organizational reasons; till a widespread consensus is reached, neurosurgeons with subspecialty interest in neurotrauma should favor pragmatism and patient safety over costs.

Contralateral sensorineural hearing loss after vestibular schwannoma surgery.

INTRODUCTION: Contralateral sensorineural hearing loss (CSNHL) after vestibular schwannoma (VS) is a severe complication, especially in those cases in which hearing preservation in the operated side was not possible. There are several theories that attempt to explain this issue, but there is no established guideline of treatment. MATERIAL AND METHODS: We report 4 patients treated in our institution who developed a severe CSNHL after surgery. RESULTS: Of the 185 cases of VS treated with surgery, 4 patients (2.2%) developed a CSNHL after VS surgery. After medical treatment, partial recovery of hearing occurred in one patient the other 3 patients presented a well-established severe SNHL. CONCLUSIONS: Established treatment guidelines do not exist, but the use of high doses of corticosteroids has been recommended and cochlear implant in cases with no recovery and complete hearing loss may be useful.

Intracranial Solitary Fibrous Tumors: A Heterogeneous Entity with an Uncertain Clinical Behavior.

BACKGROUND: Intracranial solitary fibrous tumors (ISFTs) are rare mesenchymal neoplasms originating in the meninges and characterized by very different biologic and clinical behaviors. Benign histotypes, such as hemangiopericytomas, are now considered a cellular phenotypic variant of this heterogeneous group of rare spindle-cell tumors. Owing to their rarity and resemblance to other, more common brain tumors, ISFTs are often poorly recognized and remain a diagnostic challenge. METHODS: We describe a surgical series of 29 patients treated for ISFTs confirmed histologically and through immunohistochemistry. We attempt to provide a focus on the natural history of these pathologies and the need for tailored management. RESULTS: This was a retrospective consecutive series of 29 patients with either solitary fibrous tumor (n = 14) or hemangiopericytoma (n = 15) over a 10-year period. Mean follow-up time was 37.71 months. Recurrence rate was 42.9% for solitary fibrous tumors versus 26.7% for hemangiopericytomas. STAT6 expression was 66.7% in hemangiopericytomas versus 42.9% in SFTs. CONCLUSIONS: Histopathology and immunohistochemical staining (characterized by positive expression of mainly STAT6 but also CD34, Bcl-2 protein, and vimentin) are key in diagnosis and management of ISFTs. Although ISFTs are still considered benign lesions with very rare aggressive evolution, their clinical behavior is largely unpredictable. This study highlights the importance of relying on immunohistochemistry for a thorough definition of the management strategy.

Hypoxic Environment and Paired Hierarchical 3D and 2D Models of Pediatric H3.3-Mutated Gliomas Recreate the Patient Tumor Complexity.

BACKGROUND: Pediatric high-grade gliomas (pHGGs) are facing a very dismal prognosis and representative pre-clinical models are needed for new treatment strategies. Here, we examined the relevance of collecting functional, genomic, and metabolomics data to validate patient-derived models in a hypoxic microenvironment. METHODS: From our biobank of pediatric brain tumor-derived models, we selected 11 pHGGs driven by the histone H3.3K28M mutation. We compared the features of four patient tumors to their paired cell lines and mouse xenografts using NGS (next generation sequencing), aCGH (array comparative genomic hybridization), RNA sequencing, WES (whole exome sequencing), immunocytochemistry, and HRMAS (high resolution magic angle spinning) spectroscopy. We developed a multicellular in vitro model of cell migration to mimic the brain hypoxic microenvironment. The live cell technology Incucyte© was used to assess drug responsiveness in variable oxygen conditions. RESULTS: The concurrent 2D and 3D cultures generated from the same tumor sample exhibited divergent but complementary features, recreating the patient intra-tumor complexity. Genomic and metabolomic data described the metabolic changes during pHGG progression and supported hypoxia as an important key to preserve the tumor metabolism in vitro and cell dissemination present in patients. The neurosphere features preserved tumor development and sensitivity to treatment. CONCLUSION: We proposed a novel multistep work for the development and validation of patient-derived models, considering the immature and differentiated content and the tumor microenvironment of pHGGs.

[Complications and sequelae in acoustic neuroma surgery]. / Complicaciones y secuelas en la cirugía de los neurinomas del acústico.

OBJECTIVE: To evaluate the complications and sequelae of acoustic neuroma surgery, according to tumour size. PATIENTS AND METHOD: A retrospective analysis of 120 patients who underwent microsurgical resection of vestibular schwannomas between November 1994 and September 2006 was undertaken. Tumour size, extent of removal, preservation of facial and cochlear nerves, complications, and sequelae were considered. The degree of hearing preservation after surgery was determined by the Gardner-Robertson classification. RESULTS: There were 39 small (<1.5 cm), 59 medium (1.5-3 cm), and 22 large tumours (>3 cm). Gross total resection was accomplished in 106 cases (88.3 %). The facial nerve was anatomically and functionally preserved in 103 cases on long-term follow-up (85.4 %). The cochlear nerve was functionally preserved (Gardner-Robertson class 1 and 2) in 54.4 % of the small tumours with useful preoperative hearing. Two patients died due to postoperative complications (mortality rate, 1.6 %), and 15 (12.5 %) developed a CSF leak. CONCLUSIONS: Despite the progress in the surgical treatment of acoustic neuromas, a considerable rate of complications and sequelae still remains. Therefore, there is a need to balance pros and cons of surgery in each patient according to the concurrent circumstances, as well as to consider other therapeutic strategies such as radiosurgery or a wait-and-see policy.

Characterization of the transcriptional and metabolic responses of pediatric high grade gliomas to mTOR-HIF-1α axis inhibition.

Pediatric high grade glioma (pHGGs), including sus-tentorial and diffuse intrinsic pontine gliomas, are known to have a very dismal prognosis. For instance, even an increased knowledge on molecular biology driving this brain tumor entity, there is no treatment able to cure those patients. Therefore, we were focusing on a translational pathway able to increase the cell resistance to treatment and to reprogram metabolically tumor cells, which are, then, adapting easily to a hypoxic microenvironment. To establish, the crucial role of the hypoxic pathways in pHGGs, we, first, assessed their protein and transcriptomic deregulations in a pediatric cohort of pHGGs and in pHGG's cell lines, cultured in both normoxic and hypoxic conditions. Secondly, based on the concept of a bi-therapy targeting in pHGGs mTORC1 (rapamycin) and HIF-1α (irinotecan), we hypothesized that the balanced expressions between RAS/ERK, PI3K/AKT and HIF-1α/HIF-2α/MYC proteins or genes may provide a modulation of the cell response to this double targeting. Finally, we could evidence three protein, genomic and metabolomic profiles of response to rapamycin combined with irinotecan. The pattern of highly sensitive cells to mTOR/HIF-1α targeting was linked to a MYC/ERK/HIF-1α over-expression and the cell resistance to a major hyper-expression of HIF-2α.

An Innovative Fluorescent Semi-quantitative Methylation-specific PCR Method for the Determination of MGMT Promoter Methylation is Reflecting Intra-tumor Heterogeneity.

High grade gliomas (HGG) are usually associated with a very dismal prognosis, which was moderately improving in the last decade with the introduction of the alkylating agent temozolomide in their treatment. The methylation status of MGMT (O6 methylguanine DNA-methyltransferase) promoter is one of the strongest predictive and prognostic factors for the patient chemoresponse. For instance, the molecular method of assessment for MGMT promoter status is not standardized. In this background, we developed a fluorescent capillary gel electrophoresis-based methylation specific-PCR. This technique allowed a semi-quantitative estimate of the relative ratio between methylated and unmethylated alleles. The efficacy and accuracy of the technique was assessed in a retrospective cohort of 178 newly diagnosed adult HGGs, who were homogeneously treated. First, we analyzed the impact on survival of different cut-off points in the MGMT promoter methylation and, to go further, we correlated these different rates to other well-known prognostic molecular factors involved in adult HGGs. This strategy allowed to validate our technique as a very sensitive technique (detection of a low methylation percentage, < 5%), which was feasible in fresh-frozen as well as in FFPE samples and had the propensity to detect intra-tumor heterogeneity. This technique identified a new sub-group of anaplastic oligodendrogliomas or oligoastrocytomas defined by a minor methylation and a worse outcome and, therefore, will help to substratify accurately into more homogeneous subgroups of methylated tumors.

Endoscopic treatment of choanal atresia.

INTRODUCTION: Choanal atresia (CA) is an infrequent congenital obliteration of the airway at the level of the posterior nasal aperture resulting in the absence of connection between the nasal cavity and the aerodigestive tract. We present our experience with an endoscopic technique for congenital CA without the use of intranasal stents. MATERIAL AND METHOD: We analysed a series of 10 patients with CA treated in our department from 2006 to 2012 through endoscopic surgery. We present a description of the sample and the surgical technique used. RESULTS: The sample consisted of 5 men and 5 women. Mean patient age was 8 years (range: 5 days-32 years). Fifty percent of patients were cases with re-stenosis requiring revision surgery. Bilateral presentation was 7 and unilateral was 3. All CA were mixed (bony-membranous). Fifty per cent of patients had an associated malformation. All patients underwent nasal endoscopic surgery without stenting. After a mean follow up of 27 months (range: 11-78 months), the success rate was 100%. No complications were observed. CONCLUSION: Transnasal endoscopic repair for both unilateral and bilateral CA without intranasal stenting was found to be a safe, expedient procedure that afforded minimal complications with a high success rate. Endoscopic endonasal surgery may be considered as the mainstay of treatment.