Analysis of neurosurgery resident research activity in the United States.

OBJECTIVE: Evaluation of the demographic and academic characteristics of current neurosurgery residents may provide prospective students with insight into factors that affect research output. Therefore, this study aimed to evaluate the research output among neurosurgery residents. METHODS: US neurosurgery residency programs were abstracted from the American Association of Neurological Surgeons website. Demographic data on 1690 current residents across 119 programs were collected using publicly available institutional websites, Doximity, and LinkedIn. The h-index of each resident was recorded using Scopus and exported into the NIH iCite tool to determine the weighted relative citation ratio (w-RCR) and mean relative citation ratio (m-RCR). The total number of publications, h-index, and w-RCR were used as a proxy for research output, while m-RCR was used to measure research impact. One-way ANOVA and Kruskal-Wallis H-tests were used to assess the statistical significance of relationships between demographic data and measures of research activity. RESULTS: A total of 1690 residents (25.4% female), representing 119 programs, were evaluated. Neurosurgery residents had an average of 17 publications, h-index of 5.5, m-RCR of 1.4, and w-RCR of 16.9, with an upward trend of research activity by postgraduate year (PGY) class. Male residents on average had a greater total number of publications (p < 0.001), higher h-index (p < 0.001), and higher w-RCR (p = 0.002) compared with their female peers. Significant differences in research activity were also observed by degree (Doctor of Medicine [MD], Doctor of Osteopathy [DO], or other), where those with MD and other degrees had higher metrics than those with DO degrees. International medical graduates (IMGs) also had higher research output than American medical graduates (AMGs) (p < 0.001). Differences in all measures of research activity except impact were also observed in research activity when pre-residency medical school ranks were compared. CONCLUSIONS: The authors observed overall high research activity among neurosurgery residents. Factors such as gender, degree, PGY, IMG/AMG status, and medical school rank may therefore be related to the success of matching within neurological surgery. Although large disparities in gender representation have been identified in neurosurgery, newer classes are trending toward shrinking the gap. These data may be used by prospective residents to gauge changes and progress occurring in the neurosurgery match.

Endoluminal Sigmoid Sinus Occlusion During Jugular Foramen Tumor Surgery: Novel Technique, Operative Nuances, and Clinical Experience With 33 Patients.

BACKGROUND AND IMPORTANCE: Surgery of jugular foramen tumors (JFTs) often requires vascular control by means of ligating the internal jugular vein and sigmoid sinus (SS) to allow intrabulbar access. Occlusion of the SS traditionally involves presigmoid and retrosigmoid durotomies allowing introduction of ligature devices, predisposing to cerebrospinal fluid (CSF) leakage and pseudomeningoceles. We describe a simple and novel endoluminal sigmoid sinus occlusion (ESSO) technique with Gelfoam that is entirely extradural. CLINICAL PRESENTATION: An extended anterolateral infralabyrinthine approach with ESSO was performed in 33 patients with JFTs. After ligating the internal jugular vein, the SS is opened and Gelfoam is placed endoluminally into the proximal SS. Care is taken to avoid occlusion of the venous outflow of the vein of Labbe to avoid temporal lobe venous infarction. Hemostatic gelatin matrix is injected distally to stop venous backflow from the inferior petrosal sinus. The jugular venous system is isolated, and the outer jugular wall can be opened to expose the JFT for resection. There were no complications of temporal lobe venous infarction or postoperative hematoma observed. Four patients with intradural tumor extension developed pseudomeningoceles. For patients with purely extradural JFTs, none developed postoperative incisional CSF leaks and one had pseudomeningocele. CONCLUSION: This ESSO technique is fast and effective, permitting occlusion of the SS during JFT surgery. It has the advantage of being entirely extradural, avoiding durotomy which can result in postoperative CSF leak. It is important to keep the Gelfoam distal to the transverse-sigmoid junction to avoid occlusion of the vein of Labbe inlet and temporal lobe venous infarction.

Glucose-driven histone lactylation promotes the immunosuppressive activity of monocyte-derived macrophages in glioblastoma.

Immunosuppressive macrophages restrict anti-cancer immunity in glioblastoma (GBM). Here, we studied the contribution of microglia (MGs) and monocyte-derived macrophages (MDMs) to immunosuppression and mechanisms underlying their regulatory function. MDMs outnumbered MGs at late tumor stages and suppressed T cell activity. Molecular and functional analysis identified a population of glycolytic MDM expressing GLUT1 with potent immunosuppressive activity. GBM-derived factors promoted high glycolysis, lactate, and interleukin-10 (IL-10) production in MDMs. Inhibition of glycolysis or lactate production in MDMs impaired IL-10 expression and T cell suppression. Mechanistically, intracellular lactate-driven histone lactylation promoted IL-10 expression, which was required to suppress T cell activity. GLUT1 expression on MDMs was induced downstream of tumor-derived factors that activated the PERK-ATF4 axis. PERK deletion in MDM abrogated histone lactylation, led to the accumulation of intratumoral T cells and tumor growth delay, and, in combination with immunotherapy, blocked GBM progression. Thus, PERK-driven glucose metabolism promotes MDM immunosuppressive activity via histone lactylation.

Profiling the molecular and clinical landscape of glioblastoma utilizing the Oncology Research Information Exchange Network brain cancer database.

Background: Glioblastoma exhibits aggressive growth and poor outcomes despite treatment, and its marked variability renders therapeutic design and prognostication challenging. The Oncology Research Information Exchange Network (ORIEN) database contains complementary clinical, genomic, and transcriptomic profiling of 206 glioblastoma patients, providing opportunities to identify novel associations between molecular features and clinical outcomes. Methods: Survival analyses were performed using the Logrank test, and clinical features were evaluated using Wilcoxon and chi-squared tests with q-values derived via Benjamini-Hochberg correction. Mutational analyses utilized sample-level enrichments from whole exome sequencing data, and statistical tests were performed using the one-sided Fisher Exact test with Benjamini-Hochberg correction. Transcriptomic analyses utilized a student's t-test with Benjamini-Hochberg correction. Expression fold changes were processed with Ingenuity Pathway Analysis to determine pathway-level alterations between groups. Results: Key findings include an association of MUC17, SYNE1, and TENM1 mutations with prolonged overall survival (OS); decreased OS associated with higher epithelial growth factor receptor (EGFR) mRNA expression, but not with EGFR amplification or mutation; a 14-transcript signature associated with OS > 2 years; and 2 transcripts associated with OS < 1 year. Conclusions: Herein, we report the first clinical, genomic, and transcriptomic analysis of ORIEN glioblastoma cases, incorporating sample reclassification under updated 2021 diagnostic criteria. These findings create multiple avenues for further investigation and reinforce the value of multi-institutional consortia such as ORIEN in deepening our knowledge of intractable diseases such as glioblastoma.

Microsurgical versus endovascular treatment of ethmoidal dural arteriovenous fistulas: systematic review and meta-analysis with a single-center case series.

OBJECTIVE: Ethmoidal dural arteriovenous fistulas (DAVFs) are often associated with cortical venous drainage (CVD) and a higher incidence of hemorrhage compared with DAVFs in other locations. They may be treated with open surgical disconnection or with endovascular treatment (EVT). In this systematic review and meta-analysis, the authors compare the outcomes of ethmoidal DAVFs treated with open microsurgery versus EVT and report four additional cases of ethmoidal DAVFs treated with open microsurgery in their institution. METHODS: A literature search of the PubMed and Scopus databases was conducted between December 2021 and May 2022 to identify relevant articles published between 1990 and 2021 using the PRISMA guidelines. References were reviewed and screened by two authors independently, and disagreements were resolved through consensus. Exclusion criteria included non-English-language studies, those with an incorrect study design, those reporting DAVFs in a nonethmoidal location, and studies whose outcomes were not stratified based on DAVF location. Inclusion criteria were any studies reporting on ethmoidal DAVFs treated by either microsurgery or EVT. A risk of bias assessment was performed using the Newcastle-Ottawa Scale. The authors performed a pooled proportional meta-analysis to compare patient outcomes. RESULTS: Twenty studies were included for analysis. Of 224 patients, 142 were treated with surgery, while 103 were treated with EVT. Seventy percent (148/210) of the patients were symptomatic at presentation, with hemorrhage being the most common presentation (48%). CVD was present in 98% of patients and venous ectasia in 61%. The rates of complete DAVF obliteration with surgery and EVT were 89% and 70%, respectively (95% CI -30% to -10%, p < 0.03). Twenty percent (21/103) of endovascularly treated fistulas required subsequent surgery. Procedure-related complications occurred in 10% of the surgical cases, compared with 13% of the EVT cases. The authors' case series included 4 patients with ethmoidal DAVFs treated surgically with complete obliteration, without any postoperative complications. CONCLUSIONS: The complete obliteration rates of ethmoidal DAVF appear to be higher and more definitive with microsurgical intervention than with EVT. While complication rates between the two procedures seem similar, patients treated with EVT may require further interventions for definitive treatment. The limitations of this study include its retrospective nature, the quality of studies included, and the continued evolving technologies of EVT. Future studies should focus on the association between venous drainage pattern and the proclivity toward venous ectasia or rate of hemorrhage at presentation.

Microsurgical anatomy of the olfactory filaments in the nasal mucosa.

OBJECTIVE: The aim of this study was to examine the distribution of olfactory filaments (OFs) in the nasal mucosa to facilitate preservation of olfactory function in endonasal approaches and preparation of a nasoseptal flap. METHODS: One formalin-fixed and 9 fresh cadaveric silicone-injected specimens with 20 total sides were studied to measure the distance of the OFs to the anatomical landmarks and compare the OF presence in the nasal septum mucosa (NSM) and ethmoidal mucosa (EM). RESULTS: The mean distance from the first to the last OF was 19.37 ± 2.16 mm in the NSM and 23.44 ± 5.42 mm in the EM. The NSM had a mean of 7.55 ± 1.31 OFs and the EM had 14.3 ± 1.78. Average OF lengths were measured at 6.44 ± 1.48 (range 3.75-12.40) mm in the NSM and 8.05 ± 1.76 (range 4.14-13.20) mm in the EM. The mean values of the EM measurements were compared with those of the NSM; the number of OFs, the distance between the first and last OF, the average OF length, and the number of OFs between anterior and posterior ethmoidal arteries in the NSM were significantly less (p < 0.05) than those in the EM. The distance between the first OF to the nasal bone on the NSM was greater than on the EM. CONCLUSIONS: Compared with the EM, the OFs are significantly fewer in number and smaller in size in the NSM. The uppermost edge of the nasoseptal flap incision in the NSM might be safer to start below 12 mm from the cribriform plate for OF protection.

The role of endoscopic endonasal salvage surgery in recurrent or residual craniopharyngioma after a transcranial approach: a systematic review.

BACKGROUND: The management of craniopharyngiomas is challenging due to their high rate of recurrence following resection. Excision of recurrent tumors poses further surgical challenges due to loss of arachnoidal planes and adherence to anatomical structures. The endoscopic endonasal approach (EEA) offers a favorable alternative to transcranial approaches for primary craniopharyngiomas. However, the safety and efficacy of EEA for recurrent tumors, specifically after a prior transcranial approach, needs further investigation. METHODS: We performed a systematic review using PubMed to develop a database of cases of recurrent craniopharyngiomas previously treated with a transcranial approach. RESULTS: Fifteen articles were included in this review with a total of 75 cases. There were 50 males and 25 females with a mean age of 38 years (range 2-80). One prior transcranial surgery was done in 80.0% of cases, while 8.0% had two and 12.0% had more than two prior surgeries. Radiotherapy after transcranial resection was given in 18 cases (24.0%). Following EEA, vision improved in 60.0% of cases, and vision worsened in 8.6% of the cases. Of cases, 64.4% had pre-existing anterior hypopituitarism, and 43.8% had diabetes insipidus prior to EEA. New anterior hypopituitarism and diabetes insipidus developed in 24.6% and 21.9% of cases, respectively following EEA. Gross total resection (GTR) was achieved in 64.0%, subtotal resection in 32.0%, and partial resection in 4.0% revision EEA cases. GTR rate was higher in cases with no prior radiotherapy compared to cases with prior radiotherapy (72.0% vs 39.0%, p = 0.0372). The recurrence rate was 17.5% overall but was significantly lower at 10.0% following GTR (p = 0.0019). The average follow-up length was 41.2 months (range, 1-182 months). CONCLUSION: The EEA can be utilized for resection of recurrent or residual craniopharyngiomas previously managed by a transcranial approach.

Iatrogenic Pseudo-Duane Retraction Syndrome Following Orbitozygomatic Craniotomy.

Restrictive strabismus is a known complication of orbitozygomatic craniotomy. However, a pseudo-Duane syndrome has not been described following this procedure. The authors describe a 58-year-old woman who after craniotomy developed incomitant left exotropia with an adduction deficit; the globe retracted and palpebral fissure narrowed with attempted ocular adduction. [J Pediatr Ophthalmol Strabismus. 2024;61(1):e7-e10.].

Jugular Foramen Tumors: Surgical Strategies and Representative Cases.

(1) Background: Jugular foramen tumors are complex lesions due to their relationship with critical neurovascular structures within the skull base. It is necessary to have a deep knowledge of the anatomy of the jugular foramen and its surroundings to understand each type of tumor growth pattern and how it is related to the surrounding neurovascular structures. This scope aims to provide a guide with the primary surgical approaches to the jugular foramen and familiarize the neurosurgeons with the anatomy of the region. (2) Methods and (3) Results: A comprehensive description of the surgical approaches to jugular foramen tumors is summarized and representative cases for each tumor type is showcased. (4) Conclusions: Each case should be carefully assessed to find the most suitable approach for the patient, allowing the surgeon to remove the tumor with minimal neurovascular damage. The combined transmastoid retro- and infralabyrinthine transjugular transcondylar transtubercular high cervical approach can be performed in a stepwise fashion for the resection of complex jugular foramen tumors.

Clinical outcomes of melanoma brain metastases treated with nivolumab and ipilimumab alone versus nivolumab and ipilimumab with stereotactic radiosurgery.

PURPOSE: Upfront dual checkpoint blockade with immune checkpoint inhibitors (ICI) has demonstrated efficacy for treating melanoma brain metastases (MBM) in asymptomatic patients. Whether the combination of stereotactic radiosurgery (SRS) with dual checkpoint blockade improves outcomes over dual-checkpoint blockade alone is unknown. We evaluated clinical outcomes of patients with MBM receiving ICI with nivolumab and ipilimumab, with and without SRS. METHODS: 49 patients with 158 MBM receiving nivolumab and ipilimumab for untreated MBM between 2015 and 2022 were identified at our institution. Patient and tumor characteristics including age, Karnofsky Performance Status (KPS), presence of symptoms, cancer history, MBM burden, and therapy course were recorded. Outcomes measured from initiation of MBM-directed therapy included overall survival (OS), local control (LC), and distant intracranial control (DIC). Time-to-event analysis was conducted with the Kaplan-Meier method. RESULTS: 25 patients with 74 MBM received ICI alone, and 24 patients with 84 MBM received concurrent SRS. Median follow-up was 24 months. No differences in age (p = 0.96), KPS (p = 0.85), presence of symptoms (p = 0.79), prior MBM (p = 0.68), prior MBM-directed surgery (p = 0.96) or SRS (p = 0.68), MBM size (p = 0.67), or MBM number (p = 0.94) were seen. There was a higher rate of nivolumab and ipilimumab course completion in the SRS group (54% vs. 24%; p = 0.029). The SRS group received prior immunotherapy more often than the ICI alone group (54% vs. 8.0%; p < 0.001). There was no significant difference in 1-year OS (72% vs. 71%, p = 0.20) and DIC (63% v 51%, p = 0.26) between groups. The SRS group had higher 1-year LC (92% vs. 64%; p = 0.002). On multivariate analysis, LC was improved with combination therapy (AHR 0.38, p = 0.01). CONCLUSION: In our analysis, patients who received SRS with nivolumab and ipilimumab had superior LC without increased risk of toxicity or compromised immunotherapy treatment completion despite the SRS cohort having higher rates of prior immunotherapy. Further prospective study of combination nivolumab and ipilimumab with SRS is warranted.

Development of a "Geo-Tagged" tumor sample registry: intra-operative linkage of sample location to imaging.

PURPOSE: There is a growing body of literature documenting glioma heterogeneity in terms of radiographic, histologic, molecular, and genetic characteristics. Incomplete spatial specification of intraoperative tumor samples may contribute to variability in the results of pathological and biological investigations. We have developed a system, termed geo-tagging, for routine intraoperative linkage of each tumor sample to its location via neuronavigation. METHODS: This is a single-institution, IRB approved, prospective database of undergoing clinically indicated surgery. We evaluated relevant factors affecting data collection by this registry, including tumor and surgical factors (e.g. tumor volume, location, grade and surgeon). RESULTS: Over a 2-year period, 487 patients underwent craniotomy for an intra-axial tumor. Of those, 214 underwent surgery for a newly diagnosed or recurrent glioma. There was significant variation in the average number of samples collected per registered case, with a range of samples from 2.53 to 4.75 per tumor type. Histology and grade impacted on sampling with a range of 2.0 samples per tumor in Grade four, IDH-WT gliomas to 4.5 samples in grade four, IDH-mutant gliomas. The range of cases with sampling per surgeon was 6 to 99 with a mean of 47.6 cases and there was a statistically significant differences between surgeons. Tumor grade did not have a statistically significant impact on number of samples per case. No significant correlation was found between the number of samples collected and enhancing tumor volume, EOR, or volume of tumor resected. CONCLUSION: We are using the results of this analysis to develop a prospective sample collection protocol.

Bilateral infraoptic origin of the anterior cerebral artery: illustrative case.

BACKGROUND: A bilateral infraoptic origin of the anterior cerebral arteries (ACAs) is a rare anatomical variant that can be encountered during anterior skull base surgery. The ACAs arise from the internal carotid artery (ICA) at the level of the ophthalmic artery and course medially, traveling inferior to the ipsilateral optic nerves. Herein, the authors discuss the different configurations of the anatomical variant, its prevalence, and hypotheses leading to the variable configuration of this anomaly. OBSERVATIONS: A 67-year-old woman presented with worsening dizziness over a week-long period and was found to have a large left sphenocavernous meningioma with optic, cavernous, and suprasellar extension. The tumor incorporated the left supraclinoid ICA and its branches. She underwent a left modified orbitozygomatic craniotomy for tumor resection. Early identification of the aberrant ACA anatomy was crucial in avoiding vascular injury. LESSONS: While this variant is typically encountered during the treatment of vascular pathologies-namely, intracranial aneurysms-its existence should be kept in mind during the treatment of any anterior skull base pathology. Failure to account for the presence of this variant may lead to potential intraoperative complications.

Stereotactic radiosurgery and anti-PD-1 + CTLA-4 therapy, anti-PD-1 therapy, anti-CTLA-4 therapy, BRAF/MEK inhibitors, BRAF inhibitors, or conventional chemotherapy for the management of melanoma brain metastases.

BACKGROUND: Immunotherapy and targeted BRAF/MEK inhibitors (i) have revolutionised the systemic management of advanced melanoma. Given the role of stereotactic radiosurgery (SRS) in the local management of brain metastases, we sought to evaluate clinical outcomes in patients with melanoma brain metastases (MBM) treated with SRS and various systemic therapies. METHODS: Patients were included if MBM were diagnosed and treated with SRS within 3 months of receiving anti-PD-1+CTLA-4 therapy, anti-PD-1 therapy, anti-CTLA-4 therapy, BRAF/MEK-i, BRAF-i, or conventional chemotherapy. Comparisons between groups were made for overall survival (OS), distant MBM control, local MBM, systemic progression-free survival (sPFS), and neurotoxicity. RESULTS: In total, 257 patients with 1048 MBM treated over 368 SRS sessions between 2011 and 2020 were identified. On MVA, treatment with anti-PD1+anti-CTLA-4, anti-PD-1, and BRAF/MEK-i improved distant intracranial control over conventional chemotherapy. No significant differences were noted in local control (LC) between groups (p = 0.78). Kaplan-Meier OS at 12 months for anti-PD-1 + CTLA-4 therapy, anti-PD-1 therapy, anti-CTLA-4 therapy, BRAF/MEK-i, BRAF-i, and conventional chemotherapy was 68%, 59%, 45%, 62%, 21%, and 15%, respectively (p = <0.0001). The sPFS rates at 12 months were 57%, 53%, 42%, 45%, 14%, and 6% (p = <0.0001). No significant differences were noted in rates of radiation necrosis (p = 0.93). CONCLUSIONS: This is among the largest series evaluating MBM treated with SRS and various systemic therapy regimens. Our analysis noted significant differences in OS, distant MBM control, and sPFS by systemic therapy. No differences in LC or radiation necrosis risk were noted.

5-aminolevulinic acid, fluorescein sodium, and indocyanine green for glioma margin detection: analysis of operating wide-field and confocal microscopy in glioma models of various grades.

Introduction: Surgical resection remains the first-line treatment for gliomas. Several fluorescent dyes are currently in use to augment intraoperative tumor visualization, but information on their comparative effectiveness is lacking. We performed systematic assessment of fluorescein sodium (FNa), 5-aminolevulinic acid (5-ALA)-induced protoporphyrin IX (PpIX), and indocyanine green (ICG) fluorescence in various glioma models using advanced fluorescence imaging techniques. Methods: Four glioma models were used: GL261 (high-grade model), GB3 (low-grade model), and an in utero electroporation model with and without red fluorescence protein (IUE +RFP and IUE -RFP, respectively) (intermediate-to-low-grade model). Animals underwent 5-ALA, FNa, and ICG injections and craniectomy. Brain tissue samples underwent fluorescent imaging using a wide-field operative microscope and a benchtop confocal microscope and were submitted for histologic analysis. Results: Our systematic analysis showed that wide-field imaging of highly malignant gliomas is equally efficient with 5-ALA, FNa, and ICG, although FNa is associated with more false-positive staining of the normal brain. In low-grade gliomas, wide-field imaging cannot detect ICG staining, can detect FNa in only 50% of specimens, and is not sensitive enough for PpIX detection. With confocal imaging of low-intermediate grade glioma models, PpIX outperformed FNa. Discussion: Overall, compared to wide-field imaging, confocal microscopy significantly improved diagnostic accuracy and was better at detecting low concentrations of PpIX and FNa, resulting in improved tumor delineation. Neither PpIX, FNa, nor ICG delineated all tumor boundaries in studied tumor models, which emphasizes the need for novel visualization technologies and molecular probes to guide glioma resection. Simultaneous administration of 5-ALA and FNa with use of cellular-resolution imaging modalities may provide additional information for margin detection and may facilitate maximal glioma resection.

Glioblastoma Stem Cell Targeting Peptide Isolated Through Phage Display Binds Cadherin 2.

Glioblastoma stem cells (GSCs) have unique properties of self-renewal and tumor initiation that make them potential therapeutic targets. Development of effective therapeutic strategies against GSCs requires both specificity of targeting and intracranial penetration through the blood-brain barrier. We have previously demonstrated the use of in vitro and in vivo phage display biopanning strategies to isolate glioblastoma targeting peptides. Here we selected a 7-amino acid peptide, AWEFYFP, which was independently isolated in both the in vitro and in vivo screens and demonstrated that it was able to target GSCs over differentiated glioma cells and non-neoplastic brain cells. When conjugated to Cyanine 5.5 and intravenously injected into mice with intracranially xenografted glioblastoma, the peptide localized to the site of the tumor, demonstrating intracranial tumor targeting specificity. Immunoprecipitation of the peptide with GSC proteins revealed Cadherin 2 as the glioblastoma cell surface receptor targeted by the peptides. Peptide targeting of Cadherin 2 on GSCs was confirmed through ELISA and in vitro binding analysis. Interrogation of glioblastoma databases demonstrated that Cadherin 2 expression correlated with tumor grade and survival. These results confirm that phage display can be used to isolate unique tumor-targeting peptides specific for glioblastoma. Furthermore, analysis of these cell specific peptides can lead to the discovery of cell specific receptor targets that may serve as the focus of future theragnostic tumor-homing modalities for the development of precision strategies for the treatment and diagnosis of glioblastomas.

Clinical consensus guideline on the management of phaeochromocytoma and paraganglioma in patients harbouring germline SDHD pathogenic variants.

Patients with germline SDHD pathogenic variants (encoding succinate dehydrogenase subunit D; ie, paraganglioma 1 syndrome) are predominantly affected by head and neck paragangliomas, which, in almost 20% of patients, might coexist with paragangliomas arising from other locations (eg, adrenal medulla, para-aortic, cardiac or thoracic, and pelvic). Given the higher risk of tumour multifocality and bilaterality for phaeochromocytomas and paragangliomas (PPGLs) because of SDHD pathogenic variants than for their sporadic and other genotypic counterparts, the management of patients with SDHD PPGLs is clinically complex in terms of imaging, treatment, and management options. Furthermore, locally aggressive disease can be discovered at a young age or late in the disease course, which presents challenges in balancing surgical intervention with various medical and radiotherapeutic approaches. The axiom-first, do no harm-should always be considered and an initial period of observation (ie, watchful waiting) is often appropriate to characterise tumour behaviour in patients with these pathogenic variants. These patients should be referred to specialised high-volume medical centres. This consensus guideline aims to help physicians with the clinical decision-making process when caring for patients with SDHD PPGLs.

Use of phage display biopanning as a tool to design CAR-T cells against glioma stem cells.

Background: Glioblastoma (GBM) is both the most common and aggressive type of primary brain tumor, associated with high mortality rates and resistance to conventional therapy. Despite recent advancements in knowledge and molecular profiling, recurrence of GBM is nearly inevitable. This recurrence has been attributed to the presence of glioma stem cells (GSCs), a small fraction of cells resistant to standard-of-care treatments and capable of self-renewal and tumor initiation. Therefore, targeting these cancer stem cells will allow for the development of more effective therapeutic strategies against GBM. We have previously identified several 7-amino acid length peptides which specifically target GSCs through in vitro and in vivo phage display biopanning. Methods and results: We have combined two of these peptides to create a dual peptide construct (EV), and demonstrated its ability to bind GSCs in vitro and target intracranial GBM in mouse models. A peptide pull-down performed with peptide EV followed by mass spectrometry determined N-cadherin as the binding partner of the peptide, which was validated by enzyme-linked immunosorbent assay and surface plasmon resonance. To develop cytotoxic cellular products aimed at specifically targeting GSCs, chimeric antigen receptors (CARs) were engineered containing the peptide EV in place of the single-chain variable fragment (scFv) as the antigen-binding domain. EV CAR-transduced T cells demonstrated specific reactivity towards GSCs by production of interferon-gamma when exposed to GSCs, in addition to the induction of GSC-specific apoptosis as illustrated by Annexin-V staining. Conclusion: These results exemplify the use of phage display biopanning for the isolation of GSC-targeting peptides, and their potential application in the development of novel cytotoxic therapies for GBM.

Comprehensive microsurgical anatomy of the middle cranial fossa: Part I-Osseous and meningeal anatomy.

The middle cranial fossa is one of the most complex regions in neurosurgery and otolaryngology-in fact, the practice of skull base surgery originated from the need to treat pathologies in this region. Additionally, great neurosurgeons of our present and past are remembered for their unique methods of treating diseases in the middle fossa. The following article reviews the surgical anatomy of the middle fossa. The review is divided into the anatomy of the bones, dura, vasculature, and nerves-in two parts. Emphasis is paid to their neurosurgical significance and applications in skull base surgery. Part I focuses on the bony and dural anatomy.

Comprehensive microsurgical anatomy of the middle cranial fossa: Part II-neurovascular anatomy.

In order to master the surgical approaches to the middle cranial fossa, the surgeon needs to understand the relevant bony anatomy. However, she/he also needs to have a clear and sound understanding of the neural and vascular anatomy because, oftentimes, the osseous anatomy (except for the optic apparatus) should be removed to expose and protect the neurovascular anatomy. This is the second of a two-part article discussing the neurovascular anatomy of the middle cranial fossa. A brief discussion of the surgical approaches follows.

Loss of CEACAM1 in endothelial cells causes hepatic fibrosis.

OBJECTIVES: Hepatocytic CEACAM1 plays a critical role in NASH pathogenesis, as bolstered by the development of insulin resistance, visceral obesity, steatohepatitis and fibrosis in mice with global Ceacam1 (Cc1) deletion. In contrast, VECadCre+Cc1fl/fl mice with endothelial loss of Cc1 manifested insulin sensitivity with no visceral obesity despite elevated NF-κB signaling and increased systemic inflammation. We herein investigated whether VECadCre+Cc1fl/fl male mice develop hepatic fibrosis and whether this is mediated by increased production of endothelin1 (ET1), a transcriptional NF-κB target. METHODS: VECadCre+Et1.Cc1fl/fl mice with combined endothelial loss of Cc1/Et1 genes were generated. Histological and immunohistochemical analyses were conducted on their livers and on liver tissue biopsies from adult patients undergoing bariatric surgery or from patients with NASH diagnosis receiving liver transplant. RESULTS: Hepatic fibrosis and inflammatory infiltration developed in VECadCre+Cc1fl/fl liver parenchyma. This was preceded by increased ET1 production and reversed with combined endothelial loss of Et1. Conditioned media from VECadCre+Cc1fl/fl, but not VECadCre+Et1.Cc1fl/fl primary liver endothelial cells activated wild-type hepatic stellate cells; a process inhibited by bosentan, an ETAR/ETBR dual antagonist. Consistently, immunohistochemical analysis of liver biopsies from patients with NASH showed a decline in endothelial CEACAM1 in parallel with increased plasma endothelin1 levels and progression of hepatic fibrosis stage. CONCLUSIONS: The data demonstrated that endothelial CEACAM1 plays a key role in preventing hepatic fibrogenesis by reducing autocrine endothelin1 production.