Filho, Leonardo de Macêdo

Abstract Background Glioblastoma (GBM) is the most common malignant primary brain tumor and is associated with a poor prognosis. Repurposed posaconazole (PCZ) has demonstrated efficacy in vitro by targeting key metabolic pathways. The aim of this study was to determine the neuropharmacological profile of PCZ in patients with GBM through a Phase 0 first-in-human trial for this indication (NCT04825275). Methods We conducted an open-label, non-randomized, parallel-arm trial in participants with primary or recurrent GBM. Patients in the treatment arm received oral PCZ for 7-10 days presurgically to achieve steady-state concentrations. Microdialysis catheters were implanted to measure interstitial drug levels. Postoperative tissue and fluid samples were analyzed to evaluate PCZ pharmacokinetics (mass spectrometry) and pharmacodynamics, including vascular density, apoptosis, and metabolite concentrations (lactate and pyruvate) compared to controls. Results The trial was closed early due to slow accrual, enrolling 2 participants in the PCZ arm and three in the control arm. No drug-related safety issues were observed. Although PCZ was undetectable in microdialysate fluid, it accumulated in tumor tissue, with concentrations showing an association with CD31-measured endothelial content. PCZ-treated tumors exhibited trends toward lower BCL2 expression indicative of increased apoptosis, and significantly lower pyruvate levels in the tumor periphery compared to controls. Plasma lactate levels in treated patients normalized to control levels over 24 h. Conclusions Despite limited accrual, this trial provides the first clinical evidence that oral PCZ accumulates in human GBM tissue and shows preliminary signals of metabolic modulation. These findings provide biological rationale warranting further clinical investigation, potentially utilizing direct tissue sampling rather than microdialysis.

Abstract Traumatic brain injury (TBI) can lead to chronic complications, including headache and facial hypersensitivity. Second-impact syndrome (SIS), occurring when a second TBI precedes recovery from an initial injury, often causes severe long-term symptoms. Neuroinflammation is implicated, but the comprehensive pathophysiology of SIS remains unclear. This study characterized neurological/behavioral outcomes, facial nociception, plasma inflammatory markers, and central nervous system (CNS) histopathology in rat models of SIS and single mild TBI. Female Wistar rats (n = 6/group) were assigned to naïve control, sham surgery, single impact (TBI), or double impact (SIS; intervals: 1h, 24h, 3d, 7d, 14d). Mild TBI was induced using a modified Marmarou weight-drop model. Assessments (facial mechanical sensitivity via von Frey, Neurological Severity Scale (NSS), Neurobehavioral Scale (NBS)) were performed pre-injury and on days 1,3,5,7 post-injury. Plasma IL-6 and TNF-α were measured by ELISA. Histopathology (H&E) assessed CNS inflammation. All impact groups developed transient facial mechanical allodynia and acute neurobehavioral deficits (impaired NSS/NBS at day 1). SIS groups, particularly with longer intervals (≥ 24h), exhibited more prolonged facial allodynia and significant neurological deficits compared to single TBI at specific timepoints. Plasma cytokines showed minimal changes. Histopathology revealed significantly elevated CNS inflammation in both TBI and SIS groups versus controls, with SIS groups (intervals 24h-14d) showing robust responses. Repeated TBI, especially with longer recovery intervals between injuries, results in more severe and prolonged facial allodynia, neurological deficits, and CNS neuroinflammation than a single mild TBI. These findings illuminate SIS pathophysiology and underscore the critical need for protection post-concussion.

OBJECTIVE Chordomas are rare tumors from notochordal remnants and account for 1%–4% of all primary bone malignancies, often arising from the clivus and sacrum. Despite margin-negative resection and postoperative radiotherapy, chordomas often recur. Further, immunohistochemical (IHC) markers have not been assessed as predictive of chordoma recurrence. The authors aimed to identify the IHC markers that are predictive of postoperative long-term (≥ 1 year) chordoma recurrence by using trained multiple tree-based machine learning (ML) algorithms. METHODS The authors reviewed the records of patients who had undergone treatment for clival and spinal chordomas between January 2017 and June 2021 across the Mayo Clinic enterprise (Minnesota, Florida, and Arizona). Demographics, type of treatment, histopathology, and other relevant clinical factors were abstracted from each patient record. Decision tree and random forest classifiers were trained and tested to predict long-term recurrence based on unseen data using an 80/20 split. RESULTS One hundred fifty-one patients diagnosed and treated for chordomas were identified: 58 chordomas of the clivus, 48 chordomas of the mobile spine, and 45 chordomas sacrococcygeal in origin. Patients diagnosed with cervical chordomas were the oldest among all groups (58 ± 14 years, p = 0.009). Most patients were male (n = 91, 60.3%) and White (n = 139, 92.1%). Most patients underwent resection with or without radiation therapy (n = 129, 85.4%). Subtotal resection followed by radiation therapy (n = 51, 33.8%) was the most common treatment modality, followed by gross-total resection then radiation therapy (n = 43, 28.5%). Multivariate analysis showed that S100 and pan-cytokeratin are more likely to predict the increase in the risk of postoperative recurrence (OR 3.67, 95% CI 1.09–12.42, p= 0.03; and OR 3.74, 95% CI 0.05–2.21, p = 0.02, respectively). In the decision tree analysis, a clinical follow-up > 1897 days was found in 37% of encounters and a 90% chance of being classified for recurrence (accuracy = 77%). Random forest analysis (n = 500 trees) showed that patient age, type of surgical treatment, location of tumor, S100, pan-cytokeratin, and EMA are the factors predicting long-term recurrence. CONCLUSIONS The IHC and clinicopathological variables combined with tree-based ML tools successfully demonstrated a high capacity to identify recurrence patterns with an accuracy of 77%. S100, pan-cytokeratin, and EMA were the IHC drivers of recurrence. This shows the power of ML algorithms in analyzing and predicting outcomes of rare conditions of a small sample size.

Background: The complex nature and heterogeneity involving pituitary surgery results have increased interest in machine learning (ML) applications for prediction of outcomes over the last decade. This study aims to systematically review the characteristics of ML models involving pituitary surgery outcome prediction and assess their reporting quality. Methods: We searched the PubMed, Scopus, and Web of Knowledge databases for publications on the use of ML to predict pituitary surgery outcomes. We used the Transparent Reporting of a multivariable prediction model for Individual Prognosis Or Diagnosis (TRIPOD) to assess report quality. Our search strategy was based on the terms “artificial intelligence”, “machine learning”, and “pituitary”. Results: 20 studies were included in this review. The principal models reported in each article were post-surgical endocrine outcomes (n = 10), tumor management (n = 3), and intra- and postoperative complications (n = 7). Overall, the included studies adhered to a median of 65% (IQR = 60–72%) of TRIPOD criteria, ranging from 43% to 83%. The median reported AUC was 0.84 (IQR = 0.80–0.91). The most popular algorithms were support vector machine (n = 5) and random forest (n = 5). Only two studies reported external validation and adherence to any reporting guideline. Calibration methods were not reported in 15 studies. No model achieved the phase of actual clinical applicability. Conclusion: Applications of ML in the prediction of pituitary outcomes are still nascent, as evidenced by the lack of any model validated for clinical practice. Although studies have demonstrated promising results, greater transparency in model development and reporting is needed to enable their use in clinical practice. Further adherence to reporting guidelines can help increase AI’s real-world utility and improve clinical practice.

Introduction. Pituitary adenomas have the potential to infiltrate the dura mater, skull, and the venous sinuses. Tumor extension into the cavernous sinus is often observed in pituitary adenomas and techniques and results of surgery in this region are vastly discussed in the literature. Infiltration of parasellar dura and its impact for pituitary surgery outcomes is significantly less studied but recent studies have suggested a role of endoscopic resection of the medial wall of the cavernous sinus, in selected cases. In this study, we discuss the techniques and outcomes of recently proposed techniques for selective resection of the medial wall of the cavernous sinus in endoscopic pituitary surgery. Methods. We performed a systematic review of the literature using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and protocol and a total of 4 studies with 106 patients that underwent an endoscopic approach for resection of pituitary tumors with resection of medial wall from cavernous sinus were included. Clinical and radiological data were extracted (sex, mean age, Knosp, prior surgery, tumor size and type, complication rate, and remission) and a meta-analysis using the RevMan 5.4 software was performed. Results. A total of 5 studies with 208 patients were included in this analysis. The mean age of the study population was 48.87 years (range 25–82) with a female/male ratio of 1:1.36. Majority of the patients had Knosp Grade 1 (n = 77, 37.02%) and Grade 2 (n = 53, 25.48%). The complication rate was 4.81% (n = 33/106) and the most common complication observed was a new transient CN dysfunction and diplopia. Early disease remission was observed in 94.69% of the patients (n = 196/207). The prevalence rate of CS medial wall invasion varied from 10.4 % up to 36.7%. This invasion rate increased in frequency with higher Knosp Grade. The forest plot of persistent disease vs. remission in this surgery approach showed a p < 0.00001 and heterogeneity (I^2 = 0%). Discussion. Techniques to achieve resection of the medial wall of the cavernous sinus via the endoscopic endonasal approach include the “anterior to posterior” technique (opening of the anterior wall of the cavernous sinus) and the “medial to lateral” technique (opening of the inferior intercavernous sinus and). Although potentially related with improved endocrinological outcomes, these are advanced surgical techniques and require extensive anatomical knowledge and extensive surgical experience. Furthermore, to avoid procedure complications, extensive study of the patient’s configuration of cavernous ICA, Doppler-guided intraoperative imaging, surgical navigation system, and blunt tip knives to dissect the ICA’s plane are recommended. Conclusion. Endoscopic resection of the medial wall of the cavernous sinus has been associated with reports of high rates of postoperative hormonal control in functioning pituitary adenomas. However, it represents a more complex approach and requires advanced experience in endoscopic skull base surgery. Additional studies addressing case selection and studies evaluating long term results of this technique are still necessary.

Abstract OBJECTIVE: The present study aimed to investigate postoperative swallowing disorders in patients diagnosed with CM I after decompression neurosurgery.METHODS: We selected 54 patients after decompression neurosurgery procedure for CM I from January 2017 to December 2019. We evaluated the speech-language assessment (CSLSA) 24-hours after post-surgical extubation. CSLSA observed aspects of posture, sensitivity, tone, and extra- and intraoral mobility of the FAO and visualizing the functions of breathing, phonation, articulation, chewing, and swallowing. We correlated the severity of the dysphagia and the presence of associated malformations in the CM I patients.RESULTS: In our study, 39 patients were female (mean age 41.3±47.1 years). Thirty-seven patients had associated malformations (p=0.0243): 21 patients syringomyelia, 11 basilar invagination and 5 syringomyelia and basilar invagination. Dysphagia was present in 37 of the cases (68.5%;p=0.0016). Dysphonia in 13 (24.1%;p=0.4785) and dysarthria in 3 (5.6%;p=0.0042). We observed in the CSLSA: orofacial hypomobility (29-patients–53.7%;p=0.0204), orofacial hyposensitivity (26-patients–48.1%; p=0.3023), reduced GAG reflex (24 patients–44.5%;p=0.1041), ineffective cough (19 patients–35.2%;p=0.0022), ineffective saliva swallowing (18-patients–33.3%;p=0.0396), dyspnea (13-patients–24.1%;p=0.4785), orofacial hypotonia (11-patients–20.4%;p=0.0004), altered cervical auscultation (10-patients–18.5%;p=0.0003), and dysarthria (3-patients–9.3%;p=0.0042). The presence of associated malformations significantly influenced the appearance of swallowing disorders, the severity of oropharyngeal dysphagia, the post-surgical complications (17-patients–31.5%;p<0.001), and the clinical outcomes (p=0.0029) of patients with CM type I. CONCLUSION: Decompressive neurosurgery for CM I had low rates of post-surgical complications overall. However, there was a high incidence of dysphagia. The presence of associated malformations is related with poorer prognosis and greater severity of oropharyngeal dysphagia in patients with CM I.