Early experience and perioperative risk of GammaTile for upfront brain metastases: Report from a prospective multicenter study.

Background: GammaTile (GT), a form of brachytherapy utilizing cesium-131 seeds in a bioresorbable collagen tile, has gained popularity for the treatment of recurrent intracranial tumors and more recently for newly diagnosed metastases. This study reports early experience utilizing GT in upfront brain metastases with a focus on clinical applications and perioperative safety. Methods: The STaRT Registry (NCT04427384) was queried for all patients receiving GT for upfront metastases from August 2021 to August 2023. Data regarding patient demographics, procedure details, and adverse events (AEs) were extracted and analyzed. Results: Twenty-eight patients, median age 65 years (range 28-81), with 30 treated metastases were reported from 6 institutions. Patients had 2.8 metastases on average (range 1-15) at the time of surgery; however, most patients had a single metastasis (60.7%). The mean diameter of treated metastases was 3.4 cm (range 1.5-4.7). A median of 4.0 tiles (range 1-10) were used per tumor. The median follow-up was 3.0 months (range 1.0-11.2) with 6 attributed AEs (21.4%), including 1 grade ≥ 3 (infection). In the immediate postoperative period (<14 days), 2 patients reported pain or headache, and 1 reported facial edema. One patient developed seizures on postoperative day 8 requiring medication. At 1-month follow-up, there was 1 superficial wound infection, in a previously colonized patient, requiring surgical intervention without explantation of tiles. At 3-month follow-up, 1 patient reported facial pain not requiring treatment. There were no symptomatic hematomas. Conclusions: GT demonstrates a favorable safety profile in upfront brain metastases with a 3.6% rate of serious AEs (grade ≥ 3) within 90 days of the procedure.

Rare presentations of glioblastoma multiforme in the septum pellucidum: illustrative case.

BACKGROUND: Glioblastoma multiforme (GBM), a high-grade primary brain tumor, presents a formidable challenge in neuro-oncology because of its aggressive nature, infiltrative growth, and limited response to treatment. The septum pellucidum represents an uncommon and unexpected location for GBM, adding complexity to the diagnosis and management of this rare intracranial malignancy. OBSERVATIONS: A 69-year-old male with a previous history of prostate carcinoma presented to an outside hospital with a 2-week history of a "trance-like state" and cognitive decline. Initial head computed tomography showed prominent ventricles without distinct mass lesions. Upon admission, magnetic resonance imaging demonstrated a mass within the inferior septum pellucidum extending to the third and both lateral ventricles. Biopsy findings indicated a GBM, World Health Organization central nervous system tumor grade 4, with immunopositivity for glial fibrillary acidic protein and a Ki-67 labeling index of 60%-70%. LESSONS: Identifying only 5 cases in more than 60 years of literature, this systematic review illustrates the diverse clinical presentations, diagnostic advancements, and management approaches for septum pellucidum GBM. https://thejns.org/doi/10.3171/CASE23770.

Understanding the Genomic Landscape of Glioblastoma: Opportunities for Targeted Therapies.

Glioblastoma (GBM) is categorized by the World Health Organization (WHO) as a grade 4 glioma and is a uniformly fatal tumor of the central nervous system. With the discovery of specific gene anomalies, GBM classification has been modified several times to provide better diagnostic and prognostic accuracy. Survival outcomes remain dismal despite the current therapeutic modalities, which include a combination of surgical resection, adjuvant chemotherapy, and radiotherapies, providing brief control of tumor progression. GBM remains aggressive and reoccurs primarily due to the presence of a unique population of untreatable glioblastoma stem cells (GSC). The presence of high mutation rates and a dysregulated transcriptional landscape increase GSC resistance to conventional chemotherapy and radiation therapy, contributing to poor outcomes seen in GBM patients. Accordingly, GSCs have emerged as targets of interest in new GBM treatment paradigms. Consequently, it is important to understand their distinct properties, such as GSC interactions with the hypoxic microenvironment, enhancing their growth. The epigenomic regulators and fundamental molecular components of the signaling pathways represent potential targets for GBM therapies. In this review, we aimed to describe the evolution of GBM classification and highlight the current therapeutic modalities, including gene and immunotherapies, and mammalian target of rapamycin (mTOR) inhibitors to target GBM. Furthermore, we explored the molecular pathway of GSCs and the ongoing investigation of circulating tumor cells (CTC), along with precision therapeutics, which aim to provide novel discoveries and effective treatments for GBM with improved survival.

Conservative management of spinal pathology with autologous conditioned serum: A systematic review of the literature.

BACKGROUND: Chronic inflammatory pain is associated with increased expression of interleukin (IL)-1, an inflammatory cytokine, and activity on its receptor (IL-1R). In response, the body produces IL-1R antagonist (IL-1Ra) to reduce this signaling. Autologous conditioned serum (ACS) is the only biologic therapy for spinal pathologies that enhances the action of endogenous IL-1Ra reserves to improve symptoms. This systematic review investigates the effectiveness of ACS in treating pain and disability caused by spinal pathologies. AIM: To evaluate the use of ACS as a conservative management option for spinal pathology. METHODS: A systematic review of PubMed/Medline was performed to identify studies investigating administration of ACS for treatment of any spinal pathology. RESULTS: Six articles were included, comprising 684 patients treated with epidural (n = 133) or transforaminal (n = 551) ACS injections. Patients had an average age of 54.0 years with slight female predominance (53.2%). The lumbar spine was most commonly treated, with 567 patients (82.9%) receiving injections for lumbar radiculopathy (n = 67), degenerative disc disease (DDD) (n = 372), or spinal stenosis (n = 128); cervical injections were performed in 109 patients (15.9%). Mean (SD) follow-up was 21.7 (4.8) weeks from first ACS injection. All studies investigating mechanical lumbar and lumbar or cervical radicular pain reported significant pain reduction at final follow-up compared to baseline. ACS achieved comparable or superior results to lumbar epidural steroid injections. Adverse events were reported in 21 patients (3.1%), with no serious adverse events. CONCLUSION: ACS injection is a safe and effective intervention for pain reduction in many spinal pathologies, including cervical and lumbar radiculopathies.

Central Nervous System Infections in Patients With Ventriculoperitoneal Shunts Admitted for Primary Abdominal Infections: A US Nationwide Cohort Analysis.

BACKGROUND AND OBJECTIVES: Although ventriculoperitoneal (VP) shunts are a common treatment for hydrocephalus, there are complication risks including infections. Late complications such as ventriculitis from ascending abdominal infections can have severe consequences. However, the incidence of central nervous system (CNS) infections in VP shunt patients with abdominal infections is not well understood. We aimed to determine the incidence of CNS infections in VP shunt patients admitted with abdominal infections. METHODS: Using the National Inpatient Sample, we studied patients from 2016 to 2019 to determine the incidence of CNS infections in VP shunt patients admitted with abdominal infections. Results were compared with VP shunt patients admitted for primary pneumonia. RESULTS: Among 725 VP shunt patients presenting with abdominal infections, 20 (2.8%) had CNS infections. Chronic obstructive pulmonary disease, hypertension, older age, and a smoking history were more common in patients with CNS infections and primary abdominal infection (P < .05). Patients who developed CNS infection had a significantly higher likelihood of both blood transfusion and coma but a lower likelihood of seizures. VP shunt patients with CNS infections were more likely to undergo shunt removal (odds ratio [OR] = 23.167, P < .001). 4.1% of VP shunt patients with primary abdominal infections died during admission. In a population of primary abdominal infection and pneumonia patients with VP shunts, a multivariate logistic regression analysis controlling for age, sex, and comorbidities identified abdominal infection as an independent risk factor for both CNS infection (OR = 51.208, P < .001) and inpatient death (OR = 3.417, P < .001). Among 6620 VP shunt patients admitted with primary pneumonia, only 5 (0.1%) had CNS infection compared with 20 (2.8%) in those with a primary abdominal infection (OR = 37.532, P < .001), and mortality was 1.6% vs 4.1% for those with a primary abdominal infection (P < .05). CONCLUSION: CNS infections in VP-shunted patients with abdominal infections are relatively rare but may lead to increased risks of death and other serious adverse outcomes.

Critical Care of Spinal Cord Injury.

PURPOSE OF REVIEW: Spinal cord injury (SCI) is a major cause of morbidity and mortality, posing a significant financial burden on patients and the healthcare system. While little can be done to reverse the primary mechanical insult, minimizing secondary injury due to ischemia and inflammation and avoiding complications that adversely affect neurologic outcome represent major goals of management. This article reviews important considerations in the acute critical care management of SCI to improve outcomes. RECENT FINDINGS: Neuroprotective agents, such as riluzole, may allow for improved neurologic recovery but require further investigation at this time. Various forms of neuromodulation, such as transcranial magnetic stimulation, are currently under investigation. Early decompression and stabilization of SCI is recommended within 24 h of injury when indicated. Spinal cord perfusion may be optimized with a mean arterial pressure goal from a lower limit of 75-80 to an upper limit of 90-95 mmHg for 3-7 days after injury. The use of corticosteroids remains controversial; however, initiation of a 24-h infusion of methylprednisolone 5.4 mg/kg/hour within 8 h of injury has been found to improve motor scores. Attentive pulmonary and urologic care along with early mobilization can reduce in-hospital complications.

Socioeconomic Disparities in Pediatric Traumatic Brain Injury Transfer Patterns: An Analysis of Area Deprivation Index and Clinical Outcomes.

BACKGROUND: Traumatic brain injury (TBI) poses a significant health burden, particularly among pediatric populations, leading to long-term cognitive, physical, and psychosocial impairments. Timely transfer to specialized trauma centers is crucial for optimal management, yet the influence of socioeconomic factors, such as the Area Deprivation Index (ADI), on transfer patterns remains understudied. METHODS: A retrospective study was conducted on pediatric TBI patients presenting to a Level I Pediatric Trauma Center between January 2012 and July 2023. Transfer status, distance, mode of transport, and clinical outcomes were analyzed in relation to ADI. Statistical analyses were performed using Student t-test and analysis of variance. RESULTS: Of 359 patients, 53.5% were transferred from outside hospitals, with higher ADI scores observed in transfer patients (P<0.01). Air transport was associated with greater distances traveled and higher ADI compared to ground ambulance (P<0.01). Despite similarities in injury severity, intensive care unit admission rates differed between transfer modes, with no significant impact on mortality. CONCLUSIONS: High ADI patients were more likely to be transferred, suggesting disparities in access to specialized care. Differences in transfer modes highlight the influence of socioeconomic factors on logistical aspects. While transfer did not independently impact outcomes, disparities in intensive care unit admission rates were observed, possibly influenced by injury severity. Integrating socioeconomic data into clinical decision-making processes can inform targeted interventions to optimize care delivery and improve outcomes for all pediatric TBI patients. Prospective, multicenter studies are warranted to further elucidate these relationships.

Application of Brain Injury Guidelines at a Pediatric Level 1 Trauma Center predicts reliability, safety, and improved resource utilization.

PURPOSE: Brain Injury Guidelines (BIG) have been established to guide management related to TBI in adults. Here, BIG criteria were applied to pediatric TBI patients to evaluate reliability, safety, and resource utilization. METHODS: A retrospective study was performed on all pediatric TBI patients aged 18 years or younger from January 2012 to July 2023 at a Level 1 Pediatric Trauma Center. The severity of TBI (BIG 1/2/3) was rated by review of initial cranial imaging by two independent observers. Inter-observer reliability was assessed. Predictions based on BIG criteria regarding repeat cranial imaging, ICU admission, and neurosurgical consultation were compared with observations from the cohort. Outcome data was collected, including neurosurgical intervention and mortality rate. RESULTS: Three hundred fifty-nine patients were included with mean age of 5.3 years. Injury severity included 44 BIG 1 (12.2%), 170 BIG 2 (47.4%), and 145 BIG 3 injuries (40.4%). Inter-rater reliability was 96.4%. Neurosurgical consultation was obtained in all patients, though only predicted by guidelines in 40.4%. Repeat imaging was obtained in 166 BIG 1/2 patients, with an average of 1.3 CT scans and 0.8 MRIs/rapid MRIs per patient. ICU was utilized in 104 (77.6%) patients not recommended per BIG criteria. Ultimately, 37 patients, all BIG 3, required neurosurgical intervention; no neurosurgical interventions were required in those classified as BIG 1/2. CONCLUSIONS: BIG criteria can be applied to pediatric TBI with high inter-observer reliability and without formal neurosurgical training. Retrospective application of BIG predicted fewer imaging studies, ICU admissions, and neurosurgical consults without overlooking patients requiring neurosurgical intervention.

Evaluation of the Safety of Liberalized Systolic Blood Pressure Goals in the Postoperative Period After Intracranial Tumor Resection.

BACKGROUND AND OBJECTIVES: Postoperative intracranial hemorrhage (POH) is a serious neurosurgical complication occurring in approximately 1.4% of patients after intracranial tumor resection. The convention across the United States is to maintain an immediate postoperative systolic blood pressure (SBP) of < 140 mm Hg to minimize this risk; however, this SBP goal lacks support in the literature despite widespread adoption. This study aims to investigate the safety of SBP liberalization to 160 mm Hg in the immediate postoperative setting after intracranial tumor resection. METHODS: A retrospective review was conducted on consecutive patients, aged 18 to 75 years, undergoing craniotomy for intracranial tumor resection from October 2020 until June 2023. Data were gathered from the electronic medical record per Institutional Review Board guidelines regarding demographics, operative details, perioperative vital signs, resource utilization, and complications. Pharmaceutical prices and insurance charges were approximated from costs provided by the institution's pharmacy. POH was defined as symptomatic hemorrhage within 48 hours requiring intervention. RESULTS: The study included 147 patients, with 104 in the liberalized cohort (SBP <160 mm Hg) and 43 in the standard cohort (SBP <140 mm Hg). The average age was 54.5 ± 14.9 years and 57.6 ± 10.6 years in the liberalized and standard groups, respectively (P = .23). Intensive care unit and hospital length of stay were not significantly different between groups. The liberalized group used $81.88 ± $280.19 (95% CI $53.01-$110.75) on as-needed antihypertensive medications vs $108.39 ± $215.91 (95% CI $75.96-$140.82) in the standard (P = .29), with significantly lower labetalol (P = .04). There was no POH in either cohort. CONCLUSION: Liberalization of SBP goals to <160 mm Hg appears safe in the immediate postoperative period after craniotomy for tumor resection without an increased POH risk. Liberalized SBP parameters may allow reduced antihypertensive medication usage, thereby avoiding excess hospital cost and medication side effects.

Discrete Mechanistic Target of Rapamycin Signaling Pathways, Stem Cells, and Therapeutic Targets.

The mechanistic target of rapamycin (mTOR) is a serine/threonine kinase that functions via its discrete binding partners to form two multiprotein complexes, mTOR complex 1 and 2 (mTORC1 and mTORC2). Rapamycin-sensitive mTORC1, which regulates protein synthesis and cell growth, is tightly controlled by PI3K/Akt and is nutrient-/growth factor-sensitive. In the brain, mTORC1 is also sensitive to neurotransmitter signaling. mTORC2, which is modulated by growth factor signaling, is associated with ribosomes and is insensitive to rapamycin. mTOR regulates stem cell and cancer stem cell characteristics. Aberrant Akt/mTOR activation is involved in multistep tumorigenesis in a variety of cancers, thereby suggesting that the inhibition of mTOR may have therapeutic potential. Rapamycin and its analogues, known as rapalogues, suppress mTOR activity through an allosteric mechanism that only suppresses mTORC1, albeit incompletely. ATP-catalytic binding site inhibitors are designed to inhibit both complexes. This review describes the regulation of mTOR and the targeting of its complexes in the treatment of cancers, such as glioblastoma, and their stem cells.

Brain Metastases Are Regulated by Immuno-inflammatory Signaling Pathways Governed by STAT3, MAPK and Tumor Suppressor p53 Status: Possible Therapeutic Targets.

BACKGROUND/AIM: Brain metastasis (BM) is a complex multi-step process involving various immune checkpoint proteins. Mitogen-activated protein kinase (MAPK), extracellular signal-regulated kinases 1/2 (ERK1/2), and signal transducer and activator of transcription 3 (STAT3) are implicated in tumorigenesis and are critical upstream regulators of Programmed Death Ligand 1 (PD-L1), an immunotherapy target. Tumor suppressor p53, dysregulated in cancers, regulates STAT3 and ERK1/2 signaling. This study examined the roles of STAT3, MAPK and p53 status in BM initiation and maintenance. MATERIALS AND METHODS: Twenty-six BM, with various primary malignancies, were used (IRB-approved) to determine mutant p53 (p53mt), pSTAT3Tyr705, pERK1/2Thr202/Tyr204, and PD-L1 expression using immunohistochemistry. cDNA microarray was used for gene expression analysis. Brain-metastatic breast cancer cells (MDA-MB-231) were treated with STAT3 (NSC74859) or MAPK/ERK1/2 (U0126) inhibitors in regular or astrocytic media. ERK1/2 pathway was assessed using western blotting, and cell proliferation and migration were determined using MTT and scratch-wound assays, respectively. RESULTS: pSTAT3Tyr705 and pERK1/2Thr202/Tyr204 were expressed at tumor margins, whereas p53mt and PD-L1 were uniformly expressed, with significant overlap between expression of these proteins. Gene expression analysis identified alterations in 18 p53- and 32 STAT3- or MAPK-associated genes contributing to dysregulated immune responses and cell cycle regulation. U0126 and NSC74859 reduced pERK1/2Thr202/Tyr204 expression. Cell proliferation decreased following each treatment (p≤0.01). Migration stagnated following U0126 treatment in astrocytic media (p≤0.01). CONCLUSION: Activation of STAT3 and ERK1/2 promotes BM and provides compelling evidence for use of STAT3, ERK1/2 and p53 status as potential immunotherapeutic targets in BM.

Synthesis and biological evaluation of largazole zinc-binding group analogs.

Histone acetylation is an extensively investigated post-translational modification that plays an important role as an epigenetic regulator. It is controlled by histone acetyl transferases (HATs) and histone deacetylases (HDACs). The overexpression of HDACs and consequent hypoacetylation of histones have been observed in a variety of different diseases, leading to a recent focus of HDACs as attractive drug targets. The natural product largazole is one of the most potent natural HDAC inhibitors discovered so far and a number of largazole analogs have been prepared to define structural requirements for its HDAC inhibitory activity. However, previous structure-activity relationship studies have heavily investigated the macrocycle region of largazole, while there have been only limited efforts to probe the effect of various zinc-binding groups (ZBGs) on HDAC inhibition. Herein, we prepared a series of largazole analogs with various ZBGs and evaluated their HDAC inhibition and cytotoxicity. While none of the analogs tested were as potent or selective as largazole, the Zn2+-binding affinity of each ZBG correlated with HDAC inhibition and cytotoxicity. We expect that our findings will aid in building a deeper understanding of the role of ZBGs in HDAC inhibition as well as provide an important basis for the future development of new largazole analogs with non-thiol ZBGs as novel therapeutics for cancer.

Modulation of Activity Profiles for Largazole-Based HDAC Inhibitors through Alteration of Prodrug Properties.

Largazole is a potent and class I-selective histone deacetylase (HDAC) inhibitor purified from marine cyanobacteria and was demonstrated to possess antitumor activity. Largazole employs a unique prodrug strategy, via a thioester moiety, to liberate the bioactive species largazole thiol. Here we report alternate prodrug strategies to modulate the pharmacokinetic and pharmacodynamics profiles of new largazole-based compounds. The in vitro effects of largazole analogues on cancer cell proliferation and enzymatic activities of purified HDACs were comparable to the natural product. However, in vitro and in vivo histone hyperacetylation in HCT116 cells and implanted tumors, respectively, showed differences, particularly in the onset of action and oral bioavailability. These results indicate that, by employing a different approach to disguise the "warhead" moiety, the functional consequence of these prodrugs can be significantly modulated. Our data corroborate the role of the pharmacokinetic properties of this class of compounds to elicit the desired and timely functional response.

Evaluation of class I HDAC isoform selectivity of largazole analogues.

Largazole is a potent class I selective histone deacetylase (HDAC) inhibitor. The majority of largazole analogues to date have modified the thiazole-thiazoline and the warhead moiety. In order to elucidate class I-specific structure-activity relationships, a series of analogues with modifications in the valine or the linker region were prepared and evaluated for their class I isoform selectivity. The inhibition profile showed that the C2 position of largazole has an optimal steric requirement for efficient HDAC inhibition and that substitution of the trans-alkene in the linker with an aromatic group results in complete loss of activity. This data will aid the design of class I isoform selective HDAC inhibitors.