Gamma knife radiosurgery for clival metastasis: case series and systematic review.

PURPOSE: Clival metastatic cancer is rare and has limited literature to guide management. We describe management of clival metastasis with Gamma Knife radiosurgery (GKRS). We augment our findings with a systematic review of all forms of radiation therapy for clival metastasis. METHODS: Records of 14 patients with clival metastasis who underwent GKRS at the University of Pittsburgh Medical Center from 2002 to 2023 were reviewed. Treatment parameters and clinical outcomes were assessed. A systematic review was conducted using evidence-based guidelines. RESULTS: The average age was 61 years with male predominance (n = 10) and average follow-up of 12.4 months. The most common primary cancers were prostate (n = 3) and lung (n = 3). The average time from cancer diagnosis to clival metastasis was 34 months. The most common presenting symptoms were headache (n = 9) and diplopia (n = 7). Five patients presented with abducens nerve palsies, and two presented with oculomotor nerve palsies. The median tumor volume was 9.3 cc, and the median margin dose was 15 Gy. Eleven patients achieved tumor control after one procedure, and three with progression obtained tumor control after repeat GKRS. One patient recovered abducens nerve function. The median survival from cancer diagnosis and GKRS were 49.7 and 15.3 months, respectively. The cause of death was progression of systemic cancer in six patients, clival metastasis in one, and unknown in four. The systematic review included 31 studies with heterogeneous descriptions of treatment and outcomes. CONCLUSION: Clival metastasis is rare and associated with poor prognosis. GKRS is a safe, effective treatment for clival metastasis.

Magnetic Hyperthermia Therapy for High-Grade Glioma: A State-of-the-Art Review.

Magnetic hyperthermia therapy (MHT) is a re-emerging treatment modality for brain tumors where magnetic nanoparticles (MNPs) are locally delivered to the brain and then activated with an external alternating magnetic field (AMF) to generate localized heat at a site of interest. Due to the recent advancements in technology and theory surrounding the intervention, clinical and pre-clinical trials have demonstrated that MHT may enhance the effectiveness of chemotherapy and radiation therapy (RT) for the treatment of brain tumors. The future clinical success of MHT relies heavily on designing MNPs optimized for both heating and imaging, developing reliable methods for the local delivery of MNPs, and designing AMF systems with integrated magnetic particle imaging (MPI) for use in humans. However, despite the progression of technological development, the clinical progress of MHT has been underwhelming. This review aims to summarize the current state-of-the-art of MHT and offers insight into the current barriers and potential solutions for moving MHT forward.

The neurosurgery research & education foundation-young neurosurgeons committee webinar series: Providing education and inspiration during the COVID-19 pandemic.

OBJECTIVE: During the COVID-19 pandemic, the American Association of Neurological Surgeons (AANS) Young Neurosurgeons Committee (YNC) and Neurosurgery Research & Education Foundation (NREF) launched the YNC-NREF Webinar Series to provide young and aspiring neurosurgeons with timely information, education, and inspiration in the absence of in-person programming. DESIGN: Five 90-minute Zoom webinars were evaluated, each including 1-2 keynote speakers, a panel discussion, and an audience question-and-answer section. Topics included overviews of neurosurgery, the match, subspecialties, and inspirational career stories. Optional pre- and post-webinar surveys with 11-point Likert-type scores were distributed to attendees. We compared groups using chi-squared and Kruskal-Willis tests, and perceptions pre- and post-webinar using Mann-Whitney tests. SETTING: The webinars were live using Zoom, and the recordings were published on NREF's YouTube channel. PARTICIPANTS: The webinar series targeted young neurosurgeons. The first five episodes had a particular focus on medical students and undergraduates. RESULTS: A total of 673 unique participants attended the webinar series; 257 (38%) and 78 (11%) attendees completed the pre- and post-webinar survey, respectively. Respondents had high baseline interest in neurosurgery and were motivated to learn about the match and training in the US, understand neurosurgeons' day-to-day lives, and ask questions. There were significant differences in perceptions between USMSs, IMSs, and undergraduate students. The webinar improved attendees' knowledge about neurosurgical specialties, the match, and US neurosurgery training. CONCLUSIONS: The YNC and NREF effectively engaged a large, diverse audience through an online webinar series, building a foundation for future virtual programming by organized neurosurgery. ACGME competencies.

Infant Rudimentary Meningocele with Tethering of the Cervical Cord: A Case Report.

Rudimentary meningoceles of the spine with dural extension are very rare and warrant surgical excision to prevent infection and long-term neurological deficits in pediatric patients. We present the case of a 5-month-old infant with a tethered spinal cord secondary to a rudimentary meningocele. The patient presented shortly after birth with a midline cervical dimple that was evaluated for a suspected dermal sinus tract. Magnetic resonance imaging scan of the spine showed a sinus tract with intradural extension to C2-3 and external opening at the level of spinous process C5. En bloc surgical excision and spinal cord release were successfully performed. Histological analysis of the specimen confirmed the presence of two blunt sinus tracts and staining was consistent with a rudimentary meningocele. Intradural rudimentary meningoceles in infants can successfully be managed with surgical intervention. Surgery is indicated to prevent future motor complications from spinal cord tethering and neoplastic growth from the rudimentary meningocele.

Intraoperative Imaging and Optical Visualization Techniques for Brain Tumor Resection: A Narrative Review.

Advancements in intraoperative visualization and imaging techniques are increasingly central to the success and safety of brain tumor surgery, leading to transformative improvements in patient outcomes. This comprehensive review intricately describes the evolution of conventional and emerging technologies for intraoperative imaging, encompassing the surgical microscope, exoscope, Raman spectroscopy, confocal microscopy, fluorescence-guided surgery, intraoperative ultrasound, magnetic resonance imaging, and computed tomography. We detail how each of these imaging modalities contributes uniquely to the precision, safety, and efficacy of neurosurgical procedures. Despite their substantial benefits, these technologies share common challenges, including difficulties in image interpretation and steep learning curves. Looking forward, innovations in this field are poised to incorporate artificial intelligence, integrated multimodal imaging approaches, and augmented and virtual reality technologies. This rapidly evolving landscape represents fertile ground for future research and technological development, aiming to further elevate surgical precision, safety, and, most critically, patient outcomes in the management of brain tumors.

Circulating tumor DNA - A potential aid in the management of chordomas.

Chordomas are a locally invasive, low-grade, CNS malignancy that are primarily found in the skull base, spine, and sacrum. They are thought to be derived from notochordal remnants and remain a significant clinical challenge due to their local invasiveness, resistance to chemoradiation, and difficulty in achieving a complete resection. Adjuvant therapy such as proton beam therapy is critical in preventing recurrence in patients who are at high risk, however this treatment is associated with increased risk of complication. Currently, intraoperative observation and imaging findings are used to determine recurrence and success of gross total resection. These methods can be unreliable due to limited operative view, bony and soft tissue involvement, and complex post-operative changes on MRI. Earlier detection of incomplete resection or recurrence will allow for earlier ability to intervene and potentially improve patient outcomes. Circulating-tumor DNA (ctDNA) is cell-free DNA that is released by tumor cells as they undergo cellular turn-over. Monitoring ctDNA has been shown to be more sensitive at predicting residual tumor than imaging in numerous solid malignancies. Furthermore, ctDNA could be detected earlier in peripheral blood as opposed to imaging changes, allowing for earlier intervention. In this review, we intend to give a brief overview of the current state of molecular diagnosis for skull base chordomas. We will then discuss current advances in the utilization of ctDNA for the management of CNS pathologies such as glioblastoma (GBM) and brain metastases. We will also discuss the role ctDNA has in the management of non-CNS pathologies such as osteosarcoma and Ewing sarcoma (EWS). Finally, we will discuss potential implications of ctDNA monitoring for chordoma management.

Predictors and Impact of Postoperative 30-Day Readmission in Glioblastoma.

BACKGROUND: Postoperative 30-day readmissions have been shown to negatively affect survival and other important outcomes in patients with glioblastoma (GBM). OBJECTIVE: To further investigate patient readmission risk factors of primary and recurrent patients with GBM. METHODS: The authors retrospectively reviewed records of 418 adult patients undergoing 575 craniotomies for histologically confirmed GBM at an academic medical center. Patient demographics, comorbidities, and clinical characteristics were collected and compared by patient readmission status using chi-square and Mann-Whitney U testing. Multivariable logistic regression was performed to identify risk factors that predicted 30-day readmissions. RESULTS: The cohort included 69 (12%) 30-day readmissions after 575 operations. Readmitted patients experienced significantly lower median overall survival (11.3 vs 16.4 months, P = .014), had a lower mean Karnofsky Performance Scale score (66.9 vs 74.2, P = .005), and had a longer initial length of stay (6.1 vs 5.3 days, P = .007) relative to their nonreadmitted counterparts. Readmitted patients experienced more postoperative deep vein thromboses or pulmonary embolisms (12% vs 4%, P = .006), new motor deficits (29% vs 14%, P = .002), and nonhome discharges (39% vs 22%, P = .005) relative to their nonreadmitted counterparts. Multivariable analysis demonstrated increased odds of 30-day readmission with each 10-point decrease in Karnofsky Performance Scale score (odds ratio [OR] 1.32, P = .002), each single-point increase in 5-factor modified frailty index (OR 1.51, P = .016), and initial presentation with cognitive deficits (OR 2.11, P = .013). CONCLUSION: Preoperatively available clinical characteristics strongly predicted 30-day readmissions in patients undergoing surgery for GBM. Opportunities may exist to optimize preoperative and postoperative management of at-risk patients with GBM, with downstream improvements in clinical outcomes.

Frailty in Patients Undergoing Surgery for Brain Tumors: A Systematic Review of the Literature.

BACKGROUND: Emerging literature suggests that frailty may be an important driver of postoperative outcomes in patients undergoing surgery for brain tumors. We systematically reviewed the literature on frailty in patients with brain tumor with respect to 3 questions: What methods of frailty assessment have been applied to patients with brain tumor? What thresholds have been defined to distinguish between different levels of frailty? What clinical outcomes does frailty predict in patients with brain tumor? METHODS: A literature search was conducted using PubMed, Embase, The Cochrane Library, Web of Science, Scopus, and ClinicalTrials.gov. Included studies were specific to patients with brain tumor, used a validated instrument to assess frailty, and measured the impact of frailty on postoperative outcomes. RESULTS: Of 753 citations, 21 studies met our inclusion criteria. Frailty instruments were studied, in order of frequency reported, including the 5-factor modified frailty index, 11-factor modified frailty index, Johns Hopkins Adjusted Clinical Groups frailty-defining diagnosis indicator, and Hopkins Frailty Score. Multiple different conventions and thresholds were reported for distinguishing the levels of frailty. Clinical outcomes associated with frailty included mortality, survival, complications, length of stay, charges, costs, discharge disposition, readmissions, and operative time. CONCLUSIONS: Frailty is an increasingly popular concept in patients with brain tumor that is associated with important clinical outcomes. However, the extant literature is largely comprised of retrospective studies with heterogeneous definitions of frailty, thresholds for defining levels of frailty, and patient populations. Further work is needed to understand best practices in assessing frailty in patients with brain tumor and applying these concepts to clinical practice.

Adapting the 5-factor modified frailty index for prediction of postprocedural outcome in patients with unruptured aneurysms.

OBJECTIVE: The 5-factor modified frailty index (mFI-5) is a practical tool that can be used to estimate frailty by measuring five accessible factors: functional status, history of diabetes, chronic obstructive pulmonary disease, congestive heart failure, and hypertension. The authors aimed to validate the utility of mFI-5 for predicting endovascular and microsurgical treatment outcomes in patients with unruptured aneurysms. METHODS: A prospectively maintained database of consecutive patients with unruptured aneurysm who were treated with clip placement or endovascular therapy was used. Because patient age is an important predictor of treatment outcomes in patients with unruptured aneurysm, mFI-5 was supplemented with age to create the age-supplemented mFI-5 (AmFI-5). Associations of scores on these indices with major complications (symptomatic ischemic or hemorrhagic stroke, pulmonary embolism, pneumonia, or surgical site infection requiring reoperation) were evaluated. Validation was carried out with the American College of Surgeons National Surgical Quality Improvement Program (NSQIP) database (2006-2017). RESULTS: The institutional database included 275 patients (88 underwent clip placement, and 187 underwent endovascular treatment). Multivariable analysis of the surgical cohort showed that major complication was significantly associated with mFI-5 (OR 2.0, p = 0.046) and AmFI-5 (OR 1.9, p = 0.028) scores. Significant predictive accuracy for major complications was provided by mFI-5 (c-statistic = 0.709, p = 0.011) and AmFI-5 (c-statistic = 0.720, p = 0.008). The American Society of Anesthesiologists Physical Status Classification System (ASA) provided poor discrimination (area under the curve = 0.541, p = 0.618) that was significantly less than that of mFI-5 (p = 0.023) and AmFI-5 (p = 0.014). Optimal relative fit was achieved with AmFI-5, which had the lowest Akaike information criterion value. Similar results were obtained after equivalent analysis of the endovascular cohort, with additional significant associations between index scores and length of stay (ß = 0.6 and p = 0.009 for mFI-5; ß = 0.5 and p = 0.003 for AmFI-5). In 1047 patients who underwent clip placement and were included in the NSQIP database, mFI-5 (p = 0.001) and AmFI-5 (p < 0.001) scores were significantly associated with severe postoperative adverse events and provided greater discrimination (c-statistic = 0.600 and p < 0.001 for mFI-5; c-statistic = 0.610 and p < 0.001 for AmFI-5) than ASA score (c-statistic = 0.580 and p = 0.003). CONCLUSIONS: mFI-5 and AmFI-5 represent potential predictors of procedure-related complications in unruptured aneurysm patients. After further validation, integration of these tools into clinical workflows may optimize patients for intervention.

Synergy between glutamate modulation and anti-programmed cell death protein 1 immunotherapy for glioblastoma.

OBJECTIVE: Immune checkpoint inhibitors such as anti-programmed cell death protein 1 (anti-PD-1) have shown promise for the treatment of cancers such as melanoma, but results for glioblastoma (GBM) have been disappointing thus far. It has been suggested that GBM has multiple mechanisms of immunosuppression, indicating a need for combinatorial treatment strategies. It is well understood that GBM increases glutamate in the tumor microenvironment (TME); however, the significance of this is not well understood. The authors posit that glutamate upregulation in the GBM TME is immunosuppressive. The authors utilized a novel glutamate modulator, BHV-4157, to determine synergy between glutamate modulation and the well-established anti-PD-1 immunotherapy for GBM. METHODS: C57BL/6J mice were intracranially implanted with luciferase-tagged GL261 glioma cells. Mice were randomly assigned to the control, anti-PD-1, BHV-4157, or combination anti-PD-1 plus BHV-4157 treatment arms, and median overall survival was assessed. In vivo microdialysis was performed at the tumor site with administration of BHV-4157. Intratumoral immune cell populations were characterized with immunofluorescence and flow cytometry. RESULTS: The BHV-4157 treatment arm demonstrated improved survival compared with the control arm (p < 0.0001). Microdialysis demonstrated that glutamate concentration in TME significantly decreased after BHV-4157 administration. Immunofluorescence and flow cytometry demonstrated increased CD4+ T cells and decreased Foxp3+ T cells in mice that received BHV-4157 treatment. No survival benefit was observed when CD4+ or CD8+ T cells were depleted in mice prior to BHV-4157 administration (p < 0.05). CONCLUSIONS: In this study, the authors showed synergy between anti-PD-1 immunotherapy and glutamate modulation. The authors provide a possible mechanism for this synergistic benefit by showing that BHV-4157 relies on CD4+ and CD8+ T cells. This study sheds light on the role of excess glutamate in GBM and provides a basis for further exploring combinatorial approaches for the treatment of this disease.

Disulfiram and copper combination therapy targets NPL4, cancer stem cells and extends survival in a medulloblastoma model.

BACKGROUND: Medulloblastoma (MB) is the most common brain malignancy in children, and is still responsible for significant mortality and morbidity. The aim of this study was to assess the safety and efficacy of Disulfiram (DSF), an FDA-approved inhibitor of Aldehyde-Dehydrogenase (ALDH), and Copper (Cu++) in human SSH-driven and Group 3 MB. The molecular mechanisms, effect on cancer-stem-cells (CSC) and DNA damage were investigated in xenograft models. METHODS: The cytotoxic and anti-CSC effects of DSF/Cu++ were evaluated with clonogenic assays, flow-cytometry, immunofluorescence, western-blotting. ONS76, UW228 (SHH-driven with Tp53m), D425med, D283 and D341 (Group 3) cell-lines were used. In vivo survival and nuclear protein localization protein-4 (NPL4), Ki67, Cleaved-Caspase-3, GFAP and NeuN expression were assessed in two Group 3 MB xenografts with immunohistochemistry and western-blotting. RESULTS: Significant in vitro cytotoxicity was demonstrated at nanomolar concentrations. DSF/Cu++ induced cell-death through NPL4 accumulation in cell-nucleus and buildup of poly-ubiquitylated proteins. Flow-cytometry demonstrated a significant decrease in ALDH+, Nestin+ and CD133+ following treatment, anti-CSC effect was confirmed in vitro and in vivo. DSF/Cu++ prolonged survival, and increased nuclear NPL4 expression in vivo. CONCLUSIONS: Our data suggest that this combination may serve as a novel treatment, as monotherapy or in combination with existing therapies, for aggressive subtypes of pediatric MB.

Targeting of cyclin-dependent kinases in atypical teratoid rhabdoid tumors with multikinase inhibitor TG02.

OBJECTIVE: Atypical teratoid rhabdoid tumors (ATRTs) are aggressive pediatric brain tumors with no current standard of care and an estimated median patient survival of 12 to 18 months. Previous genetic analyses have implicated cyclin D1 and enhancer of zeste homolog 2 (EZH2), a histone methyltransferase that is implicated in many cancers, as key drivers of tumorigenicity in ATRTs. Since the effects of EZH2 and cyclin D1 are facilitated by a host of cyclin-dependent kinases (CDKs), the authors sought to investigate the potential therapeutic effects of targeting CDKs in ATRTs with the multi-CDK inhibitor, TG02. METHODS: Human ATRT cell lines BT12, BT37, CHLA05, and CHLA06 were selected for investigation. The effects of TG02 on cell viability, proliferation, clonogenicity, and apoptosis were assessed via Cell Counting Kit-8 assays, cell counting, clonogenic assays, and flow cytometry, respectively. Similar methods were used to determine the effects of TG02 combined with radiation therapy (RT) or cisplatin. Synergism indices for TG02-cisplatin combination therapy were calculated using CompuSyn software. RESULTS: TG02 was observed to significantly impair ATRT cell growth in vitro by limiting cell proliferation and clonogenicity, and by inducing apoptosis. TG02 inhibited ATRT cell proliferation and decreased cell viability in a dose-dependent manner with nanomolar half maximal effective concentration (EC50) values (BT12, 207.0 nM; BT37, 127.8 nM; CHLA05, 29.7 nM; CHLA06, 18.7 nM). TG02 (150 nM) dramatically increased the proportion of apoptotic ATRT cells 72 hours posttreatment (TG02 8.50% vs control 1.52% apoptotic cells in BT12, p < 0.0001; TG02 70.07% vs control 15.36%, p < 0.0001). Combination therapy studies revealed that TG02 acted as a potent radiosensitizer in ATRT cells (BT12 surviving fraction, RT 51.2% vs RT + TG02 21.7%). Finally, CompuSyn analysis demonstrated that TG02 acted synergistically with cisplatin against ATRT cells at virtually all therapeutic doses. These findings were consistent in cell lines that cover all three molecular subgroups of ATRTs. CONCLUSIONS: The results of this investigation have established that TG02 is an effective therapeutic against ATRTs in vitro. Given the lack of standard therapy for ATRTs, these findings help fill an unmet need and support further study of TG02 as a potential therapeutic option for patients with this deadly disease.

Patient-Specific Factors Drive Intensive Care Unit and Total Hospital Length of Stay in Operative Patients with Brain Tumor.

BACKGROUND: Hospital length of stay (LOS) is an important cost driver in neurosurgery. Broader surgical literature has shown that patient-related factors, including comorbidities, and procedure-related factors, such surgeon experience, may be associated with LOS. Because value optimization strategies may be targeted toward either domain, this study investigated the contributions of patient-related and procedure-related factors in predicting prolonged intensive care unit LOS (iLOS) and total hospital LOS (tLOS). METHODS: Data for adult patients undergoing brain tumor surgery (2017-2019) were collected. Bivariate analyses for iLOS and tLOS were performed using the Mann-Whitney U test and Fisher exact test. Variables associated with either outcome with P < 0.10 were included in patient-only, procedure-only, and patient+procedure factor multivariate linear regression models. Model discrimination was quantified using C-statistics. RESULTS: Our 654 patients had a mean age of 57.54 years (standard deviation, ± 14.34 years). For iLOS, the patient-only model significantly outperformed the procedure-only model (P < 0.0001) and performed similarly to the patient+procedure model (P = 0.50). Other than tumor diagnosis, 5-Factor Modified Frailty Index score was the only factor associated with iLOS (P < 0.001) and tLOS (P < 0.001) on multivariate analysis. When predicting prolonged tLOS, the patient-only model significantly outperformed the procedure-only model (P < 0.0001), and performed similarly to patient+procedure models (P = 0.49). CONCLUSIONS: Patient-specific factors are the main drivers of prolonged iLOS and tLOS among patients with brain tumor. Frailty was significantly associated with both iLOS and tLOS on multivariate analysis. Efforts to improve care value should focus on strategies to optimize patient status, such as prehabilitation and enhanced recovery after surgery.

Captopril inhibits Matrix Metalloproteinase-2 and extends survival as a temozolomide adjuvant in an intracranial gliosarcoma model.

BACKGROUND: Captopril is a well-characterized, FDA-approved drug that has demonstrated promise as a repurposed oncology therapeutic. Captopril's known anti-cancer effects include inhibition of Matrix Metalloproteinase-2 (MMP-2), an endopeptidase which selectively breaks down the extracellular matrix to promote cell migration. MMP-2 is a known therapeutic target in gliomas, tumors with significant clinical need. Using an aggressive gliosarcoma model, we assessed captopril's effects on MMP-2 expression in vitro and in vivo as well as its efficacy as an adjuvant in combination therapy regimens in vivo. METHODS: Following captopril treatment, MMP-2 protein expression and migratory capabilities of 9 L gliosarcoma cells were assessed in vitro via western blots and scratch wound assays, respectively. Rats were intracranially implanted with 9 L gliosarcoma tumors, and survival was assessed in the following groups: control; captopril (30 mg/kg/day); temozolomide (TMZ) (50 mg/kg/day), and captopril+TMZ. In vivo experiments were accompanied by immunohistochemistry for MMP-2 from brain tissue. RESULTS: In vitro, captopril decreased MMP-2 protein expression and reduced migratory capacity in 9 L gliosarcoma cells. In a gliosarcoma animal model, captopril decreased MMP-2 protein expression and extended survival as a TMZ adjuvant relative to untreated controls, captopril monotherapy, and TMZ monotherapy groups (27.5 versus 14 (p < 0.001), 16 (p < 0.001), and 23 (p = 0.018) days, respectively). CONCLUSIONS: Captopril decreases gliosarcoma cell migration, which may be mediated by reduction in MMP-2 protein expression. Captopril provided a survival advantage as a TMZ adjuvant in a rat intracranial gliosarcoma model. Captopril may represent a promising potential adjuvant to TMZ therapy in gliosarcoma as a modulator of the MMP-2 pathway.

A novel radiographic marker of sarcopenia with prognostic value in glioblastoma.

OBJECTIVE: Sarcopenia is an important prognostic consideration in surgical oncology that has received relatively little attention in brain tumor patients. Temporal muscle thickness (TMT) has recently been proposed as a novel radiographic marker of sarcopenia that can be efficiently obtained within existing workflows. We investigated the prognostic value of TMT in primary and progressive glioblastoma. METHODS: TMT measurements were performed on magnetic resonance images of 384 patients undergoing 541 surgeries for glioblastoma. Relationships between TMT and clinical characteristics were examined on bivariate analysis. Optimal TMT cutpoints were established using maximally selected rank statistics. Predictive value of TMT upon postoperative survival (PS) was assessed using Cox proportional hazards regression adjusted for age, sex, Karnofsky performance status (KPS), Stupp protocol completion, extent of resection, and tumor molecular markers. RESULTS: Average TMT for the primary and progressive glioblastoma cohorts was 9.55 mm and 9.40 mm, respectively. TMT was associated with age (r = -0.14, p = 0.0008), BMI (r = 0.29, p < 0.0001), albumin (r = 0.11, p = 0.0239), and KPS (r = 0.11, p = 0.0101). Optimal TMT cutpoints for the primary and progressive cohorts were ≤ 7.15 mm and ≤ 7.10 mm, respectively. High TMT was associated with increased Stupp protocol completion (p = 0.001). On Cox proportional hazards regression, high TMT predicted increased PS in progressive [HR 0.47 (95% confidence interval (CI)) 0.25-0.90), p = 0.023] but not primary [HR 0.99 (95% CI 0.64-1.51), p = 0.949] glioblastoma. CONCLUSIONS: TMT correlates with important prognostic variables in glioblastoma and predicts PS in patients with progressive, but not primary, disease. TMT may represent a pragmatic neurosurgical biomarker in glioblastoma that could inform treatment planning and perioperative optimization.

Alpha-1 adrenergic receptor antagonists to prevent hyperinflammation and death from lower respiratory tract infection.

In severe viral pneumonia, including Coronavirus disease 2019 (COVID-19), the viral replication phase is often followed by hyperinflammation, which can lead to acute respiratory distress syndrome, multi-organ failure, and death. We previously demonstrated that alpha-1 adrenergic receptor (⍺1-AR) antagonists can prevent hyperinflammation and death in mice. Here, we conducted retrospective analyses in two cohorts of patients with acute respiratory distress (ARD, n = 18,547) and three cohorts with pneumonia (n = 400,907). Federated across two ARD cohorts, we find that patients exposed to ⍺1-AR antagonists, as compared to unexposed patients, had a 34% relative risk reduction for mechanical ventilation and death (OR = 0.70, p = 0.021). We replicated these methods on three pneumonia cohorts, all with similar effects on both outcomes. All results were robust to sensitivity analyses. These results highlight the urgent need for prospective trials testing whether prophylactic use of ⍺1-AR antagonists ameliorates lower respiratory tract infection-associated hyperinflammation and death, as observed in COVID-19.

Web-Based Calculator Predicts Surgical-Site Infection After Thoracolumbar Spine Surgery.

BACKGROUND: Surgical-site infection (SSI) after spine surgery leads to increased length of stay, reoperation, and worse patient quality of life. We sought to develop a web-based calculator that computes an individual's risk of a wound infection following thoracolumbar spine surgery. METHODS: We performed a retrospective review of consecutive patients undergoing elective degenerative thoracolumbar spine surgery at a tertiary-care institution between January 2016 and December 2018. Patients who developed SSI requiring reoperation were identified. Regression analysis was performed and model performance was assessed using receiver operating curve analysis to derive an area under the curve. Bootstrapping was performed to check for overfitting, and a Hosmer-Lemeshow test was employed to evaluate goodness-of-fit and model calibration. RESULTS: In total, 1259 patients were identified; 73% were index operations. The overall infection rate was 2.7%, and significant predictors of SSI included female sex (odds ratio [OR] 3.0), greater body mass index (OR 1.1), active smoking (OR 2.8), worse American Society of Anesthesiologists physical status (OR 2.1), and greater surgical invasiveness (OR 1.1). The prediction model had an optimism-corrected area under the curve of 0.81. A web-based calculator was created: https://jhuspine2.shinyapps.io/Wound_Infection_Calculator/. CONCLUSIONS: In this pilot study, we developed a model and simple web-based calculator to predict a patient's individualized risk of SSI after thoracolumbar spine surgery. This tool has a predictive accuracy of 83%. Through further multi-institutional validation studies, this tool has the potential to alert both patients and providers of an individual's SSI risk to improve informed consent, mitigate risk factors, and ultimately drive down rates of SSIs.

Preclinical efficacy of ribavirin in SHH and group 3 medulloblastoma.

OBJECTIVE: Medulloblastoma, the most common pediatric brain malignancy, has Sonic Hedgehog (SHH) and group 3 (Myc driven) subtypes that are associated with the activity of eukaryotic initiation factor 4E (eIF4E), a critical mediator of translation, and enhancer of zeste homolog 2 (EZH2), a histone methyltransferase and master regulator of transcription. Recent drug repurposing efforts in multiple solid and hematologic malignancies have demonstrated that eIF4E and EZH2 are both pharmacologically inhibited by the FDA-approved antiviral drug ribavirin. Given the molecular overlap between medulloblastoma biology and known ribavirin activity, the authors investigated the preclinical efficacy of repurposing ribavirin as a targeted therapeutic in cell and animal models of medulloblastoma. METHODS: Multiple in vitro assays were performed using human ONS-76 (a primitive SHH model) and D425 (an aggressive group 3 model) cells. The impacts of ribavirin on cellular growth, death, migration, and invasion were quantified using proliferation and Cell Counting Kit-8 (CCK-8) assays, flow cytometry with annexin V (AnnV) staining, scratch wound assays, and Matrigel invasion chambers, respectively. Survival following daily ribavirin treatment (100 mg/kg) was assessed in vivo in immunodeficient mice intracranially implanted with D425 cells. RESULTS: Compared to controls, ribavirin treatment led to a significant reduction in medulloblastoma cell growth (ONS-76 proliferation assay, p = 0.0001; D425 CCK-8 assay, p < 0.0001) and a significant increase in cell death (flow cytometry for AnnV, ONS-76, p = 0.0010; D425, p = 0.0284). In ONS-76 cells, compared to controls, ribavirin significantly decreased cell migration and invasion (Matrigel invasion chamber assay, p = 0.0012). In vivo, ribavirin significantly extended survival in an aggressive group 3 medulloblastoma mouse model compared to vehicle-treated controls (p = 0.0004). CONCLUSIONS: The authors demonstrate that ribavirin, a clinically used drug known to inhibit eIF4E and EZH2, has significant antitumor effects in multiple preclinical models of medulloblastoma, including an aggressive group 3 animal model. Ribavirin may represent a promising targeted therapeutic in medulloblastoma.