Search

OBJECTIVE Although it has been shown that surgery for glioblastoma (GBM) at high-volume facilities (HVFs) may be associated with better postoperative outcomes, the use of such hospitals may not be equally distributed. The authors aimed to evaluate racial and socioeconomic differences in access to surgery for GBM at high-volume Commission on Cancer (CoC)–accredited hospitals. METHODS The National Cancer Database was queried for patients with GBM that was newly diagnosed between 2004 and 2015. Patients who received no surgical intervention or those who received surgical intervention at a site other than the reporting facility were excluded. Annual surgical case volume was calculated for each hospital, with volume ≥ 90th percentile defined as an HVF. Multivariable logistic regression was performed to identify patient-level predictors for undergoing surgery at an HVF. Furthermore, multiple subgroup analyses were performed to determine the adjusted odds ratio of the likelihood of undergoing surgery at an HVF in 2016 as compared to 2004 for each patient subpopulation (by age, race, sex, educational group, etc.). RESULTS A total of 51,859 patients were included, with 10.7% (n = 5562) undergoing surgery at an HVF. On multivariable analysis, Hispanic White patients (OR 0.58, 95% CI 0.49–0.69, p < 0.001) were found to have significantly lower odds of undergoing surgery at an HVF (reference = non-Hispanic White). In addition, patients from a rural residential location (OR 0.55, 95% CI 0.41–0.72, p < 0.001; reference = metropolitan); patients with nonprivate insurance status (Medicare [OR 0.78, 95% CI 0.71–0.86, p < 0.001], Medicaid [OR 0.68, 95% CI 0.60–0.78, p < 0001], other government insurance [OR 0.68, 95% CI 0.52–0.86, p = 0.002], or who were uninsured [OR 0.61, 95% CI 0.51–0.72, p < 0.001]); and lower-income patients ($50,354–$63,332 [OR 0.68, 95% CI 0.63–0.74, p < 0.001], $40,227–$50,353 [OR 0.84, 95% CI 0.76–0.92, p < 0.001]; reference = ≥ $63,333) were also found to be significantly associated with a lower likelihood of surgery at an HVF. Subgroup analyses revealed that elderly patients (age ≥ 65 years), both male and female patients and non-Hispanic White patients, and those with private insurance, Medicare, metropolitan residential location, median zip code–level household income in the first and second quartiles, and educational attainment in the first and third quartiles had increased odds of undergoing surgery at an HVF in 2016 compared to 2004 (all p ≤ 0.05). On the other hand, patients with other governmental insurance, patients with a rural residence, and those from a non-White racial category did not show a significant difference in odds of surgery at an HVF over time (all p > 0.05). CONCLUSIONS The present analysis from the National Cancer Database revealed significant disparities in access to surgery at an HVF for GBM within the United States. Furthermore, there was evidence that these racial and socioeconomic disparities may have widened between 2004 and 2016. The findings should assist health policy makers in the development of strategies for improving access to HVFs for racially and socioeconomically disadvantaged populations.

OBJECTIVE The objective of this study was to determine the frequency with which brain biopsy for presumed CNS relapse of systemic hematological malignancies yields new, actionable diagnostic information. Hematological malignancies represent a disparate group of genetic and histopathological disorders. Proclivity for brain involvement is dependent on the unique entity and may occur synchronously or metasynchronously with the systemic lesion. Diffuse large B-cell lymphomas (DLBCLs) have a high propensity for brain involvement. Patients in remission from systemic DLBCL may present with a lesion suspicious for brain relapse. These patients often undergo brain biopsy. The authors’ a priori hypothesis was that brain biopsy in patients with a history of systemic DLBCL and a new brain MRI lesion would have lower diagnostic utility compared with patients with non-DLBCL systemic malignancies. METHODS The authors performed a retrospective review of patients who underwent brain biopsy between 2000 and 2019. Inclusion criteria were patients ≥ 18 years of age with a prior systemic hematological malignancy in remission presenting with a new brain MRI lesion concerning for CNS relapse. Patients with a history of any CNS neoplasms, demyelinating disorders, or active systemic disease were excluded. The main outcome was the proportion of patients with a distinct histopathological brain diagnosis compared with the systemic malignancy. The authors secondarily assessed overall survival, procedure-related morbidity, and 30-day mortality. RESULTS Sixty patients met inclusion criteria (40 males and 20 females); the median age at brain biopsy was 67 years (range 23–88 years). The median follow-up was 8.5 months (range 0.1–231 months). Thirty-nine (65.0%) patients had DLBCL and 21 (35%) had non-DLBCL malignancies. Thirty-five of 36 (97.2%) patients with prior systemic DLBCL and a diagnostic biopsy had histopathological confirmation of the original systemic disease versus 0 of 21 patients with non-DLBCL systemic malignancies (p < 0.001). Morbidity and 30-day mortality were 8.3% and 10.0%, respectively; 2 of 6 30-day mortalities were directly attributable to the biopsy. The median overall survival following brain biopsy was 10.8 months. CONCLUSIONS Patients with a history of systemic DLBCL and presumed CNS relapse gained minimal clinical benefit from brain biopsy but were at high risk of morbidity and mortality. In patients with a history of non-DLBCL systemic malignancies, brain biopsy remained critical given the high likelihood for discovery of distinct diagnostic entities. It was determined that patients with a prior systemic DLBCL and presumed brain relapse should likely receive empirical therapy obviating treatment delay and the risks of brain biopsy.

We present an image of diffuse intrinsic pontine glioma (DIPG) showing its relationship to white matter structures based on reconstructed tractography (figure). An 8-year-old girl presented with diplopia, right abducens nerve palsy, and mild ataxia. Reconstruction showed at the level of the pontine decussation a right-sided disruption of the pontocerebellar fibers anterior to the descending corticospinal fibers involving the pontine nuclei region. Understanding the white matter tract anatomy of DIPG in relation to surrounding structures critical for function by this method may have the potential to assist in minimizing functional deficit risk during biopsy, but requires future validation.

The surgical treatment of insular gliomas requires specialized knowledge. Over the last three decades, increased momentum in surgical resection of insular gliomas shifted the focus from one of expectant management to maximal safe resection to establish a diagnosis, characterize tumor genetics, treat preoperative symptoms (i.e., seizures), and delay malignant transformation through tumor cytoreduction. A comprehensive review of the literature was performed regarding insular glioma classification/genetics, insular anatomy, surgical approaches, and patient outcomes. Modern large, published series of insular resections have reported a median 80% resection, 80% improvement in preoperative seizures, and postsurgical permanent neurologic deficits of less than 10%. Major complication avoidance includes recognition and preservation of eloquent cortex for language and respecting the lateral lenticulostriate arteries.

OBJECTIVE Idiopathic normal pressure hydrocephalus (iNPH) results in significant morbidity in the elderly with symptoms of dementia, gait instability, and urinary incontinence. In well-selected patients, ventriculoperitoneal shunt (VPS) placement often results in clinical improvement. Most postshunt assessments of patients rely on subjective scales. The goal of this study was to assess the utility of remote activity monitoring to provide objective evidence of gait improvement following VPS placement for iNPH. METHODS Patients with iNPH were prospectively enrolled and fitted with 5 activity monitors (on the hip and bilateral thighs and ankles) that they wore for 4 days preoperatively within 30 days of surgery and for 4 days within 30 days postoperatively. Monitors collected continuous data for number of steps, cadence, body position (upright, prone, supine, and lateral decubitus), gait entropy, and the proportion of each day spent active or static. Data were retrieved from the devices and a comparison of pre- and postoperative movement assessment was performed. The gait data were also correlated with formal clinical gait assessments before and after lumbar puncture and with motion analysis laboratory testing at baseline and 1 month and 1 year after VPS placement. RESULTS Twenty patients fulfilled the inclusion and exclusion criteria (median age 76 years). The baseline median number of daily steps was 1929, the median percentage of the day spent inactive was 70%, the median percentage of the day with a static posture was 95%, the median gait velocity was 0.49 m/sec, and the median number of steps required to turn was 8. There was objective improvement in median entropy from pre- to postoperatively, increasing from 0.6 to 0.8 (p = 0.002). There were no statistically significant differences for any of the remaining variables measured by the activity monitors when comparing the preoperative to the 1-month postoperative time point. All variables from motion analysis testing showed statistically significant differences or a trend toward significance at 1 year after VPS placement. Among the significantly correlated variables at baseline, cadence was inversely correlated with percentage of gait cycle spent in the support phase (contact with ground vs swing phase). CONCLUSIONS This pilot study suggests that activity monitoring provides an early objective measure of improvement in gait entropy after VPS placement among patients with iNPH, although a more significant improvement was noted on the detailed clinical gait assessments. Further long-term studies are needed to determine the utility of remote monitoring for assessing gait improvement following VPS placement.

Chordoma is a rare but devastating tumor that arises in the cranial skull base or spine. There are currently no US Food and Drug Administration-approved targeted therapies for chordoma, and little understanding of whether using more than one therapy has benefit over monotherapy. The objective of this study was to systematically review the current status of clinical trials completed for patients with chordoma to determine if multimodal therapy offers a benefit in progression-free survival over monomodal therapy. We performed a systematic review of the literature according to Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines to review the available clinical trials of targeted therapy for chordoma. We compiled the clinical data to determine if there is a benefit of multimodal therapy over monotherapy. Our search resulted in 11 clinical trials including 270 patients with advanced chordoma who were treated with targeted therapies. The most commonly employed targeted therapies acted within the following pathways: platelet-derived growth factor receptor (187 patients), vascular endothelial growth factor (66 patients), and mammalian target of rapamycin (43 patients). Reported progression-free survival for included studies ranged from 2.5 to 58 months, with the longest progression-free survival in a trial that included a platelet-derived growth factor receptor inhibitor, nilotinib, and concurrent radiotherapy (58.2 months). There was a higher range of progression-free survival for trials treating patients with multimodal therapy (10.2–14 months vs 2.5–9.2 months, except for a monotherapy trial published in 2020 with a progression-free survival of 18 months), and those published in 2018 or later (14–58.2 months vs 2.5–10.2 months). Only 23% of patients with chordoma in published clinical trials have been treated with multimodal therapy. Progression-free survival may be enhanced by the use of targeted therapy with concurrent radiotherapy, use of multimodal therapy, and use of newer targeted therapy. Future clinical trials should consider use of concurrent radiotherapy and multimodal therapy for patients with advanced chordoma.

Introduction: Supratentorial primitive neuroectodermal tumor is a rare, aggressive intrinsic brain tumor with limited treatment options for recurrent disease. SRS as a treatment modality in the recurrent setting was investigated. Methods: A retrospective review of 8 patients treated with SRS for local or distant recurrence of supratentorial PNET from 1999 to 2014 was conducted. Results: Thirty-six tumors were treated in 15 sessions in 8 patients. The median patient age was 22.5 (interquartile range [IQR], 14.75–43.5 years) with a median 21-month period from diagnosis until SRS (IQR, 16–23.75 months). The median prescription isodose volume was 1.85 cm3 (IQR, 1.85–7.02 cm3); median tumor margin dose was 18 Gy (IQR 14–20 Gy); and median isocenters was 2 (range 1–13). No patients experienced adverse radiation effects. All but 1 patient died, and the median overall survival was 32 months (IQR, 26.75–53.5 months) with median overall survival following SRS of 9.5 months (IQR, 5.25–30 months). Univariate analysis failed to demonstrate a statistically significant association between age, number of gamma knife treatments, interval to gamma knife, and margin radiation dose with overall survival. Discussion/Conclusion: This series supports the use of SRS in patients with recurrent supratentorial PNET following multimodal therapy.

OBJECTIVEGlioblastoma (GBM) during infancy is rare, and the clinical outcomes of congenital GBM are not well understood. Correspondingly, the aim of this study was to present a long-term survivor case from the authors’ institution, and establish an integrated cohort of cases across the published literature to better understand the clinical course of this disease in this setting.METHODSThe authors report the outcomes of an institutional case of congenital GBM diagnosed within the first 3 months of life, and performed a comprehensive literature search for published cases from 2000 onward for an integrated survival analysis. All cases were integrated into 1 cohort, and Kaplan-Meier estimations, Fisher’s exact test, and logistic regression were used to interrogate the data.RESULTSThe integrated cohort of 40 congenital GBM cases consisted of 23 (58%) females and 17 (42%) males born at a median gestational age of 38 weeks (range 22–40 weeks). Estimates of overall survival (OS) at 1 month was 67%, at 1 year it was 59%, and at 10 years it was 45%, with statistically superior outcomes for subgroups in which patients survived to be treated by resection and chemotherapy. In the overall cohort, multivariable analysis confirmed resection (p < 0.01) and chemotherapy (p < 0.01) as independent predictors of superior OS. Gestational age > 38 weeks (p < 0.01), Apgar scores ≥ 7 at 5 minutes (p < 0.01), absence of prenatal hydrocephalus (p < 0.01), and vaginal delivery (p < 0.01) were associated with greater odds of surgical diagnosis versus autopsy diagnosis.CONCLUSIONSCongenital GBM can deviate from the expected poor prognosis of adult GBM in terms of OS. Both resection and chemotherapy confer statistically superior prognostic advantages in those patients who survive within the immediate postnatal period, and should be first-line considerations in the initial management of this rare disease.

Background Glioblastoma (GBM), the most common primary brain tumor, has a median survival of 15–16 months. Immunotherapy is promising but GBM-mediated immunosuppression remains a barrier. GBMs express the interferon-gamma (IFN-γ)-responsive immunosuppressive molecules programmed cell death ligand 1 (PD-L1) and indoleamine 2,3-dioxygenase 1 (IDO1). Extracellular vesicles (EVs) have also been implicated in GBM-mediated immunosuppression, in part through PD-L1. We therefore sought to determine if GBM IFN-γ exposure increased GBM EV-mediated immunosuppression and mechanisms underlying this. Methods Human GBM-derived cells were cultured in the presence/absence of IFN-γ. EVs were harvested. PD-L1, IDO1, and EV-associated protein expression was assessed. GBM EVs (+/−IFN-γ) were cultured with healthy donor monocytes. Immunosuppressive myeloid-derived suppressor cell (MDSC) and nonclassical monocyte (NCM) frequency was determined. Impact of GBM (+/−IFN-γ) EV-treated monocytes on CD3/CD28-mediated T cell proliferation was assessed. The impact of PD-L1 and IDO1 knockdown in GBM EVs in this system was evaluated. Results IFN-γ exposure increased PD-L1 and IDO1 expression in GBM cells and EVs without altering EV size or frequency. IFN-γ-exposed GBM EVs induced more MDSC and NCM differentiation in monocytes and these monocytes caused more T cell inhibition than IFN-γ-naive GBM EVs. PD-L1 and/or IDO1 knockdown in GBM cells abrogated the immunosuppressive effects of IFN-γ-exposed GBM EVs on monocytes. Conclusions IFN-γ exposure such as might occur during an antitumor immune response results in superinduction of GBM EVs’ baseline immunosuppressive effects on monocytes. These effects are mediated by increased PD-L1 and IDO1 expression in GBM EVs. These data highlight mechanisms of GBM EV-mediated immunosuppression and identify therapeutic targets (PD-L1, IDO1) to reverse these effects.

WHO grades II (atypical) and III (malignant) meningiomas are associated with significant morbidity and mortality. The role of adjuvant radiotherapy (RT) in management remains controversial. The goal of this study was to evaluate the impact of adjuvant RT on 5-year survival in patients with atypical and malignant meningiomas. We secondarily aimed to assess contemporary practice patterns and the impact of sociodemographic factors on outcome. We queried the National Cancer Database for patients ≥ 18 years of age with cranial atypical or malignant meningiomas from 2010 through 2015 who underwent surgical resection with or without adjuvant radiotherapy. Subjects with unknown WHO grade or radiation status and those not receiving any surgical procedure were excluded from analysis. The study includes 7486 patients, 6788 with atypical and 698 with malignant meningiomas. Overall 5-year survival was 76.9% (95% CI 75.5–78.3%) and 43.3% (95% CI 38.8–48.2%) among patients with WHO grades II and III meningiomas, respectively. Adjuvant RT correlated with improved survival in a multivariable model in patients with grade II tumors (HR 0.78; p = 0.029) regardless of the extent of resection. Age (HR 2.33; p

Background and Objective The goal of this study is to show using 5 illustrative cases that the transcortical route for resection of mediobasal temporal region (MBTR) lesions is safe and effective when performed with awake functional mapping and knowledge of the relevant subcortical anatomy. Although several have been proposed, there is a paucity of reports on transcorticosubcortical approaches to these lesions, particularly in patients with posterior-superior extension. We present a case series of 5 patients with left posterior MBTR gliomas and summarize the relevant subcortical anatomy knowledge of what is a prerequisite for safe resection. Methods Five patients with left posterior MBTR gliomas underwent awake resection with functional corticosubcortical electric mapping. Details of the approach are presented with a review of relevant anatomy. Results Gross total resection was achieved in 4 patients. One patient who had previously undergone radiation therapy had a subtotal resection. There were 4 cases of World Health Organization grade II glioma and 1 case of World Health Organization grade IV glioma. All patients underwent preoperative and postoperative neurologic and neuropsychological assessment and there were no new or worsening sensorimotor, visual, language, or cognitive deficits. Conclusions The transcorticosubcortical approach is a safe and effective approach to lesions of the posterior MBTR. The approach is safe and effective even in patients with superior extension, if the surgical approach is predicated on knowledge of individual functional anatomy. Awake resection with cortical and axonal mapping with well-selected paradigms is invaluable in maximizing extent of resection and ensuring patient safety.

OBJECTIVEMultiple endocrine neoplasia type 1 (MEN1) is a rare, autosomal-dominant tumor disorder characterized by the development of pituitary tumors and other endocrine neoplasms. Diagnosis is made clinically based on the development of 2 or more canonical lesions (parathyroid gland, anterior pituitary, and enteropancreatic tumors) or in family members of a patient with a clinical diagnosis of MEN1 and the occurrence of one of the MEN1-associated tumors. The goal of this study was to characterize pituitary tumors arising in the setting of MEN1 at a single institution. The probability of tumor progression and the likelihood of surgical intervention in patients with asymptomatic nonfunctional pituitary adenomas were also analyzed.METHODSA retrospective review of a prospectively maintained institutional database was performed for patients with MEN1 diagnosed from 1970 to 2017. Data included patient demographics, tumor characteristics, treatment strategies, and outcomes.RESULTSA review of the database identified 268 patients diagnosed with MEN1, of whom 158 (59%) were female. Among the 268 patients, 139 (51.8%) had pituitary adenomas. There was a higher prevalence in women than in men (65% vs 35%, p < 0.005). Functional adenomas (57%) were more common. Prolactin-secreting adenomas were the most common functional tumors. Macroadenomas were seen in 27% of patients and were more likely to be symptomatic and locally aggressive (p < 0.001). Forty-nine patients (35%) underwent transsphenoidal resection at some point during their disease course. In 52 patients who were initially observed with MEN1 asymptomatic nonfunctional adenomas, only 5 (10%) progressed to need surgery. In MEN1 patients, an initial parathyroid lesion is most likely followed in order by pituitary, pancreatic, adrenal, and, finally, rare carcinoid tumors.CONCLUSIONSAsymptomatic nonfunctional pituitary adenomas in patients with MEN1 may be followed safely with MRI. In this series, parathyroid tumors developed at the lowest median age of all cardinal tumors, and development of additional cardinal MEN1 lesions followed a predictable pattern. This pattern of disease progression could have significant implications for disease surveillance in clinical practice and may help to target clinical resources to the lesions most likely to develop next. This may aid with early detection and treatment and warrants further study.

OBJECTIVEThe authors sought to investigate the incidence and predictors of venous thromboembolic events (VTEs) after craniotomy for tumor resection, which are not well established, and the efficacy of and risks associated with VTE chemoprophylaxis, which remains controversial.METHODSThe authors investigated the incidence of VTEs in a consecutive series of patients presenting to the authors’ institution for resection of an intracranial lesion between 2012 and 2017. Information on patient and tumor characteristics was collected and independent predictors of VTEs were determined using stepwise multivariate logistic regression analysis. Review of the literature was performed by searching MEDLINE using the keywords “venous thromboembolism,” “deep venous thrombosis,” “pulmonary embolism,” “craniotomy,” and “brain neoplasms.”RESULTSThere were 1622 patients included for analysis. A small majority of patients were female (52.6%) and the mean age of the cohort was 52.9 years (SD 15.8 years). A majority of intracranial lesions were intraaxial (59.3%). The incidence of VTEs was 3.0% and the rates of deep venous thromboses and pulmonary emboli were 2.3% and 0.9%, respectively. On multivariate analysis, increasing patient age (unit OR 1.02, 95% CI 1.00–1.05; p = 0.018), history of VTE (OR 7.26, 95% CI 3.24–16.27; p < 0.001), presence of motor deficit (OR 2.64, 95% CI 1.43–4.88; p = 0.002), postoperative intracranial hemorrhage (OR 4.35, 95% CI 1.51–12.55; p < 0.001), and prolonged intubation or reintubation (OR 3.27, 95% CI 1.28–8.32; p < 0.001) were independently associated with increased odds of a VTE. There were 192 patients who received VTE chemoprophylaxis (11.8%); the mean postoperative day of chemoprophylaxis initiation was 4.6 (SD 3.8). The incidence of VTEs was higher in patients receiving chemoprophylaxis than in patients not receiving chemoprophylaxis (8.3% vs 2.2%; p < 0.001). There were 30 instances of clinically significant postoperative hemorrhage (1.9%), with only 1 hemorrhage occurring after initiation of VTE chemoprophylaxis (0.1%).CONCLUSIONSThe study results show the incidence and predictors of VTEs after craniotomy for tumor resection in this patient population. The incidence of VTE within this cohort appears low and comparable to that observed in other institutional series, despite the lack of routine prophylactic anticoagulation in the postoperative setting.

Digital, OBJECTIVE Recent studies have proposed resection of the T2 FLAIR hyperintensity beyond the T1 contrast enhancement (supramarginal resection [SMR]) for IDH–wild-type glioblastoma (GBM) to further improve patients’ overall survival (OS). GBMs have significant variability in tumor cell density, distribution, and infiltration. Advanced mathematical models based on patient-specific radiographic features have provided new insights into GBM growth kinetics on two important parameters of tumor aggressiveness: proliferation rate (ρ) and diffusion rate (D). The aim of this study was to investigate OS of patients with IDH–wild-type GBM who underwent SMR based on a mathematical model of cell distribution and infiltration profile (tumor invasiveness profile). METHODS Volumetric measurements were obtained from the selected regions of interest from pre- and postoperative MRI studies of included patients. The tumor invasiveness profile (proliferation/diffusion [ρ/D] ratio) was calculated using the following formula: ρ/D ratio = (4π/3)2/3 × (6.106/[VT21/1 − VT11/1])2, where VT2 and VT1 are the preoperative FLAIR and contrast-enhancing volumes, respectively. Patients were split into subgroups based on their tumor invasiveness profiles. In this analysis, tumors were classified as nodular, moderately diffuse, or highly diffuse. RESULTS A total of 101 patients were included. Tumors were classified as nodular (n = 34), moderately diffuse (n = 34), and highly diffuse (n = 33). On multivariate analysis, increasing SMR had a significant positive correlation with OS for moderately and highly diffuse tumors (HR 0.99, 95% CI 0.98–0.99; p = 0.02; and HR 0.98, 95% CI 0.96–0.99; p = 0.04, respectively). On threshold analysis, OS benefit was seen with SMR from 10% to 29%, 10% to 59%, and 30% to 90%, for nodular, moderately diffuse, and highly diffuse, respectively. CONCLUSIONS The impact of SMR on OS for patients with IDH–wild-type GBM is influenced by the degree of tumor invasiveness. The authors’ results show that increasing SMR is associated with increased OS in patients with moderate and highly diffuse IDH–wild-type GBMs. When grouping SMR into 10% intervals, this benefit was seen for all tumor subgroups, although for nodular tumors, the maximum beneficial SMR percentage was considerably lower than in moderate and highly diffuse tumors., Ciencias Médicas y de la Salud

BackgroundThe extracellular microenvironment modulates cancer behavior. Although radiographic contrast enhancement is an ominous finding in gliomas, it remains unclear if the associated blood-brain barrier disruption merely reflects or functionally supports tumor aggressiveness.MethodsWe utilized intra-operative microdialysis to sample the extracellular metabolome of radiographically diverse regions during fifteen neurosurgical resections. The global extracellular metabolome of recovered microdialysate was evaluated via ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) and assessed using enrichment and correlation analyses.ResultsAmong 162 named metabolites identified via ultra-performance liquid chromatography tandem mass spectrometry, guanidinoacetate (GAA), was 126.32x higher in enhancing tumor than in adjacent brain. 48 additional metabolites were 2.05-10.18x more abundant in enhancing tumor than brain. With exception of GAA, and 2-HG in IDH-mutant gliomas, differences between non-enhancing tumor and brain microdialysate were comparatively modest and less consistent. The enhancing but not the non-enhancing glioma metabolome was significantly enriched for plasma-associated metabolites largely comprising amino acids and carnitines.ConclusionsOur findings suggest that metabolite diffusion through a disrupted blood-brain barrier may largely define the enhancing extracellular glioma metabolome. Future studies are needed to determine how the altered extracellular metabolome impacts glioma behavior.

OBJECTIVE The authors’ goal was to use a multicenter, observational cohort study to determine whether supramarginal resection (SMR) of FLAIR-hyperintense tumor beyond the contrast-enhanced (CE) area influences the overall survival (OS) of patients with isocitrate dehydrogenase–wild-type (IDH-wt) glioblastoma after gross-total resection (GTR). METHODS The medical records of 888 patients aged ≥ 18 years who underwent resection of GBM between January 2011 and December 2017 were reviewed. Volumetric measurements of the CE tumor and surrounding FLAIR-hyperintense tumor were performed, clinical variables were obtained, and associations with OS were analyzed. RESULTS In total, 101 patients with newly diagnosed IDH-wt GBM who underwent GTR of the CE tumor met the inclusion criteria. In multivariate analysis, age ≥ 65 years (HR 1.97; 95% CI 1.01–2.56; p < 0.001) and contact with the lateral ventricles (HR 1.59; 95% CI 1.13–1.78; p = 0.025) were associated with shorter OS, but preoperative Karnofsky Performance Status ≥ 70 (HR 0.47; 95% CI 0.27–0.89; p = 0.006), MGMT promotor methylation (HR 0.63; 95% CI 0.52–0.99; p = 0.044), and increased percentage of SMR (HR 0.99; 95% CI 0.98–0.99; p = 0.02) were associated with longer OS. Finally, 20% SMR was the minimum percentage associated with beneficial OS (HR 0.56; 95% CI 0.35–0.89; p = 0.01), but > 60% SMR had no significant influence (HR 0.74; 95% CI 0.45–1.21; p = 0.234). CONCLUSIONS SMR is associated with improved OS in patients with IDH-wt GBM who undergo GTR of CE tumor. At least 20% SMR of the CE tumor was associated with beneficial OS, but greater than 60% SMR had no significant influence on OS.

OBJECTIVEThe clinical course of high-grade central nervous system gliomas is occasionally complicated by hydrocephalus. The risks of shunt placement and clinical outcome following CSF diversion in this population are not well defined.METHODSThe authors retrospectively reviewed the outcomes of patients with pathologically confirmed WHO grade III or IV gliomas with shunt-treated hydrocephalus at their institution. Outcomes of patients in this cohort were compared with those of patients who underwent shunt treatment for normal pressure hydrocephalus (NPH). Hospital-reported outcomes in a national database for malignant primary brain tumor patients undergoing a ventricular shunt procedure were also reviewed.RESULTSForty-one patients undergoing CSF shunting between 2001 and 2016 at the authors’ institution were identified. Noncommunicating and communicating hydrocephalus occurred at similar rates (51.2% vs 48.8%). Symptomatic improvement after shunting was observed in 75.0% of patients. A major complication occurred in 17.1% of cases, with 2 patients suffering an intracranial hemorrhage. Prior administration of bevacizumab was significantly associated with the incidence of hemorrhage (p = 0.026). Three patients (7.3%) died during admission, and 8 (19.5%) died within 30 days of shunt placement. The presence of ependymal or leptomeningeal enhancement was more common in patients who died within 30 days (75.0% vs 11.1%, p = 0.001). Six patients (18.1%) required readmission to the hospital within 30 days of discharge. Revision surgery was necessary in 7 patients (17.1%). The median time from shunt placement to death was 150.5 days. In comparison with patients with NPH, shunt-treated high-grade glioma patients had increased in-hospital (7.3% vs 0.5%, p = 0.008) and 30-day (19.5% vs 0.8%, p < 0.001) mortality but no difference in the incidence of revision surgery (17.1% vs 17.5%, p = 0.947). Similarly, in the national Vizient Clinical Database Resource Manager, shunt-treated patients with malignant primary brain tumors had an increased length of stay (6.9 vs 3.5 days, p < 0.001), direct cost of admission ($15,755.80 vs $9871.50, p < 0.001), and 30-day readmission rates (20.6% vs 2.4%, p < 0.001) compared with patients without brain tumors who received a shunt for NPH.CONCLUSIONSShunting can be an effective treatment for the symptoms of hydrocephalus in patients with high-grade gliomas. However, the authors’ results suggest that this procedure carries a significant risk of complications in this patient population.

BACKGROUND Glioblastoma is a fatal infiltrative primary brain tumor, and standard care includes maximal safe surgical resection followed by radiation and Temozolomide (TMZ). Therapy-resistant residual cells persist in a latent state a long time before inevitable recurrence. Conventional radiation and Temozolomide (TMZ) treatment cause oxidative stress and DNA damage resulting senescent-like state of cell-cycle arrest. However, increasing evidence demonstrates escaping senescence leads to tumor recurrence. Thus, the ablation of senescent tumor cells after chemoradiation may be an avenue to limit tumor recurrence. METHODS 100uM TMZ for 7days or 10-20Gy radiation (cesium gamma radiator) was used for senescence induction in human glioblastoma in vitro and confirmed by SA-Beta gal staining and PCR. Replication arrest assessed by automated quantification of cellular confluence (Thermo Scientific Series 8000 WJ Incubator). We evaluated the IC50 for several senolytics targeting multiple SCAPs, including Dasatinib, Quercetin, AMG-232, Fisetin, Onalespib, Navitoclax, and A1331852, and in senescent vs. proliferating cells. RESULTS Among the senolytic tested, the Bcl-XL inhibitors A1331852 and Navitoclax both shown senolytic effect by selectively killing radiated, senescent tumor cells at lower concentrations as compared to 0Gy treated non-senescent cells. Across 12 GBM cell lines, IC50 for senescent cells was 6–500 times lower than non-senescent GBM(p< 0.005). Such differential sensitivity to Bcl-XL inhibition after radiation has also observed by BCL-XL knockdown in radiated glioma. CONCLUSION These findings suggest the potential to harness radiation-induced biology to ablate surviving quiescent cells and demonstrate Bcl-XL dependency as a potential vulnerability of surviving tumor cells after exposure to chemoradiation.

BACKGROUND Glioblastoma (GBM) is an infiltrative, uniformly fatal brain tumor, treated with surgery, radiation, and Temozolomide (TMZ). Chemoradiation induces a senescent-like phenotype, which contributes to disease recurrence. We recently found that, radiated GBM cells can be eliminated by inhibition of BCL-XL. However, it remains unknown whether p53 is involved in this process and whether the elimination of senescent cells by BCL-XL inhibition could be augmented by MDM2 inhibition, a negative p53 regulator. METHODS p53-mutant (GBM6/GBM123) and p53-WT (GBM39/GBM76) human GBM cells were treated with 5Gy or TMZ following 48 hours of MDM2 inhibitor (AMG232) or vehicle treatment and maintained for seven days to establish a senescent-like phenotype. We evaluated the IC50 for BCL-XL inhibitor (A1331852) in radiated vs. non-radiated cells with or without MDM2 inhibitor pre-treatment. RESULTS MDM2-inhibitor treatment prior to radiation increased the expression of p21 and lead to increased cell death when combined with BCL-XL inhibition in p53-WT GBM cells. IC50 of BCL-XL inhibitor after prior MDM2 pretreatment and radiation in GBM76 was 4.5□M compared to 33.5□M, 18.1□M, and 32.3□M in vehicle without radiation, vehicle with radiation, and MDM2 inhibitor-alone treatment groups, respectively(p=0.0036). The IC50 of BCL-XL inhibitor without MDM2-inhibition in non-irradiated and radiated, as well as pre-administration of MDM2 inhibitor in non-irradiated and radiated GBM39 cells was 5618nM, 16117nM, 3926nM and 276.5nM, respectively(p=0.0003). Conversely, MDM2 co-inhibition with BCL-XL did not lead to increased rates of cell death in p53-mutant cell(p>0.05). CONCLUSION We previously identified that BCL-XL inhibition promotes cell death in senescent GBM cells. We build upon that work, demonstrating the increased rates of cell death can be augmented by MDM2 inhibition, but only in p53-WT cells. These findings highlight a novel therapeutic target for treating latent GBM tumors prior to recurrence, with the additional of MDM2 inhibition greatly increasing the efficacy of BCL-XL targeting agents.

INTRODUCTION Laser Interstitial Thermal Therapy (LITT) is a novel treatment modality that has been used for an array of intracranial pathology. In the current manuscript, we sought to conduct a systematic review and meta-analysis to summarize all available literature to date, on outcomes of patients with recurrent GBM (r-GBM) undergoing LITT, pooling together quantitatively the overall survival and progression-free survival data. METHODS A comprehensive literature search was performed to retrieve all studies investigating overall survival, post-procedure survival, and progression-free survival outcomes of patients with r-GBM undergoing LITT. All statistics were pooled together by the meta-analysis of the mean using a weighted random-effects (RE) or fixed-effect (FE) model. RESULTS Eleven studies were included in the final cohort, representing a total of 134 patients with rGBM. The pooled mean age of the cohort at the time of recurrence diagnosis was found to be 56.7 ± 4.56 while 41% of the cohort were females. For the delivery of LITT, two studies utilized neodymium-yttrium aluminum-garnet laser (Neodp-YAG Laser), three studies utilized the Visualase system, five studies utilized the Neuroblate system, and one study used both the Neuroblate and the Visualase system. A total of eight studies with 107 patients had available data for overall median survival. The pooled overall survival was found to be 18.6 months (95%CI 16.2-21.1). A total of six studies with 93 patients had available data for post-LITT survival. The pooled post-LITT survival was found to be 10.1 months (95%CI 8.8-11.6). A total of eight studies with 119 patients had available data for progression-free survival. The pooled progression-free survival was found to be 6 months (95%CI 5.3-6.7). CONCLUSION LITT is a novel minimally invasive procedure which, when used with optimal adjuvant therapy, may confer survival benefit for patients with r-GBM.

As an uncommon cause of spinal cord infarction, anterior spinal cord syndrome can manifest with motor paralysis, loss of pain, and temperature sensation distal to the site of the lesion. The main pathogenesis of this syndrome is the disruption of blood flow in the anterior spinal artery. Mortality and morbidity differ with the etiology of the syndrome. So knowing the etiology of blood flow disruption is essential for patient management. This review article highlights the important clinical manifestation of Anterior spinal artery syndrome. Also describes etiology, pathogenesis, diagnosis, prognosis, possible management, and complications.

Introduction We utilized a national administrative database to investigate drivers of immediate adverse economic and hospital outcomes, including non-routine discharge, prolonged length of stay (LOS), and admission costs among patients undergoing surgery for idiopathic normal pressure hydrocephalus (iNPH). Methods The National Inpatient Sample (NIS) was queried from 2007 to 2017 for patients aged ≥60 with a diagnosis code for iNPH undergoing surgery. Multivariable logistic-regression models and Wald χ2 were used to identify drivers of non-routine discharge, prolonged length of stay (LOS) (>75th percentile) and higher admission costs (>90th percentile). Results A total of 13,363 patients with iNPH undergoing surgical management were identified. The most common comorbidity reported in the cohort was a cardiovascular pathology (56.9 %, n = 7,787), followed by urinary pathology (37.2 %, n = 5,084), osteoarthritis (7.8 %, n = 1,071), Alzheimer’s disease (4.6 %, n = 626) and cerebrovascular pathology (4.2 %, n = 569). The most frequently employed procedure was ventriculo-peritoneal (VP) shunt placement (65.6 %, n = 8,942) of which 89.8 % (n = 8,027) were performed open and 10.2 % (n = 915) laparoscopically. This was followed by lumbo-peritoneal (LP) shunting (15.5 %, n = 2,115), lumbar puncture alone (screened, serial CSF removal) (14.8 %, n = 2,013), endoscopic third ventriculostomy (ETV) (2%, n = 274), ventriculo-atrial (VA) shunt (0.95 %, n = 130) and ventriculo-pleural (Vpleural) shunt (0.46 %, n = 64). The median (IQR) LOS was 3 days (2–5), the rate of non-routine discharge was 37.3 % and median (IQR) cost was $11,230 ($7,735–15,590). On multivariable-analysis, emergent-admission (OR 2.91), older age (76–90: OR 1.55; 90+: OR 2.66), VP shunt (open: OR 3.09; laparoscopic: OR 2.32), ETV (OR 3.16), VA/VPleural shunt (OR 2.73) and hospital admission in Northeast-region compared to Midwest (OR 1.27) were found to be associated with increased risk of non-routine discharge. Some of the highly significant associated factors for prolonged LOS included emergent-admission (OR 11.34), ETV (OR 10.92), VA/VPleural shunt (OR 7.79) and open VP shunt (OR 8.24). For increased admission costs, some of the highly associated factors included VA/VPleural shunt (OR 18.48), laparoscopic VP shunt (OR 9.92), open VP shunt (OR 12.72) and ETV (OR 9.34). Predictor importance analysis revealed emergent admission, number of diagnosis codes (comorbidities) open VP shunt, hospital region, age] and revision or removal of shunt to be the most important drivers of these outcomes. Conclusion Analyses from a national database indicate that among patients with iNPH, an emergent-admission may be the most significant risk-factor of adverse economic outcomes and higher costs.

Objective:Patients diagnosed with glioblastoma (GBM) are treated with surgery followed by fractionated radiotherapy with concurrent and adjuvant temozolomide. Patients are monitored with serial magnetic resonance imaging (MRI). However, treatment-related changes frequently mimic disease progression. We reviewed a series of patients undergoing surgery for presumed first-recurrence GBM, where pathology reports were available for tissue diagnosis, in order to better understand factors associated with a diagnosis of treatment-related changes on final pathology.Methods:Patient records at a single institution between 2005 and 2015 were retrospectively reviewed. Pathology reports were reviewed to determine diagnosis of recurrent GBM or treatment effect. Survival analysis was performed interrogating overall survival (OS) and progression-free survival (PFS). Correlation with radiation treatment plans was also examined.Results:One-hundred-twenty-three patients were identified. One-hundred-sixteen patients (94%) underwent resection and seven underwent biopsy. Treatment-related changes were reported in 20 cases (16%). These patients had longer median OS and PFS from the time of recurrence than patients with true disease progression. However, there was no significant difference in OS from the time of initial diagnosis. Treatment effect was associated with surgery within 90 days of completing radiation. In patients receiving radiation at our institution (n = 53), larger radiation target volume and a higher maximum dose were associated with treatment effect.Conclusion:Treatment effect was associated with surgery nearer to completion of radiation, a larger radiation target volume, and a higher maximum point dose. Treatment effect was associated with longer PFS and OS from the time of recurrence, but not from the time of initial diagnosis.

OBJECTIVECushing’s disease arises from functioning adrenocorticotropic hormone (ACTH)–secreting pituitary adenomas. These tumors can be very small and evade detection by MRI. Empty sella syndrome is a phenomenon by which an arachnoid outpouching of CSF into the sella leads to compression of the pituitary, likely due to intracranial hypertension (a common issue in Cushing’s disease), further leading to difficulty in visualizing the pituitary gland that may contribute to difficulty in finding a tumor on MRI, so-called MRI-negative Cushing’s disease. The authors sought to examine the association between empty sella syndrome and MRI-negative Cushing’s disease.METHODSA single-institution database of Cushing’s disease cases from 2000 to 2017 was reviewed, and 197 cases were included in the analysis. One hundred eighty patients had a tissue diagnosis of Cushing’s disease and 17 had remission with surgery, but no definitive tissue diagnosis was obtained. Macroadenomas (tumors > 1 cm) were excluded. The degree of empty sella syndrome was graded on the degree of CSF visualized in the sella on midline sagittal T1-weighted MRI.RESULTSOf the 197 cases identified, 40 (20%) presented with MRI-negative disease, and empty sella syndrome was present in 49 cases (25%). MRI-negative disease was found in 18 (37%) of 49 empty sella cases versus 22 (15%) of 148 cases without empty sella syndrome present. Empty sella syndrome was significantly associated with MRI-negative disease (OR 3.32, 95% CI 1.61–6.74, p = 0.0018). Decreased thickness of the pituitary gland was also associated with MRI-negative disease (mean thickness 5.6 vs 6.8 mm, p = 0.0002).CONCLUSIONSEmpty sella syndrome is associated with an increased rate of MRI-negative Cushing’s disease. Pituitary compression causing a relative reduction in the volume of the pituitary for imaging is a plausible cause for not detecting the tumor mass with MRI.

Gliomas are molecularly complex neoplasms and require a multidisciplinary approach to treatment. Maximal safe resection is often the initial goal of treatment and extent of resection (EOR) is an important prognostic factor correlating with both progression-free-survival (PFS) and overall survival (OS). Postoperative patient outcome is also a critical and independent prognosticator and high EOR must not be achieved at the expense of good functional outcome. Several intraoperative adjuvant techniques have been developed to help the surgeon push the boundaries of EOR while maintaining safety. Fluorescence-guided surgery for brain tumors is a contemporary adjuvant technique that allows for intraoperative delineation of diseased and normal brain thus improving maximal safe resection. The most extensively used fluorophores are 5-aminolevulinic acid (5-ALA) and sodium fluorescein (SFL). These fluorophores have different spectrophotometric properties, mechanisms of action and considerations for use. Both have demonstrated utility in neurosurgical oncology. They are safe and both are FDA approved for use as surgical adjuncts during resection of primary CNS neoplasms although they have been used with varying success for other tumor types. When combined with other surgical adjuvant strategies such as neuronavigation, intraoperative ultrasound, intraoperative MRI, awake resection and/or electrophysiological mapping/monitoring, fluorescence-guided resection appears to further improve resection quality in regard to EOR and safety. In this article, we review the current knowledge related to both fluorophores for brain tumor resection, their benefits, and pitfalls, as well as the major advantages associated with their use. We also briefly review additional fluorophores in early clinical development. Fluorescence-guided surgery is a novel surgical adjuvant which allows for real-time delineation of neoplastic tissues. The most widely used fluorophores are 5-ALA and SFL. They are safe compounds and there is a large body of evidence suggesting improvement in EOR when these are employed. There are nuances to the use of each; the fluorescence intensity is dose-dependent in either case and the sensitivity and specificity for various tumors vary widely. Additional prospective studies will be necessary to parse the impact of this technique and these fluorophores on survival metrics.

As an uncommon cause of spinal cord infarction, anterior spinal cord syndrome can manifest with motor paralysis, loss of pain, and temperature sensation distal to the site of the lesion. The main pathogenesis of this syndrome is the disruption of blood flow in the anterior spinal artery. Mortality and morbidity differ with the etiology of the syndrome. So knowing the etiology of blood flow disruption is essential for patient management. This review article highlights the important clinical manifestation of Anterior spinal artery syndrome. Also describes etiology, pathogenesis, diagnosis, prognosis, possible management, and complications.

Epstein-Barr virus–associated smooth-muscle tumors are rare tumors seen in immunocompromised patients. Most cases occur in the context of AIDS and organ transplantation, and very rarely in the setting of congenital immunodeficiency, with only 5 case reports of the latter published so far in the literature. The authors report the case of a previously healthy 8-year-old girl with headaches and precocious puberty who was found to have a large skull base lesion. There was a synchronous left adrenal lesion. She underwent resection of the skull base lesion and a left adrenalectomy. Thorough evaluation for immunodeficiency was negative for a known congenital immunodeficiency syndrome. She had a short course of intravenous immunoglobulin and has had no recurrence of disease or new lesions in the 17 months since presentation. Continued surveillance for the development of opportunistic infections and new or recurrent lesions is warranted in this case. Repeat surgery for surgically accessible tumors or chemoradiation would be recommended for any additional lesions.

Brain metastases are the most common malignant tumors of the brain. Leptomeningeal dissemination is a late-stage complication of intracranial metastasis and portends an extremely poor prognosis. An increased risk of leptomeningeal disease (LMD) from metastatic breast cancer compared to other cancer types after stereotactic radiosurgery (SRS) has been reported. Validation of this observation has significant public health ramifications. The aim of this study was to determine the consistency of this association in the available literature via formal meta-analysis and systematic review of the literature. Searches of seven electronic databases from inception to August 2019 were conducted following PRISMA guidelines and appropriate selection criteria. Prognostic hazard ratios (HRs) for LMD in breast cancer brain metastases derived from multivariate regression analysis were analyzed using meta-analysis of proportions. Our search strategy identified 8 studies meeting inclusion criteria which provided data on 2555 unique brain metastases patients treated with SRS. The risk of LMD in the setting of breast cancer brain metastasis was significantly greater compared to other histologic cancer types (pooled HR = 2.22; 95% CI 1.69–2.93; P