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OBJECTIVE Although seizures are a relatively common phenomenon in the setting of brain metastases (BMs), there are no discrete recommendations regarding the use of antiepileptic drugs (AEDs) in this population, either in general or in the context of treatment. The authors’ aim was to better understand the underlying pathological factors as well as the therapeutic techniques that may lead to seizures following the radiosurgical treatment of BMs with the goal of guiding appropriate AED prophylaxis. METHODS Adult patients with BMs diagnosed from 2013 to 2020 at a single academic institution and treated with radiation therapy were included in this study. The authors evaluated factors associated with the incidence of seizures throughout the disease course, with a focus on seizures in the 90-day period following stereotactic radiosurgery (SRS). RESULTS Four hundred forty-four patients with newly diagnosed BMs were identified, 10% of whom had seizures at the time of presentation and 28% of whom had a seizure at any point during the study period. Tumor histology was significantly associated with initial seizure risk. AED use was highly variable. In the 90-day post-SRS period, the summed total planning target volume (PTV) was independently predictive of post-SRS seizures, regardless of the fractionation scheme (single fraction vs hypofractionated) and other clinical factors. The number of supratentorial BMs was not predictive of post-SRS seizures. CONCLUSIONS PTV is a superior predictor of post-SRS seizures relative to the number of supratentorial BMs, as it serves as a volumetric proxy for intracranial disease burden. A larger PTV, alongside tumor histology and prior seizure history, should be considered in the decision-making process for AED use following radiosurgery.

BACKGROUND Uterine leiomyosarcoma is a rare, extremely aggressive tumor with a high rate of metastasis. Five-year survival for individuals with metastatic disease is only 10%–15%. Metastases to the brain are exceptionally rare and are associated with poor survival. OBSERVATIONS The authors report a case of uterine leiomyosarcoma that metastasized to the brain in a 51-year-old woman. A single lesion on magnetic resonance imaging was discovered in the right posterior temporo-occipital region 44 months after resection of the primary uterine tumor. The patient underwent a right occipital craniotomy with gross-total resection of the tumor and is receiving adjuvant stereotactic radiosurgery and chemotherapy with gemcitabine and docetaxel. At 8 months postresection, the patient remains alive and asymptomatic with no sign of recurrence. A literature review of prior reported cases was conducted to analyze patterns of approach to patient treatment and survival. LESSONS The authors found an apparent survival benefit in patients receiving adjuvant radiation therapy.

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The successes of checkpoint blockade immunotherapy (CBI) and BRAFV600-targeted therapy trials have generated substantial promise for revolutionizing the management of patients with advanced melanoma. However, because early clinical trials of CBIs and BRAFV600-targeted therapy either excluded or included disproportionately fewer cases of melanoma brain metastases (MBMs), the survival benefit of these novel therapies for MBM remains unknown. We, therefore, evaluated the characteristics, management, and overall survival (OS) of patients who presented with cutaneous MBMs during 2010 to 2015 using the National Cancer Database, which comprises 70% of all newly diagnosed U.S. cancers. OS was analyzed with risk-adjusted proportional hazards and compared by Kaplan–Meier techniques. We found that 2,753 (36%) of patients presenting with stage 4 melanoma had MBMs. Following the 2011 FDA approvals for CBI and BRAFV600-targeted therapy, MBM patients demonstrated a 91% relative increase in 4-year OS to 14.1% from 7.4% preapproval (P < 0.001). Postapproval, the proportion of MBM patients who received CBI rose from 10.5% in 2011 to 34.0% in 2015 (P < 0.001). Initial CBI in MBM patients displayed an improved median and 4-year OS of 12.4 months (compared with 5.2 months; P < 0.001) and 28.1% (compared with 11.1%), respectively. These benefits were pronounced in MBM patients without extracranial metastases, in which CBI demonstrated improved median and 4-year OS of 56.4 months (compared with 7.7 months; P < 0.001) and 51.5% (compared with 16.9%), respectively. Using a large national cohort composed of a “real-life” MBM treatment population, we demonstrated the dramatic OS improvements associated with novel checkpoint blockade immunotherapies. Cancer Immunol Res; 6(9); 1039–45. ©2018 AACR.

Objectives The aim of this study was to identify the reasons for patient messages, phone calls, and emergency department (ED) visits prior to the first postoperative visit following discharge after endoscopic transnasal transsphenoidal (eTNTS) surgery. Design This is a retrospective review of patients at a tertiary care academic center who underwent eTNTS for resection of a sellar region tumor between May 2020 and August 2021. Patient, tumor, and surgical characteristics were collected, along with postoperative, postdischarge, and readmission information. Regression analyses were performed to investigate risk factors associated with postdischarge phone calls, messages, ED visits, and readmissions. Main Outcome Measures The main outcomes were the number of and reasons for phone calls, patient messages, and ED visits between hospital discharge and the first postoperative visit. We additionally determined whether these reasons were addressed in each patient's discharge instructions. Results A total of 98 patients underwent eTNTS during the study period. The median length of hospital stay was 2 days (interquartile range [IQR]: 1–4 days), at which point most patients (82%) were provided with eTNTS-specific discharge instructions. First postoperative visit took place 9 days after discharge (IQR: 7–10 days). Within that time, 54% of patients made at least one phone call or sent at least electronic message and 17% presented to the ED. Most common reasons for call/message were nasal care, appointment scheduling, and symptom and medication questions. Conclusion Through this work, we highlight the most common reasons for resource utilization via patient phone calls, messages, and ED visits among our cohort to better understand any shortfall or gap in the discharge process that may reduce these events.

MRI-guided focused ultrasound thalamotomy has been shown to be an effective treatment for medication refractory essential tremor. Here, we report a clinical-radiological analysis of 123 cases of MRI-guided focused ultrasound thalamotomy, and explore the relationships between treatment parameters, lesion characteristics and outcomes. All patients undergoing focused ultrasound thalamotomy by a single surgeon were included. The procedure was performed as previously described, and patients were followed for up to 1 year. MRI was performed 24 h post-treatment, and lesion locations and volumes were calculated. We retrospectively evaluated 118 essential tremor patients and five tremor-dominant Parkinson’s disease patients who underwent thalamotomy. At 24 h post-procedure, tremor abated completely in the treated hand in 81 essential tremor patients. Imbalance, sensory disturbances and dysarthria were the most frequent acute adverse events. Patients with any adverse event had significantly larger lesions, while inferolateral lesion margins were associated with a higher incidence of motor-related adverse events. Twenty-three lesions were identified with irregular tails, often extending into the internal capsule; 22 of these patients experienced at least one adverse event. Treatment parameters and lesion characteristics changed with increasing surgeon experience. In later cases, treatments used higher maximum power (normalized to skull density ratio), accelerated more quickly to high power, and delivered energy over fewer sonications. Larger lesions were correlated with a rapid rise in both power delivery and temperature, while increased oedema was associated with rapid rise in temperature and the maximum power delivered. Total energy and total power did not significantly affect lesion size. A support vector regression was trained to predict lesion size and confirmed the most valuable predictors of increased lesion size as higher maximum power, rapid rise to high-power delivery, and rapid rise to high tissue temperatures. These findings may relate to a decrease in the energy efficiency of the treatment, potentially due to changes in acoustic properties of skull and tissue at higher powers and temperatures. We report the largest single surgeon series of focused ultrasound thalamotomy to date, demonstrating tremor relief and adverse events consistent with reported literature. Lesion location and volume impacted adverse events, and an irregular lesion tail was strongly associated with adverse events. High-power delivery early in the treatment course, rapid temperature rise, and maximum power were dominant predictors of lesion volume, while total power, total energy, maximum energy and maximum temperature did not improve prediction of lesion volume. These findings have critical implications for treatment planning in future patients.

Superior semicircular canal dehiscence (SSCD) is becoming increasingly recognized as a pathology underlying various auditory and vestibular complaints. To date, our understanding of the pathology has yet to attribute specific symptoms to the anatomic location of dehiscence in patients with SSCD. This study aims to address this issue by evaluating the relationship between symptomatology and anatomic location of dehiscence.A single-institution retrospective review of SSCD patients was performed. Information was collected on patient demographics, symptomatology, and anatomic location of dehiscence. High-resolution computed tomography scans of the temporal bones were used to categorize the anatomic SSCD location into 1 of 3 groups: anterior limb, apex, and posterior limb. Lastly, we performed statistical analysis to determine the degree of association between each of the various perioperative factors and anatomic SSCD location.We studied 54 patients in total (32 women, 22 men). Mean age at diagnosis was 53 years (range: 20-82 years) and mean follow-up length was 5.5 months (range: 0.03-27.0 months). The most common anatomical location of superior semicircular canal dehiscence was the apex, which was seen in 68.5% of cases. While preoperative symptomatology was similar among the 3 cohorts, those with apical dehiscences had a significantly higher rate of postoperative improvement of autophony (P = 0.03), aural fullness (P = 0.03), and tinnitus (P = 0.05) as compared to their counterparts.Although our results do not support an association between preoperative characteristics-including symptomatology-and anatomic SSCD location, our findings do suggest that apical dehiscences are associated with greater postoperative symptomatic resolution.

Butterfly glioblastomas (bGBMs) are grade IV gliomas that infiltrate the corpus callosum and spread to bilateral cerebral hemispheres. Due to the rarity of cases, there is a dearth of information in existing literature. Herein, we evaluate clinical and genetic characteristics, associated predictors, and survival outcomes in an institutional series and compare them to a national cohort. We identified all adult patients with bGBM treated at Brigham & Women’s Hospital (2008–2018). The National Cancer Database (NCDB) was also queried for bGBM patients. Survival was analyzed with Kaplan–Meier methods, and Cox models were built to assess for predictive factors. Of 993 glioblastoma patients, 62 cases (6.2%) of bGBM were identified. Craniotomy for resection was attempted in 26 patients (41.9%), with a median volumetric extent of resection (vEOR) of 72.3% (95% confidence interval [95%CI] 58.3–82.1). The IDH1 R132H mutation was detected in two patients (3.2%), and MGMT promoter was methylated in 55.5% of the assessed cases. In multivariable regression, factors predictive of longer OS were increased vEOR, MGMT promoter methylation, and receipt of adjuvant therapy. Median OS for the resected cases was 11.5 months (95%CI 7.7–18.8) vs. 6.3 (95%CI 5.1–8.9) for the biopsied. Of 21,353 GBMs, 719 (3.37%) bGBM patients were identified in the NCDB. Resection was more likely to be pursued in recent years, and GTR was independently associated with prolonged OS (p

Primary intraosseous meningioma (PIM) is a rare subtype of extradural meningiomas that originates within bone. We aimed to characterize the clinical, radiographic, and pathologic features of PIM and the resulting outcomes following resection. Herein we examined a retrospective case series of all patients with a pathologically confirmed WHO grade I PIM that were managed at one of three tertiary care centers. Patients with tumors that demonstrated extraosseous extension or involvement of the dura mater were excluded. The main outcomes included surgical safety and duration of local tumor control. Nine patients were identified with benign PIMs, presenting with headaches or painless enlarging subcutaneous masses if involving the calvarium or with neurologic deficits if involving the skull base, or otherwise incidentally identified. Surgery was pursued for symptomatic relief and/or tissue diagnosis. Lesions were evaluated by radiographic imaging – including sensitive detection by plain X-ray films – and definitive diagnosis ascertained by histopathological examination. Maximal resection of both calvarial and skull base lesions was safely tolerated. PIM represents a rare benign skull lesion, whose identification depends on the integration of radiographic findings with intraoperative findings and histopathological confirmation; it should be considered in the differential for slow-growing expansile intraosseous lesions of the skull.

OBJECTIVETraumatic brain injury (TBI) is a leading cause of morbidity and mortality in the US, but the true incidence of TBI is unknown.METHODSThe National Trauma Data Bank National Sample Program (NTDB NSP) was queried for 2007 and 2013, and population-based weighted estimates of TBI-related emergency department (ED) visits, hospitalizations, and deaths were calculated. These data were compared to the 2017 Centers for Disease Control and Prevention (CDC) report on TBI, which used the Healthcare Cost and Utilization Project’s National (“Nationwide” before 2012) Inpatient Sample and National Emergency Department Sample.RESULTSIn the NTDB NSP the incidence of TBI-related ED visits was 59/100,000 in 2007 and 62/100,000 in 2013. However, in the CDC report there were 534/100,000 in 2007 and 787/100,000 in 2013. The CDC estimate for ED visits was 805% higher in 2007 and 1169% higher in 2013. In the NTDB NSP, the incidence of TBI-related deaths was 5/100,000 in 2007 and 4/100,000 in 2013. In the CDC report, the incidence was 18/100,000 in both years. The CDC estimate for deaths was 260% higher in 2007 and 325% higher in 2013.CONCLUSIONSThe databases disagreed widely in their weighted estimates of TBI incidence: CDC estimates were consistently higher than NTDB NSP estimates, by an average of 448%. Although such a discrepancy may be intuitive, this is the first study to quantify the magnitude of disagreement between these databases. Given that research, funding, and policy decisions are made based on these estimates, there is a need for a more accurate estimate of the true national incidence of TBI.

Epithelial membrane protein 2 (EMP2) is a cell surface protein composed of approximately 160 amino acids and encoded by the growth arrest-specific 3 (GAS3)/peripheral myelin protein 22 kDa (PMP22) gene family. Although EMP2 expression has been investigated in several diseases, much remains unknown regarding its mechanism of action and the extent of its role in pathogenesis. Our aim was to perform a systematic review on the involvement of EMP2 in disease processes and the current usage of anti-EMP2 therapies.A Boolean search of the English-language medical literature was performed. PubMed, Scopus, Cochrane, and Web of Science were used to identify relevant citations. This study followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines.52 studies met the inclusion criteria for qualitative analysis. Of those, 28 (53.8%) were human-only studies, 11 (21.2%) were animal-only studies, and 13 (25%) studies included both human and animal models. Furthermore, 34 (65.4%) studies focused on EMP2's role in neoplasms, while the remaining 18 (34.6%) articles evaluated its role in other pathologies.Overall, the evidence suggests the mechanisms of action of EMP2 are context dependent. Promising results have been produced by utilizing EMP2 as a biomarker and therapeutic target. More studies are warranted to better understand the mechanism and comprehend the role of EMP2 in the pathogenesis of diseases.

OBJECTIVELoss of pituitary function due to nonfunctional pituitary adenoma (NFPA) may be due to compression of the pituitary gland. It has been proposed that the size of the gland and relative perioperative gland expansion may relate to recovery of pituitary function, but the extent of this is unclear. This study aims to assess temporal changes in hormonal function after transsphenoidal resection of NFPA and the relationship between gland reexpansion and endocrine recovery.METHODSPatients who underwent endoscopic transsphenoidal surgery by a single surgeon for resection of a nonfunctional macroadenoma were selected for inclusion. Patients with prior pituitary surgery or radiosurgery were excluded. Patient characteristics and endocrine function were extracted by chart review. Volumetric segmentation of the pre- and postoperative (≥ 6 months) pituitary gland was performed using preoperative and long-term postoperative MR images. The relationship between endocrine function over time and clinical attributes, including gland volume, were examined.RESULTSOne hundred sixty eligible patients were identified, of whom 47.5% were female; 56.9% of patients had anterior pituitary hormone deficits preoperatively. The median tumor diameter and gland volume preoperatively were 22.5 mm (interquartile range [IQR] 18.0–28.8 mm) and 0.18 cm3 (IQR 0.13–0.28 cm3), respectively. In 55% of patients, endocrine function normalized or improved in their affected axes by median last clinical follow-up of 24.4 months (IQR 3.2–51.2 months). Older age, male sex, and larger tumor size were associated with likelihood of endocrine recovery. Median time to recovery of any axis was 12.2 months (IQR 2.5–23.9 months); hypothyroidism was the slowest axis to recover. Although the gland significantly reexpanded from preoperatively (0.18 cm3, IQR 0.13–0.28 cm3) to postoperatively (0.33 cm3, IQR 0.23–0.48 cm3; p < 0.001), there was no consistent association with improved endocrine function.CONCLUSIONSRecovery of endocrine function can occur several months and even years after surgery, with more than 50% of patients showing improved or normalized function. Tumor size, and not gland volume, was associated with preserved or recovered endocrine function.

Surgery in neutropenic patients is challenging due to both atypical manifestations of common conditions and higher perioperative risk. We sought to describe the outcomes of neutropenic patients undergoing abdominal surgery and to identify factors contributing to morbidity and mortality. A retrospective chart review was performed for all patients neutropenic in the 24-hours prior to an abdominal operation at our institution between 1998 and 2017. The primary and secondary outcomes were 30-day mortality and morbidity, respectively. The chi-square test and two-tailed Student’s t test were used for univariable comparisons (non-parametric tests used when appropriate). To determine the optimal threshold of absolute neutrophil count (ANC) to discriminate 30-day mortality, we maximized the Youden index (J). Amongst 237 patients, mortality was 11.8% (28/237) and morbidity 54.5% (130/237). Absolute neutrophil count

BackgroundAccurate brain meningioma detection, segmentation and volumetric assessment are critical for serial patient follow-up, surgical planning and monitoring response to treatment. Current gold standard of manual labeling is a time-consuming process, subject to inter-user variability. Fully-automated algorithms for meningioma detection and segmentation have the potential to bring volumetric analysis into clinical and research workflows by increasing accuracy and efficiency, reducing inter-user variability and saving time. Previous research has focused solely on segmentation tasks without assessment of impact and usability of deep learning solutions in clinical practice. MethodsWe developed a three-dimensional convolutional neural network (3D-CNN) to perform expert-level, automated meningioma segmentation and volume estimation on MRI scans. A 3D-CNN was initially trained by segmenting entire brain volumes using a dataset of 10,099 healthy brain MRIs. Using transfer learning, the network was then specifically trained on meningioma segmentation using 806 expert-labeled MRIs. The algorithm tumor-labeling performance was assessed with standard metrics of tumor segmentation performance (i.e., Dice score). To evaluate clinical applicability, we compared volume estimation accuracy and segmentation time based on current practice versus the use of our automated algorithm. FindingsThe final model achieved a median performance of 88.2% reaching the spectrum of current inter-expert variability (82.6% - 91.6%). Compared to current workflows, the use of the algorithm reduced processing time by 99% and produced tumor volume calculations with an almost perfect correlation with the expert manual segmentations (r=0.98, p

Butterfly glioblastomas (bGBMs) are grade IV gliomas that infiltrate the corpus callosum and spread to bilateral cerebral hemispheres. Due to the rarity of cases, there is a dearth of information in existing literature. Herein, we evaluate clinical and genetic characteristics, associated predictors, and survival outcomes in an institutional series and compare them to a national cohort.We identified all adult patients with bGBM treated at BrighamWomen's Hospital (2008-2018). The National Cancer Database (NCDB) was also queried for bGBM patients. Survival was analyzed with Kaplan-Meier methods, and Cox models were built to assess for predictive factors.Of 993 glioblastoma patients, 62 cases (6.2%) of bGBM were identified. Craniotomy for resection was attempted in 26 patients (41.9%), with a median volumetric extent of resection (vEOR) of 72.3% (95% confidence interval [95%CI] 58.3-82.1). The IDH1 R132H mutation was detected in two patients (3.2%), and MGMT promoter was methylated in 55.5% of the assessed cases. In multivariable regression, factors predictive of longer OS were increased vEOR, MGMT promoter methylation, and receipt of adjuvant therapy. Median OS for the resected cases was 11.5 months (95%CI 7.7-18.8) vs. 6.3 (95%CI 5.1-8.9) for the biopsied. Of 21,353 GBMs, 719 (3.37%) bGBM patients were identified in the NCDB. Resection was more likely to be pursued in recent years, and GTR was independently associated with prolonged OS (p 0.01).Surgical resection followed by adjuvant chemoradiation is associated with significant survival gains and should be pursued in carefully selected bGBM patients.

OBJECTIVE Deep brain stimulation (DBS) is traditionally performed on an awake patient with intraoperative recordings and test stimulation. DBS performed under general anesthesia with intraoperative MRI (iMRI) has demonstrated high target accuracy, reduced operative time, direct confirmation of target placement, and the ability to place electrodes without cessation of medications. The authors describe their initial experience with using iMRI to perform asleep DBS and discuss the procedural and radiological outcomes of this procedure. METHODS All DBS electrodes were implanted under general anesthesia by a single surgeon by using a neuronavigation system with 3-T iMRI guidance. Clinical outcomes, operative duration, complications, and accuracy were retrospectively analyzed. RESULTS In total, 103 patients treated from 2015 to 2019 were included, and all but 1 patient underwent bilateral implantation. Indications included Parkinson’s disease (PD) (65% of patients), essential tremor (ET) (29%), dystonia (5%), and refractory epilepsy (1%). Targets included the globus pallidus pars internus (12.62% of patients), subthalamic nucleus (56.31%), ventral intermedius nucleus of the thalamus (30%), and anterior nucleus of the thalamus (1%). Technically accurate lead placement (radial error ≤ 1 mm) was obtained for 98% of leads, with a mean (95% CI) radial error of 0.50 (0.46–0.54) mm; all leads were placed with a single pass. Predicted radial error was an excellent predictor of real radial error, underestimating real error by only a mean (95% CI) of 0.16 (0.12–0.20) mm. Accuracy remained high irrespective of surgeon experience, but procedure time decreased significantly with increasing institutional and surgeon experience (p = 0.007), with a mean procedure duration of 3.65 hours. Complications included 1 case of intracranial hemorrhage (asymptomatic) and 1 case of venous infarction (symptomatic), and 2 patients had infection at the internal pulse generator site. The mean ± SD voltage was 2.92 ± 0.83 V bilaterally at 1-year follow-up. Analysis of long-term clinical efficacy demonstrated consistent postoperative improvement in clinical symptoms, as well as decreased drug doses across all indications and follow-up time points, including mean decrease in levodopa-equivalent daily dose by 53.57% (p < 0.0001) in PD patients and mean decrease in primidone dose by 61.33% (p < 0.032) in ET patients at 1-year follow-up. CONCLUSIONS A total of 205 leads were placed in 103 patients by a single surgeon under iMRI guidance with few operative complications. Operative time trended downward with increasing institutional experience, and technical accuracy of radiographic lead placement was consistently high. Asleep DBS implantation with iMRI appears to be a safe and effective alternative to standard awake procedures.

Butterfly glioma (BG) is a rare glioma subtype defined by contiguous extension of the tumor into both hemispheres through the corpus callosum. The impairment of higher cognitive functions in BG patients is a well-known condition encountered in the clinical practice. Given the peculiar anatomical features and clinical repercussions of butterfly gliomas, we conducted a systematic review of the literature to assess the role of structured neurocognitive evaluation in this patient population. A systematic search of the literature (Embase, Pubmed, Cochrane databases) was conducted following PRISMA guidelines to identify English language studies reporting on clinical evaluation, treatment strategies and outcomes in BG patients. Screening and extraction were conducted in duplicate. Results were analyzed qualitatively. 493 unique references yielded 49 full-text papers for review; 19 studies were included in the final analysis reporting on 181 patients. A descriptive approach was used in the majority of cases to report on patients' cognitive status, where memory loss, confusion and non-specific cognitive impairment were the most frequently reported issues (67–69% of cases). Three studies conducted specific neurocognitive evaluations: one series reported on the post-operative incidence of abulia/akinesis and its resolution, two case reports applied a complete battery of neuro-psychological tests assessing attention, executive functions and memory skills. This review highlights a gap between the wide availability of validated neuropsychological tests and their utilization in the management of BG patients, according to the literature. Additional data from multi-institutional studies are needed to evaluate the actual implementation of these tests in the daily clinical practice.

INTRODUCTION Although diffuse gliomas of oligodendrocytic lineage demonstrate chemosensitivity, the survival outcomes associated with single- (i.e. temozolomide; TMZ) or multi-agent (i.e. PCV) chemotherapy regimens remain uncertain for anaplastic oligodendrogliomas (AO). METHODS Patients presenting between 2010–2016 with 1p/19q-codeleted WHO grade III AO were identified by ICD-O3 and site-specific factors from the National Cancer Database, which comprises >70% of cancers newly-diagnosed in the U.S. Predictors of receiving first-line single- vs. multi-agent chemotherapy were assessed by multivariable logistic regression. Overall survival (OS) was estimated by Kaplan-Meyer approaches and evaluated by multivariable Cox regression. RESULTS There were 952 patients with 1p/19q-codeleted WHO grade III AO and complete first-line chemotherapy data, with: 13.9% (n=132) no-, 75.0% (n=714) single-, and 11.1% (n=106) multi-agent chemotherapy. In logistic regression of chemotherapy-treated AOs, more recent diagnosis was associated with higher multi-agent (OR=1.48/year, 95%CI=1.25–1.74, p< 0.001) rates; otherwise there were no associations of single- vs. multi-agent chemotherapy with patient sex, age-at-diagnosis, race, insurance status (reference=privately insured), comorbidity index, tumor greatest dimension, tumor location (reference=frontal lobe) or crossing of midline, nor with radiotherapy or EOR (all p >0.05). Multi-agent usage rose from 3.6% in 2010 to 24.3% in 2016. Median follow-up was 34.9mos (IQR=18.8–54.8). The unadjusted 5yr-OS rate was 57.4% (95%CI=43.5–69.1) for no chemotherapy, 72.1% (95%CI=67.1–76.5) for single-agent, and 77.5% (95%CI=59.9–88.1) for multi-agent. Cox regression (adjusting for the above variables of radiotherapy and EOR, patient demographics, and tumor characteristics) demonstrated no significant OS difference between single- and multi-agent (HR=0.91, 95%CI=0.38–2.15, p=0.82) chemotherapy. CONCLUSIONS In a national database of AOs managed in the ‘real-world’ setting, there is increasing utilization of multi-agent (i.e. PCV) chemotherapy; but no significant difference in risk-adjusted short-term mortality (i.e. ~3-5yrs after diagnosis) between first-line multi- and single-agent (i.e. TMZ) chemotherapy. These findings provide preliminary data while we await the long-term PFS and OS results from the CODEL trial.

INTRODUCTION Herein we examine the epidemiology across all pediatric intracranial tumors in the U.S. METHODS Pediatric patients (< 20yo) presenting between 2010–2015 with an intracranial tumor as the first evidence of cancer were queried from the National Cancer Database, which comprises >70% of cancers newly-diagnosed in the U.S. Tumor types were classified by WHO2016 ICD-O3. RESULTS 14,952 pediatric patients without a history of cancer presented with intracranial tumors between 2010–2015. Across all ages, these were comprised of 1) 22% diffuse astrocytic and oligodendroglial (n=3,328), 2) 17% sellar region (n=2,530), 3) 16% other astrocytic (n=2,378, 2,131 were pilocytic and pilomyxoid), 4) 13% embryonal (n=1,896; 1,092 were classic histology medulloblastomas), 5) 7% neuronal and mixed neuronal-glial (n=981), 6) 5% ependymal (n=752), 7) 4% GCTs (n=615), 8) 3% mesenchymal non-meningothelial (n=492), 9) 3% nerve sheath (n=428), and 10) ≤2% each of meningioma, choroid plexus, brain metastatic (44% from neuroblastoma), pineal region, hematologic, and other glioma tumors. Embryonal tumors predominated in neonates and infants (0-2yo), diffuse gliomas in childhood (3-11yo), and sellar tumors in adolescents (12-19yo). Females represented 49% of the cases, but sellar tumors predominated (23%, vs. only 11% in males); whereas in males diffuse gliomas predominated (23%; vs. 22% in females) overall and in pediatric patients older than 2yo. CONCLUSIONS In U.S. pediatric patients that present with a new intracranial tumor, embryonal tumors and diffuse gliomas predominate in infants ≤2yo, and continue to predominate in male children 3-11yo, whereas female children 3-11yo shifted towards a predominance by diffuse gliomas and other astrocytic tumors (e.g. pilocytic and pilomyxoid). In female adolescents 12-19yo, sellar tumors predominated, followed by diffuse gliomas; whereas in male adolescents diffuse gliomas predominated, followed by other astrocytic tumors and sellar tumors. Our findings demonstrate that newly-diagnosed intracranial masses in pediatric patients significantly vary by both age and sex.

BACKGROUND Urothelial carcinoma is a common malignancy with ~79,000 new cases diagnosed annually. However, urothelial brain metastases (UBM) are encountered uncommonly. Herein we evaluate their national prevalence, predictors, and treatment outcomes in the contemporary era. METHODS The characteristics, management, and overall survival (OS) of UBM patients (2010–2015) were evaluated using the National Cancer Database, which comprises >70% of all newly diagnosed cancers in the U.S. OS was analyzed with Kaplan-Meier methods and log-rank tests. National outcomes were compared to our institutional cohort of UBMs. RESULTS Out of 208,600 patients diagnosed with urothelial carcinoma, 8.4% presented with stage IV disease--of these only 216 (1.2%) had BMs at the time of diagnosis. Patients presenting with bone, liver, or lung metastases were more likely to present with synchronous BMs. Brain involvement demonstrated significantly worse median OS (3.9mos, 95%CI: 3.1–4.9) than non-BM stage IV disease (10.9mos, 95%CI: 10.6–11.2, p< 0.001). Compared to non-BM stage IV disease, UBMs were more likely to have surgery for metastatic disease and receive radiotherapy (p< 0.001); but were less likely to have primary resection or chemotherapy. In multivariable analysis of stage IV urothelial cancer, BMs demonstrated significantly worse OS (HR 1.43, 95%CI: 1.20–1.72, p< 0.001). In our institutional data, 10 urothelial cancer patients developed BMs; of which 7 were male, median age and KPS at diagnosis were 64.9yo (IQR 56.4–72.0) and 85 (IQR 75–100). Four patients had synchronous metastases; the median number of BM lesions was 2 (IQR 1–2), with a median size of 2.6cm (IQR 1.6–3.3). All 10 underwent GTR, 3 also with SRS and 7 with WBRT, associated with a median OS of 16.5mos. CONCLUSIONS Our results confirm the rarity of UBMs and suggest that BM screening may only be indicated in stage IV patients with neurological symptoms. Systemic therapies demonstrate improved OS in these patients.

Background Although surgery plays a crucial diagnostic role in World Health Organization (WHO) grade II 1p/19q-codeleted oligodendrogliomas, the role of maximal tumor surgical resection remains unclear, with early retrospective series limited by lack of molecular classification or appropriate control groups. Methods The characteristics, management, and overall survival (OS) of patients ≥20 years old presenting with histology-proven WHO grade II 1p/19q-codeleted oligodendrogliomas during 2010–2016 were evaluated using the National Cancer Database and validated using multi-institutional data. Patients were stratified by watchful waiting (biopsy only) versus surgical resection. OS was analyzed using Kaplan–Meier methods and risk-adjusted proportional hazards. Results Five hundred ninety adults met inclusion criteria, of whom 79.0% (n = 466) underwent surgical resection. Of patient and tumor characteristics, younger patients were more likely to be resected. Achieving gross total resection (GTR; n = 320) was significantly associated with smaller tumors, management at integrated network cancer programs (vs community cancer programs), and Medicare insurance (as compared with no, private, or Medicaid/other government insurance) and independent of other patient or tumor characteristics. In risk-adjusted analyses, GTR, but not subtotal resection (STR), demonstrated improved OS (vs biopsy only: hazard ratio 0.28, 95% CI: 0.09–0.85, P = 0.02). Conclusions WHO grade II 1p/19q-codeleted oligodendrogliomas amenable to resection demonstrated improved OS with GTR, but not STR, compared with biopsy-only watchful waiting. The OS benefits of GTR were independent of age, tumor size, or tumor location. Medicare-insured and integrated network cancer program patients were significantly more likely to have GTR than other patients, suggesting that insurance status and care setting may play important roles in access to timely diagnosis or innovations that improve maximal resection.

The cervicothoracic junction (CTJ) has often been identified as an area of biomechanical vulnerability; however, few studies have examined the relative merits of extending fusions across this area. In this study, we sought to investigate the tradeoffs involved in fusing across the CTJ in cases of elective posterior cervical laminectomy and fusion.We conducted a single-institution retrospective cohort study of patients undergoing elective, multilevel, posterior cervical decompression and fusion for degenerative cervical stenosis. Data were collected on baseline clinical and radiographic variables as well any subsequent complications or reoperations. Outcomes measures were compared between those who received fusion stopping at C7 with those who received fusion crossing the CTJ, with multivariate logistic regression used to adjust for any known confounders.Patients whose fusion crossed the CTJ were found to have more levels fused (mean: 5.8 vs. 3.5 levels, P0.0001), longer surgical times (mean: 216 vs. 149 minutes, P0.0001), and higher estimated blood losses (mean: 475 vs. 116 mL, P0.0001) despite no significant differences in number of levels decompressed (mean: 4.2 vs. 4.3 levels, P = 0.63). The groups did not differ in overall reoperation rate (10.8% vs. 9.4%, P = 1.00), but crossing the CTJ was associated with a higher rate of wound dehiscence (7.8% vs. 0%, P = 0.03). This difference persisted in multivariate analysis (P0.001).Crossing the CTJ was associated with increased surgical time, estimated blood loss, and the rates of wound dehiscence. These tradeoffs should be considered in planning posterior cervical decompression and fusion procedures.

Although French psychiatrist-turned-neurosurgeon Jean Talairach (1911–2007) is perhaps best known for the stereotaxic atlas he produced with Pierre Tournoux and Gábor Szikla, he has left his mark on most aspects of modern stereotactic and functional neurosurgery. In the field of psychosurgery, he expressed critique of the practice of prefrontal lobotomy and subsequently was the first to describe the more selective approach using stereotactic bilateral anterior capsulotomy. Turning his attention to stereotaxy, Talairach spearheaded the team at Hôpital Sainte-Anne in the construction of novel stereotaxic apparatus. Cadaveric investigation using these tools and methods resulted in the first human stereotaxic atlas where the use of the anterior and posterior commissures as intracranial reference points was established. This work revolutionized the approach to cerebral localization as well as leading to the development of numerous novel stereotactic interventions by the Sainte-Anne team, including tumor biopsy, interstitial irradiation, thermal ablation, and endonasal procedures. Together with epileptologist Jean Bancaud, Talairach invented the field of stereo-electroencephalography and developed a robust scientific methodology for the assessment and treatment of epilepsy. In this article the authors review Talairach’s career trajectory in its historical context and in view of its impact on modern stereotactic and functional neurosurgery.

Purpose: The integrated histopathologic and molecular diagnoses of the 2016 WHO classification of central nervous system tumors have revolutionized patient care by improving diagnostic accuracy and reproducibility; however, the frequency and consequences of misclassification of histologically diagnosed diffuse gliomas are unknown. Experimental Design: Patients with newly diagnosed ICD-O-3 (International Classification of Diseases) histologically encoded diffuse gliomas from 2010–2015 were identified from the National Cancer Database, the misclassification rates and overall survival (OS) of which were assessed by WHO grade and 1p/19q status. In addition, misclassification rates by isocitrate dehydrogenase (IDH), ATRX, and p53 statuses were examined in an analogous multi-institutional cohort of registry-encoded diffuse gliomas. Results: Of 74,718 patients with diffuse glioma, only 74.4% and 78.8% of molecularly characterized WHO grade II and III oligodendrogliomas were in fact 1p/19q-codeleted. In addition, 28.9% and 36.8% of histologically encoded grade II and III “oligoastrocytomas”, and 6.3% and 8.8% of grade II and III astrocytomas had 1p/19q-codeletion, thus molecularly representing oligodendrogliomas if also IDH mutant. OS significantly depended on accurate WHO grading and 1p/19q status. Conclusions: On the basis of 1p/19q, IDH, ATRX, and p53, the misclassification rates of histologically encoded oligodendrogliomas, astrocytomas, and glioblastomas are approximately 21%–35%, 6%–9%, and 9%, respectively; with significant clinical implications. Our findings suggest that when compared with historical histology-only classified data, in national registry, as well as, institutional databases, there is the potential for false-positive results in contemporary trials of molecularly classified diffuse gliomas, which could contribute to a seemingly positive phase II trial (based on historical comparison) failing at the phase III stage. Critically, findings from diffuse glioma clinical trials and historical cohorts using prior histology-only WHO schemes must be cautiously reinterpreted.

While surgery and radiation remain the mainstays of therapy for all patients with brain metastases (BM), the management is moving to a more individualized approach based on the underlying tumor. We sought to identify prognostic factors of both intracranial progression (IC-PFS) and overall survival (OS) in a surgical cohort. We retrospectively reviewed the records of 1015 patients treated surgically for BM at Brigham and Women’s Hospital (2007–2017). Kaplan–Meier curves were used for OS and IC-PFS and Cox proportional hazards models were built to assess for predictive factors. Common origins were lung (43.9%), breast (14.4%), and melanoma (13.8%). Median OS for the cohort was 15.4 months (95% confidence interval [95%CI] 14.1–17.1). Breast cancer (22.1 months, 95%CI 17.8–30.3) and colorectal cancer (10.6 months, 95%CI 7.2–15.4) had the longest and shortest OS, respectively. On multivariable Cox regression, significant prognostic factors of shorter OS were age (HR 1.01, 95%CI 1.01–1.02), number of lesions (HR 1.56, 95%CI 1.28–1.89), extracranial spread at BM diagnosis (HR 1.26, 95%CI 1.05–1.52), and KPS (HR 0.98, 95%CI 0.98–0.99). Regarding molecular factors, all driver mutations in lung adenocarcinoma had a favorable effect (EGFR, HR 0.53, 95%CI 0.31–0.89; ALK, HR 0.28, 95%CI 0.12–0.66; KRAS, HR 0.65, 95%CI 0.47–0.92), triple negative status predicted poor prognosis in breast adenocarcinoma (HR 2.04, 95%CI 1.13–3.69), while no effect of BRAF/NRAS mutations was demonstrated in melanoma BMs. Our results corroborate the role of tumor origin and systemic as well as intracranial spread in OS. Heterogeneity within histologies was further explained by molecular alterations.

Background: Approximately 15-25% of patients with atypical ductal hyperplasia (ADH) diagnosed on breast core needle biopsy (CNB) are upgraded to ductal carcinoma in situ (DCIS) or invasive carcinoma (IC) on surgical excision. The reproducible identification of patients with ADH on CNB who are more likely to have upgrades at excision remains elusive. We hypothesized that a machine learning approach could be utilized to train models to recognize ADH on digitized pathology images and to identify cases of ADH more likely to be upgraded to DCIS or IC at excision. The purpose of this study was to determine the accuracy of the machine learning approach to identify ADH. Methods: 726 digitized images of CNB slides derived from 306 cases with a diagnosis of ADH between 11/2004-3/2018 were included in this study. Independent histologic review by two breast pathologists identified slides with and without ADH from each case. 39 board certified pathologists with experience in evaluation of breast biopsies were employed for tissue region annotation on the PathAI research platform (not intended for diagnostic purposes), yielding 14,118 tissue region annotations. Region annotations included ADH, ADH stroma, flat epithelial atypia (FEA), lobular neoplasia (LN), calcifications (Ca), columnar cell change/hyperplasia, sclerosing adenosis, papilloma, normal terminal duct lobular units and other non-atypical breast tissue regions. These annotations were used to train a convolutional neural network (CNN) with 35 layers and approximately 9 million parameters to identify ADH. The data were split into training and testing sets, representing 61.1% and 38.9% of the data respectively. The distribution of cases, images with ADH and cases with upgrade were balanced between the training and testing sets. Results: CNB specimens were assigned labels of “ADH” or “No ADH” based on histologic assessment. AI models were able to predict the diagnosis of ADH with 85% sensitivity (144 of 168 images within the test set) and 69% specificity (78 of 113 images within the test set). The slide-level area under the receiver operator curve (ROC) for this model was 0.84. Conclusions: A deep learning-based classifier showed strong performance for the identification of ADH from whole slide images of H&E stained breast CNBs. With further development, this approach may improve the reproducibility and standardization of the diagnosis of ADH. Future analyses will focus on determining if morphologic features of ADH extracted by the deep learning system can be used to predict upgrade to DCIS and IC. This approach may help stratify patients with ADH on CNB into those who require surgical excision and those who can be followed with active surveillance. Citation Format: Jennifer K. Kerner, Allison Cleary, Suyog Jain, Harsha Pokkalla, Benjamin Glass, Sam Grossmith, Maya Harary, Elizabeth Mittendorf, Andrew H. Beck, Aditya Khosla, Stuart J. Schnitt, Ilan Wapinski, Tari King. Artificial intelligence powered predictive analysis of atypical ductal hyperplasia from digitized pathology images [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P5-02-02.

Glioma constitutes the most common type of primary brain tumor with a dismal survival, often measured in terms of months or years. The thin line between treatment effectiveness and patient harm underpins the importance of tailoring clinical management to the individual patient. Randomized trials have laid the foundation for many neuro-oncological guidelines. Despite this, their findings focus on group-level estimates. Given our current tools, we are limited in our ability to guide patients on what therapy is best for them as individuals, or even how long they should expect to survive. Machine learning, however, promises to provide the analytical support for personalizing treatment decisions, and deep learning allows clinicians to unlock insight from the vast amount of unstructured data that is collected on glioma patients. Although these novel techniques have achieved astonishing results across a variety of clinical applications, significant hurdles remain associated with the implementation of them in clinical practice. Future challenges include the assembly of well-curated cross-institutional datasets, improvement of the interpretability of machine learning models, and balancing novel evidence-based decision-making with the associated liability of automated inference. Although artificial intelligence already exceeds clinical expertise in a variety of applications, clinicians remain responsible for interpreting the implications of, and acting upon, each prediction.

Brain metastases (BMs) have become increasingly prevalent and present unique considerations for patients, including neurocognitive sequelae and advanced disease burden. Therefore, assessing health-related quality of life (HRQoL) via patient-reported outcome measures (PROMs) is an important element of managing these patients. A systematic review of the literature was conducted with the aims of (1) assessing how PROMS used in BM patients were validated, (2) assessing PROM content, and (3) evaluating quality of PROM-results reporting. PROM validation and quality of reporting were assessed using the COnsensus-based Standards for the selection of health Measurement INstruments (COSMIN) grading criteria and International Society of Quality of Life (ISOQOL)-recommended PROM-reporting standards, respectively. Forty-seven studies reporting on 5178 patients with a range of primacy cancer types were included. Eight different PROMs were applied, ranging from general to brain-specific questionnaires. Weaknesses in the validation of these PROMs were assessed by the COSMIN criteria. Many of these PROMs were not developed for BM patients and contained little information on cognitive symptoms. The overall quality of PROM reporting was insufficient based on the ISOQOL scale. Given the unique clinical considerations in BM patients, our results indicate the need for a standardized, validated questionnaire to assess HRQoL in this population. Additionally, there is room for quality improvement with regard to reporting of PROM-related results.

BACKGROUND: Merkel cell carcinoma (MCC) is a rare cutaneous malignancy of neuroendocrine origin, with about 30 cases of brain metastasis (BM) reported in the literature. Historically, the treatment of neuro-metastatic MCC has largely included chemotherapy (CT) and radiotherapy (RT). The aim was to investigate predictors of overall survival (OS) in neuro-metastatic MCC. METHODS: In this retrospective study, we surveyed institutional databases and additionally conducted a systematic review of the literature to identify cases reporting on management of distant MCC BM. A pooled analysis was performed on the institutional and literature cases to assess predictors of OS. Survival analysis was done on R (ver 3.4.0) using a Log Rank statistic and cox proportional hazard ratio. RESULTS: Forty cases were included for analysis, describing operative (14) and non-operative (26) management. Median time from initial MCC diagnosis to CNS involvement was 17.0-mos (IQR 10.5- 26.5), and most patients had a single BM (62.5%). Management of intracranial disease included RT (84.2%), systemic therapy (59.5%) and surgical resection (35%). Operative management was associated with a lower intracranial burden of disease (BoD, single BM: op 92.9% vs. non-op 46.2%, p=0.004), but similar systemic BoD. Median OS was longer in patients treated with neurosurgery (73-mos, 95%CI:31–115 vs. 25-mos, 95%CI:17–44, p ‹ 0.001). Both neurosurgery (HR 0.18, 95%CI:0.06–0.54, p=0.002) and having a single BM (multiple BM or leptomeningeal disease: HR 2.51, 95%CI:1.12–5.6, p=0.03) conferred an OS benefit on risk-unadjusted analysis. On multivariable analysis, only neurosurgical resection was an independent predictor of OS (HR 0.16, 95%CI:0.04–0.59, p=0.006), controlling for age, BoD and RT. Systemic therapy and RT were not associated with OS. CONCLUSIONS: Resection of MCC BM may confer a survival benefit relative to non-operative management given appropriate patient selection. Prospective investigation of multimodal management of neurometastatic MCC is warranted, especially given the promise of new immunotherapy agents in treating MCC.

Direct Oral Anticoagulants (DOAC) are increasingly used as an alternative to vitamin-K antagonists (VKA) for anticoagulation and have shown lower rates of intracranial hemorrhage; however, there is disagreement in the literature over the outcomes of the intraparenchymal hemorrhages (IPH) associated with DOACs, and clinical concern regarding the lack of standardized reversal strategies for DOACs. Thus, the aim of this meta-analysis was to compare mortality, hematoma volume, and risk of hematoma expansion in patients who developed an IPH on DOACs versus VKA. A systematic review of the literature was conducted in accordance with the PRISMA guidelines. Studies were selected that reported on mortality, hematoma expansion, and hematoma volume in DOAC-associated IPH. Pooled risk ratios (RR) were calculated for mortality and hematoma expansion and pooled mean difference (MD) was calculated for hematoma volume (ml) using random-effect models. 15 studies reporting on 1238 patients were included in the systematic review. Eleven of these compared DOAC-IPH to VKA-IPH and were pooled quantitatively. DOAC-IPH was not associated with increased mortality risk (RR: 0.95, 95%-CI: 0.72 –1.27) or increased hematoma expansion risk (RR: 0.92; 95%-CI: 0.75–1.12) compared to VKA-IPH. The hematoma volume of DOAC- IPH was statistically significantly smaller than VKA-IPH (MD: −12.14 ml; 95%-CI: −15.38; −8.89). In conclusion, DOAC-IPH was not associated with increased mortality or hematoma expansion compared to VKA-IPH and may be associated with a smaller hematoma volume.

Background The predominant neurosurgical approach to medication-refractory essential tremor is thalamic deep brain stimulation (DBS). The emergence of magnetic resonance-guided focused ultrasound (MRgFUS) thalamotomy has reawakened the debate surrounding the use of DBS versus thalamotomy for this indication. Herein, we aimed to provide a contemporary comparison between DBS and MRgFUS. Methods Two controlled trials that evaluated DBS and MRgFUS for the unilateral treatment of refractory essential tremor were compared. Clinical outcomes extracted included postural tremor score in the treated upper extremity, quality of life (QoL), and incidence of adverse events (AE). Results Baseline patient characteristics were comparable in the 2 studies, except that DBS patients were younger and had more severe baseline tremor. Both DBS- and MRgFUS-treated patients had significant tremor improvement that was sustained for 1-year posttreatment, and significant improvement in QoL. The MRgFUS cohort had higher rates of persistent neurologic AE, whereas the DBS group had higher rates of surgery- and hardware-related AEs, including intracranial hemorrhage. Conclusions In context of prior literature, both DBS and MRgFUS significantly improve tremor control and QoL. The 2 approaches are predominantly differentiated by their AE-profile. Additional head-to-head comparison on matched clinical populations are required to more accurately compare clinical efficacy and long-term outcomes.

Background Merkel cell carcinoma (MCC) is a rare cutaneous malignancy of neuroendocrine origin, with about 30 cases of brain metastasis (BM) reported in the literature. Historically, the treatment of neurometastatic MCC has largely included chemotherapy and radiotherapy. The aim was to investigate predictors of overall survival (OS) in neurometastatic MCC. Methods In this retrospective study, we surveyed institutional databases and conducted a systematic review of the literature to identify cases reporting on management of distant MCC BM. A pooled survival analysis was performed on the institutional and literature cases to assess predictors of OS. Results Forty cases were included for analysis, describing operative [14] and non-operative [26] management. Median time to central nervous system involvement was 17.0-mos (interquartile range 10.5–26.5), and most patients had a single BM (62.5%). Management of intracranial disease included radiotherapy (82.5%), systemic therapy (59.5%) and surgical resection (35%). Operative management was associated with a lower intracranial burden of disease (BoD), but similar systemic BoD. Both neurosurgery (hazard ratio [HR] 0.18, 95% confidence interval [CI]: 0.06–0.54, p = 0.002), having RT (HR 0.37, 95% CI: 0.14:0.93, p = 0.04) and having a single BM (extensive intracranial BoD: HR 2.51, 95% CI: 1.12–5.6, p = 0.03) conferred an OS benefit on risk-unadjusted analysis. Only, neurosurgical resection was an independent predictor of OS (HR 0.12, 95% CI: 0.03–0.49, p = 0.003), controlling for age, BoD and radiotherapy. Conclusions Resection of MCC BM may confer a survival benefit given appropriate patient selection. Prospective investigation of multimodal management of neurometastatic MCC is warranted, especially given the promise of new immunotherapy agents in treating MCC.

The successes of checkpoint blockade immunotherapy (CBI) and BRAFV600-targeted therapy trials have generated substantial promise for revolutionizing the management of patients with advanced melanoma. However, because early clinical trials of CBIs and BRAFV600-targeted therapy either excluded or included disproportionately fewer cases of melanoma brain metastases (MBMs), the survival benefit of these novel therapies for MBM remains unknown. We, therefore, evaluated the characteristics, management, and overall survival (OS) of patients who presented with cutaneous MBMs during 2010 to 2015 using the National Cancer Database, which comprises 70% of all newly diagnosed U.S. cancers. OS was analyzed with risk-adjusted proportional hazards and compared by Kaplan–Meier techniques. We found that 2,753 (36%) of patients presenting with stage 4 melanoma had MBMs. Following the 2011 FDA approvals for CBI and BRAFV600-targeted therapy, MBM patients demonstrated a 91% relative increase in 4-year OS to 14.1% from 7.4% preapproval (P < 0.001). Postapproval, the proportion of MBM patients who received CBI rose from 10.5% in 2011 to 34.0% in 2015 (P < 0.001). Initial CBI in MBM patients displayed an improved median and 4-year OS of 12.4 months (compared with 5.2 months; P < 0.001) and 28.1% (compared with 11.1%), respectively. These benefits were pronounced in MBM patients without extracranial metastases, in which CBI demonstrated improved median and 4-year OS of 56.4 months (compared with 7.7 months; P < 0.001) and 51.5% (compared with 16.9%), respectively. Using a large national cohort composed of a “real-life” MBM treatment population, we demonstrated the dramatic OS improvements associated with novel checkpoint blockade immunotherapies. Cancer Immunol Res; 6(9); 1039–45. ©2018 AACR.

Focused ultrasound (FUS) has been under investigation for neurosurgical applications since the 1940s. Early experiments demonstrated ultrasound as an effective tool for the creation of intracranial lesions; however, they were limited by the need for craniotomy to avoid trajectory damage and wave distortion by the skull, and they also lacked effective techniques for monitoring. Since then, the development and hemispheric distribution of phased arrays has resolved the issue of the skull and allowed for a completely transcranial procedure. Similarly, advances in MR technology have allowed for the real-time guidance of FUS procedures using MR thermometry. MR-guided FUS (MRgFUS) has primarily been investigated for its thermal lesioning capabilities and was recently approved for use in essential tremor. In this capacity, the use of MRgFUS is being investigated for other ablative indications in functional neurosurgery and neurooncology. Other applications of MRgFUS that are under active investigation include opening of the blood-brain barrier to facilitate delivery of therapeutic agents, neuromodulation, and thrombolysis. These recent advances suggest a promising future for MRgFUS as a viable and noninvasive neurosurgical tool, with strong potential for yet-unrealized applications.

OBJECTIVEMagnetic resonance–guided focused ultrasound (MRgFUS) thalamotomy was recently approved for use in the treatment of medication-refractory essential tremor (ET). Previous work has described lesion appearance and volume on MRI up to 6 months after treatment. Here, the authors report on the volumetric segmentation of the thalamotomy lesion and associated edema in the immediate postoperative period and 1 year following treatment, and relate these radiographic characteristics with clinical outcome.METHODSSeven patients with medication-refractory ET underwent MRgFUS thalamotomy at Brigham and Women’s Hospital and were monitored clinically for 1 year posttreatment. Treatment effect was measured using the Clinical Rating Scale for Tremor (CRST). MRI was performed immediately postoperatively, 24 hours posttreatment, and at 1 year. Lesion location and the volumes of the necrotic core (zone I) and surrounding edema (cytotoxic, zone II; vasogenic, zone III) were measured on thin-slice T2-weighted images using Slicer 3D software.RESULTSPatients had significant improvement in overall CRST scores (baseline 51.4 ± 10.8 to 24.9 ± 11.0 at 1 year, p = 0.001). The most common adverse events (AEs) in the 1-month posttreatment period were transient gait disturbance (6 patients) and paresthesia (3 patients). The center of zone I immediately posttreatment was 5.61 ± 0.9 mm anterior to the posterior commissure, 14.6 ± 0.8 mm lateral to midline, and 11.0 ± 0.5 mm lateral to the border of the third ventricle on the anterior commissure–posterior commissure plane. Zone I, II, and III volumes immediately posttreatment were 0.01 ± 0.01, 0.05 ± 0.02, and 0.33 ± 0.21 cm3, respectively. These volumes increased significantly over the first 24 hours following surgery. The edema did not spread evenly, with more notable expansion in the superoinferior and lateral directions. The spread of edema inferiorly was associated with the incidence of gait disturbance. At 1 year, the remaining lesion location and size were comparable to those of zone I immediately posttreatment. Zone volumes were not associated with clinical efficacy in a statistically significant way.CONCLUSIONSMRgFUS thalamotomy demonstrates sustained clinical efficacy at 1 year for the treatment of medication-refractory ET. This technology can create accurate, predictable, and small-volume lesions that are stable over time. Instances of AEs are transient and are associated with the pattern of perilesional edema expansion. Additional analysis of a larger MRgFUS thalamotomy cohort could provide more information to maximize clinical effect and reduce the rate of long-lasting AEs.

INTRODUCTION Metastases comprise a significant subset of all intracranial neoplasms, but their national composition remains unclear and challenging to track in national cancer registries. METHODS The patient demographics and histologic distribution of newly-diagnosed brain metastasis (BM) patients aged >18yo without a prior history of cancer (2010–2015) were evaluated using the National Cancer Database, which comprises >70% of all newly-diagnosed cancers in the U.S. RESULTS 91,686 adults presented with a newly-diagnosed BM between 2010–2015. The most common sites of brain metastases overall were lung (82% of metastatic cases), breast (4.1%), melanoma (3.2%), kidney (2.9%), and colorectal (1.8%). The overall 1-year and 5-year OS rates for all metastatic tumors were 27.0% (95%CI=26.7–27.3]) and 5.3% (95%CI=5.1–5.5), respectively. The distribution of primary sites for newly diagnosed intracranial metastases varied by sex, age, and race. Compared to males, more females had BMs from breast (8.4% versus 0.8%) and fewer had BMs from kidney (1.9% versus 3.8%), melanoma (1.9% versus 4.5%), and esophagus (0.3% versus 2.0%). In young adults, particularly those 20-29yo, BMs were more likely from melanoma, genitourinary (in males), and soft tissue than adults in middle and advanced age. Lung carcinomas comprised fewer BMs in Hispanics (66%) compared to Whites (82%), Blacks (83%), and Asian/Pacific Islanders (85%). BMs from kidney and genitourinary primaries were higher in Hispanics (7.3% and 2.4% of BMs, respectively) than in Whites (2.8% and 0.3%, respectively), Blacks (1.8% and 0.1%, respectively), and Asian/Pacific Islanders (2.6% and 0.2%, respectively). Melanoma was more frequent in Whites (3.8% of BMs) and Hispanics (2.5%) compared to Blacks (0.3%) and Asian/Pacific Islanders (0.6%). CONCLUSION Our results illustrate the national distribution of newly-diagnosed BMs and investigates how the distribution varies by patient demographics.

INTRODUCTION: Urothelial carcinoma is a common malignancy with ~79,000 new cases diagnosed annually. However, urothelial brain metastases (UBM) are encountered uncommonly. Herein we evaluate their national prevalence, predictors, and treatment outcomes in the contemporary era. METHODS: The characteristics, management, and overall survival (OS) of UBM patients (2010–2015) were evaluated using the National Cancer Database, which comprises >70% of all newly diagnosed cancers in the U.S. OS was analyzed with Kaplan-Meier methods and log-rank tests. National outcomes were compared to our institutional cohort of UBMs. RESULTS: Out of 208,600 patients diagnosed with urothelial carcinoma, 8.4% presented with stage IV disease--of these only 216 (1.2%) had BMs at the time of diagnosis. Patients presenting with bone, liver, or lung metastases were more likely to present with synchronous BMs. Brain involvement demonstrated significantly worse median OS (3.9mos, 95%CI: 3.1–4.9) than non-BM stage IV disease (10.9mos, 95%CI: 10.6–11.2, p< 0.001). Compared to non-BM stage IV disease, UBMs were more likely to have surgery for metastatic disease and receive radiotherapy (p< 0.001); but were less likely to have primary resection or chemotherapy. In multivariable analysis of stage IV urothelial cancer, BMs demonstrated significantly worse OS (HR 1.43, 95%CI: 1.20–1.72, p< 0.001). In our institutional data, 10 urothelial cancer patients developed BMs; of which 7 were male, median age and KPS at diagnosis were 64.9yo (IQR 56.4–72.0) and 85 (IQR 75–100). Four patients had synchronous metastases; the median number of BM lesions was 2 (IQR 1–2), with a median size of 2.6cm (IQR 1.6–3.3). All 10 underwent GTR, 3 also with SRS and 7 with WBRT, associated with a median OS of 16.5mos. CONCLUSION: Our results confirm the rarity of UBMs and suggest that BM screening may only be indicated in stage IV patients with neurological symptoms. Systemic therapies demonstrate improved OS in these patients.

INTRODUCTION Herein we examine the epidemiology and outcomes of the entire spectrum of intracranial tumors in the contemporary era. METHODS Adult patients (≥20yo) presenting between 2010–2015 where the first evidence of cancer involves an intracranial tumor were queried from the National Cancer Database, which comprises >70% of cancers newly-diagnosed in the U.S. Tumor types were classified by WHO2016 ICD-O3, and stratified by patient characteristics. RESULTS 361,841 adults without a history of cancer presented with intracranial tumors between 2010–2015. Across all ages, these were comprised of 1) brain metastases (BMs; 25%: 29% in males vs. 23% in females); 2) meningiomas (25%: 15% in males, but 34% in females) including atypical (n=4,565) and anaplastic (n=833); 3) diffuse infiltrative gliomas (21%: 26% in males vs. 17% in females), mostly GBMs (14%); followed by 4) sellar (14%), 5) cranial nerve (6%), and PCNSL (3%) tumors. The remaining types each comprised ≤2 % of brain tumors, including mesenchymal non-meningothelial tumors (2%), intracranial ependymal (0.8%), mixed neuronal-glial (0.7%), circumscribed “other astrocytomas” (0.6%, mostly pilocytic astrocytomas n=1,307 and PXAs n=272), CNS embryonal (0.3%), pineal (0.2%), GCTs (0.1%), and choroid plexus (0.1%) tumors. In the 91,686 patients presenting with a BM, the most common primaries were lung adenocarcinoma (39%), lung SmallCC (14%), lung SqCC (8%), breast (8% of females), melanoma (3%), kidney (3%), colorectal (2%), and esophageal (1%). The distributions of brain tumor types differed significantly by age, sex, race/ethnicity, and insurance status. CONCLUSIONS In adult patients where the first manifestation of cancer includes an intracranial tumor, the most common diagnosis is either metastatic disease (predominantly from NSCLC) in males or benign meningiomas in females; but varies substantially by age group. Notably, our results adjust the traditional teaching that half of all new brain masses are BMs, which in fact represent only ~25% of new intracranial masses.