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OBJECTIVE Status epilepticus (SE) is associated with significant mortality, cost, and risk of future seizures. In one of the first studies of SE after neurosurgery, the authors assess the incidence, risk factors, and outcome of postneurosurgical SE (PNSE). METHODS Neurosurgical admissions from the MarketScan Claims and Encounters database (2007 through 2015) were assessed in a longitudinal cross-sectional sample of privately insured patients who underwent qualifying cranial procedures in the US and were older than 18 years of age. The incidence of early (in-hospital) and late (postdischarge readmission) SE and associated mortality was assessed. Procedural, pathological, demographic, and anatomical covariates parameterized multivariable logistic regression and Cox models. Multivariable logistic regression and Cox proportional hazards models were used to study the incidence of early and late PNSE. A risk-stratification simulation was performed, combining individual predictors into singular risk estimates. RESULTS A total of 197,218 admissions (218,217 procedures) were identified. Early PNSE occurred during 637 (0.32%) of 197,218 admissions for cranial neurosurgical procedures. A total of 1045 (0.56%) cases of late PNSE were identified after 187,771 procedure admissions with nonhospice postdischarge follow-up. After correction for comorbidities, craniotomy for trauma, hematoma, or elevated intracranial pressure was associated with increased risk of early PNSE (adjusted OR [aOR] 1.538, 95% CI 1.183–1.999). Craniotomy for meningioma resection was associated with an increased risk of early PNSE compared with resection of metastases and parenchymal primary brain tumors (aOR 2.701, 95% CI 1.388–5.255). Craniotomies for infection or abscess (aHR 1.447, 95% CI 1.016–2.061) and CSF diversion (aHR 1.307, 95% CI 1.076–1.587) were associated with highest risk of late PNSE. Use of continuous electroencephalography in patients with early (p < 0.005) and late (p < 0.001) PNSE rose significantly over the study time period. The simulation regression model predicted that patients at high risk for early PNSE experienced a 1.10% event rate compared with those at low risk (0.07%). Similarly, patients predicted to be at highest risk for late PNSE were significantly more likely to eventually develop late PNSE than those at lowest risk (HR 54.16, 95% CI 24.99–104.80). CONCLUSIONS Occurrence of early and late PNSE was associated with discrete neurosurgical pathologies and increased mortality. These data provide a framework for prospective validation of clinical and perioperative risk factors and indicate patients for heightened diagnostic suspicion of PNSE.

Introduction While recent studies have focused on confirming satisfaction with telemedicine during the coronavirus disease 2019 (COVID-19) era, we leveraged a novel survey instrument to identify associations between patient experience and telemedicine-specific factors such as device selection, audio/visual resolution, and connection stability. Methods Telemedicine visit data were gathered from our institution between June 22, 2020 and February 14, 2021. Each patient indicated their overall visit score, likelihood-to-recommend (LTR) score, and device used for the encounter. Remaining questions were randomly distributed to patients to ensure equal distribution across respondents. Results Over 34 weeks, there were 901 unique neurosurgical telemedicine visits linked to a post-visit survey at our institution. The LTR top box score percentage showed no significant change across 34 weeks (p = 0.218). After adjusting across available covariates, patients who experienced wait times exceeding 20 min were significantly less likely to report high overall scores (aOR: 0.12; 95% CI: 0.03–0.41; p = 0.001). Patients who indicated they were less able to understand the provider (aOR: 0.22; 95% CI: 0.07–0.66; p = 0.007), or who indicated the provider was not able to properly see them (aOR: 0.11; 95% CI: 0.03–0.43; p = 0.002) were associated with substantially lower overall scores. Visits with interrupted connectivity or those forced to move to a regular phone call were not important predictors of overall score. Conclusions In the largest description of patient satisfaction with telemedicine in the neurosurgical setting during the COVID-19 era, we identified timely and high-quality physician-patient visualization and communication as among the most important predictors of patient satisfaction in virtual settings.

BACKGROUND CONTEXT Despite increased awareness of the ongoing opioid epidemic, opioid and benzodiazepine use remain high after spine surgery. In particular, long-term co-prescription of opioids and benzodiazepines have been linked to high risk of overdose-associated death. Tumor patients represent a unique subset of spine surgery patients and few studies have attempted to develop predictive models to anticipate long-term opioid and benzodiazepine use after spinal tumor resection. METHODS The IBM Watson Health MarketScan Database and Medicare Supplement were assessed to identify admissions for intradural tumor resection between 2007 and 2015. Adult patients were required to have at least 6 months of continuous preadmission baseline data and 12 months of continuous postdischarge follow-up. Primary outcomes were long-term opioid and benzodiazepine use, defined as at least 6 prescriptions within 12 months. Secondary outcomes were durations of opioid and benzodiazepine prescribing. Logistic regression models, with and without regularization, were trained on an 80% training sample and validated on the withheld 20%. RESULTS A total of 1,942 patients were identified. The majority of tumors were extramedullary (74.8%) and benign (62.5%). A minority of patients received arthrodesis (9.2%) and most patients were discharged to home (79.1%). Factors associated with postdischarge opioid use duration include tumor malignancy (vs benign, B=19.8 prescribed-days/year, 95% confidence interval [CI] 1.1–38.5) and intramedullary compartment (vs extramedullary, B=18.1 prescribed-days/year, 95% CI 3.3–32.9). Pre- and perioperative use of prescribed nonsteroidal anti-inflammatory drugs and gabapentin/pregabalin were associated with shorter and longer duration opioid use, respectively. History of opioid and history of benzodiazepine use were both associated with increased postdischarge opioid and benzodiazepine use. Intramedullary location was associated with longer duration postdischarge benzodiazepine use (B=10.3 prescribed-days/year, 95% CI 1.5–19.1). Among assessed models, elastic net regularization demonstrated best predictive performance in the withheld validation cohort when assessing both long-term opioid use (area under curve [AUC]=0.748) and long-term benzodiazepine use (AUC=0.704). Applying our model to the validation set, patients scored as low-risk demonstrated a 4.8% and 2.4% risk of long-term opioid and benzodiazepine use, respectively, compared to 35.2% and 11.1% of high-risk patients. CONCLUSIONS We developed and validated a parsimonious, predictive model to anticipate long-term opioid and benzodiazepine use early after intradural tumor resection, providing physicians opportunities to consider alternative pain management strategies.

Background: The coronavirus disease 2019 (COVID-19) pandemic heralded a number of indirect perturbations to patient behavior and disease epidemiology, and mounting evidence suggests that the COVID-19 pandemic may have exacerbated underlying health disparities along racial and socioeconomic (SES) groups for acute ischemic stroke (AIS). We used 1 large national insurance database to identify whether patient demographics, disease severity, or mechanical thrombectomy (MT) rates changed for the treatment and management of AIS during COVID-19. Methods: AIS patient records were queried from the Clinformatics® Data Mart Optum SES Database from the following 2 time periods: March 1, 2019-June 30, 2019 (pre-COVID-19), and March 1, 2020–June 30, 2020 (COVID-19). The database contains the longitudinal healthcare claims of approximately 77 million patients covered by a major insurance provider between 2003 and June 30, 2020 across all 50 states. Interrupted time-series analyses were used to assess trend differences before and after the COVID-19 pandemic. Results: During the pre-COVID-19 period (March 1, 2019-June 30, 2019), there were 9,072 patients who presented for AIS, compared to 7,366 during COVID-19 (March 1, 2020-June 30, 2020). In both periods, the majority of patients were white (66.83% pre-COVID-19 and 67.91% during COVID-19). The average hospitalization duration was not different during the 2 time periods (p = 0.632), nor were rates of MT (p = 0.260). Total inpatient costs rose slightly for the COVID-19 period (USD 30,739 vs. USD 29,406; p = 0.015), and the median National Institutes of Health Stroke Scale (NIHSS) score was higher during CO­VID-19 (5 vs. 4; p = 0.023). When longitudinal trends were assessed for rates of MT and average NIHSS score for black and white patients, no differences were noted during the CO­VID-19 pandemic. Patients without any undergraduate experience did not present with AIS in increasing or decreasing incidence during COVID-19 (p = 0.268), but they did undergo declining rates of MT (p = 0.013). Conclusions: In the largest SES analysis of AIS patients during the COVID-19 era, we found that several SES factors, including race and income, did not seem to significantly impact utilization of MT for the treatment of AIS or the severity of the stroke at presentation.

OBJECTIVE Although past studies have associated external-beam radiation therapy (EBRT) with higher incidences of secondary neoplasms (SNs), its effect on SN development from pediatric low-grade gliomas (LGGs), defined as WHO grade I and II gliomas of astrocytic or oligodendrocytic origin, is not well understood. Utilizing a national cancer registry, the authors sought to characterize the risk of SN development after EBRT treatment of pediatric LGG. METHODS A total of 1245 pediatric patient (aged 0–17 years) records from 1973 to 2015 were assembled from the Surveillance, Epidemiology, and End Results (SEER) database. Univariable and multivariable subdistribution hazard regression models were used to evaluate the prognostic impact of demographic, tumor, and treatment-related covariates. Propensity score matching was used to balance baseline characteristics. Cumulative incidence analyses measured the time to, and rate of, SN development, stratified by receipt of EBRT and controlled for competing mortality risk. The Fine and Gray semiparametric model was used to estimate future SN risk in EBRT- and non–EBRT-treated pediatric patients. RESULTS In this study, 366 patients received EBRT and 879 did not. Forty-six patients developed SNs after an LGG diagnosis, and 27 of these patients received EBRT (OR 3.61, 95% CI 1.90–6.95; p < 0.001). For patients alive 30 years from the initial LGG diagnosis, the absolute risk of SN development in the EBRT-treated cohort was 12.61% (95% CI 8.31–13.00) compared with 4.99% (95% CI 4.38–12.23) in the non–EBRT-treated cohort (p = 0.013). Cumulative incidence curves that were adjusted for competing events still demonstrated higher rates of SN development in the EBRT-treated patients with LGGs. After matching across available covariates and again adjusting for the competing risk of mortality, a clear association between EBRT and SN development remained (subhazard ratio 2.26, 95% CI 1.21–4.20; p = 0.010). CONCLUSIONS Radiation therapy was associated with an increased risk of future SNs for pediatric patients surviving LGGs. These data suggest that the long-term implications of EBRT should be considered when making treatment decisions for this patient population

Introduction Venous thromboembolism (VTE) management increasingly involves anticoagulation with direct oral anticoagulants (DOACs). Few studies have used competing-risks analyses to ascertain the mortality-adjusted hemorrhage and recurrent VTE (rVTE) risk of individual DOACs. Furthermore, hemorrhage risk factors in patients treated with apixaban remain underexplored. Materials and methods Patients diagnosed with VTE receiving anticoagulation were identified from the Optum Clinformatics Data Mart (2003–2019). Study endpoints included readmissions for intracranial hemorrhage (ICH), non-intracranial hemorrhage (non-ICH hemorrhage), and rVTE. Coarsened exact matching was used to balance baseline clinical characteristics. Complication incidence was evaluated using a competing-risks framework. We additionally modeled hemorrhage risk in apixaban-treated patients. Results Overall, 225,559 patients were included, of whom 34,201 received apixaban and 46,007 received rivaroxaban. Compared to rivaroxaban, apixaban was associated with decreased non-ICH hemorrhage (sHR = 0.560, 95%CI = 0.423–0.741), but not ICH, and rVTE (sHR = 0.802, 95%CI = 0.651–0.988) risk. This was primarily in emergent readmissions (sHR[emergent hemorrhage] = 0.515, 95%CI = 0.372–0.711; sHR[emergent rVTE] = 0.636, 95%CI = 0.488–0.830). Contributors to emergent hemorrhage in apixaban-treated patients include older age (sHR = 1.025, 95%CI = 1.011–1.039), female sex (sHR = 1.662, 95%CI = 1.252–2.207), prior prescription antiplatelet therapy (sHR = 1.591, 95%CI = 1.130–2.241), and complicated hypertension (sHR = 1.936, 95%CI = 1.134–3.307). Patients anticipated to be “high-risk” experienced elevated ICH (sHR = 3.396, 95%CI = 1.375–8.388) and non-ICH hemorrhage (sHR = 3.683, 95%CI = 2.957–4.588) incidence. Conclusions In patients with VTE receiving anticoagulation, apixaban was associated with reduced non-ICH hemorrhage and rVTE risk, compared to rivaroxaban. Risk reduction was restricted to emergent readmissions. We present a risk-stratification approach to predict hemorrhage in patients receiving apixaban, potentially guiding future clinical decision-making.

OBJECTIVE Traumatic brain injury (TBI) is a major cause of mortality and morbidity in Uganda and other low- and middle-income countries (LMICs). Due to the difficulty of long-term in-person follow-up, there is a paucity of literature on longitudinal outcomes of TBI in LMICs. Using a scalable phone-centered survey, this study attempted to investigate factors associated with both mortality and quality of life in Ugandan patients with TBI. METHODS A prospective registry of adult patients with TBI admitted to the neurosurgical ward at Mulago National Referral Hospital was assembled. Long-term follow-up was conducted between 10.4 and 30.5 months after discharge (median 18.6 months). Statistical analyses included univariable and multivariable logistic regression and Cox proportional hazards regression to elucidate factors associated with mortality and long-term recovery. RESULTS A total of 1274 adult patients with TBI were included, of whom 302 (23.7%) died as inpatients. Patients who died as inpatients received surgery less frequently (p < 0.001), had more severe TBI at presentation (p < 0.001), were older (p < 0.001), and were more likely to be female (p < 0.0001). Patients presenting with TBI resulting from assault were at reduced risk of inpatient death compared with those presenting with TBI caused by road traffic accidents (OR 0.362, 95% CI 0.128–0.933). Inpatient mortality and postdischarge mortality prior to follow-up were 23.7% and 9%, respectively. Of those discharged, 60.8% were reached through phone interviews. Higher Glasgow Coma Scale score at discharge (continuous HR 0.71, 95% CI 0.53–0.94) was associated with improved long-term survival. Tracheostomy (HR 4.38, 95% CI 1.05–16.7) and older age (continuous HR 1.03, 95% CI 1.009–1.05) were associated with poor long-term outcomes. More than 15% of patients continued to suffer from TBI sequelae years after the initial injury, including seizures (6.1%) and depression (10.0%). Despite more than 60% of patients seeking follow-up healthcare visits, mortality was still 9% among discharged patients, suggesting a need for improved longitudinal care to monitor recovery progress. CONCLUSIONS Inpatient and postdischarge mortality remain high following admission to Uganda’s main tertiary hospital with the diagnosis of TBI. Furthermore, posttraumatic sequelae, including seizures and depression, continue to burden patients years after discharge. Effective scalable solutions, including phone interviews, are needed to elucidate and address factors limiting in-hospital capacity and access to follow-up healthcare.

Purpose Although consensus guidelines for postresection stereotactic radiosurgery (SRS) for brain metastases recommend the surgical corridor leading to the resection cavity be included in the SRS plan, no study has reported patterns of tumor recurrence based on inclusion or exclusion of the corridor as a target. We reviewed tumor control and toxicity outcomes of postresection SRS for deep brain metastases based on whether or not the surgical corridor was targeted. Materials and Methods We retrospectively reviewed patients who had resected brain metastases treated with SRS between 2007 and 2018 and included only “deep” tumors (defined as located ≥1.0 cm from the pial surface before resection). Results In 66 deep brain metastases in 64 patients, the surgical corridor was targeted in 43 (65%). There were no statistical differences in the cumulative incidences of progression at 12 months for targeting versus not targeting the corridor, respectively, for overall local failure 2% (95% confidence interval [CI], 0%-11%) versus 9% (95% CI, 1%-25%; P = .25), corridor failure 0% (95% CI, 0%-0%) versus 9% (95% CI, 1%-25%; P = .06), cavity failure 2% (95% CI, 0%-11%) versus 0% (95% CI, 0%-0%; P = .91), and adverse radiation effect 5% (95% CI, 1%-15%) versus 13% (95% CI, 3%-30%; P = .22). Leptomeningeal disease (7%; 95% CI, 2%-18%) versus 26% (95% CI, 10%-45%; P = .03) was higher in those without the corridor targeted. Conclusions Omitting the surgical corridor in postoperative SRS for resected brain metastases was not associated with statistically significant differences in corridor or cavity recurrence or adverse radiation effect. As seen in recent prospective trials of postresection SRS, the dominant pattern of progression is within the resection cavity; omission of the corridor would yield a smaller SRS volume that could allow for dose escalation to potentially improve local cavity control.

Medullary thyroid carcinoma (MTC) often presents with advanced disease and takes an aggressive course as compared with more well-differentiated thyroid cancers. The role of adjuvant therapy, specifically external beam radiotherapy (EBRT), remains disputed. This study investigated the impact of EBRT on survival in MTC.Cross-sectional analysis of a national database.Patients with MTC were identified from the SEER program (Surveillance, Epidemiology, and End Results).Collected variables included age, sex, race, T and N stages, lymph node yield, and use of EBRT. Propensity score matching was performed to determine the association of EBRT with overall and disease-specific survival.A total of 2046 patients with locoregional MTC were identified. Of these, 152 received EBRT. Patients receiving EBRT were older and had more advanced disease. EBRT was not associated with differences in overall survival (hazard ratio, 1.12; 95% CI, 0.76-1.65) or disease-specific survival (1.66; 0.93-2.95), as well as in subset analysis of age and disease extent. Long-term overall survival was similar, with 77.3% (95% CI, 70.1%-85.3%) and 58.3% (48.2%-70.5%) of patients without EBRT alive at 5 and 10 years, respectively (vs 70.7% [63.2%-79.1%] and 52.3% [43.3%-63.2%] of patients with EBRT). There were no differences in 5- and 10-year disease-specific survival.EBRT was not associated with improved overall or disease-specific survival in patients with MTC. Decisions regarding EBRT must be made with consideration of morbidity relative to benefit for individual patients.

OBJECTIVECavernous malformations (CMs) are commonly treated cerebrovascular anomalies in the pediatric population; however, the data on radiographic recurrence of pediatric CMs after surgery are limited. The authors aimed to study the clinical presentation, outcomes, and recurrence rate following surgery for a large cohort of CMs in children.METHODSPediatric patients (≤ 18 years old) who had a CM resected at a single institution were identified and retrospectively reviewed. Fisher’s exact test of independence was used to assess differences in categorical variables. Survival curves were evaluated using the Mantel-Cox method.RESULTSFifty-three patients aged 3 months to 18 years underwent resection of 74 symptomatic CMs between 1996 and 2018 at a single institution. The median length of follow-up was 5.65 years. Patients most commonly presented with seizures (45.3%, n = 24) and the majority of CMs were cortical (58.0%, n = 43). Acute radiographic hemorrhage was common at presentation (64.2%, n = 34). Forty-two percent (n = 22) of patients presented with multiple CMs, and they were more likely to develop de novo lesions (71%) compared to patients presenting with a single CM (3.4%). Both radiographic hemorrhage and multiple CMs were independently prognostic for a higher risk of the patient requiring subsequent surgery. Fifty percent (n = 6) of the 12 patients with both risk factors required additional surgery within 2.5 years of initial surgery compared to none of the patients with neither risk factor (n = 9).CONCLUSIONSPatients with either acute radiographic hemorrhage or multiple CMs are at higher risk for subsequent surgery and require long-term MRI surveillance. In contrast, patients with a single CM are unlikely to require additional surgery and may require less frequent routine imaging.

BackgroundWhile dual antiplatelet therapy (dAPT) is standard of care following carotid artery stenting (CAS), the optimal dAPT regimen and duration has not been established.MethodsWe canvassed a large national database (IBM MarketScan) to identify patients receiving carotid endarterectomy (CEA) or CAS for treatment of ischemic stroke or carotid artery stenosis from 2007 to 2016. We performed univariable and multivariable regression methods to evaluate the impact of covariates on post-CAS stroke-free survival, including post-discharge antiplatelet therapy.ResultsA total of 79 084 patients diagnosed with ischemic stroke or carotid stenosis received CEA (71 178; 90.0%) or CAS (7906; 10.0%). After adjusting for covariates, ConclusionsIncreased duration of post-CAS dAPT is associated with lower rates of readmissions for stroke, and with increased risk of hemorrhagic complications, particularly extracranial hemorrhage. The potential benefit of prolonging dAPT with regard to ischemic complications must be balanced with the corresponding increased risk of predominantly extracranial hemorrhagic complications.

Radiologic screening of high-risk adults reduces lung-cancer-related mortality1,2; however, a small minority of eligible individuals undergo such screening in the United States3,4. The availability of blood-based tests could increase screening uptake. Here we introduce improvements to cancer personalized profiling by deep sequencing (CAPP-Seq)5, a method for the analysis of circulating tumour DNA (ctDNA), to better facilitate screening applications. We show that, although levels are very low in early-stage lung cancers, ctDNA is present prior to treatment in most patients and its presence is strongly prognostic. We also find that the majority of somatic mutations in the cell-free DNA (cfDNA) of patients with lung cancer and of risk-matched controls reflect clonal haematopoiesis and are non-recurrent. Compared with tumour-derived mutations, clonal haematopoiesis mutations occur on longer cfDNA fragments and lack mutational signatures that are associated with tobacco smoking. Integrating these findings with other molecular features, we develop and prospectively validate a machine-learning method termed 'lung cancer likelihood in plasma' (Lung-CLiP), which can robustly discriminate early-stage lung cancer patients from risk-matched controls. This approach achieves performance similar to that of tumour-informed ctDNA detection and enables tuning of assay specificity in order to facilitate distinct clinical applications. Our findings establish the potential of cfDNA for lung cancer screening and highlight the importance of risk-matching cases and controls in cfDNA-based screening studies.

Glioblastoma (GBM) is the most common primary central nervous system malignancy in adults and continues to carry a poor prognosis despite standard of care involving surgical resection and concomitant chemoradiotherapy. Recently, immunotherapy has become a rapidly evolving area of novel therapies for various cancers. For gliomas, antibodies including immune checkpoint inhibitors, such as anti-PD-1, and agents targeting tumor neovascularization were studied, but results from clinical trials show no survival benefit with immunotherapy in GBM. Combination immunotherapy and novel forms of targeted therapy are critical to ongoing and current GBM research. Because the glioma microenvironment is so immunosuppressive, therapies that address tumor-promoting cell populations and mechanisms are promising and could be synergistic with existing agents. Chemokine and chemokine receptors important to GBM development and malignancy include CXCL12 and its receptors CXCR4 and CXCR7, and targeting those axes has shown promise in improving survival rates in glioma models and deserves ongoing study in patients.

While machine learning has occupied a niche in clinical medicine for decades, continued method development and increased accessibility of medical data have led to broad diversification of approaches. These range from humble regression-based models to more complex artificial neural networks; yet, despite heterogeneity in foundational principles and architecture, the spectrum of machine learning approaches to clinical prediction modeling have invariably led to the development of algorithms advancing our ability to provide optimal care for our patients. In this chapter, we briefly review early machine learning approaches in medicine before delving into common approaches being applied for clinical prediction modeling today. For each, we offer a brief introduction into theory and application with accompanying examples from the medical literature. In doing so, we present a summarized image of the current state of machine learning and some of its many forms in medical predictive modeling.

OBJECTIVE Optimal management of pediatric Chiari malformation type I (CM-I) is much debated, chiefly due to the lack of validated tools for outcome assessment, with very few tools incorporating patient-centered measures of health-related quality of life (HRQOL). Although posterior fossa decompression (PFD) benefits a subset of patients, prediction of its impact across patients is challenging. The primary aim of this study was to investigate the role of patient-centered HRQOL measures in the assessment and prediction of outcomes after PFD. METHODS The authors collected HRQOL data from a cohort of 20 pediatric CM-I patients before and after PFD. The surveys included assessments of selected Patient-Reported Outcomes Measurement Information System (PROMIS) health domains and were used to generate the PROMIS preference (PROPr) score, which is a measure of HRQOL. PROMIS is a reliable standardized measure of HRQOL domains such as pain, fatigue, depression, and physical function, which are all relevant to CM-I. The authors then compared the PROPr scores with Chicago Chiari Outcome Scale (CCOS) scores derived from time-matched clinical documentation. Finally, the authors used the PROPr scores as an outcome measure to predict postsurgical HRQOL improvement at 1 year on the basis of patient demographic characteristics, comorbidities, and radiological and physical findings. The Wilcoxon signed-rank test, Mann-Whitney U-test, and Kendall’s correlation were used for statistical analysis. RESULTS Aggregate analysis revealed improvement of pain severity after PFD (p = 0.007) in anatomical patterns characteristic of CM-I. Most PROMIS domain scores trended toward improvement after surgery, with anxiety and pain interference reaching statistical significance (p < 0.002 and p < 0.03, respectively). PROPr scores also significantly improved after PFD (p < 0.008). Of the baseline patient characteristics, preexisting scoliosis was the most accurate negative predictor of HRQOL improvement after PFD (median −0.095 vs 0.106, p < 0.001). A correlation with modest magnitude (Kendall’s tau range 0.19–0.47) was detected between the patient-centered measures and CCOS score. CONCLUSIONS The authors observed moderate improvement of HRQOL, when measured using a modified panel of PROMIS question banks, in this pilot cohort of pediatric CM-I patients after PFD. Further investigations are necessary to validate this tool for children with CM-I and to determine whether these scores correlate with clinical and radiographic findings.

Background There is a lack of literature guiding treatment of giant cell glioblastoma (gcGBM), a rare subtype of glioblastoma (GBM). We used a national hospital-based registry to explore treatment patterns and outcomes associated with gcGBM. Methods Adult patients (age ≥18 years) diagnosed with gcGBM or GBM between 2004 and 2014 were identified from the National Cancer Database. χ2 analysis and Wilcoxon rank sum testing were used to compare characteristics between the gcGBM and GBM cohorts. Kaplan-Meier statistics, univariable and multivariable Cox regression, and propensity score matching were used to evaluate association between patient, tumor and treatment factors, and survival outcomes. Correlation analysis was used to evaluate historical trends in the treatment of gcGBM. Landmark analysis allowed for accounting of immortal time. Results In total, 683 patients with gcGBM were identified. Patients with gcGBM had improved survival compared with patients with GBM (15.5 months from landmark vs. 11.7; P $63,000 (P = 0.004) predisposed patients to improved outcomes. Patients receiving trimodal therapy (biopsy and/or surgery, radiotherapy, and chemotherapy) experienced better outcomes compared with those receiving either biopsy and/or surgery only or biopsy and/or surgery and radiotherapy without systemic therapy (median survival, 17.55 months vs. 6.68 months; P Conclusions gcGBM has favorable prognosis compared with GBM and should be aggressively managed with trimodal therapy. Prospective studies of gcGBM are warranted to better characterize gcGBM treatment outcomes.

Objective In the wake of the COVID-19 pandemic, the Centers for Medicare & Medicaid Services (CMS) has recommended the temporary cessation of all elective surgeries. The effects on patients' interest of elective neurosurgical procedures are currently unexplored. Methods Using Google Trends, search terms of 7 different neurosurgical procedure categories (trauma, spine, tumor, movement disorder, epilepsy, endovascular, and miscellaneous) were assessed in terms of relative search volume (RSV) between January 2015 and September 2020. Analyses of search terms were performed for over the short term (February 18, 2020, to April 18, 2020), intermediate term (January 1, 2020, to May 31, 2020), and long term (January 2015 to September 2020). State-level interest during phase I reopening (April 28, 2020, to May 31, 2020) was also evaluated. Results In the short term, RSVs of 4 categories (epilepsy, movement disorder, spine, and tumor) were significantly lower in the post-CMS announcement period. In the intermediate term, RSVs of 5 categories (miscellaneous, epilepsy, movement disorder, spine, and tumor) were significantly lower in the post-CMS announcement period. In the long term, RSVs of nearly all categories (endovascular, epilepsy, miscellaneous, movement disorder, spine, and tumor) were significantly lower in the post-CMS announcement period. Only the movement disorder procedure category had significantly higher RSV in states that reopened early. Conclusions With the recommendation for cessation of elective surgeries, patient interests in overall elective neurosurgical procedures have dropped significantly. With gradual reopening, there has been a resurgence in some procedure types. Google Trends has proven to be a useful tracker of patient interest and may be used by neurosurgical departments to facilitate outreach strategies.

We set to identify prognostic factors in a retrospective cohort of consecutive patients with stage I-II diffuse large B-cell lymphoma treated with rituximab-chemotherapy with or without radiotherapy from 2001 through 2017 at our institution. We identified 143 patients with median follow-up of 7.7 years. The majority were male (59.4%), had stage II (53.1%), had stage-modified IPI 0-1 (smIPI, 58.1%), and had non-bulky disease (7 cm, 68.5%). 99 patients (69.2%) received rituximab-chemotherapy followed by radiotherapy, and 44 patients (30.8%) received rituximab-chemotherapy alone. The 5-year progression-free survival (PFS) and overall survival (OS) were 81.2% and 88.9%, respectively. The 5-year PFS for those with smIPI 0-1 versus 2-4 was 89.5% versus 69.7%, respectively (

To describe opioid stewardship in ambulatory otologic surgery from 2005 to 2017.Descriptive study of US private insurance claims.Nationwide deidentified private insurance claims database (Clinformatics DataMart; Optum).A total of 17,431 adult opioid-naïve outpatients were included in the study. Patients were identified fromThe mean prescribed perioperative dose over the examined period was 203.03 MMEs (95% CI, 200.27-205.79; 5-mg hydrocodone pill equivalents, 40.61). In multivariate analysis, patients undergoing mastoid surgery were prescribed more opioids than those undergoing middle ear surgery (mean difference, 39.89 MME [95% CI, 34.37-45.41],While the amount of opioids prescribed perioperatively has declined in recent years, otologists should continue to be cognizant of potential overprescribing in light of previous studies of patients' relatively low opioid intake.

PURPOSE Patients with Diffuse Large B-cell Lymphoma (DLBCL) in need of immediate therapy are largely under-represented in clinical trials. The diagnosis-to-treatment interval (DTI) has recently been described as a metric to quantify such patient selection bias, with short DTI being associated with adverse risk factors and inferior outcomes. Here, we characterized the relationships between DTI, circulating tumor DNA (ctDNA), conventional risk factors, and clinical outcomes, with the goal of defining objective disease metrics contributing to selection bias. PATIENTS AND METHODS We evaluated pretreatment ctDNA levels in 267 patients with DLBCL treated across multiple centers in Europe and the United States using Cancer Personalized Profiling by Deep Sequencing. Pretreatment ctDNA levels were correlated with DTI, total metabolic tumor volumes (TMTVs), the International Prognostic Index (IPI), and outcome. RESULTS Short DTI was associated with advanced-stage disease ( P < .001) and higher IPI ( P < .001). We also found an inverse correlation between DTI and TMTV ( RS = −0.37; P < .001). Similarly, pretreatment ctDNA levels were significantly associated with stage, IPI, and TMTV (all P < .001), demonstrating that both DTI and ctDNA reflect disease burden. Notably, patients with shorter DTI had higher pretreatment ctDNA levels ( P < .001). Pretreatment ctDNA levels predicted short DTI independent of the IPI ( P < .001). Although each risk factor was significantly associated with event-free survival in univariable analysis, ctDNA level was prognostic of event-free survival independent of DTI and IPI in multivariable Cox regression (ctDNA: hazard ratio, 1.5; 95% CI [1.2 to 2.0]; IPI: 1.1 [0.9 to 1.3]; −DTI: 1.1 [1.0 to 1.2]). CONCLUSION Short DTI largely reflects baseline tumor burden, which can be objectively measured using pretreatment ctDNA levels. Pretreatment ctDNA levels therefore have utility for quantifying and guarding against selection biases in prospective DLBCL clinical trials.

Both artificial intelligence (AI) and clinical data acquisition are advancing at a rapid pace, making this an exciting time as clinicians and computer scientists collaborate to develop automated tools for understanding disease pathophysiology and improving patient care. The development of machine learning algorithms specific to pediatric diseases may help compensate for the pediatric evidence gap as well as the lack of pediatric subspecialists outside of major tertiary care centers. In this chapter, we review early efforts and ongoing advances in applying AI to pediatric disease diagnosis, prognosis, and management. Specifically we discuss studies addressing prematurity, childhood brain tumors, epilepsy, autism spectrum disorder, mood and psychotic disorders, hydrocephalus, traumatic brain injury, and other entities. We highlight the ongoing transition of clinical pediatrics into an increasingly computer-assisted field and discuss challenges and opportunities for growth in this arena.

7565 Background: Detection of circulating tumor DNA (ctDNA) has prognostic value in diverse tumors, including DLBCL. Despite uses for assessing molecular response to therapy, current methods using immunoglobulin or hybrid-capture sequencing have suboptimal sensitivity, particularly when disease-burden is low. This contributes to a high false negative rate at key milestones such as at the end of therapy (EOT; Kumar A, ASH 2020). We explored the utility of detecting multiple mutations (phased variants, PVs) on individual cell-free DNA (cfDNA) strands to improve MRD in DLBCL. Methods: We applied Phased Variant Enrichment and Detection Sequencing to track PVs from 485 specimens from 117 DLBCL patients undergoing first-line therapy. We sequenced cfDNA prior to, during, and after therapy to assess the prognostic value of MRD. We compared the performance of PhasED-Seq to current techniques, including SNV-based CAPP-Seq and duplex sequencing. Results: To establish its detection limit for ctDNA, we compared the background error-profile of of PVs and SNVs in cfDNA sequencing from healthy subjects. PV-detection by PhasED-Seq demonstrated a lower background profile than SNVs, even when considering duplex molecules (n = 12; 8.0e-7 vs 3.3e-5 and 1.2e-5; P < 0.0001). We also assessed analytical sensitivity within a ctDNA limiting dilution series from 3 patients, simulating tumor fractions from 0.1% to 0.00005% (1:2,000,000). PhasED-Seq outperformed SNV-based methods and duplex sequencing for recovery of expected tumor content below 0.01% (P < 0.0001 and P = 0.005 respectively by paired t-test). We then explored disease detection in clinical samples. We identified SNVs and PVs from pretreatment tumor or plasma and followed these variants in serial cfDNA. Using SNV-based methods, 40% and 59% of patients had undetectable ctDNA after 1 or 2 cycles (n = 82 and 88). However, 24% and 25% of these cases had detectable ctDNA by PhasED-Seq. Importantly, MRD detection by PhasED-Seq was prognostic for event-free survival even in patients with undetectable ctDNA by SNVs. We next explored the utility of PhasED-Seq at the EOT in 19 subjects, 5 of whom experienced eventual disease progression. While only 2/5 cases with progression had detectable disease at EOT using SNVs, PhasED-Seq detected all 5/5 cases. PhasED-Seq also correctly identified all patients (14/14) without clinical relapse as having no residual disease, including one patient who discontinued therapy after 1 cycle due to toxicity, but remains in remission > 5 years after this single treatment. This resulted in superior classification of patients for EFS using PVs compared with SNVs (C-statistic: 0.98 vs 0.60, P = 0.02). Conclusions: Tracking PVs results in significantly lower background rates than SNV-based approaches, enabling detection to parts per million range. PhasED-Seq improves on disease detection in DLBCL at the EOT, allowing possible MRD-driven consolidative approaches.

Oral corticosteroids are treatment mainstays for idiopathic sudden sensorineural hearing loss (SSNHL). Recent studies suggest that intratympanic (IT) steroid injections may be effective as an alternate or adjunctive therapy. We sought to investigate nationwide trends in treatment patterns for SSNHL.Retrospective cross-sectional study.A large nationwide health care claims database spanning 2007 to 2016.Patients with SSNHL were identified from the IBM Watson Health MarketScan Database. Multivariable logistic, linear, and Cox regression were used for demographic- and comorbidity-adjusted analyses.Overall, 19,670 patients were included. Between 2007 and 2016, use of oral corticosteroids alone decreased (83.6% to 64.6%,SSNHL management increasingly involves early IT steroids as an alternative or adjunctive option to oral steroids. Use of repeat IT corticosteroid injections has also increased but may raise risk of persistent tympanic membrane perforations and subsequent tympanoplasty. Future decision analysis and cost-effectiveness studies are necessary to identify an optimal care pattern for SSNHL.

Introduction: Road traffic injuries (RTIs) are an important contributor to the morbidity and mortality of developing countries. In Uganda, motorcycle taxis, known as boda bodas, are responsible for a growing proportion of RTIs. This study seeks to evaluate and comment on traffic safety trends from the past decade. Methods: Traffic reports from the Ugandan police force (2009 to 2017) were analyzed for RTI characteristics. Furthermore, one month of casualty ward data in 2015 and 2018 was collected from the Mulago National Referral Hospital and reviewed for casualty demographics and trauma type. Results: RTI motorcycle contribution rose steadily from 2009 to 2017 (24.5% to 33.9%). While the total number of crashes dropped from 22,461 to 13,244 between 2010 and 2017, the proportion of fatal RTIs increased from 14.7% to 22.2%. In the casualty ward, RTIs accounted for a greater proportion of patients and traumas in 2018 compared to 2015 (10%/41% and 36%/64%, respectively). Conclusions: Although RTIs have seen a gross reduction in Uganda, they have become more deadly, with greater motorcycle involvement. Hospital data demonstrate a rising need for trauma and neurosurgical care to manage greater RTI patient burden. Combining RTI prevention and care pathway improvements may mitigate current RTI trends.

Objective:We report a case of facial nerve paralysis post-endovascular embolization of a sigmoid sinus dural arterio-venous fistula from initial presentation to current management and discuss the merits of observation versus decompression through a systematic review of relevant literature.Patient:61 F with right facial palsy.Intervention:Following a single intravenous dexamethasone injection with oral steroids over 2 months, patient was observed with no additional treatment other than Botox chemodenervation and facial rehabilitation.Outcome and Results:The patient initially presented with complete right facial palsy (HB 6/6). Post-op CT imaging indicated Onyx (ev3, Irvine, California, USA) particles present at the geniculate segment of the facial nerve. Observation was chosen over surgical intervention. At the most current follow up of 8 months, facial function has improved substantially (HB 2/6).Conclusion:Facial palsy is a serious, though rare, complication of transarterial endovascular embolization. With our case report and literature review, we highlight not only how conservative observation is the recommended treatment, but also that facial nerve recovery should be expected to reach near complete recovery, but not sooner than in 3 months.

Introduction: Consensus is limited regarding optimal transcranial approaches (TCAs) for the surgical resection of olfactory groove meningiomas (OGMs). This systematic review and meta-analysis aims to examine operative and peri-operative outcomes of unilateral compared to bilateral TCAs for OGMs. Methods: Electronic databases were searched from inception until December 2019 for studies delineating TCAs for OGM patients. Patient demographics, pre-operative symptoms, surgical outcomes, and complications were evaluated and analyzed with a meta-analysis of proportions. Results: A total of 27 observational case series comparing 554 unilateral vs. 451 bilateral TCA patients were eligible for review. The weighted pooled incidence of gross total resection is 94.6% (95% CI, 90.7-97.5%; I 2 = 59.0%; p = 0.001) for unilateral and 90.9% (95% CI, 85.6-95.4%; I 2 = 58.1%; p = 0.003) for bilateral cohorts. Similarly, the incidence of OGM recurrence is 2.6% (95% CI, 0.4-6.0%; I 2 = 53.1%; p = 0.012) and 4.7% (95% CI, 1.4-9.2%; I 2 = 55.3%; p = 0.006), respectively. Differences in oncologic outcomes were not found to be statistically significant (p = 0.21 and 0.35, respectively). Statistically significant differences in complication rates in bilateral vs. unilateral TCA cohorts include meningitis (1.0 vs. 0.0%; p = 0.022) and mortality (3.2 vs. 0.2%; p = 0.007). Conclusions: While both cohorts have similar oncologic outcomes, bilateral TCA patients exhibit higher post-operative complication rates. This may be explained by underlying tumor characteristics necessitating more radical resection but may also indicate increased morbidity with bilateral approaches. However, evidence from more controlled, comparative studies is warranted to further support these findings.

Importance There is no consensus regarding optimal management of pleomorphic adenoma in adults. Objectives To compare parotidectomy with observation for the management of pleomorphic adenoma in patients 50 years or older by age. Design and Setting This decision analytical model was performed from November 21, 2019, to June 15, 2020, using a Markov model. Model variables and ranges were selected based on a literature review. A 1-way sensitivity analysis was performed to evaluate the age threshold at which each algorithm, either upfront elective parotidectomy or observation, would be favored. A Monte Carlo probabilistic sensitivity analysis using variable ranges was then performed 5 times with patients in the model assigned a starting age of 50, 60, 70, 80, and 90 years to assess how age at diagnosis would be associated with the model results. Main Outcomes and Measures Model outcomes were measured with quality-adjusted life-years (QALYs). Results In the study models, the age thresholds at which observation became more beneficial than parotidectomy were 88.5 years for patients with superficial lobe tumors (5.37 QALYs in favor of parotidectomy below this age, and 5.37 QALYs in favor of observation above this age) and 83.4 years for patients with deep lobe tumors (7.51 QALYs in favor of surgery below this age, and 7.51 QALYs in favor of observation above this age). There was no significant difference in outcomes between parotidectomy and observation among patients aged 70 to 80 years. Conclusions and Relevance This study suggests that the outcomes associated with parotidectomy and observation are similar at 70 years or older among patients with pleomorphic adenoma and that observation may be the favorable treatment in that age group.

BACKGROUND CONTEXT Despite established guidelines, long-term management of surgically-treated low back pain (LBP) and lower extremity pain (LEP) remains heterogeneous. Understanding care heterogeneity could inform future approaches for standardization of practices. PURPOSE To describe treatment heterogeneity in surgically-managed LBP and LEP. STUDY DESIGN/SETTING Retrospective study of a nationwide commercial database spanning inpatient and outpatient encounters for enrollees of eligible employer-supplied healthcare plans (2007-2016). PATIENT SAMPLE A population-based sample of opioid-naive adult patients with newly-diagnosed LBP or LEP were identified. Inclusion required at least 12-months of pre-diagnosis and post-diagnosis continuous follow-up. EXPOSURE Included treatments/evaluations include conservative management (chiropractic manipulative therapy, physical therapy, epidural steroid injections), imaging (x-ray, MRI, CT), pharmaceuticals (opioids, benzodiazepines), and spine surgery (decompression, fusion). OUTCOME MEASURES Primary outcomes-of-interest were 12-month net healthcare expenditures (inpatient and outpatient) and 12-month opioid usage. METHODS Analyses include interrogation of care sequence heterogeneity and temporal trends in sequence-initiating services. Comparisons were conducted in the framework of sequence-specific treatment sequences, which reflect the personalized order of healthcare services pursued by each patient. Outlier sequences characterized by high opioid use and costs were identified from frequently observed surgical treatment sequences using Mahalanobis distance. RESULTS A total of 2,496,908 opioid-naive adult patients with newly-diagnosed LBP or LEP were included (29,519 surgical). In the matched setting, increased care sequence heterogeneity was observed in surgical patients (0.51 vs. 0.12 previously-unused interventions/studies pursued per month). Early opioid and MRI use has decreased between 2008 and 2015 but is matched by increases in early benzodiazepine and x-ray use. Outlier sequences, characterized by increased opioid use and costs, were found in 5.8% of surgical patients. Use of imaging prior to conservative management was common in patients pursuing outlier sequences compared to non-outlier sequences (96.5% vs. 63.8%, p

OBJECTIVES Assess national trends in opioid prescription following pediatric tonsillectomy: 1) overall percentage receiving opioids and mean quantity, 2) changes during 2009-2017, and 3) determinants of prescription patterns. METHODS Cross-sectional analysis using 2009-2017 Optum claims data to identify opioid-naive children aged 1-18 with claims codes for tonsillectomy (n = 82,842). Quantities of opioids filled in outpatient pharmacies during the perioperative period were extracted and converted into milligram morphine equivalents (MMEs) for statistical comparison. Demographic, clinical, and socioeconomic predictors of opioid fill rate and quantity were determined using regression analyses. RESULTS In 2009, 83.3% of children received opioids, decreasing to 58.3% by 2017. Rates of all-cause readmissions and post-tonsillectomy hemorrhages were similar over time. Mean quantity received was 153.47MME (95% confidence intervals [95%CI]: 151.19, 155.76) and did not significantly change during 2009-2017. Opioids were more likely in older children and those with higher household income, but less likely in children with obstructive sleep apnea, other comorbidities, and Hispanic race. Higher quantities of opioids were more likely in older children, while lower quantities were associated with female sex, Hispanic race, and higher household income. Outpatient steroids were prescribed to 8.04% of patients, who were less likely to receive opioids. CONCLUSION While the percentage of children receiving post-tonsillectomy opioids decreased during 2009-2017, prescribed quantities remain high and have not decreased over time. Prescription practices were also influenced by clinical and sociodemographic factors. These results highlight the need for guidance, particularly with regard to opioid quantity, in children after tonsillectomy. LEVEL OF EVIDENCE N/A Laryngoscope, 131:E1722-E1729, 2021.

Objective Anticipating postdischarge complications after neurosurgery remains difficult. The LACE index, based on 4 hospitalization descriptors, stratifies patients by risk of 30-day postdischarge adverse events but has not been validated in a procedure-specific manner in neurosurgery. Our study sought to explore the usefulness of the LACE index in a population undergoing cranial neurosurgery and to develop an enhanced model, LACE-Cranial. Methods The OptumClinformatics Database was used to identify cranial neurosurgery admissions (2004–2017). Procedures were grouped as trauma/hematoma/intracranial pressure, open vascular, functional/pain, skull base, tumor, or endovascular. Adverse events were defined as postdischarge death/readmission. LACE-Cranial was developed using a logistic regression framework incorporating an expanded feature set in addition to the original LACE components. Results A total of 40,431 admissions were included. Predictions of 30-day readmissions was best for skull base (area under the curve [AUC], 0.636) and tumor (AUC, 0.63) admissions but was generally poor. Predictive ability of 30-day mortality was best for functional/pain admissions (AUC, 0.957) and poorest for trauma/hematoma/intracranial pressure admissions (AUC, 0.613). Across procedure types except for functional/pain, a high-risk LACE score was associated with higher postdischarge bundled payment costs. Incorporating features identified to contribute independent predictive value, the LACE-Cranial model achieved procedure-specific 30-day mortality AUCs ranging from 0.904 to 0.98. Prediction of 30-day and 90-day readmissions was also improved, with tumor and skull base cases achieving 90-day readmission AUCs of 0.718 and 0.717, respectively. Conclusions Although the unmodified LACE index shows inconsistent classification performance, the enhanced LACE-Cranial model offers excellent prediction of short-term postdischarge mortality across procedure groups and significantly improved anticipation of short-term postdischarge readmissions.

Medical malpractice is an important but often underappreciated topic within neurosurgery, particularly for surgeons in the early phases of practice. The practice of spinal neurosurgery involves substantial risk for litigation, as both the natural history of the conditions being treated and the operations being performed almost always carry the risk of permanent damage to the spinal cord or nerve roots, a cardiopulmonary event, death, or other dire outcomes. In this review, the authors discuss important topics related to medical malpractice in spine surgery, including tort reform, trends and frequency of litigation claims in spine surgery, wrong-level and wrong-site surgery, catastrophic outcomes including spinal cord injury and death, and ethical considerations.

Background Despite putative benefits associated with proton radiotherapy in the setting of CNS tumors, numerous barriers limit treatment accessibility. Given these challenges, we explored the association of proton use with variations in treatment timing. Methods Pediatric and adult patients with histologically confirmed CNS tumors were identified from the National Cancer Database (2004-2015). Univariable and multivariable regression models were constructed to assess factors impacting radiation timing. Multivariable Cox regression was used to evaluate the effect of treatment delay on survival. Results A total of 76 157 patients received photon or proton radiotherapy. Compared to photons, time to proton administration was longer in multiple pediatric (embryonal, ependymal, nonependymal glial, and other) and adult (ependymal, nonependymal glial, meningeal, other) tumor histologies. On adjusted analysis, proton radiotherapy was associated with longer delays in radiotherapy administration in pediatric embryonal tumors (+3.00 weeks, P = .024) and in all adult tumors (embryonal [+1.36 weeks, P = .018], ependymal [+3.15 weeks, P < .001], germ cell [+2.65 weeks, P = .024], glial [+2.15 weeks, P < .001], meningeal [+5.05 weeks, P < .001], and other [+3.06 weeks, P < .001]). In patients with high-risk tumors receiving protons, delays in adjuvant radiotherapy were independently associated with poorer survival (continuous [weeks], adjusted hazard ratio = 1.09, 95% CI = 1.02-1.16). Conclusions Proton radiotherapy is associated with later radiation initiation in pediatric and adult patients with CNS tumors. In patients with high-risk CNS malignancies receiving protons, delayed adjuvant radiotherapy is associated with poorer survival. Further studies are needed to understand this discrepancy to maximize the potential of proton radiotherapy for CNS malignancies.

PD-1 Immunotherapy is integral in treating multiple cancers, but has been associated with neurological adverse events (nAEs). Our study was aimed at identifying the clinical spectrum of nAEs associated with pembrolizumab and nivolumab. We performed an IRB approved single-center retrospective cohort study on patients receiving either pembrolizumab or nivolumab. Patients that developed nAEs within 12 months of treatment were identified. Descriptive statistics were conducted, and differences between groups were analyzed by the Chi-square or t test method. In total, 649 patients were identified. Seventeen patients (2.6%) developed nAEs. Eight of those were on pembrolizumab and nine were on nivolumab. Average age was 62.1 years. Ten were males and 7 were females. Most patients had melanoma (6, 35.3%). Patients who developed nAEs more frequently had intracranial lesions at initiation of anti PD-1 therapy compared to those who did not develop nAEs (76.5% vs 27.8%; p-value

Korrespondenz zu 10.1200/JCO.2018.78.5246

Background: Mutations in chromatin modifying genes (CMGs) including KMT2D, CREBBP, EZH2, and EP300 have been inferred as early events in follicular lymphoma (FL) by truncal status in mature tumors and persistence between diagnosis and relapse. We previously reported frequent detection of CREBBP lysine acetyltransferase (KAT) domain mutations in pre-diagnostic blood and tissue specimens from individuals later developing FL (Schroers-Martin et al, ASH Annual Meeting 2017). However, the limited availability of paired tumor biopsies has precluded confirmation of concordance between precursor lesions and subsequent clinical malignancy. Methods: The American Cancer Society (ACS) Cancer Prevention Study-II (CPS-II) LifeLink cohort collected screening blood or saliva samples from over 100,000 cancer-free American participants between 1998 and 2002. To evaluate detection of tumor-confirmed variants in pre-diagnostic specimens, we identified 29 FL patients with available FFPE tumor biopsy and screening sample (Fig A). The median age at screening was 71 years (range 56-83) with a median time to FL diagnosis of 56 months (TTD, range 6-139). Tumor biopsies were sequenced utilizing hybrid capture sequencing for commonly mutated lymphoma genes. DNA extracted from pre-diagnostic blood or saliva cell pellet specimens was sequenced utilizing error-corrected CAPP-Seq (Newman et al Nat Biotech 2016) to a median depth of 5204x. We sequenced to similar depths peripheral blood DNA from control cohorts of individuals with detectable t(14;18) but no subsequent lymphoma diagnosis (n=14) and healthy individuals without detectable t(14;18) by PCR (n=20). Results: Coding mutations were identified from all tumors with a mutational distribution similar to prior FL sequencing studies. Tumor-derived variants were detected in 7 of 29 paired pre-diagnostic specimens (24%) at a median TTD of 44 months (range 11-112 months, Fig B). The statistical significance of detection was assessed using a previously described approach based on Monte Carlo sampling (Newman et al Nat Biotech 2016) and the error distribution of affected loci in control cohorts. While an outlier case contained concordant TNFRSF14, FOXO1, and STAT6 mutations 90 months pre-diagnosis at an elevated allelic fraction (AF) of 1.8%, the mean AF of other detected precursor variants was 0.091%. Individuals with detected variants were not older (Fig C) nor significantly closer to clinical diagnosis (Fig D). The most frequently detected lesions were CREBBP (6/15 cases, 40%) and BCL2 (3/13, 23%) with one case demonstrating a fuller mutational profile including FOXO1 and ARID1A at 44 months before diagnosis. All detected precursor CREBBP variants localized to the KAT domain, reflecting prior observations in pre-diagnostic samples without confirmatory biopsy (Fig E). Of note, saliva cell pellets may contain 30% or more hematopoietic DNA (Kaur et al Chimerism 2012) and we detected tumor-confirmed variants in both saliva and blood screening specimens (Fig F) with no significant difference in AF (Fig G). In an illustrative independent case with available imaging, a patient undergoing radical prostatectomy was found to have involvement of a pelvic lymph node with in situ follicular neoplasia (ISFN). Staging PET/CT showed no evidence of FL (Fig H) and he was followed expectantly for 4 years without emergent disease. Eight years after surgery he presented with inguinal swelling and bilateral FDG-avid adenopathy on PET/CT. Excisional biopsy confirmed low grade FL and sequencing for M7-FLIPI revealed a CREBBP KAT domain variant. Retrospective sequencing of serial peripheral blood specimens from his initial surveillance showed detectable CREBBP R1446C at the earliest collected time point (AF range 0.019-0.046%) rising to AF 0.082% after clinical diagnosis. Conclusions: Precursor FL mutations are detectable in peripheral blood and saliva years prior to clinical diagnosis with a spectrum of variants enriched in CREBBP and BCL2 and concordant with subsequent FL tumors. Such lesions may assist in stratifying individuals at elevated risk of clinical malignancy, including after identification of pathologic precursors such as ISFN. Figure 1 Figure 1. Disclosures Kurtz: Foresight Diagnostics: Consultancy, Current holder of stock options in a privately-held company; Roche: Consultancy; Genentech: Consultancy. Khodadoust: Alexion, AstraZeneca Rare Disease: Other: Study investigator; CRISPR Therapeutics, Nutcracker Therapeutics: Research Funding; Myeloid Therapeutics: Membership on an entity's Board of Directors or advisory committees. Diehn: Roche: Consultancy; AstraZeneca: Consultancy; RefleXion: Consultancy; BioNTech: Consultancy; Varian Medical Systems: Research Funding; Illumina: Research Funding; CiberMed: Current holder of stock options in a privately-held company, Patents & Royalties; Foresight Diagnostics: Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Roulland: BMS: Research Funding. Alizadeh: Bristol Myers Squibb: Research Funding; Gilead: Consultancy; CAPP Medical: Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company; Celgene: Consultancy, Research Funding; Roche: Consultancy, Honoraria; Janssen Oncology: Honoraria; Foresight Diagnostics: Consultancy, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company; Cibermed: Consultancy, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company; Forty Seven: Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company.

Introduction Gliosarcomas are clinically aggressive tumors, histologically distinct from glioblastoma. Data regarding the impact of extent of resection and post-operative adjuvant therapy on gliosarcoma outcomes are limited. Methods Patients with histologically-confirmed gliosarcoma diagnosed between 1999 and 2019 were identified. Clinical, molecular, and radiographic data were assembled based on historical records. Comparisons of categorical variables used Pearson’s Chi-square and Fisher’s exact test while continuous values were compared using the Wilcoxon signed-rank test. Survival comparisons were assessed using Kaplan-Meier statistics and Cox regressions. Results Seventy-one gliosarcoma patients were identified. Secondary gliosarcoma was not associated with worse survival when compared to recurrent primary gliosarcoma (median survival 9.8 [3.8 to 21.0] months vs 7.6 [1.0 to 35.7], p = 0.7493). On multivariable analysis, receipt of temozolomide (HR = 0.02, 95% CI 0.001 to 0.21) and achievement of gross total resection (GTR; HR = 0.13, 95% CI 0.02 to 0.77) were independently prognostic for improved progression-free survival (PFS) while only receipt of temozolomide was independently associated with extended overall survival (OS) (HR = 0.03, 95% CI 0.001 to 0.89). In patients receiving surgical resection followed by radiotherapy and concomitant temozolomide, achievement of GTR was significantly associated with improved PFS (median 32.97 [7.1 to 79.6] months vs 5.45 [1.8 to 26.3], p = 0.0092) and OS (median 56.73 months [7.8 to 104.5] vs 14.83 [3.8 to 29.1], p = 0.0252). Conclusion Multimodal therapy is associated with improved survival in gliosarcoma. Even in patients receiving aggressive post-operative multimodal management, total surgical removal of macroscopic disease remains important for optimal outcomes.

Background Ventriculoperitoneal shunts are used to alleviate elevated intracranial pressure due to either hydrocephalus or idiopathic intracranial hypertension; however, shunt failure is a significant neurosurgical problem. Despite increases in intraoperative stereotactic navigation usage over the past decade, its effect on shunt survival remains unclear. Methods Shunt-naive pediatric and adult patients receiving ventriculoperitoneal shunting between 2007 and 2015 were identified in a national administrative database. Multivariable logistic and Cox regressions were used to evaluate factors affecting stereotaxy usage and shunt survival. Matched cohorts were generated by propensity score balancing. Results Of 9677 patients identified, 932 received image-guided shunt placement. Total shunt failure rate was not associated with stereotaxy use (20.3% with stereotaxy vs. 19.4% without, P = 0.4602). In the matched setting, shunt survival was not extended by use of image guidance during placement (hazard ratio = 1.134, 95% confidence interval 0.923–1.393). Late shunt failures (defined as failures occurring at least 30 days after shunt placement) caused by infection occurred more frequently in the stereotaxy cohort (hazard ratio = 2.207, 95% confidence interval 1.115–4.366), whereas late shunt failures attributable to mechanical shunt failure were more common in the nonstereotaxy cohort (hazard ratio = 1.406, 95% confidence interval 1.002–1.973). Conclusions Our findings suggest stereotaxy use during ventriculoperitoneal shunt placement does not affect shunt survival. Late shunt failures caused by infection occurred more frequently in the stereotaxy cohort, whereas late failures caused by mechanical shunt malfunction were more commonly encountered in the nonstereotaxy cohort.

Postoperative stereotactic radiosurgery (SRS) has less detrimental effect on cognition and quality of life compared with whole brain radiation therapy (WBRT) and is increasingly used for resected brain metastases (BMs). Postoperative SRS techniques are not standardized, and there is a concern for a different pattern of failure after postoperative SRS compared with WBRT. We aim to study the efficacy, toxicity, and failure pattern of postoperative SRS.We retrospectively reviewed outcomes of patients with resected BMs treated with postoperative SRS between 2007 and 2018. Overall survival and cumulative incidences of local failure, overall distant intracranial failure (distant parenchymal failure, nodular leptomeningeal disease [nLMD], classical leptomeningeal disease [cLMD]), and adverse radiation effect were reported. Neurologic death was determined for patients with leptomeningeal disease (LMD).A total of 442 patients with 501 resected BMs were treated over 475 total SRS courses. Median clinical follow-up and overall survival after SRS were 10.1 months (interquartile range, 3.6-20.7 months) and 13.9 months (95% confidence interval [CI], 11.8-15.2 months), respectively. At 12 months, event rates were 7% (95% CI, 5%-10%) for local failure, 9% (95% CI, 7%-12%) for adverse radiation effect, 44% (95% CI, 40%-49%) for overall distant intracranial failure, 37% (95% CI, 33%-42%) for distant parenchymal failure, and 13% (95% CI, 10%-17%) for LMD. The overall incidence of LMD was 15.8% (53% cLMD, 46% nLMD). cLMD was associated with shorter survival than nLMD (2.0 vs 11.2 months, P.01) and a higher proportion of neurologic death (67% vs 41%, P = .02). A total of 15% of patients ultimately received WBRT.We report the largest clinical experience of postoperative SRS for resected BMs, showing excellent local control and low toxicity. Intracranial failure was predominantly distant, with a rising incidence of LMD.

OBJECTIVE For patients with head and neck squamous cell carcinoma (HNSCC), delays in the initiation of radiotherapy (RT) have been closely associated with worse outcomes. We sought to investigate whether RT modality (proton vs. photon) is associated with differences in the time to initiation of RT. METHODS The National Cancer Database was queried for patients diagnosed with nonmetastatic HNSCC between 2004 and 2015 who received either proton or photon RT as part of their initial treatment. Wilcoxon rank-sum and chi-square tests were used to compare continuous and categorical variables, respectively. Multivariable logistic regression was used to determine the association between use of proton RT and delayed RT initiation. RESULTS A total of 175,088 patients with HNSCC receiving either photon or proton RT were identified. Patients receiving proton RT were more likely to be white, reside in higher income areas, and have private insurance. Proton RT was associated with delayed RT initiation compared to photon RT (median 59 days vs. 45, P

BACKGROUND Pediatric pineoblastomas are highly aggressive tumors that portend poor outcomes despite multimodal management. Controversy remains regarding optimal disease management. OBJECTIVE To evaluate patterns of care and optimal clinical management of pediatric pineoblastoma. METHODS A total of 211 pediatric (age 0-17 yr) histologically confirmed pineoblastoma patients diagnosed between 2004 and 2015 were queried from the National Cancer Database. Wilcoxon rank-sum statistics and chi-squared analyses were used to compare continuous and categorical variables, respectively. Univariable and multivariable Cox regressions were used to evaluate prognostic impact of covariates. Propensity-score matching was used to balance baseline characteristics. RESULTS Older patients (age ≥ 4 yr) experienced improved overall survival compared to younger patients (age

Importance The incidence of thyroid cancer is increasing by 3% annually. This increase is often thought to be attributable to overdiagnosis in adults. A previous study reported a 1.1% annual increase in the incidence of pediatric thyroid cancer. However, the analysis was limited to the period from 1973 to 2004 and was performed in a linear fashion, which does not account for changes in incidence trends over time. Objective To analyze trends in pediatric thyroid cancer incidence based on demographic and tumor characteristics at diagnosis. Design, Setting, and Participants This cross-sectional study included individuals younger than 20 years who had a diagnosis of thyroid cancer in the Surveillance, Epidemiology, and End Results (SEER) 9 database from 1973 to 2013. Cases of thyroid cancer were identified using theInternational Classification of Diseases for Oncology, Third Editionand were categorized by histologic type, stage, and tumor size. Main Outcomes and Measures Annual percent change (APC) in the incidence rates was calculated using joinpoint regression analysis. Results Among 1806 patients included in the analysis, 1454 (80.5%) were female and 1503 (83.2%) were white; most patients were aged 15 to 19 years. The overall incidence rates of thyroid cancer increased annually from 0.48 per 100 000 person-years in 1973 to 1.14 per 100 000 person-years in 2013. Incidence rates gradually increased from 1973 to 2006 (APC, 1.11%; 95% CI, 0.56%-1.67%) and then markedly increased from 2006 to 2013 (APC, 9.56%; 95% CI, 5.09%-14.22%). The incidence rates of large tumors (>20 mm) gradually increased from 1983 to 2006 (APC, 2.23%; 95% CI, 0.93%-3.54%) and then markedly increased from 2006 to 2013 (APC, 8.84%; 95% CI, 3.20%-14.79%); these rates were not significantly different from incidence rates of small (1-20 mm) tumors. The incidence rates of regionally extended thyroid cancer gradually increased from 1973 to 2006 (APC, 1.44%; 95% CI, 0.68%-2.21%) and then markedly increased from 2006 to 2013 (APC, 11.16%; 95% CI, 5.26%-17.40%); these rates were not significantly different from the incidence rates of localized disease. Conclusions and Relevance The incidence rates of pediatric thyroid cancer increased more rapidly from 2006 to 2013 than from 1973 to 2006. The findings suggest that there may be a co-occurring increase in thyroid cancer in the pediatric population in addition to enhanced detection.

Objective/Background: We report efficacy and toxicity outcomes with stereotactic radiosurgery (SRS) for intracranial and spinal ependymoma. Methods: We analyzed adult and pediatric patients with newly diagnosed or recurrent intracranial or spinal ependymoma lesions treated with SRS at our institution. Following SRS, local failure (LF) was defined as failure within or adjacent to the SRS target volume, while distant failure (DF) was defined as failure outside of the SRS target volume. Time to LF and DF was analyzed using competing risk analysis with death as a competing risk.Overall survival (OS) was calculated from the date of first SRS to the date of death or censored at the date of last follow-up using the Kaplan-Meier method. Results: Twenty-one patients underwent SRS to 40 intracranial (n = 30) or spinal (n = 10) ependymoma lesions between 2007 and 2018, most commonly with 18 or 20 Gy in 1 fraction. Median follow-up for all patients after first SRS treatment was 54 months (range 2–157). The 1-year, 2-year, and 5-year rates of survival among patients with initial intracranial ependymoma were 86, 74, and 52%, respectively. The 2-year cumulative incidences of LF and DF after SRS among intracranial ependymoma patients were 25% (95% CI 11–43) and 42% (95% CI 22–60), respectively. No spinal ependymoma patient experienced LF, DF, or death within 2 years of SRS. Three patients had adverse radiation effects. Conclusions: SRS is a viable treatment option for intracranial and spinal ependymoma with excellent local control and acceptable toxicity.

BACKGROUND: The morbidity and mortality associated with opioid and benzodiazepine co-prescription is a pressing national concern. Little is known about patterns of opioid and benzodiazepine use in patients with acute low back pain or lower extremity pain. OBJECTIVE: To characterize patterns of opioid and benzodiazepine prescribing among opioid-naïve, newly diagnosed low back pain (LBP) or lower extremity pain (LEP) patients and to investigate the relationship between benzodiazepine prescribing and long-term opioid use. DESIGN/SETTING: We performed a retrospective analysis of a commercial database containing claims for more than 75 million enrollees in the USA. PARTICIPANTS: Participants were adult patients newly diagnosed with LBP or LEP between 2008 and 2015 who did not have a red flag diagnosis, had not received an opioid prescription in the 6 months prior to diagnosis, and had 12 months of continuous enrollment after diagnosis. MAIN OUTCOMES AND MEASURES: Among patients receiving at least one opioid prescription within 12 months of diagnosis, we defined discrete patterns of benzodiazepine prescribing—continued use, new use, stopped use, and never use. We tested the association of these prescription patterns with long-term opioid use, defined as six or more fills within 12 months. RESULTS: We identified 2,497,653 opioid-naïve patients with newly diagnosed LBP or LEP. Between 2008 and 2015, 31.9% and 11.5% of these patients received opioid and benzodiazepine prescriptions, respectively, within 12 months of diagnosis. Rates of opioid prescription decreased from 34.8% in 2008 to 27.0% in 2015 (P

OBJECTIVEAdjuvant radiotherapy has become a common addition to the management of high-grade meningiomas, as immediate treatment with radiation following resection has been associated with significantly improved outcomes. Recent investigations into particle therapy have expanded into the management of high-risk meningiomas. Here, the authors systematically review studies on the efficacy and utility of particle-based radiotherapy in the management of high-grade meningioma.METHODSA literature search was developed by first defining the population, intervention, comparison, outcomes, and study design (PICOS). A search strategy was designed for each of three electronic databases: PubMed, Embase, and Scopus. Data extraction was conducted in accordance with the PRISMA guidelines. Outcomes of interest included local disease control, overall survival, and toxicity, which were compared with historical data on photon-based therapies.RESULTSEleven retrospective studies including 240 patients with atypical (WHO grade II) and anaplastic (WHO grade III) meningioma undergoing particle radiation therapy were identified. Five of the 11 studies included in this systematic review focused specifically on WHO grade II and III meningiomas; the others also included WHO grade I meningioma. Across all of the studies, the median follow-up ranged from 6 to 145 months. Local control rates for high-grade meningiomas ranged from 46.7% to 86% by the last follow-up or at 5 years. Overall survival rates ranged from 0% to 100% with better prognoses for atypical than for malignant meningiomas. Radiation necrosis was the most common adverse effect of treatment, occurring in 3.9% of specified cases.CONCLUSIONSDespite the lack of randomized prospective trials, this review of existing retrospective studies suggests that particle therapy, whether an adjuvant or a stand-alone treatment, confers survival benefit with a relatively low risk for severe treatment-derived toxicity compared to standard photon-based therapy. However, additional controlled studies are needed.