Safety and accuracy of stereoelectroencephalography for pediatric and young adult patients with prior craniotomy.

OBJECTIVE: The authors assessed the safety and accuracy of stereoelectroencephalography (SEEG) electrode implantation in pediatric patients who had previously undergone craniotomy compared to those without prior cranial surgery. METHODS: The authors performed a retrospective analysis of patients under 25 years of age with medically refractory epilepsy at a single institution who underwent SEEG electrode placement between March 2016 and July 2023. Surgical history and demographic characteristics were collected from the electronic medical records. The coordinates of the anchor bolts and their respective SEEG electrode contacts were manually annotated using postoperative head CT scans. Bolt coordinates were used to calculate the initiated electrode trajectory set by the bolt by using the least-squares method to define a line along the bolt, projected along the length of the electrode. The shortest distance from each electrode contact to this line was calculated to obtain the error measurement. Statistical analysis was conducted using the Kolmogorov-Smirnov test to compare the distribution of errors between groups, the Student t-test was used for continuous variables, and the chi-square/Fisher's exact test was used for categorical variables. RESULTS: Fifty-eight patients underwent a total of 60 SEEG placements and met the inclusion criteria. Eighteen had a history of prior craniotomy and 40 without prior surgery, indicating entirely native cranial bone. Mean age, sex, and mean number of electrodes implanted per surgery were similar between groups. For the electrode contact furthest from the bolt, a mean (IQR) deviation of 1.32 (0.73-2.53) mm was noted for the prior craniotomy group and 1.08 (0.65-1.55) mm for the native bone group (p < 0.0001). A greater number of outliers for the contact furthest from the bolt, defined as > 6 mm from the initiated electrode trajectory, was seen in the prior craniotomy group (p < 0.0001). The complication rate was low and not statistically different between groups. CONCLUSIONS: The authors' analysis draws attention to the effect of the intracranial biomechanical environment along the path of the electrode after traversing past the anchor bolt and found that prior craniotomy was associated with a higher number of contacts with a significant deviation from the initiated trajectory. Despite these deviations, we did not find a difference in the overall low complication rate in both groups. Therefore, the authors conclude that SEEG electrode placement is a safe option in pediatric patients even after prior craniotomy.

Predicting post-surgical functional status in high-grade glioma with resting state fMRI and machine learning.

PURPOSE: High-grade glioma (HGG) is the most common and deadly malignant glioma of the central nervous system. The current standard of care includes surgical resection of the tumor, which can lead to functional and cognitive deficits. The aim of this study is to develop models capable of predicting functional outcomes in HGG patients before surgery, facilitating improved disease management and informed patient care. METHODS: Adult HGG patients (N = 102) from the neurosurgery brain tumor service at Washington University Medical Center were retrospectively recruited. All patients completed structural neuroimaging and resting state functional MRI prior to surgery. Demographics, measures of resting state network connectivity (FC), tumor location, and tumor volume were used to train a random forest classifier to predict functional outcomes based on Karnofsky Performance Status (KPS < 70, KPS ≥ 70). RESULTS: The models achieved a nested cross-validation accuracy of 94.1% and an AUC of 0.97 in classifying KPS. The strongest predictors identified by the model included FC between somatomotor, visual, auditory, and reward networks. Based on location, the relation of the tumor to dorsal attention, cingulo-opercular, and basal ganglia networks were strong predictors of KPS. Age was also a strong predictor. However, tumor volume was only a moderate predictor. CONCLUSION: The current work demonstrates the ability of machine learning to classify postoperative functional outcomes in HGG patients prior to surgery accurately. Our results suggest that both FC and the tumor's location in relation to specific networks can serve as reliable predictors of functional outcomes, leading to personalized therapeutic approaches tailored to individual patients.

Predicting survival in glioblastoma with multimodal neuroimaging and machine learning.

PURPOSE: Glioblastoma (GBM) is the most common and aggressive malignant glioma, with an overall median survival of less than two years. The ability to predict survival before treatment in GBM patients would lead to improved disease management, clinical trial enrollment, and patient care. METHODS: GBM patients (N = 133, mean age 60.8 years, median survival 14.1 months, 57.9% male) were retrospectively recruited from the neurosurgery brain tumor service at Washington University Medical Center. All patients completed structural neuroimaging and resting state functional MRI (RS-fMRI) before surgery. Demographics, measures of cortical thickness (CT), and resting state functional network connectivity (FC) were used to train a deep neural network to classify patients based on survival (< 1y, 1-2y, >2y). Permutation feature importance identified the strongest predictors of survival based on the trained models. RESULTS: The models achieved a combined cross-validation and hold out accuracy of 90.6% in classifying survival (< 1y, 1-2y, >2y). The strongest demographic predictors were age at diagnosis and sex. The strongest CT predictors of survival included the superior temporal sulcus, parahippocampal gyrus, pericalcarine, pars triangularis, and middle temporal regions. The strongest FC features primarily involved dorsal and inferior somatomotor, visual, and cingulo-opercular networks. CONCLUSION: We demonstrate that machine learning can accurately classify survival in GBM patients based on multimodal neuroimaging before any surgical or medical intervention. These results were achieved without information regarding presentation symptoms, treatments, postsurgical outcomes, or tumor genomic information. Our results suggest GBMs have a global effect on the brain's structural and functional organization, which is predictive of survival.

Deferoxamine Prevents Neonatal Posthemorrhagic Hydrocephalus Through Choroid Plexus-Mediated Iron Clearance.

Posthemorrhagic hydrocephalus occurs in up to 30% of infants with high-grade intraventricular hemorrhage and is associated with the worst neurocognitive outcomes in preterm infants. The mechanisms of posthemorrhagic hydrocephalus after intraventricular hemorrhage are unknown; however, CSF levels of iron metabolic pathway proteins including hemoglobin have been implicated in its pathogenesis. Here, we develop an animal model of intraventricular hemorrhage using intraventricular injection of hemoglobin at post-natal day 4 that results in acute and chronic hydrocephalus, pathologic choroid plexus iron accumulation, and subsequent choroid plexus injury at post-natal days 5, 7, and 15. This model also results in increased expression of aquaporin-1, Na+/K+/Cl- cotransporter 1, and Na+/K+/ATPase on the apical surface of the choroid plexus 24 h post-intraventricular hemorrhage. We use this model to evaluate a clinically relevant treatment strategy for the prevention of neurological sequelae after intraventricular hemorrhage using intraventricular administration of the iron chelator deferoxamine at the time of hemorrhage. Deferoxamine treatment prevented posthemorrhagic hydrocephalus for up to 11 days after intraventricular hemorrhage and prevented the development of sensorimotor gating deficits. In addition, deferoxamine treatment facilitated acute iron clearance through the choroid plexus and subsequently reduced choroid plexus iron levels at 24 h with reversal of hemoglobin-induced aquaporin-1 upregulation on the apical surface of the choroid plexus. Intraventricular administration of deferoxamine at the time of intraventricular hemorrhage may be a clinically relevant treatment strategy for preventing posthemorrhagic hydrocephalus and likely acts through promoting iron clearance through the choroid plexus to prevent hemoglobin-induced injury.

Etiology- and region-specific characteristics of transependymal cerebrospinal fluid flow.

OBJECTIVE: Transependymal flow (TEF) of CSF, often delineated as T2-weighted hyperintensity adjacent to the lateral ventricles on MRI, is a known imaging finding, usually in the setting of CSF flow disturbances. Specific radiological features of TEF and their relationships with clinical markers of hydrocephalus and underlying disease pathology are not known. Here, the authors describe the radiological features and clinical associations of TEF with implications for CSF circulation in the setting of intracranial pathology. METHODS: After obtaining IRB review and approval, the authors reviewed the radiological records of all patients who underwent intracranial imaging with CT or MRI at St. Louis Children's Hospital, St. Louis, Missouri, between 2008 and 2019 to identify individuals with TEF. Then, under direct review of imaging, TEF pattern, degree, and location and underlying pathology and other radiological and clinical features pertaining to CSF circulation and CSF disturbances were noted. RESULTS: TEF of CSF was identified in 219 patients and was most prevalent in the setting of neoplasms (72%). In 69% of the overall cohort, TEF was seen adjacent to the anterior aspect of the frontal horns and the posterior aspect of the occipital horns of the lateral ventricles, and nearly half of these patients also had TEF dorsal to the third ventricle near the splenium of the corpus callosum. This pattern was independently associated with posterior fossa medulloblastoma when compared with pilocytic astrocytoma (OR 4.75, 95% CI 1.43-18.53, p = 0.0157). Patients with congenital or neonatal-onset hydrocephalus accounted for 13% of patients and were more likely to have TEF circumferentially around the ventricles without the fronto-occipital distribution. Patients who ultimately required permanent CSF diversion surgery were more likely to have the circumferential TEF pattern, a smaller degree of TEF, and a lack of papilledema at the time of CSF diversion surgery. CONCLUSIONS: CSF transmigration across the ependyma is usually restricted to specific periventricular regions and is etiology specific. Certain radiological TEF characteristics are associated with tumor pathology and may reflect impaired or preserved ependymal fluid handling and global CSF circulation. These findings have implications for TEF as a disease-specific marker and in understanding CSF handling within the brain.

Prescription Smoking-Cessation Medication Fills and Spending, 2009-2019.

INTRODUCTION: Smoking is the leading cause of preventable disease and death. However, effective medicines, including prescription medications often covered by health insurance, are available to aid cessation. METHODS: Trends of 7 U.S. Food and Drug Administration-approved prescription medications for smoking cessation during 2009-2019 (before and during Affordable Care Act implementation), including fill counts and spending (total and patient, adjusted to 2019 U.S. dollars), were assessed among U.S. adults aged ≥18 years. Symphony Health's Integrated Dataverse combines data on >90% of outpatient prescription fills with market purchasing data to create national estimates. Analyses were conducted in 2021. RESULTS: Annually, total fills (spending) decreased from 3.7 million ($577 million) in 2009 to 2.5 million ($465 million) in 2013 and increased to 4.5 million ($1.279 billion) in 2019; patient spending decreased from $174 million (30% of total annual spending) in 2009 to $54 million (4%) in 2019. Comparing 2009 with 2019, the total spending per fill increased by 80% (from $157 to $282), whereas patient spending per fill decreased by 75% (from $47 to $12). The total spending per fill for branded products increased by 175% (from $166 to $459) and decreased by 41% (from $75 to $44) for generic products. Branded product percentage decreased from 89% to 57%. CONCLUSIONS: Total fills and spending decreased from 2009 to 2013 and then increased through 2019, whereas patient spending decreased. Earlier studies suggest possible reasons for these trends, such as gradual implementation of federal requirements for insurance coverage of cessation medications and reduced cost sharing and financial barriers.

Multivariate analysis of associations between clinical sequencing and outcome in glioblastoma.

BACKGROUND: Many factors impact survival in patients with glioblastoma, including age, Karnofsky Performance Status, postoperative chemoradiation, IDH1/2 mutation status, MGMT promoter methylation status, and extent of resection. High-throughput next-generation sequencing is a widely available diagnostic tool, but the independent impact of tumors harboring specific mutant genes on survival and the efficacy of extent of resection are not clear. METHODS: We utilized a widely available diagnostic platform (FoundationOne CDx) to perform high-throughput next-generation sequencing on 185 patients with newly diagnosed glioblastoma in our tertiary care center. We performed multivariate analysis to control for clinical parameters with known impact on survival to elucidate the independent prognostic value of prevalent mutant genes and the independent impact of gross total resection. RESULTS: When controlling for factors with known prognostic significance including IDH1/2 mutation and after multiple comparisons analysis, CDKN2B and EGFR mutations were associated with reduced overall survival while PTEN mutation was associated with improved overall survival. Gross total resection, compared to other extent of resection, was associated with improved overall survival in patients with tumors harboring mutations in CDKN2A, CDKN2B, EGFR, PTEN, TERT promoter, and TP53. All patients possessed at least one of these 6 mutant genes. CONCLUSIONS: This study verifies the independent prognostic value of several mutant genes in glioblastoma. Six commonly found mutant genes were associated with improved survival when gross total resection was achieved. Thus, even when accounting for known predictors of survival and multiple mutant gene comparisons, extent of resection continues to be strongly associated with survival.

Single-center cost comparison analysis of stereoelectroencephalography with subdural grid and strip implantation.

OBJECTIVE: Use of invasive stereoelectroencephalography (SEEG) has gained traction recently. However, scant research has investigated the costs and resource utilization of SEEG compared with subdural grid (SDG)-based techniques in pediatric patients. Here, the authors have presented a retrospective analysis of charges associated with SEEG and SDG monitoring at a single institution. METHODS: The authors performed a retrospective case series analysis of pediatric patients with similar characteristics in terms of age, sex, seizure etiology, and epilepsy treatment strategy who underwent SEEG or SDG monitoring and subsequent craniotomy for resection of epileptogenic focus at St. Louis Children Hospital, St. Louis, Missouri, between 2013 and 2020. Financial data, including hospital charges, supplies, and professional fees (i.e., those related to anesthesia, neurology, neurosurgery, and critical care), were adjusted for inflation to 2020 US dollars. RESULTS: The authors identified 18 patients (9 underwent SEEG and 9 underwent SDG) with similar characteristics in terms of age (mean [range] 13.6 [1.9-21.8] years for SDG patients vs 11.9 [2.4-19.6] years for SEEG patients, p = 0.607), sex (4 females underwent SDG vs 6 females underwent SEEG, p = 0.637), and presence of lesion (5 patients with a lesion underwent SDG vs 8 underwent SEEG, p = 0.294). All patients underwent subsequent craniotomy for resection of epileptogenic focus. SEEG patients were more likely to have a history of status epilepticus (p = 0.029). Across 1 hospitalization for each SDG patient and 2 hospitalizations for each SEEG patient, SEEG patients had a significantly shorter mean operating room time (288 vs 356 minutes, p = 0.015), mean length of stay in the ICU (1.0 vs 2.1 days, p < 0.001), and tended to have a shorter overall length of stay in the hospital (8.4 vs 10.6 days, p = 0.086). Both groups underwent invasive monitoring for similar lengths of time (5.2 days for SEEG patients vs 6.4 days for SDG patients, p = 0.257). Time to treatment from the initial invasive monitoring evaluation was significantly longer in SEEG patients (64.6 vs 6.4 days, p < 0.001). Neither group underwent readmission within the first 30 days after hospital discharge. Seizure outcomes and complication rates were similar. After adjustment for inflation, the average total perioperative charges were $104,442 for SDG and $106,291 for SEEG (p = 0.800). CONCLUSIONS: Even though 2 hospitalizations were required for SEEG and 1 hospitalization was required for SDG monitoring, patients who underwent SEEG had a significantly shorter average length of stay in the ICU and operating room time. Surgical morbidity and outcomes were similar. Total perioperative charges for invasive monitoring and resection were approximately 2% higher for SEEG patients when corrected for inflation, but this difference was not statistically significant.

Nonmedical Marijuana Use and Cardiovascular Events: A Systematic Review.

INTRODUCTION: Although marijuana use has increased since 2012, the perceived risk of adverse outcomes has decreased. This systematic review summarizes articles that examined the association between nonmedical marijuana use (ie, observed smoking, self-report, or urinalysis) and cardiovascular events in observational or experimental studies of adults aged ≥18. METHODS: We searched Medline, EMBASE, PsycInfo, CINAHL, Cochrane Library Database, and Global Health from January 1, 1970, through August 31, 2018. Of 3916 citations, 16 articles fit the following criteria: (1) included adults aged ≥18; (2) included marijuana/cannabis use that is self-reported smoked, present in diagnostic coding, or indicated through a positive diagnostic test; (3) compared nonuse of cannabis; (4) examined events related to myocardial infarction, angina, acute coronary syndrome, and/or stroke; (5) published in English; and (6) had observational or experimental designs. RESULTS: Of the 16 studies, 4 were cohort studies, 8 were case-control studies, 1 was a case-crossover study, 2 were randomized controlled trials, and 1 was a descriptive study. Studies ranged from 10 participants to 118 659 619 hospitalizations. Marijuana use was associated with an increased likelihood of myocardial infarction within 24 hours in 2 studies and stroke in 6 studies. Results of studies suggested an increased risk for angina and acute coronary syndrome, especially among people with a history of a cardiovascular event. CONCLUSION: This review suggests that people who use marijuana may be at increased risk for cardiovascular events. As states expand new laws permitting marijuana use, it will be important to monitor the effect of marijuana use on cardiovascular disease outcomes, perhaps through the inclusion of data on nonmedical marijuana use in diverse national and local surveillance systems.

Resting-State Functional Magnetic Resonance Imaging Networks as a Quantitative Metric for Impact of Neurosurgical Interventions.

Objective: Resting-state functional MRI (rs-fMRI) has been used to evaluate brain network connectivity as a result of intracranial surgery but has not been used to compare different neurosurgical procedures. Laser interstitial thermal therapy (LITT) is an alternative to conventional craniotomy for the treatment of brain lesions such as tumors and epileptogenic foci. While LITT is thought of as minimally invasive, its effect on the functional organization of the brain is still under active investigation and its impact on network changes compared to conventional craniotomy has not yet been explored. We describe a novel computational method for quantifying and comparing the impact of two neurosurgical procedures on brain functional connectivity. Methods: We used a previously described seed-based correlation analysis to generate resting-state network (RSN) correlation matrices, and compared changes in correlation patterns within and across RSNs between LITT and conventional craniotomy for treatment of 24 patients with singular intracranial tumors at our institution between 2014 and 2017. Specifically, we analyzed the differences in patient-specific changes in the within-hemisphere correlation patterns of the contralesional hemisphere. Results: In a post-operative follow-up period up to 2 years within-hemisphere connectivity of the contralesional hemisphere after surgery was more highly correlated to the pre-operative state in LITT patients when compared to craniotomy patients (P = 0.0287). Moreover, 4 out of 11 individual RSNs demonstrated significantly higher degrees of correlation between pre-operative and post-operative network connectivity in patients who underwent LITT (all P < 0.05). Conclusion: Rs-fMRI may be used as a quantitative metric to determine the impact of different neurosurgical procedures on brain functional connectivity. Global and individual network connectivity in the contralesional hemisphere may be more highly preserved after LITT when compared to craniotomy for the treatment of brain tumors.

Neonatal hydrocephalus: an atypical presentation of malignant infantile osteopetrosis.

PURPOSE: Autosomal recessive osteopetrosis has a variable presentation, most commonly including failure to thrive, hypocalcemia, seizures, hepatosplenomegaly, hydrocephalus, vision or hearing loss, and cytopenias. Multiple symptoms are usually seen at presentation. The variability of presentation often delays diagnosis and subsequent treatment. Here, we present a case of an infant with this condition who initially presented with triventricular hydrocephalus with Chiari I malformation. This alone is not a common presentation of this disease, and we present this case to highlight autosomal recessive osteopetrosis as a potential diagnosis in infants presenting with hydrocephalus and discuss the other associated symptoms, management, and prognosis of this condition. CASE REPORT: The patient was a full-term infant with a routine newborn period. At 6 months, the infant had macrocephaly and frontal bossing with a bulging fontanelle. She was found to have hydrocephalus with moderate ventriculomegaly involving the third and lateral ventricles with an associated Chiari 1 malformation. The infant was asymptomatic at the time. The infant was promptly referred to neurosurgery and underwent an uncomplicated ventriculoperitoneal shunt placement. Post-operative X-rays showed increased density of the skull with other bone changes suggestive of autosomal recessive osteopetrosis. Subsequent lab work and imaging studies were consistent with this condition. The diagnosis was confirmed by genetic testing, and the patient has undergone treatment with hematopoietic stem cell transplant. CONCLUSION: Hydrocephalus is a common feature of this condition, typically seen in conjunction with other systemic symptoms and laboratory findings. Our patient had a limited initial presentation of triventricular hydrocephalus with Chiari I malformation and was otherwise clinically asymptomatic. There is limited literature of such a presentation, and we highlight this case to increase awareness, as timely diagnosis of these patients is critical for treatment and future outcomes.

Characteristics and trends of PCSK9 inhibitor prescription fills in the United States.

BACKGROUND: PCSK9 inhibitors were approved by the Food and Drug Administration in 2015 to lower low-density lipoprotein cholesterol (LDL-C) levels. In the years following, additional research findings, changes in national guideline recommendations, and price reductions have occurred. OBJECTIVE: The goal of the study is to describe the characteristics and trends in PCSK9 inhibitor prescription fills and price, from initial FDA approval in Quarter 3 2015 through Quarter 4 2019, at the national and state levels. METHODS: Cross-sectional study of fills obtained using the IQVIA National Prescription Audit®, Extended Insights, New to Brand, and Regional databases. Prescription fills included injections that provided cholesterol-lowering therapy from 14 to 90 days for the two PCSK9 inhibitors: alirocumab (75 mg/mL and 150 mg/mL) or evolocumab (140 mg/mL and 420 mg/3.5 mL). Quarterly prescription fills obtained nationally for Quarter 3 2015 through Quarter 4 2019, by sex, age, and state during 2019. RESULTS: Over the time period examined, 2.75 million PCSK9 inhibitor prescriptions were filled nationally (alirocumab: 38%; evolocumab: 62%), and the average retail price per fill (unadjusted $US) from retail pharmacies decreased by 40% from $1502 to $896 per fill. Year-over-year percent change in new PCSK9 inhibitor users increased throughout the observation period, with 9611 new alirocumab users and 25,381 new evolocumab users in Q4 2019. PCSK9 inhibitor fill rates ranged from 5.6 per 1000 in the Northeast to 3.4 per 1000 in the West in 2019, with the highest rate per 1000 in Louisiana (9.1), and lowest in Wyoming (1.3). CONCLUSIONS: PCSK9 inhibitor prescriptions have increased nationally since 2015, coinciding with additional evidence supporting their use for LDL-C lowering and cardiovascular event reduction. Although the retail price has decreased since introduction, cost and delivery mode likely continue as barriers.

Chemotherapy Knowledge Base Management in the Era of Precision Oncology.

Cancer medicine has grown increasingly complex in recent years with the advent of precision oncology and wide utilization of multidrug regimens. Representing this increasingly granular knowledge is a significant challenge. As users and managers of a freely available chemotherapy drug and regimen database, we describe the changes we have made to accommodate these challenges. These include the development of a domain ontology and increased granularity in the classification of cancer types on the website.

Seven decades of chemotherapy clinical trials: a pan-cancer social network analysis.

Clinical trials establish the standard of cancer care, yet the evolution and characteristics of the social dynamics between the people conducting this work remain understudied. We performed a social network analysis of authors publishing chemotherapy-based prospective trials from 1946 to 2018 to understand how social influences, including the role of gender, have influenced the growth and development of this network, which has expanded exponentially from fewer than 50 authors in 1946 to 29,197 in 2018. While 99.4% of authors were directly or indirectly connected by 2018, our results indicate a tendency to predominantly connect with others in the same or similar fields, as well as an increasing disparity in author impact and number of connections. Scale-free effects were evident, with small numbers of individuals having disproportionate impact. Women were under-represented and likelier to have lower impact, shorter productive periods (P < 0.001 for both comparisons), less centrality, and a greater proportion of co-authors in their same subspecialty. The past 30 years were characterized by a trend towards increased authorship by women, with new author parity anticipated in 2032. The network of cancer clinical trialists is best characterized as strategic or mixed-motive, with cooperative and competitive elements influencing its appearance. Network effects such as low centrality, which may limit access to high-profile individuals, likely contribute to the observed disparities.

The effect of thermal therapy on the blood-brain barrier and blood-tumor barrier.

The blood-brain and blood-tumor barriers represent highly specialized structures responsible for tight regulation of molecular transit into the central nervous system. Under normal circumstances, the relative impermeability of the blood-brain barrier (BBB) protects the brain from circulating toxins and contributes to a brain microenvironment necessary for optimal neuronal function. However, in the context of tumors and other diseases of central nervous system, the BBB and the more recently appreciated blood-tumor barrier (BTB) represent barriers that prevent effective drug delivery. Overcoming both barriers to optimize treatment of central nervous system diseases remains the subject of intense scientific investigation. Although many newer technologies have been developed to overcome these barriers, thermal therapy, which dates back to the 1890 s, has been known to disrupt the BBB since at least the early 1980s. Recently, as a result of several technological advances, laser interstitial thermal therapy (LITT), a method of delivering targeted thermal therapy, has gained widespread use as a surgical technique to ablate brain tumors. In addition, accumulating evidence indicates that laser ablation may also increase local BBB/BTB permeability after treatment. We herein review the structure and function of the BBB and BTB and the impact of thermal injury, including LITT, on barrier function.

Standardizing Chemotherapy Regimen Nomenclature: A Proposal and Evaluation of the HemOnc and National Cancer Institute Thesaurus Regimen Content.

PURPOSE: Due to decades of nonstandardized approaches to the naming of chemotherapy regimens, representation in electronic health records and secondary systems is highly variable. This hampers efforts to understand patterns of chemotherapy usage at the population level. In this article, we describe a proposal for rules to standardize the nomenclature of chemotherapy regimens and illustrate applications of these rules. METHODS: Through our experience with building HemOnc.org, which has been under construction since 2011, we formulated a set of guidelines and recommendations for the standard representation of chemotherapy regimen names. We then performed a mapping between the HemOnc and National Cancer Institute Thesaurus vocabulary's regimens and evaluated conformance with the naming conventions. Finally, we assembled a database of acronyms and names for multiple myeloma regimens to illustrate the scope of the problem. RESULTS: For the first use case, 242 of 527 (45.1%) of the regimen names differed. The schema was able to allocate a preferred source for 217 (89.4%) of these regimens. For the second use case, we expanded 130 multiple myeloma regimens to 1,138 unique regimen names and demonstrate ways in which the schema can collapse these into disambiguated, but abbreviated, regimen names. CONCLUSION: To our knowledge, this is the first proposal to normalize chemotherapy regimen nomenclature. If our recommendations are adopted, we expect that the uniformity of treatment exposure representation in hematology/oncology will increase, which will enable large-scale efforts such as ASCO's CancerLinQ to achieve better standardization.

HemOnc: A new standard vocabulary for chemotherapy regimen representation in the OMOP common data model.

Systematic application of observational data to the understanding of impacts of cancer treatments requires detailed information models allowing meaningful comparisons between treatment regimens. Unfortunately, details of systemic therapies are scarce in registries and data warehouses, primarily due to the complex nature of the protocols and a lack of standardization. Since 2011, we have been creating a curated and semi-structured website of chemotherapy regimens, HemOnc.org. In coordination with the Observational Health Data Sciences and Informatics (OHDSI) Oncology Subgroup, we have transformed a substantial subset of this content into the OMOP common data model, with bindings to multiple external vocabularies, e.g., RxNorm and the National Cancer Institute Thesaurus. Currently, there are >73,000 concepts and >177,000 relationships in the full vocabulary. Content related to the definition and composition of chemotherapy regimens has been released within the ATHENA tool (athena.ohdsi.org) for widespread utilization by the OHDSI membership. Here, we describe the rationale, data model, and initial contents of the HemOnc vocabulary along with several use cases for which it may be valuable.

Computerized Approach to Creating a Systematic Ontology of Hematology/Oncology Regimens.

Purpose: The systemic treatment of cancer is primarily through the administration of complex chemotherapy protocols. To date, this knowledge has not been systematized, because of the lack of a consistent nomenclature and the variation in which regimens are documented. For example, recording of treatment events in electronic health record notes is often through shorthand and acronyms, limiting secondary use. A standardized hierarchic ontology of cancer treatments, mapped to standard nomenclatures, would be valuable to a variety of end users. Methods: We leveraged the knowledge contained in a large wiki of hematology/oncology drugs and treatment regimens, HemOnc.org. Through algorithmic parsing, we created a hierarchic ontology of treatment concepts in the World Wide Web Consortium Web Ontology Language. We also mapped drug names to RxNorm codes and created optional filters to restrict the ontology by disease and/or drug class. Results: As of December 2017, the main ontology includes 30,526 axioms (eg, doxorubicin is an anthracycline), 1,196 classes (eg, regimens used in the neoadjuvant treatment of human epidermal growth factor receptor 2-positive breast cancer, nitrogen mustards), and 1,728 individual entities. More than 13,000 of the axioms are annotations including RxNorm codes, drug synonyms, literature references, and direct links to published articles. Conclusion: This approach represents, to our knowledge, the largest effort to date to systematically categorize and relate hematology/oncology drugs and regimens. The ontology can be used to reason individual components from regimens mentioned in electronic health records (eg, R-CHOP maps to rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) and also to probabilistically reconstruct regimens from individual drug components. These capabilities may be particularly valuable in the implementation of rapid-learning health systems on the basis of real-world evidence. The derived Web Ontology Language ontology is freely available for noncommercial use through the Creative Commons 4.0 Attribution-NonCommercial-ShareAlike license.

Subcellular Parkinson's Disease-Specific Alpha-Synuclein Species Show Altered Behavior in Neurodegeneration.

Parkinson's disease and other synucleinopathies are characterized by the presence of intra-neuronal protein aggregates enriched in the presynaptic protein α-synuclein. α-synuclein is considered an intrinsically disordered 14 kDa monomer, and although poorly understood, its transition to higher-order multimeric species may play central roles in healthy neurons and during Parkinson's disease pathogenesis. In this study, we demonstrate that α-synuclein exists as defined, subcellular-specific species that change characteristics in response to oxidative stress in neuroblastoma cells and in response to Parkinson's disease pathogenesis in human cerebellum and frontal cortex. We further show that the phosphorylation patterns of different α-synuclein species are subcellular specific and dependent on the oxidative environment. Using high-performance liquid chromatography and mass spectrometry, we identify a Parkinson's disease enriched, cytosolic ~36-kDa α-synuclein species which can be recapitulated in Parkinson's disease model neuroblastoma cells. The characterization of subcellular-specific α-synuclein features in neurodegeneration will allow for the identification of neurotoxic α-synuclein species, which represent prime targets to reduce α-synuclein pathogenicity.

Overcoming the Straw Man Effect in Oncology: Visualization and Ranking of Chemotherapy Regimens Using an Information Theoretic Approach.

PURPOSE: Despite the plethora of randomized controlled trial (RCT) data, most cancer treatment recommendations are formulated by experts. Alternatively, network meta-analysis (NMA) is one method of analyzing multiple indirect treatment comparisons. However, NMA does not account for mixed end points or temporality. Previously, we described a prototype information theoretical approach for the construction of ranked chemotherapy treatment regimen networks. Here, we propose modifications to overcome an apparent straw man effect, where the most studied regimens were the most negatively valued. METHODS: RCTs from two scenarios-upfront treatment of chronic myelogenous leukemia and relapsed/refractory multiple myeloma-were assembled into ranked networks using an automated algorithm based on effect sizes, statistical significance, surrogacy of end points, and time since RCT publication. Vertex and edge color, transparency, and size were used to visually analyze the network. This analysis led to the additional incorporation of value propagation. RESULTS: A total of 18 regimens with 42 connections (chronic myelogenous leukemia) and 28 regimens with 25 connections (relapsed/refractory multiple myeloma) were analyzed. An initial negative correlation between vertex value and size was ameliorated after value propagation, although not eliminated. Updated rankings were in close agreement with published guidelines and NMAs. CONCLUSION: Straw man effects can distort the comparative efficacy of newer regimens at the expense of older regimens, which are often cheaper or less toxic. Using an automated method, we ameliorated this effect and produced rankings consistent with common practice and published guidelines in two distinct cancer settings. These findings are likely to be generalizable and suggest a new means of ranking efficacy in cancer trials.