Progression-free survival versus post-progression survival and overall survival in WHO grade 2 gliomas.

BACKGROUND AND PURPOSE: Progression-free survival (PFS) remains to be validated as an outcome measure for diffuse WHO grade 2 gliomas, and knowledge about the relationships between PFS, post-progression survival (PPS), and overall survival (OS) in this subset of tumors is limited. We sought to assess correlations between PFS and OS, and identify factors associated with PFS, PPS, and OS in patients treated for diffuse supratentorial WHO grade 2 gliomas. MATERIAL AND METHODS: We included 319 patients from three independent observational cohorts. The correlation between PFS and OS was analyzed using independent exponential distributions for PFS and time from progression to death. Cox proportional hazards models were used to determine the effects of covariates on PFS, PPS, and OS. RESULTS: The overall correlation between PFS and OS was rs0.31. The correlation was rs 0.37 for astrocytomas and rs 0.19 for oligodendrogliomas. Longer PFS did not predict longer PPS. Patients with astrocytomas had shorter PFS, PPS, and OS. Larger preoperative tumor volume was a risk factor for shorter PFS, while older age was a risk factor for shorter PPS and OS. Patients who received early radio- and chemotherapy had longer PFS, but shorter PPS and OS. INTERPRETATION: We found a weak correlation between PFS and OS in WHO grade 2 gliomas, with the weakest correlation observed in oligodendrogliomas. Our analyses did not demonstrate any association between PFS and PPS. Critically, predictors of PFS are not necessarily predictors of OS. There is a need for validation of PFS as an endpoint in diffuse WHO grade 2 gliomas.

A multicenter study of clinical outcomes and volumetric trends in suspected microprolactinomas.

The diagnosis of pituitary microprolactinomas is often obscured by relatively low levels of elevated prolactin compared to macroprolactinomas. This may lead to varying patterns of medical therapy versus observation. We sought to correlate prolactin levels in suspected microprolactinomas with tumor volumes and clinical outcomes. This was a multicenter retrospective study of patients with pituitary microadenomas with baseline prolactin levels > 18ng/ml for males and > 30ng/ml for females. A linear-mixed model was used to depict changes in tumor volume over time. There were 65 patients with a mean tumor volume of 95.9mm3 and mean prolactin level of 59.4ng/ml. There were significantly higher prolactin levels in patients with tumors above the mean volume versus below (74.0 versus 53.4ng/ml, p = 0.027). 26 patients were observed, 31 were treated with anti-dopaminergic therapy, and 8 had surgery. There were significantly greater baseline prolactin levels for patients who were treated surgically (mean 86.4ng/ml) than those treated medically (mean 61.7 g/ml) or observed (mean 48.5ng/ml) (p = 0.02). Among the 26 patients who were surveilled, 13 patients demonstrated spontaneous tumor shrinkage, 12 remained stable, and 1 patient's tumor grew but was lost to follow-up. Linear mixed modeling demonstrated a statistically significant rate of tumor shrinkage over time of 3.67mm3/year (p = 0.03). When analyzing patients who were observed versus those requiring surgery after initially being surveilled, there were significantly greater baseline PRL/volume ratios in surgical patients versus those observed (8.1 ng/ml/mm3 versus 2.4 ng/ml/mm3, p = 0.025). Suspected microprolactinomas may demonstrate more convincingly elevated prolactin levels when measuring over 95.9mm3. Tumors with baseline prolactin levels over 50ng/ml may be more inclined to undergo medical treatment. In tumors with levels below 50ng/ml, it may be reasonable to undergo surveillance as these tumors tend to spontaneously shrink over time. In tumors that are surveilled, an elevated baseline PRL/volume ratio of > 8 ng/ml/mm3 may be indicate serial tumor growth that may necessitate medical and/or surgical intervention.

Methodological and ethical challenges in the use of focused ultrasound for blood-brain barrier disruption in neuro-oncology.

BACKGROUND: Focused ultrasound (FUS) shows promise for enhancing drug delivery to the brain by temporarily opening the blood-brain barrier (BBB), and it is increasingly used in the clinical setting to treat brain tumours. It remains however unclear whether FUS is being introduced in an ethically and methodologically sound manner. The IDEAL-D framework for the introduction of surgical innovations and the SYRCLE and ROBINS-I tools for assessing the risk of bias in animal studies and non-randomized trials, respectively, provide a comprehensive evaluation for this. OBJECTIVES AND METHODS: A comprehensive literature review on FUS in neuro-oncology was conducted. Subsequently, the included studies were evaluated using the IDEAL-D framework, SYRCLE, and ROBINS-I tools. RESULTS: In total, 19 published studies and 12 registered trials were identified. FUS demonstrated successful BBB disruption, increased drug delivery, and improved survival rates. However, the SYRCLE analysis revealed a high risk of bias in animal studies, while the ROBINS-I analysis found that most human studies had a high risk of bias due to a lack of blinding and heterogeneous samples. Of the 15 pre-clinical stage 0 studies, only six had formal ethical approval, and only five followed animal care policies. Both stage 1 studies and stage 1/2a studies failed to provide information on patient data confidentiality. Overall, no animal or human study reached the IDEAL-D stage endpoint. CONCLUSION: FUS holds promise for enhancing drug delivery to the brain, but its development and implementation must adhere to rigorous safety standards using the established ethical and methodological frameworks. The complementary use of IDEAL-D, SYRCLE, and ROBINS-I tools indicates a high risk of bias and ethical limitations in both animal and human studies, highlighting the need for further improvements in study design for a safe implementation of FUS in neuro-oncology.

Effect of awake craniotomy in glioblastoma in eloquent areas (GLIOMAP): a propensity score-matched analysis of an international, multicentre, cohort study.

BACKGROUND: Awake mapping has been associated with decreased neurological deficits and increased extent of resection in eloquent glioma resections. However, its effect within clinically relevant glioblastoma subgroups remains poorly understood. We aimed to assess the benefit of this technique in subgroups of patients with glioblastomas based on age, preoperative neurological morbidity, and Karnofsky Performance Score (KPS). METHODS: In this propensity score-matched analysis of an international, multicentre, cohort study (GLIOMAP), patients were recruited at four tertiary centres in Europe (Erasmus MC, Rotterdam and Haaglanden MC, The Hague, Netherlands, and UZ Leuven, Leuven, Belgium) and the USA (Brigham and Women's Hospital, Boston, MA). Patients were eligible if they were aged 18-90 years, undergoing resection, had a histopathological diagnosis of primary glioblastoma, their tumour was in an eloquent or near-eloquent location, and they had a unifocal enhancing lesion. Patients either underwent awake mapping during craniotomy, or asleep resection, as per treating physician or multidisciplinary tumour board decision. We used propensity-score matching (1:3) to match patients in the awake group with those in the asleep group to create a matched cohort, and to match patients from subgroups stratified by age (<70 years vs ≥70 years), preoperative National Institute of Health Stroke Scale (NIHSS) score (score of 0-1 vs ≥2), and preoperative KPS (90-100 vs ≤80). We used Cox proportional hazard regressions to analyse the effect of awake mapping on the primary outcomes including postoperative neurological deficits (measured by deterioration in NIHSS score at 6 week, 3 months, and 6 months postoperatively), overall survival, and progression-free survival. We used logistic regression to analyse the predictive value of awake mapping and other perioperative factors on postoperative outcomes. FINDINGS: Between Jan 1, 2010, and Oct 31, 2020, 3919 patients were recruited, of whom 1047 with tumour resection for primary eloquent glioblastoma were included in analyses as the overall unmatched cohort. After propensity-score matching, the overall matched cohort comprised 536 patients, of whom 134 had awake craniotomies and 402 had asleep resection. In the overall matched cohort, awake craniotomy versus asleep resection resulted in fewer neurological deficits at 3 months (26 [22%] of 120 vs 107 [33%] of 323; p=0·019) and 6 months (30 [26%] of 115 vs 125 [41%] of 305; p=0·0048) postoperatively, longer overall survival (median 17·0 months [95% CI 15·0-24·0] vs 14·0 months [13·0-16·0]; p=0·00054), and longer progression-free survival (median 9·0 months [8·0-11·0] vs 7·3 months [6·0-8·8]; p=0·0060). In subgroup analyses, fewer postoperative neurological deficits occurred at 3 months and at 6 months with awake craniotomy versus asleep resection in patients younger than 70 years (3 months: 22 [21%] of 103 vs 93 [34%] of 272; p=0·016; 6 months: 24 [24%] of 101 vs 108 [42%] of 258; p=0·0014), those with an NIHSS score of 0-1 (3 months: 22 [23%] of 96 vs 97 [38%] of 254; p=0·0071; 6 months: 27 [28%] of 95 vs 115 [48%] of 239; p=0·0010), and those with a KPS of 90-100 (3 months: 17 [19%] of 88 vs 74 [35%] of 237; p=0·034; 6 months: 24 [28%] of 87 vs 101 [45%] of 223, p=0·0043). Additionally, fewer postoperative neurological deficits were seen in the awake group versus the asleep group at 3 months in patients aged 70 years and older (two [13%] of 16 vs 15 [43%] of 35; p=0·033; no difference seen at 6 months), with a NIHSS score of 2 or higher (3 months: three [13%] of 23 vs 21 [36%] of 58; p=0·040) and at 6 months in those with a KPS of 80 or lower (five [18%] of 28 vs 34 [39%] of 88; p=0·043; no difference seen at 3 months). Median overall survival was longer for the awake group than the asleep group in the subgroups younger than 70 years (19·5 months [95% CI 16·0-31·0] vs 15·0 months [13·0-17·0]; p<0·0001), an NIHSS score of 0-1 (18·0 months [16·0-31·0] vs 14·0 months [13·0-16·5]; p=0·00047), and KPS of 90-100 (19·0 months [16·0-31·0] vs 14·5 months [13·0-16·5]; p=0·00058). Median progression-free survival was also longer in the awake group than in the asleep group in patients younger than 70 years (9·3 months [95% CI 8·0-12·0] vs 7·5 months [6·5-9·0]; p=0·0061), in those with an NIHSS score of 0-1 (9·5 months [9·0-12·0] vs 8·0 months [6·5-9·0]; p=0·0035), and in those with a KPS of 90-100 (10·0 months [9·0-13·0] vs 8·0 months [7·0-9·0]; p=0·0010). No difference was seen in overall survival or progression-free survival between the awake group and the asleep group for those aged 70 years and older, with NIHSS scores of 2 or higher, or with a KPS of 80 or lower. INTERPRETATION: These data might aid neurosurgeons with the assessment of their surgical strategy in individual glioblastoma patients. These findings will be validated and further explored in the SAFE trial (NCT03861299) and the PROGRAM study (NCT04708171). FUNDING: None.

Academic Output in Global Surgery after the Lancet Commission on Global Surgery: A Scoping Review.

BACKGROUND: The Lancet Commission on Global Surgery (LCoGS) published its seminal report in 2015, carving a niche for global surgery academia. Six years after the LCoGS, a scoping review was conducted to see how the term 'global surgery' is characterized by the literature and how it relates to LCoGS and its domains. METHODS: PubMed was searched for publications between January 2015 and February 2021 that used the term 'global surgery' in the title, abstract, or key words or cited the LCoGS. Variables extracted included LCoGS domains, authorship metrics, geographic scope, and clinical specialty. RESULTS: The search captured 938 articles that qualified for data extraction. Nearly 80% of first and last authors had high-income country affiliations. Africa was the most frequently investigated region, though many countries within the region were under-represented. The World Journal of Surgery was the most frequent journal, publishing 13.9% of all articles. General surgery, pediatric surgery, and neurosurgery were the most represented specialties. Of the LCoGS domains, healthcare delivery and management were the most studied, while economics and financing were the least studied. CONCLUSION: A lack of consensus on the definition of global surgery remains. Additional research is needed in economics and financing, while obstetrics and trauma are under-represented in literature using the term 'global surgery'. Efforts in academic global surgery must give a voice to those carrying the global surgery agenda forward on the frontlines. Focusing on research capacity-building and encouraging contribution by local partners will lead to a stronger, more cohesive global surgery community.

Passive Data Use for Ethical Digital Public Health Surveillance in a Postpandemic World.

There is a fundamental need to establish the most ethical and effective way of tracking disease in the postpandemic era. The ubiquity of mobile phones is generating large amounts of passive data (collected without active user participation) that can be used as a tool for tracking disease. Although discussions of pragmatism or economic issues tend to guide public health decisions, ethical issues are the foremost public concern. Thus, officials must look to history and current moral frameworks to avoid past mistakes and ethical pitfalls. Past pandemics demonstrate that the aftermath is the most effective time to make health policy decisions. However, an ethical discussion of passive data use for digital public health surveillance has yet to be attempted, and little has been done to determine the best method to do so. Therefore, we aim to highlight four potential areas of ethical opportunity and challenge: (1) informed consent, (2) privacy, (3) equity, and (4) ownership.

A Multimedia Fate Model to Support Chemical Management in China: A Case Study for Selected Trace Organics.

SESAMe v3.3, a spatially explicit multimedia fate model for China, is a tool suggested to support quantitative risk assessment for national scale chemical management. The key advantage over the previous version SESAMe v3.0 is consideration of spatially varied environmental pH. We evaluate the model performance using estimates of emission from total industry usage of three UV filters (benzophenone-3, octocrylene, and octyl methoxycinnamate) and three antimicrobials (triclosan, triclocarban, and climbazole). The model generally performs well for the six case study chemicals as shown by the comparison between predictions and measurements. The importance of accounting for chemical ionization is demonstrated with the fate and partitioning of both triclosan and climbazole sensitivity to environmental pH. The model predicts ionizable chemicals (triclosan, climbazole, benzophenone-3) to primarily partition into soils at steady state, despite hypothetically only being released to freshwaters, as a result of agricultural irrigation by freshwater. However, further model calibration is needed when more field data becomes available for soils and sediments and for larger areas of water. As an example, accounting for the effect of pH in the environmental risk assessment of triclosan, limited freshwater areas (0.03% or ca. 55 km(2)) in mainland China are modeled to exceed its conservative environmental no-effect threshold. SESAMe v3.3 can be used to support the development of chemical risk assessment methodologies with the spatial aspects of the model providing a guide to the identification regions of interest in which to focus monitoring campaigns or develop a refined risk assessment.

Evaluating the Utility of Repeat Computed Tomography Scans in Patients with Isolated Mild Traumatic Subarachnoid Hemorrhage.

BACKGROUND: Traumatic subarachnoid hemorrhage (tSAH) is a common consequence of head trauma. Treatment of patients with tSAH commonly involves serial computed tomography (CT) scans to assess for expansile hemorrhage. However, growing evidence suggests that these patients rarely deteriorate or require neurosurgical intervention. We assessed the utility of repeat CT scans in adult patients with isolated tSAH and an intact initial neurological examination. METHODS: Patients presenting to Mass General Brigham hospitals with tSAH between 2000 and 2021 were eligible for inclusion in this retrospective cohort study. Patients were excluded if subarachnoid hemorrhage was nontraumatic, they experienced another form of intracerebral hemorrhage, or they had a documented Glasgow Coma Scale score of ≤12 and/or poor presenting neurological examination. Univariate and multivariate regression models were used for statistical analysis. RESULTS: Overall, 405 patients were included (191 male). The most common mechanism of trauma was fall from standing (58%). The mean number of total CT scans for all patients was 2.3, with 329 patients (80%) receiving ≥2 scans. In 309 patients, no significant neurological symptoms were present. No patients developed acute neurological deterioration or required neurosurgical intervention related to their bleed, although 5 patients had mild hemorrhagic expansion on follow-up imaging. CONCLUSIONS: In this study, repeat imaging rarely demonstrated meaningful hemorrhagic expansion in this cohort of neurologically intact patients with isolated tSAH. In these patients with mild traumatic brain injury, excessive CT scans are perhaps unlikely to affect patient management and may present unnecessary burden to patients and hospital systems.

Comparative effectiveness of stereotactic, subdural, or hybrid intracranial EEG monitoring in epilepsy surgery.

OBJECTIVE: Surgical intervention can be curative or palliative for drug-resistant focal epilepsy. However, if the seizure onset zone (SOZ) cannot be adequately localized via noninvasive tests, intracranial EEG (iEEG) recordings are often carried out to develop surgical plans in appropriate candidates. Stereotactic EEG (SEEG), subdural EEG (SDE), and SDE with depth electrodes (hybrid) are major tools used for investigation, but there is no class 1 or 2 evidence comparing the effectiveness of these modalities. METHODS: The authors identified an institutional cohort of patients who underwent iEEG monitoring between 2001 and 2022. Demographic data, preoperative clinical features, iEEG intervention, and follow-up data were identified. Primary study endpoints included the following: 1) likelihood of SOZ localization; 2) likelihood of surgical treatment after iEEG; 3) seizure outcomes; and 4) complications. RESULTS: A total of 329 patients were identified (176 in the SEEG, 60 in the SDE, and 93 in the hybrid cohort) who were followed for a median of 5.4 (IQR 6.8) years. Baseline characteristics, including demographics, mean age at epilepsy diagnosis, mean age at iEEG investigation, number of preoperative antiseizure medications, and preoperative seizure frequency, were not statistically different across the 3 cohorts. Patients in the SEEG cohort were more likely to have their SOZ localized than were the patients in the SDE group (OR 2.3) and were less likely to undergo subsequent resection (OR 0.3) or to have complications (OR 0.4), although there was no statistical difference with respect to likelihood of undergoing any subsequent neurosurgical treatment, or with respect to favorable seizure outcomes. Patients in the hybrid cohort were more likely to have SOZ localized than were patients in the SDE group (OR 3.1), but were more likely to undergo resection (OR 4.9) or any neurosurgical treatment (OR 2.5) compared to patients in the SEEG group. Patients in the hybrid cohort had better seizure outcomes compared to the SDE (OR 2.3) but not to the SEEG group. CONCLUSIONS: Patients in the SEEG group were more likely to have their SOZ localized and patients in the SDE group were more likely to undergo resection, but they did not differ with respect to seizure outcomes.

Assessing Mobility in Patients With Glioblastoma Using Digital Phenotyping-Piloting the Digital Assessment in Neuro-Oncology.

BACKGROUND AND OBJECTIVES: Digital phenotyping (DP) enables objective measurements of patient behavior and may be a useful tool in assessments of quality-of-life and functional status in neuro-oncology patients. We aimed to identify trends in mobility among patients with glioblastoma (GBM) using DP. METHODS: A total of 15 patients with GBM enrolled in a DP study were included. The Beiwe application was used to passively collect patient smartphone global positioning system data during the study period. We estimated step count, time spent at home, total distance traveled, and number of places visited in the preoperative, immediate postoperative, and late postoperative periods. Mobility trends for patients with GBM after surgery were calculated by using local regression and were compared with preoperative values and with values derived from a nonoperative spine disease group. RESULTS: One month postoperatively, median values for time spent at home and number of locations visited by patients with GBM decreased by 1.48 h and 2.79 locations, respectively. Two months postoperatively, these values further decreased by 0.38 h and 1.17 locations, respectively. Compared with the nonoperative spine group, values for time spent at home and the number of locations visited by patients with GBM 1 month postoperatively were less than control values by 0.71 h and 2.79 locations, respectively. Two months postoperatively, time spent at home for patients with GBM was higher by 1.21 h and locations visited were less than nonoperative spine group values by 1.17. Immediate postoperative values for distance traveled, maximum distance from home, and radius of gyration for patients with GBM increased by 0.346 km, 2.24 km, and 1.814 km, respectively, compared with preoperative values. CONCLUSIONS: :Trends in patients with GBM mobility throughout treatment were quantified through the use of DP in this study. DP has the potential to quantify patient behavior and recovery objectively and with minimal patient burden.

Clinical Decision Support for Hypertension Management in Chronic Kidney Disease: A Randomized Clinical Trial.

Importance: Chronic kidney disease (CKD) affects 37 million adults in the United States, and for patients with CKD, hypertension is a key risk factor for adverse outcomes, such as kidney failure, cardiovascular events, and death. Objective: To evaluate a computerized clinical decision support (CDS) system for the management of uncontrolled hypertension in patients with CKD. Design, Setting, and Participants: This multiclinic, randomized clinical trial randomized primary care practitioners (PCPs) at a primary care network, including 15 hospital-based, ambulatory, and community health center-based clinics, through a stratified, matched-pair randomization approach February 2021 to February 2022. All adult patients with a visit to a PCP in the last 2 years were eligible and those with evidence of CKD and hypertension were included. Intervention: The intervention consisted of a CDS system based on behavioral economic principles and human-centered design methods that delivered tailored, evidence-based recommendations, including initiation or titration of renin-angiotensin-aldosterone system inhibitors. The patients in the control group received usual care from PCPs with the CDS system operating in silent mode. Main Outcomes and Measures: The primary outcome was the change in mean systolic blood pressure (SBP) between baseline and 180 days compared between groups. The primary analysis was a repeated measures linear mixed model, using SBP at baseline, 90 days, and 180 days in an intention-to-treat repeated measures model to account for missing data. Secondary outcomes included blood pressure (BP) control and outcomes such as percentage of patients who received an action that aligned with the CDS recommendations. Results: The study included 174 PCPs and 2026 patients (mean [SD] age, 75.3 [0.3] years; 1223 [60.4%] female; mean [SD] SBP at baseline, 154.0 [14.3] mm Hg), with 87 PCPs and 1029 patients randomized to the intervention and 87 PCPs and 997 patients randomized to usual care. Overall, 1714 patients (84.6%) were treated for hypertension at baseline. There were 1623 patients (80.1%) with an SBP measurement at 180 days. From the linear mixed model, there was a statistically significant difference in mean SBP change in the intervention group compared with the usual care group (change, -14.6 [95% CI, -13.1 to -16.0] mm Hg vs -11.7 [-10.2 to -13.1] mm Hg; P = .005). There was no difference in the percentage of patients who achieved BP control in the intervention group compared with the control group (50.4% [95% CI, 46.5% to 54.3%] vs 47.1% [95% CI, 43.3% to 51.0%]). More patients received an action aligned with the CDS recommendations in the intervention group than in the usual care group (49.9% [95% CI, 45.1% to 54.8%] vs 34.6% [95% CI, 29.8% to 39.4%]; P < .001). Conclusions and Relevance: These findings suggest that implementing this computerized CDS system could lead to improved management of uncontrolled hypertension and potentially improved clinical outcomes at the population level for patients with CKD. Trial Registration: ClinicalTrials.gov Identifier: NCT03679247.

The role of surgical management for prolactin-secreting tumors in the era of dopaminergic agonists: An international multicenter report.

OBJECTIVE: First-line prolactin-secreting tumor (PST) management typically involves treatment with dopamine agonists and the role of surgery remains to be further explored. We examined the international experience of 12 neurosurgical centers to assess the patient characteristics, safety profile, and effectiveness of surgery for PST management. METHODS: Patients surgically treated for PST from January 2017 through December 2020 were evaluated for surgical characteristics, outcomes, and safety. RESULTS: Among 272 patients identified (65.1% female), the mean age was 38.0 ± 14.3 years. Overall, 54.4% of PST were macroadenomas. Minor complications were seen in 39.3% of patients and major complications were in 4.4%. The most common major complications were epistaxis and worsened vision. Most minor complications involved electrolyte/sodium dysregulation. At 3-6 months, local control on imaging was achieved in 94.8% of cases and residual/recurrent tumor was seen in 19.3%. Reoperations were required for 2.9% of cases. On multivariate analysis, previous surgery was significantly predictive of intraoperative complications (6.14 OR, p < 0.01) and major complications (14.12 OR, p < 0.01). Previous pharmacotherapy (0.27 OR, p = 0.02) and cavernous sinus invasion (0.19 OR, p = 0.03) were significantly protective against early endocrinological cure. Knosp classification was highly predictive of residual tumor or PST recurrence on 6-month follow-up imaging (4.60 OR, p < 0.01). There was noted institutional variation in clinical factors and outcomes. CONCLUSION: Our results evaluate a modern, multicenter, global series of PST. These data can serve as a benchmark to compare with DA therapy and other surgical series. Further study and longer term outcomes could provide insight into how patients benefit from surgical treatment.

Onco-functional outcome after resection for eloquent glioblastoma (OFO): A propensity-score matched analysis of an international, multicentre, cohort study.

BACKGROUND: The combined impact of complete resection (oncological goal) and no functional loss (functional goal) in glioblastoma subgroups is currently unknown. This study aimed to develop a novel onco-functional outcome (OFO) to merge these two goals into one outcome, resulting in four classes: complete without deficits (OFO1), incomplete without deficits (OFO2), complete with deficits (OFO3), or incomplete with deficits (OFO4). METHODS: Between 2010-2020, 858 patients with tumor resection for eloquent glioblastoma were included. We analyzed the impact of OFO class on postoperative surgical outcomes using Cox proportional-hazards models with hazard ratios (HR) or logistic regression with odds ratios (OR), followed by specific subgroup analyses. We developed a risk model to predict OFO class preoperatively using logistic regression. RESULTS: The OFO classification stratified the four OFO classes for overall survival (OS:19.0 versus 14.0 versus 12.0 versus 9.0 months), progression-free survival (PFS), and adjuvant therapy. OFO1 was associated with improved OS [HR= 0.67, (0.55-0.81); p < 0.001], and PFS [HR = 0.68, (0.57-0.81); p < 0.001] in the overall cohort and all clinical and molecular subgroups, except for MGMT-unmethylated tumors; and higher rate of adjuvant therapy [OR= 2.81, (1.71-4.84);p < 0.001]. In patients≥ 70 years, only OFO1 improved their survival outcomes. Safe surgery was especially important in patients with a preoperative KPS ≤ 80 to qualify for adjuvant treatment. Awake craniotomy more often led to OFO1 compared to asleep resection [OR = 1.93, (1.19-3.14); p = 0.008]. CONCLUSIONS: OFO1 was associated with improved OS, PFS, and receipt of adjuvant therapy in all glioblastoma patients with IDH-wildtype and MGMT-methylated tumors. Awake craniotomy was associated with achieving this optimal OFO status. Preventing deficits was more important than complete surgery.

Open(ing) Access: Top Health Publication Availability to Researchers in Low- and Middle-Income Countries.

Introduction: Improving access to information for health professionals and researchers in low- and middle-income countries (LMICs) is under-prioritized. This study examines publication policies that affect authors and readers from LMICs. Methods: We used the SHERPA RoMEO database and publicly available publishing protocols to evaluate open access (OA) policies, article processing charges (APCs), subscription costs, and availability of health literature relevant to authors and readers in LMICs. Categorical variables were summarized using frequencies with percentages. Continuous variables were reported with median and interquartile range (IQR). Hypothesis testing procedures were performed using Wilcoxon rank sum tests, Wilcoxon rank sum exact tests, and Kruskal-Wallis test. Results: A total of 55 journals were included; 6 (11%) were Gold OA (access to readers and large charge for authors), 2 (3.6%) were subscription (charge for readers and small/no charge for authors), 4 (7.3%) were delayed OA (reader access with no charge after embargo), and 43 (78%) were hybrid (author's choice). There was no significant difference between median APC for life sciences, medical, and surgical journals ($4,850 [$3,500-$8,900] vs. $4,592 [$3,500-$5,000] vs. $3,550 [$3,200-$3,860]; p = 0.054). The median US individual subscription costs (USD/Year) were significantly different for life sciences, medical, and surgical journals ($259 [$209-$282] vs. $365 [$212-$744] vs. $455 [$365-$573]; p = 0.038), and similar for international readers. A total of seventeen journals (42%) had a subscription price that was higher for international readers than for US readers. Conclusions: Most journals offer hybrid access services. Authors may be forced to choose between high cost with greater reach through OA and low cost with less reach publishing under the subscription model under current policies. International readers face higher costs. Such hindrances may be mitigated by a greater awareness and liberal utilization of OA policies.

Refining Clinical Phenotypes to Improve Clinical Decision Support and Reduce Alert Fatigue: A Feasibility Study.

BACKGROUND: Chronic kidney disease (CKD) is common and associated with adverse clinical outcomes. Most care for early CKD is provided in primary care, including hypertension (HTN) management. Computerized clinical decision support (CDS) can improve the quality of care for CKD but can also cause alert fatigue for primary care physicians (PCPs). Computable phenotypes (CPs) are algorithms to identify disease populations using, for example, specific laboratory data criteria. OBJECTIVES: Our objective was to determine the feasibility of implementation of CDS alerts by developing CPs and estimating potential alert burden. METHODS: We utilized clinical guidelines to develop a set of five CPs for patients with stage 3 to 4 CKD, uncontrolled HTN, and indications for initiation or titration of guideline-recommended antihypertensive agents. We then conducted an iterative data analytic process consisting of database queries, data validation, and subject matter expert discussion, to make iterative changes to the CPs. We estimated the potential alert burden to make final decisions about the scope of the CDS alerts. Specifically, the number of times that each alert could fire was limited to once per patient. RESULTS: In our primary care network, there were 239,339 encounters for 105,992 primary care patients between April 1, 2018 and April 1, 2019. Of these patients, 9,081 (8.6%) had stage 3 and 4 CKD. Almost half of the CKD patients, 4,191 patients, also had uncontrolled HTN. The majority of CKD patients were female, elderly, white, and English-speaking. We estimated that 5,369 alerts would fire if alerts were triggered multiple times per patient, with a mean number of alerts shown to each PCP ranging from 0.07-to 0.17 alerts per week. CONCLUSION: Development of CPs and estimation of alert burden allows researchers to iteratively fine-tune CDS prior to implementation. This method of assessment can help organizations balance the tradeoff between standardization of care and alert fatigue.

External Ventricular Drains versus Intraparenchymal Pressure Monitors in the Management of Moderate to Severe Traumatic Brain Injury: Experience at Two Academic Centers over a Decade.

OBJECTIVE: The choice between external ventricular drain (EVD) and intraparenchymal monitor (IPM) for managing intracranial pressure in moderate-to-severe traumatic brain injury (msTBI) patients remains controversial. This study aimed to investigate factors associated with receiving EVD versus IPM and to compare outcomes and clinical management between EVD and IPM patients. METHODS: Adult msTBI patients at 2 similar academic institutions were identified. Logistic regression was performed to identify factors associated with receiving EVD versus IPM (model 1) and to compare EVD versus IPM in relation to patient outcomes after controlling for potential confounders (model 2), through odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: Of 521 patients, 167 (32.1%) had EVD and 354 (67.9%) had IPM. Mean age, sex, and Injury Severity Score were comparable between groups. Epidural hemorrhage (EDH) (OR 0.43, 95% CI 0.21-0.85), greater midline shift (OR 0.90, 95% CI 0.82-0.98), and the hospital with higher volume (OR 0.14, 95% CI 0.09-0.22) were independently associated with lower odds of receiving an EVD whereas patients needing a craniectomy were more likely to receive an EVD (OR 2.04, 95% CI 1.12-3.73). EVD patients received more intense medical treatment requiring hyperosmolar therapy compared to IPM patients (64.1% vs. 40.1%). No statistically significant differences were found in patient outcomes. CONCLUSIONS: While EDH, greater midline shift, and hospital with larger patient volume were associated with receiving an IPM, the need for a craniectomy was associated with receiving an EVD. EVD patients received different clinical management than IPM patients with no significant differences in patient outcomes.

Impact of maximal extent of resection on postoperative deficits, patient functioning, and survival within clinically important glioblastoma subgroups.

BACKGROUND: The impact of extent of resection (EOR), residual tumor volume (RTV), and gross-total resection (GTR) in glioblastoma subgroups is currently unknown. This study aimed to analyze their impact on patient subgroups in relation to neurological and functional outcomes. METHODS: Patients with tumor resection for eloquent glioblastoma between 2010 and 2020 at 4 tertiary centers were recruited from a cohort of 3919 patients. RESULTS: One thousand and forty-seven (1047) patients were included. Higher EOR and lower RTV were significantly associated with improved overall survival (OS) and progression-free survival (PFS) across all subgroups, but RTV was a stronger prognostic factor. GTR based on RTV improved median OS in the overall cohort (19.0 months, P < .0001), and in the subgroups with IDH wildtype tumors (18.5 months, P = .00055), MGMT methylated tumors (35.0 months, P < .0001), aged <70 (20.0 months, P < .0001), NIHSS 0-1 (19.0 months, P = .0038), KPS 90-100 (19.5 months, P = .0012), and KPS ≤80 (17.0 months, P = .036). GTR was significantly associated with improved OS in the overall cohort (HR 0.58, P = .0070) and improved PFS in the NIHSS 0-1 subgroup (HR 0.47, P = .012). GTR combined with preservation of neurological function (OFO 1 grade) yielded the longest survival times (median OS 22.0 months, P < .0001), which was significantly more frequently achieved in the awake mapping group (50.0%) than in the asleep group (21.8%) (P < .0001). CONCLUSIONS: Maximum resection was especially beneficial in the subgroups aged <70, NIHSS 0-1, and KPS 90-100 without increasing the risk of postoperative NIHSS or KPS worsening. These findings may assist surgical decision making in individual glioblastoma patients.

Crooke Cell Adenoma Confers Poorer Endocrinological Outcomes Compared with Corticotroph Adenoma: Results of a Multicenter, International Analysis.

BACKGROUND: Crooke cell adenomas (CCAs) are a rare, aggressive subset of secretory pituitary corticotroph adenomas (sCTAs) found in 5%-10% of patients with Cushing disease. Multiple studies support worse outcomes in CCAs but are limited by small sample size and single-institution databases. We compared outcomes in CCA and sCTA using a multicenter, international retrospective database of high-volume skull base centers. METHODS: Patients surgically treated for pituitary adenoma from January 2017 through December 2020 were included. RESULTS: Among 2826 patients from 12 international centers, 20 patients with CCA and 480 patients with sCTA were identified. No difference in baseline demographics, tumor characteristics, or postoperative complications was seen. Microsurgical approaches (60% CCA vs. 62.3% sCTA) were most common. Gross total resection was higher in CCA patients (100% vs. 83%, P = 0.05). Among patients with gross total resection according to intraoperative findings, fewer CCA patients had postoperative hormone normalization of pituitary function (50% vs. 77.8%, P < 0.01) and remission of hypersecretion by 3-6 months (75% vs. 84.3%, P < 0.01). This was the case despite CCA having better local control rates (100% vs. 96%, P < 0.01) and fewer patients with remnant on magnetic resonance imaging (0% vs. 7.2%, P < 0.01). A systematic literature review of 35 studies reporting on various treatment strategies reiterated the high rate of residual tumor, persistent hypercortisolism, and tumor-related mortality in CCA patients. CONCLUSIONS: This modern, multicenter series of patients with CCA reflects their poor prognosis and reduced postsurgical hormonal normalization. Further work is necessary to better understand the pathophysiology of CCA to devise more targeted treatment approaches.

Defining benchmark outcomes for transsphenoidal surgery of pituitary adenomas: a multicenter analysis.

IMPORTANCE: Benchmarks aid in improve outcomes for surgical procedures. However, best achievable results that have been validated internationally for transsphenoidal surgery (TS) are not available. OBJECTIVE: We aimed to establish standardized outcome benchmarks for TS of pituitary adenomas. DESIGN: A total of 2685 transsphenoidal tumor resections from 9 expert centers in 3 continents were analyzed. SETTING: Patients were risk stratified, and the median values of each center's outcomes were established. The benchmark was defined as the 75th percentile of all median values for a particular outcome. The postoperative benchmark outcomes included surgical factors, endocrinology-specific values, and neurology-specific values. RESULTS: Of 2685 patients, 1149 (42.8%) defined the low-risk benchmark cohort. Within these benchmark cases, 831 (72.3%) patients underwent microscopic TS, and 308 (26.8%) patients underwent endoscopic endonasal resection. Of all tumors, 799 (29.8%) cases invaded the cavernous sinus. The postoperative complication rate was 19.6% with mortality between 0.0% and 0.8%. Benchmark cutoffs were ≤2.9% for reoperation rate, ≤1.9% for cerebrospinal fluid leak requiring intervention, and ≤15.5% for transient diabetes insipidus. At 6 months, benchmark cutoffs were calculated as follows: readmission rate: ≤6.9%, new hypopituitarism ≤6.0%, and tumor remnant ≤19.2%. CONCLUSIONS: This analysis defines benchmark values for TS targeting morbidity and mortality and represents the best outcomes in the best patients in expert centers. These cutoffs can be used to assess different centers, patient populations, and novel surgical techniques. It should be noted that the benchmark values may influence each other and must be evaluated in their own context.