Multiomic screening of invasive GBM cells reveals targetable transsulfuration pathway alterations.

While the poor prognosis of glioblastoma arises from the invasion of a subset of tumor cells, little is known of the metabolic alterations within these cells that fuel invasion. We integrated spatially addressable hydrogel biomaterial platforms, patient site-directed biopsies, and multiomics analyses to define metabolic drivers of invasive glioblastoma cells. Metabolomics and lipidomics revealed elevations in the redox buffers cystathionine, hexosylceramides, and glucosyl ceramides in the invasive front of both hydrogel-cultured tumors and patient site-directed biopsies, with immunofluorescence indicating elevated reactive oxygen species (ROS) markers in invasive cells. Transcriptomics confirmed upregulation of ROS-producing and response genes at the invasive front in both hydrogel models and patient tumors. Among oncologic ROS, H2O2 specifically promoted glioblastoma invasion in 3D hydrogel spheroid cultures. A CRISPR metabolic gene screen revealed cystathionine γ-lyase (CTH), which converts cystathionine to the nonessential amino acid cysteine in the transsulfuration pathway, to be essential for glioblastoma invasion. Correspondingly, supplementing CTH knockdown cells with exogenous cysteine rescued invasion. Pharmacologic CTH inhibition suppressed glioblastoma invasion, while CTH knockdown slowed glioblastoma invasion in vivo. Our studies highlight the importance of ROS metabolism in invasive glioblastoma cells and support further exploration of the transsulfuration pathway as a mechanistic and therapeutic target.

Multi-omic screening of invasive GBM cells in engineered biomaterials and patient biopsies reveals targetable transsulfuration pathway alterations.

While the poor prognosis of glioblastoma arises from the invasion of a subset of tumor cells, little is known of the metabolic alterations within these cells that fuel invasion. We integrated spatially addressable hydrogel biomaterial platforms, patient site-directed biopsies, and multi-omics analyses to define metabolic drivers of invasive glioblastoma cells. Metabolomics and lipidomics revealed elevations in the redox buffers cystathionine, hexosylceramides, and glucosyl ceramides in the invasive front of both hydrogel-cultured tumors and patient site-directed biopsies, with immunofluorescence indicating elevated reactive oxygen species (ROS) markers in invasive cells. Transcriptomics confirmed upregulation of ROS-producing and response genes at the invasive front in both hydrogel models and patient tumors. Amongst oncologic ROS, hydrogen peroxide specifically promoted glioblastoma invasion in 3D hydrogel spheroid cultures. A CRISPR metabolic gene screen revealed cystathionine gamma lyase (CTH), which converts cystathionine to the non-essential amino acid cysteine in the transsulfuration pathway, to be essential for glioblastoma invasion. Correspondingly, supplementing CTH knockdown cells with exogenous cysteine rescued invasion. Pharmacologic CTH inhibition suppressed glioblastoma invasion, while CTH knockdown slowed glioblastoma invasion in vivo. Our studies highlight the importance of ROS metabolism in invasive glioblastoma cells and support further exploration of the transsulfuration pathway as a mechanistic and therapeutic target.

Pituitary adenomas and cerebrovascular disease: A review on pathophysiology, prevalence, and treatment.

Pituitary adenomas (PAs) have been shown to cause excess cardiovascular disease comorbidity and mortality. Cerebrovascular disease (CeVD) is a small subset of cardiovascular disease with high morbidity, and its risk in patients with pituitary adenomas has been sparingly explored. In this review, we examine what is known about the prevalence of cerebrovascular disease in patients with PAs, from its initial discovery in 1970 to present. An abundance of literature describes increased cerebrovascular mortality in patients with acromegaly, while research on other PA subtypes is less frequent but shows a similarly elevated CeVD mortality relative to healthy populations. We also review how cerebrovascular risk changes after PAs are treated, with PA treatment appearing to prevent further accumulation of cerebrovascular risk without reversing prior elevations. While acromegaly-associated CeVD appears to be caused by elevated growth hormone (GH) levels and Cushing disease's elevated glucocorticoids similarly cause durable alterations in cerebrovascular structure and function, less is known about the mechanisms behind CeVD in other PA subpopulations. Proposed pathophysiologies include growth hormone deficiency inducing vessel wall damage or other hormone deficits causing increased atherosclerotic disease. Early diagnosis and treatment of PAs may be the key to minimizing lifetime CeVD risk elevations. More research is needed to better understand the mechanisms behind the increased CeVD seen in patients with PAs. Physicians caring for PA patients must remain vigilant for signs and symptoms of cerebrovascular disease in this patient population.

Diversity in Plastic Surgery: Analysis of Representation of Sex and Ethnic Diversity in Plastic Surgery Residency Social Media Accounts.

BACKGROUND: Increasing health care diversity is critical to overcoming disparities. Plastic surgery has been working to improve diversity through various efforts, including social media movements like Diversify PRS and #ilooklikeasurgeon. Because residency programs' social media sites serve as a public symbol of the programs' values and can attract potential applicants, we sought to analyze such platforms for content highlighting sex and ethnic diversity. METHODS: Integrated plastic surgery residency programs during the 2020 to 2021 academic year were found on the American Council of Academic Plastic Surgeons website, and their associated social media accounts were identified. The authors reviewed each program's account for all posts published by November 8, 2021, for content promoting sex or ethnic diversity. Any hashtags related to diversity were also recorded. Nonparametric Mann-Whitney U and Kruskal-Wallis tests were used to compare percentages of total social media posts related to sex and ethnic diversity between programs (α = 0.05). RESULTS: Of 82 programs, 76 (92.7%) had active Instagram accounts, 29 (35.4%) had active Facebook accounts, and 29 (35.4%) had active Twitter accounts. Across all platforms, 19.0% of all posts were promoting sex diversity and 3.3% were promoting ethnic diversity. Of 4651 posts promoting sex diversity, 4067 (87.4%) highlighted women, 1017 (21.9%) featured all-women teams, 779 (16.7%) used sex diversity-related hashtags, and 300 (6.5%) included purposeful statements. Of 808 posts promoting ethnic diversity, 527 (65.2%) used ethnic diversity-related hashtags, 224 (27.7%) included purposeful statements, 199 (24.6%) mentioned ethnic background, and 36 (4.5%) used different skin-toned emojis. Programs did not vary in percentages of posts related to diversity by geographic region, ranking, accreditation length, or engagement rate. The percentage of posts promoting sex diversity was greater than that promoting ethnic diversity (P < 0.001). The most used diversity hashtag was #ilooklikeasurgeon. CONCLUSIONS: Despite the importance of increasing recruitment of trainees from diverse backgrounds to plastic surgery and the global reach of social media movements like #ilooklikeasurgeon, sex and ethnic diversity are still poorly promoted on residency social media accounts. Increasing such content is a simple yet powerful way to create a culture of inclusivity for all applicants.

The Impact of Social Determinants of Health on 30 and 90-Day Readmission Rates After Spine Surgery.

BACKGROUND: Since its 2012 inception, the U.S. Centers for Medicare & Medicaid Services Hospital Readmissions Reduction Program (HRRP) has espoused cost-effective health-care delivery by financially penalizing hospitals with excessive 30-day readmission rates. In this study, we hypothesized that socioeconomic factors impact readmission rates of patients undergoing spine surgery. METHODS: In this study, 2,830 patients who underwent a spine surgical procedure between 2012 and 2018 were identified retrospectively from our institutional database, with readmission (postoperative day [POD] 0 to 30 and POD 31 to 90) as the outcome of interest. Patients were linked to U.S. Census Tracts and ZIP codes using the Geographic Information Systems (ArcGIS) mapping program. Social determinants of health (SDOH) were obtained from publicly available databases. Patient income was estimated at the Public Use Microdata Area level based on U.S. Census Bureau American Community Survey data. Univariate and multivariable stepwise regression analyses were conducted. Significance was defined as p < 0.05, with Bonferroni corrections as appropriate. RESULTS: Race had a significant effect on readmission only among patients whose estimated incomes were <$31,650 (χ2 = 13.4, p < 0.001). Based on a multivariable stepwise regression, patients with estimated incomes of <$31,000 experienced greater odds of readmission by POD 30 compared with patients with incomes of >$62,000; the odds ratio (OR) was 11.06 (95% confidence interval [CI], 6.35 to 15.57). There were higher odds of 30-day readmission for patients living in neighborhoods with higher diabetes prevalence (OR, 3.02 [95% CI, 1.60 to 5.49]) and patients living in neighborhoods with limited access to primary care providers (OR, 1.39 [95% CI, 1.10 to 1.70]). Lastly, each decile increase in the Area Deprivation Index of a patient's Census Tract was associated with higher odds of 30-day readmission (OR, 1.40 [95% CI, 1.30 to 1.51]). CONCLUSIONS: Socioeconomically disadvantaged patients and patients from areas of high social deprivation have a higher risk of readmission following a spine surgical procedure. LEVEL OF EVIDENCE: Prognostic Level IV. See Instructions for Authors for a complete description of levels of evidence.

Racial and Social Determinants of Health Disparities in Spine Surgery Affect Preoperative Morbidity and Postoperative Patient Reported Outcomes: Retrospective Observational Study.

STUDY DESIGN: Retrospective observational study. OBJECTIVE: To elucidate racial and socioeconomic factors driving preoperative disparities in spine surgery patients. SUMMARY OF BACKGROUND DATA: There are racial and socioeconomic disparities in preoperative health among spine surgery patients, which may influence outcomes for minority and low socioeconomic status (SES) populations. METHODS: Presenting, postoperative day 90 (POD90), and 12-month (12M) outcome scores (PROMIS global physical and mental [GPH, GMH] and visual analog scale pain [VAS]) were collected for patients undergoing deformity arthrodesis or cervical, thoracic, or lumbar laminotomy or decompression/fusion; these procedures were the most common in our cohort. Social determinants of health for a patient's neighborhood (county, zip code, or census tract) were extracted from public databases. Multivariable linear regression with stepwise selection was used to quantify the association between a patient's preoperative GPH score and sociodemographic variables. RESULTS: Black patients presented with 1 to 3 point higher VAS pain scores (7-8 vs. 5-6) and lower (worse) GPH scores (6.5-10 vs. 11-12) than White patients (P < 0.05 for all comparisons); similarly, lower SES patients presented with 1.5 points greater pain (P < 0.0001) and 3.5 points lower GPH (P < 0.0001) than high SES patients. Patients with lowest-quartile presenting GPH scores reported 36.8% and 37.5% lower (worse) POD-90 GMH and GPH scores than the highest quartile, respectively (GMH: 12 vs. 19, P < 0.0001; GPH: 15 vs. 24, P < 0.0001); this trend extended to 12 months (GMH: 19.5 vs. 29.5, P < 0.0001; GPH: 22 vs. 30, P < 0.0001). Reduced access to primary care (B = -1.616, P < 0.0001) and low SES (B = -1.504, P = 0.001), proxied by median household value, were independent predictors of worse presenting GPH scores. CONCLUSION: Racial and socioeconomic disparities in patients' preoperative physical and mental health at presentation for spine surgery are associated adversely with postoperative outcomes. Renewed focus on structural factors influencing preoperative presentation, including timeliness of care, is essential.Level of Evidence: 3.

Transcriptomic Profiles of Normal Pituitary Cells and Pituitary Neuroendocrine Tumor Cells.

The pituitary gland is one of the most cellularly diverse regions of the brain. Recent advancements in transcriptomic biology, such as single-cell RNA sequencing, bring an unprecedented glimpse into the molecular composition of the pituitary, both in its normal physiological state and in disease. Deciphering the normal pituitary transcriptomic signatures provides a better insight into the ontological origin and development of five types of endocrine cells, a process involving complex cascades of transcription factors that are still being established. In parallel with these observations about normal pituitary development, recent transcriptomic findings on pituitary neuroendocrine tumors (PitNETs) demonstrate both preservations and changes in transcription factor expression patterns compared to those seen during gland development. Furthermore, recent studies also identify differentially expressed genes that drive various tumor behaviors, including hormone hypersecretion and tumor aggression. Understanding the comprehensive multiomic profiles of PitNETs is essential in developing molecular profile-based therapies for PitNETs not curable with current treatment modalities and could eventually help align PitNETs with the breakthroughs being made in applying precision medicine to other tumors.

Trends in physician reimbursements and procedural volumes for radiosurgery versus open surgery in brain tumor care: an analysis of Medicare data from 2009 to 2018.

OBJECTIVE: Given its minimally invasive nature and effectiveness, stereotactic radiosurgery (SRS) has become a mainstay for the multimodal treatment of intracranial neoplasm. However, no studies have evaluated recent trends in the use of SRS versus those of open resection for the management of brain tumor or trends in the involvement of neurosurgeons in SRS (which is primarily delivered by radiation oncologists). Here, the authors used publicly available Medicare data from 2009 to 2018 to elucidate trends in the treatment of intracranial neoplasm and to compare reimbursements between these approaches. METHODS: By using CPT Professional 2019, the authors identified 10 open resection and 9 SRS codes (4 for neurosurgery and 5 for radiation oncology) for the treatment of intracranial neoplasm. Medicare payments (inflation adjusted) and allowed services (number of reimbursed procedures) for each code were abstracted from the Centers for Medicare and Medicaid Services Part B National Summary Data File (2009-2018). Payments per procedure and procedures per 100,000 Medicare enrollees were analyzed with linear regression and compared with tests for equality of slopes (α = 0.05). The average payment per procedure over the study period was compared by using the 2-tailed Welsh unequal variances t-test, and more granular comparisons were conducted by using ANOVA with post hoc Tukey honestly significant difference (HSD) tests. RESULTS: From 2009 to 2018, the number of SRS treatments per 100,000 Medicare enrollees for intracranial neoplasm increased by 3.97 cases/year (R2 = 0.99, p < 0.001), while comparable open resections decreased by 0.34 cases/year (R2 = 0.85, p < 0.001) (t16 = 7.5, p < 0.001). By 2018, 2.6 times more SRS treatments were performed per 100,000 enrollees than open resections (74.9 vs 28.7 procedures). However, neurosurgeon involvement in SRS treatment declined over the study period, from 23.4% to 11.5% of SRS treatments; simultaneously, the number of lesions treated per session increased from 1.46 to 1.84 (R2 = 0.98, p < 0.001). Overall, physician payments from 2013 to 2018 averaged $1816.08 (95% CI $1788.71-$1843.44) per SRS treatment and $1565.59 (95% CI $1535.83-$1595.34) per open resection (t10 = 15.9, p < 0.001). For neurosurgeons specifically, reimbursements averaged $1566 per open resection, but this decreased to $1031-$1198 per SRS session; comparatively, radiation oncologists were reimbursed even less (average $359-$898) per SRS session (p < 0.05 according to the Tukey HSD test for all comparisons). CONCLUSIONS: Over a decade, the number of open resections for intracranial neoplasm in Medicare enrollees declined slightly, while the number of SRS procedures increased greatly. This latter expansion is largely attributable to radiation oncologists; meanwhile, neurosurgeons have shifted their involvement in SRS toward sessions for the management of multiple lesions.

An ACGME-based comparison of neurosurgical and orthopedic resident training in adult spine surgery via a case volume and hours-based analysis.

OBJECTIVE: In a 2014 analysis of orthopedic and neurological surgical case logs published by the Accreditation Council for Graduate Medical Education (ACGME), it was reported that graduating neurosurgery residents performed more than twice the number of spinal procedures in their training compared with graduating orthopedic residents. There has, however, been no follow-up assessment of this trend. Moreover, whether this gap in case volume equates to a similar gap in procedural hours has remained unstudied. Given the association between surgical volume and outcomes, evaluating the status of this disparity has value. Here, the authors assess trends in case volume and procedural hours in adult spine surgery for graduating orthopedic and neurological surgery residents from 2014 to 2019. METHODS: A retrospective analysis of ACGME case logs from 2014 to 2019 for graduating orthopedic and neurological surgery residents was conducted for adult spine surgeries. Case volume was converted to operative hours by using periprocedural times from the 2019 Medicare/Medicaid Physician Fee Schedule. Graduating residents' spinal cases and hours, averaged over the study period, were compared between the two specialties by using 2-tailed Welch's unequal variances t-tests (α = 0.05). Longitudinal trends in each metric were assessed by linear regression followed by cross-specialty comparisons via tests for equality of slopes. RESULTS: From 2014 to 2019, graduating neurosurgical residents logged 6.8 times as many spinal cases as their orthopedic counterparts, accruing 431.6 (95% CI 406.49-456.61) and 63.8 (95% CI 57.08-70.56) cases (p < 0.001), respectively. Accordingly, graduating neurosurgical residents logged 6.1 times as many spinal procedural hours as orthopedic surgery residents, accruing 1020.7 (95% CI 964.70-1076.64) and 166.6 (95% CI 147.76-185.35) hours (p < 0.001), respectively. Over these 5 years, both fields saw a linear increase in graduating residents' adult spinal case volumes and procedural hours, and these growth rates were higher for neurosurgery (+16.2 cases/year vs +4.4 cases/year, p < 0.001; +36.4 hours/year vs +12.4 hours/year, p < 0.001). CONCLUSIONS: Graduating neurosurgical residents accumulated substantially greater adult spinal case volumes and procedural hours than their orthopedic counterparts from 2014 to 2019. This disparity has been widened by a higher rate of growth in adult spinal cases among neurosurgery residents. Accordingly, targeted efforts to increase spinal exposure for orthopedic surgery residents-such as using cross-specialty collaboration-should be explored.

Perceived involvement in health care decisions among US adults: Sociodemographic and medical condition correlates.

OBJECTIVE: To explore factors associated with how often US adults perceived that they were "always" involved in decisions about health care to the degree that they desired. METHODS: We examined cross-sectional, nationally representative data from the 2018 Health Information National Trends Survey. There were 3504 responses in the full HINTS dataset; 2499 remained after eliminating respondents with missing data for any factor of interest. Sociodemographic factors included age, gender, race/ethnicity, and education. Medical conditions included diabetes, hypertension, heart disease, lung disease, arthritis, cancer, and depression. Participants were asked to think about communication with health professionals during the last 12 months and how often health professionals involved them in decisions about health care. RESULTS: In univariate analyses, Asian and Hispanic race were associated with lower odds of always being involved in decisions about health care; whereas higher education and a history of cancer were associated with higher odds of "always" being involved in decisions about health care, p < 0.05. In multivariate analyses, race and education both remained significant; however, history of cancer did not. CONCLUSION: Differences by race/ethnicity and educational attainment exist regarding perceived involvement in decisions about health care. PRACTICE IMPLICATIONS: Findings may inform future shared decision making interventions.

Health literacy among neurosurgery and other surgical subspecialties: Readability of online patient materials found with Google.

OBJECTIVE: To both determine whether the most high-yield online patient materials for surgical specialties meet the 6th grade readability level recommended by the National Institutes of Health (NIH) and American Medical Association (AMA), and to discover differences in readability across specialties. We hypothesize average readability scores will exceed an 11th grade level. METHODS: The top five most common procedures for each of seven surgical specialties (neurological, orthopedic, plastic, general, thoracic, pediatric, and vascular) were searched using an incognito Google query to minimize location bias. The text from the top five patient-relevant links per procedure, excluding Wikipedia, journal articles, and videos, was extracted and inserted into Readability Studio Software for analysis. RESULTS: The combined average grade level of materials (± standard deviation) was: 10.47 ±â€¯2.51 Flesh-Kincaid Grade Level (FKGL), 11-12 New Dale-Chall (NDC), 10.09 ±â€¯1.97 Simple Measure of Gobbledygook (SMOG), 12 Fry Graph (FG). Thoracic, neurologic, vascular, plastic, and orthopedic were least readable (grade level 10+ by all metrics). CONCLUSIONS: High readability of procedure materials for patients is not unique to neurosurgery: all specialties exceeded the recommended 6th grade level by three or more grades. Online patient education materials related to surgical subspecialties must be written more comprehensibly.

Ribosomal protein S11 influences glioma response to TOP2 poisons.

Topoisomerase II poisons are one of the most common class of chemotherapeutics used in cancer. We and others had shown that a subset of glioblastomas, the most malignant of all primary brain tumors in adults, is responsive to TOP2 poisons. To identify genes that confer susceptibility to this drug in gliomas, we performed a genome-scale CRISPR knockout screen with etoposide. Genes involved in protein synthesis and DNA damage were implicated in etoposide susceptibility. To define potential biomarkers for TOP2 poisons, CRISPR hits were overlapped with genes whose expression correlates with susceptibility to this drug across glioma cell lines, revealing ribosomal protein subunit RPS11, 16, and 18 as putative biomarkers for response to TOP2 poisons. Loss of RPS11 led to resistance to etoposide and doxorubicin and impaired the induction of proapoptotic gene APAF1 following treatment. The expression of these ribosomal subunits was also associated with susceptibility to TOP2 poisons across cell lines from gliomas and multiple other cancers.