Targeted gene expression profiling predicts meningioma outcomes and radiotherapy responses.

Surgery is the mainstay of treatment for meningioma, the most common primary intracranial tumor, but improvements in meningioma risk stratification are needed and indications for postoperative radiotherapy are controversial. Here we develop a targeted gene expression biomarker that predicts meningioma outcomes and radiotherapy responses. Using a discovery cohort of 173 meningiomas, we developed a 34-gene expression risk score and performed clinical and analytical validation of this biomarker on independent meningiomas from 12 institutions across 3 continents (N = 1,856), including 103 meningiomas from a prospective clinical trial. The gene expression biomarker improved discrimination of outcomes compared with all other systems tested (N = 9) in the clinical validation cohort for local recurrence (5-year area under the curve (AUC) 0.81) and overall survival (5-year AUC 0.80). The increase in AUC compared with the standard of care, World Health Organization 2021 grade, was 0.11 for local recurrence (95% confidence interval 0.07 to 0.17, P < 0.001). The gene expression biomarker identified meningiomas benefiting from postoperative radiotherapy (hazard ratio 0.54, 95% confidence interval 0.37 to 0.78, P = 0.0001) and suggested postoperative management could be refined for 29.8% of patients. In sum, our results identify a targeted gene expression biomarker that improves discrimination of meningioma outcomes, including prediction of postoperative radiotherapy responses.

COVID-19 in patients with classic and variant hairy cell leukemia.

Hairy cell leukemia (HCL), similar to its variant HCLv, is a B-cell malignancy associated with decreased humoral immunity. We prospectively monitored the largest cohort of patients with HCL/HCLv to date (n = 503) for COVID-19 by symptoms, antibody, and polymerase chain reaction (PCR) and/or antigen positivity. Fifty percent (253 of 503) of the patients with HCL/HCLv (238 HCL and 15 HCLv) had evidence of COVID-19, with 210 (83%) testing positive by PCR or rapid-antigen test. Of the 43 patients without positive tests, all had nucleocapsid antibodies indicating COVID-19 exposure, 7 recalled no symptoms, and 36 had mild symptoms. Of the 210 who tested positive, 23, 46, 129, and 12 cases occurred in 2020, 2021, 2022, and 2023, respectively. Among them, 175 began treatment for HCL/HCLv 0.4 to 429 (median, 66) months before, and 132 had their last dose of anti-CD20 monoclonal antibody 0.2 to 229 (median, 63) months before. Two patients died, including a young woman who began rituximab 2 months after first-line cladribine before vaccine availability. Nearly all patients with HCL/HCLv recovered uneventfully from COVID-19 including those without vaccination or those with significant immunosuppression and recent treatment. However, decreased normal B cells from HCL or treatment was associated with lower spike antibody levels as a response to COVID-19 (P = .0094) and longer recovery time (P = .0036). Thus, in a large cohort of patients with HCL/HCLv and in the first to determine relationships between COVID-19 outcome and immune markers, mortality was relatively low (∼1%), sequelae were uncommon, and recovery from COVID-19 was longer if normal B cells were low after recent treatment. The trials are registered at www.clinicaltrials.gov as #NCT01087333 and #NCT04362865.

Targeted gene expression profiling predicts meningioma outcomes and radiotherapy responses.

Background: Surgery is the mainstay of treatment for meningioma, the most common primary intracranial tumor, but improvements in meningioma risk stratification are needed and current indications for postoperative radiotherapy are controversial. Recent studies have proposed prognostic meningioma classification systems using DNA methylation profiling, copy number variants, DNA sequencing, RNA sequencing, histology, or integrated models based on multiple combined features. Targeted gene expression profiling has generated robust biomarkers integrating multiple molecular features for other cancers, but is understudied for meningiomas. Methods: Targeted gene expression profiling was performed on 173 meningiomas and an optimized gene expression biomarker (34 genes) and risk score (0 to 1) was developed to predict clinical outcomes. Clinical and analytical validation was performed on independent meningiomas from 12 institutions across 3 continents (N = 1856), including 103 meningiomas from a prospective clinical trial. Gene expression biomarker performance was compared to 9 other classification systems. Results: The gene expression biomarker improved discrimination of postoperative meningioma outcomes compared to all other classification systems tested in the independent clinical validation cohort for local recurrence (5-year area under the curve [AUC] 0.81) and overall survival (5-year AUC 0.80). The increase in area under the curve compared to the current standard of care, World Health Organization 2021 grade, was 0.11 for local recurrence (95% confidence interval [CI] 0.07-0.17, P < 0.001). The gene expression biomarker identified meningiomas benefiting from postoperative radiotherapy (hazard ratio 0.54, 95% CI 0.37-0.78, P = 0.0001) and re-classified up to 52.0% meningiomas compared to conventional clinical criteria, suggesting postoperative management could be refined for 29.8% of patients. Conclusions: A targeted gene expression biomarker improves discrimination of meningioma outcomes compared to recent classification systems and predicts postoperative radiotherapy responses.

Blunt splenic injury: Assessment of follow-up CT utility using quantitative volumetry.

Purpose: Trials of non-operative management (NOM) have become the standard of care for blunt splenic injury (BSI) in hemodynamically stable patients. However, there is a lack of consensus regarding the utility of follow-up CT exams and relevant CT features. The purpose of this study is to determine imaging predictors of splenectomy on follow-up CT using quantitative volumetric measurements. Methods: Adult patients who underwent a trial of non-operative management (NOM) with follow-up CT performed for BSI between 2017 and 2019 were included (n = 51). Six patients (12% of cohort) underwent splenectomy; 45 underwent successful splenic salvage. Voxelwise measurements of splenic laceration, hemoperitoneum, and subcapsular hematoma were derived from portal venous phase images of admission and follow-up scans using 3D slicer. Presence/absence of pseudoaneurysm on admission and follow-up CT was assessed using arterial phase images. Multivariable logistic regression was used to determine independent predictors of decision to perform splenectomy. Results: Factors significantly associated with splenectomy in bivariate analysis incorporated in multivariate logistic regression included final hemoperitoneum volume (p = 0.003), final subcapsular hematoma volume (p = 0.001), change in subcapsular hematoma volume between scans (p = 0.09) and new/persistent pseudoaneurysm (p = 0.003). Independent predictors of splenectomy in the logistic regression were final hemoperitoneum volume (unit OR = 1.43 for each 100 mL change; 95% CI: 0.99-2.06) and new/persistent pseudoaneurysm (OR = 160.3; 95% CI: 0.91-28315.3). The AUC of the model incorporating both variables was significantly higher than AAST grading (0.91 vs. 0.59, p = 0.025). Mean combined effective dose for admission and follow up CT scans was 37.4 mSv. Conclusion: Follow-up CT provides clinically valuable information regarding the decision to perform splenectomy in BSI patients managed non-operatively. Hemoperitoneum volume and new or persistent pseudoaneurysm at follow-up are independent predictors of splenectomy.

Dual-Energy CT and Cinematic Rendering to Improve Assessment of Pelvic Fracture Instability.

Background Grading of pelvic fracture instability is challenging in patients with pelvic binders. Dual-energy CT (DECT) and cinematic rendering can provide ancillary information regarding osteoligamentous integrity, but the utility of these tools remains unknown. Purpose To assess the added diagnostic value of DECT and cinematic rendering, with respect to single-energy CT (SECT), for discriminating any instability and translational instability in patients with pelvic binders. Materials and Methods In this retrospective analysis, consecutive adult patients (age ≥18 years) were stabilized with pelvic binders and scanned in dual-energy mode using a 128-section CT scanner at one level I trauma center between August 2016 and January 2019. Young-Burgess grading by orthopedists served as the reference standard. Two radiologists performed blinded consensus grading with the Young-Burgess system in three reading sessions (session 1, SECT; session 2, SECT plus DECT; session 3, SECT plus DECT and cinematic rendering). Lateral compression (LC) type 1 (LC-1) and anteroposterior compression (APC) type 1 (APC-1) injuries were considered stable; LC type 2 and APC type 2, rotationally unstable; and LC type 3, APC type 3, and vertical shear, translationally unstable. Diagnostic performance for any instability and translational instability was compared between reading sessions using the McNemar and DeLong tests. Radiologist agreement with the orthopedic reference standard was calculated with the weighted κ statistic. Results Fifty-four patients (mean age, 41 years ± 16 [SD]; 41 men) were analyzed. Diagnostic performance was greater with SECT plus DECT and cinematic rendering compared with SECT alone for any instability, with an area under the receiver operating characteristic curve (AUC) of 0.67 for SECT alone and 0.82 for SECT plus DECT and cinematic rendering (P = .04); for translational instability, the AUCs were 0.80 for SECT alone and 0.95 for SECT plus DECT and cinematic rendering (P = .01). For any instability, corresponding sensitivities were 61% (22 of 36 patients) for SECT alone and 86% (31 of 36 patients) for SECT plus DECT and cinematic rendering (P < .001). The corresponding specificities were 72% (13 of 18 patients) and 78% (14 of 18 patients), respectively (P > .99). Agreement (κ value) between radiologists and orthopedist reference standard improved from 0.44 to 0.76 for SECT versus the combination of SECT, DECT, and cinematic rendering. Conclusion Combined use of single-energy CT, dual-energy CT, and cinematic rendering improved instability assessment over that with single-energy CT alone. © RSNA, 2022 Online supplemental material is available for this article.

Aberrant DNA damage response and DNA repair pathway in high glucose conditions.

BACKGROUND: Higher cancer rates and more aggressive behavior of certain cancers have been reported in populations with diabetes mellitus. This association has been attributed in part to the excessive reactive oxygen species generated in diabetic conditions and to the resulting oxidative DNA damage. It is not known, however, whether oxidative stress is the only contributing factor to genomic instability in patients with diabetes or whether high glucose directly also affects DNA damage and repair pathways. RESULTS: Normal renal epithelial cells and renal cell carcinoma cells are more chemo- and radiation resistant when cultured in high concentrations of glucose. In high glucose conditions, the CHK1-mediated DNA damage response is not activated properly. Cells in high glucose also have slower DNA repair rates and accumulate more mutations than cells grown in normal glucose concentrations. Ultimately, these cells develop a transforming phenotype. CONCLUSIONS: In high glucose conditions, defective DNA damage responses most likely contribute to the higher mutation rate in renal epithelial cells, in addition to oxidative DNA damage. The DNA damage and repair are normal enzyme dependent mechanisms requiring euglycemic environments. Aberrant DNA damage response and repair in cells grown in high glucose conditions underscore the importance of maintaining good glycemic control in patients with diabetes mellitus and cancer.