Comparison of dynamic susceptibility contrast (DSC) using gadolinium and iron-based contrast agents in high-grade glioma at high-field MRI.

PURPOSE: To compare DSC-MRI using Gadolinium (GBCA) and Ferumoxytol (FBCA) in high-grade glioma at 3T and 7T MRI field strengths. We hypothesized that using FBCA at 7T would enhance the performance of DSC, as measured by contrast-to-noise ratio (CNR). METHODS: Ten patients (13 lesions) were assigned to 3T (6 patients, 6 lesions) or 7T (4 patients, 7 lesions). All lesions received 0.1 mmol/kg of GBCA on day 1. Ten lesions (4 at 3T and 6 at 7T) received a lower dose (0.6 mg/kg) of FBCA, followed by a higher dose (1.0-1.2 mg/kg), while 3 lesions (2 at 3T and 1 at 7T) received only a higher dose on Day 2. CBV maps with leakage correction for GBCA but not for FBCA were generated. The CNR and normalized CBV (nCBV) were analyzed on enhancing and non-enhancing high T2W lesions. RESULTS: Regardless of FBCA dose, GBCA showed higher CNR than FBCA at 7T, which was significant for high-dose FBCA (p < .05). Comparable CNR between GBCA and high-dose FBCA was observed at 3T. There was a trend toward higher CNR for FBCA at 3T than 7T. GBCA also showed nCBV twice that of FBCA at both MRI field strengths with significance at 7T. CONCLUSION: GBCA demonstrated higher image conspicuity, as measured by CNR, than FBCA on 7T. The stronger T2* weighting realized with higher magnetic field strength, combined with FBCA, likely results in more signal loss rather than enhanced performance on DSC. However, at clinical 3T, both GBCA and FBCA, particularly a dosage of 1.0-1.2 mg/kg (optimal for perfusion imaging), yielded comparable CNR.

Deciphering spatially distinct immune microenvironments in glioblastoma using ferumoxytol and gadolinium-enhanced and FLAIR hyperintense MRI phenotypes.

Background: MRI with gadolinium (Gd)-contrast agents is used to assess glioblastoma treatment response but does not specifically reveal heterogeneous biology or immune microenvironmental composition. Ferumoxytol (Fe) contrast is an iron nanoparticle that localizes glioblastoma macrophages and microglia. Therefore, we hypothesized that the use of Fe contrast improves upon standard Gd-based T1-weighted and T2/FLAIR analysis by specifically delineating immune processes. Methods: In this, HIPAA-compliant institutional review board-approved prospective study, stereotactic biopsy samples were acquired from patients with treatment-naïve and recurrent glioblastoma based on MR imaging phenotypes; Gd and Fe T1 enhancement (Gd+, Fe+) or not (Gd-, Fe-), as well as T2-Flair hyperintensity (FLAIR+, FLAIR-). Analysis of genetic expression was performed with RNA microarrays. Imaging and genomic expression patterns were compared using false discovery rate statistics. Results: MR imaging phenotypes defined a variety of immune pathways and Hallmark gene sets. Gene set enrichment analysis demonstrated that Gd+, Fe+, and FLAIR+ features were individually correlated with the same 7 immune process gene sets. Fe+ tissue showed the greatest degree of immune Hallmark gene sets compared to Gd+ or Flair+ tissues and had statistically elevated M2 polarized macrophages, among others. Importantly, the FLAIR+ Gd+ and Fe- imaging phenotypes did not demonstrate expression of immune Hallmark gene sets. Conclusions: Our study demonstrates the potential of Fe and Gd-enhanced MRI phenotypes to reveal spatially distinct immune processes within glioblastoma. Fe improves upon the standard of care Gd enhancement by specifically localizing glioblastoma-associated inflammatory processes, providing valuable insights into tumor biology.

Screening, Referral, Behavioral Counseling, and Preventive Interventions for Oral Health in Children and Adolescents Aged 5 to 17 Years: A Systematic Review for the US Preventive Services Task Force.

Importance: Dental caries is common in children and adolescents aged 5 to 17 years and potentially amenable to primary care screening and prevention. Objective: To systematically review the evidence on primary care screening and prevention of dental caries in children and adolescents aged 5 to 17 years to inform the US Preventive Services Task Force. Data Sources: MEDLINE, Cochrane Central Register of Controlled Trials, and Cochrane Database of Systematic Reviews (to October 3, 2022); surveillance through July 21, 2023. Study Selection: Diagnostic accuracy of primary care screening instruments and oral examination; randomized and nonrandomized trials of screening and preventive interventions and systematic reviews of such studies; cohort studies on primary care oral health screening and preventive intervention harms. Data Extraction and Synthesis: One investigator abstracted data; a second checked accuracy. Two investigators independently rated study quality. Random-effects meta-analysis was performed for fluoride supplements and xylitol; for other preventive interventions, pooled estimates were used from good-quality systematic reviews. Main Outcomes and Measures: Dental caries, morbidity, functional status, quality of life, harms; diagnostic test accuracy. Results: Three systematic reviews (total 20 684 participants) and 19 randomized clinical trials, 3 nonrandomized trials, and 1 observational study (total 15 026 participants) were included. No study compared screening vs no screening. When administered by dental professionals or in school settings, fluoride supplements compared with placebo or no intervention were associated with decreased change from baseline in the number of decayed, missing, or filled permanent teeth (DMFT index) or decayed or filled permanent teeth (DFT index) (mean difference, -0.73 [95% CI, -1.30 to -0.19]) at 1.5 to 3 years (6 trials; n = 1395). Fluoride gels were associated with a DMFT- or DFT-prevented fraction of 0.18 (95% CI, 0.09-0.27) at outcomes closest to 3 years (4 trials; n = 1525), fluoride varnish was associated with a DMFT- or DFT-prevented fraction of 0.44 (95% CI, 0.11-0.76) at 1 to 4.5 years (5 trials; n = 3902), and resin-based sealants were associated with decreased risk of carious first molars (odds ratio, 0.21 [95% CI, 0.16-0.28]) at 48 to 54 months (4 trials; n = 440). No trial evaluated primary care counseling or dental referral. Evidence on screening accuracy, silver diamine fluoride, xylitol, and harms was very limited, although serious harms were not reported. Conclusions and Relevance: Administration of fluoride supplements, fluoride gels, varnish, and sealants in dental or school settings improved caries outcomes. Research is needed on the effectiveness of oral health preventive interventions in primary care settings and to determine the benefits and harms of screening.

Multiparametric magnetic resonance imaging discerns glioblastoma immune microenvironmental heterogeneity.

RATIONALE AND OBJECTIVE: Poor clinical outcomes for patients with glioblastoma are in part due to dysfunction of the tumor-immune microenvironment. An imaging approach able to characterize immune microenvironmental signatures could provide a framework for biologically based patient stratification and response assessment. We hypothesized spatially distinct gene expression networks can be distinguished by multiparametric Magnetic Resonance Imaging (MRI) phenotypes. MATERIALS AND METHODS: Patients with newly diagnosed glioblastoma underwent image-guided tissue sampling allowing for co-registration of MRI metrics with gene expression profiles. MRI phenotypes based on gadolinium contrast enhancing lesion (CEL) and non-enhancing lesion (NCEL) regions were subdivided based on imaging parameters (relative cerebral blood volume (rCBV) and apparent diffusion coefficient (ADC)). Gene set enrichment analysis and immune cell type abundance was estimated using CIBERSORT methodology. Significance thresholds were set at a p-value cutoff 0.005 and an FDR q-value cutoff of 0.1. RESULTS: Thirteen patients (eight men, five women, mean age 58 ± 11 years) provided 30 tissue samples (16 CEL and 14 NCEL). Six non-neoplastic gliosis samples differentiated astrocyte repair from tumor associated gene expression. MRI phenotypes displayed extensive transcriptional variance reflecting biological networks, including multiple immune pathways. CEL regions demonstrated higher immunologic signature expression than NCEL, while NCEL regions demonstrated stronger immune signature expression levels than gliotic non-tumor brain. Incorporation of rCBV and ADC metrics identified sample clusters with differing immune microenvironmental signatures. CONCLUSION: Taken together, our study demonstrates that MRI phenotypes provide an approach for non-invasively characterizing tumoral and immune microenvironmental glioblastoma gene expression networks.

Day 4 collection of granulocyte colony-stimulating factor-mobilized HLA-matched sibling donor peripheral blood allografts demonstrates no long-term increase in chronic graft-versus-host disease or relapse rates.

BACKGROUND AIMS: In a previous pilot study of HLA-matched sibling donor hematopoietic cell transplantation (HCT), the authors determined the feasibility of day 4 versus day 5 granulocyte colony-stimulating factor (G-CSF)-mobilized peripheral blood stem cell (PBSC) collection compared with a historical cohort. Given identified differences in the PBSC product (day 4 cohort with significantly lower infused total nucleated, mononuclear and CD3 cells compared with other collection cohorts), the authors performed a follow-up study to determine long-term post-HCT outcomes, including detailed characterization of chronic graft-versus-host disease (GVHD). METHODS: This was a prospective observational study, and the authors collected data on chronic GVHD, staging, sites of involvement and treatments. Performance status, incidence of relapse, overall survival and duration of immunosuppressive therapy (IST) were also evaluated. Data were examined retrospectively. To account for differences in length of follow-up among cohorts, the authors also determined performance status and chronic GVHD staging, sites and treatment at 2 years post-HCT. RESULTS: At 2 years post-HCT, the overall survival rate was 71.7% in the day 4 cohort compared with 61.5%, 52% and 56% in the day 5, 2-day and historical cohorts, respectively (P = 0.283). The cumulative incidence of chronic GVHD was 65.2% in the day 4 cohort versus 46.4% in the day 5 cohort, 51.1% in the 2-day cohort and 65% in the historical cohort (P = 0.26). There was no significant difference in the maximum overall stage of chronic GVHD (P = 0.513), median number of sites involved (P = 0.401) or cumulative incidence of discontinuation of IST (P = 0.32). Death from chronic GVHD was less common in the day 4 and day 5 cohorts compared with the 2-day and historical cohorts, though this did not reach statistical significance. CONCLUSIONS: The authors' preliminary results demonstrated that collection of allogeneic matched sibling donor PBSCs on day 4 of G-CSF was feasible, reduced donor exposure to growth factor and was associated with an initial cost savings. Importantly, the authors now demonstrate that transplantation of day 4 mobilized PBSCs is not associated with any adverse outcomes post-HCT, including late effects such as chronic GVHD. Further investigation of donor G-CSF collection algorithms is merited in other HCT settings, including unrelated and mismatched related donors.

Systemic corticosteroids for radicular and non-radicular low back pain.

BACKGROUND: Corticosteroids are medications with anti-inflammatory and immunosuppressant properties. Systemic corticosteroids administered through the oral, intravenous, or intramuscular routes have been used to treat various types of low back pain, including radicular back pain (not due to spinal stenosis), non-radicular back pain, and spinal stenosis. However, there is uncertainty about the benefits and harms of systemic corticosteroids for low back pain. OBJECTIVES: To evaluate the benefits and harms of systemic corticosteroids versus placebo or no corticosteroid for radicular low back pain, non-radicular low back pain, and symptomatic spinal stenosis in adults. SEARCH METHODS: We used standard, extensive Cochrane search methods. The latest search date was September 2021. SELECTION CRITERIA: We included randomized and quasi-randomized trials in adults of systematic corticosteroids versus placebo or no corticosteroid. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methods. The major outcomes were pain, function, need for surgery, serious adverse effect, and presence of hyperglycemia. The minor outcomes were quality of life, successful outcomes, non-serious adverse events, and withdrawal due to adverse events. We used GRADE to assess the certainty of evidence for each outcome. MAIN RESULTS: Thirteen trials (1047 participants) met the inclusion criteria. Nine trials included participants with radicular low back pain, two trial with low back pain, and two trials with spinal stenosis. All trials blinded participants to receipt of systemic corticosteroids. Seven trials were at low risk of bias, five at unclear risk, and one at high risk of selection bias. Two trials were at high risk of attrition bias. Doses and duration of systemic corticosteroid therapy varied. Radicular low back pain For radicular low back pain, moderate-certainty evidence indicated that systemic corticosteroids probably slightly decrease pain versus placebo at short-term follow-up (mean difference (MD) 0.56 points better, 95% confidence interval (CI) 1.08 to 0.04 on a 0 to 10 scale) and may slightly increase the likelihood of experiencing improvement in pain at short-term follow-up (risk ratio (RR) 1.21, 95% CI 0.88 to 1.66; absolute effect 5% better (95% CI 5% worse to 15% better). Systemic corticosteroids may not improve function at short-term follow-up (standardized mean difference (SMD) 0.14 better; range 0.49 better to 0.21 worse) and probably increase the likelihood of improvement in function at short-term follow-up (RR 1.52, 95% CI 1.22 to 1.91; absolute effect 19% better, 95% CI 8% better to 30% better). Systemic corticosteroids were associated with greater improvement in function versus placebo at long-term follow-up (MD -7.40, 95% CI -12.55 to -2.25 on the 0 to 100 Oswestry Disability Index) and greater likelihood of functional improvement (RR 1.29, 95% CI 1.06 to 1.56), based on a single trial. There was no difference in likelihood of surgery (RR 1.00, 95% CI 0.68 to 1.47). Evidence indicated that systemic corticosteroids (administered as a single dose or as a short course of therapy) are not associated with increased risk of any adverse event, serious adverse events, withdrawal due to adverse events, or hyperglycemia, but estimates were imprecise as some trials did not report harms, and harms reporting was suboptimal in trials that did provide data. Limitations included variability across trials in interventions (e.g. corticosteroid used, dose and duration of treatment), clinical settings, and participants (e.g. duration of symptoms, methods for diagnosis); limited utility of subgroup analyses due to small numbers of trials; methodologic limitations or suboptimal reporting of methods by some trials; and too few trials to formally assess for publication bias using graphical or statistical tests for small sample effects. Non-radicular low back pain Evidence on systemic corticosteroids versus placebo for non-radicular pain was limited and suggested that systemic corticosteroids may be associated with slightly worse short-term pain but slightly better function. Spinal stenosis For spinal stenosis, limited evidence indicated that systemic corticosteroids are probably no more effective than placebo for short-term pain or function. AUTHORS' CONCLUSIONS: Systemic corticosteroids appear to be slightly effective at improving short-term pain and function in people with radicular low back pain not due to spinal stenosis, and might slightly improve long-term function. The effects of systemic corticosteroids in people with non-radicular low back pain are unclear and systemic corticosteroids are probably ineffective for spinal stenosis. A single dose or short course of systemic corticosteroids for low back pain does not appear to cause serious harms, but evidence is limited.

Safety of intra-arterial chemotherapy with or without osmotic blood-brain barrier disruption for the treatment of patients with brain tumors.

Background: Intra-arterial administration of chemotherapy with or without osmotic blood-brain barrier disruption enhances delivery of therapeutic agents to brain tumors. The aim of this study is to evaluate the safety of these procedures. Methods: Retrospectively collected data from a prospective database of consecutive patients with primary and metastatic brain tumors who received intra-arterial chemotherapy without osmotic blood-brain barrier disruption (IA) or intra-arterial chemotherapy with osmotic blood-brain barrier disruption (IA/OBBBD) at Oregon Health and Science University (OHSU) between December 1997 and November 2018 is reported. Chemotherapy-related complications are detailed per Common Terminology Criteria for Adverse Events (CTCAE) guidelines. Procedure-related complications are grouped as major and minor. Results: 4939 procedures (1102 IA; 3837 IA/OBBBD) were performed on 436 patients with various pathologies (primary central nervous system lymphoma [26.4%], glioblastoma [18.1%], and oligodendroglioma [14.7%]). Major procedure-related complications (IA: 12, 1%; IA/OBBBD: 27, 0.7%; P = .292) occurred in 39 procedures including 3 arterial dissections requiring intervention, 21 symptomatic strokes, 3 myocardial infarctions, 6 cervical cord injuries, and 6 deaths within 3 days. Minor procedure-related complications occurred in 330 procedures (IA: 41, 3.7%; IA/OBBBD: 289, 7.5%; P = .001). Chemotherapy-related complications with a CTCAE attribution and grade higher than 3 was seen in 359 (82.3%) patients. Conclusions: We provide safety and tolerability data from the largest cohort of consecutive patients who received IA or IA/OBBBD. Our data demonstrate that IA or IA/OBBBD safely enhance drug delivery to brain tumors and brain around the tumor.

Screening for Glaucoma in Adults: Updated Evidence Report and Systematic Review for the US Preventive Services Task Force.

Importance: Two 2013 systematic reviews to inform the US Preventive Services Task Force (USPSTF) found insufficient evidence to assess benefits and harms of screening for primary open-angle glaucoma (OAG) in adults. Objective: To update the 2013 reviews on screening for glaucoma, to inform the USPSTF. Data Sources: Ovid MEDLINE, the Cochrane Central Register of Controlled Trials, and the Cochrane Database of Systematic Reviews (to February 2021); surveillance through January 21, 2022. Study Selection: Randomized clinical trials (RCTs) of screening, referral, and treatment; and studies of screening test diagnostic accuracy. Data Extraction and Synthesis: One investigator abstracted data and a second checked accuracy. Two investigators independently assessed study quality. Results: Eighty-three studies (N = 75 887) were included (30 trials and 53 diagnostic accuracy studies). One RCT (n = 616) found screening of frail elderly persons associated with no difference in vision outcomes vs no screening but with significantly greater falls risk (relative risk [RR], 1.31 [95% CI, 1.13-1.50]). No study evaluated referral to an eye health professional. For glaucoma diagnosis, spectral domain optical coherence tomography (providing high-resolution cross-sectional imaging; 15 studies, n = 4242) was associated with sensitivity of 0.79 (95% CI, 0.75-0.83) and specificity of 0.92 (95% CI, 0.87-0.96) and the Humphrey Visual Field Analyzer (for perimetry, or measurement of visual fields; 6 studies, n = 11 244) with sensitivity of 0.87 (95% CI, 0.69-0.95) and specificity 0.82 (95% CI, 0.66-0.92); tonometry (for measurement of intraocular pressure; 13 studies, n = 32 892) had low sensitivity (0.48 [95% CI, 0.31-0.66]). Medical therapy for ocular hypertension and untreated glaucoma was significantly associated with decreased intraocular pressure and decreased likelihood of glaucoma progression (7 trials, n = 3771; RR, 0.68 [95% CI, 0.49-0.96]; absolute risk difference -4.2%) vs placebo, but 1 trial (n = 461) found no differences in visual acuity, quality of life, or function. Selective laser trabeculoplasty and medical therapy had similar outcomes (4 trials, n = 957). Conclusions and Relevance: This review found limited direct evidence on glaucoma screening, showing no association with benefits. Screening tests can identify persons with glaucoma and treatment was associated with a lower risk of glaucoma progression, but evidence of improvement in visual outcomes, quality of life, and function remains lacking.

Diagnostic performance of DSC perfusion MRI to distinguish tumor progression and treatment-related changes: a systematic review and meta-analysis.

Background: In patients with high-grade glioma (HGG), true disease progression and treatment-related changes often appear similar on magnetic resonance imaging (MRI), making it challenging to evaluate therapeutic response. Dynamic susceptibility contrast (DSC) MRI has been extensively studied to differentiate between disease progression and treatment-related changes. This systematic review evaluated and synthesized the evidence for using DSC MRI to distinguish true progression from treatment-related changes. Methods: We searched Ovid MEDLINE and the Ovid MEDLINE in-process file (January 2005-October 2019) and the reference lists. Studies on test performance of DSC MRI using relative cerebral blood volume in HGG patients were included. One investigator abstracted data, and a second investigator confirmed them; two investigators independently assessed study quality. Meta-analyses were conducted to quantitatively synthesize area under the receiver operating curve (AUROC), sensitivity, and specificity. Results: We screened 1177 citations and included 28 studies with 638 patients with true tumor progression, and 430 patients with treatment-related changes. Nineteen studies reported AUROC and the combined AUROC is 0.85 (95% CI, 0.81-0.90). All studies contributed data for sensitivity and specificity, and the pooled sensitivity and specificity are 0.84 (95% CI, 0.80-0.88), and 0.78 (95% CI, 0.72-0.83). Extensive subgroup analyses based on study, treatment, and imaging characteristics generally showed similar results. Conclusions: There is moderate strength of evidence that relative cerebral blood volume obtained from DSC imaging demonstrated "excellent" ability to discriminate true tumor progression from treatment-related changes, with robust sensitivity and specificity.

Ferumoxytol-Enhanced MRI Is Not Inferior to Gadolinium-Enhanced MRI in Detecting Intracranial Metastatic Disease and Metastasis Size.

OBJECTIVE. The goal of this intraindividual comparison study was to investigate whether ferumoxytol-enhanced MRI is as effective as standard-of-care gadolinium-enhanced MRI in detecting intracranial metastatic disease. MATERIALS AND METHODS. We retrospectively reviewed all patients who underwent imaging as part of two ongoing ferumoxytol-enhanced and gadolinium-enhanced MRI protocol studies to compare the number and size of enhancing metastatic lesions. Two neuroradiologists independently measured enhancing metastases on ferumoxytol-enhanced MR images and on control gadolinium-enhanced MR images. The number and size of metastases were compared on an intraindividual basis. Primary diagnoses were recorded. A linear mixed-effects model was used to compare differences in cubic root of volume between gadolinium-enhanced and ferumoxytol-enhanced MRI. A signed rank test was used to evaluate differences between reviewers. RESULTS. MR images from 19 patients with brain metastases were analyzed (seven with lung cancer, three with breast cancer, three with melanoma, two with ovarian cancer, one with colon cancer, one with renal cell carcinoma, one with carcinoid tumor, and one with uterine cancer). Reviewer 1 identified 77 masses on ferumoxytol-enhanced MRI and 72 masses on gadolinium-enhanced MRI. Reviewer 2 identified 83 masses on ferumoxytol-enhanced MRI and 78 masses on gadolinium-enhanced MRI. For reviewer 1, ferumoxytol-enhanced MRI showed a mean tumor size measuring 1.1 mm larger in each plane compared with gadolinium-enhanced MRI (p = 0.1887). For reviewer 2, ferumoxytol-enhanced MRI showed a mean tumor size measuring 1.0 mm larger in each plane (p = 0.2892). No significant differences in number of metastases or tumor sizes were observed between contrast agents or reviewers. CONCLUSION. Intracranial metastatic disease detection with ferumoxytol-enhanced MRI was not inferior to detection with gadolinium-enhanced MRI. Ferumoxytol-enhanced MRI could improve workup and monitoring of patients with brain metastases if gadolinium-enhanced MRI is contraindicated.

Effectiveness of Patient Navigation to Increase Cancer Screening in Populations Adversely Affected by Health Disparities: a Meta-analysis.

BACKGROUND: This study evaluates the effectiveness of patient navigation to increase screening for colorectal, breast, and cervical cancer in populations adversely affected by health care disparities. METHODS: Eligible studies were identified through English-language searches of Ovid® MEDLINE®, PsycINFO®, SocINDEX, and Veterans Affairs Health Services database (January 1, 1996, to July 5, 2019) and manual review of reference lists. Randomized trials and observational studies of relevant populations that evaluated the effectiveness of patient navigation on screening rates for colorectal, breast, or cervical cancer compared with usual or alternative care comparison groups were included. Two investigators independently abstracted study data and assessed study quality and applicability using criteria adapted from the U.S. Preventive Services Task Force. Discrepancies were resolved by consensus with a third reviewer. Results were combined using profile likelihood random effects models. RESULTS: Thirty-seven studies met inclusion criteria (28 colorectal, 11 breast, 4 cervical cancers including 3 trials with multiple cancer types). Screening rates were higher with patient navigation for colorectal cancer overall (risk ratio [RR] 1.64; 95% confidence interval [CI] 1.42 to 1.92; I2 = 93.7%; 22 trials) and by type of test (fecal occult blood or immunohistochemistry testing [RR 1.69; 95% CI 1.33 to 2.15; I2 = 80.5%; 6 trials]; colonoscopy/endoscopy [RR 2.08; 95% CI 1.08 to 4.56; I2 = 94.6%; 6 trials]). Screening was also higher with navigation for breast cancer (RR 1.50; 95% CI 1.22 to 1.91; I2 = 98.6%; 10 trials) and cervical cancer (RR 1.11; 95% CI 1.05 to 1.19; based on the largest trial). The high heterogeneity of cervical cancer studies prohibited meta-analysis. Results were similar for colorectal and breast cancer regardless of prior adherence to screening guidelines, follow-up time, and study quality. CONCLUSIONS: In populations adversely affected by disparities, colorectal, breast, and cervical cancer screening rates were higher in patients provided navigation services. Registration: PROSPERO: CRD42018109263.

Screening for Unhealthy Drug Use: Updated Evidence Report and Systematic Review for the US Preventive Services Task Force.

Importance: Illicit drug use is among the most common causes of preventable morbidity and mortality in the US. Objective: To systematically review the literature on screening and interventions for drug use to inform the US Preventive Services Task Force. Data Sources: MEDLINE, PubMed, PsycINFO, Embase, and Cochrane Central Register of Controlled Trials through September 18, 2018; literature surveillance through September 21, 2019. Study Selection: Test accuracy studies to detect drug misuse and randomized clinical trials of screening and interventions to reduce drug use. Data Extraction and Synthesis: Critical appraisal and data abstraction by 2 reviewers and random-effects meta-analyses. Main Outcomes and Measures: Sensitivity, specificity, drug use and other health, social, and legal outcomes. Results: Ninety-nine studies (N = 84 206) were included. Twenty-eight studies (n = 65 720) addressed drug screening accuracy. Among adults, sensitivity and specificity of screening tools for detecting unhealthy drug use ranged from 0.71 to 0.94 and 0.87 to 0.97, respectively. Interventions to reduce drug use were evaluated in 52 trials (n = 15 659) of psychosocial interventions, 7 trials (n = 1109) of opioid agonist therapy, and 13 trials (n = 1718) of naltrexone. Psychosocial interventions were associated with increased likelihood of drug use abstinence (15 trials, n = 3636; relative risk [RR], 1.60 [95% CI, 1.24 to 2.13]; absolute risk difference [ARD], 9% [95% CI, 5% to 15%]) and reduced number of drug use days (19 trials, n = 5085; mean difference, -0.49 day in the last 7 days [95% CI, -0.85 to -0.13]) vs no psychosocial intervention at 3- to 4-month follow-up. In treatment-seeking populations, opioid agonist therapy and naltrexone were associated with decreased risk of drug use relapse (4 trials, n = 567; RR, 0.75 [95% CI, 0.59 to 0.82]; ARD, -35% [95% CI, -67% to -3%] and 12 trials, n = 1599; RR, 0.73 [95% CI, 0.62 to 0.85]; ARD, -18% [95% CI, -26% to -10%], respectively) vs placebo or no medication. While evidence on harms was limited, it indicated no increased risk of serious adverse events. Conclusions and Relevance: Several screening instruments with acceptable sensitivity and specificity are available to screen for drug use, although there is no direct evidence on the benefits or harms of screening. Pharmacotherapy and psychosocial interventions are effective at improving drug use outcomes, but evidence of effectiveness remains primarily derived from trials conducted in treatment-seeking populations.

Use of an Online Breast Cancer Risk Assessment and Patient Decision Aid in Primary Care Practices.

Background: U.S. Preventive Services Task Force (USPSTF) recommendations for mammography screening, genetic counseling and testing for pathogenic BRCA1/2 mutations, and use of risk-reducing medications require assessment of breast cancer risk for clinical decision-making, but efficient methods for risk assessment in clinical practice are lacking. Materials and Methods: A cross-sectional study evaluating a web-based breast cancer risk assessment and decision aid (MammoScreen) was conducted in an academic general internal medicine clinic. All eligible women, 40-74 years of age without previous diagnosis of breast or ovarian cancer and who were enrolled in the Epic MyChart patient portal were invited. MammoScreen uptake and completion rates and consistency between breast cancer risk determined by MammoScreen and existing risk information in the Epic record were measured. Patient and physician experiences were summarized from interviews. Results: Of 448 invited participants, 339 (75.7%) read their MyChart invitation and 125 (36.9%) who read invitations enrolled in the study; 118 (94.4% of enrolled) completed MammoScreen. Twenty-one women were categorized as above-average risk from either MammoScreen data or the chart review and 7 (33.3%) were identified by both sources. Physicians and patients believed MammoScreen was easy to use and was helpful in identifying risks and facilitating shared decision-making. Conclusions: Breast cancer risk assessment and mammography screening decision support were efficiently implemented through a web-based tool for patients sent through an electronic patient portal. Integration of patient decision aids with risk algorithms in clinical practice may help support the implementation of USPSTF recommendations that include risk assessment and shared decision-making.

Screening for Hepatitis C Virus Infection in Adolescents and Adults: Updated Evidence Report and Systematic Review for the US Preventive Services Task Force.

IMPORTANCE: A 2013 review for the US Preventive Services Task Force (USPSTF) of hepatitis C virus (HCV) screening found interferon-based antiviral therapy associated with increased likelihood of sustained virologic response (SVR) and an association between achieving an SVR and improved clinical outcomes. New direct-acting antiviral (DAA) regimens are available. OBJECTIVE: To update the 2013 review on HCV screening to inform the USPSTF. DATA SOURCES: Ovid MEDLINE, the Cochrane Central Register of Controlled Trials, and the Cochrane Database of Systematic Reviews through February 2019, with surveillance through September 2019. STUDY SELECTION: Randomized clinical trials (RCTs) and nonrandomized treatment studies of HCV screening and DAA therapy; cohort studies on screening, antiviral therapy, and the association between an SVR after antiviral therapy and clinical outcomes. DATA EXTRACTION AND SYNTHESIS: One investigator abstracted data; a second checked accuracy. Two investigators independently rated study quality. MAIN OUTCOMES AND MEASURES: Mortality, morbidity, quality of life, screening and treatment harms, and screening diagnostic yield. RESULTS: Eight RCTs of DAA therapy vs placebo or an outdated antiviral regimen, 48 other treatment studies, and 33 cohort studies, with a total of 179 230 participants, were included. No study evaluated effects of HCV screening vs no screening. One new study since the 2013 review (n = 5917) found similar diagnostic yield of risk-based screening (sensitivity, 82%; number needed to screen to identify 1 HCV case, 15) and birth cohort screening (sensitivity, 76%; number needed to screen, 29), assuming perfect implementation. Ten open-label studies (n = 3292) reported small improvements in some quality-of-life and functional outcomes (eg, less than 3 points on the 0 to 100 36-Item Short Form Health Survey physical and mental component summary scales) after DAA treatment compared with before treatment. Two cohort studies (n = 24 686) found inconsistent associations of antiviral therapy vs no therapy with risk of hepatocellular carcinoma. Forty-nine treatment studies (n = 10 181) found DAA regimens associated with pooled SVR rates greater than 95% across genotypes, and low short-term rates of serious adverse events (1.9%) and withdrawal due to adverse events (0.4%). An SVR after antiviral therapy was associated with decreased adjusted risk of all-cause mortality (13 studies, n = 36 986; pooled hazard ratio [HR], 0.40 [95% CI, 0.28-0.56) and hepatocellular carcinoma (20 studies, n = 84 491; pooled HR, 0.29 [95% CI, 0.23 to 0.38]) vs no SVR. CONCLUSIONS AND RELEVANCE: Direct evidence on the effects of HCV screening on clinical outcomes remains unavailable, but DAA regimens were associated with SVR rates greater than 5% and few short-term harms relative to older antiviral therapies. An SVR after antiviral therapy was associated with improved clinical outcomes compared with no SVR.

Impact of maintenance rituximab on duration of response in primary central nervous system lymphoma.

PURPOSE: The role of maintenance immunotherapy with anti-CD20 monoclonal antibody rituximab in primary central nervous system lymphoma (PCNSL) is unclear. We retrospectively reviewed the medical records of all immunocompetent adults with newly diagnosed PCNSL treated at our institution between1996 and 2017. METHODS: We identified 66 patients who attained complete response (CR) after completion of first-line regimen; 20 received maintenance therapy (maintenance therapy group) and 46 were observed with serial MRI scans without maintenance therapy (no-maintenance therapy group). RESULTS: Compared to the surveillance group, there was a significant increase in duration of survival (HR 0.27, 95% CI 0.08-0.98, P = 0.046) in the maintenance therapy group while the reduction in the risk of progression was not significant (HR: 0.61, 95% CI 0.26-1.43, P = 0.259). CONCLUSION: We are evaluating the effectiveness of maintenance immunotherapy in PCNSL in a prospective multicenter randomized clinical trial.

Clinical Factors Associated With Pediatric Brain Neoplasms Versus Primary Headache: A Case-Control Analysis.

OBJECTIVE: Pediatric headaches are a common presentation to emergency departments accounting for almost half a million annual visits. Providers are left with the difficult task of deciding who has a secondary headache etiology that warrants neuroimaging. METHODS: We conducted a retrospective case-control study. Patients from a pediatric neuro-oncology clinic database with brain cancer and a headache at presentation were identified as cases. Controls were patients from 2 local pediatric tertiary care emergency departments with a final diagnosis of headache after negative neuroimaging. Clinical factors were decided a priori, and logistic regression was used to determine which clinical factors were related to case/control status. RESULTS: A total of 334 patients (203 controls and 131 cases) were included. Patients with a history of headaches had 0.5 (95% confidence interval [CI]: 0.3-0.9; P = 0.03) times the odds of being a case. Patients with vomiting had increased odds of being a case compared with controls regardless of the time of day (early morning 1.8 [95% CI: 1.0-3.2; P = 0.04] and non-early morning 6.6 [95% CI: 2.0-21.7; P < 0.01]). Patients with neurological signs had 10.3 (95% CI: 5.4-19.4; P < 0.01) times the odds of being a case, and patients with an associated seizure had 10.9 (95% CI: 3.8-30.7; P < 0.01) times the odds of being a case. CONCLUSIONS: This study identified clinical factors associated with pediatric brain neoplasms that may guide acute neuroimaging decisions. This study also provides insight into potential clinical factors to be studied prospectively to derive a clinical decision rule.

Representation of therapy-related myelodysplastic syndrome in clinical trials over the past 20 years.

Therapy-related myelodysplastic syndrome (t-MDS), defined as MDS occurring after previous exposure to chemotherapy or radiotherapy, constitutes 10% to 20% of all MDS diagnoses. t-MDS patients tend to have higher-risk disease and worse outcomes than de novo MDS patients and are often excluded from therapeutic clinical trials. To explore this further, we extracted clinical trials across all status types registered on ClinicalTrials.gov from 1999 to 2018 studying untreated MDS patients. Using these specific search criteria, we analyzed 317 therapeutic MDS trials based on study status, therapeutic indication, eligibility criteria, and sponsor type to examine if these factors influenced t-MDS patient inclusion. Only 18 studies (5.7%) accrued 231 t-MDS patients in total, representing 3.2% of the total accrued MDS trial patient population. Fewer t-MDS patients were accrued in therapeutic trials sponsored by pharmaceutical sponsors vs nonpharmaceutical sponsors (2.8% vs 4.0%; P = .0073). This pattern of exclusion continues in actively enrolling trials; only 5 (10%) of 49 studies specifically mention the inclusion of t-MDS patients in their eligibility criteria. Our results indicate that therapeutic MDS trials seem to exclude t-MDS patients, rendering study results less applicable to this subset of MDS patients, who often have poor outcomes. Our study emphasizes the importance of the recent focus by National Cancer Institute cooperative groups and societies to broaden eligibility criteria for all patients.

Medication Use for the Risk Reduction of Primary Breast Cancer in Women: Updated Evidence Report and Systematic Review for the US Preventive Services Task Force.

Importance: Medications to reduce risk of breast cancer are effective for women at increased risk but also cause adverse effects. Objective: To update the 2013 US Preventive Services Task Force systematic review on medications to reduce risk of primary (first diagnosis) invasive breast cancer in women. Data Sources: Cochrane Central Register of Controlled Trials and Database of Systematic Reviews, EMBASE, and MEDLINE (January 1, 2013, to February 1, 2019); manual review of reference lists. Study Selection: Discriminatory accuracy studies of breast cancer risk assessment methods; randomized clinical trials of tamoxifen, raloxifene, and aromatase inhibitors for primary breast cancer prevention; studies of medication adverse effects. Data Extraction and Synthesis: Investigators abstracted data on methods, participant characteristics, eligibility criteria, outcome ascertainment, and follow-up. Results of individual trials were combined by using a profile likelihood random-effects model. Main Outcomes and Measures: Probability of breast cancer in individuals (area under the receiver operating characteristic curve [AUC]); incidence of breast cancer, fractures, thromboembolic events, coronary heart disease events, stroke, endometrial cancer, and cataracts; and mortality. Results: A total of 46 studies (82 articles [>5 million participants]) were included. Eighteen risk assessment methods in 25 studies reported low accuracy in predicting the probability of breast cancer in individuals (AUC, 0.55-0.65). In placebo-controlled trials, tamoxifen (risk ratio [RR], 0.69 [95% CI, 0.59-0.84]; 4 trials [n = 28 421]), raloxifene (RR, 0.44 [95% CI, 0.24-0.80]; 2 trials [n = 17 806]), and the aromatase inhibitors exemestane and anastrozole (RR, 0.45 [95% CI, 0.26-0.70]; 2 trials [n = 8424]) were associated with a lower incidence of invasive breast cancer. Risk for invasive breast cancer was higher for raloxifene than tamoxifen in 1 trial after long-term follow-up (RR, 1.24 [95% CI, 1.05-1.47]; n = 19 747). Raloxifene was associated with lower risk for vertebral fractures (RR, 0.61 [95% CI, 0.53-0.73]; 2 trials [n = 16 929]) and tamoxifen was associated with lower risk for nonvertebral fractures (RR, 0.66 [95% CI, 0.45-0.98]; 1 trial [n = 13 388]) compared with placebo. Tamoxifen and raloxifene were associated with increased thromboembolic events compared with placebo; tamoxifen was associated with more events than raloxifene. Tamoxifen was associated with higher risk of endometrial cancer and cataracts compared with placebo. Symptomatic effects (eg, vasomotor, musculoskeletal) varied by medication. Conclusions and Relevance: Tamoxifen, raloxifene, and aromatase inhibitors were associated with lower risk of primary invasive breast cancer in women but also were associated with adverse effects that differed between medications. Risk stratification methods to identify patients with increased breast cancer risk demonstrated low accuracy.

Safety and efficacy of high-dose methotrexate for osteosarcoma in adolescents compared with young adults.

BACKGROUND: Doxorubicin, cisplatin, and high-dose methotrexate (HDMTX) are the backbone of pediatric osteosarcoma treatment. However, due to toxicity concerns and the lack of data regarding efficacy in adults, high-dose methotrexate is rarely used in the adult population. METHODS: This single-center retrospective study examined 33 patients who received HDMTX (12 g/m2 , maximum 20 g) for the treatment of osteosarcoma at Oregon Health and Science University (OHSU) from 2011 to 2017. Time to serum methotrexate level ≤0.1 µmol/L was the primary outcome. Secondary outcomes included number of HDMTX doses received, methotrexate-related toxicities, and disease outcomes including histologic response at resection and metastasis-free survival. RESULTS: Median age was 20 years [range 7-38]; 14 patients ≤18 years old and 19 patients >18 years old. Median time to clearance for patients ≤18 years was 79 hours (range 63-116) compared to 120 hours (range 77-315) for patients >18 years (P < 0.001). No correlation between age and histologic response at resection was observed (P = 0.50), but there was a significant positive correlation between the number of HDMTX doses received before resection and histologic response (r = 0.49, P = 0.006). There was no significant difference in metastasis-free survival between age groups, although a trend toward improved survival was noted for patients who received at least seven doses of HDMTX. CONCLUSION: Age over 18 years correlates with delayed methotrexate clearance and fewer administered doses of methotrexate, without increased toxicity. The potential benefit of HDMTX in young adults with osteosarcoma may outweigh toxicity risks.

Cerebral blood volume mapping with ferumoxytol in dynamic susceptibility contrast perfusion MRI: Comparison to standard of care.

BACKGROUND: Cerebral blood volume (CBV) mapping with a dynamic susceptibility contrast (DSC) perfusion technique has become a clinical tool in diagnosing and follow-up of brain tumors. Ferumoxytol, a long-circulating iron oxide nanoparticle, has been tested for CBV mapping, but the optimal dose has not been established. PURPOSE: To compare ferumoxytol DSC of two different doses to standard of care gadoteridol by analyzing time-intensity curves and CBV maps in normal-appearing brain regions. STUDY TYPE: Retrospective. SUBJECTS: Fifty-four patients with various brain disorders. FIELD STRENGTH/SEQUENCE: 3T MRI. DSC-MRI was performed with 0.1 mmol/kg gadoteridol and 1 day later with ferumoxytol in doses of 1 or 2 mg/kg. ASSESSMENT: Signal changes during first pass, relative CBV (rCBV) in normal-appearing thalamus, putamen, and globus pallidus, and contrast-to-noise ratio (CNR) of the CBV maps were compared between gadoteridol and various doses of ferumoxytol using an automated method. To subjectively assess the quality of the CBV maps, two blinded readers also assessed visual conspicuity of the putamen. STATISTICAL TESTS: Linear mixed effect model was used for statistical comparison. RESULTS: Compared to gadoteridol, 1 mg/kg ferumoxytol showed no difference in CNR (P = 0.6505), peak ΔR2*, and rCBV in the putamen (P = 0.2669, 0.0871) or in the thalamus (P = 0.517, 0.9787); 2 mg/kg ferumoxytol increased peak ΔR2* as well as the CNR (P < 0.0001), but also mildly increased rCBV in putamen and globus pallidus (P = 0.0005, 0.0012). Signal intensities during first pass remained highly above the noise level, with overlapping of 95% confidence intervals with noise only in 3 out of 162 tested regions. Compared to gadoteridol, the visual image quality showed mild improvement with 1 mg/kg (P = 0.02) and marked improvement with 2 mg/kg ferumoxytol (P < 0.0001). DATA CONCLUSION: 1 mg/kg ferumoxytol provides similar imaging results to standard gadoteridol for DSC-MRI, and 2 mg/kg has a benefit of increased CNR, but may also result in mildly increased rCBV values. LEVEL OF EVIDENCE: 3 Technical Efficacy: Stage 1 J. MAGN. RESON. IMAGING 2018;48:441-448.