Rochelle Fu

Effectiveness of Breast Cancer Screening: Systematic Review and Meta-analysis to Update the 2009 U.S. Preventive Services Task Force Recommendation

In 2009, the U.S. Preventive Services Task Force (USPSTF) recommended biennial mammography screening for women aged 50 to 74 years (1) on the basis of evidence of benefits and harms (2). The USPSTF concluded that screening decisions for women aged 40 to 49 years should be based on individual considerations, and that evidence was insufficient to assess benefits and harms for women aged 75 years or older (1). Mammography screening in the United States is generally opportunistic, unlike many screening programs organized as public health services in other countries. Despite changes in practice guidelines and variation in clinical practices (3), overall screening rates in the United States have remained relatively stable for the past decade (4, 5). Data from the Healthcare Effectiveness Data and Information Set indicate that mammography screening in 2014 in HMOs was performed for 74% of eligible women covered by commercial plans, 72% by Medicare, and 59% by Medicaid (6). This systematic review updates evidence for the USPSTF on the effectiveness of mammography screening in reducing breast cancer mortality, all-cause mortality, and advanced breast cancer for women at average risk; and how effectiveness varies by age, risk factors, screening intervals, and imaging modalities. Systematic reviews of harms of screening (7), performance characteristics of screening methods (8), and accuracy of breast density determination and use of supplemental screening technologies (9) are provided in separate reports. Methods Scope, Key Questions, and Analytic Framework The USPSTF determined the scope and key questions for this review by using established methods (10, 11). A standard protocol was developed and publicly posted on the USPSTF Web site. A technical report further describes the methods and includes search strategies and additional information (7). Investigators created an analytic framework outlining the key questions, patient populations, interventions, and outcomes reviewed (Appendix Figure 1). Key questions include the effectiveness of screening in reducing breast cancer mortality, all-cause mortality, and advanced breast cancer, and how effectiveness differs by age, risk factors, screening intervals, and modalities (mammography [film, digital, tomosynthesis], magnetic resonance imaging [MRI], and ultrasonography). Appendix Figure 1. Analytic framework and key questions. KQ = key question. * Excludes women with preexisting breast cancer; clinically significant BRCA1 or BRCA2 mutations, LiFraumeni syndrome, Cowden syndrome, hereditary diffuse gastric cancer, or other familial breast cancer syndromes; high-risk lesions (ductal carcinoma in situ, lobular carcinoma in situ, atypical ductal hyperplasia, atypical lobular hyperplasia); or previous large doses of chest radiation (20 Gy) before age 30 y. Risk factors include family history; breast density; race/ethnicity; menopausal status; current use of menopausal hormone therapy or oral contraceptives; prior benign breast biopsy; and, for women aged >50 y, body mass index. Morbidity includes physical adverse effects of treatment, quality-of-life measures, and other measures of impairment. Screening modalities include mammography (film, digital, tomosynthesis), magnetic resonance imaging, ultrasonography, and clinical breast examination (alone or in combination). The target population for the USPSTF recommendation includes women aged 40 years or older, and excludes women with known physical signs or symptoms of breast abnormalities and those at high-risk for breast cancer whose surveillance and management are beyond the scope of the USPSTFs recommendations for prevention services (i.e., preexisting breast cancer or high-risk breast lesions, hereditary genetic syndromes associated with breast cancer, or previous large doses of chest radiation before age 30 years). Risk factors considered in this review are common among women who are not at high risk for breast cancer (12) (Appendix Figure 1). Data Sources and Searches A research librarian conducted electronic database searches of the Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, and Ovid MEDLINE to 4 June 2015. Searches were supplemented by references identified from additional sources, including reference lists and experts. Additional unpublished data were provided by the investigators of the Canadian National Breast Screening Study (CNBSS) and Swedish Two-County Trial. Study Selection Two investigators independently evaluated each study to determine inclusion eligibility on the basis of prespecified criteria. Discrepancies were resolved through consensus. We included randomized, controlled trials (RCTs); observational studies of screening cohorts; and systematic reviews that compared outcomes of women exposed to screening versus not screening. For advanced cancer outcomes, studies that reported the incidence of late-stage disease among screened and unscreened populations were included, whereas those reporting comparisons of detection methods that did not capture a womans longitudinal screening experience were not included (e.g., rates of screen-detected vs. nonscreen-detected cancer). Studies providing outcomes specific to age, risk factors, screening intervals, and modalities were preferred over studies providing general outcomes, when available. Studies most clinically relevant to practice in the United States were selected over studies that were less relevant. Relevance was determined by practice setting, population, date of publication, and use of technologies and therapies in current practice. Studies meeting criteria for high quality and those with designs ranked higher in the study designbased hierarchy of evidence were emphasized because they are less susceptible to bias (e.g., RCTs over observational studies). Data Extraction and Quality Assessment Details of the study design, patient population, setting, screening method, interventions, analysis, follow-up, and results were abstracted by one investigator and confirmed by a second. Two investigators independently applied criteria developed by the USPSTF (10, 11) to rate the quality of each study as good, fair, or poor for studies designed as RCTs, cohort studies, casecontrol studies, and systematic reviews; criteria to rate other study designs included in this review are not available. Discrepancies were resolved through consensus. Data Synthesis We conducted several meta-analyses to determine more precise summary estimates when adequate data were reported by trials rated as fair- or good-quality. In each meta-analysis, the number of included trials was counted as the number of discrete data sources contributing to the summary estimate using their most recent results. To determine the appropriateness of meta-analysis, we considered clinical and methodological diversity and assessed statistical heterogeneity. All outcomes were binary (breast cancer mortality, all-cause mortality, and advanced cancer incidence defined by stage and tumor size). We used a random-effects model to combine relative risks (RRs) as the effect measure of the meta-analyses, while incorporating variation among studies. A profile-likelihood model was used to combine studies in the primary analyses (13). We assessed the presence of statistical heterogeneity among the studies by using the standard Cochran chi-square test, and the magnitude of heterogeneity by using the I 2 statistic (14). To account for clinical heterogeneity and obtain clinically meaningful estimates, we stratified the analyses by age group whenever possible (39 to 49 years, 50 to 59 years, 60 to 69 years, 70 to 74 years, and 50 years). We obtained additional age-stratified data for the meta-analysis from the investigators of 3 trials (15, 16) (Tabr L. Personal communication). For breast cancer mortality, we used 2 methods of including cases to help clarify discrepancies between estimates. The long case accrual method counts all breast cancer cases contributing to breast cancer deaths. In this method, the case accrual time is equivalent to or close to the follow-up time. The short case accrual method includes only deaths that occur among cases of breast cancer diagnosed during the screening intervention period, and in some trials, within an additional defined case accrual period. The longest follow-up times available for each trial were selected for inclusion in the initial meta-analyses, and sensitivity analyses were conducted by using results of short case accrual methods. We calculated the absolute rate reduction for 100000 woman-years of follow-up (i.e., 10000 women followed for 10 years) for each age group on the basis of the combined RR and the combined cancer rate of the control group. We estimated combined cancer rates for each age group for controls with a random effects Poisson model using data from the trials. All analyses were performed by using Stata/IC, version 13.1 (StataCorp). We assessed the aggregate internal validity (quality) of the body of evidence for each key question as good, fair, or poor by using methods developed by the USPSTF that are based on the number, quality, and size of studies; consistency of results between studies; and directness of evidence (10, 11). Role of the Funding Source This research was funded by the Agency for Healthcare Research and Quality (AHRQ) under a contract to support the work of the USPSTF. The investigators worked with USPSTF members and AHRQ staff to develop and refine the scope, analytic framework, and key questions; resolve issues during the project; and finalize the report. The AHRQ had no role in study selection, quality assessment, synthesis, or development of conclusions. The AHRQ provided project oversight; reviewed the draft report; and distributed the draft for peer review, including to representatives of professional societies and federal agencies. The AHRQ performed a final review of the manuscript to ensure that the

Systemic Pharmacologic Therapies for Low Back Pain: A Systematic Review for an American College of Physicians Clinical Practice Guideline.

Low back pain is one of the most frequently encountered conditions in clinical practice (1, 2). The most commonly prescribed medications for low back pain are nonsteroidal anti-inflammatory drugs (NSAIDs), skeletal muscle relaxants, antidepressants, and opioids (35); benzodiazepines, systemic corticosteroids, and antiseizure medications are also prescribed (3). Patients often use over-the-counter acetaminophen and NSAIDs. A 2007 guideline (6) and associated systematic review (7) from the American College of Physicians (ACP) and American Pain Society (APS) found evidence to support the use of acetaminophen and NSAIDs as first-line pharmacologic options for low back pain; secondary options were skeletal muscle relaxants, benzodiazepines, and antidepressants. New evidence and medications are now available. Here, we review the current evidence on benefits and harms of medications for low back pain. This article has been used by ACP to update a clinical practice guideline, also in this issue. Methods Detailed methods and data for our review, including the analytic framework, additional medications (topical capsaicin and lidocaine), nonpharmacologic therapies (addressed in a separate article) (8), search strategies, inclusion criteria, data extraction and quality-rating methods, and additional outcomes (for example, quality of life, global improvement, and patient satisfaction), are available in the full report (9). The protocol was developed by using a standardized process (10) with input from experts and the public and is registered in the PROSPERO database (11). This article addresses the key question, what are the comparative benefits and harms of different systemic pharmacologic therapies for acute or chronic nonradicular low back pain, radicular low back pain, or spinal stenosis? Data Sources and Searches A research librarian searched Ovid MEDLINE (January 2007 through April 2015), the Cochrane Central Register of Controlled Trials, and the Cochrane Database of Systematic Reviews (through April 2015). We used the prior ACP/APS review (12) to identify earlier studies. Updated searches were performed through November 2016. We also reviewed reference lists and searched ClinicalTrials.gov. Study Selection Two investigators independently reviewed abstracts and full-text articles against prespecified eligibility criteria. The population was adults with nonradicular or radicular low back pain of any duration (categorized as acute [<4 weeks], subacute [4 to 12 weeks], and chronic [12 weeks]). Excluded conditions were low back pain due to cancer, infection, inflammatory arthropathy, high-velocity trauma, or fracture; low back pain during pregnancy; and presence of severe or progressive neurologic deficits. We evaluated acetaminophen, NSAIDs, opioids, tramadol and tapentadol, antidepressants, skeletal muscle relaxants, benzodiazepines, corticosteroids, and antiseizure medications versus placebo, no treatment, or other therapies. We also evaluated the combination of 2 medications versus 1 medication alone. Outcomes were long-term (1 year) or short-term (6 months) pain or function, mood (for antidepressants), risk for surgery (for corticosteroids), and harms. Given the large number of medications addressed, we included systematic reviews of randomized trials (13, 14). For each medication, we selected the most recent, most relevant, and highest-quality comprehensive systematic review based on a validated assessment tool (14, 15). If more than 1 good-quality systematic review was available, we preferentially selected updates of those used in the ACP/APS review. We supplemented systematic reviews with additional trials. Although we did not include systematic reviews identified in update searches, we checked reference lists for additional studies. We excluded nonEnglish-language articles and abstract-only publications. Data Extraction and Quality Assessment One investigator extracted study data, and a second verified accuracy. For systematic reviews, we abstracted details about inclusion criteria, search strategy, databases searched, search dates, number and characteristics of included studies, quality assessment methods and ratings, synthesis methods, and results. For randomized trials, we abstracted details about the setting, sample size, eligibility criteria, population characteristics, treatment characteristics, results, and funding source. Two investigators independently assessed the quality of each study as good, fair, or poor using criteria developed by the U.S. Preventive Services Task Force (for randomized trials) (16) and AMSTAR (A Measurement Tool to Assess Systematic Reviews) (14). For primary studies included in systematic reviews, we used both the quality ratings and the overall grade (for example, good, fair, or poor, or high or low) as determined in the reviews. We classified the magnitude of effects as small/slight, moderate, or large/substantial based on the definitions in the ACP/APS review (Table 1) (6, 17). We also reported risk estimates based on the proportion of patients achieving successful pain or function outcomes (for example, >30% or >50% improvement). Table 1. Definitions for Magnitude of Effects, Based on Mean Between-Group Differences Data Synthesis and Analysis We synthesized data qualitatively for each medication, stratified according to the duration of symptoms (acute, subacute, or chronic) and presence or absence of radicular symptoms. We reported meta-analysis results from systematic reviews. When statistical heterogeneity was present, we examined the degree of inconsistency and evaluated subgroup and sensitivity analyses. We did not conduct an updated meta-analysis; rather, we qualitatively examined whether results of new studies were consistent with pooled or qualitative findings from prior systematic reviews. Qualitative assessments were based on whether the findings from the new studies were in the same direction as the prior systematic reviews and whether the magnitude of effects was similar; when prior meta-analyses were available, we analyzed whether the estimates and CIs from new studies were encompassed in the CIs from pooled estimates. We assessed the strength of evidence (SOE) for each body of evidence as high, moderate, low, or insufficient based on aggregate study quality, precision, consistency, and directness (18). Role of the Funding Source The Agency for Healthcare Research and Quality (AHRQ) of the U.S. Department of Health and Human Services funded this review. AHRQ staff assisted in developing the scope and key questions. The AHRQ had no role in study selection, quality assessment, or synthesis. Results Literature Search The search and selection of articles are summarized in the Figure. Database searches found 2847 potentially relevant articles. After dual review of abstracts and titles, we selected 746 articles for full-text dual review; 46 publications met inclusion criteria. Quality ratings are summarized in Supplement Tables 1 and 2. Supplement. Data Supplement. Figure. Summary of evidence search and selection. ACP = American College of Physicians; AHRQ = Agency for Healthcare Research and Quality; APS = American Pain Society; NSAID = nonsteroidal anti-inflammatory drug; RCT = randomized, controlled trial; SR = systematic review. * Cochrane databases include the Cochrane Central Register of Controlled Trials and the Cochrane Database of Systematic Reviews. Other sources include prior reports, reference lists of relevant articles, and systematic reviews. Publications may be included or excluded for multiple reasons. Acetaminophen Ten trials evaluated acetaminophen; 9 of these (sample sizes, 39 to 456) were included in the ACP/APS review (19). We identified 1 additional large (n= 1643), good-quality, placebo-controlled trial (20). Six trials compared acetaminophen with NSAIDs and were included in a systematic review of NSAIDs (Supplement Table 3) (21, 22). Along with the new trial, 3 others (2325) were rated good- or high-quality. For acute low back pain, 1 new trial found no differences between 4 weeks or less of scheduled or as-needed acetaminophen (about 4 g/d) and placebo in pain (differences, 0.20 point on a 0- to 10-point scale), function (differences, 0.60 point on the 0- to 24-point RolandMorris Disability Questionnaire [RDQ]), or risk for serious adverse events (about 1% in each group) after 12 weeks (Supplement Table 4) (20). One trial of acetaminophen versus no treatment included in the ACP/APS review (26) also found no differences. We found no difference between acetaminophen and NSAIDs in pain intensity (standardized mean difference [SMD], 0.21 [95% CI, 0.02 to 0.43]) at 3 weeks or less based on 3 low-quality trials, although estimates favored NSAIDs (22). Acetaminophen had a lower risk for adverse events than NSAIDs (relative risk [RR], 0.57 [CI, 0.36 to 0.89]). Evidence was insufficient to determine the effects of acetaminophen versus various nonpharmacologic therapies (24, 27, 28) or amitriptyline (25); each comparison was evaluated in 1 trial with methodological shortcomings. No study evaluated acetaminophen for chronic or radicular low back pain. NSAIDs Seventy trials evaluated NSAIDs; 57 were in the ACP/APS review. Sixty-five trials (total n= 11237; sample sizes, 20 to 690), 28 of which were high-quality, were included in a systematic review (Supplement Table 3) (22). We identified 5 additional trials (n= 54 to 525) (Supplement Table 5) (2933). One trial was rated good-quality (31), and 4 were rated fair-quality (29, 30). For acute back pain, 1 systematic review (22) found that NSAIDs were associated with greater mean improvements in pain intensity than placebo (4 trials: weighted mean difference, 8.39 points on a 0- to 100-point scale [CI, 12.68 to 4.10 points]; chi-square test, 3.47 points; P> 0.10) (3437). One additional trial (n= 171) reported consistent findings (29). Three trials in this review found no differences between an NSAID and placeb

Temporal daily associations between pain and sleep in adolescents with chronic pain versus healthy adolescents

&NA; Adolescents with chronic pain frequently report sleep disturbances, particularly short sleep duration, night wakings, and poor sleep quality. Prior research has been limited by assessment of subjectively reported sleep only and lack of data on daily relationships between sleep and pain. The current study utilized multilevel modeling to compare daily associations between sleep and pain in adolescents with chronic pain and healthy adolescents. Ninety‐seven adolescents (n = 39 chronic pain; n = 58 healthy) aged 12–18, 70.1% female participated. Adolescents completed pain diary ratings (0–10 NRS) and actigraphic sleep monitoring for 10 days. Actigraphic sleep variables (duration, efficiency, WASO) and self‐reported sleep quality were tested as predictors of next‐day pain, and daytime pain was tested as a predictor of sleep that night. Effects of age, gender, study group, and depressive symptoms on daily associations between sleep and pain were also tested. Multivariate analyses revealed that nighttime sleep (p < .001) and minutes awake after sleep onset (WASO) (p < .05) predicted next‐day pain, with longer sleep duration and higher WASO associated with higher pain. Contrary to hypotheses, neither nighttime sleep quality nor sleep efficiency predicted pain the following day. The interaction between nighttime sleep efficiency and study group was significant, with adolescents with pain showing stronger associations between sleep efficiency and next‐day pain than healthy participants (p = .05). Contrary to hypotheses, daytime pain did not predict nighttime sleep. Daily associations between pain and sleep suggest that further work is needed to identify specific adolescent sleep behaviors (e.g., compensatory sleep behaviors) that may be targeted in interventions.

Pressure Ulcer Treatment Strategies: A Systematic Comparative Effectiveness Review

BACKGROUND Pressure ulcers affect as many as 3 million Americans and are major sources of morbidity, mortality, and health care costs. PURPOSE To summarize evidence comparing the effectiveness and safety of treatment strategies for adults with pressure ulcers. DATA SOURCES MEDLINE, EMBASE, CINAHL, Evidence-Based Medicine Reviews, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, Database of Abstracts of Reviews of Effects, and Health Technology Assessment Database for English- or foreign-language studies; reference lists; gray literature; and individual product packets from manufacturers (January 1985 to October 2012). STUDY SELECTION Randomized trials and comparative observational studies of treatments for pressure ulcers in adults and noncomparative intervention series (n > 50) for surgical interventions and evaluation of harms. DATA EXTRACTION Data were extracted and evaluated for accuracy of the extraction, quality of included studies, and strength of evidence. DATA SYNTHESIS 174 studies met inclusion criteria and 92 evaluated complete wound healing. In comparison with standard care, placebo, or sham interventions, moderate-strength evidence showed that air-fluidized beds (5 studies [n = 908]; high consistency), protein-containing nutritional supplements (12 studies [n = 562]; high consistency), radiant heat dressings (4 studies [n = 160]; moderate consistency), and electrical stimulation (9 studies [n = 397]; moderate consistency) improved healing of pressure ulcers. Low-strength evidence showed that alternating-pressure surfaces, hydrocolloid dressings, platelet-derived growth factor, and light therapy improved healing of pressure ulcers. The evidence about harms was limited. LIMITATION Applicability of results is limited by study quality, heterogeneity in methods and outcomes, and inadequate duration to assess complete wound healing. CONCLUSION Moderate-strength evidence shows that healing of pressure ulcers in adults is improved with the use of air-fluidized beds, protein supplementation, radiant heat dressings, and electrical stimulation.

Influence of menopause on mood: a systematic review of cohort studies

Objective This systematic evidence review evaluates the independent influence of the menopausal transition on mood including depression, anxiety, and other psychological symptoms. Methods Community-based, prospective cohort studies of mid-life women transitioning through menopause that assessed at least one mood symptom on two or more occasions were identified by searches of MEDLINE (1966–2007) and PsycINFO (1974–2007) databases. Articles were selected based on predetermined inclusion and exclusion criteria. Each study was quality-rated by three authors; poor quality studies were excluded. Results Nine studies met inclusion criteria. They varied broadly in design, outcome measures, statistical methodology, and in consideration of and adjustment for important confounders. Five found no association between the menopausal transition and depression, negative mood, major depressive disorder, other psychological symptoms, and general mental health. Three found that women entering or completing the menopausal transition were more likely than premenopausal women to be depressed. One found that well-being increased from the early to late menopausal transition. Conclusion There is no demonstrated pattern of an adverse independent influence of the menopausal transition on mood symptoms in mid-life women. However, the available studies are too methodologically diverse to be definitive.

Educational group visits for the management of chronic health conditions: A systematic review

OBJECTIVE Review the effectiveness of group visits (appointments of multiple patients) on quality of life, function, self-efficacy, utilization, and biophysical outcomes in randomized controlled trials of patients with chronic conditions. METHODS We searched MEDLINE(®), Cochrane, CINAHL, and PsycINFO to January 2013 for English-language trials of educational group visits led by non-prescribing facilitators (e.g., peer educators). RESULTS We report on 80 arthritis/falls (n=22), asthma/COPD (n=10), CHF/hypertension (n=12), diabetes (n=29), multiple conditions (n=4), and pain (n=4) studies. We found moderate evidence of improved short-term self-efficacy in patients with arthritis (10 studies) and diabetes (10 studies). We found no consistent evidence of improved quality of life; however a moderately strong body of evidence suggests peer-led community-based programs might improve quality of life and utilization in patients with multiple chronic conditions. Meta-analyses found short- (14 studies; mean change HbA1c=-0.27, CI=-0.44, 0.11) and long-term (10 studies; mean change HbA1c=-0.23, CI=-0.44, -0.02) glycemic improvement. CONCLUSIONS Group visits may improve self-efficacy and glycemic control. There was little consistent evidence of improved quality of life, functional status, or utilization. PRACTICE IMPLICATIONS Group visits represent a reasonable alternative for educating patients with chronic illness, though varied participation/retention suggests they should not be the sole alternative.

What Does the Boxed Warning Tell Us? Safe Practice of Using Ferumoxytol as an MRI Contrast Agent

BACKGROUND AND PURPOSE: Despite the label change and the FDAs boxed warning added to the Feraheme (ferumoxytol) label in March 2015, radiologists have shown increasing interest in using ferumoxytol as an MR imaging contrast agent as a supplement or alternative to gadolinium. The goals of this study were to provide information regarding ferumoxytol safety as an imaging agent in a single center and to assess how the Feraheme label change may affect this potential, currently off-label indication. MATERIALS AND METHODS: This retrospective study evaluated the overall frequency of ferumoxytol-related adverse events when used for CNS MR imaging. Patients with various CNS pathologies were enrolled in institutional review board–approved imaging studies. Ferumoxytol was administered as multiple rapid bolus injections. The risk of adverse events was correlated with demographic data/medical history. RESULTS: The safety of 671 ferumoxytol-enhanced MR studies in 331 patients was analyzed. No anaphylactic, life-threatening, or fatal (grade 4 or 5) adverse events were recorded. The overall proportion of ferumoxytol-related grade 1–3 adverse events was 10.6% (8.6% occurring within 48 hours), including hypertension (2.38%), nausea (1.64%), diarrhea (1.04%), and headache (1.04%). History of 1 or 2 allergies was associated with an increased risk of adverse events (14.61% versus 7.51% [no history]; P = .007). CONCLUSIONS: The frequency of mild ferumoxytol-related adverse events was comparable with literature results, and no serious adverse event was recorded. Although the recommendations in the boxed warning should be followed, serious adverse events appear to be rare, and with proper precautions, ferumoxytol may be a valuable MR imaging agent.

Enhancing the cytotoxicity of chemoradiation with radiation-guided delivery of anti-MGMT morpholino oligonucleotides in non-methylated solid tumors

The DNA repair enzyme O6-methylguanine DNA methyltransferase (MGMT) is epigenetically silenced in some tumors by MGMT gene promoter methylation. MGMT-hypermethylated solid tumors have enhanced susceptibility to the cytotoxic effects of alkylating chemotherapy such as temozolomide, compared with non-methylated tumors. In glioblastoma, subjects with MGMT hypermethylation have significantly longer survival rates after chemoradiotherapy. We report the first successful use of a non-ablative dose of ionizing radiation to prime human cancer cells to enhance the uptake of unmodified anti-MGMT morpholino oligonucleotide (AMON) sequences. We demonstrate >40% reduction in the in vitro proliferation index and cell viability in radiation-primed MGMT-expressing human solid tumor cells treated with a single dose of AMONs and temozolomide. We further demonstrate the feasibility of using a non-ablative dose of radiation in vivo to guide and enhance the delivery of intravenously administered AMONs to achieve 50% MGMT knockdown only at radiation-primed tumor sites in a subcutaneous tumor model. Local upregulation of physiological endocytosis after radiation may have a role in radiation-guided uptake of AMONs. This approach holds direct translational significance in glioblastoma and brain metastases where radiation is part of the standard of care; our approach to silence MGMT could overcome the significant problem of MGMT-mediated chemoresistance.