Clinical validation of the PrecivityAD2 blood test: A mass spectrometry-based test with algorithm combining %p-tau217 and Aß42/40 ratio to identify presence of brain amyloid.

BACKGROUND: With the availability of disease-modifying therapies for Alzheimer's disease (AD), it is important for clinicians to have tests to aid in AD diagnosis, especially when the presence of amyloid pathology is a criterion for receiving treatment. METHODS: High-throughput, mass spectrometry-based assays were used to measure %p-tau217 and amyloid beta (Aß)42/40 ratio in blood samples from 583 individuals with suspected AD (53% positron emission tomography [PET] positive by Centiloid > 25). An algorithm (PrecivityAD2 test) was developed using these plasma biomarkers to identify brain amyloidosis by PET. RESULTS: The area under the receiver operating characteristic curve (AUC-ROC) for %p-tau217 (0.94) was statistically significantly higher than that for p-tau217 concentration (0.91). The AUC-ROC for the PrecivityAD2 test output, the Amyloid Probability Score 2, was 0.94, yielding 88% agreement with amyloid PET. Diagnostic performance of the APS2 was similar by ethnicity, sex, age, and apoE4 status. DISCUSSION: The PrecivityAD2 blood test showed strong clinical validity, with excellent agreement with brain amyloidosis by PET.

Amyloid Positron Emission Tomography and Subsequent Health Care Use Among Medicare Beneficiaries With Mild Cognitive Impairment or Dementia.

Importance: Results of amyloid positron emission tomography (PET) have been shown to change the management of patients with mild cognitive impairment (MCI) or dementia who meet Appropriate Use Criteria (AUC). Objective: To determine if amyloid PET is associated with reduced hospitalizations and emergency department (ED) visits over 12 months in patients with MCI or dementia. Design, Setting, and Participants: This nonrandomized controlled trial analyzed participants in the Imaging Dementia-Evidence for Amyloid Scanning (IDEAS) study, an open-label, multisite, longitudinal study that enrolled participants between February 2016 and December 2017 and followed up through December 2018. These participants were recruited at 595 clinical sites that provide specialty memory care across the US. Eligible participants were Medicare beneficiaries 65 years or older with a diagnosis of MCI or dementia within the past 24 months who met published AUC for amyloid PET. Each IDEAS study participant was matched to a control Medicare beneficiary who had not undergone amyloid PET. Data analysis was conducted on December 13, 2022. Exposure: Participants underwent amyloid PET at imaging centers. Main Outcomes and Measures: The primary end points were the proportions of patients with 12-month inpatient hospital admissions and ED visits. One of 4 secondary end points was the rate of hospitalizations and rate of ED visits in participants with positive vs negative amyloid PET results. Health care use was ascertained from Medicare claims data. Results: The 2 cohorts (IDEAS study participants and controls) each comprised 12 684 adults, including 6467 females (51.0%) with a median (IQR) age of 77 (73-81) years. Over 12 months, 24.0% of the IDEAS study participants were hospitalized, compared with 25.1% of the matched control cohort, for a relative reduction of -4.49% (97.5% CI, -9.09% to 0.34%). The 12-month ED visit rates were nearly identical between the 2 cohorts (44.8% in both IDEAS study and control cohorts) for a relative reduction of -0.12% (97.5% CI, -3.19% to 3.05%). Both outcomes fell short of the prespecified effect size of 10% or greater relative reduction. Overall, 1467 of 6848 participants (21.4%) with positive amyloid PET scans were hospitalized within 12 months compared with 1081 of 4209 participants (25.7%) with negative amyloid PET scans (adjusted odds ratio, 0.83; 95% CI, 0.78-0.89). Conclusions and Relevance: Results of this nonrandomized controlled trial showed that use of amyloid PET was not associated with a significant reduction in 12-month hospitalizations or ED visits. Rates of hospitalization were lower in patients with positive vs negative amyloid PET results.

Racial and Ethnic Differences in Amyloid PET Positivity in Individuals With Mild Cognitive Impairment or Dementia: A Secondary Analysis of the Imaging Dementia-Evidence for Amyloid Scanning (IDEAS) Cohort Study.

Importance: Racial and ethnic groups with higher rates of clinical Alzheimer disease (AD) are underrepresented in studies of AD biomarkers, including amyloid positron emission tomography (PET). Objective: To compare amyloid PET positivity among a diverse cohort of individuals with mild cognitive impairment (MCI) or dementia. Design, Setting, and Participants: Secondary analysis of the Imaging Dementia-Evidence for Amyloid Scanning (IDEAS), a single-arm multisite cohort study of Medicare beneficiaries who met appropriate-use criteria for amyloid PET imaging between February 2016 and September 2017 with follow-up through January 2018. Data were analyzed between April 2020 and January 2022. This study used 2 approaches: the McNemar test to compare amyloid PET positivity proportions between matched racial and ethnic groups and multivariable logistic regression to assess the odds of having a positive amyloid PET scan. IDEAS enrolled participants at 595 US dementia specialist practices. A total of 21 949 were enrolled and 4842 (22%) were excluded from the present analysis due to protocol violations, not receiving an amyloid PET scan, not having a positive or negative scan, or because of small numbers in some subgroups. Exposures: In the IDEAS study, participants underwent a single amyloid PET scan. Main Outcomes and Measures: The main outcomes were amyloid PET positivity proportions and odds. Results: Data from 17 107 individuals (321 Asian, 635 Black, 829 Hispanic, and 15 322 White) with MCI or dementia and amyloid PET were analyzed between April 2020 and January 2022. The median (range) age of participants was 75 (65-105) years; 8769 participants (51.3%) were female and 8338 (48.7%) were male. In the optimal 1:1 matching analysis (n = 3154), White participants had a greater proportion of positive amyloid PET scans compared with Asian participants (181 of 313; 57.8%; 95% CI, 52.3-63.2 vs 142 of 313; 45.4%; 95% CI, 39.9-50.9, respectively; P = .001) and Hispanic participants (482 of 780; 61.8%; 95% CI, 58.3-65.1 vs 425 of 780; 54.5%; 95% CI, 51.0-58.0, respectively; P = .003) but not Black participants (359 of 615; 58.4%; 95% CI, 54.4-62.2 vs 333 of 615; 54.1%; 95% CI, 50.2-58.0, respectively; P = .13). In the adjusted model, the odds of having a positive amyloid PET scan were lower for Asian participants (odds ratio [OR], 0.47; 95% CI, 0.37-0.59; P < .001), Black participants (OR, 0.71; 95% CI, 0.60-0.84; P < .001), and Hispanic participants (OR, 0.68; 95% CI, 0.59-0.79; P < .001) compared with White participants. Conclusions and Relevance: Racial and ethnic differences found in amyloid PET positivity among individuals with MCI and dementia in this study may indicate differences in underlying etiology of cognitive impairment and guide future treatment and prevention approaches.

Assessment of a Plasma Amyloid Probability Score to Estimate Amyloid Positron Emission Tomography Findings Among Adults With Cognitive Impairment.

Importance: The diagnostic evaluation for Alzheimer disease may be improved by a blood-based diagnostic test identifying presence of brain amyloid plaque pathology. Objective: To determine the clinical performance associated with a diagnostic algorithm incorporating plasma amyloid-ß (Aß) 42:40 ratio, patient age, and apoE proteotype to identify brain amyloid status. Design, Setting, and Participants: This cohort study includes analysis from 2 independent cross-sectional cohort studies: the discovery cohort of the Plasma Test for Amyloidosis Risk Screening (PARIS) study, a prospective add-on to the Imaging Dementia-Evidence for Amyloid Scanning study, including 249 patients from 2018 to 2019, and MissionAD, a dataset of 437 biobanked patient samples obtained at screenings during 2016 to 2019. Data were analyzed from May to November 2020. Exposures: Amyloid detected in blood and by positron emission tomography (PET) imaging. Main Outcomes and Measures: The main outcome was the diagnostic performance of plasma Aß42:40 ratio, together with apoE proteotype and age, for identifying amyloid PET status, assessed by accuracy, sensitivity, specificity, and area under the receiver operating characteristic curve (AUC). Results: All 686 participants (mean [SD] age 73.2 [6.3] years; 368 [53.6%] men; 378 participants [55.1%] with amyloid PET findings) had symptoms of mild cognitive impairment or mild dementia. The AUC of plasma Aß42:40 ratio for PARIS was 0.79 (95% CI, 0.73-0.85) and 0.86 (95% CI, 0.82-0.89) for MissionAD. Ratio cutoffs for Aß42:40 based on the Youden index were similar between cohorts (PARIS: 0.089; MissionAD: 0.092). A logistic regression model (LRM) incorporating Aß42:40 ratio, apoE proteotype, and age improved diagnostic performance within each cohort (PARIS: AUC, 0.86 [95% CI, 0.81-0.91]; MissionAD: AUC, 0.89 [95% CI, 0.86-0.92]), and overall accuracy was 78% (95% CI, 72%-83%) for PARIS and 83% (95% CI, 79%-86%) for MissionAD. The model developed on the prospectively collected samples from PARIS performed well on the MissionAD samples (AUC, 0.88 [95% CI, 0.84-0.91]; accuracy, 78% [95% CI, 74%-82%]). Training the LRM on combined cohorts yielded an AUC of 0.88 (95% CI, 0.85-0.91) and accuracy of 81% (95% CI, 78%-84%). The output of this LRM is the Amyloid Probability Score (APS). For clinical use, 2 APS cutoff values were established yielding 3 categories, with low, intermediate, and high likelihood of brain amyloid plaque pathology. Conclusions and Relevance: These findings suggest that this blood biomarker test could allow for distinguishing individuals with brain amyloid-positive PET findings from individuals with amyloid-negative PET findings and serve as an aid for Alzheimer disease diagnosis.

Association Between Ambient Air Pollution and Amyloid Positron Emission Tomography Positivity in Older Adults With Cognitive Impairment.

Importance: Amyloid-ß (Aß) deposition is a feature of Alzheimer disease (AD) and may be promoted by exogenous factors, such as ambient air quality. Objective: To examine the association between the likelihood of amyloid positron emission tomography (PET) scan positivity and ambient air quality in individuals with cognitive impairment. Design, Setting, and Participants: This cross-sectional study used data from the Imaging Dementia-Evidence for Amyloid Scanning Study, which included more than 18 000 US participants with cognitive impairment who received an amyloid PET scan with 1 of 3 Aß tracers (fluorine 18 [18F]-labeled florbetapir, 18F-labeled florbetaben, or 18F-labeled flutemetamol) between February 16, 2016, and January 10, 2018. A sample of older adults with mild cognitive impairment (MCI) or dementia was selected. Exposures: Air pollution was estimated at the patient residence using predicted fine particulate matter (PM2.5) and ground-level ozone (O3) concentrations from the Environmental Protection Agency Downscaler model. Air quality was estimated at 2002 to 2003 (early, or approximately 14 [range, 13-15] years before amyloid PET scan) and 2015 to 2016 (late, or approximately 1 [range, 0-2] years before amyloid PET scan). Main Outcomes and Measures: Primary outcome measure was the association between air pollution and the likelihood of amyloid PET scan positivity, which was measured as odds ratios (ORs) and marginal effects, adjusting for demographic, lifestyle, and socioeconomic factors and medical comorbidities, including respiratory, cardiovascular, cerebrovascular, psychiatric, and neurological conditions. Results: The data set included 18 178 patients, of which 10 991 (60.5%) had MCI and 7187 (39.5%) had dementia (mean [SD] age, 75.8 [6.3] years; 9333 women [51.3%]). Living in areas with higher estimated biennial PM2.5 concentrations in 2002 to 2003 was associated with a higher likelihood of amyloid PET scan positivity (adjusted OR, 1.10; 95% CI, 1.05-1.15; z score = 3.93; false discovery rate [FDR]-corrected P < .001; per 4-µg/m3 increments). Results were similar for 2015 to 2016 data (OR, 1.15; 95% CI, 1.05-1.26, z score = 3.14; FDR-corrected P = .003). An average marginal effect (AME) of +0.5% (SE = 0.1%; z score, 3.93; 95% CI, 0.3%-0.7%; FDR-corrected P < .001) probability of amyloid PET scan positivity for each 1-µg/m3 increase in PM2.5 was observed for 2002 to 2003, whereas an AME of +0.8% (SE = 0.2%; z score = 3.15; 95% CI, 0.3%-1.2%; FDR-corrected P = .002) probability was observed for 2015 to 2016. Post hoc analyses showed no effect modification by sex (2002-2003: interaction term ß = 1.01 [95% CI, 0.99-1.04; z score = 1.13; FDR-corrected P = .56]; 2015-2016: ß = 1.02 [95% CI, 0.98-1.07; z score = 0.91; FDR-corrected P = .56]) or clinical stage (2002-2003: interaction term ß = 1.01 [95% CI, 0.99-1.03; z score = 0.77; FDR-corrected P = .58]; 2015-2016: ß = 1.03; 95% CI, 0.99-1.08; z score = 1.46; FDR-corrected P = .47]). Exposure to higher O3 concentrations was not associated with amyloid PET scan positivity in both time windows. Conclusions and Relevance: This study found that higher PM2.5 concentrations appeared to be associated with brain Aß plaques. These findings suggest the need to consider airborne toxic pollutants associated with Aß pathology in public health policy decisions and to inform individual lifetime risk of developing AD and dementia.

Validation of online functional measures in cognitively impaired older adults.

INTRODUCTION: Assessment of functional status is associated with risk of cognitive decline and diagnosis of dementia, and can be assessed by participants and study partners (SPs). METHODS: In 770 older adults enrolled in the Imaging Dementia-Evidence for Amyloid Scanning (IDEAS) study and the online Brain Health Registry (BHR), we estimated associations between online assessments and clinical variables related to Alzheimer's disease (AD) risk. RESULTS: Worse online learning scores and SP-reported functional decline were associated with higher probability of AD dementia diagnosis and poor in-clinic cognitive assessment, and with higher odds of amyloid beta (Aß) positivity when combined with participants' report of less decline. SP report of functional decline conferred predictive value independent of online cognitive assessments. Participants underreported decline compared to SPs. DISCUSSION: The results support the validity of online assessments and their greater utilization in healthcare and research settings. Online SP-reported functional decline is an indicator of dementia and AD risk.

MRI Evaluation of the Contralateral Breast in Women with Recently Diagnosed Breast Cancer: 2-Year Follow-up.

OBJECTIVE: The American College of Radiology Imaging Network Trial 6667 showed that MRI can detect cancer in the contralateral breast that is missed by mammography and clinical examination at the time of the initial breast cancer diagnosis, based on 1-year follow-up. This study is a continuation of the trial that evaluates the diagnostic accuracy of MRI for contralateral breast cancer after 2 years of follow-up. METHODS: In total, 969 women with a diagnosis of unilateral breast cancer and no clinical or imaging abnormalities in the contralateral breast underwent breast MRI. The cancer status of all participants was monitored for 2 years after the initial MRI. Follow-up included documentation of any clinical, imaging, or interventional procedures performed. A study participant was considered positive for cancer if she had a tissue diagnosis of in situ or invasive breast cancer in the contralateral breast within 730 days of her initial MRI. RESULTS: Three additional cancers were diagnosed in the study population in the second year of the trial. The diagnostic yield for MRI for the 2-year period was 3% (31/969). After 2 years of follow-up, breast MRI has a sensitivity of 86% and specificity of 88% for detection of contralateral breast cancer. Its negative predictive value was 99%, and its positive predictive value was 22%. These values did not change significantly from the 1-year data. CONCLUSION: A negative contralateral breast MRI has a very high and reliable negative predictive value over 2 years, and, therefore, is helpful in managing and counseling patients during the period of initial diagnosis and early treatment.

Association of Amyloid Positron Emission Tomography With Subsequent Change in Clinical Management Among Medicare Beneficiaries With Mild Cognitive Impairment or Dementia.

Importance: Amyloid positron emission tomography (PET) detects amyloid plaques in the brain, a core neuropathological feature of Alzheimer disease. Objective: To determine if amyloid PET is associated with subsequent changes in the management of patients with mild cognitive impairment (MCI) or dementia of uncertain etiology. Design, Setting, and Participants: The Imaging Dementia-Evidence for Amyloid Scanning (IDEAS) study was a single-group, multisite longitudinal study that assessed the association between amyloid PET and subsequent changes in clinical management for Medicare beneficiaries with MCI or dementia. Participants were required to meet published appropriate use criteria stating that etiology of cognitive impairment was unknown, Alzheimer disease was a diagnostic consideration, and knowledge of PET results was expected to change diagnosis and management. A total of 946 dementia specialists at 595 US sites enrolled 16 008 patients between February 2016 and September 2017. Patients were followed up through January 2018. Dementia specialists documented their diagnosis and management plan before PET and again 90 (±30) days after PET. Exposures: Participants underwent amyloid PET at 343 imaging centers. Main Outcomes and Measures: The primary end point was change in management between the pre- and post-PET visits, as assessed by a composite outcome that included Alzheimer disease drug therapy, other drug therapy, and counseling about safety and future planning. The study was powered to detect a 30% or greater change in the MCI and dementia groups. One of 2 secondary end points is reported: the proportion of changes in diagnosis (from Alzheimer disease to non-Alzheimer disease and vice versa) between pre- and post-PET visits. Results: Among 16 008 registered participants, 11 409 (71.3%) completed study procedures and were included in the analysis (median age, 75 years [interquartile range, 71-80]; 50.9% women; 60.5% with MCI). Amyloid PET results were positive in 3817 patients with MCI (55.3%) and 3154 patients with dementia (70.1%). The composite end point changed in 4159 of 6905 patients with MCI (60.2% [95% CI, 59.1%-61.4%]) and 2859 of 4504 patients with dementia (63.5% [95% CI, 62.1%-64.9%]), significantly exceeding the 30% threshold in each group (P < .001, 1-sided). The etiologic diagnosis changed from Alzheimer disease to non-Alzheimer disease in 2860 of 11 409 patients (25.1% [95% CI, 24.3%-25.9%]) and from non-Alzheimer disease to Alzheimer disease in 1201 of 11 409 (10.5% [95% CI, 10.0%-11.1%]). Conclusions and Relevance: Among Medicare beneficiaries with MCI or dementia of uncertain etiology evaluated by dementia specialists, the use of amyloid PET was associated with changes in clinical management within 90 days. Further research is needed to determine whether amyloid PET is associated with improved clinical outcomes. Trial Registration: ClinicalTrials.gov Identifier: NCT02420756.

Utility of Diffusion-weighted Imaging to Decrease Unnecessary Biopsies Prompted by Breast MRI: A Trial of the ECOG-ACRIN Cancer Research Group (A6702).

PURPOSE: Conventional breast MRI is highly sensitive for cancer detection but prompts some false positives. We performed a prospective, multicenter study to determine whether apparent diffusion coefficients (ADCs) from diffusion-weighted imaging (DWI) can decrease MRI false positives.Experimental Design: A total of 107 women with MRI-detected BI-RADS 3, 4, or 5 lesions were enrolled from March 2014 to April 2015. ADCs were measured both centrally and at participating sites. ROC analysis was employed to assess diagnostic performance of centrally measured ADCs and identify optimal ADC thresholds to reduce unnecessary biopsies. Lesion reference standard was based on either definitive biopsy result or at least 337 days of follow-up after the initial MRI procedure. RESULTS: Of 107 women enrolled, 67 patients (median age 49, range 24-75 years) with 81 lesions with confirmed reference standard (28 malignant, 53 benign) and evaluable DWI were analyzed. Sixty-seven of 81 lesions were BI-RADS 4 (n = 63) or 5 (n = 4) and recommended for biopsy. Malignancies exhibited lower mean in centrally measured ADCs (mm2/s) than benign lesions [1.21 × 10-3 vs.1.47 × 10-3; P < 0.0001; area under ROC curve = 0.75; 95% confidence interval (CI) 0.65-0.84]. In centralized analysis, application of an ADC threshold (1.53 × 10-3 mm2/s) lowered the biopsy rate by 20.9% (14/67; 95% CI, 11.2%-31.2%) without affecting sensitivity. Application of a more conservative threshold (1.68 × 10-3 mm2/s) to site-measured ADCs reduced the biopsy rate by 26.2% (16/61) but missed three cancers. CONCLUSIONS: DWI can reclassify a substantial fraction of suspicious breast MRI findings as benign and thereby decrease unnecessary biopsies. ADC thresholds identified in this trial should be validated in future phase III studies.

ACRIN 6684: Multicenter, phase II assessment of tumor hypoxia in newly diagnosed glioblastoma using magnetic resonance spectroscopy.

A multi-center imaging trial by the American College of Radiology Imaging Network (ACRIN) "A Multicenter, phase II assessment of tumor hypoxia in glioblastoma using 18F Fluoromisonidazole (FMISO) with PET and MRI (ACRIN 6684)", was conducted to assess hypoxia in patients with glioblastoma (GBM). The aims of this study were to support the role of proton magnetic resonance spectroscopic imaging (1H MRSI) as a prognostic marker for brain tumor patients in multi-center clinical trials. Seventeen participants from four sites had analyzable 3D MRSI datasets acquired on Philips, GE or Siemens scanners at either 1.5T or 3T. MRSI data were analyzed using LCModel to quantify metabolites N-acetylaspartate (NAA), creatine (Cr), choline (Cho), and lactate (Lac). Receiver operating characteristic curves for NAA/Cho, Cho/Cr, lactate/Cr, and lactate/NAA were constructed for overall survival at 1-year (OS-1) and 6-month progression free survival (PFS-6). The OS-1 for the 17 evaluable patients was 59% (10/17). Receiver operating characteristic analyses found the NAA/Cho in tumor (AUC = 0.83, 95% CI: 0.61 to 1.00) and in peritumoral regions (AUC = 0.95, 95% CI 0.85 to 1.00) were predictive for survival at 1 year. PFS-6 was 65% (11/17). Neither NAA/Cho nor Cho/Cr was effective in predicting 6-month progression free survival. Lac/Cr in tumor was a significant negative predictor of PFS-6, indicating that higher lactate/Cr levels are associated with poorer outcome. (AUC = 0.79, 95% CI: 0.54 to 1.00). In conclusion, despite the small sample size in the setting of a multi-center trial comprising different vendors, field strengths, and varying levels of expertise at data acquisition, MRS markers NAA/Cho, Lac/Cr and Lac/NAA predicted overall survival at 1 year and 6-month progression free survival. This study validates that MRSI may be useful in evaluating the prognosis in glioblastoma and should be considered for incorporating into multi-center clinical trials.

Hospice Admission and Survival After 18F-Fluoride PET Performed for Evaluation of Osseous Metastatic Disease in the National Oncologic PET Registry.

We have previously reported that PET using 18F-fluoride (NaF PET) for assessment of osseous metastatic disease was associated with substantial changes in intended management in Medicare beneficiaries participating in the National Oncologic PET Registry (NOPR). Here, we use Medicare administrative data to examine the association between NaF PET results and hospice claims within 180 d and 1-y survival. Methods: We classified NOPR NaF PET results linked to Medicare claims by imaging indication (initial staging [IS]; detection of suspected first osseous metastasis [FOM]; suspected progression of osseous metastasis [POM]; or treatment monitoring [TM]) and type of cancer (prostate, lung, breast, or other). Results were classified as definitely positive scan findings versus probably positive scan findings versus negative scan findings for osseous metastasis for IS and FOM; more extensive disease versus no change or less extensive disease for POM; and worse prognosis versus no change or better prognosis for TM, based on the postscan assessment. Our study included 21,167 scans obtained from 2011 to 2014 of consenting NOPR participants aged 65 y or older. Results: The relative risk of hospice claims within 180 d of a NaF PET scan was 2.0-7.5 times higher for patients with evidence of new or progressing osseous metastasis than for those without, depending on indication and cancer type (all P < 0.008). The percentage difference in hospice claims for those with a finding of new or more advanced osseous disease ranged from 3.9% for IS prostate patients to 28% for FOM lung patients. Six-month survival was also associated with evidence of new or increased osseous disease; risk of death was 1.8-5.1 times as likely (all P ≤ 0.0001), with percentage differences of approximately 30% comparing positive and negative scans in patients with lung cancer imaged for IS or FOM. Conclusion: Our analyses demonstrated that NaF PET scan results are highly associated with subsequent hospice claims and, ultimately, with patient survival. NaF PET provides important information on the presence of osseous metastasis and prognosis to assist patients and their physicians when making decisions on whether to select palliative care and transition to hospice or whether to continue treatment.

Intended Versus Inferred Treatment After 18F-Fluoride PET Performed for Evaluation of Osseous Metastatic Disease in the National Oncologic PET Registry.

We have previously reported that PET with 18F-fluoride (NaF PET) for assessment of osseous metastatic disease led to changes in intended management in a substantial fraction of patients with prostate or other types of cancer participating in the National Oncologic PET Registry. This study was performed to assess the concordance of intended patient management after NaF PET and inferred management based on analysis of Medicare claims. Methods: We analyzed linked post-NaF PET data of consenting National Oncologic PET Registry participants age 65 y or older from 2011 to 2014 and their corresponding Medicare claims. Post-NaF PET treatment plans, including combinations of 2 modes of therapy, were assessed for their concordance with clinical actions inferred from Medicare claims. NaF PET studies were stratified by indication (initial staging [IS] or suspected first osseous metastasis [FOM]) and cancer type (prostate, lung, or other cancers). Agreement was assessed between post-NaF PET intended management plans for treatment (surgery, radiotherapy, or systemic therapy) within 90 d for lung and 180 d for prostate or other cancers, and for watching (the absence of treatment claims for ≥60 d) as compared with claims-inferred care. Results: Actions after 9,898 scans were assessed. After NaF PET for IS, there was claims agreement for planned surgery in 76.0% (19/25) lung, 75.4% (98/130) other cancers, and 58.9% (298/506) prostate cancer. Claims confirmed chemotherapy plans after NaF PET done for IS or FOM in 81.0% and 73.5% for lung cancer (n = 148 and 136) and 69.4% and 67.5% for other cancers (n = 111 and 228). For radiotherapy plans, agreement ranged from 80.0% to 84.4% after IS and 68.4% to 74.0% for suspected FOM. Concordance was greatest for androgen deprivation therapy (ADT) (86.0%, n = 308) alone or combined with radiotherapy in prostate cancer IS (80.8%, n = 517). In prostate FOM, the concordance across all treatment plans was lower if the patients had ADT claims within 180 d before NaF PET. Agreement with nontreatment plans was high for FOM (87.2% in other cancers and 78.6% if no prior ADT in prostate) and low after IS (40.7%-62.5%). Conclusion: Concordance of post-NaF PET plans and claims was substantial and higher overall for IS than for FOM.

Impact on Patient Management of [18F]-Fluorodeoxyglucose-Positron Emission Tomography (PET) Used for Cancer Diagnosis: Analysis of Data From the National Oncologic PET Registry.

INTRODUCTION: We assessed the impact of [(18)F]-fluorodeoxyglucose (FDG)-positron emission tomography (PET) on intended management of patients in the National Oncologic PET Registry (NOPR) for three different diagnostic indications: (a) determining whether a suspicious lesion is cancer (Dx), (b) detecting an unknown primary tumor site when there is confirmed or strongly suspected metastatic disease (cancer of unknown primary origin [CUP]), and (c) detecting a primary tumor site when there is a presumed paraneoplastic syndrome (PNS). METHODS: We reviewed a sample of randomly selected reports of NOPR subjects who underwent PET for Dx and CUP and all reports for PNS to find subjects for analysis. For these studies, we evaluated the impact of PET on referring physicians' intended management, based on their management plans reported before and after PET. RESULTS: Intended management was changed more frequently in the CUP group (43.1%) than in the Dx (23.9%) and PNS (25.4%) groups (CUP vs. Dx, p < .0001; PNS vs. Dx, p < .0001; CUP vs. PNS, p < .0002). Referring physicians reported that, in light of PET results, they were able to avoid further testing in approximately three-fourths of patients (71.8%-74.6%). At the time when the post-PET forms were completed, biopsies of suspicious sites had been performed in 21.2%, 32.4%, and 23.2%, respectively, of Dx, CUP, and PNS cases. CONCLUSION: Our analysis of NOPR data shows that PET appears to have a substantial impact on intended management when used for three common diagnostic indications. IMPLICATIONS FOR PRACTICE: [(18)F]-fluorodeoxyglucose-positron emission tomography appears to have a substantial impact on intended management when used for three targeted diagnostic indications: (a) determining whether a suspicious lesion is cancer, (b) detecting an unknown primary tumor site in a patient with confirmed or strongly suspected metastatic disease, and (c) detecting a primary tumor site in a patient with a presumed paraneoplastic syndrome.

ACRIN 6684: Assessment of Tumor Hypoxia in Newly Diagnosed Glioblastoma Using 18F-FMISO PET and MRI.

PURPOSE: Structural and functional alterations in tumor vasculature are thought to contribute to tumor hypoxia which is a primary driver of malignancy through its negative impact on the efficacy of radiation, immune surveillance, apoptosis, genomic stability, and accelerated angiogenesis. We performed a prospective, multicenter study to test the hypothesis that abnormal tumor vasculature and hypoxia, as measured with MRI and PET, will negatively impact survival in patients with newly diagnosed glioblastoma. EXPERIMENTAL DESIGN: Prior to the start of chemoradiation, patients with glioblastoma underwent MRI scans that included dynamic contrast enhanced and dynamic susceptibility contrast perfusion sequences to quantitate tumor cerebral blood volume/flow (CBV/CBF) and vascular permeability (ktrans) as well as 18F-Fluoromisonidazole (18F-FMISO) PET to quantitate tumor hypoxia. ROC analysis and Cox regression models were used to determine the association of imaging variables with progression-free and overall survival. RESULTS: Fifty patients were enrolled of which 42 had evaluable imaging data. Higher pretreatment 18F-FMISO SUVpeak (P = 0.048), mean ktrans (P = 0.024), and median ktrans (P = 0.045) were significantly associated with shorter overall survival. Higher pretreatment median ktrans (P = 0.021), normalized RCBV (P = 0.0096), and nCBF (P = 0.038) were significantly associated with shorter progression-free survival. SUVpeak [AUC = 0.75; 95% confidence interval (CI), 0.59-0.91], nRCBV (AUC = 0.72; 95% CI, 0.56-0.89), and nCBF (AUC = 0.72; 95% CI, 0.56-0.89) were predictive of survival at 1 year. CONCLUSIONS: Increased tumor perfusion, vascular volume, vascular permeability, and hypoxia are negative prognostic markers in newly diagnosed patients with gioblastoma, and these important physiologic markers can be measured safely and reliably using MRI and 18F-FMISO PET. Clin Cancer Res; 22(20); 5079-86. ©2016 AACR.

Repeatability of 18F-FDG PET/CT in Advanced Non-Small Cell Lung Cancer: Prospective Assessment in 2 Multicenter Trials.

UNLABELLED: PET/CT with the glucose analog (18)F-FDG has several potential applications for monitoring tumor response to therapy in patients with non-small cell lung cancer (NSCLC). A prerequisite for many of these applications is detailed knowledge of the repeatability of quantitative parameters derived from (18)F-FDG PET/CT studies. METHODS: The repeatability of the (18)F-FDG signal was evaluated in 2 prospective multicenter trials. Patients with advanced NSCLC (tumor stage III-IV) underwent two (18)F-FDG PET/CT studies while not receiving therapy. Tumor (18)F-FDG uptake was quantified by measurement of the maximum standardized uptake value within a lesion (SUVmax) and the average SUV within a small volume of interest around the site of maximum uptake (SUVpeak). Analysis was performed for the lesion in the chest with the highest (18)F-FDG uptake and a size of at least 2 cm (target lesion) as well as for up to 6 additional lesions per patient. Repeatability was assessed by Bland-Altman plots and calculation of 95% repeatability coefficients (RCs) of the log-transformed SUV differences. RESULTS: Test-retest repeatability was assessed in 74 patients (34 from the ACRIN 6678 trial and 40 from the Merck MK-0646-008 trial). SUVpeak was 11.57 ± 7.89 g/mL for the ACRIN trial and 6.89 ± 3.02 for the Merck trial. The lower and upper RCs were -28% (95% confidence interval [CI], -35% to -23%) and +39% (95% CI, 31% to 54%) in the ACRIN trial, indicating that a decrease of SUVpeak by more than 28% or an increase by more than 39% has a probability of less than 2.5%. The corresponding RCs from the Merck trial were -35% (95% CI, -42% to -29%) and +53% (95% CI, 41% to 72%). Repeatability was similar for SUVmax of the target lesion, averaged SUVmax, and averaged SUVpeak of up to 6 lesions per patient. CONCLUSION: The variability of repeated measurements of tumor (18)F-FDG uptake in patients with NSCLC is somewhat larger than previously reported in smaller single-center studies but comparable to that of gastrointestinal malignancies in a previous multicenter trial. The variability of measurements supports the definitions of tumor response according to PET Response Criteria in Solid Tumors.

18F-fluoride PET used for treatment monitoring of systemic cancer therapy: results from the National Oncologic PET Registry.

UNLABELLED: In a national prospective registry, we previously studied the impact of (18)F-sodium fluoride PET (NaF PET) on the intended management of cancer patients with osseous metastases. The clinical impact of NaF PET for monitoring the response to systemic therapies in such patients is unknown. The objective of this study was to assess the impact of NaF PET results obtained for treatment monitoring of systemic cancer therapy. METHODS: Before and after NaF PET, we collected prospective data from referring and interpreting physicians for cancer patients 65 y or older receiving systemic therapy (use of 1 or more categories including hormonal, chemotherapy, bisphosphonates, or immunotherapy). The analysis set consisted of 2,217 patients who underwent 2,839 scans (68% prostate, 17% breast, 6% lung, and 8% other cancers) ordered for treatment monitoring. Two or more categories of systemic therapy were planned in 56% of prostate and 43% of breast cancer patients. RESULTS: The overall rates of prior radionuclide bone imaging were 78%, 76%, and 66% for prostate, breast, and other cancers, respectively. Fifty-seven percent of patients underwent prior NaF PET. Overall change in management associated with NaF PET was 40%. In patients with prior NaF PET scans for comparison, continuing current therapy was planned in 79% when scans showed no change or a decrease or absence of osseous metastasis. Treating physicians planned to switch therapy in 59% of patients after scans showed evidence of new or progressive metastasis. When an additional parameter, estimated prognosis, was worse, switching therapy was even more common (76%). CONCLUSION: The impact of NaF PET used for treatment monitoring was high in patients with evidence of progressive osseous metastasis. Most such patients had plans to switch to a new cancer-directed therapy.

Contralateral prophylactic mastectomy in the American College of Radiology Imaging Network 6667 trial: effect of breast MR imaging assessments and patient characteristics.

PURPOSE: To assess which patient and magnetic resonance (MR) imaging factors are associated with the likelihood of contralateral prophylactic mastectomy (CPM) in patients with newly diagnosed breast cancer. MATERIALS AND METHODS: The American College of Radiology Imaging Network 6667 trial was compliant with HIPAA; institutional review board approval was obtained at each site. All patients provided written informed consent. This study was a retrospective review of data from 934 women enrolled in the trial who did not have a known contralateral breast cancer at the time of surgical planning. The authors assessed age, menopausal status, index breast cancer histologic results, contralateral breast histologic results, breast density, family history, race and/or ethnicity, MR imaging Breast Imaging Reporting and Data System (BI-RADS) assessment, and number of MR imaging lesions for association with CPM by using the Fisher exact test, exact χ(2) test, and multivariate logistic regression analyses. RESULTS: Eighty-six of the 934 (9.2%) women underwent CPM and were more likely to be younger (mean age, 48 years [range, 27-78 years] vs mean age, 54 years [range, 25-86 years]; P < .0001), be premenopausal (55 of 86 [64%] vs 349 of 845 [41%], P < .0001), have ductal carcinoma in situ (DCIS) in the index breast (31% [27 of 86] vs 19% [164 of 848], P = .02), have greater breast density (71 of 86 [83%] vs 572 of 848 [68%], P = .004), and have a family history of breast cancer (44 of 86 [30%] vs 150 of 488 [18%], P = .01) than those who did not undergo CPM. Distributions of race and/or ethnicity, contralateral lesion pathologic results, and number of MR imaging lesions were similar in both groups. With multivariate modeling, younger age, greater breast density, DCIS index cancer, and family history remained significant, whereas menopausal status did not. Positive MR imaging assessments were not significantly more frequent in the CPM group than in the group of women who did not undergo CPM (14 of 86 [16.3%] vs 113 of 848 [13.3%], P = .43). CONCLUSION: In patients with newly diagnosed breast cancer who underwent breast MR imaging at which a contralateral breast cancer was not identified, patient factors and not breast MR imaging BI-RADS scores were chief determinants in decisions regarding CPM. Online supplemental material is available for this article.

Impact of (18)F-Fluoride PET on Intended Management of Patients with Cancers Other Than Prostate Cancer: Results from the National Oncologic PET Registry.

UNLABELLED: The National Oncologic PET Registry prospectively assessed the impact of PET with (18)F-sodium fluoride (NaF PET) on intended management of Medicare patients with suspected or known osseous metastasis. We report our findings for cancers other than prostate and make selected comparisons to our previously reported prostate cancer cohort. METHODS: Data were collected from both referring and interpreting physicians before and after NaF PET in patients (age ≥ 65 y) stratified for initial staging (IS; n = 570), for suspected first osseous metastasis (FOM; n = 1,814; breast, 781 [43%]; lung, 380 [21%]; and all other cancers, 653 [36%]), and for suspected progression of osseous metastasis (POM; n = 435). RESULTS: The dominant indication was bone pain. If NaF PET were unavailable, conventional bone scintigraphy would have been ordered in 85% of patients. In IS, 28% of patients had suspected or confirmed nonosseous metastasis. If neither conventional bone scintigraphy nor NaF PET were available, referring physicians would have ordered other advanced imaging more than 70% of the time rather than initiate treatment for suspected FOM (11%-16%) or POM (18%-22%). When intended management was classified as either treatment or nontreatment, the intended management change for each cancer type was highest in POM, lower in IS, and lowest in FOM. For suspected FOM, intended management change was lower in breast (24%), lung (36%), or other cancers (31%), compared with prostate cancer (44%) (P < 0.0001), but the NaF PET finding (normal/benign/equivocal, probable, or definite metastases) frequencies were similar across cancer types. After normal/benign/equivocal PET results, 15% of breast, 30% lung, and 38% prostate cancer patients had treatment, likely reflecting differences in management of nonosseous disease. For patients with definite metastasis on NaF PET, nonprostate, compared with prostate, cancer patients had post-PET plans for more frequent biopsy, alternative imaging, chemotherapy, and radiotherapy. In the smaller IS and POM cohorts, differences among cancer types were not significant. CONCLUSION: Overall, NaF PET led to change in intended management in a substantial fraction of nonprostate cancer patients. In the setting of suspected FOM, NaF PET had a lower immediate impact on the treat/nontreat decision in nonprostate versus prostate cancer patients, which is consistent with current practice guidelines.

Consequences of false-positive screening mammograms.

IMPORTANCE: False-positive mammograms, a common occurrence in breast cancer screening programs, represent a potential screening harm that is currently being evaluated by the US Preventive Services Task Force. OBJECTIVE: To measure the effect of false-positive mammograms on quality of life by measuring personal anxiety, health utility, and attitudes toward future screening. DESIGN, SETTING, AND PARTICIPANTS: The Digital Mammographic Imaging Screening Trial (DMIST) quality-of-life substudy telephone survey was performed shortly after screening and 1 year later at 22 DMIST sites and included randomly selected DMIST participants with positive and negative mammograms. EXPOSURE: Mammogram requiring follow-up testing or referral without a cancer diagnosis. MAIN OUTCOMES AND MEASURES: The 6-question short form of the Spielberger State-Trait Anxiety Inventory state scale (STAI-6) and the EuroQol EQ-5D instrument with US scoring. Attitudes toward future screening as measured by women's self-report of future intention to undergo mammographic screening and willingness to travel and stay overnight to undergo a hypothetical new type of mammography that would identify as many cancers with half the false-positive results. RESULTS: Among 1450 eligible women invited to participate, 1226 (84.6%) were enrolled, with follow-up interviews obtained in 1028 (83.8%). Anxiety was significantly higher for women with false-positive mammograms (STAI-6, 35.2 vs 32.7), but health utility scores did not differ and there were no significant differences between groups at 1 year. Future screening intentions differed by group (25.7% vs 14.2% more likely in false-positive vs negative groups); willingness to travel and stay overnight did not (9.9% vs 10.5% in false-positive vs negative groups). Future screening intention was significantly increased among women with false-positive mammograms (odds ratio, 2.12; 95% CI, 1.54-2.93), younger age (2.78; 1.5-5.0), and poorer health (1.63; 1.09-2.43). Women's anticipated high-level anxiety regarding future false-positive mammograms was associated with willingness to travel overnight (odds ratio, 1.94; 95% CI, 1.28-2.95). CONCLUSIONS AND RELEVANCE: False-positive mammograms were associated with increased short-term anxiety but not long-term anxiety, and there was no measurable health utility decrement. False-positive mammograms increased women's intention to undergo future breast cancer screening and did not increase their stated willingness to travel to avoid a false-positive result. Our finding of time-limited harm after false-positive screening mammograms is relevant for clinicians who counsel women on mammographic screening and for screening guideline development groups.

Impact of 18F-fluoride PET in patients with known prostate cancer: initial results from the National Oncologic PET Registry.

UNLABELLED: Under Medicare's Coverage with Evidence Development policy, PET using (18)F-sodium fluoride (NaF PET) to identify osseous metastasis became a covered service if prospective registry data were collected. The National Oncologic PET Registry (NOPR) developed a NaF PET registry built on the foundation of its prior registry for PET with (18)F-FDG. Men with prostate cancer represented 72% of the cases. METHODS: Prospective data before and after NaF PET were collected from referring and interpreting physicians. The analysis set consisted of consenting men age 65 y or older with prostate cancer undergoing NaF PET for initial staging (IS, n = 1,024), suspected first osseous metastasis (FOM, n = 1,997), or suspected progression of osseous metastasis (POM, n = 510). RESULTS: Referring physicians indicated that if NaF PET were not available, other advanced imaging (body CT, MR imaging, or (18)F-FDG PET) would be their plan in about half of the cases. After NaF PET, the postimaging plan was revised to treatment in 77%, 52%, and 71% for IS, FOM, and POM, respectively. When intended management was classified as either treatment or nontreatment, the overall change in intended management ranged from 44% to 52% and from 12% to 16% if no effect was assumed for those cases with pre-PET plans for other imaging (imaging-adjusted impact). Interpreting physicians recorded definite findings of bone metastasis in 14%, 29%, and 76% for IS, FOM, and POM, respectively. The intended care patterns varied widely across indication and scan abnormality category combinations. CONCLUSION: NaF PET has high overall impact, principally related to its effect on replacing intended use of other advanced imaging. Its imaging-adjusted impact was similar to that observed with (18)F-FDG PET for restaging or suspected recurrence in other cancer types.