Brenda F. Kurland

Neuropathology of nondemented aging: Presumptive evidence for preclinical Alzheimer disease

OBJECTIVE To determine the frequency and possible cognitive effect of histological Alzheimers disease (AD) in autopsied older nondemented individuals. DESIGN Senile plaques (SPs) and neurofibrillary tangles (NFTs) were assessed quantitatively in 97 cases from 7 Alzheimers Disease Centers (ADCs). Neuropathological diagnoses of AD (npAD) were also made with four sets of criteria. Adjusted linear mixed models tested differences between participants with and without npAD on the quantitative neuropathology measures and psychometric test scores prior to death. Spearman rank-order correlations between AD lesions and psychometric scores at last assessment were calculated for cases with pathology in particular regions. SETTING Washington University Alzheimers Disease Research Center. PARTICIPANTS Ninety-seven nondemented participants who were age 60 years or older at death (mean=84 years). RESULTS About 40% of nondemented individuals met at least some level of criteria for npAD; when strict criteria were used, about 20% of cases had npAD. Substantial overlap of Braak neurofibrillary stages occurred between npAD and no-npAD cases. Although there was no measurable cognitive impairment prior to death for either the no-npAD or npAD groups, cognitive function in nondemented aging appears to be degraded by the presence of NFTs and SPs. CONCLUSIONS Neuropathological processes related to AD in persons without dementia appear to be associated with subtle cognitive dysfunction and may represent a preclinical stage of the illness. By age 80-85 years, many nondemented older adults have substantial AD pathology.

Quantitative Diffusion-Weighted Imaging as an Adjunct to Conventional Breast MRI for Improved Positive Predictive Value

OBJECTIVE The purpose of our study was to investigate whether adding diffusion-weighted imaging (DWI) to dynamic contrast-enhanced MRI (DCE-MRI) could improve the positive predictive value (PPV) of breast MRI. MATERIALS AND METHODS The retrospective study included 70 women with 83 suspicious breast lesions on DCE-MRI (BI-RADS 4 or 5) who underwent subsequent biopsy. DWI was acquired during clinical breast MRI using b = 0 and 600 s/mm(2). Apparent diffusion coefficient (ADC) values were compared for benign and malignant lesions. PPV was calculated for DCE-MRI alone (based on biopsy recommendations) and DCE-MRI plus DWI (adding an ADC threshold) for the same set of lesions. Results were further compared by lesion type (mass, nonmasslike enhancement) and size. RESULTS Of the 83 suspicious lesions, 52 were benign and 31 were malignant (11 ductal carcinoma in situ [DCIS], 20 invasive carcinoma). Both DCIS (mean ADC, 1.31 +/- 0.24 x 10(-3) mm(2)/s) and invasive carcinoma (mean ADC, 1.29 +/- 0.29 x 10(-3) mm(2)/s) exhibited lower mean ADC than benign lesions (1.70 +/- 0.44 x 10(-3) mm(2)/s, p < 0.001). Applying an ADC threshold of 1.81 x 10(-3) mm(2)/s for 100% sensitivity produced a PPV of 47% versus 37% for DCE-MRI alone, which would have avoided biopsy for 33% (17/52) of benign lesions without missing any cancers. DWI increased PPV similarly for masses and nonmasslike enhancement and preferentially improved PPV for smaller (< or = 1 cm) versus larger lesions. CONCLUSION DWI shows potential for improving the PPV of breast MRI for lesions of varied types and sizes. However, considerable overlap in ADC of benign and malignant lesions necessitates validation of these findings in larger studies.

Patient-reported quality of life is associated with severity of chronic graft-versus-host disease as measured by NIH criteria: report on baseline data from the Chronic GVHD Consortium

Quality of life (QOL) after hematopoietic cell transplantation (HCT) is compromised by chronic GVHD. In a prospectively assembled multicenter cohort of adults with chronic GVHD (n = 298), we examined the relationship between chronic GVHD severity defined by National Institutes of Health (NIH) criteria and QOL as measured by the SF-36 and FACT-BMT instruments at time of enrollment. Chronic GVHD severity was independently associated with QOL, adjusting for age. Compared with population normative data, SF-36 scores were more than a SD (10 points) lower on average for the summary physical component score (PCS) and role-physical subscale, and significantly lower (with magnitude 4-10 points) for several other subscales. Patients with moderate and severe cGVHD had PCS scores comparable with scores reported for systemic sclerosis, systemic lupus erythematosus, and multiple sclerosis, and greater impairment compared with common chronic conditions including diabetes, hypertension, and chronic lung disease. Moderate to severe cGVHD as defined by NIH criteria is associated with significant compromise in multiple QOL domains, with PCS scores in the range of other systemic autoimmune diseases. Compromised QOL provides a functional assessment of the effects of chronic GVHD, and may be measured in cGVHD clinical studies using either the SF-36 or the FACT-BMT.

Differential diagnosis of mammographically and clinically occult breast lesions on diffusion‐weighted MRI

To investigate the diagnostic performance of diffusion‐weighted imaging (DWI) for mammographically and clinically occult breast lesions.

Apparent Diffusion Coefficient Values for Discriminating Benign and Malignant Breast MRI Lesions: Effects of Lesion Type and Size

OBJECTIVE The purpose of this study was to determine whether lesion type and size affect discrimination of benign and malignant breast lesions with diffusion-weighted MRI. MATERIALS AND METHODS This study included 91 women with 116 breast lesions identified with dynamic contrast-enhanced MRI. Diffusion-weighted images were acquired during clinical breast MRI at b values of 0 and 600 s/mm(2). Differences in the apparent diffusion coefficients (ADCs) of benign and malignant lesions were compared by lesion type (mass or nonmasslike enhancement) and size (<or= 1 cm or > 1 cm), and receiver operating characteristics analysis was performed to evaluate diagnostic performance based on ADC thresholds. RESULTS Sixteen of 71 masses and 13 of 45 lesions with nonmasslike enhancement were malignant. The mean ADC was significantly lower for malignant than for benign lesions for both masses (mean difference, 0.49 x 10(-3) mm(2)/s; p < 0.001) and lesions with nonmasslike enhancement (mean difference, 0.20 x 10(-3) mm(2)/s; p = 0.02). The area under the receiver operating characteristics curve (AUC) was greater for masses (AUC, 0.80) than for lesions with nonmasslike enhancement (AUC, 0.66). The mean ADC for malignant masses (1.25 x 10(-3) mm(2)/s) was lower than that for malignant lesions with nonmasslike enhancement (1.41 x 10(-3) mm(2)/s; p = 0.07). The median lesion size was 1.1 cm (range, 0.5-8.3 cm); 45 of 71 masses (63%) measured 1 cm or smaller, and 37 of 45 lesions with nonmasslike enhancement (82%) were larger than 1 cm. There was no relation (p > 0.05) between ADC value and lesion size for benign or malignant lesions, and there were no differences in AUC based on lesion size (p > 0.05). CONCLUSION Diffusion-weighted MRI shows promise in differentiation of benign and malignant masses and lesions with nonmasslike enhancement found at breast MRI and is not affected by lesion size. However, ADC measurements may be more useful for discriminating masses than for discriminating lesions with nonmasslike enhancement.

Tumor Metabolism and Blood Flow Changes by Positron Emission Tomography: Relation to Survival in Patients Treated With Neoadjuvant Chemotherapy for Locally Advanced Breast Cancer

PURPOSE Patients with locally advanced breast carcinoma (LABC) receive preoperative chemotherapy to provide early systemic treatment and assess in vivo tumor response. Serial positron emission tomography (PET) has been shown to predict pathologic response in this setting. We evaluated serial quantitative PET tumor blood flow (BF) and metabolism as in vivo measurements to predict patient outcome. PATIENTS AND METHODS Fifty-three women with primary LABC underwent dynamic [(18)F]fluorodeoxyglucose (FDG) and [(15)O]water PET scans before and at midpoint of neoadjuvant chemotherapy. The FDG metabolic rate (MRFDG) and transport (FDG K(1)) parameters were calculated; BF was estimated from the [(15)O]water study. Associations between BF, MRFDG, FDG K(1), and standardized uptake value and disease-free survival (DFS) and overall survival (OS) were evaluated using the Cox proportional hazards model. RESULTS Patients with persistent or elevated BF and FDG K(1) from baseline to midtherapy had higher recurrence and mortality risks than patients with reductions. In multivariable analyses, BF and FDG K(1) changes remained independent prognosticators of DFS and OS. For example, in the association between BF and mortality, a patient with a 5% increase in tumor BF had a 67% higher mortality risk compared with a patient with a 5% decrease in tumor BF (hazard ratio = 1.67; 95% CI, 1.24 to 2.24; P < .001). CONCLUSION LABC patients with limited or no decline in BF and FDG K(1) experienced higher recurrence and mortality risks that were greater than the effects of clinical tumor characteristics. Tumor perfusion changes over the course of neoadjuvant chemotherapy measured directly by [(15)O]water or indirectly by dynamic FDG predict DFS and OS.

Cisplatin and Radiotherapy With or Without Erlotinib in Locally Advanced Squamous Cell Carcinoma of the Head and Neck: A Randomized Phase II Trial

PURPOSE The combination of cisplatin and radiotherapy is a standard treatment for patients with locally advanced squamous cell carcinoma of the head and neck (SCCHN). Cetuximab-radiotherapy is superior to radiotherapy alone in this population, validating epidermal growth factor receptor (EGFR) as a target. Erlotinib is a small-molecule inhibitor of EGFR. Adding EGFR inhibition to standard cisplatin-radiotherapy may improve efficacy. PATIENTS AND METHODS Patients with locally advanced SCCHN were randomly assigned to receive cisplatin 100 mg/m(2) on days 1, 22, and 43 combined with 70 Gy of radiotherapy (arm A) or the same chemoradiotherapy with erlotinib 150 mg per day, starting 1 week before radiotherapy and continued to its completion (arm B). The primary end point was complete response rate (CRR), evaluated by central review. The secondary end point was progression-free survival (PFS). Available tumors were tested for p16 and EGFR by fluorescent in situ hybridization. RESULTS Between December 2006 and October 2011, 204 patients were randomly assigned. Arms were well balanced for all patient characteristics including p16, with the exception of more women on arm A. Patients on arm B had more rash, but treatment arms did not differ regarding rates of other grade 3 or 4 toxicities. Arm A had a CRR of 40% and arm B had a CRR of 52% (P = .08) when evaluated by central review. With a median follow-up time of 26 months and 54 progression events, there was no difference in PFS (hazard ratio, 0.9; P = .71). CONCLUSION Erlotinib did not increase the toxicity of cisplatin and radiotherapy in patients with locally advanced HNSCC but failed to significantly increase CRR or PFS.

Longitudinal Data with Follow-up Truncated by Death: Match the Analysis Method to Research Aims

Diverse analysis approaches have been proposed to distinguish data missing due to death from nonresponse, and to summarize trajectories of longitudinal data truncated by death. We demonstrate how these analysis approaches arise from factorizations of the distribution of longitudinal data and survival information. Models are illustrated using cognitive functioning data for older adults. For unconditional models, deaths do not occur, deaths are independent of the longitudinal response, or the unconditional longitudinal response is averaged over the survival distribution. Unconditional models, such as random effects models fit to unbalanced data, may implicitly impute data beyond the time of death. Fully conditional models stratify the longitudinal response trajectory by time of death. Fully conditional models are effective for describing individual trajectories, in terms of either aging (age, or years from baseline) or dying (years from death). Causal models (principal stratification) as currently applied are fully conditional models, since group differences at one timepoint are described for a cohort that will survive past a later timepoint. Partly conditional models summarize the longitudinal response in the dynamic cohort of survivors. Partly conditional models are serial cross-sectional snapshots of the response, reflecting the average response in survivors at a given timepoint rather than individual trajectories. Joint models of survival and longitudinal response describe the evolving health status of the entire cohort. Researchers using longitudinal data should consider which method of accommodating deaths is consistent with research aims, and use analysis methods accordingly.

BI-RADS Lesion Characteristics Predict Likelihood of Malignancy in Breast MRI for Masses But Not for Nonmasslike Enhancement

OBJECTIVE The purpose of our study was to evaluate the predictive features of BI-RADS lesion characteristics and the risk of malignancy for mammographically and clinically occult lesions detected initially on breast MRI. MATERIALS AND METHODS We reviewed 1,523 consecutive breast MRI examinations performed from January 1, 2003, to June 30, 2005, to identify all lesions initially detected on MRI and assessed as BI-RADS 4 or 5 for which the patient underwent subsequent imaging-guided needle or excisional biopsy. BI-RADS lesion features were recorded for each case, and the risk of malignancy was assessed using generalized estimating equations. Separate multivariate models were constructed for lesions classified as masses. RESULTS Included in the analysis were 258 suspicious lesions in 196 women. Among all lesions, those of 1 cm or greater were significantly more often malignant (50/147, 34%) than lesions of less than 1 cm (22/111, 20%; odds ratio, 2.09; 95% CI, 1.13-3.83). For masses, size, BI-RADS margin, and enhancement pattern predicted malignancy. In multivariate analysis of combinations of features, masses of 1 cm or greater with heterogeneous enhancement and irregular margins had a 68% probability of malignancy. Masses of 1 cm or greater with smooth margins and homogeneous enhancement had the lowest predicted probability of malignancy of 3%. BI-RADS descriptors and size were not significant predictors of malignancy for nonmasslike enhancement (NMLE). CONCLUSION Combinations of BI-RADS lesion descriptors can predict the probability of malignancy for breast MRI masses but not for NMLE. If our model is validated, masses with a low probability of malignancy may be eligible for short-interval follow-up rather than biopsy. Further research focused on predictive features of NMLE is needed.

Quantitative imaging biomarkers: A review of statistical methods for technical performance assessment

Technological developments and greater rigor in the quantitative measurement of biological features in medical images have given rise to an increased interest in using quantitative imaging biomarkers to measure changes in these features. Critical to the performance of a quantitative imaging biomarker in preclinical or clinical settings are three primary metrology areas of interest: measurement linearity and bias, repeatability, and the ability to consistently reproduce equivalent results when conditions change, as would be expected in any clinical trial. Unfortunately, performance studies to date differ greatly in designs, analysis method, and metrics used to assess a quantitative imaging biomarker for clinical use. It is therefore difficult or not possible to integrate results from different studies or to use reported results to design studies. The Radiological Society of North America and the Quantitative Imaging Biomarker Alliance with technical, radiological, and statistical experts developed a set of technical performance analysis methods, metrics, and study designs that provide terminology, metrics, and methods consistent with widely accepted metrological standards. This document provides a consistent framework for the conduct and evaluation of quantitative imaging biomarker performance studies so that results from multiple studies can be compared, contrasted, or combined.