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Introduction Some Alzheimer's disease biomarker studies found amyloid changes 20 years or more in advance of expected symptoms, while cognitive changes lagged for more than a decade, but this apparent lag might reflect the sensitivities of the biomarker and cognitive assays used. How far in advance of incident amnestic mild cognitive impairment (MCI) does cognition begin to decline? Methods Longitudinal neuropsychological study of an apolipoprotein E e4 enriched cohort of cognitively normal individuals at entry. Linear mixed models for MCI converters (n = 65) and nonconverters (n = 719) fitted for each neuropsychological measure; annual changes compared between groups before and after linear model intersections (inflection points). Results 34 of 35 cognitive measures and 9 of 18 behavioral measures declined faster post-inflection in the MCI converters; the earliest cognitive inflection point was nearly 20 years in advance of MCI diagnosis. Discussion The preclinical duration of cognitive and behavioral changes approaches the earliest reported biomarker changes.

Randomized controlled trials have been considered the gold standard in informing clinical decision-making while observational studies have generally been utilized to generate hypotheses for future studies. The rising cost of randomized studies along with increased difficulty in accrual has led the clinical community to consider utilizing observational studies to inform clinical decisions. Various statistical methods exist to analyze observational data. Researchers must consider each method carefully, paying specific attention to its ability to answer the hypotheses, while ensuring the underlying assumptions are met. While each has its own strengths and weaknesses, research has shown that each method may yield similar estimates of treatment effect when conducted appropriately. We describe several commonly used analytical methods including their: strengths, weaknesses, and common missteps in order to inform and serve as a reference to the broader oncology community.

Background Design, conduct, and analysis of randomized clinical trials (RCTs) with time to event end points rely on a variety of assumptions regarding event rates (hazard rates), proportionality of treatment effects (proportional hazards), and differences in intensity and type of events over time and between subgroups. Design and methods In this article, we use the experience of the recently reported Adjuvant Lapatinib and/or Trastuzumab Treatment Optimization (ALTTO) RCT, which enrolled 8381 patients with human epidermal growth factor 2-positive early breast cancer between June 2007 and July 2011, to highlight how routinely applied statistical assumptions can impact RCT result reporting. Results and conclusions We conclude that (i) futility stopping rules are important to protect patient safety, but stopping early for efficacy can be misleading as short-term results may not imply long-term efficacy, (ii) biologically important differences between subgroups may drive clinically different treatment effects and should be taken into account, e.g. by pre-specifying primary subgroup analyses and restricting end points to events which are known to be affected by the targeted therapies, (iii) the usual focus on the Cox model may be misleading if we do not carefully consider non-proportionality of the hazards. The results of the accelerated failure time model illustrate that giving more weight to later events (as in the log rank test) can affect conclusions, (iv) the assumption that accruing additional events will always ensure gain in power needs to be challenged. Changes in hazard rates and hazard ratios over time should be considered, and (v) required family-wise control of type 1 error ≤ 5% in clinical trials with multiple experimental arms discourages investigations designed to answer more than one question. Trial Registration clinicaltrials.gov Identifier NCT00490139.

Background Myeloproliferative neoplasm (MPN) patients suffer from significant symptoms, inflammation and reduced quality of life. Yoga improves these outcomes in other cancers, but this hasn’t been demonstrated in MPNs. The purpose of this study was to: (1) explore the limited efficacy (does the program show promise of success) of a 12-week online yoga intervention among MPN patients on symptom burden and quality of life and (2) determine feasibility (practicality: to what extent a measure can be carried out) of remotely collecting inflammatory biomarkers. Methods Patients were recruited nationally and randomized to online yoga (60 min/week of yoga) or wait-list control (asked to maintain normal activity). Weekly yoga minutes were collected with Clicky (online web analytics tool) and self-report. Those in online yoga completed a blood draw at baseline and week 12 to assess inflammation (interleukin-6, tumor necrosis factor-alpha [TNF-α]). All participants completed questionnaires assessing depression, anxiety, fatigue, pain, sleep disturbance, sexual function, total symptom burden, global health, and quality of life at baseline, week seven, 12, and 16. Change from baseline at each time point was computed by group and effect sizes were calculated. Pre-post intervention change in inflammation for the yoga group was compared by t-test. Results Sixty-two MPN patients enrolled and 48 completed the intervention (online yoga = 27; control group = 21). Yoga participation averaged 40.8 min/week via Clicky and 56.1 min/week via self-report. Small/moderate effect sizes were generated from the yoga intervention for sleep disturbance (d = − 0.26 to − 0.61), pain intensity (d = − 0.34 to − 0.51), anxiety (d = − 0.27 to − 0.37), and depression (d = − 0.53 to − 0.78). A total of 92.6 and 70.4% of online yoga participants completed the blood draw at baseline and week 12, respectively, and there was a decrease in TNF-α from baseline to week 12 (− 1.3 ± 1.5 pg/ml). Conclusions Online yoga demonstrated small effects on sleep, pain, and anxiety as well as a moderate effect on depression. Remote blood draw procedures are feasible and the effect size of the intervention on TNF-α was large. Future fully powered randomized controlled trials are needed to test for efficacy. Trial registration This trial was retrospectively registered with clinicaltrials.gov (ID: NCT03503838) on 4/19/2018.

Objectives Utilization of parametric or nonparametric methods for testing Likert scale data is often debated. This 2-part simulation study aims to investigate the sampling distribution of various Likert scale distributions (including floor/ceiling effects) and analyze the effectiveness of using parametric versus nonparametric tests with varying sample sizes. Methods We simulated populations from parametric distributions binned into Likert scales. In study 1, replicates were sampled from each distribution with sizes ranging from 5 to 150 observations, calculating means with simulated 95% CIs at each sample size. In study 2, floor/ceiling effects were introduced such that the proportion of patients responding with the lowest rating varied from approximately 40% to 90%. Two-sample tests were then conducted for the 90% floor effect distribution against all other floor distributions to determine effectiveness of parametric versus nonparametric methods via 2-sided pooled t tests and Wilcoxon rank-sum tests. Coverage of the difference in means, realized P values, relative efficiency, measures of agreement in direction, and conclusion of tests were plotted by sample size. Results The sampling distributions of the 1-sample means and SDs for most distributions converged quickly to Gaussian, with 95% coverage. One- and 2-sample t tests of the mean demonstrated acceptable coverage, type I error, and agreement. Conclusions Simulations confirm that the sampling distribution of the mean rapidly approaches normality and appropriate tests provide adequate coverage and type I error. Two-sample t tests demonstrate appropriateness and increased statistical power gained by using parametric over nonparametric approaches, suggesting t tests should be implemented with few restrictions.

Literature regarding impact of genetic testing is wide ranging. For BRCA testing, findings suggest temporary impact on psychological state or quality of life (QOL) [1]. While some report perceived ...

BACKGROUND: MRI-based modeling of tumor cell density (TCD) can significantly improve targeted treatment of Glioblastoma (GBM). Unfortunately, interpatient variability limits the predictive ability of many modeling approaches. We present a Transfer Learning (TL) method that generates individualized patient models, grounded in the wealth of population data, while also detecting and adjusting for interpatient variabilities based on each patient’s own histologic data. METHODS: We recruited primary GBM patients undergoing image-guided biopsies and preoperative imaging including contrast-enhanced MRI (CE-MRI), Dynamic-Susceptibility-Contrast (DSC)-MRI, and Diffusion Tensor Imaging (DTI). We calculated relative cerebral blood volume (rCBV) from DSC-MRI and mean diffusivity (MD) and fractional anisotropy (FA) from DTI. Following image coregistration, we assessed TCD for each biopsy and identified corresponding localized MRI measurements. We then explored a range of univariate and multivariate predictive models of TCD based on MRI measurements in a generalized one-model-fits-all (OMFA) approach. We then implemented both univariate and multivariate individualized TL predictive models, which harness the available population level data but allow for individual variability in their predictions. Finally, we compared Pearson correlation coefficients and mean absolute error between the individualized TL versus generalized OMFA models. RESULTS: TCD significantly correlated with rCBV (r=0.33,p

Administering questionnaires to patients is an efficient and effective method for assessing patients' symptoms. However, item nonresponse (skipped questions) potentially compromises the utility of these questionnaires. Using an international sample of 2,067 patients with myeloproliferative neoplasms, we evaluated the impact of item nonresponse on scoring of the Myeloproliferative Neoplasms Symptom Assessment Form Total Symptom Score (MPN-SAF TSS or MPN-10). We characterized item nonresponse on the MPN-10 and compared strategies for addressing item nonresponse (available-case analysis, proration, and multiple imputation) on the MPN-10 (multi-symptom assessment) and Brief Fatigue Inventory (BFI; single-symptom assessment). Characteristics of multi-symptom assessments would be expected to adversely affect proration, yet proration and multiple imputation provided very similar results for both the MPN-10 and BFI. This is likely because the MPN-10 item missing data rates were low, consistent with prior clinic- and internet-based studies. These results support the published scoring method for the MPN-10 (proration).

Subtle and gradual changes occur in the brain years prior to cognitive impairment due to age-related neurodegenerative disorders. We examined the utility of hippocampal texture analysis and volumetric features extracted from brain magnetic resonance (MR) data to differentiate between three cognitive groups (cognitively normal (CN), Mild Cognitive Impairment (MCI), and Alzheimer’s disease (AD)), and neuropsychological Clinical Dementia Rating (CDR) scores. Data from 173 unique patients with 3T T1-weighted MR images from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database were analyzed. A variety of texture and volumetric features were extracted from bilateral hippocampal regions and were used to perform binary classification of cognitive groups and CDR scores. We used Diagonal Quadratic Discriminant Analysis (DQDA) in a leave one out cross validation scheme. Sensitivity, specificity, and area under the receiver operating characteristic curve (AUC) were used to assess the performance of models. Our results show promise for hippocampal texture analysis to distinguish between no impairment and early stages of impairment (AUCs of 0.86 for CN-MCI and 0.95 for CDR0-CDR1 models, respectively). Volumetric features were more successful at differentiating between no impairment and advanced stages of impairment (AUCs of 0.89 for CN-AD and 0.98 for CDR0-CDR2, respectively). MR radiomics may be a promising tool to classify various cognitive groups.

Objective.Outcome Measures in Rheumatology (OMERACT) convened a premeeting in 2018 to bring together patients, regulators, researchers, clinicians, and consumers to build upon previous OMERACT drug safety work, with patients fully engaged throughout all phases.Methods.Day 1 included a brief introduction to the history of OMERACT and methodology, and an overview of current efforts within and outside OMERACT to identify patient-reported medication safety concerns. On Day 2, two working groups presented results; after each, breakout groups were assembled to discuss findings.Results.Five themes pertaining to drug safety measurement emerged.Conclusion.Current approaches have failed to include data from the patient’s perspective. A better understanding of how individuals with rheumatic diseases view potential benefits and harms of therapies is essential.

Symptom monitoring during chemotherapy via web-based patient-reported outcomes (PROs) was previously demonstrated to lengthen survival in a single-center study. A multicenter randomized clinical trial comparedweb-based monitoring vs standard scheduled imaging to detect symptomatic recurrence in patients with lung cancer following initial treatment. A planned interim analysis (9-month follow-up) founda significant survival benefit (19-month survival in the PRO group vs 12 months in the control group). We now present the final overall survival analysis.

Objective: To investigate the association of a 6-month Zumba intervention with cognition and quality of life among older cognitively unimpaired apolipoprotein ∊4 (APOE4) carrier and noncarrier women. Methods: Fifty-three women were randomly assigned to either twice-weekly Zumba group classes or maintenance of habitual exercise (control group) for 6 months. At baseline, 3, and 6 months, all participants underwent neuropsychological, physical activity, and quality-of-life assessments. Results: Overall, neuropsychological test scores and level of physical activity did not differ between intervention and control groups at any time. However, compared to the control group, quality of life was higher at 3 months, and visuospatial working memory and response inhibition improved more in the intervention group by 6 months. Apolipoprotein ∊4 status did not affect the results. Discussion: Zumba may strengthen performance on visuospatial working memory among cognitively unimpaired older women but this needs to be tested in a larger clinical trial.

// Michael T. Barrett 1 , Karen S. Anderson 2 , Elizabeth Lenkiewicz 1 , Mariacarla Andreozzi 1 , Heather E. Cunliffe 3 , Christine L. Klassen 4 , Amylou C. Dueck 5 , Ann E. McCullough 6 , Srikanth K. Reddy 7 , Ramesh K. Ramanathan 8 , Donald W. Northfelt 8 , Barbara A. Pockaj 4 1 Department of Research, Mayo Clinic in Arizona, Scottsdale, Arizona, United States of America 2 Biodesign Institute, Arizona State University, Tempe, Arizona, United States of America 3 Department of Pathology, Dunedin School of Medicine, University of Otago, Dunedin, New Zealand 4 Division of General Surgery, Section of Surgical Oncology, Mayo Clinic in Arizona, Phoenix, Arizona, United States of America 5 Section of Biostatistics, Mayo Clinic in Arizona, Scottsdale, Arizona, United States of America 6 Department of Pathology and Laboratory Medicine, Mayo Clinic in Arizona, Scottsdale, Arizona, United States of America 7 Vanderbilt University, Nashville, Tennessee, United States of America 8 Division of Hematology-Oncology, Mayo Clinic in Arizona, Scottsdale, Arizona, United States of America Correspondence to: Michael T. Barrett, e-mail: Barrett.michael@mayo.edu Keywords: 9p24.1 amplicon, flow sorting, triple negative breast cancer, JAK2, PD-L1 Received: May 05, 2015 Accepted: June 22, 2015 Published: July 03, 2015 ABSTRACT We used DNA content flow cytometry followed by oligonucleotide array based comparative genomic hybridization to survey the genomes of 326 tumors, including 41 untreated surgically resected triple negative breast cancers (TNBC). A high level (log 2 ratio ≥1) 9p24 amplicon was found in TNBC (12/41), glioblastomas (2/44), and colon carcinomas (2/68). The shortest region of overlap for the amplicon targets 9p24.1 and includes the loci for PD-L1 , PD-L2 , and JAK2 (PDJ amplicon). In contrast this amplicon was absent in ER+ (0/8) and HER2+ (0/15) breast tumors, and in pancreatic ductal adenocarcinomas (0/150). The PDJ amplicon in TNBCs was correlated with clinical outcomes in group comparisons by two-sample t -tests for continuous variables and chi-squared tests for categorical variables. TNBC patients with the PDJ amplicon had a worse outcome with worse disease-free and overall survival. Quantitative RT-PCR confirmed that the PDJ amplicon in TNBC is associated with elevated expression of JAK2 and of the PD-1 ligands. These initial findings demonstrate that the PDJ amplicon is enriched in TNBC, targets signaling pathways that activate the PD-1 mediated immune checkpoint, and identifies patients with a poor prognosis.

Background Many surgical options exist for breast cancer, including breast conserving therapy (BCT), mastectomy with reconstruction (MAST+RECON) or without reconstruction (MAST). Long-term results regarding oncologic outcomes are few and primarily retrospective studies. Methods A retrospective review of a prospectively collected database of patients undergoing breast surgery for breast cancer from 2002 to 2014 was performed. Patients were separated into 3 time periods for analysis: 2002 to 2005, 2006 to 2009, and 2010 to 2014. Recurrence outcomes were compared at 4 years between MAST+RECON patients. Results Two thousand seventy-six patients were identified: 61.2% underwent BCT, 19.7% had MAST, and 19.1% had MAST+RECON. BCT patients were older and had smaller tumors. MAST+RECON increased in prevalence, whereas BCT decreased. Implant-based reconstruction and conservative mastectomy rates increased over the study period. Four-year local recurrence–free rates were similar in nipple-sparing and skin-sparing mastectomy groups. Conclusions BCT usage has decreased, trending toward immediate, nipple-sparing mastectomy, implant-based reconstruction. Surgeons should be aware of trends to optimally offer patients their surgical options.

A cancer diagnosis requires significant information to facilitate health care decision making, understand management options, and health care system navigation. Patient knowledge deficit can decrease quality of life and health care compliance. Surveys were distributed to attendees of the Mayo Clinic "Living with and Surviving Cancer" patient symposium January 2015. Follow-up survey was sent to participants 3 months after the symposium. Surveys included demographic data and patient-reported disease comprehension, symptom burden, desired information, and quality-of-life assessment. Demographics: 113 patients completed the pre-intervention survey. Average age was 64.7 years. Disease types included hematologic (N = 50) and solid malignancies (N = 77). Most patients self-reported adequate baseline understanding of their disease (80 %), screening tests (74 %), and monitoring tools (72 %). Lowest knowledge topics were legal issues (13 %) and pain management (35 %). Pre- and post-analysis: 79 of the initial 113 participants completed both surveys. In the post-symposium setting, durable knowledge impact was noted in disease understanding (pre 80 % vs post 92 %), treatment options (pre 60 % vs post 76 %), nutrition (pre 68 % vs post 84 %), and legal issues (pre 15 % vs post 32 %). Most patients desired increased understanding regarding disease, screening tests, nutrition, and stress and fatigue management. The level of desired information for these topics decreased in the post-symposium setting, statistically significant decrease noted in 4 of 5 topics assessed. Knowledge needs and deficit in cancer care range from disease-specific topics, social stressors, and health care navigation. A cancer patient-centered symposium can improve patient-reported knowledge deficit, with durable responses at 3 months, but patient needs persist.

Background Glioblastoma (GBM) exhibits profound intratumoral genetic heterogeneity. Each tumor comprises multiple genetically distinct clonal populations with different therapeutic sensitivities. This has implications for targeted therapy and genetically informed paradigms. Contrast-enhanced (CE)-MRI and conventional sampling techniques have failed to resolve this heterogeneity, particularly for nonenhancing tumor populations. This study explores the feasibility of using multiparametric MRI and texture analysis to characterize regional genetic heterogeneity throughout MRI-enhancing and nonenhancing tumor segments. Methods We collected multiple image-guided biopsies from primary GBM patients throughout regions of enhancement (ENH) and nonenhancing parenchyma (so called brain-around-tumor, [BAT]). For each biopsy, we analyzed DNA copy number variants for core GBM driver genes reported by The Cancer Genome Atlas. We co-registered biopsy locations with MRI and texture maps to correlate regional genetic status with spatially matched imaging measurements. We also built multivariate predictive decision-tree models for each GBM driver gene and validated accuracies using leave-one-out-cross-validation (LOOCV). Results We collected 48 biopsies (13 tumors) and identified significant imaging correlations (univariate analysis) for 6 driver genes: EGFR, PDGFRA, PTEN, CDKN2A, RB1, and TP53. Predictive model accuracies (on LOOCV) varied by driver gene of interest. Highest accuracies were observed for PDGFRA (77.1%), EGFR (75%), CDKN2A (87.5%), and RB1 (87.5%), while lowest accuracy was observed in TP53 (37.5%). Models for 4 driver genes (EGFR, RB1, CDKN2A, and PTEN) showed higher accuracy in BAT samples (n = 16) compared with those from ENH segments (n = 32). Conclusion MRI and texture analysis can help characterize regional genetic heterogeneity, which offers potential diagnostic value under the paradigm of individualized oncology.

BACKGROUND A small percentage of patients will have positive histological margins after primary wide local excision (WLE) of cutaneous melanoma (CM). Risk factors that predict marginal involvement at WLE remain unclear. OBJECTIVE To identify risk factors associated with positive margins after WLE of CM. MATERIALS AND METHODS A retrospective review of patients treated at a single institution for CM with sentinel lymph node biopsy from 1997 to 2011 was conducted. RESULTS Positive margins occurred in 6% of patients. Patients with positive margins were older (72.4 vs 60.7, p < .001), had thicker tumors (3.6 vs 1.9 mm, p < .001), and often involved the head and neck region (p < .001). Patients with positive margins at WLE had positive margins on initial biopsy (p = .012) and a higher rate of a melanoma in situ component on initial biopsy (24% vs 11%, p = .02). The 5-year local recurrence rate was significantly different between those with positive and negative margins at WLE (16.0% vs 6.9%; p = .047). CONCLUSION Positive margins after WLE are uncommon. When a patient has multiple risk factors for positive margins at WLE, histologically clear margins should be obtained through mapped serial excision or Mohs micrographic surgery.

IMPORTANCE: Standard adverse event (AE) reporting in oncology clinical trials has historically relied on clinician grading, which prior research has shown can lead to underestimation of rates of symptomatic AEs. Industry sponsors are beginning to implement in trials the National Cancer Institute’s Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE), which was developed to allow patients to self-report symptomatic AEs and improve the quality of symptomatic AE detection. OBJECTIVES: To evaluate the feasibility of implementing PRO-CTCAE in a prespecified correlative analysis of the phase 3 COMET-2 trial and enumerate statistically significant between-group differences in symptomatic AEs using PRO-CTCAE and the CTCAE. DESIGN, SETTING, AND PARTICIPANTS: This correlative study of 119 men in the randomized, double-blind, placebo-controlled phase 3 COMET-2 trial with metastatic castration-resistant prostate cancer who had undergone at least 2 prior lines of systemic treatment was conducted from March 2012 to July 2014. Participants completed PRO-CTCAE items using an automated telephone system from home prior to treatment and every 3 weeks during treatment. Statistical analysis was performed from May 2018 to June 2019. MAIN OUTCOMES AND MEASURES: The proportion of patients who completed expected PRO-CTCAE self-reports was computed as a measure of feasibility. RESULTS: Among the 119 men in the study (median age, 65 years [range, 44-80 years]), 534 of 587 (91.0%) expected PRO-CTCAE self-reports were completed, with consistently high rates of completion throughout participation. Rates of self-report adherence were similar between groups (cabozantinib s-maleate, 286 of 317 [90.2%]; and mitoxantrone hydrochloride-prednisone, 248 of 270 [91.9%]). Of 12 measured, patient-reported PRO-CTCAE symptomatic AEs, 4 reached statistical significance when comparing the proportion of patients with at least 1 postbaseline score greater than 0 between groups (differences ranged from 20.1% to 34.1% with higher proportions in the cabozantinib group; all P

Myeloproliferative neoplasms (MPN), including polycythemia vera, essential thrombocythemia, and primary myelofibrosis, have a propensity to evolve into accelerated and blast-phase disease (MPN-AP/BP), carrying a dismal prognosis. Conventional antileukemia therapy has limited efficacy in this setting. Thus, MPN-AP/BP is an urgent unmet clinical need. Modest responses to hypomethylating agents and single-agent ruxolitinib have been reported. More recently, combination of ruxolitinib and decitabine has demonstrated synergistic in vitro activity in human and murine systems. These observations led us to conduct a phase 1 study to explore the safety of combined decitabine and dose-escalated ruxolitinib in patients with MPN-AP/BP. A total of 21 patients were accrued to this multicenter study. Ruxolitinib was administered at doses of 10, 15, 25, or 50 mg twice daily in combination with decitabine (20 mg/m2 per day for 5 days) in 28-day cycles. The maximum tolerated dose was not reached. The most common reasons for study discontinuation were toxicity/adverse events (37%) and disease progression (21%). Fourteen patients died during study treatment period or follow-up. The median overall survival for patients on study was 7.9 months (95% confidence interval, 4.1-not reached). Among evaluable patients, the overall response rate by protocol-defined criteria (complete remission with incomplete count recovery + partial remission) was 9/17 (53%) and by intention-to-treat analysis was 9/21 (42.9%). The combination of decitabine and ruxolitinib was generally well tolerated by patients with MPN-AP/BP and demonstrates potentially promising clinical activity. A phase 2 trial evaluating the efficacy of this combination regimen is ongoing within the Myeloproliferative Disorder Research Consortium.

As new cancer treatment regimens demonstrate increased potential to improve patients’ survival, more focus is directed toward the quality of that extension of life and to obtaining additional information from patients regarding their experience with treatment. The utility of capturing patient-reported treatment-related symptoms to complement traditional clinician-rated symptomatic adverse event reporting is well-documented. The National Cancer Institute’s Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events is an item library aimed at capturing patient-reported symptoms to inform the patient perspective on a treatment’s tolerability. The U.S. Food and Drug Administration has recommended using the Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events in clinical trials. A practical guideline is needed to inform a priori selection of specific Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events items for use in any given industry-sponsored oncology clinical trial. Standardizing this selection process will foster systematic and consistent data collection as part of drug development and enhance our knowledge on how to use patient-relevant information as part of a treatment’s risk/benefit assessment. This article presents methods and consensus recommendations for selecting specific Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events items to include in early-phase and late-phase oncology clinical trials.

INTRODUCTION Roughly 4% to 23% of the population embody stress prone personality and other traits characterizing a subclinical "broad autism phenotype" (BAP). Subjective cognitive impairment (SCI) among healthy elderly is associated with psychological distress leading us to predict BAP would be associated with SCI. METHODS The Autism Spectrum Quotient, a self-administered 50 item questionnaire, was completed by 419 consecutive members of the Arizona APOE Cohort who underwent neuropsychological testing every 2 years. SCI was assessed with self and informant versions of the Multidimensional Assessment of Neurodegenerative Symptoms (MANS) Questionnaire. RESULTS A total of 45 individuals scored in the BAP range, designated BAP+, and the rest were BAP-. At entry, both Multidimensional Assessment of Neurodegenerative Symptoms Questionnaire Self and Informant scores were higher in the BAP+ group (P

Mutational profiling has demonstrated utility in predicting the likelihood of disease progression in patients with myelofibrosis (MF). However, there is limited data regarding the prognostic utility of genetic profiling in MF patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HCT). We performed high-throughput sequencing of 585 genes on pre-transplant samples from 101 patients with MF who underwent allo-HCT and evaluated the association of mutations and clinical variables with transplantation outcomes. Overall survival (OS) at 5 years post-transplantation was 52%, and relapse-free survival (RFS) was 51.1 % for this cohort. Nonrelapse mortality (NRM) accounted for most deaths. Patient's age, donor's age, donor type, and Dynamic International Prognostic Scoring System score at diagnosis did not predict for outcomes. Mutations known to be associated with increased risk of disease progression, such as ASXL1, SRSF2, IDH1/2, EZH2, and TP53, did not impact OS or RFS. The presence of U2AF1 (P = .007) or DNMT3A (P = .034) mutations was associated with worse OS. A Mutation-Enhanced International Prognostic Scoring System 70 score was available for 80 patients (79%), and there were no differences in outcomes between patients with high risk scores and those with intermediate and low risk scores. Collectively, these data identify mutational predictors of outcome in MF patients undergoing allo-HCT. These genetic biomarkers in conjunction with clinical variables may have important utility in guiding transplantation decision making.

We evaluated the feasibility of ruxolitinib therapy followed by a reduced-intensity conditioning (RIC) regimen for patients with myelofibrosis (MF) undergoing transplantation in a 2-stage Simon phase II trial. The aims were to decrease the incidence of graft failure (GF) and nonrelapse mortality (NRM) compared with data from the previous Myeloproliferative Disorders Research Consortium 101 Study. The plan was to enroll 11 patients each in related donor (RD) and unrelated donor (URD) arms, with trial termination if ≥3 failures (GF or death by day +100 post-transplant) occurred in the RD arm or ≥6 failures occurred in the URD. A total of 21 patients were enrolled, including 7 in the RD arm and 14 in the URD arm. The RD arm did not meet the predetermined criteria for proceeding to stage II. Although the URD arm met the criteria for stage II, the study was terminated owing to poor accrual and a significant number of failures. In all 19 transplant recipients, ruxolitinib was tapered successfully without significant side effects, and 9 patients (47%) had a significant decrease in symptom burden. The cumulative incidences of GF, NRM, acute graft-versus-host disease (GVHD), and chronic GVHD at 24 months were 16%, 28%, 64%, and 76%, respectively. On an intention-to-treat basis, the 2-year overall survival was 61% for the RD arm and 70% for the URD arm. Ruxolitinib can be integrated as pretransplantation treatment for patients with MF, and a tapering strategy before transplantation is safe, allowing patients to commence conditioning therapy with a reduced symptom burden. However, GF and NRM remain significant.

Renal insufficiency is common in patients with relapsed multiple myeloma and can often limit choice of therapy. Lenalidomide, a critical agent in the treatment of relapsed multiple myeloma, is renally cleared., This phase I/II trial evaluated the efficacy and safety of lenalidomide with dexamethasone in patients with relapsed multiple myeloma and renal insufficiency. Three groups were treated, with creatinine clearance 30–60 cc/hr (group A), CrCl 30, and can be given daily to those with CrCl

Patients with myeloproliferative neoplasms (MPNs) are faced with high disease-related symptom burden and quality of life (QoL) decrements. This analysis assesses the extent to which individual symptoms or summary measures across symptoms impact QoL overall and within MPN subgroups. Four sets of summary measures were constructed assessing symptom prevalence and severity within group-standardized and patient-individualized approaches. Among 1,416 international patients with MPNs, mean symptom severity and prevalence were highly correlated (P

Hematopoietic stem cell transplantation (HCT) is a curative treatment for patients with myelofibrosis (MF); however, many HCT-eligible patients decline this potentially life-saving procedure. The reasons behind this decision are not clear. We sought to survey patients with MF to understand their perspective on HCT. A 63-question survey was posted on myeloproliferative neoplasm patient advocacy websites. A total of 129 patients with MF responded to the survey. Among these patients, 49 (41%) were referred for HCT, and 41(32%) attended the transplantation consult. Of the patients who attended the transplantation consult, 24 (59%) did not plan on going on to HCT, and 16 (41%) intended to proceed with HCT. Reasons for the decision to not undergo transplantation included the desire to not be ill, desire to not spend time in the hospital, and concerns about overall quality of life. Specifically, concerns related to financial impact and the risk of graft-versus-host disease (GVHD) were expressed. Patients who decided to proceed with HCT felt that this would extend their survival and allow them to be around family for longer. This is the first survey to investigate patient perceptions regarding HCT for MF. Less than one-half of the patients were referred for HCT, and of those, less than one-half planned on proceeding with the transplantation, suggesting that many patients do not receive this life-saving procedure. Further exploration of the basis of patients' reluctance to proceed with HCT is warranted.

Mixed results have been reported regarding whether older cancer patients are at a greater risk for chemotherapy‐induced neuropathy. This article further evaluates the age‐based risk of this adverse event., Purpose. A few previous studies report a direct relationship between older age and chemotherapy‐induced neuropathy. This study further evaluated this adverse event's age‐based risk. Methods. CALGB 40101 investigated adjuvant paclitaxel (80 mg/m2 once per week or 175 mg/m2 every 2 weeks) in patients with breast cancer and served as a platform for the current study that investigated age‐based differences in neuropathy. Grade 2 or worse neuropathy, as per Common Terminology Criteria for Adverse Events version 4, was the primary endpoint; patients were assessed at baseline, every 6 months for 2 years, and then annually for 15 years. Results. Among these 1,881 patients, 230 were 65 years of age or older, 556 were 55–64 years, and 1,095 were younger than 55; 1,226 neuropathy events (commonly grade 1 or 2) were reported in 65% of the cohort. The number of grade 2 or worse events was 63 (27%), 155 (28%), and 266 (24%) within respective age groups (p = .14). In univariate analysis, only motor neuropathy had a higher age‐based incidence: 19 (8%), 43 (8%), and 60 (5%), respectively (p = .04); in multivariate analyses, this association was no longer statistically significant. Other endpoints, such as time to onset of neuropathy (time from trial enrollment to neuropathy development) and time to improvement (time from maximal grade sensory neuropathy to a one‐category improvement), showed no statistically significant age‐based differences. In contrast, obesity was associated with neuropathy, and every 2‐week paclitaxel was associated with trends toward neuropathy. Conclusion. Although paclitaxel‐induced neuropathy is common, older age is not an independent risk factor. Clinical trial identification number. NCT00041119 (CALGB 40101). Implications for Practice. Age alone is not an independent risk factor for paclitaxel‐induced neuropathy.

Background Treatment outcomes have improved in lymphoid malignancies but relapse remains inevitable for most patients. Everolimus and lenalidomide have shown clinical activity as single agents in patients with relapsed and refractory Hodgkin and non-Hodgkin lymphomas. Patients and Methods The present phase I/II trial for patients with relapsed and refractory lymphoid malignancy opened at Mayo Clinic from January 2011 to May 2013. The trial used a standard cohort 3 + 3 design to determine the maximum tolerated dose for the combination. Stem cell transplantation had failed in 27 of the patients (49%), 63% had stage IV disease, and ≥ 3 previous therapies had failed in 78%. Results Of the 58 patients, enrolled, 55 were evaluable for analysis. The maximum tolerated dose was 5 mg/d for everolimus plus 10 mg/d for 21 days for lenalidomide. The most common grade ≥ 3 toxicities were hematologic and included neutropenia (56%), leukopenia (38%), and thrombocytopenia (33%). Seven patients discontinued the study because of adverse events. One patient died of disease progression. The overall response rate was 27% (15 of 55), with 38% (21 of 55) having stable disease. Conclusion The present phase I/II trial of everolimus and lenalidomide for R/R lymphoma has shown the combination to be tolerable, with neutropenia as the main dose-limiting toxicity. Encouraging responses were seen in this heavily pretreated group, and the patients with a response had meaningful duration of response.

Although patient-reported outcomes (PROs), such as health-related quality of life, are important endpoints in randomised controlled trials (RCTs), there is little consensus about the analysis, interpretation, and reporting of these data. We did a systematic review to assess the variability, quality, and standards of PRO data analyses in advanced breast cancer RCTs. We searched PubMed for English language articles published in peer-reviewed journals between Jan 1, 2001, and Oct 30, 2017. Eligible articles were those that reported PRO results from RCTs of adult patients with advanced breast cancer receiving anti-cancer treatments with reported sample sizes of at least 50 patients-66 RCTs met the selection criteria. Only eight (12%) RCTs reported a specific PRO research hypothesis. Heterogeneity in the statistical methods used to assess PRO data was observed, with a mixture of longitudinal and cross-sectional techniques. Not all articles addressed the problem of multiple testing. Fewer than half of RCTs (28 [42%]) reported the clinical significance of their findings. 48 (73%) did not report how missing data were handled. Our systematic review shows a need to improve standards in the analysis, interpretation, and reporting of PRO data in cancer RCTs. Lack of standardisation makes it difficult to draw robust conclusions and compare findings across trials. The Setting International Standards in the Analyzing Patient-Reported Outcomes and Quality of Life Data Consortium was set up to address this need and develop recommendations on the analysis of PRO data in RCTs.

The hematologic response is critical in patients with light chain amyloidosis because a good response is known to improve organ response and overall survival. We present a retrospective analysis to compare the hematologic and organ response in patients who received bortezomib-based therapy before autologous stem cell transplantation (ASCT) versus those who received non-bortezomib-based therapy before ASCT and those who underwent ASCT at diagnosis.Of a total of 63 patients who underwent ASCT for light chain amyloidosis, 34 received bortezomib-based therapy before ASCT (Bor-ASCT) and 29 did not receive bortezomib therapy (non-Bor-ASCT). A greater number of patients had involvement of ≥ 3 organs and cardiac involvement in the Bor-ASCT group, suggesting a greater risk at baseline in the Bor-ASCT group.At 3, 6, and 12 months after ASCT, the hematologic response was better in the Bor-ASCT group, with a statistically significance difference at 6 months (partial response or better in 82% vs. 20%; P = .002) and 12 months (partial response or better in 76% vs. 33%; P = .02). Organ responses (66% vs. 21%; P .001) and median overall survival (not reached vs. 53 months; P = .001) were also greater in the Bor-ASCT group.Our study has shown that bortezomib-based therapy before ASCT improves the hematologic response, organ response and overall survival, potentially by decreasing the light chain load before ASCT.

Summary Tremendous progress in treatment and outcomes has been achieved across the whole range of haematological malignancies in the past two decades. Although cure rates for aggressive malignancies have increased, nowhere has progress been more impactful than in the management of typically incurable forms of haematological cancer. Population-based data have shown that 5-year survival for patients with chronic myelogenous and chronic lymphocytic leukaemia, indolent B-cell lymphomas, and multiple myeloma has improved markedly. This improvement is a result of substantial changes in disease management strategies in these malignancies. Several haematological malignancies are now chronic diseases that are treated with continuously administered therapies that have unique side-effects over time. In this Commission, an international panel of clinicians, clinical investigators, methodologists, regulators, and patient advocates representing a broad range of academic and clinical cancer expertise examine adverse events in haematological malignancies. The issues pertaining to assessment of adverse events examined here are relevant to a range of malignancies and have been, to date, underexplored in the context of haematology. The aim of this Commission is to improve toxicity assessment in clinical trials in haematological malignancies by critically examining the current process of adverse event assessment, highlighting the need to incorporate patient-reported outcomes, addressing issues unique to stem-cell transplantation and survivorship, appraising challenges in regulatory approval, and evaluating toxicity in real-world patients. We have identified a range of priority issues in these areas and defined potential solutions to challenges associated with adverse event assessment in the current treatment landscape of haematological malignancies.

BACKGROUND: Desmoid tumors (also referred to as aggressive fibromatosis) are connective tissue neoplasms that can arise in any anatomical location and infiltrate the mesentery, neurovascular structures, and visceral organs. There is no standard of care. METHODS: In this double-blind, phase 3 trial, we randomly assigned 87 patients with progressive, symptomatic, or recurrent desmoid tumors to receive either sorafenib (400-mg tablet once daily) or matching placebo. Crossover to the sorafenib group was permitted for patients in the placebo group who had disease progression. The primary end point was investigator-assessed progression-free survival; rates of objective response and adverse events were also evaluated. RESULTS: With a median follow-up of 27.2 months, the 2-year progression-free survival rate was 81% (95% confidence interval [CI], 69 to 96) in the sorafenib group and 36% (95% CI, 22 to 57) in the placebo group (hazard ratio for progression or death, 0.13; 95% CI, 0.05 to 0.31; P

Symptoms suggestive of gastroparesis are non-specific and conflicting reports exist regarding the ability of symptoms to predict the presence of gastroparesis. Our aim, therefore, was to evaluate the relationships between gastroparetic symptoms and their impact on quality of life and determine their relationship with clinical factors and gastric emptying.Gastric emptying scintigraphy, sociodemographic features, health care resource utilization, gastroparetic symptoms, and quality of life using validated questionnaires were obtained from consecutive patients referred for gastric emptying testing (GET). Descriptive analyses were conducted and logistic regression was performed to evaluate associations with abnormal gastric emptying after controlling for other covariates.Two hundred and sixty-six patients participated (195 females; mean age, 49.1 ± 17.6 years); 75% met Rome III criteria for functional dyspepsia. Gastric emptying was delayed in 28.2% at 4 h; the delay was mild in 48%, moderate in 20% and severe in 32%. Nausea/emesis and postprandial fullness, but not bloating, were significantly greater in those with delayed emptying. Postprandial fullness was most severe. Weak correlations were identified between symptom severity and the severity of gastric emptying delay. Quality of life was also lower in the delayed emptying group. Logistic regression analysis demonstrated associations between delayed gastric emptying and lower quality of life and increased symptom severity.In patients referred for GET, gastroparetic symptoms were more severe in those with delayed emptying. A decrease in quality of life in those with delayed gastric emptying was also present; this was not related to the severity of the delay in gastric emptying.

Background There have been conflicting results from studies that have evaluated psychological disturbances in functional dyspepsia (FD). We conducted a comprehensive survey of psychological measures in patients undergoing gastric emptying testing (GET) in order to determine the relationship among psychological distress, gastric emptying, and dyspeptic symptoms. Methods Consecutive patients referred for GET were prospectively enrolled. Details regarding patient characteristics, health care utilization, dyspeptic symptoms, quality of life, and psychological dysfunction were obtained. Depression, anxiety, somatization, stress, positive and negative affect, and alexithymia were queried using validated questionnaires. We compared those dyspeptic patients who met Rome III criteria for FD to those who did not meet these criteria. Key Results Two hundred and nine patients (160 female; mean age 46.6 years ± 17.3 years) participated. Around 151 patients (72%) met Rome III criteria for FD. In the entire group, a high level of depression, anxiety, somatization, and perceived stress was present compared to population norms. Health care seeking behavior and symptom severity were greater in those with FD and quality of life was lower compared to non-FD. Gastric emptying did not differentiate the two groups and similar degrees of psychological distress were present whether emptying was delayed or normal. Conclusions & Inferences In patients referred for GET, substantial psychological distress is present. The degree of distress was similar regardless of whether the patient met Rome III FD criteria or not. Further evaluation of psychological dysfunction in FD patients may lead to improved diagnosis and determination of the most appropriate treatment.

A recent multidisciplinary consensus defined an adequate breast cancer margin as no ink on tumor. The purpose of this study was to analyze rates of residual disease at re-excision by margin width.A prospective database at a single institution was reviewed from 2000 to 2012. Institutional protocol had been to perform re-excision surgery when margins were2 millimeters (mm).There were 2520 procedures. Re-excision surgery was performed for 12% of breast conserving therapy (BCT) procedures and 2% of mastectomies; residual disease was present in 38% and 26%, respectively. The rates of residual disease for all patients with positive, 0.1-0.9 mm, and 1.0-1.9 mm margins were 40%, 38%, and 33%, respectively. Age, race, menopause status, width of closest final margin, tumor histology, hormone receptor status, triple-negative disease and presence of lymphovascular invasion (LVI) were not significantly associated with the presence of residual disease. The presence of multiple margins2 mm trended toward significance (p = 0.06). Median follow-up was 43 months. The five-year local recurrence rates (5-year LR) were 1.1% for mastectomy patients and 1.9% for BCT patients.Breast cancer patients with margins of excision2 mm have a substantial risk of residual disease but the rates far exceed LR rates. These findings suggest that using residual disease rates to determine the appropriate margin width is not reliable, but also serve as a note of caution to track LR rates as institutions conform to new national guidelines for margin management.

Background The clinical phenotype of patients with myeloproliferative neoplasms (MPNs) including primary myelofibrosis (PMF), polycythemia vera (PV), and essential thrombocytosis (ET) whom manifest WHO grade 1 marrow fibrosis is poorly defined. Current IWG-MRT criteria require 2+ marrow fibrosis for diagnosis of post PV/ET myelofibrosis (MF). In contrast, the 2008 WHO definition of PMF does not require a minimum fibrosis threshold. Methods We retrospectively analyzed the clinical characteristics of 91 MPN patients with 1+ marrow fibrosis. We compared the clinical phenotype of sub threshold fibrosis PV/ET with that manifested by PMF. We applied the IWG-MRT criteria for post-PV/ET MF with the fibrosis component omitted and evaluated for percentage of criteria fulfillment. Results When IWG-MRT criteria were applied to the PV/ET group, 38/58 (66%) of patients fulfilled criteria for diagnosis of post-PV/ET myelofibrosis except for the 2+ fibrosis requirement. Comparison of sub threshold fibrotic PV/ET clinical phenotype to PMF revealed similar characteristics including heavy symptomatic burden (57% and 52%), presence of splenomegaly (43% and 55%), leukoerythroblastic blood smear (38% and 45%), and median hemoglobin (12.8 g/dL and 11.1 g/dL). Conclusion MPN progression represents a biological spectrum and definitions of progression in ET/PV may benefit from criteria not restricted by degree of fibrosis.

Controversy continues regarding the use of adjuvant radiation therapy (RT) and hormonal therapy (HT) for patients undergoing breast-conserving therapy (BCT) for ductal carcinoma in situ (DCIS). A prospective database was queried to identify women 18 years of age or older treated for DCIS from 2002 to 2013. BCT was completed for 300 patients with a median age of 66 years. The median DCIS size was 0.7 cm (range 0.1–6.0 cm). The DCIS grades were high (44 %), intermediate (37 %), and low (19 %). The closest margin was wider than 3 mm in 80 % and wider than 5 mm in 63 % of the cases. Adjuvant RT was administered to 183 patients (61 %), and the RT status of 9 patients (3 %) was unknown. RT was associated with age, DCIS size, comedo necrosis, grade, and treatment in 2002–2007 versus 2008–2013. Adjuvant HT was administered to 86 estrogen receptor-positive patients (39 %), and the HT status of 4 patients (2 %) was unknown. The median follow-up period was 63 months (range 4–151 months). The 5-year overall local recurrence (LR) rate was 4 % (95 % confidence interval [CI] 2.1–7.4 %). The 5-year LR rate was 3.9 % (95 % CI 1.8–8.6 %) for the RT patients and 4.1 % (95 % CI 1.6–10.7 %) for the patients not receiving RT. Of 13 LRs, 10 (77 %) were DCIS, and 3 (23 %) were invasive including one node-positive recurrence. Multidisciplinary and joint decision making in the treatment of DCIS results in a substantial and increasing number of patients forgoing adjuvant RT, adjuvant HT, or both. Reasonable 5-year LR rates suggest that such decision making can appropriately allocate patients to adjuvant therapies.

Bone mineral density (BMD) measurement can vary depending upon anatomical site, machine, and normative values used. This analysis compared different BMD endpoints in two clinical trials. Trial results differed across endpoints. Future clinical trials should consider inclusion of multiple endpoints in sensitivity analysis to ensure sound overall study conclusions.Methodological issues hamper efficacy assessment of osteoporosis prevention agents in cancer survivors. Osteoporosis diagnosis can vary depending upon which bone mineral density (BMD) anatomical site and machine is used and which set of normative values are applied. This analysis compared different endpoints for osteoporosis treatment efficacy assessment in two clinical studies.Data from North Central Cancer Treatment Group phase III clinical trials N02C1 and N03CC (Alliance) were employed involving 774 patients each comparing two treatments for osteoporosis prevention. Endpoints for three anatomical sites included raw BMD score (RawBMD); raw machine-based, sample-standardized, and reference population-standardized T scores (RawT, TSamp, TRef); and standard normal percentile corresponding to the reference population-standardized T score (TPerc). For each, treatment arm comparison was carried out using three statistical tests using change and percentage change from baseline (CB, %CB) at 1 year.Baseline correlations among endpoints ranged from 0.79 to 1.00. RawBMD and TPerc produced more statistically significant results (14 and 19 each out of 36 tests) compared to RawT (11/36), TSamp (8/36), and TRef (7/36). Spine produced the most statistically significant results (26/60) relative to femoral neck (20/60) and total hip (13/60). Lastly, CB resulted in 44 statistically significant results out of 90 tests, whereas %CB resulted in only 15 significant results.Treatment comparisons and interpretations were different across endpoints and anatomical sites. Transforming via sample statistics provided similar results as transforming via reference or machine-based norms. However, RawBMD and TPerc may be more sensitive to change as clinical trial endpoints.

To evaluate the impact of a patient-centered symposium as an educational intervention on a broad population of cancer patients. We developed a comprehensive patient symposium. Through voluntary questionnaires, we studied the impact of this cancer symposium on quality of life, cancer-specific knowledge, and symptom management among cancer patients. Symposium attendees were provided surveys prior to and 3 months following the educational intervention. Surveys included (1) EORTC-QLQ-C30; (2) disease understanding tool developed for this conference; (3) validated disease-specific questionnaires. Changes over time were assessed using McNemar's tests and paired t-tests for categorical and continuous variables, respectively. A total of 158 attendees completed the pre-convention survey. Most respondents reported at least "quite a bit" of understanding regarding treatment options, screening modalities, symptomatology, and cancer-related side effects. Attendees endorsed the least understanding of disease-related stress, risk factors, fatigue management, and legal issues related to disease/treatment. At 3 months, there was improvement in understanding (12 of 14 areas of self-reported knowledge especially regarding nutrition, and stress/fatigue management). However, no significant change was seen in QLQ-C30 functioning, fatigue, pain, or insomnia. A patient symposium, as an educational intervention improves a solid knowledge base amongst attendees regarding their disease, increases knowledge in symptom management, but may be insufficient to impact QoL as a single intervention.

Myeloproliferative neoplasms (essential thrombocythemia, ET; polycythemia vera, PV; myelofibrosis, MF) are monoclonal malignancies associated with genomic instability, dysregulated signaling pathways, and subsequent overproduction of inflammatory markers. Acknowledged for their debilitating symptom profiles, recent investigations have aimed to determine the identity of these markers, the upstream sources stimulating their development, their prevalence within the MPN population, and the role they play in symptom development. Creation of dedicated Patient Reported Outcome (PRO) tools, in combination with expanded access to cytokine analysis technology, has resulted in a surge of investigations evaluating the potential associations between symptoms and inflammation. Emerging data demonstrates clear relationships between individual MPN symptoms (fatigue, abdominal complaints, microvascular symptoms, and constitutional symptoms) and cytokines, particularly IL-1, IL-6, IL-8, and TNF-α. Information is also compiling on the role symptoms paradoxically play in the development of cytokines, as in the case of fatigue-driven sedentary lifestyles. In this paper, we explore the symptoms inherent to the MPN disorders and the potential role inflammation plays in their development.

Myeloproliferative neoplasms (MPNs) including polycythemia vera (PV), essential thrombocythemia (ET), and myelofibrosis (MF) are clonal, progressive, hematological malignancies resulting in the risk of vascular events, splenomegaly, and significant symptom burden, with a high prevalence of fatigue.[

BACKGROUND AND PURPOSE: The optimal TE must be calculated to minimize the variance in CBV measurements made with DSC MR imaging. Simulations can be used to determine the influence of the TE on CBV, but they may not adequately recapitulate the in vivo heterogeneity of precontrast T2*, contrast agent kinetics, and the biophysical basis of contrast agent–induced T2* changes. The purpose of this study was to combine quantitative multiecho DSC MRI T2* time curves with error analysis in order to compute the optimal TE for a traditional single-echo acquisition. MATERIALS AND METHODS: Eleven subjects with high-grade gliomas were scanned at 3T with a dual-echo DSC MR imaging sequence to quantify contrast agent–induced T2* changes in this retrospective study. Optimized TEs were calculated with propagation of error analysis for high-grade glial tumors, normal-appearing white matter, and arterial input function estimation. RESULTS: The optimal TE is a weighted average of the T2* values that occur as a contrast agent bolus transverses a voxel. The mean optimal TEs were 30.0 ± 7.4 ms for high-grade glial tumors, 36.3 ± 4.6 ms for normal-appearing white matter, and 11.8 ± 1.4 ms for arterial input function estimation (repeated-measures ANOVA, P CONCLUSIONS: Greater heterogeneity was observed in the optimal TE values for high-grade gliomas, and mean values of all 3 ROIs were statistically significant. The optimal TE for the arterial input function estimation is much shorter; this finding implies that quantitative DSC MR imaging acquisitions would benefit from multiecho acquisitions. In the case of a single-echo acquisition, the optimal TE prescribed should be 30–35 ms (without a preload) and 20–30 ms (with a standard full-dose preload).

ASCO believes that high-quality observational studies can advance evidence-based practice for cancer care and are complementary to randomized controlled trials (RCTs). Observational studies can generate hypotheses by evaluating novel exposures or biomarkers and by revealing patterns of care and relationships that might not otherwise be discovered. Researchers can then test these hypotheses in RCTs. Observational studies can also answer or inform questions that either have not been or cannot be answered by RCTs. In addition, observational studies can be used for postmarketing surveillance of new cancer treatments, particularly in vulnerable populations. The incorporation of observational research as part of clinical decision making is consistent with the position of many leading institutions. ASCO identified five overarching recommendations to enhance the role of observational research in clinical decision making: (1) improve the quality of electronic health data available for research, (2) improve interoperability and the exchange of electronic health information, (3) ensure the use of rigorous observational research methodologies, (4) promote transparent reporting of observational research studies, and (5) protect patient privacy.

Effective assessment and management of pain in patients with cancer is strengthened by the patient's report of how much pain interferes with daily functioning. This requires a clear delineation of different levels of pain interference. We derived optimal cutpoints for differentiating between mild, moderate, and severe pain interference assessed by the Brief Pain Inventory (BPI) and describe the prevalence and characteristics of pain-induced functional impairment in patients with cancer. Data were pooled across 3 Phase III pivotal trials. Patient-completed questionnaires included the EuroQol 5 dimensions questionnaire (EQ5D), Functional Assessment of Cancer Therapy-General Measure (FACT-G), and BPI. Optimal cutpoints for categorizing pain interference into 3 levels were derived using analysis of variance, with different cutpoint sets for BPI total interference (BPI-PITS, the average score of all 7 items), activity-related interference (BPI-WAW, the average score of work, general activity, and walking), and mood-related interference (BPI-REM, the average score of relations with others, enjoyment of life, and mood) as independent variables and EQ5D-visual analog scale and total FACT-G score as dependent variables. To validate the cutpoints, we assessed whether interference categories were in concordance with Eastern Cooperative Oncology Group performance status (ECOG-PS) levels. The optimal cutpoints were (2,5) for BPI-PITS, (2,6) for BPI-WAW, and (2,5) for BPI-REM. The mild (2), moderate (2-5 or 2-6), and severe (5 or6) pain interference groups were significantly concordant with ECOG-PS levels (P0.0001). We empirically derived patient-reported pain interference categories in relation to clinician-rated performance status. These cutpoints may facilitate the conduct and interpretation of clinical evaluation, symptom epidemiology, and clinical trials.

Therapy-related myeloid neoplasms are a potentially life-threatening consequence of treatment for autoimmune disease (AID) and an emerging clinical phenomenon.To query the association of cytotoxic, anti-inflammatory, and immunomodulating agents to treat patients with AID with the risk for developing myeloid neoplasm.This retrospective case-control study and medical record review included 40 011 patients with an International Classification of Diseases, Ninth Revision, coded diagnosis of primary AID who were seen at 2 centers from January 1, 2004, to December 31, 2014; of these, 311 patients had a concomitant coded diagnosis of myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML). Eighty-six cases met strict inclusion criteria. A case-control match was performed at a 2:1 ratio.Odds ratio (OR) assessment for AID-directed therapies.Among the 86 patients who met inclusion criteria (49 men [57%]; 37 women [43%]; mean [SD] age, 72.3 [15.6] years), 55 (64.0%) had MDS, 21 (24.4%) had de novo AML, and 10 (11.6%) had AML and a history of MDS. Rheumatoid arthritis (23 [26.7%]), psoriasis (18 [20.9%]), and systemic lupus erythematosus (12 [14.0%]) were the most common autoimmune profiles. Median time from onset of AID to diagnosis of myeloid neoplasm was 8 (interquartile range, 4-15) years. A total of 57 of 86 cases (66.3%) received a cytotoxic or an immunomodulating agent. In the comparison group of 172 controls (98 men [57.0%]; 74 women [43.0%]; mean [SD] age, 72.7 [13.8] years), 105 (61.0%) received either agent (P = .50). Azathioprine sodium use was observed more frequently in cases (odds ratio [OR], 7.05; 95% CI, 2.35- 21.13; P .001). Notable but insignificant case cohort use among cytotoxic agents was found for exposure to cyclophosphamide (OR, 3.58; 95% CI, 0.91-14.11) followed by mitoxantrone hydrochloride (OR, 2.73; 95% CI, 0.23-33.0). Methotrexate sodium (OR, 0.60; 95% CI, 0.29-1.22), mercaptopurine (OR, 0.62; 95% CI, 0.15-2.53), and mycophenolate mofetil hydrochloride (OR, 0.66; 95% CI, 0.21-2.03) had favorable ORs that were not statistically significant. No significant association between a specific length of time of exposure to an agent and the drug's category was observed.In a large population with primary AID, azathioprine exposure was associated with a 7-fold risk for myeloid neoplasm. The control and case cohorts had similar systemic exposures by agent category. No association was found for anti-tumor necrosis factor agents. Finally, no timeline was found for the association of drug exposure with the incidence in development of myeloid neoplasm.

Myelofibrosis is a myeloproliferative neoplasm associated with progressive cytopenias and high symptom burden. MF patients with thrombocytopenia have poor prognosis but the presence of thrombocytopenia frequently precludes the use of JAK2 inhibitors. In this study, we assessed quality of life and symptom burden in 418 MF patients with (n = 89) and without (n = 329) thrombocytopenia using prospective data from the MPN-QOL study group database, including the Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF) and Total Symptom Score (MPN10). Thrombocytopenia, defined as platelet count 9/L (moderate 51–100 × 109/L; severe ≤50 × 109/L), was associated with anemia (76% vs. 45%, p < 0.001), leukopenia (29% vs. 11%, p < 0.001), and need for red blood cell transfusion (35% vs. 19%, p = 0.002). Thrombocytopenic patients had more fatigue, early satiety, inactivity, dizziness, sad mood, cough, night sweats, itching, fever, and weight loss; total symptom scores were also higher (33 vs. 24, p < 0.001). Patients with severe thrombocytopenia were more likely to have anemia (86% vs. 67%, p = 0.04), leukopenia (40% vs. 20%, p = 0.04), and transfusion requirements (51% vs. 20%, p = 0.002) but few differences in symptoms when compared to patients with moderate thrombocytopenia. These results suggest that MF patients with thrombocytopenia experience greater symptomatic burden than MF patients without thrombocytopenia and may benefit from additional therapies.

Purpose To assess the feasibility of measuring symptomatic adverse events (AEs) in a multicenter clinical trial using the National Cancer Institute's Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE). Methods and Materials Patients enrolled in NRG Oncology's RTOG 1012 (Prophylactic Manuka Honey for Reduction of Chemoradiation Induced Esophagitis-Related Pain during Treatment of Lung Cancer) were asked to self-report 53 PRO-CTCAE items representing 30 symptomatic AEs at 6 time points (baseline; weekly ×4 during treatment; 12 weeks after treatment). Reporting was conducted via wireless tablet computers in clinic waiting areas. Compliance was defined as the proportion of visits when an expected PRO-CTCAE assessment was completed. Results Among 226 study sites participating in RTOG 1012, 100% completed 35-minute PRO-CTCAE training for clinical research associates (CRAs); 80 sites enrolled patients, of which 34 (43%) required tablet computers to be provided. All 152 patients in RTOG 1012 agreed to self-report using the PRO-CTCAE (median age 66 years; 47% female; 84% white). Median time for CRAs to learn the system was 60 minutes (range, 30-240 minutes), and median time for CRAs to teach a patient to self-report was 10 minutes (range, 2-60 minutes). Compliance was high, particularly during active treatment, when patients self-reported at 86% of expected time points, although compliance was lower after treatment (72%). Common reasons for noncompliance were institutional errors, such as forgetting to provide computers to participants; patients missing clinic visits; Internet connectivity; and patients feeling “too sick.” Conclusions Most patients enrolled in a multicenter chemoradiotherapy trial were willing and able to self-report symptomatic AEs at visits using tablet computers. Minimal effort was required by local site staff to support this system. The observed causes of missing data may be obviated by allowing patients to self-report electronically between visits, and by using central compliance monitoring. These approaches are being incorporated into ongoing studies.

IMPORTANCE: In cancer clinical trials, symptomatic adverse events (AEs), such as nausea, are reported by investigators rather than by patients. There is increasing interest to collect symptomatic AE data via patient-reported outcome (PRO) questionnaires, but it is unclear whether it is feasible to implement this approach in multicenter trials. OBJECTIVE: To examine whether patients are willing and able to report their symptomatic AEs in multicenter trials. DESIGN, SETTING, AND PARTICIPANTS: A total of 361 consecutive patients enrolled in any 1 of 9 US multicenter cancer treatment trials were invited to self-report 13 common symptomatic AEs using a PRO adaptation of the National Cancer Institute���s Common Terminology Criteria for Adverse Events (CTCAE) via tablet computers at 5 successive clinic visits. Patient adherence was tracked with reasons for missed self-reports. Agreement with clinician AE reports was analyzed with weighted �� statistics. Patient and investigator perspectives were elicited by survey. The study was conducted from March 15, 2007, to August 11, 2011. Data analysis was performed from August 9, 2013, to March 21, 2014. RESULTS: Of the 361 patients invited to participate, 285 individuals enrolled, with a median age of 57 years (range, 24-88), 202 (74.3%) female, 241 (85.5%) white, 73 (26.8%) with a high school education or less, and 176 (64.7%) who reported regular internet use (denominators varied owing to missing data). Across all patients and trials, there were 1280 visits during which patients had an opportunity to self-report (ie, patients were alive and enrolled in a treatment trial at the time of the visit). Self-reports were completed at 1202 visits (93.9% overall adherence). Adherence was highest at baseline and declined over time (visit 1, 100%; visit 2, 96%; visit 3, 95%; visit 4, 91%; and visit 5, 85%). Reasons for missing PROs included institutional errors in 27 of 48 (56.3%) of the cases (eg, staff forgetting to bring computers to patients at visits), patients feeling ���too ill��� in 8 (16.7%), patient refusal in 8 (16.7%), and internet connectivity problems in 5 (10.4%). Patient-investigator CTCAE agreement was moderate or worse for most symptoms (most �� < 0.05), with investigators reporting fewer AEs than patients across symptoms. Most patients believed that the system was easy to use (234 [93.2%]) and useful (230 [93.1%]), and investigators thought that the patient-reported AEs were useful (133 [94.3%]) and accurate (119 [83.2%]). CONCLUSIONS AND RELEVANCE: Participants in multicenter cancer trials are willing and able to report their own symptomatic AEs at most clinic visits and report more AEs than investigators. This approach may improve the precision of AE reporting in cancer trials.

Objective To explore the self-expressed desire for, envisioned reaction to, and basic understanding of presymptomatic Alzheimer disease (AD)–related genetic and biomarker tests. Patients and Methods The Alzheimer's Prevention Registry is an online community of people at least 18 years of age who are interested in AD prevention research for purely informational purposes or to be considered for possible research participation in future studies. Information about presymptomatic testing and an online multiple choice format survey were posted from November 1, 2012, through June 20, 2013, on the registry website. Results Of 4036 respondents, 80.8% (3195/3952) wanted genetic testing if paid by insurance and 58.7% (2261/3851) if it would cost them at least $100. A total of 80.2% (3112/3879) wanted biomarker testing. If at high risk for AD, 90.5% (3478/3841) endorsed that they would "pursue a healthier lifestyle," but 11.6% (427/3706) endorsed "seriously consider suicide." The implication of a positive genetic test result was incorrectly understood by 13.1% (500/3812) and 32.6% (1255/3848) failed to view a positive biomarker test result as evidence of increased risk for or the presence of AD. Conclusion Despite efforts to increase public awareness of AD, our survey results suggest that greater education of the public is needed. Interested patients should probably undergo psychological screening to identify those at high risk of adverse psychological outcomes, and disclosure of presymptomatic test results should be anchored to tangible constructive action plans, such as healthy lifestyle changes, long-term care planning, and, when available and appropriate, participation in research trials.