Reliability and validity of PRO-CTCAE® daily reporting with a 24-hour recall period.

PURPOSE: The standard recall period for the patient-reported outcomes version of the common terminology criteria for adverse events (PRO-CTCAE®) is the past 7 days, but there are contexts where a 24-hour recall may be desirable. The purpose of this analysis was to investigate the reliability and validity of a subset of PRO-CTCAE items captured using a 24-hour recall. METHODS: 27 PRO-CTCAE items representing 14 symptomatic adverse events (AEs) were collected using both a 24-hour recall (24 h) and the standard 7 day recall (7d) in a sample of patients receiving active cancer treatment (n = 113). Using data captured with a PRO-CTCAE-24h on days 6 and 7, and 20 and 21, we computed intra-class correlation coefficients (ICC); an ICC ≥ 0.70 was interpreted as demonstrating high test-retest reliability. Correlations between PRO-CTCAE-24h items on day 7 and conceptually relevant EORTC QLQ-C30 domains were examined. In responsiveness analysis, patients were deemed changed if they had a one-point or greater change in the corresponding PRO-CTCAE-7d item (from week 0 to week 1). RESULTS: PRO-CTCAE-24h captured on two consecutive days demonstrated that 21 of 27 items (78%) had ICCs ≥ 0.70 (day 6/7 median ICC 0.76), (day 20/21 median ICC 0.84). Median correlation between attributes within a common AE was 0.75, and the median correlation between conceptually relevant EORTC QLQ-C30 domains and PRO-CTCAE-24 h items captured on day 7 was 0.44. In the analysis of responsiveness to change, the median standardized response mean (SRM) for patients with improvement was - 0.52 and that for patients with worsening was 0.71. CONCLUSION: A 24-hour recall period for PRO-CTCAE items has acceptable measurement properties and can inform day-to-day variations in symptomatic AEs when daily PRO-CTCAE administration is implemented in a clinical trial.

Differential effects of an electronic symptom monitoring intervention based on the age of patients with advanced cancer.

BACKGROUND: Symptom monitoring interventions enhance patient outcomes, including quality of life (QoL), health care utilization, and survival, but it remains unclear whether older and younger patients with cancer derive similar benefits. We explored whether age moderates the improved outcomes seen with an outpatient electronic symptom monitoring intervention. PATIENTS AND METHODS: We carried out a secondary analysis of data from a randomized trial of 766 patients receiving chemotherapy for metastatic solid tumors. Patients received an electronic symptom monitoring intervention integrated with oncology care or usual oncology care alone. The intervention consisted of patients reporting their symptoms, which were provided to their physicians at clinic visits, and nurses receiving alerts for severe/worsening symptoms. We used regression models to determine whether age (older or younger than 70 years) moderated the effects of the intervention on QoL (EuroQol EQ-5D), emergency room (ER) visits, hospitalizations, and survival outcomes. RESULTS: Enrollment rates for younger (589/777 = 75.8%) and older (177/230 = 77.0%) patients did not differ. Older patients (median age = 75 years, range 70-91 years) were more likely to have an education level of high school or less (26.6% versus 20.9%, P = 0.029) and to be computer inexperienced (50.3% versus 23.4%, P < 0.001) compared with younger patients (median age = 58 years, range 26-69 years). Younger patients receiving the symptom monitoring intervention experienced lower risk of ER visits [hazard ratio (HR) = 0.74, P = 0.011] and improved survival (HR = 0.76, P = 0.011) compared with younger patients receiving usual care. However, older patients did not experience significantly lower risk of ER visits (HR = 0.90, P = 0.613) or improved survival (HR = 1.06, P = 0.753) with the intervention. We found no moderation effects based on age for QoL and risk of hospitalizations. CONCLUSIONS: Among patients with advanced cancer, age moderated the effects of an electronic symptom monitoring intervention on the risk of ER visits and survival, but not QoL. Symptom monitoring interventions may need to be tailored to the unique needs of older adults with cancer.

Are we assuming too much with our statistical assumptions? Lessons learned from the ALTTO trial.

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.

Endpoint comparison for bone mineral density measurements in North Central Cancer Treatment Group cancer clinical trials N02C1 and N03CC (Alliance).

UNLABELLED: 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. INTRODUCTION: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

EGFR expression is associated with decreased benefit from trastuzumab in the NCCTG N9831 (Alliance) trial.

BACKGROUND: Epidermal growth factor receptor (EGFR) has been hypothesised to modulate the effectiveness of anti-HER2 therapy. We used a standardised, quantitative immunofluorescence assay and a novel EGFR antibody to evaluate the correlation between EGFR expression and clinical outcome in the North Central Cancer Treatment Group (NCCTG) N9831 trial. METHODS: Tissue microarrays were constructed that allowed analysis of 1365 patients randomly assigned to receive chemotherapy alone (Arm A), sequential trastuzumab after chemotherapy (Arm B) and chemotherapy with concurrent trastuzumab (Arm C). Measurement of EGFR was performed using the EGFR antibody, D38B1, on the fluorescence-based AQUA platform. The result was validated using an independent retrospective metastatic breast cancer cohort (n=130). RESULTS: Epidermal growth factor receptor assessed as a continuous (logarithmic transformed) variable shows an association with disease-free survival in Arm C (P=0.009) but not in Arm A or B. High EGFR expression was associated with worse outcome (Hazard ratio (HR)=2.15; 95% CI 1.28-3.60, P=0.004). Validation in a Greek metastatic breast cancer cohort showed an HR associated with high EGFR expression of 1.92 (P=0.0073). CONCLUSIONS: High expression of EGFR appears to be associated with decreased benefit from adjuvant concurrent trastuzumab. Since other treatment options exist for HER2-driven tumours, further validation of these data may select patients for alternative or additive therapy.

N0539 phase II trial of fulvestrant and bevacizumab in patients with metastatic breast cancer previously treated with an aromatase inhibitor: a North Central Cancer Treatment Group (now Alliance) trial.

BACKGROUND: Based on preclinical studies, the vascular endothelial pathway is an important mechanism for estrogen receptor resistance. We conducted a phase II study of fulvestrant and bevacizumab in patients with aromatase inhibitor pretreated metastatic breast cancer. PATIENTS AND METHODS: A single-stage phase II study was conducted with these objectives: 6-month progression-free survival (PFS), tumor response, toxic effect, and overall survival. Regimen: 250 mg fulvestrant days 1 and 15 (cycle 1) then day 1 (cycle 2 and beyond) and 10 mg/kg bevacizumab days 1 and 15 of each 4-week cycle. RESULTS: At interim analysis, 20 eligible patients initiated treatment, 11 were progression free and on treatment at 3 months, not meeting the protocol-specified efficacy requirements (at least 12 of 20). Accrual remained open during interim analysis with 36 patients enrolling before final study closure. Among the 33 eligible patients, the median PFS was 6.2 months [95% confidence interval (CI) 3.6-10.1 months]. Of the 18 with measurable disease, 4 (22%) patients (95% CI 6% to 48%) had a confirmed tumor response (1 complete, 3 partial). The most common grade 3/4 adverse events were hypertension 3 (9%) and headache 3 (9%). CONCLUSIONS: The fulvestrant/bevacizumab combination is safe and tolerable; however, it did not meet its statistical end point.

The changing landscape of axillary surgery: which breast cancer patients may still benefit from complete axillary lymph node dissection?

BACKGROUND AND OBJECTIVES: Many breast cancer patients undergoing completion axillary lymph node dissection (CALND) for sentinel lymph node (SLN) metastases have no further disease. Predicting patients at high risk of non-sentinel lymph node (NSLN) metastasis may help guide effective utilization of CALND. METHODS: SLN+ breast cancer patients undergoing frozen section (FS) analysis at a single institution (2004-2010) were studied retrospectively. Factors associated with NSLN metastases were identified. RESULTS: Two-hundred forty SLN+ patients were identified. The incidence of NSLN metastases was 45% in FS(+) patients undergoing CALND, compared to 10% of FS(-) patients following CALND (P < 0.001). Multivariate analysis revealed that FS positivity, tumor size, and the presence of angiolymphatic invasion were significant factors associated with NSLN metastases (all P < 0.05). Further analysis of FS(+) patients revealed that tumor size, ER(-) status, and lymph node metastasis size were also associated with risk of NSLN metastases. An algorithm for the management of the axilla in SLN+ breast cancer patients was devised, based on clinic-pathologic predictors of NSLN metastases. CONCLUSION: A SLN+ biopsy by FS predicts the presence of NSLN metastases and, in combination with other factors, may justify immediate CALND. CALND may, however, be avoided in selected low-risk SLN+ patients.

North Central Cancer Treatment Group (NCCTG) N0432: phase II trial of docetaxel with capecitabine and bevacizumab as first-line chemotherapy for patients with metastatic breast cancer.

BACKGROUND: Docetaxel (T; Taxotere) with capecitabine (X) is active against metastatic breast cancer (MBC); bevacizumab (BV) has demonstrated efficacy with taxanes in the first-line setting. This study was conducted to assess the safety and efficacy of TX-BV in patients with MBC. PATIENTS AND METHODS: In this single-arm, multicenter phase II study, patients received first-line bevacizumab 15 mg/kg and docetaxel 75 mg/m(2) on day 1 and capecitabine 825 mg/m(2) twice per day on days 1-14 every 21 days. Primary and secondary end points were tumor response rate (RR), overall survival (OS), progression-free survival (PFS), and toxicity. RESULTS: A total of 45 assessable patients received TX-BV for a median of seven cycles. Two complete and 20 partial responses were observed (overall RR 49%); nine patients had stable disease >6 months, for a clinical benefit rate of 69%. Median response duration was 11.8 months. Median OS and PFS were 28.4 and 11.1 months, respectively. Grade 3/4 adverse events included hand-foot syndrome (29%), fatigue (20%), febrile neutropenia (18%), and diarrhea (18%). In cycles 3-10, median dose levels of docetaxel and capecitabine were 60 mg/m(2) and 660 mg/m(2), respectively. CONCLUSION: TX-BV demonstrated significant activity; dose modifications were required to manage drug-related toxic effects.

Modulation of motorcortical excitability by methylphenidate in adult voluntary test persons performing a go/nogo task.

This study investigated the interaction between motorcortical excitability (short interval cortical inhibition, intracortical facilitation and long interval cortical inhibition), different requirement conditions [choice reaction test (CRT), attention/go/nogo], and their pharmacological modulation by methylphenidate (MPH) in normal healthy adults (n = 31) using a transcranial magnetic stimulation paradigm. MPH was administered in a dosage of 1 mg/kg body weight, maximum 60 mg. Additionally, serum level and clearance of MPH were controlled. The statistical analysis of variance revealed a significant three-way interaction of 2 (MPH) x 3 (CRT) x 6 (ISI) predicting motor evoked potential amplitudes (P = 0.032, MPH none and full dose, n = 31). In order to compare effects of dosage an additional between-subjects factor (half vs. full MPH dose) was introduced. None of the interactions involving this between-subject factor reached statistical significance. Exploring interactions with MPH only, a 3 (MPH none, half and full dose) x 3 (CRT) x 6 (ISI) analysis of variance revealed significant two-way interactions for MPH x ISI (P = 0.040) and condition x ISI (P < 0.001, n = 18). Effects observed for MPH were strongest on facilitatory processes, weaker for intracortical inhibition. In sum, MPH seems to interact via striato-thalamo-cortical pathways with original motorcortical processes (ISI), to a lesser extent with task-dependent or behavioral parameters (CRT).

A phase III randomized, double-blind, placebo-controlled trial of gabapentin in the management of hot flashes in men (N00CB).

INTRODUCTION: Hot flashes represent a significant problem in men undergoing androgen deprivation therapy. MATERIALS AND METHODS: Via a prospective, double-blind, placebo-controlled clinical trial, men with hot flashes, on a stable androgen deprivation therapy program for prostate cancer, received a placebo or gabapentin at target doses of 300, 600, or 900 mg/day. Hot flash frequencies and severities were recorded daily during a baseline week and for 4 weeks while the patients took the study medication. RESULTS: In the 214 eligible patients who began the study drug on this trial, comparing the fourth treatment week to the baseline week, mean hot flash scores decreased in the placebo group by 4.1 units and in the three increasing dose gabapentin groups by, 3.2, 4.6, and 7.0 units. Comparing the three combined gabapentin arms to the placebo arm did not result in significant hot flash differences. Wilcoxon rank-sum P values for change in hot flash scores and frequencies after 4 weeks of treatment were 0.10 and 0.02, comparing the highest dose gabapentin arm to the placebo arm, respectively. The gabapentin was well tolerated in this trial. CONCLUSION: These results support that gabapentin decreases hot flashes, to a moderate degree, in men with androgen ablation-related vasomotor dysfunction.

Deep brain stimulation of globus pallidus internus in a 16-year-old boy with severe tourette syndrome and mental retardation.

A 16- year-old boy with long-standing severe Tourette syndrome (TS) and mental retardation, non-responsive to complex pharmocological and behavioural treatment was selected for bilateral deep brain stimulation (DBS) of the globus pallidus internus (GPi). Pre-operative and post-operative Yale Tourette syndrome scale (YTSS) scores and several other scores were used to quantify the effect of DBS up to one year follow-up. Although subscores of the YTSS improved, the overall outcome of chronic GPi-DBS showed no substantial therapeutic effect. This finding is in contrast to markedly improved TS of the only two adolescent TS patients in whom DBS has been performed so far. In this article we discuss possible reasons for the poor therapeutic effect of GPi-DBS in our patient contributing to the on-going debate on DBS inclusion criteria for adolescent TS patients.

Accurate Patient-Specific Machine Learning Models of Glioblastoma Invasion Using Transfer Learning.

BACKGROUND AND PURPOSE: MR imaging-based modeling of tumor cell density can substantially improve targeted treatment of glioblastoma. Unfortunately, interpatient variability limits the predictive ability of many modeling approaches. We present a transfer learning 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. MATERIALS AND METHODS: We recruited patients with primary glioblastoma undergoing image-guided biopsies and preoperative imaging, including contrast-enhanced MR imaging, dynamic susceptibility contrast MR imaging, and diffusion tensor imaging. We calculated relative cerebral blood volume from DSC-MR imaging and mean diffusivity and fractional anisotropy from DTI. Following image coregistration, we assessed tumor cell density for each biopsy and identified corresponding localized MR imaging measurements. We then explored a range of univariate and multivariate predictive models of tumor cell density based on MR imaging measurements in a generalized one-model-fits-all approach. We then implemented both univariate and multivariate individualized transfer learning predictive models, which harness the available population-level data but allow individual variability in their predictions. Finally, we compared Pearson correlation coefficients and mean absolute error between the individualized transfer learning and generalized one-model-fits-all models. RESULTS: Tumor cell density significantly correlated with relative CBV (r = 0.33, P < .001), and T1-weighted postcontrast (r = 0.36, P < .001) on univariate analysis after correcting for multiple comparisons. With single-variable modeling (using relative CBV), transfer learning increased predictive performance (r = 0.53, mean absolute error = 15.19%) compared with one-model-fits-all (r = 0.27, mean absolute error = 17.79%). With multivariate modeling, transfer learning further improved performance (r = 0.88, mean absolute error = 5.66%) compared with one-model-fits-all (r = 0.39, mean absolute error = 16.55%). CONCLUSIONS: Transfer learning significantly improves predictive modeling performance for quantifying tumor cell density in glioblastoma.

Endovascular repair of popliteal artery aneurysms with Anaconda limbs: technique and early results.

OBJECTIVES: The objective is to report the feasibility and technique of treating popliteal artery aneurysms (PAA) with a stent made of nitinol rings externally supported by thin polyester (Anaconda limbs). BACKGROUND: PAA are the most common peripheral aneurysms. The main limitations of stents used in these settings are: short lengths, longitudinal and horizontal compliance mismatch; graft failure from angulation and movement at the joint level; and dislodgment. METHODS: This is a prospective multicenter cohort study of consecutive symptomatic and asymptomatic PAA treated in tertiary vascular centers. Outcomes included patency of the stent and postoperative time-to-independent-ambulation and to-climb-a-flight-of-stairs. RESULTS: Fourteen PAA were treated in 12 men, age 72 +/- 3 years. The median ASA classification was 2.5. The length of artery covered was 147 +/- 41 mm. The PAA diameter was 31 +/- 5 mm, 6 were symptomatic. One stent was used in 6 aneurysms, two in 7, and three in 1. The average stent diameter was 10 +/- 1 mm. The length of the proximal neck was 24 +/- 6 mm with a diameter of 9.8 +/- 1.9, and length of the distal neck 23 +/- 3 mm with a diameter of 8.7 +/- 1.2 mm. In 6 aneurysms, the stent crossed the knee joint. There was no mortality, and one stent occluded (primary patency 93% at 6 +/- 3 months). The median hospital stay was 1.7 days, time to independent ambulation was 3 hr and the time to climbing a flight of stairs was 1 day. CONCLUSIONS: The use of Anaconda limbs for endovascular repair of PAA is feasible and safe.

Carotid artery stenting: to be or not to be?

Carotid endarterectomy (CEA) has been the standard of care for suitable patients with symptomatic or asymptomatic high grade carotid stenosis since the landmark NASCET (North American Symptomatic Carotid Endarterectomy Trial), ECST (European Carotid Surgery Trial) and ACAS (Asymptomatic Carotid Artery Surgery) studies performed in the 1990s and more recently the ACST (Asymptomatic Carotid Surgery Trial). Carotid artery stenting (CAS) in the treatment of both symptomatic and asymptomatic patients with high grade carotid stenosis has recently been investigated as an alternative to CEA. We present a review of the most recent CAS trials and examine some of the controversies that surround them.

The contribution of pain in determining the health status of cancer patients with bone metastases: A secondary analysis of data from three Phase III registration trials.

BACKGROUND: We aimed to provide a simple, descriptive health-status profile for cancer patients with bone metastases, based on the EuroQol EQ-5D, a tool commonly used to measure health utility scores, and to evaluate its association with the Brief Pain Inventory (BPI), a legacy pain-assessment tool. Although pain is one of five health-status dimensions measured by the EQ-5D, our understanding of how pain relates to the other EQ-5D dimensions is limited. METHODS: We derived data from 5500 patients with bone metastases who completed the EQ-5D and BPI. Regression analyses examined how BPI severity and interference scores correlated with EQ-5D utility scores and how BPI items associated with EQ-5D items, for the entire sample and by disease-type subgroup. RESULTS: Regardless of cancer site, the percentage of patients reporting moderate/severe problems in each of the five EQ-5D dimensions were pain/discomfort, 78%; usual activities, 58%; mobility, 55%; anxiety/depression, 57%; and self-care, 26%. BPI pain interference explained more of the variability in the EQ-5D utility scores than did pain severity (R2  = 41% vs. 34%). BPI worst pain, average pain, pain now, interference with general activity, and interference with work significantly predicted EQ-5D pain/discomfort, with odds ratio estimates <1. CONCLUSIONS: Pain/discomfort was the worst-rated dimension of the EQ-5D in this population, but the relationship of this item to BPI pain severity was modest, suggesting that the single pain item of the EQ-5D may be of limited utility in studies for which pain is an endpoint. SIGNIFICANCE: Health-status dimensions include more than pain. We examine the contribution of pain severity and pain-related functional interference in determining the health status of cancer patients with bone metastases. The pain dimension from a health-status measure may be an inadequate metric in clinical trials/clinical practice when pain is an important outcome.

Multicenter phase 2 study of combination therapy with ruxolitinib and danazol in patients with myelofibrosis.

Myelofibrosis is a myeloproliferative neoplasm that is characterized by splenomegaly, profound symptom burden, and cytopenias. JAK inhibitor therapy offers improvements in splenomegaly, symptom burden, and potentially survival; however, cytopenias remain a significant challenge. Danazol has previously demonstrated improvements in myelofibrosis-associated anemia. We conducted a phase II clinical trial evaluating the efficacy and tolerability of combination therapy with ruxolitinib, an oral JAK inhibitor, and danazol. Fourteen intermediate or high-risk MF patients were enrolled at 2 institutions. Responses per IWG-MRT criteria were stable disease in 9 patients (64.2%) clinical improvement in 3 (21.4%) all of which were spleen responses, partial response in 1 (7.1%) and progressive disease in 1 (7.1%). Despite limited IWG-MRT response, stabilization of anemia and thrombocytopenia was demonstrated. In JAK inhibitor naïve patients, 4/5 (80%) had stable or increasing hemoglobin. Of the 9 patients on prior JAK inhibitor, 5 patients (55.5%) and 8 patients (88.9%) had stable or increasing hemoglobin or platelet levels, respectively. Adverse events possibly related included grade 3 or greater hematologic toxicity in ten patients (71.4%) and non-hematologic toxicity in two patients (14.3%). Although combination therapy did not lead to increased hematologic response per IWG-MRT criteria, hematologic stabilization was observed and may be clinically useful.

Prognostic significance of baseline fatigue for overall survival: A patient-level meta-analysis of 43 oncology clinical trials with 3915 patients.

We have previously identified a single-item measure for baseline overall quality of life (QOL) as a strong prognostic factor for survival, and that fatigue was an important component of patient QOL. To explore whether patient-reported fatigue was supplemental or redundant to the prognostic information of overall QOL, we performed a patient-level pooled analysis of 43 North Central Cancer Treatment Group (NCCTG) and Mayo Clinic Cancer Center (MCCC) oncology clinical trials assessing the effect of baseline fatigue on overall survival (OS). 3,915 patients participating in 43 trials provided data at baseline for fatigue on a single-item 0-100 point scale. OS was tested for association with clinically deficient fatigue (CDF, score 0-50, n = 1,497) versus not clinically deficient fatigue (nCDF, score 51-100, n = 2,418). We explored whether fatigue contributed to overall survival in the presence of performance status and overall QOL. We used Cox proportional hazards models that adjusted for the effects of overall QOL, performance score, race, disease site, age and gender. Baseline fatigue was a strong predictor of OS for the entire patient cohort (CDF vs. nCDF: 31.5 months vs > 83.9 months, p < 0.0001). The effect sizes of fatigue on survival were more variable across different disease sites than was seen for overall QOL (GI, esophageal, head and neck, prostate, lung, breast and others). After controlling for covariates, including performance status and overall QOL, baseline fatigue remained a strong prognostic factor in multivariate models (CDF vs. nCDF: HR = 1.23, p = 0.02). Baseline fatigue is a strong and independent prognostic factor for OS over and above performance status (PS) and overall QOL in a wide variety of oncology patient populations. Single-item measures of overall QOL and fatigue can help to identify vulnerable subpopulations among cancer patients. We recommend these single-item measures for routine inclusion as a stratification factor or key covariate in the design and analysis of oncology treatment trials.

Optimization of DSC MRI Echo Times for CBV Measurements Using Error Analysis in a Pilot Study of High-Grade Gliomas.

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 < .001). 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).

The relationship among gastroparetic symptoms, quality of life, and gastric emptying in patients referred for gastric emptying testing.

BACKGROUND: 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. METHODS: 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. KEY RESULTS: 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. CONCLUSIONS & INFERENCES: 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.

Psychological distress in Rome III functional dyspepsia patients presenting for testing of 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.