Bortezomib-based therapy for relapsed/refractory multiple myeloma in real-world medical practice.

OBJECTIVE: The efficacy and safety of bortezomib-based therapy for relapsed/refractory multiple myeloma (RRMM) in clinical trials may differ from the oncology practice experience. The electronic VELCADE® OBservational Study was designed to prospectively evaluate bortezomib for multiple myeloma (MM) in real-world medical practice. METHOD: Patients scheduled to receive intravenous bortezomib for MM were eligible. The primary objective was to evaluate clinical outcomes, including response, time to response, time to next therapy, treatment-free interval, progression-free survival (PFS), and overall survival (OS). Secondary objectives included safety and healthcare resource utilization. RESULTS: In total, 873 patients with a median of two therapy lines prior to initiating bortezomib were included. The overall response rate (≥partial response) was 69%, including 37% complete response/near-complete response. Median time to response was 1.8 months, median time to next therapy was 9.7 months, and median treatment-free interval was 7.9 months. After 22.6 months' median follow-up, median PFS was 12.0 months and median OS was 36.1 months. The most common adverse events (AEs) were neuropathy not otherwise specified (19%), diarrhea NOS, and thrombocytopenia (each 17%); 230 (26%) patients discontinued bortezomib due to AEs. Of 689 (79%) patients without baseline peripheral neuropathy (PN), the rate of new-onset any-grade PN increased to 51% (12% grade 3/4) by cycle 8. Overall, 244 (28%) patients were hospitalized, 372 (43%) attended an outpatient visit, and 341 (39%) underwent a diagnostic/therapeutic procedure during bortezomib treatment. CONCLUSION: These prospective real-world data demonstrate the effectiveness and safety of bortezomib-based therapy for RRMM and confirm high response rates and long OS for this population.

Economic burden of relapsed or refractory multiple myeloma: Results from an international trial.

OBJECTIVE: The direct cost of relapsed or refractory multiple myeloma (RRMM) is documented; indirect costs are being explored. Healthcare payers seek cost-offsets from therapies that improve clinical outcomes but challenge budgets; employers seek lower absenteeism and better productivity. Study goals were to: (i) identify direct and indirect economic factors of RRMM, and (ii) explore longitudinal relationships between clinical, economic, and health-related quality of life (HRQoL) assessments. METHODS: Economic questionnaire, clinical, and HRQoL data from a multisite, international, randomized, controlled study in RRMM were analyzed. RESULTS: Patients (n=263) were 53.6% male, 91.6% Caucasian; mean age of 62.9 years, median Eastern Cooperative Oncology Group status of 1 (56.3%). Moderate to severe pain or fatigue was reported by 30.4% and 70.6%, respectively. At baseline, ≥1 hospitalization was reported by 107 (41.8%); 182 (71.1%) and 86 (33.6%) reported specialist and family physician visits, respectively. A total of 28 (10.8%) were working: 10 (37.0%) of which reported RRMM-driven absenteeism ≥1 day. Of those who were not working, 110 (48.2%) indicated that it was due to RRMM. Multivariate modeling showed lower hospitalization with a major tumor response (ß=-1.44, CI: -2.89 to 0.01, P=.05). CONCLUSIONS: Substantial RRMM indirect, social costs were observed. Better major tumor response may reduce hospital visits.

The influence of baseline characteristics and disease stage on health-related quality of life in multiple myeloma: findings from six randomized controlled trials.

This descriptive, cross-sectional analysis evaluated the impact of baseline characteristics on health-related quality of life (HR-QoL) at different stages of multiple myeloma (MM). The bortezomib clinical-trial programme evaluated HR-QoL early and consistently, producing a large multi-study dataset. Baseline data, captured using the European Organization for Research and Treatment of Cancer (EORTC) quality-of-life questionnaire (QLQ-C30), were pooled from six bortezomib randomized trials conducted in different disease-stage categories: 'New' (previously untreated; n = 753), 'Early' (1-3 prior therapies; n = 1569) and 'Late' (≥4 prior therapies; n = 239) disease. Mean EORTC global health scores were similar across the three stages. Unexpectedly, emotional, physical and role functioning were higher in the later stages, indicating better perceived health. Symptom scores, including pain, were largely similar or lower in the later versus earlier stages, signifying a lower symptom burden/better symptom control with more advanced disease. Notable variation in HR-QoL was observed by age and clinical parameters within and across stages. Multivariate modelling indicated that opioid use and performance status were key factors driving overall HR-QoL across stages. Using an age-restricted analysis, transplant eligibility had little impact on HR-QoL in New disease patients. Thus, changes in HR-QoL over the treatment course of MM are complex and impacted by baseline factors. A prospective observational international inception cohort study that captures key clinical, HR-QoL and demographic characteristics, along with safety and supportive care information, is needed.

Clinical characteristics and healthcare utilization of patients with multicentric Castleman disease.

Multicentric Castleman disease (MCD) is a rare lymphoproliferative disease. Little is known about how patient clinical features and healthcare utilization varies by human immunodeficiency virus (HIV) status and disease subtype. Data of MCD patients identified between 2000 and 2009 were collected from medical records at two United States treatment centres. Clinical, demographic, and biochemical characteristics, drug therapies and medical utilization were descriptively reported by HIV status and cell histology, and statistically compared with the Fisher's Exact and Kruskal-Wallis tests. Patients (n = 59) had a pathologically and clinically confirmed MCD diagnosis: plasmacytic (42%), hyaline vascular (29%) and mixed (15%); 10% had HIV infection. In the first year after diagnosis, MCD patients on average saw a healthcare provider more than six times, were hospitalized at least once and underwent frequent radiological and laboratory testing. Rituximab was the most commonly used drug therapy, followed by corticosteroids and conventional chemotherapy. One- and 2-year survival was excellent in HIV-negative patients (100% and 97%, respectively) but inferior for HIV-positive cases (67% and 67%, respectively). Heterogeneous treatment decisions were observed in this MCD study; HIV status was the only distinguishing clinical criteria associated with pharmacotherapies. Additional research is necessary to guide treatment of this rare lymphoproliferative disorder.

Bortezomib, thalidomide and dexamethasone, with or without cyclophosphamide, for patients with previously untreated multiple myeloma: 5-year follow-up.

This follow-up extension of a randomised phase II study assessed differences in long-term outcomes between bortezomib-thalidomide-dexamethasone (VTD) and VTD-cyclophosphamide (VTDC) induction therapy in multiple myeloma. Newly diagnosed patients (n = 98) were randomised 1:1 to intravenous bortezomib (1·3 mg/m(2); days 1, 4, 8, 11), thalidomide (100 mg; days 1-21), and dexamethasone (40 mg; days 1-4, 9-12), with/without cyclophosphamide (400 mg/m(2); days 1, 8), for four 21-day cycles before stem-cell mobilisation/transplantation. After a median follow-up of 64·8 months, median time-to-next therapy was 51·8 and 47·9 months with VTD and VTDC, respectively. Type of subsequent therapy was similar in both arms. After adjusting for asymmetric censoring, median time to progression was not significantly different between VTD and VTDC [35·7 vs. 34·5 months; Hazard ratio (HR) 1·26, 95% confidence interval: 0·76-2·09; P = 0·370]. Five-year survival was 69·1% and 65·3% with VTD and VTDC, respectively. When analysed by minimal residual disease (MRD) status, overall survival was longer in MRD-negative versus MRD-positive patients with bone marrow-confirmed complete response (HR 3·66, P = 0·0318). VTD induction followed by transplantation provides long-term disease control and, consistent with the primary analysis, there is no additional benefit from adding cyclophosphamide. This study was registered at ClinicalTrials.gov (NCT00531453).

Clinical epidemiology and treatment patterns of patients with multicentric Castleman disease: results from two US treatment centres.

Multicentric Castleman disease (MCD) is a rare lymphoproliferative disease with little known about its epidemiology or treatment modalities. Clinical and demographic data of MCD patients identified between 2000 and 2009 were collected from medical records at two United States (US) MCD referral centres. ZIP codes identified patient residences; prevalence and incidence were estimated based on catchment areas. Patient clinical, demographic, and biochemical characteristics, drug therapies and medical utilization were descriptively reported. MCD patients (n = 59) were 61% male, mean age of 53 years (median = 55 years) and 68% Caucasian. Of those with known human immunodeficiency virus (HIV) status (n = 41), 85% (n = 35) were negative, 15% (n = 6) were positive. Most frequent physician-reported symptoms (n = 33) were fatigue (49%, n = 16), fever (39%, n = 13), and night sweats (30%, n = 10). The estimated US 10-year prevalence was 2·4 per million. During first year of follow-up after study entry, the top two systemic therapies (n = 27) were monotherapies: prednisone (33%, n = 9) and rituximab (19%, n = 5). After a follow-up of 2 years, 92% of patients were alive. This study provides new information on MCD population demographics, treatment patterns, and medical utilization; a minimal US period prevalence rate is proposed. Study replication is needed to improve external validity.

Health-related quality of life in elderly, newly diagnosed multiple myeloma patients treated with VMP vs. MP: results from the VISTA trial.

OBJECTIVES: The phase 3 VISTA study (ClinicalTrials.gov NCT00111319) in transplant-ineligible myeloma patients demonstrated superior efficacy with bortezomib-melphalan-prednisone (VMP; nine 6-wk cycles) vs. melphalan-prednisone (MP) but also increased toxicity. Health-related quality of life (HRQoL; exploratory endpoint) was evaluated using the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ-C30). The phase 3 VISTA study (ClinicalTrials.gov NCT00111319) in transplant-ineligible myeloma patients demonstrated superior efficacy with bortezomib-melphalan-prednisone (VMP; nine 6-wk cycles) vs. melphalan-prednisone (MP) but also increased toxicity. Health-related quality of life (HRQoL; exploratory endpoint) was evaluated using the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ-C30). METHODS: EORTC QLQ-C30 was administered at screening, on day 1 of each cycle, at the end-of-treatment visit, and every 8 wk until progression. EORTC QLQ-C30 scores were evaluated among patients with a valid baseline and at least one post-baseline HRQoL assessment. RESULTS: At baseline, domain scores were similar between arms. By cycle 4, mean differences were clinically meaningful for most domains, indicating poorer health status with VMP. From cycle 5 onwards, improvements relative to baseline/MP were observed for all domains with VMP. Mean scores were generally improved by the end-of-treatment assessment vs. baseline in both arms. Among responding patients, mean scores generally improved from time of response to end-of-treatment assessment, substantially driven by patients achieving complete response (CR). Multivariate analysis showed a significant impact of duration of response/CR on improving global health status, pain, and appetite loss scores. Analyses by bortezomib dose intensity indicated better HRQoL in patients receiving lower dose intensity. CONCLUSIONS: These findings demonstrate clinically meaningful, transitory HRQoL decrements with VMP and relatively lower HRQoL vs. MP during early treatment cycles, associated with the expected additional toxicities. However, HRQoL is not compromised in the long term, recovering by the end-of-treatment visit to be comparable vs. MP.

An artificial neural network (ANN)-based lung-tumor motion predictor for intrafractional MR tumor tracking.

PURPOSE: To address practical issues of implementing artificial neural networks (ANN) for lung-tumor motion prediction in MRI-based intrafractional lung-tumor tracking. METHODS: A feedforward four-layered ANN structure is used to predict future tumor positions. A back-propagation algorithm is used for ANN learning. Adaptive learning is incorporated by continuously updating weights and learning rate during prediction. An ANN training scheme specific for MRI-based tracking is developed. A multiple-ANN structure is developed to reduce tracking failures caused by the lower imaging rates of MRI. We used particle swarm optimization to optimize the ANN structure and initial weights (IW) for each patient and treatment fraction. Prediction accuracy is evaluated using the 1D superior-inferior lung-tumor motions of 29 lung cancer patients for system delays of 120-520 ms, in increments of 80 ms. The result is compared with four different scenarios: (1), (2) ANN structure optimization + with∕without IW optimization, and (3), (4) no ANN structure optimization + with∕without IW optimization, respectively. An additional simulation is performed to assess the value of optimizing the ANN structure for each treatment fraction. RESULTS: For 120-520 ms system delays, mean RMSE values (ranges 0.0-2.8 mm from 29 patients) of 0.5-0.9 mm are observed, respectively. Using patient specific ANN structures, a 30%-60% decrease in mean RMSE values is observed as a result of IW optimization, alone. No significant advantages in prediction performance are observed, however, by optimizing for each fraction. CONCLUSIONS: A new ANN-based lung-tumor motion predictor is developed for MRI-based intrafractional tumor tracking. The prediction accuracy of our predictor is evaluated using a realistic simulated MR imaging rate and system delays. For 120-520 ms system delays, mean RMSE values of 0.5-0.9 mm (ranges 0.0-2.8 mm from 29 patients) are achieved. Further, the advantage of patient specific ANN structure and IW in lung-tumor motion prediction is demonstrated by a 30%-60% decrease in mean RMSE values.

Evaluation of a lung tumor autocontouring algorithm for intrafractional tumor tracking using low-field MRI: a phantom study.

PURPOSE: The first aim of this study is to investigate the feasibility of online autocontouring of tumor in low field MR images (0.2 and 0.5 T) by means of a phantom and simulation study for tumor-tracking in linac-MR systems. The second aim of this study is to develop an MR compatible, lung tumor motion phantom. METHODS: An autocontouring algorithm was developed to determine both the position and shape of a lung tumor from each intra fractional MR image. To initiate the algorithm, an expert user contours the tumor and its maximum anticipated range of motion (herein termed the Background) using pretreatment scan data. During treatment, the algorithm processes each intrafractional MR image and automatically contours the tumor. To evaluate this algorithm, the authors built a phantom that replicates the low field contrast parameters (proton density, T(1), T(2)) of lung tumors and healthy lung parenchyma. This phantom allows simulation of MR images with the expected lung tumor CNR at 0.2 and 0.5 T by using a single 3 T scanner. Dynamic bSSFP images (approximately 4 images per second) are acquired while the phantom undergoes a series of preprogrammed motions based on patient lung tumor motion data. These images are autocontoured off-line using our algorithm. The fidelity of autocontouring is assessed by comparing autocontoured tumor shape and its centroid position to the actual tumor shape and its position. RESULTS: The algorithm successfully contoured the shape of a moving tumor model from dynamic MR images acquired every 275 ms. Dice's coefficients of > 0.96 and > 0.93 are achieved in 0.5 and 0.2 T equivalent images, respectively. Also, the algorithm tracked tumor position during dynamic studies, with root mean squared error (RMSE) values of < 0.55 and < 0.92 mm for 0.5 and 0.2 T equivalent images, respectively. Autocontouring speed is approximately 5 ms for each image. CONCLUSIONS: Dice's coefficients of > 0.96 and > 0.93 are achieved between autocontoured and real tumor shapes, and the position of a tumor can be tracked with RMSE values of < 0.55 and < 0.92 mm in 0.5 and 0.2 T equivalent images, respectively. These results demonstrate the feasibility of lung tumor autocontouring in low field MR images, and, by extension, intrafractional lung tumor tracking with our laboratory's linac-MR system.

An evaluation of the Clarity 3D ultrasound system for prostate localization.

The purpose of this study is to evaluate the accuracy and precision of the Clarity 3D ultrasound system to track prostate gland positional variations due to setup error and organ motion. Seventeen patients (n = 17) undergoing radical external beam radiation therapy for localized prostate cancer were studied. Subsequent to initial reference ultrasound and planning CT scans, each patient underwent seven repeat weekly tracking CT and ultrasound (US) scans during the course of treatment. Variations in the location of the prostate between reference and tracking scans were measured. Differences reported by CT and ultrasound scans are compared. Ultrasound tracking was initially performed clinically by a group of trained general users. Retrospective prostate localization was then performed by a trained dedicated user upon the original raw data set and also a reduced data set derived from the original by an expert user from Resonant Medical. Correlation accuracy between ultrasound and CT shifts acquired and delineated by a pool of trained general users was deemed unacceptable for radiotherapy purposes. A mean discrepancy between CT and US localizations of greater than 10 mm, with a 5 mm or greater discrepancy rate of nearly 90%, was observed. Retrospective analysis by a dedicated user of both the original and Resonant Medical reduced data sets yielded mean CT-Us discrepancies of 8.7 mm and 7.4 mm, respectively. Unfortunately, the 5 mm or greater CT-US discord rate for these retrospective analyses failed to drop below 80%. The greatest disparity between CT and ultrasound was consistently observed in the superior-inferior direction, while greatest agreement was achieved in the lateral dimension. Despite an expert reanalysis of the original data, the Clarity ultrasound system failed to deliver an acceptable level of geometric accuracy required for modern radiotherapy purposes.

Rapid Standardized CT-Based Method to Determine Lean Body Mass SUV for PET-A Significant Improvement Over Prediction Equations.

In 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET) studies, maximum standardized uptake value (SUVmax) is the parameter commonly used to provide a measurement of the metabolic activity of a tumor. SUV normalized by body mass is affected by the proportions of body fat and lean tissue, which present high variability in patients with cancer. SUV corrected by lean body mass (LBM), denoted as SUL, is recommended to provide more accurate, consistent, and reproducible SUV results; however, LBM is frequently estimated rather than measured. Given the increasing importance of a quantitative PET parameter, especially when comparing PET studies over time to evaluate disease response clinically, and its use in oncological clinical trials, we set out to evaluate the commonly used equations originally derived by James (1976) and Janmahasatian et al. (2005) against computerized tomography (CT)-derived measures of LBM. Methods: Whole-body 18F-FDG PET images of 195 adult patients with cancer were analyzed retrospectively. Representative liver SUVmean was normalized by total body mass. SUL was calculated using a quantitative determination of LBM based on the CT component of the PET/CT study (LBMCT) and compared against the equation-estimated SUL. Bland and Altman plots were generated for SUV-SUL differences. Results: This consecutive sample of patients undergoing usual care (men, n = 96; women, n = 99) varied in body mass (38-127 kg) and in Body Mass Index (BMI) (14.7-47.2 kg/m2). LBMCT weakly correlated with body mass (men, r2 = 0.32; women, r2 = 0.22), and thus SUV and SULCT were also weakly correlated (men, r2 = 0.24; women, r2 = 0.11). Equations proved inadequate for the assessment of LBM. LBM estimated by James' equation showed a mean bias (overestimation of LBM compared with LBMCT) in men (+6.13 kg; 95% CI 4.61-7.65) and in women (+6.32 kg; 95% CI 5.26-7.39). Janmahasatian's equation provided similarly poor performance. Conclusions: CT-based LBM determinations incorporate the patient's current body composition at the time of a PET/CT study, and the information garnered can provide care teams with information with which to more accurately determine FDG uptake values, allowing comparability over multiple scans and treatment courses and will provide a robust basis for the use of PET Response Criteria in Solid Tumors (PERCIST) in clinical trials.

Determination of Ir-192 micrselectron-V2 HDR/PDR dwell position reproducibility using a slit camera.

PURPOSE: To examine the limits of dwell position reproducibility of an ELEKTA microSelectron-V2 HDR/PDR remote afterloader. METHODS AND MATERIALS: The variability in source dwell position of an ELEKTA Microselectron mHDR - V2 HDR/PDR Microselectron was assessed using a slit camera. 100 consecutive extensions each of the source were made to positions of 1200 mm and 1470 mm and the variations in dwell position were observed. RESULTS: Maximum deviations of 0.4 mm from the median dwell position were observed. 72% of all deviations from median dwell position were 0.15 mm or less while 96% were no greater than 0.3 mm. CONCLUSION: Guide wire flexibility makes buckling over the length of source extension an unavoidable reality which, in turn, produces variability in the dwell position achieved. Fortunately these deviations in source dwell position are small and may be compensated for using margins along the dose distribution length.

Association between patient unconscious or not alert conditions and cardiac arrest or high-acuity outcomes within the Medical Priority Dispatch System "Falls" protocol.

INTRODUCTION: Falls are one of the most common types of complaints received by 9-1-1 emergency medical dispatch centers. They can be accidental or may be caused by underlying medical problems. Though "not alert" falls patients with severe outcomes mostly are "hot" transported to the hospital, some of these cases may be due to other acute medical events (cardiac, respiratory, circulatory, or neurological), which may not always be apparent to the emergency medical dispatcher (EMD) during call processing. OBJECTIVES: The objective of this study was to characterize the risk of cardiac arrest and "hot-transport" outcomes in patients with "not alert" condition, within the Medical Priority Dispatch System (MPDS®) Falls protocol descriptors. METHODS: This retrospective study used 129 months of de-identified, aggregate, dispatch datasets from three US emergency communication centers. The communication centers used the Medical Priority Dispatch System version 11.3-OMEGA type (released in 2006) to interrogate Emergency Medical System callers, select dispatch codes assigned to various response configurations, and provide pre-arrival instructions. The distribution of cases and percentages of cardiac arrest and hot-transport outcomes, categorized by MPDS® code, was profiled. Assessment of the association between MPDS® Delta-level 3 (D-3) "not alert" condition and cardiac arrest and hot-transport outcomes then followed. RESULTS: Overall, patients within the D-3 and D-2 "long fall" conditions had the highest proportions (compared to the other determinants in the "falls" protocol) of cardiac arrest and hot-transport outcomes, respectively. "Not alert" condition was associated significantly with cardiac arrest and hot-transport outcomes (p<0.001). CONCLUSIONS: The "not alert" determinant within the MPDS® "fall" protocol was associated significantly with severe outcomes for short falls (<6 feet; 2 meters) and ground-level falls. As reported to 9-1-1, the complaint of a "fall" may include the presence of underlying conditions that go beyond the obvious traumatic injuries caused by the fall itself.

The burden of autoimmune disease: a comparison of prevalence ratios in patients with psoriatic arthritis and psoriasis.

BACKGROUND: Current research has confirmed that many inflammatory autoimmune (AI) diseases are due to derangements in multiple cytokine pathways. Some of these cytokines appear to play comparable key roles across diseases, suggesting that a similar underlying systemic inflammatory cascade could be responsible for various disease states. A recent study supports the hypothesis of a common cytokine-based pathology by showing that having one AI disease significantly increased the risk of having another AI disease. Psoriasis is an AI, manifesting as a chronic inflammatory skin condition and is clearly associated with other conditions, most obviously psoriatic arthritis (PsA). OBJECTIVE: We sought to examine whether patients with PsA enrolled in managed health care plans carry a higher AI disease burden than patients with cutaneous psoriasis only (PsO). METHODS: Patients 18 years or older enrolled in a health claims database were classified by two clinical subtypes: PsA and PsO. Control subjects were matched 3:1 to patients with psoriasis on age, sex, census region, and length of previous medical insurance coverage. AI disease diagnoses were identified through International Classification of Diseases, Ninth Revision codes. The association of other AI diseases with each psoriasis cohort was assessed using a prevalence ratio. RESULTS: PsO was associated with a higher prevalence ratio for the 3 gastrointestinal diseases: Crohn disease (1.6 [confidence interval {CI} 1.4-2.0]), ulcerative colitis (1.3 [CI 1.1-1.6]), and inflammatory bowel disease (1.4 [CI 1.2-1.6]). PsA was also associated with a higher prevalence ratio for the gastrointestinal diseases: Crohn disease (2.1 [CI 1.3-3.3]), ulcerative colitis (2.0 [CI 1.3-3.1]), and inflammatory bowel disease (1.8 [CI 1.3-2.5]). Patients with PsA had an increased prevalence ratio associated with giant cell arteritis (4.8 [CI 1.5-15.7]) and pulmonary fibrosis (1.9 [CI 1.2-3.0]). LIMITATIONS: Detection and misclassification biases may have affected these findings. CONCLUSIONS: These findings support the hypothesis that PsA and PsO are associated with development of other AI diseases. The data suggest that evaluating patients with psoriasis for other associated disorders in a prospective manner may be important, because they may be more likely to experience the onset of another AI disease. Treatment planning for these patients could, therefore, require the medical management of more than one AI disease. Further, our data suggest that PsA and PsO may be divergent in ways previously not described that could inform future research.

Bortezomib retreatment for relapsed and refractory multiple myeloma in real-world clinical practice.

AIMS: Studies have shown that bortezomib retreatment is effective in relapsed/refractory multiple myeloma (MM). The observational, prospective electronic VELCADE® OBservational Study (eVOBS) study assessed bortezomib-based therapies for patients with MM in everyday practice. Here, we report on those patients receiving retreatment with bortezomib. METHODS: Consenting adults scheduled to receive bortezomib for MM were enrolled at 162 sites across Europe, Canada, Brazil, Russia, and Turkey between 2006 and 2010. Retrospective data on prior therapies and prospective observational data after bortezomib initiation were captured electronically at baseline, after every bortezomib cycle, and every 12 weeks after discontinuation or progression. Investigator-assessed responses and adverse events (AEs) were evaluated. RESULTS: Ninety-six of 873 patients enrolled to eVOBS received bortezomib as first retreatment for progressive disease during the prospective observation period. Median age was 62 years, 53% were male, and median number of prior therapies at retreatment was 4. Overall, 41% of patients initiated bortezomib retreatment in combination with dexamethasone, 16% in combination with lenalidomide, and 21% received monotherapy. Rate of partial response or better (≥PR) was 75% at initial bortezomib therapy, including 44% complete response (CR)/near CR (nCR); at retreatment, ≥PR rate was 46%, including 15% CR/nCR. Median progression-free survival was 11.4 months (95% confidence interval [CI]: 9.1-12.7) from start of initial bortezomib treatment and 6.4 months (95% CI: 4.4-7.2) from start of retreatment. Median overall survival from start of retreatment was 17.6 months (95% CI: 14.4-23.5). Of the 96 patients retreated with bortezomib, 77% reported an AE. Peripheral neuropathy during bortezomib retreatment occurred in 49% of patients, including 10% grade 3/4. CONCLUSION: These data suggest that retreatment with bortezomib is a feasible option for patients with relapsed/refractory MM.

Autoimmune disease concomitance among inflammatory bowel disease patients in the United States, 2001-2002.

BACKGROUND: Recent studies suggest that inflammatory bowel disease (IBD) may share an underlying pathogenesis with other autoimmune diseases. METHODS: Two United States data sets with patient-level medical and drug claims were used to explore the occurrence of autoimmune diseases in patients with IBD, particularly Crohn's disease (CD) and ulcerative colitis (UC), with that in controls. From 2001 to 2002 IBD patients were identified using International Classification of Diseases, 9th revision, diagnosis codes in the IMS Health Integrated Administration Claims Database and the Market Scan Commercial Claims and Encounters Database. Controls were selected by matching on sex, age, Census Bureau region, and length of previous medical insurance coverage. Odds ratios (ORs) evaluated the risk relationship between IBD patients and controls within an estimated Mantel-Haenszel 95% confidence interval. Sensitivity analysis tested the case identification method used to select IBD patients. RESULTS: The risk for ankylosing spondylitis (AS) was substantially increased across both data sets: OR (95% confidence interval [CI]) of 7.8 (5.6-10.8) in IMS Health and 5.8 (3.9-8.6) in MarketScan. The risk for rheumatoid arthritis (RA) was 2.7 (2.4-3.0) and 2.1 (1.8-2.3), respectively; for multiple sclerosis (MS); the ORs were 1.5 (1.2-1.9) and 1.6 (1.2-2.1), respectively. There was no increased risk for type 1 diabetes mellitus, and the results for psoriatic arthritis (PsA) were inconsistent. The sensitivity analysis supported these findings. CONCLUSIONS: A much higher risk for RA, AS, PsA, and MS was observed in IBD patients compared with controls. Prospective epidemiologic studies are needed to confirm these findings and explore the pathogenic mechanism of this relationship.

A multicenter, phase II study of infliximab plus gemcitabine in pancreatic cancer cachexia.

To evaluate the safety and efficacy of infliximab administered with gemcitabine to treat cancer cachexia and to explore a functional measure of clinical benefit, investigators involved in this multicenter, phase II, placebo-controlled study randomized 89 patients with stage II-IV pancreatic cancer and cachexia to receive either placebo or 3 mg/ kg or 5 mg/kg of infliximab at weeks 0, 2, and 4 and then every 4 weeks to week 24; patients also received 1,000 mg/m2 of gemcitabine weekly from weeks 0-6 and then for 3 of every 4 weeks until their disease progressed. The primary endpoint was change in lean body mass (LBM) at 8 weeks from baseline; major secondary endpoints included overall survival, progression-free survival, Karnofsky performance status, and 6-minute walk test distance. In addition, quality of life was measured. The mean change in LBM at 8 weeks was +0.4 kg for patients receiving placebo, +0.3 kg for those receiving 3 mg/kg of infliximab, and +1.7 kg for those receiving 5 mg/kg of infliximab. No statistically significant differences in LBM or secondary endpoints were observed among the groups. Safety findings were similar in all groups. Adding infliximab to gemcitabine to treat cachexia in advanced pancreatic cancer patients was not associated with statistically significant differences in safety or efficacy when compared with placebo.

Inhomogeneity correction and the analytic anisotropic algorithm.

The ability of the analytic anisotropic algorithm (AAA), a superposition- convolution algorithm implemented in the Eclipse (Varian Medical Systems, Palo Alto, CA) treatment planning system (TPS), to accurately account for the presence of inhomogeneities in simple geometries is examined. The goal of 2% accuracy, as set out by the American Association of Physicists in Medicine Task Group 65, serves as a useful benchmark against which to evaluate the inhomogeneity correction capabilities of this treatment planning algorithm. A planar geometry phantom consisting of upper and lower layers of Solid Water (Gammex rmi, Middleton, WI) separated by a heterogeneity region of variable thickness, is modeled within the Eclipse TPS. Results obtained with the AAA are compared with experimental measurements. Seven different materials, spanning the range from air to aluminum, constitute the inhomogeneity layer. In general, the AAA overpredicts dose beyond low-density regions and underpredicts dose distal to volumes of high density. In many cases, the deviation between the AAA and experimental results exceeds the Task Group 65 target of 2%. The source of these deviations appears to arise from an inability of the AAA to correctly account for altered attenuation along primary ray paths.

Iterative threshold segmentation for PET target volume delineation.

The purpose of this work is to create a rigorous method of segmenting PET images using an automated iterative technique. To this end a phantom study employing spherical targets was used to determine local (slice specific) threshold levels which produce correct cross-sections based on the contrast between target and background. Numerous target to background activity concentration ratios were investigated but found to have minimal effect in comparison to the influence of target size. Functions were fit to this data and used to construct an iterative threshold segmentation algorithm. In all cases this approach yielded convergence within ten iterations. Iterative threshold segmentation was applied using both an axial and tri-axial approach to the spherical targets and also to two irregularly shaped volumes. Of these two approaches, the tri-axial method proved less susceptible to image noise and better at dealing with partial volume effects at the interface between target and background. For comparative purposes, single thresholds of 28% and 40% were also applied to the spherical data sets. The tri-axial iterative method was found capable of delineating cross sections with areas greater than 250 mm2 to within the maximum resolution possible (1 pixel width). Cross sections of less than 250 mm2 in area were resolved by the tri-axial method to within 2 pixel widths of their true physical extent. Local contrast based iterative threshold segmentation shows promise as a method of rigorously delineating PET target volumes with good accuracy subject to the limitations imposed by the image resolution which currently characterizes this modality.

Symptom burden among patients with renal cell carcinoma (RCC): content for a symptom index.

BACKGROUND: Renal cell carcinoma (RCC) has multiple symptoms stemming from disease and treatments. There are few validated scales for evaluating RCC symptoms. METHODS: A national cross-sectional study of adult RCC patients was conducted from October to December 2003 to define patient-reported RCC symptomology. Participants were asked open-ended questions regarding their signs and symptoms and completed an 86-item pilot questionnaire of physical and psychological symptoms. Patients were asked to rate the relevancy and clarity of each pilot question using a 5-point Likert scale. Subsequent open-ended caregiver interviews and a provider panel relevance ranking contributed additional information. RESULTS: The average age of the participants (n = 31) was 55 years; 55% of patients were male, 74% had attended college, and 97% were Caucasian. The five most frequent symptoms among localized-stage patients (n = 14) were irritability (79%), pain (71%), fatigue (71%), worry (71%), and sleep disturbance (64%). Among metastatic patients (n = 17), the five most frequent symptoms were fatigue (82%), weakness (65%), worry (65%), shortness of breath (53%), and irritability (53%). More than 50% of localized and metastatic-stage patients reported pain, weakness, fatigue, sleep disturbance, urinary frequency, worry, and mood disorders as being moderately to highly relevant. CONCLUSION: A brief, self-administered RCC Symptom Index was created that captures the relevant signs and symptoms of both localized and metastatic patients. Pending additional content validation, the Index can be used to assess the signs and symptoms of RCC and the clinical benefit resulting from RCC treatment.