A validated gene expression model of high-risk multiple myeloma is defined by deregulated expression of genes mapping to chromosome 1.

To molecularly define high-risk disease, we performed microarray analysis on tumor cells from 532 newly diagnosed patients with multiple myeloma (MM) treated on 2 separate protocols. Using log-rank tests of expression quartiles, 70 genes, 30% mapping to chromosome 1 (P < .001), were linked to early disease-related death. Importantly, most up-regulated genes mapped to chromosome 1q, and down-regulated genes mapped to chromosome 1p. The ratio of mean expression levels of up-regulated to down-regulated genes defined a high-risk score present in 13% of patients with shorter durations of complete remission, event-free survival, and overall survival (training set: hazard ratio [HR], 5.16; P < .001; test cohort: HR, 4.75; P < .001). The high-risk score also was an independent predictor of outcome endpoints in multivariate analysis (P < .001) that included the International Staging System and high-risk translocations. In a comparison of paired baseline and relapse samples, the high-risk score frequency rose to 76% at relapse and predicted short postrelapse survival (P < .05). Multivariate discriminant analysis revealed that a 17-gene subset could predict outcome as well as the 70-gene model. Our data suggest that altered transcriptional regulation of genes mapping to chromosome 1 may contribute to disease progression, and that expression profiling can be used to identify high-risk disease and guide therapeutic interventions.

Clinical presentation of delirium in patients undergoing hematopoietic stem cell transplantation.

BACKGROUND: Delirium is common in patients undergoing hematopoietic stem cell transplantation (HSCT) and is associated with considerable morbidity and excess mortality in diverse patient samples. Although delirium can be treated successfully, it is largely undiagnosed. Understanding the clinical presentation of delirium may help improve the recognition of delirium in these patients. In the current study, the authors investigated the clinical presentation of delirium in HSCT patients, including the time course of these symptoms and comorbid affective distress, fatigue, and pain. METHODS: Ninety patients ages 22-62 years were recruited prior to undergoing their first allogeneic or autologous HSCT. Delirium, distress, and pain symptom assessments were conducted prospectively 3 times per week from pretransplantation through Day 30 posttransplantation. RESULTS: Delirium episodes occurred in 50% of patients and lasted approximately 10 days, with peak severity at the end of the second week posttransplantation. Factor analysis revealed three groups of delirium symptoms representing psychosis-behavior, cognition, and mood-consciousness. Delirium episodes were characterized by rapid onset of psychomotor and sleep-wake cycle disturbance that persisted and cognitive symptoms that continued to worsen throughout much of the episode. Rises in psychosis-behavior and cognitive symptoms predated the start of delirium episodes by approximately 4 days. Affective distress and fatigue were common and appeared to be associated most with psychosis-behavioral delirium symptoms. CONCLUSIONS: The results describe in detail the clinical presentation of delirium in patients undergoing HSCT. Affective distress and fatigue commonly were associated with delirium. These findings may aid clinicians in improving the recognition and treatment of delirium in this population and avoiding further morbidity and potential mortality.

Psychiatric illness after mild traumatic brain injury in children.

OBJECTIVE: To determine the incidence of psychiatric illness 3 years after mild traumatic brain injury (TBI) in children. DESIGN: Prospective cohort study with 3-year follow-up. SETTING: Emergency department, hospital, and outpatient clinics in a large health maintenance organization. PARTICIPANTS: Children, 14 years old or less (n=490), who sustained a mild TBI in 1993. Three TBI unexposed subjects per TBI exposed patient were matched by sex, age, and enrollment at the time of injury (n=1470). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Computerized records were examined to identify psychiatric diagnoses, psychiatric medication prescription, and utilization of psychiatric services for the year before TBI and 3 years after. Adjusted relative risks for incidence of psychiatric illness were estimated for those with and without a premorbid psychiatric disorder. RESULTS: The cumulative incidence estimates for any psychiatric illness in the 3 years after mild TBI were 30% in children exposed to mild TBI and 20% in unexposed children (P=.0001). Cumulative incidence estimates were particularly high in both TBI exposed (55%) and unexposed children (63%) who had psychiatric illness in the year before the index TBI (psychiatric history). The exposed and unexposed children with psychiatric history did not have significantly different estimates of incidence during follow-up for any of the studied indicators of psychiatric illness. In those with no psychiatric history, 26% of exposed and 16% of unexposed children (P<.0001) had evidence of a psychiatric illness in the 3 years after mild TBI. For those with no psychiatric history, the adjusted relative risk estimate of any psychiatric illness in TBI exposed versus unexposed children, in the first year after TBI, was 2.03 (95% confidence interval [CI], 1.4-2.9). Children with mild TBI but no psychiatric history were at higher risk for hyperactivity (diagnosis of hyperkinetic syndrome of childhood or prescription of psychostimulants) in the first year after injury (incidence, 3%; first year relative risk, 7.59; 95% CI, 2.7-21.6). CONCLUSIONS: In the 3 years after mild TBI, children with no evidence of prior-year psychiatric history were at significantly increased risk for psychiatric illness, particularly hyperactivity in the first year after injury. Prior-year psychiatric history conferred a significant independent risk for subsequent psychiatric illness. There was no evidence for an additional increase in risk in the 3-year follow-up that is attributable to mild TBI in children with prior psychiatric history.

Flexible implementations of group sequential stopping rules using constrained boundaries.

Group sequential stopping rules are often used during the conduct of clinical trials in order to attain more ethical treatment of patients and to better address efficiency concerns. Because the use of such stopping rules materially affects the frequentist operating characteristics of the hypothesis test, it is necessary to choose an appropriate stopping rule during the planning of the study. It is often the case, however, that the number and timing of interim analyses are not precisely known at the time of trial design, and thus the implementation of a particular stopping rule must allow for flexible determination of the schedule of interim analyses. In this article, we consider the use of constrained stopping boundaries in the implementation of stopping rules. We compare this approach when used on various scales for the test statistic. When implemented on the scale of boundary crossing probabilities, this approach is identical to the error spending function approach of Lan and DeMets (1983).

Delirium in patients undergoing hematopoietic stem cell transplantation.

BACKGROUND: Delirium is common in patients with malignant disease and is associated with significant morbidity. Studies have not examined the epidemiology of delirium in patients undergoing hematopoietic stem cell transplantation (HSCT). The objectives of this study were to determine the prevalence, incidence, severity, and duration of delirium in the acute phase of HSCT and to determine the pretransplantation risk factors for the occurrence and severity of delirium during this period. METHODS: Ninety adult patients with malignancies who were admitted to the Fred Hutchinson Cancer Research Center for their first HSCT were assessed prospectively from 1 week pretransplantation to 30 days posttransplantation. Delirium occurrence using the Delirium Rating Scale (DRS) and severity using the Memorial Delirium Assessment Scale (MDAS) were assessed three times per week. Pretransplantation risk factors were assessed by patient self-report, charts, and computerized records. RESULTS: The cumulative posttransplantation incidence of delirium events (DRS score > 12) was 66 (73%), and the incidence of delirium episodes (DRS score > 12 for 2 of 3 consecutive assessments) was 45 (50%). The mean +/- standard deviation duration of delirium episodes was 4.8 +/- 2.8 assessments (approximately 10 days). Pretransplantation risk factors for having a delirium episode were lower cognitive functioning (Trailmaking B test [a standardized test of visual conceptual and visuomotor tracking and cognitive flexibility]; P = 0.0008), higher blood urea nitrogen (P = 0.002), higher alkaline phosphatase (P = 0.008), lower physical functioning (SF-12 [self report questionnaire that is a general measure of functioning]; P = 0.03), and higher magnesium (P = 0.03). Pretransplantation risk factors for higher delirium severity scores were higher creatinine (P < 0.0001), the presence of total body irradiation (P = 0.0001), higher magnesium (P = 0.0003), lower Mini-Mental State Examination score (P = 0.002), malignancy diagnosis category (P = 0.002), female gender (P = 0.008), higher alkaline phosphatase (P = 0.02), older age (P = 0.03), and prior alcohol or drug abuse (P = 0.046). CONCLUSIONS: Half of patients who undergo HSCT experience a delirium episode during the 4 weeks posttransplantation. Pretransplantation risk factors can assist in identifying patients who are more likely to develop delirium posttransplantation.