Obexelimab in Systemic Lupus Erythematosus With Exploration of Response Based on Gene Pathway Co-Expression Patterns: A Double-Blind, Randomized, Placebo-Controlled, Phase 2 Trial.

OBJECTIVE: Obexelimab is an investigational, bifunctional, noncytolytic monoclonal antibody that binds CD19 and FcyRIIb to inhibit B cells, plasmablasts, and plasma cells. This trial evaluated the efficacy and safety of obexelimab in the treatment of patients with systemic lupus erythematosus (SLE). METHODS: During screening, patients with active, non-organ-threatening SLE received corticosteroid injections to ameliorate symptoms while immunosuppressants were withdrawn (≤10 mg/day prednisone equivalent and ≤400 mg/day hydroxychloroquine allowed). Patients with improved disease activity were randomized 1:1 to obexelimab 5 mg/kg intravenously or placebo once every 2 weeks until week 32 or loss of improvement (LOI). RESULTS: In this study, 104 patients were randomized. Analysis of the primary endpoint, proportion of patients reaching week 32 without LOI, used an efficacy-evaluable (EE) population defined as patients who completed the study or withdrew for flare or treatment-related toxicity. This endpoint did not reach statistical significance: 21 of 50 obexelimab-treated patients (42.0%) versus 12 of 42 patients (28.6%) treated with a placebo (P = 0.183). Time to LOI was increased in obexelimab-treated patients versus patients treated with a placebo in the EE (hazard ratio [HR] 0.53, P = 0.025) and intention-to-treat (HR 0.59, P = 0.062) populations. In obexelimab-treated patients, B cells decreased approximately 50%, and trough concentration and inclusion in baseline gene expression clusters with high B cell pathway modules were associated with increased time to LOI. Obexelimab was associated with infusion reactions but was generally safe and well-tolerated. CONCLUSION: Although the primary endpoint was not reached, secondary analysis showed time to LOI was significantly increased in obexelimab-treated patients, and analysis of patient subsets defined by gene expression patterns at baseline suggests a responding subpopulation.

Evaluation of the safety, efficacy, and mechanism of action of obexelimab for the treatment of patients with IgG4-related disease: an open-label, single-arm, single centre, phase 2 pilot trial.

BACKGROUND: Obexelimab is a bifunctional, non-cytolytic, humanised monoclonal antibody that binds CD19 and Fc gamma receptor IIb to inhibit B cells, plasmablasts, and CD19-expressing plasma cells. We aimed to evaluate the safety, clinical efficacy, and pharmacodynamic effects of obexelimab in patients with active IgG4-related disease. METHODS: We conducted an open-label, single-arm, single centre, phase 2 pilot trial at the Massachusetts General Hospital in Boston, MA, USA. Eligible patients were aged 18-80 years and had active IgG4-related disease confirmed by an IgG4-related disease responder index score of 3 or more. Patients received 5 mg/kg of obexelimab intravenously every 2 weeks for 24 weeks. Patients on glucocorticoids at baseline were expected to discontinue usage within 2 months following enrolment. The primary endpoint was the proportion of patients with a decrease of 2 or more from baseline in the IgG4-related disease responder index at day 169 (ie, primary responders). Patients who achieved a decrease of 2 or more at any visit were designated as responders. Adverse events were graded on a scale of 1-5 (ie, mild, moderate, severe, life-threatening, or death) according to the Common Terminology Criteria for Adverse Events grading scale (version 4.3). Exploratory analyses were quantification of B-cell CD19 receptor occupancy, plasmablast, total B-cell and CD4+ cytotoxic T-cell count by flow cytometry, and immunoglobulin concentrations by nephelometry. This study is registered with ClinicalTrials.gov, NCT02725476. FINDINGS: Between Feb 24, 2016, and Dec 21, 2016, we enrolled 15 patients. The median age was 63 years (IQR 52-65). Ten (67%) of 15 patients were male, five (33%) were female, and 12 (80%) were White. At baseline, 12 (80%) of 15 patients had an elevated median serum IgG4 concentration of 220 mg/dL (IQR 124-441), and the median IgG4-related disease responder index score was 12 (IQR 7-13). 12 (80%) of 15 patients achieved the primary endpoint (ie, primary responders), 14 (93%) were defined as responders. Reductions from baseline in serum B cells and plasmablasts were observed following treatment with obexelimab. However, in most patients with follow-up data, serum B cells recovered to 75% of baseline concentrations within 42 days of the final obexelimab dose. 13 (87%) of 15 patients reported adverse events, one of which (an infusion reaction) resulted in treatment discontinuation. INTERPRETATION: All patients except for one had clinical responses to obexelimab treatment. Both reductions in circulating B cells without evidence of apoptosis during obexelimab treatment and their rapid rebound after treatment discontinuation suggest that obexelimab might lead to B-cell sequestration in lymphoid organs or the bone marrow. These results support the continued development of obexelimab for the treatment of IgG4-related disease. FUNDING: Xencor, Zenas BioPharma, National Institute of Arthritis and Musculoskeletal and Skin Diseases, and National Institute of Allergy and Infectious Diseases.

Dynamics of mutations in patients with essential thrombocythemia treated with imetelstat.

In a phase-2 study, the telomerase inhibitor imetelstat induced rapid hematologic responses in all patients with essential thrombocythemia who were refractory or intolerant to prior therapies. Significant molecular responses were achieved within 3-6 months in 81% of patients with phenotypic driver mutations in JAK2, CALR and MPL. Here, we investigated the dynamics of additional somatic mutations in response to imetelstat. At study entry, 50% of patients carried 1-5 additional mutations in the genes ASXL1, CBL, DNMT3A, EZH2, IDH1, SF3B1, TET2, TP53 and U2AF1. Three patients with baseline mutations also had late-emerging mutations in TP53, IDH1 and TET2. Most clones with additional mutations were responsive to imetelstat and decreased with the driver mutation, including the poor prognostic ASXL1, EZH2 and U2AF1 mutations while SF3B1 and TP53 mutations were associated with poorer molecular response. Overall, phenotypic driver mutation response was significantly deeper in patients without additional mutations (P = 0.04) and correlated with longer duration of response. In conclusion, this detailed molecular analysis of highly pretreated and partly resistant patients with essential thrombocythemia reveals a high individual patient complexity. Moreover, imetelstat demonstrates potential to inhibit efficiently co-incident mutations occurring in neoplastic clones in patients with essential thrombocythemia. (ClinicalTrials.gov number, NCT01243073. N Engl J Med 2015; 373:920-928, DOI: 10.1056/NEJMoa1503479.).

Telomerase Inhibitor Imetelstat in Patients with Essential Thrombocythemia.

BACKGROUND: Imetelstat, a 13-mer oligonucleotide that is covalently modified with lipid extensions, competitively inhibits telomerase enzymatic activity. It has been shown to inhibit megakaryocytic proliferation in vitro in cells obtained from patients with essential thrombocythemia. In this phase 2 study, we investigated whether imetelstat could elicit hematologic and molecular responses in patients with essential thrombocythemia who had not had a response to or who had had unacceptable side effects from prior therapies. METHODS: A total of 18 patients in two sequential cohorts received an initial dose of 7.5 or 9.4 mg of imetelstat per kilogram of body weight intravenously once a week until attainment of a platelet count of approximately 250,000 to 300,000 per cubic millimeter. The primary end point was the best hematologic response. RESULTS: Imetelstat induced hematologic responses in all 18 patients, and 16 patients (89%) had a complete hematologic response. At the time of the primary analysis, 10 patients were still receiving treatment, with a median follow-up of 17 months (range, 7 to 32 [ongoing]). Molecular responses were seen in 7 of 8 patients who were positive for the JAK2 V617F mutation (88%; 95% confidence interval, 47 to 100). CALR and MPL mutant allele burdens were also reduced by 15 to 66%. The most common adverse events during treatment were mild to moderate in severity; neutropenia of grade 3 or higher occurred in 4 of the 18 patients (22%) and anemia, headache, and syncope of grade 3 or higher each occurred in 2 patients (11%). All the patients had at least one abnormal liver-function value; all persistent elevations were grade 1 or 2 in severity. CONCLUSIONS: Rapid and durable hematologic and molecular responses were observed in patients with essential thrombocythemia who received imetelstat. (Funded by Geron; ClinicalTrials.gov number, NCT01243073.).

CD40 pathway activation status predicts response to CD40 therapy in diffuse large B cell lymphoma.

The primary function of B cells, critical components of the adaptive immune response, is to produce antibodies against foreign antigens, as well as to perform isotype class switching, which changes the heavy chain of an antibody so that it can interact with different repertoires of effector cells. CD40 is a member of the tumor necrosis factor superfamily of cell surface receptors that transmits survival signals to B cells. In contrast, in B cell cancers, stimulation of CD40 signaling results in a heterogeneous response in which cells can sometimes undergo cell death in response to treatment, depending on the system studied. We found an association between sensitivity to CD40 stimulation and mutation of the tumor suppressor p53 in a panel of non-Hodgkin's lymphoma cell lines. Consistent with p53's tumor suppressor role, we found that higher levels of intrinsic DNA damage and increased proliferation rates, as well as higher levels of BCL6, a transcriptional repressor proto-oncogene, were associated with sensitivity to CD40 stimulation. In addition, CD40 treatment-resistant cell lines were sensitized to CD40 stimulation after the introduction of DNA-damaging agents. Using gene expression analysis, we also showed that resistant cell lines exhibited a preexisting activated CD40 pathway and that an mRNA expression signature comprising CD40 target genes predicted sensitivity and resistance to CD40-activating agents in cell lines and mouse xenograft models. Finally, the gene signature predicted tumor shrinkage and progression-free survival in patients with diffuse large B cell lymphoma treated with dacetuzumab, a monoclonal antibody with partial CD40 agonist activity. These data show that CD40 pathway activation status may be useful in predicting the antitumor activity of CD40-stimulating therapeutic drugs.

Statistical techniques to construct assays for identifying likely responders to a treatment under evaluation from cell line genomic data.

BACKGROUND: Developing the right drugs for the right patients has become a mantra of drug development. In practice, it is very difficult to identify subsets of patients who will respond to a drug under evaluation. Most of the time, no single diagnostic will be available, and more complex decision rules will be required to define a sensitive population, using, for instance, mRNA expression, protein expression or DNA copy number. Moreover, diagnostic development will often begin with in-vitro cell-line data and a high-dimensional exploratory platform, only later to be transferred to a diagnostic assay for use with patient samples. In this manuscript, we present a novel approach to developing robust genomic predictors that are not only capable of generalizing from in-vitro to patient, but are also amenable to clinically validated assays such as qRT-PCR. METHODS: Using our approach, we constructed a predictor of sensitivity to dacetuzumab, an investigational drug for CD40-expressing malignancies such as lymphoma using genomic measurements of cell lines treated with dacetuzumab. Additionally, we evaluated several state-of-the-art prediction methods by independently pairing the feature selection and classification components of the predictor. In this way, we constructed several predictors that we validated on an independent DLBCL patient dataset. Similar analyses were performed on genomic measurements of breast cancer cell lines and patients to construct a predictor of estrogen receptor (ER) status. RESULTS: The best dacetuzumab sensitivity predictors involved ten or fewer genes and accurately classified lymphoma patients by their survival and known prognostic subtypes. The best ER status classifiers involved one or two genes and led to accurate ER status predictions more than 85% of the time. The novel method we proposed performed as well or better than other methods evaluated. CONCLUSIONS: We demonstrated the feasibility of combining feature selection techniques with classification methods to develop assays using cell line genomic measurements that performed well in patient data. In both case studies, we constructed parsimonious models that generalized well from cell lines to patients.

Estimating duration in partnership studies: issues, methods and examples.

BACKGROUND AND OBJECTIVES: Understanding the time course of sexual partnerships is important for understanding sexual behaviour, transmission risks for sexually transmitted infections (STI) and development of mathematical models of disease transmission. STUDY DESIGN: The authors describe issues and biases relating to censoring, truncation and sampling that arise when estimating partnership duration. Recommendations for study design and analysis methods are presented and illustrated using data from a sexual-behaviour survey that enrolled individuals from an adolescent-health clinic and two STD clinics. Survey participants were queried, for each of (up to) four partnerships in the last 3 months, about the month and year of first sex, the number of days since last sex and whether partnerships were limited to single encounters. Participants were followed every 4 months for up to 1 year. RESULTS: After adjustment for censoring and truncation, the estimated median duration of sexual partnerships declined from 9 months (unadjusted) to 1.6 months (adjusted). Similarly, adjustment for censoring and truncation reduced the bias in relative risks for the effect of age in a Cox model. Other approaches, such as weighted estimation, also reduced bias in the estimated duration distribution. CONCLUSION: Methods are available for estimating partnership duration from censored and truncated samples. Ignoring censoring, truncation and other sampling issues results in biased estimates.

Tumor cell gene expression changes following short-term in vivo exposure to single agent chemotherapeutics are related to survival in multiple myeloma.

Changes in global gene expression patterns in tumor cells following in vivo therapy may vary by treatment and provide added or synergistic prognostic power over pretherapy gene expression profiles (GEP). This molecular readout of drug-cell interaction may also point to mechanisms of action/resistance. In newly diagnosed patients with multiple myeloma (MM), microarray data were obtained on tumor cells prior to and 48 hours after in vivo treatment using dexamethasone (n = 45) or thalidomide (n = 42); in the case of relapsed MM, microarray data were obtained prior to (n = 36) and after (n = 19) lenalidomide administration. Dexamethasone and thalidomide induced both common and unique GEP changes in tumor cells. Combined baseline and 48-hour changes in GEP in a subset of genes, many related to oxidative stress and cytoskeletal dynamics, were predictive of outcome in newly diagnosed MM patients receiving tandem transplants. Thalidomide-altered genes also changed following lenalidomide exposure and predicted event-free and overall survival in relapsed patients receiving lenalidomide as a single agent. Combined with baseline molecular features, changes in GEP following short-term single-agent exposure may help guide treatment decisions for patients with MM. Genes whose drug-altered expression were found to be related to survival may point to molecular switches related to response and/or resistance to different classes of drugs.

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.

The molecular classification of multiple myeloma.

To better define the molecular basis of multiple myeloma (MM), we performed unsupervised hierarchic clustering of mRNA expression profiles in CD138-enriched plasma cells from 414 newly diagnosed patients who went on to receive high-dose therapy and tandem stem cell transplants. Seven disease subtypes were validated that were strongly influenced by known genetic lesions, such as c-MAF- and MAFB-, CCND1- and CCND3-, and MMSET-activating translocations and hyperdiploidy. Indicative of the deregulation of common pathways by gene orthologs, common gene signatures were observed in cases with c-MAF and MAFB activation and CCND1 and CCND3 activation, the latter consisting of 2 subgroups, one characterized by expression of the early B-cell markers CD20 and PAX5. A low incidence of focal bone disease distinguished one and increased expression of proliferation-associated genes of another novel subgroup. Comprising varying fractions of each of the other 6 subgroups, the proliferation subgroup dominated at relapse, suggesting that this signature is linked to disease progression. Proliferation and MMSET-spike groups were characterized by significant overexpression of genes mapping to chromosome 1q, and both exhibited a poor prognosis relative to the other groups. A subset of cases with a predominating myeloid gene expression signature, excluded from the profiling analyses, had more favorable baseline characteristics and superior prognosis to those lacking this signature.

Frequent gain of chromosome band 1q21 in plasma-cell dyscrasias detected by fluorescence in situ hybridization: incidence increases from MGUS to relapsed myeloma and is related to prognosis and disease progression following tandem stem-cell transplantation.

Using fluorescence in situ hybridization we investigated amplification of chromosome band 1q21 (Amp1q21) in more than 500 untreated patients with monoclonal gammopathy of undetermined significance (MGUS; n = 14), smoldering multiple myeloma (SMM; n = 31), and newly diagnosed MM (n = 479) as well as 45 with relapsed MM. The frequency of Amp1q21 was 0% in MGUS, 45% in SMM, 43% in newly diagnosed MM, and 72% in relapsed MM (newly diagnosed versus relapsed MM, P < .001). Amp1q21 was detected in 10 of 12 patients whose disease evolved to active MM compared with 4 of 19 who remained with SMM (P < .001). Patients with newly diagnosed MM with Amp1q21 had inferior 5-year event-free/overall survival compared with those lacking Amp1q21 (38%/52% versus 62%/78%, both P < .001). Thalidomide improved 5-year EFS in patients lacking Amp1q21 but not in those with Amp1q21 (P = .004). Multivariate analysis including other major predictors revealed that Amp1q21 was an independent poor prognostic factor. Relapsed patients who had Amp1q21 at relapse had inferior 5-year postrelapse survival compared with those lacking Amp1q21 at relapse (15% versus 53%, P = .027). The proportion of cells with Amp1q21 and the copy number of 1q21 tended to increase at relapse compared with diagnosis. Our data suggest that Amp1q21 is associated with both disease progression and poor prognosis.

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.

A comparison between the vaginal ring and oral contraceptives.

OBJECTIVE: To investigate whether contraceptive vaginal ring use results in similar estimated genital symptoms, signs, examination, and laboratory findings compared with oral contraceptive use. METHODS: Women were randomly assigned to either contraceptive vaginal ring or a 20 microg ethinyl estradiol oral contraceptive pill use for 3 consecutive 28-day cycles, directly followed by 3 cycles of the study drug not initially assigned. Subjects scored genital symptoms on a daily diary using a 0-4 scale and underwent a baseline, cycle 2, cycle 4, and exit pelvic examination including vaginal discharge evaluation, vaginal Gram stain and white cell count, and culture for yeast and Lactobacillus, including colony count and hydrogen peroxide production. RESULTS: Of the 40 subjects assigned to each arm, 33 (82.5%) subjects in the ring-first arm and 31 (77.5%) subjects in the pill-first arm completed all study visits (P =.58). Most subjects reported few genital symptoms with either method, but 63% of subjects reported vaginal wetness during ring use compared with 43% during pill use. During ring use larger numbers of Lactobacillus colonies present were positive for hydrogen peroxide production (fold difference 2.67, 95% confidence interval 1.49, 4.78, P <.001). All other laboratory data, including yeast colony counts, Nugent Gram stain score, vaginal white blood cell count, vaginal pH, and discharge weight, were not significantly different by method. CONCLUSION: Some women may notice an increase in vaginal wetness during contraceptive ring use yet the method is well tolerated and appears to improve the vaginal flora.

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.

Psychiatric illness following traumatic brain injury in an adult health maintenance organization population.

BACKGROUND: Psychiatric illness after traumatic brain injury (TBI) has been shown to be prevalent in hospitalized and tertiary care patient populations. OBJECTIVE: To determine the risk of psychiatric illness after TBI in an adult health maintenance organization population. DESIGN: Prospective cohort study. SETTING: Large staff-model health maintenance organization. PARTICIPANTS: Nine hundred thirty-nine health plan members diagnosed as having TBI in 1993 and enrolled in the prior year, during which no TBI was ascertained. Three health plan members per TBI-exposed subject were randomly selected as unexposed comparisons, matched for age, sex, and reference date. MAIN OUTCOME MEASURE: Psychiatric illness in the 3 years after the TBI reference date, determined using computerized records of psychiatric diagnoses according to the International Classification of Diseases, Ninth Revision, Clinical Modification, prescriptions, and service utilization. RESULTS: Prevalence of any psychiatric illness in the first year was 49% following moderate to severe TBI, 34% following mild TBI, and 18% in the comparison group. Among subjects without psychiatric illness in the prior year, the adjusted relative risk for any psychiatric illness in the 6 months following moderate to severe TBI was 4.0 (95% confidence interval [CI], 2.4-6.8) and following mild TBI was 2.8 (95% CI, 2.1-3.7; P<.001) compared with those without TBI. Among subjects with prior psychiatric illness, the adjusted relative risk for any psychiatric illness in the 6 months following moderate to severe TBI was 2.1 (95% CI, 1.3-3.3) and following mild TBI was 1.6 (95% CI, 1.2-2.0; P =.005). Prior psychiatric illness significantly modified the relationship between TBI and subsequent psychiatric illness (P =.04) and was a significant predictor (P<.001). Persons with mild TBI and prior psychiatric illness had evidence of persisting psychiatric illness. CONCLUSIONS: Both moderate to severe and mild TBI are associated with an increased risk of subsequent psychiatric illness. Whereas moderate to severe TBI is associated with a higher initial risk, mild TBI may be associated with persistent psychiatric illness.

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.