Donald L. Rosenstein

The neuropsychiatric effects of treatment with interleukin-2 and lymphokine-activated killer cells

STUDY OBJECTIVE To study the neuropsychiatric manifestations of therapy with interleukin-2 and lymphokine-activated killer cells. DESIGN Longitudinal survey of consecutive patients who were given the treatment. Each patient was initially interviewed within 5 days before treatment, and a personal and family psychiatric history was obtained during this first session. Cognitive tests and mood self-rating instruments were administered at the beginning and end of interleukin-2 and lymphokine-activated killer cell treatments, before discharge, and at a follow-up visit 2 to 4 weeks after discharge. SETTING National Cancer Institute inpatient units at the National Institutes of Health. PATIENTS OR OTHER PARTICIPANTS Sequential samples of 44 patients with metastatic cancer (age range, 28 to 69 years) who were treated systemically with recombinant interleukin-2 combined with autologous lymphokine-activated killer cells between 30 December 1985 and 31 March 1986. MEASUREMENTS AND MAIN RESULTS Of the 44 patients studied, 15 developed severe behavioral changes that necessitated acute intervention, and 22 patients had severe cognitive changes (all 22 became disoriented and many also had psychometric evidence of cognitive deterioration). The neuropsychiatric side effects were dose and time related, appearing more frequently at the higher dose and almost uniformly at the end of each treatment phase. All 39 patients who were seen at follow-up had a return to their baseline cognitive scores. None of the factors investigated was found to be predictive of the development of neuropsychiatric toxicity. CONCLUSIONS The development of clinically significant neuropsychiatric changes during the administration of interleukin-2 and lymphokine-activated killer cells was common and may be treatment limiting. A marked latency in the appearance of neuropsychiatric changes after treatment onset was noted in almost all patients. Every patient studied recovered from the neuropsychiatric side effects.

Fluoxetine in the Treatment of Premenstrual Dysphoria

We performed a double-blind, placebo-controlled, crossover trial of fluoxetine in 17 women with prospectively confirmed PMS who also met criteria for premenstrual dysphoric disorder (PMDD). A subset of 10 women with PMDD and an additional 10 controls participated in a single-dose m-chlorophenylpiperazine (m-CPP) challenge during the follicular and luteal phases of the menstrual cycle. We evaluated the ability of the acute behavioral response to luteal phase m-CPP administration to predict therapeutic response to fluoxetine. Compared with baseline, fluoxetine, but not placebo, treatment significantly improved both emotional and physical symptoms. We identified 11 (65%) fluoxetine responders who no longer met diagnostic criteria for PMDD during fluoxetine but remained symptomatic during placebo treatment. In addition, acute symptomatic improvement also occurred following m-CPP administration in 7 of 10 women with PMDD. The small number of m-CPP nonresponders did not respond to fluoxetine either. Our findings confirm that fluoxetine is an effective treatment of PMDD.

Survivorship care planning after the Institute of Medicine recommendations: how are we faring?

IntroductionThis study evaluates the concordance of treatment summaries (TSs) and survivorship care plans (SCPs) delivered to breast cancer survivors within the LIVESTRONG™ Network of Survivorship Centers of Excellence with Institute of Medicine (IOM) recommendations and describes additional structure/process variables.MethodSeven NCI-designated comprehensive cancer centers and six community-based centers participated. TS/SCPs for 65 patients were rated against IOM recommendations using a study-derived checklist, and surveys were administered to better understand the structure and process of delivering TSs/SCPs.ResultsOn average, fewer than half of IOM content recommendations were met for TSs (M = 46%) and less than two thirds for SCPs (M = 59%). No sites achieved ≥75% overall concordance with IOM recommendations for TSs and only two of 13 met this criterion for SCPs. Content domain scores across sites varied widely, as did the number of sites addressing domain content with ≥75% concordance. Nonetheless, resources required for document preparation and delivery were substantial.DiscussionGaps in concordance with IOM recommendations exist even in dedicated survivorship centers. A substantial time burden was also noted. Further research is needed to determine which informational elements are essential, to develop and test strategies for improving efficiency and reach, and to determine if outcomes of survivorship care planning warrant the resources required in their preparation and delivery.Implications for survivorsTSs and SCPs have been recommended for all cancer survivors. Essential elements must be determined, approaches made more efficient, outcome improvements demonstrated, and cost-benefit analyses determined before survivors should expect widespread implementation of this recommendation for survivorship care.

Ask Suicide-Screening Questions (ASQ): A brief instrument for the pediatric emergency department

OBJECTIVE To develop a brief screening instrument to assess the risk for suicide in pediatric emergency department patients. DESIGN A prospective, cross-sectional instrument-development study evaluated 17 candidate screening questions assessing suicide risk in young patients. The Suicidal Ideation Questionnaire served as the criterion standard. SETTING Three urban, pediatric emergency departments associated with tertiary care teaching hospitals. PARTICIPANTS A convenience sample of 524 patients aged 10 to 21 years who presented with either medical/surgical or psychiatric chief concerns to the emergency department between September 10, 2008, and January 5, 2011. MAIN EXPOSURES Participants answered 17 candidate questions followed by the Suicidal Ideation Questionnaire. MAIN OUTCOME MEASURES Sensitivity, specificity, predictive values, likelihood ratios, and area under the receiver operating characteristic curves of the best-fitting combinations of screening questions for detecting elevated risk for suicide. RESULTS A total of 524 patients were screened (344 medical/surgical and 180 psychiatric). Fourteen of the medical/surgical patients (4%) and 84 of the psychiatric patients (47%) were at elevated suicide risk on the Suicidal Ideation Questionnaire. Of the 17 candidate questions, the best-fitting model comprised 4 questions assessing current thoughts of being better off dead, current wish to die, current suicidal ideation, and past suicide attempt. This model had a sensitivity of 96.9% (95% CI, 91.3-99.4), specificity of 87.6% (95% CI, 84.0-90.5), and negative predictive values of 99.7% (95% CI, 98.2-99.9) for medical/surgical patients and 96.9% (95% CI, 89.3-99.6) for psychiatric patients. CONCLUSIONS A 4-question screening instrument, the Ask Suicide-Screening Questions (ASQ), with high sensitivity and negative predictive value, can identify the risk for suicide in patients presenting to pediatric emergency departments.

A literature review of suicide in cancer patients.

Background:Cancer survivors have a higher suicide rate than the general population. Oncology nurses need to have knowledge and skills in assessing risk for suicide in this population. Objective:This study aimed to conduct a literature review on risk factors for and incidence of suicide in patients with cancer and to identify potential screening tools. Methods:PubMed, CINAHL, and PsycINFO databases were searched to identify research articles in peer-reviewed journals from 1999 to 2009. The variables under study included suicide rate, cancer type, demographic characteristics, and signs and symptoms associated with suicide. In addition, articles focused on suicide risk assessment tools were also included. Results:Twenty-four articles met the inclusion criteria. As in the general population, suicide risk was higher among men with cancer as compared with women with cancer. Patients aged 65 years or older with cancer have a higher rate of suicide compared with those younger than 65 years, with rates highest among men 80 years or older. Specific diagnoses associated with higher suicide rates include prostate, lung, pancreatic, and head and neck cancers. The first year after diagnosis carries a higher risk for completed suicide. Multiple risk assessment tools have been developed and are effective in identifying patients with depression or hopelessness, factors associated with higher risk for suicide. However, no tools exist that sensitively and specifically predict suicide. Conclusion:The incidence of suicide in someone with a cancer diagnosis is approximately double the incidence of suicide in the general population. Early detection of depression in special cancer populations, such as older male patients, may help identify those at greatest suicide risk. Implications for Practice:Oncology nurses should be aware of cancer patients considered at higher risk for suicide. Systematic screening for suicidal ideation and behavior may identify cancer patients at high risk and facilitate appropriate mental health evaluation and treatment.

Neuropsychiatric Toxicity Associated With Cytokine Therapies

The cytokines interleukin-2 and interferon-alpha are potent biological agents used to treat malignancy, infectious diseases, and neurodegenerative disorders. While these medications show substantial therapeutic promise, the neuropsychiatric toxicity associated with these agents is often treatment-limiting. The pathophysiology of this toxicity is not well delineated, and adverse effects to the central nervous system are often misdiagnosed by clinicians. This report reviews the preclinical and clinical literature describing the morbidity associated with these agents and suggests appropriate clinical management strategies and future directions for research.

The Met66 allele of the functional Val66Met polymorphism in the brain-derived neurotrophic factor gene confers protection against neurocognitive dysfunction in systemic lupus erythematosus

Background: A common functional polymorphism of the brain-derived neurotrophic factor gene (BDNF Val66Met) was previously associated with diminished episodic memory performance in healthy people. As cognitive function is commonly impaired in patients with systemic lupus erythematosus (SLE), the association of the BDNF Val66Met with neurocognitive function was studied. Objective: To study the association of the BDNF Val66Met with neurocognitive function in a cohort of patients with SLE. Methods: Cognitive function was assessed in 59 patients with SLE with no previous or current central nervous system involvement. Cognitive tests were grouped into five domains (memory, attention/executive function, visuospatial skills, motor function and psychomotor speed) and used to obtain domain Z scores, reflecting the difference between averaged scores of performance on individual tests and published norms in each domain. Genotyping was carried out using a 5′-nuclease assay with 99.9% accuracy. Unpaired t test was used to assess the relationship between genotypes and cognitive function, whereas the effect of possible confounders was assessed in a multivariate analysis. Results: Patients carrying the Met66 allele scored significantly higher on psychomotor, attention/executive and motor function tests, resulting in significantly higher domain Z scores for the psychomotor (p = 0.005) and motor (p = 0.002) domains. Conclusions: The BDNF Met66 allele was associated with better cognitive functioning in the psychomotor and motor domains, even after controlling for differences in ethnicity, sex, depression status and prednisone treatment. These data suggest that the BDNF Met66 allele confers protection against the decline of motor and psychomotor cognitive functions in patients with longstanding SLE.

Reporting of ethical issues in publications of medical research

Clinical investigators rarely describe the rationale for ethically controversial features of study design or procedures instituted to enhance the protection of patients taking part in research, or how they ensured informed consent. We recommend a policy of extensive reporting of pertinent ethical issues to promote public accountability for clinical research. Guidelines are presented, and possible objections to this recommended policy are addressed.

Feasibility of Screening Patients With Nonpsychiatric Complaints for Suicide Risk in a Pediatric Emergency Department: A Good Time to Talk?

Objective: Screening children for suicide risk when they present to the emergency department (ED) with nonpsychiatric complaints could lead to better identification and treatment of high-risk youth. Before suicide screening protocols can be implemented for nonpsychiatric patients in pediatric EDs, it is essential to determine whether such efforts are feasible. Methods: As part of an instrument validation study, ED patients (10-21 years old) with both psychiatric and nonpsychiatric presenting complaints were recruited to take part in suicide screening. Clinically significant suicidal thoughts, as measured by the Suicidal Ideation Questionnaire, and suicidal behaviors were assessed, as well as patient opinions about suicide screening. Recruitment rates for the study as well as impact on length of stay were assessed. Results: Of the 266 patients and parents approached for the study, 159 (60%) agreed to participate. For patients entering the ED for nonpsychiatric reasons (n = 106), 5.7% (n = 6) reported previous suicidal behavior, and 5.7% (n = 6) reported clinically significant suicidal ideation. There were no significant differences for mean length of stay in the ED for nonpsychiatric patients with positive triggers and those who screened negative (means, 382 [SD, 198] and 393 [SD, 166] minutes, respectively; P = 0.80). Ninety-six percent of participants agreed that suicide screening should occur in the ED. Conclusions: Suicide screening of nonpsychiatric patients in the ED is feasible in terms of acceptability to parents, prevalence of suicidal thoughts and behaviors, practicality to ED flow, and patient opinion. Future endeavors should address brief screening tools validated on nonpsychiatric populations.

Magnesium measures across the menstrual cycle in premenstrual syndrome.

The purpose of this study was to evaluate blood magnesium (Mg) measures across the menstrual cycle in women with premenstrual syndrome (PMS) and control women. Longitudinal determinations of plasma, red blood cell (RBC) and mononuclear blood cell (MBC) Mg were made in 26 women with prospectively confirmed PMS and in a control group of 19 women. Data were analyzed using analysis of variance with repeated measures and Spearman rank correlations. Significant diagnostic group effects were observed for RBC and MBC Mg concentrations (p < 0.05). These effects reflected lower Mg concentrations in PMS patients at each sampling time. No significant effects were observed for either plasma Mg or MBC Mg content, nor were there significant time by diagnosis effects for any of the measures. Consistent with earlier studies, we found decreased RBC Mg concentrations and additionally observed decreased MBC Mg concentrations in women with PMS. However, neither of these relative deficits were confined to the luteal phase.