Alan D. Valentine

Pattern of neurobehavioral deficits associated with interferon alfa therapy for leukemia.

Article abstract—We evaluated the neuropsychological and personality profiles of 25 patients with chronic myeloge-nous leukemia treated with interferon alfa (IFN-α). This group of persons performed well below expectation on tests of cognitive speed, verbal memory, and executive functions. Personality changes included depression, increased somatic concern, and stress reactions. A control group of leukemia patients not treated with IFN-α had significantly better cognitive speed and mood. The pattern of cognitive and personality changes in patients receiving IFN-α is highly suggestive of frontal-subcortical brain dysfunction.

Evaluation of the neurobehavioral functioning of patients before, during, and after bone marrow transplantation.

PURPOSE To evaluate the cognitive and emotional functioning of patients undergoing bone marrow transplantation (BMT) in the protected environment (PE). PATIENTS AND METHODS Patients were given tests of cognition and mood before their hospitalization in the PE, after 2 weeks, at discharge, and at 8 months post-BMT. Locus of control, degree of social support, previous biotherapy, and on-treatment psychiatric consultation were also analyzed. RESULTS Before BMT, 20% of patients had mild cognitive dysfunction, and nearly 40% had significant anxiety. Although few patients developed problems with cognition or mood during the study, short-term memory deficits nearly doubled at follow-up compared with baseline. Anxiety decreased significantly during hospitalization and remained low at follow-up. In contrast, depression increased throughout hospitalization, but decreased at follow-up. Pre-BMT emotional status and cognitive functioning were highly related to long-term outcome. Type of BMT, locus of control, and degree of social support were related to psychologic distress and cognitive functioning, both during and after BMT. Patient age was not a predictor of neurobehavioral symptoms during or after BMT. CONCLUSION Pretransplant emotional and cognitive functioning are important determinants of long-term outcome and quality of life (QOL) in BMT patients. In addition, a few patients undergoing BMT develop short-term memory difficulties and mood disturbance that may persist. Pretransplant identification of patients at risk for neurobehavioral difficulties may guide early interventions during hospitalization. Posttransplant assessment may then be used to develop rehabilitation programs and other interventions for individuals with persisting complaints.

Treatment of Neurotoxic Side Effects of Interferon-α with Naltrexone

Interferon-a (IFN-α) has potential dose-limiting neurotoxic side effects when used in cancer therapy. The nature of this neurotoxicity is speculative, and there is no definitive treatment. Because animal studies suggest that IFN-α acts at opioid receptor sites, we gave naltrexone, a long-acting opioid antagonist, to 9 patients who had hematological malignancies and who suffered from IFN-α side effects. Seven of these patients experienced complete or moderate relief of side effects. Five of the patients tested before and during naltrexone treatment showed improvement of cognitive functioning. Two patients could not tolerate naltrexone side effects. This study suggests an intervention against IFN-α side effects and provides support for the role of opioid receptor interaction in IFN-α neurotoxicity.

A retrospective study of the psychiatric management and outcome of delirium in the cancer patient

This report describes the evaluation and treatment of delirium in the cancer patient in a major comprehensive cancer center. Ninety consecutive cases of delirium seen by the inpatient psychiatry consultation/liaison service were analyzed in a retrospective fashion to evaluate demographic information, alcohol use, central nervous system disease, coexisting medical disease, and past psychiatric history. Delirium cases were divided into hyperalert, hypoalert, and mixed subtypes. For these three subtypes, medication profiles including dose of medication, duration of delirium, outcome, and the venue where the delirium began were also evaluated. The hyperalert subtype of delirium was the commonest type observed (71%) and had the shortest duration (P <0.0001) and best outcome (P <0.001). The patients with a hyperalert delirium subtype were treated with the least amount of haloperidol (P <0.0001). Patients were delirious for longer when the delirium began in the intensivecare units (P < 0.04). In general, patients who received no haloperidol experienced delirium of longer duration (P < 0.02) than those receiving haloperidol. Since the data represent patients who were referred for psychiatric treatment, this may explain the increased number of hyperalert deliriums and, therefore, the generalizability of the results is limited. Delirium in the cancer patient is particularly problematic given the coexisting medical problems these patients experience. Because the outcome of delirium is better when the duration is shorter, it is important for clinicians to be sensitive to early symptoms so that treatment can be implemented faster, leading to less morbidity and mortality.

Depression and oropharynx cancer outcome

Background Studies have shown a modest relationship between depression and mortality in patients with cancer. Our study addressed methodological weaknesses in the literature by restricting the sample to patients with one cancer type, adjusting for factors known to affect outcome, and following up patients for a sufficient period. Methods We prospectively followed patients newly diagnosed with squamous cell oropharyngeal cancer from the start of radiation therapy until death or until date of last clinical visit. All patients were optimally treated with radiation and sometimes chemotherapy. After adjusting for tumor stage, treatment, comorbidities, smoking, excessive alcohol use, and demographic factors, we assessed the effects of baseline self-reported depression on overall survival and recurrence. Results One hundred thirty participants were followed for a median of 5 years. The average age was 56 years, and 83% were male. Eighteen participants died during the study and 15 experienced disease recurrence. Self-reported depression was associated with decreased overall survival duration (hazard ratio = 3.6, 95% confidence interval = 1.2–10.8) and disease recurrence (hazard ratio = 3.8, 95% confidence interval = 1.2–12.2) in multivariate analysis. In addition, smoking was associated with disease recurrence. Conclusions Patients with oropharyngeal cancer may benefit from depression screening and evidence-based treatments, if appropriate. Future studies are needed to determine whether depression is an independent prognostic factor of outcome and to elucidate biobehavioral mechanisms involved in patients with oropharyngeal cancer.

Delirium frequency among advanced cancer patients presenting to an emergency department: A prospective, randomized, observational study

The frequency of delirium among patients with cancer presenting to the emergency department (ED) is unknown. The purpose of this study was to determine delirium frequency and recognition by ED physicians among patients with advanced cancer presenting to the ED of The University of Texas MD Anderson Cancer Center.

Impact of cardiovascular comorbidity on ovarian cancer mortality

Background: A retrospective cohort study utilizing prospectively collected data was conducted from August 2003 until March 2008 at M.D. Anderson Cancer Center. It is unknown whether cardiovascular comorbidity and chronic stress impact ovarian cancer outcome, which remains poor despite advances in therapy. The purpose of this study was to determine whether cardiovascular disease and markers that may be associated with stress are also associated with survival in patients with ovarian cancer. Methods: Participants with newly diagnosed epithelial ovarian cancer were followed until time of death or truncation of study period (median follow-up = 4.2 years; n = 271). Tumor characteristics (stage, tumor grade, histology, debulking status), demographic variables, and cardiovascular comorbidity were documented and compared to overall survival. Results: Of the nine cardiovascular events tracked during follow-up, venous thromboembolism [VTE; HR, 3.2; 95% confidence interval (CI), 1.8–5.5] and pulmonary hypertension (HR, 8.5; 95% CI, 3.9–18.7) were associated with shorter survival in multivariate analysis. In addition, high tumor grade, suboptimal cytoreduction, and baseline heart rate (HR, 1.02; 95% CI, 1.01–1.04) were related to decreased survival. Conclusion: Careful management of certain cardiovascular comorbidities may extend survival in patients with ovarian cancer. Our findings suggest that increased baseline heart rate and the development of VTE and pulmonary hypertension after cancer diagnosis may be significant predictors of survival in women with ovarian cancer. Impact: Our study emphasizes the importance of identifying and optimally treating tachycardia, VTE, and pulmonary hypertension in conjunction with cancer therapy. Cancer Epidemiol Biomarkers Prev; 22(11); 2102–9. ©2013 AACR.

Studies with [11C]alprazolam: an agonist for the benzodiazepine receptor

We have built a system for the synthesis of high specific activity carbon-11 alprazolam (Xanax), a high affinity agonist for the benzodiazepine receptor. The system produces 30-40 mCi of the compound with a specific activity of > 12,000 Ci per millimole. Using this compound we have performed PET studies on 6 normal subjects and studied the cerebral influx and efflux of the compound. The uptake in the brain was low, approx. 1% of the administered dose. However, the levels of the compound in the circulation at early time points are heavily affected by the specific activity of the tracer, i.e. when pharmacologically active doses are used as blocking doses the concentration of radioactive material is higher in the circulation and more material enters the brain. We attribute this to a depot effect where the compound is trapped in saturatable sites in an organ, probably the lungs, and is slowly released over time. In the presence of blocking doses of agonist, the compound washes out of the brain more quickly suggesting that some blockade of the receptors is occurring. However, the pharmacological activity of the compound does not permit the administration of enough material to ensure complete receptor blockade. The compound shows definite signs of acting as a receptor binding ligand but the unusual pharmacokinetics complicate the interpretation of the data.

Managing the Neuropsychiatric Adverse Effects of Interferon Treatment

Patients who receive interferons are vulnerable to a wide variety of neuropsychiatric adverse effects which can seriously compromise otherwise effective therapy. The nature and severity of the adverse effects are, in part, dose dependent, though there is significant variability. Effective treatment of interferon adverse effects is hindered by the absence of an identified mechanism of toxicity and lack of controlled intervention trials. Successful management of adverse effects is facilitated by a multimodal approach, starting with pre-treatment screening and discussion. Behavioural techniques help maintain daily function. Dose reduction or drug holidays may be required. Pharmacological treatment is based largely on clinical experience, though formal studies are underway. Familiarity with several classes of psychotropic medications is required, including antidepressants, anxiolytics, antipsychotics and psychostimulants. Together, these interventions may be used to reduce severity of interferon behavioural adverse effects to tolerable levels.

Neuroleptics for Delirium: More Research Is Needed

Author Contributions: Drs Auer and Berthet had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Auer, Concha-Lozano, Jacot-Sadowski, Berthet. Acquisition, analysis, or interpretation of data: Auer, Concha-Lozano, Jacot-Sadowski, Cornuz, Berthet. Drafting of the manuscript: Auer, Concha-Lozano, Berthet. Critical revision of the manuscript for important intellectual content: Concha-Lozano, Jacot-Sadowski, Cornuz. Statistical analysis: Concha-Lozano. Obtained funding: Cornuz, Berthet. Administrative, technical, or material support: Concha-Lozano, Berthet