Showing papers by "David Spiegel published in 2012"

Effects of Phosphate Binders in Moderate CKD

Abstract: Some propose using phosphate binders in the CKD population given the association between higher levels of phosphorus and mortality, but their safety and efficacy in this population are not well understood. Here, we aimed to determine the effects of phosphate binders on parameters of mineral metabolism and vascular calcification among patients with moderate to advanced CKD. We randomly assigned 148 patients with estimated GFR=20–45 ml/min per 1.73 m 2 to calcium acetate, lanthanum carbonate, sevelamer carbonate, or placebo. The primary endpoint was change in mean serum phosphorus from baseline to the average of months 3, 6, and 9. Serum phosphorus decreased from a baseline mean of4.2mg/dlinbothactiveandplaceboarmsto3.9mg/dlwithactivetherapyand4.1mg/dlwithplacebo (P=0.03). Phosphate binders, but not placebo, decreased mean 24-hour urine phosphorus by 22%. Median serum intact parathyroid hormone remained stable with active therapy and increased with placebo (P=0.002). Active therapy did not significantly affect plasma C-terminal fibroblast growth factor 23 levels. Active therapy did, however, significantly increase calcification of the coronary arteries and abdominal aorta (coronary: median increases of 18.1% versus 0.6%, P=0.05; abdominal aorta: median increases of 15.4% versus 3.4%, P=0.03). In conclusion, phosphate binders significantly lower serum and urinary phosphorus and attenuate progression of secondary hyperparathyroidism among patients with CKD who have normal or near-normal levels of serum phosphorus; however, they also promote the progression of vascular calcification. The safety and efficacy of phosphate binders in CKD remain uncertain.

Evaluation of the Evidence for the Trauma and Fantasy Models of Dissociation

Abstract: The relationship between a reported history of trauma and dissociative symptoms has been explained in 2 conflicting ways. Pathological dissociation has been conceptualized as a response to antecedent traumatic stress and/or severe psychological adversity. Others have proposed that dissociation makes individuals prone to fantasy, thereby engendering confabulated memories of trauma. We examine data related to a series of 8 contrasting predictions based on the trauma model and the fantasy model of dissociation. In keeping with the trauma model, the relationship between trauma and dissociation was consistent and moderate in strength, and remained significant when objective measures of trauma were used. Dissociation was temporally related to trauma and trauma treatment, and was predictive of trauma history when fantasy proneness was controlled. Dissociation was not reliably associated with suggestibility, nor was there evidence for the fantasy model prediction of greater inaccuracy of recovered memory. Instead, dissociation was positively related to a history of trauma memory recovery and negatively related to the more general measures of narrative cohesion. Research also supports the trauma theory of dissociation as a regulatory response to fear or other extreme emotion with measurable biological correlates. We conclude, on the basis of evidence related to these 8 predictions, that there is strong empirical support for the hypothesis that trauma causes dissociation, and that dissociation remains related to trauma history when fantasy proneness is controlled. We find little support for the hypothesis that the dissociation–trauma relationship is due to fantasy proneness or confabulated memories of trauma.

The dissociative subtype of posttraumatic stress disorder: rationale, clinical and neurobiological evidence, and implications.

Abstract: BACKGROUND: Clinical and neurobiological evidence for a dissociative subtype of posttraumatic stress disorder (PTSD) has recently been documented. A dissociative subtype of PTSD is being considered for inclusion in the forthcoming Diagnostic and Statistical Manual of Mental Disorders-Fifth Edition (DSM-5) to address the symptoms of depersonalization and derealization found among a subset of patients with PTSD. This article reviews research related to the dissociative subtype including antecedent, concurrent, and predictive validators as well as the rationale for recommending the dissociative subtype. METHODS: The relevant literature pertaining to the dissociative subtype of PTSD was reviewed. RESULTS: Latent class analyses point toward a specific subtype of PTSD consisting of symptoms of depersonalization and derealization in both veteran and civilian samples of PTSD. Compared to individuals with PTSD, those with the dissociative subtype of PTSD also exhibit a different pattern of neurobiological response to symptom provocation as well as a differential response to current cognitive behavioral treatment designed for PTSD. CONCLUSIONS: We recommend that consideration be given to adding a dissociative subtype of PTSD in the revision of the DSM. This facilitates more accurate analysis of different phenotypes of PTSD, assist in treatment planning that is informed by considering the degree of patients' dissociativity, will improve treatment outcome, and will lead to much-needed research about the prevalence, symptomatology, neurobiology, and treatment of individuals with the dissociative subtype of PTSD. Language: en

Functional Brain Basis of Hypnotizability

Abstract: Results: High compared with low hypnotizable individuals had greater functional connectivity between the left dorsolateral prefrontal cortex, an executive-control region of the brain, and the salience network composed of the dorsal anterior cingulate cortex, anterior insula, amygdala, and ventral striatum, involved in detecting, integrating, and filtering relevant somatic, autonomic, and emotional information using independent component analysis. Seed-based analysis confirmed elevated functional coupling between the dorsal anterior cingulate cortex and the dorsolateral prefrontal cortex in high compared with low hypnotizable individuals. These functional differences were not due to any variation in brain structure in these regions, including regional gray and white matter volumes and white matter microstructure.

Antibody-recruiting molecules: an emerging paradigm for engaging immune function in treating human disease.

Abstract: Synthetic immunology, the development of synthetic systems capable of modulating and/or manipulating immunological functions, represents an emerging field of research with manifold possibilities. One focus of this area has been to create low molecular weight synthetic species, called antibody-recruiting molecules (ARMs), which are capable of enhancing antibody binding to disease-relevant cells or viruses, thus leading to their immune-mediated clearance. This article provides a thorough discussion of contributions in this area, beginning with the history of small-molecule-based technologies for modulating antibody recognition, followed by a systematic review of the various applications of ARM-based strategies. Thus, we describe ARMs capable of targeting cancer, bacteria, and viral pathogens, along with some of the scientific discoveries that have resulted from their development. Research in this area underscores the many exciting possibilities at the interface of organic chemistry and immunobiology and is ...

Mind matters in cancer survival.

Abstract: The field of psycho-oncology is hung up on the hyphen in its name. How do we understand the link between mind and body? Is that hyphen merely an arrow to the left, indicating that cancer in the body affects the mind? Can it be an arrow to the right as well, mind affecting the course of cancer? We know that social support affects survival, 1 including that with cancer.2 Also, people tend to die after rather than before their birthdays and major holidays.3,4 Depression worsens survival outcome with cancer.5,6 Yet we have been understandably delicate about mind-body influence, not wanting to claim too much, or to provide unwitting support for overstated claims that wishing away cancer or picturing white blood cells killing cancer cells would actually do it. That arrow to the right is a connection, not a superhighway. Yet in our desire to be respected members of the oncology community we have often minimized a natural ally in the battle against cancer – the patient’s physiological stress coping mechanisms. Even at the end of life, helping patients face death, make informed decisions about level of care, and controlling pain and distress is not only humane but appears to be medically more effective than simply carrying on with intensive anti-cancer treatment alone.7 A recent randomized clinical trial of palliative care for non-small cell lung cancer patients8 makes that case strongly. The authors reported a clear but apparently paradoxical finding: “Despite receiving less aggressive end-of-life care, patients in the palliative care group had significantly longer survival than those in the standard care group (median survival, 11.65 vs. 8.9 months; P=0.02)” (p. 738). Those randomized to palliative care became less depressed as well. The palliative care condition consisted of an average of 4 visits that focused on choices about resuscitation preferences, pain control, and quality of life. The study suggests that at the end of life the most aggressive treatments may not be the most effective, not only psychologically, but also medically. How could living better at the end of life lead to living longer? When we began to investigate the effects of support groups for people with cancer in the 1970’s, we and others were concerned that watching others die of the same disease would demoralize patients, and might even hasten their death. We evaluated mood and discussion content minute-by-minute to determine whether bad news about other group members was despressogenic. We found that these women with advanced breast cancer talked more seriously about death and dying, but showed no signs of depression or panic.9 Indeed our initial studies, confirmed by many others, indicated that we reduced distress and pain.10,11 But now the results are showing something more profound than reduced distress and pain or feeling better, they are showing that facing death better helps people to live longer with cancer. We reported in 1989 the results of a clinical trial demonstrating that women with metastatic breast cancer randomized to a year of weekly group therapy lived 18 months longer than control patients, and that the difference was not due to differences in initial disease severity or subsequent chemo- and radiotherapy. The result of this 10 year study, cited at last count on Google Scholar 2,222 times, was first greeted with great excitement and later skepticism. Now 21 years later, the findings are being confirmed. A decade later we conducted an IRB-approved replication study that showed no overall effect of a similar group therapy on breast cancer survival, but a significant interaction with tumor type, such that those with estrogen receptor negative cancers who were randomized to group therapy lived significantly longer than did ER negative patients receiving standard care alone.12 While this is a clear disconfirmation of the hypothesis that facing death together could improve survival, major advances in hormonal and chemotherapies had improved overall survival for women with metastatic breast cancer in the interim.13 However, women with ER negative tumors were largely excluded from the benefit of hormonal treatments, which could account for the difference in findings.13 Further support for this explanation comes from the fact that overall survival of our cohorts of women with metastatic breast cancer has improved over the decades (See Figure 1). Figure 1 Comparison of Survival across 3 Spiegel Metastatic Breast Cancer Studies More recently, a randomized trial of psychoeducational groups for women with primary breast cancer found both significantly reduced rates of relapse and longer survival. 14,15 In addition to this, our original study16, and the recent palliative care study referred to above,8 three other published randomized psychotherapy trials17–20 and one matched cohort trial21 have reported that psychosocial treatment for patients with a variety of cancers enhanced both psychological and survival outcome (See Table 1). However, six other published studies, 22–27 four involving breast cancer patients,24–27 found no survival benefit for those treated with psychotherapy. (See Table 2) Three of these six studies reported no emotional benefit from the interventions,23–25 making enhanced survival unlikely. In another major multicenter replication trial,26 Supportive-Expressive Group Psychotherapy did significantly reduce depression, but did not improve survival. However, the odd thing about this study is that the women randomized to treatment were more depressed to begin with, making their medical prognosis worse at baseline.6 Furthermore, the outcome of all of these studies is not random: no studies show that gathering cancer patients together in groups and directing their attention to emotional expression and mortality shortens survival.28 Table 1 Randomized Trials Showing Survival Benefit from Psychotherapy Table 2 Randomized Trials Showing No Survival Benefit of Psychotherapy The most provocative but also discordant results have occurred in studies of women with breast cancer, where treatment for ER positive and also human epidermal growth factor receptor 2-positive (HER2+) tumors has improved substantially. Among cancers with poorer medical prognosis, such as ER negative breast cancer, malignant melanoma, non-small cell lung cancer, leukemia, and gastrointestinal cancers, intensive emotional support seems to extend survival. Patients who benefit from a targeted and highly effective chemotherapeutic approach obtain less apparent survival benefit from emotional support than do those with less effective biomedical interventions. Thus, especially in the palliative settling in which aggressive anti-tumor treatments are less efficacious, supportive approaches become more useful. One would think that psychosocial support would have the least biomedical effect in more advanced cancers, and yet our original observation involved women with metastatic breast cancer. By the time someone dies with cancer, they usually have a kilogram of tumor in their body. Yet this may be when the body’s resources for coping with physiological as well as psychological stress matter the most.

Where Are We Going? An Update on Assessment, Treatment, and Neurobiological Research in Dissociative Disorders as We Move Toward the DSM-5

Abstract: This article provides an overview of the process of developing the 5th edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) of the American Psychiatric Association with a focus on issues related to the trauma-related disorders, particularly the dissociative disorders (DD). We also discuss the highlights of research within the past 5 years in the assessment, treatment, and neurobiological basis of trauma disorders. Recent research shows that DD are associated with severe symptoms as well as a higher rate of utilization of mental health treatment compared with other psychiatric disorders. As a result, DD, like other complex posttraumatic disorders, exact a high economic as well as personal burden for patients and society. The latest research indicates that DD patients show a suboptimal response to standard exposure-based treatments for posttraumatic stress disorder as well as high levels of attrition from treatment. An emerging body of research on DD treatment, primarily of naturalistic and open trials, indicates that patients who receive specialized treatment that addresses their trauma-based, dissociative symptoms show improved functioning and reduced symptoms. Recent studies of the underlying neurobiological basis for dissociation support a model of excessive limbic inhibition in DD that is consistent with the phenomenology and clinical presentation of these patients. We are optimistic that the forthcoming DSM-5 will stimulate research on dissociation and the DD and suggest areas for future studies.

Stress, coping, and circadian disruption among women awaiting breast cancer surgery

Abstract: Psychological distress and coping related to a breast cancer diagnosis can profoundly affect psychological adjustment, possibly resulting in the disruption of circadian rest/activity and cortisol rhythms, which are prognostic for early mortality in metastatic colorectal and breast cancers, respectively. This study aims to explore the relationships of cancer-specific distress and avoidant coping with rest/activity and cortisol rhythm disruption in the period between diagnosis and breast cancer surgery. Fifty-seven presurgical breast cancer patients provided daily self-reports of cancer-specific distress and avoidant coping as well as actigraphic and salivary cortisol data. Distress and avoidant coping were related to rest/activity rhythm disruption (daytime sedentariness, inconsistent rhythms). Patients with disrupted rest/activity cycles had flattened diurnal cortisol rhythms. Maladaptive psychological responses to breast cancer diagnosis were associated with disruption of circadian rest/activity rhythms. Given that circadian cycles regulate tumor growth, we need greater understanding of possible psychosocial effects in cancer-related circadian disruption.

Exploring post-translational arginine modification using chemically synthesized methylglyoxal hydroimidazolones.

Abstract: The methylglyoxal-derived hydroimidazolones (MG-Hs) comprise the most prevalent class of non-enzymatic, post-translational modifications of protein arginine residues found in nature. These adducts form spontaneously in the human body, and are also present at high levels in the human diet. Despite numerous lines of evidence suggesting that MG-H-arginine adducts play critical roles in both healthy and disease physiology in humans, detailed studies of these molecules have been hindered by a lack of general synthetic strategies for their preparation in chemically homogeneous form, and on scales sufficient to enable detailed biochemical and cellular investigations. To address this limitation, we have developed efficient, multigram-scale syntheses of all MG-H-amino acid building blocks, suitably protected for solid-phase peptide synthesis, in 2-3 steps starting from inexpensive, readily available starting materials. Thus, MG-H derivatives were readily incorporated into oligopeptides site-specifically using standard solid-phase peptide synthesis. Access to synthetic MG-H-peptide adducts has enabled detailed investigations, which have revealed a series of novel and unexpected findings. First, one of the three MG-H isomers, MG-H3, was found to possess potent, pH-dependent antioxidant properties in biochemical and cellular assays intended to replicate redox processes that occur in vivo. Computational and mechanistic studies suggest that MG-H3-containing constructs are capable of participating in mechanistically distinct H-atom-transfer and single-electron-transfer oxidation processes. Notably, the product of MG-H3 oxidation was unexpectedly observed to disassemble into the fully unmodified arginine residue and pyruvate in aqueous solution. We believe these observations provide insight into the role(s) of MG-H-protein adducts in human physiology, and expect the synthetic reagents reported herein to enable investigations into non-enzymatic protein regulation at an unprecedented level of detail.

A review of safety, efficacy, and utilization of erythropoietin, darbepoetin, and peginesatide for patients with cancer or chronic kidney disease: a report from the Southern Network on Adverse Reactions (SONAR).

Abstract: The erythropoiesis-stimulating agents (ESAs) erythropoietin and darbepoetin prevent transfusions among chemotherapy-associated anemia patients Clinical trials, meta-analyses, and guidelines identify mortality, tumor progression, and venous thromboembolism (VTE) risks with ESA administration in this setting Product labels advise against administering ESAs with potentially curative chemotherapy (United States) or to conduct risk–benefit assessments (Europe/Canada) Since 2007, fewer chemotherapy-associated anemia patients in the United States and Europe receive ESAs ESAs and the erythropoietin receptor agonist peginesatide prevent transfusions among chronic kidney disease (CKD) patients; clinical trials, guidelines, and meta-analyses demonstrate myocardial infarction, stroke, VTE, or mortality risks with ESAs targeting high hemoglobin levels US labels recommend administering ESAs or peginesatide at doses sufficient to prevent transfusions among dialysis CKD patients For dialysis CKD patients, Canadian and European labels recommend targeting hemoglobin levels of 10 to 12 g/dL and 11 to 12 g/dL, respectively, with ESAs ESA utilization for dialysis CKD patients has decreased in the United States

Reprogramming urokinase into an antibody-recruiting anticancer agent

Abstract: The present invention relates to chimeric (preferably, bifunctional) compounds, compositions comprising those compounds and methods of treating cancer in a patient or subject, especially including metastatic cancer where cancer cells exhibit overexpression (heightened expression) of cell surface urokinase-type plasminogen activator receptor (urokinase receptor) compared to normal (non-cancerous) cells. The compounds preferably covalently bind to the urokinase receptor and recruit native antibodies of the patient or subject where the antibodies can selectively degrade and/or deactivate targeted cancer cells through antibody-dependent cellular phagocytosis and/or antibody-dependent cellular cytotoxicity (ADCC) against a large number and variety of cancers, thus providing cancer cell death and/or an inhibition of growth, elaboration and/or metastasis of the cancer, including remission and cure of the patient's cancer.

Disorders of extreme stress.

Abstract: In this chapter we review the concepts of stress and trauma and describe conditions within the American Psychiatric Association's (APA) Diagnostic and Statistical Manual of Mental Disorders–Fourth Edition (DSM-IV; APA, 1994, 2000) that include trauma as an etiological criterion (i.e., acute stress disorder and posttraumatic stress disorder or PTSD), as well as disorders strongly associated with extreme stress and trauma—namely, the dissociative and conversion disorders. We also discuss how proposed changes for the DSM-5 may impact current diagnostic criteria. Although they are not covered in this chapter, depression, anxiety, substance abuse, adjustment, and other disorders can also occur as responses to traumatic stress. Keywords: stress; trauma; PTSD; ASD; dissociative disorders; conversion disorder

Divided consciousness: dissociation in DSM-5.

Abstract: Dr. David Spiegel, M.D., is Jack, Lulu & Sam Willson Professor in the School of Medicine, Associate Chair of Psychiatry & Behavioral Sciences, Director of the Center on Stress and Health, and is founder and Medical Director of the Center for Integrative Medicine at Stanford University School of Medicine, where he has been a member of the academic faculty since 1975 and was Faculty Senate Chair in 2010–2011. He is Past President of the American College of Psychiatrists and of the Society for Clinical and Experimental Hypnosis. He has published 10 books, 368 scientific journal articles, and 156 book chapters on hypnosis, psychosocial oncology, stress physiology, trauma, and psychotherapy. He introduced Acute Stress Disorder in the DSMIV, and serves on the DSM-5 work group on anxiety, trauma-related disorders, and dissociative disorders. He is winner of 22 awards, including the 2011 Arthur Sutherland Award from the International Society of Psycho-Oncology for Lifetime Achievement, the 2004 Judd Marmor Award from the American Psychiatric Association for contributions to biopsychosocial research, and the Hilgard Research Award from the International Society of Hypnosis. He was featured in Bill Moyers’ Emmy award winning PBS series, Healing and the Mind, and recently on the Jane Pauley Show and Good Morning America.

Functional Brain Basis of Hypnotizability

Abstract: CONTEXT Focused hypnotic concentration is a model for brain control over sensation and behavior. Pain and anxiety can be effectively alleviated by hypnotic suggestion, which modulates activity in brain regions associated with focused attention, but the specific neural network underlying this phenomenon is not known. OBJECTIVE To investigate the brain basis of hypnotizability. DESIGN Cross-sectional, in vivo neuroimaging study performed from November 2005 through July 2006. SETTING Academic medical center at Stanford University School of Medicine. PATIENTS Twelve adults with high and 12 adults with low hypnotizability. MAIN OUTCOME MEASURES Functional magnetic resonance imaging to measure functional connectivity networks at rest, including default-mode, salience, and executive-control networks; structural T1 magnetic resonance imaging to measure regional gray and white matter volumes; and diffusion tensor imaging to measure white matter microstructural integrity. RESULTS High compared with low hypnotizable individuals had greater functional connectivity between the left dorsolateral prefrontal cortex, an executive-control region of the brain, and the salience network composed of the dorsal anterior cingulate cortex, anterior insula, amygdala, and ventral striatum, involved in detecting, integrating, and filtering relevant somatic, autonomic, and emotional information using independent component analysis. Seed-based analysis confirmed elevated functional coupling between the dorsal anterior cingulate cortex and the dorsolateral prefrontal cortex in high compared with low hypnotizable individuals. These functional differences were not due to any variation in brain structure in these regions, including regional gray and white matter volumes and white matter microstructure. CONCLUSIONS Our results provide novel evidence that altered functional connectivity in the dorsolateral prefrontal cortex and dorsal anterior cingulate cortex may underlie hypnotizability. Future studies focusing on how these functional networks change and interact during hypnosis are warranted.

Outpatient red blood cell transfusion payments among patients on chronic dialysis

Abstract: Payments for red blood cell (RBC) transfusions are separate from US Medicare bundled payments for dialysis-related services and medications. Our objective was to examine the economic burden for payers when chronic dialysis patients receive outpatient RBC transfusions. Using Truven Health MarketScan® data (1/1/02-10/31/10) in this retrospective micro-costing economic analysis, we analyzed data from chronic dialysis patients who underwent at least 1 outpatient RBC transfusion who had at least 6 months of continuous enrollment prior to initial dialysis claim and at least 30 days post-transfusion follow-up. A conceptual model of transfusion-associated resource use based on current literature was employed to estimate outpatient RBC transfusion payments. Total payments per RBC transfusion episode included screening/monitoring (within 3 days), blood acquisition/administration (within 2 days), and associated complications (within 3 days for acute events; up to 45 days for chronic events). A total of 3283 patient transfusion episodes were included; 56.4% were men and 40.9% had Medicare supplemental insurance. Mean (standard deviation [SD]) age was 60.9 (15.0) years, and mean Charlson comorbidity index was 4.3 (2.5). During a mean (SD) follow-up of 495 (474) days, patients had a mean of 2.2 (3.8) outpatient RBC transfusion episodes. Mean/median (SD) total payment per RBC transfusion episode was $854/$427 ($2,060) with 72.1% attributable to blood acquisition and administration payments. Complication payments ranged from mean (SD) $213 ($168) for delayed hemolytic transfusion reaction to $19,466 ($15,424) for congestive heart failure. Payments for outpatient RBC transfusion episodes were driven by blood acquisition and administration payments. While infrequent, transfusion complications increased payments substantially when they occurred.

A Computerized Treatment Algorithm Trial to Optimize Mineral Metabolism in ESRD

Abstract: Summary Background and objectives Achievement of mineral targets in patients receiving dialysis remains challenging. This study sought to evaluate outcomes for phosphorus, calcium, and parathyroid hormone when a dialysis population was switched from a predominantly active vitamin D analogue treatment regimen to a computerized algorithm incorporating both cinacalcet and active vitamin D as potential first-line therapies. Design, setting, participants, & measurements This longitudinal prospective trial enrolled 92 patients undergoing maintenance hemodialysis. Baseline measures (the average of the 3 months before computerized algorithm implementation) were compared with the proportion of patients achieving the prespecified targets at 6 and 12 months. Results After 6 months there was a statistically significant improvement in the percentage of patients achieving the primary and secondary phosphorus targets (primary: phosphorus ≤ 5.5 mg/dl, increase from 41% to 75%, P P =0.005). These improvements were sustained at 12 months. There was a statistically significant improvement in the percentage of patients achieving all three prespecified secondary endpoints (an increase from 12.8% to 25.6% at 12 months; P =0.04); however, this was mainly driven by improved phosphorus control. The proportion of patients achieving the primary or secondary parathyroid hormone targets did not improve. Conclusions A greater proportion of dialysis patients achieved improved phosphorus but not parathyroid hormone control by switching from a predominantly active vitamin D analogue–based treatment regimen for mineral and bone disorder to a computer-driven algorithm that incorporated cinacalcet and low-dose active vitamin D analogues as first-line therapy.

Circadian rest-activity rhythm as a predictor of survival in metastatic colorectal cancer.

Abstract: e14006 Background: Experimental disruption of the Circadian Timing System (CTS) accelerates cancer progression. The relative amount of activity in-bed versus out-of-bed (I