Aparna Keshaviah

Five years of letrozole compared with tamoxifen as initial adjuvant therapy for postmenopausal women with endocrine-responsive early breast cancer: update of study BIG 1-98

PURPOSE Previous analyses of the Breast International Group (BIG) 1-98 four-arm study compared initial therapy with letrozole or tamoxifen including patients randomly assigned to sequential treatment whose information was censored at the time of therapy change. Because this presentation may unduly reflect early events, the present analysis is limited to patients randomly assigned to the continuous therapy arms and includes protocol-defined updated results. PATIENTS AND METHODS Four thousand nine hundred twenty-two of the 8,028 postmenopausal women with receptor-positive early breast cancer randomly assigned (double-blind) to the BIG 1-98 trial were assigned to 5 years of continuous adjuvant therapy with either letrozole or tamoxifen; the remainder of women were assigned to receive the agents in sequence. Disease-free survival (DFS) was the primary end point. RESULTS At a median follow-up time of 51 months, we observed 352 DFS events among 2,463 women receiving letrozole and 418 events among 2,459 women receiving tamoxifen. This reflected an 18% reduction in the risk of an event (hazard ratio, 0.82; 95% CI, 0.71 to 0.95; P = .007). No predefined subsets showed differential benefit. Adverse events were similar to previous reports. Patients on tamoxifen experienced more thromboembolic events, endometrial pathology, hot flashes, night sweats, and vaginal bleeding. Patients on letrozole experienced more bone fractures, arthralgia, low-grade hypercholesterolemia, and cardiovascular events other than ischemia and cardiac failure. CONCLUSION The present updated analysis, which was limited to patients on monotherapy arms in BIG 1-98, yields results similar to those from the previous primary analysis but more directly comparable with results from other trials of continuous therapy using a single endocrine agent.

Complicated grief and related bereavement issues for DSM‐5

Bereavement is a severe stressor that typically incites painful and debilitating symptoms of acute grief that commonly progresses to restoration of a satisfactory, if changed, life. Normally, grief does not need clinical intervention. However, sometimes acute grief can gain a foothold and become a chronic debilitating condition called complicated grief. Moreover, the stress caused by bereavement, like other stressors, can increase the likelihood of onset or worsening of other physical or mental disorders. Hence, some bereaved people need to be diagnosed and treated. A clinician evaluating a bereaved person is at risk for both over‐and under‐diagnosis, either pathologizing a normal condition or neglecting to treat an impairing disorder. The authors of DSM IV focused primarily on the problem of over‐diagnosis, and omitted complicated grief because of insufficient evidence. We revisit bereavement considerations in light of new research findings. This article focuses primarily on a discussion of possible inclusion of a new diagnosis and dimensional assessment of complicated grief. We also discuss modifications in the bereavement V code and refinement of bereavement exclusions in major depression and other disorders. Depression and Anxiety, 2011.

Impact of a Mixed Strength and Endurance Exercise Intervention on Insulin Levels in Breast Cancer Survivors

PURPOSE Accumulating data suggest that exercise may affect breast cancer risk and outcomes. Studies have demonstrated that high levels of insulin, often seen in sedentary individuals, are associated with increased risk of breast cancer recurrence and death. We sought to analyze whether exercise lowered insulin concentrations in breast cancer survivors. METHODS One hundred one sedentary, overweight breast cancer survivors were randomly assigned either to a 16-week cardiovascular and strength training exercise intervention or to a usual care control group. Fasting insulin and glucose levels, weight, body composition, and circumference at the waist and hip were collected at baseline and 16 weeks. RESULTS Baseline and 16-week measurements were available for 82 patients. Fasting insulin concentrations decreased by an average of 2.86 microU/mL in the exercise group (P = .03), with no significant change in the control group (decrease of 0.27 microU/mL, P = .65). The change in insulin levels in the exercise group seemed greater than the change in controls, but the comparison did not reach statistical significance (P = .07). There was a trend toward improvement in insulin resistance in the exercise group (P = .09) but no change in fasting glucose levels. The exercise group also experienced a significant decrease in hip measurements, with no change in weight or body composition. CONCLUSION Participation in an exercise intervention was associated with a significant decrease in insulin levels and hip circumference in breast cancer survivors. The relationship between physical activity and breast cancer prognosis may be mediated, in part, through changes in insulin levels and/or changes in body fat or fat deposition.

Trastuzumab plus vinorelbine or taxane chemotherapy for HER2‐overexpressing metastatic breast cancer: The trastuzumab and vinorelbine or taxane study

The optimal trastuzumab‐based chemotherapy regimen for HER2‐overexpressing, metastatic breast cancer is not known. The trastuzumab and vinorelbine or taxane (TRAVIOTA) study was a prospective, multicenter, randomized trial that was designed to compare these regimens.

Deficits in Conditioned Fear Extinction in Obsessive-Compulsive Disorder and Neurobiological Changes in the Fear Circuit

IMPORTANCE Obsessive-compulsive disorder (OCD) may be characterized by impaired self-regulation and behavioral inhibition. Elevated fear and anxiety are common characteristics of this disorder. The neurobiology of fear regulation and consolidation of safety memories have not been examined in this patient population. OBJECTIVE To examine the psychophysiological and neurobiological correlates of conditioned fear extinction in patients with OCD. DESIGN Cross-sectional, case-control, functional magnetic resonance imaging study. SETTING Academic medical center. PARTICIPANTS Twenty-one patients with OCD and 21 healthy participants. MAIN OUTCOMES AND MEASURES Skin conductance responses and blood oxygenation level-dependent responses. RESULTS The between-group difference noted in our psychophysiological measure (skin conductance responses) was during extinction recall: patients with OCD showed impaired extinction recall relative to control subjects. Regarding the functional magnetic resonance imaging data, patients with OCD showed significantly reduced activation in the ventromedial prefrontal cortex across training phases. Moreover, reduced activation in the patients with OCD was noted in the caudate and hippocampus during fear conditioning, as well as in the cerebellum, posterior cingulate cortex, and putamen during extinction recall. Contrary to our prediction, OCD symptom severity was positively correlated with the magnitude of extinction memory recall. Also contrary to our prediction, functional responses of the ventromedial prefrontal cortex were positively correlated with symptom severity, and functional responses of the dorsal anterior cingulate cortex were inversely correlated with symptom severity. CONCLUSIONS AND RELEVANCE As expected, our study showed that fear extinction and its neural substrates are impaired in patients with OCD. However, this study also yielded some surprising and unexpected results regarding the correlates between extinction capacity and its neural substrates and the severity of symptoms expressed in this disorder. Thus, our data report neural correlates of deficient fear extinction in patients with OCD. The negative correlations between fear extinction deficits and Yale-Brown Obsessive-Compulsive Scale symptoms in OCD suggest that there may be other factors, in addition to fear extinction deficiency, that contribute to the psychopathology of OCD.

A Longitudinal Investigation of Mortality in Anorexia Nervosa and Bulimia Nervosa

OBJECTIVE Although anorexia nervosa has a high mortality rate, our understanding of the timing and predictors of mortality in eating disorders is limited. The authors investigated mortality in a long-term study of patients with eating disorders. METHOD Beginning in 1987, 246 treatment-seeking female patients with anorexia nervosa or bulimia nervosa were interviewed every 6 months for a median of 9.5 years to obtain weekly ratings of eating disorder symptoms, comorbidity, treatment participation, and psychosocial functioning. From January 2007 to December 2010 (median follow-up of 20 years), vital status was ascertained with a National Death Index search. RESULTS Sixteen deaths (6.5%) were recorded (lifetime anorexia nervosa, N=14; bulimia nervosa with no history of anorexia nervosa, N=2). The standardized mortality ratio was 4.37 (95% CI=2.4-7.3) for lifetime anorexia nervosa and 2.33 (95% CI=0.3-8.4) for bulimia nervosa with no history of anorexia nervosa. Risk of premature death among patients with lifetime anorexia nervosa peaked within the first 10 years of follow-up, resulting in a standardized mortality ratio of 7.7 (95% CI=3.7-14.2). The standardized mortality ratio varied by duration of illness and was 3.2 (95% CI=0.9-8.3) for patients with lifetime anorexia nervosa for 0 to 15 years (4/119 died), and 6.6 (95% CI=3.2-12.1) for those with lifetime anorexia nervosa for >15 to 30 years (10/67 died). Multivariate predictors of mortality included alcohol abuse, low body mass index, and poor social adjustment. CONCLUSIONS These findings highlight the need for early identification and intervention and suggest that a long duration of illness, substance abuse, low weight, and poor psychosocial functioning raise the risk for mortality in anorexia nervosa.

A neural survival factor is a candidate oncogene in breast cancer

Using serial analysis of gene expression (SAGE), we identified a SAGE tag that was present only in invasive breast carcinomas and their lymph node metastases. The transcript corresponding to this SAGE tag, dermcidin (DCD), encodes a secreted protein normally expressed only in the pons of the brain and sweat glands. Array comparative genomic hybridization, fluorescence in situ hybridization, and immunohistochemical analyses determined that DCD is overexpressed in ≈10% of invasive breast carcinomas; in some cases its overexpression is coupled with a focal copy number gain of its locus at 12q13.1, and its expression is associated with advanced clinical stage and poor prognosis. Expression of DCD in breast cancer cells promotes cell growth and survival and reduces serum dependency. Putative high- and low-affinity receptors for DCD are present on the cell surface of breast carcinomas and neurons of the brain. Based on these data we hypothesize that DCD may play a role in tumorigenesis by means of enhancing cell growth and survival in a subset of breast carcinomas.

Cardiovascular Adverse Events During Adjuvant Endocrine Therapy for Early Breast Cancer Using Letrozole or Tamoxifen: Safety Analysis of BIG 1-98 Trial

PURPOSE Previous analyses of adjuvant studies of aromatase inhibitors versus tamoxifen, including the Breast International Group (BIG) 1-98 study, have suggested a small numerical excess of cardiac adverse events (AEs) on aromatase inhibitors, a reduction in the incidence of hypercholesterolemia on tamoxifen, and significantly higher incidence of thromboembolic AEs on tamoxifen. The purpose of the present study is to provide detailed updated information on these AEs in BIG 1-98. PATIENTS AND METHODS Eight thousand twenty-eight postmenopausal women with receptor-positive early breast cancer were randomly assigned (double-blind) between March 1998 and May 2003 to receive 5 years of adjuvant endocrine therapy with letrozole, tamoxifen, or a sequence of these agents. Seven thousand nine hundred sixty-three patients who actually received therapy are included in this safety analysis, which focuses on cardiovascular events. AE recording ceased 30 days after therapy completion (or after switch on the sequential arms). RESULTS Baseline comorbidities were balanced. At a median follow-up time of 30.1 months, we observed similar overall incidence of cardiac AEs (letrozole, 4.8%; tamoxifen, 4.7%), more grade 3 to 5 cardiac AEs on letrozole (letrozole, 2.4%; tamoxifen, 1.4%; P = .001)--an excess only partially attributable to prior hypercholesterolemia--and more overall (tamoxifen, 3.9%; letrozole, 1.7%; P < .001) and grade 3 to 5 thromboembolic AEs on tamoxifen (tamoxifen, 2.3%; letrozole, 0.9%; P < .001). There was no significant difference between tamoxifen and letrozole in incidence of hypertension or cerebrovascular events. CONCLUSION The present safety analysis, limited to cardiovascular AEs in BIG 1-98, documents a low overall incidence of cardiovascular AEs, which differed between treatment arms.

The Epidemiology of the Proposed DSM-5 Hoarding Disorder: Exploration of the Acquisition Specifier, Associated Features, and Distress

OBJECTIVE Compulsive hoarding, characterized by the acquisition of and failure to discard a large number of possessions, is increasingly recognized as a significant public health burden. Many facets of the phenomenology, including an understanding of the population prevalence and associated features, are not yet fully understood. There is growing evidence that hoarding may warrant its own diagnosis in DSM-5, and it is therefore imperative to investigate the proposed cardinal symptoms along with correlated features that may be diagnostically relevant. METHOD The present investigation examined the point prevalence of hoarding disorder in a nationally representative sample from the German population (N = 2,512). The hoarding definition considered in this study was derived from the Hoarding Rating Scale (HRS) and informed by 3 of the proposed DSM-5 criteria. Several hypothesized core components of hoarding disorder were also assessed using questions from the HRS and the UCLA Hoarding Severity Scale, including types of acquisition, perfectionism, indecision, procrastination, distress, and impairment. Data were collected from May 16, 2009, to June 19, 2009. RESULTS Analyses revealed a current population estimate of 5.8%. Hoarding prevalence did not differ between men and women. Hoarders were significantly more likely to buy items, acquire free things, and steal items they did not need, compared to nonhoarders (P < .001). Perfectionism, indecision, and procrastination were all uniquely and significantly associated with hoarding status (P < .001). Relationships between the proposed core features and distress/impairment are also detailed. CONCLUSIONS The current investigation identified the proposed hoarding disorder as a highly prevalent syndrome; however, it should be noted that we were not able to fully ascertain the DSM-5 criteria and that the current estimate may be higher than the actual population rate. Future research on the diagnostic criteria and associated features will be necessary to help clarify etiologic underpinnings, treatment efforts, and diagnostic nosology.

Informing the Symptom Profile of Complicated Grief

Background: Complicated Grief (CG) is under consideration as a new diagnosis in DSM5. We sought to add empirical support to the current dialogue by examining the commonly used Inventory of Complicated Grief (ICG) scale completed by 782 bereaved individuals. Methods: We employed IRT analyses, factor analyses, and sensitivity and specificity analyses utilizing our full sample (n = 782), and also compared confirmed CG cases (n = 288) to noncases (n = 377). Confirmed CG cases were defined as individuals bereaved at least 6 months who were seeking care for CG, had an ICG≥30, and received a structured clinical interview for CG by a certified clinician confirming CG as their primary illness. Noncases were bereaved individuals who did not present with CG as a primary complaint (including those with depression, bipolar disorder, anxiety disorders, and controls) and had an ICG<25. Results: IRT analyses provided guidance about the most informative individual items and their association with CG severity. Factor analyses demonstrated a single factor solution when the full sample was considered, but within CG cases, six symptom clusters emerged: (1) yearning and preoccupation with the deceased, (2) anger and bitterness, (3) shock and disbelief, (4) estrangement from others, (5) hallucinations of the deceased, and (6) behavior change, including avoidance and proximity seeking. The presence of at least one symptom from three different symptom clusters optimized sensitivity (94.8%) and specificity (98.1%). Conclusions: These data, derived from a diverse and predominantly clinical help seeking population, add an important perspective to existing suggestions for DSM5 criteria for CG. Depression and Anxiety, 2011.  © 2010 Wiley‐Liss, Inc.