Occurrence and outcome of de novo metastatic breast cancer by subtype in a large,diverse population

Purpose

To examine the occurrence and outcomes of de novo metastatic (Stage IV) breast cancer, particularly with respect to tumor HER2 expression.

Methods

We studied all 6,268 de novo metastatic breast cancer cases diagnosed from 1 January 2005 to 31 December 2011 and reported to the California Cancer Registry. Molecular subtypes were classified according to HER2 and hormone receptor (HR, including estrogen and/or progesterone receptor) expression. Multivariable logistic regression was used to estimate odds ratios (ORs) and 95 % confidence intervals (CIs) of Stage IV versus Stage I–III breast cancer; Cox proportional hazards regression was used to assess relative hazard (RH) of mortality.

Results

Five percent of invasive breast cancer was metastatic at diagnosis. Compared to patients with earlier stage disease, patients with de novo metastatic disease were significantly more likely to have HER2+ tumors (HR+/HER2+: OR 1.29, 95 % CI 1.17–1.42; HR?/HER2+: OR 1.40, 95 %CI 1.25–1.57, vs. HR+/HER2?). Median survival improved over time, but varied substantially across race/ethnicity (Asians: 34 months; African Americans: 6 months), neighborhood socioeconomic status (SES) (highest: 34 months, lowest: 20 months), and molecular subtype (HR+/HER2+: 45 months; triple negative: 12 months). In a multivariable model, triple negative (RH 2.85, 95 % CI 2.50–3.24) and HR?/HER2+ (RH 1.60, 95 % CI 1.37–1.87) had worse, while HR+/HER2+ had similar, risk of all-cause death compared to HR+/HER2? breast cancer.

Conclusions

De novo metastatic breast cancer was more likely to be HER2+. Among metastatic tumors, those that were HER2+ had better survival than other subtypes.

     

Social intelligence in the normal and autistic brain: an fMRI study.

There is increasing support for the existence of 'social intelligence' [Humphrey (1984) Consciousness Regained], independent of general intelligence. Brothers et al. 1990) J. Cog. Neurosci., 4, 107-118] proposed a network of neural regions that comprise the 'social brain': the orbito-frontal cortex (OFC), superior temporal gyrus (STG) and amygdala. We tested Brothers' theory by examining both normal subjects as well as patients with high-functioning autism or Asperger syndrome (AS), who are well known to have deficits in social intelligence, and perhaps deficits in amygdala function [Bauman & Kemper (1988) J. Neuropath. Exp. Neurol., 47, 369]. We used a test of judging from the expressions of another person's eyes what that other person might be thinking or feeling. Using functional magnetic resonance imaging (fMRI) we confirmed Brothers' prediction that the STG and amygdala show increased activation when using social intelligence. Some areas of the prefrontal cortex also showed activation. In contrast, patients with autism or AS activated the fronto-temporal regions but not the amygdala when making mentalistic inferences from the eyes. These results provide support for the social brain theory of normal function, and the amygdala theory of autism.     

Functional MR imaging of confounded hypofrontality.

Comparatively reduced blood flow to frontal brain regions in patients with schizophrenia (hypofrontality) has been frequently observed in the last 25 years. However, there is an inconstant quality to hypofrontality, suggesting either confounded observation of a static (trait-like) abnormality, or that it is a genuinely dynamic (state-like) phenomenon. Possible confounds in functional magnetic resonance imaging (fMRI) studies of hypofrontality are classified. Methods for assessment and correction of stimulus correlated motion (an extracerebral confound) are reviewed in the context of fMRI data acquired from five schizophrenic patients and five comparison subjects during performance of a verbal fluency task. Factorial analysis of these and other data, acquired from the same subjects during a semantic decision task, is used to exclude a number of possible intracerebral confounds. By analogy to the historical controversy concerning the appearance of the planet Saturn viewed through early telescopes, understanding the inconstancy of hypofrontality in schizophrenia is likely to progress more by theoretically driven experiments that exploit the repeatability of fMRI than by further technological development alone.     

Methods for diagnosis and treatment of stimulus‐correlated motion in generic brain activation studies using fMRI

Movement‐related effects in realigned fMRI timeseries can be corrected by regression on linear functions of estimated positional displacements of an individual subject's head during image acquisition. However, this entails biased (under)estimation of the experimental effect whenever subject motion is not independent of the experimental input function. Methods for diagnosing such stimulus‐correlated motion (SCM) are illustrated by application to fMRI data acquired from 5 schizophrenics and 5 normal controls during periodic performance of a verbal fluency task. The schizophrenic group data were more severely affected by SCM than the control group data. Analysis of covariance (ANCOVA) was used, with a voxelwise measure of SCM as a covariate, to estimate between‐group differences in power of periodic signal change while controlling for variability in SCM across groups. Failure to control for SCM in this way substantially exaggerated the number of voxels, apparently demonstrating a between‐group difference in task response. Hum. Brain Mapping 7:38–48, 1999. © 1999 Wiley‐Liss, Inc.     

Neural correlates of body dissatisfaction in anorexia nervosa

Body dissatisfaction is an important precipitating and maintenance factor in anorexia nervosa (AN) and behavioral studies suggest that a cognitive-affective component and a perceptual component (perceptual disturbance of one's own body) are both important in this pathophysiology. However, the functional neuroanatomy of body dissatisfaction in AN is largely unknown. This study has investigated self-other body-shape comparison to establish neural correlates of body dissatisfaction in patients with AN. 17 women with AN and 18 age and sex-matched healthy control (HC) subjects were scanned using functional magnetic resonance imaging while comparing themselves with images of slim idealized female bodies (active condition) or viewing images of interior home designs (control condition). Participants were asked to compare their body shape or room design with those presented.Patients with AN (in comparison to the HC group) showed greater anxiety to the self-other body-shape comparison, and they were less satisfied with their current body shape. In the patient group (in comparison to the HC group) the self-other body-shape comparison induced more activation of the right sensorimotor brain regions (insula, premotor cortex) and less activation of the rostral anterior cingulate cortex (ACC). Insula hyperactivation along with ACC hypoactivation may be critical for altered interoceptive awareness to body self-comparison and/or for altered implicit motivation to thin-idealized body images in AN patients.     

Effect of Trastuzumab on Health-Related Quality of Life in Patients With HER2-Positive Metastatic Breast Cancer: Data From Three Clinical Trials

BackgroundTrastuzumab (Herceptin®; Genentech, Inc.; South San Francisco, CA) provides clinical benefit when combined with chemotherapy or as monotherapy in patients with HER2-positive metastatic breast cancer (MBC). Given the demonstrated improvement in standard outcomes, it is important to assess this therapy—s effect on patients' health-related quality of life (HRQOL).Patients and MethodsThe QLQ-C30 and BR-23 questionnaires were used to assess global HRQOL; physical, social, and role functioning; and fatigue as secondary endpoints in trials of trastuzumab monotherapy (H0649g and H0650g) or in combination with chemotherapy (H0648g). Patients completed assessments at baseline, week 8 (H0648g only), and at 12-week intervals until disease progression.ResultsIn H0648g (n = 400), more patients exhibited improved global QOL in the chemotherapy-plus-trastuzumab versus chemotherapy arms (51% vs. 36%; P < .05). In the chemotherapy-plus-trastuzumab arm, fatigue was significantly improved at week 32 (chemotherapy completed at week 20) compared with baseline in both study arms (P < .05); more patients in the chemotherapy-plus-trastuzumab arm also showed improved physical and role functioning. Subscale scores in H0649g (n = 154) and H0650g (n = 74) were similar at all time points. In H0649g, clinical responders showed meaningful improvements (≥ 10 points) in all 5 subscales by week 12 through week 36. Nonresponders had meaningful decreases in all subscale scores. In H0650g, clinical responders exhibited meaningful increases in social and role functioning and global QOL by week 12; nonresponder scores worsened for all subscales.ConclusionTrastuzumab has a beneficial effect on HRQOL in patients with HER2-positive MBC, particularly those with responsive disease.     

The effect of different warming methods on sensory nerve conduction velocity in shipyard workers occupationally exposed to hand–arm vibration

OBJECTIVES: Segmental sensory nerve conduction velocity (SNCV) was measured from the wrists to the hands and digits in a population of 134 (126 men and 8 women) vibration-exposed shipyard workers following systemic warming using a bicycle ergometer. Results were compared to earlier nerve conduction tests, identical in execution, except that the warming process was segmental and cutaneous. The study was designed to investigate whether SNCVs, which were selectively slow in the fingers after segmental cutaneous (skin surface) warming, would be affected differently by systemic warming. METHODS: Wrist-palm, palm-proximal digit, and digital sensory nerve segments were assessed antidromically by stimulating at the wrist with recording electrodes placed distally. The same subjects were cutaneously warmed in 2001 to >/=31 degrees C and were systemically warmed 28 months later in 2004 by ramped sustained exercise to 100 W for 12 min. Skin temperatures were measured by traditional thermistry and by infrared thermal images taken over the hand and wrist surfaces. RESULTS: When systemic warming was compared to segmental cutaneous warming, SNCVs were increased by 15.1% in the third digit and 20.4% in the fifth digit of the dominant hand. Respective increases in the non-dominant hand were 11.0% and 19.4%. A strong association between increased surface skin temperature and faster SNCV, which had been observed after segmental cutaneous warming, was largely eliminated for both digit and palmar anatomic segments after systemic warming. Significant differences in SNCV between vibration-exposed and non-exposed workers, which had been observed after segmental cutaneous warming, were eliminated after systemic warming. Systemic warming had only a small effect on the wrist-palm (transcarpal) segmental SNCVs. CONCLUSIONS: Reduced SNCV in the digits was observed in vibration-exposed and non-exposed workers. Substituting exercise-induced systemic warming for segmental cutaneous warming significantly increased SNCV in the digits and appeared to reduce differences in SNCV between vibration-exposed and non-exposed workers. These findings persisted despite a substantial time interval between tests, during which the subjects continued to work. There may be more general implications for diagnosing clinical conditions in industrial workers, such as the carpal tunnel syndrome and the hand-arm vibration syndrome.     

Outcomes in patients with multiple myeloma with TP53 deletion after autologous hematopoietic stem cell transplant

TP53 gene deletion is associated with poor outcomes in multiple myeloma (MM). We report the outcomes of patients with MM with and without TP53 deletion who underwent immunomodulatory drug (IMiD) and/or proteasome inhibitor (PI) induction followed by autologous hematopoietic stem cell transplant (auto‐HCT). We identified 34 patients with MM and TP53 deletion who underwent IMiD and/or PI induction followed by auto‐HCT at our institution during 2008–2014. We compared their outcomes with those of control patients (n = 111) with MM without TP53 deletion. Median age at auto‐HCT was 59 years in the TP53‐deletion group and 58 years in the control group (P = 0.4). Twenty‐one patients (62%) with TP53 deletion and 69 controls (62%) achieved at least partial remission before auto‐HCT (P = 0.97). Twenty‐three patients (68%) with TP53 deletion and 47 controls (42%) had relapsed disease at auto‐HCT (P = 0.01). Median progression‐free survival was 8 months for patients with TP53 deletion and 28 months for controls (P < 0.001). Median overall survival was 21 months for patients with TP53 deletion and 56 months for controls (P < 0.001). On multivariate analysis of both groups, TP53 deletion (hazard ratio 3.4, 95% confidence interval 1.9–5.8, P < 0.001) and relapsed disease at auto‐HCT (hazard ratio 2.0, 95% confidence interval 1.2–3.4, P = 0.008) were associated with a higher risk of earlier progression. In MM patients treated with PI and/or IMiD drugs, and auto‐HCT, TP53 deletion and relapsed disease at the time of auto‐HCT are independent predictors of progression. Novel approaches should be evaluated in this high‐risk population. Am. J. Hematol. 91:E442–E447, 2016. © 2016 Wiley Periodicals, Inc.     

Human attachment security is mediated by the amygdala: evidence from combined fMRI and psychophysiological measures

The neural basis of human attachment security remains unexamined. Using event-related functional magnetic resonance imaging (fMRI) and simultaneous recordings of skin conductance levels, we measured neural and autonomic responses in healthy adult individuals during a semantic conceptual priming task measuring human attachment security "by proxy". Performance during a stress but not a neutral prime condition was associated with response in bilateral amygdalae. Furthermore, levels of activity within bilateral amygdalae were highly positively correlated with attachment insecurity and autonomic response during the stress prime condition. We thereby demonstrate a key role of the amygdala in mediating autonomic activity associated with human attachment insecurity.