Pertuzumab plus trastuzumab in combination with standard neoadjuvant anthracycline-containing and anthracycline-free chemotherapy regimens in patients with HER2-positive early breast cancer: a randomized phase II cardiac safety study (TRYPHAENA).

BACKGROUND: Pertuzumab (P) combined with trastuzumab (H)-based chemotherapy improves efficacy in early and advanced HER2-positive breast cancer. We assessed the tolerability, with particular focus on cardiac safety, of H and P with chemotherapy in the neoadjuvant treatment of HER2-positive early breast cancer. PATIENTS AND METHODS: In this multicenter, open-label phase II study, patients with operable, locally advanced, or inflammatory breast cancer were randomized 1 : 1 : 1 to receive six neoadjuvant cycles q3w (Arm A: 5-fluorouracil, epirubicin, cyclophosphamide [FEC] + H + P ×3 → docetaxel [T] + H + P ×3; Arm B: FEC ×3 → T + H + P ×3; Arm C: T + carboplatin + H [TCH]+P ×6). pCR was assessed at surgery and adjuvant therapy given to complete 1 year of H. RESULTS: Two hundred twenty-five patients were randomized. During neoadjuvant treatment, two patients (2.7%; Arm B) experienced symptomatic left ventricular systolic dysfunction (LVSD) and 11 patients (Arm A: 4 [5.6%]; Arm B: 4 [5.3%]; Arm C: 3 [3.9%]) had declines in left ventricular ejection fraction of ≥10% points from baseline to <50%. Diarrhea was the most common adverse event. pCR (ypT0/is) was reported for 61.6% (Arm A), 57.3% (Arm B), and 66.2% (Arm C) of patients. CONCLUSION: The combination of P with H and standard chemotherapy resulted in low rates of symptomatic LVSD.

Ginkgo biloba extract enhances noncontact erection in rats: the role of dopamine in the paraventricular nucleus and the mesolimbic system.

Penile erection is essential for successful copulation in males. Dopaminergic projections from the paraventricular nucleus (PVN) to the ventral tegmental area (VTA) and from the VTA to the nucleus accumbens (NAc) are thought to exert a facilitatory effect on penile erection. Our previous study showed that treatment with an extract of Ginkgo biloba leaves (EGb 761) enhances noncontact erection (NCE) in male rats. However, the relationship between NCE and dopaminergic activity in the PVN, VTA, and NAc remains unknown. The present study examined the relationship between NCE and central dopaminergic activity following EGb 761 treatment. We report here that, in comparison with the controls, there was a significant increase in the number of NCEs in rats after treatment with 50 mg/kg of EGb 761 for 14 days. EGb 761-treated rats also showed more NCEs than the same group before EGb 761 treatment. A significant increase in the expression of catecholaminergic neurons in the PVN and the VTA was seen by means of tyrosine hydroxylase immunohistochemistry, and tissue levels of dopamine and 3,4-dihydroxyphenylacetic acid in the NAc were also markedly increased in the EGb 761-treated animals. However, the norepinephrine tissue levels in the PVN and the NAc in the EGb 761-treated group were not significantly different from those in the controls. Together, these results suggest that administration of EGb 761 increases dopaminergic activity in the PVN and the mesolimbic system to facilitate NCE in male rats.

Prevalence, correlates, and self-management of HIV-related depressive symptoms.

Depressive symptoms are highly prevalent yet undertreated in people living with HIV/AIDS (PLHAs). As part of a larger study of symptom self-management (N=1217), this study examined the prevalence, correlates, and characteristics (intensity, distress, and impact) of depressive symptoms, and the self-care strategies used to manage those symptoms in PLHAs in five countries. The proportion of respondents from each country in the total sample reporting depressive symptoms in the past week varied and included Colombia (44%), Norway (66%), Puerto Rico (57%), Taiwan (35%), and the USA (56%). Fifty-four percent (n=655) of the total sample reported experiencing depressive symptoms in the past week, with a mean of 4.1 (SD 2.1) days of depression. Mean depression intensity 5.4 (SD 2.7), distressfulness 5.5 (SD 2.86), and impact 5.5 (SD 3.0) were rated on a 1-10 scale. The mean Center for Epidemiologic Studies Depression Scale score for those reporting depressive symptoms was 27 (SD 11; range 3-58), and varied significantly by country. Respondents identified 19 self-care behaviors for depressive symptoms, which fell into six categories: complementary therapies, talking to others, distraction techniques, physical activity, medications, and denial/avoidant coping. The most frequently used strategies varied by country. In the US sample, 33% of the variance in depressive symptoms was predicted by the combination of education, HIV symptoms, psychological and social support, and perceived consequences of HIV disease.

Symptom management and self-care for peripheral neuropathy in HIV/AIDS.

Peripheral neuropathy is the most common neurological complication in HIV and is often associated with antiretroviral therapy. As part of a larger study on self-care for symptoms in HIV disease, this study analyzed the prevalence and characteristics of peripheral neuropathy in HIV disease, sociodemographic and disease-related correlates and self-care strategies. A convenience sample of 1,217 respondents was recruited from data collection sites in several US cities, Puerto Rico, Colombia and Taiwan. Results of the study indicated that respondents with peripheral neuropathy (n=450) identified 20 self-care behaviors including complementary therapies, use of medications, exercise and rest and/or elevation of extremities. Ratings of frequency and effectiveness were also included. An activities checklist summarized into five categories of self-care behaviors including activities/thoughts, exercise, medications, complementary therapies and substance was used to determine self-care behaviors. Taking a hot bath was the most frequent strategy used by those with peripheral neuropathy (n=292) and received the highest overall rating of effectiveness of any self-management strategies included in this study at 8.1 (scale 1-10). Other self-care strategies to manage this symptom included: staying off the feet (n=258), rubbing the feet with cream (n=177), elevating the feet (n=236), walking (n=262), prescribed anti-epileptic agent (n=80), prescribed analgesics (n=84), over-the-counter medications (n=123), vitamin B (n=122), calcium supplements (n=72), magnesium (n=48), massage (n=156), acupuncture (n=43), reflexology (n=23) and meditation (n=80). Several behaviors that are often deemed unhealthy were included among the strategies reported to alleviate peripheral neuropathy including use of marijuana (n=67), cigarette smoking (n=139), drinking alcohol (n=81) and street drugs (n=30).

Strategies for self-management of HIV-related anxiety.

This study examines the frequency and effectiveness of commonly used strategies for self management of anxiety in an international sample of 502 participants from Norway (n=42, 8%), Taiwan (n=35, 7%), and the US (n=426, 85%). An activities checklist summarized into five categories of self-care behaviours including activities/thoughts, exercise, medications, complementary therapies, and substance use determined self-care behaviours. Ratings of frequency and effectiveness for each self-care activity were also included. Praying received the highest overall rating of effectiveness of any self-management strategies included in this study at 8.10 (scale 1 to 10), followed by meditation (7.37), exercising (7.32), using relaxation techniques (7.22), cooking (6.98), and walking (6.90). An analysis of effectiveness scores for each self-care strategy by country reflected a wide variation. The three most effective anxiety self-care strategies reported by participants from Norway included exercise (7.31), walking (6.96), and reading (6.44). Highest ratings of effectiveness by participants from Taiwan included talking with others with HIV (6.0), attending support groups (6.0), and exercising (6.0). US participants allocated highest ratings of effectiveness to complementary/alternative therapies, including praying (8.10), meditating (7.43), and using relaxation techniques (7.35). Regardless of the country, watching television and talking with family and friends were the two most frequently reported strategies. These strategies for self-management of HIV-related anxiety are important for clinicians to be aware of in the care of persons with HIV/AIDS.

Changes in sleep patterns by intralaminar thalamic microinjection of fluoxetine in rats.

Sleep patterns were investigated in rats by analysis of EEG recorded for 6 hours following fluoxetine or saline (control) microinjection into the centromedial intralaminar thalamus (CIT) at either 9:30 AM or 1:30 PM, 4 or 8 hours after lights on, respectively. The treatment of fluoxetine at 9:30 AM did not affect any sleep patterns. In contrast, fluoxetine significantly suppressed total paradoxical sleep (PS) time and the number of PS episodes during the second and third hour after administration at 1:30 PM. In addition, microinjection of fluoxetine produced an apparent enhancement of the duration of slow wave sleep (SWS) episodes and a small non-significant increase in total SWS time. On the other hand, no obvious changes in the basal sleep-wakefulness pattern were found between the two saline-treated control groups. These results indicate that CIT microinjection of fluoxetine at different time points acts differentially in sleep patterns and suggest that CIT may be one of the action sites for peripherally administered fluoxetine to alter sleep patterns.

Norepinephrine levels in the vomeronasal system and their responses to male urine in young and aged female rats.

Norepinephrine (NE) levels in brain areas of the vomeronasal system in young (4-5 months) and aged (25-26 months) ovariectomized Sprague-Dawley rats, which were implanted with a 17 beta-estradiol silastic capsule and then exposed to male rat urine, were investigated. The unilateral vomeronasal organ was removed in all rats one week before exposure to urine stimulation. NE levels in the medial nucleus of the amygdala (MA), medial preoptic area (MPOA), ventromedial nucleus of hypothalamus (VMH) and bed nucleus of stria terminalis (BST) were measured. NE concentrations in these brain areas of the surgical side served as the control. Urine collected from young adult male rats was poured into the female's cage at 12:00h and the animals were sacrificed before and 1, 2, or 3 hours after the male urine was given. The NE basal levels in the MA and MPOA of young rats decreased significantly from 13:00h to 15:00h, and those in young rat VMH declined markedly from 13:00h to 14:00h compared to those at 12:00h. No marked alterations in NE basal levels in young rat BST were found. In contrast, no obvious changes in the NE concentrations were observed in these brain areas of old rats. Continuous exposure to male urine did not affect the NE levels in any of these brain areas of young and aged rats. We concluded that (1) the time-dependent fluctuation of the NE basal levels in some brain areas of the vomeronasal system in female rats is age-related, and (2) the NE in all these nuclei of the vomeronasal system is not involved in pheromone-induced effects.

Influence of long-term continuous illumination on the nuclear volume of hypothalamic neurons in female rats.

A light microscopic quantitative analysis was performed for studying the effects of long-term exposure to continuous illumination on hypothalamic morphology in female rats. Nuclear volumes of neurons in the suprachiasmatic nucleus, paraventricular nucleus, ventromedial nucleus and preoptic area were measured in 16-18 month-old Long-Evans female rats which had been exposed to continuous light for 11 months. Significant nuclear volume shrinkage could be observed in all investigated regions except for the preoptic area in these animals when compared to that of control rats kept under a photoperiod of 14h light and 10h dark. The relationship between morphological changes of hypothalamic neurons and the marked alteration of melatonin and estrogen levels induced by long-term exposure to continuous light is discussed.

Morphological changes in the hypothalamic neurons of female rats exposed to continuous illumination.

The morphological changes of neurons in the paraventricular nucleus (PVN), suprachiasmatic nucleus (SCN), ventromedial nucleus (VMN), preoptic area (POA), supraoptic nucleus (SON) and arcuate nucleus (ARN) were studied in 16-18 month-old Long-Evans female rats which had been exposed to continuous illumination (LL) for 11 months. Most neurons in those hypothalamic areas showed compact cytoplasm with abundant Nissl substances and evenly distributed chromatin. These morphological features were not found in the same hypothalamic regions of rats placed under a regular alternative light-dark regimen (14h light and 10h dark). These findings suggest that decreased melatonin and elevated estrogen levels induced by long-term exposure to LL might be involved in the morphological changes in hypothalamic neurons of female rats.