Trastuzumab deruxtecan in patients with previously treated HER2-low advanced breast cancer and active brain metastases: the DEBBRAH trial.

BACKGROUND: Trastuzumab deruxtecan (T-DXd) is approved for human epidermal growth factor receptor 2 (HER2)-positive and HER2-low advanced breast cancer (ABC). T-DXd has shown encouraging intracranial activity in HER2-positive ABC patients with stable or active brain metastases (BMs); however, its efficacy in patients with HER2-low ABC with BMs is not well established yet. METHODS: DEBBRAH is a single-arm, five-cohort, phase II study evaluating T-DXd in patients with central nervous system involvement from HER2-positive and HER2-low ABC. Here, we report results from patients with heavily pretreated HER2-low ABC and active BMs, enrolled in cohorts 2 (n = 6, asymptomatic untreated BMs) and 4 (n = 6, progressing BMs after local therapy). Patients received 5.4 mg/kg T-DXd intravenously once every 21 days. The primary endpoint was intracranial objective response rate per Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) for both cohorts. RESULTS: Intracranial objective response rate per RANO-BM was 50.0% [3/6 patients; 95% confidence interval (CI) 11.8% to 88.2%] and 33.3% [2/6 patients; 95% CI 4.3% to 77.7%; P = 0.033 (one-sided)] in cohorts 2 and 4, respectively. All responders had partial responses. Median time to intracranial response was 2.3 months (range, 1.5-4.0 months) and median duration of intracranial response was 7.2 months (range, 2.8-16.8 months). Median progression-free survival per RECIST v.1.1. was 5.4 months (95% CI 4.1-10.0 months). Treatment-emergent adverse events occurred in all patients included (16.7% grade 3). Three patients (25.0%) had grade 1 interstitial lung disease/pneumonitis. CONCLUSIONS: T-DXd demonstrated promising intracranial activity in pretreated HER2-low ABC patients with active BMs. Further studies are needed to validate these results in larger cohorts. This trial is registered with ClinicalTrials.gov, NCT04420598.

High Levels of Heavy Metals detected in Feathers of an Avian Scavenger Warn of a High Pollution Risk in the Atacama Desert (Chile).

The Atacama Desert represents the highest levels of mining exploitation in Chile, which inexorably results in high levels of pollution. Raptors, and particularly scavengers, have shown their usefulness to evaluate exposure to environmental contaminants in polluted scenarios. In this study, we used primary feathers from a local avian scavenger, turkey vulture Cathartes aura, to evaluate the exposure to cadmium (Cd), lead (Pb), copper (Cu) and zinc (Zn) in two locations from the southern Atacama Desert (coastal and inland) and a third location from the bordering semiarid region, in northern Chile. All metals were detected in all analyzed samples (n = 54). Mean concentrations in Coastal Atacama were 0.68 ± 0.84 ppm for Cd; 1.97 ± 2.01 ppm for Pb; 59.11 ± 80.69 ppm for Cu; and 107.96 ± 51.00 ppm for Zn, while mean concentrations in Inland Atacama were 0.55 ± 0.42 ppm for Cd; 3.37 ± 2.61 ppm for Pb; 91.66 ± 77.74 ppm for Cu; and 214.03 ± 99.08 ppm for Zn. Mean concentrations in Coastal Coquimbo were 0.63 ± 0.69 ppm for Cd; 1.57 ± 0.92 ppm for Pb; 18.09 ± 6.12 ppm for Cu; and 149.37 ± 105.56 ppm for Zn. These differences could be explained by differences on abundance of mining settlements among areas. According to the literature, these values are very high for all metals, exceeding in some cases those values referred as responsible of health disorders in birds. We strongly recommend further research looking at potential adverse effects caused by heavy metal pollution on the health of human and wildlife populations in the southern Atacama Desert.

Anti-conflict-like actions of intralateral septal infusions of allopregnanolone in Wistar rats.

The aim of the present study was to test the hypothesis that allopregnanolone infused into the lateral septal nuclei will reduce conflict-like behavior in ovariectomized rats. The interaction with systemic administration of several agonists and antagonists of the GABA-A receptor was assessed. Results showed that intralateral septal doses of allopregnanolone (1.0 microg, P<.05; 2.0 microg, P<.05) or systemic injections of allopregnanolone (1.0 mg/kg s.c., P<.05; 2.0 mg/kg s.c., P<.05), diazepam (2.0 mg/kg i.p., P<.05), or muscimol (0.3 mg/kg i.p., P<.05; 0.6 mg/kg i.p., P<.05) reduced conflict-like behavior. Subthreshold doses of intralateral septal infusions of allopregnanolone (0.5 microg/side) synergized with systemic subthreshold doses of GABA-A agonists: allopregnanolone (0.5 mg/kg, P<.05), diazepam (1.5 mg/kg, P<.05), or muscimol (0.1 mg/kg, P<.05). The GABA-A antagonists, flumazenil (0.1 mg/kg i.p.) and bicuculline (2.0 mg/kg i.p.) attenuated the synergism between intralateral septal infusions of allopregnanolone and diazepam or muscimol, respectively. Conversely, neither flumazenil (P<.05) nor bicuculline (P<.05) attenuated the synergism of the combination allopregnanolone (intralateral septum nuclei; 0.5 microg/side) plus systemic injections of allopregnanolone. In conclusion, allopregnanolone reduced conflict-like behavior probably acting at the GABA-A receptors found in the lateral septal nuclei.

Isolation rearing induced fear-like behavior without affecting learning abilities of Wistar rats.

1. Isolation-reared rats display fear-like behavior and depressive-like behavior in several behavioral tasks, suggesting that isolation rearing may model certain aspects of human psychopathologies. 2. After weaning (20 days old), male and female Wistar rats were isolation-reared during 20, 50 or 70 days. After that, they were tested in the elevated plus maze test, and in the open field test. Another group of isolation-reared rats (70 days of isolation) were tested in an auto-shaping task. 3. Isolation-reared rats displayed high levels of fear-like behavior in the elevated plus-maze test, and hyperlocomotion in the open field test. But, isolation-reared rats learned an auto-shaping task. 4. In conclusion, isolation rearing induced fear-like behavior, without affect learning abilities of rats.

[Trying vaginal delivery in 1000 patients with previous cesarean section in the Antiguo Hospital Civil de Guadalajara]. / Intento de parto vaginal en 1000 pacientes con antecedente de una cesárea previa en el Antiguo Hospital Civil de Guadalajara.

Because of the main justification for practicing a cesarean section is due to a previous cesarean and the rasing rates frequency of this operation, we concluded a descriptive and prospective investigation in order to analize the factibility and security of vaginal delivery after one cesarean section. We include 1000 patients with a past history of one previous cesarean section and with the following main characteristics: normal evaluation of the actual pregnancy and a gestational age of at least 36 weeks of pregnancy, no pelvis stenosis and a normal fetal status. The management were expectant and or with the use of oxitocin, prostaglandin PGEJ, uterionhibition and or amnioinfusion according to medical indication, 679 (67.9%) patients had a vaginal delivery; one ruterine rupture (0.001 x 1000) happened (the place of the rupture were not in the scar of the previous cesarean); two uterine dehicence (0.002 x 1000) of the previous uterine scar; one of this require laparotomy and sture of the dehiscence scar and the other one only require observation. We had two intrapartum fetal dead (0.002 x 1000) on due to the uterine rupture and the other one because of a taquisitolia not corrected by betamimetics. The factibility and security of vaginal delivery after one previous cesarean section is a logical and reasonable strategy in order to decrease the actual high rates of cesarean section. Whenever we try a viginal delivery in a patients with one previous cesarean is imperative to keep in mind that if something is not going well during the attempts we must repeat another cesarean.