PARP Inhibitors for Breast Cancer: Germline BRCA1/2 and Beyond.

Poly-adenosine diphosphate ribose polymerase (PARP) inhibitors (PARPi) are approved for BRCA1/2 carriers with HER2-negative breast cancer in the adjuvant setting with a high risk of recurrence as well as the metastatic setting. However, the indications for PARPi are broader for patients with other cancer types (e.g., prostate and ovarian cancer), involving additional biomarkers (e.g., ATM, PALB2, and CHEK) and genomic instability scores. Herein, we summarize the data on PARPi and breast cancer and discuss their use beyond BRCA carriers.

Endothelial injury in COVID-19 and septic patients.

Systemic inflammatory response, as observed in sepsis and severe COVID-19, may lead to endothelial damage. Therefore, we aim to compare the extent of endothelial injury and its relationship to inflammation in both diseases. We included patients diagnosed with sepsis (SEPSIS group, n = 21), mild COVID-19 (MILD group, n = 31), and severe COVID-19 (SEVERE group, n = 24). Clinical and routine laboratory data were obtained, circulating cytokines (INF-γ, TNF-α, and IL-10) and endothelial injury markers (E-Selectin, Tissue Factor (TF) and von Willebrand factor (vWF)) were measured. Compared to the SEPSIS group, patients with severe COVID-19 present similar clinical and laboratory data, except for lower circulating IL-10 and E-Selectin levels. Compared to the MILD group, patients in the SEVERE group showed higher levels of TNF-α, IL-10, and TF. There was no clear relationship between cytokines and endothelial injury markers among the three studied groups; however, in SEVERE COVID-19 patients, there is a positive relationship between INF-γ with TF and a negative relationship between IL-10 and vWF. In conclusion, COVID-19 and septic patients have a similar pattern of cytokines and endothelial dysfunction markers. These findings highlight the importance of endothelium dysfunction in COVID-19 and suggest that endothelium should be better evaluated as a therapeutic target for the disease.

Cardiology referral during the COVID-19 pandemic.

OBJECTIVES: This study presents the cardiology referral model adopted at the University of São Paulo-Hospital das Clínicas complex during the initial period of the coronavirus disease (COVID-19) pandemic, main reasons for requesting a cardiologic evaluation, and clinical profile of and prognostic predictors in patients with COVID-19. METHODS: In this observational study, data of all cardiology referral requests between March 30, 2020 and July 6, 2020 were collected prospectively. A descriptive analysis of the reasons for cardiologic evaluation requests and the most common cardiologic diagnoses was performed. A multivariable model was used to identify independent predictors of in-hospital mortality among patients with COVID-19. RESULTS: Cardiologic evaluation was requested for 206 patients admitted to the ICHC-COVID. A diagnosis of COVID-19 was confirmed for 180 patients. Cardiologic complications occurred in 77.7% of the patients. Among these, decompensated heart failure was the most common complication (38.8%), followed by myocardial injury (35%), and arrhythmias, especially high ventricular response atrial fibrillation (17.7%). Advanced age, greater need of ventilatory support on admission, and pre-existing heart failure were independently associated with in-hospital mortality. CONCLUSIONS: A hybrid model combining in-person referral with remote discussion and teaching is a viable alternative to overcome COVID-19 limitations. Cardiologic evaluation remains important during the pandemic, as patients with COVID-19 frequently develop cardiovascular complications or decompensation of the underlying heart disease.

Lower peripheral blood Toll-like receptor 3 expression is associated with an unfavorable outcome in severe COVID-19 patients.

The role of innate immunity in COVID-19 is not completely understood. Therefore, this study explored the impact of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection on the expression of Pattern Recognition Receptors (PRRs) in peripheral blood cells and their correlated cytokines. Seventy-nine patients with severe COVID-19 on admission, according to World Health Organization (WHO) classification, were divided into two groups: patients who needed mechanical ventilation and/or deceased (SEVERE, n = 50) and patients who used supplementary oxygen but not mechanical ventilation and survived (MILD, n = 29); a control group (CONTROL, n = 17) was also enrolled. In the peripheral blood, gene expression (mRNA) of Toll-like receptors (TLRs) 3, 4, 7, 8, and 9, retinoic-acid inducible gene I (RIGI), NOD-like receptor family pyrin domain containing 3 (NLRP3), interferon alpha (IFN-α), interferon beta (IFN-ß), interferon gamma (IFN-γ), interferon lambda (IFN-λ), pro-interleukin(IL)-1ß (pro-IL-1ß), and IL-18 was determined on admission, between 5-9 days, and between 10-15 days. Circulating cytokines in plasma were also measured. When compared to the COVID-19 MILD group, the COVID-19 SEVERE group had lower expression of TLR3 and overexpression of TLR4.

SARS-CoV-2 pneumonia-receptor binding and lung immunopathology: a narrative review.

The current pandemic of COVID-19 caused thousands of deaths and healthcare professionals struggle to properly manage infected patients. This review summarizes information about SARS-CoV-2 receptor binding dynamics and intricacies, lung autopsy findings, immune response patterns, evidence-based explanations for the immune response, and COVID-19-associated hypercoagulability.

Double-blind, Randomized, Placebo-controlled Trial With N-acetylcysteine for Treatment of Severe Acute Respiratory Syndrome Caused by Coronavirus Disease 2019 (COVID-19).

BACKGROUND: A local increase in angiotensin 2 after inactivation of angiotensin-converting enzyme 2 by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) may induce a redox imbalance in alveolar epithelium cells, causing apoptosis, increased inflammation and, consequently, impaired gas exchange. We hypothesized that N-acetylcysteine (NAC) administration could restore this redox homeostasis and suppress unfavorable evolution in patients with coronavirus disease 2019 (COVID-19). METHODS: This was a double-blind, randomized, placebo-controlled, single-center trial conducted at the Emergency Department of Hospital das Clínicas, São Paulo, Brazil, to determine whether NAC in high doses can avoid respiratory failure in patients with COVID-19. We enrolled 135 patients with severe COVID-19 (confirmed or suspected), with an oxyhemoglobin saturation <94% or respiratory rate >24 breaths/minute. Patients were randomized to receive NAC 21 g (~300 mg/kg) for 20 hours or dextrose 5%. The primary endpoint was the need for mechanical ventilation. Secondary endpoints were time of mechanical ventilation, admission to the intensive care unit (ICU), time in ICU, and mortality. RESULTS: Baseline characteristics were similar between the 2 groups, with no significant differences in age, sex, comorbidities, medicines taken, and disease severity. Also, groups were similar in laboratory tests and chest computed tomography scan findings. Sixteen patients (23.9%) in the placebo group received endotracheal intubation and mechanical ventilation, compared with 14 patients (20.6%) in the NAC group (P = .675). No difference was observed in secondary endpoints. CONCLUSIONS: Administration of NAC in high doses did not affect the evolution of severe COVID-19. CLINICAL TRIALS REGISTRATION: Brazilian Registry of Clinical Trials (REBEC): U1111-1250-356 (http://www.ensaiosclinicos.gov.br/rg/RBR-8969zg/).

Cardiology referral during the COVID-19 pandemic

OBJECTIVES: This study presents the cardiology referral model adopted at the University of São Paulo-Hospital das Clínicas complex during the initial period of the coronavirus disease (COVID-19) pandemic, main reasons for requesting a cardiologic evaluation, and clinical profile of and prognostic predictors in patients with COVID-19. METHODS: In this observational study, data of all cardiology referral requests between March 30, 2020 and July 6, 2020 were collected prospectively. A descriptive analysis of the reasons for cardiologic evaluation requests and the most common cardiologic diagnoses was performed. A multivariable model was used to identify independent predictors of in-hospital mortality among patients with COVID-19. RESULTS: Cardiologic evaluation was requested for 206 patients admitted to the ICHC-COVID. A diagnosis of COVID-19 was confirmed for 180 patients. Cardiologic complications occurred in 77.7% of the patients. Among these, decompensated heart failure was the most common complication (38.8%), followed by myocardial injury (35%), and arrhythmias, especially high ventricular response atrial fibrillation (17.7%). Advanced age, greater need of ventilatory support on admission, and pre-existing heart failure were independently associated with in-hospital mortality. CONCLUSIONS: A hybrid model combining in-person referral with remote discussion and teaching is a viable alternative to overcome COVID-19 limitations. Cardiologic evaluation remains important during the pandemic, as patients with COVID-19 frequently develop cardiovascular complications or decompensation of the underlying heart disease.