Assessment of cardiac dysfunction in a randomized trial comparing doxorubicin and cyclophosphamide followed by paclitaxel, with or without trastuzumab as adjuvant therapy in node-positive, human epidermal growth factor receptor 2-overexpressing breast cancer: NSABP B-31.

PURPOSE: Trastuzumab is effective in treating human epidermal growth factor receptor 2 (HER2) -positive breast cancer, but it increases frequency of cardiac dysfunction (CD) when used with or after anthracyclines. PATIENTS AND METHODS: National Surgical Adjuvant Breast and Bowel Project trial B-31 compared doxorubicin and cyclophosphamide (AC) followed by paclitaxel with AC followed by paclitaxel plus 52 weeks of trastuzumab beginning concurrently with paclitaxel in patients with node-positive, HER2-positive breast cancer. Initiation of trastuzumab required normal post-AC left ventricular ejection fraction (LVEF) on multiple-gated acquisition scan. If symptoms suggestive of congestive heart failure (CHF) developed, source documents were blindly reviewed by an independent panel of cardiologists to determine whether criteria were met for a cardiac event (CE), which was defined as New York Heart Association class III or IV CHF or possible/probable cardiac death. Frequencies of CEs were compared between arms. RESULTS: Among patients with normal post-AC LVEF who began post-AC treatment, five of 814 control patients subsequently had confirmed CEs (four CHFs and one cardiac death) compared with 31 of 850 trastuzumab-treated patients (31 CHFs and no cardiac deaths). The difference in cumulative incidence at 3 years was 3.3% (4.1% for trastuzumab-treated patients minus 0.8% for control patients; 95% CI, 1.7% to 4.9%). Twenty-seven of the 31 patients in the trastuzumab arm have been followed for > or = 6 months after diagnosis of a CE; 26 were asymptomatic at last assessment, and 18 remained on cardiac medication. CHFs were more frequent in older patients and patients with marginal post-AC LVEF. Fourteen percent of patients discontinued trastuzumab because of asymptomatic decreases in LVEF; 4% discontinued trastuzumab because of symptomatic cardiotoxicity. CONCLUSION: Administering trastuzumab with paclitaxel after AC increases incidence of CHF and lesser CD. Potential cardiotoxicity should be carefully considered when discussing benefits and risks of this therapy.     

Next-Generation Sequencing Analysis of CpG Methylation of a Tumor Suppressor Gene SHP-1 Promoter in Stable Cell Lines and HCV-Positive Patients

Hepatitis C virus (HCV) is the major causative pathogen associated with hepatocellular carcinoma and liver cirrhosis. The main virion component, the Core (C) protein, is involved in multiple aspects of HCV pathology including oncogenesis and immune evasion. In this study, we established a next-generation bisulfite sequencing (NGS-BS) protocol to analyze the CpG methylation profile at the tumor suppressor gene SHP-1 P2 promoter as a model system. Our data show that HCV C protein expression in the immortalized T cells correlated with a specific CpG methylation profile at the SHP-1 P2. The NGS-BS on HCV-positive (HCV⁺) patient-derived PBMCs revealed a considerably different CpG methylation profile compared to the HCV C protein immortalized T cells. Notably, the CpG methylation profile was very similar in healthy and HCV⁺ PBMCs, suggesting that the SHP-1 P2 CpG methylation profile is not altered in the HCV⁺ individuals. Collectively, the NGS-BS is a highly sensitive method that can be used to quantitatively characterize the CpG methylation status at the level of individual CpG position and also allows the characterization of cis-acting effects on epigenetic regulation.     

Examining disparities in the early adoption of Covid-19 personal mitigation across family structures

The United States'' response to the COVID-19 pandemic has relied heavily on personal mitigation behaviors versus centralized governmental prevention strategies, especially early in the virus''s outbreak. This study examines how family structure shapes mitigation, focusing on the intersectional effects of gender, marital status, and the presence of children while accounting for differences in worry about infection from the virus. Using data from a national survey of 10,368 United States adults early in the pandemic (March 2020), survey-weighted logistic regression models show important differences in the likelihood of personal mitigation adoption across family structures. Unmarried women with children were most likely to report personal mitigation behaviors, including washing hands more frequently and avoiding social gatherings. Our findings highlight the differential impacts of the pandemic on those living in specific family circumstances.     

Renal Dysfunction in Patients with Left Ventricular Assist Device

Late-stage heart failure and renal dysfunction are often seen in conjunction. Cardiorenal syndrome (CRS) describes the complex interaction between the two disease states. Early literature described the pathophysiology of CRS as related only to reduced cardiac output and decreased renal perfusion. Recent literature suggests a more multifaceted mechanism. Left ventricular assist devices (LVAD), used as bridge-to-transplant and destination therapy in patients with heart failure, impact not only cardiac function but also renal function, especially in those patients with preoperative renal dysfunction. The mechanism by which LVAD implantation affects renal function is complex and understated in early literature. In this review, we discuss the pathogenesis of CRS, the impact of preoperative renal dysfunction in patients undergoing LVAD implantation, and the effect of LVAD implantation on postoperative renal function.     

Using a Very Low Energy Diet to Achieve Substantial Preconception Weight Loss in Women with Obesity: A Review of the Safety and Efficacy

Obesity in women of reproductive age is common. Emerging evidence suggests that maternal obesity not only increases the risk of adverse pregnancy outcomes but also has an enduring impact on the metabolic health of the offspring. Given this, management of obesity prior to pregnancy is critically important. Almost all international guidelines suggest that women with obesity should aim to achieve weight loss prior to pregnancy. However, current pre-conception weight loss therapies are sub-optimal. Lifestyle modification typically results in modest weight loss. This may assist fertility but does not alter pregnancy outcomes. Bariatric surgery results in substantial weight loss, which improves pregnancy outcomes for the mother but may be harmful to the offspring. Alternative approaches to the management of obesity in women planning pregnancy are needed. Very low energy diets (VLEDs) have been proposed as a possible tool to assist women with obesity achieve weight loss prior to conception. While VLEDs can induce substantial and rapid weight loss, there are concerns about the impact of rapid weight loss on maternal nutrition prior to pregnancy and about inadvertent exposure of the early fetus to ketosis. The purpose of this review is to examine the existing literature regarding the safety and efficacy of a preconception VLED program as a tool to achieve substantial weight loss in women with obesity.     

Mitigating ipatasertib‐induced glucose increase through dose and meal timing modifications

Ipatasertib, an AKT inhibitor, in combination with prednisone and abiraterone, is under evaluation for the treatment of metastatic castration‐resistant prostate cancer (mCRPC). Hyperglycemia is an on‐target effect of ipatasertib. An open‐label, single‐arm, single‐sequence, signal‐seeking study (n = 25 mCRPC patients) was conducted to evaluate the glucose changes across four different treatment periods: ipatasertib alone, ipatasertib‐prednisone combination, ipatasertib‐prednisone‐abiraterone combination (morning dose), and ipatasertib‐prednisone‐abiraterone combination (evening dose). Continuous glucose monitoring (CGM) was used in this study to compare the dynamic glucose changes across the different treatment periods. Four key parameters: average glucose, peak glucose and % time in range (70–180 and >180 mg/dl) were evaluated for this comparison. Ipatasertib‐prednisone‐abiraterone combination when administered in the morning after an overnight fast significantly increased average glucose, peak glucose and % time in range >180 mg/dl compared to ipatasertib monotherapy. Ipatasertib, when co‐administered with abiraterone, increased ipatasertib and M1 (G‐037720) metabolite exposures by approximately 1.5‐ and 2.2‐fold, respectively. Exposure–response analysis results show that increased exposures of ipatasertib in combination with abiraterone are associated with increased glucose levels. When ipatasertib‐prednisone‐abiraterone combination was administered as an evening dose compared to a morning dose, lowered peak glucose and improved % time in range was observed. The results from this study suggest that dosing ipatasertib after an evening meal followed by overnight fasting can be an effective strategy for managing increased glucose levels.

Study Highlights WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC? Clinical development of PI3K/AKT inhibitors has been particularly challenging given their toxicity profiles, hyperglycemia being one of the on‐target effects. WHAT QUESTION DID THIS STUDY ADDRESS? This study evaluated the real‐time changes in glucose levels post‐ipatasertib administration using a continuous glucose‐monitoring wearable device. This study further evaluated morning versus evening dosing of ipatasertib in combination with prednisone and abiraterone. WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE? The results from this study suggest that offering ipatasertib, an AKT inhibitor, as an evening dose after evening meal may offer a better option at de‐risking hyperglycemia incidences. The study also provides preliminary information that a low dose of steroids does not lead to a marked increase in glucose levels when administered in combination with ipatasertib. HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE? This is a novel clinical pharmacology study, wherein a safety finding was investigated using an innovative continuous glucose‐monitoring device and results were discussed in the context of pharmacokinetic results and drug–drug interactions. The conclusions and the methodology are supportive of further investigations to mitigate hyperglycemia risk for oncology drugs that inhibit the AKT/PI3K pathway, as this class of drugs are known to cause an increase in blood glucose.     

Allograft tracheoplasty technique for management of refractory tracheal stenosis

OBJECTIVES: Extensive tracheal airway defects represent a clinical dilemma. Although resection and reanastomosis and staged tracheoplasty may prove beneficial in some cases, recurrent or extensive circumferential stenosis remains a reconstructive challenge. We report the use of the allograft tracheoplasty technique for the reconstruction of recurrent, extensive defects of the trachea and cricoid. METHODS: Nine consecutive patients with recurrent tracheal stenosis were treated with the two-stage allograft tracheoplasty technique. A retrospective review was performed to evaluate for prior surgery, length of stenosis, surgical technique, and outcome. All 9 patients underwent multiple surgical procedures for acquired tracheal stenosis (average, 3.4 procedures) before undergoing the allograft tracheoplasty technique. Before surgery, all patients were tracheotomy-dependent. RESULTS: The patients were assessed 8 to 39 months after allograft tracheoplasty. The primary airway disorders included postintubation stenosis (n = 6), surgical resection for malignancy (n = 1), and idiopathic stenosis (n = 2). Three defects involved 30% to 60% of the cricoid cartilage, and 4 defects were complete circumferential tracheal defects. Five patients underwent an island deltopectoral flap for closure of the tracheoplasty site. One patient had a superficial wound infection at the cartilage recipient site, and 1 patient had a hematoma at the deltopectoral flap donor site. All 9 patients were successfully decannulated without shortness of breath, stridor, or recurrent stenosis at the time of follow-up. CONCLUSIONS: Allograft tracheoplasty is a new technique for the reconstruction of recurrent tracheal stenosis. It appears to be reliable for extensive airway defects that are refractory to conventional tracheoplasty techniques.     

Role of site selective substitution,magnetic parameter tuning,and self heating in magnetic hyperthermia application: Eu-doped magnetite nanoparticles

Various researchers have provided considerable insight into the fundamental mechanisms behind the power absorption of single-domain magnetic nanoparticles (MNPs) in magnetic hyperthermia applications. However, the role of all parameters pertinent to magnetic relaxation continues to be debated. Herein, to explore the role of magnetic anisotropy with the site selective substitution related to magnetic relaxation has generally been missing, which is critically essential in respective of hyperthermia treatment. Our study unravels contradictory results of rare earth (RE) interaction effects in ferrite to that of recently reported literature. Despite this, rare earth atoms have unique f-block properties, which significantly impact the magnetic anisotropy as well as the relaxation mechanism. Here, we use appropriate Eu doping concentration in magnetite and analyze its effect on the matrix. Furthermore, a positive SAR can effectively reduce the relative dose assigned to a patient to a minimal level. This study indicates that the introduction of Eu ion positively influenced the heating efficiency of the examined magnetite systems.

Various researchers have provided considerable insight into the fundamental mechanisms behind the power absorption of single-domain magnetic nanoparticles (MNPs) in magnetic hyperthermia applications.