Meta-analysis of breast cancer outcome and toxicity in adjuvant trials of aromatase inhibitors in postmenopausal women

The present meta-analysis examines randomized trials of third-generation aromatase inhibitors (AIs) as alternatives to tamoxifen in three treatment settings: monotherapy, sequenced therapy and extended therapy. Eleven randomized controlled trials (RCTs) were chosen based on their similarity in terms of study design and included 34,070 post-menopausal women who had undergone surgery for estrogen-sensitive early breast cancer. DFS was significantly improved by AI monotherapy (Hazard Ratio (HR): 0.89, p = 0.001), sequenced therapy (HR: 0.7, p < 0.00001) and extended therapy (HR: 0.62, p < 0.00001). All of the patients benefited significantly from sequenced therapy (HR: 0.81, p = 0.003), and hormone receptor-positive patients benefited from AI monotherapy (HR = 0.92, p = 0.046) with respect to OS. AI monotherapy conferred significantly lower risks for thromboembolic events (OR = 0.61; p < 0.001) and endometrial cancer (OR = 0.26; p < 0.001) compared with tamoxifen monotherapy; however, there was a greater risk of cardiovascular events (OR = 1.20; p = 0.030). Sequenced therapy was also superior in terms of endometrial cancer but was inferior with respect to fractures, thromboembolic and cardiovascular events.     

Impact of Vitamin D Status on Cardiometabolic Complications among Children and Adolescents with Type 1 Diabetes Mellitus

Objective:

There is an ongoing interest in the relationship between vitamin D status and diabetes control and complications. However, data from Saudi Arabia are limited. To determine the impact of vitamin D status on glycemic control and cardiometabolic complications of children and adolescents with type 1 diabetes mellitus (T1DM) attending a tertiary care diabetes clinic in Saudi Arabia.

Methods:

Demographic, clinical, and laboratory data of 301 children and adolescent subjects with T1DM (53.5% females) of a mean age of 13.9 years attending King Abdulaziz Medical City-Jeddah during 2010-2013 were retrospectively collected. Relationships between vitamin D status and frequency of hypoglycemia, hemoglobin A1c (HbA1c) level, body mass index (BMI), blood pressure, and lipid profile were evaluated.

Results:

The mean duration of diabetes was 7.7±3.7 years. Mean BMI value was 21.1±4.5 kg/m2 and HbA1c was 9.6±1.9% in both genders. Only 26.2% of the patients had a satisfactory HbA1c level. The mean level of 25-hydroxyvitamin D [25(OH)D] was 35.15 and that of cholesterol was 4.75. Vitamin D deficiency [25(OH)D≤37.5 nmol/L] was detected in 63.6% of the male and 67.7% of the female subjects. In males, it was inversely associated with frequency of hypoglycemia (p<0.01), BMI (p<0.05), diastolic blood pressure (p<0.05), and triglyceride levels (p<0.01), while in females, it was inversely associated with current age (p<0.05), age at diagnosis (p<0.01), and triglyceride levels (p<0.01). No significant correlation between HbA1c and vitamin D deficiency was observed.

Conclusion:

Vitamin D deficiency was highly prevalent in our study sample and was found to be associated with frequency of hypoglycemic episodes and with adverse cardiometabolic control.     

Is the Change of Late Potential Over Time Related to Enzyme Levels?Ichemic Burden in Acute Myocardial Infarction

Background: The ventricular late potential (VLP) detected using the technique of signal average electrocardiography (SAECG) interacts with several factors, primarily time. Method: In this study, we examined the interaction, over time, of VLP with the initial ischemic burden and enzyme levels in acute myocardial infarction. Patients diagnosed as having acute myocardial infarction were included in the study. On the first day, the patients underwent enzyme analysis and electrocardiography (ECG) follow‐up every 6 hours. A 24‐hour ambulatory ECG was performed on the seventh day in order to determine the ischemic burden. SAECG findings (TQRS, RMS, LAS were obtained on the seventh day, in the first and third months. The study was continued with the patients who did not require angioplasty as decided with angiographic evaluation in the first month. Results: The study included 30 patients with acute myocardial infarction (mean age 51 ± 12, 28 males and 2 females). The initial mean CK‐MB levels and the mean ischemic burden were 98 ± 31 U/L and 44 ± 96 minutes. The TQRS (ms), LAS (ms), and RMS (μV) values (mean ± SD) obtained at day 7, month 1, and month 3 are 97 ± 12, 96 ± 9, 103 ± 11, P = 0.01; 31 ± 10, 31 ± 11, 32 ± 10, P = 0.46; 43 ± 28, 41 ± 26, 33 ± 25, P = 0.01, respectively. We observed that the TQRS and RMS values changed significantly with time, but these levels of significance disappeared when adjusted for the initial ischemic burden and CK‐MB levels (P = 0.06; P = 0.53). The VLP frequency was 33% at day 7 and 23% at month 3. Unlike the CK‐MB level, the initial ischemic burden was significantly different between the patients with and without VLP at month 3 (150.85 ± 149.28, 12.34 ± 26.48, P = 0.001). When tested together with age and gender, it was found that the high initial ischemic burden increased the possibility of VLP (OR: 24, Cl: 2.09–279.52, P = 0.01) at month 3. Conclusion: SAECG findings in patients with myocardial infarction changed with time; however, this change occurred depending on the initial ischemic burden and CK‐MB levels. Of these, only the initial ischemic burden, especially in high levels, was a determinant for the presence of VLP in the late period of myocardial infarction. A.N.E. 2002;7(3):242–246     

Prevalence of tuberculosis infection and its relationship to stunting in children (under five years) household contact with new tuberculosis cases

BackgroundChildren who inhabit the same house with tuberculosis (TB) patients are at high risk for infection and illness with TB. Nutritional status (stunting) in children is related to the child's ability to withstand MTB (Mycobacterium Tuberculosis). This study aims to estimated the prevalence of tuberculosis infection and its relationship to stunting in children (under five years) with household contact (HHC) with new TB cases.MethodsA cross-sectional design was implemented. Conducted in July 2018–April 2019 at 13 Public Health Center in Makassar City. The sample size was calculated using one sample situation-about precision formula. Samples were children under five who had contact with new diagnosed TB cases. Tuberculosis infection was measured by TST (tuberculin skin test). Logistic regression with causal model to examine TB infection relationship with stunting and covariate variable, analyzed using Stata/MP 13.0 software.ResultsOne hundred twenty-six (126) eligible children. Prevalence of tuberculosis infection was 38.10%. Frequency of stunted was 31 children (24.60%). Stunted nutritional status (aPR): 2.36, 95% CI 1.60–3.44), boys (aPR: 1.47, 95% CI 0.96–2.25), not getting BCG immunization (aPR: 1.58, 95%) CI 0.89–2.82), and high contact intensity (aPR: 2.62, 95% CI 1.10–6.22) best predicted the tuberculosis infection in children with TB case household contacts with a model contribution of 64%.ConclusionStunted nutritional status (moderate and severe), boys, not getting BCG immunization, and high contact intensity are the determinants of TB infection transmission in children HHC with TB. Children under five years of age who have close contact with TB cases should be targeted for priority interventions to prevent the transmission of TB infection and progressing to TB cases.     

Tobacco smoke exposure, wheeze, and atopy

We investigated the effect of in utero and postnatal environmental tobacco smoke (ETS) exposure on respiratory symptoms and atopy in the first 3 years of life in children at high risk of allergic disease (both parents atopic). Three hundred and sixty-nine children were followed from birth and reviewed at ages 1 and 3 years (respiratory questionnaire, skin testing). Parental smoking questionnaires were administered, and plasma cotinine in cord and peripheral blood (at age 1 year) was measured (capillary column gas-liquid chromatography). Wheezing starting in the first year of life was significantly more common in children of smoking mothers (54.2% vs. 39.5%, P = 0.017), but not wheezing starting after age 1 year (10.8% vs. 10.9%, smoking and nonsmoking mothers, P = 0.99). Detectable cord cotinine was not associated with wheeze. More frequent wheeze in infancy was significantly more common in those with detectable 1-year cotinine (e.g., wheeze without colds, 17.8% vs. 5.6%, P = 0.02; wheeze most days, 6.5% vs. 0%, P = 0.04). ETS exposure was not associated with atopy. In the multivariate regression analysis, maternal smoking during pregnancy and/or in the first year of life remained associated with wheeze in the first year of life (odds ratio, 1.88; 95% confidence interval, 1.14-3.12; P = 0.01). ETS exposure in "high-risk" infants increases the risk of wheezing starting in the first year of life, but not after age 1 year. However, ETS exposure has little or no effect on the development of atopy. Measurement of plasma cotinine was no more useful than tobacco exposure assessment by questionnaire in our cohort.     

The relationship between hospital or operator volume and outcomes of coronary patients undergoing percutaneous coronary interventions

Summary The relationship between volume and outcome in medicine has been intensively investigated in the last few decades. The large amount of accumulated data demonstrates that for many surgical or non-surgical procedures and medical conditions, patients being treated in high-volume hospitals or by high-volume physicians have lower mortality rates and better quality of life compared to those treated by low-volume hospitals or by low-volume physicians. Although the degree of the relationship between high volume and better outcome varies, it is persistent across a wide range of procedures and conditions.Percutaneous coronary interventions (PCIs) have an important impact on public health, given the frequency of coronary heart disease for which these procedures are performed. Studies carried out before and after the advent of stents on the relationship between volume and outcome for PCIs have almost consistently reported that performance of PCIs in high-volume institutions or by high-volume operators is associated with improved outcomes for patients, regardless of the specific indication for PCI.For those procedures for which a relationship between high volume and better outcome has been clearly demonstrated, patients as well as their referring physicians should be informed that patients can benefit both in terms of reduced mortality and improved quality of life if they are treated by high-volume health care providers. Consequently, for these procedures, a health care policy aiming at their concentration in high-volume institutions should be strongly considered.     

LC-ESI-MS/MS reveals the formation of reactive intermediates in brigatinib metabolism: elucidation of bioactivation pathways

Brigatinib (BGB) is a newly approved anaplastic lymphoma kinase (ALK) inhibitor. On April 28, 2017, BGB was approved by the U.S. FDA for the treatment of metastatic anaplastic lymphoma kinase-positive non-small cell lung cancer. The toxicity profile of BGB includes nausea, fatigue, diarrhea, elevated lipase, dyspnoea, hypertension, hypoxia, pneumonia, elevated amylase, pulmonary embolism, elevated ALT, hyponatraemia and hypophosphatemia. Using LC-MS/MS, we investigated the in vitro phase I metabolism of for BGB in rat liver microsomes (RLMs). In the in vitro metabolism of BGB, iminium reactive intermediates were trapped by potassium cyanide forming a stable complex that can be characterized by LC-MS/MS. Four BGB in vitro phase I metabolites were identified. In vitro phase I metabolic pathways were N-dealkylation, α hydroxylation and α oxidation. Additionally, three iminium reactive metabolites were found and the bioactivation mechanisms were proposed. A piperidine ring was found to be responsible for BGB bioactivation. The presence of these three reactive metabolites may be the main reason for BGB side effects. A literature review showed no previous article reported the in vitro phase I metabolism study of BGB or structural identification of the formed reactive metabolites.

Four phase I BGB metabolites and three cyano adducts for BGB were detected using LC-MS/MS. The piperidine ring was found to be responsible for BGB bioactivation and the bioactivation pathways are proposed.