Pilot study evaluating the pharmacokinetics, pharmacodynamics, and safety of the combination of exemestane and tamoxifen.

PURPOSE: We conducted a pilot study assessing the effects of the selective estrogen receptor modulator, tamoxifen, on the pharmacokinetics, pharmacodynamics, and safety of the steroidal, irreversible aromatase inhibitor (AI), exemestane, when the two were coadministered in postmenopausal women with metastatic breast cancer. EXPERIMENTAL DESIGN: Patients with documented or unknown hormone receptor sensitivity were eligible. Patients received oral exemestane at 25-mg once daily. Starting day 15, oral tamoxifen at 20-mg once daily, was added. We measured plasma concentrations of exemestane, estrone, estrone sulfate, and estradiol after 14 days of exemestane monotherapy and after approximately 4 weeks of combination therapy. The incidence and severity of adverse events were assessed by physical examination and patient reporting. RESULTS: We treated 18 patients. All had received prior chemotherapy and/or hormonal therapy, eight and six, respectively, with single-agent selective estrogen receptor modulators or irreversible aromatase inhibitors; no hormonal therapy was given within 30 days of study entry. Plasma exemestane concentrations and estrone, estrone sulfate, and estradiol suppression were unchanged after approximately 4 weeks of tamoxifen coadministration. All drug-related adverse events were grades 1 or 2; none was unexpected. Although not a formal study end point, antitumor activity was noted, with two partial responses and four cases of stable disease among 17 evaluable patients after a 9-month median follow-up (range, 2.5-19 months). CONCLUSIONS: This pilot study provides evidence that coadministration of tamoxifen does not affect exemestane pharmacokinetics or pharmacodynamics and that the combination is well-tolerated and active. Further clinical investigation is warranted.     

The relationship between dietary fat intake and risk of colorectal cancer: evidence from the combined analysis of 13 case-control studies

The objective of this study was to examine the effects of the intakeof dietary fat upon colorectal cancer risk in a combined analysis of datafrom 13 case-control studies previously conducted in populations withdiffering colorectal cancer rates and dietary practices. Original datarecords for 5,287 cases of colorectal cancer and 10,470 controls werecombined. Logistic regression analysis was used to estimate odds ratios (OR)for intakes of total energy, total fat and its components, and cholesterol.Positive associations with energy intake were observed for 11 of the 13studies. However, there was little, if any, evidence of anyenergy-independent effect of either total fat with ORs of 1.00, 0.95, 1.01,1.02, and 0.92 for quintiles of residuals of total fat intake (P trend =0.67) or for saturated fat with ORs of 1.00, 1.08, 1.06, 1.21, and 1.06 (Ptrend = 0.39). The analysis suggests that, among these case-control studies,there is no energy-independent association between dietary fat intake andrisk of colorectal cancer. It also suggests that simple substitution of fatby other sources of calories is unlikely to reduce meaningfully the risk ofcolorectal cancer.     

Predicting abdominal adipose tissue in overweight Latino youth.

OBJECTIVES: 1) Examine associations between visceral adipose tissue (VAT), subcutaneous abdominal adipose tissue (SAAT), and anthropometric and demographic variables; 2) generate and cross-validate prediction equations for estimating VAT and SAAT in overweight Latino children. STUDY DESIGN: Cross-sectional. PARTICIPANTS: 196 overweight 8-13-year-old Latino youth. Two-thirds (n = 131) were randomly assigned to a development group to generate prediction equations for VAT and SAAT; one-third (n = 65) was used as a cross-validation group. METHODS AND PROCEDURES: Anthropometric measurements (height, weight, skinfold thicknesses, and circumferences) were performed. VAT and SAAT were measured using magnetic resonance imaging (MRI). RESULTS: The strongest univariate correlate for VAT was waist circumference (WC) (r = 0.65, p < 0.01) while the strongest correlate for SAAT was hip circumference (r = 0.88, p < 0.001). Regression analyses showed approximately 50% of the variance in VAT was explained by WC (43.8%), Tanner stage (4.2%) and calf skinfold (1.7%). Variance in the SAAT model was explained by WC (77.8%), triceps skinfold (4.2%) and gender (2.3%). Residual analyses showed no bias in either equation. Though mean differences between measured and predicted VAT and SAAT were small, there was a large degree of variability at the individual level especially for VAT. CONCLUSIONS: Both VAT and SAAT prediction equations performed well at the group level, but the relatively high degree of variability suggests limited clinical utility of the VAT equation. MRI is currently required to derive an accurate measure of VAT at the individual level.     

Dental anomalies in cleft lip and palate: A case–control comparison of total and outside the cleft prevalence

This study’s objective was to compare the total and outside the cleft prevalence of dental anomalies (DA) between patients with cleft lip and palate (CLP) and a control group. This retrospective cross-sectional study was done under a case–control design. The case group consisted of 192 non-syndromic patients with complete CLP, while the control group included 411 patients. All subjects had orthopantomography, intra, and extraoral photographs. The prevalence of dental agenesis, supernumerary teeth, impacted teeth, dental transposition, and microdontia were compared using a chi-squared test (P < .05). Next, a second test was made, but only the anomalies outside the cleft were considered for this study. Total prevalence was 89.1% for cases, and 20.9% for controls (P < .01). The prevalence of each DA was significantly higher for the case group. In the analysis of DAs outside the cleft, the total prevalence was still significantly associated (P < .01); however, only dental agenesis was statistically significant (P < .01). Further analysis found that a high rate of upper premolar absence (P < .01) could explain this event. Patients with CLP have a higher prevalence of DAs compared to controls. After considering only the DAs outside the cleft, the total prevalence remains significantly higher. However, this phenomenon is explained mainly by the elevated prevalence of upper premolars’ agenesis. This study’s results suggest that environmental factors are behind the high prevalence of DAs in subjects with CLP.     

Pulmonary artery-bronchus fistula treated with coil embolization

Bronchopulmonary arterial fistula consists of an abnormal connection between the bronchus and the vascular tree and is a rare but serious complication associated with a variety of lung interventions. We present a case of a 61-year-old female with a history of metastatic breast cancer treated with lumpectomy and radiation 20 years prior, who was found to have a fistula between the right pulmonary artery and the right mainstem bronchus. Our patient was treated endovascularly with coil embolization in the setting of massive hemoptysis flooding the trachea, which was successful in controlling the acute bleed, although care was withdrawn in the following days following a discussion with the family given the presence of advanced metastatic disease. This case illustrates the use of endovascular techniques to treat an actively bleeding bronchopulmonary arterial fistulae, including a review of the existing literature regarding the optimal endovascular management strategy. Although our patient did not achieve the best outcome, endovascular intervention with stent-placement or embolization can serve to temporarily halt blood flow through the fistula, stabilizing the patient and allowing for more radical therapy after improvement.     

Global Extension and Predominance of Human Metapneumovirus A2 Genotype with Partial G Gene Duplication

Human metapneumovirus (HMPV) is an important respiratory pathogen and is divided in two main groups (A and B). HMPV strains with partial duplications (111-nt and 180-nt duplication) of the G gene have been reported in recent years. Since the initial reports, viruses with these characteristics have been reported in several countries. We analyzed all complete HMPV G gene ectodomain sequences available at GenBank to determine if viruses with 111-nt or 180-nt duplication have become the leading HMPV strains worldwide, and to describe their temporal and geographic distribution. We identified 1462 sequences that fulfilled study criteria (764 HMPV A and 698 HMPV B) reported from 37 countries. The most frequent HMPV A genotype was A2b2 (n = 366), and the most frequent B genotype was B2 (n = 374). A total of 84 sequences contained the 111-nt duplication, and 90 sequences contained the 180-nt duplication. Since 2016, viruses with a partial duplication comprise the most frequent HMPV A sequences globally and have displaced other HMPV A viruses in Asia, Europe, and South America; no sequences of viruses with partial duplication have been reported in North America or Africa so far. Continued surveillance of HMPV is required to identify the emergence and spread of epidemiologically relevant variants.     

Genome-wide linkage analysis combined with genome sequencing in large families with intracranial aneurysms

Rupture of an intracranial aneurysm (IA) leads to aneurysmal subarachnoid haemorrhage (ASAH), a severe type of stroke. Some rare variants that cause IA in families have been identified, but still, the majority of genetic causes, as well as the biological mechanisms of IA development and rupture, remain unknown. We aimed to identify rare, damaging variants for IA in three large Dutch families with multiple affected members with IA (N = 9, 11, and 6). By combining linkage analysis and genome sequencing (GS), we identified six rare and damaging variants for which all cases within one of the families were heterozygous. These variants were p.Tyr87Cys in SYCP1, p.Phe1077Leu in FMNL2, p.Thr754Lys in TBC1D2, p.Arg321His in ZNF782, p.Arg979Trp in CCDC180, and p.Val125Met in NCBP1. None of the variants showed association with IA status in a large cohort of 937 patients from the general IA patient population and 1046 controls. Gene expression in IA and cerebral artery tissue further prioritized FMNL2 and TBC1D2 as potential important players in IA pathophysiology. Further studies are needed to characterize the functional consequences of the identified variants and their role in the biological mechanisms of IA.Subject terms: Stroke, Aneurysm, Genetic linkage study, Next-generation sequencing