The worldwide incidence trends of the lip, oral cavity, and pharyngeal cancers (LOCPs) need to be updated. This study aims to examine the temporal incidence trends of LOCPs from 1990 to 2017, using ...the latest Global Burden of Disease (GBD) study data to explore sex, age, and regional differences. GBD incidence data for LOCPs were driven by population cancer registries and were estimated from mortality data. Age-standardized incidence rates (ASIRs) were directly extracted from the 2017 GBD database to calculate the estimated annual percentage change (EAPC) over the study period. Incidence trends are mapped and compared separately by sex (females vs. males), age groups (15–49, 50–69, and 70+ y), regions (21 geographical and 5 sociodemographic regions), and countries. Among 678,900 incident cases of LOCPs notified in 2017, more than half were lip and oral cavity cancers. From 1990 to 2017, the estimated global incidence for nasopharyngeal cancers decreased dramatically (EAPC = −1.52; 95% confidence interval CI, –1.70 to −1.34), while the incidence for lip and oral cavity cancers (EAPC = 0.26; 95% CI, 0.16–0.37) and other pharyngeal cancers (EAPC = 0.62; 95% CI, 0.54–0.71) increased. Higher ASIRs were observed among males than females across all age groups. However, females had larger EAPC variation when compared to males. Population groups aged 15 to 49 y presented the lowest ASIRs, with larger values of EAPC than those aged 50 to 69 and 70+ y. While high-income countries had higher ASIRs with little EAPC variation, ASIRs varied across low/middle-income regions with larger EAPC variations. South Asia and East Asia had the highest ASIRs and EAPC for lip and oral cavity cancers, respectively. In conclusion, the global incidence of LOCPs has increased among females, those aged 15 to 49 y, and people from low/middle-income countries over the study period, excepting nasopharyngeal cancers, which had a decreasing worldwide trend.
Development of brown-like/beige adipocytes in white adipose tissue (WAT) helps to reduce obesity. Thus we investigated the effects of resveratrol, a dietary polyphenol capable of preventing obesity ...and related complications in humans and animal models, on brown-like adipocyte formation in inguinal WAT (iWAT).
CD1 female mice (5-month old) were fed a high-fat diet with/without 0.1% resveratrol. In addition, primary stromal vascular cells separated from iWAT were subjected to resveratrol treatment. Markers of brown-like (beige) adipogenesis were measured and the involvement of AMP-activated protein kinase (AMPK) α1 was assessed using conditional knockout.
Resveratrol significantly increased mRNA and/or protein expression of brown adipocyte markers, including uncoupling protein 1 (UCP1), PR domain-containing 16, cell death-inducing DFFA-like effector A, elongation of very long-chain fatty acids protein 3, peroxisome proliferator-activated receptor-γ coactivator 1α, cytochrome c and pyruvate dehydrogenase, in differentiated iWAT stromal vascular cells (SVCs), suggesting that resveratrol induced brown-like adipocyte formation in vitro. Concomitantly, resveratrol markedly enhanced AMPKα1 phosphorylation and differentiated SVC oxygen consumption. Such changes were absent in cells lacking AMPKα1, showing that AMPKα1 is a critical mediator of resveratrol action. Resveratrol also induced beige adipogenesis in vivo along with the appearance of multiocular adipocytes, increased UCP1 expression and enhanced fatty acid oxidation.
Resveratrol induces brown-like adipocyte formation in iWAT via AMPKα1 activation and suggest that its beneficial antiobesity effects may be partly due to the browning of WAT and, as a consequence, increased oxygen consumption.
With the introduction of next‐generation sequencing, the genetic landscape of the complex group of B‐cell lymphoid malignancies has rapidly been unravelled in recent years. This has provided ...important information about recurrent genetic events and identified key pathways deregulated in each lymphoma subtype. In parallel, there has been intense search and development of novel types of targeted therapy that ‘hit’ central mechanisms in lymphoma pathobiology, such as BTK, PI3K or BCL2 inhibitors. In this review, we will outline the current view of the genetic landscape of selected entities: follicular lymphoma, diffuse large B‐cell lymphoma, mantle cell lymphoma, chronic lymphocytic leukaemia and marginal zone lymphoma. We will detail recurrent alterations affecting important signalling pathways, that is the B‐cell receptor/NF‐κB pathway, NOTCH signalling, JAK‐STAT signalling, p53/DNA damage response, apoptosis and cell cycle regulation, as well as other perhaps unexpected cellular processes, such as immune regulation, cell migration, epigenetic regulation and RNA processing. Whilst many of these pathways/processes are commonly altered in different lymphoid tumors, albeit at varying frequencies, others are preferentially targeted in selected B‐cell malignancies. Some of these genetic lesions are either involved in disease ontogeny or linked to the evolution of each disease and/or specific clinicobiological features, and some of them have been demonstrated to have prognostic and even predictive impact. Future work is especially needed to understand the therapy‐resistant disease, particularly in patients treated with targeted therapy, and to identify novel targets and therapeutic strategies in order to realize true precision medicine in this clinically heterogeneous patient group.
Content List ‐ Read more articles from the symposium: Targeted therapy in B‐cell malignancies.
Summary
We developed a new tool to assess the severity of osteoporotic vertebral fracture using radiographs of the spine. Our technique can be used in patient care by helping to stratify patients ...with osteoporotic vertebral fractures into appropriate treatment pathways. It can also be used for research purposes.
Purpose
The aim of our study was to propose a semi-quantitative (SQ) grading scheme for osteoporotic vertebral fracture (OVF) on anteroposterior (AP) radiographs.
Methods
On AP radiographs, the vertebrae are divided into right and left halves, which are graded (A) vertical rectangle, (B) square, (C) traverse rectangle, and (D) trapezoid; whole vertebrae are graded (E) transverse band or (F) bow-tie. Type A and B were compared with normal and Genant SQ grade 1 OVF, Type C and D with grade 2 OVF, and Type E and F with grade 3 OVF. Spine AP radiographs and lateral radiographs of 50 females were assessed by AP radiographs SQ grading. After training, an experienced board-certified radiologist and a radiology trainee assessed the 50 AP radiographs.
Results
The height-to-width ratio of the half vertebrae varied 1.32–1.48. On lateral radiographs, 84 vertebrae of the 50 patients had OVFs (38 grade 1, 24 grade 2, and 22 grade 3). On AP radiographs, the radiologist correctly assigned 84.2%, 91.7%, and 77.2% and the trainee correctly assigned 68.4%, 79.2%, and 81.8% of grade 1, 2, and 3 OVFs, respectively. Compared with lateral radiographs, the radiologist had a weighted Kappa of 0.944 including normal vertebrae and 0.883 not including normal vertebrae, while the corresponding Kappa values for the trainee were 0.891 and 0.830, respectively.
Conclusion
We propose a new semi-quantitative grading system for vertebral fracture severity assessment on AP spine radiographs.
Muscle fatigue, as a common physiological phenomenon, has attracted much attention in the fields of rehabilitation and athletic training. A wearable technology for monitoring the muscle fatigue ...anytime and anywhere is urgently needed. In this paper we apply Electrical impedance myography (EIM) technique, usually used for non-invasive detection of neuromuscular diseases with the four-electrode array, for evaluation of the local muscle fatigue status via the variation of electrical impedance. An equivalent multilayer inhomogeneous 3D finite element model of human arm was built in order to optimize the four-electrode configuration to improve EIM detection sensitivity. Current density in muscle layer and differential potential of induction electrodes were selected as the evaluation indexes for optimization. Then the in vivo experiments of dynamic contraction with different maximal voluntary contractions (MVC) were performed on the biceps brachii muscle of eight healthy volunteers. The results showed that muscle resistance (R) decreased almost 8 Ω from the completely relaxed muscle to exhaustion, which is the same trend as for the median frequency (MF) of measured surface electromyography (sEMG) signals. The model and experiments in this paper indicate the feasibility and efficiency of EIM for detection of muscle fatigue using wearable devices.
Nintedanib (formerly known as BIBF 1120) is an intracellular inhibitor that targets multiple tyrosine kinases. A phase 2 trial suggested that treatment with 150 mg of nintedanib twice daily reduced ...lung-function decline and acute exacerbations in patients with idiopathic pulmonary fibrosis.
We conducted two replicate 52-week, randomized, double-blind, phase 3 trials (INPULSIS-1 and INPULSIS-2) to evaluate the efficacy and safety of 150 mg of nintedanib twice daily as compared with placebo in patients with idiopathic pulmonary fibrosis. The primary end point was the annual rate of decline in forced vital capacity (FVC). Key secondary end points were the time to the first acute exacerbation and the change from baseline in the total score on the St. George's Respiratory Questionnaire, both assessed over a 52-week period.
A total of 1066 patients were randomly assigned in a 3:2 ratio to receive nintedanib or placebo. The adjusted annual rate of change in FVC was -114.7 ml with nintedanib versus -239.9 ml with placebo (difference, 125.3 ml; 95% confidence interval CI, 77.7 to 172.8; P<0.001) in INPULSIS-1 and -113.6 ml with nintedanib versus -207.3 ml with placebo (difference, 93.7 ml; 95% CI, 44.8 to 142.7; P<0.001) in INPULSIS-2. In INPULSIS-1, there was no significant difference between the nintedanib and placebo groups in the time to the first acute exacerbation (hazard ratio with nintedanib, 1.15; 95% CI, 0.54 to 2.42; P=0.67); in INPULSIS-2, there was a significant benefit with nintedanib versus placebo (hazard ratio, 0.38; 95% CI, 0.19 to 0.77; P=0.005). The most frequent adverse event in the nintedanib groups was diarrhea, with rates of 61.5% and 18.6% in the nintedanib and placebo groups, respectively, in INPULSIS-1 and 63.2% and 18.3% in the two groups, respectively, in INPULSIS-2.
In patients with idiopathic pulmonary fibrosis, nintedanib reduced the decline in FVC, which is consistent with a slowing of disease progression; nintedanib was frequently associated with diarrhea, which led to discontinuation of the study medication in less than 5% of patients. (Funded by Boehringer Ingelheim; INPULSIS-1 and INPULSIS-2 ClinicalTrials.gov numbers, NCT01335464 and NCT01335477.).
Summary Background Patients with homozygous familial hypercholesterolaemia respond inadequately to existing drugs. We aimed to assess the efficacy and safety of the microsomal triglyceride transfer ...protein inhibitor lomitapide in adults with this disease. Methods We did a single-arm, open-label, phase 3 study of lomitapide for treatment of patients with homozygous familial hypercholesterolemia. Current lipid lowering therapy was maintained from 6 weeks before baseline through to at least week 26. Lomitapide dose was escalated on the basis of safety and tolerability from 5 mg to a maximum of 60 mg a day. The primary endpoint was mean percent change in levels of LDL cholesterol from baseline to week 26, after which patients remained on lomitapide through to week 78 for safety assessment. Percent change from baseline to week 26 was assessed with a mixed linear model. Findings 29 men and women with homozygous familial hypercholesterolaemia, aged 18 years or older, were recruited from 11 centres in four countries (USA, Canada, South Africa, and Italy). 23 of 29 enrolled patients completed both the efficacy phase (26 weeks) and the full study (78 weeks). The median dose of lomitapide was 40 mg a day. LDL cholesterol was reduced by 50% (95% CI −62 to −39) from baseline (mean 8·7 mmol/L SD 2·9) to week 26 (4·3 mmol/L 2·5; p<0·0001). Levels of LDL cholesterol were lower than 2·6 mmol/L in eight patients at 26 weeks. Concentrations of LDL cholesterol remained reduced by 44% (95% CI −57 to −31; p<0·0001) at week 56 and 38% (–52 to −24; p<0·0001) at week 78. Gastrointestinal symptoms were the most common adverse event. Four patients had aminotransaminase levels of more than five times the upper limit of normal, which resolved after dose reduction or temporary interruption of lomitapide. No patient permanently discontinued treatment because of liver abnormalities. Interpretation Our study suggests that treatment with lomitapide could be a valuable drug in the management of homozygous familial hypercholesterolaemia. Funding FDA Office of the Orphan Product Development, Aegerion Pharmaceuticals.
Idiopathic pulmonary fibrosis (IPF) is the most common and most lethal diffuse fibrosing lung disease, with a mortality rate that exceeds that of many cancers. Recently, there have been many clinical ...trials of novel therapies for IPF. The results have mostly been disappointing, although two treatment approaches have shown some efficacy. This Review describes the difficulties of treating IPF and the approaches that have been tried or are in development, and concludes with suggestions of future therapeutic targets and strategies.
Idiopathic pulmonary fibrosis is a progressive lung disease with a high mortality rate. Because the signaling pathways activated by several tyrosine kinase receptors have been shown to be involved in ...lung fibrosis, it has been suggested that the inhibition of these receptors may slow the progression of idiopathic pulmonary fibrosis.
In a 12-month, phase 2 trial, we assessed the efficacy and safety of four different oral doses of the tyrosine kinase inhibitor BIBF 1120 as compared with placebo in patients with idiopathic pulmonary fibrosis. The primary end point was the annual rate of decline in forced vital capacity (FVC). Secondary end points included acute exacerbations, quality of life (measured with the St. George's Respiratory Questionnaire SGRQ), and total lung capacity.
A total of 432 patients underwent randomization to receive one of four doses of BIBF 1120 (50 mg once a day, 50 mg twice a day, 100 mg twice a day, or 150 mg twice a day) or placebo. In the group receiving 150 mg of BIBF 1120 twice a day, FVC declined by 0.06 liters per year, as compared with 0.19 liters per year in the placebo group, a 68.4% reduction in the rate of loss with BIBF 1120 (P = 0.06 with the closed testing procedure for multiplicity correction; P = 0.01 with the hierarchical testing procedure). This dose also resulted in a lower incidence of acute exacerbations, as compared with placebo (2.4 vs. 15.7 per 100 patient-years, P = 0.02) and a small decrease in the SGRQ score (assessed on a scale of 0 to 100, with lower scores indicating better quality of life) as compared with an increase with placebo (-0.66 vs. 5.46, P = 0.007). Gastrointestinal symptoms (which led to more discontinuations in the group receiving 150 mg twice a day than in the placebo group) and increases in levels of liver aminotransferases were more frequent in the group receiving 150 mg of BIBF 1120 twice daily than in the placebo group.
In patients with idiopathic pulmonary fibrosis, BIBF 1120 at a dose of 150 mg twice daily, as compared with placebo, was associated with a trend toward a reduction in the decline in lung function, with fewer acute exacerbations and preserved quality of life. (Funded by Boehringer Ingelheim; ClinicalTrials.gov number, NCT00514683 .).
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