18Fluorine-fluorodeoxyglucose positron emission tomography/computed tomography total glycolytic volume in thymic epithelial neoplasms evaluation: a reproducible image biomarker

Introduction

¹⁸Fluorine-fluorodeoxyglucose positron emission tomography/computed tomography is not yet accepted as a standard pretreatment evaluation of thymic epithelial neoplasm (TEN). Statistical correlation between standardized uptake value of tumor/mediastinum ratio and patients’ WHO risk class has been reported. PET metabolic tumor volume (MTV) and total glycolytic volume (TGV) have been reported as additional prognostic imaging biomarkers in several human tumors. Purpose of study was to establish whether MTV and TGV add prognostic information in TEN.

Materials and methods

A retrospective dynamic cohort study of prospectively collected data (2006–2012) on 23 consecutive patients with pathologically proven TEN (no thymic carcinoma) was conducted. All patients underwent chest CT, and PET for staging. SUV T/M ratio, semi-quantitative and volumetric analyses of TEN were calculated. Patients were categorized according to WHO classification (low-risk and high-risk thymomas). Statistical analysis was performed with bootstrap method. Multi-collinearity was established using Pearson correlation coefficient. Cut-off point for TGV was compared using Mantel Cox log rank test.

Results

SUV T/M ratio, MTV, and TGV correlate with low- and high-risk TEN. However, the statistical correlation between TGV and WHO classification (ρ = 0.897) was higher than SUV T/M ratio (ρ = 0.873). Since sample distributions were not uniformly smooth, only one cut-off value was identified: a TGV of 383 served as a cut-off value between low-risk and high-risk TEN.

Conclusion

TGV is a PET reproducible imaging marker in patients with TEN, provides prognostic information, and could be useful in pretreatment stratification of patients. Nevertheless, it needs validation in larger cohort studies.     

Energy restriction mimetic agents to target cancer cells: Comparison between 2-deoxyglucose and thiazolidinediones

The use of energy restriction mimetic agents (ERMAs) to selectively target cancer cells addicted to glycolysis could be a promising therapeutic approach. Thiazolidinediones (TZDs) are synthetic agonists of the nuclear receptor peroxisome proliferator-activated receptor (PPAR)γ that were developed to treat type II diabetes. These compounds also display anticancer effects which appear mainly to be independent of their PPARγ agonist activity but the molecular mechanisms involved in the anticancer action are not yet well understood. Results obtained on ciglitazone derivatives, mainly in prostate cancer cell models, suggest that these compounds could act as ERMAs. In the present paper, we introduce how compounds like 2-deoxyglucose target the Warburg effect and then we discuss the possibility that the PPARγ-independent effects of various TZD could result from their action as ERMAs.     

Tirasemtiv amplifies skeletal muscle response to nerve activation in humans

Introduction: In this study we tested the hypothesis that tirasemtiv, a selective fast skeletal muscle troponin activator that sensitizes the sarcomere to calcium, could amplify the response of muscle to neuromuscular input in humans. Methods: Healthy men received tirasemtiv and placebo in a randomized, double‐blind, 4‐period, crossover design. The deep fibular nerve was stimulated transcutaneously to activate the tibialis anterior muscle and produce dorsiflexion of the foot. The force–frequency relationship of tibialis anterior dorsiflexion was assessed after dosing. Results: Tirasemtiv increased force produced by the tibialis anterior in a dose‐, concentration‐, and frequency‐dependent manner with the largest increases [up to 24.5% (SE 3.1), P < 0.0001] produced at subtetanic nerve stimulation frequencies (10 Hz ). Conclusions: The data confirm that tirasemtiv amplifies the response of skeletal muscle to nerve input in humans. This outcome provides support for further studies of tirasemtiv as a potential therapy in conditions marked by diminished neuromuscular input. Muscle Nerve 50 : 925–931, 2014     

Thymus and mediastinal node involvement in childhood langerhans cell histiocytosis: Long‐term follow‐up from the French national cohort

Background

Mediastinal involvement (MI) in Langerhans cell histiocytosis (LCH) has been rarely reported. Here, we describe the clinical, radiological, and biological presentation, and the outcome of childhood LCH with MI.

Method

From the French LCH register, which includes 1,423 patients aged less than 18 years, we retrieved the medical charts of patients with mediastinal enlargement detected on chest X‐rays.

Results

Thirty‐seven patients were retrieved, including 18 males; median age of diagnosis was 0.7 years, and median follow‐up time was 6.2 years. The prevalence of MI varied with the age at diagnosis, ranging from 7% below 1 year old to less than 1% at >5 years. Thirteen cases (35%) were diagnosed because of MI‐related symptoms, including respiratory distress (N = 4), superior venous cava syndrome (N = 2), and/or cough and polypnea (N = 10). CT scans performed in 32 cases at diagnosis showed tracheal compression (N = 5), cava thrombosis (N = 2), and/or calcification (N = 16). All patients presented multi‐system disease at LCH diagnosis, and 35/37 were initially treated with vinblastine and corticosteroids. Death occurred in five cases, due to MI (N = 1) or hematological refractory involvement (N = 4). The overall 5‐year survival was 87.1%, and immunodeficiency was not detected as a sequel.

Conclusions

MI in LCH mainly occurs in young children, and diagnosis was based on CT showing thymus enlargement and calcifications. Pediatr Blood Cancer 2013;60:1759–1765. © 2013 Wiley Periodicals, Inc.     

Differential control of CD4+ T‐cell subsets by the PD‐1/PD‐L1 axis in a mouse model of allergic asthma

Studies examining the role of PD‐1 family members in allergic asthma have yielded conflicting results. Using a mouse model of allergic asthma, we demonstrate that blockade of PD‐1/PD‐L1 has distinct influences on different CD4⁺ T‐cell subsets. PD‐1/PD‐L1 blockade enhances airway hyperreactivity (AHR), not by altering the magnitude of the underlying Th2‐type immune response, but by allowing the development of a concomitant Th17‐type immune response. Supporting differential CD4⁺ T‐cell responsiveness to PD‐1‐mediated inhibition, naïve PD‐1^?/? mice displayed elevated Th1 and Th17 levels, but diminished Th2 cytokine levels, and ligation of PD‐1 in WT cells limited cytokine production by in vitro polarized Th1 and Th17 cells, but slightly enhanced cytokine production by in vitro polarized Th2 cells. Furthermore, PD‐1 ligation enhanced Th2 cytokine production by naïve T cells cultured under nonpolarizing conditions. These data demonstrate that different CD4⁺ T‐cell subsets respond differentially to PD‐1 ligation and may explain some of the variable results observed in control of allergic asthma by the PD‐1 family members. As the PD‐1/PD‐L1 axis limits asthma severity by constraining Th17 cell activity, this suggests that severe allergic asthma may be associated with a defective PD‐1/PD‐L1 regulatory axis in some individuals.     

HLA-DRB1, DQA1 and DQB1 DNA polymorphisms in healthy Algerian and genetic relationships with other populations

Abstract: This study presents the results of HLA-DRB1, -DQA1, and -DQB1 sequence-specific oligonucleotide probe (SSOP) typings for a population sample of 47 individuals originating from Western Algeria. Allele and haplotype frequencies, as well as linkage disequilibria are computed by the standard methods used for the XIth International Histocompatibility Workshop data. A total of 24 alleles are detected at the DRB1 locus, where a very high heterozygosity level (0.914) is found. The highest DRB1 frequencies are 0.160, DRB1*1101, and 0.138, for DRB1*0301 and DRB1*0701. The DQA1 and DQB1 loci are less polymorphic. Among the 8 DQA1 alleles detected, DQA1*0501 is highly predominant with a frequency of 0.383. Thirteen DQB1 alleles are observed among which DQB1*0301 and DQB1*0201 are the most frequent (0.351 and 0.245, respectively). Three haplotypes predominate clearly: DRB1*1101-DQA1*0501-DQB1*0301 (0.138), DRB1*0701-DQA1*0201-DQB1*0201 (0.128) and DRB1*0301-DQA1*0501-DQB1*0201 (0.117). The two latter are among the most frequent haplotypes found in European and North American Caucasoid populations, but the DQA1*0501-DQB1*0201 association is not significant in Algerians. The genetic distances computed for each locus among a set of populations from different continents are significantly correlated to geography. They indicate that the Algerians are very close to South European populations, particularly to Sardinians, Italians, Romanians and French, with some intermediate characteristics between Europeans and sub-Saharan Africans. These results may serve as reference for future studies of HLA and disease in the Algerian population.