Pancreatoblastoma: a report from the European cooperative study group for paediatric rare tumours (EXPeRT)

Background

Pancreatoblastoma is a very rare malignant tumour typically occurring in the early years of life. Due to its rarity, standardised diagnostic and therapeutic guidelines are not available for pancreatoblastoma.

Methods

The newborn cooperative group denominated EXPeRT – European cooperative study group for paediatric rare tumours – combined in a joint analysis of all cases registered between 2000 and 2009 by the national groups of Italy, France, United Kingdom, Poland and Germany.

Results

Twenty patients <18 years old (median age 4 years) were analysed: nine had distant metastases at diagnosis. Seventeen patients had tumour resection, at initial or delayed surgery. Eighteen received chemotherapy (response rate 73%), seven received radiotherapy. For the whole series, 5-year event-free survival and overall survival were 58.8% and 79.4%, respectively. Outcome did not correlate with tumour site and size, but was strongly influenced by the feasibility of tumour complete resection.

Conclusions

This international study confirms the rarity of the disease, the critical role of surgical resection both as therapy and as a prognostic variable, and the potential efficacy of chemotherapy. The adoption of an intensive multidisciplinary approach is required, as well as the referral to highly experienced centres. Further international cooperation is needed to collect larger series and stimulate biological studies to improve our understanding of the biology and the natural history of PBL.     

Relationship between tumour necrosis factor‐related apoptosis inducing ligand (TRAIL) and vascular endothelial growth factor in human multiple myeloma patients

Tumour necrosis factor‐alfa (TNF‐α) is an inflammatory cytokine with a wide spectrum of biological activity, including angiogenesis. Tumour necrosis factor‐related apoptosis inducing ligand (TRAIL), which belongs to the TNF family of proteins, plays a role in the regulation of vascular responses, but its effect on the formation of new blood vessels (angiogenesis) is unclear. We analysed TRAIL concentrations in parallel with pro‐angiogenic cytokines in serum and their expression in trephine biopsy (TB) in 56 patients with newly diagnosed IgG MM and 24 healthy volunteers. The study showed statistically higher concentrations of TRAIL and TNF‐α, as well as of VEGF and its receptor, in MM patients compared to healthy volunteers and patients in advanced stages of the disease. Furthermore, we observed a significant decrease in all studied pro‐angiogenic cytokines and significant increase of TRAIL concentration after anti‐angiogenic therapy, with meaningful differences between responders (at least partial remission) and patients with progression during the induction treatment. It was also established that TRAIL correlated statistically and negatively with pro‐angiogenic cytokines such as VEGF with its receptor and expression of VEGF and syndecan‐1 in TB. In summary, our data indicate that in MM patients, both clinical course and treatment responsiveness are associated with dynamic yet corresponding changes of levels of TRAIL parallel pro‐angiogenic mediators such as VEGF with its receptor and expression of VEGF and syndecan‐1 in TB. Copyright © 2014 John Wiley & Sons, Ltd.     

Hyponatremic encephalopathy--some experimental and clinical findings

Hyponatremia is a common electrolyte disturbance occurring in a broad spectrum of patients, from asymptomatic to critically ill. The disease is defined as a decrease in serum sodium concentration to a level below 136 mmol per liter. The brain damage from hyponatremia can be associated with either hyponatremic encephalopathy or improper therapy of symptomatic hyponatremia both in patients and in experimental models of hyponatremia in rats. This review covers the clinical symptoms of hyponatremia as well as the consequences of its correction. It also summarises the effects of experimental hyponatremia associated with vasopressin on some aspects of cerebral blood flow regulation and the morphology of cerebral tissue.     

Selective changes in the levels of nicotinic acetylcholine receptor protein and of corresponding mRNA species in the brains of patients with Parkinson's disease

Reductions in the number of neuronal nicotinic acetylcholine receptors (nAChRs) have been shown to occur in connection with Parkinson's disease (PD), but it is still unclear which subtype of this receptor is affected. In the present study we examined various nAChR subtypes employing ligand binding, as well as levels of subunit protein and mRNA in the brains of PD patients and age-matched controls. Binding of [3H]epibatidine and levels of alpha3 mRNA in the caudate nucleus and temporal cortex, but not in the hippocampus were significantly decreased in the PD brain. The level of the alpha3 protein subunit was significantly reduced in all these brain regions but there was no change in the level of alpha4. The level of the beta2 protein subunit in the temporal cortex and hippocampus and the beta2 mRNA in the temporal cortex was lowered. Both the levels of the alpha7 subunit protein and [125I]alpha-bungarotoxin binding were significantly increased in the temporal cortex of PD patients whereas the alpha7 mRNA level was unchanged. These findings reveal selective losses of the alpha3- and beta2-containing nAChRs and an increase in the alpha7 nAChRs that might be related to the pathogenesis of PD.     

Incretin Hormones in Obesity and Related Cardiometabolic Disorders: The Clinical Perspective

The prevalence of obesity continues to grow rapidly worldwide, posing many public health challenges of the 21st century. Obese subjects are at major risk for serious diet-related noncommunicable diseases, including type 2 diabetes mellitus, cardiovascular disease, and non-alcoholic fatty liver disease. Understanding the mechanisms underlying obesity pathogenesis is needed for the development of effective treatment strategies. Dysregulation of incretin secretion and actions has been observed in obesity and related metabolic disorders; therefore, incretin-based therapies have been developed to provide new therapeutic options. Incretin mimetics present glucose-lowering properties, together with a reduction of appetite and food intake, resulting in weight loss. In this review, we describe the physiology of two known incretins—glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1), and their role in obesity and related cardiometabolic disorders. We also focus on the available and incoming incretin-based medications that can be used in the treatment of the above-mentioned conditions.     

Synthesis and 5-HT1A/5-HT2A receptor activity of N-(4-arylpiperazin-1-yl)alkyl derivatives of 2-azaspiro([4.4]nonane and [4.5]decane-1,3-dione

Two series of N-[(4-arylpiperazin-1-yl)-alkyl]-2-azaspiro[4.4]nonane (5-10) and [4.5]decane-1,3-dione (11-16) derivatives were synthesized and their serotonin 5-HT1A and 5-HT2A receptor affinities were determined. Compounds with the methylene spacer (5-7 and 11-13) exhibited low 5-HT1A/5-HT2A receptor affinity, in contrast to their ethylene analogues regarded as potent 5-HT1A ligands, especially those containing a cyclohexane moiety (14-16; Ki = 5.1, 2.7 and 4.3 nM, respectively) in the 3-position of the pyrrolidine-2,5-dione ring. Moreover, derivatives with 3-chloro substituent (10 and 14) showed distinct affinity for 5-HT2A receptors. The functional activity of compounds 10, 14, 15 and 16 was tested in vivo in the commonly used animal models. In those experiments, the tested compounds showed features of agonists of pre- and postsynaptic (14), agonists of presynaptic and antagonists of postsynaptic (10, 15), or agonists of postsynaptic (16) 5-HT1A receptors. Additionally, 10 and 16 exhibited properties of potential 5-HT2A receptor antagonists. The above results suggested a crucial role of the spacer between the amide fragment and 4-arylpiperazine moiety, as well as of the size of the cycloalkyl ring at the 3-position of pyrrolidine-2,5-dione ring in functional 5-HT1A/5-HT2A properties.