Percutaneous core needle biopsy of neuroblastoma in the pediatric population: what have we learned in the last decade.

INTRODUCTION: Historically, neuroblastoma has been diagnosed by surgical open biopsy (SB). In recent decades, core needle biopsy (CNB) has replaced surgical biopsy due to its safe and adequate method of obtaining tissue diagnosis. AIM: Our study aimed to assess the effectiveness of CNB in obtaining tissue diagnosis for neuroblastoma and evaluate its safety profile in terms of post-operative complications, in comparison to SB. METHODS: A retrospective cohort study, including all patients younger than 18 years who were diagnosed with neuroblastoma from 2012 until 2022 in a single tertiary medical center. Patients' demographics, tumor size and location, pathological results, and clinical outcomes were collected. RESULTS: 79 patients were included in our study: 35 biopsies were obtained using image-guided CNB and 44 using SB. Patients' and tumor characteristics including age, gender, tumor volume, and stage were similar in both groups. The biopsy adequacy rate in the CNB group was 91% and 3 patients in this group underwent repeated biopsy. The safety profile in the CNB group was similar to the SB group. CONCLUSIONS: CNB is a safe method and should be considered the first choice for obtaining tissue diagnosis when feasible due to its high adequacy in terms of tumor histopathological features.

Specific Features of Juvenile Idiopathic Arthritis Patients' Cytokine Profile.

Juvenile idiopathic arthritis (JIA) is a systemic autoimmune disease that affects the joints, leading to disability. Cytokines and signaling molecules expressed by the immune system cells play a key role in JIA pathogenesis. Understanding how their content changes during pathology development can open up new opportunities for its diagnosis and treatment. The blood plasma of 30 patients with JIA (14 males and 16 females with a mean age of 12.2 ± 4.1) and 20 relatively healthy individuals (10 males and 10 females with a mean age of 10.20 ± 5.85) was analyzed to determine the levels of cytokines using the MILLIPLEX® kit. An increase in interleukins (IL)-1α, 1ß, 2, 4, 5, 6, 7, 8, 9, 10, 13, 15, 17F, 22, and 27 and a decrease in IL-3 levels have been shown in patients with JIA. Levels of cytokines, which are important for B-cell activation and proliferation, are increased, while levels of T-cell activating factors remained similar to the control group. Based on our results, it can be assumed that the use of combination therapy aimed at inhibiting both nonspecific interleukins and cytokines that activate B-cells will be more effective for the treatment of JIA.

Loss of function of ENT3 drives histiocytosis and inflammation through TLR-MAPK signaling.

Histiocytoses are inflammatory myeloid neoplasms often driven by somatic activating mutations in mitogen-activated protein kinase (MAPK) cascade genes. H syndrome is an inflammatory genetic disorder caused by germ line loss-of-function mutations in SLC29A3, encoding the lysosomal equilibrative nucleoside transporter 3 (ENT3). Patients with H syndrome are predisposed to develop histiocytosis, yet the mechanism is unclear. Here, through phenotypic, molecular, and functional analysis of primary cells from a cohort of patients with H syndrome, we reveal the molecular pathway leading to histiocytosis and inflammation in this genetic disorder. We show that loss of function of ENT3 activates nucleoside-sensing toll-like receptors (TLR) and downstream MAPK signaling, inducing cytokine secretion and inflammation. Importantly, MEK inhibitor therapy led to resolution of histiocytosis and inflammation in a patient with H syndrome. These results demonstrate a yet-unrecognized link between a defect in a lysosomal transporter and pathological activation of MAPK signaling, establishing a novel pathway leading to histiocytosis and inflammation.

Cytoskeletal Protein Palladin in Adult Gliomas Predicts Disease Incidence, Progression, and Prognosis.

Brain tumors comprise over 100 types of masses, differing in the following: location; patient age; molecular, histological, and immunohistochemical characteristics; and prognosis and treatment. Glioma tumors originate from neuroglia, cells supporting the brain. Palladin, a structural protein widely expressed in mammalian tissues, has a pivotal role in cytoskeletal dynamics and motility in health and disease. Palladin is linked to the progression of breast, pancreatic, and renal cancers. In the central nervous system, palladin is involved in embryonic development, neuronal maturation, the cell cycle, differentiation, and apoptosis. However, the role of palladin in brain tumors is unknown. In this work, we explored palladin's role in glioma. We analyzed clinical data, along with bulk and single-cell gene expression. We then validated our results using IHC staining of tumor samples, together with qRT-PCR of glioma cell lines. We determined that wild-type palladin-4 is overexpressed in adult gliomas and is correlated with a decrease in survival. Palladin expression outperformed clinically used prognostic markers and was most prominent in glioblastoma. Finally, we showed that palladin originates from the malignant cell population. Our findings indicate that palladin expression might be linked to adult glioma progression and is associated with prognosis.

Fetal Urinoma Due to Circulatory Disorders in an Umbilical Artery: Case Report.

Fetal urinoma is defined as an encapsulated accumulation of extravasated urine within the perirenal space or retroperitoneum. It is an uncommon finding in prenatal practice, and the vast majority of known cases are strongly associated with the existence of a urinary obstruction, such as posterior urethral valves, ureteropelvic junction obstruction, or ureterocele. We report a unique case of prenatally detected fetal bladder urinoma that occurred in the absence of an apparent obstructive uropathy, but was associated with extensive ischemic necrosis and calcifications of adjacent bladder wall, coexistent with signs of vascular supply decompensation.

PAR1&2 driven placenta EVT invasion act via LRP5/6 as coreceptors.

While the involvement of protease-activated receptors (PARs) in the physiological regulation of human placenta development, as in tumor biology, is recognized, the molecular pathway is unknown. We evaluated the impact of PAR1 and PAR2 function in cytotrophoblast (CTB) proliferation and invasion in a system of extravillous trophoblast (EVT) organ culture and in human cell-lines. Activation of PAR1 - and PAR2 -induced EVT invasion and proliferation, while the shRNA silencing of low-density lipoprotein receptor-related protein 5/6 (LRP5/6) inhibited these processes. PAR1 and PAR2 effectively induce ß-catenin stabilization in a manner similar to that shown for the canonical ß-catenin stabilization pathway yet independent of Wnts. Immunoprecipitation analyses and protein-protein docking demonstrated the co-association between either PAR1 or PAR2 with LRP5/6 forming an axis of PAR-LRP5/6-Axin. Noticeably, in PAR1 -PAR2 heterodimers a dominant role is assigned to PAR2 over PAR1 as shown by inhibition of PAR1 -induced ß-catenin levels, and Dvl nuclear localization. This inhibition takes place either by shRNA silenced hPar2 or in the presence of a TrPAR2 devoid its cytoplasmic tail. Indeed, TrPAR2 cannot form the PAR1 -PAR2 complex, obstructing thereby the flow of signals downstream. Elucidation of the mechanism of PAR-induced invasion contributes to therapeutic options highlighting key partners in the process.

Hypoxia Affects Neprilysin Expression Through Caspase Activation and an APP Intracellular Domain-dependent Mechanism.

While gene mutations in the amyloid precursor protein (APP) and the presenilins lead to an accumulation of the amyloid ß-peptide (Aß) in the brain causing neurodegeneration and familial Alzheimer's disease (AD), over 95% of all AD cases are sporadic. Despite the pathologies being indistinguishable, relatively little is known about the mechanisms affecting generation of Aß in the sporadic cases. Vascular disorders such as ischaemia and stroke are well established risk factors for the development of neurodegenerative diseases and systemic hypoxic episodes have been shown to increase Aß production and accumulation. We have previously shown that hypoxia causes a significant decrease in the expression of the major Aß-degrading enzyme neprilysin (NEP) which might deregulate Aß clearance. Aß itself is derived from the transmembrane APP along with several other biologically active metabolites including the C-terminal fragment (CTF) termed the APP intracellular domain (AICD), which regulates the expression of NEP and some other genes in neuronal cells. Here we show that in hypoxia there is a significantly increased expression of caspase-3, 8, and 9 in human neuroblastoma NB7 cells, which can degrade AICD. Using chromatin immunoprecipitation we have revealed that there was also a reduction of AICD bound to the NEP promoter region which underlies the decreased expression and activity of the enzyme under hypoxic conditions. Incubation of the cells with a caspase-3 inhibitor Z-DEVD-FMK could rescue the effect of hypoxia on NEP activity protecting the levels of AICD capable of binding the NEP promoter. These data suggest that activation of caspases might play an important role in regulation of NEP levels in the brain under pathological conditions such as hypoxia and ischaemia leading to a deficit of Aß clearance and increasing the risk of development of AD.