Distribution of eosinophils in the gastrointestinal tract of children with no organic disease

Background This study aimed to assess the eosinophil (eos) density of the mucosa of the gastrointestinal (GI) tract in children undergoing endoscopic procedures following an extensive workup, without diagnosis of an organic disease. Methods Biopsies from GI endoscopies performed at 3 major children’s hospitals (Athens, Madrid and Rome), between January 2012 and June 2018, were evaluated by a single pathologist in each center. Peak eos counts were expressed /high power field and /mm2. Other histological abnormalities were also reported. Results A total of 111 children (median age 11 years; 48 boys) underwent upper endoscopy (333 biopsies), while 44 (median age 12; 25 boys) underwent ileocolonoscopy (262 biopsies). The median (interquartile range) eos/mm2 were as follows: esophagus 0 (0-0); stomach 0 (0-3); duodenum 22 (13-29); ileum 29 (19-46); cecum 39 (25-71); ascending colon 24 (20-41); transverse colon 27 (21-57); descending colon 21 (13-27); sigmoid colon 22 (13-30); and rectum 10 (6-22). Geographical variations in GI tissue eos counts were found amongst the participating centers, but the causative factors need further evaluation. Functional GI disorders according to the Rome IV criteria were diagnosed in 73 children (37 boys, median age 13 years). No differences were found between children with or without functional GI disorder diagnosis, with regard to eos density in the GI tract. Conclusion The reported peak counts of GI tissue eos in children with no organic diseases provide normative values that may be useful in the evaluation of children with GI symptoms suggestive of eosinophilic GI disorders

Immunohistochemical expression of cell cycle/apoptosis regulators and epidermal growth factor receptor in pediatric intracranial ependymomas

Intracranial ependymomas are the third most common primary brain tumor in children. We set out to investigate the expression of p-53, p-27, bcl-2, and epidermal growth factor receptor in 13 pediatric infratentorial ependymomas, in correlation with Ki-67/ MIB-1 proliferation index and prognosis. The median progression-free survival was 37.5 months, and the 5-year overall survival was 50%. There was a statistically significant higher expression of Ki-67 and p-53 index in anaplastic tumors. There was also a higher expression of p-27, bcl-2, and epidermal growth factor receptor in anaplastic tumors, but the difference was not statistical significant. No significant correlation was found between overall survival and level of expression of Ki-67, p-53, p-27, bcl-2, and epidermal growth factor receptor. Epidermal growth factor receptor detection in a considerable number of ependymomas probably reflects its role in the neoplastic transformation and can serve as a therapeutic target. © 2011 The Author(s)

Immunohistochemical expression of cell-cycle regulators in pediatric Embryonal brain tumors

Embryonal tumors constitute the most common malignant brain tumor group in children. Experimental results indicate that genes involved in cell cycle and signal transduction are deregulated in medulloblastoma (MB) and atypical teratoid/rhabdoid tumors (AT/RT). The cell cycle is regulated by protein complexes composed of a regulatory subunit called Cyclin and a catalytic domain named Cyclin-dependent kinase (CDK). Cyclins and CDKs are in turn regulated by cyclin-dependent kinase inhibitors (CDKI) which inhibit cell-cycle progression. Cyclins D and Cyclin E are important for the passage of cells through G1 to S phase. P-27, a member of the universal CDKI family, is important in regulating the G1/S transition. Thus, the purpose of this study was to investigate the expression of p-27, Cyclin D3, and Cyclin E, and their possible prognostic significance in pediatric embryonal brain tumors. We retrospectively evaluated 51 children with embryonal tumors that were treated surgically in our institute. All patients had regular follow up examinations. The streptavidin-biotin HRP method was performed on paraffin sections for detection of p-27, Cyclin D3, and Cyclin E. There were 42 cases of MB and nine cases of AT/RT. Cyclin D3 expression was detected in 11/42 MB and 3/9 AT/RT patients. Cyclin E expression was detected in 28/42 MB and 8/9 AT/RT patients. High expression of Ki-67 (>50 %) and p-27 (>50 %) was observed in 23.8-73.8 % of MB patients. Combined high Ki-67 and p-27 expression was observed in 21.4 % cases of MB. In these cases there was expression of Cyclin E in 88.8 % and Cyclin D3 in 22.2 % of MB. No significant correlation was found between Ki-67 and p-27, Cyclin D3, and E. No correlation was found between Cyclin D3, Cyclin E, p-27, and overall survival. Increased p-27 and Cyclin E expression was detected in a substantial number of MB patients and in nearly all AT/RT patients. Further studies on a larger number of patients are needed to clarify a possible correlation of p-27 and Cyclin E with tumor behavior. © Springer Science+Business Media, LLC. 2012

Expression of epidermal growth factor receptor and HER-2 in pediatric embryonal brain tumors

Background/Aims: Medulloblastomas (MBs), atypical teratoid rhabdoid tumors (AT/RTs) and central nervous system primitive neuroectodermal tumors (PNETs) are aggressive embryonal brain neoplasms in children with overlapping histological features but with different pathogenetic pathways. We set out to evaluate the role of epidermal growth factor receptor (EGFR), HER-2, Ki-67 and p53 in embryonal tumors. Material and Methods: We retrospectively evaluated 36 children with embryonic tumors (27 MBs, 7 AT/RTs and 2 supratentorial PNETs). The immunohistochemical expression of EGFR and HER-2 was correlated to histology, expression of the Ki-67/MIB-1 proliferative index, p53 tumor suppressor oncoprotein and prognosis. Results: High expression of Ki-67 was observed in all MBs being particularly increased (>50%) in 8 cases, while p53 protein was detected in 25/27 MBs showing a high expression in 16 cases. EGFR and HER-2 expression was observed in 10/27 and 17/27 MBs, respectively. High Ki-67/MIB-1 and p53 expression was revealed in all AT/RTs and PNETs, while EGFR and HER-2 were detected in 3/7 and 6/7 AT/RTs, respectively. The 5-year progression-free survival and overall survival were 55.5 and 69.2%, respectively. In MBs, the univariate analysis revealed that the Ki-67 index and male gender were both at a significant level related to the survival of the patient. In multivariate analysis, the Ki-67 index was the only independent predictive variable. Conclusions: The Ki-67 index was identified as a factor with independent prognostic power. EGFR and HER-2 expression is variable in embryonal tumors. HER-2 expression, in a considerable number of MBs and AT/RTs, suggests that HER-2 may be implicated in their pathogenesis representing a potential target for novel therapies. Copyright © 2010 S. Karger AG, Basel

Prognostic significance of cyclin A and B1 in pediatric embryonal tumors

Embryonal tumors constitute the most common malignant brain tumor group in children. Although patient prognosis has been substantially improved over recent decades, identification of prognostic markers would be of obvious significance. In the present study we evaluated the prognostic significance of cyclin A and B1 in correlation with Ki-67 index in pediatric embryonal tumors. We retrospectively evaluated 53 children with embryonic tumors who were treated surgically in our institute. All patients had regular follow-up examinations. The streptavidin-biotin-horseradish peroxidase (HRP) method was performed on paraffin sections for detection of Ki-67/MIB-1, and cyclin A and B1. There were 42 cases of medulloblastoma (MB), 9 cases of atypical teratoid/rhabdoid tumor (AT/RT), and 2 cases of supratentorial primitive neuroectodermal tumor (PNET). In MB patients, Ki-67 index >50% was associated with worse survival (P = 0.003). Cyclin A index >40% was associated with significantly poorer survival (P = 0.023). Patients with cyclin B1 index >15% exhibited a trend towards poorer survival (P = 0.068). On multivariate analysis, only Ki-67 index was identified as a factor with independent prognostic power. In AT/RT and PNET, there was high expression of Ki-67 and variable expression of cyclin A and B1. Apart from Ki-67 index, cyclin A may have a prognostic role. Study of the above indices at diagnosis could alter or intensify treatment methods, so as to improve disease outcome. There is obviously a need for future studies with larger number of patients to confirm our preliminary observations. © 2010 Springer Science+Business Media, LLC

Diagnostic accuracy of two-dimensional shear wave elastography in detecting hepatic fibrosis in children with autoimmune hepatitis, biliary atresia and other chronic liver diseases

Background: Although fibrosis is the main determinant of liver stiffness, other disease-related factors usually disregarded in studies on liver elastography, such as inflammation and cholestasis, may influence liver stiffness. Objective: To evaluate the accuracy of two-dimensional (2-D) shear wave elastography in assessing liver fibrosis in children with chronic liver disease by controlling for the confounding role of several disease- and patient-related factors. Materials and methods: Three disease groups were studied: 1) various chronic liver diseases, 2) autoimmune hepatitis and 3) biliary atresia. The METAVIR (meta-analysis of histological data in viral hepatitis) score was used for fibrosis staging and grading of necroinflammatory activity. Multiple linear regression was used to evaluate the relationship between liver stiffness measurements and disease-related factors. The diagnostic accuracy of elastography for predicting fibrosis stages was assessed by calculating the area under the receiver operating characteristic curves. Results: The various chronic liver diseases group (n=32; 7.1±4.9 [mean±standard deviation] years) showed liver stiffness of 8.9±5.0 (mean±standard deviation) kPa, the autoimmune hepatitis group (n=33; 8.1±4.4 years) of 7.1±2.7 kPa, and the biliary atresia group (n=19; 0.2±0.1 years) of 19.7±15.2 kPa. Liver stiffness measurements differed across METAVIR fibrosis categories in all disease groups. The highest values were found in biliary atresia, at fibrosis stages ≥F2 (F2: 12.4±1.6 kPa, F3: 17.8±2 kPa, F4: 41.5±12.4 kPa). Liver stiffness was strongly associated only with fibrosis (P<0.0001) in various chronic liver diseases, but with necroinflammatory activity (P<0.0001) and fibrosis (P=0.002) in autoimmune hepatitis, and with age (P<0.0001), fibrosis (P<0.0001) and cholestasis (P=0.009) in biliary atresia. Optimal cutoffs for detecting advanced fibrosis (≥F3) were 16 kPa (area under curve: 0.98; sensitivity: 87.5%; specificity: 96.7%) in biliary atresia and 8.7 kPa (area under curve: 0.98; sensitivity: 93.8%; specificity: 96.1%) in other chronic liver diseases. Conclusion: Two-dimensional shear wave elastography is reliable in assessing liver fibrosis in children with chronic liver diseases. © 2020, The Author(s), under exclusive licence to Springer-Verlag GmbH, DE part of Springer Nature

Expression of heat shock proteins in medulloblastoma: Laboratory investigation

Object. Medulloblastoma (MB) is the most common malignant brain tumor in children. Heat shock proteins (HSPs) comprise a superfamily of proteins that serve as molecular chaperones and are overexpressed in a wide range of human cancers. The purpose of the present study was to investigate the expression of HSP27 (pSer82), HSP27 (pSer15), HSP40, HSP60, HSP70, HSP90-α, Akt, and phospho-Akt by multiplex bead array assay of MBs. The results of HSP and Akt expression were correlated with MB subtype; immunohistochemical expression of Ki-67 index, bcl- 2, and p53; and patients' prognosis. Methods. The authors retrospectively evaluated 25 children with MB who underwent surgery. Immunohistochemical analysis of Ki-67, p53, and bcl-2 expression was performed in all cases. By using multiplex bead array assay, a simultaneous detection of HSP27 (pSer82), HSP27 (pSer15), HSP40, HSP60, HSP70, HSP90-α, Akt, and phospho-Akt was performed. Results. Medulloblastoma with extensive nodularity had significantly lower HSP27 (pSer15) expression (p = 0.039) but significantly higher HSP60 expression (p = 0.021) than classic MB. Large-cell MB had significantly higher HSP70 expression (p = 0.028) than classic MB. No significant difference was found between HSP27 (pSer82), HSP40, HSP90-α, Akt, or phospho-Akt expression and MB subtype. Large-cell MBs had significantly higher Ki-67 index compared with classic MBs (p = 0.033). When analyzing all MBs, there was a significant negative correlation between HSP27 (pSer15) and Ki-67 index (r = -0.475, p = 0.016); a significant positive correlation between HSP70 expression and Ki-67 index (r = 0.407, p = 0.043); and a significant positive correlation between HSP70 expression and bcl-2 index (r = 0.491, p = 0.023). Patients with large-cell MB had a worse survival than those with classic MB, but the difference did not reach statistical significance (p = 0.076). Conclusions. A substantial expression of several HSPs in MB was observed. Given that HSPs represent an attractive strategy for anticancer therapy, further studies, involving larger series of patients, are obviously necessary to clarify the relationship of HSPs with tumor aggressiveness and prognosis. © Copyright 1944-2013 American Association of Neurological Surgeons

Distribution of eosinophils in the gastrointestinal tract of children with no organic disease

Background This study aimed to assess the eosinophil (eos) density of the mucosa of the gastrointestinal (GI) tract in children undergoing endoscopic procedures following an extensive workup, without diagnosis of an organic disease. Methods Biopsies from GI endoscopies performed at 3 major children’s hospitals (Athens, Madrid and Rome), between January 2012 and June 2018, were evaluated by a single pathologist in each center. Peak eos counts were expressed /high power field and /mm2. Other histological abnormalities were also reported. Results A total of 111 children (median age 11 years; 48 boys) underwent upper endoscopy (333 biopsies), while 44 (median age 12; 25 boys) underwent ileocolonoscopy (262 biopsies). The median (interquartile range) eos/mm2 were as follows: esophagus 0 (0-0); stomach 0 (0-3); duodenum 22 (13-29); ileum 29 (19-46); cecum 39 (25-71); ascending colon 24 (20-41); transverse colon 27 (21-57); descending colon 21 (13-27); sigmoid colon 22 (13-30); and rectum 10 (6-22). Geographical variations in GI tissue eos counts were found amongst the participating centers, but the causative factors need further evaluation. Functional GI disorders according to the Rome IV criteria were diagnosed in 73 children (37 boys, median age 13 years). No differences were found between children with or without functional GI disorder diagnosis, with regard to eos density in the GI tract. Conclusion The reported peak counts of GI tissue eos in children with no organic diseases provide normative values that may be useful in the evaluation of children with GI symptoms suggestive of eosinophilic GI disorders. © 2020 Hellenic Society of Gastroenterology

In situ evidence of cellular senescence in Thymic Epithelial Cells (TECs) during human thymic involution

Cellular senescence, an age-related process in response to damage and stress, also occurs during normal development and adult life. The thymus is a central lymphoepithelial organ of the immune system that exhibits age-related changes termed thymic involution. Since the mechanisms regulating thymic involution are still not well elucidated, we questioned whether cellular senescence is implicated in this process. We demonstrate, for the first time in situ, that cellular senescence occurs during human thymic involution using SenTraGor™ a novel chemical compound that is applicable in archival tissue material, providing thus further insights in thymus histophysiology. © 2018 Elsevier B.V