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The association between acute lymphoblastic leukemia (ALL), non-Langerhans cell histiocytosis (non-LCH), and hemophagocytic lymphohistiocytosis (HLH), to the best of our knowledge, has not been published to date. Juvenile xanthogranuloma (JXG), as a type of non-LCH, is usually a benign disease limited to the skin. Systemic involvement is rarely reported. The present case report describes a 15-year-old boy diagnosed with disseminated JXG involving skin and bone marrow concurrent with severe symptoms of HLH during ALL therapy. Examination of immunoglobulin heavy chain genes in B-cell precursor leukemic blasts and histiocytes in the skin and bone marrow revealed identical rearrangements, confirming clonal relationship between both diseases. Implementation of corticosteroids, vinblastine, etoposide, cyclosporine, and tocilizumab resulted in partial skin lesion resolution with no improvement of bone marrow function; therefore, hematopoietic stem cell transplantation (HSCT) was eventually performed. The patient's hematological and general status has improved gradually; however, remarkable recovery of skin lesions was observed after empirical antitubercular therapy. Mycobacterium spp. infection should be considered as a possible secondary HLH trigger. Triple association of ALL, non-LCH, and HLH highlights heterogeneity of histiocytic disorders and possible common origin of dendritic and lymphoid cells.

Cellular stress can influence efficiency of iPSCs generation and their differentiation. However, the role of intracellular cytoprotective factors in these processes is still not well known. Therefore, we investigated the effect of HO-1 (Hmox1) or Nrf2 (Nfe2l2), two major cytoprotective genes. Hmox1-/- fibroblasts demonstrated decreased reprogramming efficiency in comparison to Hmox1+/+ cells. Reversely, pharmacological enhancement of HO-1 resulted in higher number of iPSCs colonies. Importantly, elevated level of both p53 and p53-regulated miR-34a and 14-3-3σ was observed in HO-1-deficient fibroblasts whereas downregulation of p53 in these cells markedly increased their reprogramming efficiency. In human fibroblasts HO-1 silencing also induced p53 expression and affected reprogramming outcome. Hmox1+/+ and Hmox1-/- iPSCs similarly differentiated in vitro to cells originating from three germ layers, however, lower number of contracting cells was observed during this process in HO-1-deficient cells indicating attenuated cardiac differentiation. Importantly, silencing of Hmox1 in murine ESC using CRISPR/Cas-9 editing also impaired their spontaneous cardiac differentiation. Decreased reprogramming efficiency was also observed in Nrf2-lacking fibroblasts. Reversely, sulforaphane, a Nrf2 activator, increased the number of iPSCs colonies. However, both Nfe2l2+/+ and Nfe2l2-/- iPSCs showed similar pluripotency and differentiation capacity. These results indicate that regulation of HO-1 expression can further optimize generation and cardiac differentiation of iPSCs. © 2018 IUBMB Life, 70(2):129-142, 2018.

Cellular stress can influence efficiency of iPSCs generation and their differentiation. However, the role of intracellular cytoprotective factors in these processes is still not well known. Therefore, we investigated the effect of HO-1 (Hmox1) or Nrf2 (Nfe2l2), two major cytoprotective genes. Hmox1

The coincidence of autoimmune thyroiditis (AIT) in patients with papillary thyroid carcinoma (PTC) is ranging between 10 and 58% in the general population.In the present study retrospective ultrasound, clinical and autoimmune assessment of 24 patients diagnosed with papillary thyroid carcinoma between 2000-2016 was performed.The coexistence of PTC and AIT was found in 50% of patients with PTC. Patients were divided into two groups. PTC AIT (+) group involved 12 children at the mean age 14.9 years (range 11-20 years, 9 girls) and PTC AIT (-) 12 children at the mean age 12.9 years (range 7-18 years, 5 girls). Papillary thyroid microcarcinoma (PTMC) was diagnosed in 6 patients (in 5 with AIT). US characteristics of PTC was heterogenous: hypoechogenic with/without increased vascularisation, normoechogenic with halo, with/without microcalcifications. In 70% PTC AIT (+) and in all PTC AIT (-) patients ultrasound analysis revealed that the thyroid tissue of the whole gland was normoechogenic. Local metastases in lymph nodes were found in 40% of PTMC AIT (+).Lack of increased vascularization and microcalcifications and presence of``halo`in the nodule does not exclude malignancy. Due to the presence of lymph node involvement in PTMC in all children with PTC total thyroidectomy should be performed with lymph nodes verification.

There is much evidence that high-risk human papillomavirus (HPV) plays a causative role in a subset of head and neck squamous cell cancer (HNSCC) in adults. HPV-positive tumors behave differently even in their response to treatment and are therefore a distinct subset. Both HPV-positive and HPV-negative tumors of the head and neck region are usually in the domain of adults and cases in children are rare; thus when a 2‑year-old child was diagnosed with this cancer in the external auditory canal, an in-depth assessment of the tumor was considered necessary. A 2‑year-old girl was born to a HPV-positive mother who was diagnosed with cervical cancer during pregnancy. The child was delivered by caesarean section and the mother died of her cancer 7 months after delivery. After the diagnosis of locally invasive HPV-positive squamous cell cancer of the external auditory canal, the child was treated surgically, and with chemotherapy and radiotherapy. Full remission was obtained lasting up to 325 weeks since treatment was started, resulting in over 6 years of disease-free survival. This is the first case of advanced, HPV-related HNSCC in a 2‑year-old child, in whom the tumor was located in the external auditory canal and who made a dramatic recovery after treatment with nonradical surgery, chemotherapy and radiotherapy. The child has currently been disease free for 6 years. This case supports the observation that HPV-related HNSCC tumors appear to respond favorably to treatment despite the patient’s young age and the clinically advanced stage of the tumor.

Primary epiphyseal lesions in children are rare and usually benign, with chondroblastoma being the most typical for this location and age. Very occasionally, malignant bone tumors may occur primary within long bones epiphyses during growth; few reports are given on such single cases in orthopedic and radiological scientific literature. This paper presents a case report on a malignant primitive neuroectodermal tumor affecting primary distal femoral epiphysis in a child, having a benign-looking lytic appearance. Short literature review and discussion on possible differential diagnosis of such lesion is also included.

Introduction: Neuroblastoma (NB), Hirschsprung disease (HSCR), Congenital Central Hypoventilation Syndrome (CCHS), clinically referred as the NB-HSCR-CCHS cluster, is genetic disorders linked to mutations in the PHOX2B gene on chromosome 4p12. Specific aim: The specific aim of this project is to define the PHOX2B gene mutations as the genomic basis for the clinical manifestations of the NB-HSCR-CCHS cluster. Patient: A one day old male patient presented to the JUMC neonatal ICU due to abdominal distention, vomiting, and severe apneic episodes. With the preliminary diagnosis of the NB-HSCR-CCHS, the blood and tissue samples were acquired from the child, as well as from the child’s parents. All procedures were pursued in accordance with the Declaration of Helsinki, with the patient’s Guardian Informed Consent and the approval from the Institutional Review Board. Genetic/genomic methods: Karyotyping was analyzed based upon Giemsa banding. The patient’s genomic DNA was extracted from peripheral blood and amplified by polymerase chain reaction. Direct microfluidic Sanger sequencing was performed on the genomic DNA amplicons. These procedures were pursued in addition to the routine clinical examinations and tests. Results: G-banding showed the normal 46 XY karyotype. However, genomic sequencing revealed a novel, heterozygous deletion (8 nucleotides (c.699-706, del8) in exon 3 of the PHOX2B gene on chromosome 4. This led to the frame-shift mutation and malfunctioning gene expression product. Conclusion: Herein, we report a novel PHOX2B gene mutation in the patient diagnosed with the NB-HSCRCCHS cluster. The resulting gene expression product may be a contributor to the clinical manifestations of these genetic disorders. It adds to the library of the mutations linked to this syndrome. Consequently, we suggest that screening for the PHOX2B mutations becomes an integral part of genetic counseling, prenatal screening, and preparing supportive therapy upon delivery.

Immunophenotype of isolated (disseminated or circulating) tumour cells (ITC) in the blood, bone marrow and lymph nodes were studied in patients with gastric cancer. Coexpression of metalloproteinases inducer (EMMPRIN), chemokine receptors (CCR6, CXCR4) and adhesion molecules (Ep-CAM, CD44) was determined on cytokeratin positive (CK+) cells in CD45- cell population sorted out from the blood and/or bone marrow. Eight cytospin samples of blood and 69 samples of bone marrow containing CK+ cells from patients with gastric cancer were included into study. Expression of EMMPRIN and CCR6 were noted in a half of CK+ samples (of blood/bone marrow) whereas the expression of CXCR4 and Ep-CAM was much lower. Analysis of paired data of these determinants expression on CK+ cells showed no association between them. Expression of EMMPRIN, Ep-CAM, CCR6, CCR7, CXCR1, and CXCR4 on ITC in lymph nodes was determined by flow cytometry. In 18 lymph nodes (out of 36 assayed) CK+ cells were found. The expression of CCR6 and Ep-CAM on CK+ cells was observed in almost all studied lymph nodes, CXCR1--in half of them. The expression of EMMPRIN and CCR7 cells was lower. These results suggest that ITC of gastric cancer express variably several molecules that may be involved in metastasis formation.