In spite of the improved efficacy of therapy, it still fails in 15-20 % of childhood acute lymphoblastic leukemia (ALL) patients. Recently, altered expression of certain miRNAs (miRs) have been described in ALL with potential effect on prognosis. Presence of certain miRs (miRNA-16, -21, -24, -29b, -128b, -142-3p, -155, -223) was characterized in human lymphoma and leukemia cells by real-time PCR. Expression of miRs in pediatric ALL patients (n = 24) was measured before chemotherapy, at conventional response checkpoints and at relapse. Correlation between altered miR expression and response to prednisolone at day 8 of therapy and long term prognosis was statistically analysed. Overexpression of "oncomiR/inflammamiR"-21 - which is characteristic in different tumors-was missing in human ALL cells. However, higher expression of miR-128b and lower expression of miR-223 is generally characteristic for human ALL cell lines and ALL cells isolated from pediatric patients. Correlation was shown between miR-128b expression and prognosis, prednisolone response and survival data in childhood ALL. Expression of miR-128b and miR-223-both are leukemia specific-changed in parallel with percentage of bone marrow blasts in remission and during relapse. Therefore, we suggest that overexpression of miR-128b and downregulation of miR-223 shows a significant correlation with treatment response and prognosis in childhood ALL.

Modern treatment strategies have improved the prognosis of childhood ALL; however, treatment still fails in 25–30% of patients. Further improvement of treatment may depend on the development of targeted therapies. mTOR kinase, a central mediator of several signaling pathways, has recently attracted remarkable attention as a potential target in pediatric ALL. However, limited data exists about the activity of mTOR. In the present study, the amount of mTOR activity dependent phospho-proteins was characterized by ELISA in human leukemia cell lines and in lymphoblasts from childhood ALL patients (n = 49). Expression was measured before and during chemotherapy and at relapses. Leukemia cell lines exhibited increased mTOR activity, indicated by phospho-S6 ribosomal protein (p-S6) and phosphorylated eukaryotic initiation factor 4E binding protein (p-4EBP1). Elevated p-4EBP1 protein levels were detected in ALL samples at diagnosis; efficacy of chemotherapy was followed by the decrease of mTOR activity dependent protein phosphorylation. Optical density (OD) for p-4EBP1 (ELISA) was significantly higher in patients with poor prognosis at diagnosis, and in the samples of relapsed patients. Our results suggest that measuring mTOR activity related phospho-proteins such as p-4EBP1 by ELISA may help to identify patients with poor prognosis before treatment, and to detect early relapses. Determining mTOR activity in leukemic cells may also be a useful tool for selecting patients who may benefit from future mTOR inhibitor treatments.

Diffuse large B-cell lymphoma is a heterogeneous group of diseases with different responses to therapy. Targeting mTOR (mammalian target of rapamycin) offers a new approach to improve the treatment. mTOR inhibitors are being developed and are in clinical use in mantle cell lymphoma therapy and clinical trials are ongoing in other high-grade lymphomas as well. However, there is limited data about mTOR activity and the expression of its different complexes in diffuse large B-cell lymphomas. Tissue microarray blocks were constructed from paraffin-embedded biopsy specimens. More than 700 immunohistochemical stainings (mTOR signaling-related proteins and phosphoproteins, markers for lymphoma classification) were evaluated from 68 diffuse large B-cell lymphoma biopsies from conventionally treated and followed patients. Approximately 30% of cases were characterized as germinal center-derived diffuse large B-cell lymphomas, which showed virtually no mTOR activity, as determined by phospho-ribosomal S6 expression, the most sensitive marker of mTOR activity. In about 80% of non-germinal center-derived diffuse large B-cell lymphoma cases, positivity of mTOR-related phosphoproteins was observed, denoting mTOR activity. Moreover, Rictor (a characteristic protein of the mTOR complex2) was overexpressed in 43% of all diffuse large B-cell lymphomas and in 63% of mTOR-active nongerminal center diffuse large B-cell lymphoma samples. Rictor overexpression with mTOR activity indicated significantly worse survival for patients than mTOR inactivity or mTOR activity with low Rictor expression. These results suggest that mTOR activity is characteristic in most non-germinal center-derived diffuse large B-cell lymphomas with potentially variable mTOR-inhibitor sensitivity. Taken together, mTOR inhibitors may be useful in addition to regular therapy in diffuse large B-cell lymphomas, however, patient and inhibitor selection criteria must be carefully considered.

BackgroundRhabdomyosarcoma (RMS) is a malignant tumor of mesenchymal origin and comprises the largest category of soft-tissue sarcomas both in children and adolescents. From a pediatric oncology point of view, RMS has traditionally been classified into alveolar (ARMS) and embryonal (ERMS) subtypes. The anatomical localization of the tumor may vary, but commonly involve the head/neck regions, male and female urogenital tract or the trunk and extremities.Case presentationHere, we report two challenging cases involving 17- and 9-years-olds males where diffuse and multiplex bone lesions suggested either a hematological disease or a primary bone tumor (mesenchymal chondrosarcoma). Biopsies, proved a massive infiltration of the bone marrow cavity with rhabdomyosarcoma. In both cases, the ARMS subtype was confirmed using FOXO1 break-apart probes (FISH). Radiological examination could not identify primary soft tissue component in any localization at the time of diagnosis in either cases.ConclusionsPrimary alveolar rhabdomyosarcoma of the bone as a subtype of ARMS, seems to be a distinct clinico-pathological entity with challenging diagnostic difficulties and different, yet better, biological behavior in comparison to soft tissue ARMS. However, it is difficult to be characterized or predict its prognosis and long-term survival as only sporadic cases (four) were reported so far.

Erdheim–Chester disease (ECD) is a rare histiocytic disorder, characterized by the xanthomatous infiltration of tissues by CD68-positive and CD1a-/CD100-negative foamy histiocytes. In childhood, ECD is exceptionally rare, and only a dozen cases have been published so far. The cooccurence of Langerhans cell histiocytosis (LCH) and ECD is even rarer. Here, we report a 2-year-old boy, the youngest patient in the literature so far, who was diagnosed with concomitant BRAF mutation-positive LCH and ECD. In his case, conventional LCH treatment proved to be ineffective, but he is the youngest patient who was successfully treated with the BRAF inhibitor vemurafenib.