Hyperactive mTOR pathway promotes lymphoproliferation and abnormal differentiation in autoimmune lymphoproliferative syndrome.

Autoimmune lymphoproliferative syndrome (ALPS) is a human disorder characterized by defective Fas signaling, resulting in chronic benign lymphoproliferation and accumulation of TCRαß(+) CD4(-) CD8(-) double-negative T (DNT) cells. Although their phenotype resembles that of terminally differentiated or exhausted T cells, lack of KLRG1, high eomesodermin, and marginal T-bet expression point instead to a long-lived memory state with potent proliferative capacity. Here we show that despite their terminally differentiated phenotype, human ALPS DNT cells exhibit substantial mitotic activity in vivo. Notably, hyperproliferation of ALPS DNT cells is associated with increased basal and activation-induced phosphorylation of serine-threonine kinases Akt and mechanistic target of rapamycin (mTOR). The mTOR inhibitor rapamycin abrogated survival and proliferation of ALPS DNT cells, but not of CD4(+) or CD8(+) T cells in vitro. In vivo, mTOR inhibition reduced proliferation and abnormal differentiation by DNT cells. Importantly, increased mitotic activity and hyperactive mTOR signaling was also observed in recently defined CD4(+) or CD8(+) precursor DNT cells, and mTOR inhibition specifically reduced these cells in vivo, indicating abnormal programming of Fas-deficient T cells before the DNT stage. Thus, our results identify the mTOR pathway as a major regulator of lymphoproliferation and aberrant differentiation in ALPS.

Treosulfan-fludarabine-thiotepa-based conditioning treatment before allogeneic hematopoietic stem cell transplantation for pediatric patients with hematological malignancies.

Treosulfan-based conditioning prior to allogeneic transplantation has been shown to have myeloablative, immunosuppressive, and antineoplastic effects associated with reduced non-relapse mortality (NRM) in adults. Therefore, we prospectively evaluated the safety and efficacy of treosulfan-based conditioning in children with hematological malignancies in this phase II trial. Overall, 65 children with acute lymphoblastic leukemia (35.4%), acute myeloid leukemia (44.6%), myelodysplastic syndrome (15.4%), or juvenile myelomonocytic leukemia (4.6%) received treosulfan intravenously at a dose of 10 mg/m2/day (7.7%), 12 g/m2/day (35.4%), or 14 g/m2/day (56.9%) according to their individual body surface area in combination with fludarabine and thiotepa. The incidence of complete donor chimerism at day +28 was 98.4% with no primary and only one secondary graft failure. At 36 months, NRM was only 3.1%, while relapse incidence was 21.7%, and overall survival was 83.0%. The cumulative incidence of acute graft-vs.-host disease was 45.3% for grades I-IV and 26.6% for grades II-IV. At 36 months, 25.8% overall and 19.4% moderate/severe chronic graft-vs.-host disease were reported. These data confirm the safe and effective use of treosulfan-based conditioning in pediatric patients with hematological malignancies. Therefore, treosulfan/fludarabine/thiotepa can be recommended for myeloablative conditioning in children with hematological malignancies.

Malignant epithelioid peripheral nerve sheath tumor with prominent reticular/microcystic pattern in a child: a low-grade neoplasm with 18-years follow-up.

Malignant peripheral nerve sheath tumors (MPNSTs) constitute <2% of soft tissue neoplasms in children and display a wide histologic spectrum including low-grade and epithelioid variants, although most are high-grade spindle cell sarcomas. Here, we describe an unusual case of a large retroperitoneal epithelioid MPNST diagnosed in a 7-year-old girl without family history or clinical features of neurofibromatosis type 1. The patient was treated by repeated surgical interventions, polychemotherapy, autologous stem cell transplantation, and irradiation therapy. Over the years, she developed multiple disseminated abdominal recurrences but is currently alive with very slowly progressing disseminated intra-abdominal disease 18 years from initial diagnosis. Histologically, the tumor was composed of medium-sized polygonal and ovoid-to-spindled cells set within a copious myxoid matrix with a prominent reticular and microcystic pattern reminiscent of the recently described reticular/microcystic schwannoma. Immunohistochemistry revealed strong and diffuse expression of S100, CD56, CD57, collagen IV, and neuron-specific enolase, with negativity for perineurial cell markers (claudin-1, epithelial membrane antigen, and glucose transporter-1) and other lineage-specific mesenchymal and epithelial antigens. This unusual variant of low-grade MPNST must be differentiated from a variety of other entities, in particular benign perineurioma, myxoid neurofibroma, and benign reticular/microcystic schwannoma. Confinement of the recurrent disease to the abdominal cavity emphasizes the necessity of primary curative wide excision of this highly recurring but nonmetastasizing low-grade neoplasm.

Juvenile xanthogranuloma developing after treatment of Langerhans cell histiocytosis: case report and literature review.

The synchronous or metachronous development of Langerhans cell histiocytosis and non-Langerhans cell histiocytosis in the same patient is rare. To date, only seven cases of xanthogranulomas developing in young patients with a history of Langerhans cell histiocytosis and systemic therapy have been reported in the literature. As of yet, the pathogenesis and the clinical significance of this phenomenon are unclear. We report the case of a 3 year old boy who developed juvenile Xanthogranulomas on the forehead and right upper eye lid 1.5 years after systemic therapy for monosystemic Langerhans cell histiocytosis of the bone and complete disease remission.

Ewing sarcoma of the mandible in a child: interdisciplinary treatment concepts and surgical reconstruction.

Ewing's sarcoma is the second most common primary bone malignancy in childhood and adolescence. We present a standardized interdisciplinary treatment protocol according to the EURO-E.W.I.N.G. 99 study, applied in the treatment of a 7-year-old patient with localized Ewing's sarcoma of the left mandible. After six blocks of VIDE (vincristine/ifosfamide/doxorubicin/etoposide) chemotherapy and stem cells rescue, intensity modulated external radiation with 48.6 Gy and subsequent high dose therapy with busulphan-melphalan were administered. Tumor resection and immediate bony reconstruction was performed using a microvascular fibula graft 10 weeks after radiation. Because of the effective neoadjuvant treatment, no extensive soft tissue resection was necessary. Healing of the osteosynthesis was uneventful. No local or systemic recurrence and no signs of significant facial deformity were found after 12 month follow-up. The presented case underlines the requirement for multidisciplinary protocols involving radiologists, pathologists, oncologists, radiation oncologists, and surgeons for accurate diagnosis and appropriate therapy. To preserve cosmetics and function within the craniofacial area after tumor resection in children, microvascular reconstructive procedures can be successfully performed with a vascularized fibular graft.