Off-Label Use of Sirolimus and Everolimus in a Pediatric Center: A Case Series and Review of the Literature.

BACKGROUND: It has been 15 years since sirolimus, an mTOR inhibitor, received Food and Drug Administration approval to prevent acute rejection in kidney transplantation, and 8 years since its analog everolimus acquired the same status. Since then, these drugs have become more and more utilized and their immunosuppressive and antiproliferative properties have been tested in a great variety of clinical conditions, often achieving excellent results. Despite such positive evidence, the on-label indications for these rapalogs are still very restrictive, especially in children. AIMS: The aims of this study were to describe our center's experience with sirolimus and everolimus in managing rare pediatric conditions for which mTOR inhibitors have been reported as a therapeutic option, although without conclusive approval from regulatory agencies, and to evaluate safety and tolerability of the treatment at the prescribed doses. METHODS: All the subjects who received off-label sirolimus or everolimus at the Pediatric Department of the IRCCS Burlo Garofolo in the last 13 years were included. For each disease found in our case series, we reviewed the current scientific literature. RESULTS: Off-label treatment with rapalogs was prescribed in 16 children (11 males, 5 females, median age of 9.5 years, range 1-16 years). Seven had immunologic disorders: four autoimmune lymphoproliferative syndrome (ALPS), one multicentric Castleman disease (mCD), one activated PI3K delta kinase syndrome (APDS), and one immunodysregulation with polyendocrinopathy enteropathy X-linked (IPEX). Eight had proliferative disorders or vascular anomalies: one cystic lymphangioma, two Bannayan-Riley-Ruvalcaba syndrome (BRRS), one blue rubber bleb nevus syndrome (BRBNS), two tuberous sclerosis complex (TSC), and one low-flow mixed arterial and venous malformation. One case had congenital hyperinsulinism (CHI). The average dosage administered was 1 mg/m2 for sirolimus and 7 mg/m2 for everolimus. We experienced a good measurable clinical improvement in 14 patients. Nobody experienced serious adverse events (SAEs). The therapy was interrupted in two cases, for lack of efficacy and poor tolerance in one case and for occurrence of bacterial pneumonia in the other one. A review of the literature identified 101 published reports that met our inclusion criteria. CONCLUSIONS: Although use of mTOR inhibitors has been considered to be complicated, our experience shows that, using low dosages, it is possible to obtain relevant clinical improvements, with a good profile of safety and tolerability.

Romiplostim for secondary thrombocytopenia following allogeneic stem cell transplantation in children.

The outcome of romiplostim for secondary failure of platelet recovery (SFPR) was investigated in children who had undergone hematopoietic stem cell transplantation (HSCT). Seven transfusion-dependent pediatric patients (median age 11 years), with platelet counts below 10 × 10(9)/L, received four weekly doses of subcutaneous romiplostim to treat SFPR developed after HSCT. All patients, except one (patient 4), became platelet transfusion-independent in the second week from the beginning of treatment and no patient needed to discontinue drug treatment because of adverse events. Romiplostim could represent a beneficial first-line treatment, but further studies are required.

Filling of segmental bone defects in revision knee arthroplasty using morsellized bone grafts contained within a metal mesh.

For revision knee surgery with uncontained tibial bone defects, the authors report the containment of compacted morsellized allograft using metal-wire mesh, followed by implantation of a cemented total knee prosthesis. This method is comparable to the "impaction grafting technique" described for revision hip surgery and could be an alternative to metal wedges, augmented components, custom-made implants, polymethyl-methacrylate or structural bone grafts to solve some problems of cavitary and segmental bone defects in revision total knee arthroplasty.

Dynamics of C6 astrocytoma invasion into three-dimensional collagen gels.

OBJECTIVE: The dynamic mechanisms underlying the three-dimensional invasive paradigm of C6 astrocytoma cells has been assessed. METHODS: Spheroids of C6 astrocytoma cells were implanted into three-dimensional collagen type I gels (vitrogen 100) and individual C6 astrocytoma cell invasion monitored. Time-lapsed videomicroscopy was used to assess the dynamic components of cell invasion in three dimensions while scanning and transmission electron microscopy were used to assess matrix architecture and the static aspects of cell invasion. RESULTS: Videomicroscopy outlined an invasion paradigm continuum with repeating phases. A cell surface ruffling phase was followed by invadopodia extension and pull up phases. For some cells the collagen type I matrix extracellular matrix appeared to modify the ability of C6 cells to carry out their invasion paradigm. CONCLUSIONS: C6 astrocytoma cells invading a three-dimensional collagen type I matrix utilize a invasion paradigm made up of a number of phases. A better understanding of the dynamic invasion paradigms of malignant glial cells may be useful in the development of effective treatment strategies to prevent or modify malignant glioma invasion.

Influence of intramedullary versus extramedullary alignment guides on final total knee arthroplasty component position: a radiographic analysis.

A prospective study of 116 consecutive Kinemax cemented posterior cruciate ligament-retaining total knee arthroplasties was carried out. Similar surgical technique was used with a single variable: 61 were implanted using intramedullary guides on the tibia and 55 were implanted using extramedullary guides on the tibia. A radiographic study was performed after at least 1 year of follow-up to evaluate postoperative component position and compare the difference in the accuracy of positioning of the femoral and tibial components. Radiographic analysis showed that satisfactory position was achieved using both types of instrumentation. No statistically significant difference was observed in either the coronal or sagittal plane of the femoral component and the sagittal plane positioning of the tibial component. However, the coronal plane positioning of the tibial component revealed a statistically significant difference (P < .01), with intramedullary guides being superior to extramedullary guides. Also observed, was that using either technique, patients with less accurate postoperative positioning tended to be obese, with wide intramedullary canals. Patients with significant extraarticular deformities, marked bowing, and those with prior surgery or fractures may not be suitable for intramedullary guides, and they may require the use of extramedullary guides and intraoperative radiographic control. The ideal indication for the use of intramedullary instrumentation is in the patient who is not obese, with no extraarticular deformity, and with a well-defined, but not excessively wide, tibial medullary canal. Since tibial component malalignment in general, and coronal plane malalignment in particular, may adversely affect the long-term survival of total knee arthroplasties, the use of intramedullary alignment instrumentation is recommended when possible.