Long-term clinical results show that LS is a safe and effective therapy for ITP. However, a higher number of nonresponders is needed to determine which variables predict response to LS for ITP.
2508 Background. T-ALL accounts for about 15% of pediatric ALL and more than 20% of children experience a recurrent disease which has a dismal prognosis. Characterization of molecular alterations with prognostic impact may be useful for an early identification of patients at high risk of failure in whom more intensive and/or better tailored treatments, including hematopoietic stem cell transplantation (HSCT) may be considered. PTEN/AKT pathway has been shown to be involved in children with T-ALL (Gutierrez A et al 2009), in glucocorticoid resistance (Beesley A et al 2009) and in NOTCH-1 mutated T-ALL resistant to gamma secretase inhibitors (Palomero T et al. 2009). In the attempt to better characterize the role of the PTEN/AKT/mTOR pathway in pediatric T-ALL, we have evaluated the expression of each protein in this pathway's cascade and investigated its association with outcome. Materials and Methods. We enrolled in our study 23 children with T-ALL consecutively diagnosed at our Center in Catania from 1997 to 2009. They were treated by three consecutive AIEOP protocols. We analyzed the mRNA expression of PTEN, using RT-PCR. We evaluate by western blot analysis, the expression of the following proteins: in total (AKT; GSK3β; CK2α; CK2β; PTEN; PDK1; P70S6Kβ2; mTOR; S6K) and phosphorylated [AKT(S473) (T308); GSK3β(S9); PTEN(S380); PDK1(S241); P70S6Kβ2(S371); mTOR(S2448); S6K(Ser235/236)/(Ser240/241)] conformation. The association of these variables with the Event Free Survival (EFS) was assessed using the χ2 test. A p value ≤0.05 was considered statistically significant. Furthermore, in order to measure the association level, the Relative Risk (RR) and the corresponding 95% Confidence Interval (95%CI) were calculated. Events were considered dead of complication (DOC), relapse and HSCT. Results. Seven out of the 23 patients presented an event: 5 relapses, 1 DOC and 1 HSCT. RT-PCR analysis of PTEN expression revealed that only one case did not show any product. Conversely, western blot analysis demonstrated that all patients showed total and phosphorylated PTEN proteins. Interestingly, we observed that total AKT protein was present in all the cases except one; the phosphorylated forms were detected as follows: AKT (T308) in 15 out of the 23 patients (65%), whereas none showed expression of AKT (S473). Surprisingly, we detected a statistically significant downregulation of total and phosphorylated mTOR and P70S6Kβ2 expression in eight, nine, ten and eleven out of 22 analyzed patients respectively. Downregulation or absent expression of both total and phosphorylated P70S6Kβ2 had a statistically significant impact on EFS showing a higher risk of events, when comparing those downregulated with those exhibiting phosphorylated (RR: 2,75; 95%CI: 1,25–6,01) and total protein (RR 3,33; 95%CI: 1,29–8,59) respectively. Moreover, downregulation of mTOR(S2448) confirmed the same pattern of higher risk of events (RR: 2,77; 95%CI: 1,08–7,07) comparing those downregulated with those exhibiting expression of phosphorylated protein. Conclusions. Our data for the first time have shown that the downregulation or absent expression of mTOR and P70S6Kβ2 is associated with a very poor outcome: 5 cases had very aggressive relapses (3 died for progressive disease); one child died during induction for complication related to aggressive disease (massive splenic hemorrhagic event) and one case underwent a matched-HLA familiar HSCT because of a high risk-MRD pattern. These preliminary findings need to be confirmed in a larger-population based study. Nevertheless our data identify new markers of aggressive and resistant disease, easily available at diagnosis, suggesting that mTOR and P70S6Kβ2, which play a crucial role as negative control in the PI3K/AKT cell signalling pathway, are needed to be evaluated in a future treatment plan design with specifically targeted drugs. Moreover, our data will be confirmed by the use of a reliable and robust method such as flow cytometry which will allow us to perform a sensitive and accurate measurement of single cell characteristics, emphasizing the intracellular signaling pathways of interest. Disclosures: No relevant conflicts of interest to declare.
The foot is a complex structure of the body responsible of the body support during the dynamic and static phase of the movement. The foot is composed by two components: the "talar" portion, consisting of talus, navicular bone, cuneiforms and I-II-II metatarsals, has a dynamic function during the walk, and a "calcaneus" consisting of calcaneum, cuboid, IV -V metatarsals, responsible of the load in the static phase of walking. In addition, the hindfoot acts as a rigid lever arm of the propulsion phase of the movement. The plantar vault consists of three arches: medial longitudinal arch, lateral longitudinal arch and transversal arch; the lowering of the plantar vault is often caused by a reduction in the medial longitudinal arch. The development and the function of the foot are strictly regulated by sensory and mechanical receptors located in the subtalar joint.Flat foot can be classified as flexible or rigid; the flexible foot is the most common form (95%) and it is secondary to capsuleligament laxity, decreased muscle strength, obesity, Spring ligament insufficiency or altered limb alignment; the rigid foot (5%) is caused by a congenital vertical talus, tarsal coalescence (astragalocalcaneal and calcaneo-navicular), trauma, juvenile arthritis, neuro-muscular dysfunction. Some authors define the flexible flat foot as "physiological" when it is asymptomatic and without functional alterations [1]. In the flexible foot the plantar vault is there without load and disappears under load, while in the rigid foot the reduction of the plantar vault is not affected by the load. Rigid flat foot can be accompanied by pain, due to a reduction of the subtalar articulation. This is often an expression of congenital bone deformities (accessory navicular), accompanied by neuromuscular disorders (cerebral palsy and myelomeningocele) [7]. Clinical ExaminationSuspect of flat foot is often reported by parents due to abnormal wear and tear of the shoes of their kids and rapid fatigue after sport or prolonged standing. Clinical examination starts with the evaluation of the lower limb alignment, with particular attention to the rotation of the hips (often anteversion) and knees (often in internal rotation), the presence of generalized joint laxity (Marfan Syndrome or connective tissue disorders), the brevity of the achilles tendon (Silfverskiold test), the shape of the foot with and without load, and the presence of pain. Foot pain in this case may be either medial, localized in the midfoot or plantar fascia, or lateral, at the sinus tarsi; in flat feet with short achilles tendon the pain is caused by the tendon shortening.Clinical examination should be performed by observing the front, back and lateral profiles of the lower limbs. In the front profile there is a medial load of the foot with abduction of the forefoot, internal rotation of the tibia and convergent patellar strabism, valgus deformity of the hallux (in the most severe forms); in the AbstractFlat foot is a complex three-dimensional skeletal disorder with multifactorial etio...
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