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The European Union (EU) aims at making railway a more attractive transportation method by improving its efficiency and reducing its costs. These achievements could be covered with the migration from ETCS level 2 to ETCS level 3. Many projects related to new positioning systems have been funded by The European Union. Most of these positioning systems are based on GNSS, due to the key role that GNSS will play in the migration to ETCS level 3. One of the problems on using only GNSS systems is the lack of availability of them. During railway operation, there are areas with potential GNSS outages, such as urban canyons, woods or other possible signal blockers and disturbances. Moreover, it is a fact that GNSS signals are not reachable, nor reliable in tunnels or indoor environments. For GNSS to be able to have a key role in the next years in railway security, the afore mentioned lack of availability has to be solved. To cope with this issue, a multi-sensor approach with software enhancements is proposed in this dissertation. The objective of this research work deals with fusing different sensors and creating new software strategies to achieve a higher availability with the best possible accuracy. The seamless position will benefit in all the operation modes, from the train station to a harsh environment for satellites, during the train operation. The scope of the dissertation is to create a multi-sensor positioning system including GNSS, Inertial Measurement Unit (IMU), and Ultra Wide Band (UWB) with other software techniques to obtain a position estimation with a 100% availability for railway systems. This work shows the different steps from the study of the state of the art, going through the implementation, and ending with the performance analysis of the algorithm developed. This research work has been conducted under different European projects such as ERSAT-EAV, FR8RAIL or X2Rail-2, in which CEIT has participated.

Use of IL-2 therapy after autologous transplantation is currently being explored to reduce relapse rate. Low doses of the cytokine induce significant immunomodulation avoiding the severe side-effects associated with high-dose IL-2 therapy. However, low-dose IL-2 is usually given by continuous infusion through central venous lines with the consequent risks of thrombosis and infections. Twenty-six consecutive patients who received autologous transplants received low-dose IL-2 after stable engraftment had been achieved. The first 13 patients (group A) were scheduled to receive 400,000/IU/m2/day for 3 months by continuous intravenous infusion. Ten of these patients suffered infectious episodes, mainly bacteriemias that often necessitated delaying IL-2 therapy (median delivered dose: 32% of planned). The next 13 patients were then assigned to receive IL-2 (800,000-1,000,000 IU/m2/day for 3 months) subcutaneously (group B). For group B patients, median dose intensity was 84% (P = 0.01 when compared with group A patients). Only one severe infectious episode was observed in these patients. Clinical toxicity in group B patients consisted mainly of s.c. nodules. Immunomodulation, measured as an increase in the absolute number of CD56+ cells and CD56+(bright) cells, was higher in patients who received the cytokine by the subcutaneous route (median peak increase of CD56+ cells: 160 and 220% for group A and B patients respectively; median peak increase of CD56+(bright) cells: 210% and 310% for group A and B respectively, P0.05 between groups A and B). No statistically significant increment of T lymphocytes was observed in any group. No hematologic toxicity was observed apart from eosinophilia, which was very marked in group B (P0.01). Our results show that low-dose s.c. IL-2 therapy is associated with low clinical and hematologic toxicity after autologous transplantation. The immunomodulation achieved is no less than that achieved with the i.v. approach.

We report the case of a BMT recipient who developed blindness 22 months after BMT. Microvascular retinopathy, cortical blindness and other ocular pathologies were excluded with appropriate tests. Electrophysiological studies showed retinal damage without excluding an optic nerve lesion. The patient, who had several risk factors for neurologic-induced cyclosporine toxicity, improved with cyclosporine withdrawal. Our findings stress the need of electrophysiological tests to exclude neuroretinal damage in patients receiving cyclosporine after BMT.

Imatinib mesylate (STI571) is a highly effective and well-tolerated treatment for patients with chronic-phase chronic myeloid leukaemia (CML), but information on its efficacy and tolerance in intensively pretreated patients is scarce. Thirty-three chronic-phase CML patients who were resistant or intolerant to interferon (IFN) and had been previously submitted to autologous stem cell transplantation were treated with imatinib for a median of 14 months (range: 6-19 months). Seven patients were in haematological response (HR) at the start of treatment; the remaining 26 attained a HR at a median of 3 weeks (range: 1-4 weeks). Major cytogenetic response rates at 3, 6 and 12 months were 42%, 45% and 55%, respectively, including 21%, 24% and 33% complete responses. Grade 3-4 neutropenia, thrombocytopenia and anaemia developed in 33%, 27% and 12% of patients respectively. Non-haematological toxicity included superficial oedema (21% of patients), gastrointestinal symptoms (18%), muscle cramps (15%), skin rash and liver enzyme increase (3% each). These results were not significantly different from those in 65 chronic-phase CML patients, resistant or intolerant to interferon without a previous ASCT, who were included in the same protocol. Imatinib mesylate is effective and safe in chronic-phase CML patients with a previous history of intensive treatment.

International audience; A Y-Mg-Si-Al-O-N glass was submitted to swift heavy-ion bombardment at GANIL (Caen, France) and the influence of irradiation on the mechanical properties was studied. The mechanical properties of the glass were characterized both before and after irradiation. Changes in hardness, elastic modulus and fracture toughness of the near-surface irradiated layer were determined using indentation techniques. SRIM calculations allowed to estimate the ions penetration range and the energy. deposition relative to electronic and nuclear interactions, which can be correlated to the experimental damaged depth. Meyer's hardness and Young's modulus decrease by about 30%, while fracture toughness is increased by more than 40%.

Amylase-producing tumors are mainly adenocarcinomas and, in rare instances, multiple myelomas. We describe here a first case of amylase-producing Bence Jones type myeloma with pancreatitis-like symptoms and the second in a Caucasian patient. The finding of salivary-type hyperamylasemia in a 72-year-old female with a possible pancreatitis made us suspect the diagnosis. Amylase production was observed in bone marrow cultures in which 96% of cellularity was composed of plasmablasts. Serum amylase level decreased when chemotherapy was given.

INTRODUCTION: This study analyses the factors affecting mobilisation and engraftment in autologous peripheral blood progenitor cell transplantation according to the number of CD34(+) re-infused. MATERIALS AND METHODS: A total of 190 patients underwent mobilisation with G-CSF alone (n=113) or in combination with chemotherapy (n=77). A total of 116 patients (61%) were autografted with 2 x 10(6) CD34(+) cells/kg. Rates of granulocyte and platelet recovery were estimated using the product-limit method of Kaplan-Meier and compared using a log-rank test. The Cox regression model was used for the multivariate analysis of factors influencing engraftment. Differences between cohorts were evaluated by one-way ANOVA or Mann-Whitney tests, and multivariate analysis was performed using a stepwise lineal regression. RESULTS: Neutrophil and platelet engraftment was significantly longer with 2 x 10(6)/CD34(+)/kg, the Cox model did not identify prognostic factors for haematopoietic recovery. CONCLUSION: Although mobilisation schedules and disease status influenced not only the yield of progenitor cells, but also the engraftment kinetics, the number of CD34(+) re-infused was the main predictor of haematopoietic recovery. While engraftment succeeded in most of the cases, the re-infusion of >2 x 10(6)/CD34(+)/kg resulted in significantly shorter recovery times.

Cryopreservation of hemopoietic progenitors for transplantation has been traditionally performed by the use of a controlled-rate freezer. Several groups have reported successful cryopreservation of progenitor cells at -80 degrees C without a controlled-rate freezer. In an attempt to elucidate whether both methods are equally efficient, we compared controlled-rate versus uncontrolled cryopreservation of peripheral blood progenitor cells (PBPC) in a prospective, multicenter study.Apheresis products from patients undergoing PBPC mobilization were split into two aliquots, and cryopreserved simultaneously by both methods, in autologous plasma plus 10% dimethylsulfoxide. Controlled-rate samples were placed into a programmable freezer with a cooling rate of 1-2 degrees C/min. Uncontrolled-rate samples were directly introduced into a -80 degrees C mechanical freezer. After thawing, cell counts, assays for viability, clonogenic cultures and CD34+ cell enumeration were performed.A total of 105 cases were included. No significant differences were found in viability (mean 88.8 +/- 13% in the controlled-rate group vs. 89.7 +/- 12% in the uncontrolled-rate group), nucleated cell loss (23.5 +/- 23% vs. 23 +/- 22%), mononuclear cell loss (19 +/- 23% vs. 19.1 +/- 22%), and loss of CD34+ cells (34.3 +/- 33% vs. 28.6 +/- 34%). On the other hand, recovery of granulomonocytic colony-forming units (CFU-GM), was significantly better with the controlled-rate technique, than with the non-controlled-rate method (104.3 +/- 95 vs. 86.5 +/- 80, respectively; p = 0.048).Our results indicate that both techniques are suitable for cryopreservation of PBPC, although a better recovery of committed progenitors is achieved by the controlled-rate method. Therefore, the use of controlled-rate freezer should probably be recommended.

Objective: To determine wh ether addition of Stem Cell Factor (SCF, 20 ugJ kg/day) to a mobllization regimen consistlng of cyclophosphamide (CY), 4 gJ m2 and filgrastim 5 Ilg/kg/day could increase the CD34+ cell yield ,n the first leukapheresis (LK). Design and Melhods: A total of 102 multiple myeloma (MM) patlents (pis) we re enrolled inlo th,s randomised. conlrolled study at 14 sites. Cytokines (SCF + filgraslim: n = 55; filgrastlm; n = 47) were admlnlstered once daily after CY until LK were completed. LK started when WBC reached 4 x 109/L, and continued unlil a target yield of 5;( 106 CD34+ cells/kg was achieved or 4 LK performed. CD34+ cell enumeration was performed at a central laboratory blinded to treatment group. Prophylaclic anlihislamrnes were glven to all pts recelvlng SCF. Results: A slgnlficantly higher CD34+ cell yield was obtalned in the first LK of pts treated wlth SCF + filgraslim compared to those trealed wlth fitgrastim alone (median CD34+ cells: 11.9 vs 4.3

IL-2 therapy may be useful in situations with a low tumour burden, such as after autologous transplantation. However, conflicting reports about the deleterious effects of this cytokine on haemopoiesis have precluded its widespread use. To study IL-2 effects on haemopoietic transplant progenitors we established long-term cultures (Dexter-type) with cells from allogeneic marrow and marrow/peripheral blood cell infusates of autologous transplants with different concentrations of IL-2 (0-1000 IU/ml). Percentage of CD56+ cells was also determined in cultures. IL-2 induced an inhibitory effect on stroma and an increase in the percentage of CD56+ cells compared with controls. No deleterious effect either in the production of BFU-E or CFU-GM weekly or over the whole period of culture was observed. Our results suggest that IL-2 is able to induce an increase in CD56+ cells early after transplantation without a deleterious effect on long-term haemopoiesis.

We report the results of 72 leukapheresis procedures performed for autologous peripheral blood stem cell collection in 18 patients with lymphoma and myeloma, after combined mobilization with cyclophosphamide and granulocyte colony-stimulating factor (G-CSF). The numbers of mononuclear cells (MNCs), CD34+ cells and granulocyte-macrophage colony-forming units (CFU-GM) either in the peripheral circulation (preleukapheresis sample) or in the product obtained from leukapheresis (leukapheresis sample) were evaluated. A highly superior proportion of CD34+ cells (14-fold) and CFU-GM (5-fold) resulted from the mobilization therapy. CFU-GM and CD34+ cells were highly enriched with respect to all MNCs (relative recoveries: 2.13, range 0.3-41, and 1.08, range 0.2-8.5, respectively) due to an additional mobilization effect by the leukapheresis procedure. Also, a relatively strong linear correlation between the three different parameters was found in the leukapheresis product (CD34+:CFU-GM, r = 0.81; MNCs:CD34, r = 0.69; MNCs:CFU-GM, r = 0.75; CFU-GM:CD34+, and MNCs, r = 0.85). Our data suggest that the number of MNCs and CD34+ cells obtained after combined mobilization with cyclophosphamide and G-CSF can be used as predictor of the number of granulomonocytic progenitors.

A 20-year-old male with severe bone marrow failure associated with paroxysmal nocturnal haemoglobinuria (PNH) underwent an allogeneic bone marrow transplantation (BMT). Flow cytometric analysis of phosphatidylinositol (PI) anchored membrane proteins prior to BMT showed a markedly reduced expression of monocyte CD14 and neutrophil CD16 molecules. On day +17 after BMT expression of both antigens reached normal values and remained stable throughout a follow-up period of 10 months, thus confirming the eradication of the PNH clone. To date, this is the first case in which normal expression of PI-anchored proteins after BMT is reported.

Mucormycosis is a rare fungal infection that has been described mainly in oncologic and diabetic patients. We here report the cases of two leukaemic patients in whom pulmonary mucormycosis was diagnosed. Prompt diagnosis, therapy with amphotericin B and surgery when possible, are the cornerstones in the treatment of this fungal infection. Although infrequent, this infection must be suspected in oncohaematological patients with lung infiltrates.

Background and Objectives. Imatinib mesylate has recently been shown to be highly effective in chronicphase chronic myeloid leukemia (CML). The results of imatinib treatment in chronic-phase CIVIL patients resistant or intolerant to interferon (IFN) and the factors predicting therapeutic response and progression-free survival were analyzed. Design and Methods. One hundred and fifty patients with chronic-phase CML resistant (n=111) or intolerant (n=39) to IFN were treated with imatinib. Prognostic factors for response and disease progression were assessed by multivariate analysis. Results. The median time from diagnosis was 43 months (0.5-188), median IFN therapy 21.5 months (0.5-140) and median follow-up from starting imatinib 13.6 months (range: 3-23). Complete hematologic response was achieved in 96 of 97 patients. Complete, partial and minor cytogenetic responses were present in 44%, 22%, and 8% of patients at 12 months. Grade IIIIV neutropenia, thrombocytopenia, and anemia developed in 33%, 16%, and 6% of patients, respectively. Sixty-five patients discontinued treatment for a median of 4 weeks (1-36) due to toxicity. The rate of progression-free survival (lack of accelerated/blastic phase with persistent response) was 89.2% (95% Cl: 84-94.4) at 12 months and 80.2% (95% Cl: 72.2-88.2) at 18 months. Platelets > 450x10(9)/L and treatment discontinuation > 4 weeks were associated with a lower rate of major (complete plus partial) cytogenetic response. Patients in Sokal's highrisk group and those who did not achieve a major cytogenetic response had significantly shorter progression-free survival. Interpretation and Conclusions. Imatinib is highly effective in chronic-phase CML patients resistant or intolerant to IFN, especially in those with normal platelet counts and in those not requiring prolonged treatment discontinuation due to neutropenia. (C)2003, Ferrata Storti Foundation.

This study compares the immune reconstitution of total T cells, CD4 and CD8 cell subsets, activated T cells, NK cells and B cells in 66 patients who underwent allogeneic or autologous bone marrow transplantation (BMT).The reconstitution of peripheral lymphocytes subsets was studied using two-color flow cytometry. The study group consisted of 39 patients who received allogeneic BMT compared with 27 patients who received autologous BMT. Peripheral blood was examined at different time intervals. As a measure of immune function, the response to the mitogen phytohemaglutinin (PHA) was determined.The pattern of recovery of CD3+, CD4+ and CD8+ T cells, as well as the PHA response, was similar for each type of transplant. CD3+CD5- cells were significantly higher following autologous BMT than after allogeneic BMT and during more time. An overexpression of DR on T cells following autologous or allogeneic BMT demonstrates an increasing degree of T-lymphocyte activation. This activated T-cell subset was more stable in patients transplanted with allogeneic BM than in patients treated with autologous BM. The levels of total B cells and CD19+CD5+ B-cells were increased during 2 to 12 months following autologous MBT, remaining normal afterwards; in contrast, the levels of CD19+ lymphocytes and CD19+CD5+B-cells remained higher than normal ranges until 36 months in patients transplanted with allogeneic BM. The percentage of NK cells was significantly increased following both autologous and allogeneic BMT. The highest percentage of NK cells were detected about 2 and 6 months post-transplant in patients treated with autologous or allogeneic BM, respectively.Allogeneic BMT appears to induce a slight delay recovery of B and NK cells in comparison to autologous BMT. In contrast, T-cells recovery was similar for each type of transplant, although a higher percentage of CD3+CD5- T cells and a faster recovery of activated CD3+DR+ cells to normal levels were observed in patients transplanted with autologous BM.

To analyze in patients with de novo acute promyelocytic leukemia (APL) treated with an ATRA plus anthracyclin-based protocol if the presence of additional cytogenetic aberrations to the t(15;17) influences: 1. clinical and biological presenting features; 2. disease outcome.One hundred and thirteen patients with newly diagnosed APL enrolled in the APL-96 protocol of the Spanish PETHEMA group were studied by conventional karyotyping, FISH and RT-PCR for the PML-RARa fusion. Treatment was homogeneous in all cases and consisted of anthracyclines and ATRA.Additional chromosome aberrations were observed in 30% of cases. The most frequent secondary changes were +8 (14 cases), and abnormalities of chromosomes 9 or 3 (4 patients each), and of chromosomes 1 and 8 (3 cases each). No clinical, biological, morphological, immunophenotypic or molecular differences were observed between the group of APLs with t(15;17) alone and the group of patients with additional changes. Patients with additional changes had a higher rates of complete remission (CR) and 4-year disease-free survival (DFS) (97%, and 97%, respectively) than patients with t(15;17) alone (CR, 70% and DFS, 84%) but these differences were not statistically significant.Patients with APL and additional cytogenetic abnormalities do not show different clinical, biological, morphological or molecular features as compared to patients with t(15;17) alone. The prognosis of patients with APL and t(15;17) alone and those with additional changes is similar in both groups. This study indicates that there is no rationale for administering more intensive treatment in APL patients with additional cytogenetic abnormalities receiving ATRA plus anthracycline-based chemotherapy.

Lymphocyte subset reconstitution was studied in 65 patients undergoing allogeneic and autologus bone marrow transplantation (BMT).The expression of molecules on the membrane of lymphocyte subsets was assessed by two-colour flow cytometry and a direct immunofluorescence assay. The functional capacity of the patient's T lymphocytes following transplantation was identified by stimulation whit peripheral blood lymphocytes; B cells from BMT recipients were tested for their ability to respond, in vitro, to pokeweed (PWD) mitogen.1) The proportion of CD8+ T lymphocytes was higher than the CD4+ T lymphocytes until 1 1/2 year after-BMT, with high percentage of immature T cells (CD3+, CD8+, HLA-DR+, CD25-) in the first nine months post-transplant. Moreover, a large proportion of T lymphocytes lacked CD5 expression in the first year following BMT. 2) T-cell proliferative response to PHA was low with subsequent recovery until normality. 3) Low numbers of B cells in the first two months with a significant increase since then until 1 1/2 year after-BMT; the phenotype of these B cells was mainly CD19+, CD5+. 4) High in vitro spontaneous immunoglobulin production by peripheral blood B lymphocytes and an impaired response to PWM was observed. 5) Increased percentage of cells with natural killer (CD56) cell phenotype was seen during the 2nd and 3rd months after the graft infusion. After 1 1/2 year postgrafting, this percentage returned to normal level.Taken together, these data indicate the existence of numerous abnormalities in several subsets of peripheral blood lymphocytes after BMT and suggest a slow kinetics of immune recovery after human marrow transplantation being complete between 18 and 24 months following BMT.