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Background and purpose The ability to predict high-grade meningioma preoperatively is important for clinical surgical planning. The purpose of this study is to evaluate the performance of comprehensive multiparametric MRI, including susceptibility weighted imaging (SWI) and quantitative susceptibility mapping (QSM) in predicting high-grade meningioma both qualitatively and quantitatively. Methods Ninety-two low-grade and 37 higher grade meningiomas in 129 patients were included in this study. Morphological characteristics, quantitative histogram analysis of QSM and ADC images, and tumor size were evaluated to predict high-grade meningioma using univariate and multivariate analyses. Receiver operating characteristic (ROC) analyses were performed on the morphological characteristics. Associations between Ki-67 proliferative index (PI) and quantitative parameters were calculated using Pearson correlation analyses. Results For predicting high-grade meningiomas, the best predictive model in multivariate logistic regression analyses included calcification (β = 0.874, P = 0.110), peritumoral edema (β = 0.554, P = 0.042), tumor border (β = 0.862, P = 0.024), tumor location (β = 0.545, P = 0.039) for morphological characteristics, and tumor size (β = 4 × 10−5, P = 0.004), QSM kurtosis (β = − 5 × 10−3, P = 0.058), QSM entropy (β = − 0.067, P = 0.054), maximum ADC (β = − 1.6 × 10−3, P = 0.003), ADC kurtosis (β = − 0.013, P = 0.014) for quantitative characteristics. ROC analyses on morphological characteristics resulted in an area under the curve (AUC) of 0.71 (0.61–0.81) for a combination of them. There were significant correlations between Ki-67 PI and mean ADC (r = − 0.277, P = 0.031), 25th percentile of ADC (r = − 0.275, P = 0.032), and 50th percentile of ADC (r = − 0.268, P = 0.037). Conclusions Although SWI and QSM did not improve differentiation between low and high-grade meningiomas, combining morphological characteristics and quantitative metrics can help predict high-grade meningioma.

Introduction: Obesity is a chronic disease caused by dysfunctional neurohormonal systems that result in excess weight, adiposopathy, and increased risk for many comorbidities including cardiovascular disease, type 2 diabetes, and certain types of cancer. Lorcaserin is a serotonergic agonist specific to the 5HT2C receptor that is FDA-approved for the long-term management of obesity in adults with BMI>30 kg/m2 or BMI>27 kg/m2 and at least one weight-related comorbidity.Areas covered: The authors review the pharmacodynamics and pharmacokinetic properties of lorcaserin alongside updates on serotonin's mechanism of action in the central nervous system. The efficacy of lorcaserin in the management of obesity, its related comorbidities, and potential therapeutic applications are also discussed.Expert opinion: The future of obesity management requires a multimodal and personalized approach. The high medical complexity of patients warrants polypharmacotherapy to achieve their metabolic goals. Lorcaserin has proven efficacy and safety in the treatment of obesity and its weight-related comorbidities including type 2 diabetes, cardiovascular disease, and chronic kidney disease. New evidence elucidating its effects on dopaminergic pathways and on glucose homeostasis expands its prospective uses.

Among the novel biologic therapeutics that will increase our ability to cure human cancer in the years to come, T cell therapy is one of the most promising approaches. However, with the possible exception of tumor-infiltrating lymphocytes therapy for melanoma, clinical trials of adoptive T-cell therapy for solid tumors have so far provided only clear proofs-of-principle to build on with further development. Epstein-Barr virus (EBV)-associated malignancies offer a unique model to develop T cell-based immune therapies, targeting viral antigens expressed on tumor cells. In the last two decades, EBV-specific cytotoxic T-lymphocytes (CTL) have been successfully employed for the prophylaxis and treatment of EBV-related lymphoproliferative disorders in immunocompromised hosts. More recently, this therapeutic approach has been applied to the setting of EBV-related solid tumors, such as nasopharyngeal carcinoma. The results are encouraging, although further improvements to the clinical protocols are clearly necessary to increase anti-tumor activity. Promising implementations are underway, including harnessing the therapeutic potential of CTLs specific for subdominant EBV latent cycle epitopes, and delineating strategies aimed at targeting immune evasion mechanisms exerted by tumor cells.

Different types of sensors are being used to study deglutition and mastication. These often suffer from problems related to portability, cost, reliability, comfort etc. that make it difficult to use for long term studies. An inertial measurement based sensor seems a good fit in this application; however its use has not been explored much for the specific application of deglutition research. In this paper, we present a system comprised of an IMU and EMG sensor that are integrated together as a single system. With a preliminary experiment, we determine that the system can be used for measuring the head-neck posture during swallowing in addition to other parameters during the swallowing phase. The EMG sensor may not always be a reliable source of physiological data especially for small clustered muscles like the ones responsible for swallowing. In this case, we explore the possibility of using gyroscopic data for the recognition of deglutition events.

The copper (II) acrylic monomer Cu(aaem) 2 (aaem = 2-acetoacetoxyethyl methacrylate) undergoes high-yield y-ray copolymerization with dimethylacrylamide, styrene, and hydroxoethyl methacrylate in the presence of methylene bisacrylamide as crosslinking agent in dimethylformamide. The metalloorganic copolymers are fully characterized. Polymer-protected Cu(II) results in being extremely stable toward a number of reducing agents in different media.

Poly(N,N-dimethylacylamide) resins, cross-linked up to 8 mol % with methylenebisacrylamide, have been investigated in the swollen state (dichloromethane, DCM, and tetrahydrofuran, THF) by means of inverse steric exclusion chromatography (ISEC) and electron spin resonance spectroscopy (ESR). Their behavior has been evaluated on the basis of a physicochemical model, which was previously developed to describe the behavior of the same materials in water. This model is based on the assumption that the swollen resins can be depicted as concentrated viscous polymer solutions. In DCM, this hypothesis still holds for the relatively lightly cross-linked swollen gels, while it is not acceptable when the cross-linking degree is higher than 4 mol %. When THF is used as the liquid medium, the investigated resins do not fully swell, and the spin probe employed for the ESR measurements is adsorbed from the liquid phase onto the polymer chains. Therefore, the characterization of these polymers swollen in THF did not give ...

The surface Electromyography (sEMG) signal is affected by different sources of noises: current technology is considerably robust to the interferences of the power line or the cable motion artifacts, but still there are many limitations with the baseline and the movement artifact noise. In particular, these sources have frequency spectra that include also the low‐frequency components of the sEMG frequency spectrum; therefore, a standard all‐bandwidth filtering could alter important information. The Wavelet denoising method has been demonstrated to be a powerful solution in processing white Gaussian noise in biological signals. In this paper we introduce a new technique for the denoising of the sEMG signal: by using the baseline of the signal before the task, we estimate the thresholds to apply to the Wavelet thresholding procedure. The experiments have been performed on ten healthy subjects, by placing the electrodes on the Extensor Carpi Ulnaris and Triceps Brachii on right upper and lower arms, and performing a flexion and extension of the right wrist. An Inertial Measurement Unit, developed in our group, has been used to recognize the movements of the hands to segment the exercise and the pre‐task baseline. Finally, we show better performances of the proposed method in term of noise cancellation and distortion of the signal, quantified by a new suggested indicator of denoising quality, compared to the standard Donoho technique.

Graft-versus-host disease (GVHD) represents an important complication following allogeneic bone marrow transplantation. In recent years, narrowband ultraviolet B (NB-UVB, 311-313 nm) has been found to be a beneficial adjuvant treatment in patients refractory to first-line immunosuppressive drugs.The aim of this study is to analyse retrospectively the clinical outcome of 10 GVHD paediatric patients treated with NB-UVB therapy.Ten paediatric patients (six girls and four boys: median age 12.5 years, range 4-20) with cutaneous GVHD were enrolled in the study: five patients with chronic GVHD and five patients with an overlap syndrome GVHD. All patients had already been shown to be resistant to first-choice immunosuppressive protocols, and were treated with NB-UVB phototherapy until a clinical remission of skin lesions occurred.A complete response (absence of lesions) was achieved in 80% of the cases (eight patients) after a median number of 29 treatments, corresponding to a median of 7.5 weeks (52 days) of treatment (range 3-13 weeks), with an average cumulative dose of 28.71 J cm(-2) (range 1.02-70.38 J cm(-2)). Only two patients reported a partial remission (18% of body surface area involved). During the follow-up period, a complete remission after 1 year was observed in 75% of patients and after 2 years in 71% of the evaluable patients.This study provides evidence that NB-UVB phototherapy represents a valid second-line treatment in paediatric patients affected by GVHD and refractory to immunosuppressive first-line treatment.

In recent years there has been an ever increasing amount of research and development of technologies and methods to improve the quality and the performance of advanced surgery. In several fields, such as laparoscopy, various training methods and metrics have been proposed, both to improve the surgeon's abilities and also to assess her/his skills. For neurosurgery, however, the extremely small movements and target operating space involved have prevented until now the development of similar methodologies and systems. In this paper we present the development of an ultra-miniaturized Inertial Measurement Unit (IMU) and its application for neurosurgery skill assessment in a simple pick and place scenario. This analysis is a preliminary yet fundamental step to realize a better training/evaluation system for neurosurgeons, and to objectively evaluate and understand how the neurosurgery is performed.

The study was aimed at evaluating clinical and functional assessment and results obtained following rehabilitative treatment in children affected by chronic graft versus host disease (cGVHD) after allogeneic transplantation of hemopoietic stem cells (HSCT). From 1999 to 2003 we evaluated 6 children with cGVHD after HSCT presenting severe complications and disabilities. Clinical and functional assessment was performed prior to rehabilitative treatment (T1), at follow-up at 6 (T6) and 12 (T12) months after treatment. Each child received a personalized rehabilitative treatment program based on the use of neuromotor re-education techniques, massotherapy, chest rehabilitation and occupational therapy. Six children presented sclerodermoid skin lesions, joint contractures, anchylosis, respiratory insufficiency, postural and walking alterations which led to reduction in motor performance and autonomy in daily living activity. After 1 year of rehabilitation treatment, 3 patients showed improvement in motor performance, 2 remained stable and 1 patient worsened. Rehabilitative treatment associated with pharmacological therapy has proven to be useful in patients affected by cGVHD. We believe that cGVHD is a pathology which must be seen by a physiatrist as early as possible at onset of first cutaneous signs of cGVHD to limit its invalidating evolution.

Among social infrastructure technologies, robot technology (RT) is expected to play an important role in solving the problems of both decrease of birth rate and increase of elderly people in the 21st century, specially but not only in Japan. In order to achieve this objective, the new generation of personal robots should be capable of a natural communication with humans by expressing human-like emotion. In this sense, human hands play a fundamental role in communication, because they have grasping, sensing and emotional expression ability. This paper presents the recent results of the collaboration between the Takanishi Lab of Waseda University, Tokyo, Japan, and the Arts Lab of Scuola Superiore Sant'Anna, Pisa, Italy, and ROBOCASA. In this paper, the development of a novel anthropomorphic hand for humanoid robotics RCH-1 (ROBOCASA Hand No.1) and its integration into a humanoid robotic platform, named WE-4RII (Waseda Eye No.4 Refined II) is presented.

Current prosthetic hands are basically simple grippers with one or two degrees of freedom, which barely restore the capability of the thumb-index pinch. Although most amputees consider this performance as acceptable for usual tasks, there is ample room for improvement by exploiting recent progresses in mechatronics design and technology. We are developing a novel prosthetic hand featured by multiple degrees of freedom, tactile sensing capabilities, and distributed control. Our main goal is to pursue an integrated design approach in order to fulfill critical requirements such as cosmetics, controllability, low weight, low energy consumption and noiselessness. This approach can be synthesized by the definition "biomechatronic design", which means developing mechatronic systems inspired by living beings and able to work harmoniously with them. This paper describes the first implementation of one single finger of a future biomechatronic hand. The finger has a modular design, which allows to obtain hands with different degrees of freedom and grasping capabilities. Current developments include the implementation of a hand comprising three fingers (opposing thumb, index and middle) and an embedded controller.

Background Brentuximab vedotin (BV) is an antibody-drug conjugate directed to the protein CD30, which is expressed in classical Hodgkin’s lymphoma (HL) and systemic anaplastic large cell lymphoma (sALCL). The drug received conditional marketing authorisation from the European Medicines Agency (EMA) in October 2012 as an orphan drug for relapsed or refractory HL CD30+ and relapsed or refractory sALCL. Since 01/11/2012, BV has been reimbursable by the Italian National Health System (NHS) under Law 648/96 for these indications with specific Italian Medicines Agency (AIFA) monitoring, initially through an Excel tool and, since 15/02/2013, with the new AIFA Registry. Purpose To evaluate the efficacy and safety of BV in patients with relapsed or refractory HL CD30+ treated in our clinical centre. Materials and methods A total of 12 patients have been enrolled; treatment has been carried out both under the Named Patient Programme (NPP) and with BV as part of a clinical programme reimbursed by the NHS. The drug was prepared at the Centralised Chemotherapy Preparation Unit of our Hospital Pharmacy. Results Four patients (3 F-1 M), from the Haematology Unit (3) and Paediatric Oncohaematology Unit (1) of the Foundation IRCCS San Matteo Hospital, from September 2011 to October 2012 were treated in the NPP. Characteristics were (min-max): body weight 44–91 kg, age at starting treatment with BV 13–40 years; number of cycles 6–12; previous treatments: chemotherapy, autologous transplantation (+allogeneic in one case). The responses observed after treatment with BV were: 2 complete remissions (CR), 1 stable disease (SD) and 1 disease progression (DP). There were no suspected adverse drug reactions (ADRs) during treatment with BV. Eight patients (3F and 5M) from the Haematology Unit (7) and the Paediatric Oncohaematology unit (1), received treatment under the NHS from August 2012 to October 2013. Characteristics were (min-max): body weight 51–70 kg, age at starting treatment 18–39 years; previous treatments: several lines of chemotherapy (ABVD, IGEV, bendamustine, etc.), autologous transplantation. Of these, 2 patients are still ‘ongoing’ (instrumental revaluation not yet performed); 1 patient, after the 4th cycle (partial remission) has continued the treatment at another centre and 2 patients died; we had 1 partial remission and 2 DP in other cases. Two episodes of pulmonary toxicity and one case of severe infusion reaction with bronchospasm were notified as suspected ADRs with BV, but all with outcome improvement. Conclusions BV is the first monoclonal antibody available for HL treatment; we observed a homogeneous group of patients treated with classic chemotherapy, already receiving a bone marrow transplantation, in which overall survivals obtained with conventional therapies were greatly reduced. Clinical responses noted were substantially comparable to what is described in the literature, with complete responses in 2 patients, not achievable with the other treatment scheme. Based on the results obtained, clinical studies with BV in the front line are pending. No conflict of interest.

Blind signal separation (BSS) is a recurrent problem in many multi-sensors applications where observations can be modelled as mixtures of N statistical independent source signals. We propose the estimation of the orthonormal transformation matrix Q in the case of whitened observations and a cost function based on the fourth-order moments. Q is described as combination of elementary Givens rotations and the optimization is carried out jointly for all the rotations. When sub-sets of angles are optimized separately the method reduces to the deflation approach which has been proved to be globally convergent. The joint estimation of Givens rotation matrices has a computational complexity O(7N/sup 2/) and, compared to other adaptive BSS, simulations demonstrate that it converges faster and achieves a better crosstalk attenuation.

We report the case of a patient who showed clinical and radiological signs of massive polyethylene wear 3 years after total hip replacement. Arthroscopy was performed to assess the loosening of the acetabular cup. The procedure showed the polyethylene element to be broken into three pieces in the area corresponding to the upper border.

The embryology of the pituitary gland and its normal development is described, including the importance of Pit-1. Congenital abnormalities of the hypothalamo-pituitary region are discussed.

To evaluate the safety and efficacy of a preparative regimen consisting of fractionated total-body radiation (9.9 to 12 Gy) and melphalan (140 mg/m(2) in a single dose) in children with acute myeloid leukemia in first complete remission (CR) given autologous bone marrow transplantation (ABMT).Fifty-three children (30 males and 23 females; age range, 1.5 to 18 years) were enrolled onto the study. The median time from first CR to ABMT was 3.5 months (range, 1.4 to 13 months), with 45 patients (85%) undergoing transplantation within 6 months from the diagnosis. Forty-five patients received in vitro marrow purging with standard-dose mafosfamide (100 microg/mL), seven patients were treated with interleukin-2 before marrow collection, and in the remaining child, the marrow was unmanipulated. The median infused cell dose was 1.8 x 10(8)/kg (range, 0.4 to 5.8 x 10(8)/kg).All patients but one achieved hematopoietic engraftment, with a median time to neutrophil recovery of 24 days (range,11 to 66 days). Treatment-related toxicity was moderate and consisted mainly of mucositis. One patient died from cytomegalovirus interstitial pneumonia, and one died from pulmonary hemorrhage. Fourteen patients (26%) relapsed at a median time of 6 months after ABMT (range, 2 to 17 months), with a cumulative relapse probability of 29% (95% confidence interval, 16% to 42%). The 5-year Kaplan-Meier estimate of survival for all 53 patients was 78% (range, 65% to 90%), whereas the overall 5-year disease-free survival was 68% (range, 55% to 81%), with a median follow-up duration of 40 months (range, 7 to 130 months).These data suggest that, in our cohort of patients, the combination of total-body irradiation and melphalan is safe and associated with good antileukemia activity, making ABMT an appealing alternative for postremission therapy in children with acute myeloid leukemia in first CR.

Autologous transplantation of lymphocyte-depleted peripheral blood stem cells (PBSC) has been proposed for treatment of patients with severe autoimmune disease. However, several patients have been reported to achieve only transient remissions. We report on a child with thalassaemia intermedia and immune-mediated haemolytic anaemia, given an autologous lymphocyte-depleted PBSC transplant, who relapsed 7 weeks after transplant. A complete remission, lasting 18 months to date, was obtained with allogeneic bone marrow transplantation (BMT) from an HLA-matched unrelated donor. This experience indicates that, in selected cases, allogeneic BMT may be the treatment of choice for life-threatening autoimmune disease. A graft-versus-autoimmunity effect may favour the eradication of the recipient autoaggressive lymphocytes.

We report the preliminary results of a prospective randomized study on the impact of two different dosages of Cyclosporine A (Cs-A) on probability of development of acute and chronic GVHD, transplant-related mortality (TRM), relapse rate (RR) and event-free survival (EFS). Fifty-nine pediatric patients given BMT from an HLA-identical sibling were centrally randomized to receive either Cs-A at a dosage of 1 mg/kg/die (CsA1) or at a dosage of 3 mg/kg/die (CsA3) intravenously for the first 21 days after BMT. Patients given Cs-A at a dosage of 1 mg/kg/die had a higher probability of developing acute GVHD, but a lower relapse rate, which translated into a better probability of EFS. These preliminary results to be confirmed with a longer follow-up suggest that the use of low doses of CsA is feasible even though associated with a higher incidence of GVHD, but without any increment in TRM. The reduction of immunosuppressive treatment after BMT favoured the development of a graft-versus-leukemia effect, which seems to play a relevant role in preventing leukemia recurrence and in improving the cure rate.

Forty-seven patients (age range, 7 months-18 years) with malignant (38 cases) and nonmalignant (9 cases) disorders given an allogeneic or an autologous bone marrow transplantation (BMT) were immunized with Haemophilus influenzae type b (Hib) polysaccharide-diphtheria toxoid conjugate vaccine administered in a single dose at different time points after transplantation. Results were compared with those of 13 healthy children matched for age and sex who received the same immunization schedule. Serum and saliva samples for measurement of total IgG subclass and specific antibody levels were obtained from patients and healthy controls before and 3 weeks after vaccination. Twenty-five of the 47 patients (53%) had a specific anti-Hib IgG response, while an effective IgA and IgM response was mounted by 23 (49%) and 11 (23%) children, respectively. In the control group, 13 of 13 subjects mounted a specific IgG antibody production (P0.005 in comparison to the patients' response rate), while an IgA and IgM response was demonstrated in 12 (92%; P0.01 compared to transplanted patients) and 7 (54%; P0.05 in comparison to BMT recipients) children, respectively. Lapse of time from BMT to immunization was the most important factor predicting antibody response, as proved by an effective increase in prevaccination specific IgG levels in the majority of patients vaccinated after 2 years from transplant. Our data demonstrate that BMT recipients have a reduced capacity to mount an antibody response to polysaccharide antigens compared to normal controls, even when a protein-conjugated vaccine is employed. Since time after transplant is the major factor influencing the recovery of immune reactivity to polysaccharide antigens, the ontogeny of the B cell repertoire seems to follow a predetermined sequential program of development.

Busulfan (BU) is an alkylating drug frequently used to prepare patients for bone marrow transplantation (BMT). Several studies have documented that there is important interpatient variability in BU disposition and systemic exposure, and that other drugs with a common metabolic pathway are capable of influencing BU clearance. We compared the BU pharmacokinetics and pharmacodynamics of 13 patients given BMT and receiving BU and itraconazole, with those of 26 matched controls who did not receive any anti-fungal agent, and with those of 13 matched patients treated with fluconazole as prophylaxis against fungal infections. The effect of itraconazole was best reflected in BU clearance since the BU dose was modified in some patients. BU clearance was decreased by an average of 20% in patients receiving itraconazole as compared to control patients and patients receiving fluconazole (p0.01). Mean BU clearance was 7.653 +/- 1.871 l/hr.m2 in the itraconazole patients, 10.103 +/- 2.007 l/hr.m2 in the fluconazole group and 9.373 +/- 1.702 l/hr.m2 in the control group. In this study itraconazole, but not fluconazole, markedly affected the pharmacokinetics of BU as an increase of BU plasma concentrations was observed. The nature of this interaction has not yet been fully characterized. Itraconazole and its analogues are inhibitors of both cytochrome P450 and lipoxygenase and since itraconazole can modulate BU pharmacokinetics, oxidative catabolism is probably a determinant of BU metabolism. This hypothesis should be tested in human metabolic studies.

The role of recombinant human granulocyte colony-stimulating factor (rHuG-CSF) in myeloid recovery of children given an allogeneic bone marrow transplant (BMT) from an HLA-identical sibling for acute leukemia was evaluated in a retrospectively historically controlled study, involving 20 consecutive treated patients and 30 historical controls. In order to investigate the efficacy of rHuG-CSF in patients given a matched unrelated BMT with methotrexate as part of graft-versus-host disease (GVHD) prophylaxis, we also analyzed the kinetics of engraftment in eight further children with acute or chronic leukemia, transplanted using a volunteer donor. Patients were treated with 5 micrograms/kg/day of rHuG-CSF by 1-h intravenous infusion from day +5 until the absolute neutrophil count (ANC) wasor = 2 x 10(9)/l. No adverse effect related to treatment was observed in any patients. Children transplanted from an HLA-identical sibling and treated with rHuG-CSF reached an ANC count greater than 0.5 x 10(9)/l, 1 x 10(9)/l and of 2 x 10(9)/l in a significantly shorter time than the control group (day +9, +10 and +12, vs day +15, +22 and +29, respectively). An accelerated granulocyte production was also observed in patients receiving an unrelated transplant after a GVHD prophylaxis schedule including methotrexate, the median time to neutrophil recovery above 0.5 x 10(9)/l, 1 x 10(9)/l and 2 x 10(9)/l being +14, +15 and +17 days, respectively. In comparison to historical controls, all rHuG-CSF-treated patients had fewer days of fever, of antibiotic therapy and, only for children with HLA-compatible siblings, of hospitalization, whereas in the three groups the duration and severity of mucositis were comparable. No difference between the rHuG-CSF-treated patients and the historical controls given BMT from HLA-identical sibling was seen with regard to incidence of acute or chronic GVHD, relapse rate and actuarial event-free survival at day +100 and 1 year after transplantation. Our data suggest that in children given allogeneic BMT for acute or chronic leukemia, rHuG-CSF reduces duration of neutropenia, without increasing the rate of relapse or the incidence and severity of GVHD.

Induction of a state of long-term, alloantigen-specific T cell nonresponsiveness has significant implications for human transplantation. It has been previously described that alloantigen-specific anergy may be induced by addition of cyclosporin-A together with anti-CD80(B7-1) mAb to a MLR. In this study we endeavored to verify whether alloantigen-induced PBL rendered anergic by the addition of a combination of anti-B7 mAb and cyclosporin-A during a MLR had a suppressive effect when added to autologous lymphocytes activated in MLR. We found that: 1) the addition of cells rendered anergic by this procedure to a MLR suppress both proliferative and cytotoxic response of autologous responsive PBL to either the same or third-party stimulator cells; 2) the suppressive effect is limited to alloantigen-induced T cell activation, as addition of anergic cells does not influence mitogen- or antigen-induced proliferation of autologous responsive T cells; 3) nonresponsiveness of suppressed cells cannot be reversed by either subsequent restimulation with allogeneic cells or addition of exogenous IL-2 to the cultures; 4) the suppressive effect is apparently not due to secretion of anergic cell-derived soluble factors, but it seems to be dependent on cell-cell contact between anergic, responsive, and stimulator cells. These data suggest that: 1) the delivery of a direct signal mediated by anergic lymphocytes through a cell-cell contact is likely to be the mechanism responsible for the suppressive effect here described; 2) anergic cells may propagate alloantigen-specific tolerance to potentially responsive autologous lymphocytes. Preliminary experiments indicate that anti-CD86(B7-2) mAb may play a similar role in the generation of alloantigen-induced nonresponsiveness.

Myelodysplastic syndromes (MDS) are clonal disorders of the multipotent hematopoietic stem cell characterized by ineffective hematopoiesis and associated with marrow hypercellularity, increased intramedullary cell death and peripheral cytopenias of varying severity. Patients with myelodysplasia have a propensity (20% to 30% of cases) to undergo transformation into acute myeloid leukemia (AML), and a large body of evidence indicates that MDS represent steps in the multiphasic evolution of AML. Progression of the disease is characterized by expansion of the abnormal clone and inhibition of normal hematopoiesis leading to deterioration of the blood cell count and/or development of AML. MDS are relatively unusual in childhood, representing only 3% of pediatric hematological malignancies, although it has been reported that up to 17% of pediatric AML cases may have a previous myelodysplastic phase. The first systematic attempt at morphological classification of MDS was provided by the French-American-British (FAB) group. However, the FAB classification of MDS is only partially applicable in children. Some variants are extremely rare or absent (refractory anemia with ring sideroblasts and chronic myelomonocytic leukemia), and other peculiar pediatric disorders, represented by juvenile chronic myelogenous leukemia (JCML) and the monosomy 7 syndrome, are not included. Moreover, since there is a partial overlap between pediatric MDS and myeloproliferative disorders and the variants occurring in young children have rather specific features, some confusion still surrounds the nosographical definition of childhood MDS, so that none of the proposed classifications are widely accepted and used. Characteristically, some genetic conditions such as Fanconi's anemia, Shwachman's and Down's syndromes predispose to the development of MDS in childhood. The most common variants of childhood MDS are represented by JCML and the monosomy 7 syndrome, both disorders typically occurring in young children. JCML is characterized by a spontaneous growth of granulocyte-macrophage progenitors that show a striking hypersensitivity to granulocyte-macrophage colony-stimulating factor. Clinical presentation resembles that of some myeloproliferative disorders, with massive organomegaly usually not observed in the classically reported variants of MDS. Clinical features of the monosomy 7 syndrome resemble those observed in JCML and a differential diagnosis between these two entities relies upon the higher percentage of fetal hemoglobin, the more pronounced decrease in platelet count and, in some cases, the lack of the peculiar cytogenetic abnormality in the latter. With the number of children being cured of cancer constantly rising, a significant increase in secondary or chemotherapy-related myelodysplasia is being observed, and these disorders represent a formidable challenge for pediatric hematologists due to their poor response to chemotherapy.(ABSTRACT TRUNCATED AT 400 WORDS)

We conducted a phase II study on 19 children with AML in first (10 patients) or second (nine patients) complete remission (CR) treated with ABMT, evaluating the combination of total body irradiation (TBI, 12 Gy in six divided fractions) and high-dose melphalan (140 mg/m2 in single dose) in an attempt to improve antitumour efficacy of conditioning regimen. All patients received cryopreserved and in vitro purged (mafosfamide at a dose of 100 micrograms/ml) bone marrow. The median time from first CR to ABMT was 5 months compared with a median time of 3 months for patients in second remission. One of the 19 patients, transplanted in second CR, died of transplant-related complication 10 days after transplant and another second CR patient relapsed on day +28, before engraftment. Three further patients in second CR relapsed at 6, 6 and 18 months after marrow transplant, respectively, and this determined a relapse rate of 43% in children given ABMT in second CR and 0% for patients transplanted in first remission (P0.05). Seventy-two per cent of all patients are projected to be alive and disease-free at 6 years, whereas the event-free survival of patients in first and in second CR is 100 and 44%, respectively (P0.05). Although the number of patients does not allow us to draw any firm conclusion, our results are encouraging and suggest that the association of TBI and high-dose melphalan appears to be safe and valuable.

We carried out a pilot study on the use of recombinant human erythropoietin (rHuEPO) in children undergoing allogeneic or mafosfamide-purged autologous BMT for ALL or AML. rHuEPO was administered intravenously at a dose of 75 U/kg/day for 30 days after transplant. Ten rHuEPO-treated patients receiving allogeneic BMT and 10 given autologous BMT were compared with 15 allogeneic and 10 autologous historical controls. Endogenous EPO production was appropriate for the degree of anemia after autologous BMT. In these patients, rHuEPO did not accelerate erythroid repopulation and did not modify transfusion requirements. With allogeneic BMT, erythroid marrow activity increased faster in patients given rHuEPO than in controls and resulted in higher red cell production, the mean reticulocyte count on day +30 being 187 +/- 51 x 10(9)/l in treated patients versus 107 +/- 63 x 10(9)/l in controls (p0.01). The total number of RBC units administered was 1.7 +/- 1.3 in the rHuEPO group versus 5.1 +/- 3.0 in the control group (p0.001). The total number of platelet transfusions was 4.0 +/- 2.3 for patients given allogeneic BMT and receiving rHuEPO versus 8.4 +/- 6.8 for historical controls (p0.05) whereas it was similar in rHuEPO-treated and control autologous BMT patients.(ABSTRACT TRUNCATED AT 250 WORDS)

We describe the case of a 12-year-old boy affected by cyclic neutropenia, at high risk of developing life-threatening infections, treated with recombinant human granulocyte-macrophage colony stimulating factor (rHuGM-CSF). The drug was effective in reducing the severity of neutropenia and infectious complications in our patient. It was administered for brief periods of time, in contrast to the daily continuous administration reported for rHuG-CSF. Therefore, more extensive studies must be performed to identify the most effective time schedule for the drug. In vitro studies of hemopoietic progenitor cells were useful, in this case, to predict treatment response.

Optimal allogeneic bone marrow transplantation (BMT) presupposes the use of a HLA-identical sibling as donor. Unfortunately, only about 30% of patients have an HLA-matched donor, so that the use of alternative donors has been increasingly used. We report an analysis of 13 children transplanted using an HLA-partially matched donor as source of haemopoietic stem cells. They suffered of ALL (3 pts), ANLL (1 pt), SAA (2 pts), Osteopetrosis (1 pt), Wiskott-Aldrich Syndrome (2 pts), Severe Combined Immunodeficiency Disease (2 pts) and Familial Haemophagocitic Lymphohistiocytosis (2 pts). Full engraftment was obtained in all 11 of the patients who survived longer than 14 days and, globally, a moderate incidence of acute GvHD (grade II-IV) was observed in the evaluable patients (3 out of 11 with a percentage of 27%); only a patient of the six survivors more than one hundred days after BMT had severe chronic GvHD (16.6%). Four pts (31%) are actually alive and well (mean follow-up 358 days) with a mean Karnofsky score of 95%. Our data suggest that BMT from HLA-partially matched donors could represent a possible alternative therapeutic strategy in children when a compatible donor is not available. This is especially due to the reduced severity of GvHD in childhood and because of T-cell depleted marrow transplants could obtain more satisfactory results when employed in typical pediatric non-malignant disorders (i.e. immunodeficiencies) rather than in leukemia.

Bone marrow transplantation (BMT) in patient affected by severe aplastic anemia (SAA), is successful in 70-80% of cases, when performed with HLA identical brother or syngeneic twin as donors, and in 11-45% of cases when performed from aploidentical-identical related or HLA identical unrelated donor. The different conditioning regimens (Cy alone or in combination with TBI) have shown similar results in the long term outcomes. Cyclosporin-A is very effective in avoiding rejection and controlling GVHD.

The direct synthesis of hydrogen peroxide is catalyzed by palladium catalysts supported over different solids. With the aid of a suitable plug-flow reaction cell, we carried out a preliminary X-ray absorption fine structure spectroscopy (EXAFS) characterization of a palladium catalyst supported on the commercial resin K2621 under reaction conditions (in situ). Whereas the catalyst, which in the dry catalyst presents metal Pd and PdO when fresh, is practically unaffected by the reaction medium (methanol) or by the reaction mixture (CO2/H2/O2, 86/10/4, v/v) it undergoes an apparent reduction of part of PdO to metal Pd and some metal leaching during the reaction in the presence of bromide ions. These findings suggest the role of bromide ions as enhancers of the selectivity of palladium catalysts in the direct synthesis of hydrogen peroxide could not be limited to the selective blocking of the sites responsible for the undesired formation of water, but could also entail phase modifications of the active metal.