Response In Adult Patients Research Articles

The Telomere Length In Peripheral Blood Lymphocytes Is a Useful Predictor of the Response to Immunosuppressive Therapy In Patients with Acquired Aplastic Anemia

AbstractAbstract 2042 Introduction:The ability to predict the response to immunosuppressive therapy (IST) in patients with aplastic anemia (AA) will avoid unnecessary and possibly harmful treatment. To this end, several in vitro tests have been proposed as useful predictors of response in adult patients. However, we previously reported that the presence of either human leukocyte antigen (HLA)-DR15, a minor population of paroxysmal nocturnal hemoglobinuria (PNH)-type cells, or of autoantibodies to postmeiotic segregation increased 1 (PMS1) in children with AA, were not useful predictors of the response to IST, suggesting a different etiology of AA between adults and children (Yoshida, N et al Br J Haematol. 2008). Telomeres in peripheral blood cells from AA patients are shorter than those from normal individuals in 30% of patients. This shorter telomere length in AA patients is thought to result from genetic abnormalities in the genes related to telomere maintenance, stressed hematopoiesis due to immunological attack, and increased cell division. An NIH group and we reported that cryptic forms of dyskeratosis congenita (DC) are present in just under 5% of patients with AA who do not have physical abnormalities, but who harbour the gene mutation associated with telomere maintenance (Yamaguchi, H et al. N Engl J Med. 2005, Liang, J et al. Haematologica 2006). To identify such patients is important because those who have these mutations might respond poorly to IST. However, the presence of cryptic forms of DC does not explain the causes of short telomeres in the other patients. We hypothesized that patients with short telomeres may respond poorly to IST, and thus evaluated the relationship between telomere length in hematopoietic cells before IST and the response to IST in patients with AA. Patients and Methods:We enrolled 40 newly diagnosed children with AA (median age, 10 years; range, 1 to 16 years) who received IST. We obtained peripheral blood lymphocytes from the patients with AA at the time of diagnosis and prospectively measured the telomere length of lymphocytes prior to IST by flow-fluorescence in situ hybridization (flow-FISH) using Telomere PNA kits (Dako Cytomation, Glostrup, Denmark). After gating diploid cells based on propidium iodine staining, lymphocytes were isolated according to size and granularity. Relative telomere length (RTL) was calculated as the ratio between the telomere signal of each sample and the telomere signal of the control cell line. Because telomeres shorten with age, we obtained age-adjusted measurements for comparison from 71 normal age-matched individuals. Delta RTL of each patient with AA was calculated using the distance of the RTL from the line of age-adjusted normal telomere length. Results:Of the 40 patients, at diagnosis AA was very severe in 12, severe in 13, and non-severe in 15. All received IST with horse antithymocyte globulin (ATG) and cyclosporine. The causes of AA were idiopathic in 38 patients and hepatitis in 2. In total, 25 of the 40 patients (63%) responded to IST at 6 months after administration of ATG. Between the responder and non-responder groups, no significant differences in gender, age, etiology, disease severity or interval from diagnosis, and IST were observed. Univariate analysis for IST response did not find any significant differences in median WBC count, neutrophil count, Hb level, reticulocyte count, platelet count or minor PNH clone positivity between the groups. However, delta RTL was significantly lower in non-responders than in responders (p=0.035). Multivariate analysis for response to IST revealed that only delta RTL was significantly lower in non-responders than responders (p = 0.049). Conclusion:The telomere length in lymphocytes is promising not only to identify cryptic DC but also to predict the response to IST of patients with AA. A further larger analysis is warranted to evaluate the correlation between telomere length and the response to IST in AA patients. Disclosures:No relevant conflicts of interest to declare.

A pathway-based gene signature correlates with therapeutic response in adult patients with Philadelphia chromosome-positive acute lymphoblastic leukemia

Biomarkers to predict response to therapy in adults with Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) are not yet established. In this study, we performed a meta-analysis of earlier genome-wide gene expression studies to identify pathway-based genes that are associated with therapeutic response. The predictive power of these genes was validated by transcript profiling in diagnostic bone marrow samples from Ph+ ALL patients using a quantitative real-time PCR array. Gene expression was correlated with cytogenetic and molecular characteristics, including presence of ABL1 mutations and IKZF1 deletion. A total of 43 de novo Ph+ ALL patients treated uniformly with tyrosine kinase inhibitors combined with chemotherapy were selected to validate 46 identified genes. A 9-gene signature was established to distinguish optimal responders from patients with persistent residual disease and early molecular recurrence. The signature was subsequently validated with 87% predictive accuracy in an independent validation set of patients. When initially optimal responders relapsed, their gene expression patterns also shifted. Optimal responders showed upregulation of genes involved in proliferation and apoptosis pathways, whereas poor responders had higher expression of genes that facilitate tumor cell survival in hypoxic conditions as well as development of drug resistance. This unique 9-gene signature may better enable stratification of patients to proper therapeutic regimens and provides new insights into mechanisms of Ph+ ALL response to therapy.

Motivation to change in adolescents with bulimia nervosa mediates clinical change after treatment

Several studies have related motivation to change and treatment response in adult patients with bulimia nervosa but there are no longitudinal studies analysing this relationship in adolescents. The objective was to determine whether motivation to change is related to clinical improvement after treatment in adolescent patients with bulimia nervosa. The Bulimia Nervosa Stages of Change Questionnaire, the Eating Disorders Inventory (EDI-2) and the Beck Depression Inventory (BDI) were administered at the beginning of treatment to 40 adolescent patients with bulimia nervosa (DSM-IV) (mean age = 16.2 years). Thirty-one patients were re-assessed after 6 months of treatment. The majority of clinical and psychological variables improved significantly at the second evaluation. There were significant correlations between initial motivation to change and improvement in number of binges and the EDI-2 scales of Bulimia and Interoceptive Awareness. In the stepwise multiple linear regression analysis, which included initial motivation to change and other potential confounding variables such as age, BDI, duration of disorder and body mass index, only motivation to change was selected as a predictor of improvement in number of binges (standardized β coefficient = 0.45; p = 0.012) and of decrease on the Bulimia scale (standardized β coefficient = 0.43; p = 0.029). Regarding improvement in Interoceptive Awareness, only the BDI score was selected as an independent predictor (β coefficient = 0.58; p = 0.002). In conclusion, in adolescent patients receiving treatment for bulimia nervosa, improvement in bulimic symptomatology seems to be especially related to initial motivation to change.

Long-term response of juvenile idiopathic arthritis after conditioning with 8 Gy total body irradiation followed by autologous peripheral blood stem cells: Case report

Investigations of HCT for refractory JIA have employed high dose immunosuppressive drugs, such as CY and ATG with or without low dose TBI. Initial disease response has been observed in approximately two-thirds of patients; however, relapse occurs in about half of the responders. The current report describes a regimen with substantially increased dose of TBI, previously shown to be associated with high rate of disease response in adult patients with refractory MS and severe SSc. We report outcome of the lead patient in this pilot study, who remains in complete remission now, five yr after HCT. This regimen should be considered for patients with JIA refractory to medical therapies, including previous low intensity regimen HCT.

Analysis of intracellular methotrexate polyglutamates in patients with juvenile idiopathic arthritis: Effect of route of administration on variability in intracellular methotrexate polyglutamate concentrations

Intracellular methotrexate (MTX) polyglutamates (MTXGlu) have been shown to be potentially useful biomarkers of clinical response in adult patients with rheumatoid arthritis. The present study was undertaken to measure intracellular MTXGlu concentrations in a cohort of patients with juvenile idiopathic arthritis (JIA) to determine the predictors of MTXGlu variability in these patients. Blood samples were obtained from patients with JIA who were being treated with a stable dose of MTX for >or=3 months. Clinical data were collected by chart review. Concentrations of MTXGlu(1-7) in red blood cell lysates were quantitated using an innovative ion-pairing chromatography procedure, with detection by mass spectrometry. Patients with JIA from a single center (n = 99; mean +/- SD age 117.8 +/- 56.5 months, 69 female) were included in the analysis. The mean +/- SD dose of MTX was 0.51 +/- 0.25 mg/kg per week, with a median treatment duration of 18 months (interquartile range 3-156 months). MTX was administered subcutaneously in 66 patients (67%). Fifty-six patients (57%) had active arthritis at the time of the clinic visit. Total intracellular MTXGlu (MTXGlu(TOT)) concentrations varied 40-fold, with a mean +/- SD total concentration of 85.8 +/- 48.4 nmoles/liter. Concentrations of each MTXGlu subtype (MTXGlu(1-7)) were measured individually and as a percentage of MTXGlu(TOT) in each patient. MTXGlu(3) was the most prominent subtype identified, comprising 42% of MTXGlu(TOT), and the interindividual variability in the concentration of MTXGlu(3) was the most highly correlated with that of MTXGlu(TOT) (r = 0.96). The route of MTX administration was significantly associated with MTXGlu(1-5) subtypes; higher concentrations of MTXGlu(1 + 2) were observed in patients receiving oral doses of MTX, whereas higher concentrations of MTXGlu(3-5) were observed in patients receiving subcutaneous doses of MTX (P < 0.0001). In this cohort of patients with JIA, the MTXGlu(TOT) concentration varied 40-fold. Individual MTXGlu metabolites (MTXGlu(1-7)), which have, until now, not been previously reported in patients with JIA, were detected. The route of MTX administration contributed to the variability in concentrations of MTXGlu(1-5).

Certolizumab pegol for the treatment of Crohn’s disease

Certolizumab pegol is a polyethylene glycolated FAb’ fragment of a humanized anti-TNF-α monoclonal antibody. This pegylated molecule binds with circulating TNF-α and forms an inactive complex that is then eliminated from the body. The drug has been shown to be better than placebo in the treatment of Crohn’s disease and maintaining a clinical response in adult patients with moderate-to-severe active disease who have had an inadequate response to conventional therapy, and the treatment of adults with moderately to severely active rheumatoid arthritis. Comparative trials with an active control group are lacking. The most common adverse reactions include abdominal pain, diarrhea, injection site reactions and infection. All necessary live and attenuated vaccines should be given prior to the initiation of certolizumab pegol therapy, patients should be evaluated for TB risk factors and tested for latent TB prior to initiating therapy, and the initiation of therapy should be avoided if the patient has an active infection. Concomitant use with anakinra is not recommended because of the increased risk of serious infections and neutropenia. Therapy should be discontinued if the patient develops a serious infection during therapy.

Cholera Caused by Vibrio cholerae O1 Induces T-Cell Responses in the Circulation

Considerable effort is being made to understand the acute and memory antibody responses in natural cholera infection, while rather less is known about the roles of cellular immune responses involving T and B lymphocytes. We studied responses in adult patients hospitalized with cholera caused by Vibrio cholerae O1. Peripheral blood mononuclear cells from patients (n = 15) were analyzed by flow cytometry after stimulation with V. cholerae O1 membrane protein (MP) or toxin-coregulated pilus antigen (TcpA). The gamma interferon (IFN-gamma) and interleukin-13 (IL-13) responses in stimulated-lymphocyte supernatants were studied. The responses were compared with those of healthy controls (n = 10). Patients responded with increased frequencies of gut-homing CD4(+) T cells (CD4(+) beta7(+)), gut-homing CD8(+) T cells (CD8(+) beta7(+)), and gut-homing B cells (CD19(+) beta7(+)) at the early and/or late convalescent stages compared to the acute stage. After stimulation with MP or TcpA, proliferation of CD4(+) and CD8(+) T cells was increased at the acute stage and/or early convalescent stage compared to healthy controls. Increased IL-13 and IFN-gamma responses were observed after antigenic stimulation at the acute and convalescent stages compared to healthy controls. Thus, increases in the levels of gut-homing T and B cells, as well as involvement of CD8 and CD4 Th1-mediated (IFN-gamma) and CD4 Th2-mediated (IL-13) cytokine responses, take place in acute dehydrating disease caused by V. cholerae O1. Further studies are needed to determine if such responses are also stimulated after immunization with oral cholera vaccines and if these responses play a role in protection following exposure to cholera.

Post-splenectomy response in adult patients with immune thrombocytopenic purpura

Splenectomy has been the conventional surgical treatment for patients with Immune Thrombocytopenic Purpura (ITP).Aim:To define response to surgical therapy, pre operative factors influencing outcome and tolerability of surgery in adult patients undergoing splenectomy for ITP.Method:We analyzed prospectively maintained data of 33 patients who were diagnosed as ITP and underwent splenectomy over the last 10 years. The age, presenting complaints, bleeding manifestations, clinical details and other investigations were noted. Details of immediate pre-operative administration of blood transfusions, platelet transfusions and other forms of therapy were also recorded. Operative details with regards to blood loss and the presence of accessory spleens were obtained. Postoperative course in terms of clinical improvement, rates of complications and platelet counts was also noted.Results:Skin petechiae and menorhhagia were common presenting symptoms in patients (mean age 26.5±10.5 yrs) with ITP. Eighteen patients underwent splenectomy for failure of therapy and fifteen for relapse on medical treatment. Mean platelet bags transfused in immediate pre-operative period were 2.8±0.8. Mean intra-operative blood loss was 205±70.5 ml. Accessory spleens were removed in 1 case (3.03%). The immediate postoperative response was complete in 19 cases (57.58%) and partial in 13 cases (39.39%). The platelet counts increased significantly from 23142±12680/ µL (Microliter) (mean ± SD) preoperatively to 170000±66000/µL (Microliter) within 24-48 hours after splenectomy (P < 0.05). The mean platelet count was 165000+66000/µL (Microliter) at the end of one month when steroids were tapered off gradually. Four patients (12.12%) had complications (one each of wound hematoma, wound infection, splenic fossa collection and upper GI hemorrhage) in postoperative period but all responded to therapy. One relapsed patient was detected with accessory spleen and responded after re-surgery. Response to splenectomy was better in young patients and in those patients who had higher immediate post-splenectomy thrombocytosis.Conclusions:Splenectomy is safe and effective therapy in ITP patients with no response to steroids and relapse after medical therapy. Response to splenectomy was more in young patients and in those patients who had higher immediate post-splenectomy thrombocytosis.

QRS duration in Fontan circulation in adults: A predictor of aerobic capacity

Backgrounds The univentricular circulation after a Fontan procedure is characterized by an abnormal cardiorespiratory response being attributable to an inability to increase stroke volume during exercise. In congenital heart disease a broad QRS complex has been related to increased intracardiac volume and mass being associated with poor ventricular function and prognosis. Objectives This study investigated the relation between the width of the QRS complex and parameters of cardiorespiratory response in adult patients after a Fontan procedure. Methods Clinical data and parameters of cardiorespiratory function of 56 patients (15 women, 41 men, mean age 23.7 ± 6.4 years, mean age at operation 10.0 ± 7.5 years) were related to the width of the QRS complex. Results In the whole group the mean QRS duration was 115 ± 23 ms. A QRS complex ≥ 120 ms was present in 23 patients. These patients were characterized by significantly older age at operation (13.0 ± 9.3 versus 7.9 ± 5.1; p < 0.05). Compared to individuals with smaller QRS complexes they showed a decreased oxygen uptake (PeakVO 2: 21.6 ± 5.2 versus 27.7 ± 6.6 ml/kg/min; p < 0.001), work rate (1.6 ± 0.5 versus 2.0 ± 0.5 W/kg, p < 0.05), maximum blood pressure ( p < 0.001) and increase in blood pressure ( p < 0.05). Univariate analysis showed a significant correlation between PeakVO 2 and several other parameters of cardiorespiratory exercise testing (work rate,O 2-pulse, increase in heart rate and blood pressure, maximum heart rate and blood pressure), maximum enddiastolic diameter of the systemic ventricle, age at operation. Multivariate regression analysis identified QRS duration as the only independent predictor of PeakVO 2 ( p = 0.05). Conclusion In a Fontan circulation a broad QRS complex is a negative predictor of cardiorespiratory function. Early Fontan operation may be beneficial in terms of exercise capacity.

Dasatinib induces rapid hematologic and cytogenetic responses in adult patients with Philadelphia chromosome–positive acute lymphoblastic leukemia with resistance or intolerance to imatinib: interim results of a phase 2 study

Patients with Philadelphia (Ph) chromosome-positive acute lymphoblastic leukemia (ALL) have a rapid disease course and a poor prognosis. Dasatinib, a novel, oral, multitargeted kinase inhibitor of BCR-ABL and SRC family kinases, has previously induced responses in patients with imatinib-resistant or -intolerant Ph-positive ALL. We present the interim results of a phase 2 study designed to further assess the efficacy, safety, and tolerability of dasatinib 140 mg in this patient population (n = 36). With a minimum follow-up of 8 months, treatment with dasatinib resulted in substantial hematologic and cytogenetic response rates. Major hematologic responses were achieved in 42% (15/36) of patients, 67% of whom remained progression-free. Complete cytogenetic responses were attained by 58% (21/36) of patients. The presence of BCR-ABL mutations conferring imatinib resistance did not preclude a response to dasatinib. Dasatinib was also tolerable, with 6% (2/36) of patients discontinuing therapy as a result of study-drug toxicity. Most adverse events (AEs) were grade 1 or 2; febrile neutropenia was the most frequent severe AE, but this and other cytopenias were manageable with dose reduction. Dasatinib represents a safe and effective treatment option and an important therapeutic advance for patients with Ph-positive ALL. This trial was registered at www.clinicaltrials.gov as #CA180015.

Stress Can Be Bad for Your Bowels

Source: Mawdsley JE, Macey MG, Feakinhs RM, et al. The effect of acute psychologic stress on systemic and rectal mucosal measures of inflammation in ulcerative colitis. Gastroenterology. 2006;110:410–419; doi:10.1053/j.gastro.2006.05.017The results of recent studies suggest that life events and chronic stress increase the risk of relapse in inflammatory bowel disease (IBD).1 The authors from Barts and the London, Queen Mary School of Medicine and Dentistry, Barts and London NHS Trust, and University College London conducted a study to examine the effects of experimentally induced acute psychological stress on a variety of measures of systemic and rectal mucosal inflammatory response in adult patients with inactive ulcerative colitis (UC) and in well controls. A total of 25 patients with inactive UC and 11 healthy volunteers (HV) underwent an experimental stressor involving a need to complete a 60-minute IQ test in 50 minutes while rock music played in one ear and folk music in the other. A separate group of 10 patients with UC and 11 HV underwent a control procedure involving the same 50-minute test, but with their choice of relaxing music playing in their ears. Before and after each procedure, systemic inflammatory response was assessed by measurement of serum inflammatory mediators such as serum interleukins and tumor necrosis factor. In all study patients with UC, sigmoidoscopy was performed before and after the study procedures; rectal mucosal inflammation was assessed by measurement of inflammatory mucosal blood flow (RMBF) and histology.Following the stressor, increased pulse (P<.0001) and systolic blood pressure (P<.0001) were noted in the stressed UC patients and healthy volunteers compared to the unstressed UC and HV participants who underwent the control experience. In both UC patients and HV who were stressed, numerous serum inflammatory mediators significantly increased compared to baseline measurements. However, there were no significant differences in changes between stressed UC and HV participants. There were no significant changes in markers of stress among UC patients or HV in the control group. Among stressed UC patients there was a significant change in RMBF; the changes in control UC patients were not significant. The authors suggest that stress may act as a trigger for exacerbations of UC. However, since stress-induced inflammatory markers also increased in HV, it seems unlikely that an exaggerated autonomic and inflammatory response to stress is a primary etiologic factor in UC.Dr. Nassau has disclosed no financial relationship relevant to this commentary. This commentary does not contain a discussion of a commercial product/device. This commentary does not contain a discussion of an unapproved/investigative use of a commercial product/device. Dr. LeLeiko has disclosed no financial relationship relevant to this commentary. This commentary does not contain a discussion of a commercial product/device. This commentary does not contain a discussion of an unapproved/investigative use of a commercial product/device.Every day the effect of stress on our young patients is the subject of parental questions. Patients with chronic IBD (or indeed any chronic illness) are no strangers to stress and we always endorse the virtues of trying to lessen what stressors we can and learning to manage those we cannot avoid. The overall paucity of rigorous scientific studies means that we make recommendations based on our experience, which reflects our biases, rather than on data. Although this study was performed in adults, the results are likely applicable to children with IBDs.Results from this study suggest a possible mechanism for how stress might play a role in increased risk of relapse in IBD. There is a growing body of research on the influence of stress on immunity,2 including the influence of stress on the immune system in children and adolescents with chronic medical conditions (eg, asthma).3 The current study adds to this research and reminds us that physicians who care for children with diseases associated with immunological pathophysiology, such as IBD, need to attend to the stress their patients may be experiencing.The authors also raise the interesting point that if stress may enhance the risk of relapse, then perhaps psychological treatments such as stress management training could mitigate these effects. There are data to suggest that psychological interventions can influence immunological parameters.4 The current study underscores the potential utility of psychological intervention in the total care of patients with inflammatory bowel disease.Despite that fact that stressed healthy volunteers or unstressed UC patients and healthy volunteers did not undergo sigmosidoscopy and rectal mucosal study, which would have added to their stress, the notable elevations in serum inflammatory mediators in the UC patients who were stressed are concerning. Designing a study to evaluate the utility of stress reduction in patients with IBD is a daunting challenge. In the absence of such evidence this study gives added weight to the idea that managing stress might reduce the frequency of exacerbations in patients with IBD.

Philadelphia chromosome-positive acute lymphoblastic leukemia: Impact of imatinib treatment on remission induction and allogeneic stem cell transplantation

Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) has been associated with the worst patient survival rates of the various acute leukemias. Imatinib mesylate is a novel therapeutic agent that targets the BCR-ABL tyrosine kinase, the molecular abnormality associated with Ph+ ALL. The combination of imatinib with chemotherapy has led to improved and durable treatment responses in adult patients with Ph+ ALL, including the elderly population. Hematopoietic stem cell transplantation has also integrated imatinib into its transplant strategies, with early data suggesting improved progression-free survival without clearly identifiable augmented toxicity. Second-generation tyrosine kinase inhibitors offer potentially even greater improvements on these excellent imatinib-associated outcomes. This review addresses the evolution of the management of Ph+ ALL and is intended to assist in the description of its new natural history.

Vaccination with polysaccharide-conjugate-vaccines in adult patients with specific antibody deficiency

We report on a cohort of seven adult patients with specific antibody deficiency, defined by failure to respond to 23-valent Streptococcus pneumoniae vaccine while being able to respond to tetanus toxoid. Antibodies to Hemophilus influenzae (HiB) polysaccharides either pre-existed or were readily induced by a single vaccination with the HiB–tetanus toxoid conjugate. By contrast a single vaccination with the S. pneumoniae–diphtheria conjugate failed to induce a response to any of the seven serotypes in any of the seven patients. After a second vaccination in six patients, two patients continued to show no response but four showed a 3- to 45-fold response with development of >1 μg/ml of IgG to 2–4 of the serotypes, respectively. The data show that conjugate vaccines can enforce a response in adult patients with selective antibody deficiency but, dependent on the type of polysaccharide-conjugate, repeated immunisation and monitoring of the response is required.

Earlier Administration of Rituximab Allows Higher Rate of Long-Lasting Response in Adult Patients with Autoimmune Thrombocytopenia.

BackgroundPrevious reports highlighted the potential short and mid-term therapeutic activity and safety of rituximab in adult patients with autoimmune thrombocytopenias.ObjectivesPrimary objectives of this study were to evaluate the long-term efficacy and toxicity profile. Patients and methods From October 1999 to April 2005, 37 adults patients, median age 54 years, with active and symptomatic autoimmune thrombocytopenias (30 idiopathic thrombocytopenic purpura, 1 idiopathic thrombocytopenia and neutropenia, 4 thrombocytopenia and concomitant undifferentiated connective tissue disease, 2 thrombocytopenia and concomitant B-cell lymphoprolipherative disorders) that had relapsed or were refractory to at least a full course of steroid therapy received weekly infusions of rituximab 375 mg/m2 for 4 weeks. The median interval from diagnosis to rituximab was 34 months (1–264 months) and the platelets median count was 11 x 109/L. The following parameters of efficacy and toxicity were considered: rate of complete and partial response, time to initial and maximum response, relapse rate, relapse free survival, treatment free survival, short and long-term toxicity. The possible prognostic influence of some clinical and laboratory parameters on the patients outcome were also analyzed.ResultsComplete and partial response (platelets count ≥ 100 x 109/L and ≥ 50 x 109/L) were 20/37 (54%) and 7/37 (19%), respectively. In most of the patients the time to initial and maximum response was prompt, already before the second administration of rituximab. The median period of observation from treatment was 22 months (1–48 months). Nine out 27 responding patients relapsed; 18/37 patients (49%) remained relapse free and 20/37 (54%) did not necessitated further therapy. A shorter interval period from the time of diagnosis and rituximab administration (≤ vs > 36 months) was associated with a lower relapse free survival (p= 0.03). During the period of rituximab administration, 2 patients experienced short term toxicity with one case of serum sickness syndrome; no infectious or other significant long term toxic complications were documented..ConclusionRituximab administration may allow to achieve long-lasting remission in nearly 50% of patients suffering from autoimmune thrombocytopenia with good toxic profile. The possibility to achieved long lasting response appeared related with an earlier timing of administration.

Decitabine, a Potential Targeted Therapeutic for Juvenile Myelomonocytic Leukemia.

Juvenile myelomonocytic leukemia (JMML) is a mixed myelodysplastic /myeloproliferative disorder (MDS/MPD). It occurs in infancy and young children with a progressive course leading to death within one year after diagnosis. It is characterized by monocytosis, leukocytosis, elevated fetal hemoglobin, hypersensitivity to granulocyte-macrophage colony-stimulating factor (GM-CSF), a low percentage of myeloblasts in the bone marrow, and absence of the Philadelphia chromosome or the BCR/ABL fusion gene. Mutations or other abnormalities in RAS, NF1, and PTPN11, have been linked to be responsible for the pathogenesis of JMML in up to 75% of cases. Treatment has been very difficult for JMML. Only allogeneic stem cell transplantation (SCT) can extend survival. However, the relapse rate from allogeneic SCT is inordinately high in JMML (28–55%), with 5-year disease-free survival rates of 25–40%. Decitabine, as one of the second generation of hypomethylating agents, has been demonstrated to produce encouraging responses in adult patients with chronic myelogenous leukemia or other hematopoietic disorders. Our recent studies have demonstrated that PTEN deficiency is detected in 67% of JMML patients. We hypothesize that hypermethylation of the PTEN promoter is one of the causes that lead to PTEN deficiency in JMML, and that a hypomethylating agent may improve PTEN expression in JMML cells, and thus inhibit hypersensitivity to GM-CSF. In order to test our hypothesis, we conducted an in vitro pilot study with JMML cells. Hypermethylation of the PTEN promoter was detected in 23/30 (77%) of JMML patients using Methylation-specific PCR. Sequencing confirmed that the CpG islands of the PTEN promoter were hypermethylated. A CFU-GM formation assay was used to evaluate the therapeutic sensitivity of Decitabine to JMML cells. Frozen mononuclear cells from peripheral blood samples of 5 JMML patients were plated in 0.3% agar medium with Decitabine ranging in concentration from 1nM to 1000nM. Significant inhibition of spontaneous CFU-GM growth was observed in all cultures in a dose-dependent fashion. The effective Decitabine concentrations in the cultures were lower or equivalent to the safe and tolerable plasma concentrations achievable in adult patients in clinical settings (30 mg/m2/day). Our data suggests that hypermethylation of the PTEN promoter is a common event in JMML, and Decitabine may be a potentially safe and effective reagent to treat JMML. Further pharmacokinetic studies should be conducted in the clinic to clarify the plasma concentration in pediatric patients, and the mechanism of Decitabine in inhibiting hypersensitivity of JMML cells to GM-CSF should be further explored since multiple genes are hypermethylated in cancers.

The Kinetics of Reduction of Minimal Residual Disease Impacts on Duration of Survival and Response of Adult Patients with Acute Myeloid Leukemia.

By multiprametric flow cytometry, we have previously showed that MRD negativity, as defined by a number of BM residual leukemic cells (BMRLC) <3.5x10−4 after the consolidation, was associated with a significant longer relapse free survival (RFS) and overall survival (OS), in adult AML patients. The present study was designed to confirm the prognostic role of a delayed MRD determination (at consolidation check-point) and and to verify whether the kinetics of MRD levels measured after induction and consolidation time-points is associated with outcome. One hundred and 5 patients were enrolled in the EORTC/GIMEMA protocols AML-10/AML-12 (age < 61 yrs) and AML-13 (age > 61 yrs), all consisting in intensive induction and consolidation cycles, and, for patients aged <61 years, autologous or allogeneic stem cell transplantation. Median age was 52 years (range 18–78), all FAB subtypes were represented with the exception of APL cases. The analysis of the quartile distribution of MRD levels identified a threshold of 2.0x10−4 BMRLC corresponding to the lower quartile, either after induction or consolidation; this value was selected to discriminate MRD negative (MRDneg; ≤2.0×10−4 BMRLC) from MRD positive (MRDpos; >2.0×10−4 BMRLC) patients. After induction, 30 (29%) of 105 patients were MRDneg, the remaining 75 (71%) were MRDpos. Fifthy four of 75 (72%) patients in the MRDpos group underwent relapse at a median time of 13 months (range 1–120), while in the MRDneg group 14/30 (47%) had disease relapse at a median time of 21 months (range 4–147) (P=0.014). The 5-year actuarial probability of OS and RFS was 47% and 50%, respectively, for patients in the MRDneg group, compared to 27% and 25%, respectively, for those in the MRDpos group (P=0.031 and 0.008, respectively). Seven patients had early relapse after induction therapy and 98 proceeded to receive consolidation; of these, one died of septic shock and 97 were evaluable for successive MRD assessment. At the post-consolidation time point, 26 (27%) of 97 patiens were MRDneg whereas 71 (73%) were MRDpos. Six of 26 (23%) and 55 of 71 (77%) of patients in MRDneg and in MRDpos group underwent relapse at a median time of 73 months (range 3–147) and 12 months (range 2–120), respectively, (P<0.001). The 5-year actuarial probability of OS and RFS was 67% and 74%, respectively, for patients in the MRDneg group, compared to 23% and 20%, respectively, for those in the MRDpos group (P<0.001 for both comparisons). Based on the comparative analysis of MRD levels detected at the induction and consolidation time-points, we segregated the series of 97 patients into three groups: I) 26 patients, MRDneg after consolidation; II) 12 patients, still MRDpos after consolidation but showing a reduction by at least 1-log between induction and consolidation (chemosensitive MRDpos); III) 59 patients, MRDpos after consolidation with increased levels of MRD between induction and consolidation check-points (chemoresistant MRDpos). These groups differed significantly in terms of relapse rate (23% vs 50% vs 83%, P<0.001), duration of OS and RFS (P<0.001 for both comparisons). In conclusion, 1) post-consolidation MRD determination provides the best predictive informations on patients outcome; 2) the comparative analysis of MRD levels between induction and consolidation time-points may allow the identification of MRDpos patients with different prognosis (chemosensitive vs chemoresistant).

Influence of striatal dopamine transporter availability on the response to methylphenidate in adult patients with ADHD

In this study, we investigated whether availability of striatal dopamine transporter (DAT) may have an influence on the response of adult patients with attention deficit hyperactivity disorder (ADHD) on methylphenidate (MPH). In 18 non-smoking and non-medicated adult patients with ADHD, availability of DAT was measured with [(99m)Tc] TRODAT-1 SPECT. Then, the patients received methylphenidate (MPH), individually titrated up to 60 mg per day. Ten weeks later, clinical improvement was rated by Clinical Global Impressions scale. In all, 6 patients were classified as non-responders, and 12 responded to MPH. From the non-responders, 5 presented with a DAT availability below that of normal controls of the same age, whereas in the group of responders all patients had elevated DAT availability. There was a significant negative correlation between values for global clinical improvement and striatal DAT availability. In conclusion, ADHD patients with low DAT availability seem not to respond to therapy with MPH.

Elevated plasma lactate level associated with high dose inhaled albuterol therapy in acute severe asthma

Background: Lactic acidosis is a recognised event in adult patients with status asthmaticus, particularly in the setting of intensive care. However, it has been infrequently studied in patients attending the...

Clofarabine induces a response in adult patients with acute myeloid leukaemia, and in paediatric patients with acute lymphoblastic leukaemia,

Clofarabine induces a response in adult patients with acute myeloid leukaemia, and in paediatric patients with acute lymphoblastic leukaemia,

Interferon-alpha and ribavirin therapy on chronic hepatitis C virus infection: the experience of Rio Grande do Sul State Health Department, Brazil

Chronic infection by hepatitis C virus is an important public health issue. To assess the effectiveness of a combination therapy with interferon-alpha plus ribavirin and to identify predictive factors of response in adult patients with chronic hepatitis C in a public drug supply program. A retrospective study of consecutive records of 400 patients with chronic hepatitis C treated with interferon-a plus ribavirin therapy, as part of a health program conducted by the Department of Health of the State of Rio Grande do Sul, Porto Alegre, RS, southern Brazil, between 1999 and 2000, was carried out. Sex distribution was similar, and the average age was 46.5 +/- 10.3 years. Response at the end of the treatment was observed in 49% of patients, and sustained response was observed in 32% of them. Sustained response was significantly higher in females and in patients infected by genotypes other than 1. We did not observe significant differences in terms of age or histological stage and activity score. In adult patients with chronic hepatitis C, combination therapy with interferon-alpha plus ribavirin was effective in one third of patients. Higher rates of response were observed in women and in patients infected by genotypes other than 1.