ABSTRACT
The aim was to assess the cognitive dysfunction and physical disability after autologous hematopoietic stem cell transplantation (AHSCT), to explore the potential factors influencing disability regression after AHSCT and to estimate the safety of low-dose immunosuppressive therapy in highly active Multiple Sclerosis (MS) patients. In single-center prospective study patients who failed to conventional therapies for highly active relapsing MS underwent the AHSCT. The disability was followed up with Expanded Disability Status Scale and cognition with Brief International Cognitive Assessment for Multiple Sclerosis. Twenty four patients [18 (72.0%) female] underwent AHSCT. Two patients of 13 had one relapse during the first year and three patients-during the second year after AHSCT. Disability regression was found in 84.6% of patients. The scores of information processing speed and verbal learning were significantly higher at month 12 after AHSCT. The clinical variable that explained the disability regression at months 6 and 12 after AHSCT was the disability progression over 6 months before AHSCT. No transplant related-deaths were observed. Selective cognitive improvement was found after AHSCT in MS patients. The disability may be temporarily reversible after AHSCT in a significant proportion of highly active RMS patients if AHSCT is well-timed performed.
Subject(s)
Cognitive Dysfunction/therapy , Hematopoietic Stem Cell Transplantation , Multiple Sclerosis, Relapsing-Remitting/therapy , Adult , Brain/diagnostic imaging , Cognitive Dysfunction/etiology , Disability Evaluation , Female , Humans , Magnetic Resonance Imaging , Male , Multiple Sclerosis, Relapsing-Remitting/complications , Multiple Sclerosis, Relapsing-Remitting/diagnostic imaging , Prospective Studies , Transplantation, AutologousABSTRACT
The NOPHO ALL2008 is a population-based study using an unmodified pediatric protocol in patients 1-45 years of age with acute lymphoblastic leukemia. Patients with T-ALL were given a traditional pediatric scheme if fast responding (minimal residual disease (MRD) < 0.1% day 29), or intensive block-based chemotherapy if slow responding (MRD > 0.1% day 29). Both treatment arms included pediatric doses of high-dose methotrexate and asparaginase. If MRD ≥ 5% on day 29 or ≥0.1% after consolidation, patients were assigned to allogeneic hematopoietic stem cell transplantation. The 5-year overall survival of the 278 T-ALL patients was 0.75 (95% CI 0.69-0.81), being 0.82 (0.74-0.88) for patients 1.0-9.9 years, 0.76 (0.66-0.86) for those 10.0-17.9 years, and 0.65 (0.55-0.75) for the older patients. The risk of death in first remission was significantly higher in adults (12%) compared with the 1-9 years group (4%). The MRD responses in the three age groups were similar, and only a nonsignificant increase in relapse risk was found in adults. In conclusion, an unmodified pediatric protocol in patients 1-45 years is effective in all age groups. The traditional pediatric treatment schedule was safe for all patients, but the intensive block therapy led to a high toxic death rate in adults.
Subject(s)
Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/therapy , Adolescent , Adult , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Child , Child, Preschool , Female , Hematopoietic Stem Cell Transplantation , Humans , Infant , Male , Middle Aged , Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/mortality , Treatment Outcome , Young AdultABSTRACT
Two new HLA class I alleles, HLA-C*02:02:34 and HLA-C*03:369, were characterized in a single Polish bone marrow donor.
Subject(s)
Alleles , HLA-C Antigens/genetics , Base Sequence , Bone Marrow Cells/metabolism , Bone Marrow Transplantation , Exons , Histocompatibility Testing , Humans , Poland , Sequence Analysis, DNA , Tissue DonorsABSTRACT
Amino acid substitution Val165Leu of the HLA-A*03:01:01 results in a novel allele, HLA-A*03:289.
Subject(s)
Alleles , HLA-A Antigens/genetics , Histocompatibility Testing/methods , Base Sequence , Exons/genetics , Humans , LithuaniaABSTRACT
Adults with acute lymphoblastic leukemia (ALL) do worse than children. From 7/2008 to 12/2014, Nordic and Baltic centers treated 1509 consecutive patients aged 1-45 years with Philadelphia chromosome-negative ALL according to the NOPHO ALL2008 without cranial irradiation. Overall, 1022 patients were of age 1-9 years (A), 266 were 10-17 years (B) and 221 were 18-45 years (C). Sixteen patients (three adults) died during induction. All others achieved remission after induction or 1-3 intensive blocks. Subsequently, 45 patients (12 adults) died, 122 patients relapsed (32 adults) with a median time to relapse of 1.6 years and 13 (no adult) developed a second malignancy. Median follow-up time was 4.6 years. Among the three age groups, older patients more often had higher risk ALL due to T-ALL (32%/25%/9%, P<0.001), KMT2A rearrangements (6%/5%/3%, P<0.001) and higher day 29 residual leukemia for B-lineage (P<0.001), but not T-ALL (P=0.53). Event-free survival rates (pEFS5y) were 89±1% (A), 80±3% (B) and 74±4% (C) with significant differences only for non-high risk groups. Except for thrombosis, pancreatitis and osteonecrosis, the risk of 19 specified toxicities was not enhanced by age above 10 years. In conclusion, a pediatric-based protocol is tolerable and effective for young adults, despite their increased frequency of higher risk features.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy , Adolescent , Adult , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Biomarkers, Tumor/genetics , Child , Child, Preschool , Combined Modality Therapy , Female , Hematopoietic Stem Cell Transplantation , Humans , Infant , Male , Middle Aged , Mutation , Precursor Cell Lymphoblastic Leukemia-Lymphoma/diagnosis , Precursor Cell Lymphoblastic Leukemia-Lymphoma/genetics , Precursor Cell Lymphoblastic Leukemia-Lymphoma/mortality , Remission Induction , Treatment Outcome , Young AdultABSTRACT
Amino acid substitution Glu277Lys of the HLA-B*13:02:09 results in a novel allele, HLA-B*13:99.
Subject(s)
Alleles , Exons , HLA-B13 Antigen/genetics , Polymorphism, Single Nucleotide , Unrelated Donors , Amino Acid Substitution , Base Sequence , Codon/chemistry , Gene Expression , Genotype , Germany , HLA-B13 Antigen/immunology , Hematopoietic Stem Cell Transplantation , Histocompatibility Testing , Humans , Lithuania , Polymerase Chain Reaction , Sequence Alignment , Sequence Analysis, DNAABSTRACT
The European Treatment and Outcome Study (EUTOS) population-based registry includes data of all adult patients newly diagnosed with Philadelphia chromosome-positive and/or BCR-ABL1+ chronic myeloid leukemia (CML) in 20 predefined countries and regions of Europe. Registration time ranged from 12 to 60 months between January 2008 and December 2013. Median age was 55 years and median observation time was 29 months. Eighty percent of patients were treated first line with imatinib, and 17% with a second-generation tyrosine kinase inhibitor, mostly according to European LeukemiaNet recommendations. After 12 months, complete cytogenetic remission (CCyR) and major molecular response (MMR) were achieved in 57% and 41% of patients, respectively. Patients with high EUTOS risk scores achieved CCyR and MMR significantly later than patients with low EUTOS risk. Probabilities of overall survival (OS) and progression-free survival for all patients at 12, 24 and 30 months was 97%, 94% and 92%, and 95%, 92% and 90%, respectively. The new EUTOS long-term survival score was validated: the OS of patients differed significantly between the three risk groups. The probability of dying in remission was 1% after 24 months. The current management of patients with tyrosine kinase inhibitors resulted in responses and outcomes in the range reported from clinical trials. These data from a large population-based, patient sample provide a solid benchmark for the evaluation of new treatment policies.
Subject(s)
Leukemia, Myelogenous, Chronic, BCR-ABL Positive/epidemiology , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/therapy , Adolescent , Adult , Aged , Aged, 80 and over , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Europe/epidemiology , Female , Follow-Up Studies , Humans , Incidence , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/diagnosis , Male , Middle Aged , Population Surveillance , Registries , Survival Analysis , Treatment Outcome , Young AdultABSTRACT
INTRODUCTION: BAX 855 is a pegylated full-length recombinant factor VIII (rFVIII) with an extended half-life, built on a licensed rFVIII (ADVATE(®) ). BAX 855 demonstrated efficacy and safety in prophylaxis and the treatment of bleeding episodes in previously treated patients (PTPs) with severe haemophilia A. AIM: This phase 3 surgery study evaluates the haemostatic efficacy and safety of BAX 855 for perioperative haemostasis in PTPs with severe haemophilia A undergoing surgery. METHODS: Elective procedures were prospectively classified as major or minor. The dose and frequency of BAX 855 administered perioperatively were to be guided by each patient's pharmacokinetic profile for major procedures or BAX 855 incremental recovery for minor procedures. Haemostatic efficacy was evaluated using a predefined scale. Blood loss was compared to the expected average and maximum blood loss predicted preoperatively. RESULTS: A total of 15 male patients (aged 19-52 years) underwent 15 procedures (11 major and four minor). The overall intra- and perioperative haemostatic efficacy of BAX 855 was 'excellent' in all 15 subjects (100%). Postoperatively, evaluated at postoperative Day 1, all treatments were 'excellent' except for one minor (dental) procedure which was rated 'good'. No related adverse events, allergic reactions, thrombotic events, nor signs of immunogenicity in terms of induction of binding antibodies to FVIII, PEG or PEG-VIII, or FVIII inhibitors were observed. CONCLUSION: These results demonstrate that BAX 855 is safe and haemostatically effective in patients with severe haemophilia A undergoing surgery.
Subject(s)
Coagulants/therapeutic use , Factor VIII/therapeutic use , Hemophilia A/drug therapy , Adult , Antibodies, Neutralizing/blood , Coagulants/chemistry , Coagulants/pharmacokinetics , Factor VIII/genetics , Factor VIII/metabolism , Half-Life , Hemophilia A/blood , Hemorrhage/prevention & control , Hemostasis , Humans , Male , Middle Aged , Perioperative Care , Polyethylene Glycols/chemistry , Recombinant Proteins/biosynthesis , Recombinant Proteins/chemistry , Recombinant Proteins/pharmacokinetics , Recombinant Proteins/therapeutic use , Surgical Procedures, Operative , Treatment Outcome , Young AdultABSTRACT
The Evaluating Nilotinib Efficacy and Safety in Clinical Trials as First-Line Treatment (ENEST1st) study included 1089 patients with newly diagnosed chronic myeloid leukemia in chronic phase. The rate of deep molecular response (MR(4) (BCR-ABL1⩽0.01% on the International Scale or undetectable BCR-ABL1 with ⩾10,000 ABL1 transcripts)) at 18 months was evaluated as the primary end point, with molecular responses monitored by the European Treatment and Outcome Study network of standardized laboratories. This analysis was conducted after all patients had completed 24 months of study treatment (80.9% of patients) or discontinued early. In patients with typical BCR-ABL1 transcripts and ⩽3 months of prior imatinib therapy, 38.4% (404/1052) achieved MR(4) at 18 months. Six patients (0.6%) developed accelerated or blastic phase, and 13 (1.2%) died. The safety profile of nilotinib was consistent with that of previous studies, although the frequencies of some nilotinib-associated adverse events were lower (for example, rash, 21.4%). Ischemic cardiovascular events occurred in 6.0% of patients. Routine monitoring of lipid and glucose levels was not mandated in the protocol. These results support the use of frontline nilotinib, particularly when achievement of a deep molecular response (a prerequisite for attempting treatment-free remission in clinical trials) is a treatment goal.
Subject(s)
Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy , Protein Kinase Inhibitors/therapeutic use , Protein-Tyrosine Kinases/antagonists & inhibitors , Pyrimidines/therapeutic use , Adolescent , Adult , Aged , Aged, 80 and over , Female , Fusion Proteins, bcr-abl/genetics , Humans , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/genetics , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/mortality , Male , Middle Aged , Pyrimidines/adverse effectsABSTRACT
This population-based registry was designed to provide robust and updated information on the characteristics and the epidemiology of chronic myeloid leukemia (CML). All cases of newly diagnosed Philadelphia positive, BCR-ABL1+ CML that occurred in a sample of 92.5 million adults living in 20 European countries, were registered over a median period of 39 months. 94.3% of the 2904 CML patients were diagnosed in chronic phase (CP). Median age was 56 years. 55.5% of patients had comorbidities, mainly cardiovascular (41.9%). High-risk patients were 24.7% by Sokal, 10.8% by EURO, and 11.8% by EUTOS risk scores. The raw incidence increased with age from 0.39/100,000/year in people 20-29 years old to 1.52 in those >70 years old, and showed a maximum of 1.39 in Italy and a minimum of 0.69 in Poland (all countries together: 0.99). The proportion of Sokal and Euro score high-risk patients seen in many countries indicates that trial patients were not a positive selection. Thus from a clinical point of view the results of most trials can be generalized to most countries. The incidences observed among European countries did not differ substantially. The estimated number of new CML cases per year in Europe is about 6370.
Subject(s)
Leukemia, Myelogenous, Chronic, BCR-ABL Positive/epidemiology , Registries/statistics & numerical data , Adult , Aged , Aged, 80 and over , Cohort Studies , Europe/epidemiology , Female , Follow-Up Studies , Humans , Incidence , Male , Middle Aged , Prognosis , Young AdultABSTRACT
A novel class I human leukocyte antigen allele HLA-B*56:43 is described.
Subject(s)
HLA-B Antigens/genetics , Histocompatibility Testing , Alleles , Base Sequence , Bone Marrow Transplantation , DNA Primers/genetics , Exons/genetics , Genotype , Humans , Lithuania , Male , Molecular Sequence Data , Polymerase Chain Reaction , Tissue DonorsABSTRACT
Two novel class II human leukocyte antigen alleles HLA-DRB1*11:131 and HLA-DQB1*05:01:05 are described.
Subject(s)
Alleles , HLA-DQ beta-Chains/genetics , HLA-DRB1 Chains/genetics , Mutation , Base Sequence , Bone Marrow Transplantation , Codon , Exons , Germany , HLA-DQ beta-Chains/immunology , HLA-DRB1 Chains/immunology , Haplotypes , Histocompatibility Testing , Humans , Molecular Sequence Data , Sequence Alignment , Sequence Analysis, DNA , Tissue DonorsSubject(s)
Apolipoproteins B/blood , Blood Component Removal , Cholesterol, LDL/blood , Cholesterol/blood , Hyperlipoproteinemia Type II , Blood Component Removal/instrumentation , Blood Component Removal/methods , Female , Humans , Hyperlipoproteinemia Type II/blood , Hyperlipoproteinemia Type II/therapy , MaleABSTRACT
A novel allele HLA-C*07:185 differs from HLA-C*07:02 by a single nucleotide substitution that results in a missense mutation Ala 140 Pro (GCT to CCT) encoded in exon 3.
Subject(s)
Alleles , HLA-C Antigens/genetics , Base Sequence , Codon , Exons , Female , Genetic Variation , Humans , Lithuania , Models, Genetic , Molecular Sequence Data , Mutation, Missense , Polymerase Chain Reaction/methods , Sequence Analysis, DNAABSTRACT
A novel allele HLA-B*56:31 differs from HLA-B*56:18 by three nucleotide substitutions resulting in a missense mutation Tyr171His (TAC to CAC) encoded in exon 3 and two silent substitutions at codon 188His (CAC to CAT) and codon 228Thr (ACT to ACC) encoded in exon 4.
Subject(s)
HLA-B Antigens/genetics , Histocompatibility Testing/methods , Sequence Analysis, DNA/methods , Alleles , Base Sequence , Humans , Lithuania , Male , Molecular Sequence Data , Polymorphism, Genetic , Sequence HomologyABSTRACT
The novel allele HLA-DQB1*05:01:03 differs from HLA-DQB1*05:01:01 by a silent nucleotide substitution at codon 77R (AGG to AGA).
Subject(s)
Genetic Variation/genetics , HLA-DQ Antigens/genetics , Base Sequence , HLA-DQ beta-Chains , Humans , Molecular Sequence Data , Polymerase Chain Reaction , Sequence Homology, Nucleic AcidABSTRACT
The novel allele HLA-A*030114 differs from HLA-A*03010101 by a silent nucleotide substitution at codon 153A (GCG to GCA).
Subject(s)
Alleles , HLA-A Antigens/genetics , Haplotypes , Base Sequence , Humans , Molecular Sequence Data , Sequence AlignmentABSTRACT
Recombinant granulocyte colony-stimulating factors (G-CSFs) such as filgrastim or lenograstim are being used to treat chemotherapy-induced neutropenia. The aim of the present study was to investigate a new G-CSF, XM02, in comparison to filgrastim in terms of safety and efficacy in the prevention of chemotherapy-induced neutropenia in non-Hodgkin-lymphoma (NHL). A total of 92 patients receiving chemotherapy were randomised in cycle 1 to treatment with daily injections (subcutaneous 5 microg/kg/day) of XM02 (n = 63) or filgrastim (n = 29) for at least 5 days and a maximum of 14 days. In subsequent cycles, all patients received XM02. The mean duration of severe neutropenia (DSN) was 0.5 and 0.9 days in cycle 1 for XM02 and filgrastim, respectively (p = 0.1055). In cycle 1, the incidence of febrile neutropenia (FN) was 11.1% for XM02 and 20.7% for filgrastim (p = 0.1232). The adverse event profile was similar between XM02 and filgrastim. XM02 demonstrated equivalent efficacy and similar safety profile as the reference medication filgrastim. Treatment with XM02 is as beneficial as filgrastim in ameliorating severe neutropenia and FN in patients with NHL receiving chemotherapy. XM02 is safe and well tolerated in the doses applied in this study.
Subject(s)
Granulocyte Colony-Stimulating Factor/administration & dosage , Lymphoma, Non-Hodgkin/drug therapy , Neutropenia/prevention & control , Adolescent , Adult , Aged , Aged, 80 and over , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Drug-Related Side Effects and Adverse Reactions , Female , Fever/drug therapy , Fever/prevention & control , Filgrastim , Granulocyte Colony-Stimulating Factor/adverse effects , Granulocyte Colony-Stimulating Factor/therapeutic use , Humans , Lymphoma, Non-Hodgkin/complications , Male , Middle Aged , Neutropenia/drug therapy , Recombinant Proteins , Treatment Outcome , Young AdultABSTRACT
OBJECTIVE: To identify inexpensive and simple quality parameters for the surveillance of antibiotic use in hospital settings. METHODS: A modified point-prevalence study was conducted in three university hospitals in Huddinge, Sweden, Riga, Latvia, and Vilnius, Lithuania. Each ward was visited once during May in the year 2002. All patients receiving antibiotics were identified and their medical records were reviewed by the authors according to the same protocol. Only data from corresponding departments were evaluated and compared. RESULTS: The prevalence of antibiotic use was 35%, 25% and 24% in Huddinge, Riga and Vilnius, respectively. Almost 2/3 of antibiotics were prescribed for treatment and 1/3 for either surgical or medical prophylaxis. Parenteral administration was significantly more common in Riga and Vilnius than in Huddinge. The most commonly prescribed antibiotics were cephalosporins and fluoroquinolones. Prescription of antibiotics for different diagnoses showed large variation between and within hospitals. The first or second generation cephalosporins were prescribed in most cases of surgical prophylaxis. The duration of surgical prophylaxis exceeded one day in 57%, 63% and 87% of cases in Huddinge, Riga and Vilnius, respectively. All antibiotics in Huddinge, and all except five in Riga were supplied by the hospital pharmacy. Antibiotics bought by patients and donated made up 41% of prescribed antibiotics in Vilnius. CONCLUSION: This point-prevalence survey using a simple and inexpensive method for benchmarking demonstrated quantitative and qualitative differences in the use of antibiotics between three university hospitals in the Baltic region, differences that now calls for explanations to their rationality. We suggest that the choice of an antibiotic, rates of intravenously administered treatment and duration of surgical prophylaxis are examples of suitable indicators of rational antibiotic use within a hospital but that comparison of such rates between hospitals is less meaningful.
Subject(s)
Anti-Bacterial Agents/therapeutic use , Bacterial Infections/drug therapy , Practice Patterns, Physicians'/statistics & numerical data , Quality Indicators, Health Care , Adolescent , Adult , Aged , Aged, 80 and over , Bacterial Infections/prevention & control , Benchmarking , Cephalosporins/therapeutic use , Child , Child, Preschool , Drug Administration Routes , Drug Resistance, Bacterial , Female , Fluoroquinolones/therapeutic use , Hospitals, University/statistics & numerical data , Humans , Infant , Infant, Newborn , Latvia , Lithuania , Male , Middle Aged , Quality Assurance, Health Care , SwedenABSTRACT
Recently, it has been reported that prophylactic administration of ciprofloxacin during cyclophosphamide (CY) conditioning was a high-risk factor for relapse in patients undergoing allogeneic BMT. In the present study, we investigated the possible mechanisms of this interaction in male Sprague-Dawley rats. The kinetics of CY and its active 4-OH-CY metabolite were determined, after 3 days pretreatment with ciprofloxacin (200 mg/kg) and compared to control rats without treatment. CY was administered as a high or low single intravenous dose (150 and 90 mg/kg, respectively). The expression of the CYP2B1, CYP2B2, CYP2C11, CYP3A1 and CYP3A2 genes was evaluated by SYBR Green I Dye real-time PCR for quantification of mRNA. The administration of ciprofloxacin resulted in a significant increase in the AUC (P=0.007) and a significant decrease in clearance (P=0.007) when CY was given as a high dose. In accordance, the metabolic ratio (AUC4-OH-CY/AUCCY) was significantly lower (P=0.007) compared to that found in the control group. Ciprofloxacin significantly suppressed gene expression of CYP2C11 (P=0.01) and CYP3A1 (P=0.04); however, no effect was observed on the gene expression of CYP3A2, CYP2B1 and CYP2B2. Our study revealed that ciprofloxacin interacts with CY and suppressed relevant cytochromes p450 at the transcriptional level. This study may have a great clinical impact when ciprofloxacin is used in therapy.