bluuebunny/crossref_metadata_2025_split huggingface dataset:
A randomized comparison of liposomal versus conventional amphotericin B for the treatment of pyrexia of unknown origin in neutropenic patients
Authors: Prentice H. G. , Hann I. M. , Herbrecht R , Aoun M , Kvaloy S. , Catovsky D. , Pinkerton C. R. , Schey S. A. , Jacobs F , Oakhill A. , Stevens R. F. , Darbyshire P. J. , Gibson B. E. S. 
Published: November 2003

One hundred and thirty‐four adults and 204 children were randomized in two prospective, parallel comparative multicentre trials to receive either conventional amphotericin B 1 mg/kg/d (c‐AMB), liposomal amphotericin B 1 mg/kg/d (L‐AMB1) or liposomal amphotericin B 3 mg/kg/d (L‐AMB3). Patients were entered if they had a pyrexia of unknown origin (PUO) defined as temperature of 38°C or more, not responding to 96 h of systemic broad‐spectrum antibiotic treatment, and neutropenia (< 0.5 × 109/l). The safety and toxicity of liposomal amphotericin B was compared with that of conventional amphotericin B. Efficacy of treatment was assessed, with success defined as resolution of fever for 3 consecutive days (< 38°C) without the development of any new fungal infection. Clinical and laboratory parameters were collected for safety analysis. In both the paediatric and adult populations, L‐AMB treated patients had a 2–6‐fold decrease in the incidence (P  0.01) of test‐drug‐related side‐effects, compared to c‐AMB. Severe trial‐drug‐related side‐effects were seen in 1% of L‐AMB treated patients, in contrast to 12% of patients on c‐AMB (P < 0.01). Nephrotoxicity, in the patient subset not receiving concomitant nephrotoxic agents, defined as a doubling from the patients baseline serum creatinine level, was not observed in the L‐AMB1 arm whereas the incidence was 3% in patients on L‐AMB3 and 23% in those on c‐AMB (P < 0.01). Moreover, time to develop nephrotoxicity was longer in both L‐AMB arms than c‐AMB (P < 0.01). Severe hypokalaemia was observed less frequently in both L‐AMB arms (P < 0.01).Analysis was by intention‐to‐treat and included all patients randomized. Success was defined by a minimum of 3 consecutive days with fever (< 38°C) continuing to study end indicated by recovery of neutrophils to 0.5 × 109/l. Addition of systemic antifungal therapy or development of systemic fungal infection were failures as was persistent fever to study end. Efficacy assessments indicated success in 49% of the total group treated with c‐AMB. 58% of patients responded to L‐AMB1 and 64% to L‐AMB3. A statistically significant difference was found between c‐AMB and L‐AMB3 (P = 0.03) but a Kaplan‐Meier analysis of time to deffervescence of fever showed there was no significant difference between the arms.It was concluded that liposomal amphotericin at either 1 or 3 mg/kg/d was significantly safer than conventional amphotericin B in children and adults. The main aim of this open‐label study was to compare safety between the three trial arms. However, we provide evidence for an equivalent or possibly superior efficacy of liposomal amphotericin with regard to resolution of fever of unknown origin. Subsequent trials should compare amphotericin preparations in defined fungal infections.
Cladribine (2‐CDA) given as subcutaneous bolus injections is active in pretreated Waldenström's macroglobulinaemia
Authors: Betticher D. C. , Hsu Schmitz S.‐F. , Ratschiller D. , Von Rohr A. , Egger T. , Pugin P. , Stalder M. , Hess U. , Fey M. F. , Cerny T. 
Published: November 2003

Clinical trials with intravenous cladribine infusions in pretreated patients with Waldenström's macroglobulinaemia have shown a response rate of 40%. Our pharmacokinetic studies revealed that the bioavailability of subcutaneous cladribine is complete but that the concentration–time profile is very different from intravenous administration. We designed this phase II multi‐institutional trial to study the activity and toxicity of cladribine given as s.c. bolus injections in patients with symptomatic Waldenström's macroglobulinaemia.Between May 1993 and October 1995, 25 patients were accrued: male/female 18/7, median age 65 years (range 44–85). All except one patient had been pretreated with more than one regimen (median 2, range 0–10). 18 patients had progressed under previous therapy and six were in relapse. All patients received cladribine for a total dose of 0.5 mg/kg per cycle as s.c. bolus injections divided over 5 d at  4 week intervals, for a maximum of six cycles.All 25 patients were evaluable for toxicity and response. A total of 67 cycles were administered (median 3 cycles, range 1–6). Overall response rate including disease stabilization which had been progressive under previous therapy was 68%. 10 patients (40%, 95% CI 21–61%) achieved a partial remission. Seven responders had been progressive under previous therapy. Maximum responses were reached no later than the third cycle. Median time to treatment failure and remission duration were 4.4 (range 0.5–33) and 8 months (5–29), respectively. Four patients (16%) suffered from infections W.H.O. grade  2 (pneumonia grade 2, Staphylococcus septicaemia grade 3, viral encephalitis and pneumonia, both grade 4 with complete resolution). No other severe adverse events were observed.Cladribine given as s.c. 5 d bolus injections was found to be active in pretreated Waldenström's macroglobulinaemia and resulted in durable remissions.
No effect of a new second‐generation B‐domain‐deleted recombinant product on lymphocyte transformation in vitro: a study of plasma‐derived and recombinant products
Authors: Astermark Jan , Ekman Maj , Berntorp Erik 
Published: November 2003

Immunomodulatory effects of various factor VIII and factor IX clotting factor concentrates (CFCs) and of albumin were evaluated by a sensitive assay measuring the incorporation of 3H‐thymidine in phytohaemagglutinin‐stimulated lymphocytes in the presence of monodansylthiacadaverine.In contrast to previous findings by others, we found lymphocyte transformation to be inhibited by all plasma‐derived factor VIII concentrates at concentrations of 0.02, 0.2 and 2.0 IU/ml, including those purified by monoclonal antibodies (P < 0.05). Kryobulin TIM3 had the most pronounced effect. In addition, three plasma‐derived human albumin preparations exerted a similar inhibitory effect as the factor VIII concentrates, whereas the corresponding plasma‐derived factor IX concentrates only manifested minor immunomodulatory effects.Of the recombinant preparations, only Recombinate exerted an inhibitory effect at 0.02 and 0.2 IU/ml, whereas both Kogenate and Recombinate decreased 3H‐thymidine incorporation at 2.0 IU/ml (P = 0.01). No immunomodulatory effect at all was observed with r‐VIII SQ, a new B‐domain‐deleted recombinant factor VIII preparation free from added albumin. The significance of this finding regarding immunological side‐effects including inhibitor development remains to be evaluated, but this second‐generation recombinant product opens up new and interesting perspectives yet to be explored.
New insights into the biology of Philadelphia‐chromosome‐positive acute lymphoblastic leukaemia using a combination of May‐Grünwald‐Giemsa staining and fluorescence in situ hybridization techniques at the single cell level
Authors: Haferlach Torsten , Winkemann Martin , Ramm‐Petersen Lotte , Meeder Marlies , Schoch Robert , Weber‐Matthiesen Klaus , Schlegelberger Brigitte , Schoch Claudia , Ludwig Wolf‐Dieter , Hiddemann Wolfgang , Löffler Helmut 
Published: November 2003

It is sometimes difficult to discriminate chronic myeloid leukaemia (CML) in lymphatic blast crisis from Ph‐chromosome positive acute lymphoblastic leukaemia (ALL). Previous studies have suggested that ALL is restricted to the lymphatic lineage only, whereas CML involves all cell lineages.In four cases of Ph‐positive ALL we combined the standard May‐Grünwald‐Giemsa staining with FISH at the single cell level and were able to demonstrate that  98% of lymphatic blasts carried the Philadelphia chromosome. Erythropoiesis was not involved when this technique was applied. Using immunological identification of single cells (FICTION), we detected the t(9;22) in 100% of CD19‐positive B lymphoblasts in all four cases, in some CD3‐positive T cells in two patients, and in  98% of CD34‐positive precursor cells. However, in two out of four patients the myeloid cell compartment was involved in the malignant transformation, unequivocally demonstrated not only by the combination of MGG and FISH but also by FICTION using the antibodies CD13 and CD33. The observation that both patients with myeloid cell lineage involvement had a myeloid co‐expression on their blasts and a better survival supports the concept of a separate, biologically determined subgroup in Ph‐positive ALL, leading to further investigations, and individually tailored treatment strategies.
Circulating plasma cells in multiple myeloma: characterization and correlation with disease stage
Authors: Rawstron Andrew C. , Owen Roger G. , Davies Faith E. , Johnson Roderick J. , Jones Richard A. , Richards Stephen J. , Evans Paul A. , Child J. Anthony , Smith Graeme M. , Jack Andrew S. , Morgan Gareth J. 
Published: November 2003

The aim of this study was to develop a flow cytometric test to quantitate low levels of circulating myeloma plasma cells, and to determine the relationship of these cells with disease stage. Cells were characterized using five‐parameter flow cytometric analysis with a panel of antibodies, and results were evaluated by comparison with fluorescent consensus‐primer IgH‐PCR.Bone marrow myeloma plasma cells, defined by high CD38 and Syndecan‐1 expression, did not express CD10, 23, 30, 34 or 45RO, and demonstrated weak expression of CD37 and CD45. 65% of patients had CD19−56+ plasma cells, 30% CD19−56low, and 5% CD19+56+, and these two antigens discriminated myeloma from normal plasma cells, which were all CD19+56low.Peripheral blood myeloma plasma cells had the same composite phenotype, but expressed significantly lower levels of CD56 and Syndecan‐1, and were detected in 75% (38/51) of patients at presentation, 92% (11/12) of patients in relapse, and 40% (4/10) of stem cell harvests. Circulating plasma cells were not detectable in patients in CR (n=9) or normals (n=10), at a sensitivity of up to 1 in 10 000 cells. There was good correlation between the flow cytometric test and IgH‐PCR results: myeloma plasma cells were detectable by flow cytometry in all PCR positive samples, and samples with no detectable myeloma plasma cells were PCR negative. Absolute numbers decreased in patients responding to treatment, remained elevated in patients with refractory disease, and increased in patients undergoing relapse. We conclude that flow cytometry can provide an effective aternative to IgH‐PCR that will allow quantitative assessment of low levels of residual disease.
Treatment with recombinant human erythropoietin (rHuEpo) in a patient with paroxysmal nocturnal haemoglobinuria: evaluation of membrane proteins CD55 and CD59 with cytofluorometric assay
Authors: Astori Cesare , Bonfichi Maurizio , Pagnucco Guido , Bernasconi Paolo , Lazzarino Mario , Orlandi Ester , Bernasconi Carlo 
Published: November 2003

We describe a 28‐year‐old man with paroxysmal nocturnal haemoglobinuria (PNH) and a high transfusion requirement. Prior to and during therapy with recombinant human erythropoietin (rHuEpo), we evaluated the levels of ‘decay‐accelerating‐factor’, CD55, and ‘membrane‐inhibitor‐of‐reactive‐lysis’, CD59, as markers of the disease, whilst CD58, a marker present on leucocytes, was utilized to monitor normal haemopoietic activity.The patient became transfusion independent 1 month after beginning rHuEpo and remains well. The analysis of CD55, CD59 and CD58 suggests that the efficacy of rHuEpo was due to a selective rHuEpo action on normal erythroid clones.
Coagulation abnormalities in type 1 Gaucher disease are due to low‐grade activation and can be partly restored by enzyme supplementation therapy
Authors: HLLAK Carla E. M. , Levi Marcel , Berends Fenny , Aerts Johannes M. F. G. , Van Oers Marinus H. J. 
Published: November 2003

In type 1 Gaucher disease a bleeding tendency occurs which is partly caused by thrombocytopenia due to massive splenomegaly. In addition, low levels of factors IX and XI have been described. The mechanism responsible for these clotting factor abnormalities is unknown.We performed a detailed study of parameters of coagulation and fibrinolysis in 30 type 1 Gaucher disease patients (14 splenectomized) before and after treatment with enzyme supplementation therapy. Pre‐treatment aPTT and PT were prolonged in 42% and 38% of patients, respectively. In 30–60% serious deficiencies (>50%) of coagulation factors XI, XII, VII, X, V and II were observed. The low levels of factor V correlated with platelet count and were inversely associated with splenic volume. Levels of inhibitors were mildly decreased. Markers for activation of coagulation (thrombin–antithrombin (TAT) complex) and fibrinolysis (PAP complex, fibrin cleavage product D‐dimer) were significantly elevated, especially in the splenectomized patients, indicating ongoing activation of these processes. After 12 months of enzyme supplementation therapy partial correction occurred.Thus, severe disorders of the coagulation system occur in Gaucher disease, contributing to the bleeding tendency. The deficiencies may be the result of consumption of coagulation factors caused by ongoing low‐level coagulation activation, possibly due to mononuclear cell activation.
G‐CSF‐mobilized CD34+ peripheral blood stem cells are significantly less apoptotic than unstimulated peripheral blood CD34+ cells: role of G‐CSF as survival factor
Authors: Philpott N. J. , Prue R. L. , Marsh J. C. W. , Gordon‐Smith E. C. , Gibson F. M. 
Published: November 2003

The mechanism of release of CD34+ cells into the peripheral blood (PB) after mobilization treatment with chemotherapy and/or growth factors is not clearly understood. Growth factors may induce increased proliferation and self renewal within the stem cell compartment. It is possible that they alter adhesion molecule profiles or other progenitor:stroma interactions, to allow release of these cells into the periphery. However, CD34+ cells are present in the PB under steady‐state conditions, albeit in low number. Growth factors such as granulocyte colony‐stimulating factor (G‐CSF) may promote the survival of CD34+ cells in the PB by suppressing apoptosis. In order to test this hypothesis, we have quantitated apoptotic cells in the CD34+ fraction of peripheral blood stem cell (PBSC) collections, using two‐colour flow cytometry, after staining with anti‐CD34 antibody and the fluorescent DNA binding agent, 7‐amino actinomycin D (7AAD). 7AAD differentially stains live, apoptotic and dead cells, due to the altered accessibility of DNA in each subpopulation.We have shown a significant reduction in the proportion of apoptotic cells in the CD34+ population mobilized by G‐CSF compared to CD34+ cells in unstimulated PB, consistent with the theory that G‐CSF is acting, at least in part, by suppressing apoptosis. In addition, we found that G‐CSF mobilized CD34+ cells are less apoptotic than CD34+ cells of unstimulated normal bone marrow, indicating that, at the doses used, G‐CSF is significantly altering the survival capacity of the mobilized cells.
THE EFFECTS OF CHRONIC SMOKING ON THE FIBRINOLYTIC POTENTIAL OF PLASMA AND PLATELETS
Authors: Simpson A. J. , Gray R. S. , Moore N. R. , Booth N. A. 
Published: November 2003

We studied tissue‐type plasminogen activator (t‐PA) and plasminogen activator inhibitor type 1 (PAI‐1) in healthy individuals divided by smoking habit into current smokers, former smokers and non‐smokers (who had never smoked). Plasma PAI‐1 antigen was significantly higher in smokers than in non‐smokers with intermediate levels in former smokers. A similar trend was observed for plasma PAI activity but this did not reach statistical significance. Platelet PAI‐1 and plasma t‐PA were not significantly different when comparing the three groups. After venous occlusion t‐PA rose significantly in all groups; no significant change in plasma PAI‐1 was observed. The ratio of t‐PA to PAI‐1 in plasma was similar in non‐smokers and former smokers but lower in smokers, suggesting that there is at least partial restoration of plasma fibrinolytic potential after smoking cessation. Plasma PAI‐1 antigen and PAI activity correlated with estimated pack‐years of cigarettes smoked among smokers and former smokers. When all subjects were studied collectively, plasma PAI‐1 correlated strongly with plasma t‐PA and triglycerides; plasma t‐PA also correlated strongly with triglycerdes.We conclude that chronic smoking is associated with impaired fibrinolysis in plasma and that this largely reflects elevated plasma PAI‐1 in smokers. Smoking does not appear to affect the response to venous occlusion. The postulated effect of chronic smoking on plasma PAI‐1 may be mediated by the influence of smoking on triglycerides and insulin resistance. Stopping smoking appears to return impaired fibrinolysis towards normal. Smoking does not quantitatively affect the platelet pool of PAI‐1. Smoking habit should be controlled for in clinical analyses of PAI‐1 and t‐PA.
Morphological and cytochemical findings in 150 cases of T‐lineage acute lymphoblastic leukaemia in adults
Authors: Gassmann Winfried , Löffler Helmut , THIEL ECKHARD , Ludwig Wolf‐Dieter , Schwartz Stefan , Haferlach Torsten , Maurer Jürgen , Rieder Harald , Fonatsch Christa , Gökbuget Nicola , Hoelzer Dieter 
Published: November 2003

We evaluated the morphological findings in 150 consecutive cases of T‐lineage acute lymphocytic leukaemia (T‐ALL). Cytochemistry including PAS staining and acid phosphatase reaction proved of limited value for the diagnosis of ALL.The diagnosis of acute leukaemia was easy to establish in most instances. However, in a few cases the leukaemic cells were difficult to recognize as blasts. The nuclei of such cells showed condensed chromatin and nucleoli were lacking, and was encountered particularly in thymic ALL.Basophilic cytoplasm combined with prominent vacuolization suggestive of mature B‐ALL (ALL‐L3 type), was observed in 16 cases. Other features, however, such as cell size, polymorphism, chromatin structure, sparse cytoplasm or focal positivity for acid phosphatase, excluded a diagnosis of ALL‐L3 in those cases.Distinction from hybrid leukaemia was difficult in 20 cases, because of a low percentage of peroxidase‐positive blasts or other features which suggested a separate myeloid leukaemia component. In nine of these the hybrid nature of the leukaemia was considered as certain on the basis of morphology. Seven cases had been diagnosed as biphenotypic with coexpression of myeloid and lymphoid markers by immunological techniques.In conclusion, our analysis showed some serious pitfalls of the morphology in T‐ALL, clearly indicating the need for immunological analysis of the leukaemic cells. However, morphology remains an essential component of the diagnostic repertoire, especially when the marrow is difficult to aspirate and in cases with equivocal immunological findings. Furthermore, recognition of a separate myeloid leukaemic component in addition to the lymphatic one requires a morphological analysis.
Needs and responses of parents following the diagnosis of childhood cancer
Authors: Sloper P 
Published: November 2003

SummaryThe diagnosis of childhood cancer can have wide‐ranging effects on the family. The study investigated parents' views of the effects on family life at 6 months post‐diagnosis, their satisfaction with services, and the support they needed and obtained. Ninety‐eight families took part in the study which involved interviews with the main carer and self‐report questionnaires completed by mothers and fathers. Levels of parental psychological distress were assessed, using the Malaise inventory: 55% of mothers and 41% of fathers scored above the cut‐off point held to indicate high levels of emotional distress. Relationships between scores on this measure and reported effects and support were investigated. Negative effects on parental employment, finance and family relationships and lack of emotional support were associated with higher levels of distress. Parental concerns regarding delay in diagnosis and unmet needs for counselling were noted.
Mutation screening of interferon‐gamma (IFNγ) as a candidate gene for asthma
Authors: HAYDEN C. , PEREIRA E. , RYE P. , PALMER L. , GIBSON N. , PALENQUE M. , HAGEL I. , LYNCH N. , GOLDBLATT J. , LESOUËF P. 
Published: November 2003

SummaryBackground
Reduced levels of interferon gamma (IFNγ) mRNA and protein have been detected in the bronchoalveolar lavage fluid of atopic asthmatics. IFNγ is secreted by TH1 cells while IL‐4 and IL‐5 are secreted by TH2 cells and an imbalance in the TH1/TH2 response may be responsible for atopic asthma. The gene for IFN4gM is located on chromosome 12; a region of the genome which has been shown in linkage studies to be associated with asthma.Objective
To determine if there are any mutations present in the coding exons and 5’flanking region of the IFNγ gene in atopic asthmatic subjects compared with controls to explain the lower levels of this cytokine as an inherited, rather than acquired, factor in the asthmatic subjects.Methods
The four exons and 5’flanking region of the IFNγ gene were amplified by polymerase chain reaction (PCR) from genomic DNA of 265 individuals from a Western Australian and a Venezuelan population. The PCR products were examined by single strand conformational polymorphism and heteroduplex analyses to see if there were any changes in the DNA migration patterns which would suggest the presence of a sequence variation.Results
The four exons and the 5’flanking region of the IFNγ gene were amplified from 265 individuals from two populations. Single strand conformational polymorphism and heteroduplex analyses did not reveal any mutations in the regions examined.Conclusions
The gene for IFNγ appears to be highly conserved as no sequence variations were detected in 265 individuals. These results suggest that mutations of the IFNγ gene are unlikely to be a significant cause of an inherited asthma diathesis.