bluuebunny/crossref_metadata_2025 huggingface dataset:
Novel Y283C mutation of the A subunit for coagulation factor XIII: molecular modelling predicts its impaired protein folding and dimer formation
Authors: Souri Masayoshi , Yee Vivien C. , Kasai Kenichiro , Kaneshiro Takashi , Narasaki Kakutaro , Castaman Giancarlo , Ichinose Akitada
Published: March 2003

In an Italian patient with severe factor XIII deficiency, a novel mutation, Y283C (TAT to TGT), was identified heterozygously by nucleotide sequencing analysis in exon VII of the gene for the A subunit. The presence of this mutation was confirmed using polymerase chain reaction‐restriction fragment length polymorphism (PCR‐RFLP) analysis in the proband and his brother. Molecular modelling predicts that the mutant molecule would be misfolded. It is probable that the impaired folding of the mutant Y283C A subunit led to its instability, which is at least in part responsible for the factor XIII deficiency of this patient.
Pretreatment characteristics and clinical outcome of acute promyelocytic leukaemia patients according to the PML‐RARα isoforms: a study of the PETHEMA group
Authors: González M. , Barragán E. , Bolufer P. , Chillón C. , Colomer D. , Borstein R. , Calasanz M. J. , Gómez‐Casares M. T. , Villegas A. , Marugán I. , Román J. , Martín G. , Rayón C. , Debén G. , Tormo M. , Díaz‐Mediavilla J. , Esteve J. , González‐San Miguel J. , Rivas C. , Pérez‐Equiza K. , García‐Sanz R. , Capote F. J. , Ribera J. M. , Arias J. , León A. , Sanz M. A. ,   for the Spanish Programme for the Study and Treatment of Haematological Malignancies (PETHEMA) Group
Published: March 2003

Of 167 newly diagnosed acute promyelocytic leukaemia patients, 83 patients were long (L)‐form (50%), eight variable (V)‐form (5%) and 76 short (S)‐form (45%). The V‐form and S‐form groups presented a significantly higher percentage of patients with white blood cell counts > 10 × 109/l (P < 0·05). The S‐form cases displayed a significantly higher number of cases with M3v microgranular features (P = 0·005) and CD34 expression (P < 0·0001). There were no differences between the three isoforms in complete remission (CR) rate (overall CR 90%), but the 3‐year disease‐free survival was lower for V‐form cases than it was for L‐ and S‐form cases (62% vs. 94% and 89%, P = 0·056). We conclude that the V‐form and S‐form types are associated with some negative prognostic features at diagnosis. However, our data were only able to demonstrate an association with adverse prognosis in the V‐form type and, moreover, as the number of cases was limited, needs to be confirmed in large, uniformly treated series.
High factor VIII antigen levels increase the risk of venous thrombosis but are not associated with polymorphisms in the von Willebrand factor and factor VIII gene
Authors: Kamphuisen Pieter W. , Eikenboom Jeroen C. J. , Rosendaal Frits R. , Koster Ted , Blann Andrew D. , Vos Hans L. , Bertina Rogier M.
Published: March 2003

High factor VIII levels increase the risk of venous thromboembolism, but the mechanisms that cause high factor VIII levels are unclear. In 301 thrombosis patients and 301 matched healthy controls, factor VIII antigen (VIII:Ag) levels ≥ 150 IU/dl increased the thrombosis risk more than fivefold. We investigated whether high factor VIII:Ag levels result from a genetic variation in the factor VIII or von Willebrand factor (VWF) genes. Six polymorphisms in the VWF gene and two CA‐repeats in the factor VIII gene were not associated with plasma VWF levels, factor VIII:Ag levels, or thrombosis risk. Our data do not support the hypothesis that a single functional sequence variation in the factor VIII or VWF gene explains the majority of high factor VIII levels and thrombotic risk.
Thrombogenic role of cells undergoing apoptosis
Authors: Wang Jun , Weiss Ivy , Svoboda Kristen , Kwaan Hau C.
Published: March 2003

Apoptosis is involved in many biological processes, especially during chemotherapy in cancer patients. Chemotherapy is also associated with an increased risk of thrombosis. The relationship between thrombogenicity and apoptosis was studied in various human tumour cell lines and non‐tumour cell lines. Apoptosis was induced by the chemotherapeutic agent camptothecin and by Fas ligand, then quantified by staining with fluorescein isothiocyanate‐conjugated annexin V and propidium iodide. A significant correlation between thrombin generation and degree of apoptosis was observed (P < 0·0005). Addition of anti‐tissue factor antibody in excess or of tissue factor pathway inhibitor partially inhibited thrombin generation, suggesting that tissue factor activation was responsible for this process. A statistical correlation between tissue factor activity and degree of apoptosis was also found (P < 0·005). Both thrombin generation and tissue factor activity were blocked by the addition of annexin V, which binds and inhibits phosphatidylserine. This indicates that the exteriorization and exposure of phosphatidylserine on the cell surface membrane during apoptosis were essential for both thrombin generation and tissue factor activation.
Hormone replacement therapy and acquired resistance to activated protein C: results of a randomized, double‐blind, placebo‐controlled trial
Authors: Høibraaten Else , Mowinckel Marie‐Christine , De Ronde Hans , Bertina Rogier M. , Sandset Per Morten
Published: March 2003

Recent studies suggest that low‐dose oral contraceptives may cause acquired resistance to activated protein C (APC). The aims of this study were to determine whether hormone replacement therapy (HRT) may also induce acquired APC resistance and to study the effects of APC resistance on the risk of recurrent thrombosis. The patients comprised 140 females with at least one previous venous thromboembolism (VTE), who were randomized to receive continuous treatment with 2 mg 17‐β‐oestradiol and 1 mg norethisterone acetate (n = 71) or placebo (n = 69). Normalized APC sensitivity ratios (nAPCsr) were calculated by measurement of the effect of APC on thrombin generation in plasma collected at baseline and after 3 months of treatment. Of the 140 women, 121 had plasma samples collected both at baseline and after 3 months. The nAPCsr increased significantly (P < 0·001) on HRT (n = 62), both in females not carrying the factor VLeiden mutation [mean change 0·57 (95% CI 0·45–0·70), n = 50] and in females heterozygous for the factor VLeiden mutation [mean change 1·10 (0·71–1·49), n = 12], but remained unchanged on placebo (n = 59). The baseline nAPCsr as well as the increase in nAPCsr associated with HRT use was not higher in the five women who subsequently developed recurrent VTE. Free protein S and free TFPI were both important parameters for the acquired APC resistant phenotype. We conclude that HRT diminishes the efficacy by which APC downregulates in‐vitro thrombin formation in a similar fashion to that observed with low‐dose oral contraceptives, but the increase in nAPCsr alone is not sufficient to explain the increased risk of VTE associated with use of HRT.
Risk of haematological malignancies in HLA‐B27 carriers
Authors: Au W. Y. , Hawkins B. R. , Cheng N. , Lie A. K. W. , Liang R. , Kwong Y. L.
Published: March 2003

Human leucocyte antigen (HLA)‐B27 carriers are predisposed to inflammatory and autoimmune diseases. Among 1137 patients with haematological diseases, 59 HLA‐B27 carriers were identified. Compared with 18 774 volunteers, the incidence of HLA‐B27 was increased in patients with acute leukaemia (relative risk RR = 1·67, P = 0·002), for both acute myeloid leukaemia (AML) (RR) = 1·67, P = 0·007) and acute lymphoblastic leukaemia (ALL) (RR = 1·68, P = 0·094). Of all the HLA‐B27 carriers, four patients had ankylosing spondylitis (AS), all with lymphoid malignancies (three ALL, one Hodgkin's disease), whereas no HLA‐B27 carriers with myeloid leukaemia had AS symptoms (P = 0·006). This suggests that HLA‐B27 carriers may have an increased risk of acute leukaemia and those with concomitant AS may be predisposed to lymphoid malignancies.
Mutation and methylation analysis of the transforming growth factor β receptor II gene in polycythaemia vera
Authors: Li Juan , Bench Anthony J. , Huntly Brian J. P. , Green Anthony R.
Published: March 2003

Polycythaemia vera (PV) is a myeloproliferative disorder (MPD) thought to result from transformation of a haemopoietic stem cell. Transforming growth factor β1 (TGF‐β1) is a negative regulator of haemopoietic stem cells, an effect mediated by direct binding to TGF‐β receptor II (TGF‐β RII). Reduced levels of TGF‐β RII mRNA or protein have been reported in several MPDs including PV, suggesting a role for TGF‐β RII in PV. No mutational analysis of the TGF‐β RII gene has yet been performed in PV. To investigate whether genetic or epigenetic alteration of the TGF‐β RII gene contributes to the pathogenesis of PV, we performed mutation and methylation analysis in 15 PV patients. The promoter, all seven exons and all intron/exon junctions were studied using single‐strand conformation polymorphism (SSCP) and heteroduplex analysis (HA). In total, three single nucleotide polymorphisms (SNPs) were identified. These were located in the promoter, intron 2 and exon 5. No acquired mutations were detected in any patient sample. We also present a novel method, termed methylation‐specific strand extension (MSSE), for the detection of methylated CpG dinucleotides. The combination of bisulphite modification and MSSE permits rapid analysis of the methylation status of CpG dinucleotides in multiple samples. We analysed the methylation status of the promoter and of a CpG island within exon 1 in 15 PV patients. No aberrant methylation was detected in either of these regions. These data demonstrate that neither mutation nor abnormal methylation of the TGF‐β RII gene is associated with the pathogenesis of PV. Furthermore, MSSE is a rapid and robust approach for assessing the methylation status of a given genomic region.
Evolution of myelodysplastic syndrome and acute  myelogenous leukaemia in children with hepatitis‐associated  aplastic anaemia
Authors: Ohara Akira , Kojima Seiji , Okamura Jun , Inada Hiroko , Kigasawa Hisato , Hibi Shigeyoshi , Tsukimoto Ichiro ,   for the Aplastic Anaemia Committee of the Japanese Society of Pediatric Haematology
Published: March 2003

Summary. In hepatitis‐associated aplastic anaemia (HAA), an immune‐mediated mechanism is solely responsible for the development of pancytopenia. We retrospectively analysed the clinical outcome of 61 children with HAA, diagnosed between 1988 and 1996. Of 61 patients, 41 did not receive bone marrow transplantation (BMT) and their survival rate at 7 years was 61·4 ± 9·3%(± SE). Five of these 41 patients developed myelodysplastic syndrome (MDS) or acute myelogenous leukaemia (AML) 7–57 months after the diagnosis of HAA. The incidence of MDS/AML in severe HAA patients who did not receive BMT (n = 30, 27·0 ± 10·8%) appeared to be similar to that of severe idiopathic AA patients (n = 155, 14·7 ± 3·7%) treated in the same period.
Efficacy of granulocyte colony‐stimulating factor in the treatment of acute myelogenous leukaemia: a multicentre randomized study
Authors: Usuki Kensuke , Urabe Akio , Masaoka Toru , Ohno Ryuzo , Mizoguchi Hideaki , Hamajima Nobuyuki , Miyazaki Tamotsu , Niitsu Yousirou , Yoshida Yutaka , Miura Akira , Shibata Akira , Abe Tsukasa , Miura Yasusada , Ikeda Yasuo , Nomura Takeo , Nagao Tadami , Saitou Hidehiko , Shirakawa Shigeru , Ohkuma Minoru , Matsuda Tamotsu , Nakamura Toru , Horiuchi Atsushi , Kuramoto Atsushi , Kimura Ikurou , Irino Syozo , Niho Yoshiyuki , Takatsuki Kiyoshi , Tomonaga Masao , Uchino Haruto , Takaku Fumimaro ,   the Gran AML Study Group
Published: March 2003

Summary. To investigate the efficacy and safety of granulocyte colony‐stimulating factor (G‐CSF) in patients with acute myelogenous leukaemia, a multicentre randomized study was performed. From October 1993 to September 1996, 270 patients with newly diagnosed acute myelogenous leukaemia were randomized to G‐CSF or control groups after remission induction therapy. The G‐CSF group received G‐CSF (Filgrastim) from 48 h after the completing chemotherapy until the absolute neutrophil count exceeded 1·5 × 109/l. The control group did not receive G‐CSF unless severe infection occurred. There were 245 evaluable patients (120 and 125 in the G‐CSF and control groups respectively). The complete remission rate was similar in the G‐CSF and control groups (80·8% versus 76·8%), as was the 5‐year probability of disease‐free survival (34·5% versus 33·6%) and overall survival (42·7% versus 35·6%). Neutrophil recovery was significantly faster in the G‐CSF group than in the control group (12 d versus 18 d, P = 0·0001). The median duration of febrile neutropenia was significantly shorter in the G‐CSF group than in the control group (3 d versus 4 d, P = 0·0001). In conclusion, prophylactic administration of G‐CSF after remission induction therapy for acute myelogenous leukaemia is safe and useful even in patients without infection on completing chemotherapy.
Serum erythropoietin values in erythrocytoses and in primary thrombocythaemia
Authors: Messinezy Maria , Westwood Nigel B. , El‐Hemaidi Ihab , Marsden Joanne T. , Sherwood Roy S. , Pearson Thomas C.
Published: March 2003

Summary.  Serum erythropoietin (Epo) values were estimated in samples from 125 patients with erythrocytosis to examine the specificity and sensitivity of reduced and raised values in the diagnosis of polycythaemia vera (PV) and secondary erythrocytosis (SE) respectively. Additionally, Epo values were estimated in samples from 49 patients with primary thrombocythaemia (PT) to determine whether Epo values were altered. We found high specificity (92%) and moderate sensitivity (64%) of low serum Epo values (below the reference range) in the diagnosis of PV, and also poor sensitivity (47%) of raised Epo values in the diagnosis of SE. Raised Epo values were not observed in PV patients with Hb > 14·0 g/dl and were only observed in one PV patient with a relatively low Hb recovering from a gastro‐intestinal haemorrhage. Raised Epo values occurred in some patients with apparent erythrocytosis (AE) and idiopathic erythrocytosis (IE), mainly at normal (rather than raised) Hb values (< 16 g/dl). Low Epo values occurred in a few AE, IE and SE patients at higher Hb values (> 16 g/dl). Low Epo values were less specific for PV when the Hb was raised, while raised Epo values were less specific for SE when the Hb was not raised. Approximately one third of patients with PT had a low (below the reference range) Epo value, this being associated with a high normal Hb (> 14 g/dl, P < 0·001) and showing a trend towards association with absence of treatment. The high normal Hb values were in turn associated with an increased incidence of thrombotic events (P < 0·05). These findings could influence the future investigation and management of PT patients.
Treatment of infants with lymphoblastic leukaemia: results of the UK Infant Protocols 1987–1999
Authors: Chessells J. M. , Harrison C. J. , Watson S. L. , Vora A. J. , Richards S. M. ,   for the Medical Research Council Working Party on Childhood Leukaemia*
Published: March 2003

Summary.  One hundred and twenty‐six infants with acute lymphoblastic leukaemia (ALL) were treated on two consecutive protocols, Infant 87 (n = 40) and Infant 92 (n = 86), in an attempt to improve the poor prognosis of this disease. Both included intensive induction and consolidation with intrathecal and high‐dose systemic therapy for central nervous system (CNS) protection. Intensification therapy was modified and high‐dose chemotherapy with bone marrow transplantation in first remission was permitted in Infant 92. Four‐year event‐free survival was superior in Infant 92 (33%; 95% CI 23–44%) compared with Infant 87 (22·5%; 95% CI 12–37%) (P = 0·04) and survival at 4 years was also superior, 46% (95% CI 35–57%) c.f. 32·5% (95% CI 20–48%) (P = 0·01), largely as a result of a significant reduction in remission deaths. Twelve patients in Infant 92 underwent bone marrow transplantation (BMT) in first remission, but their survival was no better than that of patients receiving chemotherapy. Multivariate analysis of prognostic factors showed the adverse influence of younger age, CNS involvement at diagnosis and a high initial leucocyte count, but not of CD10 expression. Cytogenetic analysis, available in 93% of patients in Infant 92, showed that 67% had chromosomal rearrangements involving 11q23 of which 39% had the translocation t(4;11) (q21;q23). There was no significant difference in event‐free survival between cytogenetic subgroups, although no children under 6 months of age with 11q23 abnormalities, other than the t(4;11), survived. In conclusion, infants with lymphoblastic leukaemia remain a high‐risk group, but it is unclear whether their adverse prognosis can be attributed to unfavourable cytogenetics alone. The role of high‐dose therapy and BMT in first remission remains uncertain.
Induction of HA‐1‐specific cytotoxic T‐cell clones parallels the therapeutic effect of donor lymphocyte infusion
Authors: Kircher Brigitte , Stevanovic Stefan , Urbanek Martina , Mitterschiffthaler Andrea , Rammensee Hans‐Georg , Grünewald Kurt , Gastl Günther , Nachbaur David
Published: March 2003

Summary.  Donor lymphocyte infusions (DLI) can induce a graft‐versus‐leukaemia (GvL) reaction in patients with relapsed disease. However, the mechanisms involved in remission induction are not completely known. A patient with chemotherapy‐refractory relapse 1 year after human leucocyte antigen (HLA)‐identical, unrelated stem cell transplantation (SCT) for bcr/abl‐positive common acute lymphoblastic leukaemia (ALL) received a DLI from the original donor, and achieved complete cytogenetic and molecular remission concomitantly with extensive graft‐versus‐host disease (GvHD). Seven CD8+, donor‐derived, alloreactive T‐cell clones were generated by stimulating post‐DLI remission cells with the patient's pretransplant mature dendritic cells. The minor histocompatibility antigen (mHag) recognized by these T‐cell clones was identified as HA‐1, a mHag associated with acute GvHD after SCT. Our finding provides evidence of HA‐1‐associated GvL effects after DLI that paralleled the eradication of full‐blown, chemotherapy‐refractory ALL relapse after allogeneic SCT.
Failure of a new protocol to improve treatment results in paediatric lymphoblastic leukaemia: lessons from the UK Medical Research Council trials UKALL X and UKALL XI
Authors: Chessells Judith M. , Harrison Georgina , Richards Susan M. , Gibson Brenda E. , Bailey Clifford C. , Hill Frank G. H. , Hann Ian M. ,   for the Medical, On Childhood Leukaemia Research Council Working Party
Published: March 2003

Summary. The impact of various types of intensification therapy was examined in a cohort of 3617 children aged 1–14 years with acute lymphoblastic leukaemia (ALL) enrolled in the Medical Research Council (MRC) UKALL X (1985–90) and UKALL XI (1990–97) trials. UKALL XI was modified in 1992 to incorporate the ‘best arm’ of UKALL X with two 5‐d intensification blocks at 5 and 20 weeks, and an additional randomization in respect of a third intensification at 35 weeks but omission of two consecutive injections of daunorubicin during induction. All children were eligible for randomization irrespective of risk group. The impact of the various types of intensification therapy was examined in a stratified analysis. At a median follow up of 102 months, both trials had an identical event‐free survival of 61% (95% CI 58–63%) at 8 years. Survival at 8 years in UKALL XI was significantly better in than in UKALL X, 81% (79–83%) compared with 74% (72–76%) (P = < 0·001), owing to improved management of relapse. There was a highly significant trend in reduction of the number of relapses and deaths with increased intensity of therapy both for children with initial leucocyte count < 50 × 109/l (P = < 0·001) and ≥ 50 × 109/l (P = 0·002). Introduction of a third late intensification block compensated for omission of anthracyclines during induction but produced little additional benefit. These results show, in a large cohort of patients, that minor modifications of therapy may influence relapse rate and obviate the benefit of previous randomized trials. The failure to adapt treatment for higher risk children contributed to these disappointing results.
Splenectomy in mantle cell lymphoma with leukaemia: a comparison with chronic lymphocytic leukaemia
Authors: Ruchlemer Rosa , Wotherspoon Andrew C. , Thompson Jeremy N. , Swansbury John G. , Matutes Estella , Catovsky Daniel
Published: March 2003

Summary. We reviewed data on 63 patients with mantle cell lymphoma (MCL) with leukaemia (n = 16) and chronic lymphocytic leukaemia (CLL, n = 47), splenectomized over a 10‐year period. Primary indications for surgery were cytopenia(s) or autoimmune phenomena and progressive or refractory disease with splenomegaly. The spleens removed were on average larger in MCL (median 2·6 kg) than in CLL (1·0 kg). Splenectomy improved the blood counts in 62% of patients with MCL and 47% with stage C CLL, both with cytopenias. The MCL patients showed a decrease in the leucocytosis (medians 60·3–29·1 × 109/l before and after splenectomy), whereas there was an increase in the leucocytosis in CLL (medians 24·2–44 × 109/l). With a median follow up post splenectomy of 10 months (range: < 1–128), 18 patients (four MCL and 14 CLL) have not required further therapy for up to 66 months. We conclude that splenectomy is a useful treatment in MCL and advanced CLL for the correction of cytopenias, reducing the leucocyte count and allowing prolonged periods of clinical remission without therapy. Differences seen between MCL and CLL in spleen size, and in response of the leucocytosis suggest a central role for the spleen in the evolution of MCL with leukaemia.
Randomized, dose‐finding study of darbepoetin alfa in anaemic patients with lymphoproliferative malignancies
Authors: Hedenus Michael , Hansen Sören , Taylor Kerry , Arthur Chris , Emmerich Bertold , Dewey Claire , Watson David , Rossi Gregory , Österborg Anders ,   the Darbepoetin alfa 990114 Study Group
Published: March 2003

Summary. Darbepoetin alfa is a novel erythropoiesis‐stimulating protein with a prolonged serum half‐life. This randomized, double‐blind, placebo‐controlled, dose‐finding study investigated the efficacy and safety of darbepoetin alfa in anaemic patients with lymphoproliferative malignancies who were receiving chemotherapy. Patients were randomized in a 1:2:2:1 ratio to receive darbepoetin alfa 1·0 μg/kg (n = 11), 2·25 μg/kg (n = 22), 4·5 μg/kg (n = 22) or placebo (n = 11), administered subcutaneously once weekly for 12 weeks. No dose increases were allowed during the study. A higher proportion of patients achieved a haemoglobin response (defined as a ≥ 2·0 g/dl increase from baseline) in the darbepoetin alfa 1·0 μg/kg (45%), 2·25 μg/kg (55%) and 4·5 μg/kg (62%) groups than in the placebo group (10%; P < 0·01). The mean change in haemoglobin from baseline to week 13 was 1·56 g/dl in the 1·0 μg/kg group, 1·64 g/dl in the 2·25 μg/kg group and 2·46 g/dl in the 4·5 μg/kg group, compared with a mean change of 1·00 g/dl in the placebo group. The overall safety profile of darbepoetin alfa in this study was similar to that of placebo. These results show that darbepoetin alfa effectively and safely increased haemoglobin concentrations in patients with lymphoproliferative malignancies. Confirmative studies at doses of 2·25 and/or 4·5 μg/kg/week in this population are warranted.
Hodgkin's disease in the elderly: a population‐based study
Authors: Stark Gail L. , Wood Katrina M. , Jack Fergus , Angus Brian , Proctor Stephen J. , Taylor Penelope R. ,   on behalf of the Northern Region Lymphoma Group
Published: March 2003

Summary. This study evaluated the incidence and outcome of Hodgkin's disease (HD) in older patients using a population‐based approach. In total, 102 patients (52 men, 50 women) aged ≥ 60 years presented in the Northern Health Region of England (population of 3·09 million) between 1 January 1991 and 31 December 1998 and were studied prospectively. The age‐specific incidence was 1·97/100 000 for those aged 60–69 years, and 2·18/100 000 for those aged 70 years or over. The median age of the cohort was 70 years (range 60–91) and the median follow up was 63 months (range 20–113). Out of 95 treated patients, 70 (74%) obtained complete or good partial (> 90% response) remissions. In the 60 to 69‐year‐old group, the disease‐specific survival at 5 years was 100% for those presenting with early stage disease and 52% for those with advanced stage disease. In patients aged >70 years the 5 year disease‐specific survival was 36% in patients with early stage and 14% for patients with advanced stage disease. The survival of patients with Epstein–Barr virus (EBV)‐positive tumours was significantly poorer than that of patients with EBV‐negative tumours (P = 0·007); median survival in the former group was 20 months versus undefined in the latter group. In total, 43 deaths were due to progressive HD and five were treatment‐related. This study defined the incidence of HD in our population and demonstrated that the prognosis of elderly patients, particularly those with advanced stage disease, has not improved concurrently with that of patients aged < 60 years old. Novel approaches to assessment and treatment are necessary.
Identification of an ETV6–ABL2 fusion transcript in combination with an ETV6 point mutation in a T‐cell acute lymphoblastic leukaemia cell line
Authors: Griesinger Frank , Janke Angela , Podleschny Martina , Bohlander Stefan K.
Published: March 2003

Summary. ETV6, a member of the Ets family of transcription factors, is frequently rearranged to various translocation partners in human leukaemias. We previously described a CD3+/TCRα/β+ mature T‐cell acute lymphoblastic leukaemia (T‐ALL) cell line, MT‐ALL, carrying a t(1;10;12)(q25; p13;p13) with cytokine‐inducible lineage switch into the myeloid lineage. Using reverse transcription polymerase chain reaction with primers complementary to ETV6 and ABL2, two ETV6–ABL2 fusion transcripts were identified in MT‐ALL which resulted from alternative splicing of an ABL2 exon. The fusion transcripts code for putative ETV6–ABL2 fusion proteins containing the pointed domain of ETV6 and almost the complete ABL2 protein, including the SH2, SH3 domains and the protein tyrosine kinase domain (PTK). Identical ETV6–ABL2 fusion transcripts have been reported in an acute myeloid leukaemia (AML) M3 cell line, carrying both a t(15;17)(q22;q21) and a t(1;12)(q25;p13) with unusual inducible differentiation to eosinophils, and in a patient with AML‐M4eo. Interestingly, the non‐rearranged allele of ETV6 in the MT‐ALL cell line carries an arginine to histidine (R399H) mutation which affects a conserved amino acid in the ets DNA binding domain.
Intra‐arterial catheter directed therapy for severe graft‐versus‐host disease
Authors: Shapira Michael Y. , Bloom Allan I. , Or Reuven , Sasson Talia , Nagler Arnon , Resnick Igor B. , Aker Memet , Zilberman Irina , Slavin Shimon , Verstanding Anthony
Published: March 2003

Summary. Graft‐versus‐host disease (GVHD) is a major complication of allogeneic bone marrow transplantation (BMT), resulting in death in the majority of steroid‐resistant patients. We assessed the efficacy of regional intra‐arterial treatment in patients with resistant hepatic and/or gastrointestinal (GI) GVHD. In total, 15 patients with steroid resistant grade 3–4 hepatic (n = 4), gastrointestinal (GI) (n = 8) GVHD or both (n = 3) were given intra‐arterial treatment. Patients with hepatic GVHD received methotrexate and methylprednisolone into the hepatic artery. Patients with GI GVHD were treated with infusions of methylprednisolone into the superior and inferior mesenteric arteries. Two patients with pronounced upper GI symptoms also received upper GI treatment. In total, 25 procedures were carried out (range 1–3 per patient). Hepatic response was observed in four out of seven (57%) patients with hepatic GVHD, three (43%) featuring good response. Complete responses were observed in nine (82%) GI GVHD patients, with median time to initial and complete response of 3 d (range 1–7) and 15·8 d (range 4–33) respectively. Regional treatment of severe GVHD with intra‐arterial treatment appears to be effective and safe. GI treatment maybe more effective than intrahepatic treatment. Early administration of isolated intra‐arterial therapy in high‐risk patients may further improve the outcome and reduce untoward effects of systemic immunosuppressive treatment.
High occurence of DRB1 11 in chronic lymphocytic leukaemia families
Authors: Theodorou Ioannis , Abel Laurent , Mauro Francesca , Duprey Brigitte , Magnac Christian , Payelle‐Brogard Béatrice , Davi Frederic , Dighiero Guillaume
Published: March 2003

Summary. Recently, linkage analysis of a series of familial chronic lymphocytic leukaemia (CLL) showed that affected sibling pairs did not share common major histocompatibilty complex haplotypes. We analysed Class I and II antigens in 11 Italian families with familial CLL. Although there was no association of disease status with any particular human leucocyte antigen, there was an overrepresentation of DRB1 11 alleles in these families (P = 0·009). A similar trend was also observed in a second series of nine French families (P = 0·002). Larger studies are needed to determine whether non‐inherited paternal or maternal DRB1 antigens play a role in familial CLL development.
Activation and inactivation of human factor X by proteases derived from Ficus carica
Authors: Richter Günter , Schwarz Hans Peter , Dorner Friedrich , Turecek Peter L.
Published: March 2003

Summary. We investigated the effect of proteases derived from Ficus carica (common fig) on human blood coagulation. The milky sap (latex) of several Ficus (F.) species contain ficin, which is a mixture of proteases. Ficin derived from Ficus carica shortened the activated partial thromboplastin time and the prothrombin time of normal plasmas and plasmas deficient in coagulation factors, except plasma deficient in factor X (FX) and generated activated FX (FXa) in defibrinated plasma. Chromatographic separation of ficin from Ficus carica yielded six proteolytic fractions with a different specificity towards FX. We isolated two factor X activators with molecular masses of 23·2 and 23·5 kDa, and studied their action on purified human FX. Factor X was converted to activated FXβ by consecutive proteolytic cleavage in the heavy chain between Leu178 and Asp179, Arg187 and Gly188, and Arg194and Ile195 (FX numbering system) with concomitant release of a carboxy‐terminal peptide. The cleavage pattern of FXa degradation products in the light chain was influenced by Ca2+ and Mn2+. These data suggest the haemostatic potency of Ficus proteases is based on activation of human coagulation factor X.
Mechanisms involved in the antiplatelet activity of magnesium in human platelets
Authors: Sheu Joen‐Rong , Hsiao George , Shen Ming‐Yi , Fong Tsorng‐Harn , Chen Yi‐Win , Lin Chien‐Huang , Chou Duen‐Suey
Published: March 2003

Summary. In this study, magnesium sulphate dose‐dependently (0·6–3·0 mmol/l) inhibited platelet aggregation in human platelets stimulated by agonists. Furthermore, magnesium sulphate (3·0 mmol/l) markedly interfered with the binding of fluorescein isothiocanate‐triflavin to the glycoprotein (GP)IIb/IIIa complex in platelets stimulated by collagen. Magnesium sulphate (1·5 and 3·0 mmol/l) also inhibited phosphoinositide breakdown and intracellular Ca+2 mobilization in human platelets stimulated by collagen. Magnesium sulphate (3·0 mmol/l) significantly inhibited thromboxane A2 formation stimulated by collagen in platelets. Moreover, magnesium sulphate (1·5 and 3·0 mmol/l) obviously increased the fluorescence of platelet membranes tagged with diphenylhexatriene. In addition, magnesium sulphate (1·5 and 3·0 mmol/l) increased the formation of cyclic adenosine monophosphate (AMP) in platelets. Phosphorylation of a protein of Mr 47 000 (P47) was markedly inhibited by magnesium sulphate (1·5 mmol/l). In conclusion, the antiplatelet activity of magnesium sulphate may involve the following two pathways. (1) Magnesium sulphate may initially induce membrane fluidity changes with resulting interference of fibrinogen binding to the GPIIb/IIIa complex, followed by inhibition of phosphoinositide breakdown and thromboxane A2 formation, thereby leading to inhibition of both intracellular Ca2+ mobilization and phosphorylation of P47. (2) Magnesium sulphate might also trigger the formation of cyclic AM, ultimately resulting in inhibition of the phosphorylation of P47 and intracellular Ca+2 mobilization.
Mobilization of CD34+ cells in elderly patients (≥ 70 years) with multiple myeloma: influence of age, prior therapy, platelet count and mobilization regimen
Authors: Morris Christopher L. , Siegel Eric , Barlogie Bart , Cottler‐Fox Michele , Lin Pei , Fassas Athanasios , Zangari Maurizio , Anaissie Elias , Tricot Guido
Published: March 2003

Summary. The mobilization of peripheral blood stem cells was studied in 984 multiple myeloma patients, including 106 patients aged ≥ 70 years. Increasing age correlated inversely with CD34+ yield (P < 0·0001), but also with ≥ 12 months of prior standard chemotherapy (P = 0·0001), < 200 × 109/l platelets (P = 0·0006) premobilization and mobilization with growth factors only (P = 0·0001). After controlling for these age covariates, multivariate analysis identified ≤ 12 months standard therapy and platelet count ≥ 200 × 109/l premobilization as favourable variables (both P < 0·0001), while increasing patient age remained an unfavourable factor (P = 0·0009). With both favourable variables, 85% of elderly patients collected ≥ 4 × 106/kg CD34+ cells in a median of one collection. The effect of age was incremental with no age threshold showing acceleration in the decline of CD34+ yield. Chemotherapy significantly increased CD34+ yield compared with growth factors only. However, the subgroup of patients with > 12 months prior therapy and premobilization platelet count < 200 × 109/l mobilized as many CD34+ cells with granulocyte colony‐stimulating factor (G‐CSF) alone as with chemotherapy and haematopoietic growth factors. Increasing patient age had no effect on post‐transplant neutrophil recovery, but significantly delayed platelet recovery (≥ 50 × 109/l) if < 2 × 106/kg CD34+ cells were infused, but this effect was eliminated completely with infusion of ≥ 4 × 106/kg CD34+ cells. Increasing age adversely affected CD34+ yield even with limited premobilization therapy, indicating that early collection is important in elderly patients.
Laparoscopic cholangiography: a prospective study
Authors: Sabharwal A J , Minford E J , Marson L P , Muir I M , Hill D , Auld C D
Published: March 2003

Background

The place of cholangiography has been controversial in the conventional and now in the laparoscopic setting. The aim of this study was to evaluate laparoscopic cholangiography and compare use of a portable C-arm image intensifier with conventional radiography.

Methods

One hundred and ninety-seven consecutive patients undergoing laparoscopic cholecystectomy were randomized before operation to cholangiography by either C-arm image intensifier or conventional radiography. Data were collected on a pro forma completed immediately after the operation.

Results

Cholangiography was successful in 93·0 per cent of patients. Cholangiography with an image intensifier was significantly faster. In 19 patients the ductal system was obscured by a cannula; in 17 of these cases a metal cannula was used. In 31·6 per cent of patients the clip on the cystic duct was within 1 cm or less of the common bile duct (CBD).

Conclusion

Laparoscopic cholangiography is a safe procedure. Use of an image intensifier should be the preferred method of obtaining images. Metal cannulas are more likely to obscure the ductal system. The proximity of the clip on the cystic duct to the CBD highlights the potential for injury caused by electrocautery or erroneous clip application.
Role of saphenous vein surgery in the treatment of venous ulceration
Authors: Scriven J M , Hartshorne T , Thrush A J , Bell P R F , Naylor A R , London N J M
Published: March 2003

Background

This paper describes local anaesthetic saphenous disconnection in elderly patients for the treatment of venous ulceration in legs with either saphenous venous reflux alone or in combination with deep venous reflux.

Methods

Ambulatory venous pressure was measured in 16 legs with saphenous vein reflux alone and in nine legs with combined deep and saphenous venous reflux before, immediately after and 3 months after saphenofemoral or popliteal disconnection. Ulcer area was measured by computerized planimetry before surgery and at 1 and 3 months after operation. No compression bandages or hose were applied after surgery unless the ulcers had not begun to heal after 1 month.

Results

In legs with saphenous reflux alone all ulcers healed without compression bandages at a median of 81 (range 14–253) days and the pressure relief index (PRI) improved significantly both after surgery and at follow-up. None of the ulcers in the nine limbs with saphenous and deep venous reflux healed without compression bandaging and the PRI was unchanged immediately following surgery and at follow-up.

Conclusion

Saphenous vein disconnection improves venous function and heals venous ulcers without compression bandaging if the deep veins are normal. This procedure under local anaesthetic may be particularly suitable for elderly patients, but long saphenous vein stripping should be added in young patients.
Raised endothelin 1 levels in patients with colorectal liver metastases
Authors: Shankar A , Loizidou M , Aliev G , Fredericks S , Holt D , Boulos P B , Burnstock G , Taylor I
Published: March 2003

Background

Endothelin 1 (ET-1), a vasoconstrictor peptide, has been implicated as a tumour growth stimulator and an angiogenesis factor.

Methods

To assess the involvement of ET-1 in colorectal cancer, immunoelectron microscopy for ET-1 was performed in colorectal liver metastases and normal liver (n = 6). ET-1 plasma levels were measured by radioimmunoassay in patients with colorectal cancer, with (n = 18) and without (n = 12) liver metastases, and in controls (n = 22).

Results

In normal liver, ET-1 was present in endothelial cells; in tumour, it was observed in endothelial cells, tumour cells and myofibroblasts. Mean(s.d.) plasma ET-1 levels were 2·75 (1·37) pg/ml in controls, 4·53(1·61) pg/ml in patients with colorectal liver metastases (P = 0·001) and 3·92(1·32) pg/ml in patients without metastases (P = 0·02).

Conclusion

ET-1 was present in various cell types within colorectal liver metastases and raised levels were found in the plasma of patients with colorectal cancer. ET-1 may not only modulate tumour vascular tone but also act on tumour growth and angiogenesis, both locally and systemically.
J ileal pouch–anal anastomosis for chronic ulcerative colitis: complications and long-term outcome in 1310 patients
Authors: Meagher A P , Farouk R , Dozois R R , Kelly K A , Pemberton J H
Published: March 2003

Aim

The purpose of the study was to determine the risk of postoperative complications and the functional outcome after a hand-sewn ileal pouch–anal anastomosis (IPAA) for ulcerative colitis using a single J-shaped pouch design.

Methods

Preoperative function, operative morbidity and long-term functional outcome were assessed prospectively in 1310 patients who underwent IPAA between 1981 and 1994 for ulcerative colitis.

Results

Three patients died after operation. Postoperative pelvic sepsis rates decreased from 7 per cent in 1981–1985 to 3 per cent in 1991–1994 (P=0·02). After mean follow-up of 6·5 (range 2–15) years, the mean number of stools was 5 per day and 1 per night. Frequent daytime and night-time incontinence occurred in 7 and 12 per cent of patients respectively, and did not change over a 10-year period. The cumulative probability of suffering at least one episode of ‘clinical’ pouchitis was 18 and 48 per cent at 1 and 10 years and the cumulative probability of pouch failure at 1 and 10 years was 2 and 9 per cent respectively.

Conclusion

These results indicate that increased experience decreases the risk of pouch-related complications and that with time the functional results remain stable, but the failure rate increases.
Oral colonization is unlikely to play an important role in Helicobacter pylori infection
Authors: Oshowo A , Tunio M , Gillam D , Botha A J , Holton J , Boulos P , Hobsley M
Published: March 2003

Background

This clinical and microbiological study investigated whether Helicobacter pylori colonizes the mouth en route to the pyloric antrum. It has been suggested that oral colonies are a source of reinfection after eradication of gastric infection.

Methods

Some 208 patients attending for routine diagnostic endoscopy for dyspepsia were recruited. Before endoscopy, samples were collected of saliva, supragingival and infragingival plaque, and swabs were taken from the tongue, mouth and pharynx. At endoscopy, gastric antral biopsies were taken for the rapid urease test, culture and histological examination. Gastric and duodenal juice samples were aspirated. Restriction nuclease digestion with HaeIII was employed on all specimens from patients in whom there was evidence of the organism in the mouth.

Results

H. pylori was observed in dental plaque in only 15 patients, all from the 116 who had evidence of the organism in the stomach. Restriction endonuclease digestion demonstrated that in 13 of the 15 patients the strains were identical in mouth and stomach.

Conclusion

Oral colonization is a rare event, but does occur. Its rarity suggests that it is not an important factor in reinfection.
Metachronous colorectal cancers
Authors: Fajobi O , Yiu C-Y , Sen-Gupta S B , Boulos P B
Published: March 2003

Background

Up to 9 per cent of patients who undergo resection for colorectal cancer develop metachronous cancers. There is no consensus on the detection and management of such cancers.

Methods

The literature was reviewed exhaustively regarding the incidence, clinical characteristics, detection, treatment and molecular genetics of metachronous colorectal cancers. This was based on a Medline search from 1966 to December 1997 for articles on metachronous colorectal cancers. A manual search was also performed on references quoted in these articles. All publications relevant to this study were included.

Results

Although the underlying causes for metachronous colorectal cancers are yet to be elucidated, risk factors for the disease have been identified. These include the presence of synchronous polyps or cancers, a history of metachronous cancers, and hereditary non-polyposis colorectal cancer (HNPCC).

Conclusion

Preoperative colonoscopy and postoperative colonoscopic surveillance are essential in identifying patients at risk of metachronous colorectal cancer. A total colectomy and ileorectal anastomosis should be considered for some patients, certainly for those with HNPCC.
Young age is not a poor prognostic marker in colorectal cancer
Authors: Chung Y F A , Eu K-W , Machin D , Ho J M S , Nyam D C N K , Leong A F P K , Ho Y H , Seow-Choen F
Published: March 2003

Background

There is still considerable controversy and debate regarding the features and prognosis of colorectal cancer in young patients.

Methods

One hundred and ten patients (5·1 per cent) under the age of 40 years with colorectal cancer (group Y; male: female ratio 48:62) were compared with 2064 patients with colorectal cancer aged 40 years or more (group O; 917 women, 1147 men). Mode of presentation, stage at diagnosis, tumour characteristics and survival were analysed.

Results

Predisposing malignant conditions and family history of colorectal cancer were present in 20·9 per cent of patients in group Y versus 2·2 per cent in group O (P < 0·001). Common chief complaints included change in bowel habits, bleeding from the rectum and a significantly higher incidence of abdominal pain in group Y. There was no difference in stage at presentation between the two groups (the proportion of Dukes stage A, B, C and ‘D’ lesions in group Y was 8·2, 24·5, 37·3 and 30·0 per cent respectively versus 10·5, 27·9, 33·4 and 28·1 per cent in group O). Tumour site and characteristics were similar in both groups. The incidence of mucinous/signet ring cell and poor grade tumours was 6·9 and 11·8 per cent respectively in group Y and 4·5 and 10·5 per cent in group O. With a mean follow-up of 31·8 months, the overall 5-year survival rate was 54·8 per cent in group Y and 54·1 per cent in group O. Comparing stage for stage, survival was not significantly different in the two groups. However, the adjusted hazard ratios of the age groups Y, M (40–59 years), S (60–79 years), and E (80 years and above) were 1·3, 1 (baseline for calculations), 1·4 and 2·4 respectively, suggesting an adverse outcome for patients in group Y compared with patients aged 40–59 years.

Conclusion

This study revealed no difference in tumour characteristics and survival in patients with colorectal cancer aged less than 40 years compared with those aged above 40 years. However, a higher hazard ratio in the youngest group may connote a worse prognosis than that for those aged 40–59 years. A significant family history of colorectal cancer and predisposing conditions in the young warrants aggressive screening, surveillance and treatment of the underlying conditions. The detection of colorectal cancer in young patients should be no different from that in the old but demands a high index of suspicion.
Output of chyle as an indicator of treatment for chylothorax complicating oesophagectomy
Authors: Dugue L , Sauvanet A , Farges O , Goharin A , Le Mee J , Belghiti J
Published: March 2003

Background

The management of chylothorax complicating oesophagectomy remains controversial. Even if medical management alone can be successful, some authors advocate early reoperation. The aim of this retrospective study was to identify the clinical variables associated with a high probability of full recovery with medical treatment.

Methods

Among 850 Lewis procedures performed for oesophageal carcinoma, 23 patients (2·7 per cent) developed postoperative chylothorax despite systematic preventive ligation of the main thoracic duct. Patients who responded to conservative management were compared with those requiring reoperation for preoperative radiotherapy, unilateral versus bilateral pleural effusion, delay of occurrence of the chylothorax, and ratio of mean chylous output to body-weight 1 and 5 days after its onset.

Results

Conservative management was successful in 14 patients with a mean(s.d.) delay of 12(5) (range 7–21) days and there were no hospital deaths. Reoperation was necessary in nine patients; there were two postoperative deaths and no recurrence of the chylothorax. The only significant difference between reoperated and medically treated patients was the mean(s.d.) chylous output at day 5: 23·5(16·6) versus 6·7(5·5) ml per kg body-weight (P<0·001). At this time, the output was less than 10 ml/kg in 12 of 14 patients in whom medical treatment was successful (sensitivity 86 per cent), and equal to or greater than this cut-off value in all the patients who underwent reoperation (specificity 100 per cent).

Conclusion

The ratio of chylous output to body-weight on the fifth day after the onset of a chylothorax complicating oesophagectomy seems to reliably predict the success of continuing medical treatment.