bluuebunny/crossref_metadata_2025 huggingface dataset:
Successful treatment of congenital thrombotic thrombocytopenic purpura using the intermediate purity factor VIII concentrate BPL 8Y
Authors: Lester Will A. , Williams Michael D. , Allford Sarah L. , Enayat M. Said , Machin Samuel J.
Published: March 2003

Summary. There is increasing evidence that congenital thrombotic thrombocytopenic purpura (TTP) is caused by an absolute deficiency of von Willebrand factor‐cleaving protease. The recent identification of this protease and the development of assays for its detection have enabled its quantification in a number of plasma products, including some commercial intermediate‐purity plasma‐derived factor VIII preparations. We report the successful, weekly prophylactic use of a commercial intermediate‐purity plasma‐derived factor VIII concentrate in the treatment of a 14‐year‐old girl with severe congenital TTP who had previously required transfusions of fresh‐frozen plasma every 2 weeks from the age of 4 months.
Prospective molecular monitoring of BCR/ABL transcript in children with Ph+ acute lymphoblastic leukaemia unravels differences in treatment response
Authors: Cazzaniga Giovanni , Lanciotti Marina , Rossi Vincenzo , Di Martino Daniela , Aricò Maurizio , Valsecchi Maria Grazia , Basso Giuseppe , Masera Giuseppe , Micalizzi Concetta , Biondi Andrea
Published: March 2003

Summary. Children with Philadelphia‐chromosome‐positive (Ph+) acute lymphoblastic leukaemia (ALL) represent a subgroup at very high risk for treatment failure, despite intensive chemotherapy. However, recent retrospective studies showed that Ph+ childhood ALL is a heterogeneous disease with regard to treatment response. We have prospectively monitored, by reverse transcription polymerase chain reaction (RT‐PCR) during follow‐up, the presence of the BCR/ABL fusion transcript in Ph+ ALL children diagnosed in the Italian multicentre Associazione Italiana Ematologia Oncologia Pediatrica ALL‐AIEOP‐95 therapy protocol. To our knowledge, this is the first report on the evaluation of minimal residual disease (MRD) in childhood Ph+ ALL prospectively enrolled in an intensive, Berlin–Frankfurt–Munster (BFM)‐type treatment protocol. Twenty‐seven of 36 (75·0%) Ph+ patients consecutively enrolled into the high‐risk group of the AIEOP‐ALL protocol between May 1995 and October 1999 were successfully analysed. Twenty were good responders to the pre‐phase of prednisone/intrathecal methotrexate treatment (PGR) and seven were poor responders (PPR). Within the PPR group, the RT‐PCR monitoring constantly showed positivity for the BCR/ABL fusion transcript and all the patients died of disease progression. In contrast, highly sensitive qualitative RT‐PCR monitoring revealed heterogeneity within the PGR group of Ph+ childhood ALL patients. Three different subgroups could be defined, according to the clearance of Ph+ cells within the first 5 months of treatment. This provides useful information on the capability of chemotherapy to reduce the leukaemic clone, with prognostic implications.
The value of bone marrow examination in the staging of Hodgkin's lymphoma: a review of 955 cases seen in a regional cancer centre
Authors: Howell Sacha J. , Grey Mark , Chang James , Morgenstern Godfrey R. , Cowan Richard A. , Deakin David P. , Radford John A.
Published: March 2003

Summary. Bone marrow aspirates (BMA) and trephine biopsies (BMT) are commonly performed in the staging of patients with newly diagnosed Hodgkin's lymphoma (HL) but the value of these procedures is controversial. The purpose of this study was to evaluate the predictive value of the blood count and erythrocyte sedimentation rate (ESR) for bone marrow involvement (BMI) and the influence of BMI on stage and prognostic score. A retrospective analysis of 955 patients with newly diagnosed HL entered into clinical trials in a regional cancer centre between 1975 and 1999 was performed. BMI was identified by BMT in 50 patients (5·2%) but in only five of these by BMA. The negative predictive values of a normal full blood count (FBC) and ESR for absence of BMI were 98·8% and 97·3%, respectively, and the positive predictive value of an abnormal FBC and ESR for presence of BMI were both 6·7%. BMT did not alter initial patient management in a single case but provided valuable prognostic information in certain subgroups of patients. BMA gave no additional staging information over BMT and abnormalities of blood count and ESR were poor predictors of infiltration. We conclude that BMA should be abandoned for staging purposes in HL and BMT restricted to patients with stage IIB or III disease, for whom valuable prognostic information may be obtained.
Dominant expression of interleukin 10 but not interferon γ in CD4–CD8–αβT cells of autoimmune lymphoproliferative syndrome
Authors: Ohga Shouichi , Nomura Akihiko , Takahata Yasushi , Ihara Kenji , Takada Hidetoshi , Wakiguchi Hiroshi , Kudo Yuji , Hara Toshiro
Published: March 2003

Summary. Cytokine expression in CD4–CD8– double‐negative (DN) T cells of autoimmune lymphoproliferative syndrome (ALPS) was analysed. Two patients with DN αβT‐cell expansion showed higher serum interleukin 10 (IL‐10) levels than one patient without it. Intracellular flow‐cytometric analysis indicated the IL‐10‐expressing CD3+CD4–CD8– cells in patients with lymphoproliferation. Quantitative real‐time polymerase chain reaction revealed ∼100 times higher IL‐10, but not interferon‐γ or transforming growth factor‐β in DN than in single‐positive T cells. IL‐10 was exclusively expressed in DN αβ but not γδΤ cells. Circulating DN αβT cells may constitutively express IL‐10 and contribute to the ALPS phenotype.
rHuEpo administration in patients with low‐risk myelodysplastic syndromes: evaluation of erythroid precursors' response by fluorescence in situ hybridization on May–Grunwald–Giemsa‐stained bone marrow samples
Authors: Rigolin Gian Matteo , Porta Matteo Della , Bigoni Renato , Cavazzini Francesco , Ciccone Maria , Bardi Antonella , Cuneo Antonio , Castoldi Gianluigi
Published: March 2003

Summary. The issue of whether, in patients affected by myelodysplastic syndromes (MDS), haematological response to cytokines, particularly to recombinant human erythropoietin (rHuEpo), is a phenomenon related to the stimulation of normal haemopoietic cells or to the differentiation of cells belonging to the abnormal clone remains an open question. To assess the pattern of response to rHuEpo treatment of bone marrow (BM) cells, we evaluated in 13 low‐risk MDS patients with known cytogenetic abnormalities the number of cytogenetically normal and abnormal cells by conventional cytogenetic analysis (CCA) and by a fluorescence in situ hybridization (FISH) technique, enabling the simultaneous visualization of FISH chromosomal abnormalities in morphologically and immunophenotypically identifiable BM elements. Patients responding to rHuEpo presented a lower number of abnormal metaphases at diagnosis in comparison with patients who did not respond (22·74%vs 76·23%, P = < 0·001). This was confirmed by the combined morphological FISH analysis, showing that, before treatment, BM samples from patients responding to rHuEpo had a lower proportion of both FISH abnormal erythroid (36·48%vs 66·93%, P = 0·002) and myeloid (40·76%vs 67·70%, P = 0·014) elements than unresponsive patients. After rHuEpo treatment, responding patients presented a significantly lower proportion of FISH abnormal erythroid precursors than observed before treatment (16·93%vs 36·48%, P = 0·017). Likewise, in responding patients, a significantly lower proportion of FISH abnormal erythroid elements (16·93%vs 66·30%, P < 0·001) was detected in comparison with unresponsive patients. These findings provide evidence that, in low‐risk MDS patients with known cytogenetic abnormalities, response to rHuEpo may be due to the proliferation of karyotypically normal erythroid precursors, possibly representing residual normal erythroid elements.
An unbalanced translocation involving chromosome 14 is the probable cause for loss of potentially functional rearranged immunoglobulin heavy chain genes in the Epstein–Barr virus‐positive Hodgkin's lymphoma‐derived cell line L591
Authors: Vockerodt Martina , Belge Gazanfer , Kube Dieter , Irsch Johannes , Siebert Reiner , Tesch Hans , Diehl Volker , Wolf Jürgen , Bullerdiek Jörn , Staratschek‐Jox Andrea
Published: March 2003

Summary. In the vast majority of cases, Hodgkin–Reed Sternberg (H‐RS) cells, the malignant cells in Hodgkin's lymphoma (HL), are derived from germinal centre B cells. In some cases, somatic mutations within the rearranged immunoglobulin heavy (IgH) chain genes were detected, rendering potentially functional gene rearrangements non‐functional. In these H‐RS cells the expression of high‐affinity B‐cell receptors (BCR) was prevented. As in other cases only one non‐productive IgH chain gene rearrangement was amplified from H‐RS cells, it was speculated whether, in these cases, the functionally rearranged IgH chain genes were lost. An alternative explanation might be that the rearranged genes could not be amplified owing to a high load of somatic mutations within the primer binding sites. Here, we showed that, in the HL‐derived Epstein–Barr virus (EBV)‐positive cell line L591, only one non‐functional somatically mutated IgH gene rearrangement could be detected. The other potentially functional IgH gene rearrangement was lost as a result of an unbalanced translocation affecting the long arm of chromosome 14. Moreover, L591 cells express the EBV latent membrane proteins LMP1 and LMP2A, which might have contributed to the ‘escape’ of these cells from apoptosis within the germinal centre. We conclude that, apart from the introduction of ‘crippling mutations’ into the rearranged VDJ genes rearrangement, deletions of the IGH locus may be regarded as another mechanism to prevent the expression of a BCR in H‐RS cells.
Soluble l‐selectin (sCD62L) in relapsed childhood acute lymphoblastic leukaemia
Authors: Herold Ralf , Stibenz Dietger , Hartmann Reinhard , Henze Günter , Bührer Christoph
Published: March 2003

Summary. Soluble l‐selectin (sCD62L) plasma concentrations at diagnosis and outcome were investigated in 193 children at first relapse of acute lymphoblastic leukaemia (ALL) after treatment according to the Berlin–Frankfurt–Münster relapsed ALL multicentre trials, ALL‐REZ BFM 95 and 96. sCD62L was low (< fifth paediatric reference percentile) in 63 (33%) and high (> 95th percentile) in 36 (19%) children, and was independent of remission duration, sex, BCR–ABL fusion or extramedullary disease. High sCD62L was associated with circulating blasts and T‐cell phenotype. More initial adverse events occurred in children with high and low levels of sCD62L (23 out of 99) than in those with normal levels (9 out of 94, P = 0·018). Among 75 worst‐prognosis patients (risk groups S3/S4, isolated bone marrow relapse occurring less than 6 months after elective cessation of front‐line therapy, or T‐cell phenotype with bone marrow involvement), 27 had low sCD62L and decreased event‐free survival (EFS) probability (PEFS5 = 0·09 at 5 years) and duration (219 d) compared with normal sCD62L (29 out of 75, PEFS5 = 0·24, 640 d, P = 0·01). Low (44 out of 118), normal (72 out of 118), and high (19 out of 118) sCD62L non‐S3/S4 patients fared similarly (average PEFS5 = 0·45, 1369 d; P = 0·5). Low sCD62L may be a marker of malignant blasts replacing normal sCD62L‐producing haematopoietic cells. In children with first relapse of ALL and worst prognosis, plasma sCD62L may be useful for risk‐adapted stratification.
Polymerase chain reaction (PCR)‐ and reverse transcription PCR‐based minimal residual disease detection in long‐term follow‐up of childhood acute lymphoblastic leukaemia
Authors: Gameiro Paula , Moreira Ilídia , Yetgin Sevgi , Papaioannou Mary , Potter Michael N. , Prentice H. Grant , Hoffbrand A. Victor , Foroni Letizia
Published: March 2003

Summary. Minimal residual disease (MRD) was investigated in 52 children with acute lymphoblastic leukaemia (ALL), using antigen receptor gene rearrangements and reverse transcription polymerase chain reaction for fusion transcripts as molecular targets. Patients [treated according to the Medical Research Council United Kingdom ALL (MRC UKALL) XI protocol or Total XI and XIII protocols] were monitored for a median period of 45 months (range, 9–110 months). Among 17 patients who relapsed, MRD persisted for longer (66·7%, 47·1%, 53·8% and 41·7% at 0–2, 3–5, 6–9, 10–24 months respectively) than patients who remained in continuous clinical and immunological remission (n = 35) (27·3%, 11·1%, 4·3%, 8·0%). Association between MRD tests and outcome was assessed and found to be significant at all time‐points. The difference in survival for MRD‐positive and MRD‐negative patients (using the log‐rank test) was statistically significant at all time intervals, as was risk of relapse for MRD‐positive patients (1·89, 2·20, 2·65 and 2·16) and MRD‐negative patients (0·72, 0·82, 0·65 and 0·70). Sixteen of the 52 patients had an oligoclonal pattern at presentation but oligoclonality did not have an impact on outcome. Cox regression analysis revealed that MRD assessment is an independent and prognostically significant factor during treatment and should be used for patients' stratification in future studies.
Infrequent hypermethylation of CEBPA promotor in acute myeloid leukaemia
Authors: Chim C. S. , Wong A. S. Y. , Kwong Y. L.
Published: March 2003

Summary. The gene CEBPA, encoding the transcription factor C/EBPα, is crucial for granulocyte differentiation. We investigated the frequency of aberrant CEBPA promotor methylation with the methylation‐specific polymerase chain reaction in 70 patients with acute myeloid leukaemia (AML). Two patients, both with M2 morphology, were found to have methylated CEBPA. In one of them, the fusion gene AML1/ETO, reported to cause transcription repression of CEBPA, was also present, suggesting that more than one mechanism might collaborate to suppress CEBPA gene expression. Aberrant CEBPA methylation is infrequent in AML, but may occur preferentially in the M2 phenotype.
Genetic polymorphisms in the tumour necrosis factor locus in childhood acute lymphoblastic leukaemia
Authors: Takeuchi Seisho , Takeuchi Naoko , Tsukasaki Kunihiro , Bartram Claus R. , Zimmermann Martin , Schrappe Martin , Taguchi Hirokuni , Koeffler H. Phillip
Published: March 2003

Summary. Genetic polymorphisms in the tumour necrosis factor (TNF) locus influence the outcome of non‐Hodgkin's lymphoma (NHL). We investigated whether these polymorphisms might contribute to the clinical course of childhood acute lymphoblastic leukaemia (ALL). Genomic DNA from 214 childhood ALL patients was analysed. Patients with a high‐risk haplotype were older than patients with low‐risk haplotype (P = 0·024). No statistically significant associations were found between TNF haplotype and sex, WBC counts, central nervous system involvement, immunophenotype, response to chemotherapy, and event‐free survival. These data suggest that genetic polymorphisms in the TNF locus have a limited effect on the outcome of childhood ALL.
Altered expression of retinoblastoma protein‐interacting zinc finger gene, RIZ, in human leukaemia
Authors: Sasaki Osamu , Meguro Kuniaki , Tohmiya Yasuo , Funato Tadao , Shibahara Shigeki , Sasaki Takeshi
Published: March 2003

Summary. The retinoblastoma protein‐interacting zinc finger gene (RIZ), a member of the nuclear protein methyltransferase superfamily, is characterized by the presence of the N‐terminal PR domain. The RIZ gene encodes for two proteins, RIZ1 and RIZ2. While RIZ1 contains the PR (PRDI‐BF1 and RIZ homologous) domain, RIZ2 lacks it. RIZ gene expression is altered in a variety of human cancers and RIZ1 is now considered to be a candidate tumour suppressor. To investigate the role of RIZ in leukaemogenesis, we analysed the differential expression of RIZ1 and RIZ2 by quantitative real‐time reverse‐transcription polymerase chain reaction assay. Our results showed that the expression of RIZ1 was significantly decreased in leukaemia cell lines (14 out of 17, 82%) and in patients with acute myeloblastic leukaemia (eight out of 14, 57%). In contrast, RIZ2 expression was increased in patients with acute lymphoblastic leukaemia (eight out of 11, 73%), compared with normal bone marrow cells. These findings indicate that suppression of RIZ1 expression or enhancement of RIZ2 expression may have an important role in leukaemogenesis.
Comparison of outcome following allogeneic bone marrow transplantation with cyclophosphamide–total body irradiation versus busulphan–cyclophosphamide conditioning regimens for acute myelogenous leukaemia in first remission
Authors: Litzow Mark R. , Pérez Waleska S. , Klein John P. , Bolwell Brian J. , Camitta Bruce , Copelan Edward A. , Gale Robert Peter , Giralt Sergio A. , Keating Armand , Lazarus Hillard M. , Marks David I. , McCarthy Philip L. , Miller Carole B. , Milone Gustavo , Prentice H. Grant , Russell James A. , Schultz Kirk R. , Trigg Michael E. , Weisdorf Daniel J. , Horowitz Mary M.
Published: March 2003

Summary. We evaluated transplant‐related mortality (TRM), leukaemia relapse, leukaemia‐free survival (LFS) and overall survival (OS) in patients receiving busulphan and cyclophosphamide (BuCy) or cyclophosphamide and total body irradiation (CyTBI) prior to allogeneic bone marrow transplantation (BMT) for acute myelogenous leukaemia (AML) in first remission. Outcomes of 381 human leucocyte antigen (HLA)‐matched sibling transplants using BuCy were compared with 200 transplants using CyTBI performed between 1988 and 1996. The incidence of hepatic veno‐occlusive disease was higher with BuCy (13%) than with CyTBI (6%) (P = 0·009). Risks of acute and chronic GVHD were similar. In multivariate analysis, relapse risk was higher in the BuCy group [relative risk (RR) = 1·72; 95% confidence interval (CI), 1·05–2·81; P = 0·031]. Eleven of 373 evaluable patients in the BuCy group had a central nervous system relapse in contrast to none of 194 evaluable patients in the CyTBI group (P = 0·016). There were no differences in TRM, LFS and OS. CyTBI conditioning may lower relapse risk but produces comparable TRM, LFS and OS to BuCy for HLA‐matched sibling transplantation in first remission AML.
Outcome prediction by immunophenotypic minimal residual disease detection in adult T‐cell acute lymphoblastic leukaemia
Authors: Krampera Mauro , Vitale Antonella , Vincenzi Carlo , Perbellini Omar , Guarini Anna , Annino Luciana , Todeschini Giuseppe , Camera Andrea , Fabbiano Francesco , Fioritoni Giuseppe , Nobile Francesco , Szydlo Richard , Mandelli Franco , Foà Robin , Pizzolo Giovanni
Published: March 2003

Summary.Flow‐cytometric detection of minimal residual disease (MRD) identifies patients with high relapse risk in childhood acute lymphoblastic leukaemia (ALL). We studied the efficacy of this method in adult T‐ALL treated with the Italian co‐operative GIMEMA (Gruppo Italiano Malattie Ematologiche dell'Adulto) LAL0496 protocol. Bone marrow samples from 53 patients were taken at fixed treatment time points and MRD was analysed using a leukaemia‐specific immunophenotype (cytoplasmic‐CD3/nuclear‐terminal desoxynucleotidyl transferase). The median follow‐up was 17 months (range 3–61) and a median of 4·5 analyses/patient was performed (range 3–12). Six out of 53 (11·3%) patients were refractory to treatment, 30/53 (56·6%) relapsed and 17/53 (32·1%) remain in continuous complete remission. The probability of relapse at 2 years for MRD‐positive patients at preconsolidation was 81·5%vs38·9% for MRD‐negative patients (P = 0·00078). This risk was still 54·5% for MRD‐positivevs15·8% for MRD‐negative patients pre‐third reinduction (P = 0·0098) and 50·0% for MRD‐positivevs16·4% for MRD‐negative patients pre‐sixth reinduction (P = 0·032). The relapse‐predicting value of MRD did not depend on features at diagnosis such as age, sex and leucocyte count. Our data suggest that immunophenotypic MRD monitoring in the first year of treatment is a useful outcome predictor for adult T‐ALL patients.
Identification of simultaneous mutation of fibrinogen α chain and protein C genes in a Japanese kindred
Authors: Watanabe Kumiko , Shibuya Atsushi , Ishii Eiichi , Kurihara Masako , Inoue Sumiko , Ono Miyuki , Wada Yui , Wakiyama Machiko , Zaitsu Masafumi , Iida Hiroko , Muraoka Kenji , Kinoshita Sachiko , Hamasaki Naotaka
Published: March 2003

Summary. Afibrinogenaemia usually induces a bleeding tendency during infancy, whereas protein C deficiency increases susceptibility to thrombosis in children or adolescence. Mutations of these genes have been, therefore, established as independent risk factors for coagulation disorders. We describe the homozygous mutation of the fibrinogen α chain gene and additional heterozygous mutation of the protein C gene in a male infant who showed prolonged umbilical bleeding after birth. On examination, the plasma fibrinogen was undetectable, and the activity and antigen level of protein C were reduced. The patient showed no fibrinogen Aα chain as well as Bβ and γ chains by Western blotting. The sequencing analysis showed the homozygous deletion of 1238 bases from intron 3 at position 2008 to intron 4 at position 3245 in the fibrinogen α chain gene. Both parents were heterozygous carriers of this mutation. In this patient, an additional mutation was also detected in the protein C gene: the heterozygous deletion of exon 7 at position 6161–6163 or 6164–6166, resulting the deletion of one amino acid (Lys150 or 151). His mother was also a carrier of this mutation. As the simultaneous mutation of the fibrinogen α chain and protein C genes has not been previously reported, the influence of the interaction between these two mutations on the clinical manifestations of this patient should be carefully monitored for a long period.
High frequency of t(11;18) in gastric mucosa‐associated lymphoid tissue lymphomas in Taiwan, including one patient with high‐grade transformation
Authors: Chuang Shih‐Sung , Lee Chuan , Hamoudi Rifat A. , Liu Hongxiang , Lee Po‐Shing , Ye Hongtao , Diss Tim C. , Dogan Ahmet , Isaacson Peter G. , Du Ming‐Qing
Published: March 2003

Summary. t(11;18)(q21;q21), the most frequent chromosomal aberration of mucosa‐associated lymphoid tissue (MALT) lymphoma, occurs in 30% of gastric patients.Although the translocation is often associated with an ‘aggressive’ course, it has not been described in transformed MALT lymphomas. We screened 15 gastric MALT lymphomas [three with concurrent or subsequent high‐grade transformation and 11 diffuse large B‐cell lymphomas (DLBCLs)] in Chinese patients for t(11;18). t(11;18) was found in 9/15 (60%) MALT lymphomas, but not in any DLBCLs. One patient, with subsequent high‐grade transformation, showed the translocation in low‐ and high‐grade lesions. t(11;18) was frequent in Chinese gastric MALT lymphomas and unusually one transformed lymphoma carried the translocation.
Regulated expression of MUC1 epithelial antigen in erythropoiesis
Authors: Rughetti Aurelia , Biffoni Mauro , Pierelli Luca , Rahimi Hassan , Bonanno Giuseppina , Barachini Serena , Pellicciotta Ilenia , Napoletano Chiara , Pescarmona Edoardo , Del Nero Angelo , Pignoloni Patrizia , Frati Luigi , Nuti Marianna
Published: March 2003

Summary. MUC1 is a large surface glycoprotein expressed by epithelial cells, which is overexpressed and aberrantly glycosylated in carcinomas. MUC1 is involved in epithelial cell interactions and appears to function as a signal‐transducing molecule. The finding that MUC1 can also be expressed in the haematopoietic lineages prompted us to further investigate the possible function(s) of this molecule in haematopoietic cells. In bone marrow differentiating cells, MUC1 was strongly and selectively expressed during erythropoiesis; it was also weakly expressed during megakaryocytopoiesis and granulomonocytopoiesis; however, no correlation between MUC1 and differentiation marker expression was observed in these lineages. In vitro CD34+ cells, induced towards erythroid differentiation, acquired MUC1 transiently, while expressing increasing levels of the lineage marker glycophorin A. MUC1 was absent in the circulating erythrocytes. During erythropoiesis, MUC1 expression was transcriptionally regulated and the molecule underwent phosphorylation. To investigate the possible role of MUC1 during erythropoiesis, we studied the ability of MUC1 to act as ligand for cell–cell interaction. The sialylated MUC1 glycoforms selectively expressed on erythroid cells were able to bind the macrophage‐restricted molecule sialoadhesin. These results suggest that MUC1 can function as a cross‐talk molecule between the erythroblasts and the surrounding cells during erythropoiesis.
Non‐myeloablative allografting from human leucocyte antigen‐identical sibling donors for treatment of acute myeloid leukaemia in first complete remission
Authors: Feinstein Lyle C. , Sandmaier Brenda M. , Hegenbart Ute , McSweeney Peter A. , Maloney David G. , Gooley Theodore A. , Maris Michael B. , Chauncey Thomas R. , Bruno Benedetto , Appelbaum Frederick R. , Niederwieser Dietger W. , Storb Rainer F.
Published: March 2003

Summary. Many patients with acute myeloid leukaemia (AML) in first complete remission (CR1) are ineligible for allogeneic transplantation as a result of age or medical problems other than leukaemia. Eighteen patients (median age 59 years, range 36–73 years) with de novo (n = 13) and secondary (n = 5) AML in morphological CR1, who were not candidates for conventional allografting, received non‐myeloablative peripheral blood stem cell transplants from human leucocyte antigen identical sibling donors after conditioning with 2 Gy total body irradiation (TBI; n = 10) or 2 Gy TBI and 90 mg/m2 of fludarabine (n = 8). Postgrafting immunosuppression was with cyclosporine and mycophenolate mofetil. Two rejections were observed in patients not given fludarabine and one died with relapse. Overall, 10 patients died between 77 and 841 d, seven from relapse and three from non‐relapse mortality (NRM). Day +100 NRM was 0% with a 1‐year estimated NRM of 17%[95% confidence interval (CI) 0–35%]. The median follow‐up among the eight survivors was 766 d (range, 188–1141 d). Seven of these eight survivors remain in complete remission (CR). One‐year estimates of overall and progression‐free survivals were 54% (95% CI 31–78%) and 42% (95% CI 19–66%) respectively. While follow‐up is short, this analysis demonstrates that the procedure is sufficiently safe to be studied in a wider group of patients.
Risk‐adjusted prognostic models for Hodgkin's disease (HD) and grade II non‐Hodgkin's lymphoma (NHL II): validation on 6728 British National Lymphoma Investigation patients
Authors: Low Su E. , Horsman Janet M. , Walters Stephen J. , Hancock Helen , Smith Paul , Linch David , Hancock Barry W.
Published: March 2003

Summary. Using significant factors from multivariate analyses, based on 20 putative markers from a consecutive series of 1198 Sheffield Lymphoma Group patients, risk‐adjusted prognostic models had been previously derived for Hodgkin's disease (HD) (using age, albumin and lymphocyte count) and non‐Hodgkin's lymphoma (NHL) grade II (based on albumin, age, erythrocyte sedimentation rate, lactate dehydrogenase and stage). Data from 6728 patients on the British National Lymphoma Investigation database were used for validation: thus the models were applied to 4411 patients with HD and 2317 patients with NHL grade II. Survival curves derived from these validation groups confirmed our risk models.
Incidence of potential glycosylation sites in immunoglobulin variable regions distinguishes between subsets of Burkitt's lymphoma and mucosa‐associated lymphoid tissue lymphoma
Authors: Zhu Delin , Ottensmeier Christian H. , Du Ming‐Qing , McCarthy Helen , Stevenson Freda K.
Published: March 2003

Summary. Recently, a high incidence of novel N‐glycosylation sites introduced by somatic mutation was observed in the immunoglobulin variable region genes of follicular lymphoma. As these are positively selected and are uncommon in normal B cells, they may have a role in tumour growth and behaviour. Sites are not characteristic of chronic lymphocytic leukaemia or myeloma, but are detectable in ∼50% of diffuse large cell lymphomas. Another feature of the variable region genes of certain lymphomas is ongoing somatic mutation. To determine whether glycosylation is associated with this phenomenon, we analysed variable region gene sequences of Burkitt's lymphoma (BL) and mucosa‐associated lymphoid tissue (MALT) lymphoma. Novel sites were common in endemic BL (82%) and in 4/5 patients with Iranian BL. However, sporadic BL had a lower incidence (43%). Patients with MALT lymphoma had a low frequency (9%) of novel sites, comparable to normal B cells. These findings distinguish glycosylation sites from ongoing mutation and may reflect different environmental influences on these tumours.
Glycoprotein Ib polymorphisms influence platelet plug formation under high shear rates
Authors: Jilma‐Stohlawetz Petra , Homoncik Monika , Jilma Bernd , Knechtelsdorfer Maarten , Unger Petra , Mannhalter Christine , Santoso Sentot , Panzer Simon
Published: March 2003

Summary. Platelet polymorphisms (Kozak, VNTR and HPA‐2) within glycoprotein (GP)Ibα may be associated with an increased risk of arterial thrombosis. However, the functional role of these polymorphisms has not been clarified. Their influence on platelet plug formation under high shear rates was, therefore, examined in 233 healthy individuals. Collagen–adrenaline‐induced closure time was shorter in carriers of the C/D versus C/C VNTR allele and in homozygotes with the (−5)T/T versus (−5)C/T Kozak genotype as determined by novel polymerase chain reaction methods. The HPA‐2 genotype had no effects, and the density of GPIbα molecules was not influenced by GPIbα genotypes.
Plasma interleukin 8 level predicts for survival in chronic lymphocytic leukaemia
Authors: Wierda William G. , Johnson Marcella M. , Do Kim‐Anh , Manshouri Taghi , Dey Amanda , O'Brien Susan , Giles Francis J. , Kantarjian Hagop , Thomas Deborah , Faderl Stefan , Lerner Susan , Keating Michael , Albitar Maher
Published: March 2003

Summary. The malignant B cells of patients with chronic lymphocytic leukaemia (CLL) constitutively express interleukin 8 (IL‐8) and IL‐8 receptors. Ex vivo culture with exogenous IL‐8 enhances IL‐8 expression and prolongs leukaemia cell survival, partly through increased bcl‐2 expression. IL‐8 may function as an autocrine growth and apoptosis resistance factor in CLL. Therefore, we evaluated the prognostic relevance of plasma IL‐8 levels in 151 CLL patients [median age 61 years (range, 32–84 years), median plasma IL‐8 level 18·9 pg/ml (9·1–89·1 pg/ml)]. All Rai stages were represented; advanced stage was associated with significantly higher plasma IL‐8 levels (P < 0·0001, Kruskal–Wallis). Also, plasma IL‐8 level was correlated with serum β2‐microglobulin (β2‐M) (R = 0·24, P = 0·0081), haemoglobin (R = −0·39, P < 0·0001) and platelet count (R = −0·23, P = 0·0049) by Spearman's rank correlation. Univariate analysis using Cox proportional hazards models identified elevated IL‐8 and β2‐M as significant prognostic factors with relative risks of 7·43 (P = 9·1 × 10−9) and 16·40 (P = 5·9 × 10−10) respectively. High levels of IL‐8 were associated with shorter survival independent of β2‐M level. Using recursive‐partitioning procedures, an IL‐8 cut‐off point of 26·2 pg/ml segregated a group of CLL patients with significantly shorter survival (median 9·3 months) (P < 0·0001). In conclusion, plasma IL‐8 level in CLL patients correlates with other prognostic factors, such as Rai stage and β2‐M, and is associated with increased risk of death in CLL patients. The role of IL‐8 inhibitors in the treatment of patients with CLL should be explored.
Prognostic factors and outcome for children after second central nervous system relapse of acute lymphoblastic leukaemia
Authors: Morris Emma C. , Harrison Georgina , Bailey Clifford C. , Hann Ian M. , Hill Frank G. , Gibson Brenda E. S. , Richards Susan , Webb David K. H. ,   the Medical Research Council Childhood Leukaemia Working Party
Published: March 2003

Summary. The Medical Research Council acute lymphoblastic leukaemia trials (UKALL X and XI) recruited 3702 children with ALL between January 1985 and March 1997. Seventy‐nine children had central nervous system (CNS) involvement in their first two relapses. Fourteen children survived at a median follow‐up of 22 months from second relapse; seven (9%) in third remission, two in later remissions and five with disease. Factors predictive of survival from second relapse were site (isolated CNS was better than combined CNS, P = 0·02) and time from diagnosis to second CNS relapse (longer time was better, P = 0·004). Prognosis after second CNS relapse is extremely poor, and palliative therapy is appropriate.
A prospective study of recombinant activated factor VII administered by continuous infusion to inhibitor patients undergoing elective major orthopaedic surgery: a pharmacokinetic and efficacy evaluation
Authors: Ludlam Christopher A. , Smith Mark P. , Morfini Massimo , Gringeri Alessandro , Santagostino Elena , Savidge Geoffrey F.
Published: March 2003

Summary. After surgery in haemophilia, haemostasis is difficult to maintain in the presence of an antifactor VIII antibody. This study assessed the pharmacokinetics of recombinant activated factor VII (rFVIIa) and its efficacy in securing post‐operative haemostasis in haemophiliacs with inhibitors. Continuous infusion of rFVIIa was evaluated for elective major orthopaedic surgery in nine patients with neutralizing antibodies to FVIII and at high risk of bleeding. After an initial preoperative bolus of 90 µg/kg, rFVIIa was infused at a fixed rate of 50 µg/kg/h for a median of 20 d (range 7–20 d). The median plasma FVII coagulant activity (FVII:C) at 24 h, 72 h and 20 d after surgery was 38 IU/ml (range 22–169 IU/ml), 45 IU/ml (range 17–88 IU/ml) and 31 IU/ml (range 27–46 IU/ml) respectively. The median plasma FVIIa:C at the same time points was 51 (range 24–211), 63 (range 22–99) and 44 (range 28–76) IU/ml respectively. Median total rFVIIa clearance remained stable during the rFVIIa continuous infusion period and was 40 (range 9–70), 34 (range 17–86) and 48 (range 32–55)ml/kg/h at the end of 24 h, 72 h and 20 d infusion respectively. Post‐operatively, there were bleeds in six patients, which settled readily after a single bolus of rFVIIa (60 µg/kg). There was a good clinical outcome for all patients. These data indicate that rFVIIa infusion at50 µg/kg/h achieves continuous plasma FVII procoagulant activity in excess of 30 IU/ml (12–15 nmol/l) and provides adequate haemostatic control for inhibitor patients during major orthopaedic surgery.
Genetic pathways involved in the progression of Barrett's metaplasia to adenocarcinoma
Authors: Jenkins G J S , Doak S H , Parry J M , D'Souza F R , Griffiths A P , Baxter J N
Published: March 2003

Background

The prediction of which patients with Barrett's metaplasia will develop cancer is difficult. Better genetic characterization of the condition may aid clinicians in devising more effective management and follow-up strategies.

Methods

A review was undertaken of the accumulated genetic data relating to the progression of squamous epithelium to adenocarcinoma. The normal functions of a number of cancer-related genes are described and an explanation is given of how alterations in these genes interfere with normal cell processes and lead to cancer.

Results and conclusion

The main genetic alterations accompanying the progression through dysplasia to adenocarcinoma were collated from 135 papers. The principal genetic changes implicated are the loss of p16 gene expression (by deletion or hypermethylation), the loss of p53 expression (by mutation and deletion), the increase in cyclin D1 expression, the induction of aneuploidy and the losses of the Rb, DCC and APC chromosomal loci.
Use of the St Gallen classification for patients with node-negative breast cancer may lead to overuse of adjuvant chemotherapy
Authors: Boyages J , Chua B , Taylor R , Bilous M , Salisbury E , Wilcken N , Ung O
Published: March 2003

Background

The 1998 St Gallen classification was devised to guide clinicians in the use of adjuvant systemic therapy for women with early breast cancer. In this study, the classification was applied to a historical group of patients with node-negative breast cancer who were treated without adjuvant therapy.

Methods

The St Gallen classification was applied to 421 women with breast cancer treated with conservative surgery and radiotherapy alone between 1979 and 1994. Primary tumour characteristics were reviewed centrally.

Results

When the most stringent version of the St Gallen classification was applied (grade 2 or 3 tumours classified as ‘high risk’), only 10 per cent of patients were ‘low risk’, with a 10-year distant relapse-free survival (DRFS) rate of 100 per cent, and 15 per cent were at ‘intermediate risk’ (10-year DRFS rate of 94 per cent). The high-risk group (75 per cent of women) had a 10-year DRFS rate of 77 per cent (P < 0·01). If the St Gallen classification had been applied to all patients in this series who were aged less than 70 years, up to 91 per cent would have been recommended to have chemotherapy.

Conclusion

The St Gallen classification is an inaccurate measure of prognosis for patients with node-negative breast cancer and should be used with caution.
Consequences of axillary recurrence after conservative breast surgery
Authors: Fredriksson I , Liljegren G , Arnesson L-G , Emdin S O , Palm-Sjövall M , Fornander T , Holmqvist M , Holmberg L , Frisell J
Published: March 2003

Background

The aim was to study the incidence, time course and prognosis of patients who developed axillary recurrence after breast-conserving surgery, and to evaluate possible risk factors for axillary recurrence and prognostic factors after axillary recurrence.

Methods

In a population-based cohort of 6613 women with invasive breast cancer who had breast-conserving surgery between 1981 and 1990, 92 recurrences in the ipsilateral axilla were identified. Risk factors for axillary recurrence were studied in a case–control study nested in the cohort, and late survival was documented in the women with axillary recurrence.

Results

The overall risk of axillary recurrence was 1·0 per cent at 5 years and 1·7 per cent at 10 years. The risk of axillary recurrence increased with tumour size (P = 0·033) and was highest in younger women (odds ratio (OR) 3·9 for women aged less than 40 years compared with those aged 50–59 years). Radiotherapy to the breast reduced the risk of axillary recurrence (OR 0·1 (95 per cent confidence interval 0·1 to 0·4)). The breast cancer-specific survival rate after axillary recurrence, as measured from primary treatment, was 78·0 per cent at 5 years and 52·3 per cent at 10 years. Tumour size and node status had a statistically significant effect on death from breast cancer.

Conclusion

Axillary recurrence is rare, although more common in younger women with large tumours. Radiotherapy to the breast was protective. Tumour size and node status were the most important prognostic factors in women with axillary recurrence.
The surgeon as a prognostic factor after the introduction of total mesorectal excision in the treatment of rectal cancer
Authors: Martling A , Cedermark B , Johansson H , Rutqvist L E , Holm T
Published: March 2003

Background

With conventional blunt surgical resection of rectal cancer, local recurrence rates are high and the individual surgeon putatively influences patient outcome. With total mesorectal excision (TME) local recurrence rates have been reduced and intersurgeon variability may be less important. The ‘TME project’ was a collaborative project that included surgical workshops in Stockholm between 1994 and 1997. The aim of this study was to assess the impact of the project on the practice of rectal cancer surgery in Stockholm and to analyse whether surgeon case volume and participation in the workshops influenced patient outcome.

Methods

All 652 patients who had an abdominal resection for rectal cancer in Stockholm between 1995 and 1997 were included. Outcome was compared in patients operated on by teams that included high-volume surgeons (more than 12 operations per year) with teams that included low-volume surgeons (12 operations or fewer per year), as well as between teams that including workshop participants and non-participants.

Results

Forty-six surgeons operated on the 652 patients. Five high-volume surgeons operated on 48 per cent of the patients. In these, outcome was significantly better than in patients treated by low-volume surgeons (local recurrence rate 4 versus 10 per cent (P = 0·02); rate of rectal cancer death 11 versus 18 per cent (P = 0·007)). Twenty-six surgeons were workshop participants and performed 93 per cent of the operations. Radiotherapy, TME and sphincter-preserving surgery were more common among patients treated by workshop participants.

Conclusion

The TME project has had an impact on rectal cancer surgical practice in Stockholm. Variability in patient outcome was mainly related to case volume, with better results obtained in patients treated by high-volume surgeons.
Endoscopic resection of large sessile colonic polyps by specialist and non-specialist endoscopists
Authors: Brooker J C , Saunders B P , Shah S G , Williams C B
Published: March 2003

Background

Patients with large sessile colonic polyps for which endoscopic resection might be feasible are often referred directly for operation. The aim of this study was to determine the outcome of patients with such polyps diagnosed by specialist and non-specialist colonoscopists.

Methods

Patients with large (greater than 2 cm) sessile polyps detected at colonoscopy from January 1995 to July 2000 were identified. Resection technique and clinical and endoscopic outcomes were recorded. Two of the colonoscopists (B.P.S., C.B.W.) are recognized as specialists.

Results

Some 130 polyps were identified, 100 detected by either of two specialist endoscopists (including 14 cancers) and 30 by 14 non-specialist endoscopists (including ten cancers). Endoscopic resection of benign polyps was attempted by experts in 80 (93 per cent) of 86 cases and by non-experts in 15 of 20 cases (P = 0·03), with successful management by endoscopy alone in 61 (76 per cent) of 80 and in six of 15 cases respectively (P = 0·01). Complications occurred following three polypectomies performed by an expert (bleeding, two; pain, one) and one by a non-expert (bleeding). The estimated end-cost of management by specialists was less than half of that by non-specialists.

Conclusion

Endoscopic resection of large sessile colonic polyps is feasible in the majority of patients and should be considered as first-line therapy. Prompt referral to a specialist endoscopist may improve outcomes by avoiding operation or enabling complete excision at a single endoscopy session.
Anorectal functional disorders in the absence of anorectal inflammation in patients with Crohn's disease
Authors: Mueller M H , Kreis M E , Gross M L , Becker H D , Zittel T T , Jehle E C
Published: March 2003

Background

Histological alterations in the enteric nervous system (ENS) have been described in patients suffering from Crohn's disease (CD). The aim of this study was to investigate whether patients with CD without rectal inflammation have abnormal anorectal function compared with healthy volunteers.

Methods

Fifty-four patients with CD and 26 healthy volunteers were examined by anorectal manometry and answered a standardized questionnaire. No patient had active CD in the rectum as determined by endoscopy.

Results

Maximum anal resting and squeeze pressures did not differ between patients and healthy volunteers. The rectoanal inhibitory reflex was absent in 24 of 54 patients and two of 26 healthy volunteers (P < 0·05). The first sensation to distension of the rectal balloon was reported at mean(s.e.m.) 57·9(4·4) ml by patients and 37·5(2·2) ml by healthy volunteers (P < 0·01). The standardized interview revealed additional disorders of anorectal function in patients with CD.

Conclusion

Anorectal function appears to be altered in many patients with CD even in the absence of macroscopic anorectal disease. This may be due to a disorder of the ENS.
Pain from primary inguinal hernia and the effect of repair on pain
Authors: Page B , Paterson C , Young D , O'Dwyer P J
Published: March 2003

Background

No previous study has attempted to quantify pain from a primary inguinal hernia. The aim of this study was to quantify patients' pain from inguinal hernia at rest and on moving, and to assess the effect of hernia repair on the pain.

Methods

Linear analogue pain scores at rest and on moving were recorded before operation and at 1 year after surgery in a consecutive series of patients undergoing elective repair of a primary inguinal hernia.

Results

During the study period 323 patients underwent inguinal hernia repair. Eighty-six patients (26·6 per cent) recorded no pain at rest from the hernia, and 174 (53·9 per cent) had mild pain only (score less than 10). On moving, 53 patients (16·4 per cent) had no pain and 137 (42·4 per cent) had mild pain on moving. Only 1·5 per cent experienced severe pain (score greater than 50) at rest, and 10·2 per cent had severe pain on moving. There was no association between pain and hernia type, direct or indirect, or patient occupation. One year after operation only 24·5 per cent of patients had no pain from the hernia repair site at rest, and 21·6 per cent had no pain from the site on moving. Overall there was a significant reduction in pain score at rest (mean(s.e.m.) decrease from baseline −2·9(1·2), P = 0·019) and on moving (−9·2(1·8), P = 0·001) compared with preoperative values, and this was due mainly to the large effect observed in patients with high preoperative values. Patients who had no pain at rest before operation had significant pain scores at rest at 1 year (P = 0·001).

Conclusion

Clinical trials are required to evaluate hernia repair in patients with an asymptomatic inguinal hernia. Results from such trials should help to determine whether repair is the treatment of choice for these patients.
Clinical experience in continuous graft monitoring with microdialysis early after liver transplantation
Authors: Nowak G , Ungerstedt J , Wernerman J , Ungerstedt U , Ericzon B-G
Published: March 2003

Background

Early detection of impaired graft function after transplantation is essential. Microdialysis permits continuous monitoring of metabolic changes by mimicking the passive function of a capillary blood vessel by perfusion of a tubular semipermeable membrane introduced into the tissue. Based on the results of animal experiments, a clinical pilot study was undertaken.

Methods

Ten consecutive patients undergoing whole-organ orthotopic liver transplantation were studied. Intrahepatic implantation of a microdialysis catheter was performed at the end of the operation. A reference catheter was placed in the subcutaneous tissue over the right pectoral area immediately after abdominal closure. Consecutive serial samples were collected at 1-h intervals for 3 days after the operation. Glucose, lactate, pyruvate and glycerol concentrations were measured.

Results

During the first 24 h, the glucose level was higher in the liver than in reference tissue. Initially, increased mean(s.e.m.) levels of lactate (7·0(1·9) mmol/l) were observed in the liver, with a rapid decrease (to 2·7(0·3) mmol/l) over 24 h. A decrease in, and later stabilization of, the lactate: pyruvate ratio in the liver, from 18·7(4·2) to 10·0(1·1), was observed within 24 h after transplantation. Liver glycerol levels decreased from 62·3(7·4) to 24·3(7·5) µmol/l within the first 16 h after reperfusion and remained stable thereafter.

Conclusion

Microdialysis allows continuous monitoring of tissue metabolism in the transplanted liver. The procedure is easy to perform and safe. The specific detection and monitoring of pathological changes in the liver graft (e.g. arterial and portal vein thrombosis, or early rejection) with microdialysis should be addressed in further studies.