bluuebunny/crossref_metadata_2025_split huggingface dataset:
Elevated serum levels of soluble vascular cell adhesion molecule‐1 (sVCAM‐1) closely reflect tumour burden in chronic B‐lymphocytic leukaemia
Authors: Christiansen Ilse , Sundström Christer , Tötterman Thomas H. 
Published: March 2003

The present study is the first to report elevated serum levels of soluble (s)VCAM‐1 in B‐cell chronic lymphocytic leukaemia (B‐CLL). A large cohort of 106 untreated patients was studied. sVCAM‐1 was compared to known prognostic serum markers (soluble (s)ICAM‐1; lactate dehydrogenase, LDH; sCD23; thymidine kinase, TK; β2microglobulin, β2m). The serum levels of sVCAM‐1 reflected tumour burden as expressed by Binet/Rai stages more closely than any other marker. sVCAM‐1 also reflected the kinetics of the disease as revealed by lymphocyte doubling time. sVCAM‐1 was the only one of the studied markers which showed elevated levels in smouldering disease compared to controls. sVCAM‐1, sICAM‐1 and sCD23 (but not LDH, TK, β2m) separated smouldering from non‐smouldering B‐CLL. Only sICAM‐1, sCD23 and TK added independent prognostic information for survival to that of stage and lymphocyte doubling time.The expression of both adhesion molecules was examined in lymph node and splenic specimens. VCAM‐1 and ICAM‐1 were overexpressed by vascular endothelium and stroma, but the intensity of expression correlated poorly with serum levels of the soluble molecules.In conclusion, serum levels of sVCAM‐1 correlated with tumour burden and other prognostic markers in B‐CLL. VCAM‐1 was overexpressed in tumour tissue as was ICAM‐1. sVCAM‐1 could prove a valuable marker in younger early‐stage patients eligible for therapeutic trials.
Content of long‐term culture‐initiating cells, clonogenic progenitors and CD34+cells in apheresis harvests of normal donors for allogeneic transplantation, and in patients with acute myeloid leukaemia or multiple myeloma
Authors: Kasper C. , Ryder W. D. J. , Dürig J. , Nagesh K. , Scarffe J. H. , Beelen D. W. , Schaefer U. W. , Chang J. , Testa N. G. 
Published: March 2003

Using a limiting dilution assay the frequency of long‐term culture‐initiating cells (LTC‐IC) in the apheresis products following mobilization by granulocyte‐colony stimulating factor (G‐CSF) with or without chemotherapy from 14 normal donors (ND) for allogeneic bone marrow transplantation, 16 patients with multiple myeloma (MM) and 15 patients with acute myeloid leukaemia (AML), where the aphereses were intended for autologous transplantation, were compared.The estimated median incidences of LTC‐IC in the first apheresis products from ND, MM and AML were 1/3289, 1/1775 and 1/13 075 mononuclear cells (MNC) respectively. The patients with AML had a significantly lower incidence compared with the other two groups (P < 0.0001). There was a positive correlation between the incidence of LTC‐IC and the number of CD34+cells, the number of GM‐CFC, and the number of BFU‐E. The positive association with GM‐CFC or BFU‐E was weaker. In these experiments the percentage of CD34+cells was the best predictor for the frequency of LTC‐IC in the peripheral blood progenitor cells (PBPC). In eight cases of MM the LTC‐IC assay was performed for both the first and second harvest. All cases had a lower LTC‐IC frequency in the second harvest compared with the first, an average of 23% (13–42%, 95% confidence interval) and this reduction was statistically significant (P < 0.001); CD34+cells were also lower (P < 0.001).
Identification of X‐linked severe combined immunodeficiency by mutation analysis of blood and hair roots
Authors: Ting Suk See , Leigh Don , Lindeman Robert , Ziegler John B. 
Published: March 2003

Severe combined immunodeficiency is a heterogenous syndrome of varied genetic origins of which the X‐linked type is the commonest (XSCID). The most sensitive method for diagnosis of XSCID in the absence of X‐linked inheritance pattern is by mutation analysis.In this report we have performed mutation analysis in 13 unrelated boys transplanted (BMT) for SCID without a known cause to determine the frequency of XSCID. Five boys had an affected male relative. We also assessed the utility of hair roots for children without pre‐transplant blood stored for mutation analysis since donor genotype was expressed in peripheral blood post BMT. Screening was performed by analysis of single‐strand conformational polymorphism (SSCP) followed by sequencing of candidate exons.Mutations were found in 11 cases, of which six were sporadic, and maternal mosaicism was found in one family. Three mothers of the six sporadic cases were identified as carriers. The majority (6/8) of boys with SCID had γc deficiency despite the absence of X‐linked inheritance pattern. The significant frequency of de novo mutations and the occurrence of maternal germline mosaicism highlights the importance of mutation analysis. The strategy of using DNA from hair roots was particularly valuable where no pre‐transplant blood was stored. Characterization of the mutations will also enable research into the correction of these genetic defects.
The CD69 early activation molecule is overexpressed in human bone marrow mast cells from adults with indolent systemic mast cell disease
Authors: Díaz‐Agustín Beatriz , Escribano Luis , Bravo Pilar , Herrero Sonia , Nuñez Rosa , Navalón Raquel , Navarro Lourdes , Torrelo Antonio , Cantalapiedra Alberto , Del Castillo Luz , Villarrubia Jesús , Navarro José L. , San Miguel Jesús F. , Orfao Alberto 
Published: March 2003

We have analysed the quantitative expression of surface CD69 antigen on human mast cells (MC), from both normal and pathological bone marrow (BM) samples, using flow cytometry. Our major aim was to analyse whether CD69 is constitutively expressed by normal BMMC and to explore the possible differences between CD69 expression by BMMC from normal controls and patients suffering from different pathological conditions.The constitutive expression of surface CD69 was clearly demonstrated in BMMC; however, systemic mast cell disease (SMCD) patients showed significantly higher levels of surface CD69 expression than healthy controls (P < 0.001), chronic lymphocytic leukaemia (P = 0.001), monoclonal gammopathy of unknown significance (P < 0.001), multiple myeloma (P < 0.001) patients, and myelodysplastic syndromes (P = 0.002). Furthermore, almost no overlap between the levels of CD69 expression on BMMC was observed between SMCD cases and the remaining groups of individuals except for the paediatric mastocytosis group (P > 0.05). From the other groups of patients, monoclonal gammopathy of unknown significance (P = 0.04), myelodysplastic syndromes (P = 0.03) and paediatric mastocytosis (P = 0.003) cases showed a significantly higher expression of surface CD69 as compared to normal subjects.In summary, our findings show that the CD69 antigen is overexpressed in SMCD patients.
Hepatosplenic candidiasis in patients with acute leukaemia
Authors: Sallah Sabah , Semelka Richard C. , Wehbie Robert , Sallah Waddah , Nguyen Nam P. , Vos Paul 
Published: March 2003

A retrospective study of 23 patients with acute leukaemia and hepatosplenic candidiasis (HSC) was conducted to evaluate clinical treatment characteristics in terms of amount and duration of antifungal agents and to assess treatment outcome.Patients were admitted to two major tertiary care centres between 1990 and 1998. The diagnosis of HSC was based on clinical, blood cultures, histologic and imaging studies. Patients were treated with amphotericin B without interruption of the planned chemotherapy regimens. Serial magnetic resonance imaging (MRI) studies were the main tool for following patients' response and activity of the fungal lesions in conjunction with clinical and laboratory parameters.Treatment with amphotericin B was continued until resolution of all clinical symptoms and signs attributable to HSC, obtaining negative blood cultures and the appearance of at least healed lesions on MRI. Amphotericin B was discontinued in four patients because of severe nephrotoxicity (two patients), or continuous fever and persistent fungal lesions on MRI (two patients). Amphotericin B lipid complex (ABELCET) was successfully used as salvage therapy for these refractory patients. Four patients died with evidence of HSC despite treatment and supportive measures. The response rate for treatment of HSC was 82%. The mean total dose of amphotericin B including empirical treatment was 4 g and the median duration of treatment for responding patients was 112 d. The median number of days of anti‐ fungal treatment before the disappearance of fever was 19 d.Our results confirmed the need for protracted courses of antifungal agents for the successful eradication of HSC. Chemotherapy for the underlying disorder should not be interrupted or delayed in order to treat HSC.
Efficacy and toxicity of IFN‐α2b combined with cytarabine in chronic myelogenous leukaemia
Authors: Lindauer  , Domkin  , Döhner  , Kolb  , Neubauer  , Huhn  , Kreiter  , Koch  , Huber  , Aulitzky  , Fischer  
Published: March 2003

Newly diagnosed chronic myelogenous leukaemia (CML) patients (n = 65) were treated with interferon (IFN)‐α2b (5 × 106 IU/d s.c.) combined with monthly courses of cytarabine (20 mg/d s.c. for 14 d). Median age of patients enrolled was 45 years. The endpoints of the study were clinical efficacy and toxicity. The survival rates at 3 years and 5 years were 77% and 56%, respectively. The rate of complete haematological response was 60%. Evaluation of cytogenetic response was available in 29/65 patients. A complete cytogenetic response was seen in 3/29 patients (10%). W.H.O. toxicity grade 3–4 occurred in only 22/523 evaluable treatment cycles. Since the study protocol required intermittent or definitive discontinuation of cytarabine in case of moderate leucopenia (white blood cells (WBC) <5 × 109/l), combined cytopenia (WBC < 5 × 109/l, platelets <100 × 109/l), and isolated moderate thrombocytopenia (<100 × 109/l), the drug had to be discontinued temporarily or definitively in 200 cycles and the dose of cytarabine had to be reduced in 35 cycles. Thus, only 25% of the planned dose of cytarabine could be administered. At this dosage it would appear that cytarabine had no effect on survival and did not improve remission rates.We conclude that a clinical benefit for the addition of cytarabine to the treatment of CML with IFN might only be achieved by the administration of a higher cumulative dose of cytarabine, suggesting that lower leucocyte counts of 2–4 × 109/l have to be tolerated.
Four novel non‐random chromosome rearrangements in B‐cell chronic lymphocytic leukaemia: 6p24–25 and 12p12–13 translocations, 4q21 anomalies and monosomy 21
Authors: Cuneo Antonio , Roberti Maria Grazia , Bigoni Renato , Minotto Claudia , Bardi Antonella , Milani Raffaella , Tieghi Alessia , Campioni Diana , Cavazzini Francesco , De Angeli Cristiano , Negrini Massimo , Castoldi Gianluigi 
Published: March 2003

Nine patients with previously unreported chromosome changes were identified among 209 B‐cell chronic lymphocytic leukaemia (CLL) cases: three patients had a translocation involving 6p24–25; three had a 12p12–13 translocation; two had 4q21 involvement (one with coexisting 6p anomaly); and two had monosomy 21.Interphase fluorescence in situ hybridization (FISH) detected some cryptic aberrations (+12, 6q–, 17p−, 11q−) in those patients with 6p translocations, whereas only a cytogenetically undetected 13q14 deletion was found in the remaining cases.Atypical morphology was noted in six cases, including both cases with monosomy 21, two cases with 6p and 4q21 anomaly and one case with 12p involvement. Four of these cases also had more than one phenotype deviation with respect to the classical CLL phenotype. Disease progression after 21–51 months (median 41) was noted in two cases with 6p and 4q21 involvement and in one case with 12p anomaly and monosomy 21.We arrived at the following conclusions: (i) 6p24–25 and, possibly, 4q21 lesions represent non‐random events in CLL, occurring in association with other well‐known unbalanced rearrangements; (ii) 12p rearrangements and monosomy 21 may possibly represent early chromosome defects that are not associated with the classical DNA gains and losses known to be present in the majority of CLL; and (iii) atypical morphology and immunophenotype as well as disease progression were frequently observed in these cases
Myeloma‐reactive allospecific cytotoxic T lymphocytes lyse target cells via the granule exocytosis pathway
Authors: Chiriva‐Internati Maurizio , Du Jianhui , Cannon Martin , Barlogie Bart , Yi Qing 
Published: March 2003

Accumulating evidence indicates that a graft‐vs.‐myeloma effect (GVM) and its associated clinical remission of the disease can be induced by donor lymphocyte infusion in myeloma patients who have relapsed after allogeneic bone marrow transplantation. Although it is believed that GVM is induced by allospecific T cells, T‐cell subsets and the mechanisms involved in the killing of myeloma cells by donor T cells have not been studied. In this study, we generated allospecific cytotoxic T lymphocyte (CTL) lines against three different myeloma cell lines, ARK, ARP‐1 and U266, from unmatched healthy donors and examined their cytotoxicity against the target cells. Our results demonstrate that the allospecific CTLs efficiently lysed myeloma cells. The observed cytotoxicity was mediated mainly by CD8+ T cells and inhibited by MHC class I‐blocking antibody. Furthermore, the CTLs lysed the target cells via the perforin‐mediated pathway, as concanamycin A, but not brefeldin A (the selective inhibitors for perforin‐ or Fas‐mediated pathways respectively) or tumour necrosis factor‐α (TNF‐α)‐blocking antibody, abrogated the cytolytic activity of the cells. These CTLs expressed and produced predominantly TNF‐α and interferon‐γ (IFN‐γ), indicating that they belong to the type 1 T‐cell subsets. Taken together, these results indicate that CD8+ allospecific T cells may be responsible for mediating GVM and that the granule‐mediated lysis of target cells is the major pathway in the CD8+ T‐cell response against myeloma cells.
Anti‐thrombotic and haemorrhagic effects of active site‐inhibited factor VIIa in rats
Authors: Ghrib F. , Léger P. , Ezban M. , Kristensen A. T. , Cambus J. P. , Boneu B. 
Published: March 2003

Active site‐inhibited factor VIIa (FFR‐rFVIIa) competes with factor VIIa (FVIIa) for binding to tissue factor (TF) and exerts an anti‐thrombotic effect. We report an evaluation of the anti‐thrombotic properties of FFR‐rFVIIa in a model of thrombosis involving two thrombogenic surfaces. Uncoated glass capillaries or glass capillaries coated with TF were incorporated into an arterioarterial shunt in the rat and the occlusion time (OT) of the shunt was determined. An anti‐thrombotic activity of FFR‐rFVIIa was shown only on the TF‐coated surface: the OT of the shunt was significantly prolonged, from 167 ± 34 s in control animals to 312 ± 42 s after i.v. bolus administration of 4 mg/kg FFR‐rFVIIa. This OT was similar to those observed with the uncoated shunts in untreated animals (353 ± 84 s). In vitro preincubation of the TF‐coated shunt with FFR‐rFVIIa significantly prolonged the OT to 245 ± 45 s in the absence of detectable amounts of FFR‐rFVIIa in the plasma. rFFR‐rFVIIa weakly prolonged the tail template bleeding time by a factor of 1·5. This effect was more pronounced in animals pretreated with heparin. The anti‐thrombotic and prohaemorrhagic effects of FFR‐rFVIIa were totally reversed by administration of an equidose of rFVIIa. These results provide new information on the pharmacological properties of FFR‐rFVIIa that will be useful for its clinical development.
In vitro drug resistance and prognostic impact of p16INK4A/P15INK4B deletions in childhood T‐cell acute lymphoblastic leukaemia
Authors: Ramakers‐van Woerden N. L. , Pieters R. , Slater R. M. , Loonen A. H. , Beverloo H. B. , Van Drunen E. , Heyman M. , Calero Moreno T. , Rots M. G. , Van Wering E. R. , Kamps W. A. , Janka‐Schaub G. E. , Veerman A. J. P. 
Published: March 2003

p16 gene deletions are present in about 70% of primary paediatric T‐cell acute lymphoblastic leukaemia (T‐ALL) and 20% of common/precursor B‐cell ALL cases. It is not clear what the impact of the frequent p16 deletions is within the subgroup of T‐lineage ALL. We studied the relationship between p16/p19ARF deletions, using fluorescence in situ hybridization, and in vitro drug resistance and prognosis in childhood T‐ALL at diagnosis. The cellular drug resistance was measured with the methyl thiazol tetrazoliumbromide assay using a panel of drugs and the thymidylate synthase inhibition assay for methotrexate. There was a complete overlap of individual LC50 values of p16 gene homozygously deleted and p16 germ‐line cases for most of the nine classes of drugs tested. The only difference was for dexamethasone: the p16‐deleted group was more sensitive than the germ‐line p16 group (P = 0·030). The homozygously deleted p16 T‐ALL patients (n = 34) treated with the modern multiagent chemotherapy schemes of the Dutch Childhood Leukaemia Study Group ALL‐VII/‐VIII or Co‐operative ALL‐92/‐97 protocols have a significantly lower 5‐year disease‐free survival (DFS) than germ‐line p16 T‐ALL (n = 25) (65·1 ± 9·1% vs. 95·5 ± 4·4%, Plog rank= 0·021). Hence, this study identifies a subpopulation of primary childhood T‐ALL that appears to have an extremely high DFS. However, the observed differences in outcome do not seem to be related to intrinsic resistance for the tested drugs.
Donor interleukin 1 receptor antagonist genotype associated with acute graft‐versus‐host disease in human leucocyte antigen‐matched sibling allogeneic transplants
Authors: Cullup H. , Dickinson A. M. , Jackson G. H. , Taylor P. R. , Cavet J. , Middleton P. G. 
Published: March 2003

Interleukin 1 (IL‐1) is involved in various autoimmune and inflammatory diseases. IL‐1 receptor antagonist (IL‐1Ra) is the naturally occurring antagonist to IL‐1α and ‐1β. Polymorphisms of IL‐1β have been associated with variations in IL‐1β production (nucleotides +3953 and −511). A variable number tandem repeat (VNTR) polymorphism in the IL‐1Ra gene has been associated (allele 2) with increased IL‐1Ra production. We examined these polymorphisms in human leucocyte antigen (HLA)‐matched allogeneic bone marrow transplant patients and donors. IL‐1Ra VNTR (allele 2) in the donor genotype was more frequent with milder acute graft‐versus‐host disease (aGvHD) grades 0–II (29 out of 59 transplants) than severe GvHD grades III–IV (2 out of 18 transplants) (P = 0·0032). This association was confirmed in a subgroup with cyclosporine monotherapy prophylaxis: donor possession of allele 2 was again associated with milder aGvHD, grades 0–II (19 out of 38 transplants), than grades III–IV (1 out of 14) (P = 0·0042) transplants. No association was found between the IL‐1β−511 or IL‐1β+3953 polymorphism and severity of GvHD. Recipient IL‐1Ra VNTR genotype (allele 2) showed a strong trend towards association with aGvHD severity (P = 0·0697). Thus, the donor genotype for the IL‐1Ra polymorphism has an apparent protective role against acute GvHD following transplantation and may be an additional factor for individual risk assessment for complications, including GvHD, post transplant.
Detection and clinical significance of human acute myeloid leukaemia progenitors capable of long‐term proliferation in vitro
Authors: Sutherland Heather , Blair Allison , Vercauteren Suzanne , Zapf Richard 
Published: March 2003

Acute myeloid leukaemia (AML) blasts within individual patients are heterogeneous in their surface antigen expression and proliferative ability suggesting that, subsequent to transformation, differentiation occurs creating a hierarchy of progenitors in AML. Cells that can produce AML colonies (colony forming units, CFU) in growth factor containing suspension cultures (SC) over 4–8 weeks have a phenotype similar to AML progenitors that engraft non‐obese diabetic/severe combined immunodeficient (NOD/SCID) mice, but different from bulk AML blasts, suggesting that these AML SC‐initiating cells (SC‐IC) may be early progenitors. In this study, we evaluated culture conditions that provide for optimal growth of AML progenitors capable of long‐term proliferation. The frequency of CFU, both initially and after 2–4 weeks of SC, varied over four logs between individual patients and was not related to French–American–British subtype. Using limiting dilution, the proliferative potential of individual SC‐IC varied from 1 to 480 CFU. The frequency of CFU from SC after > 4 weeks was prognostic for patient survival, and correlated with NOD/SCID engrafting ability. These results suggest the use of long‐term culture as an assay for AML cells with leukaemia sustaining potential.
Acute myeloblastic leukaemias of FAB types M6 and M4, with cryptic PML/RARα fusion gene formation, relapsing as acute promyelocytic leukaemia M3
Authors: Virchis Andres , Massey Edwin , Butler Tina , Devaraj Prema , Wright Faith , Secker‐Walker Lorna , Prentice H. Grant , Mehta Atul 
Published: March 2003

Demonstration of either the translocation t(15;17)(q22;q21) or the fusion of PML and RARα genes is regarded as diagnostic for acute myeloid leukaemia (AML) of FAB type M3, but has occasionally been seen in other FAB types. We present two such cases. Case 1 presented with FAB type M6 and a complex karyotype involving chromosomes 1, 2, 11 and 17. Bone marrow relapse of FAB type M3 followed autologous bone marrow transplantation. Subsequent marrow dysplasia and an M6 relapse were accompanied by a new cytogenetic clone involving chromosomes X, 2, 4, 6, 7 and 16. Fluorescence in situ hybridization (FISH) of metaphase chromosomes at diagnosis showed insertion of material from chromosome 17 into a ‘normal’ 15 with juxtaposition of PML and RARα. Case 2 presented as AML M4 and relapsed as M3. Cytogenetic analysis at diagnosis and in relapse showed 46,XY,t(15;17)(q22;q11),del(16)(q22). FISH analysis showed this to be a three‐way translocation involving chromosomes 15, 16 and 17 again with juxtaposition of PML and RARα. Reverse transcription‐polymerase chain reaction (RT‐PCR) revealed PML/RARα fusion at diagnosis, in remission and in first relapse. These examples strengthen the case for RT‐PCR screening of all AML patients for these fusion genes.
Radical and nerve-preserving surgery for rectal cancer in the Netherlands: a prospective study on morbidity and functional outcome
Authors: Maas C P , Moriya Y , Steup W H , Kiebert G M , Klein Kranenbarg W M , van de Velde C J H 
Published: March 2003

Abstract

Background
Operative procedures for primary rectal cancer from Japan combine pelvic nerve-preserving techniques with radical tumour resection to ensure optimal local tumour control with minimal bladder and sexual dysfunction. A prospective study was undertaken to evaluate morbidity and functional outcome of such a technique in Dutch patients.

Methods
Forty-seven patients were operated on by a Japanese surgeon. Postoperative course was monitored. Voiding and sexual function were analysed using questionnaires completed by patients.

Results
After operation, only prolonged paralytic ileus (five of 47 patients) and perineal wound dehiscence (five of 18) occurred more frequently than reported in literature. There were no deaths. No patient developed urinary incontinence. Three of 11 women and 19 of 30 men were sexually active. Two men were impotent after operation. Impotence was related to sacrifice of the inferior hypogastric plexus (P = 0·037). Preservation of the superior hypogastric plexus was crucial for ejaculation (P = 0·003).

Conclusion
A relationship between sacrifice of specific nerve structures and accompanying dysfunction was established. The nerve-preserving technique yields good results in terms of morbidity and functional outcome, and should be considered for adoption as a standard surgical procedure for primary rectal cancer.