Search

6‐Thioguanine treatment in childhood acute lymphoblastic leukaemia (ALL) has been shown to cause hepatic veno‐occlusive disease, but this usually resolved with drug withdrawal. Recent reports suggested that treatment of ALL with 6‐thioguanine can lead to chronic hepatotoxicity and portal hypertension. We describe our experience from 2 UK centres of chronic hepatotoxicity in children receiving maintenance 6‐thioguanine for ALL in the national leukaemia protocol ALL 97/99. Retrospective review of children who were referred with liver disease secondary to 6‐thioguanine treatment of ALL was performed. A paediatric pathologist blinded to the clinical features reviewed liver histology slides. Ten of 75 children (13%) treated with 6‐thioguanine in both centres were referred at a median of 6 months (range, 2‐29) after discontinuation of chemotherapy. In 8 cases, referral was due to persistent thrombocytopenia and splenomegaly. Two children presented with acute variceal bleeding. All had thrombocytopenia at referral, and ultrasonography showed coarse hepatic echo texture and splenomegaly in all. Endoscopy showed oesophageal varices in 7 and gastric varices in 1. Nine underwent liver biopsy that showed features compatible with nodular regenerative hyperplasia in 5 cases. After a median follow‐up of 36 months, a further child has had a variceal haemorrhage and all but 2 children remain thrombocytopenic. 6‐Thioguanine‐induced chronic hepatotoxicity is a significant complication in children treated with this agent for ALL. Children may present several months to years after discontinuation of 6‐thioguanine. All children given maintenance treatment of ALL with this agent should be screened, and affected children require long‐term surveillance.

To investigate possible causes of the variable response to treatment in pediatric B-precursor acute lymphoblastic leukemia (ALL) and to establish potential novel therapeutic targets, we used ionizing radiation (IR) exposure as a model of DNA damage formation to identify tumors with resistance to p53-dependent apoptosis. Twenty-one of 40 ALL tumors responded normally to IR, exhibiting accumulation of p53 and p21 proteins and cleavage of caspases 3, 7, and 9 and of PARP1. Nineteen tumors exhibited apoptotic resistance and lacked PARP1 and caspase cleavage; although 15 of these tumors had normal accumulation of p53 and p21 proteins, examples exhibited abnormal expression of TRAF5, TRAF6, and cIAP1 after IR, suggesting increased NF-κB prosurvival signaling as the mechanism of apoptotic resistance. The presence of a hyperactive PARP1 mutation in one tumor was consistent with such increased NF-κB activity. PARP1 inhibition restored p53-dependent apoptosis after IR in these leukemias by reducing NF-κB DNA binding and transcriptional activity. In the remaining 4 ALL tumors, apoptotic resistance was associated with a TP53 mutation or with defective activation of p53. We conclude that increased NF-κB prosurvival signaling is a frequent mechanism by which B-precursor ALL tumors develop apoptotic resistance to IR and that PARP1 inhibition may improve the DNA damage response of these leukemias.

Killer immunoglobulin–like receptors (KIRs) regulate cell activity of natural killer (NK) cells and some T cells. The predominant ligand for inhibitory KIRs is HLA-C, which subdivides into 2 groups based on the specificity of inhibitory KIRs. The ligands for activatory KIRs are unknown. Following hematopoietic stem cell transplantation (HSCT), recipient tissues may not express a ligand for KIRs present within the graft, and the combination of donor KIR and recipient HLA-C types could influence outcome. HLAand KIRgenotypes were determined in 220 donor-recipient pairs from HLA-matched sibling HSCTs performed for myeloid (n = 112) and lymphoid (n = 108) diseases. In HSCTs performed for myeloid disease, overall survival was worse in patients homozygous for group 2 HLA-C (C2) than in patients who carried a group 1 HLA-C (C1) allele (P< .005). Moreover, this effect is seen only when the donor additionally carries the activating KIR gene KIR2DS2(P= .045). No effect was seen in patients with lymphoid disease. Thus, in HLA-matched sibling HSCT for myeloid leukemia, patients homozygous for C2 alleles receiving a graft from a donor carrying the KIR gene KIR2DS2have a significantly reduced chance of survival.

Killer immunoglobulin–like receptors (KIRs) regulate cell activity of natural killer (NK) cells and some T cells. The predominant ligand for inhibitory KIRs is HLA-C, which subdivides into 2 groups based on the specificity of inhibitory KIRs. The ligands for activatory KIRs are unknown. Following hematopoietic stem cell transplantation (HSCT), recipient tissues may not express a ligand for KIRs present within the graft, and the combination of donor KIR and recipient HLA-C types could influence outcome. HLA and KIR genotypes were determined in 220 donor-recipient pairs from HLA-matched sibling HSCTs performed for myeloid (n = 112) and lymphoid (n = 108) diseases. In HSCTs performed for myeloid disease, overall survival was worse in patients homozygous for group 2 HLA-C (C2) than in patients who carried a group 1 HLA-C (C1) allele (P < .005). Moreover, this effect is seen only when the donor additionally carries the activating KIR gene KIR2DS2 (P = .045). No effect was seen in patients with lymphoid disease. Thus, in HLA-matched sibling HSCT for myeloid leukemia, patients homozygous for C2 alleles receiving a graft from a donor carrying the KIR gene KIR2DS2 have a significantly reduced chance of survival.

The emergence and spread of vancomycin-resistant Enterococcus faecium(VREF) has presented serious therapeutic difficulties because of the lack of reliably active antibiotics. Quinupristin/dalfopristin is a new injectable streptogramin antibiotic that is active against most strains of VREF. Experience with this agent in adults with VREF infections is well-documented; however, there are few reports of its use in children. We report on eight children with VREF infections who received quinupristin/dalfopristin under a compassionate use protocol.

Current prognostic indicators such as age, sex, and white blood cell count (WBC) fail to identify all children with more aggressive forms of B-precursor acute lymphoblastic leukemia (ALL), and a proportion of patients without poor prognostic indicators still relapse. Results obtained from an analysis of 65 pediatic B-precursor ALL patients indicated that subclone formation leading to clonal diversity, as detected by Ig and T-cell receptor (TCR) gene rearrangements, may represent a very useful prognostic indicator, independent of age, sex, and WBC. Disease-free survival was significantly shorter in those patients showing clonal diversity at presentation. Furthermore, clonal diversity was detected not only in the majority of high-risk patients who relapsed but was also associated with a high probability of relapse in standard-risk patients. Sixty-five percent (13/20) of standard-risk patients who also showed clonal diversity subsequently relapsed, whereas the percentage of relapses among standard-risk patients without clonal diversity was much lower at 19% (7/36). Continued clonal evolution during disease progression is an important feature of aggressive B-precursor ALL. All 5 patients with clonal diversity who were followed up in our study showed a change in the pattern of clonality between presentation and relapse. This implies an important role for clonal diversity as a mechanism of disease progression through the process of clonal variation and clonal selection. © 1998 by The American Society of Hematology.

Cayouette, J. & Darbyshire, S. J.: Taxa described by Steudel from the Labrador plants collected by the Moravian missionary Albrecht and distributed by Hohenacker. — Taxon43: 169‐180. 1994. – ISSN 0040‐0262. Types of names of seven taxa described by Steudel in his Synopsis plantarum glumacearumfrom the Labrador collections of the Moravian missionary Albrecht were examined. Information compiled from the specimen labels as well as biographic and bibliographic sources suggest this material was collected at Hopedale between 1846 and 1848. Samples of the handwriting of Albrecht, Steudel, and possibly Hohenacker are presented. Reinterpretation of the types is provided and a lectotype of Calamagrostis hirtiglumais designated. Biographical information on C. G. Albrecht, as well as several poorly known Moravian missionaries, is presented.

Darbyshire, S. J. & Cayouette. J.: An examination of the holotype of × Dupontopoa dezhneviiProb. (Poaceae). ‐ Taxon41: 737‐743. 1992. ‐ ISSN 0040‐0262. The type specimen of ×Dupontopoa dezhneviiProb, was examined. It is composed of 3 discordant elements, none of which would seem to be a hybrid resulting from the proposed parentage. The name is lectotypified on an element identified as Poa eminens. Taxonomic and nomenclatural implications of the observations are discussed. The synonymy for P. eminensis given.

Forty‐three vascular plant specimens were found recently at the National Herbarium of Canada that were collected by Sir Joseph Banks on his voyage to Newfoundland and Labrador in 1766. A list of these specimens is presented together with a discussion of the relationship that they bear to collections at the British Museum (Natural History) in London as well as information contained in Banks's personal diary and plant catalogue.