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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.

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.

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.

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 hyperactivePARP1mutation 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 aTP53mutation 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.

Phytogeographic, ecological, morphological, anatomical, cytological, isozyme, and endonuclease restriction site evidence is presented demonstrating thatPoa labradorica is of intergeneric hybrid origin betweenDupontia fisheri subsp.psilosantha (pistillate parent) andPoa eminens (staminate parent).Poa labradorica is endemic to recently deglaciated areas of northern Quebec and Labrador which are within the overlapping range of the putative parents. Incapable of sexual reproduction,P. labradorica dominates large areas of coastal marsh through vigorous production of rhizomes. Most morphological, anatomical, cytological, isozyme, and DNA characters studied inP. labradorica showed states intermediate or additive to those of the putative parents.

Many estuaries of medium to high tidal range exhibit an accumulation of fine cohesive material in their upper reaches in the region of the limit of saline intrusion. Much, or all, of this material is suspended each tidal cycle and the entire region undergoes a seasonal variation which appears to depend on fluvial input.

This paper reports on an investigation into the lower Forth estuary where a combination of hydrody namic, dye and salinity measurement techniques have been employed to quantify the effects of temporally varying vertical and transverse density gradients on the diffusion and dispersion processes. It is concluded that the interaction of velocity shear and weak longitudinal salinity induced density gradient produces a complex and profound effect on estuarine solute mixing processes.

To define the determinants of diarrhea after bone marrow transplantation (BMT) and its nutritional sequelae, the medical records of 20 consecutive children (median age, 9 years; 13 boys and 7 girls) undergoing BMT at Children's Hospital in Birmingham, UK were surveyed. All patients who received total body irradiation (TBI) required parenteral nutrition (PN). Seventy-eight percent of TBI patients and 73% of children who received allografts developed diarrhea compared with only 27% of non-TBI patients and 22% of those who received auto grafts (P < 0.05). Ninety percent of children with diarrhea required PN. Duration of PN in these children was longer than in those without diarrhea who requested PN (P < 0.05). Despite PN, weight loss at discharge was still greater in the study group (P < 0.05). Diarrhea was associated with a significant fall in serum albumin (P < 0.005). Diarrhea and weight loss occur in children after BMT despite active PN support. Pretransplant TBI and the we of all grafts are important determinants of these complications.

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.

A 7-year-old girl with hypereosinophilic syndrome is described, the first such patient to present with inflammatory bowel disease. Hepatosplenomegaly, anaemia, and hypergammaglobulinaemia were also prominent features. Colonoscopy revealed a frank colitis of nonspecific histologic appearance. An elemental diet was unhelpful, but there was a prompt clinical and partial haematological response to systemic steroids. She has remained well receiving a small maintenance dose of prednisolone for 3 years.

We carried out a pilot study using ceftazidime alone in the treatment of febrile, neutropenic children. A total of 16 episodes were treated before the study was re-evaluated and tobramycin was added. Nineteen episodes have now been treated with a combination of ceftazidime and tobramycin. Of the first group, seven episodes failed to respond to ceftazidime; in five resistant or only partially sensitive organisms were thought to be the cause of failure. The most serious problem was our inability to predict two severe staphylococcal infections only partially sensitive to ceftazidime. These initial findings led us to add tobramycin to the regimen and to conclude that ceftazidime is not an appropriate antibiotic as a single agent in this group of patients.

A 7-year-old girl with hypereosinophilic syndrome is described, the first such patient to present with inflammatory bowel disease. Hepatosplenomegaly, anaemia, and hypergammaglobulinaemia were also prominent features. Colonoscopy revealed a frank colitis of nonspecific histologic appearance. An elemental diet was unhelpful, but there was a prompt clinical and partial haematological response to systemic steroids. She has remained well receiving a small maintenance dose of prednisolone for 3 years.

In the absence of an HLA identical donor, T-cell depleted haploidentical hematopoietic stem cell transplantation (HSCT) is an alternative option to treat children with high risk or relapsed acute leukaemia. However very few data is available in a large series of children. With the aim to study risk factors of outcomes we have analyzed 196 children (<16 years old) with ALL (n=131) or AML (n=65) transplanted with a T-cell depleted bone marrow (n=18) or peripheral blood related haploidentical HSCT from 1995 to 2004 in Europe. The median age was 8 years and median follow-up 22 months. In the AML group, 13 (20%) children were transplanted in CR1, 22 (34%) in CR2 and 30 (46%) in advanced phase and in ALL group, 28 (21%) in CR1, 74 (56%) in CR2 and 81 (62%) in more advanced phase. The majority of the patients did not receive drugs for GVHD prophylaxis and all received myeloablative conditioning (61% of TBI). Cumulative incidence with competing risk and KM estimates were used to calculate outcomes probabilities. The median days of neutrophil recovery was 14 days (4–72) and 85% of patients had signs of engraftment. Acute GVHD II–IV was observed in 17% of the patients (8% had grade III–IV). Two-years overall LFS, relapse incidence and TRM were 27±4%, 43±3%, 30±3%, respectively. Patients transplanted with AML or ALL had similar outcomes. LFS was 28±6%for AML and 27±4% for ALL. Among the risk factors analysed only the disease status at transplantation was associated with LFS and relapse incidence. Outcomes are listed below according to disease status at transplant. Outcomes at two years CR1 (n=41) CR2 (n=74) Advanced (n=81) p value Transplant related mortality 32+/−8% 26+/−5% 33+/−5% 0.44 Relapse 32+/−8% 40+/−6% 51+/−6% 0.03 Leukaemia free survival 36+/−8% 34+/−6% 16+/−4% <0.0001 In fact, in a multivariate analysis for LFS and relapse only patients transplanted in remission had better LFS and decreased relapse incidence compared with non remission patients (p<0.001 and p=0.006, respectively). No risk factor was found to be associated with TRM. Most frequently, causes of death were relapse (60%) or infections (22%). In conclusion, haploidentical HSCT is an alternative option to treat children with high risk acute leukaemia in the absence of HLA identical donor.

In the absence of an HLA identical donor, T-cell depleted haploidentical hematopoietic stem cell transplantation (HSCT) is an alternative option to treat children with high risk or relapsed acute leukaemia. However very few data is available in a large series of children. With the aim to study risk factors of outcomes we have analyzed 196 children (<16 years old) with ALL (n=131) or AML (n=65) transplanted with a T-cell depleted bone marrow (n=18) or peripheral blood related haploidentical HSCT from 1995 to 2004 in Europe. The median age was 8 years and median follow-up 22 months. In the AML group, 13 (20%) children were transplanted in CR1, 22 (34%) in CR2 and 30 (46%) in advanced phase and in ALL group, 28 (21%) in CR1, 74 (56%) in CR2 and 81 (62%) in more advanced phase. The majority of the patients did not receive drugs for GVHD prophylaxis and all received myeloablative conditioning (61% of TBI). Cumulative incidence with competing risk and KM estimates were used to calculate outcomes probabilities. The median days of neutrophil recovery was 14 days (4–72) and 85% of patients had signs of engraftment. Acute GVHD II–IV was observed in 17% of the patients (8% had grade III–IV). Two-years overall LFS, relapse incidence and TRM were 27±4%, 43±3%, 30±3%, respectively. Patients transplanted with AML or ALL had similar outcomes. LFS was 28±6%for AML and 27±4% for ALL. Among the risk factors analysed only the disease status at transplantation was associated with LFS and relapse incidence. Outcomes are listed below according to disease status at transplant.

The West Midlands Regional Children's Tumour Registry collects detailed information on all cases of childhood cancer in the West Midlands Health Authority Region (WMHAR). The distribution by electoral ward of all cases diagnosed in the WMHAR between 1980 and 1984 has been determined. Analysis has also been performed for leukaemias/non-Hodgkin's lymphomas alone. We suggest that this latter grouping should be universally employed, owing to the difficulty of accurately separating out cases of leukaemia. Both spatial analyses showed several wards with significantly excessive rates on the basis of their cumulative Poisson probability. Observed/expected ratios of 3–35 were seen for cases in significant wards, which are similar to the ratios seen in analasis of incidence around nuclear installations. However, further detailed consideration of the these individual significance levels in the light of the number of statistically significant wards which would occur by chance alone, due to the multiple use of the test, accounted completely for the number of wards obtained in each of the groups considered. Thus, apparent ‘clustering’ of cases could be mere statistical artefact. In the WMHAR, therefore, using the technique of probability mapping, no true spatial pattern of incidence was found, other than that which would occur by chance alone. This, in a large area without nuclear installations and an even mix of rural and industralised regions, could be seen as control data for those studies which have considered cases of childhood leukaemia around nuclear facilities, where the observation of single point clusters associated with suspected sites restricts assessments of spatial pattern in the rest of the area. Consideration is given to the problems of using probability mapping alone in analysis of data such as ours, which highlights the low power and inherent limitations of the technique. We conclude that results obtained using this method need to be supplemented using further tests and suggestions are made as to useful future developments.