The burden of chemotherapy-induced nausea and vomiting in children receiving hematopoietic stem cell transplantation conditioning: a prospective study.

This prospective study describes chemotherapy-induced nausea and vomiting (CINV) in children (4-18 years) receiving their first hematopoietic stem cell transplant. Emetic episodes, nausea severity (assessed using a validated, self-report nausea severity assessment tool) and antiemetic administration were documented from the start of conditioning until 24 h after the last conditioning agent was administered (acute) and for a further 7 days (delayed). Relationships between CINV control and parenteral nutrition (PN) use and acute gut GvHD (aGvHD) were explored. Fifty-nine children (4.6-17.4 years) were evaluable. Complete chemotherapy-induced vomiting (CIV; acute: 24%; delayed 22%) and chemotherapy-induced nausea (CIN; acute 7%; delayed 12%) control rates were low. Few children experienced complete CINV control (no vomiting/retching and no nausea) during the acute (5%) or delayed phases (12%). Children experiencing complete acute or delayed CIN control or complete delayed CIV control were more likely to have received: a lower proportion of their total energy requirement as PN at the end of the delayed phase (P<0.036) and PN for a shorter time (P<0.044). Low patient numbers did not permit evaluation of the association between gut aGvHD and CINV control. Effective and safe interventions aimed at improving CINV control in children are required.

Using Genomic Location and Coalescent Simulation to Investigate Gene Tree Discordance in Medicago L.

Several well-documented evolutionary processes are known to cause conflict between species-level phylogenies and gene-level phylogenies. Three of the most challenging processes for species tree inference are incomplete lineage sorting, hybridization and gene duplication, which may result in unwarranted comparisons of paralogous genes. Several existing methods have dealt with these processes but none has yet been able to untangle all three at once. Here, we propose a stepwise method by which these processes can be discerned using information on genomic location coupled with coalescent simulations. In the first step, highly discordant genes within genomic blocks (putative paralogs) are identified and excluded from the data set and, in the second step, blocks of linked genes are grouped according to their hybrid history. Existing multispecies coalescent software can then be applied to recover the principal tree(s) that make up the species tree/network without violating the underlying model. The potential of the approach is evaluated on simulated data derived from a species network composed of nine species, of which one is of hybrid origin, and displaying a single-gene duplication that leads to paralogous comparisons. We apply our method to an empirical set of 12 genes from 7 species sampled in the plant genus Medicago that display phylogenetic discordance. We identify the causes of the discordance and demonstrate that the Medicago orbicularis lineage experienced an episode of ancient hybridization. Our results show promise as a new way to explore phylogenetic sequence data that can significantly improve species tree inference in presence of hybridization and undetected paralogy or other causes leading to extremely discordant gene trees. [Coalescent simulation; gene tree; genomic location; hybridization; incomplete lineage sorting; paralogy; phylogenetic incongruence; principal tree; species tree.].

Allogeneic hematopoietic cell transplantation for neuroblastoma: the CIBMTR experience.

Although the role of autologous hematopoietic cell transplantation (auto-HCT) is well established in neuroblastoma (NBL), the role of allogeneic HCT (allo-HCT) is controversial. The Center for International Blood and Marrow Transplant Research conducted a retrospective review of 143 allo-HCT for NBL reported in 1990-2007. Patients were categorized into two different groups: those who had not (Group 1) and had (Group 2) undergone a prior auto-HCT (n=46 and 97, respectively). One-year and five-year OS were 59% and 29% for Group 1 and 50% and 7% for Group 2, respectively. Among donor types, disease-free survival (DFS) and OS were significantly lower for unrelated transplants at 1 and 3 years but not at 5 years post HCT. Patients in CR or very good partial response (VGPR) at transplant had lower relapse rates and better DFS and OS, compared with those not in CR or VGPR. Our analysis indicates that allo-HCT can cure some neuroblastoma patients, with lower relapse rates and improved survival in patients without a history of prior auto-HCT as compared with those patients who had previously undergone auto-HCT. Although the data do not address why either strategy was chosen for patients, allo-HCT after a prior auto-HCT appears to offer minimal benefit. Disease recurrence remains the most common cause of treatment failure.

Transgressive physiological and transcriptomic responses to light stress in allopolyploid Glycine dolichocarpa (Leguminosae).

Allopolyploidy is often associated with increased photosynthetic capacity as well as enhanced stress tolerance. Excess light is a ubiquitous plant stress associated with photosynthetic light harvesting. We show that under chronic excess light, the capacity for non-photochemical quenching (NPQ(max)), a photoprotective mechanism, was higher in a recently formed natural allotetraploid (Glycine dolichocarpa, designated 'T2') than in its diploid progenitors (G. tomentella, 'D3'; and G. syndetika, 'D4'). This enhancement in NPQ(max) was due to an increase in energy-dependent quenching (qE) relative to D3, combined with an increase in zeaxanthin-dependent quenching (qZ) relative to D4. To explore the genetic basis for this phenotype, we profiled D3, D4 and T2 leaf transcriptomes and found that T2 overexpressed genes of the water-water cycle relative to both diploid progenitors, as well as genes involved in cyclic electron flow around photosystem I (CEF-PSI) and the xanthophyll cycle, relative to D4. Xanthophyll pigments have critical roles in NPQ, and the water-water cycle and CEF-PSI are non-photosynthetic electron transport pathways believed to facilitate NPQ formation. In the absence of CO(2), T2 also exhibited greater quantum yield of photosystem II than either diploid, indicating a greater capacity for non-photosynthetic electron transport. We postulate that, relative to its diploid progenitors, T2 is able to achieve higher NPQ(max) due to an increase in xanthophyll pigments coupled with enhanced electron flow through the water-water cycle and CEF-PSI.

High alpha-1 antitrypsin clearance predicts severity of gut graft-versus-host disease (GVHD) in children.

The clinical evaluation and management of gut GVHD is a significant challenge in pediatric HSCT. It is often difficult to obtain pathological evidence to confirm diagnosis and/or to determine response to treatment. The severity of the disease itself may not be related to just the classic symptom of diarrhea. The objectives of this study were to prospectively evaluate patients with suspected gut GVHD for PLE as measured by AATC in stools at two different times for each patient and to compare the severity of the PLE with the severity of clinical acute gut GVHD. Thirteen patients were suspected of gut GVHD by clinical criteria (diarrhea > 10 mL/kg/24 h); one patient was excluded for being unable to complete the stool collection. Therefore, 12 patients, 10 boys and two girls, were studied. Median stool volume was 27.5 mL/kg/day (range 10.1-109.0).The median age at BMT was 11.1 yr (range 3.9-17.0 yr). All patients had negative stool electron microscopy for viruses and cultures for C. difficile on their first collection. Nine patients (75%) had two 24-h stool collections performed at a median of eight days apart (range 7-14 days). At the time of the first collection, six patients had ≥ stage 2 acute gut GVHD, and at second collection, four patients had ≥ stage 2 gut GVHD and four collections were of non-diarrheal stool (hence treatment response). Median AATC from all 21 collections was 19.0 mL/day (range 3.0-561.0), and levels >22 mL/day indicate the diagnosis of PLE. The four children initially suspected of GVHD but who had a negative biopsy completed a total of five collections with a median AATC of 5.0 mL/day (range 3.0-16.0) vs. a median of 33.5 for the remainder of the collections (range 3-561). Stage of gut GVHD correlated with elevated AATC and with stool volume. AATC > 22 mL/day showed a sensitivity of 70% and specificity of 82% for significant gut GVHD (≥ stage 2). Seven stool collections were taken at ≥ stage 3 gut GVHD; six of those seven patients were positive for PLE. Larger stool volumes were more predictive, and five collections with stool volumes >30 mL/kg/day were positive for PLE. We conclude that a significant positive correlation exists between the severity of PLE and the stage of gut GVHD (p < 0.04), particularly obvious in patients with stages 2-4 GVHD (p = 0.03). Despite the small number of patients recruited, this study emphasizes the need to consider PLE as a useful aspect of the clinical picture. We suggest that in order to see a response to therapy and therefore a decrease in AATC, clinicians should wait at least 2 wk from the initiation of therapy before repeating AATC test. In light of the significant morbidity and mortality associated with ≥ stage 2 gut GVHD, and as an important therapeutic decision for these patients, one may consider evaluating AATC if a biopsy is not an option.

Comparative outcome of hematopoietic stem cell transplantation for pediatric acute lymphoblastic leukemia following cyclophosphamide and total body irradiation or VP16 and total body irradiation conditioning regimens.

To compare the outcome of hematopoietic stem cell transplantation (HSCT) in pediatric acute lymphoblastic leukemia (ALL) conditioned with two different regimens: (1) single dose of VP16 (60 mg/kg over 4 h) and total body irradiation (TBI; 1200 cGy, in six fractions) or (2) Cyclophosphamide 50 mg/kg over 1 h daily for 4 days followed by the same dose of TBI. One hundred and seven children with ALL received fully matched HSCT from 1990 to 2003 in the Hospital for Sick Children, Toronto. All received cyclosporin A and a short course of methotrexate for graft-versus-host disease (GVHD) prophylaxis. The VP16 group, there were 36 matched related donor transplants (MRD) and 26 matched unrelated donor transplants (MUD), and in the cyclophosphamide group there were 23 MRD and 22 MUD transplants. Neutrophil engraftment occurred at a median of 18 and 17 days for the VP16/TBI and the CY/TBI groups, respectively. The 3 year event-free survival and overall survival were 47 +/- 7 and 55 +/- 7% for those receiving VP16/TBI, and 51 +/- 8 and 53 +/- 8% for the CY/TBI group. There were no significant differences in the prevalence of acute or chronic GVHD and transplant-related mortality between the two groups. Both VP16/FTBI and CY/FTBI regimen are equally effective regimens.

Direct costs of glaucoma and severity of the disease: a multinational long term study of resource utilisation in Europe.

BACKGROUND: Resource utilisation and direct costs associated with glaucoma progression in Europe are unknown. As population progressively ages, the economic impact of the disease will increase. METHODS: From a total of 1655 consecutive cases, the records of 194 patients were selected and stratified by disease severity. Record selection was based on diagnoses of primary open angle glaucoma, glaucoma suspect, ocular hypertension, or normal tension glaucoma; 5 years minimum follow up were required. Glaucoma severity was assessed using a six stage glaucoma staging system based on static threshold visual field parameters. Resource utilisation data were abstracted from the charts and unit costs were applied to estimate direct costs to the payer. Resource utilisation and estimated direct cost of treatment, per person year, were calculated. RESULTS: A statistically significant increasing linear trend (p = 0.018) in direct cost as disease severity worsened was demonstrated. The direct cost of treatment increased by an estimated 86 for each incremental step ranging from 455 euro per person year for stage 0 to 969 euro per person year for stage 4 disease. Medication costs ranged from 42% to 56% of total direct cost for all stages of disease. CONCLUSIONS: These results demonstrate for the first time in Europe that resource utilisation and direct medical costs of glaucoma management increase with worsening disease severity. Based on these findings, managing glaucoma and effectively delaying disease progression would be expected to significantly reduce the economic burden of this disease. These data are relevant to general practitioners and healthcare administrators who have a direct influence on the distribution of resources.

Placing paleopolyploidy in relation to taxon divergence: a phylogenetic analysis in legumes using 39 gene families.

Young polyploid events are easily diagnosed by various methods, but older polyploid events become increasingly difficult to identify as chromosomal rearrangements, tandem gene or partial chromosome duplications, changes in substitution rates among duplicated genes, pseudogenization or locus loss, and interlocus interactions complicate the means of inferring past genetic events. Genomic data have provided valuable information about the polyploid history of numerous species, but on their own fail to show whether related species, each with a polyploid past, share a particular polyploid event. A phylogenetic approach provides a powerful method to determine this but many processes may mislead investigators. These processes can affect individual gene trees, but most likely will not affect all genes, and almost certainly will not affect all genes in the same way. Thus, a multigene approach, which combines the large-scale aspect of genomics with the resolution of phylogenetics, has the power to overcome these difficulties and allow us to infer genomic events further into the past than would otherwise be possible. Previous work using synonymous distances among gene pairs within species has shown evidence for large-scale duplications in the legumes Glycine max and Medicago truncatula. We present a case study using 39 gene families, each with three or four members in G. max and the putative orthologues in M. truncatula, rooted using Arabidopsis thaliana. We tested whether the gene duplications in these legumes occurred separately in each lineage after their divergence (Hypothesis 1), or whether they share a round of gene duplications (Hypothesis 2). Many more gene family topologies supported Hypothesis 2 over Hypothesis 1 (11 and 2, respectively), even after synonymous distance analysis revealed that some topologies were providing misleading results. Only ca. 33% of genes examined support either hypothesis, which strongly suggests that single gene family approaches may be insufficient when studying ancient events with nuclear DNA. Our results suggest that G. max and M. truncatula, along with approximately 7000 other legume species from the same clade, share an ancient round of gene duplications, either due to polyploidy or to some other process.

Health-related quality of life (HRQL) scores reported from parents and their children with chronic illness differed depending on utility elicitation method.

OBJECTIVE: To describe the relationship between health-related quality of life (HRQL) as measured by utility when elicited from parents and their children with chronic illness. STUDY DESIGN AND SETTING: We enrolled families of children admitted for cancer chemotherapy and those attending outpatient rheumatology, hemophilia and bone marrow transplantation clinics. Children in grade 6 or higher were included. The child's HRQL was rated by parent and child using the Standard Gamble (SG), Visual Analogue Scale (VAS), Time Trade-Off (TTO), and Health Utilities Index Mark 2/3 (HUI2 and HUI3). RESULTS: 22 families were included. The mean parent SG was 0.92 +/- 0.09, which was similar to the mean SG elicited from their children of 0.92 +/- 0.10. The parent and child SG were moderately concordant (ICC=0.64, 95% CI=0.30, 0.83; P=.0005). In contrast, TTO scores were not concordant (ICC=0.14, 95% CI=-0.29, 0.53; P=.3), with parents (mean TTO=0.77 +/- 0.31) rating HRQL worse than children (mean TTO=0.92 +/- 0.11; P=.04). Similarly, the mean parent HUI2 of 0.82 +/- 0.22 was lower than the child HUI2 of 0.95 +/- 0.07; P=.02 and HUI2 were not concordant (ICC=0.11, 95% CI=-0.35, 0.53; P=.3) between parents and children. CONCLUSION: Parents and children rate HRQL similarly according to SG, but parents rate HRQL significantly worse using TTO and HUI2.

Underlying chronic granulomatous disease in a patient with bronchocentric granulomatosis.

We present a case of bronchocentric granulomatosis in a woman with no history of asthma who was colonised with Aspergillusfumigatus. A family history of chronic granulomatous disease prompted further testing that demonstrated severely depressed neutrophil oxidant production and gp91(phox) deficiency compatible with the X linked carrier state of chronic granulomatous disease. Only one report of the association of these two rare diseases has previously appeared in the literature. We postulate that an ineffective immune response led to the prolonged colonisation of Afumigatus resulting in a hypersensitivity reaction that was manifest clinically as bronchocentric granulomatosis.

Validity of a modified standard gamble elicited from parents of a hospital-based cohort of children.

OBJECTIVES: To examine the validity of a modified standard gamble (Mod SG) (nondeath baseline) by comparing these scores to SG (death baseline), time trade off (TTO), visual analog scale (VAS), Health Utilities Index (HUI), and Child Health Questionnaire (CHQ). METHODS: Respondents were parents of in-patients with cancer receiving chemotherapy and parents of children without cancer attending outpatient clinics. Construct validity was determined by comparing a priori hypotheses to actual correlations between measures. Discriminant validity was examined by anticipating that in-patients with cancer would have lower HRQL than outpatients. RESULTS: 85 families were included. Both Mod SG and SG were moderately correlated with TTO (r=0.50 and r=0.49; P<.01 for both). Both Mod SG and SG were moderately correlated with TTO (r=0.47 and r=0.05, P<0.002 for both). CONCLUSION: The Mod SG did not perform better than SG. Two nonoverlapping groups of HRQL measures were demonstrated.

Life-threatening pulmonary hemorrhages post bone marrow transplantation in Hurler syndrome. Report of three cases and review of the literature.

Hurler syndrome (MPS-IH) is an autosomal recessive mucopolysaccharide storage disorder caused by deficiency of lysosomal alpha-L-iduronidase (IDU) enzyme activity. This results in accumulation of heparan sulfate and dermatan sulfate substances. Untreated children develop progressive developmental deterioration and multisystem morbidity with a median survival of 5 years. Allogeneic bone marrow transplantation (BMT) is the only long-lasting treatment that ameliorates or halts the aggressive course of the disease. Pulmonary hemorrhage (PH) is an unusual complication of BMT and has not been previously reported in MPS-IH post-BMT. We report three children with MPS-IH with life-threatening PH around the time of engraftment. All needed intensive-care support and one child developed recurrent PH that required prolonged ventilation.

Low-intensity hematopoietic stem-cell transplantation across human leucocyte antigen barriers in dyskeratosis congenita.

Since the results of conventional hematopoietic stem-cell transplantation (HSCT) for patients with dyskeratosis congenita (DC) are poor owing to the high incidence of transplant-related complications, we explored the use of a low-intensity HSCT regimen. We report two children with DC with severe cytopenia, who underwent successful HSCT from a matched unrelated donor after conditioning with fludarabine, cyclophosphamide, and antithymocyte globulin. Graft-versus-host-disease (GVHD) prophylaxis consisted of corticosteroids and cyclosporin A. The regimen was well tolerated, no significant transplant-related complications were observed, and engraftment was rapid and complete. At 15 and 16 months after HSCT, the children were fully engrafted, in excellent clinical condition, full-donor chimerism, and no signs of GVHD. We conclude that a low-intensity regimen is sufficient to induce durable engraftment using matched unrelated donor HSCT in DC patients, with minimal 1-year transplant-related toxicity. Longer follow-up will determine whether this regimen also reduces long-term toxicity.

Construct validation of the Health Utilities Index and the Child Health Questionnaire in children undergoing cancer chemotherapy.

The objective of this study was to evaluate the construct validity of two questionnaire-based measures of health-related quality of life (HRQL) in children undergoing cancer chemotherapy: the Health Utilities Index (HUI) and the Child Health Questionnaire (CHQ). Subjects were children hospitalised for chemotherapy. To examine construct validity: (1). a priori expected relations between CHQ concepts and HUI attributes were examined; (2). HUI and CHQ summary scores were compared to visual analogue scale (VAS) scores. Ease of completion was rated using a 5-point categorical scale and completion time was recorded. A total of 36 subjects were included. The maximum score was seen in 15 (47%) of HUI3 assessments. As predicted, CHQ body pain was moderately correlated with HUI3 pain (r=0.51), CHQ physical functioning was moderately correlated with HUI2 mobility (r=0.58) and CHQ mental health was moderately correlated with HUI2 emotion (r=0.53). Only the CHQ psychosocial subscale (and not HUI) was correlated with VAS (r=0.44). The CHQ and the HUI were both easy to use. The HUI questionnaires required less time to complete (mean=3.1, s.d.=1 min) compared with CHQ (mean=13.1, s.d.=3.4 min, P<0.0001). In conclusion, HUI and CHQ demonstrated construct validity in children undergoing cancer chemotherapy. The Health Utilities Index is subject to a ceiling effect whereas CHQ requires more time to complete.

A cost-effectiveness evaluation of amlodipine usage in patients with coronary artery disease in Sweden.

The objective of this analysis was to calculate the cost-effectiveness of amlodipine therapy in patients with coronary artery disease in Sweden. It is hypothesised that treatment with amlodipine will have an impact on overall cardiovascular disease treatment costs, resulting in a positive cost-effectiveness profile. A Markov cohort simulation model was constructed to simulate event-related and procedure-related health economic outcomes of coronary artery disease populations on amlodipine versus those on placebo. Patient level data from the Prospective Evaluation of the Vascular Effects of Norvasc Trial was used to populate the model. The total number of adverse cardiovascular clinical outcomes experienced over a three-year period was lower for patient on amlodipine than for those on placebo. The rate of hospitalisation per patient due to angina, coronary artery bypass graft, percutaneous transluminal coronary angioplasty, congestive heart failure, and myocardial infarction in the placebo cohort was 64.7%, while the rate in the amlodipine cohort was 46.9%. The cost per patient was Swedish kroner (SEK)26,600 for amlodipine patients and SEK27,400 for placebo patients. The use of amlodipine resulted in improved clinical outcomes as well as a slight savings in cost over a three-year period.