Risk factors for moderate-to-severe chronic graft-versus-host disease after allogeneic hematopoietic stem cell transplantation

AbstractAmong 810 consecutive hematopoietic stem cell transplantation (HSCT) patients, 679 survived more than 3 months and were evaluated for chronic GVHD. The aim of this study was to find predisposing factors increasing the risk of development of moderate-to-severe chronic GVHD. Many of the donors were HLA-identical siblings or related (n = 435), 185 were HLA-matched unrelated, and 59 were mismatched related or unrelated donors. Most of the patients had a hematological malignancy (n = 568), but 111 patients with a nonmalignant disease were included. Two hundred twenty-three patients (33%) developed mild, 41 (6%) moderate, and 15 (2.2%) severe chronic GVHD. The 5-year probability of development of moderate-to-severe chronic GVHD was 10%. We analyzed 30 potential risk factors for chronic GVHD. In the multivariate analysis, acute GVHD grades II to IV (relative hazard [RH], 2.30; 95% CI, 1.29- 4.10; P = .005), CML diagnosis (RH, 2.37; CI, 1.38-4.08; P = .002) and transplantation from an immunized female donor to a male recipient (RH, 2.16; CI, 1.14-4.11; P = .02) were independent risk factors for moderate-to-severe chronic GVHD. Recipient age also was significant (RH, 2.42; CI, 1.23-4.77; P = .01) if CML was not included in the analysis. In patients with no risk factors, the 5-year probability of development of moderate-to-severe chronic GVHD was 5%. In patients with 1 risk factor, the probability was 13%; 2 risk factors, 23%; and 3 risk factors, 45%. Among patients who developed chronic GVHD (n = 279), acute GVHD grades II to IV (RH, 2.18; CI, 1.23-3.86; P < .01) was the only predictive factor for moderate-to-severe chronic GVHD versus mild disease. Patients with previous acute GVHD grades II to IV may benefit from more aggressive initial treatment. This possibility would have to be examined in clinical trials.Biol Blood Marrow Transplant 2002;8(12):674-82

The developing rat kidney : the dopamine system and related serine/threonine kinases and phosphatases

The kidney originates from the fusion and conversion of two tissues: the metanephric mesenchyme and the ureter epithelium, an evagination from the Wolffian duct. Although a number of candidate molecules have been shown to be of importance for the differentiation of the embryonic kidney, many of the signalling pathway leading to this development are still obscure. A large proportion of important functions in eukaryotic cells is meticulously regulated by reversible protein phosphorylation, carried out by protein kinases and phosphates. This thesis presents data from five studieson serine/threonine protein phosphorylation during the foetal and postnatal development of the rat kidney. The isoforms of protein phosphatases (PP) 1 and PP2A had differential and age-dependent expression patterns, initially with a general distribution, shifting to restricted distributions later in nephrogenesis. All were present in the peripheral, nephrogenic, zone. Inhibition of PP1 and PP2A with okadaic acid in metanephric culture severely disturbed growth and differentiation and induced apoptosis. Protein kinase C (PKC) isoforms [alpha], [delta], [zeta] and [lambda]were age-dependently expressed with individual distribution patterns. Inhibition of PKC in primary culture of proximal tubule cells and in metanephric organ culture resulted in disrupted morphogenesis, increased apoptosis and age-dependent growth inhibition. Inhibitor-1, an endogenous and specific inhibitor of PP1, was specifically expressed in uninduced metanephric mesenchyme at embryonic day (E) 15. Inhibitor-1 is the first known marker of these cells. DARPP-32, another specific PP1 inibitor with a central position in dopaminergic cell signalling, was not detected until E 18. From that age, DARPP-32 was highly concentrated in ureter bud tips, the inducing tissue. The same distribution of DARPP-32 was observed in foetal mouse kidneys. Mice deficient in DARPP-32 had a 28% nephron deficit. They were also unable to regulate natriuresis in response to atrial natriuretic peptide. Furthermore, these mice were hypertensive. Dopamine and its synthesizing (AADC) and metabolizing (COMT) enzymes, as well as the dopamine D1A receptor, were all detected in foetal rat kidneys, each with specific distribution. Conclusion: Reversible protein phosphorylation is an important intracellular modulating system for kidney morphogenesis. This study also presents, for the first time, data indicating important roles for dopamine and dopamine-related signalling during nephrogenesis. The DARPP-32 deficient mice constitute a new model for limited nephron deficit and may be valuable in future research on renal insufficiency and hypertension

Renal, gastrointestinal, and hepatic late effects in survivors of childhood acute myeloid leukemia treated with chemotherapy only--a NOPHO-AML study.

To access publisher's full text version of this article. Please click on the hyperlink in Additional Links field.We investigated the spectrum, frequency, and risk factors for renal, gastrointestinal, and hepatic late adverse effects in survivors of childhood acute myeloid leukemia (AML) without relapse treated with chemotherapy alone according to three consecutive AML trials by the Nordic Society of Pediatric Hematology and Oncology (NOPHO).A population-based cohort of children treated for AML according to the NOPHO-AML-84, -88, and -93 trials included 138 eligible survivors of whom 102 (74%) completed a questionnaire and 104 (75%) had a clinical examination and blood sampling performed. Eighty-five of 94 (90%) eligible sibling controls completed a similar questionnaire. Siblings had no clinical examination or blood sampling performed.At a median of 11 years (range 4-25) after diagnosis, renal, gastrointestinal, and hepatic disorders were rare both in survivors of childhood AML and in sibling controls, with no significant differences. Ferritin was elevated in 21 (21%) AML survivors but none had biochemical signs of liver damage. Viral hepatitis was present in three and cholelithiasis in two AML survivors. One adult survivor had hypertension, two had slightly elevated systolic blood pressure, and eight survivors had slightly elevated diastolic blood pressure. These persons all had normal creatinine and cystatin C levels. Marginal abnormalities in potassium, magnesium, calcium, or bicarbonate levels were found in 34 survivors.Survivors of childhood AML treated with chemotherapy only experienced few renal, gastrointestinal, and hepatic late effects.Danish Cancer Society Danish Childhood Cancer Foundation Karen Elise Jensen Foundation Swedish Childhood Cancer Foundatio

Quality of health in survivors of childhood acute myeloid leukemia treated with chemotherapy only: a NOPHO-AML study.

To access publisher full text version of this article. Please click on the hyperlink in Additional Links field.BACKGROUND: More than 60% of children with acute myeloid leukemia (AML) become long-term survivors, and approximately 50% are cured with chemotherapy only. Limited data exist about their long-term morbidity and social outcomes. The aim of the study was to compare the self-reported use of health care services, health experience, social outcomes, and lifestyle behavior of AML survivors with that of their sibling controls. METHODS: This population-based study included 138 children treated for AML according to the Nordic Society of Pediatric Hematology and Oncology (NOPHO)-AML-84, -88, and -93 trials, and alive by June 30, 2007. Patients treated with hematopoietic stem cell transplantation (HSCT) or relapse were not included. Altogether, 102 (74%) survivors and 91% of their siblings completed a questionnaire. RESULTS: The median follow-up was 11 (range 4-25) years after diagnosis. AML survivors had no increased rate of hospitalization compared with sibling controls, but were more often receiving prescription drugs, especially for asthma (23% vs. 9%, P = 0.03). Self-reported health experience was excellent or very good in 77% and comparable with that of siblings. Educational achievement, employment, and marital status were comparable in the two groups. Among surviving AML patients, 23% were current smokers and 24% of their siblings were current smokers. CONCLUSIONS: The self-reported health of children treated on NOPHO-AML protocols without HSCT was good, and their use of health care services was limited. Reported health and social outcomes were comparable to those of their siblings. Many survivors were smoking which may increase the risk of late effects.A. P. Moller Foundation for the Advancement of Medical Science Aarhus University Hospital Research Initiative Foundation Aase and Ejnar Danielsen Foundation Anders Hasselbalch Foundation Bent Bogh and wife Inge Bogh Foundation Carl J. Beckers Foundation Dagmar Marshall Foundation Danish Cancer Society Danish Childhood Cancer Foundation Danish Graduate School in Clinical Oncology Eva and Henry Fraenkel Foundation Frode V. Nyegaard and Wife Foundation Johannes Fogh-Nielsen and wife Ella Fogh-Nielsen Grant Karen Elise Jensen Foundation Kurt Bonnelycke and wife Grethe Bonnelycke Foundation M. Brogaard and Wife Foundation Max and Anna Friedmann Grant Meta and Haakon Bagger Foundation Oticon Foundation Otto Christensen Foundation Simon Fougner Hartmann and Family Foundation Sophus Jacobsen and wife Astrid Jacobsen Foundation Swedish Childhood Cancer Foundation Thora and Viggo Grove Grant University of Aarhu