Chronische myeloproliferative Erkrankungen

Zusammenfassung Die chronischen myeloproliferativen Erkrankungen (CMPE) sind neoplastische Erkrankungen der hämatopoetischen Stammzelle. Sie umfassen die chronische myeloische Leukämie (CML), die Polycythaemia vera, die essentielle Thrombozythämie, die primäre Osteomyelofibrose und Übergangsformen innerhalb dieser Erkrankungen sowie zwischen den CMPE und den Myelodysplasien. Hauptziele der Initialdiagnostik sind die genaue Klassifizierung der Erkrankung, die Erfassung von Risiko- und Prognosefaktoren sowie die Charakterisierung des malignen Klons mittels Zytogenetik und molekulargenetischer Methoden. Herkömmliche Therapeutika für alle CMPE sind Hydroxyurea und Interferon-. Bei der CML führt die gezielte Hemmung der BCR-ABL-Tyrosinkinase mit Imatinib klinisch zu hohen Ansprechraten. Die bisher einzige kurative Therapie für alle Entitäten ist die allogene Stammzelltransplantation. Bei der CML sollte die Indikation auf der Basis der neueren Risikoscores gestellt werden. Bei den BCR-ABL-negativen CMPE ist sie nur bei ungünstigem Krankheitsverlauf in Erwägung zu ziehen.

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Replicative aging of human articular chondrocytes during ex vivo expansion

OBJECTIVE: To investigate the contribution of clinical ex vivo expansion protocols to replicative aging of human chondrocytes. METHODS: Primary human chondrocytes were cultured as monolayers after isolation from 7 articular cartilage specimens. Cells were passaged corresponding to 12-19 cell population doublings (cpd). Aliquots of the cells were collected from each passage and analyzed for telomere length and telomerase activity. RESULTS: The rate of telomere shortening was heterogeneous, ranging from 147 to 431 bp/cpd (mean +/- SD 305 +/- 122). Telomerase activity was detected at various time points during passaging in 5 of 7 primary chondrocytes analyzed, but not in native human articular cartilage specimens. According to our data, an 8-10-fold ( approximately 3 cpd) ex vivo expansion of articular chondrocytes, as typically performed for transplantation procedures, leads to telomere erosion in the range of 900 bp. This is comparable with 30 years of aging based on the in vivo rate of telomere shortening of 30 bp/year recently found in chondrocytes. CONCLUSION: If telomere shortening is an important determinant of aging in human articular cartilage, an additional telomere loss due to ex vivo expansion might affect the incidence or time of onset of age-related cartilage disorders. However, given the limited extent of expansion performed in the clinical setting to date, a significant telomere-mediated increase in the risk of malignant transformation or replicative exhaustion of the transplanted cells seems unlikely.     

Effect on blood pressure of lumiracoxib versus ibuprofen in patients with osteoarthritis and controlled hypertension: a randomized trial

OBJECTIVES: Nonsteroidal anti-inflammatory drugs vary in their impact on blood pressure and the effect of lumiracoxib 100 mg once daily has not been studied previously. To examine whether lumiracoxib 100 mg once daily would result in lower 24-h mean systolic ambulatory blood pressure than ibuprofen 600 mg three times daily in osteoarthritis patients with controlled hypertension, a 4-week, randomized, double-blind, parallel-group study was conducted in 79 centres in nine countries. METHODS: Hypertensive osteoarthritis patients of 50 years at least whose office blood pressure was less than 140/90 mmHg on stable antihypertensive treatment were randomized to lumiracoxib (n = 394) 100 mg once daily or ibuprofen 600 mg three times daily (n = 393) and 24-h ambulatory blood pressure monitoring was performed at baseline and end of study. The primary outcome measure was a comparison of the change in 24-h mean systolic ambulatory blood pressure from baseline to week 4. Secondary analyses included other blood pressure-related endpoints and efficacy (pain) measurements. RESULTS: Compared with baseline, the 24-h mean systolic ambulatory blood pressure (least square mean) decreased in lumiracoxib-treated patients (-2.7 mmHg) and increased in ibuprofen-treated patients (+2.2 mmHg) at 4 weeks, estimated difference -5.0 mmHg (95% confidence interval -6.1 to -3.8) in favour of lumiracoxib. The 24-h mean diastolic ambulatory blood pressure changes were -1.5 mmHg (lumiracoxib), +0.5 mmHg (ibuprofen), difference -2.0 mmHg (95% confidence interval -2.7 to -1.3). Efficacy results were comparable. CONCLUSIONS: Treatment with lumiracoxib 100 mg once daily resulted in clinically significant lower blood pressure compared with ibuprofen 600 mg three times daily in osteoarthritis patients with well controlled hypertension.     

Polymorphisms within glutathione S-transferase genes in pediatric non-Hodgkin's lymphoma

BACKGROUND AND OBJECTIVES: Glutathione S-transferases (GSTs) are involved in the metabolism of a number of cancer chemotherapeutic agents. Certain members within the GST superfamily exhibit phenotypically relevant genetic polymorphisms which have been associated with outcome in hematologic malignant disease. DESIGN AND METHODS: In the present study we genotyped a cohort of 169 pediatric non-Hodgkin's lymphoma (NHL) patients with available specimens from the NHL-BFM trials 86 and 90 conducted by the Berlin-Frankfurt-Münster (BFM) study group to assess a potential association of phenotypically relevant glutathione S-transferase polymorphisms (GSTM1, GSTT1, GSTP1 codon 105) with treatment outcome in this patient group. RESULTS: Treatment failure in patients with mature B-cell NHL was significantly less likely to occur in patients carrying at least one GSTM1 allele in comparison to those with a homozygous deletion of GSTM1. This protective effect mediated by the presence of GSTM1 was even more pronounced within the subset of therapy group B patients at highest clinical risk of treatment failure (B-ALL, disease stage IV, disease stage III with unresected abdominal tumor, and LDH activity > or = 500 U/L). Of all events in therapy group B, 87.5% occurred in this high risk group. Within this subset, the multivariate relative risk reached 4.98 (95% CI = 1.27-19.52; p= 0.021). INTERPRETATION AND CONCLUSIONS: Our results suggest that genetic variation at the GSTM1 locus may be of clinical importance in pediatric NHL and may be a potential candidate for indicating future treatment stratification strategies.     

Acute lymphoblastic leukemia of childhood: identification of two distinct regions of deletion on the short arm of chromosome 12 in the region of TEL and KIP1

Cytogenetic analysis of acute lymphoblastic leukemia (ALL) of childhood identified nonrandom chromosomal abnormalities of the short arm of chromosome 12. The alterations include deletions that are thought to be indicative of the presence of a tumor suppressor gene that is mutated on the remaining allele. To refine further the chromosomal localization of this gene, we analyzed the loss of heterozygosity (LOH) of chromosome 12 in 100 primary ALL samples using 22 polymorphic markers and identified two distinct smallest common deleted regions on chromosome 12p13. One region is flanked by D12S77 and D12S98 and has a size of 4 cM. Twenty-six percent of informative patients showed LOH in this region. This region may contain the TEL gene. The other region is flanked by D12S269 and D12S308 including the KIP1 gene. Forty-four percent of informative patients showed LOH in this second region. Mutational analysis of KIP1 using polymerase chain reaction-single- strand conformation polymorphism analysis and Southern blot analysis showed no homozygous deletions and point mutations suggesting that the altered gene in this second region is not the KIP1. Clinical data showed that LOH of 12p was demonstrated more frequently in precursor-B ALLs (32 of 80; 40%) than in T-ALLs (1 of 20; 5%) (P = .0027). Furthermore, patients with 12p LOH were younger (P = .013), with a lower DNA index (P = .046), but they had the same survival rates at 3 years. In summary, these data suggest that two different tumor suppressor genes are on chromosome arm 12p, which act separately in the development of childhood precursor-B ALLs. One of the tumor suppressor genes is in the region the KIP1 gene, but our data suggest this gene is not abnormal. The other target is in the region of the TEL gene; and this candidate deserves further study.     

Relapse of Philadelphia chromosome positive acute lymphoblastic leukaemia after marrow transplantation: sustained molecular remission after early and dose-escalating infusion of donor leucocytes

We present a patient who underwent sibling allogeneic BMT because of refractory Ph+ve ALL and remained BCR-ABL-positive after marrow grafting. Haemopoietic precursor cells were predominantly BCR-ABL-negative and of donor origin. In T cells an exclusively donor genotype was demonstrated. Despite donor leucocyte infusion (DLI), 20 weeks after BMT BCR-ABL fusion mRNA increased in semiquantitative polymerase chain reaction and leukaemic infiltration of the patient's bone marrow was seen. After a second course of DLI the patient achieved sustained molecular remission but he developed severe graft-versus-host disease (GvHD) and died from bacterial sepsis 9 months after DLI.     

Elevated ambient temperature retards the atrophic response of the neuroendocrine-reproductive axis of male Syrian hamsters to either daily afternoon melatonin injections or to short photoperiod exposure

Adult male Syrian (golden) hamsters, maintained under either 22 +/- 2 or 32 +/- 2 degrees C, were treated with 8 or 11 weeks of exposure to either long photoperiod (14:10), short photoperiod (8:16), or to long photoperiod with a daily afternoon melatonin injection. By 8 weeks, the animals kept at 22 degrees C and treated with daily afternoon melatonin injection exhibited a dramatic reduction in testicular and accessory sex organ weight, but the animals kept at 32 degrees C and treated in the same way exhibited only slight decreases in testicular and accessory organ weights. Short photoperiod caused a slight decrease in testicular and accessory organ weights of hamster kept at 22 degrees C, while it had no significant effects on reproductive organ weights of the animals maintained under 32 degrees C. By 11 weeks, the daily afternoon melatonin injection elicited further reduction in testicular and accessory organ weights of the animals maintained under both 22 and 32 degrees C. However, the reduction in animals kept at 32 degrees C was not as great as that in animals kept at 22 degrees C. Although short photoperiod caused an obvious decline in reproductive organ weights of the animals at 22 degrees C, only a slight decrease was seen in hamsters at 32 degrees C. As with reproductive organ weights, testosterone levels were depressed more rapidly and completely in animals maintained at 22 degrees C. These results indicate that elevated ambient temperature changes the rate at which the gonads of hamsters regress in response to daily afternoon melatonin injections or short photoperiod.(ABSTRACT TRUNCATED AT 250 WORDS)