Patients (pts) with truly refractory acute myeloid leukaemia (AML) have a particular poor prognosis after allogeneic stem cell transplantation (aSCT). In this prospective analysis, high-dose ...melphalan for induction of marrow aplasia followed by a myeloablative conditioning regimen before aSCT was evaluated in 50 consecutive pts (median age 55, range 19-70 years) after failure of primary double induction (n=8) or salvage chemotherapy for AML-relapse (n=42). The projected pretransplant assessment of mortality score (PAM-Score, Parimon T et al.) of this cohort revealed a median overall probability of death within 2 years of 67% (range 49-85%). 40 pts received 140mg/m.sup.2 and 10 pts 200mg/m.sup.2 melphalan followed by a total body irradiation (TBI) based conditioning regimen in 20 pts (40%) or a chemotherapybased regimen in 30 pts (60%) within 10 days after melphalan application. 18 pts received grafts from sibling (ISD) (36%) and 32 pts from matched unrelated donors (MUD) (64%). Complete remission of AML was obtained in all but one patient (98%). The transplant-related mortality (TRM) estimate at 2 yrs after aSCT was 34%. The 2-year probability of death was 64% and the 2-year event-free survival estimate was 35% with the last event occurring at 1.5 yrs. Explorative data analysis identified a MUD transplant, a melphalan-dose of 140mg/m.sup.2, and chemotherapeutic conditioning using treosulfan 42g/m.sup.2 combining with fludarabine 150mg/m.sup.2 as favourable outcome predictors. This resulted from a significantly lower 2-year relapse estimate after MUD compared to ISD (21% vs. 81%, p<0.02) and a lower 2-year TRM after 140mg/m.sup.2 melphalan combined with treosulfan + fludarabine compared to other combinations (17% vs. 54%, p<0.03). The 2-year event-free survival estimate for the 18 pts with all favourable treatment was 68% opposed to 19% in the 32 pts not fulfilling all these characteristics (p<0.006). In conclusion, the concept of aplasiogenic high-dose melphalan together with myeloablative conditioning can rescue more than 1/3 of otherwise refractory AML pts. The beneficial influence of MUD in this study further supports a stronger antileukemic potential compared to ISD in pts with refractory AML, which translates into a comparatively high event-free survival in combination with 140mg/m.sup.2 melphalan followed by a conditioning regimen with treosulfan + fludarabine. This sequential protocol deserves further evaluation against other sequential conditioning approaches in refractory AML pts.
CMV-reaction (CMV-R) after transplant occurs frequently and is generally thought to be associated with a increased TRM. WE aimed to evalute AML in vitro, and further, the clinical outcome of patients ...with AML with a documented CMV-R after transplant. We retrospectively evaluated 236 pat.with AML in two cohorts (108 pat. in 1st cohort transpl.from an HLA-ident.sibling donor, and 127 pat. transpl. from an HLA-ident.URD. Pat. were transplanted in Essen and Rostock. For the definition of a CMV-R treatment with ganciclovir and the detection of pp65 pos.cells in PMCs at minimum at two different occasions were required. For in vitro studies we used the cell lines Kasumi-1 (AML-M2), SD-1 (ALL) and K562 (CML in blast crises) and infected them with the AD169 CMV strain. 14 days after infection we evaluated the apoptosis rate by measuring annexin V by FACS, the proliferation rate by BRDU assay, the expression of MRD and apoptosis marker p21, c-myc. Infection of CMV in Kasumi-1 cells and SD-1 cells induced in 99.8% and 31.3% of cells apoptosis, whereas no impact on the apoptosis rate was seen for K562 cells. HCMV-induced cell death in AML cells was mediated by a caspase-dependent mechanism and could be prevented by the specific caspase inhibitor zVAD.fmk. These results were in concordance with the clinical observation of a CMV-R after transplant in AML, ALL, and CML. AML-Patients with a documented CMV-R had in both cohorts a markedly reduced risk for relapse (prob. at 5-year 9.2% versus 52.6% in cohort 1 (p<0.0005) and 12.2% versus 47.2% in cohort 2 (p<0.013), which resulted in a sign.improved OS cohort 1 OS 73.6% versus 42.5% (p<0.04) and 48.0% versus 33.5% in cohort 2 (p<0.04). There were no sign. differences in the characteristics of pat. with or without CMV-R. Patients with CMV-R had a higher incidence of acute GVHD grade 2-4 (82% versus 38%, p <0.0001), but this was also seen in pat.with ALL and CML who did not have a reduced risk for relapse after a CMV-R. When stratified according to the occurrence of acute GVHD, the probability for risk of relapse remained sign.lower in pat.with a CMV-R compared to their counterparts (p<0.003). In multivariate analyses the sign.factors impacting the outcome and relapse rate were disease stage, chronic GVHD, unfavorable cytogenetics and CMV-R. Our data indicate an unrecognized role of CMV reactivation after HSCT for AML, which is probably mediated by CMV induced apoptosis.
Immunological disorders seem to be of considerable relevance to the pathogenesis of Crohn's disease (CD). T-cells play a central role in immunoregulation. The T-cell subpopulations of 70 patients ...with CD were compared to those of age- and sex-matched healthy controls. The suppressor-inducer subpopulations were found to be reduced in CD patients irrespective of wether they were taking steroids or not. In contrast to other subpopulations suppressor-inducer cells remained unchanged during follow-up. The results point to a disturbance in the regulation of suppressor T-cells in patients with Crohn's disease.
Analyses of big datasets signal important directions for the archaeology of religion in the Archaic to Mississippian Native North America
Across North America, huge data accumulations derived from ...decades of cultural resource management studies, combined with old museum collections, provide archaeologists with unparalleled opportunities to explore new questions about the lives of ancient native peoples. For many years the topics of technology, economy, and political organization have received the most research attention, while ritual, religion, and symbolic expression have largely been ignored. This was often the case because researchers considered such topics beyond reach of their methods and data.
In Archaeology and Ancient Religion in the American Midcontinent , editors Brad H. Koldehoff and Timothy R. Pauketat and their contributors demonstrate that this notion is outdated through their analyses of a series of large datasets from the midcontinent, ranging from tiny charred seeds to the cosmic alignments of mounds, they consider new questions about the religious practices and lives of native peoples. At the core of this volume are case studies that explore religious practices from the Cahokia area and surrounding Illinois uplands. Additional chapters explore these topics using data collected from sites and landscapes scattered along the Mississippi and Ohio River valleys.
This innovative work facilitates a greater appreciation for, and understanding of, ancient native religious practices, especially their seamless connections to everyday life and livelihood. The contributors do not advocate for a reduced emphasis on technology, economy, and political organization; rather, they recommend expanding the scope of such studies to include considerations of how religious practices shaped the locations of sites, the character of artifacts, and the content and arrangement of sites and features. They also highlight analytical approaches that are applicable to archaeological datasets from across the Americas and beyond.
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