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Refractory chronic GVHD (cGVHD) remains a major cause of morbidity after transplantation. Many drugs are used but there is no consensus on the standard of care. We investigated the efficacy of TLI in corticosteroid-refractory cGVHD. We analyzed retrospectively 31 patients receiving one or more TLI session for refractory cGVHD from 2000 to 2007. The main objective was to evaluate the response rate after TLI. Decreased corticosteroid doses and/or discontinued immunosuppressive agents were considered to be surrogate markers of response. All but one patient presented with severe cGVHD at the time of TLI. The median number of previous immunosuppressive treatment lines was 3 (range: 2–4). Fourteen patients (45%) achieved an objective response after TLI and 8 (25%) were cGVHD free at long-term follow-up. In all, 5 (29%) of the 17 nonresponsive patients did not show the features of progressive cGVHD and could decrease the amount of immunosuppressive drugs taken. Response after TLI significantly improved 5-year GVHD-related mortality (14% vs 42%, P =0.038) but not OS (58%vs 64% P =0.27). Regarding the promising response rate in this heavily pretreated population, we reasoned that TLI could be an alternative treatment for corticosteroid-refractory cGVHD.

Background and purpose: Sensory neuropathy develops in the presence of cardiovascular risk factors (e.g. diabetes, dyslipidemia), but its pathological consequences in the heart are unclear. We have previously shown that systemic sensory chemodenervation by capsaicin leads to impaired myocardial relaxation and diminished cardiac nitric oxide (NO) content. Here we examined the mechanism of diminished NO formation and if it may lead to a reduction of peroxynitrite (ONOO−)‐induced S‐nitrosylation of sarcoendoplasmic reticulum Ca2+‐ATPase (SERCA2a). Experimental approach: Male Wistar rats were treated with capsaicin for 3 days to induce sensory chemodenervation. Seven days later, myocardial function and biochemical parameters were measured. Key results: Capsaicin pretreatment significantly increased left ventricular end‐diastolic pressure (LVEDP) decreased cardiac NO level, Ca2+‐dependent NO synthase (NOS) activity, and NOS‐3 mRNA. Myocardial superoxide content, xanthine oxidoreductase and NADPH oxidase activities did not change, although superoxide dismutase (SOD) activity increased. Myocardial and serum ONOO− concentration and S‐nitrosylation of SERCA2a were significantly decreased. Conclusions and implications: Our results show that sensory chemodenervation decreases cardiac NO via decreased expression and activity of Ca2+‐dependent NOS and increases SOD activity, thereby leading to decreased basal ONOO− formation and reduction of S‐nitrosylation of SERCA2a, which causes impaired myocardial relaxation characterized by increased left ventricular end‐diastolic pressure (LVEDP). This suggests that capsaicin sensitive sensory neurons regulate myocardial relaxation via maintaining basal ONOO− formation and SERCA S‐nitrosylation. British Journal of Pharmacology (2008) 153, 488–496; doi:10.1038/sj.bjp.0707599; published online 26 November 2007

In this retrospective study, 63 patients >60 years with hematological malignancies and treated with allo-SCT and with reduced-intensity conditioning (RIC) were reviewed. A total of 51% of patients suffered from AML or myelodysplastic syndromes. Disease status before transplantation was CR or PR 71 with 29% transplanted with active disease. Patients were classified according to three published prognostic indexes: (1) hematopoietic cell transplantation comorbidity index (HCT-CI); (2) European BMT (EBMT) score; and (3) Pretransplantation Assessment of Mortality (PAM) score. The 100-day and 1-year treatment-related mortality (TRM) were 6 and 22%, respectively, for the entire group. The 2-year OS and PFS were 60 and 58%, respectively. The incidence of grade II–IV acute GVHD (aGVHD) and extensive chronic GVHD was 46 and 48%, respectively. In a univariate analysis, neither the HCT-CI nor the EBMT score, nor the PAM score were predictive of TRM and OS. Only the occurrence of aGVHD affected the TRM and OS. ALLO-RIC is feasible in elderly patients. Even if those prognostic scores were not adapted to elderly patients, they did not predict for TRM and OS. aGVHD is the main cause of TRM and more efforts should be made to reduce its incidence without sacrificing graft vs tumor effect.

We previously reported that reduced intensity conditioning (RIC) regimen with fludarabine, BU and 2.5 mg/kg of rabbit anti-thymocyte globulin (r-ATG) was effective but associated with a high rate of acute and chronic GVHD. Therefore, we increased the dose of r-ATG to 5 mg/kg. In this report, we analyzed 87 patients with AML or myelodysplastic syndrome (MDS) undergoing allo-SCT from an HLA-identical sibling donor from 2000 to 2010. RIC consisted of fludarabine, BU and r-ATG 2.5 mg/kg on 1 day (r-ATG1; n =53) or 2.5 mg/kg per day over 2 days (r-ATG2; n =22). Grade 2–4 acute GVHD incidence at day 100 was 30.2% and 8.8% in the r-ATG1 and r-ATG2 groups, respectively ( P =0.038). Extensive chronic GVHD incidence was 60.4% and 12% in the r-ATG1 and r-ATG2 groups, respectively ( P <0.001). The relapse incidences (RI) at 24 months were 18.9% and 28.5% in r-ATG1 and r-ATG2 groups, respectively ( P =0.640). Overall and PFS were not different between the r-ATG1 and r-ATG2 groups. r-ATG dose at 5 mg/kg in the setting of RIC seems a good balance allowing GVHD prevention and antitumor effect with a remarkable reduction of GVHD incidence without an identical level of increased relapse rate.

Unmanipulated haploidentical transplantation (Haplo-SCT) using post-transplantation cyclophosphamide (PT-Cy) represents an alternative for patients with high-risk diseases lacking HLA-identical donor. Although it provides low incidences of GVHD, the efficacy of Haplo-SCT is still questioned, especially for patients with myeloid malignancies. Thus, we analyzed 60 consecutive patients with refractory ( n =30) or high-risk CR ( n =30) AML or myelodysplastic syndromes (MDSs) who underwent PT-Cy Haplo-SCT. The median age was 57 years (22–73 years), hematopoietic cell transplantation comorbidity index was ⩾3 in 38 patients (63%) and Haplo-SCT was the second allogeneic transplantation for 10 patients (17%). Although most of patients received PBSC as graft source ( n =48, 80%), we found low incidences of grade 3–4 acute (2%) and severe chronic GVHD (4%). Among patients with high-risk CR diseases, 1-year non-relapse mortality, cumulative incidence of relapse, progression-free and overall survivals were 20%, 32%, 47% and 62%, respectively. In patients with refractory disease, corresponding results were 34%, 35%, 32% and 37%, respectively. We conclude that PT-Cy Haplo-SCT could provide promising anti-leukemic effect even in the setting of very advanced diseases. Thus, it represents a viable alternative for high-risk AML/MDS patients without HLA-identical donor.

Purinergic signaling is involved in the proper functioning of virtually all organs of the body. Although in some cases purines have a major influence on physiological functions (e.g. thrombocyte aggregation), more often they are just background modulators contributing to fine tuning of biological events. However, under pathological conditions, when a huge amount of adenosine 5-triphosphate (ATP) can reach the extracellular space, their significance is increasing. ATP and its various degradation products activate membrane receptors divided into two main classes: the metabotropic P2Y and the ionotropic P2X family. This latter group, the purine ionotropic receptor, is the object of this review. After providing a description about the distribution and functional properties of P2X receptors in the body, their pharmacology will be summarized. In the second part of this review, the role of purines in those organ systems and body functions will be highlighted, where the (patho)physiological role of P2X receptors has been suggested or is even well established. Besides the regulation of organ systems, for instance in the cardiovascular, respiratory, genitourinary or gastrointestinal system, some special issues will also be discussed, such as the role of P2X receptors in pain, tumors, central nervous system (CNS) injury and embryonic development. Several examples will indicate that purine ionotropic receptors might serve as attractive targets for pharmacological interventions in various diseases, and that selective ligands for these receptors will probably constitute important future therapeutic tools in humans.