We retrospectively evaluated the efficacy of autologous hematopoietic stem cell transplantation (AHSCT) in 18 patients with rapidly progressive diffuse cutaneous systemic sclerosis (rp-dcSSc), and compared their disease outcomes with those of 36 demographically-and clinically-matched patients treated with conventional therapies. Cutaneous involvement, by performing modified Rodnan skin score (mRss), lung diffusion capacity, by measuring diffusing capacity of lung for carbon monoxide (DLCO), and disease activity, by applying the European Scleroderma Study Group (ESSG) scoring system, were the outcome variables measured at the baseline time and then every 12 months for the following 60 months in both the AHSCT-treated patients and the control group. In the AHSCT group, treatment-related mortality was 5.6%. In this group, both mRss and ESSG scores showed a significant reduction 1 year after AHSCT (P o 0.002); and these results were maintained until the end of follow-up. Conversely, DLCO values remained stable during the whole period of follow-up. Survival rate of AHSCT group was much higher than that observed in the whole control group (P = 0.0005). The probability that the ESSG score and mRss would remain at a high level, and DLCO could decrease, was significantly higher in the control group as a whole and in the subgroup of control patients treated with cyclophosphamide than in the AHSCT group. This study confirms that the AHSCT is effective in prolonging survival, as well as in inducing a rapid reduction of skin involvement and disease activity, and preserving lung function in patients with rp-dcSSc.
In spite of an increasing array of investigations, the relationships between viral infections and allogeneic hematopoietic stem cell transplantation (HSCT) are still controversial, and almost exclusively regard DNA viruses. Viral infections per se account for a considerable risk of morbidity and mortality among HSCT recipients, and available antiviral agents have proven to be of limited effectiveness. Therefore, an optimal management of viral infection represents a key point in HSCT strategies. On the other hand, viruses bear the potential of shaping immunologic recovery after HSCT, possibly interfering with control of the underlying disease and graft-versus-host disease (GvHD), and eventually with HSCT outcome. Moreover, preliminary data are available about the possible role of some virome components as markers of immunologic recovery after HSCT. Lastly, HSCT may exert an immunotherapeutic effect against some viral infections, notably HIV and HTLV-1, and has been considered as an eradicating approach in these indications.
SummaryCompelling evidence indicates the role of sphingosine kinase 1 (SPHK1) deregulation in the processes of carcinogenesis and acquisition of drug resistance, providing the rationale for an effective anti-cancer therapy. However, no highly selective inhibitors of SPHK1 are available for in vitro and in vivo studies, except for the newly discovered 'SK inhibitor' (SKI). The present study showed that, in a panel of myeloid leukaemia cell lines, basal level of SPHK1 correlated with the degree of kinase inhibition by SKI. Exposure to SKI caused variable anti-proliferative, cytotoxic effects in all cell lines. In particular, SKI induced an early, significant inhibition of SPHK1 activity, impaired cell cycle progression and triggered apoptosis in K562 cells. Moreover, SKI acted synergistically with imatinib mesylate (IM) to inhibit cell growth and survival. Finally, the inhibitor affected the clonogenic potential and viability of primary cells from chronic myeloid leukaemia (CML) patients, including one harbouring the IM-insensitive Abl kinase domain mutation T315I. Due to the fact that the phenomenon of resistance to IM remains a major issue in the treatment of patients with CML, the identification of alternative targets and new drugs may be of clinical relevance.
An increasing body of evidence has shown that hematologic malignancies, alike normal hematopoiesis, has a hierarchical structure including a stem cell compartment with self renewal capability, endowed in a neoplastic niche bearing resemblance to its normal hematopoietic counterpart. According to experimental data on NOD-SCID mice, leukemic stem cells are characterized by a CD34+/CD38- surface profile and account for 1 in 10(3) to 1 in 10(6) of the total amount of leukemic cells. The available knowledge about leukemic stem cells (LSC) has arisen the question as to whether some targeting of LSC is achieved by current treatments; the answer is dubitative at best, with the possible exception of arsenic trioxide in promyelocytic leukemia. On the other side, the unsatisfactory results in the treatment of many hematological neoplasms has prompted many research groups to find out whether direct targeting of LSC, possibly in its niche, would result in an improvement in cure rates. This approach implies the identification of LSC specific markers, clearly distinct from their normal counterpart in order to spare normal hematopoietic stem cells. Adhesion/surface antigens, metabolic pathways involved in LSC survival and renewal, telomerase, commonly mutated genes and epigenetic phenomena have been investigated as candidate targets for newer therapeutic strategies. So far, most of the possibly effective agents have been studied in experimental models only. FLT-3 inhibitors account for a notable exception since they have resulted effective in vivo in AML with mutated, but not over expressed, FLT-3. A main task for the future is to find out whether some common LSC specific markers would be identifiable in a substantial proportion of AML cases, or whether each AML case shows a unique fingerprint of markers. In the latter event, targeting of LSC could result in an arduous task.
The term metabolic syndrome (MS) defines a clustering of cardiovascular risk factors, formerly known as syndrome X. There is some debate about the diagnostic criteria; but the most widely accepted framework is that defined by the National Cholesterol Education Program Adult Treatment Panel III, which requires the simultaneous occurrence of at least three of abdominal obesity, arterial hypertension, hyperglycemia, hypertrigliceridemia and low high-density lipoprotein cholesterol (HDL-C). The prevalence of MS increases with age and varies depending on genetic factors. An abnormally high prevalence has been observed in patients with heterogeneous conditions, such as solid organ transplant recipients, AIDS patients and long-term cancer survivors. As some of the pathogenetic factors possibly involved include cyclosporine A, corticosteroids and cancer chemoradiotherapy, it is possible that MS may also be a complication in hematological patients. Some of the characteristics of MS have been reported with a certain frequency in thalassemia patients, and are mainly attributed to iron overload. Impaired hemostasis is a feature of MS rather than a factor predisposing to its development. In oncohematology, an abnormally high prevalence of MS features has been observed in survivors of pediatric acute lymphoblastic leukemia. In addition to corticosteroid- and cancer therapy-related hypogonadism, hypothyroidism and defective growth hormone incretion are other factors related to the development of MS. Moreover, the highest frequency of MS is observed in hematopoietic stem cell transplantation (HSCT) recipients. Pediatric patients and allogeneic HSCT recipients have been the subject of foremost investigations; but adult patients and autologous HSCT recipients have also been studied more recently. A wide range of factors may contribute to the development of MS in HSCT recipients. Unfortunately, the real entity of the problem is far from clear because of the retrospective design of the studies, the limited size of their populations and their heterogeneous selection criteria, thus making it difficult to determine whether MS is a transient and possibly reversible phenomenon or a true late effect of the procedure.
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