Interactions between the gut microbiota, short-chain fatty acids and the immune system in pediatric patients undergoing hematopoietic stem cell transplantation

The gut microbiota (GM) is essential for human health and contributes to several diseases; indeed it can be considered an extension of the self and, together with the genetic makeup, determines the physiology of an organism. In this thesis has been studied the peripheral immune system reconstitution in pediatric patients undergoing allogeneic hematopoietic stem cell transplantation (aHSCT) in the early phase; in parallel, have been also explored the gut microbiota variations as one of the of primary factors in governing the fate of the immunological recovery, predisposing or protecting from complications such as the onset of acute graft-versus-host disease (GvHD). Has been demonstrated, to our knowledge for the first time, that aHSCT in pediatric patients is associated to a profound modification of the GM ecosystem with a disruption of its mutualistic asset. aGvHD and non-aGvHD subjects showed differences in the process of GM recovery, in members abundance of the phylum Bacteroidetes, and in propionate fecal concentration; the latter are higher in the pre-HSCT composition of non-GvHD subjects than GvHD ones. Short-chain fatty acids (SCFAs), such as acetate, butyrate and propionate, are end-products of microbial fermentation of macronutrients and distribute systemically from the gut to blood. For this reason, has been studied their effect in vitro on human DCs, the key regulators of our immune system and the main player of aGvHD onset. Has been observed that propionate and, particularly, butyrate show a strong and direct immunomodulatory activity on DCs reducing inflammatory markers such as chemokines and interleukins. This study, with the needed caution, suggests that the pre-existing GM structure can be protective against aGvHD onset, exerting its protective role through SCFAs. They, indeed, may regulate cell traffic within secondary lymphoid tissues, influence T cell development during antigen recognition, and, thus, directly shape the immune system.

Hematopoietic stem cell transplantation in Switzerland: a comprehensive quality control report on centre effect

QUESTIONS UNDER STUDY / PRINCIPLES: Interest groups advocate centre-specific outcome data as a useful tool for patients in choosing a hospital for their treatment and for decision-making by politicians and the insurance industry. Haematopoietic stem cell transplantation (HSCT) requires significant infrastructure and represents a cost-intensive procedure. It therefore qualifies as a prime target for such a policy. METHODS: We made use of the comprehensive database of the Swiss Blood Stem Cells Transplant Group (SBST) to evaluate potential use of mortality rates. Nine institutions reported a total of 4717 HSCT - 1427 allogeneic (30.3%), 3290 autologous (69.7%) - in 3808 patients between the years 1997 and 2008. Data were analysed for survival- and transplantation-related mortality (TRM) at day 100 and at 5 years. RESULTS: The data showed marked and significant differences between centres in unadjusted analyses. These differences were absent or marginal when the results were adjusted for disease, year of transplant and the EBMT risk score (a score incorporating patient age, disease stage, time interval between diagnosis and transplantation, and, for allogeneic transplants, donor type and donor-recipient gender combination) in a multivariable analysis. CONCLUSIONS: These data indicate comparable quality among centres in Switzerland. They show that comparison of crude centre-specific outcome data without adjustment for the patient mix may be misleading. Mandatory data collection and systematic review of all cases within a comprehensive quality management system might, in contrast, serve as a model to ascertain the quality of other cost-intensive therapies in Switzerland.

Autologous stem cell transplantation: leukapheresis product has anti-angiogenic effects in vivo correlating with neutrophil-derived VEGFR1

High-dose chemotherapy (HDC) followed by autologous stem cell transplantation (ASCT) is used for the treatment of hemato-oncologic malignancies. In this study, we measured the effect of HDC/ASCT on plasma concentrations of antiangiogenic soluble vascular endothelial growth factor receptor 1 (sVEGFR1) and of leukapheresis products (LP) and patient serum on chick chorioallantoic (CAM) angiogenesis.

Validation of prognostic factors and survival of patients with multiple myeloma in a real-life autologous stem cell transplantation setting: a Swiss single centre experience

High-dose chemotherapy with subsequent autologous stem cell transplantation (ASCT) is an important treatment option in younger patients with multiple myeloma (MM). We analysed the outcome of patients treated at our institution outside the clinical trials framework and tried to identify risk factors prognostic for survival.

Autologous peripheral blood stem cell transplantation for acute myeloid leukemia

We report the results of a prospective, randomized phase 3 trial evaluating autologous peripheral blood stem cell transplantation (ASCT) versus intensive consolidation chemotherapy in newly diagnosed AML patients in complete remission (CR1). Patients with AML (16-60 years) in CR1 after 2 cycles of intensive chemotherapy and not eligible for allogeneic SCT were randomized between intensive chemotherapy with etoposide and mitoxantrone or ASCT ater high-dose cyclophosphamide and busulfan. Of patients randomized (chemotherapy, n = 259; ASCT, n = 258), more than 90% received their assigned treatment. The 2 groups were comparable with regard to prognostic factors. The ASCT group showed a markedly reduced relapse rate (58% vs 70%, P = .02) and better relapse-free survival at 5 years (38% vs 29%, P = .065, hazard ratio = 0.82; 95% confidence interval, 0.66-1.1) with nonrelapse mortality of 4% versus 1% in the chemotherapy arm (P = .02). Overall survival was similar (44% vs 41% at 5 years, P = .86) because of more opportunities for salvage with second-line chemotherapy and stem cell transplantation in patients relapsing on the chemotherapy arm. This large study shows a relapse advantage for ASCT as postremission therapy but similar survival because more relapsing patients on the chemotherapy arm were salvaged with a late transplantation for relapse. This trial is registered at www.trialregister.nl as #NTR230 and #NTR291.

Thrombotic microangiopathic syndromes associated with drugs, HIV infection, hematopoietic stem cell transplantation and cancer

Thrombotic microangiopathy (TMA) has multiple etiologies. In the four disorders described in this review, the primary organ involved is the kidney. Drug-associated TMA can be an acute, immune-mediated disorder or the result of gradual, dose-dependent toxicity. TMA may occur in patients with advanced HIV infection, possibly mediated by angio-invasive infections. TMA following allogeneic hematopoietic stem cell transplantation may also be caused by drug toxicity; the pathogenesis may involve inhibition of vascular endothelial cell growth factor in renal podocytes. Malignancies of many types with systemic microvascular involvement may cause TMA. Recognition that these syndromes may mimic TTP is important to provide appropriate management and to avoid the inappropriate use of plasma exchange treatment.

First-line tandem high-dose chemotherapy and autologous stem cell transplantation versus single high-dose chemotherapy and autologous stem cell transplantation in multiple myeloma, a systematic review of controlled studies

Several clinical studies have compared single with tandem (also called double) autologous stem cell transplantation (ASCT) as first-line treatment in patients with symptomatic multiple myeloma (MM), one of the leading indications for ASCT worldwide.

Haematopoietic stem cell transplantation: activity in Switzerland compared with surrounding European countries

Haematopoietic stem cell transplantation (HSCT) is a highly specialised procedure used to treat malignancies of the lymphohaematopoietic system as well as some acquired and inherited disorders of the blood. This analysis by the Swiss Blood Stem Cell Transplantation Group, based on data from 2008-2011, describes, treatment rates in Switzerland for specific indications and compares this with data from Germany, France, Italy and the Netherlands, corrected for the size of the population. Differences in transplant rates, in rates for particular indications, and in the use of specific transplant technologies such as use of unrelated donors, use of cord blood or mismatched family donors are described. These data are put in correlation with donor availability from international registries and with number of transplant teams and number of procedures per team all corrected for population size.

Comparative analysis of the value of allogeneic hematopoietic stem-cell transplantation in acute myeloid leukemia with monosomal karyotype versus other cytogenetic risk categories

To determine to what extent allogeneic hematopoietic stem-cell transplantation (alloHSCT) quantitatively reduces relapse in acute myeloid leukemia with monosomal karyotype (MK-AML) compared with alternative postremission therapy and how it compares with other cytogenetic subcategories.