Transplant-associated thrombotic microangiopathy (TA-TMA) is a life-threatening complication of allogeneic hematopoietic cell transplantation (HCT). We hypothesized that pretransplant genetic susceptibility is evident in adult TA-TMA and further investigated the association of TMA-associated variants with clinical outcomes. We studied 40 patients with TA-TMA, donors of 18 patients and 40 control non-TMA HCT recipients, without significant differences in transplant characteristics. Genomic DNA from pretransplant peripheral blood was sequenced for TMA-associated genes. Donors presented significantly lower frequency of rare variants and variants in exonic/splicing/untranslated region (UTR) regions, compared with TA-TMA patients. Controls also showed a significantly lower frequency of rare variants in ADAMTS13, CD46, CFH, and CFI. The majority of TA-TMA patients (31/40) presented with pathogenic or likely pathogenic variants. Patients refractory to conventional treatment (62%) and patients that succumbed to transplant-related mortality (65%) were significantly enriched for variants in exonic/splicing/UTR regions. In conclusion, increased incidence of pathogenic, rare and variants in exonic/splicing/UTR regions of TA-TMA patients suggests genetic susceptibility not evident in controls or donors. Notably, variants in exonic/splicing/UTR regions were associated with poor response and survival. Therefore, pretransplant genomic screening may be useful to intensify monitoring and early intervention in patients at high risk for TA-TMA.
In our study, we evaluated the safety and efficacy of Brentuximab vedotin (BV) with or without the addition of donor lymphocyte infusion (DLI) after allogeneic stem cell transplantation (allo-SCT) in 16 patients with advanced Hodgkin lymphoma (HL). Thirteen patients with relapsed HL after allo-SCT received BV as treatment for active disease. Three patients without progression of HL after allo-SCT received BV as consolidation. Twelve patients had been previously exposed to BV for treatment of relapse after autologous-SCT. Ten out of 16 patients received BV in combination with DLI. Among the 13 patients treated for active disease, CR and PR was observed in 7 and 2 patients, respectively. With a median follow-up of 13 months, 13 out of 16 patients are alive, while 3 died because of disease progression. The median PFS was 6 months. DLI-associated GVHD occurred in seven patients. Five patients with GVHD required immunosuppression, and in all cases, GVHD resolved after a short course of low dose steroids, implying that an anti-GVHD modulating effect could be induced by the concurrent administration of BV. No serious adverse event was observed in any of the patients.
IT SummaryA method is described by means of which the chemical effects of 81 Br (η, γ) 82m Br and 82m Br -82 Br in npropyl bromide can be determined separately. In the latter case effects due to the decay of n-C 3 H 7 -82m Br and to the decay of inorganic « 2m Br can also be separated, not only in the pure system but also in solutions of η-propyl bromide in methyl alcohol containing Br -. The results obtained show that (n, y) activation produces much lower organic retention than activation by isomeric transition. Moreover the organic yield of 82 Bris much higher when it is born from n-C s H,-82m Brthan when it is born from inorganic 82m Br. These are explained by assuming that the probability of recombination of 82 Br with the parent radical, after bond rupture, is very high in isomeric transition activation but lower in (η, γ) activation, owing probably to the different recoil energies of the two processes.Retentions as parent compound are high and their ratio to total organic yield is constant in all cases.The half-life of 82m Br has been determined through its chemical effects but this shows a small variation with change in temperature.
ZusammenfassungWir geben ein Verfahren an, um die chemischen Wirkungen der Kernreaktion 81 Br(n, γ) 82 ™Br und des isomeren Übergangs 82m Br -> 82 Br in 1-Brompropan getrennt zu bestimmen. Beim Übergang kann man sogar die Auswirkungen des Zerfalls in n-C 3 H 7 -82,n Br und in anorganischem 82,ll Br unterscheiden, sowohl im reinen System als auch in Lösungen von 1-Brompropan in Br~-haltigem Methanol. Die Ergebnisse zeigen, daß bei der (n, y)-Aktiviervmg die organische Retention viel geringer ist als bei der Aktivierung durch Isomerenübergang. Zudem ist die Ausbeute an organisch gebundenem 82 Br aus n-C 3 H 7 -82m Br viel höher als aus anorganischem 82m Br. Es ist also anzunehmen, daß die Wahrscheinlichkeit für die Rekombination des abgetrennten 82 Br mit dem Mutterradikal bei der Aktivierung durch isomeren Übergang sehr hoch im Vergleich zu der bei (η, γ)-Aktivierung ist, was wahrscheinlich an den verschiedenen Rückstoßenergien der beiden Reaktionen liegt. Die Retention ist hoch und ihr Verhältnis zur organischen Gesamtausbeute in allen Fällen konstant. Die Halbwertszeit des 82m Br wurde aus seinen chemischen Wirkungen bestimmt, die sich allerdings mit der Temperatur etwas ändern. Brought to you by | New York University Bobst Library Technical Services Authenticated Download Date | 7/21/15 6:50 PM
RésuméOn décrit une méthode pour déterminer séparément les effets chimiques de la réaction 81 Br (η, γ) 82 »Br et de la transition isomérique 82m Br -> 82 Br dans le 1-bromo-propane. Dans le cas de la transition on peut même séparer les effets dus aux désintégrations du n-C3H7-82 ™Br d'une part, du 82m Br minéral d'autre part, non seulement pour le système pur, mais aussi pour les solutions du 1-bromopropane dans le méthanol contenant des ions Br -. Les résultats montrent que l'activation (η, γ) conduit à une rétention organique beaucoup plus basse que l'activation par transition isomé...
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