ABSTRACT
PURPOSE: Primary hypothyroidism is a main endocrine complication after allogeneic stem cells transplantation (allo-SCT) in children, but in adults data on post-SCT hypothyroidism are limited. The aims of this observational, cross-sectional study were to assess the prevalence of hypothyroidism in adult allo-SCT recipients according to time from transplantation, and to identify risk factors. METHODS: One hundred and eighty-six patients (M 104; F 82; median age 53.4 years) who underwent allo-SCT between January 2010 and December 2017 were enrolled and divided into three groups, according to time from allo-SCT (1-3 years; 3-5 years; > 5 years). Pre-transplant TSH and fT4 levels were available for all patients. After transplantation, TSH, fT4 and anti-thyroperoxidase antibodies (TPO-Ab) were evaluated. RESULTS: After a follow-up of 3.7 years, 34 (18.3%) patients developed hypothyroidism, with higher prevalence in females (p < 0.001) and in patients who received matched unrelated donor grafts (p < 0.05). No difference in prevalence was found at different time points. Patients who developed hypothyroidism showed higher rate of TPO-Ab positivity (p < 0.05) and higher pre-transplant TSH levels (median 2.34 µU/ml) compared to those with preserved thyroid function (median 1.53 µU/ml; p < 0.001). Multivariable analysis identified higher pre-transplant TSH levels as a positive predictor of hypothyroidism (p < 0.005). The ROC curve analysis identified a pre-SCT TSH cutoff of 1.84 µU/ml, which can predict hypothyroidism with sensitivity 74.1% and specificity 67.2%. CONCLUSIONS: About one out of four patients developed hypothyroidism after allo-SCT, with a greater incidence in females. Pre-transplant TSH levels seem to predict the onset of post-SCT hypothyroidism.
Subject(s)
Hematopoietic Stem Cell Transplantation , Hypothyroidism , Adult , Child , Female , Humans , Middle Aged , Cross-Sectional Studies , Transplantation, Homologous/adverse effects , Hematopoietic Stem Cell Transplantation/adverse effects , Hypothyroidism/epidemiology , Hypothyroidism/etiology , ThyrotropinSubject(s)
Hematopoietic Stem Cell Transplantation , Hodgkin Disease/mortality , Hodgkin Disease/therapy , Transplantation Conditioning , Adolescent , Adult , Allografts , Disease-Free Survival , Female , Follow-Up Studies , Hodgkin Disease/pathology , Humans , Male , Middle Aged , Recurrence , Survival RateABSTRACT
We investigated the activity of ITF2357, a novel histone deacetylase inhibitor (HDACi) with antitumor activity, on cells carrying the JAK2(V617F) mutation obtained from polycythemia vera (PV) and essential thrombocythemia (ET) patients as well as the HEL cell line. The clonogenic activity of JAK2(V617F) mutated cells was inhibited by low concentrations of ITF2357 (IC(50) 0.001-0.01 microM), 100- to 250-fold lower than required to inhibit growth of normal or tumor cells lacking this mutation. Under these conditions, ITF2357 allowed a seven fold increase in the outgrowth of unmutated over mutated colonies. By western blotting we showed that in HEL cells, ITF2357 led to the disappearance of total and phosphorylated JAK2(V617F) as well as pSTAT5 and pSTAT3, but it did not affect the wild-type JAK2 or STAT proteins in the control K562 cell line. By real-time PCR, we showed that, upon exposure to ITF2357, JAK2(V617F) mRNA was not modified in granulocytes from PV patients while the expression of the PRV-1 gene, a known target of JAK2, was rapidly downmodulated. Altogether, the data presented suggest that ITF2357 inhibits proliferation of cells bearing the JAK2(V617F) mutation through a specific downmodulation of the JAK2(V617F) protein and inhibition of its downstream signaling.
