Suicide deaths among patients with end-stage renal disease receiving dialysis: A population-based retrospective cohort study of 64,000 patients in Taiwan.

BACKGROUND: Patients with end-stage renal disease (ESRD) who receive dialysis may experience increased distress and risk of suicide. METHODS: This population-based retrospective cohort study linked Taiwan's national register of ESRD patients on dialysis and the cause-of-death mortality data file. A separate multiple-cause-of-death data file was used to investigate the detailed suicide methods used. Standardized mortality ratios (SMRs) were calculated for the overall patient group and by sex, age, year of initiating dialysis, method of suicide, and time since initiation of dialysis. RESULTS: Among 63,854 ESRD patients on dialysis, 133 died by suicide in Taiwan in 2006-2012; the suicide rate was 76.3 per 100,000 patient-years. The SMR for suicide was 2.38 (95% confidence interval [CI] 1.99-2.82) in this patient group. Suicide risk was highest in the first year of dialysis (SMR = 3.15, 95% CI 2.39-4.08). The risk of suicide by cutting was nearly 20 times (SMR = 19.91, 95% CI 12.88-29.39) that of the general population. Detailed information on death certificates indicated that three quarters of patients who killed themselves by cutting cut vascular accesses used for hemodialysis. LIMITATIONS: Information on risk factors such as socioeconomic position and mental disorders was unavailable. CONCLUSION: In a country where the national health insurance program covers most expenses associated with dialysis treatment, the suicide risk in ESRD patients on dialysis still increased nearly 140%. Adequate support for ESRD patients initiating dialysis and the assessment of risk of cutting vascular access as a potential means of suicide could be important strategies for suicide prevention.

Targeting JAK1/2 and mTOR in murine xenograft models of Ph-like acute lymphoblastic leukemia.

CRLF2 rearrangements, JAK1/2 point mutations, and JAK2 fusion genes have been identified in Philadelphia chromosome (Ph)-like acute lymphoblastic leukemia (ALL), a recently described subtype of pediatric high-risk B-precursor ALL (B-ALL) which exhibits a gene expression profile similar to Ph-positive ALL and has a poor prognosis. Hyperactive JAK/STAT and PI3K/mammalian target of rapamycin (mTOR) signaling is common in this high-risk subset. We, therefore, investigated the efficacy of the JAK inhibitor ruxolitinib and the mTOR inhibitor rapamycin in xenograft models of 8 pediatric B-ALL cases with and without CRLF2 and JAK genomic lesions. Ruxolitinib treatment yielded significantly lower peripheral blast counts compared with vehicle (P < .05) in 6 of 8 human leukemia xenografts and lower splenic blast counts (P < .05) in 8 of 8 samples. Enhanced responses to ruxolitinib were observed in samples harboring JAK-activating lesions and higher levels of STAT5 phosphorylation. Rapamycin controlled leukemia burden in all 8 B-ALL samples. Survival analysis of 2 representative B-ALL xenografts demonstrated prolonged survival with rapamycin treatment compared with vehicle (P < .01). These data demonstrate preclinical in vivo efficacy of ruxolitinib and rapamycin in this high-risk B-ALL subtype, for which novel treatments are urgently needed, and highlight the therapeutic potential of targeted kinase inhibition in Ph-like ALL.

Aberrant STAT5 and PI3K/mTOR pathway signaling occurs in human CRLF2-rearranged B-precursor acute lymphoblastic leukemia.

Adults and children with high-risk CRLF2-rearranged acute lymphoblastic leukemia (ALL) respond poorly to current cytotoxic chemotherapy and suffer unacceptably high rates of relapse, supporting the need to use alternative therapies. CRLF2 encodes the thymic stromal lymphopoietin (TSLP) receptor, which activates cell signaling in normal lymphocytes on binding its ligand, TSLP. We hypothesized that aberrant cell signaling occurs in CRLF2-rearranged ALL and can be targeted by signal transduction inhibitors of this pathway. In a large number of primary CRLF2-rearranged ALL samples, we observed increased basal levels of pJAK2, pSTAT5, and pS6. We thus characterized the biochemical sequelae of CRLF2 and JAK alterations in CRLF2-rearranged ALL primary patient samples via analysis of TSLP-mediated signal transduction. TSLP stimulation of these leukemias further induced robust JAK/STAT and PI3K/mTOR pathway signaling. JAK inhibition abrogated phosphorylation of JAK/STAT and, surprisingly, of PI3K/mTOR pathway members, suggesting an interconnection between these signaling networks and providing a rationale for testing JAK inhibitors in clinical trials. The PI3K/mTOR pathway inhibitors rapamycin, PI103, and PP242 also inhibited activated signal transduction and translational machinery proteins of the PI3K/mTOR pathway, suggesting that signal transduction inhibitors targeting this pathway also may have therapeutic relevance for patients with CRLF2-rearranged ALL and merit further preclinical testing.