No abstract

No abstract

We conducted a case–control study to evaluate the association between paternal smoking and childhood leukemia and to evaluate potential modification by polymorphisms in CYP1A1. Histologically confirmed childhood leukemia cases (n = 164) and non-cancer controls (n = 164) were recruited from three teaching hospitals in Seoul, Korea. Five single nucleotide polymorphisms in CYP1A1 (–17961T>C, –9893G>A, I462V, 1188C>T (*2A), and 11599C>G) were genotyped and haplotypes were estimated by the expectation-maximization method. We also conducted a meta-analysis of 12 studies that have reported the association between paternal smoking and childhood leukemia risk. Paternal smoking at home was associated with all leukemias (OR = 1.8, 95% CI = 1.1–2.8) and acute lymphoblastic leukemia (ALL) (2.0, 1.2–3.4). An increasing trend in risk was observed for pack-years smoked after birth (Ptrend = 0.06 and 0.02, respectively) and the number of smokers in the home during the child's life (Ptrend = 0.05 and 0.03, respectively). Among those without the CGACC haplotype, ALL risk was significantly increased by the father's smoking at home (2.8, 1.5–5.3) and the presence of at least one smoker in the home (2.3, 1.2–4.4), and the test for interaction was significant (Pinteraction = 0.03 and 0.02, respectively). The meta-analysis showed that overall paternal smoking (1.13, 1.04–1.24) and smoking before the pregnancy of the child (1.12, 1.04–1.21) were significantly associated with childhood leukemia risk. Our results suggest that paternal smoking is a risk factor for childhood leukemia and the effect may be modified by CYP1A1 genotype.

A novel homozygous Fas ligand mutation leads to early protein truncation, abrogation of death receptor and reverse signaling and a severe form of the autoimmune lymphoproliferative syndrome. Clin Immunol 2014;155:231-7. 6. Bi LL, Pan G, Atkinson TP, Zheng L, Dale JK, Makris C, et al. Dominant inhibition of Fas ligand-mediated apoptosis due to a heterozygous mutation associated with autoimmune lymphoproliferative syndrome (ALPS) type Ib.

No abstract

The substitution of piperacillin/tazobactam for extended-spectrum cephalosporins successfully decreased the prevalence of ESBL production of K. pneumoniae and E. coli in an institute for children where ESBLs were endemic. The impact of change in antibiotic policy was more evident in K. pneumoniae than E. coli.

Background NUT carcinoma is a rare aggressive disease caused by BRD4/3‐NUT fusion, and C‐MYC upregulation plays a key role in the pathogenesis. Here, we report on the clinicopathological characteristics of Korean patients with NUT carcinoma and the in vitro efficacy of MYC‐targeting agents against patient‐derived NUT carcinoma cell lines. Materials and Methods Thirteen patients with NUT carcinoma were evaluated for p53, C‐MYC, epidermal growth factor receptor (EGFR), HER2, and programmed cell death ligand 1 (PD‐L1) by immunohistochemistry. The half maximal inhibitory concentration (IC50) values of NUT carcinoma cell lines (SNU‐2972‐1, SNU‐3178S, HCC2429, and Ty‐82) were determined using MYC‐targeting agents, including bromodomain and extraterminal (BET) inhibitors (I‐BET, OTX‐015, AZD5153) and histone deacetylase (HDAC) inhibitors (vorinostat, romidepsin, panobinostat, CUDC‐907). Results Primary tumor sites included head and neck (n = 9) and lung (n = 4). The patient age ranged from 8 to 73 years with the male/female ratio of 1.2:1. Nine patients died at 3–23.6 months (median, 10.6) after diagnosis. Eight patients had been misdiagnosed initially with other diseases. One patient with metastatic NUT carcinoma who received mass excision plus metastasectomy followed by chemoradiotherapy was a long‐term survivor (>27 months). Although expressions of C‐MYC (8/12, 73%) and p53 (12/12, 100%) were commonly observed, EGFR, HER2, and PD‐L1 expressions were observed in 2 of 7 (29%), 2 of 8 (25%), and 1 of 12 (8.3%) patients, respectively. BET and HDAC inhibitors showed variable but limited in vitro efficacy. However, a dual HDAC/PI3K inhibitor, CUDC‐907, was most potent against NUT carcinoma cells, with an IC50 of 5.5–9.0 pmol/L. Consistent with these findings, kinome short interfering RNA screening showed a positive hit for PI3KCA in NUT carcinoma cells. Panobinostat (IC50, 0.4–1.3 nmol/L) and a bivalent BET inhibitor, AZD5153 (IC50, 3.7–8.2 nmol/L), also showed remarkable efficacies. Conclusion East Asian patients with NUT carcinoma showed dismal survival outcomes like Western patients, and CUDC‐907 might be promising in NUT carcinoma treatment. Implications for Practice NUT carcinoma (NC) is a disease caused by BRD‐NUT fusion leading to C‐MYC upregulation. NC is often misdiagnosed and very aggressive, requiring development of effective therapeutic strategy. This article presents the clinicopathological features of the largest series of NCs in East Asians and preclinical sensitivities to MYC‐targeting agents in NC cell lines. Patients with NC had grave outcomes and poor response to treatment. Among MYC‐targeting agents, including BET and HDAC inhibitors, CUDC‐907 (a dual PI3K/HDAC inhibitor) was most effective against NC cells, followed by panobinostat (an HDAC inhibitor) and AZD5153 (a bivalent BET inhibitor). CUDC‐907 might be promising in NC treatment.

BackgroundSince it was suggested that B cells play a role in the pathogenesis of chronic graft-versus-host disease, rituximab, an anti-CD20 monoclonal antibody targeting B cells, has been shown to be effective in steroid-refractory, chronic graft-versus-host disease. However, most of the data were from small numbers of patients or retrospective analyses. We, therefore, conducted a multicenter phase II study to confirm the efficacy of this treatment strategy that targets B cells. Design and MethodsWe diagnosed and evaluated chronic graft-versus-host disease according to the National Institute of Health criteria for clinical trials on this condition. The treatment consisted of weekly intravenous infusions of rituximab for 4 weeks followed by monthly rituximab for 4 months. We evaluated the patients' responses and monitored their disease activity until their final visit, which was on day 365. We also assessed the patients' subsequent quality of life and serum levels of B-cell-activating factor of the tumor necrosis factor family. ResultsAmong 37 patients enrolled (median age, 29 years; range 8-57 years), 32 patients responded to rituximab with 8 complete and 24 partial responses. Twenty-one patients maintained their response for 1 year, so their steroid treatment was discontinued or its dose reduced (21/37, or 56.8%), and their scores representing quality of life were improved although these changes were not statistically significant. The responses were better for clinical manifestations of the skin, oral cavity and musculoskeletal system (response rate, 71.4-100%) than for other organs. However, infectious complications and primary disease relapse accounted for the majority of treatment failure. The pre-treatment serum level of B cell-activating factor of the tumor necrosis factor family was not associated with better treatment outcome (P=0.147). ConclusionsRituximab could improve clinical responses and quality of life of patients with steroid-refractory chronic graft-versus-host disease, although such patients may need active prophylaxis against infection. (ClinicalTrials.